Efficient Deep-Blue Light-Emitting Diodes from Highly Luminescent Eu2+-Doped Alkali Metal Halide Nanocrystals via Lattice Field Modulation.

Lead-halide perovskite nanocrystals (NCs) are promising for fabricating deep-blue (<460 nm) light-emitting diodes (LEDs), but their development is plagued by low electroluminescent performance and lead toxicity. Herein, the synthesis of 12 kinds of highly luminescent and eco-friendly deep-blue europium (Eu2+)-doped alkali-metal halides (AX:Eu2+; A = Na+, K+, Rb+, Cs+; X = Cl-, Br-, I-) NCs is reported. Through adjustment of the coordination environment, efficient deep-blue emission from Eu-5d → Eu-4f transitions is realized. The representative CsBr:Eu2+ NCs exhibit a high photoluminescence quantum yield of 91.1% at 441 nm with a color coordinate at (0.158, 0.023) matching with the Rec. 2020 blue specification. Electrically driven deep-blue LEDs from CsBr:Eu2+ NCs are demonstrated, achieving a record external quantum efficiency of 3.15% and half-lifetime of ∼1 h, surpassing the reported metal-halide deep-blue NCs-based LEDs. Importantly, large-area LEDs with an emitting area of 12.25 cm2 are realized with uniform emission, representing a milestone toward commercial display applications.

Melanin theranostic nanoplatform as an efficient drug delivery system for imaging-guided renal fibrosis therapy.

As renal fibrosis nanotherapeutics, the endogenous biomaterial melanin not only has natural biocompatibility and biodegradability but also has inherent photoacoustic imaging ability and certain anti-inflammatory effects. These properties determine that melanin can not only as a carrier of medication but also track the biodistribution and renal uptake of drugs in vivo by photoacoustic imaging in real-time. Curcumin is a natural compound with biological activity, which has excellent ROS scavenging ability and good anti-inflammatory property. These materials appear more advantages in the development of nanoscale diagnostic and therapeutic platforms for future clinical translation. Herein, this study developed curcumin-loaded melanin nanoparticles (MNP-PEG-CUR NPs) as an efficient medication delivery system for photoacoustic imaging guidance renal fibrosis treatment. The nanoparticles are about 10 nm in size, exhibit good renal clearance efficiency, excellent photoacoustic imaging ability, and good in vitro and in vivo biocompatibility. These preliminary results indicated that MNP-PEG-CUR have clinically applicable potential as a therapeutic nanoplatform for renal fibrosis.

Interactions Between Body Mass Index and Glomerular Filtration Rate Increase the Identification Ability of Obstructive Sleep Apnea in Patients with Hypertrophic Cardiomyopathy.

Purpose: Obstructive sleep apnea (OSA) is common in hypertrophic cardiomyopathy (HCM) patients and is related to worse adverse prognosis in HCM patients. However, there are no acknowledged warning characteristics to help to identify OSA in HCM patients. Methods: Seventy-one HCM patients and forty-nine hypertensive (HTN) patients as control group underwent polysomnography (PSG) examination at the Second Affiliated Hospital of Nanchang University from January 2015 to December 2019 patients were consecutively enrolled. The characteristics were analyzed and compared between HCM patients with OSA and without OSA. Results: A total of 37 (52%) HCM patients and 25 (51%) HTN patients were diagnosed with OSA. High body mass index (BMI) (OR = 1.228, 95% CI: 1.032,1.461, P = 0.020) and low estimated glomerular filtration rate (eGFR) (OR = 0.959, 95% CI: 0.931,0.989, P = 0.007) independently correlated with the occurrence of OSA in HCM patients, respectively. Multiplicative interaction was shown between high BMI and low eGFR on the risk of OSA in HCM patients (OR: 6.050, 95% CI: 1.598, 22.905, P = 0.008). The additive interaction analysis further suggested that 70.1% of HCM patients developed OSA due to the additive interaction between BMI and eGFR. The identification ability of OSA in HCM patients was significantly enhanced by using both BMI and eGFR (area under receiver-operating characteristic analysis curve 0.785; P = 0.000038) as compared with BMI (area under curve 0.683, P = 0.008) or eGFR (area under curve 0.700, P = 0.004), respectively. Conclusion: High BMI or low eGFR independently related to the occurrence of OSA in HCM patients, and the multiplicative and additive interactions between BMI and eGFR increased the identification ability of OSA in HCM patients.

Inhibition of semaphorin-3a alleviates lipopolysaccharide-induced vascular injury.

Alleviating vascular injury improves the prognosis of atherosclerosis. Semaphorin-3a (Sema3A) is a special membrane-associated secreted protein with various biological properties, like pro-inflammation, anti-tumor and et al. This study aims to investigate the effects of inhibition of Sema3A on lipopolysaccharide (LPS)-induced vascular injury in mice. The mice were randomized into three groups: control, LPS, and LPS + siRNA. Mice in the combined group were given siRNA through fast tail vein injection, then LPS was injected intraperitoneally 7 days later, finally the mice were euthanized 24 h later. Vascular function and structure were assessed by vascular injury biomarkers and relevant stainings. LPS-induced vascular dysfunction and pathological injury were substantially improved by inhibition of Sema3A. Western blot and quantitative real-time polymerase chain reaction assays were used for investigating molecular pathways. The relevant proteins of vascular endothelial cells activation, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), increased after LPS stimulation, while these effects were reversed by inhibition of Sema3A. The levels of inflammatory cytokines (IL-1ß, IL-6 and NLRP3) were upregulated after LPS stimulation, however, inhibition of Sema3A reversed it through NF-κB and MAPKs signaling pathways involvement. Moreover, inhibition of Sema3A alleviated LPS-induced oxidative stress, evidenced by a decrease in total reactive oxygen species and an increase in antioxidant protein of SOD-1. The results showed that inhibition of Sema3A protects against LPS-induced vascular injury by suppressing vascular endothelial cells activation, vascular inflammation, and vascular oxidative stress, implying that inhibition of Sema3A might be used as a therapeutic strategy for septic vascular injury or atherosclerosis.

Early Passive Leg Movement Prevents Against the Development of Heart Failure With Preserved Ejection Fraction in Rats.

Exercising was reported by several studies to bring great benefits to heart failure with preserved ejection fraction (HFpEF), which reduced the hospitalization and the mortality of heart failure. However, the underlying mechanism of exercising on HFpEF remains unclear. In the present study, we designed and constructed a device that can perform early passive leg movement (ePLM) in rats and further observed whether treatment of ePLM exerts protective effects on HFpEF of rats. Rats were fed with high salt feed to establish an animal model of pre-clinical diastolic dysfunction (PDD), which would eventually develop into HFpEF, and then treated rats with ePLM. We conducted several experiments to evaluate the conditions of heart and blood vessel. The results show that diastolic functions of heart and blood vessel in rats were significantly improved by treatment of ePLM. We also found that pathological injuries of heart and blood vessel were ameliorated after treatment of ePLM. Moreover, treatment of ePLM decreased the protein levels of Collagen type I, Collagen type III, MMP2, and MMP9 in heart and blood vessel, indicating that cardiac and vascular fibrosis were reduced apparently by treatment of ePLM. Further investigation suggested that treatment of ePLM probably inhibit the activation of TGF-ß1/Smad3 signaling pathway as well as promote the activation of Akt/eNOS signaling pathway in high salt diet induced HFpEF. In conclusion, treatment of ePLM alleviated high salt diet induced HFpEF by inhibiting fibrosis via suppressing TGF-ß1/Smad3 signaling pathway as well as activating Akt/eNOS signaling pathway, implicating treatment of ePLM as a promising novel non-pharmacological approach for HFpEF.

Sacubitril/Valsartan Reduces Fibrosis and Alleviates High-Salt Diet-Induced HFpEF in Rats.

Previous studies have confirmed the clinical efficacy of sacubitril/valsartan (Sac/Val) for the treatment of heart failure with reduced ejection fraction (HFrEF). However, the role of Sac/Val in heart failure with preserved ejection fraction (HFpEF) remains unclear. Sac/Val is a combination therapeutic medicine comprising sacubitril and valsartan that acts as a first angiotensin receptor blocker and neprilysin inhibitor (angiotensin-receptor neprilysin inhibitor (ARNI)). Here, we investigated the role of Sac/Val in high-salt diet-induced HFpEF coupled with vascular injury as well as the underlying mechanism. Rats were fed with high-salt feed, followed by intragastric administration of Sac/Val (68 mg/kg; i.g.). The results of functional tests revealed that a high-salt diet caused pathological injuries in the heart and vascular endothelium, which were significantly reversed by treatment with Sac/Val. Moreover, Sac/Val significantly decreased the levels of fibrotic factors, including type I collagen and type Ⅲ collagen, thus, reducing the ratio of MMP2/TIMP2 while increasing Smad7 levels. Further investigation suggested that Sac/Val probably reversed the effects of high-salt diet-induced HFpEF by inhibiting the activation of the TGF-ß1/Smad3 signaling pathway. Thus, treatment with Sac/Val effectively alleviated the symptoms of high-salt diet-induced HFpEF, probably by inhibiting fibrosis via the TGF-ß1/Smad3 signaling pathway, supporting the therapeutic potential of Sac/Val for the treatment of HFpEF.

Strategy of Solution-Processed All-Inorganic Heterostructure for Humidity/Temperature-Stable Perovskite Quantum Dot Light-Emitting Diodes.

Recently, a pressing requirement of solid-state lighting sources with high performance and low cost has motivated increasing research in metal halide perovskites. However, the relatively low emission efficiency and poor operation stability of perovskite light-emitting diodes (LEDs) are still critical drawbacks. In this study, a strategy of solution-processed all-inorganic heterostructure was proposed to overcome the emission efficiency and operation stability issues facing the challenges of perovskite LEDs. Solution-processed n-ZnO nanoparticles and p-NiO are used as the carrier injectors to fabricate all-inorganic heterostructured CsPbBr3 quantum dot LEDs, and a high-efficiency green emission is achieved with maximum luminance of 6093.2 cd/m2, external quantum efficiency of 3.79%, and current efficiency of 7.96 cd/A. More importantly, the studied perovskite LEDs possess a good operation stability after a long test time in air ambient. Typically, the devices can endure a high humidity (75%, 12 h) and a high working temperature (393 K, three heating/cooling cycles) even without encapsulation, and the operation stability is better than any previous reports. It is anticipated that this work will provide an effective strategy for the fabrication of high-performance perovskite LEDs with good stability under ambient and harsh conditions, making practical applications of such LEDs a real possibility.

Vapor-Assisted Solution Approach for High-Quality Perovskite CH3NH3PbBr3 Thin Films for High-Performance Green Light-Emitting Diode Applications.

The vapor-assisted solution method was developed to prepare high-quality organic-inorganic halide perovskite CH3NH3PbBr3 (MAPbBr3) thin films. We detailedly investigated the effect of evaporation time and temperature of MABr powder on the microstructure, crystallinity, and optical characterizations of MAPbBr3 thin films, and a controllable morphology evolution with varying surface coverage was observed. Temperature-dependent and time-resolved photoluminescence measurements were carried out to investigate the optical transition mechanisms and carrier recombination dynamics of MAPbBr3 thin films. Our results revealed that no structural phase transition occurred within the heating process (10-300 K). In addition to the exciton-related emission, a trapped charge-carrier emission appeared at a critical temperature of 140 K. The corresponding temperature sensitivity coefficient of band gap, exciton binding energy, and optical phonon energy of the MAPbBr3 thin films were extracted from the experimental data. Furthermore, planar perovskite light-emitting diodes (PeLEDs) based on a Al/LiF/TPBi/MAPbBr3/NiO/ITO structure were fabricated, and a high-purity green emission at ∼532 nm with a low line width (25 nm) was achieved. The devices demonstrated remarkable performances with high luminance (6530 cd/m2), current efficiency (8.16 cd/A), external quantum efficiency (4.36%), and power efficiency (4.49 lm/W). This research will provide valuable information for the preparation of high-quality perovskite thin films, facilitating their future applications in novel high-performance PeLEDs.

[Protein composition analysis and cytotoxicity of gulbulin hydrolysates of Brucea javanica seeds].

To analyze the protein composition of Brucea javanica seeds and evaluate the cytotoxicity of its gulbulin hydrolysates. Four protein fractions of albumin, gulbulin, prolamin and glutelin were sequentially extracted and then quantified by Kjeldahl method. Different kinds of proteases were applied to hydrolyze B.javanica gulbulin, and MTT assay was used to evaluate the cytotoxicity of low molecular weight hydrolysates (≤3 kDa) on human breast cancer MCF-7 cell. The results showed that： the total protein content of B.javanica seeds was 17.47%, albumin, gulbulin, coxin, glutelin and residue protein accounted for 15.01%, 8.11%, 2.47%, 44.92% and 23.62% of the total protein content, respectively. The hydrolysates (≤3 kDa) of B.javanica globulin produced by pepsin showed significant growth inhibitory activity on MCF-7 cells, and the IC50 value was（6.52±0.01） mg•L⁻¹ after 72 h of incubation. Protein was abundant in B.javanica seeds, and its peptides demonstrated specific cytotoxicity on MCF-7 cell line in vitro, suggesting antitumor active ingredient can be further generated from B.javanica seeds.

Functional characterization of ether-à-go-go-related gene potassium channels in midbrain dopamine neurons - implications for a role in depolarization block.

Bursting activity by midbrain dopamine neurons reflects the complex interplay between their intrinsic pacemaker activity and synaptic inputs. Although the precise mechanism responsible for the generation and modulation of bursting in vivo has yet to be established, several ion channels have been implicated in the process. Previous studies with nonselective blockers suggested that ether-à-go-go-related gene (ERG) K(+) channels are functionally significant. Here, electrophysiology with selective chemical and peptide ERG channel blockers (E-4031 and rBeKm-1) and computational methods were used to define the contribution made by ERG channels to the firing properties of midbrain dopamine neurons in vivo and in vitro. Selective ERG channel blockade increased the frequency of spontaneous activity as well as the response to depolarizing current pulses without altering spike frequency adaptation. ERG channel block also accelerated entry into depolarization inactivation during bursts elicited by virtual NMDA receptors generated with the dynamic clamp, and significantly prolonged the duration of the sustained depolarization inactivation that followed pharmacologically evoked bursts. In vivo, somatic ERG blockade was associated with an increase in bursting activity attributed to a reduction in doublet firing. Taken together, these results show that dopamine neuron ERG K(+) channels play a prominent role in limiting excitability and in minimizing depolarization inactivation. As the therapeutic actions of antipsychotic drugs are associated with depolarization inactivation of dopamine neurons and blockade of cardiac ERG channels is a prominent side effect of these drugs, ERG channels in the central nervous system may represent a novel target for antipsychotic drug development.

CyPPA, a Positive SK3/SK2 Modulator, Reduces Activity of Dopaminergic Neurons, Inhibits Dopamine Release, and Counteracts Hyperdopaminergic Behaviors Induced by Methylphenidate.

Dopamine (DA) containing midbrain neurons play critical roles in several psychiatric and neurological diseases, including schizophrenia and attention deficit hyperactivity disorder, and the substantia nigra pars compacta neurons selectively degenerate in Parkinson's disease. Pharmacological modulation of DA receptors and transporters are well established approaches for treatment of DA-related disorders. Direct modulation of the DA system by influencing the discharge pattern of these autonomously firing neurons has yet to be exploited as a potential therapeutic strategy. Small conductance Ca(2+)-activated K(+) channels (SK channels), in particular the SK3 subtype, are important in the physiology of DA neurons, and agents modifying SK channel activity could potentially affect DA signaling and DA-related behaviors. Here we show that cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (CyPPA), a subtype-selective positive modulator of SK channels (SK3 > SK2 > > > SK1, IK), decreased spontaneous firing rate, increased the duration of the apamin-sensitive afterhyperpolarization, and caused an activity-dependent inhibition of current-evoked action potentials in DA neurons from both mouse and rat midbrain slices. Using an immunocytochemically and pharmacologically validated DA release assay employing cultured DA neurons from rats, we show that CyPPA repressed DA release in a concentration-dependent manner with a maximal effect equal to the D2 receptor agonist quinpirole. In vivo studies revealed that systemic administration of CyPPA attenuated methylphenidate-induced hyperactivity and stereotypic behaviors in mice. Taken together, the data accentuate the important role played by SK3 channels in the physiology of DA neurons, and indicate that their facilitation by CyPPA profoundly influences physiological as well as pharmacologically induced hyperdopaminergic behavior.

Tuning the excitability of midbrain dopamine neurons by modulating the Ca2+ sensitivity of SK channels.

Small conductance Ca(2+) -activated K(+) (SK) channels play a prominent role in modulating the spontaneous activity of dopamine (DA) neurons as well as their response to synaptically-released glutamate. SK channel gating is dependent on Ca(2+) binding to constitutively bound calmodulin, which itself is subject to endogenous and exogenous modulation. In the present study, patch-clamp recording techniques were used to examine the relationship between the apparent Ca(2+) affinity of cloned SK3 channels expressed in cultured human embryonic kidney 293 cells and the excitability of DA neurons in slices from rat substantia nigra using the positive and negative SK channel modulators, 6,7-dichloro-1H-indole-2,3-dione-3-oxime and R-N-(benzimidazol-2-yl)-1,2,3,4-tetrohydro-1-naphtylamine. Increasing the apparent Ca(2+) affinity of SK channels decreased the responsiveness of DA neurons to depolarizing current pulses, enhanced spike frequency adaptation and slowed spontaneous firing, effects attributable to an increase in the amplitude and duration of an apamin-sensitive afterhyperpolarization. In contrast, decreasing the apparent Ca(2+) affinity of SK channels enhanced DA neuronal excitability and changed the firing pattern from a pacemaker to an irregular or bursting discharge. Both the reduction in apparent Ca(2+) affinity and the bursting associated with negative SK channel modulation were gradually surmounted by co-application of the positive SK channel modulator. These results underscore the importance of SK channels in 'tuning' the excitability of DA neurons and demonstrate that gating modulation, in a manner analogous to physiological regulation of SK channels in vivo, represents a means of altering the response of DA neurons to membrane depolarization.

Computational model predicts a role for ERG current in repolarizing plateau potentials in dopamine neurons: implications for modulation of neuronal activity.

Blocking the small-conductance (SK) calcium-activated potassium channel promotes burst firing in dopamine neurons both in vivo and in vitro. In vitro, the bursting is unusual in that spiking persists during the hyperpolarized trough and frequently terminates by depolarization block during the plateau. We focus on the underlying plateau potential oscillation generated in the presence of both apamin and TTX, so that action potentials are not considered. We find that although the plateau potentials are mediated by a voltage-gated Ca(2+) current, they do not depend on the accumulation of cytosolic Ca(2+), then use a computational model to test the hypothesis that the slowly voltage-activated ether-a-go-go-related gene (ERG) potassium current repolarizes the plateaus. The model, which includes a material balance on calcium, is able to reproduce the time course of both membrane potential and somatic calcium concentration, and can also mimic the induction of plateau potentials by the calcium chelator BAPTA. The principle of separation of timescales was used to gain insight into the mechanisms of oscillation and its modulation using nullclines in the phase space. The model predicts that the plateau will be elongated and ultimately result in a persistent depolarization as the ERG current is reduced. This study suggests that the ERG current may play a role in burst termination and the relief of depolarization block in vivo.

Lateral habenula stimulation inhibits rat midbrain dopamine neurons through a GABA(A) receptor-mediated mechanism.

Transient changes in the activity of midbrain dopamine neurons encode an error signal that contributes to associative learning. Although considerable attention has been devoted to the mechanisms contributing to phasic increases in dopamine activity, less is known about the origin of the transient cessation in firing accompanying the unexpected loss of a predicted reward. Recent studies suggesting that the lateral habenula (LHb) may contribute to this type of signaling in humans prompted us to evaluate the effects of LHb stimulation on the activity of dopamine and non-dopamine neurons of the anesthetized rat. Single-pulse stimulation of the LHb (0.5 mA, 100 micros) transiently suppressed the activity of 97% of the dopamine neurons recorded in the substantia nigra and ventral tegmental area. The duration of the cessation averaged approximately 85 ms and did not differ between the two regions. Identical stimuli transiently excited 52% of the non-dopamine neurons in the ventral midbrain. Electrolytic lesions of the fasciculus retroflexus blocked the effects of LHb stimulation on dopamine neurons. Local application of bicuculline but not the SK-channel blocker apamin attenuated the effects of LHb stimulation on dopamine cells, indicating that the response is mediated by GABA(A) receptors. These data suggest that LHb-induced suppression of dopamine cell activity is mediated indirectly by orthodromic activation of putative GABAergic neurons in the ventral midbrain. The habenulomesencephalic pathway, which is capable of transiently suppressing the activity of dopamine neurons at a population level, may represent an important component of the circuitry involved in encoding reward expectancy.