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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. [ABSTRACT FROM AUTHOR]

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. Author summary: Cytokinesis is the final stage of cell division, and in the early branching eukaryote Trypanosoma brucei cytokinesis occurs uni-directionally along the cell division plane that is placed between the new and the old flagella of a bi-flagellated cell. Regulation of cytokinesis in T. brucei depends on actomyosin-independent machineries and trypanosome-specific signaling pathways, but the mechanisms underlying cell division plane placement remain enigmatic. In this work, we report a kinesin-13 family protein named KIN13-5 that determines cell division plane positioning. KIN13-5 localizes to the plus ends of cytoskeletal microtubules at multiple locations and functions downstream of the cytokinesis regulator FPRC in the cytokinesis regulatory pathway. Knockdown of KIN13-5 by RNAi disrupts microtubule bundling, causing mis-placement of the cleavage furrow and asymmetrical cytokinesis and the formation of a blunt posterior. Purified recombinant KIN13-5 bundles microtubules in vitro, which provides biochemical evidence for the molecular function of KIN13-5 in cytokinesis and posterior morphogenesis. Together, through its microtubule bundling activity KIN13-5 plays an essential function in cleavage furrow placement and posterior cytoskeleton morphogenesis in T. brucei. [ABSTRACT FROM AUTHOR]

Graphene has a high work function of 4.6 eV, and it can't be directly used as thermionic emission material. The graphene work function shows a decreasing trend in alkali metal/oxygen (AM/O) coadsorption experiments. Anderson–Newns (AN) model is a classical theoretical model for calculating the work function of adsorption surface. The present study, aiming at AM/O adsorption system, modifies and optimizes the AN model by redefining the calculation method of adsorption bond length λ and establishes the relationship between material work function, thermionic emission performance, and surface coverage. Based on the modified model, the influence of work function decline and thermionic emission performance of cesium/oxygen, potassium/oxygen, and sodium/oxygen graphene adsorption systems is studied. The results show that the work function of graphene affected by the three AM/O adsorbents is basically the same with the increase of coverage, and all of them quickly decrease to the lowest value and then increase slightly. The maximum work function declines are 3.51, 3.30, and 2.83 eV, respectively. At 1000 K, the maximum output current densities are 340, 36, and 0.15 A cm−2, respectively. [ABSTRACT FROM AUTHOR]

Purpose: Prolonged exposure to plasma free fatty acids (FFAs) leads to impaired glucose tolerance (IGT) which can progress to type 2 diabetes (T2D) in the absence of timely and effective interventions. High-fat diet (HFD) leads to chronic inflammation and oxidative stress, impairing pancreatic beta cell (PBC) function. While Didymin, a flavonoid glycoside derived from citrus fruits, has beneficial effects on inflammation dysfunction, its specific role in HFD-induced IGT remains yet to be elucidated. Hence, this study aims to investigate the protective effects of Didymin on PBCs. Methods: HFD-induced IGT mice and INS-1 cells were used to explore the effect and mechanism of Didymin in alleviating IGT. Serum glucose and insulin levels were measured during the glucose tolerance and insulin tolerance tests to evaluate PBC function and insulin resistance. Next, RNA-seq analysis was performed to identify the pathways potentially influenced by Didymin in PBCs. Furthermore, we validated the effects of Didymin both in vitro and in vivo. Mitochondrial electron transport inhibitor (Rotenone) was used to further confirm that Didymin exerts its ameliorative effect by enhancing mitochondria function. Results: Didymin reduces postprandial glycemia and enhances 30-minute postprandial insulin levels in IGT mice. Moreover, Didymin was found to enhance mitochondria biogenesis and function, regulate insulin secretion, and alleviate inflammation and apoptosis. However, these effects were abrogated with the treatment of Rotenone, indicating that Didymin exerts its ameliorative effect by enhancing mitochondria function. Conclusions: Didymin exhibits therapeutic potential in the treatment of HFD-induced IGT. This beneficial effect is attributed to the amelioration of PBC dysfunction through improved mitochondrial function. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated fatty liver disease (MAFLD) is frequently linked to type 2 diabetes mellitus (T2DM), and both conditions exacerbate the progression of the other. However, there is currently no standardized treatment or drug for MAFLD. In this study, A MAFLD animal model through a high-fat diet (HFD) along with administration of streptozotocin (STZ), and palmitic acid (PA)-induced AML12 cells were treated by puerarin. The objective of this study was to assess the therapeutic effect of puerarin, a flavonoid substance that possesses various pharmacological properties, on MAFLD. The results showed that puerarin administration enhanced glucose tolerance and insulin sensitivity, while also mitigating liver dysfunction and hyperlipidemia in MAFLD mice. Moreover, puerarin attenuated oxidative stress levels and inflammation in the liver. Transmission electron microscopy and Western blot analysis indicated that puerarin inhibited ferroptosis in vivo. Further mechanistic investigations revealed that puerarin upregulated SIRT1 expression, increased nuclear factor erythroid 2-related factor 2 (Nrf2) protein levels, and facilitated translocation into the nucleus. The protective effect of puerarin on PA-induced AML12 cells was diminished by the utilization of EX-527 (a SIRT1 inhibitor) and Nrf2 siRNA. Overall, the results demonstrate that puerarin ameliorates MAFLD by suppressing ferroptosis and inflammation via the SIRT1/Nrf2 signaling pathway. The results emphasize the possible medicinal application of puerarin for managing MAFLD. [ABSTRACT FROM AUTHOR]

Cadmium, a common metal, is an environmental contaminant that is hepatotoxic and immunotoxic. Cadmium exposure may affect hepatitis B immunity. The purpose of this study was to assess the association between cadmium exposure and hepatitis B serology in the US population and to develop a model to predict susceptibility of hepatitis B. The study included 50,588 individuals in the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2016. Univariate and multivariate logistic regression and dose–response curves were used to evaluate the relationship between cadmium exposure and hepatitis B serology. Through multivariate logistic regression results, a predictive model was established, and relevant indicators were used to verify the clinical value of the model and evaluate prognostic value of serum cadmium concentration in patients with hepatitis B. We selected 5989 (≥ 6 years old) participants. Univariate logistic regression analysis showed that gender (aOR = 0.7192, 95% CI = 0.6492–0.7968), age (aOR = 1.030, 95% CI = 1.026–1.033), race (aOR = 0.8974, 95% CI = 0.8591–0.9374), poverty ratio (aOR = 1.042, 95% CI = 0.9872–1.101), body mass index (BMI) (aOR = 1.052, 95% CI = 1.044–1.061), hypertension (aOR = 2.017, 95% CI = 1.763–2.306), diabetes (aOR = 2.673, 95% CI = 2.119–3.370), vigorous recreational activities (aOR = 0.6369, 95% CI = 0.5725–0.7085), moderate recreational activity (aOR = 0.7681, 95% CI = 0.6935–0.8574) and cadmium (aOR = 1.295, 95% CI = 1.168–1.436) were closely related to hepatitis B virus (HBV) susceptibility. After adjusting for these confounding factors, multivariate logistic regression analysis showed that the odds ratio of HBV susceptibility was positively correlated with the level of cadmium in serum. The effectiveness of the model was then evaluated by establishing a nomogram, and by calibration curves, ROC curves, and clinical decision curves. Our study shows that cadmium exposure is positively associated with HBV susceptibility risk in the US population, and the constructed model has clinical significance. [ABSTRACT FROM AUTHOR]

Exposure to ethylene oxide may cause a number of diseases. The purpose of this study was to investigate whether there is an association between hemoglobin ethylene oxide (HbEO) and the risk of developing kidney stones in US adults. We analyzed 3348 patients from the National Health and Nutrition Survey (NHANES) 2013–2016 and conducted a cross-sectional study. Dose–response analysis curves of restricted cubic spline function, multiple logistic regression, and subgroup analysis were used to investigate the association between HbEO and the risk of kidney stones. Logistic regression models were used to analyze the correlation between HbEO and kidney stones. Among the 3348 participants, 3016 people self-reported having a kidney stone. After adjusting for age, sex, race, marital status, education level, diabetes, vigorous recreational activity, moderate recreational activity, body mass index, blood urea nitrogen, creatinine, eGFR, and uric acid, we found a positive association between HbEO and the risk of kidney stones. We divided patients into four groups based on quartiles of HbEO levels and performed multifactorial logistic regression after adjusting for confounders, which showed that the incidence of kidney stones increased with increasing HbEO concentrations compared with Q1 (Q2, OR = 0.922, 95% CI, 0. 657–1.295, P = 0.639; Q3, OR = 1.004, 95% CI, 0.713–1.414, P = 0.983; Q4, OR = 1.535, 95% CI, 1.114–2.114, P = 0.009). High levels of HbEO were positively correlated with the risk of kidney stone development and could be used as an indicator of kidney stone prevention. [ABSTRACT FROM AUTHOR]

In order to deal with the biochemical metabolic disorder and the lack of end metabolites caused by hereditary metabolic diseases, a quantitative detection method of amino acids and carnitine in human blood and the quality control method of polypeptide drugs were proposed. First, a method for the detection of 10 amino acids and 32 acylcarnitine metabolites in human blood was established and analyzed by liquid chromatography tandem mass spectrometry. Through the experimental research on typical peptide drugs, combined with the classical synthesis process and the PLS-DA model of human body in different regions, the relevant detection methods for the quality control of peptide drugs were established, which provided a reference for the formulation of peptide drug quality standards. The experimental results show that the quantitative detection method proposed in this paper can effectively detect the content of most amino acids and acylcarnitine. The classical detection method achieved a loss of 16.74% smaller mass-to-charge ratio, and based on this, the quantitative standard for polypeptide drug delivery was determined, which verifies the correctness and superiority of the detection method in this paper. [ABSTRACT FROM AUTHOR]

Aim: Patients with type 2 diabetes (T2DM) often suffer from muscle cramps of varying severity. Studies have shown that muscle cramp is closely related to local microcirculation perfusion disorders. Diabetic retinopathy can not only reflect the microcirculation perfusion in the eye but also the systemic microcirculation in patients with diabetes. The aims of this study were to investigate the relationship between muscle cramps and diabetic retinopathy in patients with type 2 diabetes. Methods: A total of 150 adult patients with type 2 diabetes were enrolled and administered a questionnaire on muscle cramping, along with a visual analogue scale for pain. Diabetic retinopathy (DR) was determined by using fundus photography and graded as non-proliferative DR (NPDR) and proliferative DR (PDR). To assess whether there was an association between the muscle cramps and diabetic retinopathy, we conducted binomial logistic regression analysis. Results: Our study revealed that 48% of patients with T2DM experienced muscle cramps in the past three months. Patients self-reported suffering from muscle cramps exhibited a higher prevalence of DR (61% vs 38%, P < 0.05) and PDR (22% vs 4%, P < 0.05) compared with patients without muscle cramps. Serum 25-(OH) vitamin D, calcium, and magnesium levels were not significantly different between patients with and without muscle cramps. After adjusting for age, duration of diabetes, HbA1c, vitamin D, potassium, calcium, and magnesium, we demonstrated that diabetic retinopathy (OR, 2.18; 95% CI, 1.01– 4.69; P< 0.05) and albumin (OR, 0.90; 95% CI, 0.82– 1.00; P< 0.05) were highly associated with muscle cramps. Binomial logistic regression analysis also indicated that severity of DR is associated with muscle cramps. In addition, DR and PDR were found to be associated with muscle cramp frequency (P for trend < 0.05), duration (P for trend < 0.05), and pain severity (P for trend < 0.05). Conclusion: Muscle cramps occur frequently in diabetes and are correlated with diabetic retinopathy and albumin. Patients with PDR exhibited a higher frequency, severity, and longer duration relative to those with NPDR or without DR. Our findings suggested that muscle cramps in individuals with T2DM might be a result of microvascular dysfunction. Modulation of microvascular perfusion might thus provide a therapeutic target for alleviating muscle cramps. [ABSTRACT FROM AUTHOR]

We use a two-stage hierarchical growth method to encapsulate the blue KSN and yellow RhB molecules into a MOF crystal. By aligning these two conjugate plane-structured molecules in the MOF channel, a polarised white-light emission is obtained, with CIE coordinates of (0.3285, 0.3204) and a polarization ratio of 2.98. [ABSTRACT FROM AUTHOR]

Background: Mesenchymal stem cells (MSCs) show promising therapeutic potential in treating type 2 diabetes mellitus (T2DM) in clinical studies. Accumulating evidence has suggested that the therapeutic effects of MSCs are not due to their direct differentiation into functional β-cells but are instead mediated by their paracrine functions. Among them, exosomes, nano-sized extracellular vesicles, are important substances that exert paracrine functions. However, the underlying mechanisms of exosomes in ameliorating T2DM remain largely unknown. Methods: Bone marrow mesenchymal stem cell (bmMSC)-derived exosomes (bmMDEs) were administrated to T2DM rats and high-glucose-treated primary islets in order to detect their effects on β-cell dedifferentiation. Differential miRNAs were then screened via miRNA sequencing, and miR-146a was isolated after functional verification. TargetScan, reporter gene detection, insulin secretion assays, and qPCR validation were used to predict downstream target genes and involved signaling pathways of miR-146a. Results: Our results showed that bmMDEs reversed diabetic β-cell dedifferentiation and improved β-cell insulin secretion both in vitro and in vivo. Results of miRNA sequencing in bmMDEs and subsequent functional screening demonstrated that miR-146a, a highly conserved miRNA, improved β-cell function. We further found that miR-146a directly targeted Numb, a membrane-bound protein involved in cell fate determination, leading to activation of β-catenin signaling in β-cells. Exosomes derived from miR-146a-knockdown bmMSCs lost the ability to improve β-cell function. Conclusions: These findings demonstrate that bmMSC-derived exosomal miR-146a protects against diabetic β-cell dysfunction by acting on the NUMB/β-catenin signaling pathway, which may represent a novel therapeutic strategy for T2DM. [ABSTRACT FROM AUTHOR]

Passing the flagellum in trypanosomes: The single flagellum of the unicellular parasite Trypanosoma brucei is critical for virulence, and Polo-like kinase (TbPLK) is required for flagellum inheritance during T. brucei proliferation. An et al. found that flagellum inheritance required dephosphorylation of TbPLK Thr125 by the phosphatase KPP1 at flagellum-associated structures during specific phases of the cell cycle to reduce TbPLK activity. In the absence of this inhibition, flagellum inheritance was disrupted because of hyperphosphorylation of the TbPLK substrate TbCentrin2. In human and fish PLK homologs, dephosphorylation of serine residues corresponding to TbPLK Thr125 also reduces kinase activity, demonstrating conservation of this important mechanism for precisely regulating PLK activity during the cell cycle. Trypanosoma brucei, an important human parasite, has a flagellum that controls cell motility, morphogenesis, proliferation, and cell-cell communication. Inheritance of the newly assembled flagellum during the cell cycle requires the Polo-like kinase homolog TbPLK and the kinetoplastid-specific protein phosphatase KPP1, although whether TbPLK acts on KPP1 or vice versa has been unclear. Here, we showed that dephosphorylation of TbPLK on Thr125 by KPP1 maintained low TbPLK activity in the flagellum-associated hook complex structure, thereby ensuring proper flagellum positioning and attachment. This dephosphorylation event required the recognition of phosphorylated Thr198 in the activation loop of TbPLK by the N-terminal Plus3 domain of KPP1 and the dephosphorylation of phosphorylated Thr125 in TbPLK by the C-terminal catalytic domain of KPP1. Dephosphorylation of TbPLK by KPP1 prevented hyperphosphorylation of the hook complex protein TbCentrin2, thereby allowing timely dephosphorylation of phosphorylated TbCentrin2 for hook complex duplication and flagellum positioning and attachment. Thus, KPP1 attenuates TbPLK activity by dephosphorylating TbPLK to facilitate flagellum inheritance. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Freezing of gait (FOG), a disabling symptom of Parkinson's disease (PD), severely affects PD patients' life quality. Previous studies found neuropathologies in functional connectivity related to FOG, but few studies detected abnormal regional activities related to FOG in PD patients. In the present study, we analyzed the amplitude of low-frequency fluctuations (ALFF) to detect brain regions showing abnormal activity in PD patients with FOG (PD-with-FOG) and without FOG (PD-without-FOG). As different frequencies of neural oscillations in brain may reflect distinct brain functional and physiological properties, we conducted this study in three frequency bands, slow-5 (0.01-0.027 Hz), slow-4 (0.027-0.073 Hz), and classical frequency band (0.01-0.08 Hz). We acquired rs-fMRI data from 18 PD-with-FOG patients, 18 PD-without-FOG patients, and 17 healthy controls, then calculated voxel-wise ALFF across the whole brain and compared ALFF among the three groups in each frequency band. We found: (1) in slow-5, both PD-with-FOG and PD-without-FOG patients showed lower ALFF in the bilateral putamen compared to healthy controls, (2) in slow-4, PD-with-FOG patients showed higher ALFF in left inferior temporal gyrus (ITG) and lower ALFF in right middle frontal gyrus (MFG) compared to either PD-without-FOG patients or healthy controls, (3) in classical frequency band, PD-with-FOG patients also showed higher ALFF in ITG compared to either PD-without-FOG patients or healthy controls. Furthermore, we found that ALFF in MFG and ITG in slow-4 provided the highest classification accuracy (96.7%) in distinguishing PD-with-FOG from PD-without-FOG patients by using a stepwise multivariate pattern analysis. Our findings indicated frequency-specific regional spontaneous neural activity related to FOG, which may help to elucidate the pathogenesis of FOG. [ABSTRACT FROM AUTHOR]

Background. More and more studies focus on the relationship between the gastrointestinal microbiome and type 2 diabetes, but few of them have actually explored the relationship between enterotypes and type 2 diabetes. Materials and Methods. We enrolled 134 patients with type 2 diabetes and 37 nondiabetic controls. The anthropometric and clinical indices of each subject were measured. Fecal samples of each subject were also collected and were processed for 16S rDNA sequencing. Multiple logistic regression analysis was used to determine the associations of enterotypes with type 2 diabetes. Multiple linear regression analysis was used to explore the relationship between lipopolysaccharide levels and insulin sensitivity after adjusting for age, BMI, TG, HDL-C, DAO, and TNF-α. The correlation analysis between factors and microbiota was identified using Spearman correlation analysis. The correlation analysis between factors was identified using partial correlation analysis. Results. Gut microbiota in type 2 diabetes group exhibited lower bacterial diversity compared with nondiabetic controls. The fecal communities from all subjects clustered into two enterotypes distinguished by the levels of Bacteroides and Prevotella. Logistic regression analysis showed that the Bacteroides enterotype was an independent risk factor for type 2 diabetes by decreasing insulin sensitivity. The levels of lipopolysaccharide and tumor necrosis factor-alpha were higher in the Bacteroides enterotype compared to the Prevotella enterotype. Partial correlation analysis showed that lipopolysaccharide was closely associated with diamine oxidase, tumor necrosis factor-alpha, and Gutt insulin sensitivity index after adjusting for multiple covariates. Furthermore, the level of lipopolysaccharide was found to be an independent risk factor for insulin sensitivity. Conclusions. We identified two enterotypes, Bacteroides and Prevotella, among all subjects. Our results showed that the Bacteroides enterotype was an independent risk factor for type 2 diabetes, which was due to increased levels of lipopolysaccharide causing decreased insulin sensitivity. [ABSTRACT FROM AUTHOR]

Summary: The flagellated eukaryote Trypanosoma brucei alternates between the insect vector and the mammalian host and proliferates through an unusual mode of cell division. Cell division requires flagellum motility‐generated forces, but flagellum motility exerts distinct effects between different life cycle forms. Motility is required for the final cell abscission of the procyclic form in the insect vector, but is necessary for the initiation of cell division of the bloodstream form in the mammalian host. The underlying mechanisms remain elusive. Here we carried out functional analyses of a flagellar axonemal inner‐arm dynein complex in the bloodstream form and investigated its mechanistic role in cytokinesis initiation. We showed that the axonemal inner‐arm dynein heavy chain TbIAD5‐1 and TbCentrin3 form a complex, localize to the flagellum, and are required for viability in the bloodstream form. We further demonstrated the interdependence between TbIAD5‐1 and TbCentrin3 for maintenance of protein stability. Finally, we showed that depletion of TbIAD5‐1 and TbCentrin3 arrested cytokinesis initiation and disrupted the localization of multiple cytokinesis initiation regulators. These findings identified the essential role of an axonemal inner‐arm dynein complex in cell division, and provided molecular insights into the flagellum motility‐mediated cytokinesis initiation in the bloodstream form of T. brucei. [ABSTRACT FROM AUTHOR]

Background: Bipolar disorder (BD) has been associated with altered brain structural and functional connectivity. However, little is known regarding alterations of the structural brain connectome in BD. The present study aimed to use diffusion-tensor imaging (DTI) and graph theory approaches to investigate the rich club organization and white matter structural connectome in BD. Methods: Forty-two patients with unmedicated BD depression and 59 age-, sex- and handedness-matched healthy control participants underwent DTI. The whole-brain structural connectome was constructed by a deterministic fiber tracking approach. Graph theory analysis was used to examine the group-specific global and nodal topological properties, and rich club organizations, and then nonparametric permutation tests were used for group comparisons of network parameters. Results: Compared with healthy control participants, the patients with BD showed abnormal global properties, including increased characteristic path length, and decreased global efficiency and local efficiency. Locally, the patients with BD showed abnormal nodal parameters (nodal strength, nodal efficiency, and nodal betweenness) predominantly in the parietal, orbitofrontal, occipital, and cerebellar regions. Moreover, the patients with BD showed decreased rich club and feeder connectivity density. Conclusions: Our results may reflect the disrupted white matter topological organization in the whole-brain, and abnormal regional connectivity supporting cognitive and affective functioning in depressed BD, which, in part, be due to impaired rich club connectivity. [ABSTRACT FROM AUTHOR]

A number of studies have indicated that disorders of consciousness result from multifocal injuries as well as from the impaired functional and anatomical connectivity between various anterior forebrain regions. However, the specific causal mechanism linking these regions remains unclear. In this study, we used spectral dynamic causal modeling to assess how the effective connections (ECs) between various regions differ between individuals. Next, we used connectome-based predictive modeling to evaluate the performance of the ECs in predicting the clinical scores of DOC patients. We found increased ECs from the striatum to the globus pallidus as well as from the globus pallidus to the posterior cingulate cortex, and decreased ECs from the globus pallidus to the thalamus and from the medial prefrontal cortex to the striatum in DOC patients as compared to healthy controls. Prediction of the patients’ outcome was effective using the negative ECs as features. In summary, the present study highlights a key role of the thalamo-basal ganglia-cortical loop in DOCs and supports the anterior forebrain mesocircuit hypothesis. Furthermore, EC could be potentially used to assess the consciousness level. [ABSTRACT FROM AUTHOR]

The present study investigated the relationship between Hong Kong people's stereotype toward Mainland people and their own national attachment (i.e., national identity, constructive patriotism, and uncritical patriotism). The role of inter-group relationship as mediator and age as moderator of that relationship were also tested. A total of 1753 local Hong Kong people aged 17-80 (mean age = 20.35 years, SD = 5.02) completed anonymous questionnaires regarding their stereotypes toward Mainland people, inter-group relationship with Mainland people, and national attachment. As expected, stereotypes toward Mainland people, inter-group relationship and national attachment showed significant positive associations with each other. More interestingly, it was found that the inter-group relationship mediated the relationship between stereotypes toward Mainland people and three domains of national attachment, with this indirect link being weaker for younger Hong Kong adults than for older Hong Kong adults. Implications of the present findings for future research are discussed, as well as potential interventions for increasing subjective national attachment to China, especially in young Hong Kong people. [ABSTRACT FROM AUTHOR]

The Polo-like kinase homolog in Trypanosoma brucei, TbPLK, plays essential roles in basal body segregation, flagellum attachment and cytokinesis. The level of TbPLK protein is tightly controlled, but the underlying mechanism remains elusive. Here, we report a Cullin-RING ubiquitin ligase composed of Cullin4, the DNA damage-binding protein 1 homolog TbDDB1 and a WD40-repeat protein WDR1 that controls TbPLK abundance in the basal body and the bilobe. WDR1, through its C-terminal domain, interacts with the PEST motif in TbPLK and, through its N-terminal WD40 motif, binds to TbDDB1. Depletion of WDR1 inhibits bilobe duplication and basal body segregation, disrupts the assembly of the new flagellum attachment zone filament and detaches the new flagellum. Consistent with its role in TbPLK degradation, depletion of WDR1 causes excessive accumulation of TbPLK in the basal body and the bilobe, leading to continuous phosphorylation of TbCentrin2 in the bilobe at late cell cycle stages. Together, these results identify a novel WD40-repeat protein as a TbPLK receptor in the Cullin4-DDB1 ubiquitin ligase complex for degrading TbPLK in the basal body and the bilobe after the G1/S cell cycle transition, thereby promoting bilobe duplication, basal body separation and flagellum-cell body adhesion. [ABSTRACT FROM AUTHOR]

Authors Xinghong Guo and Xinguo Hou agree with this retraction but disagree with the wording of the retraction notice. Retraction Note: Stem Cell Research & Therapy (2020) 11:223 https://doi.org/10.1186/s1328... The Editors-in-Chief have retracted this article because of the following concerns: Figure 2I: overlapping regions are present within this image Figure 3D: overlapping regions are present within this image Figure 5A: this image is incorrect Figure 5E and 6H: overlapping regions are present within and between these images The Editors-in-Chief therefore no longer have confidence in the data presented. [Extracted from the article]

Retraction Note: Mesenchymal stem cell-derived exosomal miR-146a reverses diabetic -cell dedifferentiation Retraction Note to: Stem Cell Research & Therapy (2021) 12:449 https://doi.org/10.1186/s1... The Editors-in-Chief have retracted this article because there are regions of overlap between Fig. None of the other authors has responded to any correspondence from the publisher about this retraction. [Extracted from the article]

Acid rain can directly or indirectly affect plant physiological functions, especially photosynthesis. The enzyme ATP synthase is the key in photosynthetic energy conversion, and thus, it affects plant photosynthesis. To clarify the mechanism by which acid rain affects photosynthesis, we studied the effects of acid rain on plant growth, photosynthesis, chloroplast ATP synthase activity and gene expression, chloroplast ultrastructure, intracellular H level, and water content of rice seedlings. Acid rain at pH 4.5 remained the chloroplast structure unchanged but increased the expression of six chloroplast ATP synthase subunits, promoted chloroplast ATP synthase activity, and increased photosynthesis and plant growth. Acid rain at pH 4.0 or less decreased leaf water content, destroyed chloroplast structure, inhibited the expression of six chloroplast ATP synthase subunits, decreased chloroplast ATP synthase activity, and reduced photosynthesis and plant growth. In conclusion, acid rain affected the chloroplast ultrastructure, chloroplast ATPase transcription and activity, and P by changing the acidity in the cells, and thus influencing the plant growth and development. Finally, the effects of simulated acid rain on the test indices were found to be dose-dependent. [ABSTRACT FROM AUTHOR]

Acid rain and rare earth element (REE) pollution exist simultaneously in many agricultural regions. However, how REE pollution and acid rain affect plant growth in combination remains largely unknown. In this study, the combined effects of simulated acid rain and lanthanum chloride (LaCl) on chloroplast morphology, chloroplast ultrastructure, functional element contents, chlorophyll content, and the net photosynthetic rate ( P) in rice ( Oryza sativa) were investigated by simulating acid rain and rare earth pollution. Under the combined treatment of simulated acid rain at pH 4.5 and 0.08 mM LaCl, the chloroplast membrane was smooth, proteins on this membrane were uniform, chloroplast structure was integrated, and the thylakoids were orderly arranged, and simulated acid rain and LaCl exhibited a mild antagonistic effect; the Mg, Ca, Mn contents, the chlorophyll content, and the P increased under this combined treatment, with a synergistic effect of simulated acid rain and LaCl. Under other combined treatments of simulated acid rain and LaCl, the chloroplast membrane surface was uneven, a clear 'hole' was observed on the surface of chloroplasts, and the thylakoids were dissolved and loose; and the P and contents of functional elements (P, Mg, K, Ca, Mn, Fe, Ni, Cu, Zn and Mo) and chlorophyll decreased. Under these combined treatments, simulated acid rain and LaCl exhibited a synergistic effect. Based on the above results, a model of the combined effects of simulated acid rain and LaCl on plant photosynthesis was established in order to reveal the combined effects on plant photosynthesis, especially on the photosynthetic organelle-chloroplast. Our results would provide some references for further understanding the mechanism of the combined effects of simulated acid rain and LaCl on plant photosynthesis. [ABSTRACT FROM AUTHOR]

In this study, a new type of the MgZnO/CeSmO (MZSDC) composite electrolyte was synthesized using a co-precipitation method. Large-sized engineering cells have been fabricated and tested to meet the demands of applications. X-ray diffraction scanning electron microscopy and X-ray photoelectron spectroscopy have been employed to characterize the microstructure and the morphology of the synthesized samples. MZSDC is a composite system. X-ray electron spectroscopy shows that Ce (3d) binding energy shifted from high to low and the ratio of Ce decreased in comparison to pure CeO, due to the doping effect. The doping and composite caused the material to have an excellent electrical property, 0.089 S · cm, and device performance, with a maximum power of 16.4 W (648 mW · cm) achieved at 600 °C for a larger-sized (6 cm × 6 cm × 1 mm) fuel cell. The open circuit voltage and power of the fuel cell only slightly degrades (less than 1 %) after continually tested for 100 h. This is the first report regarding the large size engineering cell performance for using this new composite electrolyte with both excellent performance and low cost. [ABSTRACT FROM AUTHOR]

Adhesion of motile flagella to the cell body in Trypanosoma brucei requires a filamentous cytoskeletal. structure termed the flagellum attachment zone (FAZ). Despite its essentiality, the complete molecular composition of the FAZ filament and its roles in FAZ filament assembly remain poorly understood. By localization-based screening, we here identified a new FAZ protein, which we called FAZ2. Knockdown of FAZ2 disrupted the FAZ filament, destabilized multiple FAZ filament proteins and caused a cytokinesis defect. We also showed that FAZ2 depletion destabilized another new FAZ filament protein and several flagellum and cytoskeleton proteins. Furthermore, we identified CC2D and KMP11 as FAZ2 partners through affinity purification, and showed that they are each required for maintaining a stable complex. Finally, we demonstrated that FAZ filament proteins are incorporated into the FAZ filamentfrom the proximal region, in contrast to the flagellum components, which are incorporated from the distal tip. In summary, we identified three new FAZ filament proteins and a FAZ filament protein complex, and our results suggest that assembly of the FAZ filament occurs at the proximal region and is essential to maintain the stability of FAZ filament proteins. [ABSTRACT FROM AUTHOR]

Bisphenol A (BPA) is ubiquitous in the environment because of its continual application in plastics and the epoxy resin industry. Cadmium (Cd) is a highly toxic heavy metal element mainly used in smelting, electroplating, and plastic and dye manufacturing. Pollution as a result of BPA and Cd exists simultaneously in many agricultural regions. However, little information is available regarding the combined effects of BPA and Cd on plants. The combined effects of BPA and Cd on the photosynthesis, chlorophyll fluorescence, and chlorophyll content of soybean seedlings were investigated using noninvasive technology. Combined treatment with 1.5 mg/L BPA and 0.2 mg/L Cd synergistically improved the net photosynthetic rate ( Pn), initial fluorescence ( F0), maximal photochemical efficiency ( Fv/ Fm), effective quantum yield of photosystem II ( ΦPSII), photosynthetic electron transport rate (ETR), and chlorophyll content. Combined treatment with 1.5 mg/L BPA and 3.0 mg/L Cd increased the F0 and decreased the Pn, Fv/ Fm, ΦPSII, and ETR, whereas BPA and Cd exhibited an antagonistic effect. Furthermore, combined treatment with 17.2/50.0 mg/L BPA and 3.0/10.0 mg/L Cd synergistically decreased the Pn, Fv/ Fm, ΦPSII, ETR, and chlorophyll content, although it increased the F0. Finally, the effects of BPA and Cd on photosynthesis, chlorophyll fluorescence, and chlorophyll content ceased when BPA stress was stopped. Environ Toxicol Chem 2014;33:2455-2462. © 2014 SETAC [ABSTRACT FROM AUTHOR]

To explore how lead (Pb) and acid rain simultaneously affect plants, the combined effects of Pb and acid rain on the chlorophyll content, chlorophyll fluorescence reaction, Hill reaction rate, and Mg-ATPase activity in soybean seedlings were investigated. The results indicated that, when soybean seedlings were treated with Pb or acid rain alone, the chlorophyll content, Hill reaction rate, Mg-ATPase activity, and maximal photochemical efficiency ( F/ F) were decreased, while the initial fluorescence ( F) and maximum quantum yield ( Y) were increased, compared with those of the control. The combined treatment with Pb and acid rain decreased the chlorophyll content, Hill reaction rate, Mg-ATPase activity, F/ F, and Y and increased F in soybean seedlings. Under the combined treatment with Pb and acid rain, the two factors showed additive effects on the chlorophyll content in soybean seedlings and exhibited antagonistic effects on the Hill reaction rate. Under the combined treatment with high-concentration Pb and acid rain, the two factors exhibited synergistic effects on the Mg-ATPase activity, F, F/ F, as well as Y. In summary, the inhibition of the photosynthetic process is an important physiological basis for the simultaneous actions of Pb and acid rain in soybean seedlings. [ABSTRACT FROM AUTHOR]

In order to probe into the enzymological mechanism for the regulation of lanthanum chloride (LaCl) on flavonoid synthesis in plants under enhanced ultraviolet-B (UV-B) radiation, the effects of LaCl (20 and 60 mg l) on the content of flavonoids as well as the activities of phenylalanine ammonia-lyase (PAL), cinnamate-4-hydroxylase (C4H), 4-coumarate : coenzyme A ligase (4CL), and chalcone synthase (CHS) in soybean seedlings under enhanced UV-B radiation (2.6 and 6.2 kJ m day) were investigated. Enhanced UV-B radiation (2.6 and 6.2 kJ m day) caused the increase in the content of flavonoids as well as the activities of PAL, C4H, 4CL, and CHS in soybean seedlings. The treatment of 20 mg l LaCl also efficiently increased these indices, which promoted the flavonoid synthesis and provided protective effects for resisting enhanced UV-B radiation. On the contrary, the treatment of 60 mg l LaCl decreased the content of flavonoids as well as the activities of C4H, 4CL, and CHS in soybean seedlings except increasing the activity of PAL, which were not beneficial to the flavonoid synthesis and provided negative effects for resisting enhanced UV-B radiation. In conclusion, enhanced UV-B radiation caused the increase in the flavonoid synthesis by promoting the activities of PAL, C4H, 4CL, and CHS in soybean seedlings. The treatment of LaCl could change flavonoid synthesis in soybean seedlings under enhanced UV-B radiation by regulating the activities of PAL, C4H, 4CL, and CHS, which is an enzymological mechanism for the regulation of LaCl on flavonoid synthesis in plants under enhanced UV-B radiation. [ABSTRACT FROM AUTHOR]

The chromosomal passenger complex ( CPC) in animals, consisting of Aurora B kinase and three evolutionarily conserved proteins, plays crucial roles in mitosis and cytokinesis. However, Trypanosoma brucei expresses an unusual CPC consisting of an Aurora-like kinase, TbAUK1, and two kinetoplastid-specific proteins, TbCPC1 and TbCPC2. Despite their essential functions, little is known about the regulation of TbAUK1 and the roles of TbCPC1 and TbCPC2. Here, we investigate the effect of post-translational modification on the activity and spatiotemporal control of TbAUK1, and demonstrate that phosphorylation of two conserved threonine residues in the activation loop of the kinase domain contributes to TbAUK1 activation and function. TbAUK1 is SUMOylated in vivo, and mutation of the SUMO-conjugation site compromises TbAUK1 function. Degradation of TbAUK1 requires two destruction boxes and is mediated by the anaphase-promoting complex/cyclosome ( APC/ C), whereas degradation of TbCPC1 and TbCPC2 is not dependent on the predicted destruction boxes and is APC/ C-independent. Moreover, we determine the domains in CPC subunits that mediate the pairwise interactions, and show that disruption of the interaction impairs the localization of TbAUK1 and TbCPC2 but not TbCPC1. Our results demonstrate the requirement of post-translational modifications for TbAUK1 function and a crucial role of TbCPC1 in mediating TbAUK1 localization. [ABSTRACT FROM AUTHOR]

Cyclins and cyclin-dependent kinases ( CDKs) represent the fundamental, crucial regulators of the cell division cycle in eukaryotes. Trypanosoma brucei expresses a large number of cyclins and Cdc2- related kinases ( CRKs). However, how these cyclins and CRKs cooperate to regulate cell cycle progression remains poorly understood. Here, we carry out directional yeast two-hybrid assays to identify the interactions between the 10 cyclins and the 11 CRKs and detect a total of 26 cyclin- CRK pairs, among which 20 pairs are new. Our current efforts are focused on four PHO80-like cyclins, CYC2, CYC4, CYC5 and CYC7, and their physical and functional interactions with CRK1. Silencing of the four cyclins and CRK1 leads to the increase of G1 cells and defective DNA replication, suggesting their important roles in promoting the G1/ S transition. Additionally, CYC2-, CYC7- and CRK1-deficient cells possess an elongated posterior that is filled with newly assembled microtubules. Further, we show that the four cyclins display distinct subcellular localizations and half-lives, suggesting that they likely undergo distinct regulation. Altogether, our results demonstrate the involvement of four CRK1-associated cyclins, CYC2, CYC4, CYC5 and CYC7, in promoting the G1/ S transition and the requirement of CYC2 and CYC7 in maintaining posterior cytoskeletal morphogenesis during the G1/ S transition. [ABSTRACT FROM AUTHOR]

The cytoskeleton of Trypanosoma brucei, a unicellular eukaryote and a parasitic protozoan, is defined by the subpellicular microtubule corset that is arranged underneath the plasma membrane. We recently identified two orphan kinesins, TbKIN-C and TbKIN-D, that cooperate to regulate the organization of the subpellicular microtubule corset and thereby maintain cell morphology in the procyclic form of T. brucei. In this report, we characterize the function of TbKIN-C and TbKIN-D in the bloodstream form of T. brucei and investigate their functional cooperation in both the bloodstream and procyclic forms. TbKIN-C and TbKIN-D form a tight complex in vivo in the bloodstream form. TbKIN-C is strongly enriched at the posterior tip of the cell, whereas TbKIN-D is distributed throughout the cell body at all cell cycle stages. RNAi of TbKIN-C or TbKIN-D in the bloodstream form inhibits cell proliferation and leads to cell death, due to cytokinesis defects. RNAi of TbKIN-C and TbKIN-D also results in defects in basal body segregation, but does not affect the synthesis and segregation of the flagellum and the flagellum attachment zone (FAZ) filament. Knockdown of TbKIN-C and TbKIN-D does not disrupt the organization of the subpellicular microtubule corset, but produces multinucleated cells with an enlarged flagellar pocket and misplaced flagella. Interestingly, depletion of TbKIN-C results in rapid degradation of TbKIN-D and, similarly, knockdown of TbKIN-C destabilizes TbKIN-D, suggesting that formation of TbKIN-C/TbKIN-D complex stabilizes both kinesins and is required for the two kinesins to execute their essential cellular functions. Altogether, our results demonstrate the essential role of the two kinesins in cell morphogenesis and cytokinesis in the bloodstream form and the requirement of heteromeric complex formation for maintaining the stability of the two kinesins. [ABSTRACT FROM AUTHOR]

Summary Kinesins are motor-based transport proteins that play diverse roles in various cellular processes. The trypanosome genome lacks the homologues of many conserved mitotic kinesins, but encodes a number of trypanosome-specific kinesins with unknown function. Here, we report the biochemical and functional characterization of TbKIN-C, a trypanosome-specific kinesin, which was initially identified through an RNAi screen for cytokinesis genes in T. brucei. TbKIN-C possesses in vitro ATPase activity and associates with cytoskeletal tubulin microtubules in vivo. It is distributed throughout the cytoskeleton with a focal enrichment at the posterior end of the cell during early cell cycle stages. RNAi of TbKIN-C resulted in distorted cell shape with an elongated posterior filled with tyrosinated tubulin microtubules. Silencing of TbKIN-C impaired the segregation of organelles and cytoskeletal structures and led to detachment of the new flagellum and a small portion of the cytoplasm. We also show that RNAi of TbKIN-C compromised cytokinesis and abolished the trans-localization of TbCPC1, a subunit of the chromosomal passenger complex, from the central spindle to the initiation site of cytokinesis. Our results suggest an essential role of TbKIN-C in maintaining cell morphology, likely through regulating microtubule dynamics at the posterior end of the cell. [ABSTRACT FROM AUTHOR]