PRMT6 deficiency or inhibition alleviates neuropathic pain by decreasing glycolysis and inflammation in microglia.

Microglia induced chronic inflammation is the critical pathology of Neuropathic pain (NP). Metabolic reprogramming of macrophage has been intensively reported in various chronic inflammation diseases. However, the metabolic reprogramming of microglia in chronic pain remains to be elusive. Here, we reported that immuno-metabolic markers (HIF-1α, PKM2, GLUT1 and lactate) were related with increased expression of PRMT6 in the ipsilateral spinal cord dorsal horn of the chronic construction injury (CCI) mice. PRMT6 deficiency or prophylactic and therapeutic intrathecal administration of PRMT6 inhibitor (EPZ020411) ameliorated CCI-induced NP, inflammation and glycolysis in the ipsilateral spinal cord dorsal horn. PRMT6 knockout or knockdown inhibited LPS-induced inflammation, proliferation and glycolysis in microglia cells. While PRMT6 overexpression exacerbated LPS-induced inflammation, proliferation and glycolysis in BV2 cells. Recent research revealed that PRMT6 could interact with and methylate HIF-1α, which increased HIF-1α protein stability. In sum, increased expression of PRMT6 exacerbates NP progress by increasing glycolysis and neuroinflammation through interacting with and stabilizing HIF-1α in a methyltransferase manner, which outlines novel pathological mechanism and drug target for NP.

Asymmetric Synthesis of P-Stereogenic Secondary Phosphine-Boranes by an Unsymmetric Bisphosphine Pincer-Nickel Complex.

The first highly enantioselective catalytic synthesis of P-stereogenic secondary phosphine-boranes was realized by the asymmetric addition of primary phosphine to electron-deficient alkenes with a newly developed unsymmetric bisphosphine (PCP') pincer-nickel complex. Various P-stereogenic secondary phosphine-boranes were obtained in 57-92% yields with up to 99% ee and >20:1 dr. The follow-up alkylation upon P-C bond formation with alkyl halides provided a practical way to access P-chiral compounds with diverse functional groups.

Risk factors for mortality in patients over 70 years old with COVID-19 in Wuhan at the early break: retrospective case series.

BACKGROUND: Elderly patients with COVID-19 were shown to have a high case-fatality rate. We aimed to explore the risk factors associated with death in patients over 70 years old (yr). METHODS: In this retrospective study, we enrolled consecutively hospitalized patients over 70 yr with COVID-19 between January 20 and February 15, 2020 in Renmin Hospital of Wuhan University. Epidemiological, demographic, and clinical data were collected. Clinical subtypes, including mild, moderate, severe, and critical types, were used to evaluate the severity of disease. Patients were classified into two groups: survivor and non-survivor groups. Clinical data were compared between the two groups. Univariable and multivariable Cox regression methods were used to explore the risk factors. RESULTS: A total of 147 patients were enrolled. The case-fatality rate was 28.6%. Multivariable Cox proportional hazard regression showed that clinical subtypes, including the severe type (HR = 2.983, 95% CI: 1.231-7.226, P = 0.016) and the critical type (HR = 3.267, 95%CI: 1.009-10.576, P = 0.048), were associated with increasing risk of death when compared with the general type. Blood urea nitrogen greater than 9.5 mmol/L (HR = 2.805, 95% CI: 1.141-6.892, P = 0.025) on admission was an independent risk factor for death among laboratory findings. CONCLUSION: The patients over 70 yr with COVID-19 had a high case-fatality rate. The risk factors, including clinical subtypes and blood urea nitrogen greater than 9.5 mmol/L, could help physicians to identify elderly patients with poor clinical outcomes at an early stage.

Cobalt-Doped Nickel Phosphite for High Performance of Electrochemical Energy Storage.

Compared to single metallic Ni or Co phosphides, bimetallic Ni-Co phosphides own ameliorative properties, such as high electrical conductivity, remarkable rate capability, upper specific capacity, and excellent cycle performance. Here, a simple one-step solvothermal process is proposed for the synthesis of bouquet-like cobalt-doped nickel phosphite (Ni11 (HPO3 )8 (OH)6 ), and the effect of the structure on the pseudocapacitive performance is investigated via a series of electrochemical measurements. It is found that when the cobalt content is low, the glycol/deionized water ratio is 1, and the reaction is under 200 °C for 20 h, the morphology of the sample is uniform and has the highest specific surface area. The cobalt-doped Ni11 (HPO3 )8 (OH)6 electrode presents a maximum specific capacitance of 714.8 F g-1 . More significantly, aqueous and solid-state flexible electrochemical energy storage devices are successfully assembled. The aqueous device shows a high energy density of 15.48 mWh cm-2 at the power density of 0.6 KW cm-2 . The solid-state device shows a high energy density of 14.72 mWh cm-2 at the power density of 0.6 KW cm-2 . These excellent performances confirm that the cobalt-doped Ni11 (HPO3 )8 (OH)6 are promising materials for applications in electrochemical energy storage devices.

Ultrathin Nanosheet Assembled Sn0.91 Co0.19 S2 Nanocages with Exposed (100) Facets for High-Performance Lithium-Ion Batteries.

Ultrathin 2D inorganic nanomaterials are good candidates for lithium-ion batteries, as well as the micro/nanocage structures with unique and tunable morphologies. Meanwhile, as a cost-effective method, chemical doping plays a vital role in manipulating physical and chemical properties of metal oxides and sulfides. Thus, the design of ultrathin, hollow, and chemical doped metal sulfides shows great promise for the application of Li-ion batteries by shortening the diffusion pathway of Li ions as well as minimizing the electrode volume change. Herein, ultrathin nanosheet assembled Sn0.91 Co0.19 S2 nanocages with exposed (100) facets are first synthesized. The as-prepared electrode delivers an excellent discharge capacity of 809 mA h g-1 at a current density of 100 mA g-1 with a 91% retention after 60 discharge-charge cycles. The electrochemical performance reveals that the Li-ion batteries prepared by Sn0.91 Co0.19 S2 nanocages have high capacity and great cycling stability.

Comparative analysis of drought indices in the tropical zones of China.

The intensity and frequency of drought are increasing in the tropical zone of China under global warming, and accurate assessment of drought severity and duration is critical for sustainable ecosystem management. Previous studies usually rely on one or more drought indices calculated from meteorological station or reanalysis data. However, the assessment results based on these drought indices are not consistent, which can be due to the differences in data sources and index parameters. In this study, we aim to identify the optimal dataset and drought index, and accurately evaluate the drought severity and drought duration in the tropical zone of China. We assessed the accuracy of five drought indices, namely Precipitation Anomaly in Percentage (PA), Relative Moisture Index (MI), Standardized Precipitation Index (SPI), Standardized Precipitation Evapotranspiration Index (SPEI) and Meteorological Drought Composite Index (MCI), calculated from meteorological station data and the China Meteorological Forcing Dataset (CMFD) with respect to drought records compiled by local government. Results indicate that the drought index calculated based on meteorological station data can better match the government-compiled drought records than CMFD. MI is the optimal index for drought severity and duration assessment in study area, especially for winter-spring drought and severe drought, followed by PA. The normalized bell-shaped line of fitted precipitation in winter and spring is biased towards the less rainy side in SPI calculations, which leads to more underestimation even for officially recommended MCI, and actual water supply are also misrepresented in SPEI calculations. This study offers valuable insights for policymakers to use optimal dataset and drought index to accurately assess the drought events, and take effective measures to alleviate its impact on tropical ecosystems in China.

S100A9 aggravates early brain injury after subarachnoid hemorrhage via inducing neuroinflammation and inflammasome activation.

Subarachnoid hemorrhage (SAH) is a stroke subtype with high mortality, and its severity is closely related to the short-term prognosis of SAH patients. S100 calcium-binding protein A9 (S100A9) has been shown to be associated with some neurological diseases. In this study, the concentration of S100A9 in clinical cerebrospinal fluid samples was detected by enzyme-linked immunosorbent assay (ELISA), and the relationship between S100A9 and the prognosis of patients was explored. In addition, WT mice and S100A9 knockout mice were used to establish an in vivo SAH model. Neurological scores, brain water content, and histopathological staining were performed after a specified time. A co-culture model of BV2 and HT22 cells was treated with heme chloride to establish an in vitro SAH model. Our study confirmed that the expression of S100A9 protein in the CSF of SAH patients is increased, and it is related to the short-term prognosis of SAH patients. S100A9 protein is highly expressed in microglia in the central nervous system. S100A9 gene knockout significantly improved neurological function scores and reduced neuronal apoptosis. S100A9 protein can activate TLR4 receptor, promote nuclear transcription of NF-κB, increase the activation of inflammatory body, and ultimately aggravate nerve injury.

Efficacy and safety of remimazolam-based sedation for intensive care unit patients undergoing upper gastrointestinal endoscopy: a cohort study.

BACKGROUND: Remimazolam is a novel ultra-short-acting sedative, but its safety and adverse events (AEs) in high-risk patients in the intensive care unit (ICU) setting remain unknown. METHODS: This was a single-center, retrospective study that compared remimazolam to propofol and midazolam in patients undergoing upper gastrointestinal endoscopy. The primary outcome was the incidence of treatment-related AEs. The secondary outcomes were the time to extubation, the length of ICU stay, and the average cost of sedative per case. RESULTS: Of the 88 patients analyzed, 47 were treated with remimazolam (mean dose, 7.90±4.84 mg), and 41 were treated with propofol (21.19±17.98 mg) or midazolam (3.08±2.17 mg). There was no statistically significant difference in the average duration of the endoscopic procedure (35.89±13.37 min vs. 44.51±21.68 min, P=0.133) or the time to extubation (15.00±9.75 h vs. 20.59±18.71 h, P=0.211) in the remimazolam group (group I) compared to the propofol or midazolam group (group II). ICU stays (5.40±2.93 d vs. 4.63±3.31 d, P=0.072) and treatment-related AEs (48.61% vs. 51.38%, P=0.056) were similar between groups. The average cost of sedative per case was significantly lower in the group I than in the group II (RMB 16.07±10.58 yuan vs. RMB 24.37±15.46 yuan, P=0.016). CONCLUSION: Remimazolam-based sedation was noninferior to the classic sedatives and had lower average cost per case, indicating that it may be used as a promising sedative for high-risk patients during endoscopic procedures in the ICU setting.

[A comparative study on clinical effects of dexmedetomidine and midazolam on patients with severe coronavirus disease 2019 on non-invasive ventilation].

OBJECTIVE: To compare the therapeutic effects and safety of dexmedetomidine and midazolam on patients with severe coronavirus disease 2019 (COVID-19) who received non-invasive ventilation. METHODS: Patients with COVID-19 who needed non-invasive ventilation in one critical care medicine ward of Wuhan Jinyintan Hospital during the team support period from the department of critical care medicine of Renmin Hospital of Wuhan University from January 23rd to February 15th in 2020 were investigated retrospectively. Ramsay score, mean arterial pressure (MAP), heart rate (HR), respiratory rate (RR), arterial oxygen partial pressure (PaO2) before sedation and at 1, 12, 24 hours after sedation, sleep time were collected, and the side effects such as excessive sedation, fall of tongue, abdominal distension, aspiration, bradycardia, escalation to invasive mechanical ventilation during 24 hours were also collected. According to different sedative drugs, patients were divided into the control group (without sedative drugs), dexmedetomidine group and midazolam group. The changes of indicators among the three groups were compared. RESULTS: Fourteen patients were injected with dexmedetomidine (loading dose of 1 µg/kg for 10 minutes, maintained at 0.2-0.7 µg×kg-1×h-1); 9 patients were injected with midazolam (loading dose of 0.05 mg/kg for 2 minutes, maintained at 0.02-0.10 mg×kg-1×h-1); 12 patients didn't use sedative drugs due to limitations of previous hospital or patients' rejection. In dexmedetomidine group and midazolam group, the Ramsay score was maintained at 2-3 points after sedation, which were higher than those of control group at different time points after sedation, and there was no significant difference between dexmedetomidine group and midazolam group. MAP of dexmedetomidine group and midazolam group decreased gradually after sedation. MAP after 1-hour sedation was significantly lower than that before sedation, and MAP after 24 hours sedation was significantly lower than that in the control group [mmHg (1 mmHg = 0.133 kPa): 109.7±11.5, 107.1±12.3 vs. 121.1±13.3, both P < 0.05]. HR decreased gradually after sedation treatment, which was significantly lower after 12 hours of sedation than that before sedation, and HR in dexmedetomidine group was significantly lower than that in control group after 12 hours of sedation (bpm: 84.0±13.9 vs. 92.8±15.4 at 12 hours; 81.0±16.7 vs 92.6±12.7 at 24 hours, both P < 0.05). PaO2 increased and RR decreased in all three groups after ventilation. PaO2 in dexmedetomidine group and midazolam group were significantly higher than that in the control group after 12 hours of sedation [cmH2O (1 cmH2O = 0.098 kPa): 79.0±6.5, 79.0±8.9 vs. 70.0±7.8, both P < 0.05]; the decreases of RR in dexmedetomidine group and midazolam group were significant than that in control group after 1 hour of sedation (bpm: 34.0±3.9, 33.8±4.6 vs. 39.0±3.6, both P < 0.05). There were no differences of MAP, HR, PaO2 and RR between dexmedetomidine group and midazolam group at different time points. The sleep duration in dexmedetomidine group and midazolam group were significantly longer than that in the control group (hours: 4.9±1.9, 5.8±2.4 vs. 3.0±1.8, both P < 0.05), but there was no difference between dexmedetomidine group and midazolam group (P > 0.05). Adverse events occurred in all three groups. In midazolam group, there were 2 cases of excessive sedation with fall of tongue and abdominal distension, including 1 case of aspiration, 1 case receiving intubation due to refractory hypoxemia and 1 case due to unconsciousness. In dexmedetomidine group, there were 2 cases of bradycardia, 1 case of intubation due to refractory hypoxemia. In control group, 4 cases underwent intubation due to refractory hypoxemia. CONCLUSIONS: Non-invasive mechanical ventilation is an important respiratory support technology for patients with severe COVID-19. Appropriate sedation can increase the efficiency of non-invasive mechanical ventilation. Dexmedetomidine is more effective and safer than midazolam in these patients, but attention should be paid to HR and blood pressure monitoring.

Ectopic expression of GmZAT4, a putative C2H2-type zinc finger protein, enhances PEG and NaCl stress tolerances in Arabidopsis thaliana.

The zinc finger protein (ZFP) transcription factor family plays an important role in regulating plant growth, development, and response to abiotic stress. In this study, we aimed to determine the role of GmZAT4, a C2H2-type transcription factor, in abiotic stress tolerance. The complete coding sequence of the GmZAT4 gene was isolated from soybean root RNA, which shows highest expression level compared with leaf, flower and other tissues. Using multiple sequence alignment and conserved domain analysis, we showed that GmZAT4 is a typical C2H2-type transcription factor which is comprised of two C2H2 domains, including a highly conserved QALGGH motif, and implied the regulation of abiotic stress tolerance in plant. A phylogenetic tree revealed that the soybean GmZAT4 gene clustered with ZAT4 from Glycine soja and AZF1, AZF2, and AZF3 from Arabidopsis thaliana. The mRNA expression levels of GmZAT4 were determined in two soybean cultivars by quantitative reverse transcription (qRT)-PCR and compared. The results showed higher expression (up to 60, 25 and 4 times, respectively) in the drought-tolerant type (Jinda 74) compared to the drought-sensitive soybean cultivar (Jinda 53) following treatment with 18% PEG, 150 mM NaCl, or 100 µM abscisic acid (ABA). GmZAT4 was ectopically over-expressed in A. thaliana to determine its role in abiotic stress tolerance. GmZAT4 overexpression enhanced the tolerance of A. thaliana to treatment with 20% PEG and 150 mM NaCl, and improved the germination rate following treatment with 1 µM or 2 µM ABA. The expression profiles of marker genes in the ABA signaling pathway, such as RD29A, RD29B, ABI, and RAD, indicated that GmZAT4 enhanced the abiotic stress tolerance of Arabidopsis. These results suggest that the C2H2-type ZFP encoded by GmZAT4 plays an important role in PEG and NaCl stress tolerance and ABA responses in soybean and A. thaliana.

Lipopolysaccharide Stimulates Surfactant Protein-A in Human Renal Epithelial HK-2 Cells through Upregulating Toll-like Receptor 4 Dependent MEK1/2-ERK1/2-NF-κB Pathway.

BACKGROUND: Surfactant protein-A (SP-A) contributes to the regulation of sepsis-induced acute kidney injury. In a previous study, we demonstrated that the expression of SP-A in the human renal tubular epithelial (HK-2) cells can be stimulated by lipopolysaccharide (LPS). The present study evaluated the possible signal-transducing mechanisms of LPS-induced SP-A biosynthesis in the HK-2 cells. METHODS: Tetrazolium salt colorimetry (MTT) assay was used to detect cell viability of HK-2 cells after LPS stimulation on different time points. HK-2 cells were stimulated with 100 ng/ml of LPS for different durations to determine the effects of LPS on SP-A and toll-like receptor 4 (TLR4) messenger RNA (mRNA) expression, as well as phosphorylation of mitogen-activated/extracellular signal-regulated kinase (MEK) 1, extracellular signal-regulated kinase 1/2 (ERK1/2), p38 mitogen-activated protein kinase (p38MAPK), and nuclear factor-kappa B (NF-κB) inhibitor-alpha (IkB-α). Then, HK-2 cells were pretreated with CLI-095, a TLR4 inhibitor, to analyze mRNA and protein levels of SP-A and TLR4 and expression of NF-κB in the cytoplasm and nucleus of HK-2 before LPS exposure. RESULTS: HK-2 cells exposed to 100 ng/ml of LPS for 1, 6, and 24 h did not affect cell viability which showed no toxic effect of 100 ng/ml LPS on cells (P = 0.16); however, the biosynthesis of SP-A mRNA and protein in HK-2 cells was significantly increased (P = 0.02). As to the mechanism, LPS enhanced transmembrane receptor TLR4 protein expression. Sequentially, LPS time dependently augmented phosphorylation of MEK1, ERK1/2, and p38MAPK. In addition, levels of phosphorylated IκB-α and nuclear NF-κB were augmented with LPS exposure for 2 h. LPS-induced SP-A and TLR4 mRNA as well as NF-κB expression were significantly inhibited by pretreatment with CLI-095. CONCLUSIONS: The present study exhibited that LPS can increase SP-A synthesis in human renal epithelial cells through sequentially activating the TLR4-related MEK1-ERK1/2-NF-κB-dependent pathway.