A series of novel 8-OMe ciprofloxacin (CPFX)-hydrazone/azole hybrids were designed, synthesized, and evaluated for their in vitro biological activities. Our results reveal that all of the ...hydrozone-containing hybrids (except for
) show potency against
(MTB) H
Rv (minimum inhibitory concentration (MIC): <0.5 μM), which is better than the parent drug CPFX, and comparable to moxifloxacin and isoniazid, some of the tested Gram-positive strains (MIC: 0.06-4 μg/mL), and most Gram-negative strains (MIC: ≤0.03-4 μg/mL).
The spinal cord is extremely vulnerable to ischemia-reperfusion (I/R) injury, and the mitochondrion is the most crucial interventional target. Rapamycin can promote autophagy and exert ...neuroprotective effects in several diseases of the central nervous system. However, the impact of rapamycin via modulating mitophagy and apoptosis after spinal cord ischemia-reperfusion injury remains unclear. This study was undertaken to investigate the potential role of rapamycin in modulating mitophagy and mitochondria-dependent apoptosis using the spinal cord ischemia-reperfusion injury (SCIRI) mouse model. We found that rapamycin significantly (
< 0.05) enhanced mitophagy by increasing the translocation of p62 and Parkin to the damaged mitochondria in the mouse spinal cord injury model. At the same time, rapamycin significantly (
< 0.05) decreased mitochondrial apoptosis related protein (Apaf-1, Caspase-3, Caspase-9) expression by inhibiting Bax translocation to the mitochondria and the release of the cytochrome c from the mitochondria. After 24 h following SCIRI, rapamycin treatment reduced the TUNEL
cells in the spinal cord ischemic tissue and improved the locomotor function in these mice. Our results therefore demonstrate that rapamycin can improve the locomotor function by promoting mitophagy and attenuating SCIRI -induced apoptosis, indicating its potential therapeutic application in a spinal cord injury.
Cognitive impairment in the late stage of traumatic brain injury (TBI) is associated with the NOD-, LRR and pyrin domain-containing protein 3 (NLRP3) inflammasome, which plays an important role in ...neuroinflammation. Although classical inflammatory pathways have been well-documented in the late stage of TBI (4-8 weeks post-injury), the mechanism by which the NLRP3 inflammasome impairs cognition is still unclear.
Mice lacking the gene encoding for NLRP3 (NLRP3-knockout mice) and their wild-type littermates were used in a controlled cortical impact model of TBI. Levels of NLRP3 inflammasome and inflammatory factors such as IL-1β and HMGB1 were detected in post-injury hippocampal tissue, as well as long-term potentiation. Behaviors were assessed by T-maze test, novel object recognition, and nesting tests. Glycyrrhizin was used to antagonize HMGB1. Calcium imaging were performed on primary neuronal cultures.
By using the NLRP3-knockout TBI model, we found that the continuous activation of the NLRP3 inflammasome and high mobility group box 1 (HMGB1) release were closely related to cognitive impairment. We also found that inhibition of HMGB1 improved LTP reduction and cognitive function by increasing the phosphorylation level of the NMDAR1 subunit at serine 896 while reducing NLRP3 inflammasome activation.
NLRP3 inflammasome damages memory in the late stage of TBI primarily through HMGB1 upregulation and provides an explanation for the long-term progression of cognitive dysfunction.
Recent studies have demonstrated that exosomal microRNAs (miRNAs) are novel biomarkers and therapeutic targets for various diseases including vascular disease. However, specific exosomal miRNAs ...expression in stroke patients has not been reported yet. Here, we explored whether circulating exosomal miRNAs can serve as potential biomarkers for the diagnosis of acute ischemic stroke and discussed the potential for clinical application. Blood samples were collected from acute ischemic stroke patients within the first 72 h (
= 50). Circulating exosomes were exacted by Exoquick exosome isolation kit and characterized by transmission electron microscopy. Western blot was performed to assess the expression of exosomal protein makers. Exosomal miRNA-223 (miR-223) was detected by RT-PCR assay. The relationship between the expression levels of miR-223 and National Institutes of Health Stroke Scale (NIHSS) scores, brain infarct volume, and neurological outcomes were analyzed. Circulating exosomes were isolated and the size of vesicles ranged between 30 and 100 nm. The identification of exosomes was further confirmed by the detection of specific exosomal protein markers CD9, CD63, and Tsg101. Exosomal miR-223 in acute ischemic stroke patients was significantly upregulated compared to control group (
< 0.001). Exosomal miR-223 level was positively correlated with NIHSS scores (
= 0.31,
= 0.03). Exosomal miR-223 expression in stroke patients with poor outcomes was higher than those with good outcomes (
< 0.05). Increased exosomal miR-223 was associated with acute ischemic stroke occurrence, stroke severity, and short-term outcomes. Future studies with large sample are needed to assess the clinical application of exosomal miR-223 as a novel biomarker for ischemic stroke diagnosis.
The synoptic-scale wave train is a dominant pattern of the synoptic variability over the tropical western Pacific and usually affects the extreme weather over South China and Southeast Asia. Whether ...it could extend its influence and contribute to the Henan extreme rainfall in July 2021 still needs to be unraveled. We found that during the Henan extreme rainfall days a positively synoptic-scale vorticity disturbance dominated Henan province, China, which was embedded in the synoptic-scale wave train that originated from the western North Pacific. Moreover, the propagating pathway of this synoptic-scale wave train located northward and was likely modulated by the latitudinal location change of the monsoon trough over the western North Pacific. A northernmost displacement of the monsoon trough in July 2021 (∼23.2°N) would facilitate the synoptic-scale wave train to propagate farther northwestward via shifting the related barotropic conversion northward. Therefore, the synoptic-scale wave train from the tropics could reach Henan, provide the necessary lifting forcing, and supply abundant water vapor associated with the anomalous southerly for the occurrence of Henan extreme rainfall event. The results implicate that the pre-existing synoptic-scale wave train regulated by the location of the monsoon trough may be a potential precursor for heavy rainfalls in northern Central China.
Numerous studies have been conducted to investigate the potential effect of educational robots, but what appears to be missing is an up-to-date and thorough review of the learning effectiveness of ...educational robots and the various influencing factors. In this study, a meta-analysis was conducted to systematically synthesize studies’ findings on the effects of educational robots on students’ learning outcomes. After searching for randomized studies describing educational robots interventions to improve learning outcomes, 34 effect sizes described in 17 articles met the selection criteria. The results of our work evidence a moderate but significantly positive effect of educational robots on learning outcomes (g = 0.57, 95% CI 0.49, 0.65, p < 0.00001). Moreover, moderator analyses were conducted to investigate important factors relating to the variation of the impact, including educational level and assessment type. Based on the findings of this study, we provide researchers and practitioners with insights into what characteristics of educational robot interventions appear to benefit students’ learning outcomes and how pedagogical approaches can be applied in various educational settings to guide the design of future educational robot interventions.
Objective
Brain arteriovenous malformations (AVMs) are the most common cause of nontraumatic intracerebral hemorrhage in young adults. The genesis of brain AVM remains enigmatic. We investigated ...microRNA (miRNA) expression and its contribution to the pathogenesis of brain AVMs.
Methods
We used a large‐scale miRNA analysis of 16 samples including AVMs, hemangioblastoma, and controls to identify a distinct AVM miRNA signature. AVM smooth muscle cells (AVMSMCs) were isolated and identified by flow cytometry and immunohistochemistry, and candidate miRNAs were then tested in these cells. Migration, tube formation, and CCK‐8–induced proliferation assays were used to test the effect of the miRNAs on phenotypic properties of AVMSMCs. A quantitative proteomics approach was used to identify protein expression changes in AVMSMCs treated with miRNA mimics.
Results
A distinct AVM miRNA signature comprising a large portion of lowly expressed miRNAs was identified. Among these miRNAs, miR‐137 and miR‐195* levels were significantly decreased in AVMs and constituent AVMSMCs. Experimentally elevating the level of these microRNAs inhibited AVMSMC migration, tube formation, and survival in vitro and the formation of vascular rings in vivo. Proteomics showed the protein expression signature of AVMSMCs and identified downstream proteins regulated by miR‐137 and miR‐195* that were key signaling proteins involved in vessel development.
Interpretation
Our results indicate that miR‐137 and miR‐195* act as vasculogenic suppressors in AVMs by altering phenotypic properties of AVMSMCs, and that the absence of miR‐137 and miR‐195* expression leads to abnormal vasculogenesis. Ann Neurol 2017;82:371–384
Polycomb repressive complex 2 (PRC2) plays crucial roles in transcriptional regulation and stem cell development. However, the context-specific functions associated with alternative subunits remain ...largely unexplored. Here we show that the related enzymatic subunits EZH1 and EZH2 undergo an expression switch during blood cell development. An erythroid-specific enhancer mediates transcriptional activation of EZH1, and a switch from GATA2 to GATA1 controls the developmental EZH1/2 switch by differential association with EZH1 enhancers. We further examine the in vivo stoichiometry of the PRC2 complexes by quantitative proteomics and reveal the existence of an EZH1-SUZ12 subcomplex lacking EED. EZH1 together with SUZ12 form a non-canonical PRC2 complex, occupy active chromatin, and positively regulate gene expression. Loss of EZH2 expression leads to repositioning of EZH1 to EZH2 targets. Thus, the lineage- and developmental stage-specific regulation of PRC2 subunit composition leads to a switch from canonical silencing to non-canonical functions during blood stem cell specification.
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•During blood cell development there is a switch from EZH2 to EZH1 expression•GATA switch regulates EZH2 to EZH1 switch through lineage-specific EZH1 enhancers•EZH1 and SUZ12 form a non-canonical PRC2 complex in transcriptional activation•Alternative PRC2 subunit composition confers a switch to non-canonical functions
Xu et al. show that the developmental switch of lineage-specifying GATA factors controls an expression switch of EZH2 to EZH1 during blood cell differentiation. EZH1 and SUZ12 assemble a non-canonical complex independent of EED and positively regulate gene expression. Thus, the alternative PRC2 subunit composition confers non-canonical functions during development.
Can we observe the solar eclipses in the neutrino light? In principle, this is possible by identifying the lunar matter effects on the flavor conversions of solar neutrinos when they traverse the ...Moon before reaching the detectors at the Earth. Unfortunately, we show that the lunar matter effects on the survival probability of solar B8 neutrinos are suppressed by an additional factor of 1.2%, compared to the day-night asymmetry. However, we point out that the matter effects on the flavor conversions of high-energy astrophysical neutrinos, when they propagate through the Sun, can be significant. Though the flavor composition of high-energy neutrinos can be remarkably modified, it is quite challenging to observe such effects even in the next-generation of neutrino telescopes.
In addition to their original applications to lowering cholesterol, statins display multiple neuroprotective effects. N-methyl-D-aspartate (NMDA) receptors interact closely with the dopaminergic ...system and are strongly implicated in therapeutic paradigms of Parkinson's disease (PD). This study aims to investigate how simvastatin impacts on experimental parkinsonian models via regulating NMDA receptors.
Regional changes in NMDA receptors in the rat brain and anxiolytic-like activity were examined after unilateral medial forebrain bundle lesion by 6-hydroxydopamine via a 3-week administration of simvastatin. NMDA receptor alterations in the post-mortem rat brain were detected by ³HMK-801(Dizocilpine) binding autoradiography. 6-hydroxydopamine treated PC12 was applied to investigate the neuroprotection of simvastatin, the association with NMDA receptors, and the anti-inflammation. 6-hydroxydopamine induced anxiety and the downregulation of NMDA receptors in the hippocampus, CA1(Cornu Ammonis 1 Area), amygdala and caudate putamen was observed in 6-OHDA(6-hydroxydopamine) lesioned rats whereas simvastatin significantly ameliorated the anxiety-like activity and restored the expression of NMDA receptors in examined brain regions. Significant positive correlations were identified between anxiolytic-like activity and the restoration of expression of NMDA receptors in the hippocampus, amygdala and CA1 following simvastatin administration. Simvastatin exerted neuroprotection in 6-hydroxydopamine-lesioned rat brain and 6-hydroxydopamine treated PC12, partially by regulating NMDA receptors, MMP9 (matrix metalloproteinase-9), and TNF-a (tumour necrosis factor-alpha).
Our results provide strong evidence that NMDA receptor modulation after simvastatin treatment could partially explain its anxiolytic-like activity and anti-inflammatory mechanisms in experimental parkinsonian models. These findings contribute to a better understanding of the critical roles of simvastatin in treating PD via NMDA receptors.
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