Supercoiled DNA percentage: A key in-process control of linear DNA template for mRNA drug substance manufacturing.

The development of messenger RNA (mRNA) vaccines and therapeutics necessitates the production of high-quality in vitro-transcribed mRNA drug substance with specific critical quality attributes (CQAs), which are closely tied to the uniformity of linear DNA template. The supercoiled plasmid DNA is the precursor to the linear DNA template, and the supercoiled DNA percentage is commonly regarded as a key in-process control (IPC) during the manufacturing of linear DNA template. In this study, we investigate the influence of supercoiled DNA percentage on key mRNA CQAs, including purity, capping efficiency, double-stranded RNA (dsRNA), and distribution of poly(A) tail. Our findings reveal a significant impact of supercoiled DNA percentage on mRNA purity and in vitro transcription yield. Notably, we observe that the impact on mRNA purity can be mitigated through oligo-dT chromatography, alleviating the tight range of DNA supercoiled percentage to some extent. Overall, this study provides valuable insights into IPC strategies for DNA template chemistry, manufacturing, and controls (CMC) and process development for mRNA drug substance.

Advancements in the research of immune checkpoint inhibitors for the treatment of advanced esophageal squamous cell carcinoma.

Esophageal cancer (EC) has a high mortality rate and poor prognosis. Most patients are diagnosed at an advanced stage or with distant metastasis, making surgery impossible. Traditional curative radiotherapy and chemotherapy have limited efficacy. In recent years, with the development of clinical trials, immune checkpoint inhibitors (ICIs) have shown promising results in treating advanced and metastatic esophageal squamous cell carcinoma (ESCC) patients. ICIs have gradually become a primary therapeutic approach for EC. This review summarizes and provides an overview of the current research status and progress of ICIs in the treatment of advanced ESCC patients.

Electro-Mechanical Coupling Analysis of L-Shaped Three-Dimensional Braided Piezoelectric Composites Vibration Energy Harvester.

In this article, an L-shaped three-dimensional (3D) braided piezoelectric composite energy harvester (BPCEH) is established, which consists of an elastic layer composed of a 3D braided composite, flanked by upper and lower layers of piezoelectric material and two tuning mass blocks. Glass fiber and epoxy resin are used to produce a 3D braided composite. This L-shaped 3D BPCEH is mechanically designable and can be adapted to different work requirements by varying the braided angle of the 3D braided composite layer. The material parameters of 3D braided composites are predicted for different braided angles by means of a representative volume element (RVE). Electro-mechanical coupled vibration equations for the L-shaped 3D BPCEH are established. The impact of braided angles on voltage and power output is discussed in this article. Simulations using finite element method are conducted to analyze the voltage and power output responses at various braided angles. In addition, the effects of the mass of mass block B and the length of the beam on the output performance of the L-shaped 3D BPCEH are analyzed.

High-efficiency and economical uranium extraction from seawater with easily prepared supramolecular complexes.

Developing effective adsorbents for uranium extraction from natural seawater is strategically significant for the sustainable fuel supply of nuclear energy. Herein, stable and low-cost supramolecular complexes (PA-bPEI complexes) were facilely constructed through the assembly of phytic acid and hyperbranched polyethyleneimine based on the multiple modes of electrostatic interaction and hydrogen bonding. The PA-bPEI complexes exhibited not only high uptake (841.7 mg g-1) and selectivity (uranium/vanadium selectivity = 84.1) toward uranium but also good antibacterial ability against biofouling. Mechanism analysis revealed that phosphate chelating groups and amine assistant groups coordinated the uranyl ions together with a high affinity. To be more suitable for practical applications, powdery PA-bPEI complexes were compounded with sodium alginate to fabricate various macroscopic adsorbents with engineered forms, which achieved an extraction capacity of 9.0 mg g-1 in natural seawater after 50 days of testing. Impressively, the estimated economic cost of the macroscopic adsorbent for uranium extraction from seawater ($96.5 âˆ¼ 138.1 kg-1 uranium) was lower than that of all currently available uranium adsorbents. Due to their good uranium extraction performance and low economic cost, supramolecular complex-based adsorbents show great potential for industrial uranium extraction from seawater.

GREAP: a comprehensive enrichment analysis software for human genomic regions.

The rapid development of genomic high-throughput sequencing has identified a large number of DNA regulatory elements with abundant epigenetics markers, which promotes the rapid accumulation of functional genomic region data. The comprehensively understanding and research of human functional genomic regions is still a relatively urgent work at present. However, the existing analysis tools lack extensive annotation and enrichment analytical abilities for these regions. Here, we designed a novel software, Genomic Region sets Enrichment Analysis Platform (GREAP), which provides comprehensive region annotation and enrichment analysis capabilities. Currently, GREAP supports 85 370 genomic region reference sets, which cover 634 681 107 regions across 11 different data types, including super enhancers, transcription factors, accessible chromatins, etc. GREAP provides widespread annotation and enrichment analysis of genomic regions. To reflect the significance of enrichment analysis, we used the hypergeometric test and also provided a Locus Overlap Analysis. In summary, GREAP is a powerful platform that provides many types of genomic region sets for users and supports genomic region annotations and enrichment analyses. In addition, we developed a customizable genome browser containing >400 000 000 customizable tracks for visualization. The platform is freely available at http://www.liclab.net/Greap/view/index.

A Low-Cost SiO x /C@Graphite Composite Derived from Oat Husk as an Advanced Anode for High-Performance Lithium-Ion Batteries.

Silicon monoxide (SiO x ), as a promising anode for the next-generation high-power lithium-ion batteries, has some advantages such as higher lithium storage capacity (∼2400 mAh g-1), suitable working potential, and smaller volume variations during cycling compared with pure silicon. However, its disadvantages such as its inherent low conductivity and high cost impede its extensive applications. Herein, we have developed a low-cost and high-capacity SiO x /C@graphite (SCG) composite derived from oat husks by a simple argon/hydrogen reduction method. For further practical application, we also investigated the electrochemical performances of SiO x mixed with different ratios of graphite. As an advanced anode for lithium-ion batteries, the SCG-1 composite exhibits an excellent electrochemical performance in terms of lithium storage capacity (809.5 mAh g-1 at 0.5 A g-1 even after the 250th cycle) and high rate capability (479.7 mAh g-1 at 1 A g-1 after the 200th cycle). This work may pave the way for developing a low-cost silicon-based anode derived from biomass with a large reversible capacity and long cycle life in lithium-ion batteries.

Identification and Validation of Autophagy-Related Genes in Sepsis-Induced Acute Respiratory Distress Syndrome and Immune Infiltration.

Purpose: Autophagy-related genes (ARGs) play an important role in the pathophysiology processes of sepsis-induced acute respiratory distress syndrome (ARDS). However, expression profiles of ARGs have rarely been used to explore the relationship between autophagy and sepsis-induced ARDS. Therefore, we aim to identify and validate the potential ARGs of sepsis-induced ARDS through bioinformatics analysis and experiment validation. Methods: We downloaded GSE32707 data from the Gene Expression Omnibus (GEO) database. The potential differentially expressed genes (DEGs) and differentially expressed ARGs (DEARGs) of sepsis-induced ARDS were screened by R software. Then, we performed functional enrichment analyses to explore the potential biological functions of DEARGs and constructed protein-protein interaction (PPI) networks. Subsequently, correlation analysis and receiver operating characteristic (ROC) curve were used for the DEARGs. In addition, we estimated the proportions of 22 immune cell subsets by using CIBERSORT algorithm. Finally, RNA expression of seven DEARGs were validated by qRT-PCR in blood samples from sepsis-induced ARDS and healthy controls. Results: We identified 28 DEARGs, including 11 up-regulated genes and 17 down-regulated genes, which were primarily involved in autophagy and apoptosis. Seven genes (BAG3, CTSD, ERBB2, MYC, PEA15, RAB24 and SIRT1) with AUC >0.70 were considered possible to be sepsis-induced ARDS hub genes for ROC curve analysis. CIBERSORT results shown that sepsis-induced ARDS contained a higher proportion of naive CD4+ T cells, gamma delta T cells, monocytes, and neutrophils, and lower levels of CD8+ T cells, memory resting CD4+ T cells, follicular helper T cells were relatively lower. The results of qRT-PCR also demonstrated that the expression levels of BAG3, CTSD, ERBB2, MYC and SIRT1 in sepsis-induced ARDS patients and healthy controls had differences. Conclusion: We identified an association between DEGs and immune infiltration in sepsis-induced ARDS and validated BAG3, CTSD, ERBB2, MYC and SIRT1 that may be have excellent diagnostic performance.

Characteristics and Prognostic Factors of Non-HIV Immunocompromised Patients With Pneumocystis Pneumonia Diagnosed by Metagenomics Next-Generation Sequencing.

Objective: The aim of this study was to evaluate the potential of metagenomic next-generation sequencing (mNGS) for the diagnosis of pneumocystis pneumonia (PCP) in patients with non-human immunodeficiency virus-infection and to discuss the clinical characteristics and identify prognostic factors associated with patients with non-HIV PCP. Methods: Forty-six patients with PCP who were admitted in respiratory intensive care unit (ICU) between May 2018 and May 2020 were retrospectively reviewed. The subjects were divided into survivor and non-survivor groups according to the patients' outcome. Conventional methods and mNGS for detecting Pneumocystis jirovecii (P. jirovecii) were analyzed. The patients' demographics, comorbidities, laboratory parameters, and treatments were compared and evaluated in both groups to identify risk factors for mortality by using univariate and multivariate logistic regression. Results: Metagenomic next-generation sequencing (mNGS) showed a satisfying diagnostic performance of 100% positive of detecting P. jirovecii from bronchoalveolar lavage (BAL) specimens in forty-six patients with non-HIV PCP, compared to only 15.2% for Gomori Methenamine silver (GMS) staining and 84.8% for Serum 1,3-beta-D-glucan (BDG). Among them, the mean age was 46.4-year-old (range 18-79-year-old) and mortality rate was 43.5%. The dominant underlying conditions were connective tissue diseases (34.8%), autoimmune kidney diseases (30.4%), followed by hematologic malignancies (10.9%), and solid organ transplantation (6.5%). A total of 38 cases (82.6%) received glucocorticoid and 19 cases (41.3%) used immunosuppressant within 3 months before diagnosed PCP. Multiple infections were very common, over two thirds' cases had mixed infections. Compared with survivors, non-survivors had a higher acute physiology and chronic health evaluation II (APACHE II) score (14.4 ± 4.8 vs. 10 ± 3.4), Procalcitonin (PCT) [ng/ml: 0.737 (0.122-1.6) vs. 0.23 (0.095-0.35)], lactic dehydrogenase (LDH) [U/L: 1372 (825.5-2150) vs. 739 (490.5-956)], and neutrophil-lymphocyte ratio (NLR) [21.6 (15.67-38.2) vs. 11.75 (5.1-15.52)], but had a lower PaO2/FiO2 ratio (mmHg:108.8 ± 42.4 vs. 150.5 ± 47.5), lymphocytes [×109/L: 0.33 (0.135-0.615) vs. 0.69 (0.325-1.07)] and CD4+ T cells [cell/µl: 112 (53.5-264) vs. 255 (145-303.5)], all P < 0.05. Furthermore, we found non-survivors' PaO2/FiO2 ratio of day 3 and day 7 had not improved when compared with that of day one, and platelet level and NLR became worse. Multivariate analysis showed that other pathogens' co-infection (OR = 9.011, 95% CI was 1.052-77.161, P = 0.045) and NLR (OR = 1.283, 95% CI was 1.046-1.547, P = 0.017) were the independent risk factors of poor prognosis. Conclusion: mNGS is a very sensitive diagnostic tool for identifying P. jirovecii in patients who are non-HIV immunocompromised. PCP in patients who are non-HIV infected is associated with a high rate of multiple infections and severe condition. Mixed infection and elevation of NLR were the independent risk factors of poor prognosis.

Doubly bi-allelic variants of MTHFR and MTHFD1 in a Chinese patient with hyperhomocysteinemia and failure of folic acid therapy.

Background: Hyperhomocysteinemia (HHcy) is a risk factor for thromboembolic disease. Defects in one-carbon metabolism (1-CM)-related genes, such as methylenetetrahydrofolate reductase (MTHFR), methylenetetrahydrofolate dehydrogenase, cyclohydrolase, and formyltetrahydrofolate synthetase 1 (MTHFD1), can cause HHcy and may also affect the efficacy of folic acid therapy. The details of mechanisms are yet to be further investigated. Method: We described a Chinese family with hereditary HHcy. The proband suffered from severe thromboembolic disease and experienced failure of folic acid therapy. Two sons of the proband were also diagnosed with HHcy but were sensitive to folic acid therapy. Whole-exome sequencing (WES) was conducted to evaluate the genetic lesion of this family. Results: Compound heterozygous variants (a common polymorphism, p. A222V, and a novel variant, p. C631*fs*1) of the MTHFR gene and a homozygous missense variant (p. K134R) of the MTHFD1 gene were identified in the proband. The two sons, with successful intervention, only harbored the homozygous p. A222V variant of the MTHFR gene. Conclusion: The clinical manifestations and genetic research synergistically confirmed the diagnosis of HHcy and clarified the failure of folic acid therapy in the proband caused by doubly bi-allelic variants of the MTHFR and MTHFD1 genes. Our study increased our understanding of the molecular basis of 1-CM-related gene defects on folic acid therapy in HHcy.

Insulin-Like Growth Factor-1 Enhances Motoneuron Survival and Inhibits Neuroinflammation After Spinal Cord Transection in Zebrafish.

Insulin-like growth factor-1 (IGF-1) is a neurotrophic factor produced locally in the central nervous system which can promote axonal regeneration, protect motoneurons, and inhibit neuroinflammation. In this study, we used the zebrafish spinal transection model to investigate whether IGF-1 plays an important role in the recovery of motor function. Unlike mammals, zebrafish can regenerate axons and restore mobility in remarkably short period after spinal cord transection. Quantitative real-time PCR and immunofluorescence showed decreased IGF-1 expression in the lesion site. Double immunostaining for IGF-1 and Islet-1 (motoneuron marker)/GFAP (astrocyte marker)/Iba-1 (microglia marker) showed that IGF-1 was mainly expressed in motoneurons and was surrounded by astrocyte and microglia. Following administration of IGF-1 morpholino at the lesion site of spinal-transected zebrafish, swimming test showed retarded recovery of mobility, the number of motoneurons was reduced, and increased immunofluorescence density of microglia was caused. Our data suggested that IGF-1 enhances motoneuron survival and inhibits neuroinflammation after spinal cord transection in zebrafish, which suggested that IGF-1 might be involved in the motor recovery.

A Low-Cost and High-Capacity SiO x /C@graphite Hybrid as an Advanced Anode for High-Power Lithium-Ion Batteries.

Silicon suboxide (SiO x ) is one of the most promising anodes for the next-generation high-power lithium-ion batteries because of its higher lithium storage capacity than current commercial graphite, relatively smaller volume variations than pure silicon, and appropriate working potential. However, the high cost, poor cycling stability, and rate capability hampered its industrial applications due to its complex production process, volume changes during Li+ insertion/extraction, and low conductivity. Herein, a low-cost and high-capacity SiO x /C@graphite (SCG) hybrid was designed and synthesized by a facile one-pot carbonization/hydrogen reduction process of the rice husk and graphite. As an advanced anode for lithium-ion batteries, the SiO x /C@graphite hybrid delivers a high reversible capacity with significantly enhanced cycling stability (842 mAh g-1 after 300 cycles at 0.5 A g-1) and rate capability (562 mAh g-1 after 300 cycles at 1 A g-1). The great improvement in performances could be attributed to the positive synergistic effect of SiO x nanoparticles as lithium storage active materials, the in situ-formed carbon matrix network derived from biomass functioning as an efficient three-dimensional conductive network and spacer to improve the rate capability and buffer the volume changes, and graphite as a conductor to further improve the rate capabilities and cycling stability by increasing the conductivity. The low-cost and high-capacity SCG derived from rice husk synthesized by a facile, scalable synthetic method turns out to be a promising anode for the next-generation high-power lithium-ion batteries.

Sodium Butyrate Exacerbates Parkinson's Disease by Aggravating Neuroinflammation and Colonic Inflammation in MPTP-Induced Mice Model.

The abnormal production of short chain fatty acid (SCFAs) caused by gut microbial dysbiosis plays an important role in the pathogenesis and progression of Parkinson's disease (PD). This study sought to evaluate how butyrate, one of SCFAs, affect the pathology in a subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) treated mouse model of PD. Sodium butyrate (NaB; 165 mg/kg/day i.g., 7 days) was administrated from the day after the last MPTP injection. Interestingly, NaB significantly aggravated MPTP-induced motor dysfunction (P < 0.01), decreased dopamine (P < 0.05) and 5-HT (P < 0.05) levels, exacerbated declines of dopaminergic neurons (34%, P < 0.05) and downregulated expression of tyrosine hydroxylase (TH, 47%, P < 0.05), potentiated glia-mediated neuroinflammation by increasing the number of microglia (17%, P < 0.05) and activating astrocytes (28%, P < 0.01). In vitro study also confirmed that NaB could significantly exacerbate pro-inflammatory cytokines expression (IL-1ß, 4.11-fold, P < 0.01; IL-18, 3.42-fold, P < 0.01 and iNOS, 2.52-fold, P < 0.05) and NO production (1.55-fold, P < 0.001) in LPS-stimulated BV2 cells. In addition, NaB upregulated the expression of pro-inflammatory cytokines (IL-6, 3.52-fold, P < 0.05; IL-18, 1.72-fold, P < 0.001) and NLRP3 (3.11-fold, P < 0.001) in the colon of PD mice. However, NaB had no effect on NFκB, MyD88 and TNF-α expression in PD mice. Our results indicate that NaB exacerbates MPTP-induced PD by aggravating neuroinflammation and colonic inflammation independently of the NFκB/MyD88/TNF-α signaling pathway.

Long Noncoding RNA NRAV Promotes Respiratory Syncytial Virus Replication by Targeting the MicroRNA miR-509-3p/Rab5c Axis To Regulate Vesicle Transportation.

Respiratory syncytial virus (RSV) is an enveloped RNA virus which is responsible for approximately 80% of lower respiratory tract infections in children. Current lines of evidence have supported the functional involvement of long noncoding RNA (lncRNA) in many viral infectious diseases. However, the overall biological effect and clinical role of lncRNAs in RSV infection remain unclear. In this study, lncRNAs related to respiratory virus infection were obtained from the lncRNA database, and we collected 144 clinical sputum specimens to identify lncRNAs related to RSV infection. Quantitative PCR (qPCR) detection indicated that the expression of lncRNA negative regulator of antiviral response (NRAV) in RSV-positive patients was significantly lower than that in uninfected patients, but lncRNA psoriasis-associated non-protein coding RNA induced by stress (PRINS), nuclear paraspeckle assembly transcript 1 (NEAT1), and Nettoie Salmonella pas Theiler's (NeST) showed no difference in vivo and in vitro Meanwhile, overexpression of NRAV promoted RSV proliferation in A549 and BEAS-2B cells, and vice versa, indicating that the downregulation of NRAV was part of the host antiviral defense. RNA fluorescent in situ hybridization (FISH) confirmed that NRAV was mainly located in the cytoplasm. Through RNA sequencing, we found that Rab5c, which is a vesicle transporting protein, showed the same change trend as NRAV. Subsequent investigation revealed that NRAV was able to favor RSV production indirectly by sponging microRNA miR-509-3p so as to release Rab5c and facilitate vesicle transportation. The study provides a new insight into virus-host interaction through noncoding RNA, which may contribute to exploring potential antivirus targets for respiratory virus.IMPORTANCE The mechanism of interaction between RSV and host noncoding RNAs is not fully understood. In this study, we found that the expression of long noncoding RNA (lncRNA) negative regulator of antiviral response (NRAV) was reduced in RSV-infected patients, and overexpression of NRAV facilitated RSV production in vitro, suggesting that the reduction of NRAV in RSV infection was part of the host antiviral response. We also found that NRAV competed with vesicle protein Rab5c for microRNA miR509-3p in cytoplasm to promote RSV vesicle transport and accelerate RSV proliferation, thereby improving our understanding of the pathogenic mechanism of RSV infection.

Sodium butyrate causes α-synuclein degradation by an Atg5-dependent and PI3K/Akt/mTOR-related autophagy pathway.

Aggregation of α-Synuclein is central to the pathogenesis of Parkinson's disease (PD). However, these α-Synuclein inclusions are not only present in brain, but also in gut. Enteroendocrine cells (EECs), which are directly exposed to the gut lumen, can express α-Synuclein and directly connect to α-Synuclein-containing nerves. Dysbiosis of gut microbiota and microbial metabolite short-chain fatty acids (SCFAs) has been implicated as a driver for PD. Butyrate is an SCFA produced by the gut microbiota. Our aim was to demonstrate how α-Synuclein expression in EECs responds to butyrate stimulation. Interestingly, we found that sodium butyrate (NaB) increases α-Synuclein mRNA expression, enhances Atg5-mediated autophagy (increased LC3B-II and decreased SQSTM1 (also known as p62) expression) in murine neuroendocrine STC-1 cells. Further, α-Synuclein mRNA was decreased by the inhibition of autophagy by using inhibitor bafilomycin A1 or by silencing Atg5 with siRNA. Moreover, the PI3K/Akt/mTOR pathway was significantly inhibited and cell apoptosis was activated by NaB. Conditioned media from NaB-stimulated STC-1 cells induced inflammation in SH-SY5Y cells. Collectively, NaB causes α-Synuclein degradation by an Atg5-dependent and PI3K/Akt/mTOR-related autophagy pathway.

[Clinical characteristics and prognostic factors of adult patients with acute respiratory failure due to influenza infection].

OBJECTIVE: To investigate the clinical characteristics and prognostic predictors of adult patients with acute respiratory failure due to influenza infection. METHODS: A retrospective analysis was performed on adult patients with acute respiratory failure due to confirmed influenza infection admitted to intensive care units (ICU) of the First Affiliated Hospital of Zhengzhou University and the Sixth People's Hospital of Zhengzhou between January 2018 and January 2020. The subjects were divided into survival and death groups according to whether the patients died before discharge. Demographic and clinical data including underlying conditions, laboratory variables, therapy and prognostic factors of hospital mortality between the two groups were analyzed. The risk factors of mortality were evaluated by univariate and multivariate Logistic regression analysis. Then, the correlation between lymphocyte (LYM) count and LYM subsets were analyzed. The survival rates of different acute physiologic and chronic health evaluation II (APACHE II) and LYM level subgroups were compared. RESULTS: A total of 104 patients were enrolled. Among them, 67 cases (64.4%) had underlying conditions, 91.3% of the patients (95 cases) were infected by influenza A virus, and the hospital mortality rate was 39.4% (41 cases). Compared with survival group, the patients of death group had higher respiratory rate (times/min: 26.0±5.6 vs. 23.7±5.0), APACHE II score (18.20±4.88 vs. 12.35±4.58), procalcitonin [PCT (µg/L): 0.82 (0.23, 4.63) vs. 0.39 (0.11, 0.92)], higher percentage of cardiovascular disease [24.4% (10/41) vs. 7.9% (5/63)] and invasive mechanical ventilation [63.4% (26/41) vs. 17.5% (11/63), all P < 0.01], but had lower oxygenation index [PaO2/FiO2 (mmHg, 1 mmHg = 0.133 kPa): 131.8±34.5 vs. 181.7±31.6] at ICU admission, LYM (×109/L: 0.53±0.40 vs. 0.92±0.44), hemoglobin [Hb (g/L): 105.66±28.17 vs. 118.29±28.29], platelet count [PLT (×109/L): 135.12±85.40 vs. 199.81±110.11], T lymphocyte count [cells/µL: 181 (131, 275) vs. 319 (238, 528)], CD4+ count [cells/µL: 110 (71, 161) vs. 190 (120, 311)] and CD8+ count [cells/µL: 71 (33, 100) vs. 121 (81, 188), all P < 0.01]. Patients of death group also had a shorter length of hospital stay [days: 7.0 (4.0, 11.0) vs. 12.0 (8.0, 20.0), P < 0.01]. Univariate analysis showed that APACHE II score [odds ratio (OR) = 1.207, 95% confidence interval (95%CI) was 1.094-1.332, P < 0.001], LYM (OR = 0.070, 95%CI was 0.018-0.271, P < 0.001), Hb (OR = 0.984, 95%CI was 0.970-0.999, P = 0.031), PLT (OR = 0.992, 95%CI was 0.987-0.997, P = 0.003), T lymphocyte count (OR = 0.996, 95%CI was 0.993-0.998, P = 0.001) and PaO2/FiO2 (OR = 0.955, 95%CI was 0.938-0.972, P < 0.001) were the risk factors for the prognosis of influenza patients with acute respiratory failure. Further multivariate Logistic analysis also showed that APACHE II score (OR = 1.195, 95%CI was 1.041-1.372, P = 0.011), LYM (OR = 0.063, 95%CI was 0.011-0.369, P = 0.002) and PaO2/FiO2 (OR = 0.953, 95%CI was 0.933-0.973, P < 0.001) were the predictors of mortality. Moreover, patients with peripheral blood LYM < 0.65×109/L or APACHE II score > 14 had a higher risk of poor outcome. There were significantly positive correlation between LYM and LYM subsets (T lymphocyte, CD4+ and CD8+ lymphocyte, r value was 0.593, 0.563, and 0.500, respectively, all P < 0.001). CONCLUSIONS: Influenza patients with acute respiratory failure were critically ill and had a high mortality rate. APACHE II score, PaO2/FiO2 and LYM at ICU admission were independent risk factors affecting the prognosis of patients.

Precise Point Positioning Using Dual-Frequency GNSS Observations on Smartphone.

The update of the Android system and the emergence of the dual-frequency GNSS chips enable smartphones to acquire dual-frequency GNSS observations. In this paper, the GPS L1/L5 and Galileo E1/E5a dual-frequency PPP (precise point positioning) algorithm based on RTKLIB and GAMP was applied to analyze the positioning performance of the Xiaomi Mi 8 dual-frequency smartphone in static and kinematic modes. The results showed that in the static mode, the RMS position errors of the dual-frequency smartphone PPP solutions in the E, N, and U directions were 21.8 cm, 4.1 cm, and 11.0 cm, respectively, after convergence to 1 m within 102 min. The PPP of dual-frequency smartphone showed similar accuracy with geodetic receiver in single-frequency mode, while geodetic receiver in dual-frequency mode has higher accuracy. In the kinematic mode, the positioning track of the smartphone dual-frequency data had severe fluctuations, the positioning tracks derived from the smartphone and the geodetic receiver showed approximately difference of 3-5 m.

Neuroprotection of Fasting Mimicking Diet on MPTP-Induced Parkinson's Disease Mice via Gut Microbiota and Metabolites.

Parkinson's disease (PD) is strongly associated with life style, especially dietary habits, which have gained attention as disease modifiers. Here, we report a fasting mimicking diet (FMD), fasting 3 days followed by 4 days of refeeding for three 1-week cycles, which accelerated the retention of motor function and attenuated the loss of dopaminergic neurons in the substantia nigra in 1-methyl-4-phenyl-1,2,3,6-tetrathydropyridine (MPTP)-induced PD mice. Levels of brain-derived neurotrophic factor (BDNF), known to promote the survival of dopaminergic neurons, were increased in PD mice after FMD, suggesting an involvement of BDNF in FMD-mediated neuroprotection. Furthermore, FMD decreased the number of glial cells as well as the release of TNF-α and IL-1ß in PD mice, showing that FMD also inhibited neuro-inflammation. 16S and 18S rRNA sequencing of fecal microbiota showed that FMD treatment modulated the shifts in gut microbiota composition, including higher abundance of Firmicutes, Tenericutes, and Opisthokonta and lower abundance of Proteobacteria at the phylum level in PD mice. Gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry revealed that FMD modulated the MPTP-induced lower propionic acid and isobutyric acid, and higher butyric acid and valeric acid and other metabolites. Transplantation of fecal microbiota, from normal mice with FMD treatment to antibiotic-pretreated PD mice increased dopamine levels in the recipient PD mice, suggesting that gut microbiota contributed to the neuroprotection of FMD for PD. These findings demonstrate that FMD can be a new means of preventing and treating PD through promoting a favorable gut microbiota composition and metabolites.

Neuroprotective effects of Astilbin on MPTP-induced Parkinson's disease mice: Glial reaction, α-synuclein expression and oxidative stress.

Astilbin (AST), a dihydro-flavonol glycoside, is a major bioactive ingredient in Astilbe thunbergii, Engelhardia roxburghiana, Smilax corbularia and Erythroxylum gonocladum, and has been shown to have anti-inflammatory, antioxidative and neuroprotective effects, suggesting potential therapeutic value in the treatment of Parkinson's disease (PD). We explored the neuroprotective effects of AST in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease mice. Mice were administered with MPTP (30 mg/kg, i.p) daily for 5 days, to establish a subacute Parkinson's disease model, followed by daily treatment with AST or saline for 7 days. Pole and traction tests showed that AST ameliorated the impaired motor functions in MPTP-induced Parkinson's disease mice. High performance liquid chromatography analysis revealed that AST treatment prevented MPTP-induced decreases in striatal dopamine levels. Immunofluorescence assays showed that AST reduced the loss of dopaminergic neurons and the activation of microglia and astrocytes in the substantia nigra. Western blot analyses revealed that AST suppressed α-synuclein overexpression and activated PI3K/Akt in the striatum following MPTP treatment. AST also prevented the MPTP-induced reduction in total superoxide dismutase and glutathione activity in the striatum. AST exerts neuroprotective effects on MPTP-induced PD mice by suppressing gliosis, α-synuclein overexpression and oxidative stress, suggesting that AST could serve as a therapeutic drug to ameliorate PD.

Aucubin alleviates glial cell activation and preserves dopaminergic neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonian mice.

Aucubin (AUC) is a major bioactive ingredient in Eucommia ulmoides, Plantain asiatica, and Aucuba japonica, and has been shown to exert anti-inflammatory, antioxidative, and neuroprotective effects. We explore the neuroprotective effects of AUC in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian mice. Mice were administered MPTP (30 mg/kg) daily for 5 days, followed by treatment with AUC for 7 days. Measurement of dopamine levels was performed by high-performance liquid chromatography and tyrosine hydroxylase expression was assessed by western blot. Our results showed that AUC treatment improved mobility in the pole descent test and the traction test, and reduced the loss of dopaminergic neurons in MPTP-induced parkinsonian mice. AUC treatment rescued the decreased dopamine and tyrosine hydroxylase levels in the striatum of parkinsonian mice. Furthermore, AUC treatment reduced both microglia and astrocyte activation in the substantia nigra of parkinsonian mice. These findings suggest that AUC exerts neuroprotective effects, in part by reducing inflammation and preserving dopaminergic neurons. Possible protection mechanisms involved in MPTP-induced parkinsonian mice need to be clarified further.

Dysbiosis of gut microbiota and microbial metabolites in Parkinson's Disease.

Gut microbial dysbiosis and alteration of microbial metabolites in Parkinson's disease (PD) have been increasingly reported. Dysbiosis in the composition and abundance of gut microbiota can affect both the enteric nervous system and the central nervous system (CNS), indicating the existence of a microbiota-gut-brain axis and thereby causing CNS diseases. Disturbance of the microbiota-gut-brain axis has been linked to specific microbial products that are related to gut inflammation and neuroinflammation. Future directions should therefore focus on the exploration of specific gut microbes or microbial metabolites that contribute to the development of PD. Microbiota-targeted interventions, such as antibiotics, probiotics and fecal microbiota transplantation, have been shown to favorably affect host health. In this review, recent findings regarding alterations and the role of gut microbiota and microbial metabolites in PD are summarized, and potential molecular mechanisms and microbiota-targeted interventions in PD are discussed.