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Objective: Synaptic plasticity is critical for neurorehabilitation after focal cerebral ischemia. Connexin 43 (Cx43), the main component of the gap junction, has been shown to be pivotal for synaptic plasticity. The objective of this study was to investigate the role of the Cx43 inhibitor (Gap26) and gap junction modifier (GAP-134) in neurorehabilitation and to study their contribution to synaptic plasticity after focal ischemia.Methods: Time course expression of both total and phosphorylated Cx43 (p-Cx43) were detected by western blotting at 3, 7, and 14 d after focal ischemia. Gap26 and GAP-134 were administered starting from 3 d post focal ischemia. Neurological performances were evaluated by balance beam walking test and Y-maze test at 1, 3, and 7 d. Golgi staining and transmission electron microscope (TEM) detection were conducted at 7 d for observing dendritic spine numbers and synaptic ultrastructure, respectively. Immunofluorescent staining was used at 7 d for detection of synaptic plasticity markers, including synaptophysin (SYN) and growth-associated protein-43 (GAP-43).Results: Expression levels of both total Cx43 and p-Cx43 were increased after focal cerebral ischemia, peaking at 7 d. Compared with the MCAO group, Gap26 worsened the neurological behavior and decreased the dendritic spine number while GAP-134 improved the neurobehavior and increased the number of dendritic spines. Moreover, Gap26 further destroyed the synaptic structure, concomitant with downregulated SYN and GAP-43, whereas GAP-134 alleviated synaptic destruction and upregulated SYN and GAP-43.Conclusion: These findings suggested that Cx43 or the gap junction was involved in synaptic plasticity, thereby promoting neural recovery after ischemic stroke. Treatments enhancing gap junctions may be potential promising therapeutic measures for neurorehabilitation after ischemic stroke.

ObjectiveTo identify DNA methylation related biomarkers in patients with breast cancer (BC).Materials and MethodsA total of seven BC methylation studies including 1,438 BC patients or breast tissues were included in this study. An elastic net regularized Cox proportional hazards regression (CPH) model was used to build a multi-5′-C-phosphate-G-3′ methylation panel. The diagnosis and prognosis power of the panel was evaluated and validated using a Kaplan–Meier curve, univariate and multivariable CPH, subgroup analysis. A nomogram containing the panel was developed. The relationships between the panel-based methylation risk and the immune landscape and genomic metrics were investigated.ResultsSixty-eight CpG sites were significantly correlated with the overall survival (OS) of BC patients, and based on the result of penalized CPH, a 28-CpG site based multi CpG methylation panel was found. The prognosis and diagnosis role of the panel was validated in the discovery set, validation set, and six independent cohorts, which indicated that higher methylation risk was associated with poor OS, and the panel outperformed currently available biomarkers and remained an independent factor after adjusting for other clinical features. The methylation risk was negatively correlated with innated and adaptive immune cells, and positively correlated with total mutation load, SCNA, and MATH.ConclusionsWe validated a multi CpG methylation panel that could independently predict the OS of BC patients. The Th2-mediated tumor promotion effect—suppression of innate and adaptive immunity—participated in the progression of high-risk BC. Patients with high methylation risk were associated with tumor heterogeneity and poor survival.

MicroRNAs (miRNAs) are a class of small non-coding RNAs which regulate gene expression at post-transcriptional level. Alterations of miR-186 expression were demonstrated in numerous cancers, shown to play a vital role in oncogenesis, invasion, metastasis, apoptosis, and drug resistance. MiR-186 was documented as a tumor suppressor miRNA in the majority of studies, while conflicting reports verified miR-186 as an oncomir. The contradictory role in cancers may impede the application of miR-186, as well as other dual-functional miRNAs, as a diagnostic and therapeutic target. This review emphasizes the alterations and functions of miR-186 in cancers and discusses the mechanisms behind the contradictory findings. Among these, target abundance and dose-dependent effects of miR-186 are highlighted. The paper aims to review the challenges involved in developing diagnostic and therapeutic strategies for cancer treatment based on dual-functional miRNAs.

Altered lipid metabolism in macrophages is associated with various important inflammatory conditions. Although lipid metabolism is an important target for therapeutic intervention, the metabolic requirement involved in lipid accumulation during pro-inflammatory activation of macrophages remains incompletely characterized. We show here that macrophage activation with IFNγ results in increased aerobic glycolysis, iNOS-dependent inhibition of respiration, and accumulation of triacylglycerol. Surprisingly, metabolite tracing with 13C-labeled glucose revealed that the glucose contributed to the glycerol groups in triacylglycerol (TAG), rather than to de novo synthesis of fatty acids. This is in stark contrast to the otherwise similar metabolism of cancer cells, and previous results obtained in activated macrophages and dendritic cells. Our results establish a novel metabolic pathway whereby glucose provides glycerol to the headgroup of TAG during classical macrophage activation.

Abstract Background Antimicrobial resistance (AMR) has been a worldwide public health concern. Current widespread AMR pollution has posed a big challenge in accurately disentangling source-sink relationship, which has been further confounded by point and non-point sources, as well as endogenous and exogenous cross-reactivity under complicated environmental conditions. Because of insufficient capability in identifying source-sink relationship within a quantitative framework, traditional antibiotic resistance gene (ARG) signatures-based source-tracking methods would hardly be a practical solution. Results By combining broad-spectrum ARG profiling with machine-learning classification SourceTracker, here we present a novel way to address the question in the era of high-throughput sequencing. Its potential in extensive application was firstly validated by 656 global-scale samples covering diverse environmental types (e.g., human/animal gut, wastewater, soil, ocean) and broad geographical regions (e.g., China, USA, Europe, Peru). Its potential and limitations in source prediction as well as effect of parameter adjustment were then rigorously evaluated by artificial configurations with representative source proportions. When applying SourceTracker in region-specific analysis, excellent performance was achieved by ARG profiles in two sample types with obvious different source compositions, i.e., influent and effluent of wastewater treatment plant. Two environmental metagenomic datasets of anthropogenic interference gradient further supported its potential in practical application. To complement general-profile-based source tracking in distinguishing continuous gradient pollution, a few generalist and specialist indicator ARGs across ecotypes were identified in this study. Conclusion We demonstrated for the first time that the developed source-tracking platform when coupling with proper experiment design and efficient metagenomic analysis tools will have significant implications for assessing AMR pollution. Following predicted source contribution status, risk ranking of different sources in ARG dissemination will be possible, thereby paving the way for establishing priority in mitigating ARG spread and designing effective control strategies.

Abstract Background Perilla frutescens is well known for its high α-linolenic acid (ALA) accumulation in seeds and medicinal values as well as a source of edible and general-purpose oils. However, the regulatory mechanisms of the biosynthesis of fatty acid in its seeds remain poorly understood due to the lacking of sequenced genome. For better understanding the regulation of lipid metabolism and further increase its oil content or modify oil composition, time-course transcriptome and lipid composition analyses were performed. Results Analysis of fatty acid content and composition showed that the α-linolenic acid and oleic acid accumulated rapidly from 5 DAF to 15 DAF and then kept relatively stable. However, the amount of palmitic acid and linoleic acid decreased quickly from 5 DAF to 15DAF. No significant variation of stearic acid content was observed from 5 DAF to 25DAF. Our transcriptome data analyses revealed that 110,176 unigenes were generated from six seed libraries at 5, 10, 20 DAF. Of these, 53 (31 up, 22 down) and 653 (259 up, 394 down) genes showed temporal and differentially expression during the seed development in 5 DAF vs 10 DAF, 20 vs 10 DAF, respectively. The differentially expressed genes were annotated and found to be involved in distinct functional categories and metabolic pathways. Deep mining of transcriptome data led to the identification of key genes involved in fatty acid and triacylglycerol biosynthesis and metabolism. Thirty seven members of transcription factor family AP2, B3 and NFYB putatively involved in oil synthesis and deposition were differentially expressed during seed development. The results of qRT-PCR for selected genes showed a strong positive correlation with the expression abundance measured in RNA-seq analysis. Conclusions The present study provides valuable genomic resources for characterizing Perilla seed gene expression at the transcriptional level and will extend our understanding of the complex molecular and cellular events of oil biosynthesis and accumulation in oilseed crops.

Background/Aims: Alzheimer disease (AD) is a common neurodegenerative disease that is characterized by the deposition of beta-amyloid peptide and formation of intracellular neurofibrillary tangles. Due to the failure of various clinical trials of novel drugs for AD, effective drugs for AD treatment are urgently required. Methods: In this study, we used the classic APP/PS1 mouse model to explore the neuroprotective effects of a new compound, bajijiasu, and the mechanisms involved. Behavioral tests and western blotting were performed to assess the beneficial effects of bajijiasu in APP/PS1 mice. Results: Morris water maze and Y-maze test results showed that oral administration of bajijiasu (35 mg/kg/day and 70 mg/kg/day) improved learning and memory abilities in APP/PS1 mice. Bajijiasu reduced ROS and MDA levels in both the hippocampus and cortex. Moreover, western blotting results showed that bajijiasu protected neurons from apoptosis, elevated the expression levels of neurotrophic factors, and alleviated endoplasmic reticulum stress in both the hippocampus and cortex. Conclusion: These results indicate that the mechanisms underlying the effects of bajijiasu on AD might be related to beta-amyloid-downstream pathologies, particularly endoplasmic reticulum stress.

Abstract The relaxation behaviors of thin polymer films show a strong dependence on temperature and film thickness. Direct quantitative detection of the relaxation behaviors of thin polymer films at nanometer scale by traditional instruments is however challenging. In this study, we employed atomic force microscopy (AFM)-based force-distance curve to study the relaxation dynamics and the film thickness dependence of glass transition temperature (T g ) for normal thin polystyrene (PS) films supported on silicon substrate. The adhesion force (Fad) between AFM tip and normal thin PS film surfaces was quantitatively detected in situ under the variation of temperature and film thickness. The T g of normal thin PS film was successfully obtained by the abrupt variation of Fad under temperature stimulation. Our result showed that the T g of normal thin PS films decreased with the decreasing film thickness. The study here could be beneficial for understanding the relaxation dynamics of normal thin polymer films.