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Structural supercapacitors hold promise to expand the energy capacity of a system by integrating load-bearing and energy-storage functions in a multifunctional structure, resulting in weight savings and safety improvements. Here, we develop strategies based on interfacial engineering to advance multifunctional efficiency. The structural electrodes were reinforced by coating carbon-fiber weaves with a uniquely stable conjugated redox polymer and reduced graphene oxide that raised pseudocapacitive capacitance and tensile strength. The solid polymer electrolyte was tuned to a gradient configuration, where it facilitated high ionic conductivity at the electrode-electrolyte interfaces and transitioned to a composition with high mechanical strength in the bulk for load support. The gradient design enabled the multilayer structural supercapacitors to reach state-of-the-art performance matching the level of monofunctional supercapacitors. In situ electrochemical-mechanical measurements established the device durability under mechanical loads. The structural supercapacitor was made into the hull of a model boat to demonstrate its multifunctionality.

As a major public health problem, posttraumatic stress disorder (PTSD) has a substantial impact on individuals and society. The total excess economic burden of PTSD in the US is estimated to be more than $232.2 billion a year. Acupuncture is widely used in patients with PTSD, and an increasing number of studies have been undertaken to assess the efficacy and underlying mechanisms of acupuncture for the treatment of individuals with PTSD. However, there has not yet been a review that simultaneously elucidates the therapeutic efficacy and biological mechanisms of acupuncture. We wished to examine the efficacy and underlying mechanisms of acupuncture for the treatment of individuals with PTSD. We conducted this review in three sections as follows: a meta-analysis, an acupoint analysis, and mechanism research. PubMed, Web of Science, Embase, Cochrane Library, China National Knowledge Infrastructure Database (CNKI), WanFang Database, China Biology Medicine Database (CBM), Chinese Science and Technology Journals Database (VIP), and other databases were searched from 1 January 2012 to 27 November 2022. Based on the included studies, we first determined whether acupuncture is more effective than psychological treatment or pharmacological treatment for treating and improving the quality of life of individuals with PTSD by meta-analysis. Second, the most commonly used acupoints and parameters of acupuncture were summarized based on animal and clinical studies. Third, we attempt to summarize the current mechanisms of acupuncture in the treatment of PTSD. Finally, 56 acupoint analyses, eight meta-analyses, and 33 mechanistic studies were included. Acupuncture outperformed pharmacotherapy treatment in improving symptom scores by CAPS, HAMA, HAMD, PCL-C, and SCL-90 somatization for PTSD and outperformed psychotherapy treatment in improving symptom scores by CAPS PCL-C and HAMD, according to the meta-analysis. GV20 was the most frequently used acupuncture point in clinical studies and animal studies, with a 78.6% application rate. Acupuncture may be effective in treating PTSD by regulating the structure and components of several brain areas, regulating the neuroendocrine system, and involving signaling pathways. In conclusion, this finding indicates that acupuncture has promising potential for treating PTSD.

BackgroundInsulin resistance (IR) is one of the common pathological manifestations of metabolic-related diseases, and the prevalence of relevant diseases is high. Acupuncture is beneficial to IR patients, but the central mechanism underlying this treatment remains unclear. This study provides mechanistic insights into how electroacupuncture (EA) improves IR through the response of Pro-opiomelanocortin (POMC) neurons to adiponectin (Adipo).MethodsGlucose tolerance tests (GTT), Insulin tolerance tests (ITT) and fasting blood glucose (FBG) were detected by glucometer. Serum insulin, Adipo and skeletal muscle adiponectin receptor 1 (AdipoR1) protein levels were examined by ELISA. Homeostasis model assessment estimated insulin resistance (HOMA-IR) was calculated using the following formula: HOMA-IR = fasting insulin (FINS) (mU/L) × FBG (mmol/L)/22.5. The expression levels of AdipoR1 and Adipo mRNA in skeletal muscle were detected by real-time PCR quantification. The co-marking of c-Fos/AdipoR1 and POMC neurons were investigated using immunofluorescence. Spontaneous excitatory postsynaptic currents (sEPSCs) of POMC neurons and the response of POMC neurons to Adipo were detected via electrophysiology.ResultsEA significantly ameliorated HFD-induced impairment of GTT, ITT, FBG, and HOMA-IR which was correlated with recovery of the expression level of AdipoR1 and Adipo in skeletal muscle. The improved response of POMC neurons to Adipo in the hypothalamus may be a key factor in correcting abnormal glucose tolerance and improving IR.ConclusionThis study demonstrates that EA can ameliorate HFD-induced impaired glucose tolerance through improved response of POMC neurons to Adipo in the hypothalamus, providing insight into the central mechanism of improving IR through EA.

BRAF V600E-mutated glioma patients are in urgent need of new treatments, since standard chemoradiotherapy and surgery achieves tumor control in less than 30% of patients. BRAF and MEK inhibitor combinations have shown promising results against several types of BRAF V600E mutated cancers. Patients with high-grade BRAF V600E mutated gliomas frequently experience therapy failure with concurrent BRAF V600E and MEK inhibition (BRAFi+MEKi). Overcoming therapy resistance begins with understanding how these inhibitors affect tumor cells and the immune microenvironment. In novel syngeneic murine models and patient-derived cell lines of BRAF V600E-mutated high-grade astrocytomas, we analyzed effects of BRAF V600E expression and BRAF V600E inhibitor Dabrafenib and MEK inhibitor Trametinib (BRAFi+MEKi). BRAF V600E expression disrupted asymmetric cell division and glial differentiation, and BRAFi+MEKi restored these defects, and enriched for potentially therapy resistant CD133+ tumor cells. Increased interferon alpha and gamma signatures and pro-inflammatory cytokines were detected. Programmed death (PD-1) receptor ligand was found to be expressed in murine and human BRAF V600E mutated high-grade gliomas, and BRAFi+MEKi upregulated the frequency of tumor-infiltrating T cells expressing inhibitory immune checkpoints, suggestive of T cell exhaustion. Combining dual MAPK pathway with immune checkpoint inhibition by anti-PD-L1 and anti-CTLA-4 treatment decreased T cell deactivation and resulted in a T cell-dependent survival benefit of mice with orthotopic BRAF V600E-mutated high-grade gliomas. These data showed that clinically relevant dual MAPK pathway inhibition sensitized high-grade gliomas to the anti-tumor activity of concurrent dual immune checkpoint blockades. Therefore, we propose that in patients with BRAF V600E high-grade gliomas, improved therapeutic benefits could be derived from combining BRAFi+MEKi with immune checkpoint inhibitors.

Interleukin 6 (IL-6) is a cytokine with dual functions of pro-inflammation and anti-inflammation. It is mainly produced by mononuclear macrophages, Th2 cells, vascular endothelial cells and fibroblasts. IL-6 binds to glycoprotein 130 and one of these two receptors, membrane-bound IL-6R or soluble IL-6R, forming hexamer (IL-6/IL-6R/gp130), which then activates different signaling pathways (classical pathway, trans-signaling pathway) to exert dual immune-modulatory effects of anti-inflammation or pro-inflammation. Abnormal levels of IL-6 can cause multiple pathological reactions, including cytokine storm. Related clinical studies have found that IL-6 levels in severe COVID-19 patients were much higher than in healthy population. A large number of studies have shown that IL-6 can trigger a downstream cytokine storm in patients with COVID-19, resulting in lung damages, aggravating clinical symptoms and developing excessive inflammation and acute respiratory distress syndrome (ARDS). Monoclonal antibodies against IL-6 or IL-6R, such as tocilizumab, sarilumab, siltuximab and olokizumab may serve as therapeutic options for COVID-19 infection.

Molecular cloning techniques enabling contemporaneous expression of two or more protein-coding sequences in a cell type of interest provide an invaluable tool for understanding the molecular regulation of cellular functions. DNA recombination employing the Cre-lox system is commonly used as a molecular switch for inducing the expression of recombinant proteins encoded within a bicistronic cassette. In such an approach, the two protein-coding sequences are separated by a 2A peptide or internal ribosome entry site (IRES), and expression is designed to be strictly Cre-dependent by using a lox-STOP-lox cassette or flip-excision (FLEX) switch. However, low-level or ‘leaky’ expression of recombinant proteins is often observed in the absence of Cre activity, potentially compromising the utility of this approach. To investigate the mechanism of leaky gene expression, we generated pCAG-lox-GFP-STOP-lox-Transgene A-2A-Transgene B vectors, which are designed to express nuclear-targeted GFP in the absence of Cre, and express both transgenes A and B after Cre-mediated recombination. We found that cells transfected with these bicistronic vectors exhibited low-level Cre-independent expression specifically of the transgene positioned 3′ of the 2A peptide. We observed similar results in vivo by viral transduction of the adult mouse cerebral cortex with AAV-mutagenesis of putative transcription factor binding sites that the 5′ transgene confers promoter-like activity that drives expression of the 3′ transgene. Finally, we demonstrate that inclusion of an additional lox-STOP-lox cassette between the 2A sequence and 3′ transgene dramatically reduces the extent of Cre-independent leaky gene expression. Our findings highlight that caution should be applied to the use of Cre-dependent bicistronic constructs when tight regulation of transgene expression is desired and provide a guide to preventing leaky gene expression when the expression of more than one protein is required.

The isotropic nanoparticles (NPs) and anisotropic bulk samples of MnBi were prepared from Mn NPs by using zero-field and field-assisted reactive sintering, respectively. The MnBi NPs are irregular in shape with size d

The identification of factors that regulate myelination provides important insight into the molecular mechanisms that coordinate nervous system development and myelin regeneration after injury. In this study, we investigated the role of amyloid precursor protein (APP) and its paralogue amyloid precursor-like protein 2 (APLP2) in myelination using APP and APLP2 knockout (KO) mice. Given that BACE1 regulates myelination and myelin sheath thickness in both the peripheral and central nervous systems, we sought to determine if APP and APLP2, as alternate BACE1 substrates, also modulate myelination, and therefore provide a better understanding of the events regulating axonal myelination. In the peripheral nervous system, we identified that adult, but not juvenile KO mice, have lower densities of myelinated axons in their sciatic nerves while in the central nervous system, axons within both the optic nerves and corpus callosum of both KO mice were significantly hypomyelinated compared to wild-type (WT) controls. Biochemical analysis demonstrated significant increases in BACE1 and myelin oligodendrocyte glycoprotein and decreased NRG1 and proteolipid protein levels in both KO brain tissue. The acute cuprizone model of demyelination/remyelination revealed that whereas axons in the corpus callosum of WT and APLP2-KO mice underwent similar degrees of demyelination and subsequent remyelination, the myelinated callosal axons in APP-KO mice were less susceptible to cuprizone-induced demyelination and showed a failure in remyelination after cuprizone withdrawal. These data identified APP and APLP2 as modulators of normal myelination and demyelination/remyelination conditions. Deletion of APP and APLP2 identifies novel interplays between the BACE1 substrates in the regulation of myelination.

Magnetic powders containing ferrimagnetic Mn4C phase and antiferromagnetic MnO phase were prepared from a Mn-C alloy by using the laser ablation method. The Mn-C alloys were composed of Mn4C and α-Mn(C) solid solution, which decomposed into Mn4C and Mn23C6 during laser ablation. The Mn clusters precipitated from the Mn(C) solid solution were spontaneously oxidized into MnO when exposed to air, forming an exchange bias system of Mn4C/MnO with ferrimagnetic/antiferromagnetic interfaces. The exchange bias field (22.3 mT at 5 K) of the Mn4C/MnO micro-powders, which show irregular shapes and a wide size distribution in the range of ~ 100 nm to ~ 20 μm, decreases with increasing temperature. Both the interface spins and the surface spins contribute to the exchange bias effect in these powders. The coercivity of the laser-ablated micro-powders reached up to ~ 150 mT at 5 K and ~ 40 mT at 400 K, respectively.

Additional file 2 Figure S2. Effect of DCS injection on neural activity in schizophrenia-like model mice in vivo. These data were the raw data obtained in the same experiments as those in Fig. 4. Amplitude, frequency or integrated area of spontaneous Ca2+ responses were shown before and after DCS injection, measured using CAG-GCaMP6s or CaMKII-GCaMP6s. A. Higher neuronal activity was observed in the anti-Nrg1 group but no effect of DCS, measured by the amplitude of Ca2+ responses. For CAG-GCaMP6s, basal activity, Rag vs. Nrg1, F1, 292 = 16.21, P

Additional file 4 Figure S4. Effect of glycine on locomotion in the open field test and in vivo neuronal spike rate. A. Anti-Nrg1 mice showed hyperlocomotion compared to anti-Rag group. Glycine injection did not significantly alter locomotion in either anti-Rag or anti Nrg1 mice. 8 mice (Rag), 8 mice (Nrg1). B. Mean spike rate showed large reduction after glycine injection in both anti-Rag and anti-Nrg1 group (paired t-test, Pâ

Additional file 1 Figure S1. Effect of DCS on locomotion in the open field test. Hyperlocomotion was seen in anti-Nrg1 mice, which was not affected by injection of DCS (bar). 8 mice (Rag), 8 mice (Nrg1).

Additional file 3 Figure S3. Sarcosine does not affect neural activity in schizophrenia-like model mice. These data were the raw data obtained in the same experiments as those in Fig. 5. Amplitude, frequency or integrated area of spontaneous Ca2+ responses were shown before and after sarcosine injection, measured using Synapsin-GCaMP6s (A), or CaMKII-GCaMP6s (B). A. In neurons expressing synapsin-GCaMP6s virus, injection of 0.3 g/kg or 1 g/kg sarcosine did not significantly change the amplitude (A1), frequency (A2) or total activity (A3) of spontaneous Ca2+ responses, in either anti-Nrg1 or anti-Rag mice. Increased basal neural activity was observed in the anti-Nrg1 group. A1. 0.3 g/kg, basal activity, Rag vs. Nrg1, F1, 442 = 43.78, P

Recent advances in transgenic tools have allowed us to peek into the earliest stages of vertebrate development to study axon-glial communication in the control of peri-natal myelination. The emerging role of neuronal activity in regulating oligodendrocyte progenitor cell behavior during developmental myelination has opened up an exciting possibility-a role for neuronal activity in the early stages of remyelination. Recent work from our laboratory and others has also shown that contrary to previously established dogma in the field, complete remyelination up to pre-demyelination levels can be achieved in mouse models of MS by oligodendrogenic neural precursor cells that derive from the adult subventricular zone. These cells are electrically active and can be depolarized, suggesting that neuronal activity may have a modulatory role in their development and remyelination potential. In this review, we summarize recent advances in our understanding of the development of axon-glia communication and apply those same concepts to remyelination, with an emphasis on the particular roles of different sources of oligodendrocyte progenitor cells.

Mounting evidence suggests that neuronal activity influences myelination, potentially allowing for experience-driven modulation of neural circuitry. The degree to which neuronal activity is capable of regulating myelination at the individual axon level is unclear. Here we demonstrate that stimulation of somatosensory axons in the mouse brain increases proliferation and differentiation of oligodendrocyte progenitor cells (OPCs) within the underlying white matter. Stimulated axons display an increased probability of being myelinated compared to neighboring non-stimulated axons, in addition to being ensheathed with thicker myelin. Conversely, attenuating neuronal firing reduces axonal myelination in a selective activity-dependent manner. Our findings reveal that the process of selecting axons for myelination is strongly influenced by the relative activity of individual axons within a population. These observed cellular changes are consistent with the emerging concept that adaptive myelination is a key mechanism for the fine-tuning of neuronal circuitry in the mammalian CNS., Neuronal activity is known to increase myelination by oligodendrocytes in the mouse brain. Here, Mitew et al. demonstrate that chemogenetic manipulations of somatosensory axon activity both increase the generation of new oligodendrocytes and preferentially enhance myelination of the activated axons.

Parenchymal oligodendrocyte progenitor cells (pOPCs) are considered the principal cell type responsible for oligodendrogenesis and remyelinaton in demyelinating diseases. Recent studies have demonstrated that neural precursor cells (NPCs) from the adult subventricular zone (SVZ) can also generate new oligodendrocytes after demyelination. However, the relative contribution of NPCs versus pOPCs to remyelination is unknown. We usedin vivogenetic fate mapping to assess the behavior of each progenitor type within the corpus callosi (CCs) of mice subjected to cuprizone-induced demyelination.Nestin-CreERT2andPdgfra-CreERT2transgenic mice were crossed with fluorescent Cre reporter strains to map the fate of NPCs and pOPCs respectively. In cuprizone-challenged mice, substantial numbers of NPCs migrated into the demyelinated CC and contributed to oligodendrogenesis. This capacity was most prominent in rostral regions adjacent to the SVZ where NPC-derived oligodendrocytes significantly outnumbered those generated from pOPCs. Sixty-two percent of all nodes of Ranvier in this region were flanked by at least one paranode generated from an NPC-derived oligodendrocyte. Remarkably, g-ratios (ratio of the axon diameter to the diameter of the axon plus myelin sheath) of myelinated axons in regions subject to significant NPC-derived remyelination were equivalent to those of unchallenged controls, and immunoelectron microscopy revealed that NPC-derived myelin was significantly thicker than that generated by pOPCs, regardless of axonal caliber. We also demonstrate that a reduced efficiency of remyelination in the caudal CC was associated with long-term impairment in the maturation of oligodendrogenic NPCs but only transient delay in pOPC differentiation. Collectively, our data define a major distinct role for NPCs in remyelination, identifying them as a key target for enhancing myelin repair in demyelinating diseases.

The critical role of oligodendrocytes in producing and maintaining myelin that supports rapid axonal conduction in CNS neurons is well established. More recently, additional roles for oligodendrocytes have been posited, including provision of trophic factors and metabolic support for neurons. To investigate the functional consequences of oligodendrocyte loss, we have generated a transgenic mouse model of conditional oligodendrocyte ablation. In this model, oligodendrocytes are rendered selectively sensitive to exogenously administered diphtheria toxin (DT) by targeted expression of the diphtheria toxin receptor in oligodendrocytes. Administration of DT resulted in severe clinical dysfunction with an ascending spastic paralysis ultimately resulting in fatal respiratory impairment within 22 d of DT challenge. Pathologically, at this time point, mice exhibited a loss of ∼26% of oligodendrocyte cell bodies throughout the CNS. Oligodendrocyte cell-body loss was associated with moderate microglial activation, but no widespread myelin degradation. These changes were accompanied with acute axonal injury as characterized by structural and biochemical alterations at nodes of Ranvier and reduced somatosensory-evoked potentials. In summary, we have shown that a death signal initiated within oligodendrocytes results in subcellular changes and loss of key symbiotic interactions between the oligodendrocyte and the axons it ensheaths. This produces profound functional consequences that occur before the removal of the myelin membrane, i.e., in the absence of demyelination. These findings have clear implications for the understanding of the pathogenesis of diseases of the CNS such as multiple sclerosis in which the oligodendrocyte is potentially targeted.