Transcriptional profiling of microglia in the injured brain reveals distinct molecular features underlying neurodegeneration.

Neurotrauma has been recognized as a risk factor for neurodegenerative diseases, and sex difference of the incidence and outcome of neurodegenerative diseases has long been recognized. Past studies suggest that microglia could play a versatile role in both health and disease. So far, the microglial mechanisms underlying neurodegeneration and potentially lead to sex-specific therapies are still very open. Here we applied whole transcriptome analysis of microglia acutely isolated at different timepoints after a cortical stab wound injury to gain insight into genes that might be dysregulated and transcriptionally different between males and females after cortical injury. We found that microglia displayed distinct temporal and sexual molecular signatures of transcriptome after cortical injury. Hypotheses and gene candidates that we presented in the present study could be worthy to be examined to explore the roles of microglia in neurotrauma and in sex-biased neurodegenerative diseases.

Autistic and Non-autistic Children's Pain Perception is Modulated by Their First-Hand Pain Sensitivity and Theory of Mind.

The current study examined whether autistic children's perception of others' pain could be modulated by their first-hand pain sensitivity and theory of mind (ToM). We measured the first-hand pain sensitivity, the rating of others' pain intensity, and the performance in the ToM tasks in 43 5- to 8-year-old autistic and 30 neurotypical children. Our results revealed hyposensitivity to first-hand pain, underestimation of others' pain intensity, as well as difficulties in the False Belief subtasks of ToM in autistic children. Furthermore, we detected an interaction between children's first-hand pain sensitivity and ToM in predicting their perception of others' pain. To be specific, for autistic and NT children with normal or hyper-sensitivity to first-hand pain, better performance on ToM predicted higher ratings for others' pain intensity; while for autistic and NT children with hyposensitivity to first-hand pain, ToM did not predict ratings for others' pain intensity. Our study contributes to the understanding of pain perception in young children and provides implications for clinical practices to improve social understanding in autistic children.

Molecular mechanism of Wilms' tumor (Wt1) (+/-KTS) variants promoting proliferation and migration of ovarian epithelial cells by bioinformatics analysis.

Epithelial ovarian cancer (EOC) is a gynecological disease with the highest mortality. With the lack of understanding of its pathogenesis, no accurate early diagnosis and screening method has been established for EOC. Studies revealed the multi-faceted function of Wilms' tumor (Wt1) genes in cancer, which may be related to the existence of multiple alternative splices. Our results show that Wt1 (+KTS) or Wt1 (-KTS) overexpression can significantly promote the proliferation and migration of human ovarian epithelial cells HOSEpiC, and Wt1 (+KTS) effects were more evident. To explore the Wt1 (+/-KTS) variant mechanism in HOSEpiC proliferation and migration and ovarian cancer (OC) occurrence and development, this study explored the differential regulation of Wt1 (+/-KTS) in HOSEpiC proliferation and migration by transcriptome sequencing. OC-related hub genes were screened by bioinformatics analysis to further explore the differential molecular mechanism of Wt1 (+/-KTS) in the occurrence of OC. Finally, we found that the regulation of Wt1 (+/-KTS) variants on the proliferation and migration of HOSEpiC may act through different genes and signaling pathways and screened out key genes and differentially regulated genes that regulate the malignant transformation of ovarian epithelial cells. The implementation of this study will provide new clues for the early diagnosis and precise treatment of OC.

Luteolin regulates the distribution and function of organelles by controlling SIRT1 activity during postovulatory oocyte aging.

The quality of oocytes determines their development competence, which will be rapidly lost if the oocytes are not fertilized at the proper time after ovulation. SIRT1, one of the sirtuin family members, has been proven to protect the quality of oocytes during postovulatory oocyte aging. However, evidence of the effect of SIRT1 on the activity of organelles including the mitochondria, the endoplasmic reticulum (ER), the Golgi apparatus, and the lysosomes in postovulatory aging oocyte is lacking. In this study, we investigated the distribution and function of organelles in postovulatory aged oocytes and discovered abnormalities. Luteolin, which is a natural flavonoid contained in vegetables and fruits, is an activator of SIRT1. When the oocytes were treated with luteolin, the abnormal distribution of mitochondria, ER, and Golgi complex were restored during postovulatory oocyte aging. The ER stress protein GRP78 and the lysosome protein LAMP1 increased, while the mitochondrial membrane potential and the Golgi complex protein GOLPH3 decreased in aged oocytes, and these were restored by luteolin treatment. EX-527, an inhibitor of SIRT1, disrupted the luteolin-mediated normal distribution and function of mitochondria, ER, Golgi apparatus, and lysosomes. In conclusion, we demonstrate that luteolin regulates the distribution and function of mitochondria, ER, Golgi apparatus, and lysosomes during postovulatory oocyte aging by activating SIRT1.

The Role and Mechanism of Transglutaminase 2 in Regulating Hippocampal Neurogenesis after Traumatic Brain Injury.

Traumatic brain injury usually results in neuronal loss and cognitive deficits. Promoting endogenous neurogenesis has been considered as a viable treatment option to improve functional recovery after TBI. However, neural stem/progenitor cells (NSPCs) in neurogenic regions are often unable to migrate and differentiate into mature neurons at the injury site. Transglutaminase 2 (TGM2) has been identified as a crucial component of neurogenic niche, and significantly dysregulated after TBI. Therefore, we speculate that TGM2 may play an important role in neurogenesis after TBI, and strategies targeting TGM2 to promote endogenous neural regeneration may be applied in TBI therapy. Using a tamoxifen-induced Tgm2 conditional knockout mouse line and a mouse model of stab wound injury, we investigated the role and mechanism of TGM2 in regulating hippocampal neurogenesis after TBI. We found that Tgm2 was highly expressed in adult NSPCs and up-regulated after TBI. Conditional deletion of Tgm2 resulted in the impaired proliferation and differentiation of NSPCs, while Tgm2 overexpression enhanced the abilities of self-renewal, proliferation, differentiation, and migration of NSPCs after TBI. Importantly, injection of lentivirus overexpressing TGM2 significantly promoted hippocampal neurogenesis after TBI. Therefore, TGM2 is a key regulator of hippocampal neurogenesis and a pivotal therapeutic target for intervention following TBI.

Microglial transglutaminase 2 deficiency causes impaired synaptic remodelling and cognitive deficits in mice.

Microglia are the primary source of transglutaminase 2 (TGM2) in the brain; however, the roles of microglial TGM2 in neural development and disease are still not well known. The aim of this study is to elucidate the role and mechanisms of microglial TGM2 in the brain. A mouse line with a specific knockout of Tgm2 in microglia was generated. Immunohistochemistry, Western blot and qRT-PCR assays were performed to evaluate the expression levels of TGM2, PSD-95 and CD68. Confocal imaging, immunofluorescence staining and behavioural analyses were conducted to identify phenotypes of microglial TGM2 deficiency. Finally, RNA sequencing, qRT-PCR and co-culture of neurons and microglia were used to explore the potential mechanisms. Deletion of microglial Tgm2 causes impaired synaptic pruning, reduced anxiety and increased cognitive deficits in mice. At the molecular level, the phagocytic genes, such as Cq1a, C1qb and Tim4, are significantly down-regulated in TGM2-deficient microglia. This study elucidates a novel role of microglial TGM2 in regulating synaptic remodelling and cognitive function, indicating that microglia Tgm2 is essential for proper neural development.

Abnormal microglial polarization induced by Arid1a deletion leads to neuronal differentiation deficits.

OBJECTIVE: Microglia, the prototypical innate immune cells of the central nervous system (CNS), are highly plastic and assume their phenotypes dependent on intrinsically genetic, epigenetic regulation or extrinsically microenvironmental cues. Microglia has been recognized as key regulators of neural stem/progenitor cells (NSPCs) and brain functions. Chromatin accessibility is implicated in immune cell development and functional regulation. However, it is still unknown whether and how chromatin remodelling regulates the phenotypic plasticity of microglia and exerts what kind of effects on NSPCs. METHODS: We investigated the role of chromatin accessibility in microglia by deleting chromatin remodelling gene Arid1a using microglia-specific Cx3cr1-cre and Cx3cr1-CreERT2 mice. RNA-seq and ATAC-seq were performed to dissect the molecular mechanisms. In addition, we examined postnatal M1/M2 microglia polarization and analysed neuronal differentiation of NSPCs. Finally, we tested the effects of microglial Arid1a deletion on mouse behaviours. RESULTS: Increased chromatin accessibility upon Arid1a ablation resulted in enhanced M1 microglial polarization and weakened M2 polarization, which led to abnormal neurogenesis and anxiety-like behaviours. Switching the polarization state under IL4 stimulation could rescue abnormal neurogenesis, supporting an essential role for chromatin remodeler ARID1A in balancing microglial polarization and brain functions. CONCLUSIONS: Our study identifies ARID1A as a central regulator of microglia polarization, establishing a mechanistic link between chromatin remodelling, neurogenesis and mouse behaviours, and highlights the potential development of innovative therapeutics exploiting the innate regenerative capacity of the nervous system.

PRIN/SPRIN: On Extracting Point-Wise Rotation Invariant Features.

Point cloud analysis without pose priors is very challenging in real applications, as the orientations of point clouds are often unknown. In this paper, we propose a brand new point-set learning framework PRIN, namely, Point-wise Rotation Invariant Network, focusing on rotation invariant feature extraction in point clouds analysis. We construct spherical signals by Density Aware Adaptive Sampling to deal with distorted point distributions in spherical space. Spherical Voxel Convolution and Point Re-sampling are proposed to extract rotation invariant features for each point. In addition, we extend PRIN to a sparse version called SPRIN, which directly operates on sparse point clouds. Both PRIN and SPRIN can be applied to tasks ranging from object classification, part segmentation, to 3D feature matching and label alignment. Results show that, on the dataset with randomly rotated point clouds, SPRIN demonstrates better performance than state-of-the-art methods without any data augmentation. We also provide thorough theoretical proof and analysis for point-wise rotation invariance achieved by our methods. The code to reproduce our results will be made publicly available.

TensorFlow solver for quantum PageRank in large-scale networks.

Google PageRank is a prevalent algorithm for ranking the significance of nodes or websites in a network, and a recent quantum counterpart for PageRank algorithm has been raised to suggest a higher accuracy of ranking comparing to Google PageRank. The quantum PageRank algorithm is essentially based on quantum stochastic walks and can be expressed using Lindblad master equation, which, however, needs to solve the Kronecker products of an O(N4) dimension and requires severely large memory and time when the number of nodes N in a network increases above 150. Here, we present an efficient solver for quantum PageRank by using the Runge-Kutta method to reduce the matrix dimension to O(N2) and employing TensorFlow to conduct GPU parallel computing. We demonstrate its performance in solving quantum stochastic walks on Erdös-Rényi graphs using an RTX 2060 GPU. The test on the graph of 6000 nodes requires a memory of 5.5 GB and time of 223 s, and that on the graph of 1000 nodes requires 226 MB and 3.6 s. Compared with QSWalk, a currently prevalent Mathematica solver, our solver for the same graph of 1000 nodes reduces the required memory and time to only 0.2% and 0.05%. We apply the solver to quantum PageRank for the USA major airline network with up to 922 nodes, and to quantum stochastic walk on a glued tree of 2186 nodes. This efficient solver for large-scale quantum PageRank and quantum stochastic walks would greatly facilitate studies of quantum information in real-life applications.