RobustMat: Neural Diffusion for Street Landmark Patch Matching Under Challenging Environments.

For autonomous vehicles (AVs), visual perception techniques based on sensors like cameras play crucial roles in information acquisition and processing. In various computer perception tasks for AVs, it may be helpful to match landmark patches taken by an onboard camera with other landmark patches captured at a different time or saved in a street scene image database. To perform matching under challenging driving environments caused by changing seasons, weather, and illumination, we utilize the spatial neighborhood information of each patch. We propose an approach, named RobustMat, which derives its robustness to perturbations from neural differential equations. A convolutional neural ODE diffusion module is used to learn the feature representation for the landmark patches. A graph neural PDE diffusion module then aggregates information from neighboring landmark patches in the street scene. Finally, feature similarity learning outputs the final matching score. Our approach is evaluated on several street scene datasets and demonstrated to achieve state-of-the-art matching results under environmental perturbations.

Deep Succinylproteomics of Brain Tissues from Intracerebral Hemorrhage with Inhibition of Toll-Like Receptor 4 Signaling.

It is unclear how Toll-like receptor (TLR) 4 signaling affects protein succinylation in the brain after intracerebral hemorrhage (ICH). Here, we constructed a mouse ICH model to investigate the changes in ICH-associated brain protein succinylation, following a treatment with a TLR4 antagonist, TAK242, using a high-resolution mass spectrometry-based, quantitative succinyllysine proteomics approach. We characterized the prevalence of approximately 6700 succinylation events and quantified approximately 3500 sites, highlighting 139 succinyllysine site changes in 40 pathways. Further analysis showed that TAK242 treatment induced an increase of 29 succinyllysine sites on 28 succinylated proteins and a reduction of 24 succinyllysine sites on 23 succinylated proteins in the ICH brains. TAK242 treatment induced both protein hypersuccinylations and hyposuccinylations, which were mainly located in the mitochondria and cytoplasm. GO analysis showed that TAK242 treatment-induced changes in the ICH-associated succinylated proteins were mostly located in synapses, membranes and vesicles, and enriched in many cellular functions/compartments, such as metabolism, synapse, and myelin. KEGG analysis showed that TAK242-induced hyposuccinylation was mainly linked to fatty acid metabolism, including elongation and degradation. Moreover, a combined analysis of the succinylproteomic data with previously published transcriptome data revealed that most of the differentially succinylated proteins induced by TAK242 treatment were mainly distributed throughout neurons, astrocytes, and endothelial cells, and the mRNAs of seven and three succinylated proteins were highly expressed in neurons and astrocytes, respectively. In conclusion, we revealed that several TLR4 signaling pathways affect the succinylation processes and pathways in mouse ICH brains, providing new insights on the ICH pathophysiological processes. Data are available via ProteomeXchange with identifier PXD025622.

The Effective Coverage of Homogeneous Teams with Radial Attenuation Models.

For the area coverage (e.g., using a WSN), despite the comprehensive research works on full-plane coverage using a multi-node team equipped with the ideal constant model, only very few works have discussed the coverage of practical models with varying intensity. This paper analyzes the properties of the effective coverage of multi-node teams consisting of a given numbers of nodes. Each node is equipped with a radial attenuation disk model as its individual model of coverage, which conforms to the natural characteristics of devices in the real world. Based on our previous analysis of 2-node teams, the properties of the effective coverage of 3-node and n-node (n≥4) teams in regular geometric formations are analyzed as generalized cases. Numerical analysis and simulations for 3-node and n-node teams (n≥4) are conducted separately. For the 3-node cases, the relations between the side lengths of equilateral triangle formation and the effective coverage of the team equipped with two different types of models are respectively inspected. For the n-node cases (n≥4), the effective coverage of a team in three formations, namely regular polygon, regular star, and equilateral triangular tessellation (for n=6), are investigated. The results can be applied to many scenarios, either dynamic (e.g., robots with sensors) or static, where a team of multiple nodes cooperate to produce a larger effective coverage.

Succinylation profiles of brain injury after intracerebral hemorrhage.

Protein posttranslational modifications (PTMs) regulate the biological processes of human diseases by genetic code expansion and cellular pathophysiology regulation; however, system-wide changes in PTM levels in the intracerebral hemorrhage (ICH) brain remain poorly understood. Succinylation refers to a major PTM during the regulation of multiple biological processes. In this study, according to the methods of quantitative succinyllysine proteomics based on high-resolution mass spectrometry, we investigated ICH-associated brain protein succinyllysine modifications and obtained 3,680 succinylated sites and quantified around 3,530 sites. Among them, 25 succinyllysine sites on 23 proteins were upregulated (hypersuccinylated), whereas 13 succinyllysine sites on 12 proteins were downregulated (hyposuccinylated) following ICH. The cell component enrichment analysis of these succinylproteins with significant changes showed that 58.3% of the hyposuccinylated proteins were observed in the mitochondria, while the hyper-succinylproteins located in mitochondria decreased in the percentage to about 35% in ICH brains with a concomitant increase in the percentage of cytoplasm to 30.4%. Further bioinformatic analysis showed that the succinylproteins were mostly mitochondria and synapse-related subcellular located and involved in many pathophysiological processes, like metabolism, synapse working, and ferroptosis. Moreover, the integrative analysis of our succinylproteomics data and previously published transcriptome data showed that the mRNAs matched by most differentially succinylated proteins were especially highly expressed in neurons, endothelial cells, and astrocytes. Our study uncovers some succinylation-affected processes and pathways in response to ICH brains and gives us novel insights into understanding pathophysiological processes of brain injury caused by ICH.

Role of eotaxin-1/CCL11 in sepsis-induced myocardial injury in elderly patients.

Myocardial injury is a serious complication of sepsis. The present study aimed to identify potential biomarkers of sepsis-induced myocardial injury. Differentially expressed genes (DEGs) in patients and mice with sepsis-induced myocardial injury were identified via bioinformatic analysis. The identified DEG was tested in elderly patients with sepsis-induced myocardial injury. We identified 19 co-expressed DEGs. The most significant DEG was eotaxin-1/CCL11. We enrolled 25 controls without infections and 28 patients with sepsis-induced myocardial injury. Six of patients died within 30 days. Circulating eotaxin-1/CCL11 levels were significantly higher in patients with sepsis-induced myocardial injury than controls and were higher in non-survivors than survivors (both P < 0.01). Eotaxin-1/CCL11 was positively correlated with troponin I (r=0.48, P=0.01), B-type natriuretic peptide (BNP, r=0.44, P=0.02), and white blood cell (WBC) count (r=0.41, P=0.03). For the prediction of 30-day mortality, eotaxin-1/CCL11 had the greatest discriminatory ability (AUC 0.97) compared with troponin I (AUC 0.89), BNP (AUC 0.80), and WBC count (AUC 0.86). Taken together, eotaxin-1/CCL11 was upregulated in sepsis-injured myocardium and circulating eotaxin-1/CCL11 was a biomarker for predicting severity and mortality of elderly patients with sepsis-induced myocardial injury. These results suggest that eotaxin-1/CCL11 may become a useful biomarkers and potential therapeutic target for sepsis-induced myocardial injury.

Vinpocetine alleviate cerebral ischemia/reperfusion injury by down-regulating TLR4/MyD88/NF-κB signaling.

Inflammatory responses play crucial roles in cerebral ischemia/reperfusion injury. Toll-like receptor 4 (TLR4) is an important mediator of the neuroinflammatory response to cerebral ischemia/reperfusion injury. Vinpocetine is a derivative of the alkaloid vincamine and exerts an anti-inflammatory effect by inhibiting NF-κB activation. However, the effects of vinpocetine on pathways upstream of NF-κB signaling, such as TLR4, have not been fully elucidated. Here, we used mouse middle cerebral artery occlusion (MCAO) and cell-based oxygen-glucose deprivation (OGD) models to evaluate the therapeutic effects and mechanisms of vinpocetine treatment. The vinpocetine treatment significantly reduced mice cerebral infarct volumes and neurological scores. Moreover, the numbers of TUNEL+ and Fluoro-Jade B+ cells were significantly decreased in the ischemic brain tissues after vinpocetine treatment. In the OGD model, the vinpocetine treatment also increased the viability of cultured cortical neurons. Interestingly, vinpocetine exerted a neuroprotective effect on the mouse MCAO model and cell-based OGD model by inhibiting TLR4-mediated inflammatory responses and decreasing proinflammatory cytokine release through the MyD88-dependent signaling pathway, independent of TRIF signaling pathway. In conclusion, vinpocetine exerts anti-inflammatory effects to ameliorate cerebral ischemia/reperfusion injury in vitro and in vivo. Vinpocetine may inhibit inflammatory responses through the TLR4/MyD88/NF-κB signaling pathway, independent of TRIF-mediated inflammatory responses. Thus, vinpocetine may be an attractive therapeutic candidate for the treatment of ischemic cerebral injury or other inflammatory diseases.

CD36 Gene Polymorphisms Are Associated with Intracerebral Hemorrhage Susceptibility in a Han Chinese Population.

The CD36 gene encodes a membrane glycoprotein (type B scavenger receptor, SR-B2) that plays a crucial role in lipid sensing, innate immunity, atherogenesis, and glycolipid metabolism. In this study, we aimed to investigate the association between CD36 gene polymorphisms and intracerebral hemorrhage (ICH) in a Han Chinese population. We performed genotype and allele analyses for eleven single nucleotide polymorphisms (SNPs) of CD36 in a case-controlled study involving 292 ICH patients and 298 control participants. Eleven SNPs were genotyped by the Improved Multiple Ligase Detection Reaction (iMLDR) method. The results indicated that the SNP rs1194182 values were significantly different between ICH group and control group in a dominant model after adjusting for confounding factors. The subgroup analysis conducted for rs1194182 showed that the allele G frequencies were significantly different between ICH patients and controls in hypertension group via a dominant model. We then analyzed the rs1194182 genotype distributions among different groups of the serum lipid groups, including BMI, TC, TG, HDL, and LDL. However, no significant differences were found in the analysis of other subgroups. Taken together, these findings indicate that rs1194182 polymorphism in the CD36 gene was associated with ICH, and genotype GG could be an independent predictor.

Mfsd2a (Major Facilitator Superfamily Domain Containing 2a) Attenuates Intracerebral Hemorrhage-Induced Blood-Brain Barrier Disruption by Inhibiting Vesicular Transcytosis.

BACKGROUND: Blood-brain barrier (BBB) disruption aggravates brain injury induced by intracerebral hemorrhage (ICH); however, the mechanisms of BBB damage caused by ICH remain elusive. Mfsd2a (major facilitator superfamily domain containing 2a) has been known to play an essential role in BBB formation and function. In this study, we investigated the role and underlying mechanisms of Mfsd2a in BBB permeability regulation after ICH. METHODS AND RESULTS: Using ICH models, we found that Mfsd2a protein expression in perihematomal brain tissues was significantly decreased after ICH. Knockdown and knockout of Mfsd2a in mice markedly increased BBB permeability, neurological deficit score, and brain water contents after ICH, and these were rescued by overexpressing Mfsd2a in perihematomas. Moreover, we found that Mfsd2a regulation of BBB permeability after ICH correlated with changes in vesicle number. Expression profiling of tight junction proteins showed no differences in Mfsd2a knockdown, Mfsd2a knockout, and Mfsd2a overexpression mice. However, using electron microscopy following ICH, we observed a significant increase in pinocytotic vesicle number in Mfsd2a knockout mice and decreased the number of pinocytotic vesicles in mouse brains with Mfsd2a overexpression. Finally, using multiple reaction monitoring, we screened out 3 vesicle trafficking-related proteins (Srgap2, Stx7, and Sec22b) from 31 vesicle trafficking-related proteins that were markedly upregulated in Mfsd2a knockout mice compared with controls after ICH. CONCLUSIONS: In summary, our results suggest that Mfsd2a may protect against BBB injury by inhibiting vesicular transcytosis following ICH.

Regulatory T cells ameliorate intracerebral hemorrhage-induced inflammatory injury by modulating microglia/macrophage polarization through the IL-10/GSK3ß/PTEN axis.

Inflammation mediated by the peripheral infiltration of inflammatory cells plays an important role in intracerebral hemorrhage (ICH) induced secondary injury. Previous studies have indicated that regulatory T lymphocytes (Tregs) might reduce ICH-induced inflammation, but the precise mechanisms that contribute to ICH-induced inflammatory injury remain unclear. Our results show that the number of Tregs in the brain increases after ICH. Inducing Tregs deletion using a CD25 antibody or Foxp3DTR-mice increased neurological deficient scores (NDS), the level of inflammatory factors, hematoma volumes, and neuronal degeneration. Meanwhile, boosting Tregs using a CD28 super-agonist antibody reduced the inflammatory injury. Furthermore, Tregs depletion shifted microglia/macrophage polarization toward the M1 phenotype while boosting Tregs shifted this transition toward the M2 phenotype. In vitro, a transwell co-culture model of microglia and Tregs indicated that Tregs changed the polarization of microglia, decreased the expression of MHC-II, IL-6, and TNF-α and increased CD206 expression. IL-10 originating from Tregs mediated the microglia polarization by increasing the expression of Glycogen Synthase Kinase 3 beta (GSK3ß), which phosphorylates and inactivates Phosphatase and Tensin homologue (PTEN) in microglia, TGF-ß did not participate in this conversion. Thus, Tregs ameliorated ICH-induced inflammatory injury by modulating microglia/macrophage polarization toward the M2 phenotype through the IL-10/GSK3ß/PTEN axis.

Decreased PPAR-γ expression after internal carotid artery stenting is associated with vascular lesions induced by smooth muscle cell proliferation and systemic inflammation in a minipig model.

Vascular restenosis after stenting is known to be largely mediated by proliferation of vascular smooth muscle cells. Recently, peroxisome proliferator-activated receptor gamma (PPAR-γ) has been implicated as a regulator of cellular inflammatory responses, and the PPAR-γ agonist rosiglitazone (ROSI) has been shown to attenuate atherosclerosis formation. However, whether ROSI can inhibit neointimal formation by regulating the inflammatory response and inhibiting vascular smooth muscle hyperplasia after stenting-induced injury remains to be clarified. Accordingly, in this study, 10 minipigs were randomly divided into two groups: the stenting group (n = 5) and the ROSI group (n = 5). Morphometric analysis was conducted for the stented arteries. The protein expressions of PPAR-γ and smooth muscle 22-alpha (SM22α) were analyzed by immunohistochemistry and western blotting, and the serum interferon-γ and interleukin-10 levels were measured by enzyme-linked immunosorbent assay. Three months after implantation, morphometric analysis revealed that administration of ROSI (0.5 mg/kg/d, continuous administration for 90 days) resulted in significant reductions of luminal stenosis, the neointimal area, and neointimal thickness, as compared to the stenting groups. The expression of PPAR-γ and the PPAR-γ/SM22α ratio in the ROSI group were higher than in the stenting group. Furthermore, the serum interferon-γ and interleukin-10 levels were found to be increased and to reach peak levels at 4 h and 7 days after stenting, respectively, after which both declined. However, ROSI treatment resulted in decreased interferon-γ and increased interleukin-10 levels after stenting. In both groups, the cytokine levels returned to the baseline levels on day 56 after stenting. Taken together, these results suggest that ROSI can reduce neointimal formation after stenting by inhibiting the local and systemic inflammatory responses as well as vascular smooth muscle hyperplasia.

A20 Ameliorates Intracerebral Hemorrhage-Induced Inflammatory Injury by Regulating TRAF6 Polyubiquitination.

Reducing excessive inflammation is beneficial for the recovery from intracerebral hemorrhage (ICH). Here, the roles and mechanisms of A20 (TNFAIP3), an important endogenous anti-inflammatory factor, are examined in ICH. A20 expression in the PBMCs of ICH patients and an ICH mouse model was detected, and the correlation between A20 expression and neurologic deficits was analyzed. A20 expression was increased in PBMCs and was negatively related to the modified Rankin Scale score. A20 expression was also increased in mouse perihematomal tissues. A20-/- and A20-overexpressing mice were generated to further analyze A20 function. Compared with wild-type (WT) mice, A20-/- and A20-overexpressing mice showed significant increases and decreases, respectively, in hematoma volume, neurologic deficit score, mortality, neuronal degeneration, and proinflammatory factors. Moreover, WT-A20-/- parabiosis was established to explore the role of A20 in peripheral blood in ICH injury. ICH-induced damage, including brain edema, neurologic deficit score, proinflammatory factors, and neuronal apoptosis, was reduced in A20-/- parabionts compared with A20-/- mice. Finally, the interactions between TRAF6 and Ubc13 and UbcH5c were increased in A20-/- mice compared with WT mice; the opposite occurred in A20-overexpressing mice. Enhanced IκBα degradation and NF-κB activation were observed in A20-/- mice, but the results were reversed in A20-overexpressing mice. These results suggested that A20 is involved in regulating ICH-induced inflammatory injury in both the central and peripheral system and that A20 reduces ICH-induced inflammation by regulating TRAF6 polyubiquitination. Targeting A20 may thus be a promising therapeutic strategy for ICH.

Interleukin-23 Secreted by Activated Macrophages Drives γδT Cell Production of Interleukin-17 to Aggravate Secondary Injury After Intracerebral Hemorrhage.

BACKGROUND: Neuroinflammation plays a key role in intracerebral hemorrhage (ICH)-induced secondary brain injury, but the specific roles of peripheral inflammatory cells such as macrophages and lymphocytes remain unknown. The purpose of this study was to explore the roles of macrophages, T lymphocytes, and the cytokines they secrete as potential targets for treating secondary brain injury after ICH. METHODS AND RESULTS: Our results showed that peripheral macrophages and T lymphocytes successively infiltrated the brain, with macrophage counts peaking 1 day after ICH and T-lymphocyte counts peaking after 4 days. These peaks in cellular infiltration corresponded to increases in interleukin (IL)-23 and IL-17 expression, respectively. We found that hemoglobin from the hematoma activated IL-23 secretion by infiltrating macrophages by inducing the formation of toll-like receptor (TLR) 2/4 heterodimer. This increased IL-23 expression stimulated γδT-cell production of IL-17, which increased brain edema and neurologic deficits in the model mice as a proinflammatory factor. Finally, we found that sparstolonin B (SsnB) could ameliorate brain edema and neurologic deficits in ICH model mice via inhibition of TLR2/TLR4 heterodimer formation, and notably, SsnB interacted with myeloid differentiation factor 88 Arg196. CONCLUSIONS: Together, our results reveal the importance of the IL-23/IL-17 inflammatory axis in secondary brain injury after ICH and thus provide a new therapeutic target for ICH treatment.

Toll-Like Receptor 4/MyD88-Mediated Signaling of Hepcidin Expression Causing Brain Iron Accumulation, Oxidative Injury, and Cognitive Impairment After Intracerebral Hemorrhage.

BACKGROUND: Disturbance of brain iron metabolism after intracerebral hemorrhage (ICH) results in oxidative brain injury and cognition impairment. Hepcidin plays an important role in regulating iron metabolism, and we have reported that serum hepcidin is positively correlated with poor outcomes in patients with ICH. However, the roles of hepcidin in brain iron metabolism after ICH remain largely unknown. METHODS: Parabiosis and ICH models combined with in vivo and in vitro experiments were used to investigate the roles of hepcidin in brain iron metabolism after ICH. RESULTS: Increased hepcidin-25 was found in serum and primarily in astrocytes after ICH. The brain iron efflux, oxidative brain injury, and cognition impairment were improved in Hepc-/- ICH mice but aggravated by the human hepcidin-25 peptide in C57BL/6 ICH mice. Data obtained in in vitro studies showed that increased hepcidin inhibited the intracellular iron efflux of brain microvascular endothelial cells but was rescued by a hepcidin antagonist, fursultiamine. Using parabiosis ICH models also shows that increased serum hepcidin prevents brain iron efflux. In addition, Toll-like receptor 4 (TLR4)/MyD88 signaling pathway increased hepcidin expression by promoting interleukin-6 expression and signal transducer and activator of transcription 3 phosphorylation. TLR4-/- and MyD88-/- mice exhibited improvement in brain iron efflux at 7, 14, and 28 days after ICH, and the TLR4 antagonist (6R)-6-[N-(2-chloro-4-fluorophenyl) sulfamoyl] cyclohex-1-ene-1-carboxylate significantly decreased brain iron levels at days 14 and 28 after ICH and improved cognition impairment at day 28. CONCLUSIONS: The results presented here show that increased hepcidin expression caused by inflammation prevents brain iron efflux via inhibition of the intracellular iron efflux of brain microvascular endothelial cells entering into circulation and aggravating oxidative brain injury and cognition impairment, which identifies a mechanistic target for muting inflammation to promote brain iron efflux and to attenuate oxidative brain injury after ICH.