•An integrated temperature-dependent phase-field Li-dendrite model is presented.•The presented model is validated by using the published experimental data.•The effects of temperature on the shape and ...size of the dendrites are investigated.•The effects of the ambient temperature on dendritic morphologies are discussed.•The influence of the internal heat on Li dendrites is discussed in detail.
This paper aims to computationally investigate the thermal effect, combining the internal heat and the ambient temperature, on the lithium (Li) dendrite growth process. To achieve this, the recently developed phase-field Li-dendrite model is further extended by coupling with a heat transfer model. The two models are linked via a temperature-dependent ion diffusion coefficient to investigate the evolution of the morphology and size of dendrites. Three levels of cases are used to progressively investigate the thermal effect on Li dendrites: (1) uniform ambient temperature, (2) temperature gradient along the charging direction, and (3) internal heat-induced spatially distributed temperature. The results show that the normalized dendrite length decreases as the ambient temperature increases, which agrees well with the published experimental measurements. The temperature gradient is applied in the 2-D system showing that the formation of lateral branches can be prevented with the presence of the temperature gradient. The third case shows that the temperature significantly increases at the dendrite-electrolyte interface, and the dendrite deviates from the tree-type shape to a nearly rhombic shape. The simulation results provide valuable bases for the future comprehensive studies of the temperature-dependent Li dendrite growth process.
Neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) had been analysed in many kind of tumours, but its role of predict the oesophageal squamous cell carcinoma (ESCC) patients’ ...prognosis was not reach a consensus. Relationship between NLR, PLR and ESCC located in the middle or lower segment was evaluated. 317 patients with ESCC who underwent attempted curative oesophagectomy were analysed in this study. 157 and 98 patients had elevated NLR and PLR respectively (NLR >3.3 and PLR >150). The median overall survival time (OS) and disease‐free survival (DFS) was 34.1 and 19.2 months respectively. Multivariate analysis found PLR >150 (P = 0.018, HR 1.426, 95%CI 1.063–1.912) accompanied by male, lymphatic metastases, tumour size more than 3 cm, tumour located at middle segment and poor differentiation were associated with significantly worse DFS. Meanwhile, gender, lymphatic metastases, tumour location and differentiation along with PLR >150 (P = 0.003, HR 1.595, 95% CI 1.172–2.170) and NLR>3.3 (P = 0.039, HR 1.367, 95% CI 1.015–1.840) were all independent prognostic factors for OS. Preoperative NLR and PLR might be used as predictive factors in patients with ESCC. For DFS, elevated PLR compared to NLR may have an advantage to indicate poor prognosis.
Mutations in SCN1A, the gene encoding the α subunit of Nav1.1 channel, can cause epilepsies with wide ranges of clinical phenotypes, which are associated with the contrasting effects of channel ...loss-of-function or gain-of-function. In this project, CRISPR/Cas9- and TALEN-mediated genome-editing techniques were applied to induced pluripotent stem cell (iPSC)-based-disease model to explore the mechanism of epilepsy caused by SCN1A loss-of-function mutation. By fluorescently labeling GABAergic subtype in iPSC-derived neurons using CRISPR/Cas9, we for the first time performed electrophysiological studies on SCN1A-expressing neural subtype and monitored the postsynaptic activity of both inhibitory and excitatory types. We found that the mutation c.A5768G, which led to no current of Nav1.1 in exogenously transfected system, influenced the properties of not only Nav current amount, but also Nav activation in Nav1.1-expressing GABAergic neurons. The two alterations in Nav further reduced the amplitudes and enhanced the thresholds of action potential in patient-derived GABAergic neurons, and led to weakened spontaneous inhibitory postsynaptic currents (sIPSCs) in the patient-derived neuronal network. Although the spontaneous excitatory postsynaptic currents (sEPSCs) did not change significantly, when the frequencies of both sIPSCs and sEPSCs were further analyzed, we found the whole postsynaptic activity transferred from the inhibition-dominated state to excitation in patient-derived neuronal networks, suggesting that changes in sIPSCs alone were sufficient to significantly reverse the excitatory level of spontaneous postsynaptic activity. In summary, our findings fill the gap of our knowledge regarding the relationship between SCN1A mutation effect recorded on exogenously transfected cells and on Nav1.1-expressing neurons, and reveal the physiological basis underlying epileptogenesis caused by SCN1A loss-of-function mutation.
Long-term use of morphine induces analgesic tolerance, which limits its clinical efficacy. Evidence indicated morphine-evoked neuroinflammation mediated by toll-like receptor 4 (TLR4) - NOD-like ...receptor protein 3 (NLRP3) inflammasome was important for morphine tolerance. In our study, we investigated whether other existing alternative pathways caused morphine-induced activation of TLR4 in microglia. We focused on heat shock protein 70 (HSP70), a damage-associated molecular pattern (DAMP), which was released from various cells upon stimulations under the control of K
channel and bound with TLR4-inducing inflammation. Glibenclamide, a classic K
channel blocker, can improve neuroinflammation by inhibiting the activation of NLRP3 inflammasome. Our present study investigated the effect and possible mechanism of glibenclamide in improving morphine tolerance via its specific inhibition on the release of HSP70 and activation of NLRP3 inflammasome induced by morphine.
CD-1 mice were used for tail-flick test to evaluate morphine tolerance. The microglial cell line BV-2 and neural cell line SH-SY5Y were used to investigate the pharmacological effects and the mechanism of glibenclamide on morphine-induced neuroinflammation. The activation of microglia was accessed by immunofluorescence staining. Neuroinflammation-related cytokines were measured by western blot and real-time PCR. The level of HSP70 and related signaling pathway were evaluated by western blot and immunofluorescence staining.
Morphine induced the release of HSP70 from neurons. The released HSP70 activated microglia and triggered TLR4-mediated inflammatory response, leading to the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) p65 and the activation of NLRP3 inflammasome. Moreover, anti-HSP70 neutralizing antibody partly attenuated chronic morphine tolerance. The secretion of HSP70 was under the control of MOR/AKT/K
/ERK signal pathway. Glibenclamide as a classic K
channel blocker markedly inhibited the release of HSP70 induced by morphine and suppressed HSP70-TLR4-NLRP3 inflammasome-mediated neuroinflammation, which consequently attenuated morphine tolerance.
Our study indicated that morphine-induced extracellular HSP70 was an alternative way for the activation of TLR4-NLRP3 in analgesic tolerance. The release of HSP70 was regulated by MOR/AKT/K
/ERK pathway. Our study suggested a promising target, K
channel and a new leading compound, glibenclamide, for treating morphine tolerance.
24-h blood pressure (BP) has significant prognostic value for cardiovascular risk screening, but the present BP devices are mainly cuff-based, which are unsuitable for long-term BP measurement, ...especially during nighttime. In this paper, we developed an armband wearable pulse transit time (PTT) system for 24-h cuff-less BP measurement and evaluated it in an unattended out-of-laboratory setting. Ten healthy young subjects participated in this ambulatory study, where PTT was measured at 30-min interval by this wearable system and the reference BP was measured by a standard oscillometric ambulatory BP monitor. Due to the misalignment of BP and PTT on their recording time caused by the different measurement principles of the two BP devices, a new estimation method has been proposed: transients in PTT were removed from the raw data by defined criteria, and then evenly interpolated, low-pass filtered, and resampled to synchronize at the time when BP was recorded. The results show that with the proposed method, the correlation between PTT and systolic BP (SBP) during nighttime with dynamic range of 21.8 ± 14.2 mmHg has improved from -0.50 ± 0.24 to -0.62 ± 0.20 (p<;0.1), and the difference between the estimated and reference SBP has improved from 0.7 ± 10.7 to 2.8 ± 8.2 mmHg with root mean square error reduced from 10.7 to 8.7 mmHg. In addition, the correlation between a very low frequency component of SBP and PTT obtained from the proposed method during nighttime is -0.80 ± 0.10 and the difference is 2.4 ± 5.7 mmHg for a dynamic BP range of 13.5 ± 8.0 mmHg. It is therefore concluded from this study that the proposed wearable system has great potential to be used for overnight SBP monitoring, especially to measure the averaged SBP over a long period.
The initial cluster of severe pneumonia cases that triggered the COVID-19 epidemic was identified in Wuhan, China in December 2019. While early cases of the disease were linked to a wet market, ...human-to-human transmission has driven the rapid spread of the virus throughout China. The Chinese government has implemented containment strategies of city-wide lockdowns, screening at airports and train stations, and isolation of suspected patients; however, the cumulative case count keeps growing every day. The ongoing outbreak presents a challenge for modelers, as limited data are available on the early growth trajectory, and the epidemiological characteristics of the novel coronavirus are yet to be fully elucidated.
We use phenomenological models that have been validated during previous outbreaks to generate and assess short-term forecasts of the cumulative number of confirmed reported cases in Hubei province, the epicenter of the epidemic, and for the overall trajectory in China, excluding the province of Hubei. We collect daily reported cumulative confirmed cases for the 2019-nCoV outbreak for each Chinese province from the National Health Commission of China. Here, we provide 5, 10, and 15 day forecasts for five consecutive days, February 5th through February 9th, with quantified uncertainty based on a generalized logistic growth model, the Richards growth model, and a sub-epidemic wave model.
Our most recent forecasts reported here, based on data up until February 9, 2020, largely agree across the three models presented and suggest an average range of 7409–7496 additional confirmed cases in Hubei and 1128–1929 additional cases in other provinces within the next five days. Models also predict an average total cumulative case count between 37,415 and 38,028 in Hubei and 11,588–13,499 in other provinces by February 24, 2020.
Mean estimates and uncertainty bounds for both Hubei and other provinces have remained relatively stable in the last three reporting dates (February 7th – 9th). We also observe that each of the models predicts that the epidemic has reached saturation in both Hubei and other provinces. Our findings suggest that the containment strategies implemented in China are successfully reducing transmission and that the epidemic growth has slowed in recent days.
The bark of magnolia has been used in Oriental medicine to treat a variety of remedies, including some neurological disorders. Magnolol (Mag) and honokiol (Hon) are isomers of polyphenolic compounds ...from the bark of Magnolia officinalis, and have been identified as major active components exhibiting anti-oxidative, anti-inflammatory, and neuroprotective effects. In this study, we investigate the ability of these isomers to suppress oxidative stress in neurons stimulated by the ionotropic glutamate receptor agonist N-methyl-D-aspartate (NMDA) and oxidative and inflammatory responses in microglial cells activated by interferon-γ (IFNγ) and lipopolysaccharide (LPS). We also attempt to elucidate the mechanism and signaling pathways involved in cytokine-induced production of reactive oxygen species (ROS) in microglial cells.
Dihydroethidium (DHE) was used to assay superoxide production in neurons, while CM-H2DCF-DA was used to test for ROS production in murine (BV-2) and rat (HAPI) immortalized microglial cells. NADPH oxidase inhibitors (for example, diphenyleneiodonium (DPI), AEBSF, and apocynin) and immunocytochemistry targeting p47phox and gp91phox were used to assess the involvement of NADPH oxidase. Western blotting was used to assess iNOS and ERK1/2 expression, and the Griess reaction protocol was employed to determine nitric oxide (NO) concentration.
Exposure of Hon and Mag (1-10 μM) to neurons for 24 h did not alter neuronal viability, but both compounds (10 μM) inhibited NMDA-stimulated superoxide production, a pathway known to involve NADPH oxidase. In microglial cells, Hon and Mag inhibited IFNγ±LPS-induced iNOS expression, NO, and ROS production. Studies with inhibitors and immunocytochemical assay further demonstrated the important role of IFNγ activating the NADPH oxidase through the p-ERK-dependent pathway. Hon and, to a lesser extent, Mag inhibited IFNγ-induced p-ERK1/2 and its downstream pathway for ROS and NO production.
This study highlights the important role of NADPH oxidase in mediating oxidative stress in neurons and microglial cells and has unveiled the role of IFNγ in stimulating the MAPK/ERK1/2 signaling pathway for activation of NADPH oxidase in microglial cells. Hon and Mag offer anti-oxidative or anti-inflammatory effects, at least in part, through suppressing IFNγ-induced p-ERK1/2 and its downstream pathway.
A high-fat diet (HFD) has been previously associated with the development of diseases such as chronic colitis. While chlorogenic acid (CGA) is known to exhibit potent antioxidant, antibacterial, and ...anti-inflammatory properties, little is known about its effects on intestinal inflammation. In this study, we investigated the effects of CGA on intestinal inflammation in an HFD-induced obesity rat model and assessed whether these effects were related to changes in gut microbiota composition. This was achieved by examining physiological and biochemical indicators, the liver transcriptome, and the structure of the fecal microflora. CGA treatment significantly reduced HFD-induced internal organ weight gain, promoted colon tissue repair, downregulated the expression of inflammatory cytokines, and promoted the accumulation of the tight junction protein. KEGG enrichment analysis of differentially expressed genes, applied to data from the RNA-seq of rat liver tissue, revealed that CGA treatment significantly affected amino acid and lipid metabolism in the liver. Furthermore, CGA decreased the abundance of bacteria belonging to the genera Blautia, Sutterella, and Akkermansia and increased butyric acid levels, which were positively correlated with the abundance of Ruminococcus (butyric acid producer). Moreover, the beneficial changes observed in the HFD group were not as pronounced as those in the CGA treatment group. In summary, CGA can alleviate colitis in HFD-induced obesity through its anti-inflammatory effects associated with changes in gut microbiota composition and an increase in the production of short-chain fatty acids and thus can be used as a potential drug for the treatment of this pathology.
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