The prognostic value of combined uric acid and neutrophil-to-lymphocyte ratio in acute ischemic stroke patients treated with intravenous thrombolysis.

BACKGROUND: Serum uric acid (UA) and the neutrophil-to-lymphocyte ratio (NLR) have been reported to be associated with outcomes in acute ischemic stroke (AIS). However, whether UA is related to the prognosis of AIS patients undergoing intravenous thrombolysis (IVT) remains inconclusive. We sought to explore the combined effect of UA and NLR on the prognosis of AIS treated with IVT. METHODS: A total of 555 AIS patients receiving IVT treatment were enrolled. Patients were categorized into four groups according to the levels of UA and NLR: LNNU (low NLR and normal UA), LNHU (low NLR and high UA), HNNU (high NLR and normal UA), and HNHU (high NLR and high UA). Multivariable logistic regression analysis was used to evaluate the value of serum UA level and NLR in predicting prognosis. The primary outcomes were major disability (modified Rankin scale (mRS) score 3-5) and death within 3 months. RESULTS: After multivariate adjustment, a high NLR (≥ 3.94) increased the risk of 3-month death or major disability (OR, 2.23; 95% CI, 1.42 to 3.55, p < 0.001). However, there was no statistically significant association between a high UA level (≥ 313.00 µmol/L) and clinical outcome. HNHU was associated with a 5.09-fold increase in the risk of death (OR, 5.09; 95% CI, 1.31-19.83; P value = 0.019) and a 1.98-fold increase in the risk of major disability (OR, 1.98; 95% CI 1.07-3.68; P value = 0.030) in comparison to LNNU. CONCLUSIONS: High serum UA levels combined with high NLR were independently associated with 3-month death and major disability in AIS patients after IVT.

An engineered Cas12i nuclease that is an efficient genome editing tool in animals and plants.

The type V-I CRISPR-Cas system is becoming increasingly more attractive for genome editing. However, natural nucleases of this system often exhibit low efficiency, limiting their application. Here, we used structure-guided rational design and protein engineering to optimize an uncharacterized Cas12i nuclease, Cas12i3. As a result, we developed Cas-SF01, a Cas12i3 variant that exhibits significantly improved gene editing activity in mammalian cells. Cas-SF01 shows comparable or superior editing performance compared to SpCas9 and other Cas12 nucleases. Compared to natural Cas12i3, Cas-SF01 has an expanded PAM range and effectively recognizes NTTN and noncanonical NATN and TTVN PAMs. In addition, we identified an amino acid substitution, D876R, that markedly reduced the off-target effect while maintaining high on-target activity, leading to the development of Cas-SF01HiFi (high-fidelity Cas-SF01). Finally, we show that Cas-SF01 has high gene editing activities in mice and plants. Our results suggest that Cas-SF01 can serve as a robust gene editing platform with high efficiency and specificity for genome editing applications in various organisms.

C-to-U RNA deamination is the driving force accelerating SARS-CoV-2 evolution.

Understanding the molecular mechanism underlying the rampant mutation of SARS-CoV-2 would help us control the COVID-19 pandemic. The APOBEC-mediated C-to-U deamination is a major mutation type in the SARS-CoV-2 genome. However, it is unclear whether the novel mutation rate u is higher for C-to-U than for other mutation types, and what the detailed driving force is. By analyzing the time course SARS-CoV-2 global population data, we found that C-to-U has the highest novel mutation rate u among all mutation types and that this u is still increasing with time (du/dt > 0). Novel C-to-U events, rather than other mutation types, have a preference over particular genomic regions. A less local RNA structure is correlated with a high novel C-to-U mutation rate. A cascade model nicely explains the du/dt > 0 for C-to-U deamination. In SARS-CoV-2, the RNA structure serves as the molecular basis of the extremely high and continuously accelerating C-to-U deamination rate. This mechanism is the driving force of the mutation, adaptation, and evolution of SARS-CoV-2. Our findings help us understand the dynamic evolution of the virus mutation rate.

Immunotherapy and Prognosis of Non-small Cell Lung Carcinoma by Monomethoxy polyethylene glycol-hyaluronic acid-platinum Combined with Immune CT4+ and CT8+ Detection.

To investigate the changes in CT4+ and CT8+ lymphocyte subpopulations of patients with non-small cell lung carcinoma (NSCLC) by monomethoxy polyethylene glycol-hyaluronic acid-platinum (MPEG-HA-Pt) and the correlation between efficacy evaluation and the changes in T lymphocyte subpopulation, 76 NSCLC patients treated at oncology department of Chengdu First People's Hospital were selected and randomly divided into the treatment group and the control group (38 cases in each). mPEG-HA-Pt was used for the treatment of the included patients in the research. The patients in the control group were performed with traditional chemotherapy for 2 treatment courses. The changes in the T-lymphocyte subpopulation before and after the treatment were detected and the therapeutic effects on the patients in the two groups were compared. The particle size of mPEG-HA-Pt ranged between 78nm and 100nm with an average of 84.6±7.5nm. After that, a transmission electron microscope (TEM) was used to observe the spheres with uniform size. The drug loading capacity and entrapped efficiency of mPEG-HA-Pt were 18.7% and 87.4%, respectively. After the treatment for NSCLC patients by nanomicelle, cellular immune functions were all improved. In particular, cellular immune functions of the patients with good efficacy evaluation were improved more apparently.

Polymelamine Formaldehyde-Coated MIL-101 as an Efficient Dual-Functional Core-Shell Composite to Catalyze the Deacetalization-Knoevenagel Tandem Reaction.

Porous organic polymer (POP) coated on a metal-organic framework (MOF) has the functions and advantages of MOF and POP at the same time and has excellent catalytic ability. In this study, an efficient dual-functional core-shell composite MOF@POP with Lewis acid and Brønsted base sites was synthesized using the impregnation method in which MIL-101(Cr) was the core component and polymelamine formaldehyde (PMF) was the shell component. Most importantly, the obtained MIL-101(Cr)@PMF showed perfect catalytic activity in the deacetalization-Knoevenagel tandem reaction. In addition, it could still maintain ultrahigh physical and chemical stability.

Autoimmune glial fibrillary acidic protein astrocytopathy mimicking acute disseminated encephalomyelitis: A case report.

INTRODUCTION: Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is an increasingly recognized type of steroid-responsive autoimmune disease of the nervous system. Defined in 2016, it is associated with the presence of anti-GFAP immunoglobulinG in the serum or cerebrospinal fluid (CSF) of affected patients. PATIENT CHARACTERISTICS: Herein, we report a case of acute neurological symptoms, including headache, fever, confusion, and paralysis of the lower extremities. CSF analysis revealed lymphocytic pleocytosis and elevated protein levels, indicating acute disseminated encephalomyelitis, and the patient was given immunotherapy. Cranial magnetic resonance imaging showed multifocal T2/fluid-attenuated inversion recovery hyperintense signal changes in the periventricular white matter, and electromyography testing showed changes consistent with severe sensorimotor neuropathy, indicating the involvement of the brain and peripheral nerves. DIAGNOSES: Finally, a diagnosis of autoimmune GFAP astrocytopathy was confirmed due to the presence of GFAP-immunoglobulinG in the patient's CSF. INTERVENTIONS: The patient was treated with one course of intravenous immunoglobulin therapy, then followed with intravenous methylprednisolone (1.0 g/d for 3 days) and oral prednisolone. OUTCOMES: At 1 week after intravenous immunoglobulin therapy, his level of consciousness improved. However, flaccid paralysis persisted without substantial improvement. CONCLUSION: In conclusion, the provision of an accurate early diagnosis and appropriate treatment are crucial for improving the prognosis of patients with autoimmune GFAP astrocytopathy. Further, this case highlights the importance of recognizing the role of peripheral nerve involvement in GFAP autoimmunity.

Liposome-Coated Arsenic-Manganese Complex for Magnetic Resonance Imaging-Guided Synergistic Therapy Against Carcinoma.

PURPOSE: A liposome-coated arsenic-manganese complex, denoted as LP@MnAsx was constructed for the targeted delivery of arsenic trioxide (ATO) against carcinoma. METHODS: Arsenite, the prodrug of ATO, was encapsulated within a liposome via electrostatic interaction with the manganese ions. The as-prepared material was characterized with dynamic light scattering and transmission electron microscopy. The entrapment efficiency and drug loading of arsenic in the carrier were measured using inductively coupled plasma spectrometry. The in vitro release of arsenic was evaluated by using the dialysis bag method. Furthermore, the Fenton-like activity and in vitro cytodynamics research of LP@MnAsx were monitored in this work. And the cellular uptake study was used to investigate the in vitro entry mechanism. Furthermore, the cytotoxicity, cell apoptosis and cell cycle study were performed to evaluate the tumor-killing efficiency. Also, the pharmacokinetic and antitumor studies were investigated in HepG2 tumor-bearing nude mice. RESULTS: The as-prepared LP@MnAsx possessed a spherical morphology, uniformly distributed hydrodynamic diameter, and excellent drug-loading efficiency. LP@MnAsx displayed robust stability and sustained-release profile under physiological environments. LP@MnAsx could degrade with high sensitivity to the pH variation in the tumor microenvironment. As such, this could lead to a burst release profile of Mn2+ and arsenite to achieve a synergistic therapy of chemodynamic therapy and chemotherapy. When compared to the carrier-free arsenate, in vitro experiments revealed that LP@MnAsx exhibited enhanced cellular uptake and tumor-killing efficiency. LP@MnAsx also demonstrated significantly enhanced tumor-specific in vivo distribution of arsenic, prolonged systemic circulation lifetime, and increased accumulation at the tumor site. CONCLUSION: Based on the experimental results, LP@MnAsx is an ideal arsenic-based nanodelivery system, whereby it can improve the non-specific distribution of NaAsO2 in vivo. Thus, this work can expand the research and application of arsenic trioxide against solid tumors.

Tolerance and distribution of cadmium in an ornamental species Althaea rosea Cavan.

The ornamental plants of Althaea rosea Cavan. were exposed to cadmium (Cd) at concentrations of 0, 5, 10, 50 and 100 mg·kg-1 to evaluate the potential of accumulation capacity and tolerance ability. The results showed that A. rosea was a Cd tolerance plant, and Cd accumulation was 4.57 mg·kg-1 in shoot and 9.43 mg·kg-1 in root at 100 mg·kg-1 Cd concentration. The high tolerance ability could be explained by the distribution characteristics and the defense mechanism. The accumulated Cd was allocated in root, older leaves, and subcellular level of the cell wall and supernatant soluble fraction to protect the physiological leaves from damage. The defense systems included the enzyme systems of superoxide dismutase (SOD), peroxidase (POD), catalase (CAT) and ascorbate peroxidase (APX) that could effectively eliminate the excessive ROS, and the non-enzymes system of total soluble proteins and non-protein thiols (NP-SH) that played an important role in detoxification. Thus, A. rosea could be used as a potential species for phytoremediation in Cd contaminated areas and beautify the environment.

Ti-Doped Tunnel-Type Na4Mn9O18 Nanoparticles as Novel Anode Materials for High-Performance Supercapacitors.

Nanomaterials with tunnel structures are extremely attractive to be used for electrode materials in electrochemical energy storage devices. Tunnel-structured Ti-doped Na4Mn9O18 nanoparticles (TNMO-NPs) were synthesized by a facile and high-production method of the solid-state reaction with a high-energy ball-milling process. As electrode materials in the supercapacitor cell, the as-synthesized TNMO-NPs exhibit a high specific capacity of 284.93 mA h g-1 (0.57 mA h cm-2/1025.75 F g-1). A superior rate capability with a decay of 36% is achieved by increasing the scan rates from 2 to 25 mV s-1. To further explore the storage mechanism of Ti-doped Na4Mn9O18 materials, density functional theory (DFT) calculations were used to calculate the activation energy for the ion immigration in the electrode, and the results show that the minimum ion diffusion barrier energy is 0.272 eV, indicating that the sodium ions could insert into the system easily. Through the scan-rate-dependent cyclic voltammetry analysis, the capacity value indicates a mixed charge storage of capacitive behavior and Na+ intercalation progress. A maximum energy density of 77.81 W h kg-1 at a power density of 125 W kg-1 is achieved, and a high energy density of 54.79 W h kg-1 is maintained even at an ultrahigh power density of 3750 W kg-1. The TNMO-NP supercapacitors show excellent flexibility at various bent (0-180°) states. The capacitive performance of the TNMO-NPs makes them promising cathode materials for flexible supercapacitors with high specific capacities and high energy densities.

MicroRNA-30e regulates TGF-ß-mediated NADPH oxidase 4-dependent oxidative stress by Snai1 in atherosclerosis.

MicroRNAs (miRNAs) are small non­coding RNA molecules that regulate gene expression at a post­transcription level in living organisms. Great attention has been paid to the role of miRNAs in the pathogenesis of atherosclerosis (AS). The present study was designed to investigate the function of miRNA­30e in atherosclerosis and to explore potential mechanisms. The expression of miRNA­30e was decreased in an AS model, compared with the normal group. The downregulation of miRNA­30e increased oxidative stress and reactive oxygen species (ROS) levels in vitro. Then, overexpression of miRNA­30e led to decreased oxidative stress and ROS levels in vitro. The downregulation of miRNA­30e induced the protein expression of Snai1, transforming growth factor (TGF)­ß and mothers against decapentaplegic homolog 2 (Smad2) and suppressed that of NADPH oxidase 4 (Nox4) in vitro. The activation of Snai1 or TGF­ß attenuated the effects of miRNA­30e on oxidative stress in vitro. Consistently, the inhibition of Nox4 attenuated the effects of miRNA­30e on oxidative stress in vitro. These findings demonstrated for the first time that miRNA­30e regulated AS by TGF­ß­mediated NADPH oxidase 4­dependent oxidative stress via Snai1.

Effects of Urban-rural Atmospheric Environment on Heavy Metal Accumulation and Resistance Characteristics of Pinus tabulaeformis in Northern China.

The washed and unwashed current (C) and previous year (C + 1) needles, branches and top soils of Pinus tabulaeformis trees were sampled at five sites Haitai industrial district (HT), Puji River (PJ), Fukang road (FK), Residential area (RA) and Baxian Mountain (BX) in Tianjin along an urban-rural gradient and analyzed for heavy metals (Cu, Mn, Zn, Pb and Cd) concentrations via ICP. C + 1 needles generally had higher Mn, Pb, Cd than C needles while the opposite was for Cu and Zn. Total Cu, Zn, Pb, Cd in soils peaked at HT and decreased at RA and BX. Heavy metals were generally higher in the unwashed needles than the washed needles at all sites. Meanwhile MDA, soluble sugar and free proline concentration in needles were increased with the increasing of heavy metal contents along the urban-rural gradient, further correlated with the heavy metal contents.

The impact of diet on the composition and relative abundance of rumen microbes in goat.

OBJECTIVE: This experiment was conducted to explore the impact of diet on the ruminal microbial community in goats. METHODS: Twelve goats were divided into two groups and fed complete feed (CF) or all forage (AF) diet. The total microbial DNAs in the rumen liquid were extracted. The V4 region of microbial 16S rRNA genes was amplified and sequenced using high-throughput. Information of sequences was mainly analyzed by QIIME 1.8.0. RESULTS: The results showed that Bacteroidetes and Firmicutes were the most predominant microbial phyla in the rumen of all goats. At genus level, the abundance of fiber-digesting bacteria such as Ruminococcus and Lachnospiracea incertae sedis was significantly higher in AF than that in CF, while the levels of fat-degrading bacterium Anaerovibrio and protein-degrading bacterium Pseudomonas were opposite. The core shared genera, Prevotella and Butyrivibrio were widespread in the rumen of goats and no significant difference was observed in relative abundance between groups. CONCLUSION: We concluded that the richness of fiber-, protein-, and fat-digesting bacteria was affected by diet and tended to increase with the rise of their corresponding substrate contents in the ration; some bacteria shared by all goats maintained stable despite the difference in the ration, and they might be essential in maintaining the normal function of rumen.

Arctigenin antagonizes mineralocorticoid receptor to inhibit the transcription of Na/K-ATPase.

CONTEXT: Hypertension is one of the most important risk factors in cardiovascular disease and is the most common chronic disease. Mineralocorticoid receptor (MR) antagonists have been successfully used in clinic for the treatment of hypertension. OBJECTIVE: Our study aims to investigate whether Arctigenin can antagonize MR and inhibit the transcription of Na/K-ATPase. MATERIALS AND METHODS: The yeast two-hybrid assay was used to screen natural products and Arctigenin was identified as an MR antagonist. The direct binding of Arctigenin to MR was determined using assays based on surface plasmon resonance, differential scanning calorimetry and fluorescence quenching. Furthermore, results from mammalian one-hybrid and transcriptional activation experiments also confirmed that Arctigenin can potently antagonize MR in cells. We demonstrated that Arctigenin can decrease the level of Na/K-ATPase mRNA by antagonizing MR in HK-2 cells. RESULTS: Our findings show that Arctigenin can effectively decrease Na/K-ATPase transcription; thus highlight its potential as an anti-hypertensive drug lead compound. DISCUSSION AND CONCLUSION: Our current findings demonstrate that Arctigenin is an antagonist of MR and effectively decreases the Na/K-ATPase 1 gene expression. Our work provides a hint for the drug discovery against cardiovascular disease.

Draft genome sequence of Mesorhizobium alhagi CCNWXJ12-2T, a novel salt-resistant species isolated from the desert of northwestern China.

Mesorhizobium alhagi strain CCNWXJ12-2(T) is a novel species of soil-dwelling, nitrogen-fixing bacteria that can form symbiotic root nodules with Alhagi sparsifolia. Moreover, the strain has high resistance to salt and alkali. Here we report the draft genome sequence of Mesorhizobium alhagi strain CCNWXJ12-2(T). A large number of osmotic regulation-related genes have been identified.