Human-derived fecal microbiota transplantation alleviates social deficits of the BTBR mouse model of autism through a potential mechanism involving vitamin B6 metabolism.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition characterized by social communication deficiencies and stereotypic behaviors influenced by hereditary and/or environmental risk factors. There are currently no approved medications for treating the core symptoms of ASD. Human fecal microbiota transplantation (FMT) has emerged as a potential intervention to improve autistic symptoms, but the underlying mechanisms are not fully understood. In this study, we evaluated the effects of human-derived FMT on behavioral and multi-omics profiles of the BTBR mice, an established model for ASD. FMT effectively alleviated the social deficits in the BTBR mice and normalized their distinct plasma metabolic profile, notably reducing the elevated long-chain acylcarnitines. Integrative analysis linked these phenotypic changes to specific Bacteroides species and vitamin B6 metabolism. Indeed, vitamin B6 supplementation improved the social behaviors in BTBR mice. Collectively, these findings shed new light on the interplay between FMT and vitamin B6 metabolism and revealed a potential mechanism underlying the therapeutic role of FMT in ASD.IMPORTANCEAccumulating evidence supports the beneficial effects of human fecal microbiota transplantation (FMT) on symptoms associated with autism spectrum disorder (ASD). However, the precise mechanism by which FMT induces a shift in the microbiota and leads to symptom improvement remains incompletely understood. This study integrated data from colon-content metagenomics, colon-content metabolomics, and plasma metabolomics to investigate the effects of FMT treatment on the BTBR mouse model for ASD. The analysis linked the amelioration of social deficits following FMT treatment to the restoration of mitochondrial function and the modulation of vitamin B6 metabolism. Bacterial species and compounds with beneficial roles in vitamin B6 metabolism and mitochondrial function may further contribute to improving FMT products and designing novel therapies for ASD treatment.

Development of a reliable cell-based reporter gene assay to measure the bioactivity of anti-HER2 therapeutic antibodies.

Human epidermal growth factor receptor 2 (HER2) is a key player in the pathogenesis and progression of breast cancer and is currently a primary target for breast cancer immunotherapy. Bioactivity determination is necessary to guarantee the safety and efficacy of therapeutic antibodies targeting HER2. Nevertheless, currently available bioassays for measuring the bioactivity of anti-HER2 mAbs are either not representative or have high variability. Here, we established a reliable reporter gene assay (RGA) based on T47D-SRE-Luc cell line that expresses endogenous HER2 and luciferase controlled by serum response element (SRE) to measure the bioactivity of anti-HER2 antibodies. Neuregulin-1 (NRG-1) can lead to the heterodimerization of HER2 on the cell membrane and induce the expression of downstream SRE-controlled luciferase, while pertuzumab can dose-dependently reverse the reaction, resulting in a good dose-response curve reflecting the activity of the antibody. After optimizing the relevant assay parameters, the established RGA was fully validated based on ICH-Q2 (R1), which demonstrated that the method had excellent specificity, accuracy, precision, linearity, and stability. In summary, this robust and innovative bioactivity determination assay can be applied in the development and screening, release control, biosimilar assessment and stability studies of anti-HER2 mAbs.

Adenosine mediates the amelioration of social novelty deficits during rhythmic light treatment of 16p11.2 deletion female mice.

Non-invasive brain stimulation therapy for autism spectrum disorder (ASD) has shown beneficial effects. Recently, we and others demonstrated that visual sensory stimulation using rhythmic 40 Hz light flicker effectively improved cognitive deficits in mouse models of Alzheimer's disease and stroke. However, whether rhythmic visual 40 Hz light flicker stimulation can ameliorate behavioral deficits in ASD remains unknown. Here, we show that 16p11.2 deletion female mice exhibit a strong social novelty deficit, which was ameliorated by treatment with a long-term 40 Hz light stimulation. The elevated power of local-field potential (LFP) in the prefrontal cortex (PFC) of 16p11.2 deletion female mice was also effectively reduced by 40 Hz light treatment. Importantly, the 40 Hz light flicker reversed the excessive excitatory neurotransmission of PFC pyramidal neurons without altering the firing rate and the number of resident PFC neurons. Mechanistically, 40 Hz light flicker evoked adenosine release in the PFC to modulate excessive excitatory neurotransmission of 16p11.2 deletion female mice. Elevated adenosine functioned through its cognate A1 receptor (A1R) to suppress excessive excitatory neurotransmission and to alleviate social novelty deficits. Indeed, either blocking the A1R using a specific antagonist DPCPX or knocking down the A1R in the PFC using a shRNA completely ablated the beneficial effects of 40 Hz light flicker. Thus, this study identified adenosine as a novel neurochemical mediator for ameliorating social novelty deficit by reducing excitatory neurotransmission during 40 Hz light flicker treatment. The 40 Hz light stimulation warrants further development as a non-invasive ASD therapeutics.

Diagnostic performance of dynamic contrast-enhanced magnetic resonance imaging parameters and serum tumor markers in rectal carcinoma prognosis.

BACKGROUND: Rectal carcinoma (RC), one of the most common malignancies globally, presents an increasing incidence and mortality year by year, especially among young people, which seriously affects the prognosis and quality of life of patients. At present, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters and serum carbohydrate antigen 19-9 (CA19-9) and CA125 Levels have been used in clinical practice to evaluate the T stage and differentiation of RC. However, the accuracy of these evaluation modalities still needs further research. This study explores the application and value of these methods in evaluating the T stage and differentiation degree of RC. AIM: To analyze the diagnostic performance of DCE-MRI parameters combined with serum tumor markers (TMs) in assessing pathological processes and prognosis of RC patients. METHODS: A retrospective analysis was performed on 104 RC patients treated at Yantai Yuhuangding Hospital from May 2018 to January 2022. Patients were categorized into stages T1, T2, T3, and T4, depending on their T stage and differentiation degree. In addition, they were assigned to low (L group) and moderate-high differentiation (M + H group) groups based on their differentiation degree. The levels of DCE-MRI parameters and serum CA19-9 and CA125 in different groups of patients were compared. In addition, the value of DCE-MRI parameters [volume transfer constant (Ktrans), rate constant (Kep), and extravascular extracellular volume fraction (Ve) in assessing the differentiation and T staging of RC patients was discussed. Furthermore, the usefulness of DCE-MRI parameters combined with serum CA19-9 and CA125 Levels in the evaluation of RC differentiation and T staging was analyzed. RESULTS: Ktrans, Ve, CA19-9 and CA125 were higher in the high-stage group and L group than in the low-stage group and M + H Group, respectively (P < 0.05). The areas under the curve (AUCs) of the Ktran and Ve parameters were 0.638 and 0.694 in the diagnosis of high and low stages, respectively, and 0.672 and 0.725 in diagnosing moderate-high and low differentiation, respectively. The AUC of DCE-MRI parameters (Ktrans + Ve) in the diagnosis of high and low stages was 0.742, and the AUC in diagnosing moderate-high and low differentiation was 0.769. The AUCs of CA19-9 and CA-125 were 0.773 and 0.802 in the diagnosis of high and low stages, respectively, and 0.834 and 0.796 in diagnosing moderate-high and low differentiation, respectively. Then, we combined DCE-MRI (Ktrans + Ve) parameters with CA19-9 and CA-125 and found that the AUC of DCE-MRI parameters plus serum TMs was 0.836 in the diagnosis of high and low stages and 0.946 in the diagnosis of moderate-high and low differentiation. According to the Delong test, the AUC of DCE-MRI parameters plus serum TMs increased significantly compared with serum TMs alone in the diagnosis of T stage and differentiation degree (P < 0.001). CONCLUSION: The levels of the DCE-MRI parameters Ktrans and Ve and the serum TMs CA19-9 and CA125 all increase with increasing T stage and decreasing differentiation degree of RC and can be used as indices to evaluate the differentiation degree of RC in clinical practice. Moreover, the combined evaluation of the above indices has a better effect and more obvious clinical value, providing important guiding importance for clinical condition judgment and treatment selection.

Multi-Emission Carbon Dots Combining Turn-On Sensing and Fluorescence Quenching Exhibit Ultrahigh Selectivity for Mercury in Real Water Samples.

Mercury is a ubiquitous heavy-metal pollutant and poses serious ecological and human-health risks. There is an ever-growing demand for rapid, sensitive, and selective detection of mercury in natural waters, particularly for regions lacking infrastructure specialized for mercury analysis. Here, we show that a sensor based on multi-emission carbon dots (M-CDs) exhibits ultrahigh sensing selectivity toward Hg(II) in complex environmental matrices, tested in the presence of a range of environmentally relevant metal/metalloid ions as well as natural and artificial ligands, using various real water samples. By incorporating structural features of calcein and folic acid that enable tunable emissions, the M-CDs couple an emission enhancement at 432 nm and a simultaneous reduction at 521 nm, with the intensity ratio linearly related to the Hg(II) concentration up to 1200 µg/L, independent of matrix compositions. The M-CDs have a detection limit of 5.6 µg/L, a response time of 1 min, and a spike recovery of 94 ± 3.7%. The intensified emission is attributed to proton transfer and aggregation-induced emission enhancement, whereas the quenching is due to proton and electron transfer. These findings also have important implications for mercury identification in other complex matrices for routine, screening-level food safety and health management practices.

The effects of repeated freezing and thawing on bovine sperm morphometry and function.

Refreezing the remaining genetic resources after in vitro fertilization (IVF) can conserve genetic materials. However, the precise damage inflicted by repeated freezing and thawing on bovine sperm and its underlying mechanism remain largely unexplored. Thus, this study investigates the impact of repeated freeze-thaw cycles on sperm. Our findings indicate that such cycles significantly reduce sperm viability and motility. Furthermore, the integrity of the sperm plasma membrane and acrosome is compromised during this process, exacerbating the advanced apoptosis triggered by oxidative stress. Additionally, transmission electron microscopy exposed severe damage to the plasma membranes of both the sperm head and tail. Notably, the "9 + 2" structure of the tail was disrupted, along with a significant decrease in the level of the axonemal protein DNAH10, leading to reduced sperm motility. IVF outcomes revealed that repeated freeze-thaw cycles considerably impair sperm fertilization capability, ultimately reducing the blastocyst rate. In summary, our research demonstrates that repeated freeze-thaw cycles lead to a decline in sperm viability and motility, attributed to oxidative stress-induced apoptosis and DNAH10-related dynamic deficiency. As a result, the utility of semen is compromised after repeated freezing.

Thrombomodulin reduces α-synuclein generation and ameliorates neuropathology in a mouse model of Parkinson's disease.

The neurotoxic α-synuclein (α-syn) oligomers play an important role in the occurrence and development of Parkinson's disease (PD), but the factors affecting α-syn generation and neurotoxicity remain unclear. We here first found that thrombomodulin (TM) significantly decreased in the plasma of PD patients and brains of A53T α-syn mice, and the increased TM in primary neurons reduced α-syn generation by inhibiting transcription factor p-c-jun production through Erk1/2 signaling pathway. Moreover, TM decreased α-syn neurotoxicity by reducing the levels of oxidative stress and inhibiting PAR1-p53-Bax signaling pathway. In contrast, TM downregulation increased the expression and neurotoxicity of α-syn in primary neurons. When TM plasmids were specifically delivered to neurons in the brains of A53T α-syn mice by adeno-associated virus (AAV), TM significantly reduced α-syn expression and deposition, and ameliorated the neuronal apoptosis, oxidative stress, gliosis and motor deficits in the mouse models, whereas TM knockdown exacerbated these neuropathology and motor dysfunction. Our present findings demonstrate that TM plays a neuroprotective role in PD pathology and symptoms, and it could be a novel therapeutic target in efforts to combat PD. Schematic representation of signaling pathways of TM involved in the expression and neurotoxicity of α-syn. A TM decreased RAGE, and resulting in the lowered production of p-Erk1/2 and p-c-Jun, and finally reduce α-syn generation. α-syn oligomers which formed from monomers increase the expression of p-p38, p53, C-caspase9, C-caspase3 and Bax, decrease the level of Bcl-2, cause mitochondrial damage and lead to oxidative stress, thus inducing neuronal apoptosis. TM can reduce intracellular oxidative stress and inhibit p53-Bax signaling by activating APC and PAR-1. B The binding of α-syn oligomers to TLR4 may induce the expression of IL-1ß, which is subsequently secreted into the extracellular space. This secreted IL-1ß then binds to its receptor, prompting p65 to translocate from the cytoplasm into the nucleus. This translocation downregulates the expression of KLF2, ultimately leading to the suppression of TM expression. By Figdraw.

Mouse serum albumin induces neuronal apoptosis and tauopathies.

The elderly frequently present impaired blood-brain barrier which is closely associated with various neurodegenerative diseases. However, how the albumin, the most abundant protein in the plasma, leaking through the disrupted BBB, contributes to the neuropathology remains poorly understood. We here demonstrated that mouse serum albumin-activated microglia induced astrocytes to A1 phenotype to remarkably increase levels of Elovl1, an astrocytic synthase for very long-chain saturated fatty acids, significantly promoting VLSFAs secretion and causing neuronal lippoapoptosis through endoplasmic reticulum stress response pathway. Moreover, MSA-activated microglia triggered remarkable tau phosphorylation at multiple sites through NLRP3 inflammasome pathway. Intracerebroventricular injection of MSA into the brains of C57BL/6J mice to a similar concentration as in patient brains induced neuronal apoptosis, neuroinflammation, increased tau phosphorylation, and decreased the spatial learning and memory abilities, while Elovl1 knockdown significantly prevented the deleterious effect of MSA. Overall, our study here revealed that MSA induced tau phosphorylation and neuron apoptosis based on MSA-activated microglia and astrocytes, respectively, showing the critical roles of MSA in initiating the occurrence of tauopathies and cognitive decline, and providing potential therapeutic targets for MSA-induced neuropathology in multiple neurodegenerative disorders.

Impacts of COVID-19 pandemic on the collection and use of blood and blood components in Taiwan.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has significantly impacted the supply and transfusion of blood components. This study aims to evaluate changes in blood collection and transfusions during the period following the nationwide Level 3 alert (May-July 2021). METHODS: We retrieved usage data for red blood cells (RBC) from the Taiwan National Health Insurance (NHI) database 2019-2021. RESULTS: During the Level 3 alert period, approximately 85% of COVID-19 cases (11,455/13,624) were in Taipei. In Taipei, blood collection declined by 26.34% and RBC transfusions decreased by 17.14% compared to pre-pandemic levels. RBC usage decreased across all service types, with a significant decrease observed in hematology/oncology by 15.62% (-483 patients, -2,425 units). In non-Taipei regions, blood collection declined by 12.54%, rebounding around one month earlier than in Taipei. The decline in RBC transfusions occurred one month later than in Taipei, with a much lower magnitude (4.57%). Strain on the blood supply occurred in May and June in both Taipei and non-Taipei regions. Among 7,532 hospitalized COVID-19 patients, approximately 6.9% patients required a total of 1,873 RBC transfusions. The rapid increase in COVID-19 inpatients did not significantly increase the burden of blood demands. SUMMARY: During the Level 3 alert, the most significant decline in both RBC collection and transfusions was observed in Taipei. In non-Taipei regions, the decrease in RBC use was only marginal. Notably, there was a significant decrease in RBC use in hematology/oncology in Taipei. This study supports transfusion specialists in seeking efficient ways to address similar future challenges.

Soil amendments reduce CH4 and CO2 but increase N2O and NH3 emissions in saline-alkali paddy fields.

Limited research has been conducted on ammonia (NH3) volatilization and greenhouse gases (GHGs) emissions in saline-alkali paddy fields, along with complex interaction involving various genes (16sRNA, amoA, narG, nirK, nosZ, and nifH). This study employed mesocosm-scale experiment to investigate NH3 volatilization and GHGs emissions, focusing on bacterial communities and genic abundance, in saline-alkali paddy fields with desulfurized gypsum (DG) and organic fertilizer (OF) amendments. Compared to the control (CK) treatment, DG and OF treatments reduced methane (CH4) and carbon dioxide (CO2) emissions by 78.05 % and 26.18 %, and 65.84 % and 11.62 %, respectively. However, these treatments increased NH3 volatilization by 26.26 % and 45.23 %, and nitrous oxide (N2O) emission by 41.00 % and 12.31 %. Notably, NH3 volatilization primarily stemmed from ammonia nitrogen (NH4+-N), rather than total nitrogen (TN) in soil and water. N2O was mainly produced from nitrate nitrogen (NO3--N) in soil and water, as well as NH4+-N in water. The increase in NH3 volatilization and N2O emission in DG and OF treatments, was attributed to the reduced competition among bacterial communities, rather than the increased bacterial activity and genic copies. These findings offer valuable insights for managing nutrient loss and gaseous emissions in saline-alkali paddy fields.

Portably and Visually Sensing Cytisine through Smartphone Scanning Based on a Post-Modified Luminescence Center Strategy in Zinc-Organic Frameworks.

Cytisine (CTS) is a useful medicine for treating nervous disorders and smoking addiction, and exploring a convenient method to detect CTS is of great significance for long-term/home medication to avoid the risk of poisoning, but it is full of challenges. Here, a modified metal-organic framework sensor Tb@Zn-TDA-80 with dual emission centers was prepared using a post-modified luminescence center strategy. The obtained Tb@Zn-TDA-80 can serve as a CTS sensor with high sensitivity and selectivity. To achieve portable detection, Tb@Zn-TDA-80 was further fabricated as a membrane sensor, M-Tb@Zn-TDA-80, which displayed an obvious CTS-responsive color change by simply dropping a CTS solution onto its surface. Benefiting from this unique functionality, M-Tb@Zn-TDA-80 successfully realized the visual detection and quantitative monitoring of CTS in the range of 5.26-52.6 mM by simply scanning the color with a smartphone. The results of nuclear magnetic resonance spectroscopy and theoretical computation illustrated that the high sensing efficiency of Tb@Zn-TDA-80 for CTS was attributed to the N-H⋅⋅⋅π and π⋅⋅⋅π interactions between the ligand and CTS. And luminescence quenching may result from the intramolecular charge transfer. This study provides a convenient method for ensuring long-term medication safety at home.

NGF facilitates ICAM-1-dependent monocyte adhesion and M1 macrophage polarization in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder in which monocytes adhering to synovial tissue differentiate into the pro-inflammatory M1 macrophage phenotype. Nerve growth factors (NGF) referred to as neurotrophins have been associated with inflammatory events; however, researchers have yet to elucidate the role of NGF in RA. Our examination of clinical tissue samples and analysis of data sourced from the Gene Expression Omnibus dataset unveiled elevated expression levels of M1 macrophage markers in human RA synovial tissue samples compared to normal tissue, with no such distinction observed for M2 markers. Furthermore, immunofluorescence data depicted increased expression levels of NGF and M1 macrophages in RA mice in contrast to normal mice. It appears that NGF stimulation facilitates macrophage polarization from the M0 to the M1 phenotype. It also appears that NGF promotes ICAM-1 production in human RA synovial fibroblasts, which enhances monocyte adhesion through the TrkA, MEK/ERK, and AP-1 signaling cascades. Our findings indicate NGF/TrkA axis as a novel target for the treatment of RA.

Highly drug/target-tolerant neutralizing antibody (NAb) assay development through target-based drug depletion and drug-based NAb extraction for an anti-EGFR therapeutic monoclonal antibody.

The reduction of immunogenicity is fundamental for the development of biobetter Erbitux, given that the development of an immune response reduces treatment efficacy and may lead to potential side effects. One of the requirements for the clinical research of a Erbitux biobetter candidate (CMAB009) is to develop a neutralizing antibody (NAb) assay, and sufficient drug and target tolerance for the assay is necessary. Here, we describe the development of a competitive ligand binding (CLB) assay for CMAB009 with high drug and target tolerance through target-based drug depletion and drug-based NAb extraction, the integrated experimental strategy was implemented to simultaneously mitigate drug interference and enhance target tolerance. Following troubleshooting and optimization, the NAb assay was validated for clinical sample analysis with the sensitivity of 92 ng/mL, drug tolerance of 70 µg/mL and target tolerance of 798 ng/mL. The innovative drug depletion and NAb extraction achieved though the combination of drug and target beads would enable the development of reliable NAb assays for many other therapeutics that overcome drug and its target interference for more precise and sensitive NAb assessment.

Seroprevalence of Anti-SARS-CoV-2 Remained Extremely Low in Taiwan Until the Vaccination Program Was Implemented.

Background: The Taiwanese government made a concerted effort to contain a coronavirus disease 2019 (COVID-19) nosocomial outbreak of variant B.1.429, shortly before universal vaccination program implementation. This study aimed to investigate seroprevalence in the highest-risk regions. Methods: Between January and February 2021, we retrieved 10 000 repository serum samples from blood donors to examine for antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid (N) and spike (S) antigens. A positive result was confirmed if anti-N and anti-S antibodies were positive. Overall, 2000 donors residing in the highest-risk district and donating blood in January 2021 were further examined for SARS-CoV-2 RNA. We estimated seroprevalence and compared the epidemic curve between confirmed COVID-19 cases and blood donors with positive antibodies or viral RNA. Results: Twenty-one cases with COVID-19 were confirmed in the nosocomial cluster, with an incidence of 1.27/100 000 in the COVID-affected districts. Among 4888 close contacts of the nosocomial cases, 20 (0.4%) became confirmed cases during isolation. Anti-SARS-CoV-2 was detected in 2 of the 10000 blood donors, showing a seroprevalence of 2/10000 (95% CI, 0.55-7.29). None of the 2000 donors who underwent tests for SARS-CoV-2 RNA were positive. The SARS-CoV-2 infection epidemic curve was observed sporadically in blood donors compared with the nosocomial cluster. Conclusions: In early 2021, an extremely low anti-SARS-CoV-2 seroprevalence among blood donors was observed. Epidemic control measures through precise close contact tracing, testing, and isolation effectively contained SARS-CoV-2 transmission before universal vaccination program implementation.

The impact of digital transformation and earnings management on ESG performance: evidence from Chinese listed enterprises.

The improvement of enterprise ESG performance is one of the key driving forces to achieve the goal of economic and social green development. There is a gap between knowledge and practice in the ESG performance of Chinese enterprises, and digital transformation (DT) provides new ideas for ESG development. The research purpose of this paper is to explore the impact mechanism of DT on ESG and the specific path of DT to drive ESG. It provides a reference for listed enterprises to rely on DT to empower their sustainable development capability. This paper takes the panel data of A-share listed enterprises from 2011 to 2021 as the sample and measures the core indicators using the text mining method, modified Jones model, and Roy-Chowdhury model. On this basis, using a combination of econometric models and qualitative comparative analysis, we empirically analyze the impact mechanisms of DT on ESG as well as the specific grouping paths that drive ESG performance. The main conclusions are shown as follows. First, DT can significantly reduce ESG, with an impact coefficient of - 0.013, which is significant at the 5% level. It reflects that the DT of enterprises at this stage has certain deficiencies. There is a matching lag in the enterprise's internal organizational resources. The entry of digital technology will have a certain impact on traditional operations, and the high uncertainty of DT adds some hidden costs to the enterprise. Secondly, there is an indirect suppression effect of accrued earnings management (AEM) in the transmission mechanism of DT affecting ESG. It is verified that DT can reduce information asymmetry and inhibit EM activities, thus reducing the impact on ESG. Finally, a total of six configurations achieved high ESG valuations. High technology practice-low performance manipulation; digital intelligence-low performance manipulation; digital intelligence-digital resources; digital resources-inadequate digital infrastructure.; high technology practice-bottom technology deficiency; digital intelligence-high performance manipulation. Through configuration analysis, the suppression effect of EM is further verified. The lack of AEM is usually the core condition of the high-valuation group. Meanwhile, digital intelligence, digital resources, and digital technology practice can drive the improvement of enterprise ESG. The instrumental variables approach and robustness tests support these findings.

Inhibition of EphA4 reduces vasogenic edema after experimental stroke in mice by protecting the blood-brain barrier integrity.

Cerebral vasogenic edema, a severe complication of ischemic stroke, aggravates neurological deficits. However, therapeutics to reduce cerebral edema still represent a significant unmet medical need. Brain microvascular endothelial cells (BMECs), vital for maintaining the blood-brain barrier (BBB), represent the first defense barrier for vasogenic edema. Here, we analyzed the proteomic profiles of the cultured mouse BMECs during oxygen-glucose deprivation and reperfusion (OGD/R). Besides the extensively altered cytoskeletal proteins, ephrin type-A receptor 4 (EphA4) expressions and its activated phosphorylated form p-EphA4 were significantly increased. Blocking EphA4 using EphA4-Fc, a specific and well-tolerated inhibitor shown in our ongoing human phase I trial, effectively reduced OGD/R-induced BMECs contraction and tight junction damage. EphA4-Fc did not protect OGD/R-induced neuronal and astrocytic death. However, administration of EphA4-Fc, before or after the onset of transient middle cerebral artery occlusion (tMCAO), reduced brain edema by about 50%, leading to improved neurological function recovery. The BBB permeability test also confirmed that cerebral BBB integrity was well maintained in tMCAO brains treated with EphA4-Fc. Therefore, EphA4 was critical in signaling BMECs-mediated BBB breakdown and vasogenic edema during cerebral ischemia. EphA4-Fc is promising for the treatment of clinical post-stroke edema.

Hypoxia-regulated exosomes mediate M2 macrophage polarization and promote metastasis in chondrosarcoma.

Chondrosarcoma is a primary malignant bone tumor. Traditional therapy is not very effective, and it is prone to metastasis in the late stage. The tumor microenvironment (TME) plays a key role in the progression and metastasis of chondrosarcoma, and hypoxia is one of the key factors in the formation of TME. However, the detailed mechanism of how hypoxia affects tumor progression and metastasis in chondrosarcoma is still not fully understood. In this study, we focused on the mechanism of interaction between hypoxic chondrosarcoma cells (SW1353) and macrophages. Our results suggest that hypoxia enhances the release of exosomes from chondrosarcoma cells. These hypoxia-induced exosomes promoted macrophage polarization towards the M2 phenotype, characterized by the expression of CD163 and CD206, but not the M1 phenotype, characterized by CD86 expression. Further analysis revealed that M2 macrophages polarized by exosomes expressed arginase-1 and feedback to chondrosarcoma cells to promote migration. These results suggest that chondrosarcoma cells secrete more exosomes in a hypoxic microenvironment, and these hypoxia-derived exosomes induce the polarization of macrophages into an M2 phenotype, ultimately promoting the metastatic behavior of chondrosarcoma cells.

Rapamycin Exerts an Antidepressant Effect and Enhances Myelination in the Prefrontal Cortex of Chronic Restraint Stress Mice.

Depressive disorder is a psychiatric condition that is characterized by the core symptoms of anhedonia and learned helplessness. Myelination loss was recently found in the prefrontal cortex (PFC) of patients with depression and animal models, but the mechanism of this loss is unclear. In our previous study, chronic restraint stress (CRS) mice showed depressive-like symptoms. In this study, we found that myelin was reduced in the PFC of CRS mice. We also observed increased mammalian target of rapamycin (mTOR) phosphorylation levels in the PFC. Chronic injections of rapamycin, a mTOR complex inhibitor, prevented depressive behavior as shown by the forced swimming test and sucrose preference test. Rapamycin also increased myelination in the PFC of CRS mice. In summary, we found that CRS enhanced mTOR signaling and reduced myelination in the PFC and that rapamycin could prevent it. Our study provides the etiology of reduced myelin in depressive symptoms and suggests that mTOR signaling could be a target for treating depression or improving myelination deficits in depressive disorders.

Soil aggregate-driven changes in nutrient redistribution and microbial communities after 10-year organic fertilization.

Research studies on nutrient content and microbial communities after the application of organic manure have been reported, while available information about multi-interaction mechanisms of nutrient stoichiometry and microbial succession in soil aggregates remains limited. This work conducted a 10-year field experiment amended with cow manure (1.5 t/ha), during which the application of organic manure stimulated the fragmentation of soil macro-aggregates (>5 mm) and the agglomeration of soil micro-aggregates (<0.25 mm). Hence, the proportion of medium-size aggregates (0.25-5 mm) was increased in bulk soil, and there was an insignificant difference in the stability of soil aggregates. Meanwhile, the application of organic manure increased soil organic carbon (SOC), total nitrogen (TN) and phosphorus (TP) in all soil aggregate fractions. SOC, TN and TP were higher in micro-aggregates (<0.25 mm) after the application of organic manure, thus the dominating phylum of bacteria and fungi was more abundance in micro-aggregates due to the increase in nutrient level. During the organic fertilization process, fungal communities significantly changed because the variation of carbon-to-nitrogen ratio (C:N) in soil aggregates. Cultivated farmland in Northeast China showed a considerable capacity to sequestrate SOC during the organic fertilization process, but nitrogen may be a primary macro-element limiting soil productivity. Theoretically, organic manure amended with nitrogen fertilizer could be an effective measure to maintain microbial diversity and crop productivity in agro-ecosystems in Northeast China.