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Naked mole-rats (NMRs) (Heterocephalus glaber) are highly social and subterranean rodents with large communal colonies in burrows containing low oxygen levels. The inhibition of severe hypoxic conditions is of particular interest to this study. To understand the mechanisms that facilitate neuronal preservation during hypoxia, we investigated the proteins regulating hypoxia tolerance in NMR hippocampal neurons. Caveolin-1 (Cav-1), a transmembrane scaffolding protein, confers prosurvival signalling in the central nervous system. The present study aimed to investigate the role of Cav-1 in hypoxia-induced neuronal injury. Western blotting analysis and immunocytochemistry showed that Cav-1 expression was significantly upregulated in NMR hippocampal neurons under 8% O

The key cytosolic DNA sensor cyclic GMP-AMP (cGAMP) synthetase (cGAS) is essential to elicit anti-infection innate immunity whereas aberrant activation of cGAS by endogenous DNA promotes severe autoimmune diseases, thus the activity of cGAS must be strictly regulated to maintain immune homeostasis. Here we report that the E3 ISG15-protein ligase HERC5 interacts with and catalyzes the cGAS ISGylation robustly, whereas the deconjugating enzyme USP18 removes the ISG15 conjugation of cGAS. The interaction of cGAS and HERC5 depends on the cGAS N-terminal domain and the RRC1-4 and HECT domain of HERC5. Mass spectrometry reveals that the Lys21,187,219,458 are the potential ISGylation sites in human cGAS. Deficiency of ISG15 or the E1 ubiquitin-activating enzyme UBA7 greatly attenuate the downstream gene expression induced by cGAS-STING axis and the antiviral ability in mouse and human cells. Collectively, our study uncovered an important role of the HERC5-facilitated cGAS ISGylaion in promoting antiviral defense.

Non-precious transition metal electrocatalysts with high catalytic performance and low cost enable the scalable and sustainable production of hydrogen energy through water splitting. In this work, based on the polymerization of CoMoO4 nanorods and pyrrole monomer, a heterointerface of carbon-wrapped and Co/Mo2C composites are obtained by thermal pyrolysis method. Co/Mo2C composites show considerable performance for both hydrogen and oxygen evolution in alkaline media. In alkaline media, Co/Mo2C composites show a small overpotential, low Tafel slope, and excellent stability for water splitting. Co/Mo2C exhibits a small overpotential of 157 mV for hydrogen evolution reaction and 366 mV for oxygen evolution reaction at current density of 10 mA cm−2, as well as a low Tafel slope of 109.2 mV dec−1 and 59.1 mV dec−1 for hydrogen evolution reaction and oxygen evolution reaction, respectively. Co/Mo2C composites also exhibit an excellent stability, retaining 94% and 93% of initial current value for hydrogen evolution reaction and oxygen evolution reaction after 45,000 s, respectively. Overall water splitting via two-electrode water indicates Co/Mo2C can hold 91% of its initial current after 40,000 s in 1 M KOH.

Acute prolonged endurance running has been shown to alter muscle-specific circulating microRNA (miRNA) levels. Here, eighteen participants completed an 8 km run. We assessed the levels of hsa-miR-1–3p, -133a-3p, -133b, and -206 and their correlation with conventional biomarkers following exercise. Compared to before exercise (Pre), 8 km run significantly increased the lactate level immediately after exercise (0 h). Myoglobin (Mb) level increased at 0 h while creatine kinase (CK) level increased 24 h after exercise (24 h). The levels of creatine kinase MB isoenzyme (CK-MB) and cardiac troponin I (cTnI) were all elevated at 24 h and within the normal physiological range; The levels of hsa-miR-1–3p, -133a-3p, -133b significantly increased at 0 h but only hsa-miR-133a-3p still elevated at 24 h. Only hsa-miR-206 level decreased at 24 h; Additionally, the changes of hsa-miR-1–3p and hsa-miR-133a-3p were correlated with Mb at 24 h. These findings suggest that muscle-specific miRNA elevation in plasma is likely physiological and that these miRNA may be used as potential biomarkers for load monitoring in individuals.

Development of electrocatalysts composed of low cost and abundant elements that exhibit catalytic activity comparable to noble metals is important for water splitting. As such, in this study, a catalyst material with a ginger-like morphology consisting of Co6W6C is synthesized via a hydrothermal reaction and pyrolysis treatment. The Co6W6C catalyst exhibits satisfactory electrochemical properties towards both hydrogen and oxygen evolution reactions in an alkaline electrolyte, with a low overpotential, low Tafel slope, and durable stability. Co6W6C possesses a high activity for the hydrogen evolution reaction in alkaline conditions, with an onset potential and overpotential of −0.024 V and 101 mV, respectively, and low Tafel slope of 80.5 mV dec−1 at a current density of 10 mA cm−2. In addition, Co6W6C achieves a current density of 10 mA cm−2 for the oxygen evolution reaction at an overpotential of only 343 mV. Furthermore, electrochemical stability tests indicate that the Co6W6C catalyst maintains 91% of the original current after 60,000 s for the hydrogen evolution reaction and 95% of the original current after 45,000 s for the oxygen evolution reaction. Moreover, electrochemical splitting of water via a two-electrode system employing this catalyst can hold 89% of the initial current after 40,000 s in 1 M KOH.

Large-scale genomic surveys of crop germplasm are important for understanding the genetic architecture of favorable traits. The genomic basis of geographic differentiation and fiber improvement in cultivated cotton is poorly understood. Here, we analyzed 3,248 tetraploid cotton genomes and confirmed that the extensive chromosome inversions on chromosomes A06 and A08 underlies the geographic differentiation in cultivated Gossypium hirsutum. We further revealed that the haplotypic diversity originated from landraces, which might be essential for understanding adaptative evolution in cultivated cotton. Introgression and association analyses identified new fiber quality-related loci and demonstrated that the introgressed alleles from two diploid cottons had a large effect on fiber quality improvement. These loci provided the potential power to overcome the bottleneck in fiber quality improvement. Our study uncovered several critical genomic signatures generated by historical breeding effects in cotton and a wealth of data that enrich genomic resources for the research community.

Background The Ras-like guanosine triphosphatases (Ral GTPases) belongs to the Ras superfamily of small GTPases. Ras mutations occur in more than one in three human tumors. However, treatments acting directly on Ras post-translational modifications were developed and have been manufactured for many years, although they have demonstrated poor clinical performance. Ral GTPases include RalA and RalB, seem to be a new potential pathway downstream of mutant Ras. Methods In this study, we examined protein and mRNA level of Ral GTPases in lung specimens from 12 lung cancer patients using Western Blot and RT-PCR. The effects of RalA and RalB on the proliferation and migration were examined by functional tests in vitro and in vivo. The binding site in miR-215-5p and RalA or RalB was predicted using bioinformatics software and proved by Western Blot, RT-PCR and luciferase assay. The effect of miR-215-5p on RalA and RalB were examined in cell lines and xenograft mice. Results Here, we reported that miR-215-5p was downregulated in human lung cancer tissues compared with noncancerous tissues, whereas the expression level of Ral GTPases was higher. We further verified that the negative regulation of Ral GTPases by miR-215-5p could inhibit the proliferation and migration of lung cancer in vitro and in vivo. Conclusion In this study, we reported that RalA and RalB promote lung cancer proliferation and migration. Moreover, we identified miR-215-5p as a tumor suppressor that targets Ral GTPases. Our results may offer therapeutic opportunities in lung cancer.

Cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS), upon sensing cytosolic DNA, catalyzes the production of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), which activates STING-TBK1-IRF3 signaling. cGAS is also present in the nucleus, but the relevant nuclear function or mechanism remains largely unknown. Here, we report that nuclear cGAS is indispensable for inducing cytokines and chemokines triggered by RNA/DNA viruses. Unexpectedly, the DNA-binding/nucleotidyltransferase activity of cGAS is dispensable for RNA-virus-induced genes expression. cGAS deficiency does not affect the phosphorylation, dimerization, or nuclear translocation of IRF3 induced by double-stranded RNA (dsRNA). Mechanistically, nuclear-localized cGAS interacts with protein arginine methyltransferase 5 (Prmt5), which catalyzes the symmetric dimethylation of histone H3 arginine 2 at Ifnb and Ifna4 promoters, thus facilitating the access of IRF3. Deficiency of Prmt5 or disrupting its catalytic activity suppresses the production of type I interferons (IFNs), impairing the host defenses against RNA/DNA virus infections. Taken together, our study uncovers a non-canonical function of nuclear-localized cGAS in innate immunity via regulating histone arginine modification.

Binary metal oxides have recently attracted extensive attention from researchers in the energy storage and conversion field due to their high energy densities and multiple oxidation states. Novel 3D Co3V2O8 porous rose-like structures and 2D NiCo2V2O8 nanoplates were facilely synthesized via a solvothermal method, and the morphologies, Ni/Co ratios, and surface area of these samples can be easily tuned in the same procedure. The as-prepared Co3V2O8 porous rose-like structure exhibited good electrocatalytic oxygen evolution performance with excellent activity and stability. In addition, 2D NiCo2V2O8 nanoplates delivered a high specific capacitance of 1098.9 F g−1 at 4 A g−1 and good cycling stability (remaining 68% after 7000 cycles) in aqueous KOH electrolyte. The NiCo2V2O8 nanoplates inherit the pseudocapacitive benefits of both Ni3V2O8 and Co3V2O8, showing a higher specific capacitance than pure Co3V2O8 porous rose-like structures.

// Minghui Liu 1, * , Rong Yang 1, 2, * , Uzair Urrehman 1, * , Chao Ye 1 , Xin Yan 3 , Shufang Cui 1 , Yeting Hong 1 , Yuanyuan Gu 1 , Yanqing Liu 1 , Chihao Zhao 1 , Liang Yan 4 , Chen-Yu Zhang 1 , Hongwei Liang 1 , Xi Chen 1 1 State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210046, China 2 Department of Urology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, China 3 Department of Respiratory Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, China 4 Provincial Key Laboratory of Biological Macro-molecules Research, Wannan Medical College, Wuhu, Anhui 241002, China * These authors contributed equally to this work Correspondence to: Xi Chen, email: xichen@nju.edu.cn Hongwei Liang, email: lianghongwei0418@163.com Chen-Yu Zhang, email: cyzhang@nju.edu.cn Keywords: miR-19b, PTPRG, proliferation, apoptosis, migration Received: January 05, 2016 Accepted: August 22, 2016 Published: September 01, 2016 ABSTRACT Protein tyrosine phosphatase receptor type G (PTPRG) is an important tumor suppressor gene in multiple human cancers. In this study, we found that PTPRG protein levels were downregulated in breast cancer tissues while the mRNA levels varied irregularly, implying a post-transcriptional mechanism was involved. Because microRNAs are powerful post-transcriptional regulators of gene expression, we used bioinformatics analysis to search for microRNAs that potentially targets PTPRG in the setting of breast cancer. We identified two specific binding sites for miR-19b in the 3′-untranslated region of PTPRG. We further identified an inverse correlation between miR-19b and PTPRG protein levels, but not mRNA levels, in human breast cancer tissues. By overexpressing or knocking down miR-19b in MCF-7 cells and MDA-231 cells, we experimentally confirmed that miR-19b directly suppresses PTPRG expression. Furthermore, we determined that the inhibition of PTPRG by miR-19b leads to increased proliferation, stimulated cell migration and reduced apoptosis. Taken together, our findings provide the first evidence that miR-19b inhibits PTPRG expression to promote tumorigenesis in human breast cancer.

Recently, as one kind of ternary spinel metal oxide, ZnCo2O4 has attracted extensive attention in the energy storage and conversion field due to it being cost-effective, scalable, and environmentally friendly. Herein, porous ZnCo2O4 micro-spindles and truncated drums were synthesized by a solvent thermal route first and then with an annealing treatment with the precursors. The morphology and structure of ZnCo2O4 were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and high-resolution TEM (HRTEM). It is worth noting that ZnCo2O4 porous micro-spindles show a high surface area of 65.85 m2 g−1 with an average pore diameter of ∼6.34 nm. The as-prepared ZnCo2O4 materials, especially micro-spindles, exhibited good electrocatalytic water-splitting performance with excellent activity and stability. The ZnCo2O4 micro-spindle catalyst exhibits an overpotential of 0.389 V at the benchmark of a current density of 10 mA cm−2. The Tafel slope is 59.54 mV dec−1 and the OER overpotential of the catalyst shows no obvious increase during 7200 s. The high activity, low Tafel slope, and good stability will pave the way for the use of ZnCo2O4 micro-spindles in practical applications.

Clinical features of colorectal cancer patients. (DOCX 17Â kb)

Sequences of siRNAs, probe and primers. (DOCX 16Â kb)

Background Colorectal cancer (CRC) is a severe health problem worldwide. Clarifying the mechanisms for the deregulation of oncogenes and tumour suppressors in CRC is vital for its diagnosis, treatment, prognosis and prevention. Hu antigen R (HuR), which is highly upregulated in CRC, functions as a pivotal oncogene to promote CRC progression. However, the underlying cause of its dysregulation is poorly understood. Methods In CRC tissue sample pairs, HuR protein levels were measured by Western blot and immunohistochemical (IHC) staining, respectively. HuR mRNA levels were also monitored by qRT-PCR. Combining meta-analysis and microRNA (miRNA) target prediction software, we predicted miRNAs that targeted HuR. Pull-down assay, Western blot and luciferase assay were utilized to demonstrate the direct binding of miR-22 on HuR’s 3’-UTR. The biological effects of HuR and miR-22 were investigated both in vitro by CCK-8, EdU and Transwell assays and in vivo by a xenograft mice model. JASPAR and SABiosciences were used to predict transcriptional factors that could affect miR-22. Luciferase assay was used to explore the validity of putative Jun binding sites for miR-22 regulation. ChIP assay was performed to test the Jun’s occupancy on the C17orf91 promoter. Results We observed a significant upregulation of HuR in CRC tissue pairs and confirmed the oncogenic function of HuR both in vitro and in vivo. We found that an important tumour-suppressive miRNA, miR-22, was significantly downregulated in CRC tissues and inversely correlated with HuR in both CRC tissues and CRC cell lines. We demonstrated that miR-22 directly bound to the 3’-UTR of HuR and led to inhibition of HuR protein, which repressed CRC proliferation and migration in vitro and decelerated CRC xenografted tumour growth in vivo. Furthermore, we found that the onco-transcription factor Jun could inhibit the transcription of miR-22. Conclusions Our findings highlight the critical roles of the Jun/miR-22/HuR regulatory axis in CRC progression and may provide attractive potential targets for CRC prevention and treatment. Electronic supplementary material The online version of this article (10.1186/s12943-017-0751-3) contains supplementary material, which is available to authorized users.

In this work, FeCo nanoparticles encapsulated in graphitic carbon layers are derived by direct pyrolysis of Prussian blue/ZIF-67. First, the Prussian blue nanocubes with size of 100–150 nm are selected as cores for growth of ZIF-67 metal organic frameworks. Subsequent direct pyrolysis of Prussian blue/ZIF-67 in nitrogen atmosphere enables the formation of carbon nanospheres with FeCo nanoparticles embedded into the nitrogen-doped graphitic carbon layers. The encapsulation of FeCo nanoparticles into the nitrogen-doped carbon layers favors the electron penetration from the underlying FeCo nanoparticles to the nitrogen-doped graphitic carbon layers, tuning the electron density and the electronic properties at the carbon overlayers and then promoting the both hydrogen and oxygen evolution reaction activity. By optimizing the ratio between the Prussian blue and ZIF-67, the active and inexpensive carbon layers-encapsulated FeCo nanoparticles achieve high activity towards the hydrogen evolution reaction, exhibiting a low overpotential of 106 mV at 10 mA cm−2 as well as a low Tafel slope of 90.0 mV dec−1. As oxygen evolution reaction electrocatalysts, the carbon layers-encapsulated FeCo nanoparticles deliver an overpotential of 312 mV at 10 mA cm−2 and a low Tafel slope of 40.6 mV dec−1. Severing as both anode and cathode, the carbon layers-encapsulated FeCo nanoparticles show a potential of 1.495 V at 10 mA cm−2 for water splitting, which is close to the noble metal benchmarks of Pt/C and RuO2 counterparts. The carbon layers-encapsulated FeCo nanoparticles can be used as an attractive replacement for electrocatalytic water splitting.

Background Colorectal cancer (CRC) is a major worldwide health problem due to its high prevalence and mortality rate. T-cell intracellular antigen 1 (TIA1) is an important tumor suppressor involved in many aspects of carcinogenesis and cancer development. How TIA1 expression is regulated during CRC development remains to be carefully elucidated. Methods In CRC tissue sample pairs, TIA1 protein and mRNA levels were monitored by Western blot and qRT-PCR, respectively. Combining meta-analysis and miRNA target prediction software, we could predict microRNAs that targeted TIA1. Next, three CRC cell lines (SW480, Caco2 and HT29) were used to demonstrate the direct targeting of TIA1 by miR-19a. In addition, we investigated the biological effects of TIA1 inhibition by miR-19a both in vitro by CCK-8, EdU, Transwell, Ki67 immunofluorescence and Colony formation assays and in vivo by a xenograft mice model. Results In colorectal cancer (CRC), we found that TIA1 protein, but not its mRNA, was downregulated. We predicted that TIA1 was a target of miR-19a and validated that miR-19a binded directly to the 3’-UTR of TIA1 mRNA. miR-19a could promote cell proliferation and migration in CRC cells and accelerated tumor growth in xenograft mice by targeting TIA1. Conclusions This study highlights an oncomiR role for miR-19a in regulating TIA1 in CRC and suggests that miR-19a may be a novel molecular therapeutic target for CRC. Electronic supplementary material The online version of this article (doi:10.1186/s12943-017-0625-8) contains supplementary material, which is available to authorized users.

Top 29 significantly upregulated miRNAs in the colon cancer tissues compared with the normal solid tissues analyzed by meta-analysis by using YM500. (DOCX 17 kb)

Clinical features of colorectal cancer patients. (DOCX 17 kb)

Experimental autoimmune encephalomyelitis (EAE), a common model of multiple sclerosis (MS), is mainly mediated by CD4

The use of smokeless tobacco (ST) is growing rapidly and globally. The consumption of ST is associated with an increased risk for developing chronic diseases, such as diabetes, hypercholesterolemia, and myocardial infarction, and has led to many public health problems. It is very important to access the toxicity of ST. This experiment presents data from 184-day toxicology studies in Sprague-Dawley (SD) rats designed to characterize the chronic effects of a smokeless tobacco extract (STE). The control group and treatment groups were matched for a range of nicotine levels. Animals were given STE by oral gavage with doses of 3.75 (low-dose), 7.50 (mid-dose) and 15.00 (high-dose) mg · nicotine/kg body weight/day for 184 days, followed by 30 days for recovery. Variables evaluated included body weights, feed consumption, clinical observations, clinical and anatomic pathology (including organ weights), and histopathology. Decreased body weights and organ weights (heart, liver and kidney) were found in animals in the mid-dose and high-dose groups. STE also showed moderate and reversible toxicity in esophagus, stomach, liver, kidney and lung.

The acquired immunodeficiency syndrome (AIDS) has now become one of the most serious infectious disease in the world, the safe and effective AIDS vaccines would be the best tools to control the disease. Fowlpox virus has been studied recently as a potential vector for the delivery of heterologous vaccine antigen. In this study, a recombinant fowlpox virus coexpressing gp120 of Chinese prevalent HIV-1 strain and IL-2 was constructed and the cellular immune responses against HIV-1 gp120 in BALB/c mice were evaluated. Chinese vaccine strain 282E4 of fowlpox virus was used as the vector to construct the recombinant fowlpox virus (rFPV) coexpressing HIV-1 gp120 and IL-2 via homologous recombination, and the recombinant virus was identified by PCR and Western blotting. The specific DNA fragment was amplified by PCR from the genomes of rFPV. Western blotting analysis showed that HIV-1 gp120 and IL-2 was expressed not only in chicken embryo fibroblast (CEF) cells infected by rFPV, but also in mammalian cells infected by rFPV. After the recombinant fowlpox virus was inoculated into BALB/c mice, specific CTL activities in the immunized mice were detected in the spleen. The results demonstrated that rFPV had good immunogenicity and could induce BALB/c mice to produce specific cellular immunity. IL-2 played a role of immunoadjuvant and enhanced the cellular immune response. The study provides the basis for the preparation of a Chinese vaccine candidate against HIV-1.

DNA vaccines have a demonstrated ability to induce humoral and cellular immune responses in animal models and humans. To analyze the immunogenicity of HIV-1 DNA vaccine which expressing the chimeric gene gag-gp120 of Chinese prevalent HIV-1 strain and the immunoregulatory activity of IL-6, DNA vaccine plasmid pVAX1-gag-gp120 and eukaryotic expression plasmid pVAX1-IL6 were constructed and the expression in vitro was detected by RT-PCR and Western blotting, the results showed that the gene of interest expressed in the transfected HeLa cells. To explore the immune response in mice coinoculated with HIV-1 DNA vaccine and IL-6 expression plasmid, BALB/c mice were injected i.m. with eukaryotic expression plasmid pVAX1-IL6 and DNA vaccine plasmid pVAX1-gag-gp120. The specific humoral and cellular immunity in mice could be induced by inoculating separately HIV-1 DNA vaccine plasmid or coinoculating with IL-6 expression plasmid, and the specific killing activities of spleen CTL and the level of serum antibodies in the coinoculation group were significantly higher than those in the separate inoculation group. These results strongly support the use of IL-6 as a cytokine adjuvant in DNA vaccination.

Everything is a unity of quantity and quality. In order to understand a thing truly, we should not only grasp the prescriptions of its quantity, but also clear the Prescriptions of its quality. Marx pointed that a science will develop only when it is able to apply math. We often say that mathematics is the tool of thinking, in essence, by that we refers to the way of thinking. The fulfilling of mathematical sciences function mainly refers to the penetration and migration of mathematical thinking method in various fields. Mathematics should be treating as a tool to be used, thus contributing to its own development. This paper analyzed the theoretical and practice of RMI thinking method in mathematics teaching area, stimulated the method of the formation of mathematical thinking and promoted the applied mathematics capability. So it is imperative to improve the quality of teaching.