Treg cell-derived osteopontin promotes microglia-mediated white matter repair after ischemic stroke.

The precise mechanisms underlying the beneficial effects of regulatory T (Treg) cells on long-term tissue repair remain elusive. Here, using single-cell RNA sequencing and flow cytometry, we found that Treg cells infiltrated the brain 1 to 5 weeks after experimental stroke in mice. Selective depletion of Treg cells diminished oligodendrogenesis, white matter repair, and functional recovery after stroke. Transcriptomic analyses revealed potent immunomodulatory effects of brain-infiltrating Treg cells on other immune cells, including monocyte-lineage cells. Microglia depletion, but not T cell lymphopenia, mitigated the beneficial effects of transferred Treg cells on white matter regeneration. Mechanistically, Treg cell-derived osteopontin acted through integrin receptors on microglia to enhance microglial reparative activity, consequently promoting oligodendrogenesis and white matter repair. Increasing Treg cell numbers by delivering IL-2:IL-2 antibody complexes after stroke improved white matter integrity and rescued neurological functions over the long term. These findings reveal Treg cells as a neurorestorative target for stroke recovery.

Endothelial peroxiredoxin-4 is indispensable for blood-brain barrier integrity and long-term functional recovery after ischemic stroke.

The endothelial lining of cerebral microvessels is damaged relatively early after cerebral ischemia/reperfusion (I/R) injury and mediates blood-brain barrier (BBB) disruption, neurovascular injury, and long-term neurological deficits. I/R induces BBB leakage within 1 h due to subtle structural alterations in endothelial cells (ECs), including reorganization of the actin cytoskeleton and subcellular redistribution of junctional proteins. Herein, we show that the protein peroxiredoxin-4 (Prx4) is an endogenous protectant against endothelial dysfunction and BBB damage in a murine I/R model. We observed a transient upregulation of Prx4 in brain ECs 6 h after I/R in wild-type (WT) mice, whereas tamoxifen-induced, selective knockout of Prx4 from endothelial cells (eKO) mice dramatically raised vulnerability to I/R. Specifically, eKO mice displayed more BBB damage than WT mice within 1 to 24 h after I/R and worse long-term neurological deficits and focal brain atrophy by 35 d. Conversely, endothelium-targeted transgenic (eTG) mice overexpressing Prx4 were resistant to I/R-induced early BBB damage and had better long-term functional outcomes. As demonstrated in cultures of human brain endothelial cells and in animal models of I/R, Prx4 suppresses actin polymerization and stress fiber formation in brain ECs, at least in part by inhibiting phosphorylation/activation of myosin light chain. The latter cascade prevents redistribution of junctional proteins and BBB leakage under conditions of Prx4 repletion. Prx4 also tempers microvascular inflammation and infiltration of destructive neutrophils and proinflammatory macrophages into the brain parenchyma after I/R. Thus, the evidence supports an indispensable role for endothelial Prx4 in safeguarding the BBB and promoting functional recovery after I/R brain injury.

Graph-based mitochondrial genomes of three foundation species in the Saccharum genus.

KEY MESSAGE: We reported the graph-based mitochondrial genomes of three foundation species (Saccharum spontaneum, S. robustum and S. officinarum) for the first time. The results revealed pan-structural variation and evolutionary processes in the mitochondrial genomes within Saccharum. Saccharum belongs to the Andropogoneae, and cultivars species in Saccharum contribute nearly 80% of sugar production in the world. To explore the genomic studies in Saccharum, we assembled 15 complete mitochondrial genomes (mitogenome) of three foundation species (Saccharum spontaneum, S. robustum and S. officinarum) using Illumina and Oxford Nanopore Technologies sequencing data. The mitogenomes of the three species were divided into a total of eight types based on contig numbers and linkages. All mitogenomes in the three species encoded 51 unique genes, including 32 protein-coding, 3 ribosomal RNA (rRNA) and 16 transfer RNA (tRNA) genes. The existence of long and short-repeat-mediated recombinations in the mitogenome of S. officinarum and S. robustum was revealed and confirmed through PCR validation. Furthermore, employing comparative genomics and phylogenetic analyses of the organelle genomes, we unveiled the evolutionary relationships and history of the major interspecific lineages in Saccharum genus. Phylogenetic analyses of homologous fragments between S. officinarum and S. robustum showed that S. officinarum and S. robustum are phylogenetically distinct and that they were likely parallel rather than domesticated. The variations between ancient (S. sinense and S. barberi) and modern cultivated species (S. hybrid) possibly resulted from hybridization involving different S. officinarum accessions. Lastly, this project reported the first graph-based mitogenomes of three Saccharum species, and a systematic comparison of the structural organization, evolutionary processes, and pan-structural variation of the Saccharum mitogenomes revealed the differential features of the Saccharum mitogenomes.

Exosomes: compositions, biogenesis, and mechanisms in diabetic wound healing.

Diabetic wounds are characterized by incomplete healing and delayed healing, resulting in a considerable global health care burden. Exosomes are lipid bilayer structures secreted by nearly all cells and express characteristic conserved proteins and parent cell-associated proteins. Exosomes harbor a diverse range of biologically active macromolecules and small molecules that can act as messengers between different cells, triggering functional changes in recipient cells and thus endowing the ability to cure various diseases, including diabetic wounds. Exosomes accelerate diabetic wound healing by regulating cellular function, inhibiting oxidative stress damage, suppressing the inflammatory response, promoting vascular regeneration, accelerating epithelial regeneration, facilitating collagen remodeling, and reducing scarring. Exosomes from different tissues or cells potentially possess functions of varying levels and can promote wound healing. For example, mesenchymal stem cell-derived exosomes (MSC-exos) have favorable potential in the field of healing due to their superior stability, permeability, biocompatibility, and immunomodulatory properties. Exosomes, which are derived from skin cellular components, can modulate inflammation and promote the regeneration of key skin cells, which in turn promotes skin healing. Therefore, this review mainly emphasizes the roles and mechanisms of exosomes from different sources, represented by MSCs and skin sources, in improving diabetic wound healing. A deeper understanding of therapeutic exosomes will yield promising candidates and perspectives for diabetic wound healing management.

Itaconate inhibits SYK through alkylation and suppresses inflammation against hvKP induced intestinal dysbiosis.

Hypervirulent Klebsiella pneumoniae (hvKP) is a highly lethal opportunistic pathogen that elicits more severe inflammatory responses compared to classical Klebsiella pneumoniae (cKP). In this study, we investigated the interaction between hvKP infection and the anti-inflammatory immune response gene 1 (IRG1)-itaconate axis. Firstly, we demonstrated the activation of the IRG1-itaconate axis induced by hvKP, with a dependency on SYK signaling rather than STING. Importantly, we discovered that exogenous supplementation of itaconate effectively inhibited excessive inflammation by directly inhibiting SYK kinase at the 593 site through alkylation. Furthermore, our study revealed that itaconate effectively suppressed the classical activation phenotype (M1 phenotype) and macrophage cell death induced by hvKP. In vivo experiments demonstrated that itaconate administration mitigated hvKP-induced disturbances in intestinal immunopathology and homeostasis, including the restoration of intestinal barrier integrity and alleviation of dysbiosis in the gut microbiota, ultimately preventing fatal injury. Overall, our study expands the current understanding of the IRG1-itaconate axis in hvKP infection, providing a promising foundation for the development of innovative therapeutic strategies utilizing itaconate for the treatment of hvKP infections.

Long-term exposure to fine particulate matter constituents in relation to chronic kidney disease: evidence from a large population-based study in China.

The effects of long-term exposure to fine particulate matter (PM2.5) constituents on chronic kidney disease (CKD) are not fully known. This study sought to examine the association between long-term exposure to major PM2.5 constituents and CKD and look for potential constituents contributing substantially to CKD. This study included 81,137 adults from the 2018 to 2019 baseline survey of China Multi-Ethnic Cohort. CKD was defined by the estimated glomerular filtration rate. Exposure concentration data of 7 major PM2.5 constituents were assessed by satellite remote sensing. Logistic regression models were used to estimate the effect of each PM2.5 constituent exposure on CKD. The weighted quantile sum regression was used to estimate the effect of mixed exposure to all constituents. PM2.5 constituents had positive correlations with CKD (per standard deviation increase), with ORs (95% CIs) of 1.20 (1.02-1.41) for black carbon, 1.27 (1.07-1.51) for ammonium, 1.29 (1.08-1.55) for nitrate, 1.20 (1.01-1.43) for organic matter, 1.25 (1.06-1.46) for sulfate, 1.30 (1.11-1.54) for soil particles, and 1.63 (1.39-1.91) for sea salt. Mixed exposure to all constituents was positively associated with CKD (1.68, 1.32-2.11). Sea salt was the constituent with the largest weight (0.36), which suggested its importance in the PM2.5-CKD association, followed by nitrate (0.32), organic matter (0.18), soil particles (0.10), ammonium (0.03), BC (0.01). Sulfate had the least weight (< 0.01). Long-term exposure to PM2.5 sea salt and nitrate may contribute more than other constituents in increasing CKD risk, providing new evidence and insights for PM2.5-CKD mechanism research and air pollution control strategy.

STAT1 contributes to microglial/macrophage inflammation and neurological dysfunction in a mouse model of traumatic brain injury.

Traumatic brain injury (TBI) triggers a plethora of inflammatory events in the brain that aggravate secondary injury and impede tissue repair. Resident microglia (Mi) and blood-borne infiltrating macrophages (MΦ) are major players of inflammatory responses in the post-TBI brain and possess high functional heterogeneity. However, the plasticity of these cells has yet to be exploited to develop therapies that can mitigate brain inflammation and improve the outcome after TBI. This study investigated the transcription factor STAT1 as a key determinant of proinflammatory Mi/MΦ responses and aimed to develop STAT1 as a novel therapeutic target for TBI using a controlled cortical impact model of TBI on adult male mice. TBI induced robust upregulation of STAT1 in the brain at the subacute injury stage, which occurred primarily in Mi/MΦ. Intraperitoneal administration of fludarabine, a selective STAT1 inhibitor, markedly alleviated proinflammatory Mi/MΦ responses and brain inflammation burden after TBI. Such phenotype-modulating effects of fludarabine on post-TBI Mi/MΦ were reproduced by tamoxifen-induced, selective knockout of STAT1 in Mi/MΦ (STAT1 mKO). By propelling Mi/MΦ away from a detrimental proinflammatory phenotype, STAT1 mKO was sufficient to reduce long-term neurological deficits and brain lesion size after TBI. Importantly, short-term fludarabine treatment after TBI elicited long-lasting improvement of TBI outcomes, but this effect was lost on STAT1 mKO mice. Together, our study provided the first line of evidence that STAT1 causatively determines the proinflammatory phenotype of brain Mi/MΦ after TBI. We also showed promising preclinical data supporting the use of fludarabine as a novel immunomodulating therapy to TBI.SIGNIFICANCE STATEMENTThe functional phenotype of microglia and macrophages (Mi/MΦ) critically influences brain inflammation and the outcome after traumatic brain injury (TBI); however, no therapies have been developed to modulate Mi/MΦ functions to treat TBI. Here we report for the first time that the transcription factor STAT1 is a key mediator of proinflammatory Mi/MΦ responses in the post-TBI brain, the specific deletion of which ameliorates neuroinflammation and improves long-term functional recovery after TBI. We also show excellent efficacy of a selective STAT1 inhibitor fludarabine against TBI-induced functional deficits and brain injury using a mouse model, presenting STAT1 as a promising therapeutic target for TBI.

Targeted ablation of signal transducer and activator of transduction 1 alleviates inflammation by microglia/macrophages and promotes long-term recovery after ischemic stroke.

BACKGROUND: Brain microglia and macrophages (Mi/MΦ) can shift to a harmful or advantageous phenotype following an ischemic stroke. Identification of key molecules that regulate the transformation of resting Mi/MΦ could aid in the development of innovative therapies for ischemic stroke. The transcription factor signal transducer and activator of transduction 1 (STAT1) has been found to contribute to acute neuronal death (in the first 24 h) following ischemic stroke, but its effects on Mi/MΦ and influence on long-term stroke outcomes have yet to be determined. METHODS: We generated mice with tamoxifen-induced, Mi/MΦ-specific knockout (mKO) of STAT1 driven by Cx3cr1CreER. Expression of STAT1 was examined in the brain by flow cytometry and RNA sequencing after ischemic stroke induced by transient middle cerebral artery occlusion (MCAO). The impact of STAT1 mKO on neuronal cell death, Mi/MΦ phenotype, and brain inflammation profiles were examined 3-5 days after MCAO. Neurological deficits and the integrity of gray and white matter were assessed for 5 weeks after MCAO by various neurobehavioral tests and immunohistochemistry. RESULTS: STAT1 was activated in Mi/MΦ at the subacute stage (3 days) after MCAO. Selective deletion of STAT1 in Mi/MΦ did not alter neuronal cell death or infarct size at 24 h after MCAO, but attenuated Mi/MΦ release of high mobility group box 1 and increased arginase 1-producing Mi/MΦ 3d after MCAO, suggesting boosted inflammation-resolving responses of Mi/MΦ. As a result, STAT1 mKO mice had mitigated brain inflammation at the subacute stage after MCAO and less white matter injury in the long term. Importantly, STAT1 mKO was sufficient to improve functional recovery for at least 5 weeks after MCAO in both male and female mice. CONCLUSIONS: Mi/MΦ-targeted STAT1 KO does not provide immediate neuroprotection but augments inflammation-resolving actions of Mi/MΦ, thereby facilitating long-term functional recovery after stroke. STAT1 is, therefore, a promising therapeutic target to harness beneficial Mi/MΦ responses and improve long-term outcomes after ischemic stroke.

Improved FAST algorithm for non-uniform rotational distortion correction in OCT endoscopic imaging.

Optical Coherence Tomography (OCT) is widely used for endoscopic imaging in endoluminal organs because of its high imaging accuracy and resolution. However, OCT endoscopic imaging suffers from Non-Uniform Rotational Distortion (NURD), which can be caused by many factors, such as irregular motor rotation and changes in friction between the probe and the sheath. Correcting this distortion is essential to obtaining high-quality Optical Coherence Tomography Angiography (OCTA) images. There are two main approaches for correcting NURD: hardware-based methods and algorithm-based methods. Hardware-based methods can be costly, challenging to implement, and may not eliminate NURD. Algorithm-based methods, such as image registration, can be effective for correcting NURD but can also be prone to the problem of NURD propagation. To address this issue, we process frames by coarse and fine registration, respectively. The new reference frame is generated by filtering out the A-scan that may have the NURD problem by coarse registration. And the fine registration uses this frame to achieve the final NURD correction. In addition, we have improved the Features from Accelerated Segment Test (FAST) algorithm and put it into coarse and fine registration process. Four evaluation functions were used for the experimental results, including signal-to-noise ratio (SNR), peak signal-to-noise ratio (PSNR), mean squared error (MSE), and structural similarity index measure (SSIM). By comparing with Scale-invariant feature transform (SIFT), Speeded up robust features (SURF), Oriented FAST and Rotated BRIEF (ORB), intensity-based (Cross-correlation), and Optical Flow algorithms, our algorithm has a higher similarity between the corrected frames. Moreover, the noise in the OCTA data is better suppressed, and the vascular information is well preserved. Our image registration-based algorithm reduces the problem of NURD propagation between B-scan frames and improves the imaging quality of OCT endoscopic images.

Broadband tunable Raman fiber laser with monochromatic pump.

Raman fiber laser (RFL) has been widely adopted in astronomy, optical sensing, imaging, and communication due to its unique advantages of flexible wavelength and broadband gain spectrum. Conventional RFLs are generally based on silica fiber. Here, we demonstrate that the phosphosilicate fiber has a broader Raman gain spectrum as compared to the common silica fiber, making it a better choice for broadband Raman conversion. By using the phosphosilicate fiber as gain medium, we propose and build a tunable RFL, and compare its operation bandwidth with a silica fiber-based RFL. The silica fiber-based RFL can operate within the Raman shift range of 4.9 THz (9.8-14.7 THz), whereas in the phosphosilicate fiber-based RFL, efficient lasing is achieved over the Raman shift range of 13.7 THz (3.5-17.2 THz). The operation bandwidths of the two RFLs are also calculated theoretically. The simulation results agree well with experimental data, where the operation bandwidth of the phosphosilicate fiber-based RFL is more than twice of that of the silica fiber-based RFL. This work reveals the phosphosilicate fiber's unique advantage in broadband Raman conversion, which has great potential in increasing the reach and capacity of optical communication systems.

Hippocampus- and thalamus-related fiber-specific white matter reductions in mild cognitive impairment.

Early diagnosis of mild cognitive impairment (MCI) fascinates screening high-risk Alzheimer's disease (AD). White matter is found to degenerate earlier than gray matter and functional connectivity during MCI. Although studies reveal white matter degenerates in the limbic system for MCI, how other white matter degenerates during MCI remains unclear. In our method, regions of interest with a high level of resting-state functional connectivity with hippocampus were selected as seeds to track fibers based on diffusion tensor imaging (DTI). In this way, hippocampus-temporal and thalamus-related fibers were selected, and each fiber's DTI parameters were extracted. Then, statistical analysis, machine learning classification, and Pearson's correlations with behavior scores were performed between MCI and normal control (NC) groups. Results show that: 1) the mean diffusivity of hippocampus-temporal and thalamus-related fibers are significantly higher in MCI and could be used to classify 2 groups effectively. 2) Compared with normal fibers, the degenerated fibers detected by the DTI indexes, especially for hippocampus-temporal fibers, have shown significantly higher correlations with cognitive scores. 3) Compared with the hippocampus-temporal fibers, thalamus-related fibers have shown significantly higher correlations with depression scores within MCI. Our results provide novel biomarkers for the early diagnoses of AD.

The association between chemical constituents of ambient fine particulate matter and obesity in adults: A large population-based cohort study.

OBJECTIVES: Current evidence demonstrated that ambient fine particulate matter with an aerodynamic diameter ≤2.5 µm (PM2.5) and its constituents may be obesogenic in children, but evidence from adults is lacking. Our aim was to characterize the association between PM2.5 and its constituents and obesity in adults. METHODS: We included 68,914 participants from the China Multi-Ethnic Cohort (CMEC) baseline survey. Three-year average concentrations of PM2.5 and its constituents were evaluated by linking pollutant estimates to the geocoded residential addresses. Obesity was defined as body mass index (BMI) ≥ 28 kg/m2. Logistic regression was used to examine the relationship between PM2.5 and its constituents and obesity. We performed weighed quantile sum (WQS) regression to get the overall effect of PM2.5 and its constituents and the relative contribution of each constituent. RESULTS: Per-SD increase in PM2.5 (odds ratio [OR] = 1.43, 95% confidence interval [CI]: 1.37-1.49), black carbon (BC) (1.42, 1.36-1.48), ammonium (1.43, 1.37-1.49), nitrate (1.44, 1.38-1.50), organic matter (OM) (1.45, 1.39-1.51), sulfate (1.42, 1.35-1.48), and soil particles (SOIL) (1.31, 1.27-1.36) were positively associated with obesity, and SS (0.60, 0.55-0.65) was negatively associated with obesity. The overall effect (OR = 1.34, 95% CI: 1.29-1.41) of the PM2.5 and its constituents was positively associated with obesity, and ammonium made the most contribution to this relationship. Participants who were older, female, never smoked, lived in urban areas, had lower income or higher levels of physical activity were more significantly adversely affected by PM2.5, BC, ammonium, nitrate, OM, sulfate and SOIL compared to other individuals. CONCLUSION: Our study revealed that PM2.5 constituents except SS were positively associated with obesity, and ammonium played the most important role. These findings provided new evidence for public health interventions, especially the precise prevention and control of obesity.

Brain-Computer Interfaces in Visualized Medicine.

The brain-computer interface (BCI), also known as a brain-machine interface (BMI), has attracted extensive attention in biomedical applications. More importantly, BCI technologies have substantially revolutionized early predictions, diagnostic techniques, and rehabilitation strategies addressing acute diseases because of BCI's innovations and clinical translations. Therefore, in this chapter, a comprehensive description of the basic concepts of BCI will be exhibited, and various visualization techniques employed in BCI's medical applications will be discussed.

Ambient PM2.5 and its components associated with 10-year atherosclerotic cardiovascular disease risk in Chinese adults.

BACKGROUND: Exposure to particulate matter with aerodynamic diameters less than 2.5 µm (PM2.5) may increase the risk of 10-year atherosclerotic cardiovascular disease (ASCVD) risk. While PM2.5 is comprised of various components, the evidence on the correlation of its components with 10-year ASCVD risk and which component contributes most remains limited. METHODS: Data were derived from the baseline assessments of China Multi-Ethnic Cohort (CMEC). In total, 69,722 individuals aged 35-74 years were included into this study. The annual average concentration of PM2.5 and its components (black carbon, ammonium, nitrate, sulfate, organic matter, soil particles, and sea salt) were estimated by satellite remote sensing and chemical transport models. The ASCVD risk of individuals was calculated by the equations from the China-PAR Project (prediction for ASCVD risk in China). The relationship between single exposure to PM2.5 and its components and predicted 10-year ASCVD risk was assessed using the logistic regression model. The effect of joint exposure was estimated, and the most significant contributor was identified using the weighted quantile sum approach. RESULTS: Totally 69,722 participants were included, of which 95.8 % and 4.2 % had low and high 10-year ASCVD risk, respectively. Per standard deviation increases in the 3-year average concentration of PM2.5 mass (odds ratio [OR] 1.23, 95 % confidence interval [CI]: 1.12-1.35), black carbon (1.21, 1.11-1.33), ammonium (1.21, 1.10-1.32), nitrate (1.25, 1.14-1.38), organic matter (1.29, 1.18-1.42), sulfate (1.17, 1.07-1.28), and soil particles (1.15, 1.04-1.26) were related to high 10-year ASCVD risk. The overall effect (1.19, 1.11-1.28) of the PM2.5 components was positively associated with 10-year ASCVD risk, and organic matter had the most contribution to this relationship. Female participants were more significantly impacted by PM2.5, black carbon, ammonium, nitrate, organic matter, sulfate, and soil particles compared to others. CONCLUSION: Long-term exposure to PM2.5 mass, black carbon, ammonium, nitrate, organic matter, sulfate, and soil particles were positively associated with high 10-year ASCVD risk, while sea salt exhibited a protective effect. Moreover, the organic matter might take primary responsibility for the relationship between PM2.5 and 10-year ASCVD risk. Females were more susceptible to the adverse effect.

Long-term exposure to ambient PM2.5 constituents is associated with dyslipidemia in Chinese adults.

BACKGROUND: Ambient particulate matter with aerodynamic diameter ≤ 2.5 µm (PM2.5) consists of various toxic constituents. However, the health effect of PM2.5 may differ depending on its constituents, but the joint effect of PM2.5 constituents remains incompletely understood. OBJECTIVE: Our goal was to evaluate the joint effect of long-term PM2.5 constituent exposures on dyslipidemia and identify the most hazardous chemical constituent. METHODS: This study included 67,015 participants from the China Multi-Ethnic Cohort study. The average yearly levels of PM2.5 constituents for all individuals at their residences were assessed through satellite remote sensing and chemical transport modeling. Dyslipidemia was defined as one or more following abnormal blood lipid concentrations: total cholesterol (TC) ≥ 6.22 mmol/L, triglycerides (TG) ≥ 2.26 mmol/L, high-density lipoprotein cholesterol (HDL-C) < 1.04 mmol/L, and low-density lipoprotein cholesterol (LDL-C) ≥ 4.14 mmol/L. The logistic regression model was utilized to examine the single effect of PM2.5 constituents on dyslipidemia, while the weighted quantile sum regression model for the joint effect. RESULTS: The odds ratio with a 95 % confidence interval for dyslipidemia positively related to per-SD increase in the three-year average was 1.29 (1.20-1.38) for PM2.5 mass, 1.25 (1.17-1.34) for black carbon, 1.24 (1.16-1.33) for ammonium, 1.33 (1.24-1.43) for nitrate, 1.34 (1.25-1.44) for organic matter, 1.15 (1.08-1.23) for sulfate, 1.30 (1.22-1.38) for soil particles, and 1.12 (1.05-1.92) for sea salt. Stronger associations were observed in individuals < 65 years of age, males, and those with low physical activity. Joint exposure to PM2.5 constituents was positively related to dyslipidemia (OR: 1.09, 95 %CI: 1.05-1.14). Nitrate was identified as the constituent with the largest weight (weighted at 0.387). CONCLUSIONS: Long-term exposure to PM2.5 constituents poses a significant risk to dyslipidemia and nitrate might be the most responsible for the risk. These findings indicate that reducing PM2.5 constituent exposures, especially nitrate, could be beneficial to alleviate the burden of disease attributed to PM2.5-related dyslipidemia.

K2CO3-Promoted Formal [3+3]-Cycloaddition of N-Unsubstituted Isatin N,N'-Cyclic Azomethine Imine 1,3-Dipoles with Knoevenagel Adducts.

The synthesis of dicyclic spiropyridazine oxoindole derivatives by using [3+3]-cycloaddition of N-unsubstituted isatin N,N'-cyclic azomethine imine 1,3-dipoles was reported. The products bearing two consecutive stereocenters, including spiroquaternary stereocenters in one ring structure, can be effectively obtained in moderate to excellent yields (20-93%) and low to moderate diastereoselectivities (1:9-10:1 dr). The synthesized compounds (>35 examples) were characterized by single-crystal XRD, FTIR, NMR, and mass spectral analysis.

DABCO-Catalyzed Mono-/Diallylation of N-Unsubstituted Isatin N,N'-Cyclic Azomethine Imine 1,3-Dipoles with Morita-Baylis-Hillman Carbonates.

Allylation of N-unsubstituted isatin N,N'-cyclic azomethine imines with Morita-Baylis-Hillman carbonates in the presence of 1-10 mol% DABCO in DCM at room temperature, rapidly gave N-allylated and N, ß-diallylated isatin N,N'-cyclic azomethine imine 1,3-dipoles in moderate to high yields. The reaction features mild reaction conditions, easily practical operation, and short reaction times in most cases. Furthermore, the alkylated products were transformed into novel bicyclic spiropyrrolidine oxoindole derivatives through the [3+2] or [3+3]-cycloaddition with maleimides or Knoevenagel adducts.

Microglia-specific deletion of histone deacetylase 3 promotes inflammation resolution, white matter integrity, and functional recovery in a mouse model of traumatic brain injury.

BACKGROUND: Histone deacetylases (HDACs) are believed to exacerbate traumatic brain injury (TBI) based on studies using pan-HDAC inhibitors. However, the HDAC isoform responsible for the detrimental effects and the cell types involved remain unknown, which may hinder the development of specific targeting strategies that boost therapeutic efficacy while minimizing side effects. Microglia are important mediators of post-TBI neuroinflammation and critically impact TBI outcome. HDAC3 was reported to be essential to the inflammatory program of in vitro cultured macrophages, but its role in microglia and in the post-TBI brain has not been investigated in vivo. METHODS: We generated HDAC3LoxP mice and crossed them with CX3CR1CreER mice, enabling in vivo conditional deletion of HDAC3. Microglia-specific HDAC3 knockout (HDAC3 miKO) was induced in CX3CR1CreER:HDAC3LoxP mice with 5 days of tamoxifen treatment followed by a 30-day development interval. The effects of HDAC3 miKO on microglial phenotype and neuroinflammation were examined 3-5 days after TBI induced by controlled cortical impact. Neurological deficits and the integrity of white matter were assessed for 6 weeks after TBI by neurobehavioral tests, immunohistochemistry, electron microscopy, and electrophysiology. RESULTS: HDAC3 miKO mice harbored specific deletion of HDAC3 in microglia but not in peripheral monocytes. HDAC3 miKO reduced the number of microglia by 26%, but did not alter the inflammation level in the homeostatic brain. After TBI, proinflammatory microglial responses and brain inflammation were markedly alleviated by HDAC3 miKO, whereas the infiltration of blood immune cells was unchanged, suggesting a primary effect of HDAC3 miKO on modulating microglial phenotype. Importantly, HDAC3 miKO was sufficient to facilitate functional recovery for 6 weeks after TBI. TBI-induced injury to axons and myelin was ameliorated, and signal conduction by white matter fiber tracts was significantly enhanced in HDAC3 miKO mice. CONCLUSION: Using a novel microglia-specific conditional knockout mouse model, we delineated for the first time the role of microglial HDAC3 after TBI in vivo. HDAC3 miKO not only reduced proinflammatory microglial responses, but also elicited long-lasting improvement of white matter integrity and functional recovery after TBI. Microglial HDAC3 is therefore a promising therapeutic target to improve long-term outcomes after TBI.

Magnetic Field Manipulation of Tetrahedral Units in Spinel Oxides for Boosting Water Oxidation.

Magnetic field enhanced electrocatalysis has recently emerged as a promising strategy for the development of a viable and sustainable hydrogen economy via water oxidation. Generally, the effects of magnetic field enhanced electrocatalysis are complex including magnetothermal, magnetohydrodynamic and spin selectivity effects. However, the exploration of magnetic field effect on the structure regulation of electrocatalyst is still unclear whereas is also essential for underpinning the mechanism of magnetic enhancement on the electrocatalytic oxygen evolution reaction (OER) process. Here, it is identified that in a mixed NiFe2 O4 (NFO), a large magnetic field can force the Ni2+ cations to migrate from the octahedral (Oh ) sites to tetrahedral (Td ) sites. As a result, the magnetized NFO electrocatalyst (NFO-M) shows a two-fold higher current density than that of the pristine NFO in alkaline electrolytes. The OER enhancement of NFO is also observed at 1 T (NFO@1T) under an operando magnetic field. Our first-principles calculations further confirm the mechanism of magnetic field driven structure regulation and resultant OER enhancement. These findings provide a strategy of manipulating tetrahedral units of spinel oxides by a magnetic field on boosting OER performance.

Low quantum defect random Raman fiber laser.

The random Raman fiber laser (RRFL) has attracted great attention due to its wide applications in optical telecommunication, sensing, and imaging. The quantum defect (QD), as the main source of thermal load in fiber lasers, could threaten the stability and reliability of the RRFL. Conventional RRFLs generally adopt silica fiber to provide Raman gain, and the QD exceeds 4%. In this letter, we propose and demonstrate a phosphosilicate-fiber-based low-QD RRFL. There is a strong boson peak located at the frequency shift of 3.65 THz in the phosphosilicate fiber we employed. By utilizing this boson peak to provide Raman gain, we demonstrated an 11.71 W temporally stable random Raman laser at 1080 nm under a pump wavelength of 1066 nm. The corresponding QD is 1.3%, less than one third of the QD of the common silica-fiber-based RRFL. Compared with the full-cavity low-QD Raman fiber laser, this cavity-less low-QD RRFL has lower and flatter noise in the high frequency area (>100 kHz). This work provides a reference for suppressing thermal-induced effects, such as thermal-induced mode instability, thermal noise, and even fiber fusing in RRFLs.