π-Extended Nonfullerene Acceptor for Compressed Molecular Packing in Organic Solar Cells To Achieve over 20% Efficiency.

Organic photovoltaics (OPVs) suffer from a trade-off between efficient charge transport and suppressed nonradiative recombination due to the aggregation-induced luminance quenching of organic semiconductors. To resolve this grand challenge, a π-extended nonfullerene acceptor (NFA) B6Cl with large voids among the honeycomb network is designed and introduced into photovoltaic systems. We find that the presence of a small amount of (i.e., 0.5 or 1 wt %) B6Cl can compress the molecular packing of the host acceptor L8-BO, leading to shortened π-π stacking distance from 3.59 to 3.50 Å (that will improve charge transport) together with ordered alkyl chain packing (that will inhibit nonradiative energy loss due to the suppressed C-C and C-H bonds vibrations), as validated by high-energy X-ray scattering measurements. This morphology transformation ultimately results in simultaneously improved JSC, FF, and VOC of OPVs. As a result, the maximum PCEs of PM6:L8-BO and D18:L8-BO are increased from 19.1 and 19.3% to 19.8 and 20.2%, respectively, which are among the highest values for single-junction OPVs. The university of B6Cl to increase the performance of OPVs is further evidenced in a range of polymer:NFA OPVs.

Electrostatic Potential Design of Solid Additives for Enhanced Molecular Order of Polymer Donor in Efficient Organic Solar Cells.

Polymeric semiconducting materials struggle to achieve fast charge mobility due to low structural order. In this work, five 1H-indene-1,3(2H)dione-benzene structured halogenated solid additives namely INB-5F, INB-3F, INB-1F, INB-1Cl, and INB-1Br with gradually varied electrostatic potential are designed and utilized to regulate the structural order of polymer donor PM6. Molecular dynamics simulations demonstrate that although the dione unit of these additives tends to adsorb on the backbone of PM6, the reduced electrostatic potential of the halogen-substituted benzene can shift the benzene interacting site from alkyl side chains to the conjugated backbone of PM6, not only leading to enhanced π-π stacking in out-of-plane but also arising new π-π stacking in in-plane together with the appearance of multiple backbone stacking in out-of-plane, consequent to the co-existence of face-on and edge-on molecular orientations. This molecular packing transformation further translates to enhanced charge transport and suppressed carrier recombination in their photovoltaics, with a maximum power conversion efficiency of 19.4% received in PM6/L8-BO layer-by-layer deposited organic solar cells.

Prosaposin is a biomarker of mesenchymal glioblastoma and regulates mesenchymal transition through the TGF-ß1/Smad signaling pathway.

Mesenchymal glioblastoma (GBM) is the most aggressive subtype of GBM. Our previous study found that neurotrophic factor prosaposin (PSAP) is highly expressed and secreted in glioma and can promote the growth of glioma. The role of PSAP in mesenchymal GBM is still unclear. In this study, bioinformatic analysis, western blotting and RT-qPCR were used to detect the expression of PSAP in different GBM subtypes. Human glioma cell lines and patient-derived glioma stem cells were studied in vitro and in vivo, revealing that mesenchymal GBM expressed and secreted the highest level of PSAP among four subtypes of GBM, and PSAP could promote GBM invasion and epithelial-mesenchymal transition (EMT)-like processes in vivo and in vitro. Bioinformatic analysis and western blotting showed that PSAP mainly played a regulatory role in GBM invasion and EMT-like processes via the TGF-ß1/Smad signaling pathway. In conclusion, the overexpression and secretion of PSAP may be an important factor causing the high invasiveness of mesenchymal GBM. PSAP is therefore a potential target for the treatment of mesenchymal GBM. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Clinicopathological implications of TIM3+ tumor-infiltrating lymphocytes and the miR-455-5p/Galectin-9 axis in skull base chordoma patients.

Chordoma is difficult to eradicate due to high local recurrence rates. The immune microenvironment is closely associated with tumor prognosis; however, its role in skull base chordoma is unknown. The expression of Galectin-9 (Gal9) and tumor-infiltrating lymphocyte (TIL) markers was assessed by immunohistochemistry. Kaplan-Meier and multivariate Cox analyses were used to assessing local recurrence-free survival (LRFS) and overall survival (OS) of patients. MiR-455-5p was identified as a regulator of Gal9 expression. Immunopositivity for Gal9 was associated with tumor invasion (p = 0.019), Karnofsky performance status (KPS) score (p = 0.017), and total TIL count (p < 0.001); downregulation of miR-455-5p was correlated with tumor invasion (p = 0.017) and poor prognosis; and the T-cell immunoglobulin and mucin-domain 3 (TIM3)+ TIL count was associated with chordoma invasion (p = 0.010) and KPS score (p = 0.037). Furthermore, multivariate analysis indicated that only TIM3+ TIL density was an independent prognostic factor for LRFS (p = 0.010) and OS (p = 0.016). These results can be used to predict clinical outcome and provide a basis for immune therapy in skull base chordoma patients.

Clinical Application of Multimodal Neuronavigation System in Neuroendoscope-Assisted Skull Base Chordoma Resection.

Skull base chordoma is a rare tumor arising from embryonic remnants of the notochord with invasive potential. Due to the destruction of osseous landmarks and invasion of surrounding structures, surgical resection is challenging. The authors explored the clinical value of a multimodal neuronavigation system in skull base chordoma resection using a neuroendoscope. Between January 2012 and January 2016, the authors utilized neuroendoscopy to excise skull base chordoma in 93 patients. The authors performed 45 operations assisted by multimodal neuronavigation (neuronavigation group) and 48 without intraoperative imaging guidance (control group). In the control group, 35 patients (73%) underwent gross total resection. In the neuronavigation group, all patients underwent gross total resection without radiographically identified bleeding. Only 1 patient (2%) in the neuronavigation group showed a temporary reduction in vision, which improved after symptomatic treatment. In contrast, there were 4 patients (8%) with postoperative complication, including 2 patients with intracranial hematoma and 2 with neurological deficits. Complication rates were higher than the neuronavigation group. In the follow-up period, 2 patients in the control group with subtotal resection had recurrence within 24 months, but without extracranial metastases. The multimodal neuronavigation system could contribute intraoperative real-time guidance for spatial relationships between lesions and adjacent neurovascular structures, as well as eroded and distorted anatomical landmarks through multiple image fusion and 3-dimensional reconstruction. It significantly improves surgical outcome and provides a new insight into the management of skull base chordomas.

A longitudinal study on urinary cadmium and renal tubular protein excretion of nickel-cadmium battery workers after cessation of cadmium exposure.

PURPOSE: This study aimed to predict the outcome of urinary cadmium (Cd) excretion and renal tubular function by analyzing their evolution through 10 years after Cd exposure ceased. METHODS: Forty-one female, non-smoking workers were recruited from the year 2004 to 2009 when being removed from a nickel-cadmium battery factory, and they were asked to provide morning urine samples on three consecutive days at enrollment and in every follow-up year until 2014. Urinary Cd and renal tubular function biomarkers including urinary ß2-microglobulin (ß2-m) and retinol-binding protein (RBP) concentrations were determined with the graphite furnace atomic absorption spectrometry and the enzyme-linked immunosorbent assays, respectively. RESULTS: The medians of baseline Cd, ß2-m and RBP concentrations at enrollment were 6.19, 105.38 and 71.84 µg/g creatinine, respectively. Urinary ß2-m and RBP concentrations were both related to Cd concentrations over the years (ß absolute-ß2-m = 9.16, P = 0.008 and ß absolute-RBP = 6.42, P < 0.001, respectively). Cd, ß2-m and RBP concentrations in the follow-up years were all associated with their baseline concentrations (ß absolute-Cd = 0.61, P < 0.001; ß absolute-ß2-m = 0.64, P < 0.001; and ß absolute-RBP = 0.60, P < 0.001, respectively), and showed a decreasing tendency with the number of elapsed years relative to their baseline concentrations (ß relative-Cd = -0.20, P = 0.010; ß relative-ß2-m = -17.19, P = 0.002; and ß relative-RBP = -10.66, P < 0.001, respectively). CONCLUSIONS: Urinary Cd might eventually decrease to the general population level, and Cd-related tubular function would improve under the baseline conditions of this cohort.

Intervention of CXCL5 attenuated neuroinflammation and promoted neurological recovery after traumatic brain injury.

Neuroinflammation after traumatic brain injury (TBI) exhibits a strong correlation with neurological impairment, which is a crucial target for improving the prognosis of TBI patients. The involvement of CXCL5/CXCR2 signaling in the regulation of neuroinflammation in brain injury models has been documented. Therefore, the effects of CXCL5 on post-TBI neuroinflammation and its potential mechanisms need to be explored. Following TBI, C57BL/6 mice were administered intraperitoneal injections of a CXCL5 neutralizing antibody (Nab-CXCL5) (5 mg/kg, 2 times/day). Subsequently, the effects on neuroinflammation, nerve injury, and neurological function were assessed. Nab-CXCL5 significantly reduced the release of inflammatory factors, inhibited the formation of inflammatory microglia and astrocytes, and reduced the infiltration of peripheral immune cells in TBI mice. Additionally, this intervention led to a reduction in neuronal impairment and facilitated the restoration of sensorimotor abilities, as well as improvements in learning and memory functions. Peripheral administration of the Nab-CXCL5 to TBI mice could suppress neuroinflammation, reduce neurological damage, and improve neurological function. Our data suggest that neutralizing antibodies against CXCL5 (Nab-CXCL5) may be a promising agent for treating TBI.

Alkoxythiophene-Directed Fibrillization of Polymer Donor for Efficient Organic Solar Cells.

Realizing fibrillar molecular framework is highly encouraged in organic solar cells (OSCs) due to the merit of efficient charge carrier transport. This is however mainly achieved via the chemical structural design of photovoltaic semiconductors. In this work, through the utilization of three alkoxythiophene additives, T-2OMe, T-OEH, and T-2OEH, the intermolecular interactions among a series of BDT-type polymer donors, i.e., PM6, D18, PBDB-T, and PTB7-Th, are tuned to self-assemble into nanofibrils during solution casting. X-ray technique and molecular dynamics simulation reveal that the alkoxythiophene with (2-ethylhexyl)oxy (─OEH) chains can attach on the 2-ethylhexyl (EH) chains of these polymer donors and promote their self-assembly into 1D nanofibrils, in their neat films as well as photovoltaic blends with L8-BO. By adapting these fibrillar polymer donors to construct pseudo-bulk heterojunction (P-BHJ) OSCs via layer-by-layer deposition, generally improved device performance is seen, with power conversion efficiencies enhanced from 18.2% to 19.2% (certified 18.96%) and from 17.9% to 18.7% for the PM6/L8-BO and D18/L8-BO devices, respectively. This work provides a physical approach to promote the fibrillar charge transport channels for efficient photovoltaics.

Astrocyte-Derived Extracellular Vesicular miR-143-3p Dampens Autophagic Degradation of Endothelial Adhesion Molecules and Promotes Neutrophil Transendothelial Migration after Acute Brain Injury.

Pivotal roles of extracellular vesicles (EVs) in the pathogenesis of central nervous system (CNS) disorders including acute brain injury are increasingly acknowledged. Through the analysis of EVs packaged miRNAs in plasma samples from patients with intracerebral hemorrhage (ICH), it is discovered that the level of EVs packaged miR-143-3p (EVs-miR-143-3p) correlates closely with perihematomal edema and neurological outcomes. Further study reveals that, upon ICH, EVs-miR-143-3p is robustly secreted by astrocytes and can shuttle into brain microvascular endothelial cells (BMECs). Heightened levels of miR-143-3p in BMECs induce the up-regulated expression of cell adhesion molecules (CAMs) that bind to circulating neutrophils and facilitate their transendothelial cell migration (TEM) into brain. Mechanism-wise, miR-143-3p directly targets ATP6V1A, resulting in impaired lysosomal hydrolysis ability and reduced autophagic degradation of CAMs. Importantly, a VCAM-1-targeting EVs system to selectively deliver miR-143-3p inhibitor to pathological BMECs is created, which shows satisfactory therapeutic effects in both ICH and traumatic brain injury (TBI) mouse models. In conclusion, the study highlights the causal role of EVs-miR-143-3p in BMECs' dysfunction in acute brain injury and demonstrates a proof of concept that engineered EVs can be devised as a potentially applicable nucleotide drug delivery system for the treatment of CNS disorders.

The m6A methyltransferase METTL3 drives neuroinflammation and neurotoxicity through stabilizing BATF mRNA in microglia.

Persistent neuroinflammation and progressive neuronal loss are defining features of acute brain injury including traumatic brain injury (TBI) and cerebral stroke. Microglia, the most abundant type of brain-resident immune cells, continuously surveil the environment and play a central role in shaping the inflammatory state of the central nervous system (CNS). In the study, we discovered that the protein expression of METTL3 (a m6A methyltransferase) was upregulated in inflammatory microglia independent of increased Mettl3 gene transcription following TBI in both human and mouse subjects. Subsequently, we identified TRIP12, a HECT-domain E3 ubiquitin ligase, as a negative regulator of METTL3 protein expression by facilitating METTL3 K48-linked polyubiquitination. Importantly, selective ablation of Mettl3 inhibited microglial pathogenic activities, diminished neutrophil infiltration, rescued neuronal loss and facilitated functional recovery post-TBI. Using MeRIP-seq and CUT&Tag sequencing, we identified that METTL3 promoted the expression of Basic Leucine Zipper Transcriptional Factor ATF-Like (BATF), which in turn directly bound to a cohort of characteristic inflammatory cytokines and chemokine genes. Enhanced activities of BATF in microglia elicited TNF-dependent neurotoxicity and can also promote neutrophil recruitment through releasing CXCL2. Pharmacological inhibition of METTL3 using a BBB-penetrating drug-loaded nano-system showed satisfactory therapeutic effects in both TBI and stroke mouse models. Collectively, our findings identified METTL3-m6A-BATF axis as a potential therapeutic target for terminating detrimental neuroinflammation and progressive neuronal loss following acute brain injury. METTL3 protein is significantly up-regulated in inflammatory microglia due to the decreased proteasomal degradation mediated by TRIP12 and ERK-USP5 pathways. METTL3 stabilized BATF mRNA stability and promoted BATF expression through the m6A-IGF2BP2-dependent mechanism. Elevated expression of BATF elicits a pro-inflammatory gene program in microglia, and aggravates neuroinflammatory response including local immune responses and peripheral immune cell infiltration. Genetic deletion or pharmaceutically targeting METTL3-BATF axis suppressed microglial pro-inflammatory activities and promoted neurological recovery following TBI and stroke.

Clinical feasibility study of early 30-minute dynamic FDG-PET scanning protocol for patients with lung lesions.

PURPOSE: This study aimed to evaluate the clinical feasibility of early 30-minute dynamic 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) positron emission tomography (PET) scanning protocol for patients with lung lesions in comparison to the standard 65-minute dynamic FDG-PET scanning as a reference. METHODS: Dynamic 18F-FDG PET images of 146 patients with 181 lung lesions (including 146 lesions confirmed by histology) were analyzed in this prospective study. Dynamic images were reconstructed into 28 frames with a specific temporal division protocol for the scan data acquired 65 min post-injection. Ki images and quantitative parameters Ki based on two different acquisition durations [the first 30 min (Ki-30 min) and 65 min (Ki-65 min)] were obtained by applying the irreversible two-tissue compartment model using in-house Matlab software. The two acquisition durations were compared for Ki image quality (including visual score analysis and number of lesions detected) and Ki value (including accuracy of Ki, the value of differential diagnosis of lung lesions and prediction of PD-L1 status) by Wilcoxon's rank sum test, Spearman's rank correlation analysis, receiver operating characteristic (ROC) curve, and the DeLong test. The significant testing level (alpha) was set to 0.05. RESULTS: The quality of the Ki-30 min images was not significantly different from the Ki-65 min images based on visual score analysis (P > 0.05). In terms of Ki value, among 181 lesions, Ki-65 min was statistically higher than Ki-30 min (0.027 ± 0.017 ml/g/min vs. 0.026 ± 0.018 ml/g/min, P < 0.05), while a very high correlation was obtained between Ki-65 min and Ki-30 min (r = 0.977, P < 0.05). In the differential diagnosis of lung lesions, ROC analysis was performed on 146 histologically confirmed lesions, the area under the curve (AUC) of Ki-65 min, Ki-30 min, and SUVmax was 0.816, 0.816, and 0.709, respectively. According to the Delong test, no significant differences in the diagnostic accuracies were found between Ki-65 min and Ki-30 min (P > 0.05), while the diagnostic accuracies of Ki-65 min and Ki-30 min were both significantly higher than that of SUVmax (P < 0.05). In 73 (NSCLC) lesions with definite PD-L1 expression results, the Ki-65 min, Ki-30 min, and SUVmax in PD-L1 positivity were significantly higher than that in PD-L1 negativity (P < 0.05). And no significant differences in predicting PD-L1 positivity were found among Ki-65 min, Ki-30 min, and SUVmax (AUC = 0.704, 0.695, and 0.737, respectively, P > 0.05), according to the results of ROC analysis and Delong test. CONCLUSIONS: This study indicates that an early 30-minute dynamic FDG-PET acquisition appears to be sufficient to provide quantitative images with good-quality and accurate Ki values for the assessment of lung lesions and prediction of PD-L1 expression. Protocols with a shortened early 30-minute acquisition time may be considered for patients who have difficulty with prolonged acquisitions to improve the efficiency of clinical acquisitions.

An alternative extension of telomeres related prognostic model to predict survival in lower grade glioma.

OBJECTIVE: The alternative extension of the telomeres (ALT) mechanism is activated in lower grade glioma (LGG), but the role of the ALT mechanism has not been well discussed. The primary purpose was to demonstrate the significance of the ALT mechanism in prognosis estimation for LGG patients. METHOD: Gene expression and clinical data of LGG patients were collected from the Chinese Glioma Genome Atlas (CGGA) and the Cancer Genome Atlas (TCGA) cohort, respectively. ALT-related genes obtained from the TelNet database and potential prognostic genes related to ALT were selected by LASSO regression to calculate an ALT-related risk score. Multivariate Cox regression analysis was performed to construct a prognosis signature, and a nomogram was used to represent this signature. Possible pathways of the ALT-related risk score are explored by enrichment analysis. RESULT: The ALT-related risk score was calculated based on the LASSO regression coefficients of 22 genes and then divided into high-risk and low-risk groups according to the median. The ALT-related risk score is an independent predictor of LGG (HR and 95% CI in CGGA cohort: 5.70 (3.79, 8.58); in TCGA cohort: 1.96 (1.09, 3.54)). ROC analysis indicated that the model contained ALT-related risk score was superior to conventional clinical features (AUC: 0.818 vs 0.729) in CGGA cohorts. The results in the TCGA cohort also shown a powerful ability of ALT-related risk score (AUC: 0.766 vs 0.691). The predicted probability and actual probability of the nomogram are consistent. Enrichment analysis demonstrated that the ALT mechanism was involved in the cell cycle, DNA repair, immune processes, and others. CONCLUSION: ALT-related risk score based on the 22-gene is an important factor in predicting the prognosis of LGG patients.

Combining deep learning with a kinetic model to predict dynamic PET images and generate parametric images.

BACKGROUND: Dynamic positron emission tomography (PET) images are useful in clinical practice because they can be used to calculate the metabolic parameters (Ki) of tissues using graphical methods (such as Patlak plots). Ki is more stable than the standard uptake value and has a good reference value for clinical diagnosis. However, the long scanning time required for obtaining dynamic PET images, usually an hour, makes this method less useful in some ways. There is a tradeoff between the scan durations and the signal-to-noise ratios (SNRs) of Ki images. The purpose of our study is to obtain approximately the same image as that produced by scanning for one hour in just half an hour, improving the SNRs of images obtained by scanning for 30 min and reducing the necessary 1-h scanning time for acquiring dynamic PET images. METHODS: In this paper, we use U-Net as a feature extractor to obtain feature vectors with a priori knowledge about the image structure of interest and then utilize a parameter generator to obtain five parameters for a two-tissue, three-compartment model and generate a time activity curve (TAC), which will become close to the original 1-h TAC through training. The above-generated dynamic PET image finally obtains the Ki parameter image. RESULTS: A quantitative analysis showed that the network-generated Ki parameter maps improved the structural similarity index measure and peak SNR by averages of 2.27% and 7.04%, respectively, and decreased the root mean square error (RMSE) by 16.3% compared to those generated with a scan time of 30 min. CONCLUSIONS: The proposed method is feasible, and satisfactory PET quantification accuracy can be achieved using the proposed deep learning method. Further clinical validation is needed before implementing this approach in routine clinical applications.

Glioblastoma-associated microglia-derived exosomal circKIF18A promotes angiogenesis by targeting FOXC2.

Glioblastoma multiforme (GBM) is the most lethal primary tumor with active neovascularization in the central nervous system. Studying the novel molecular mechanisms of GBM angiogenesis is very important. The glioblastoma-associated microglia (GAM) M2 polarization was constructed, and microglia-derived exosomes (MDEs) were isolated to co-culture with human brain microvessel endothelial cells (hBMECs). CircRNA sequence and molecular biological experiments were used to detect the expression levels and regulation functions among circKIF18A, FOXC2, ITGB3, CXCR4, DLL4 and the PI3K/AKT signaling. The functional effects of silencing or overexpression of these molecules were evaluated in hBMECs viability, invasion, and tube formation in vitro and tumorigenicity in vivo. M2 microglia polarization is positively correlated with microvessels' density in GBM patients. M2 GAM can promote the angiogenesis of GBM via transporting exosomal circKIF18A into hBMECs. Mechanistically, circKIF18A can bind to, maintain the stability and nuclear translocation of FOXC2 in hBMECs. Furtherly, as a transcription factor, FOXC2 can directly bind to the promoter of ITGB3, CXCR4, and DLL4 and upregulate their expressions. Besides, FOXC2 can also activate the PI3K/AKT signaling and promote the angiogenesis of GBM. Our study identified a novel molecular mechanism for M2 GAM-derived exosomal circKIF18A participating in GBM angiogenesis via targeting FOXC2. This may provide a novel treatment target to improve the outcomes for anti-angiogenic therapies in GBM.

MicroRNA-124/Death-Associated Protein Kinase 1 Signaling Regulates Neuronal Apoptosis in Traumatic Brain Injury via Phosphorylating NR2B.

Death-associated protein kinase 1 (DAPK1), a Ca2+/calmodulin-dependent serine/threonine-protein kinase, promotes neurons apoptosis in ischemic stroke and Alzheimer's disease (AD). We hypothesized that knockdown DAPK1 may play a protective role in traumatic brain injury (TBI) and explore underlying molecular mechanisms. ELISA, Western blotting, immunofluorescence, dual-luciferase assay, and Reverse Transcription and quantitative Polymerase Chain Reaction (RT-qPCR) were used to determine the mechanism for the role of DAPK1 in TBI. Open field and novel objective recognition tests examined motor and memory functions. The morphology and number of synapses were observed by transmission electron microscopy and Golgi staining. DAPK1 was mainly found in neurons and significantly increased in TBI patients and TBI mice. The dual-luciferase assay showed that DAPK1 was upregulated by miR-124 loss. The number of TUNEL+ cells, expression levels of cleaved caspase3 and p-NR2B/NR2B were significantly reduced after knocking-down DAPK1 or overexpressing miR-124 in TBI mice; and motor and memory dysfunction was recovered. After Tat-NR2B were injected in TBI mice, pathological and behavioral changes were mitigated while the morphology while the number of synapses were not affected. Overall, DAPK1 is a downstream target gene of miR-124 that regulates neuronal apoptosis in TBI mice via NR2B. What's more, DAPK1 restores motor and memory dysfunctions without affecting the number and morphology of synapses.

Adiponectin/AdiopR1 signaling prevents mitochondrial dysfunction and oxidative injury after traumatic brain injury in a SIRT3 dependent manner.

Mitochondrial dysfunction and oxidative injury, which contribute to worsening of neurological deficits and poor clinical outcomes, are hallmarks of secondary brain injury after TBI. Adiponectin (APN), beyond its well-established regulatory effects on metabolism, is also essential for maintaining normal brain functions by binding APN receptors that are ubiquitously expressed in the brain. Currently, the significance of the APN/APN receptor (AdipoR) signaling pathway in secondary injury after TBI and the specific mechanisms have not been conclusively determined. In this study, we found that APN knockout aggravated brain functional deficits, increased brain edema and lesion volume, and exacerbated oxidative stress as well as apoptosis after TBI. These effects were significantly alleviated after APN receptor agonist (AdipoRon) treatment. Moreover, we found that AdipoR1, rather than AdipoR2, mediated the protective effects of APN/AdipoR signaling against oxidative stress and brain injury after TBI. In neuron-specific AdipoR1 knockout mice, mitochondrial damage was more severe after TBI, indicating a potential association between APN/AdipoR1 signaling inactivation and mitochondrial damage. Mechanistically, neuron-specific knockout of SIRT3, the most important deacetylase in the mitochondria, reversed the neuroprotective effects of AdipoRon after TBI. Then, PRDX3, a critical antioxidant enzyme in the mitochondria, was identified as a vital downstream target of the APN/SIRT3 axis to alleviate oxidative injury after TBI. Finally, we revealed that APN/AdipoR1 signaling promotes SIRT3 transcription by activating the AMPK-PGC pathway. In conclusion, APN/AdipoR1 signaling plays a protective role in post-TBI oxidative damage by restoring the SIRT3-mediated mitochondrial homeostasis and antioxidant system.

Single-Nucleus RNA Sequencing Reveals that Decorin Expression in the Amygdala Regulates Perineuronal Nets Expression and Fear Conditioning Response after Traumatic Brain Injury.

Traumatic brain injury (TBI) is a risk factor for posttraumatic stress disorder (PTSD). Augmented fear is a defining characteristic of PTSD, and the amygdala is considered the main brain region to process fear. The mechanism by which the amygdala is involved in fear conditioning after TBI is still unclear. Using single-nucleus RNA sequencing (snRNA-seq), transcriptional changes in cells in the amygdala after TBI are investigated. In total, 72 328 nuclei are obtained from the sham and TBI groups. 7 cell types, and analysis of differentially expressed genes (DEGs) reveals widespread transcriptional changes in each cell type after TBI are identified. In in vivo experiments, it is demonstrated that Decorin (Dcn) expression in the excitatory neurons of the amygdala significantly increased after TBI, and Dcn knockout in the amygdala mitigates TBI-associated fear conditioning. Of note, this effect is caused by a Dcn-mediated decrease in the expression of perineuronal nets (PNNs), which affect the glutamate-γ-aminobutyric acid balance in the amygdala. Finally, the results suggest that Dcn functions by interacting with collagen VI α3 (Col6a3). Consequently, the findings reveal transcriptional changes in different cell types of the amygdala after TBI and provide direct evidence that Dcn relieves fear conditioning by regulating PNNs.

The Specific Role of Reactive Astrocytes in Stroke.

Astrocytes are essential in maintaining normal brain functions such as blood brain barrier (BBB) homeostasis and synapse formation as the most abundant cell type in the central nervous system (CNS). After the stroke, astrocytes are known as reactive astrocytes (RAs) because they are stimulated by various damage-associated molecular patterns (DAMPs) and cytokines, resulting in significant changes in their reactivity, gene expression, and functional characteristics. RAs perform multiple functions after stroke. The inflammatory response of RAs may aggravate neuro-inflammation and release toxic factors to exert neurological damage. However, RAs also reduce excitotoxicity and release neurotrophies to promote neuroprotection. Furthermore, RAs contribute to angiogenesis and axonal remodeling to promote neurological recovery. Therefore, RAs' biphasic roles and mechanisms make them an effective target for functional recovery after the stroke. In this review, we summarized the dynamic functional changes and internal molecular mechanisms of RAs, as well as their therapeutic potential and strategies, in order to comprehensively understand the role of RAs in the outcome of stroke disease and provide a new direction for the clinical treatment of stroke.

Astrocytic NDRG2-PPM1A interaction exacerbates blood-brain barrier disruption after subarachnoid hemorrhage.

Blood-brain barrier (BBB) injury critically exacerbates the poor prognosis of patients with subarachnoid hemorrhage (SAH). The massively increased matrix metalloproteinases 9 (MMP-9) plays a deleterious role in BBB. However, the main source and mechanism of MMP-9 production after SAH remain unclear. We reported that the increased MMP-9 was mainly derived from reactive astrocytes after SAH. Ndrg2 knockout in astrocytes inhibited MMP-9 expression after SAH and attenuated BBB damage. Astrocytic Ndrg2 knockout decreased the phosphorylation of Smad2/3 and the transcription of MMP-9. Notably, cytoplasmic NDRG2 bound to the protein phosphatase PPM1A and restricted the dephosphorylation of Smad2/3. Accordingly, TAT-QFNP12, a novel engineered peptide that could block the NDRG2-PPM1A binding and reduce Smad2/3 dephosphorylation, decreased astrocytic MMP-9 production and BBB disruption after SAH. In conclusion, this study identified NDRG2-PPM1A signaling in reactive astrocytes as a key switch for MMP-9 production and provided a novel therapeutic avenue for BBB protection after SAH.