Nuclear autoantigenic sperm protein facilitates glioblastoma progression and radioresistance by regulating the ANXA2/STAT3 axis.

AIMS: Although radiotherapy is a core treatment modality for various human cancers, including glioblastoma multiforme (GBM), its clinical effects are often limited by radioresistance. The specific molecular mechanisms underlying radioresistance are largely unknown, and the reduction of radioresistance is an unresolved challenge in GBM research. METHODS: We analyzed and verified the expression of nuclear autoantigenic sperm protein (NASP) in gliomas and its relationship with patient prognosis. We also explored the function of NASP in GBM cell lines. We performed further mechanistic experiments to investigate the mechanisms by which NASP facilitates GBM progression and radioresistance. An intracranial mouse model was used to verify the effectiveness of combination therapy. RESULTS: NASP was highly expressed in gliomas, and its expression was negatively correlated with the prognosis of glioma. Functionally, NASP facilitated GBM cell proliferation, migration, invasion, and radioresistance. Mechanistically, NASP interacted directly with annexin A2 (ANXA2) and promoted its nuclear localization, which may have been mediated by phospho-annexin A2 (Tyr23). The NASP/ANXA2 axis was involved in DNA damage repair after radiotherapy, which explains the radioresistance of GBM cells that highly express NASP. NASP overexpression significantly activated the signal transducer and activator of transcription 3 (STAT3) signaling pathway. The combination of WP1066 (a STAT3 pathway inhibitor) and radiotherapy significantly inhibited GBM growth in vitro and in vivo. CONCLUSION: Our findings indicate that NASP may serve as a potential biomarker of GBM radioresistance and has important implications for improving clinical radiotherapy.

Advances in microRNA regulation of deep vein thrombosis through venous vascular endothelial cells (Review).

Deep vein thrombosis (DVT) is a prevalent clinical venous thrombotic condition that often manifests independently or in conjunction with other ailments. Thrombi have the propensity to dislodge into the circulatory system, giving rise to complications such as pulmonary embolism, thereby posing a significant risk to the patient. Virchow proposed that blood stagnation, alterations in the vessel wall and hypercoagulation are primary factors contributing to the development of venous thrombosis. Vascular endothelial cells (VECs) constitute the initial barrier to the vascular wall and are a focal point of ongoing research. These cells exert diverse stimulatory effects on the bloodstream and secrete various regulatory factors that uphold the dynamic equilibrium between the coagulation and anticoagulation processes. MicroRNAs (miRNAs) represent a class of non­coding RNAs present in eukaryotes, characterized by significant genetic and evolutionary conservation and displaying high spatiotemporal expression specificity. Typically ranging from 20 to 25 bases in length, miRNAs can influence downstream gene transcription through RNA interference or by binding to specific mRNA sites. Consequently, advancements in understanding the molecular mechanisms of miRNAs, including their functionalities, involve modulation of vascular­associated processes such as cell proliferation, differentiation, secretion of inflammatory factors, migration, apoptosis and vascular remodeling regeneration. miRNAs play a substantial role in DVT formation via venous VECs. In the present review, the distinct functions of various miRNAs in endothelial cells are outlined and recent progress in comprehending their role in the pathogenesis and clinical application of DVT is elucidated.

Construct Phenylethanoid Glycosides Harnessing Biosynthetic Networks, Protein Engineering and One-Pot Multienzyme Cascades.

Phenylethanoid glycosides (PhGs) exhibit a multitude of structural variations linked to diverse pharmacological activities. Assembling various PhGs via multienzyme cascades represents a concise strategy over traditional synthetic methods. However, the challenge lies in identifying a comprehensive set of catalytic enzymes. This study explores biosynthetic PhG reconstruction from natural precursors, aiming to replicate and amplify their structural diversity. We discovered 12 catalytic enzymes, including four novel 6'-OH glycosyltransferases and three new polyphenol oxidases, revealing the intricate network in PhG biosynthesis. Subsequently, the crystal structure of CmGT3 (2.62 Å) was obtained, guiding the identification of conserved residue 144# as a critical determinant for sugar donor specificity. Engineering this residue in PhG glycosyltransferases (FsGT61, CmGT3, and FsGT6) altered their sugar donor recognition. Finally, a one-pot multienzyme cascade was established, where the combined action of glycosyltransferases and acyltransferases boosted conversion rates by up to 12.6-fold. This cascade facilitated the reconstruction of 26 PhGs with conversion rates ranging from 5-100%, and 20 additional PhGs detectable by mass spectrometry. PhGs with extra glycosyl and hydroxyl modules demonstrated notable liver cell protection. This work not only provides catalytic tools for PhGs biosynthesis, but also serves as a proof-of-concept for cell-free enzymatic construction of diverse natural products.

Far-Field Petahertz Sampling of Plasmonic Fields.

The response of metal nanostructures to optical excitation leads to localized surface plasmon (LSP) generation with nanoscale field confinement driving applications in, for example, quantum optics and nanophotonics. Field sampling in the terahertz domain has had a tremendous impact on the ability to trace such collective excitations. Here, we extend such capabilities and introduce direct sampling of LSPs in a more relevant petahertz domain. The method allows to measure the LSP field in arbitrary nanostructures with subcycle precision. We demonstrate the technique for colloidal nanoparticles and compare the results to finite-difference time-domain calculations, which show that the build-up and dephasing of the plasmonic excitation can be resolved. Furthermore, we observe a reshaping of the spectral phase of the few-cycle pulse, and we demonstrate ad-hoc pulse shaping by tailoring the plasmonic sample. The methodology can be extended to single nanosystems and applied in exploring subcycle, attosecond phenomena.

A rare huge bladder inflammatory myofibroblastic tumor treated by en bloc resection with diode laser: a case report and literature review.

Background: Inflammatory myofibroblastic tumor (IMT) is a rare neoplasm with malignant potential. Bladder IMT is even rarer and mainly treated by surgical resection However, partial or radical cystectomy would affect the quality of life of patients due to major surgical trauma, and classical TURBT is hard to avoid intraoperative complications including obturator nerve reflex and bleeding etc. Therefore, the safe and effective better choice of surgical approaches become critical to bladder IMT. Case presentation: A 42-year-old male patient was admitted to the department of urology with persistent painless gross hematuria for more than 10 days without the presentation of hypertension. Preoperative routine urine examination of red blood cells was 7738.9/HPF (normal range ≤ 3/HPF). CTU indicated a space occupying lesion (6.0 cm×5.0 cm) in the left posterior wall of the bladder with heterogeneous enhancement in the excretory phase. MRI also indicated bladder tumor with slightly equal SI on T1WI and mixed high SI on T2WI (6.0 cm×5.1cm×3.5cm) in the left posterior wall of the bladder. En bloc resection of bladder IMT with 1470 nm diode laser in combination of removing the enucleated tumor by the morcellator system was performed. Postoperative pathological examination revealed bladder IMT, with IHC positive for Ki-67 (15-20%), CK AE1/AE3, SMA, and Desmin of bladder IMT and negative for ALK of bladder IMT as well as FISH negative for ALK gene rearrangement. Second TUR with 1470 nm diode laser was performed within 6 weeks to reduce postoperative risk of recurrence due to highly malignant potential for the high expression of Ki-67 (15-20%) and negative ALK in IHC staining. The second postoperative pathology report showed chronic inflammation concomitant with edema of the bladder mucosa without bladder IMT, furthermore no tumor was observed in muscularis propria layer of bladder. No recurrence occurred during the period of 24-month follow-up. Conclusion: En bloc resection of bladder IMT in combination of the following second transurethral resection with 1470 nm diode laser is a safe and effective surgical approach for the huge bladder IMT with highly malignant potential.

GSDMD induces hepatocyte pyroptosis to trigger alcoholic hepatitis through modulating mitochondrial dysfunction.

BACKGROUND: Mechanisms and consequences of Gasdermin D (GSDMD) activation in alcoholic hepatitis (AH) are unclear. In the present study, we investigated whether GSDMD induces hepatocyte pyroptosis by regulating mitochondrial dysfunction in AH. RESULTS: Liver damage in AH mice was assessed by HE staining, serum levels of AST, ALT, TC, and TG. The levels of IL-1ß, IL-18, LDH, inflammasome-associated proteins and hepatocyte death were assessed to determine pyroptosis. Mitochondrial dysfunction was assessed through various parameters including mitochondrial DNA (mtDNA) levels, ROS generation, mitochondrial membrane potential, ATP contents, levels of mitochondrial function-related proteins and morphological changes of mitochondria. AH induced gasdermin D (GSDMD) activation, leading to increased protein expression of N-terminal GSDMD (GSDMD-N), NLRP3, and Caspase 11 in liver tissues. Downregulation of GSDMD alleviated alcohol-induced hepatocyte pyroptosis. Alcohol also causes mitochondrial dysfunction in hepatocytes in AH, which was improved by inhibiting GSDMD. Furthermore, enhancing mitochondrial function suppressed alcohol-induced hepatocyte pyroptosis. Further, knockdown of GSDMD or dynamin-related protein 1 (Drp1) improved AH-induced liver injury, accompanied by a decrease in hepatocyte pyroptosis. CONCLUSION: GSDMD induces hepatocyte pyroptosis by modulating mitochondrial dysfunction during AH-induced inflammation and liver injury. These findings may pave the way to develop new therapeutic treatments for AH.

Satellite glial GPR37L1 and its ligand maresin 1 regulate potassium channel signaling and pain homeostasis.

G protein-coupled receptor 37-like 1 (GPR37L1) is an orphan GPCR with largely unknown functions. Here we report that Gpr37l1/GRP37L1 ranks among the most highly expressed GPCR transcripts in mouse and human dorsal root ganglia (DRGs), selectively expressed in satellite glial cells (SGCs). Peripheral neuropathy induced by streptozotoxin (STZ) and paclitaxel (PTX) led to reduced GPR37L1 expression on the plasma membrane expression in mouse and human DRGs. Transgenic mice with Gpr37l1 deficiency exhibited impaired resolution of neuropathic pain symptoms following PTX and STZ-induced pain, whereas overexpression of Gpr37l1 in mouse DRGs reversed pain. GPR37L1 is co-expressed with potassium channels, including KCNJ10 (Kir4.1) in mouse SGCs and both KCNJ3 (Kir3.1) and KCNJ10 in human SGCs. GPR37L1 regulates the surface expression and function of the potassium channels. Notably, the pro-resolving lipid mediator maresin 1 (MaR1) serves as a ligand of GPR37L1 and enhances KCNJ10 or KCNJ3-mediated potassium influx in SGCs through GPR37L1. Chemotherapy suppressed KCNJ10 expression and function in SGCs, which MaR1 rescued through GPR37L1. Finally, genetic analysis revealed that the GPR37L1-E296K variant increased chronic pain risk by destabilizing the protein and impairing the protein's function. Thus, GPR37L1 in SGCs offers a new therapeutic target for the protection of neuropathy and chronic pain.

Genetically encoded site-specific 19F unnatural amino acid incorporation in V. natriegens for in-cell NMR analysis.

Nuclear magnetic resonance (NMR) spectroscopy NMR is a well-established technique for probing protein structure, dynamics and conformational changes. Taking advantage of the high signal sensitivity and broad chemical shift range of 19F nuclei, 19F NMR has been applied to investigate protein function at atomic resolution. In this report, we extend the unnatural amino acid site-specific incorporation into V. natriegens, an alternate protein expression system. The unnatural amino acid L-4-trifluoromethylphenylalanine (tfmF) was site-specifically introduced into the mitogen-activated protein kinase MEKK3 in V. natriegens using genetically encoded technology, which will be an extensive method for in-cell protein structure and dynamic investigation.

DNA Interaction and Cleavage Modes of Anthraquinone-Fused Enediynes: A Study on Tiancimycins, Yangpumicins, and Their Semisynthetic Analogues.

Dynemicin A has been the sole prototypical anthraquinone-fused enediyne (AFE) explored since its discovery in 1989. This study investigates the distinct DNA binding and cleavage mechanisms of emerging AFEs, represented by tiancimycins and yangpumicins, along with semisynthetic analogues. Our findings reveal their potent cytotoxicity against various tumor cell lines, while 18-methoxy tiancimycin A treatment could significantly suppress breast tumor growth with minimal toxicity. One of the most potent AFEs, i.e., tiancimycin A, preferentially targets DNA sequences 5'-ATT, 5'-CTT, 5'-GAA, 5'-GAT, and 5'-TTA. Molecular dynamics simulations suggest that emerging AFEs intercalate deeper into AT-rich DNA base pairs compared to dynemicin A. Importantly, tiancimycin A may equilibrate between insertional and intercalative modes without deintercalation, enabling selective cleavage of T and A bases. This study underscores how subtle structural variations among AFEs significantly influence their DNA recognition and cleavage, facilitating future design of novel AFEs as potent and selective payloads for antibody-drug conjugates.

Cryo-EM structures of the human NaS1 and NaDC1 transporters revealed the elevator transport and allosteric regulation mechanism.

The solute carrier 13 (SLC13) family comprises electrogenic sodium ion-coupled anion cotransporters, segregating into sodium ion-sulfate cotransporters (NaSs) and sodium ion-di- and-tricarboxylate cotransporters (NaDCs). NaS1 and NaDC1 regulate sulfate homeostasis and oxidative metabolism, respectively. NaS1 deficiency affects murine growth and fertility, while NaDC1 affects urinary citrate and calcium nephrolithiasis. Despite their importance, the mechanisms of substrate recognition and transport remain insufficiently characterized. In this study, we determined the cryo-electron microscopy structures of human NaS1, capturing inward-facing and combined inward-facing/outward-facing conformations within a dimer both in apo and sulfate-bound states. In addition, we elucidated NaDC1's outward-facing conformation, encompassing apo, citrate-bound, and N-(p-amylcinnamoyl) anthranilic acid (ACA) inhibitor-bound states. Structural scrutiny illuminates a detailed elevator mechanism driving conformational changes. Notably, the ACA inhibitor unexpectedly binds primarily anchored by transmembrane 2 (TM2), Loop 10, TM11, and TM6a proximate to the cytosolic membrane. Our findings provide crucial insights into SLC13 transport mechanisms, paving the way for future drug design.

Whole-Genome Resequencing-Based Qualitative Trait Locus Mapping Correlated yellow with the Mutant Color in Honeybees, Apis cerana cerana.

The honeybee, Apis cerana cerana (Ac), is an important pollinator and has adapted to the local ecological environment with relevant coloration. The cuticle coloration of the brown (br) mutant is brown instead of black in wild-type individuals. Therefore, this study aimed to identify and characterize the gene responsible for the br mutation. Genome resequencing with allele segregation measurement using Euclidean distance followed by Lowess regression analysis revealed that the color locus linked to the mutation was located on chromosome 11. A 2-base deletion on exon 4 was identified in the g7628 (yellow) gene after genome assembly and sequence cloning. In addition, the cuticle color of the abdomen of worker bees changed from black to brown when a defect was induced in the yellow gene using short interfering RNA (siRNA); however, the survival rate did not decrease significantly. These results indicate that the yellow gene participated in the body pigmentation, and its defect was responsible for the br mutation. This study promotes the understanding of the molecular basis of body coloration in honeybees, enriching the molecular mechanisms underlying insect pigmentation.

The effects of low-dose IL-2 on Th17/Treg cell imbalance in primary biliary cholangitis mouse models.

BACKGROUND/AIMS: Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease. The imbalance of Th17/Treg cells has been reported in PBC patients. Low-dose IL-2 can alleviate disease severity through modulating CD4 + T cell subsets in patients with autoimmune diseases. Hence, the present study aimed to examine the effects and mechanism of low-dose IL-2 in PBC mouse models. METHODS: PBC models were induced in female C57BL/6 mice by two immunizations with 2OA-BSA at two-week intervals, and poly I: C every three days. PBC mouse models were divided into the IL-2 treated and untreated groups and low-dose IL-2 was injected at three different time points. Th17 and Tregs were analyzed by flow cytometry, and the related cytokines were analyzed by ELISA. Liver histopathology was examined by H&E and immunohistochemical staining. RESULTS: Twelve weeks after modeling, the serum AMA was positive and the ALP was significantly increased in PBC mouse models (P<0.05). The pathology showed lymphocyte infiltration in the portal area, damage, and reactive proliferation of the small bile duct (P<0.05). The flow cytometric showed the imbalance of Th17/Treg cells in the liver of PBC mouse models, with decreased Treg cells, increased Th17 cells, and Th17/Treg ratio (P < 0.05). After the low-dose IL-2 intervention, biochemical index and liver pathologies showed improvement at 12 weeks. Besides, the imbalance of Th17 and Treg cells recovered. Public database mining showed that Th17 cell differentiation may contribute to poor response in PBC patients. CONCLUSION: Low-dose IL-2 can significantly improve liver biochemistry and pathology by reversing the imbalance of Th17 and Treg cells, suggesting that it may be a potential therapeutic target for PBC.

miR-328-3p targets TLR2 to ameliorate oxygen-glucose deprivation injury and neutrophil extracellular trap formation in HUVECs via inhibition of the NF-κB signaling pathway.

BACKGROUND: Endothelial cell injury is one of the important pathogenic mechanisms in thrombotic diseases, and also neutrophils are involved. MicroRNAs (miRNAs) have been demonstrated to act as essential players in endothelial cell injury, but the potential molecular processes are unknown. In this study, we used cellular tests to ascertain the protective effect of miR-328-3p on human umbilical vein endothelial cells (HUVECs) treated with oxygen-glucose deprivation (OGD). METHODS: In our study, an OGD-induced HUVECs model was established, and we constructed lentiviral vectors to establish stable HUVECs cell lines. miR-328-3p and Toll-like receptor 2 (TLR2) interacted, as demonstrated by the dual luciferase reporter assay. We used the CCK8, LDH release, and EdU assays to evaluate the proliferative capacity of each group of cells. To investigate the expression of TLR2, p-P65 NF-κB, P65 NF-κB, NLRP3, IL-1ß, and IL-18, we employed Western blot and ELISA. Following OGD, each group's cell supernatants were gathered and co-cultured with neutrophils. An immunofluorescence assay and Transwell assay have been performed to determine whether miR-328-3p/TLR2 interferes with neutrophil migration and neutrophil extracellular traps (NETs) formation. RESULTS: In OGD-treated HUVECs, the expression of miR-328-3p is downregulated. miR-328-3p directly targets TLR2, inhibits the NF-κB signaling pathway, and reverses the proliferative capacity of OGD-treated HUVECs, while inhibiting neutrophil migration and neutrophil extracellular trap formation. CONCLUSIONS: miR-328-3p inhibits the NF-κB signaling pathway in OGD-treated HUVECs while inhibiting neutrophil migration and NETs formation, and ameliorating endothelial cell injury, which provides new ideas for the pathogenesis of thrombotic diseases.

Exploration of the Native Sucrose Operon Enables the Development of an Inducible T7 Expression System in Paenibacillus polymyxa.

The use of Paenibacillus polymyxa as an industrial producer is limited by the lack of suitable synthetic biology tools. In this study, we identified a native sucrose operon in P. polymyxa. Its structural and functional relationship analysis revealed the presence of multiple regulatory elements, including four ScrR-binding sites and a catabolite-responsive element (CRE). In P. polymyxa, we established a cascade T7 expression system involving an integrated T7 RNA polymerase (T7P) regulated by the sucrose operon and a T7 promoter. It enables controllable gene expression by sucrose and regulatory elements, and a 5-fold increase in expression efficiency compared with the original sucrose operon was achieved. Further deletion of SacB in P. polymyxa resulted in a 38.95% increase in the level of thermophilic lipase (TrLip) production using the cascade T7 induction system. The results highlight the effectiveness of sucrose regulation as a novel synthetic biology tool, which facilitates exploring gene circuits and enables their dynamic regulation.

Disruption of the Na+/K+-ATPase-purinergic P2X7 receptor complex in microglia promotes stress-induced anxiety.

Na+/K+-ATPase (NKA) plays an important role in the central nervous system. However, little is known about its function in the microglia. Here, we found that NKAα1 forms a complex with the purinergic P2X7 receptor (P2X7R), an adenosine 5'-triphosphate (ATP)-gated ion channel, under physiological conditions. Chronic stress or treatment with lipopolysaccharide plus ATP decreased the membrane expression of NKAα1 in microglia, facilitated P2X7R function, and promoted microglia inflammatory activation via activation of the NLRP3 inflammasome. Accordingly, global deletion or conditional deletion of NKAα1 in microglia under chronic stress-induced aggravated anxiety-like behavior and neuronal hyperexcitability. DR5-12D, a monoclonal antibody that stabilizes membrane NKAα1, improved stress-induced anxiety-like behavior and ameliorated neuronal hyperexcitability and neurogenesis deficits in the ventral hippocampus of mice. Our results reveal that NKAα1 limits microglia inflammation and may provide a target for the treatment of stress-related neuroinflammation and diseases.

Radiomic profiling for insular diffuse glioma stratification with distinct biologic pathway activities.

Current literature emphasizes surgical complexities and customized resection for managing insular gliomas; however, radiogenomic investigations into prognostic radiomic traits remain limited. We aimed to develop and validate a radiomic model using multiparametric magnetic resonance imaging (MRI) for prognostic prediction and to reveal the underlying biological mechanisms. Radiomic features from preoperative MRI were utilized to develop and validate a radiomic risk signature (RRS) for insular gliomas, validated through paired MRI and RNA-seq data (N = 39), to identify core pathways underlying the RRS and individual prognostic radiomic features. An 18-feature-based RRS was established for overall survival (OS) prediction. Gene set enrichment analysis (GSEA) and weighted gene coexpression network analysis (WGCNA) were used to identify intersectional pathways. In total, 364 patients with insular gliomas (training set, N = 295; validation set, N = 69) were enrolled. RRS was significantly associated with insular glioma OS (log-rank p = 0.00058; HR = 3.595, 95% CI:1.636-7.898) in the validation set. The radiomic-pathological-clinical model (R-P-CM) displayed enhanced reliability and accuracy in prognostic prediction. The radiogenomic analysis revealed 322 intersectional pathways through GSEA and WGCNA fusion; 13 prognostic radiomic features were significantly correlated with these intersectional pathways. The RRS demonstrated independent predictive value for insular glioma prognosis compared with established clinical and pathological profiles. The biological basis for prognostic radiomic indicators includes immune, proliferative, migratory, metabolic, and cellular biological function-related pathways.

LSPConv: local spatial projection convolution for point cloud analysis.

This study introduces a novel approach, Local Spatial Projection Convolution (LSPConv), for point cloud classification and semantic segmentation. Unlike conventional methods utilizing relative coordinates for local geometric information, our motivation stems from the inadequacy of existing techniques for representing the intricate spatial organization of unconsolidated and irregular 3D point clouds. To address this limitation, we propose a Local Spatial Projection Module utilizing a vector projection strategy, designed to capture comprehensive local spatial information more effectively. Moreover, recent studies emphasize the importance of anisotropic kernels for point cloud feature extraction, considering the distinct contributions of individual neighboring points. To cater to this requirement, we introduce the Feature Weight Assignment (FWA) Module to assign weights to neighboring points, enhancing the anisotropy crucial for accurate feature extraction. Additionally, we introduce an Anisotropic Relative Feature Encoding Module that adaptively encodes points based on their relative features, further amplifying the anisotropic characteristics. Our approaches achieve remarkable results for point cloud classification and segmentation in several benchmark datasets based on extensive qualitative and quantitative evaluation.

Sequential gene expression analysis of myelodysplastic syndrome transformation identifies HOXB3 and HOXB7 as the novel targets for mesenchymal cells in disease.

BACKGROUND: Myelodysplastic syndrome (MDS) is known to arise through the pathogenic bone marrow mesenchymal stem cells (MSC) by interacting with hematopoietic stem cells (HSC). However, due to the strong heterogeneity of MDS patients, it is difficult to find common targets in studies with limited sample sizes. This study aimed to describe sequential molecular changes and identify biomarkers in MSC of MDS transformation. METHODS: Multidimensional data from three publicly available microarray and TCGA datasets were analyzed. MDS-MSC was further isolated and cultured in vitro to determine the potential diagnostic and prognostic value of the identified biomarkers. RESULTS: We demonstrated that normal MSCs presented greater molecular homogeneity than MDS-MSC. Biological process (embryonic skeletal system morphogenesis and angiogenesis) and pathways (p53 and MAPK) were enriched according to the differential gene expression. Furthermore, we identified HOXB3 and HOXB7 as potential causative genes gradually upregulated during the normal-MDS-AML transition. Blocking the HOXB3 and HOXB7 in MSCs could enhance the cell proliferation and differentiation, inhibit cell apoptosis and restore the function that supports hematopoietic differentiation in HSCs. CONCLUSION: Our comprehensive study of gene expression profiling has identified dysregulated genes and biological processes in MSCs during MDS. HOXB3 and HOXB7 are proposed as novel surrogate targets for therapeutic and diagnostic applications in MDS.

The attenuated African swine fever vaccine HLJ/18-7GD provides protection against emerging prevalent genotype II variants in China.

Genetic changes have occurred in the genomes of prevalent African swine fever viruses (ASFVs) in the field in China, which may change their antigenic properties and result in immune escape. There is usually poor cross-protection between heterogonous isolates, and, therefore, it is important to test the cross-protection of the live attenuated ASFV vaccines against current prevalent heterogonous isolates. In this study, we evaluated the protective efficacy of the ASFV vaccine candidate HLJ/18-7GD against emerging isolates. HLJ/18-7GD provided protection against a highly virulent variant and a lower lethal isolate, both derived from genotype II Georgia07-like ASFV and isolated in 2020. HLJ/18-7GD vaccination prevented pigs from developing ASF-specific clinical signs and death, decreased viral shedding via the oral and rectal routes, and suppressed viral replication after challenges. However, HLJ/18-7GD vaccination did not provide solid cross-protection against genotype I NH/P68-like ASFV challenge in pigs. HLJ/18-7GD vaccination thus shows great promise as an alternative strategy for preventing and controlling genotype II ASFVs, but vaccines providing cross-protection against different ASFV genotypes may be needed in China.

Injured sensory neurons-derived galectin-3 contributes to neuropathic pain via programming microglia in the spinal dorsal horn.

Emerging studies have demonstrated spinal microglia play a critical role in central sensitization and contribute to chronic pain. Although several mediators that contribute to microglia activation have been identified, the mechanism of microglia activation and its functionally diversified mechanisms in pathological pain are still unclear. Here we report that injured sensory neurons-derived Galectin-3 (Gal3) activates and reprograms microglia in the spinal dorsal horn (SDH) and contributes to neuropathic pain. Firstly, Gal3 is predominantly expressed in the isolectin B4 (IB4)-positive non-peptidergic sensory neurons and significantly up-regulated in dorsal root ganglion (DRG) neurons and primary afferent terminals in SDH in the partial sciatic nerve ligation (pSNL)-induced neuropathic pain model. Gal3 knockout (Gal3 KO) mice showed a significant decrease in mechanical allodynia and Gal3 inhibitor TD-139 produced a significant anti-allodynia effect in the pSNL model. Furthermore, pSNL-induced microgliosis was compromised in Gal3 KO mice. Additionally, intrathecal injection of Gal3 produces remarkable mechanical allodynia by direct activation of microglia, which have enhanced inflammatory responses with TNF-α and IL-1ß up-regulation. Thirdly, using single-nuclear RNA sequencing (snRNA-seq), we identified that Gal3 targets microglia and induces reprogramming of microglia, which may contribute to neuropathic pain establishment. Finally, Gal3 enhances excitatory synaptic transmission in excitatory neurons in the SDH via microglia activation. Our findings reveal that injured sensory neurons-derived Gal3 programs microglia in the SDH and contribute to neuropathic pain.