Indole-3-carbinol ameliorates ovarian damage in female old mice through Nrf2/HO-1 pathway activation.

Ovarian aging leads to infertility and birth defects. We aimed to clarify the role of Indole-3-carbinol (I3C) in resistance to oxidative stress, apoptosis, and fibrosis in ovarian aging. I3C was administered via intraperitoneal injection for 3 weeks in young or old mice. Immunohistochemistry; Masson, Sirius red, and TUNEL staining; follicle counting; estrous cycle analysis; and Western blotting were used for validating the protective effect of I3C against ovarian senescence. Human granulosa-like tumor cell line and primary granulosa cells were used for in vitro assay. The results indicated that I3C inhibited ovarian fibrosis and apoptosis while increasing the number of primordial follicles. Mechanistic studies have shown that I3C promoted the nuclear translocation of nuclear factor-erythroid 2-related factor (Nrf2) and upregulated the expression of heme oxygenase 1 (HO-1). Additionally, I3C increased cell viability and decreased lactate dehydrogenase, malondialdehyde, reactive oxygen species and JC-1 levels. Furthermore, the antioxidant effect of I3C was found to be dependent on the activation of Nrf2 and HO-1, as demonstrated by the disappearance of the effect upon inhibition of Nrf2 expression. In conclusion, I3C can alleviate the ovarian damage caused by aging and may be a protective agent to delay ovarian aging.

A kinesin-13 family kinesin in Trypanosoma brucei regulates cytokinesis and cytoskeleton morphogenesis by promoting microtubule bundling.

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.

Didymin protects pancreatic beta cells by enhancing mitochondrial function in high-fat diet-induced impaired glucose tolerance.

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.

Inhibition of cisplatin-induced Acsl4-mediated ferroptosis alleviated ovarian injury.

Given that the severity of the chemotherapy-induced ovarian damage, effective fertility preservation is a necessary part of the treatment process. Ferroptosis is a regulated cell death triggered by excessive phospholipid peroxidation caused by iron and the role of ferroptosis in chemotherapy-induced ovarian damage remains unclear. In this study, we demonstrated that cisplatin treatment caused the accumulation of iron ions which induced ferroptosis in ovarian tissue. And our results show that ferrostatin-1 was able to suppress the ovarian injury and granulosa cell death caused by cisplatin (Cis) in vivo and in vitro. At the same time, we observed significant changes in the expression levels of Acyl-CoA synthetase long-chain family member 4 (Acsl4) and glutathione peroxidase 4 (GPX4). Similarly, Rosiglitazone, an inhibitor of Acsl4, administration alleviated the ovary damage of the mice undergoing chemotherapy. Further mechanistic investigation showed that cisplatin increased the expression level of specificity protein 1 (SP1), and SP1 could bind to the promoter of Acsl4 to increased Acsl4 transcription. Overall, ferroptosis plays an important role in Cis induced ovarian injury, and inhibition of ferroptosis protects ovarian tissues from damage caused by cisplatin, and for the first time, we have identified the potential of Fer-1 and Rosi to protect ovarian function in female mice undergoing chemotherapy.

Didymin alleviates metabolic dysfunction-associated fatty liver disease (MAFLD) via the stimulation of Sirt1-mediated lipophagy and mitochondrial biogenesis.

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) is one of the most prevalent metabolic syndromes worldwide. However, no approved pharmacological treatments are available for MAFLD. Chenpi, one kind of dried peel of citrus fruits, has traditionally been utilized as a medicinal herb for liver diseases. Didymin is a newly identified oral bioactive dietary flavonoid glycoside derived from Chenpi. In this study, we investigated the therapeutic potential of Didymin as an anti-MAFLD drug and elucidated its underlying mechanisms. METHODS: High-fat diet (HFD)-induced MAFLD mice and alpha mouse liver 12 (AML12) cells were utilized to evaluate the effects and mechanisms of Didymin in the treatment of MAFLD. Liver weight, serum biochemical parameters, and liver morphology were examined to demonstrate the therapeutic efficacy of Didymin in MAFLD treatment. RNA-seq analysis was performed to identify potential pathways that could be affected by Didymin. The impact of Didymin on Sirt1 was corroborated through western blot, molecular docking analysis, microscale thermophoresis (MST), and deacetylase activity assay. Then, a Sirt1 inhibitor (EX-527) was utilized to confirm that Didymin alleviates MAFLD via Sirt1. Western blot and additional assays were used to investigate the underlying mechanisms. RESULTS: Our results suggested that Didymin may possess therapeutic potential against MAFLD in vitro and in vivo. By promoting Sirt1 expression as well as directly binding to and activating Sirt1, Didymin triggers downstream pathways that enhance mitochondrial biogenesis and function while reducing apoptosis and enhancing lipophagy. CONCLUSIONS: These suggest that Didymin could be a promising medication for MAFLD treatment. Furthermore, its therapeutic effects are mediated by Sirt1.

Puerarin ameliorates metabolic dysfunction-associated fatty liver disease by inhibiting ferroptosis and inflammation.

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.

Prognostic value of total body muscle-fat ratio in patients with kidney stone disease: A US population-based study.

Purpose: To examine the relationship between the muscle-fat ratio (MFR) and kidney stone disease (KSD) in the adult population of the United States between 2011 and 2018, and whether it can be used as a predictor of KSD prognosis. Materials and methods: We conducted a cross-sectional study analysing 9326 patients from the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2018. We analyzed all participants by sex, age, race, level of education, marital status, household income-to-poverty ratio, hypertension, diabetes, vigorous physical activity, moderate physical activity, blood urea nitrogen, creatinine, uric acid, cotinine, and MFR. Dose-response curves with a restricted cubic spline function, univariate and multifactorial logistic regression were used for the analysis of the correlation between MFR and KSD. Finally, we created predictive models based on age, race, hypertension, diabetes mellitus, cotinine and MFR. The prediction model was evaluated using calibration curves, receiver operating characteristic curves and clinical decision curves from the training and test sets. Results: Of the 9326 participants, 8582 (92%) self-reported that they did not have KSD and 744 (8%) self-reported that they had KSD. Univariate and multifactorial logistic regression showed that MFR was negatively associated with the prevalence of KSD (odds ratio [OR]: 0.770, 95% CI: 0.703-0.843; OR: 0.815, 95% CI: 0.738-0.897). Similarly, the risk of developing KSD decreased with increasing MFR as shown by the dose curves in the restricted cubic bar graphs. Furthermore, there is some accuracy (AUC = 0.652) and clinical applicability to the model we constructed based on the results of multifactorial logistic regression. Conclusion: The MFR is protective factor against the developing KSD in adults in the USA.

The relationship between cadmium exposure and hepatitis B susceptibility and the establishment of its prediction model.

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.

Multi-modal MRI measures reveal sensory abnormalities in major depressive disorder patients: A surface-based study.

BACKGROUND: Multi-modal magnetic resonance imaging (MRI) measures are supposed to be able to capture different brain neurobiological aspects of major depressive disorder (MDD). A fusion analysis of structural and functional modalities may better reveal the disease biomarker specific to the MDD disease. METHODS: We recruited 30 MDD patients and 30 matched healthy controls (HC). For each subject, we acquired high-resolution brain structural images and resting-state fMRI (rs-fMRI) data using a 3 T MRI scanner. We first extracted the brain morphometric measures, including the cortical volume (CV), cortical thickness (CT), and surface area (SA), for each subject from the structural images, and then detected the structural clusters showing significant between-group differences in each measure using the surface-based morphology (SBM) analysis. By taking the identified structural clusters as seeds, we performed seed-based functional connectivity (FC) analyses to determine the regions with abnormal FC in the patients. Based on a logistic regression model, we performed a classification analysis by selecting these structural and functional cluster-wise measures as features to distinguish the MDD patients from the HC. RESULTS: The MDD patients showed significantly lower CV in a cluster involving the right superior temporal gyrus (STG) and middle temporal gyrus (MTG), and lower SA in three clusters involving the bilateral STG, temporal pole gyrus, and entorhinal cortex, and the left inferior temporal gyrus, and fusiform gyrus, than the controls. No significant difference in CT was detected between the two groups. By taking the above-detected clusters as seeds to perform the seed-based FC analysis, we found that the MDD patients showed significantly lower FC between STG/MTG (CV's cluster) and two clusters located in the bilateral visual cortices than the controls. The logistic regression model based on the structural and functional features reached a classification accuracy of 86.7% (p < 0.001) between MDD and controls. CONCLUSION: The present study showed sensory abnormalities in MDD patients using the multi-modal MRI analysis. This finding may act as a disease biomarker distinguishing MDD patients from healthy individuals.

Visual experience shapes functional connectivity between occipital and non-visual networks.

Comparisons across adults with different sensory histories (blind vs. sighted) have uncovered effects of experience on human brain function. In people born blind visual cortices are responsive to non-visual tasks and show altered functional connectivity at rest. Since almost all research has been done with adults, little is known about the developmental origins of this plasticity. Are infant visual cortices initially functionally like those of sighted adults and blindness causes reorganization? Alternatively, do infants start like blind adults, with vision required to set up the sighted pattern? To distinguish between these possibilities, we compare resting state functional connectivity across blind (n = 30) and blindfolded sighted (n = 50) adults to a large cohort of sighted infants (Developing Human Connectome Project, n = 475). Remarkably, we find that infant secondary visual cortices functionally resemble those of blind more than sighted adults, consistent with the idea that visual experience is required to set up long-range functional connectivity. Primary visual cortices show a mixture of instructive effects of vision and reorganizing effects of blindness. Specifically, in sighted adults, visual cortices show stronger functional coupling with nonvisual sensory-motor networks (i.e., auditory, somatosensory/motor) than with higher-cognitive prefrontal cortices (PFC). In blind adults, visual cortices show stronger coupling with PFC. In infants, connectivity of secondary visual cortices is stronger with PFC, while V1 shows equal sensory-motor/PFC connectivity. In contrast, lateralization of occipital-to-frontal connectivity resembles the sighted adults at birth and is reorganized by blindness, possibly due to recruitment of occipital networks for lateralized cognitive functions, such as language.

Mesenchymal stromal cells ameliorate diabetes-induced muscle atrophy through exosomes by enhancing AMPK/ULK1-mediated autophagy.

BACKGROUND: Diabetes and obesity are associated with muscle atrophy that reduces life quality and lacks effective treatment. Mesenchymal stromal cell (MSC)-based therapy can ameliorate high fat-diet (HFD) and immobilization (IM)-induced muscle atrophy in mice. However, the effect of MSCs on muscle atrophy in type 2 diabetes mellitus (T2DM) and the potential mechanism is unclear. Here, we evaluated the efficacy and explored molecular mechanisms of human umbilical cord MSCs (hucMSCs) and hucMSC-derived exosomes (MSC-EXO) on diabetes- and obesity-induced muscle atrophy. METHODS: Diabetic db/db mice, mice fed with high-fat diet (HFD), mice with hindlimb immobilization (IM), and C2C12 myotubes were used to explore the effect of hucMSCs or MSC-EXO in alleviating muscle atrophy. Grip strength test and treadmill running were used to measure skeletal muscle strength and performance. Body composition, muscle weight, and muscle fibre cross-sectional area (CSA) was used to evaluate muscle mass. RNA-seq analysis of tibialis anterior (TA) muscle and Western blot analysis of muscle atrophy signalling, including MuRF1 and Atrogin 1, were performed to investigate the underlying mechanisms. RESULTS: hucMSCs increased grip strength (P = 0.0256 in db/db mice, P = 0.012 in HFD mice, P = 0.0097 in IM mice), running endurance (P = 0.0154 in HFD mice, P = 0.0006 in IM mice), and muscle mass (P = 0.0004 in db/db mice, P = 0.0076 in HFD mice, P = 0.0144 in IM mice) in all models tested, with elevated CSA of muscle fibres (P < 0.0001 in db/db mice and HFD mice, P = 0.0088 in IM mice) and reduced Atrogin1 (P = 0.0459 in db/db mice, P = 0.0088 in HFD mice, P = 0.0016 in IM mice) and MuRF1 expression (P = 0.0004 in db/db mice, P = 0.0077 in HFD mice, P = 0.0451 in IM mice). MSC-EXO replicated all these hucMSC-mediated changes (P = 0.0103 for grip strength, P = 0.013 for muscle mass, P < 0.0001 for CSA of muscle fibres, P = 0.0171 for Atrogin1 expression, and P = 0.006 for MuRF1 expression). RNA-seq revealed that hucMSCs activated the AMPK/ULK1 signalling and enhanced autophagy. Knockdown of AMPK or inhibition of autophagy with 3-methyladenine (3-MA) diminished the beneficial anti-atrophy effects of hucMSCs or MSC-EXO. CONCLUSIONS: Our results suggest that human umbilical cord mesenchymal stromal cells mitigate diabetes- and obesity-induced muscle atrophy via enhancing AMPK/ULK1-mediated autophagy through exosomes, with implications of applying hucMSCs or hucMSC-derived exosomes to treat muscle atrophy.

The relationship between ethylene oxide levels in hemoglobin and the prevalence of kidney stones in US adults: an exposure-response analysis from NHANES 2013-2016.

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.

Polo-like kinase and Aurora B kinase phosphorylate and cooperate with the CIF1-CIF2 complex to promote cytokinesis initiation in Trypanosoma brucei.

Cytokinesis in eukaryotes is regulated by a Polo-like kinase-mediated and Aurora B kinase-mediated signalling pathway that promotes the assembly of the actomyosin contractile ring, a cytokinesis machinery conserved across evolution from yeast to humans. Trypanosoma brucei, an early divergent parasitic protozoan, employs an actomyosin-independent mechanism for its unusual cytokinesis that is controlled by a regulatory pathway comprising the Polo-like kinase TbPLK, the Aurora B kinase TbAUK1 and multiple trypanosomatid-specific regulators. However, whether any of these trypanosomatid-specific regulators function as substrates of TbPLK and/or TbAUK1 and how they cooperate with TbPLK and TbAUK1 to promote cytokinesis remain unknown. Here, we demonstrate that TbPLK and TbAUK1 phosphorylate the cytokinesis regulators CIF1 and CIF2 on multiple sites within their intrinsically disordered regions. We further show that TbPLK localization depends on its interaction with CIF1 from S/G2 phases, that TbPLK maintains CIF1 and CIF2 localization from G2 phase until early mitosis, and that TbAUK1 maintains CIF1 and CIF2 localization from late mitosis. Finally, we demonstrate that the cytokinesis regulators CIF4 and FPRC are not substrates of TbPLK and TbAUK1, and that they function upstream of TbPLK and TbAUK1 in the cytokinesis regulatory pathway. Together, these results provide insights into the functional interplay and the order of actions between the two protein kinases and the trypanosomatid-specific cytokinesis regulators in T. brucei.

cGAS-STING activation contributes to podocyte injury in diabetic kidney disease.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal diseases. DKD does not have efficacious treatment. The cGAS-STING pathway is activated in podocytes at the early stage of kidney dysfunction, which is associated with the activation of STING downstream effectors TBK1 and NF-κB but not IRF3. Lipotoxicity induces mitochondrial damage and mtDNA leakage to the cytosol through Bcl-2 associated X protein (BAX) in podocytes. BAX-mediated mtDNA cytosolic leakage can activate the cGAS-STING pathway in the absence of lipotoxicity and is sufficient to cause podocyte injury. Depletion of cytosolic mtDNA, genetic STING knockdown, or pharmacological inhibition of STING or TBK1 alleviates podocyte injury and improves renal functions in cultured podocytes or mouse models of diabetes and obesity. These results suggest that the mtDNA-cGAS-STING pathway promotes podocyte injury and is a potential therapeutic target for DKD or other obesity-related kidney diseases.

Exosomes derived from mesenchymal stem cells attenuate diabetic kidney disease by inhibiting cell apoptosis and epithelial-to-mesenchymal transition via miR-424-5p.

Diabetic kidney disease (DKD) is well-acknowledged as one of the most common complications in diabetes mellitus. Recent studies have demonstrated the promising role of mesenchymal stem cell-derived exosomes (MSC-exos) as a cell-free treatment strategy for DKD. The present study sought to investigate the therapeutic potential and the underlying mechanisms of MSC-exos in DKD. The authentication of MSC-exos was validated by western blot, transmission electron microscope (TEM), and nanosight tracking analysis (NTA). Apoptosis was detected by western blot, TUNEL staining, and flow cytometry. Epithelial-to-mesenchymal transition (EMT) was evaluated by western blot and immunofluorescence. The relationship between miR-424-5p and Yes-associated protein 1 (YAP1) was revealed by dual luciferase reporter assay. We observed that MSC-exos could attenuate DKD by decreasing cell apoptosis and inhibiting epithelial-to-mesenchymal transition (EMT) in diabetic kidneys in db/db mice. Besides, we documented that MSC-exos could reverse high glucose-induced apoptosis and EMT in HK2 cells. Interestingly, miR-424-5p derived from MSC-exos could inhibit YAP1 activation in HK2 cells, resulting in alleviation of high glucose-induced cell apoptosis and EMT. Our study provides novel insights into MSC-exos-mediated protective effect in DKD. MSC-exos could inhibit high glucose-induced apoptosis and EMT through miR-424-5p targeting of YAP1.

Typical and disrupted brain circuitry for conscious awareness in full-term and preterm infants.

One of the great frontiers of consciousness science is understanding how early consciousness arises in the development of the human infant. The reciprocal relationship between the default mode network and fronto-parietal networks-the dorsal attention and executive control network-is thought to facilitate integration of information across the brain and its availability for a wide set of conscious mental operations. It remains unknown whether the brain mechanism of conscious awareness is instantiated in infants from birth. To address this gap, we investigated the development of the default mode and fronto-parietal networks and of their reciprocal relationship in neonates. To understand the effect of early neonate age on these networks, we also assessed neonates born prematurely or before term-equivalent age. We used the Developing Human Connectome Project, a unique Open Science dataset which provides a large sample of neonatal functional MRI data with high temporal and spatial resolution. Resting state functional MRI data for full-term neonates (n = 282, age 41.2 weeks ± 12 days) and preterm neonates scanned at term-equivalent age (n = 73, 40.9 weeks ± 14.5 days), or before term-equivalent age (n = 73, 34.6 weeks ± 13.4 days), were obtained from the Developing Human Connectome Project, and for a reference adult group (n = 176, 22-36 years), from the Human Connectome Project. For the first time, we show that the reciprocal relationship between the default mode and dorsal attention network was present at full-term birth or term-equivalent age. Although different from the adult networks, the default mode, dorsal attention and executive control networks were present as distinct networks at full-term birth or term-equivalent age, but premature birth was associated with network disruption. By contrast, neonates before term-equivalent age showed dramatic underdevelopment of high-order networks. Only the dorsal attention network was present as a distinct network and the reciprocal network relationship was not yet formed. Our results suggest that, at full-term birth or by term-equivalent age, infants possess key features of the neural circuitry that enables integration of information across diverse sensory and high-order functional modules, giving rise to conscious awareness. Conversely, they suggest that this brain infrastructure is not present before infants reach term-equivalent age. These findings improve understanding of the ontogeny of high-order network dynamics that support conscious awareness and of their disruption by premature birth.

KLIF-associated cytoskeletal proteins in Trypanosoma brucei regulate cytokinesis by promoting cleavage furrow positioning and ingression.

Cytokinesis in the early divergent protozoan Trypanosoma brucei occurs from the anterior cell tip of the new-flagellum daughter toward the nascent posterior end of the old-flagellum daughter of a dividing biflagellated cell. The cleavage furrow ingresses unidirectionally along the preformed cell division fold and is regulated by an orphan kinesin named kinesin localized to the ingressing furrow (KLIF) that localizes to the leading edge of the ingressing furrow. Little is known about how furrow ingression is controlled by KLIF and whether KLIF interacts with and cooperates with other cytokinesis regulatory proteins to promote furrow ingression. Here, we investigated the roles of KLIF in cleavage furrow ingression and identified a cohort of KLIF-associated cytoskeletal proteins as essential cytokinesis regulators. By genetic complementation, we demonstrated the requirement of the kinesin motor activity, but not the putative tropomyosin domain, of KLIF in promoting furrow ingression. We further showed that depletion of KLIF impaired the resolution of the nascent posterior of the old-flagellar daughter cell, thereby stalking cleavage furrow ingression at late stages of cytokinesis. Through proximity biotinylation, we identified a subset of cytoskeleton-associated proteins (CAPs) as KLIF-proximal proteins, and functional characterization of these cytoskeletal proteins revealed the essential roles of CAP46 and CAP52 in positioning the cleavage furrow and the crucial roles of CAP42 and CAP50 in promoting cleavage furrow ingression. Together, these results identified multiple cytoskeletal proteins as cytokinesis regulators and uncovered their essential and distinct roles in cytokinesis.

Relationship Between Muscle Cramps and Diabetic Retinopathy in Patients with Type 2 Diabetes.

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.