Electrolyte Engineering Toward High Performance High Nickel (Ni ≥ 80%) Lithium-Ion Batteries.

High nickel (Ni ≥ 80%) lithium-ion batteries (LIBs) with high specific energy are one of the most important technical routes to resolve the growing endurance anxieties. However, because of their extremely aggressive chemistries, high-Ni (Ni ≥ 80%) LIBs suffer from poor cycle life and safety performance, which hinder their large-scale commercial applications. Among varied strategies, electrolyte engineering is very powerful to simultaneously enhance the cycle life and safety of high-Ni (Ni ≥ 80%) LIBs. In this review, the pivotal challenges faced by high-Ni oxide cathodes and conventional LiPF6 -carbonate-based electrolytes are comprehensively summarized. Then, the functional additives design guidelines for LiPF6 -carbonate -based electrolytes and the design principles of high voltage resistance/high safety novel electrolytes are systematically elaborated to resolve these pivotal challenges. Moreover, the proposed thermal runaway mechanisms of high-Ni (Ni ≥ 80%) LIBs are also reviewed to provide useful perspectives for the design of high-safety electrolytes. Finally, the potential research directions of electrolyte engineering toward high-performance high-Ni (Ni ≥ 80%) LIBs are provided. This review will have an important impact on electrolyte innovation as well as the commercial evolution of high-Ni (Ni ≥ 80%) LIBs, and also will be significant to breakthrough the energy density ceiling of LIBs.

Development and validation of nomograms to predict the survival probability and occurrence of a second primary malignancy of male breast cancer patients: a population-based analysis.

Background: Male breast cancer (MBC) is rare, which has restricted prospective research among MBC patients. With effective treatments, the prognosis of MBC patients has improved and developing a second primary malignancy (SPM) has become a life-threatening event for MBC survivors. However, few studies have focused on the prognosis of MBC patients and looked into the SPM issue in MBC survivors. Method: We reviewed MBC patients diagnosed between 1990 and 2016 from the latest Surveillance, Epidemiology, and End Results (SEER) Plus database. Competing risk models and nomograms were conducted for predicting the risk of cancer-specific death and SPM occurrence. C-indexes, calibration curves, ROC curves, and decision curve analysis (DCA) curves were applied for validation. Result: A total of 1,843 MBC patients with complete information were finally enrolled and 60 (3.26%) had developed an SPM. Prostate cancer (40%) was the most common SPM. The median OS of all the enrolled patients was 102.41 months, while the median latency from the initial MBC diagnosis to the subsequent diagnosis of SPM was 67.2 months. The patients who suffered from an SPM shared a longer OS than those patients with only one MBC (p = 0.027). The patients were randomly divided into the development cohort and the validation cohort (at a ratio of 7:3). The Fine and Gray competing risk model was used to identify the risk factors. Two nomograms were constructed and validated to predict the 5-year, 8-year, and 10-year survival probability of MBC patients, both of which had good performance in the C-index, ROC curves, calibration plots, and DCA curves, showing the ideal discrimination capability and predictive value clinically. Furthermore, we, for the first time, constructed a nomogram based on the competing risk model to predict the 5-year, 8-year, and 10-year probability of developing an SPM in MBC survivors, which also showed good discrimination, calibration, and clinical effectiveness. Conclusion: We, for the first time, included treatment information and clinical parameters to construct a nomogram to predict not only the survival probability of MBC patients but also the probability of developing an SPM in MBC survivors, which were helpful in individual risk estimation, patient follow-up, and counseling in MBC patients.

Complete 1 H and 13 C assignments of two new sesquiterpenoids from Dendrobium aduncum.

Two new sesquiterpenoids, dendroaduoid A (1) and dendroaduol (2), together with four known sesquiterpenoids were isolated from the stems of Dendrobium aduncum. Their structures were identified by HR-ESI-MS and NMR experiments, and the complete assignments of 1 H and 13 C NMR data for two new sesquiterpenoids were obtained by the aid of HSQC, HMBC, 1 H-1 H COSY, NOESY, and ECD techniques. The cytotoxic effects of the isolated compounds on four tumor cell lines (HCT-116, HepG2, A549, and SW1990) were evaluated using MTT assay. Otherwise, the inhibitory activity of these six sesquiterpenoids on glycosidase was also evaluated.

The ATP Level in the Medial Prefrontal Cortex Regulates Depressive-like Behavior via the Medial Prefrontal Cortex-Lateral Habenula Pathway.

BACKGROUND: Depression is the most common mental illness. Mounting evidence suggests that dysregulation of extracellular ATP (adenosine triphosphate) is involved in the pathophysiology of depression. However, the cellular and neural circuit mechanisms through which ATP modulates depressive-like behavior remain elusive. METHODS: By use of ex vivo slice electrophysiology, chemogenetic manipulations, RNA interference, gene knockout, behavioral testing, and two depression mouse models, one induced by chronic social defeat stress and one caused by a IP3R2-null mutation, we systematically investigated the cellular and neural circuit mechanisms underlying ATP deficiency-induced depressive-like behavior. RESULTS: Deficiency of extracellular ATP in both defeated susceptible mice and IP3R2-null mutation mice led to reduced GABAergic (gamma-aminobutyric acidergic) inhibition and elevated excitability in lateral habenula-projecting, but not dorsal raphe-projecting, medial prefrontal cortex (mPFC) neurons. Furthermore, the P2X2 receptor in GABAergic interneurons mediated ATP modulation of lateral habenula-projecting mPFC neurons and depressive-like behavior. Remarkably, chemogenetic activation of the mPFC-lateral habenula pathway induced depressive-like behavior in C57BL/6J mice, while inhibition of this pathway was sufficient to alleviate the behavioral impairment in both defeated susceptible and IP3R2-null mutant mice. CONCLUSIONS: Overall, our study provides compelling evidence that ATP level in the mPFC is critically involved in regulating depressive-like behavior in a pathway-specific manner. These results shed new light on the mechanisms underlying depression and the antidepressant effect of ATP.

PV network plasticity mediated by neuregulin1-ErbB4 signalling controls fear extinction.

Neuroplasticity in the medial prefrontal cortex (mPFC) is essential for fear extinction, the process of which forms the basis of the general therapeutic process used to treat human fear disorders. However, the underlying molecules and local circuit elements controlling neuronal activity and concomitant induction of plasticity remain unclear. Here we show that sustained plasticity of the parvalbumin (PV) neuronal network in the infralimbic (IL) mPFC is required for fear extinction in adult male mice and identify the involvement of neuregulin 1-ErbB4 signalling in PV network plasticity-mediated fear extinction. Moreover, regulation of fear extinction by basal medial amygdala (BMA)-projecting IL neurons is dependent on PV network configuration. Together, these results uncover the local molecular circuit mechanisms underlying mPFC-mediated top-down control of fear extinction, suggesting alterative therapeutic approaches to treat fear disorders.

Impaired calcium signaling in astrocytes modulates autism spectrum disorder-like behaviors in mice.

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder. The mechanisms underlying ASD are unclear. Astrocyte alterations are noted in ASD patients and animal models. However, whether astrocyte dysfunction is causal or consequential to ASD-like phenotypes in mice is unresolved. Type 2 inositol 1,4,5-trisphosphate 6 receptors (IP3R2)-mediated Ca2+ release from intracellular Ca2+ stores results in the activation of astrocytes. Mutations of the IP3R2 gene are associated with ASD. Here, we show that both IP3R2-null mutant mice and astrocyte-specific IP3R2 conditional knockout mice display ASD-like behaviors, such as atypical social interaction and repetitive behavior. Furthermore, we show that astrocyte-derived ATP modulates ASD-like behavior through the P2X2 receptors in the prefrontal cortex and possibly through GABAergic synaptic transmission. These findings identify astrocyte-derived ATP as a potential molecular player in the pathophysiology of ASD.

The ATP Level in the mPFC Mediates the Antidepressant Effect of Calorie Restriction.

Food deprivation can rescue obesity and overweight-induced mood disorders, and promote mood performance in normal subjects. Animal studies and clinical research have revealed the antidepressant-like effect of calorie restriction, but little is known about the mechanism of calorie restriction-induced mood modification. Previous studies have found that astrocytes modulate depressive-like behaviors. Inositol 1,4,5-trisphosphate receptor type 2 (IP3R2) is the predominant isoform in mediating astrocyte Ca2+ signals and its genetic knockout mice are widely used to study astrocyte function in vivo. In this study, we showed that deletion of IP3R2 blocked the antidepressant-like effect induced by calorie restriction. In vivo microdialysis experiments demonstrated that calorie restriction induced an increase in ATP level in the medial prefrontal cortex (mPFC) in naïve mice but this effect disappeared in IP3R2-knockout mice, suggesting a role of astrocytic ATP in the calorie restriction-induced antidepressant effect. Further experiments showed that systemic administration and local infusion of ATP into the mPFC induced an antidepressant effect, whereas decreasing ATP by Apyrase in the mPFC blocked calorie restriction-induced antidepressant regulation. Together, these findings support a role for astrocytic ATP in the antidepressant-like effect caused by calorie restriction.

Preparation and Antimicrobial Activity of Antibacterial Silver-Loaded Polyphosphazene Microspheres.

Poly(cyclotriphosphazene-co-4,4'-diaminodiphenyl ether) (PPO) microspheres were prepared via a precipitation polymerization method, using hexachlorocyclotriphosphazene (HCCP) and 4,4'-diaminodiphenyl ether (ODA) as monomers. Silver-loaded PPO (PPOA) microspheres were generated by the in situ loading of silver nanoparticles onto the surface by Ag+ reduction. Our results showed that PPOA microspheres were successfully prepared with a relatively uniform distribution of silver nanoparticles on microsphere surfaces. PPOA microspheres had good thermal stability and excellent antibacterial activity towards Escherichia coli and Staphylococcus aureus. Furthermore, PPOA microspheres exhibited lower cytotoxicity when compared to citrate-modified silver nanoparticles (c-Ag), and good sustained release properties. Our data indicated that polyphosphazene-based PPOA microspheres are promising antibacterial agents in the biological materials field.

Olanzapine combined with 5-hydroxytryptamine type 3 receptor antagonist (5-HT3 RA) plus dexamethasone for prevention and treatment of chemotherapy-induced nausea and vomiting in high and moderate emetogenic chemotherapy: a systematic review and meta-analysis of randomised controlled trials.

We performed a pooled analysis to evaluate the efficacy and adverse events (AEs) of olanzapine combined with dexamethasone plus 5-hydroxytryptamine type 3 receptor antagonist (5-HT3 RA) compared with 5-HT3 RA plus dexamethasone for the prevention and treatment of chemotherapy-induced nausea and vomiting (CINV) in high and moderate emetogenic chemotherapy based on randomised controlled trials (RCTs). PubMed, EMBASE, Web of Science, the Cochrane Library, China Biomedical Literature database (CBM), WanFang Database, China National Knowledge Infrastructure (CNKI), and Chinese Science and Technology Periodical Database (VIP) (from their inception to April 2019) were searched to capture relevant articles. Relative risk with 95% confidence intervals for CINV and AEs were all extracted or calculated. Eleven studies with 1107 cancer patients were involved in this review. The pooled RR of delayed CINV (RR 0.50, 95% CI 0.38 to 0.66; p<0.01) were significantly decreased in the olanzapine group. The occurrence of insomnia was also statistically decreased, as was the rate of acute CINV (RR 0.60, 95% CI 0.48 to 0.75; p<0.01). However, only the percentages of CINV III and CINV IV were significantly decreased in the acute and delayed phases. Subgroup analysis demonstrated that the efficacy was not statistically significantly different between 5 mg and 10 mg olanzapine. Olanzapine significantly decreased the occurrence of CINV III and IV and insomnia in high and moderately emetogenic chemotherapy. Compared with 10 mg per day, 5 mg oral olanzapine may be more appropriate for patients with cancer.

Grayanane diterpenoid glucosides as potent analgesics from Pieris japonica.

A total of fifteen grayanane diterpenoid glucosides including eight undescribed ones, pierisjaponosides A-H, were isolated from the leaves of Pieris japonica (Thunb.) D. Don ex G. Don (Ericaceae). Their structures were established by extensive spectros copic techniques including HRESIMS and NMR, as well as chemical methods. The absolute configurations of pierisjaponosides A, B, and D were finally established by single-crystal X-ray diffraction with Cu Kα radiation. This is the first time to report the crystal structure of a 5,9-epoxygrayanane diterpenoid glucoside. Pierisjaponoside E represents the first example of a 9ß-hydroxygrayan-1(10)-ene diterpenoid. All the isolated grayanane diterpenoid glucosides were evaluated for their analgesic activities in the acetic acid-induced writhing models in mice, and showed significant analgesic effects. Pierisjaponosides A and C-H, micranthanoside A, pieroside A, and craiobiosides A and B displayed significant analgesic effects with the writhe inhibition rates over 50% at a dose of 5.0 mg/kg. Pierisjaponoside E exhibited significant analgesic activities with the percentage inhibitions of 81.7%, 70.4%, and 52.1% at the doses of 5.0, 1.0, and 0.2 mg/kg, respectively. The preliminary structure-activity relationships of grayanane diterpenoid glucosides as potent analgesics were discussed, giving some clues to design novel analgesics.

Systematic review and meta-analysis of the efficacy of serum neuron-specific enolase for early small cell lung cancer screening.

We performed a pooled analysis of the efficacy of serum neuron-specific enolase (NSE) levels for early detection of small cell lung cancer (SCLC) in patients with benign lung diseases and healthy individuals. Comprehensive searches of several databases through September 2016 were conducted. The quality of the included studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Ultimately, 33 studies containing 9546 samples were included in the review. Pooled sensitivity of NSE for detecting SCLC was 0.688 (95%CI: 0.627-0.743), specificity was 0.921 (95%CI: 0.890-0.944), positive likelihood ratio was 8.744 (95%CI: 6.308-12.121), negative likelihood ratio was 0.339 (95%CI: 0.283- 0.405), diagnostic odds ratio was 25.827 (95%CI: 17.490- 38.136) and area under the curve was 0.88 (95%CI: 0.85- 0.91). Meta-regression indicated that study region was a source of heterogeneity in the sensitivity and joint models, while cut-off level was a source in the joint model. Subgroup analysis showed that enzyme linked immunosorbent assays had the highest sensitivity and radioimmunoassay assays had the highest specificity. The diagnostic performance was better in Europe [sensitivity: 0.740 (95%CI: 0.676-0.795), specificity: 0.932 (95%CI: 0.904-0.953)] than in Asia [sensitivity: 0.590 (95%CI: 0.496- 0.678), specificity: 0.901 (95%CI: 0.819-0.948)]. In Europe, 25 ng/ml is likely the most suitable NSE cut-off level. NSE thus has high diagnostic efficacy when screening for SCLC, though the efficacy differs depending on study region, assay method and cut-off level. In the clinic, NSE measurements should be considered along with clinical symptoms, image results and histopathology.

Opioid-Induced Constipation Relief From Fixed-Ratio Combination Prolonged-Release Oxycodone/Naloxone Compared With Oxycodone and Morphine for Chronic Nonmalignant Pain: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

CONTEXT: Opioid-induced constipation (OIC) is one of the most frequent and severe adverse events (AEs) after treatment with opioids. Recent studies have indicated that fixed-ratio combination prolonged-release oxycodone/naloxone (OXN PR) could decrease OIC with similar pain relief compared with other opioids. OBJECTIVES: We systematically reviewed (PROSPERO registration numbers: CRD42016036244) the constipation relief of OXN PR compared with other opioids regardless of formulation, prolonged release, or extended release used for the relief of chronic pain. METHODS: Relevant studies were identified by searching PubMed, EMBASE, Web of Science, and the Cochrane library from inception to May 2016, with an update to December 2016. We quantitatively analyzed OIC (assessed by bowel function index [BFI]), pain intensity, and AEs. RESULTS: A total of 167 articles were identified from the databases. Finally seven studies with 3217 patients were included in our meta-analysis, including 1322 patients in OXN PR treatment groups and 1885 patients in prolonged-release oxycodone (OXY PR) or prolonged-release morphine (MOR PR) control group. The relative risk (RR) of OIC was decreased in OXN PR (RR 0.52, 95% CI 0.44; 0.62). Whether BFI was better or worse at baseline, the mean difference (MD) of BFI -17.48 95% CI -21.60; -13.36) was better after treatment with OXN PR with clinical importance at the end of intervention; moreover, the BFI of the OXN PR-treated group was closer to normal BFI scores. However, clinical BFI change from baseline to the end measurement only existed in patients when the baseline BFI was high (mean [SDs] 61.0 [23.39]-67.40 [19.51]), and the MD of the BFI was -15.96 (95% CI -25.56; -15.48). The RR of AEs was also smaller (RR 0.80; 95% CI 0.69-0.93), but the severity or duration of AEs was not reported. Pain intensity was also significantly decreased in the OXN PR treatment groups (MD -3.84, 95% CI -7.14; -0.55), although there was no clinically meaningful difference. CONCLUSION: For people with chronic pain, treatment with OXN PR decreases the incidence of OIC and provides intermediate-term bowel function improvement with clinical importance; in addition, pain relief is not weakened. The OIC after treatment with OXN PR for cancer-related pain and over the long term remains unknown.

Meta-Analysis of Serum Gastrin-Releasing Peptide Precursor as a Biomarker for Diagnosis of Small Cell Lung Cancer

Background: The serum level of gastrin-releasing peptide precursor (proGRP) is generally. elevated in patients with small cell lung cancer (SCLC). However, the diagnostic sensitivity and specificity of serum proGRP in SCLC cases remains controversial. The study aimed to assess the diagnostic value of this biomarker by meta-analysis. Materials and Methods: The Cochrane, Clinical trials, Pubmed, Web of Science and Embase databases were searched and diagnostic values were calculated or extracted. Statistical analysis was accomplished with RevMan 5.3 and STATA 12.0 software. Results: A total of 27 studies with 7268 participants were included. The pooled sensitivity, specificity, PLR, NLR and DOR were 0.754 (95% CI: 0.700-0.802), 0.945 (95% CI: 0.916-0.965), 13.804 (95% CI: 9.096-20.948), 0.260 (95% CI: 0.213-0.317) and 53.101 (95% CI: 34.327-82.145) respectively. The AUC was 0.910 (95% CI: 0.880-0.930). Significant publication bias was not found (P =0.622). Conclusions: The meta-analysis indicated that serum proGRP is indeed a useful biomarker with good sensitivity and high specificity for diagnosis of SCLC. Therefore proGRP can be expected to be widely applied in the clinic for identification of lung cancer patients.

Efficacy of D5F3 IHC for detecting ALK gene rearrangement in NSCLC patients: a systematic review and meta-analysis.

We conducted a pooled analysis comparing the efficacy of an immunohistochemistry (IHC) assay using the D5F3 antibody with that of fluorescence in situ hybridization (FISH) for detecting ALK gene rearrangement in NSCLC patients. A total of 32 studies involving 5805 samples were included in this review. Pooled sensitivity for D5F3 IHC was 0.97 (95%CI: 0.93-0.98), specificity was 0.99 (95%CI: 0.98-1.00), PLR was 119.20 (95%CI: 57.79-245.89), NLR was 0.03 (95%CI: 0.02-0.07), DOR was 3526.66 (95%CI: 1344.71-9249.03), and AUROC was 1.00 (95%CI: 0.99-1.00). Meta-regression revealed that specimen type was a source of heterogeneity for specificity, and specimen type and FISH signal distance were sources of heterogeneity in the joint model. Subgroup analysis revealed that sensitivity and specificity were higher when the FISH signal distance standard was ≥ 2 than when it was ≥ 1. Sensitivity was higher for tumor specimens than for cell specimens; specificity was higher for cell specimens than for tumor specimens. In conclusion, the D5F3 IHC assay was nearly as effective as FISH for detection of ALK gene rearrangement in NSCLC patients.

The Adverse Events of Oxycodone in Cancer-Related Pain: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

The adverse events (AEs) of oxycodone in cancer-related pain were controversial, so we conducted a meta-analysis to determine it. PubMed, Embase, CBM, CNKI, WanFang database, The Cochrane library, Web of Science, and the reference of included studies were searched to recognize pertinent studies. Relative risk (RR) with 95% confidence intervals (CIs) for all AEs were all extracted. The fixed-effects model was used to calculate pooled RRs and 95% CIs. Power calculation was performed using macro embedded in SAS software after all syntheses were completed. We identified 11 eligible trials involving 1211 patients: 604 patients included in oxycodone group and 607 patients involved in control group. Our quantitative analysis included 8 AEs, and the pooled analyses indicated that oxycodone compared with other opioids in cancer-related pain were not significantly decreased RRs of all AEs (dizziness RR = 0.94, 95% CI: 0.69-1.30, Z = 0.35, P = 0.72; nausea RR = 0.88, 95% CI: 0.72-1.07, Z = 1.26, P = 0.21; vomiting RR = 0.89, 95% CI: 0.70-1.15, Z = 0.9, P = 0.37; sleepiness RR = 0.86, 95% CI: 0.38-1.36, Z = 0.36, P = 0.72; constipation RR = 0.98, 95% CI: 0.81-1.19, Z = 0.21, P = 0.83; anorexia RR = 0.97, 95% CI = 0.58-1.62, Z = 0.11, P = 0.91; pruritus RR = 0.76, 95% CI: 0.44-1.30, Z = 1.01, P = 0.31; dysuria RR = 0.33, 95% CI: 0.07-1.62, Z = 1.36, P = 0.1)]. The subgroup analysis shown that Ox controlled-release (CR) had less sleepiness compared with MS-contin (Mc) CR (RR = 0.47, 95% CI: 0.25-0.90, P = 0.02). The power analysis suggests that all AEs have low statistical power. The present meta-analysis detected that no statistically significant difference were found among oxycodone and other opioids in all AEs, but Ox CR may had less sleepiness compared with Mc CR when subgroup analysis were conducted.

Jingzhaotoxin-35, a novel gating-modifier toxin targeting both Nav1.5 and Kv2.1 channels.

Jingzhaotoxin-35 (JZTX-35), a 36-residue polypeptide, was purified from the venom of the Chinese tarantula Chilobrachys jingzhao. JZTX-35 inhibited Nav1.5 and Kv2.1 currents with the IC50 value of 1.07 µM and 3.62 µM, respectively, but showed no significant effect on either Na(+) currents or Ca(2+) currents evoked in hippocampal neurons. It shifted the activation of the Nav1.5 and Kv2.1 channels to more depolarized voltages, and markedly shifted the steady-state inactivation of Nav1.5 currents toward more hyperpolarized potentials. Moreover, JZTX-35 can bind to a close state of Nav1.5 and Kv2.1 channels. These results indicate that JZTX-35 is a new gating modifier toxin. JZTX-35 shares high sequence similarity with Jingzhaotoxins (JZTXs) targeting Nav1.5 or Kv2.1 channels, but they showed different ion channel selectivity. Structure-function analysis in this study would provide important clues for the exploration of ion channel selectivity of JZTXs.

Shear stress protects against endothelial regulation of vascular smooth muscle cell migration in a coculture system.

Vascular endothelial cells (ECs) are constantly exposed to blood flow-induced shear stress; these forces strongly influence the behaviors of neighboring vascular smooth muscle cells (VSMCs). VSMC migration is a key event in vascular wall remodeling. In this study, the authors assessed the difference between VSMC migration in VSMC/EC coculture under static and shear stress conditions. Utilizing a parallel-plate coculture flow chamber system and Transwell migration assays, they demonstrated that human ECs cocultured with VSMCs under static conditions induced VSMC migration, whereas laminar shear stress (1.5 Pa, 15 dynes/cm2) applied to the EC side for 12 h significantly inhibited this process. The changes in VSMC migration is mainly dependent on the close interactions between ECs and VSMCs. Western blotting showed that there was a consistent correlation between the level of Akt phosphorylation and the efficacy of shear stress-mediated EC regulation of VSMC migration. Wortmannin and Akti significantly inhibited the EC-induced effect on VSMC Akt phosphorylation and migration. These results indicate that shear stress protects against endothelial regulation of VSMC migration, which may be an atheroprotective function on the vessel wall.