Novel subsets of peripheral immune cells associated with promoting stroke recovery in mice.

AIMS: Peripheral immune cells infiltrating into the brain trigger neuroinflammation after an ischemic stroke. Partial immune cells reprogram their function for neural repair. Which immune cells promote ischemic brain recovery needs further identification. METHODS: We performed single-cell transcriptomic profiling of CD45high immune cells isolated from the ischemic hemisphere at subacute (5 days) and chronic (14 days) stages after ischemic stroke. RESULTS: A subset of phagocytic macrophages was associated with neuron projection regeneration and tissue remodeling. We also identified a unique type of T cells with highly expressed macrophage markers, including C1q, Apoe, Hexb, and Fcer1g, which showed high abilities in tissue remodeling, myelination regulation, wound healing, and anti-neuroinflammation. Moreover, natural killer cells decreased cytotoxicity and increased energy and metabolic function in the chronic stage after ischemic stroke. Two subgroups of neutrophils upregulated CCL signals to recruit peripheral immune cells and released CXCL2 to keep self-recruiting at the chronic stage. CONCLUSIONS: We identified subsets of peripheral immune cells that may provide potential therapeutic targets for promoting poststroke recovery.

Age-Related Alterations in Peripheral Immune Landscape with Magnified Impact on Post-Stroke Brain.

Immunosenescence refers to the multifaceted and profound alterations in the immune system brought about by aging, exerting complex influences on the pathophysiological processes of diseases that manifest upon it. Using a combination of single-cell RNA sequencing, cytometry by time of flight, and various immunological assays, we investigated the characteristics of immunosenescence in the peripheral blood of aged mice and its impact on the cerebral immune environment after ischemic stroke. Our results revealed some features of immunosenescence. We observed an increase in neutrophil counts, concurrent with accelerated neutrophil aging, characterized by altered expression of aging-associated markers like CD62L and consequential changes in neutrophil-mediated immune functions. Monocytes/macrophages in aged mice exhibited enhanced antigen-presentation capabilities. T cell profiles shifted from naive to effector or memory states, with a specific rise in T helper 1 cells and T helper 17 cells subpopulations and increased regulatory T cell activation in CD4 T cells. Furthermore, regulatory CD8 T cells marked by Klra decreased with aging, while a subpopulation of exhausted-like CD8 T cells expanded, retaining potent immunostimulatory and proinflammatory functions. Critically, these inherent disparities not only persisted but were further amplified within the ischemic hemispheres following stroke. In summary, our comprehensive insights into the key attributes of peripheral immunosenescence provide a vital theoretical foundation for understanding not only ischemic strokes but also other age-associated diseases.

Temporal dynamics of microglia-astrocyte interaction in neuroprotective glial scar formation after intracerebral hemorrhage.

The role of glial scar after intracerebral hemorrhage (ICH) remains unclear. This study aimed to investigate whether microglia-astrocyte interaction affects glial scar formation and explore the specific function of glial scar. We used a pharmacologic approach to induce microglial depletion during different ICH stages and examine how ablating microglia affects astrocytic scar formation. Spatial transcriptomics (ST) analysis was performed to explore the potential ligand-receptor pair in the modulation of microglia-astrocyte interaction and to verify the functional changes of astrocytic scars at different periods. During the early stage, sustained microglial depletion induced disorganized astrocytic scar, enhanced neutrophil infiltration, and impaired tissue repair. ST analysis indicated that microglia-derived insulin like growth factor 1 (IGF1) modulated astrocytic scar formation via mechanistic target of rapamycin (mTOR) signaling activation. Moreover, repopulating microglia (RM) more strongly activated mTOR signaling, facilitating a more protective scar formation. The combination of IGF1 and osteopontin (OPN) was necessary and sufficient for RM function, rather than IGF1 or OPN alone. At the chronic stage of ICH, the overall net effect of astrocytic scar changed from protective to destructive and delayed microglial depletion could partly reverse this. The vital insight gleaned from our data is that sustained microglial depletion may not be a reasonable treatment strategy for early-stage ICH. Inversely, early-stage IGF1/OPN treatment combined with late-stage PLX3397 treatment is a promising therapeutic strategy. This prompts us to consider the complex temporal dynamics and overall net effect of microglia and astrocytes, and develop elaborate treatment strategies at precise time points after ICH.

Dissecting human placental cells heterogeneity in preeclampsia and gestational diabetes using single-cell sequencing.

Preeclampsia (PE) and gestational diabetes mellitus (GDM) are pregnancy-specific complications, which affect maternal health and fetal outcomes. Currently, clinical and pathological studies have shown that placenta homeostasis is affected by these two maternal diseases. In this study, we aimed to gain insight into the heterogeneous changes in cell types in placental tissue-isolated from cesarean section by single-cell sequencing, including those patients diagnosed with PE (n = 5), GDM (n = 5) and healthy control (n = 5). A total of 96,048 cells (PE: 31,672; GDM: 25,294; control: 39,082) were identified in six cell types, dominated by trophoblast cells and immune cells. In addition, trophoblast cells were divided into four subtypes, including cytotrophoblast cells (CTBs), villous cytotrophoblasts (VCTs), syncytiotrophoblast (STB), and extravillous trophoblasts (EVTs). Immune cells are divided into lymphocytes and macrophages, of which macrophages have 3 subtypes (decidual macrophages, Hofbauer cells and macrophages), and lymphocytes have 4 subtypes (BloodNK, T cells, plasma cells, and decidual natural killer cells). Meanwhile, we also proved the orderly differentiation sequence of CTB into VCT, then STB and EVT. By pair-wise analysis of the expression and enrichment of differentially expressed genes in trophoblast cells between PE, GDM and control, it was found that these cells were involved in immune, nutrient transfer, hormone and oxidative stress pathways. In addition, T cells and macrophages play an immune defense role in both PE and GDM. The proportion of CTB and EVT cells in placental tissue was confirmed by flow cytometry. Taken together, our results suggested that the human placenta is a dynamic heterogenous organ dominated by trophoblast and immune cells, which perform their respective roles and interact with other cells in the environment to maintain normal placental function.

A novel phenotype of B cells associated with enhanced phagocytic capability and chemotactic function after ischemic stroke.

Accumulating evidence has demonstrated the involvement of B cells in neuroinflammation and neuroregeneration. However, the role of B cells in ischemic stroke remains unclear. In this study, we identified a novel phenotype of macrophage-like B cells in brain-infiltrating immune cells expressing a high level of CD45. Macrophage-like B cells characterized by co-expression of B-cell and macrophage markers, showed stronger phagocytic and chemotactic functions compared with other B cells and showed upregulated expression of phagocytosis-related genes. Gene Ontology analysis found that the expression of genes associated with phagocytosis, including phagosome- and lysosome-related genes, was upregulated in macrophage-like B cells. The phagocytic activity of macrophage-like B cells was verified by immunostaining and three-dimensional reconstruction, in which TREM2-labeled macrophage-like B cells enwrapped and internalized myelin debris after cerebral ischemia. Cell-cell interaction analysis revealed that macrophage-like B cells released multiple chemokines to recruit peripheral immune cells mainly via CCL pathways. Single-cell RNA sequencing showed that the transdifferentiation to macrophage-like B cells may be induced by specific upregulation of the transcription factor CEBP family to the myeloid lineage and/or by downregulation of the transcription factor Pax5 to the lymphoid lineage. Furthermore, this distinct B cell phenotype was detected in brain tissues from mice or patients with traumatic brain injury, Alzheimer's disease, and glioblastoma. Overall, these results provide a new perspective on the phagocytic capability and chemotactic function of B cells in the ischemic brain. These cells may serve as an immunotherapeutic target for regulating the immune response of ischemic stroke.

Single-Cell RNA Sequencing and Spatial Transcriptomics Reveal Pathogenesis of Meningeal Lymphatic Dysfunction after Experimental Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) is a devastating subtype of stroke with high mortality and disability rate. Meningeal lymphatic vessels (mLVs) are a newly discovered intracranial fluid transport system and are proven to drain extravasated erythrocytes from cerebrospinal fluid into deep cervical lymph nodes after SAH. However, many studies have reported that the structure and function of mLVs are injured in several central nervous system diseases. Whether SAH can cause mLVs injury and the underlying mechanism remain unclear. Herein, single-cell RNA sequencing and spatial transcriptomics are applied, along with in vivo/vitro experiments, to investigate the alteration of the cellular, molecular, and spatial pattern of mLVs after SAH. First, it is demonstrated that SAH induces mLVs impairment. Then, through bioinformatic analysis of sequencing data, it is discovered that thrombospondin 1 (THBS1) and S100A6 are strongly associated with SAH outcome. Furthermore, the THBS1-CD47 ligand-receptor pair is found to function as a key role in meningeal lymphatic endothelial cell apoptosis via regulating STAT3/Bcl-2 signaling. The results illustrate a landscape of injured mLVs after SAH for the first time and provide a potential therapeutic strategy for SAH based on mLVs protection by disrupting THBS1 and CD47 interaction.

Relationship Between Plasma Growth Differentiation Factor 15 Levels and Complications of Type 2 Diabetes Mellitus: A Cross-sectional Study.

OBJECTIVE: Our aim in this study was to identify the associations between growth differentiation factor 15 (GDF15) and type 2 diabetes mellitus (T2DM) complications in a community-based population in China. METHODS: Based on a cross-sectional study registered in the National Basic Public Health Service for disease management of Changshu in China, a total of 1,689 T2DM patients were enrolled and tested further for plasma GDF15 levels. Macrovascular (cardiovascular disease and diabetic foot) and microvascular (diabetic kidney disease [DKD], diabetic retinopathy, and neuropathy) complications were evaluated. Logistic regression models were conducted to identify the associations of GDF15 with the risk of diabetes complications, and linear regression models were used to assess relationships between GDF15 and other clinical features. RESULTS: Overall, 459 of the 1,689 T2DM patients (27.18%) had complications. GDF15 levels were significantly higher in patients with any type of complication compared with their counterparts. With each standard deviation increase of base 10 logarithms of GDF15 (lg-GDF15), the risk of overall complications increased by 1.17-fold (95% confidence interval [CI], 1.03 to 1.32). In contrast to macrovascular complications, associations of GDF15 with microvascular complications appeared to be stronger (adjusted odds ratio [OR], 1.24; 95% CI, 1.08 to 1.43), especially for DKD (adjusted OR, 1.51; 95% CI, 1.19 to 1.93). Subgroup analyses showed that the strength of association between GDF15 and complications varied by distinct age and T2DM duration subgroups. Patients with 2 or more types of complications had higher levels of GDF15 than those with fewer types of complications. Also, linear relationships were identified between GDF15 and several liver and kidney function indices. CONCLUSION: Higher GDF15 levels were associated with T2DM complications, especially DKD. GDF15 may serve as a biomarker for monitoring the deterioration of T2DM.

Genome-wide association studies of peduncle length in wheat under rain-fed and irrigating field conditions.

Drought is one of the most destructive environmental factors limiting wheat production and food security globally. Peduncle length (PLE) is an important morphological trait to determine plant architecture, photosynthate transport, and yield formation, which is also considered a useful index for drought tolerance in wheat. However, the genetic basis of wheat PLE is not well studied at present. Here, a large-scale genome-wide association study (GWAS) of PLE was performed using a panel of 282 wheat accessions with the Wheat 660K SNP array genotyping under rain-fed and irrigating field conditions. Totally, 1,301 significant marker-trait associations (MTAs) were identified using the threshold of p-value < 4.16 × 10-4, five of which were high-confidence. Furthermore, combining GWAS intervals, previously reported QTLs, expression levels, homologous genes, and selected sweep analysis, a total of 5 candidate genes were detected to associate with drought stress. Moreover, the expression levels of TraesCS2A02G082100 were significantly up-regulated under drought conditions and co-localized in the selected sweep region, suggesting it is a drought-responsive gene. Our results shed light on the genetic basis underlying wheat drought tolerance, which accelerates the marker-assistant selection and genetic improvement through genomic breeding in wheat.

New Insights of Early Brain Injury after Subarachnoid Hemorrhage: A Focus on the Caspase Family.

Spontaneous subarachnoid hemorrhage (SAH), primarily caused by ruptured intracranial aneurysms, remains a prominent clinical challenge with a high rate of mortality and morbidity worldwide. Accumulating clinical trials aiming at the prevention of cerebral vasospasm (CVS) have failed to improve the clinical outcome of patients with SAH. Therefore, a growing number of studies have shifted focus to the pathophysiological changes that occur during the periods of early brain injury (EBI). New pharmacological agents aiming to alleviate EBI have become a promising direction to improve outcomes after SAH. Caspases belong to a family of cysteine proteases with diverse functions involved in maintaining metabolism, autophagy, tissue differentiation, regeneration, and neural development. Increasing evidence shows that caspases play a critical role in brain pathology after SAH. Therefore, caspase regulation could be a potential target for SAH treatment. Herein, we provide an overview pertaining to the current knowledge on the role of caspases in EBI after SAH, and we discuss the promising therapeutic value of caspase-related agents after SAH.

Untangling microbial diversity and assembly patterns in rare earth element mine drainage in South China.

Ion-adsorption rare earth element (REE) deposits are the main reservoirs of REEs worldwide, and are widely exploited in South China. Microbial diversity is essential for maintaining the performance and function of mining ecosystems. Investigating the ecological patterns underlying the REE mine microbiome is essential to understand ecosystem responses to environmental changes and to improve the bioremediation of mining areas. We applied 16S rRNA and ITS gene sequence analyses to investigate the composition characteristics of prokaryotic (bacteria, archaea) and fungal communities in a river impacted by REE acid mine drainage (REE-AMD). The river formed a unique micro-ecosystem, including the main prokaryotic taxa of Proteobacteria, Acidobacteria, Crenarchaeota, and Euryarchaeota, as well as the main fungal taxa of Ascomycota, Basidiomycota, and Chytridiomycota. Analysis of microbial diversity showed that, unlike prokaryotic communities that responded drastically to pollution disturbances, fungal communities were less affected by REE-AMD, but fluctuated significantly in different seasons. Ecological network analysis revealed that fungal communities have lower connectivity and centrality, and higher modularity than prokaryotic networks, indicating that fungal communities have more stable network structures. The introduction of REE-AMD mainly reduced the complexity of the community network and the number of keystone species, while the proportion of negative prokaryotic-fungal associations in the network increased. Ecological process analysis revealed that, compared to the importance of environmental selection for prokaryotes, stochastic processes might have contributed primarily to fungal communities in REE mining areas. These findings confirm that the different assembly mechanisms of prokaryotic and fungal communities are key to the differences in their responses to environmental perturbations. The findings also provide the first insights into microbiota assembly patterns in REE-AMD and important ecological knowledge for the formation and development of microbial communities in REE mining areas.

Aged microglia promote peripheral T cell infiltration by reprogramming the microenvironment of neurogenic niches.

BACKGROUND: The immune cell compartment of the mammalian brain changes dramatically and peripheral T cells infiltrate the brain parenchyma during normal aging. However, the mechanisms underlying age-related T cell infiltration in the central nervous system remain unclear. RESULTS: Chronic inflammation and peripheral T cell infiltration were observed in the subventricular zone of aged mice. Cell-cell interaction analysis revealed that aged microglia released CCL3 to recruit peripheral CD8+ memory T cells. Moreover, the aged microglia shifted towards a pro-inflammation state and released TNF-α to upregulate the expression of VCAM1 and ICAM1 in brain venous endothelial cells, which promoted the transendothelial migration of peripheral T cells. In vitro experiment reveals that human microglia would also transit to a chemotactic phenotype when treated with CSF from the elderly. CONCLUSIONS: Our research demonstrated that microglia play an important role in the aging process of brain by shifting towards a pro-inflammation and chemotactic state. Aged microglia promote T cell infiltration by releasing chemokines and upregulating adhesion molecules on venous brain endothelial cells.

Phenotypic and Functional Characterizations of Mesenchymal Stem/Stromal Cells Isolated From Human Cranial Bone Marrow.

Mesenchymal stem/stromal cells (MSCs) are adult stem cells that were originally isolated from bone marrow. In contrast to long bone-derived MSCs that have been extensively characterized, our knowledge regarding to MSCs isolated from flat bones (e.g., cranial bones) remain less clear. In this study, MSCs were purified from human cranial bone marrow (CB-MSCs) and their transdifferentiation capacity and immunomodulatory functions were further characterized. Phenotypic analysis of CB-MSCs demonstrated high expression of CD73, CD90, and CD105 while negative for CD14, CD34, and HLA-DR. Further in vitro differentiation assay shown that CB-MSCs capable of differentiating into cell types of mesenchymal origin (i.e., adipocytes, osetoblasts, and chondrocytes) and collectively, these results indicated that cells isolated from cranial bone marrow in this study are bona fide MSCs according to the minimal criteria proposed by the International Society for Cellular Therapy. Following in vitro expansion, single colony-derived CB-MSCs (scCB-MSCs) were obtained and confocal microscopy analysis further revealed functional heterogeneity within primary CB-MSCs. Specifically, obtained scCB-MSCs exhibited GABA progenitor features, as determined by olig2 and nestin. As expect, scCB-MSCs were readily induced to differentiate into GABAergic neuron-like cells. Furthermore, immunomodulatory roles of scCB-MSCs were evaluated following co-culture with human peripheral blood lymphocytes and results shown that co-culturing with scCB-MSCs significantly suppressed lymphocyte proliferation and promoted differentiation of lymphocytes into regulatory T cells but not Th1/Th17 phenotype. Overall, our results indicated that CB-MSCs exhibited clonal heterogeneity with marked propensity to differentiate into neural-like cells and this might represent promising candidates for the treatment of neurodegenerative diseases.

Inhibition of caspase-1-mediated inflammasome activation reduced blood coagulation in cerebrospinal fluid after subarachnoid haemorrhage.

BACKGROUND: Neuroinflammation and blood coagulation responses in cerebrospinal fluid (CSF) contribute to the poor outcome associated with subarachnoid haemorrhage (SAH). We explored the role of caspase-1-mediated inflammasome activation on extrinsic blood coagulation in CSF after SAH. METHODS: Post-SAH proteomic changes and correlation between caspase-1 with extrinsic coagulation factors in human CSF after SAH were analysed. Time course and cell localisation of brain inflammasome and extrinsic coagulation proteins after SAH were explored in a rat SAH model. Pharmacological inhibition of caspase-1 via VX-765 was used to explore the role of caspase-1 in blood clearance and CSF circulation after SAH in rats. Primary astrocytes were used to evaluate the role of caspase-1 in haemoglobin-induced pyroptosis and tissue factor (TF) production/release. FINDINGS: Neuroinflammation and blood coagulation activated after SAH in human CSF. The caspase-1 levels significantly correlated with the extrinsic coagulation factors. The activated caspase-1 and extrinsic coagulation initiator TF was increased on astrocytes after SAH in rats. VX-765 attenuated neurological deficits by accelerating CSF circulation and blood clearance through inhibiting pyroptotic neuroinflammation and TF-induced fibrin deposition in the short-term, and improved learning and memory capacity by preventing hippocampal neuronal loss and hydrocephalus in the long-term after SAH in rats. VX-765 reduced haemoglobin-induced pyroptosis and TF production/release in primary astrocytes. INTERPRETATION: Inhibition of caspase-1 by VX-765 appears to be a potential treatment against neuroinflammation and blood coagulation in CSF after SAH. FUNDING: This study was supported by National Institutes of Health of United States of America, and National Natural Science Foundation of China.

Cepharanthine Attenuates Early Brain Injury after Subarachnoid Hemorrhage in Mice via Inhibiting 15-Lipoxygenase-1-Mediated Microglia and Endothelial Cell Ferroptosis.

BACKGROUND: Ferroptosis is a newly identified form of programmed cell death caused by iron-dependent lipid peroxidation. Our study was designed to determine the expression patterns and role of 15-lipoxygenase-1 (ALOX15) in subarachnoid hemorrhage (SAH) and to investigate whether cepharanthine (CEP) can inhibit ferroptosis by inhibiting ALOX15 in specific cell types. METHODS: A mouse model of SAH was developed by the endovascular perforation method. bEend.3 endothelial cells and BV2 microglial cells as well as RSL3 and hemin were used to simulate SAH in vitro. Mice and cell lines were treated with CEP and a group of specific oxygenase inhibitors to explore the protection effect from ferroptosis. Lipid peroxidation staining with BODIPY 581/591 C11 and transmission electron microscopy were used to identify ferroptosis in vitro and in vivo. RESULTS: In the present study, the accumulation of lipid peroxide, a defect in the glutathione peroxidase 4 (GPx4)/glutathione (GSH) antioxidant system, highly expressed ALOX15 in microglia and endothelium, and ferroptotic changes in microglial mitochondria confirmed the occurrence of ferroptosis after SAH in vivo. Further, CEP was shown to inhibit ferroptosis and improve neurological function by downregulating the expression of ALOX15. During in vitro experiments, we investigated the important role ALOX15 in RSL3-induced endothelial ferroptosis. In addition, we found that M2-type microglia are more sensitive to RSL3-induced ferroptosis than M1-type microglia and that hemin probably induced ferroptosis in M2-type microglia by increasing ALOX15 levels and decreasing GPx4 levels. The effect of CEP treatment was also demonstrated in vitro. CONCLUSIONS: In summary, to the best of our knowledge, this is the first study demonstrating that ferroptosis occurred in the microglia and endothelium after SAH, and this process was facilitated by increased ALOX15 levels. More importantly, treatment with CEP could inhibit ferroptosis through downregulating the expression of ALOX15.

ZNF382 controls mouse neuropathic pain via silencer-based epigenetic inhibition of Cxcl13 in DRG neurons.

Nerve injury-induced changes of gene expression in dorsal root ganglion (DRG) are critical for neuropathic pain genesis. However, how these changes occur remains elusive. Here we report the down-regulation of zinc finger protein 382 (ZNF382) in injured DRG neurons after nerve injury. Rescuing this down-regulation attenuates nociceptive hypersensitivity. Conversely, mimicking this down-regulation produces neuropathic pain symptoms, which are alleviated by C-X-C motif chemokine 13 (CXCL13) knockdown or its receptor CXCR5 knockout. Mechanistically, an identified cis-acting silencer at distal upstream of the Cxcl13 promoter suppresses Cxcl13 transcription via binding to ZNF382. Blocking this binding or genetically deleting this silencer abolishes the ZNF382 suppression on Cxcl13 transcription and impairs ZNF382-induced antinociception. Moreover, ZNF382 down-regulation disrupts the repressive epigenetic complex containing histone deacetylase 1 and SET domain bifurcated 1 at the silencer-promoter loop, resulting in Cxcl13 transcriptional activation. Thus, ZNF382 down-regulation is required for neuropathic pain likely through silencer-based epigenetic disinhibition of CXCL13, a key neuropathic pain player, in DRG neurons.

Association between maternal vitamin D status with pregnancy outcomes and offspring growth in a population of Wuxi, China.

BACKGROUND AND OBJECTIVES: The role of maternal vitamin D in infantile growth remains unclear. METHODS AND STUDY DESIGN: Serum 25-hydroxyvitamin D [25(OH)D] concentrations were examined for pregnancies who visited the Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University from January 2016 to December 2017. Anthropometric measurements of corresponding offspring were performed from birth to 2 to 3 years old. Infantile body mass index (BMI) was transformed into age-, sex- and height- normalized z scores, and Latent Class Growth Mixture (LCGM) model was used to identify trajectories of BMI-Z. RESULTS: Among the 329 included pregnancy women, 109 (33.13 %), 190 (57.75%) and 30 (9.12%) were defined as vitamin D deficiency [25(OH)D <30 nmol/L], insufficiency [30 nmol/L≤25(OH)D<50 nmol/L] and sufficiency [25(OH)D ≥50 nmol/L], respectively. When compared with vitamin D sufficiency, maternal vitamin D deficiency was not associated with preterm birth [odds ratio (OR)=2.69, 95% confidence interval (95% CI)=0.57-12.80], small for gestation age (OR=0.99, 95% CI=0.29-3.46), and low birth weight (OR=1.69, 95% CI=0.34-8.51). Similarly, no significant relationships were found between maternal vitamin D concentrations and anthropometric indices (such as weight, length, BMI) during 0 to 3 years old. Furthermore, LCGM model identified two patterns of offspring growth: stable moderate BMI-Z and early transient BMI-Z groups. Maternal vitamin D levels were higher in the former group than the latter (p=0.037); however, maternal vitamin D status appeared to be unrelated with offspring BMI-Z trajectories in multivariable logistic regression models. CONCLUSIONS: Maternal vitamin D deficiency may not be related to adverse pregnancy outcomes as well as offspring growth.

Transcriptome Analysis of Microglia Reveals That the TLR2/IRF7 Signaling Axis Mediates Neuroinflammation After Subarachnoid Hemorrhage.

Microglia-mediated neuroinflammatory response in the early brain injury after subarachnoid hemorrhage (SAH) has been reported to have an impact on progress, and the mechanism is not completely understood. Here, we performed genome-wide transcriptome analysis of microglia purified from damaged hemisphere of adult mice at 3 days after SAH or sham operation. Robust transcriptional changes were observed between SAH-induced and healthy microglia, indicating rapid activation of microglia after suffering from SAH. We identified 1576 differentially expressed genes (DEGs; 928 upregulated and 648 downregulated) in SAH-induced microglia compared with sham microglia, representing a strong alteration of the genome (6.85% of total ∼23,000 genes). Functional enrichment of these DEGs indicated that cell division, inflammatory response, cytokine production, and leukocyte chemotaxis were strongly activated in SAH-induced microglia. Moreover, we identified and proved that the TLR2/IRF7 signaling axis was involved in the regulation of this microglia-mediated inflammation in SAH mice by performing flow cytometry and immunofluorescence. Together, these results provided a perspective of microglia-mediated neuroinflammatory response in the early stage of SAH and might give a new therapeutic target for SAH.

Association between serum 25-hydroxyvitamin D concentrations and obesity in one-year-old Chinese infants.

Recent studies suggested that vitamin D is linked with obesity, but evidence in infants is scarce. Therefore, we aimed to make an exploration in infants. A total of 414 infants at one year old who visited Maternity and Child Health Care Hospital of Wuxi in China were recruited. Finger-stick blood sampling was conducted in all the subjects, and serum 25-hydroxyvitamin D [25(OH)D] concentrations were measured. Maternal characteristics during pregnancy and infantile information were collected by questionnaires or extracting from medical records. Multivariable linear models were performed to assess the relationship between 25(OH)D and body mass index (BMI), while multivariable logistic regression models were used to examine the association between 25(OH)D and obesity. Among the 414 infants, 69 (16.67%) and 81 (19.57%) infants were defined as obesity and vitamin D deficiency [25(OH)D < 50 nmol/L], respectively. The mean (SD) of 25(OH)D concentration was 68.05 (19.05) in infants without obesity, which was significantly higher than that of obese infants [60.36(18.49), p = .002]. Inverse linear relationships were observed between 25(OH)D level and BMI (ß = -0.017, p = .004) as well as BMI Z-score (ß = -0.010, p = .004). Furthermore, vitamin D deficiency was associated with an increased risk of obesity of infants (adjusted odds ratio = 2.74, 95% confidence interval = 1.20-6.25, with 25(OH)D ≥ 75 nmol/L as a reference). The results showed that serum 25(OH)D concentrations were significantly lower in infants with obesity, suggesting vitamin D deficiency may be an independent risk factor for obesity among one-year-old Chinese infants.

BMI Trajectories During the First 2 Years, and Their Associations With Infant Overweight/Obesity: A Registered Based Cohort Study in Taizhou, China.

Objective: The purpose of this study was to identify trajectories of body mass index (BMI) in toddlers from birth to 2 years old and examine their association with infantile overweight/obesity. Methods: Data were collected from 19,054 children born in any hospital or community healthcare center in Taizhou, China from 2018 to 2019 with at least three BMI measurements after birth. The Latent Class Growth Mixture Model was used to identify distinct BMI trajectories during the first 2 years of infants. Multiple logistic regression models were conducted to explore the associated factors of different BMI trajectories, and log-binomial regression was performed to assess the association between the trajectories and overweight/obesity. Results: Three heterogeneous BMI trajectories were identified and labeled as "lower" (36.21%, n = 6,899), "middle" (53.15%, n = 10,128) and "upper" (10.64%, n = 2,027), respectively. Several characteristics of infants and their corresponding mothers were found to be correlated with infant BMI trajectories, including infant sex, mode of delivery and weight at birth, as well as maternal parity, early pregnancy BMI and status of gestational diabetes mellitus. Furthermore, compared with those in the lower trajectory, infants in the middle [prevalence ratio (PR) = 2.63, 95% confidence interval (95%CI) = 2.17-2.63] or upper (PR = 2.98, 95%CI = 1.51-2.98) trajectory groups were prone to be overweight/obesity at their final observation. Conclusion: Heterogeneous BMI trajectories were observed in our study. Characteristics of both infants and their corresponding mothers could be potential determinants of infant growth. Moreover, infants in the middle and upper trajectory groups were more likely to suffer overweight/obesity.

The Changes of Leukocytes in Brain and Blood After Intracerebral Hemorrhage.

Preclinical and clinical research has demonstrated that inflammation is a critical factor regulating intracerebral hemorrhage (ICH)-induced brain injury. Growing evidence suggests that myeloid cells and lymphocytes have an effect on the pathophysiological processes associated with ICH, such as inflammation, immune responses, perihematomal edema formation, blood-brain barrier (BBB) integrity, and cell death. However, the underlying mechanisms remain largely unknown. We aimed to explore the role immune cells played at different stages of the ICH. To achieve this, novel bioinformatics algorithms were employed to analyze the gene expression profiles and three different analytical tools were utilized to predict the abundances of cell types. In this study, we found that natural killer (NK) cells infiltrated into the brain parenchyma after ICH. Infiltrating NK cells may mediate brain injury through degranulation and recruitment of other cells. Besides, in the acute phase of ICH, monocytes in peripheral blood carried out phagocytosis and secretion of cytokines. On the other hand, in the subacute stage, non-classical monocytes were activated and showed a stronger ability to carry out heme metabolism, wound healing, and antigen processing and presentation. In conclusion, our findings emphasize the significance of intracerebral infiltrating immunocytes in ICH and demonstrate that ICH is a systemic disease affected by peripheral blood. The hub genes identified might be promising therapeutic targets. We also provide a reference on how to use bioinformatics approaches to explore non-neoplastic immune-related diseases.