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This study aimed to investigate the roles of lysosome-related genes in BC prognosis and immunity. Transcriptome data from TCGA and MSigDB, along with lysosome-related gene sets, underwent NMF cluster analysis, resulting in two subtypes. Using lasso regression and univariate/multivariate Cox regression analysis, an 11-gene signature was successfully identified and verified. High- and low-risk populations were dominated by HR+ sample types. There were differences in pathway enrichment, immune cell infiltration, and immune scores. Sensitive drugs targeting model genes were screened using GDSC and CCLE. This study constructed a reliable prognostic model with lysosome-related genes, providing valuable insights for BC clinical immunotherapy.
Lysosome-related genes can be used to predict survival outcomes in BRCA patients.Significant differences were showed in the immune status of patient with different prognoses.Immunotherapy may show better therapeutic results in low-risk patients.The most promising targeted drugs in the low-risk group are mainly Lapatinib, Palbociclib and Ribociclib.
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Radical orchidectomy has been the standard surgery for testicular tumours. While a straightforward routine surgery, there are several finer points in the surgical technique and perioperative care that urologists should be familiar with. This mini-review discusses modifications to the conventional surgical approach such as organ-sparing surgery and the subinguinal approach, and practice points regarding prostheses and sperm banking that are pertinent to early management of a patient with a testicular tumour. PATIENT SUMMARY: We reviewed the evidence for surgical removal of a testicle for testicular cancer. There are a number of different techniques to minimise the extent of surgery. Surgeons should also discuss sperm banking and options for a testicular prosthesis with their patients.
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Entomopathogenic fungi, including Metarhizium species, represent promising environmentally friendly biopesticides. Understanding the molecular mechanisms governing their infection processes is vital for enhancing their effectiveness. Transcription factors (TFs) play critical roles in gene regulation, yet the functions of many TFs in M. robertsii remain unknown. Homeobox transcription factors, implicated in diverse cellular processes, have received limited attention in entomopathogenic fungi. Here, we identify and characterize, a homeobox TF, MrHOX7, in the model entomopathogenic fungus M. robertsii. Subcellular localization and transcriptional profiling revealed MrHOX7's nuclear localization and high expression during conidia and appressoria formation. Deletion of Mrhox7 (ΔMrhox7) enhanced conidial tolerance to heat and UV-B stress, accompanying with upregulated stress-related gene expression. Intriguingly, ΔMrhox7 exhibits inhibited virulence exclusively through topical inoculation. Further investigations unveiled reduced conidial adhesion and appressorium formation, with downregulation of the adhesion gene Mad1 and appressorium-related genes, as the underlying causes of the reduced fungal virulence. Our findings illuminate the role of MrHOX7 in stress tolerance and virulence, providing insights into the molecular basis of fungal biopesticides.
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Metarhizium , Fatores de Transcrição , Animais , Virulência/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Genes Homeobox , Agentes de Controle Biológico , Regulação Fúngica da Expressão Gênica , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Esporos Fúngicos/genéticaRESUMO
E-cadherin is an essential cellâcell adhesion protein that mediates canonical cadherin-catenin complex formation in epithelial lateral membranes. Ankyrin-G (AnkG), a scaffold protein linking membrane proteins to the spectrin-based cytoskeleton, coordinates with E-cadherin to maintain epithelial cell polarity. However, the molecular mechanisms governing this complex formation and its relationships with the cadherin-catenin complex remain elusive. Here, we report that AnkG employs a promiscuous manner to encapsulate three discrete sites of E-cadherin by the same region, a dynamic mechanism that is distinct from the canonical 1:1 molar ratio previously described for other AnkG or E-cadherin-mediated complexes. Moreover, we demonstrate that AnkG-binding-deficient E-cadherin exhibited defective accumulation at the lateral membranes and show that disruption of interactions resulted in cell polarity malfunction. Finally, we demonstrate that E-cadherin is capable of simultaneously anchoring to AnkG and ß-catenin, providing mechanistic insights into the functional orchestration of the ankyrin-spectrin complex with the cadherin-catenin complex. Collectively, our results show that complex formation between E-cadherin and AnkG is dynamic, which enables the maintenance of epithelial cell polarity by ensuring faithful targeting of the adhesion molecule-scaffold protein complex, thus providing molecular mechanisms for essential E-cadherin-mediated complex assembly at cellâcell junctions.
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Anquirinas , Polaridade Celular , Anquirinas/metabolismo , Caderinas/metabolismo , Adesão Celular , Células Epiteliais/metabolismo , Espectrina/metabolismo , HumanosRESUMO
Sensitivity and linearity are two crucial indices to assess the sensing capability of pressure sensors; unfortunately, the two mutually exclusive parameters usually result in limited applications. Although a series of microengineering strategies including micropatterned, multilayered, and porous approach have been provided in detail, the conflict between the two parameters still continues. Here, we present an efficient strategy to resolve this contradiction via modulus difference-induced embedding deformation. Both the microscopic observation and finite element simulation results confirm the embedding deformation behavior ascribed to the elastic modulus difference between soft electrode and rigid microstructures. The iontronic pressure sensor with high sensitivity (35 kPa-1) and wide linear response range (0-250 kPa) is further fabricated and demonstrates the potential applications in monitoring of high-fidelity pulse waveforms and human motion. This work provides an alternative strategy to guide targeted design of all-around and comprehensive pressure sensor.
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Here, we propose a fast and sensitive coulometric signal transduction method for ion-selective electrodes (ISEs) by utilizing a two-compartment cell. A potassium ion-selective electrode (K+-ISE) was connected as reference electrode (RE) and placed in the sample compartment. A glassy carbon (GC) electrode coated with poly(3,4-ethylenedioxythiophene) (GC/PEDOT), or reduced graphene oxide (GC/RGO), was connected as working electrode (WE) and placed in the detection compartment together with a counter electrode (CE). The two compartments were connected with an Ag/AgCl wire. The measured cumulated charge was amplified by increasing the capacitance of the WE. The observed slope of the cumulated charge with respect to the change of the logarithm of the K+ ion activity was linearly proportional to the capacitance of the GC/PEDOT and GC/RGO, estimated from impedance spectra. Furthermore, the sensitivity of the coulometric signal transduction using a commercial K+-ISE with internal filling solution as RE and GC/RGO as WE allowed to decrease the response time while still being able to detect a 0.2% change in K+ concentration. The coulometric method utilizing a two-compartment cell was found to be feasible for the determination of K+ concentrations in serum. The advantage of this two-compartment approach, compared to the coulometric transduction described earlier, was that no current passed through the K+-ISE that was connected as RE. Therefore, current-induced polarization of the K+-ISE was avoided. Furthermore, since the GCE/PEDOT and GCE/RGO (used as WE) had a low impedance, the response time of the coulometric response decreased from minutes to seconds.
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The highly variable response rates to immunotherapies underscore our limited knowledge about how tumors can manipulate immune cells. Here the membrane topology of natural killer (NK) cells from patients with liver cancer showed that intratumoral NK cells have fewer membrane protrusions compared with liver NK cells outside tumors and with peripheral NK cells. Dysregulation of these protrusions prevented intratumoral NK cells from recognizing tumor cells, from forming lytic immunological synapses and from killing tumor cells. The membranes of intratumoral NK cells have altered sphingomyelin (SM) content and dysregulated serine metabolism in tumors contributed to the decrease in SM levels of intratumoral NK cells. Inhibition of SM biosynthesis in peripheral NK cells phenocopied the disrupted membrane topology and cytotoxicity of the intratumoral NK cells. Targeting sphingomyelinase confers powerful antitumor efficacy, both as a monotherapy and as a combination therapy with checkpoint blockade.
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Células Matadoras Naturais , Neoplasias Hepáticas , Humanos , Sinapses Imunológicas , Citotoxicidade ImunológicaRESUMO
Developing efficient and recyclable membranes for water contaminant removal still remains a challenge in terms of practical applications. Herein, a recyclable membrane constituted of polyacrylonitrile-graphene and oxide-polydopamine was fabricated and demonstrated efficient adsorption capacities with respect to heavy metal ions (62.9 mg g-1 of Cu2+ ion, CuSO4 50 mg L-1) and organic dye molecules (306.7 mg g-1 of methylene blue and 339.6 mg g-1 of eriochrome black T, MB/EBT 50 mg L-1). The polyacrylonitrile fibers provide the skeleton of the membrane, while the graphene oxide and polydopamine endow the membrane with hydrophilicity, which is favorable for the adsorption of pollutants in water. Benefitting from the protonation and deprotonation effects of graphene oxide and polydopamine, the obtained membrane demonstrated promotion of the selective adsorption or desorption of pollutant molecules. This guarantees that the adsorbed pollutant molecules can be desorbed promptly from the membrane through simple pH adjustment, ensuring the reusability of the membrane. After ten adsorption-desorption cycles, the membrane could still maintain a desirable adsorption capacity. In addition, compared with other, similar membranes reported, this composite membrane displays the highest mechanical stability. This work puts forward an alternative strategy for recyclable membrane design and expects to promote the utilization of membrane techniques in practical wastewater treatment.
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OBJECTIVE: To observe the effect of acupuncture on endoplasmic reticulum calcium, apoptosis number and Caspase-12 protein expression in hippocampal neurons of convulsive rats, so as to explore its mechanisms underlying improvement of convulsion. METHODS: SD rats were randomly divided into normal control, model and acupuncture groups, with 36 rats in each group. Rats in the normal control group received intraperitoneal injection (i.p.) of normal saline (2 mL), and those of the other 2 groups received i.p. of pentylenetetrazole (50 mg/kg) for establishing convulsion model. Manual acupuncture stimulation was applied to "Baihui"(GV20) and "Dazhui"(GV14) for 30 min after modeling. The hippocampal tissues were taken at 2, 12 and 48 h after modeling. The endoplasmic reticulum Ca2+ concentration (optical density, OD) was detected by using fluorescence probe technique and laser confocal microscopy, and the number of apoptosis of hippocampal neurons at the 3 time points detected by using terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL) stain. The expression of Caspase-12 protein in hippocampus at 3 time points was observed by immunohistochemistry. RESULTS: In comparison with the normal group, the number of apoptotic cells of hippocampal neurons and the expression levels of Caspase-12 protein in hippocampus at 2, 12 and 48 h after seizures were obviously increased (P<0.01), and the OD value of Ca2+ at 3 time points significantly decreased (P<0.01) in the model group.Following acupuncture intervention, the increased levels of the number of apoptotic cells of hippocampal neurons and the expression of Caspase-12 protein in hippocampus at 3 time points and the decreased levels of OD value of Ca2+ at 3 time points were reversed in the acupuncture group (P<0.05, P<0.01). CONCLUSION: Acupuncture intervention is effective in reducing the apoptosis of hippocampal neurons in convulsion rats, which may be related to its functions in down-regulating Caspase-12 expression and promoting influx of Ca2+ in the hippocampal neurons.
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Terapia por Acupuntura , Lesões Encefálicas , Cálcio/metabolismo , Animais , Caspase 12 , Retículo Endoplasmático , Hipocampo , Neurônios , Ratos , Ratos Sprague-Dawley , ConvulsõesRESUMO
Wearable sensors reflect the real-time physiological information and health status of individuals by continuously monitoring biochemical markers in biological fluids, including sweat, tears and saliva, and are a key technology to realize portable personalized medicine. Flexible electrochemical pH sensors can play a significant role in health since the pH level affects most biochemical reactions in the human body. pH indicators can be used for the diagnosis and treatment of diseases as well as the monitoring of biological processes. The performances and applications of wearable pH sensors depend significantly on the properties of the pH-sensitive materials used. At present, existing pH-sensitive materials are mainly based on polyaniline (PANI), hydrogen ionophores (HIs) and metal oxides (MOx). In this review, we will discuss the recent progress in wearable pH sensors based on these sensitive materials. Finally, a viewpoint for state-of-the-art wearable pH sensors and a discussion of their existing challenges are presented.
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Here, we developed a wearable electrochemical sensor for pH and K+ monitoring in sweat. The sensor was composed of flexible reference electrode, pH response electrode and K+ selective electrode, which were prepared through printing ß-CD functionalized graphene (ß-CD/RGO) water suspension on conductive PET substrate with microelectronic printer. ß-CD/RGO not only served as the pH sensitive material for pH response electrode with good sensitivity, selectivity and reproducibility due to its abundant oxygen-containing functional groups, but also worked as the ion-to-electron transducer for K+ selective electrode with good sensitivity. The wearable sensor exhibited good potential stability at different bending states. On-body sweat pH and K+ measurements showed high accuracy compared with ex-situ analysis.
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Técnicas Biossensoriais , Grafite , Dispositivos Eletrônicos Vestíveis , Técnicas Eletroquímicas , Concentração de Íons de Hidrogênio , Íons , Potássio , Reprodutibilidade dos Testes , SuorRESUMO
Thermally activated delayed fluorescence (TADF) light-emitting electrochemical cells (TADF-LECs) are appealing due to their simple sandwich structure and potential applications in wearable displays and sensors. However, achieving high performance remains challenging. In this paper, we demonstrate that the use of TADF emitters with a low aggregated-caused quenching (ACQ) tendency is crucial to address this challenge. To verify it, two types of TADF-LECs are compared in parallel using different kinds of TADF emitters. The control device uses 2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile (4CzIPN) as the dopant, which suffers from a serious ACQ issue and thus dramatically limits the doping concentrations of 4CzIPN in these TADF-LECs. At the best doping condition (0.5 wt %), insufficient host-to-dopant energy transfer (ET) does exist, thereby displaying very limited efficiency and luminance, i.e., 2.43% and 1483 cd m-2. By contrast, the TADF-LECs using 3,6-di(tert-butyl)-1,8-di(4-(bis(4-(tert-butyl)phenyl)amino)phenyl)-9-(4-(4,6-diphenyl-1,3,5-triazin-2-yl) phenyl) carbazole (BPAPTC) can tolerate a much higher doping concentration because BPAPTC is a satisfactory TADF emitter featuring a low ACQ tendency. At the optimized doping condition of 18 wt %, the BPAPTC-based emissive layer possesses the best TADF property, including the longest τDF (2646 ns), the largest rDF (69%), and the highest kRISC of 7.50 × 105 s-1. Moreover, the corresponding TADF-LEC simultaneously displays the most efficient host-to-dopant ET. It thus achieves unprecedented performance, e.g., the highest external quantum efficiency (EQEmax.) of 7.6%, the highest luminance (Lmax.) of 3696 cd m-2, and an EQE of 7.01% at a practical high luminance of 1000 cd m-2.
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Heterotrimeric G-proteins are crucial for fungal growth and differentiation. The α subunits of heterotrimeric G-proteins play an essential role in controlling signal transduction. However, the function of G-protein α subunits in entomopathogenic fungi remains poorly understood. Two group II Gα subunits (MrGPA2 and MrGPA4) were characterized in the entomopathogenic fungus, Metarhizium robertsii. Bioinformatics analysis showed that the relationship between MrGPA2 and MrGPA4 was closer than that of other MrGPAs. Both green fluorescent protein (GFP)-tagged MrGPA2 and MrGPA4 were localized at the cytoplasm. Furthermore, ∆MrGpa2∆MrGpa4 double mutants showed remarkably reduced vegetative growth compared to the wild-type and single-mutant strains, which was accompanied by the downregulation of several growth-related genes, such as ssk2, pbs2, stuA, hog1, and ac. Only the ∆MrGpa2∆MrGpa4 double mutant was sensitive to Congo red stress. The insect bioassay demonstrated significantly attenuated virulence for the ∆MrGpa2∆MrGpa4 double mutant compared to the wild-type and single-mutant strains. Further analysis indicated that double deletion of MrGpa2 and MrGpa4 had no effect on appressorium formation but suppressed the expression levels of several virulence-related genes in the insect hemocoel. These findings demonstrate that MrGpa2 and MrGpa4 exhibit functional redundancy and contribute to the vegetative growth, stress tolerance, and pest control potential in M. robertsii.
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The aqueous alkaline rechargeable batteries (AARBs) have an attractive potential for electrochemical energy storage devices. In view of the advantages of high theoretical capacity and desirable negative operating window, bismuth (Bi) has been deemed as a hopeful anode material for AARBs. Unfortunately, intensive reported works of Bi anode are still confronted with limited capacity and poor cycling stability. Herein, the designed electrodes of different size Bi nanoparticles embedded in porous carbon nanofibers with a contrasting nitrogen doping content are obtained by electrospinning and thermal treatment processes. The effect of the N dopant in carbon shell is demonstrated on the Bi core, which is in favor of enhancing the capacity of Bi anodes. More importantly, the core structure with highly dispersed ultrasmall Bi nanoparticles (<20 nm) in carbon matrix plays a crucial role in long-term durability. Accordingly, the optimized polydisperse ultrasmall Bi nanoparticles confined in N-rich porous carbon nanofibers electrode (Bi@NPCF) presents an admirable capacity of 196.1 mAh g-1 at 3 A g-1 and outstanding durable lifespan (retain 116.95% after 10 000 cycles). In addition, the fabricated Bi@NPCF//NiCo2 O4 battery exhibits an exceptional energy and power density with durable stability (95.9% after 5000 cycles).
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Septins are a family of filament-forming GTP-binding proteins that regulate fundamental cellular activities, such as cytokinesis and cell polarity. In general, septin filaments function as barriers and scaffolds on the cell cortex. However, little is known about the mechanism that governs the recruitment and localization of the septin complex to the cell cortex. Here, we identified the Cdc42 GTPase-activating protein Rga6 as a key protein involved in promoting the localization of the septin complex to the cell cortex in the fission yeast Schizosaccharomyces pombe. Rga6 interacts with the septin complex and partially colocalizes with the septin complex on the cell cortex. Live-cell microscopy analysis further showed septin enrichment at the cortical regions adjacent to the growing cell tip. The septin enrichment likely plays a crucial role in confining active Cdc42 to the growing cell tip. Hence, our findings support a model whereby Rga6 regulates polarized cell growth partly through promoting targeted localization of the septin complex on the cell cortex. This article has an associated First Person interview with the first author of the paper.
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Proteínas Ativadoras de GTPase , Proteínas de Schizosaccharomyces pombe , Schizosaccharomyces , Septinas , Citocinese/genética , Proteínas Ativadoras de GTPase/genética , Proteínas Ativadoras de GTPase/metabolismo , Schizosaccharomyces/genética , Schizosaccharomyces/metabolismo , Proteínas de Schizosaccharomyces pombe/genética , Proteínas de Schizosaccharomyces pombe/metabolismo , Septinas/genética , Septinas/metabolismoRESUMO
Detection of heavy metal ions (HMIs) in water is an important topic in the field of analytical chemistry and environmental science. Fluorescence spectroscopy is one of the most promising strategies due to its simple instrument, low investment, rapid and convenient operation. However, current fluorescence probes for detecting HMIs are typically selective for certain ions. Herein we reported the development of a novel strategy that determined the total content of HMIs in water by fluorescence spectroscopy. A novel fluorescent nitrogen, sulfur co-doped carbon quantum dots (N, S-CQDs) was prepared via graphene oxide-assisted synthesis method. The results showed that, with the fluorescence quenching strategy, N, S-CQDs exhibited a wide linear response to a series of water-soluble metal ions. The fluorescence of N, S-CQDs is stable in a wide range of pH 4-11. The detection mechanism was proved that the integration, caused by coordination interaction between S element in N, S-CQDs and the d-orbital of associated metal ions, was the main reason for fluorescence quenching. In practice, the N, S-CQDs were applied to determine total content of HMIs in water successfully. Interestingly, further experiment proved that the N, S-CQDs could effectively remove HMIs in water after centrifuging and filtering thoroughly. It was shown that the fluorescence of N, S-CQDs was obviously quenched by the multiple-ions-involved water and scavenging effect of N, S-CQDs on HMIs with centrifugal in which the concentration of individuals meets the Chinese National Standard. This indicates that the N, S-CQDs are of a wide application prospect in water quality analysis.
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Metais Pesados , Pontos Quânticos , Carbono/química , Grafite , Humanos , Íons , Nitrogênio/química , Espectrometria de Fluorescência/métodosRESUMO
A complete diagnostic autopsy is the gold-standard to gain insight into Coronavirus disease 2019 (COVID-19) pathogenesis. To delineate the in situ immune responses to SARS-CoV-2 viral infection, here we perform comprehensive high-dimensional transcriptional and spatial immune profiling in 22 COVID-19 decedents from Wuhan, China. We find TIM-3-mediated and PD-1-mediated immunosuppression as a hallmark of severe COVID-19, particularly in men, with PD-1+ cells being proximal rather than distal to TIM-3+ cells. Concurrently, lymphocytes are distal, while activated myeloid cells are proximal, to SARS-CoV-2 viral antigens, consistent with prevalent SARS-CoV-2 infection of myeloid cells in multiple organs. Finally, viral load positively correlates with specific immunosuppression and dendritic cell markers. In summary, our data show that SARS-CoV-2 viral infection induces lymphocyte suppression yet myeloid activation in severe COVID-19, so these two cell types likely have distinct functions in severe COVID-19 disease progression, and should be targeted differently for therapy.
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COVID-19/imunologia , SARS-CoV-2/fisiologia , Idoso , Autopsia , COVID-19/diagnóstico , COVID-19/genética , COVID-19/virologia , China , Diagnóstico , Feminino , Receptor Celular 2 do Vírus da Hepatite A/genética , Receptor Celular 2 do Vírus da Hepatite A/imunologia , Humanos , Terapia de Imunossupressão , Ativação Linfocitária , Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Células Mieloides/imunologia , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , SARS-CoV-2/imunologia , Carga ViralRESUMO
OBJECTIVE: To observe the effect of acupuncture serum on the expression of microtubule associated protein-2 (MAP-2) and nerve growth associated protein-43 (GAP-43) in cultured hippocampal neurons of convulsive rats. METHODS: The acute convulsion model was induced by intraperitoneal injection of pentylenetetrazol in SD rats who were then randomized into model group and acupuncture group. Rats of the acupuncture group received manual acupuncture stimulation of "Baihui" (GV20) and "Dazhui" (GV14) for 30 min, once daily for 7 days. Then, the blood samples taken from the abdominal aorta of rats in the convulsion model and acupuncture groups were processed into serum samples, i.e. non-acupuncture serum and acupuncture se-rum. The primary-cultured hippocampal neurons of fetal rats were cultured for 10 days and then divided into normal extracellular fluid (normal) group, magnesium (Mg2+) free extracellular fluid group, acupuncture serum group and non-acupuncture serum group. At the 10th day, the neurons in the normal group were cultured continuously in extracellular fluid for 3 h, and then cultured in DMEM/F12(1â¶1) medium (planting fluid); neurons in the Mg2+ free group were cultured in magnesium-free fluid medium to induce epileptic-like discharge; neurons in the acupuncture serum group were cultured in the mixed medium of planting fluid and 10% acupuncture serum; and neurons in the non-acupuncture serum were cultured in the mixed culture medium of planting fluid and non-acupuncture serum (10%). At last, these neurons in the above-mentioned groups were cultured in the magnesium-free extracellular fluid continuously for 2, 12 and 48 h, respectively, followed by detecting the expression levels of MAP-2 and GAP-43 proteins at the 3 time points by using immunofluorescence and Western blot, separately. RESULTS: The rate of MAP-2 positive cells and protein expression at 2, 12 and 48 h, and the rate of GAP-43 positive cells and protein expression at 12 and 48 h in the hippocampal neurons were significantly down-regulated in the Mg2+ free group in contrast to the normal group (P<0.05ï¼P<0.01). Compared to the Mg2+ free group, the rates of MAP-2 and GAP-43 positive cells and protein expression at 2, 12 and 48 h were considerably up-regulated in the acupuncture serum group (P<0.05ï¼P<0.01), but not in the non-acupuncture serum group (P>0.05). CONCLUSION: Acupuncture serum can significantly up-regulate the expression of MAP-2 and GAP-43 proteins in hip-pocampal neurons, which may play a positive role in improving synaptic plasticity and neuronal damage in convulsion rats.