Neuronal Panx1 drives peripheral sensitization in experimental plantar inflammatory pain.

BACKGROUND: The channel-forming protein Pannexin1 (Panx1) has been implicated in both human studies and animal models of chronic pain, but the underlying mechanisms remain incompletely understood. METHODS: Wild-type (WT, n = 24), global Panx1 KO (n = 24), neuron-specific Panx1 KO (n = 20), and glia-specific Panx1 KO (n = 20) mice were used in this study at Albert Einstein College of Medicine. The von Frey test was used to quantify pain sensitivity in these mice following complete Freund's adjuvant (CFA) injection (7, 14, and 21 d). The qRT-PCR was employed to measure mRNA levels of Panx1, Panx2, Panx3, Cx43, Calhm1, and ß-catenin. Laser scanning confocal microscopy imaging, Sholl analysis, and electrophysiology were utilized to evaluate the impact of Panx1 on neuronal excitability and morphology in Neuro2a and dorsal root ganglion neurons (DRGNs) in which Panx1 expression or function was manipulated. Ethidium bromide (EtBr) dye uptake assay and calcium imaging were employed to investigate the role of Panx1 in adenosine triphosphate (ATP) sensitivity. ß-galactosidase (ß-gal) staining was applied to determine the relative cellular expression levels of Panx1 in trigeminal ganglia (TG) and DRG of transgenic mice. RESULTS: Global or neuron-specific Panx1 deletion markedly decreased pain thresholds after CFA stimuli (7, 14, and 21 d; P < 0.01 vs. WT group), indicating that Panx1 was positively correlated with pain sensitivity. In Neuro2a, global Panx1 deletion dramatically reduced neurite extension and inward currents compared to the WT group (P < 0.05), revealing that Panx1 enhanced neurogenesis and excitability. Similarly, global Panx1 deletion significantly suppressed Wnt/ß-catenin dependent DRG neurogenesis following 5 d of nerve growth factor (NGF) treatment (P < 0.01 vs. WT group). Moreover, Panx1 channels enhanced DRG neuron response to ATP after CFA injection (P < 0.01 vs. Panx1 KO group). Furthermore, ATP release increased Ca2+ responses in DRGNs and satellite glial cells surrounding them following 7 d of CFA treatment (P < 0.01 vs. Panx1 KO group), suggesting that Panx1 in glia also impacts exaggerated neuronal excitability. Interestingly, neuron-specific Panx1 deletion was found to markedly reduce differentiation in cultured DRGNs, as evidenced by stunted neurite outgrowth (P < 0.05 vs. Panx1 KO group; P < 0.01 vs. WT group or GFAP-Cre group), blunted activation of Wnt/ß-catenin signaling (P < 0.01 vs. WT, Panx1 KO and GFAP-Cre groups), and diminished cell excitability (P < 0.01 vs. GFAP-Cre group) and response to ATP stimulation (P < 0.01 vs. WT group). Analysis of ß-gal staining showed that cellular expression levels of Panx1 in neurons are significantly higher (2.5-fold increase) in the DRG than in the TG. CONCLUSIONS: The present study revealed that neuronal Panx1 is a prominent driver of peripheral sensitivity in the setting of inflammatory pain through cell-autonomous effects on neuronal excitability. This hyperexcitability dependence on neuronal Panx1 contrasts with inflammatory orofacial pain, where similar studies revealed a prominent role for glial Panx1. The apparent differences in Panx1 expression in neuronal and non-neuronal TG and DRG cells are likely responsible for the distinct impact of these cell types in the two pain models.

Is the expression of different discrete emotions related to time? Evidence from online Chinese reviews using sentiment analysis and human behavior dynamics.

Objectives: The online behavior of online users has taken on complex and diverse characteristics, and posting product reviews on e-commerce platforms is no exception. In fact, reviews contain rich and multi-dimensional discrete emotional information, and whether there is a relationship between the expression of these different discrete emotions and the time interval between product purchase and review posting as well as their related characteristics are the issues that this study needs to analyze and solve in depth. Methods: Based on the OCC model (named after three proposers) of psychological emotional cognitive evaluation theory as the basis for emotion classification, the study used the massive amounts of Chinese reviews of mobile phones on the Chinese e-commerce platform Jingdong Mall as the research object, applied supervised machine learning methods to classify discrete emotions, and constructed a large corpus containing satisfaction, disappointment, admiration, reproach, love, and hate; then the study delved into the distribution and behavioral dynamics characteristics of consumers' comments containing the different discrete emotions at different "purchase-comment" time intervals. Results: The results showed that the first peak of the distribution curves of the six discrete emotions at different "purchase-comment" time intervals occurs on the first day after purchase and then decreases gradually but at different rates. The three curves for satisfaction, love, and hate emotions also show a second peak on the eleventh day, which is more similar to the bimodal distribution, implying that the corresponding product reviews are more objective. In addition, the distribution of reviews containing the six discrete emotions at different "purchase-comment" time intervals follows a power-law distribution and has the temporal characteristics of human behavioral dynamics, that is, "strong paroxysms and weak memory". However, the reviews containing the admiration and reproach emotions were most intensively written by consumers after the purchase, indicating that the service provided by the seller, logistics, and e-commerce platform stimulates more consumers to give quick responses and detailed reviews. Conclusion: This study is not only of great significance for exploring the internal mechanisms of consumer discrete emotional expression but also provides important decision-making references for potential consumer purchasing decisions, product updates for developers, marketing strategy formulation for marketing teams, and service improvement for sellers, logistics companies, and e-commerce platforms.

Melatonin mediates elevated carbon dioxide-induced photosynthesis and thermotolerance in tomato.

Increasing carbon dioxide (CO2 ) promotes photosynthesis and mitigates heat stress-induced deleterious effects on plants, but the regulatory mechanisms remain largely unknown. Here, we found that tomato (Solanum lycopersicum L.) plants treated with high atmospheric CO2 concentrations (600, 800, and 1000 µmol mol-1 ) accumulated increased levels of melatonin (N-acetyl-5-methoxy tryptamine) in their leaves and this response is conserved across many plant species, including Arabidopsis, rice, wheat, mustard, cucumber, watermelon, melon, and hot pepper. Elevated CO2 (eCO2 ; 800 µmol mol-1 ) caused a 6.8-fold increase in leaf melatonin content, and eCO2 -induced melatonin biosynthesis preferentially occurred through chloroplast biosynthetic pathways in tomato plants. Crucially, manipulation of endogenous melatonin levels by genetic means affected the eCO2 -induced accumulation of sugar and starch in tomato leaves. Furthermore, net photosynthetic rate, maximum photochemical efficiency of photosystem II, and transcript levels of chloroplast- and nuclear-encoded photosynthetic genes, such as rbcL, rbcS, rbcA, psaD, petB, and atpA, significantly increased in COMT1 overexpressing (COMT1-OE) tomato plants, but not in melatonin-deficient comt1 mutants at eCO2 conditions. While eCO2 enhanced plant tolerance to heat stress (42°C) in wild-type and COMT1-OE, melatonin deficiency compromised eCO2 -induced thermotolerance in comt1 plants. The expression of heat shock proteins genes increased in COMT1-OE but not in comt1 plants in response to eCO2 under heat stress. Further analysis revealed that eCO2 -induced thermotolerance was closely linked to the melatonin-dependent regulation of reactive oxygen species, redox homeostasis, cellular protein protection, and phytohormone metabolism. This study unveiled a crucial mechanism of elevated CO2 -induced thermotolerance in which melatonin acts as an essential endogenous signaling molecule in tomato plants.

Proposal and thoughts on establishing and improving multi-level dental insurance in China / 中华口腔医学杂志

Oral diseases are highly prevalent in China, while oral health services are generally underutilized and public health resources are wasted. Lacking oral insurance may be one of the leading causes. The basic medical insurance of China does not cover dental care in most cities, which is worthy to further discuss. To better understand the experience of dental insurance from international dental care practice, the dental coverage scope, content, co-pay ratio, and effects of oral insurance on oral health improvement from the abroad countries with typical health insurance systems were summarized by using scoping review. Then, we discussed the coverage scope for dental health of basic medical insurance and private insurance in China. We also analyzed the current issues of dental care coverage and cost-share. At last, we proposed thoughts and suggestions to establish and improve a multi-level oral health insurance system with Chinese characteristics under the basic medical insurance frame. In particular, we gave suggestions on increasing the coverage for high dental care xpenditure by ebasic medical insurance, supplying children and teenagers with preventive dental care, and encouraging private insurance companies to cover dental care expenditure.

Positive feedback regulation of microglial glucose metabolism by histone H4 lysine 12 lactylation in Alzheimer's disease.

The pro-inflammatory activation of microglia is a hallmark of Alzheimer's disease (AD), and this process involves a switch from oxidative phosphorylation (OXPHOS) toward glycolysis. Here, we show how a positive feedback loop in microglia drives AD pathogenesis, and we demonstrate that inhibiting this cycle in microglia can ameliorate Aß burden and cognitive deficits in an AD mouse model (5XFAD). After first detecting elevated histone lactylation in brain samples from both 5XFAD mice and individuals with AD, we observed that H4K12la levels are elevated in Aß plaque-adjacent microglia. This lactate-dependent histone modification is enriched at the promoters of glycolytic genes and activates transcription, thereby increasing glycolytic activity. Ultimately, the glycolysis/H4K12la/PKM2 positive feedback loop exacerbates microglial dysfunction in AD. Pharmacologic inhibition of PKM2 attenuated microglial activation, and microglia-specific ablation of Pkm2 improved spatial learning and memory in AD mice. Thus, our study illustrates that disruption of the positive feedback loop may be a potential therapeutic approach for the treatment of AD.

Astrocytes in depression and Alzheimer's disease.

Astrocytes are an abundant subgroup of cells in the central nervous system (CNS) that play a critical role in controlling neuronal circuits involved in emotion, learning, and memory. In clinical cases, multiple chronic brain diseases may cause psychosocial and cognitive impairment, such as depression and Alzheimer's disease (AD). For years, complex pathological conditions driven by depression and AD have been widely perceived to contribute to a high risk of disability, resulting in gradual loss of self-care ability, lower life qualities, and vast burden on human society. Interestingly, correlational research on depression and AD has shown that depression might be a prodrome of progressive degenerative neurological disease. As a kind of multifunctional glial cell in the CNS, astrocytes maintain physiological function via supporting neuronal cells, modulating pathologic niche, and regulating energy metabolism. Mounting evidence has shown that astrocytic dysfunction is involved in the progression of depression and AD. We herein review the current findings on the roles and mechanisms of astrocytes in the development of depression and AD, with an implication of potential therapeutic avenue for these diseases by targeting astrocytes.

Sodium alginate/collagen/stromal cell-derived factor-1 neural scaffold loaded with BMSCs promotes neurological function recovery after traumatic brain injury.

Stem cell therapy is promising for neural repair in devastating traumatic brain injury (TBI). However, the low survival and differentiation rates of transplanted stem cells are main obstacles to efficient stem cell therapy in TBI. Stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 are key factors that regulate the survival, recruitment, and differentiation of stem cells. Herein, we synthesized a sodium alginate (SA)/collagen type I (Col)/SDF-1 hydrogel and investigated whether the SA/Col/SDF-1 hydrogel loaded with bone marrow-derived mesenchymal stem cells (BMSCs) had therapeutic effects on a TBI model. Our results showed that the SA/Col/SDF-1 scaffold could stably release SDF-1 and provide biocompatible and biodegradable microenvironment for the survival, migration, and neuronal differentiation of BMSCs in vitro. In a rat model of TBI, the SA/Col/SDF-1 hydrogel loaded with BMSCs significantly ameliorated motor and cognition dysfunction and relieved anxiety and depressive-like behaviors. In addition, the BMSCs/SA/Col/SDF-1 scaffold reduced brain lesions and neuronal cell death and mitigated neuroinflammation. Further studies demonstrated that the BMSCs/SA/Col/SDF-1 hydrogel promoted the migration of BMSCs in the lesions and partly enhanced neurogenesis by activating the SDF-1/CXCR4-mediated FAK/PI3K/AKT pathway. Taken together, our results indicate that the SA/Col/SDF-1 scaffold loaded with BMSCs exerts neuroreparative effects in a TBI rat model, and thus, it may serve as an alternative neural regeneration scaffold for brain injury repair. STATEMENT OF SIGNIFICANCE: Hydrogel facilitates the biological behaviors of transplanted stem cells for tissue regeneration. In this study, we synthesized sodium alginate (SA)/collagen type I (Col)/ scaffold to simultaneously deliver stromal cell derived factor-1 (SDF-1) and bone marrow mesenchymal stem cells (BMSCs) in a rat model of traumatic brain injury (TBI). We found that the SA/Col/SDF-1 hydrogel could continuously release SDF-1 and was conducive to the survival, migration and neuronal differentiation of BMSCs in vitro. In addition, the SA/Col/SDF-1 hydrogel loaded with BMSCs significantly ameliorated neurological deficits, mitigated neuroinflammation, promoted the recruitment of BMSCs and enhanced neurogenesis in TBI partly by activating the SDF-1/CXCR4-mediated FAK/PI3K/AKT pathway. Our results may serve as an alternative neural regeneration strategy for brain injury.

Polarization resolving and imaging with a single-photon sensitive superconducting nanowire array.

Superconducting nanowire single-photon detectors (SNSPDs) have attracted remarkable interest for visible and near-infrared single-photon detection due to their outstanding performance. However, conventional SNSPDs are generally used as binary photon-counting detectors. Another important characteristic of light, i.e., polarization, which can provide additional information of the object, has not been resolved using the standalone SNSPD. In this work, we present a first prototype of the polarimeter based on a four-pixel superconducting nanowire array, capable of resolving the polarization state of linearly-polarized light at the single-photon level. The detector array design is based on a division of focal plane configuration in which the orientation of each nanowire division (pixel) is offset by 45°. Each single nanowire pixel operates as a combination of a photon detector and almost linear polarization filter, with an average polarization extinction ratio of ∼10. The total system detection efficiency of the array is ∼1% at a total dark count rate of 680 cps, with a timing jitter of 126 ps, when the detector array is free-space coupled and illuminated with 1550-nm photons. The mean errors of the measured angle of polarization and degree of linear polarization were about -3° and 0.12, respectively. Furthermore, we successfully demonstrated polarization imaging at low-light level using the proposed detector. Our results pave the way for the development of a single-photon sensitive, fast, and large-scale integrated polarization polarimeter or imager. Such detector may find promising application in photon-starved polarization resolving and imaging with high spatial and temporal resolution.

Sixteen-channel fiber array-coupled superconducting single-photon detector array with average system detection efficiency over 60% at telecom wavelength.

We report a compact, scalable, and high-performance superconducting nanowire single-photon detector (SNSPD) array by using a multichannel optical fiber array-coupled configuration. For single pixels with an active area of 18 µm in diameter and illuminated at the telecom wavelength of 1550 nm, we achieved a pixel yield of 13/16 on one chip, an average system detection efficiency of 69% at a dark count rate of 160 cps, a minimum timing jitter of 74 ps, and a maximum count rate of ∼40Mcps. The optical crosstalk coefficient between adjacent channels is better than -60dB. The performance of the fiber array-coupled detectors is comparable with a standalone detector coupled to a single fiber. Our method is promising for the development of scalable, high-performance, and high-yield SNSPDs.

Clinical study on the treatment of rosacea with excessive heat in lung and stomach with self-made Liangxue-Qingfei Decoction combined with western medicine / 国际中医中药杂志

Objective:To evaluate the clinical efficacy of self-made Liangxue-Qingfei Decoction combined with conventional western medicine in the treatment of rosacea with excessive heat in lung and stomach. Methods:312 patients with rosacea in Longfu hospital from May 2017 to May 2019 were selected and randomly divided into two groups, 156 cases in each group. The control group was treated with Doxycyclane Hyclate Tablets combined with Metronidazole Gel The study group was additionally given self-made Liangxue-Qingfei Decoction on the basis of the control group. Both groups were treated for 4 weeks. Dermatology Life Quality Index (DLQI) was evaluated . The erythema index (EI) of lesion area was measured by multi-functional skin tester. The adverse reactions during the treatment were recorded and the clinical efficacy was evaluated. Results:The total effective rate was 80.8% (126/156) in the study group and 66.7% (104/156) in the control group, with statistically significance ( χ2=8.012, P=0.005). After the treatment, the scores of physiology, psychology, family, social activities, interpersonal and occupational restrictionsin, and treatment in the study group were lower than those in the control group ( t=17.942, 15.794, 19.465, 21.586, 31.375, 27.472, P<0.001); EI (619.69 ± 71.53 vs. 822.97 ± 89.47, t=32.348) was lower than that of the control group ( P<0.01). During the treatment, the incidence of adverse reactions was 4.5% (7/156) in the control group and 5.8% (9/156) in the study group, and there was no significant difference between the two groups ( χ2=0.439, P=0.514). Conclusion:The self-made Liangxue-Qingfei Decoction combined with routine western medicine therapy can effectively improve the clinical symptoms and quality of life of rosacea patients with lung and stomach excessive heat, improve the clinical efficacy with safety.

Evaluation of therapeutic effect and health economics of general anesthesia and routine outpatient dental treatment in children with severe early child caries / 华西口腔医学杂志

OBJECTIVES@#To evaluate the efficacy and health economics of the comprehensive therapy for the children with severe early child caries (S-ECC) under dental general anesthesia (DGA) and conventional outpatient treatment to provide references for dentists and parents in the choice of clinical treatment.@*METHODS@#A retrospective cohort study was conducted on S-ECC children aged 36-71 months and who received dental treatment under general anesthesia or routine outpatient situation. The filled tooth survival rate, treatment cost, and cost-filled tooth survival time of the two groups were compared, and the curative effect and health economics was evaluated.@*RESULTS@#The filled tooth survival rate of the DGA group was higher than that of the routine outpatient group (@*CONCLUSIONS@#Compared with the conventional outpatient treatment group, the treatment outcomes of S-ECC under general anesthesia were better, and the costs were higher. However, no significant difference was observed in the total medical cost-filled tooth survival time between these two groups, and the conventional outpatient treatment did not have evident economic advantages.

Psychological intervention in oral patients in novel coronavirus pneumonia outbreak period / 中华口腔医学杂志

Public health emergencies have an impact on the public mental health. The outbreak of the novel coronavirus has affected the normal diagnosis and treatment services in oral medical institutions across the country. Delay of non-emergency dental service will have a potential impact on the experience, cognition, treatment and rehabilitation of patients with oral diseases. Through literature review, this paper reviewed the oral psychosomatic diseases closely related to patients' psychological state, such as oral mucosal disease, temporomandibular joint disease, bruxism, periodontal disease and so on. It was believed that these patients might be more susceptible to the impact of stress events, and dental specialists should pay more attention to them. At the same time, this paper analyzes the possible psychological stress symptoms of patients with different oral diseases, and puts forward suggestions for remote consultation and emergency treatment of dentists. From the perspective of social role, dentists not only played the role of expert in dental home professional guidance, but also played the role of psychological counseling for patients.

The TRIM protein Mitsugumin 53 enhances survival and therapeutic efficacy of stem cells in murine traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is a common neurotrauma leading to brain dysfunction and death. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) hold promise in the treatment of TBI. However, their efficacy is modest due to low survival and differentiation under the harsh microenvironment of the injured brain. MG53, a member of TRIM family protein, plays a vital role in cell and tissue damage repair. The present study aims to test whether MG53 preserves hUC-MSCs against oxidative stress and enhances stem cell survival and efficacy in TBI treatment. METHODS: In this study, we performed a series of in vitro and in vivo experiments in hUC-MSCs and mice to define the function of MG53 enhancing survival, neurogenesis, and therapeutic efficacy of stem cells in murine traumatic brain injury. RESULTS: We found that recombinant human MG53 (rhMG53) protein protected hUC-MSCs against H2O2-induced oxidative damage and stimulated hUC-MSC proliferation and migration. In a mouse model of contusion-induced TBI, intravenous administration of MG53 protein preserved the survival of transplanted hUC-MSCs, mitigated brain edema, reduced neurological deficits, and relieved anxiety and depressive-like behaviors. Co-treatment of MG53 and hUC-MSCs enhanced neurogenesis by reducing apoptosis and improving PI3K/Akt-GSK3ß signaling. CONCLUSION: MG53 enhances the efficacy of hUC-MSCs in the recovery of TBI, indicating that such adjunctive therapy may provide a novel strategy to lessen damage and optimize recovery for brain injury.

Corrigendum: HDAC1 Silence Promotes Neuroprotective Effects of Human Umbilical Cord-Derived Mesenchymal Stem Cells in a Mouse Model of Traumatic Brain Injury via PI3K/AKT Pathway.

[This corrects the article DOI: 10.3389/fncel.2018.00498.].

Identification of chimeric RNAs in human infant brains and their implications in neural differentiation.

Chimeric RNAs are transcripts composed of RNA fragments from different genes and are traditionally well-known cancer-causing genetic events. Recent studies show chimeric RNAs being present in multiple non-neoplastic tissues and cells, suggesting that at least some may have roles in normal physiology. However, chimeric RNAs and their implications in brain development and neural differentiation have not been formally studied. Here, we firstly characterized the landscape of chimeric RNAs in human infant brain tissues and identified 599 chimeric RNAs. Through a series of filtering, 22 were selected and tested in a neural differentiation process starting from stem cells. Ten were validated experimentally. One of these ten chimeric RNAs, DUS4L-BCAP29, dramatically increased when human umbilical mesenchymal stem cells were induced for neural differentiation. Consistently, we found that overexpressed DUS4L-BCAP29 effectively promoted neural differentiation. Our results support the important role(s) chimeric RNAs play in neural differentiation, and are consistent with the new notion that chimeric RNAs also exist in normal physiology, and likely serve biological purposes.

Long non­coding RNA regulates hair follicle stem cell proliferation and differentiation through PI3K/AKT signal pathway.

Long non-coding RNAs (lncRNAs) are defined as non-coding transcripts (>200 nucleotides) that serve important roles in the proliferation and differentiation of stem cells. Hair follicle stem cells (HFTs) have multidirectional differentiation potential and are able to differentiate into skin, hair follicles and sebaceous glands, serving a role in skin wound healing. The aim of the present study was to analyze the regulatory role of lncRNA AK015322 (IncRNA5322) in HFTs and the potential mechanism of IncRNA5322­mediated differentiation of HFTs. The results demonstrated that lncRNA5322 transfection promoted proliferation and differentiation in HFTs. It was identified that lncRNA5322 transfection upregulated the expression and phosphorylation of phosphoinositide 3­kinase (PI3K) and protein kinase B (AKT) in HFTs. It was also observed that lncRNA5322 transfection upregulated microRNA (miR)­21 and miR­21 agonist (agomir­21) eliminated lncRNA5322­induced expression and phosphorylation of PI3K and AKT. The present study also demonstrated that agomir­21 blocked IncRNA5322­induced expression and phosphorylation of PI3K and AKT in HFTs. The results indicated that agomir­21 transfection also suppressed the IncRNA5322­induced proliferation and differentiation of HFTs. In conclusion, the results of the present study suggest that lncRNA5322 is able to promote the proliferation and differentiation of HFTs by targeting the miR­21­mediated PI3K­AKT signaling pathway in HFTs.

Potential application of an injectable hydrogel scaffold loaded with mesenchymal stem cells for treating traumatic brain injury.

In the past few decades, there have been potential applications for stem cell replacement therapy in the treatment of nervous system damage resulting from diseases or traumatic brain injury (TBI). However, the insufficient number of transplanted stem cells and low survival rate caused by a series of negative conditions limit the therapeutic effect. In this contribution, we developed an injectable hydrogel composed of sodium alginate (SA) and hyaluronic acid (HA) as a tissue scaffold to create a more optimal microenvironment for stem cells after implantation. The gelation time of the HA/SA hydrogel exceeded 6 min, which satisfied the requirements for injection performance, and the high ratios of water content and slower degradation speed affirmed that the HA/SA hydrogel is a preferable stem cell scaffold. As a tissue engineering scaffold, the HA/SA hydrogel exhibited appropriately porous structures for stem cell loading and good rheological behavior, which contributed to stem cell differentiation. The in vitro culture experiment proved that the HA/SA scaffold performed well on hUC-MSCs with higher viability ratio and proliferation. Further in vivo tests indicated that the HA/SA scaffold not only protected the injected human umbilical cord mesenchymal stem cells (hUC-MSCs) so that they could maintain a higher survival ratio, but it also contributed to the regeneration of endogenous nerve cells. In summary, this injectable HA/SA hydrogel has the potential to be used for stem cell tissue engineering and support the physiological function recovery of TBI patients.