Terkelsenduke5274
The ENS, which is known as the "second brain", could be under the direct or indirect influence of the gut microbiota and its released factors (short-chain fatty acids, neurotransmitters, gaseous factors, etc.). Thus, in addition to their actions on tissue (adipose tissue, liver, brain, etc.), microbes can have an impact on local ENS activity. This potential modification of ENS function has global repercussions in the whole body via the gut-brain axis and represents a new therapeutic strategy.AMPA receptors (AMPARs) are the major excitatory neurotransmitter receptor in the brain, and their expression at synapses is a critical determinant of synaptic transmission and therefore brain function. Synaptic plasticity involves increases or decreases in synaptic strength, caused by changes in the number or subunit-specific subtype of AMPARs expressed at synapses, and resulting in modifications of functional connectivity of neuronal circuits, a process which is thought to underpin learning and the formation or loss of memories. Furthermore, numerous neurological disorders involve dysregulation of excitatory synaptic transmission or aberrant recruitment of plasticity processes. MicroRNAs (miRNAs) repress the translation of target genes by partial complementary base pairing with mRNAs, and are the core component of a mechanism widely used in a range of cell processes for regulating protein translation. MiRNA-dependent translational repression can occur locally in neuronal dendrites, close to synapses, and can also result in relatively rapid changes in protein expression. MiRNAs are therefore well-placed to regulate synaptic plasticity via the local control of AMPAR subunit synthesis, and can also result in synaptic dysfunction in the event of dysregulation in disease. Here, I will review the miRNAs that have been identified as playing a role in physiological or pathological changes in AMPAR subunit expression at synapses, focussing on miRNAs that target mRNAs encoding AMPAR subunits, and on miRNAs that target AMPAR accessory proteins involved in AMPAR trafficking and hence the regulation of AMPAR synaptic localisation.Dupuytren's disease (DD) is a common, progressive fibroproliferative disease affecting the palmar fascia of the hands, causing fingers to irreversibly flex towards the palm with significant loss of function. Surgical treatments are limited, therefore effective new therapies for DD are urgently required. To identify key cellular and molecular pathways driving DD we employed single-cell RNA sequencing (scRNA-seq), profiling the transcriptomes of 35,250 human single cells from DD, non-pathogenic fascia, and healthy dermis. We identify a DD-specific population of pathogenic PDPN+/FAP+ mesenchymal cells displaying elevated expression of fibrillar collagens and profibrogenic genes. In silico trajectory analysis reveals resident fibroblasts to be the source of this pathogenic population. To resolve the processes governing DD progression, genes differentially expressed during fibroblast differentiation were identified including upregulated TNFRSF12A and transcription factor SCX. Knockdown of SCX and blockade of TNFRSF12A inhibited proliferation and altered pro-fibrotic gene expression of cultured human FAP+ mesenchymal cells, demonstrating a functional role for these genes in DD. The power of scRNA-seq is utilised to identify the major pathogenic mesenchymal subpopulations driving DD and key molecular pathways regulating the DD-specific myofibroblast phenotype. Using this precision medicine approach, inhibition of TNFRSF12A has shown potential clinical utility in the treatment of Dupuytren's disease.
There are many deficiencies of existing biliopancreatic duct endoscopy in the examination of early biliary and pancreatic tumors. This study aimed to evaluate the usefulness and feasibility of a novel ultrafine separable biliopancreatic duct endoscopy device with dual modalities of intraductal ultrasonography (IDUS) and optical coherence tomography (OCT) for the in vivo assessment of biliopancreatic duct system during ERCP.
Five Bama miniature pigs were selected to probe their common bile duct and branches by using this novel equipment during ERCP. The feasibility of the procedure was evaluated by clear, clinically interpretable images obtained by using spiral scanning with pull-back method. The clinical usefulness of the novel product was evaluated by postoperative choledochoscopy and assessment of the animal's general condition.
One hundred forty-one pairs of images from 5 Bama miniature pigs were acquired. Both OCT and IDUS's visualization of the bile duct was characterized by a differentiated 3-layedel and human clinic study.
Total gentamicin is a sum of five congeners C1, C1a, C2, C2a and minor C2b, which differ from each other in their methylation on the purpurosamine ring. Liquid chromatography with mass detection (LC-MS/MS) and specified calibration material enables the concentration of total gentamicin and its individual congeners to be analysed.
50µL serum was precipitated with acetonitrile in the presence of 0.5mol/L formic acid. A RP BEH C18 1.7µm 2.1x50 mm column maintained at 30°C and tobramicin as the internal standard were used. Mass detection was performed in positive electrospray. The gentamicin results were compared with fluorescence polarization immunoassay (FPIA) and chemiluminiscent microparticle immunoassay (CMIA). Passing-Bablock regression analysis and Bland-Altman analysis were used.
Calibration curves for individual gentamicin congeners were linear with correlation coefficients between 0.997 and 0.998. Recovery was 91.6-102.0% and the coefficients of variation 1.4-8.4%. The total gentamicin concentration was compared with immunoassay FPIA (LC-MS
=0.9798xPFIA
) and CMIA (LC MS
=0.9835xCMIA
) both with significant correlation (p<0.001).
The LC-MS/MS method is fast and precise and can be applied to routine TDM in patients. Comparing it to immunoassays makes it possible to measure concentration of gentamicin congeners, which may be important in the case of their different pharmacokinetics.
The LC-MS/MS method is fast and precise and can be applied to routine TDM in patients. Comparing it to immunoassays makes it possible to measure concentration of gentamicin congeners, which may be important in the case of their different pharmacokinetics.
Down syndrome (DS) is the most common human chromosomal abnormality. About 1200 laboratories carry out antenatal screening for DS in second trimester pregnancies in China. Their prenatal assessment of DS pregnancy risk is based on biometric calculations conducted on maternal serum biochemical markers and ultrasonic markers of fetal growth. However, the performance of this triple test for DS in second trimester pregnancies has a false positive rate of 5%, and a detection rate of about 60%∼65%.
A total of 58,972 pregnant women, including 49 DS cases, who had undergone DS screening in the second trimester were retrospectively included and a machine learning (ML) model based on random forest was built to predict DS. In addition, the model was applied to another hospital data set of 27,170 pregnant women, including 27 DS cases, to verify the predictive efficiency of the model.
The ML model gave a DS detection rate of 66.7%, with a 5% false positive rate in the model data set. In the external verification data set, the ML model achieved a DS detection rate of 85.2%, with a 5% false positive rate . In comparison with the current laboratory risk model, the ML model improves the DS detection rate with the same false positive rate, while the difference has no significance.
The ML model for DS detection described here has a comparable detection rate with the same false positive rate as the DS risk screening software currently used in China. Our ML model exhibited robust performance and good extrapolation, and could function as an alternative tool for DS risk assessment in second trimester maternal serum.
The ML model for DS detection described here has a comparable detection rate with the same false positive rate as the DS risk screening software currently used in China. Our ML model exhibited robust performance and good extrapolation, and could function as an alternative tool for DS risk assessment in second trimester maternal serum.Mammalian hibernation is a period that involves substantial metabolic change in order to promote survival in harsh conditions, with animals typically relying on non-carbohydrate fuel stores during long bouts of torpor. However, the use and maintenance of carbohydrate fuel stores remains important during periods of arousal from torpor as well as when exiting hibernation. Gluconeogenesis plays a key role in maintaining glucose stores; however, little is known about this process within the muscles of hibernating mammals. Here, we used 13-lined ground squirrels (Ictidomys tridecemlineatus) as our model for mammalian hibernation, and showed that skeletal muscle fructose-1,6-bisphosphatase (FBPase; EC 3.1.3.11), the rate-limiting enzyme for the gluconeogenic pathway, was suppressed during torpor as compared to the euthermic control. A physical assessment of partially purified FBPase via exposure to increasing concentrations of the denaturant urea indicated that FBPase from the two conditions were structurally distinct. Western blot analysis suggests that the kinetic and physical differences between euthermic and torpid FBPase may be derived from differential acetylation, whereby increased acetylation of the torpid enzyme makes FBPase more rigid and less active. This study increases our understanding of skeletal muscle carbohydrate metabolism during mammalian hibernation and sets forth a potentially novel mechanism for the regulation of FBPase during environmental stress.The anorectic action of the pancreatic hormone amylin is mainly mediated through the area postrema (AP). Amylin activates AP neurons using a heterodimeric receptor (AMY) composed of the calcitonin receptor (CTR) and the receptor activity modifying protein (RAMP 1, 2 or 3). The aim of the following experiments is to test the effects of the long acting amylin analogue (LAAMA) in RAMP1/3 knock-out (KO) male mice and in neuronal CTR KO Nestin-CreCTR male mice. In vitro, LAAMA exerted an equipotent effect on CTR and AMYs that was maintained across species. Following one week of 45% high fat diet, WT, RAMP1/3 KO and Nestin-CreCTR mice were injected daily for one week with vehicle or LAAMA. LAAMA decreased body weight gain in WT and in RAMP1/3 KO mice suggesting that RAMP1/3 are not necessary for LAAMA-induced effects. However, LAAMA was not able to produce any body lowering and anorectic effects in Nestin-CreCTR mice. This was accompanied by the absence of any c-Fos signal in the AP opposite to WT control mice. Together, these results suggest that LAAMA's effects are mainly mediated through CTR rather than specific AMY. The study of LAAMA or any amylin receptor agonist in different receptor KO mouse models helps disentangle the underlying mechanisms used by these molecules.The purpose of this study was to investigate the role of glycyrrhizic acid (GA) in regulating myocardial ischemia-reperfusion injury (MIRI) in rats as well as the underlying mechanism. H9c2 cells were subjected to hypoxia/re-oxygenation (H/R) to mimic the MIRI in vitro, while a rat model of ischemia-reperfusion (I/R) was constructed by occlusion of the left anterior descending coronary artery for 0.5 h followed by 2 h of reperfusion. While flow cytometry and TUNEL assay were performed to analyze apoptosis in cells and myocardial tissue, echocardiography, hematoxylin and eosin staining, and Masson's trichrome staining were conducted to evaluate cardiac function and pathological changes, respectively. Proteasome inhibitor The levels of serum CK, CK-MB, LDH, AST, TNF-α, and IL-6 as well as the contents of MDA and SOD in tissues were measured by ELISA, while Western blot analysis was performed to detect the expression of endoplasmic reticulum stress (ERS)-related proteins. GA treatment significantly reduced apoptosis in H9c2 cells, while it alleviated left ventricular dysfunction, fibrosis and myocardial apoptosis, down-regulated the levels of CK, CK-MB, LDH, AST, TNF-α, IL-6, and MDA, and up-regulated SOD levels in I/R rats.
