The early branching eukaryote Trypanosoma brucei divides uni-directionally along the longitudinal cell axis from the cell anterior toward the cell posterior, and the cleavage furrow ingresses along ...the cell division plane between the new and the old flagella of a dividing bi-flagellated cell. Regulation of cytokinesis in T. brucei involves actomyosin-independent machineries and trypanosome-specific signaling pathways, but the molecular mechanisms underlying cell division plane positioning remain poorly understood. Here we report a kinesin-13 family protein, KIN13-5, that functions downstream of FPRC in the cytokinesis regulatory pathway and determines cell division plane placement. KIN13-5 localizes to multiple cytoskeletal structures, interacts with FPRC, and depends on FPRC for localization to the site of cytokinesis initiation. Knockdown of KIN13-5 causes loss of microtubule bundling at both ends of the cell division plane, leading to mis-placement of the cleavage furrow and unequal cytokinesis, and at the posterior cell tip, causing the formation of a blunt posterior. In vitro biochemical assays demonstrate that KIN13-5 bundles microtubules, providing mechanistic insights into the role of KIN13-5 in cytokinesis and posterior morphogenesis. Altogether, KIN13-5 promotes microtubule bundle formation to ensure cleavage furrow placement and to maintain posterior cytoskeleton morphology in T. brucei.
Cognitive dysfunction often occurs in diabetes mellitus patients. This study aimed to investigate the efficacy of melatonin (MLT) in improving diabetes‐associated cognitive decline and the underlying ...mechanism involved. Type 2 diabetic mice and palmitic acid (PA)‐stimulated BV‐2 cells were treated by MLT, and the potential mechanisms among MLT, cognition, and autophagy were explored. The results showed that type 2 diabetic mice showed obvious learning and memory impairments in the Morris water maze test compared with normal controls, which could be ameliorated by MLT treatment. Meanwhile, MLT administration significantly improved neuroinflammation and regulated microglial apoptosis. Furthermore, autophagy inhibitor 3‐methyladenine (3‐MA) increased the microglial inflammation and apoptosis, indicating that the treatment effect of MLT was mediated by autophagy. Lastly, MLT treatment significantly decreased the levels of toll‐like receptors 4 (TLR4), phosphorylated‐protein kinase B (Akt), and phosphorylated‐mechanistic target of rapamycin (mTOR), indicating that blocking TLR4/Akt/mTOR pathway might be an underlying basis for the anti‐inflammatory and anti‐apoptosis effects of MLT. Collectively, our study suggested that MLT could improve learning and memory in type 2 diabetic mice by activating autophagy via the TLR4/Akt/mTOR pathway, thereby inhibiting neuroinflammation and microglial apoptosis.
A modified Anderson–Newns (A–N) model for calculating the work function and the charge transfer of Cs-O-adsorbed graphene surface with the coverage of adsorbed particles is proposed. The calculation ...of the length of adsorption bond
λ
is optimized. The work function and the amount of charge transfer for different coverage of Cs-O molecules are calculated, and the calculated results variations are in reasonable agreement with the experimental data. As coverage
θ
increases, the amount of charge transfer
Z
decreases and the work function
φ
first decreases to a certain value and then increases slightly. When
θ
= 0.8, the work function
φ
reaches a minimum value of 0.7.
•The dFC state transformed into the other state more frequently in EC than in EO.•Subjects in EC stayed longer in a hyper-connected dFC state than those in EO.•Subjects in EO stayed longer in a ...hypo-connected dFC state than those in EC.
The eyes are our windows to the brain. There are differences in brain activity between people who have their eyes closed (EC) and eyes open (EO). Previous studies focused on differences in brain functional properties between these eyes conditions based on an assumption that brain activity is a static phenomenon. However, the dynamic nature of the brain activity in different eyes conditions is still unclear. In this study, we collected resting-state fMRI data from 21 healthy subjects in the EC and EO conditions. Using a sliding time window approach and a k-means clustering algorithm, we calculated the temporal properties of dynamic functional connectivity (dFC) states in the eyes conditions. We also used graph theory to estimate the dynamic topological properties of functional networks in the two conditions. We detected two dFC states, a hyper-connected State 1 and a hypo-connected State 2. We showed the following results: (i) subjects in the EC condition stayed longer in the hyper-connected State 1 than those in the EO; (ii) subjects in the EO condition stayed longer in the hypo-connected State 2 than those in the EC; and (iii) the dFC state transformed into the other state more frequently during EC than during EO. We also found the variance of the characteristic path length was higher during EC than during EO in the hyper-connected State 1. These results indicate that brain activity may be more active and unstable during EC than during EO. Our findings may provide insights into the dynamic nature of the resting-state brain and could be a useful reference for future rs-fMRI studies.
Cisplatin is a widely used chemotherapeutic drug that can induce ovarian damage. Icariin (ICA), a natural antioxidant derived from Epimedium brevicornum Maxim., has been found to protect against ...organ injury. The aim of the present study was to investigate whether ICA can exert an ovarian-protective effect on cisplatin induced premature ovarian failure (POF) and the underlying mechanism involved. The preventive effect of ICA was evaluated using body weight, the oestrous cycle, ovarian histological analysis, and follicle counting. ICA treatment increased body weight, ovarian weight, and the number of follicles and improved the oestrous cycle in POF mice. ICA reduced cisplatin-induced oxidative damage and upregulated the protein expression levels of Nrf2, GPX4 and HO-1. Moreover, ICA reduced the expression levels of Bax and γH2AX and inhibited ovarian apoptosis. In addition, ICA activated the Nrf2 pathway in vitro and reversed changes in the viability of cisplatin-induced KGN cells, reactive oxygen species (ROS) levels, lipid peroxidation, and apoptosis, and these effects were abrogated when Nrf2 was knocked down or inhibited. Molecular docking confirmed that ICA promotes the release of Nrf2 by competing with Nrf2 for binding to Keap1. The inhibitory effects of ICA on cisplatin-induced oxidative stress, ferroptosis, and apoptosis may be mediated by its modulatory effects on the Nrf2 pathway, providing a novel perspective on the potential mechanisms by which ICA prevents POF.
•Stress elicitedactivation in the bilateral insula, thalami, amygdala, middle cingulate cortex, and premotor cortex.•Physiological stress activated the bilateral insula, thalami, middle cingulate ...cortex, and inferior parietal lobule.•Psychosocial stress activated the left amygdala, right fusiform gyrus, and the left inferior prefrontal cortex.•Men activated the thalamus during physiological stress whereas women activated the amygdala during psychosocial stress.•Physiological stress paradigms induce more consistent activation patterns than psychosocial stress paradigms.
Stress abounds in daily life and is closely related to psychiatric disease. Less is known about the neural basis for the gender differences in stress, and the common and specific neural mechanism for physiological and psychosocial stress. The current study obtained 141 stress-oriented neuroimaging experiments from 126 eligible articles and sorted them into nine types of neuroimaging datasets based on the combination of stress (general, physiological or psychosocial) and gender (overall, male or female). An activation likelihood estimation (ALE) meta-analysis was conducted on each dataset to detect the spatial convergence of activations. A hierarchical clustering analysis was also conducted to uncover the relationship between the stress-induced paradigms and spatial distribution of brain activations. We found that the physiological stress and psychosocial stress showed common activation in the bilateral anterior insula and brainstem, but different activation likelihood in the bilateral insula, thalami, middle cingulate cortex, left fusiform gyri, and left amygdala. Men were more likely to activate the bilateral thalami during physiological stress, whereas women were more likely to activate the left amygdala during psychosocial stress. The activation patterns are more consistent among different physiological stress paradigms than psychosocial stress paradigms. Our results suggest that physiological stress and psychosocial stress activate common brain regions for movement and attentional regulation but different brain regions for sensory and affective processing.
Background Mesenchymal stem cell (MSC)-based therapy is currently considered to be an effective treatment strategy for diabetes and hepatic disorders, such as liver cirrhosis and non-alcoholic fatty ...liver disease. Exosomes are important mediators of cellular connections, and increasing evidence has suggested that exosomes derived from MSCs may be used as direct therapeutic agents; their mechanisms of action, however, remain largely unclear. Here, we evaluated the efficacy and molecular mechanisms of human umbilical cord MSC-derived exosomes (HucMDEs) on hepatic glucose and lipid metabolism in type 2 diabetes mellitus (T2DM). Methods HucMDEs were used to treat T2DM rats, as well as palmitic acid (PA)-treated L-O2 cells, in order to determine the effects of HucMDEs on hepatic glucose and lipid metabolism. To evaluate the changes in autophagy and potential signaling pathways, autophagy-related proteins (BECN1, microtubule-associated protein 1 light chain 3 beta MAP 1LC3B), autophagy-related genes (ATGs, ATG5, and ATG7), AMP-activated protein kinase (AMPK), and phosphorylated AMPK (p-AMPK) were assessed by Western blotting. Results HucMDEs promoted hepatic glycolysis, glycogen storage, and lipolysis, and reduced gluconeogenesis. Additionally, autophagy potentially contributed to the effects of HucMDE treatment. Transmission electron microscopy revealed an increased formation of autophagosomes in HucMDE-treated groups, and the autophagy marker proteins, BECN1 and MAP 1LC3B, were also increased. Moreover, autophagy inhibitor 3-methyladenine significantly reduced the effects of HucMDEs on glucose and lipid metabolism in T2DM rats. Based on its phosphorylation status, we found that the AMPK signaling pathway was activated and induced autophagy in T2DM rats and PA-treated L-O2 cells. Meanwhile, the transfection of AMPK siRNA or application of the AMPK inhibitor, Comp C, weakened the therapeutic effects of HucMDEs on glucose and lipid metabolism. Conclusions These findings demonstrate that HucMDEs improved hepatic glucose and lipid metabolism in T2DM rats by activating autophagy via the AMPK pathway, which provides novel evidence suggesting the potential for HucMDEs in clinically treating T2DM patients. Keywords: Exosome, Mesenchymal stem cell, Glucose metabolism, Type 2 diabetes mellitus, Autophagy
Centrin is a conserved component of centrioles in animals and basal bodies in flagellated organisms. It also associates with axonemal inner-arm dyneins and regulates cell motility, but the underlying ...mechanism remains elusive. In Trypanosoma brucei, three of the five centrins associate with the flagellar basal body, but no centrin has been found to regulate flagellar motility. Here we show that TbCentrin3 is a flagellar protein and knockdown of TbCentrin3 compromises cell motility. Tandem affinity purification followed by mass spectrometry identifies an inner-arm dynein, TbIAD5-1, as the TbCentrin3 partner, and knockdown of TbIAD5-1 causes similar cell motility defect. Further, we demonstrate the interdependence of TbCentrin3 and TbIAD5-1 for maintaining a stable complex in the flagellar axoneme. Together, these results identify the essential role of TbCentrin3 in cell motility by maintaining the stability of an inner-arm dynein in the flagellum, which may be shared by all the centrin-containing flagellated and ciliated organisms.
Major depressive disorder (MDD) and bipolar disorder (BD) are common severe affective diseases. Although previous neuroimaging studies have investigated brain abnormalities in MDD or BD, the ...structural and functional differences between these two disorders remain unclear. In this study, we adopted a multimodal approach, combining voxel-based morphometry (VBM) and functional connectivity (FC), to study the common and distinct structural and functional alterations in unmedicated MDD and BD patients. The VBM analysis revealed that both the MDD and BD patients showed decreased gray matter volume (GMV) in the left anterior cingulate cortex (ACC_L) and right hippocampus (HIP_R) compared with the healthy controls, and the MDD patients showed decreased GMV in the left superior frontal gyrus (SFG_L) and ACC_L compared with the BD patients. Furthermore, we took these clusters as seed regions to analyze the abnormal resting-state functional connectivity (RSFC) in the patients. We found that both the MDD and BD groups had decreased RSFC between the ACC_L and the left orbitofrontal cortex (OFC_L) and that the MDD group had decreased RSFC between the SFG_L and the HIP_L, compared with the healthy controls. Our results revealed that the MDD and BD patients were more similar than different in GMV and RSFC. These findings indicate that investigating the frontal-limbic system could be useful for understanding the underlying mechanisms of these two disorders.
•Both MDD and BD patients had reduced GMV in the ACC_L and HIP_R compared with HC.•MDD patients had decreased GMV in the ACC_L and SFG_L compared with BD patients.•Both BD and MDD patients had decreased ACC-OFC RSFC compared with HC.•The MDD and BD patients were more similar than different in GMV and RSFC.
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