The role of non-coding RNAs in diabetes-induced osteoporosis.

Diabetes mellitus (DM) and osteoporosis are two major health care problems worldwide. Emerging evidence suggests that DM poses a risk for osteoporosis and can contribute to the development of diabetes-induced osteoporosis (DOP). Interestingly, some epidemiological studies suggest that DOP may be at least partially distinct from those skeletal abnormalities associated with old age or postmenopausal osteoporosis. The increasing number of DM patients who also have DOP calls for a discussion of the pathogenesis of DOP and the investigation of drugs to treat DOP. Recently, non-coding RNAs (ncRNAs) have received more attention due to their significant role in cellular functions and bone formation. It is worth noting that ncRNAs have also been demonstrated to participate in the progression of DOP. Meanwhile, nano-delivery systems are considered a promising strategy to treat DOP because of their cellular targeting, sustained release, and controlled release characteristics. Additionally, the utilization of novel technologies such as the CRISPR system has expanded the scope of available options for treating DOP. Hence, this paper explores the functions and regulatory mechanisms of ncRNAs in DOP and highlights the advantages of employing nanoparticle-based drug delivery techniques to treat DOP. Finally, this paper also explores the potential of ncRNAs as diagnostic DOP biomarkers.

Exploration of potential shared gene signatures between periodontitis and multiple sclerosis.

BACKGROUND: Although periodontitis has previously been reported to be linked with multiple sclerosis (MS), but the molecular mechanisms and pathological interactions between the two remain unclear. This study aims to explore potential crosstalk genes and pathways between periodontitis and MS. METHODS: Periodontitis and MS data were obtained from the Gene Expression Omnibus (GEO) database. Shared genes were identified by differential expression analysis and weighted gene co-expression network analysis (WGCNA). Then, enrichment analysis for the shared genes was carried out by multiple methods. The least absolute shrinkage and selection operator (LASSO) regression was used to obtain potential shared diagnostic genes. Furthermore, the expression profile of 28 immune cells in periodontitis and MS was examined using single-sample GSEA (ssGSEA). Finally, real-time quantitative fluorescent PCR (qRT-PCR) and immune histochemical staining were employed to validate Hub gene expressions in periodontitis and MS samples. RESULTS: FAM46C, SLC7A7, LY96, CFI, DDIT4L, CD14, C5AR1, and IGJ genes were the shared genes between periodontitis, and MS. GO analysis revealed that the shared genes exhibited the greatest enrichment in response to molecules of bacterial origin. LASSO analysis indicated that CFI, DDIT4L, and FAM46C were the most effective shared diagnostic biomarkers for periodontitis and MS, which were further validated by qPCR and immunohistochemical staining. ssGSEA analysis revealed that T and B cells significantly influence the development of MS and periodontitis. CONCLUSIONS: FAM46C, SLC7A7, LY96, CFI, DDIT4L, CD14, C5AR1, and IGJ were the most important crosstalk genes between periodontitis, and MS. Further studies found that CFI, DDIT4L, and FAM46C were potential biomarkers in periodontitis and MS.

Associations between sedentary behaviour patterns and depression among people aged 60 and older in Hebei Province of China.

BACKGROUND: Sedentary behaviours (SBs) are now considered a risk factor for depression. Older adults are sedentary most of the time and are at a high risk of depression. However, not all types of SBs have adverse effects on mental health. Passive SBs (such as watching TV) increase the risk of depression, whereas mentally active SBs (such as using the internet and reading) decrease the risk of depression. The aim of this study was to explore the associations between type of SBs (i.e., passive and mentally active SBs) and depression among people aged 60 years and older in the Hebei Province of China. METHODS: This cross-sectional study used data from the baseline survey of the Community-based Cohort Study on Nervous System Diseases. A total of 2679 older adults aged ≥60 years from the Hebei Province of China were included in this study. The type and time spent on SBs were self-reported. Watching TV was defined as a passive SB, whereas internet use, reading, and social SBs (including communicating with others and playing chess) were defined as mentally active SBs. Depression was evaluated using the Geriatric Depression Scale. The maximal possible score was 30 points, and ≥ 11 points indicated depression. Logistic regression analysis was used to assess the relationship between SBs and depression. Covariates included sex, age, education, employment, smoking, alcohol consumption, sleep duration, domestic work, physical exercise, body mass index (BMI), and chronic diseases. RESULTS: At baseline, the participants who spent two or more hours and 0 h on passive SBs (i.e., TV viewing) had a greater risk of depression (=0 h: adjusted OR = 2.09, 95% CI = 1.18-3.76; 2-3 h: OR = 2.21, 95% CI = 1.16-4.16; > 3 h: OR = 3.59, 95% CI = 1.93-6.68) than the participants who spent 1-2 h on passive SBs. The participants who spent > 1 h on mentally active SBs had a lower risk of depression (adjusted OR = 0.26, 95% CI = 0.06-0.71) than the participants who did not engage in mentally active SBs. Not all mentally active SBs were linked to depression. The participants who engaged in social SBs had a lower risk of depression (adjusted OR: 0.24, 95% CI: 0.06-0.66) than the participants who did not engage in social SBs. CONCLUSIONS: Spending 2 h or more per day on passive SBs (watching TV) was associated with a high risk of depression among people aged 60 years and older in the Hebei Province of China. Mentally active SBs (predominantly social SBs) could reduce the risk of depression. Some participants with depression probably did not watch TV. These findings suggested that spending more time on social SBs (such as communicating with others and playing chess) rather than watching TV may have important public health implications for preventing and managing depression among older Chinese adults. Moreover, society should attend to the mental health of elderly adults who do not watch TV as they may be more prone to suffer from depressive symptoms.

Preoperative Remnant Liver Function Evaluation Using a Routine Clinical Dynamic Gd-EOB-DTPA-Enhanced MRI Protocol in Patients with Hepatocellular Carcinoma.

BACKGROUND: To investigate the clinical feasibility of preoperative routine clinical dynamic Gd-EOB-DTPA-enhanced MRI alone to predict post-hepatectomy liver failure (PHLF) in patients with hepatocellular carcinoma (HCC). METHODS: 116 patients with HCC who underwent liver resection in Southwest Hospital from 2014 through 2017 were selected in this retrospective cohort study. The remnant function (RF) of the liver RFUR and RFRE15 were calculated by the sum of the uptake rate (UR) or relative enhancement at 15 min (RE15) from dynamic Gd-EOB-DTPA-enhanced MR images in the remnant liver regions, and standardized by standard liver volume (SLV) to generate sRFUR (standardized RFUR) and sRFRE15 (standardized RFRE15). Student's t test or Mann-Whitney U test, logistic regression, and ROC analyses were used to test the associations of preoperative RFUR, sRFUR, RFRE15, sRFRE15, the remnant liver volume (RLV)/SLV, ICG retention rate at 15 min (ICG R15) and sRFICG-K [ICG clearance rate (ICG-K) × RLV/SLV] with PHLF. RESULTS: 28 patients were found to have PHLF, who showed lower RFUR, sRFUR, RFRE15, sRFRE15, RLV/SLV, sRFICG-K, and higher ICG R15 than patients without PHLF (p < 0.001 for all). After adjusting for clinical parameters, RFUR (p = 0.001), sRFUR (p = 0.001), RFRE15 (p = 0.002), or sRFRE15 (p = 0.003) was found to be independently significant indicator in multivariable logistic regression, respectively. RFUR (0.882) and sRFUR (0.882) had larger AUCs than RLV/SLV (0.731, p = 0.008; p = 0.005), ICG R15 (0.765, p = 0.039; p = 0.044) and sRFICG-K (0.767, p = 0.031; p = 0.023). RFRE15 (0.845) and sRFRE15 (0.839) had larger AUCs than RLV/SLV (0.731, p = 0.027; p = 0.025). CONCLUSIONS: The remnant liver function parameters preoperatively estimated from a routine clinical dynamic Gd-EOB-DTPA-enhanced MRI protocol can predict PHLF in patients with HCC, and may be better predictors than conventional methods.

An accessory right hepatic artery derived from the superior mesenteric artery for anterior right liver lobe supply: a case report.

PURPOSE: During the last decades, it has been established that there are numerous individual anatomical variations of the arterial blood supply in human liver. In the present study, we examined the liver vascularization of an intrahepatic cholangiocarcinoma patient. METHODS: For surgical planning, an enhanced CT scan was performed and a three-dimensional model of liver vascularization constructed. RESULTS: The patient was diagnosed as a Michel's type VII hepatic artery variation. An accessory right hepatic artery arose from the superior mesenteric artery and had distributed into the right anterior liver to provide the blood supply of segments V and VIII, which was more medial than the territory of the right hepatic artery coming from the proper hepatic artery. At the same time, an accessory left hepatic artery originated from the left gastric artery. CONCLUSION: We present a case in which an accessory right hepatic artery provided a territory more medial than a right hepatic artery coming from the proper right artery.

Declining histone acetyltransferase GCN5 represses BMSC-mediated angiogenesis during osteoporosis.

Angiogenesis is disrupted in age-related and postmenopausal osteoporosis. However, the mechanisms of the disorder remain elusive. We confirmed in this study that, in accordance with the decrease of H-type vessels, the proangiogenic potential of bone marrow-derived mesenchymal stem cells (BMSCs) declined during osteoporosis. Screening of the histone acetyltransferase family revealed that GCN5 decreased in BMSCs derived from osteoporotic femur. Further analysis identified that GCN5 plays important roles in regulating the proangiogenic potential of BMSCs. GCN5 promoted BMSC-mediated angiogenesis by enhancing H3K9ac levels on the promoter of Vegf The decrease of GCN5 in osteoporotic BMSCs led to the decline of proangiogenic capacity. Accordingly, overexpression of GCN5 enhanced the proangiogenic potency of osteoporotic BMSCs. Furthermore, recovering GCN5 expression in vivo by lentiviral expression vector significantly attenuated the loss of angiogenesis in ovariectomized mouse femurs. Our study results revealed an epigenetic mechanism controlling BMSC-mediated angiogenesis and provided a novel therapeutic target for osteoporosis treatment.-Jing, H., Liao, L., Su, X., Shuai, Y. Zhang, X., Deng, Z., Jin, Y. Declining histone acetyltransferase GCN5 represses BMSC-mediated angiogenesis during osteoporosis.

Choledochoscopic Examination of a 3-Dimensional Printing Model Using Augmented Reality Techniques: A Preliminary Proof of Concept Study.

BACKGROUND: We applied augmented reality (AR) techniques to flexible choledochoscopy examinations. METHODS: Enhanced computed tomography data of a patient with intrahepatic and extrahepatic biliary duct dilatation were collected to generate a hollow, 3-dimensional (3D) model of the biliary tree by 3D printing. The 3D printed model was placed in an opaque box. An electromagnetic (EM) sensor was internally installed in the choledochoscope instrument channel for tracking its movements through the passages of the 3D printed model, and an AR navigation platform was built using image overlay display. The porta hepatis was used as the reference marker with rigid image registration. The trajectories of the choledochoscope and the EM sensor were observed and recorded using the operator interface of the choledochoscope. RESULTS: Training choledochoscopy was performed on the 3D printed model. The choledochoscope was guided into the left and right hepatic ducts, the right anterior hepatic duct, the bile ducts of segment 8, the hepatic duct in subsegment 8, the right posterior hepatic duct, and the left and the right bile ducts of the caudate lobe. Although stability in tracking was less than ideal, the virtual choledochoscope images and EM sensor tracking were effective for navigation. CONCLUSIONS: AR techniques can be used to assist navigation in choledochoscopy examinations in bile duct models. Further research is needed to determine its benefits in clinical settings.

Suppression of EZH2 Prevents the Shift of Osteoporotic MSC Fate to Adipocyte and Enhances Bone Formation During Osteoporosis.

During osteoporosis, the shift of mesenchymal stem cell (MSC) lineage commitment to adipocyte leads to the imbalance between bone mass and fat, which increases the risk of fracture. The Enhancer of Zeste homology 2 (EZH2), which methylates histone H3 on lysine 27 (H3K27me3), controls MSC cell lineage commitment. However, whether EZH2 is related to osteoporosis remains elusive. In our study, we found EZH2 expression was significantly increased in osteoporotic MSCs. EZH2 directly increased H3K27me3 levels on promoters of Wnt1, Wnt6, and Wnt10a to silence Wnt gene transcription. The inhibition of Wnt/ß-catenin signaling shifted MSC cell lineage commitment to adipocyte. Knockdown of EZH2 by lentivirus-expressing shRNA rescued the abnormal fate of osteoporotic MSC. By employing the H3K27me3 inhibitor DZNep, we effectively derepressed Wnt signaling and improved osteogenic differentiation of osteoporotic MSCs in vitro. Furthermore, in vivo administration of DZNep successfully increased bone formation and repressed excessive bone marrow fat formation in osteoporotic mice. Noteworthy, DZNep treatment persistently enhanced osteogenic differentiation of endogenous MSCs. In conclusion, our study demonstrated that redundant EZH2 shifted MSC cell lineage commitment to adipocyte, which contributed to the development of osteoporosis. We also provided EZH2 as a novel therapeutic target for improving bone formation during osteoporosis.

[Cross Frequency Coupling Characteristic Analysis in Subthalamic Local Field Potentials of Parkinson's Disease].

Pathological neural activity in subthalamic nucleus (STN) is closely related to the symptoms of Parkinson' s disease. Local field potentials (LFPs) recordings from subthalamic nucleus show that power spectral peaks exist at tremor, double tremor and tripble tremor frequencies, respectively. The interaction between these components in the multi-frequency tremor may be related to the generation of tremor. To study the linear and nonlinear relationship between those components, we analyzed STN LFPs from 9 Parkinson's disease patients using time frequency, cross correlation, Granger casuality and bi-spectral analysis. Results of the time-frequency analysis and cross-frequency correlation analysis demonstrated that the power density of those components significantly decreased as the alleviation of tremor and cross-correlation (0.18-0.50) exists during tremor period. Granger causality of the time-variant amplitude showed stronger contribution from tremor to double tremor components, and contributions from both tremor and double tremor components to triple tremor component. Quadratic phase couplings among these three components were detected by the bispectral approaches. The linear and nonlinear relationships existed among the multi-components and certainly confirmed that the dependence cross those frequencies and neurological mechanism of tremor involved complicate neural processes.

Dynamics of interaction between IH and IKLT currents to mediate double resonances of medial superior olive neurons related to sound localization.

Neurons in the medial superior olive (MSO) exhibit high frequency responses such as subthreshold resonance, which is helpful to sensitively detect a small difference in the arrival time of sounds between two ears for precise sound localization. Recently, except for the high frequency depolarization resonance mediated by a low threshold potassium (IKLT) current, a low frequency hyperpolarization resonance mediated by a hyperpolarization-activated cation (IH) current is observed in experiments on the MSO neurons, forming double resonances. The complex dynamics underlying double resonances are studied in an MSO neuron model in the present paper. Firstly, double resonances similar to the experimental observations are simulated as the resting membrane potential is between half-activation voltages of IH and IKLT currents, and stimulation current (IZAP) with large amplitude and exponentially increasing frequency is applied. Secondly, multiple effective factors to modulate double resonances are obtained. Especially, the decrease of time constant of IKLT current and increase of conductance of IH and IKLT currents can enhance the depolarization resonance frequency for precise sound localization. Last, different frequency responses of slow IH and fast IKLT currents in formation of the resonances are acquired. A middle phase difference between IZAP and IKLT currents appears at a high frequency, and the interaction between the positive part of IZAP and the negative IKLT current forms the depolarization resonance. Interaction between the negative part of IZAP and positive IH current with a middle phase difference results in hyperpolarization resonance at a low frequency. Furthermore, the phase difference between IZAP and resonance current can well explain the increase of depolarization resonance frequency modulated by the increase of conductance of IH or IKLT currents. The results present the dynamical and biophysical mechanisms for the double resonances mediated by two currents in the MSO neurons, which is helpful to enhance the depolarization resonance frequency for precise sound localization.

Dynamics of antiphase bursting modulated by the inhibitory synaptic and hyperpolarization-activated cation currents.

Antiphase bursting related to the rhythmic motor behavior exhibits complex dynamics modulated by the inhibitory synaptic current (Isyn), especially in the presence of the hyperpolarization-activated cation current (Ih). In the present paper, the dynamics of antiphase bursting modulated by the Ih and Isyn is studied in three aspects with a theoretical model. Firstly, the Isyn and the slow Ih with strong strength are the identified to be the necessary conditions for the antiphase bursting. The dependence of the antiphase bursting on the two currents is different for low (escape mode) and high (release mode) threshold voltages (Vth) of the inhibitory synapse. Secondly, more detailed co-regulations of the two currents to induce opposite changes of the bursting period are obtained. For the escape mode, increase of the Ih induces elevated membrane potential of the silence inhibited by a strong Isyn and shortened silence duration to go beyond Vth, resulting in reduced bursting period. For the release mode, increase of the Ih induces elevated tough value of the former part of the burst modulated by a nearly zero Isyn and lengthen burst duration to fall below Vth, resulting in prolonged bursting period. Finally, the fast-slow dynamics of the antiphase bursting are acquired. Using one-and two-parameter bifurcations of the fast subsystem of a single neuron, the burst of the antiphase bursting is related to the stable limit cycle, and the silence modulated by a strong Isyn to the stable equilibrium to a certain extent. The Ih mainly modulates the dynamics within the burst and quiescent state. Furthermore, with the fast subsystem of the coupled neurons, the silence is associated with the unstable equilibrium point. The results present theoretical explanations to the changes in the bursting period and fast-slow dynamics of the antiphase bursting modulated by the Isyn and Ih, which is helpful for understanding the antiphase bursting and modulating rhythmic motor patterns.

Caffeic acid phenethyl ester derivative exerts remarkable anti-hepatocellular carcinoma effect, non-inferior to sorafenib, in vivo analysis.

Caffeic acid phenethyl ester (CAPE) and its derivatives exhibit considerable effects against hepatocellular carcinoma (HCC), with unquestioned safety. Here we investigated CAPE derivative 1' (CAPE 1') monotherapy to HCC, compared with sorafenib. HCC Bel-7402 cells were treated with CAPE 1', the IC50 was detected using CCK-8 analysis, and acute toxicity testing (5 g/kg) was performed to evaluate safety. In vivo, tumor growth after CAPE 1' treatment was evaluated using an subcutaneous tumor xenograft model. Five groups were examined, with group 1 given vehicle solution, groups 2, 3, and 4 given CAPE 1' (20, 50, and 100 mg/kg/day, respectively), and group 5 given sorafenib (30 mg/kg/day). Tumor volume growth and tumor volume-to-weight ratio were calculated and statistically analyzed. An estimated IC50 was 5.6 µM. Acute toxicity tests revealed no animal death or visible adverse effects with dosage up to 5 g/kg. Compared to negative controls, CAPE 1' treatment led to significantly slower increases of tumor volume and tumor volume-to-weight. CAPE 1' and sorafenib exerted similar inhibitory effects on HCC tumors. CAPE 1' was non-inferior to sorafenib for HCC treatment, both in vitro and in vivo. It has great potential as a promising drug for HCC, based on effectiveness and safety profile.

Dietary Patterns Are Associated With Multi-Dimensional Cognitive Functions Among Adults Aged 55 and Older in China.

BACKGROUND: The intake of certain food and nutrients may play a crucial role in cognitive health. However, research on the relationship between dietary patterns and cognitive function is limited. This study aims to investigate the associations between dietary patterns and multi-dimensional cognitive functions, such as global cognitive status and related domain profiles, mild cognitive impairment (MCI), and four major subtypes of Chinese adults. METHODS: Using the baseline data from the Community-based Cohort Study on Nervous System Diseases (2018-2019), we selected 4,309 Chinese adults aged 55 years and older as subjects with complete diet, cognition, and other related data. We collected food data for the past 12 months with a valid semi-quantitative food frequency questionnaire. Diving 49 food items into 13 subgroups, we used factor analysis to derive the main dietary patterns. We evaluated cognitive functions based on the scores of the Montreal Cognitive Assessment (MoCA) and used quantile regression and multivariable logistic regression to examine the relationship between dietary patterns and cognitive-related outcomes. RESULTS: We identified four dietary patterns, explaining 50.11% of the total variance: "meat-preferred" pattern, "plant-preferred" pattern, "eggs- and dairy-preferred" pattern, and "grain-preferred" pattern. After adjusting for all potential confounders, the "meat-preferred" pattern and the "plant-preferred" pattern were associated with higher scores of global cognition and several cognitive domains (p <0.05), while the "grain-preferred" pattern was associated with lower scores of global cognition (ß = -0.36, p <0.05), execution (ß = -0.19, p <0.05), visuospatial (ß = -0.09, p <0.05), and language (ß = -0.05, p <0.05). Adults adhering to the "meat-preferred" pattern and the "plant-preferred" pattern had decreased odds of MCI and some MCI subtypes (p-trend <0.05); in contrast, those in the top quartiles of the "grain-preferred" pattern had increased odds of MCI [adjusted odds ratio (AOR) = 1.34, 95% CI: 1.11-1.63, p-trend = 0.003]. CONCLUSIONS: Adhering to the "plant-preferred" pattern and the "meat-preferred" pattern may help improve the multi-dimensional cognitive functions; on the contrary, adhering to the "grain-preferred" pattern may worse cognitive health. More prospective studies in this field are needed to strengthen the evidence.

Corticosterone-induced Hippocampal 5-HT Responses were Muted in Depressive-like State.

Interactions between the hypothalamic-pituitary-adrenal axis and the central 5-HT system in the depressive state remain largely unknown. The present study investigated corticosterone (CORT) regulations of extracellular 5-HT in the hippocampal CA3 in a mouse model of depression. Basal dialysate 5-HT, true extracellular 5-HT, 5-HT reuptake efficiency, and time courses of dialysate 5-HT following CORT injections at 10, 20, and 40 mg/kg were determined at baseline, depressive-like state and after subsequent fluoxetine (FLX) treatment using in vivo microdialysis in male C57BL/6 mice. Behavioral tests were used to determine behavioral phenotypes and therapeutic responses to FLX. Depressed mice showed decreased extracellular 5-HT, increased 5-HT reuptake efficiency, and absence of the increase in dialysate 5-HT response to CORT injections, which were all reversed in FLX-responsive mice. Surprisingly, the FLX nonresponsive mice continued to worsen behaviorally and exhibited lower extracellular 5-HT and higher 5-HT reuptake efficiency. Our study indicates that abolished-CORT induced 5-HT response, decreased extracellular 5-HT, and increased 5-HT reuptake efficiency might be the signature features associated with depressive-like state. Increased 5-HT reuptake efficiency was one of the underlying mechanisms, with target effectors remaining to be explored. The findings in the FLX nonresponsive mice suggest distinct neuromechanisms, which might be genetically predetermined.

Modulators of histone demethylase JMJD1C selectively target leukemic stem cells.

Leukemic stem cells (LSCs) comprise a very rare cell population that results in the development of acute myeloid leukemia. The selective targeting of drivers in LSCs with small molecule inhibitors holds promise for treatment of acute myeloid leukemia. Recently, we reported the identification of inhibitors of the histone lysine demethylase JMJD1C that preferentially kill MLL rearranged acute leukemia cells. Here, we report the identification of jumonji domain modulator #7 (JDM-7). Surface plasmon resonance analysis showed that JDM-7 binds to JMJD1C and its family homolog JMJD1B. JDM-7 did not significantly suppress cell proliferation in liquid cell culture at higher doses, although it led to a significant decrease in semi-solid colony formation experiments at lower concentrations. Moreover, low doses of JDM-7 did not suppress the proliferation of erythroid progenitor cells. We identified that JDM-7 downregulates the LSC self-renewal gene HOXA9 in leukemia cells. We further found that the structure of JDM-7 is similar to that of tadalafil, a drug approved by the US Food and Drug Administration. Molecular docking and surface plasmon resonance analysis showed that tadalafil binds to JMJD1C. Moreover, similar to JDM-7, tadalafil suppressed colony formation of leukemia cells in semi-solid cell culture at a concentration that did not affect primary umbilical cord blood cells. In summary, we have identified JDM-7 and tadalafil as potential JMJD1C modulators that selectively inhibit the growth of LSCs.

Depressive-like state sensitizes 5-HT1A and 5-HT1B auto-receptors in the dorsal raphe nucleus sub-system.

Dorsal raphe (DR) and median raphe (MR) 5-HT neurons are two distinct sub-systems known to be regulated by 5-HT1A and 5-HT1B auto-receptors. Whether the auto-receptors in each sub-system are functionally altered in depressive-like state remains unknown. The present study is aimed to study a specific circuit (DR-ventral hippocampus and MR-dorsal hippocampus) within each sub-system to investigate changes in receptor sensitivity in the pathogenesis of depression. A mouse model of depression was developed through the social defeat paradigm, and was then treated with fluoxetine (FLX). 5-HT1A auto-receptor in the neuronal cell body (DR or MR) and 5-HT1B auto-receptor in the axonal terminal (ventral or dorsal hippocampus) were directly targeted by local perfusion of antagonists (5-HT1A: WAY100635; 5-HT1B: GR127935) through reverse microdialysis. Time courses of dialysate 5-HT measured at the axonal terminal were subsequently determined for each circuit. At baseline, 5-HT1A and 5-HT1B antagonists dose-dependently increased dialysate 5-HT, with sub-circuit specificity. In the depressive-like state, greater increases in dialysate 5-HT were observed only in the DR-ventral hippocampus circuit following local delivery of both antagonists, which were then fully restored following the FLX treatment. In contrast, no changes were observed in the MR-dorsal hippocampus circuit. Our results demonstrate differential changes in sensitivities of 5-HT1A and 5-HT1B auto-receptors in the DR-ventral hippocampus and MR-dorsal hippocampus circuits. 5-HT1A and 5-HT1B auto-receptors in the DR-ventral hippocampus circuit are sensitized in the depressive-like state. Taken together, these results suggest that the DR sub-system maybe the neural substrate mediating depressive phenotypes.

Identification of an acute myeloid leukaemia associated noncoding somatic mutation at 3' end of HOXA cluster.

Noncoding somatic mutations have been demonstrated to play important role in tumourigenesis. Here we show that there exists an acute myeloid leukaemia associated noncoding somatic mutation at 3' terminal of conserved HOXA cluster. The mutation was identified in the bone marrow blasts but not peripheral blood mononuclear cells or buccal cells of two M3 (acute promyelocytic leukaemia, APL) type patients from 45 acute myeloid leukaemia patients. The mutation also existed in a pair of twins one of them developed acute myeloid leukaemia M4 (acute myelomonocytic leukaemia) type. The mutation resides in about 2-kb downstream of HOXA1 gene where a functional retinoic acid response element is located and also bound by histone demethylase KDM3B. Reporter assay showed that the mutation results in the upregulation of transcriptional activity and unresponsiveness to retinoic acid receptor. To sum up, we identified a new acute myeloid leukaemia associated noncoding somatic mutation.

Acute corticosterone treatment elicits antidepressant-like actions on the hippocampal 5-HT and the immobility phenotype.

Corticosterone (CORT) has long been shown to modulate 5-HT system, and to alter hippocampal functions in various physiological and pathological conditions. However, CORT-elicited changes in the hippocampal 5-HT transmission and the immobility phenotype had not been fully addressed. The current study sought to explore effects of acute CORT subcutaneously injected at 10, 20, 40 mg/kg on the extracellular 5-HT in the hippocampus and the immobility time in male CD-1 mice. Following an injection of CORT or vehicle, time course of the extracellular 5-HT in the hippocampal CA3 was determined using in vivo microdialysis. The immobility time was measured at 0 min, 60 min, 120 min, 180 min in the forced swimming test (FST) and the tail suspension test (TST), respectively. Results showed that the vehicle, used to dissolve CORT, did not affect the dialysate 5-HT, nor the immobility time, by comparing the pre- and post-injection. CORT was found to dose-dependently increase the dialysate 5-HT and decrease the immobility time when compared to their vehicle-treated controls. The peak increase in the dialysate 5-HT and the decrease in the immobility time were both obtained at the 120 min following the CORT injection. Furthermore, a negative correlation was detected between the immobility time and the peak increase in the dialysate 5-HT. Our results indicated that acute CORT injection elicits antidepressant-like actions on the hippocampal 5-HT and the immobility time. The study suggested that hippocampal 5-HT responses may be one of the neurochemical bases for the immobility phenotype following CORT injection.

Effect of covered self-expanding metal stents compared with multiple plastic stents on benign biliary stricture: A meta-analysis.

BACKGROUND: Endoscopic placement of multiple plastic stents (MPS) has been the first-line treatment for benign biliary stricture (BBS). Covered self-expanding metal stents (cSEMS) have been used in treatment of BBS; however, the efficacy has not been verified. Therefore, we conducted this meta-analysis according to PRISMA guidelines. METHODS: PubMed, Embase, and the Cochrane Library were electronically and manually searched for studies published between January 1, 1990 and April 12, 2017. Of 153 studies screened, 90 were excluded because of duplications. After scanning the title or abstract, only 24 studies were eligible for review and 6 were finally included. The investigators selected publications according to inclusion and exclusion criteria, processed the data, and assessed the quality of the selected studies. The primary endpoint outcome was stricture resolution, and the secondary endpoint outcomes included stricture recurrence rate, the number of endoscopic retrograde cholangiopancreatography (ERCP) sessions, and stent migration. RESULTS: A total of 6 randomized controlled trials with 330 participants were included in the current meta-analysis. There was no significant difference in stricture resolution between the cSEMS and MPS groups (odds ratio [OR] = 1.05, 95% confidence interval [CI] = 0.53-2.07, I = 29%, P = .23, Z = 0.13, P = .90). Similarly, the stricture recurrence rates (OR = 1.39, 95% CI = 0.69-2.81, I = 38%, P = .17, Z = 0.91, P = .36) were comparable between cSEMS and MPS groups. Stent migration rates (OR = 1.71, 95% CI = 0.84-3.50, I = 4%, P = .241, Z = 1.47, P = .14) were similar between cSEMS and MPS groups. There were fewer ERCP sessions in the cSEMS group than in the MPS group. CONCLUSIONS: This meta-analysis showed that cSEMS were comparable to MPS in achieving resolution of BBSs with fewer ERCP procedures.