Social complexification and pig (Sus scrofa) husbandry in ancient China : a combined geometric morphometric and isotopic approach

Funding: This work was supported by the CNRSCASS program for the training of Chinese PhD students.Peer reviewedPublisher PD

Immunomodulatory glycan LNFPIII alleviates hepatosteatosis and insulin resistance through direct and indirect control of metabolic pathways

Parasitic worms express host-like glycans to attenuate the immune response of human hosts. The therapeutic potential of this immunomodulatory mechanism in controlling metabolic dysfunction associated with chronic inflammation remains unexplored. We demonstrate here that administration of Lacto-N-fucopentaose III (LNFPIII), a LewisX containing immunomodulatory glycan found in human milk and on parasitic helminths, improves glucose tolerance and insulin sensitivity in diet-induced obese mice. This effect is mediated partly through increased Il-10 production by LNFPIII activated macrophages and dendritic cells, which reduces white adipose tissue inflammation and sensitizes the insulin response of adipocytes. Concurrently, LNFPIII treatment up-regulates nuclear receptor Fxr-α (or Nr1h4) to suppress lipogenesis in the liver, conferring protection against hepatosteatosis. At the signaling level, the extracellular signal-regulated kinase (Erk)-Ap1 pathway appears to mediate the effects of LNFPIII on both inflammatory and metabolic pathways. Our results suggest that LNFPIII may provide novel therapeutic approaches to treat metabolic diseases

Ventral Visual Pathway-Cerebellar Circuit Deficits in Alcohol Dependence: Long- and Short-Range Functional Connectivity Density Study

Objective: To identify the underlying intrinsic functional connectome changes in patients with alcohol dependence.Methods: A functional connectivity density (FCD) analysis was used to report on the functional connectivity changes in 24 male patients with alcohol dependence (age, 47.83 ± 6.93 years) and 24 healthy male subjects (age, 47.67 ± 6.99 years). We defined the voxels with a correlated threshold of r > 0.25 inside their neighborhood (radius sphere ≤ 6 mm) as shortFCD, and radius sphere > 6 mm as longFCD. We repeated the network analysis using a range of correlation r thresholds (r = 0.30, 0.35, 0.40, 0.45, 0.50, 0.6, and 0.75) to determine whether between-group differences were substantially affected by the selection of the different R-value thresholds used. A ROC curve was used to test the ability of the FCD in discriminating between the two groups. Pearson's correlation was used to evaluate the relationships between the FCD differences in brain areas and demographic characteristics.Results: The covered differences in brain areas in binarized shortFCD were larger than binarized longFCD in both groups. The intra-group FCD differences did not depend on the selection of different thresholds used. Patients with alcohol dependence were associated with the longFCD deficit in the cerebellum posterior lobe, and shortFCD deficit in the ventral system of the visual pathway and increased shortFCD in the left precentral gyrus, right salience network and right cingulate gyrus. A ROC curve demonstrated that these specific brain areas alone discriminated between the two groups with a high degree of sensitivity and specificity. In the alcohol dependence group, the cerebellum posterior lobe, visual association cortex and the salience network displayed significant correlations with demographic characteristics.Conclusions: The shortFCD analysis was more sensitive than the longFCD analysis in finding differences in the brain areas. The ventral visual pathway-cerebellar circuit deficit appeared to be altered in patients with alcohol dependence

Loss of endothelial hypoxia inducible factor-prolyl hydroxylase 2 induces cardiac hypertrophy and fibrosis

BACKGROUND: Cardiac hypertrophy and fibrosis are common adaptive responses to injury and stress, eventually leading to heart failure. Hypoxia signaling is important to the (patho)physiological process of cardiac remodeling. However, the role of endothelial PHD2 (prolyl-4 hydroxylase 2)/hypoxia inducible factor (HIF) signaling in the pathogenesis of cardiac hypertrophy and heart failure remains elusive. METHODS AND RESULTS: Mice with Egln1Tie2Cre (Tie2-Cre-mediated deletion of Egln1 [encoding PHD2]) exhibited left ventricular hypertrophy evident by increased thickness of anterior and posterior wall and left ventricular mass, as well as cardiac fibrosis. Tamoxifen-induced endothelial Egln1 deletion in adult mice also induced left ventricular hypertrophy and fibrosis. Additionally, we observed a marked decrease of PHD2 expression in heart tissues and cardiovascular endothelial cells from patients with cardiomyopathy. Moreover, genetic ablation of Hif2a but not Hif1a in Egln1Tie2Cre mice normalized cardiac size and function. RNA sequencing analysis also demonstrated HIF-2α as a critical mediator of signaling related to cardiac hypertrophy and fibrosis. Pharmacological inhibition of HIF-2α attenuated cardiac hypertrophy and fibrosis in Egln1Tie2Cre mice. CONCLUSIONS: The present study defines for the first time an unexpected role of endothelial PHD2 deficiency in inducing cardiac hypertrophy and fibrosis in an HIF-2α– dependent manner. PHD2 was markedly decreased in cardiovascular endothelial cells in patients with cardiomyopathy. Thus, targeting PHD2/HIF-2α signaling may represent a novel therapeutic approach for the treatment of pathological cardiac hypertrophy and failure

Genome-Wide Identification and Capsaicinoid Biosynthesis-Related Expression Analysis of the R2R3-MYB Gene Family in Capsicum annuum L.

Capsaicinoids are naturally specialized metabolites in pepper and are the main reason that Capsicum fruits have a pungent smell. During the synthesis of capsaicin, MYB transcription factors play key regulatory roles. In particular, R2R3-MYB subfamily genes are the most important members of the MYB family and are critical candidate factors in capsaicinoid biosynthesis. The 108 R2R3-MYB genes in pepper were identified in this study and all are shown to have two highly conserved MYB binding domains. Phylogenetic and structural analyses clustered CaR2R3-MYB genes into seven groups. Interspecies collinearity analysis found that the R2R3-MYB family contains 16 duplicated gene pairs and the highest gene density is on chromosome 00 and 03. The expression levels of CaR2R3-MYB differentially expressed genes (DEGs) and capsaicinoid-biosynthetic genes (CBGs) in fruit development stages were obtained via RNA-seq and quantitative polymerase chain reaction (qRT-PCR). Co-expression analyses reveal that highly expressed CaR2R3-MYB genes are co-expressed with CBGs during early stages of pericarp and placenta development processes. It is speculated that six candidate CaR2R3-MYB genes are involved in regulating the synthesis of capsaicin and dihydrocapsaicin. This study is the first systematic analysis of the CaR2R3-MYB gene family and provided references for studying their molecular functions. At the same time, these results also laid the foundation for further research on the capsaicin characteristics of CaR2R3-MYB genes in pepper

A novel liposomal S-propargyl-cysteine: a sustained release of hydrogen sulfide reducing myocardial fibrosis via TGF-β1/Smad pathway

Purpose: S-propargyl-cysteine (SPRC; alternatively known as ZYZ-802) is a novel modulator of endogenous tissue H2S concentrations with known cardioprotective and anti-inflammatory effects. However, its rapid metabolism and excretion have limited its clinical application. To overcome these issues, we have developed some novel liposomal carriers to deliver ZYZ-802 to cells and tissues and have characterized their physicochemical, morphological and pharmacological properties. Methods :Two liposomal formulations of ZYZ-802 were prepared by thin-layer hydration and the morphological characteristics of each liposome system were assessed using a laser particle size analyzer and transmission electron microscopy. The entrapment efficiency and ZYZ-802 release profiles were determined following ultrafiltration centrifugation, dialysis tube and HPLC measurements. LC-MS/MS was used to evaluate the pharmacokinetic parameters and tissue distribution profiles of each formulation via the measurements of plasma and tissues ZYZ-802 and H2S concentrations. Using an in vivo model of heart failure (HF), the cardio-protective effects of liposomal carrier were determined by echocardiography, histopathology, western blot and the assessment of antioxidant and myocardial fibrosis markers.Results: Both liposomal formulations improved ZYZ-802 pharmacokinetics and optimized H2S concentrations in plasma and tissues. Liposomal ZYZ-802 showed enhanced cardioprotective effects in vivo. Importantly, liposomal ZYZ-802 could inhibit myocardial fibrosis via the inhibition of the TGF-β1/Smad signaling pathway. Conclusion: The liposomal formulations of ZYZ-802 have enhanced pharmacokinetic and pharmacological properties in vivo. This work is the first report to describe the development of liposomal formulations to improve the sustained release of H2S within tissues.Key word: Liposome; S-Propargyl-cysteine (SPRC, ZYZ-802); Hydrogen sulfide; Heart failure; Myocardial fibrosis; TGF-β1/Smad pathwa

A diurnal serum lipid integrates hepatic lipogenesis and peripheral fatty acid utilization

Food intake increases the activity of hepatic de novo lipogenesis, which mediates the conversion of glucose to fats for storage or utilization. In mice, this program follows a circadian rhythm that peaks with nocturnal feeding1,2 and is repressed by Rev-erbα/β and an HDAC3-containing complex3–5 during the day. The transcriptional activators controlling rhythmic lipid synthesis in the dark cycle remain poorly defined. Disturbances in hepatic lipogenesis are also associated with systemic metabolic phenotypes6–8, suggesting that lipogenesis in the liver communicates with peripheral tissues to control energy substrate homeostasis. Here we identify a PPARδ-dependent de novo lipogenic pathway in the liver that modulates fat utilization by muscle via a circulating lipid. The nuclear receptor PPARδ controls diurnal expression of lipogenic genes in the dark/feeding cycle. Liver-specific PPARδ activation increases, while hepatocyte-Ppard deletion reduces, muscle fatty acid (FA) uptake. Unbiased metabolite profiling identifies PC(18:0/18:1), or 1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine (SOPC), as a serum lipid regulated by diurnal hepatic PPARδ activity. PC(18:0/18:1) reduces postprandial lipid levels and increases FA utilization through muscle PPARα. High fat feeding diminishes rhythmic production of PC(18:0/18:1), whereas PC(18:0/18:1) administration in db/db mice improves metabolic homeostasis. These findings reveal an integrated regulatory circuit coupling lipid synthesis in the liver to energy utilization in muscle by coordinating the activity of two closely related nuclear receptors. These data implicate alterations in diurnal hepatic PPARδ-PC(18:0/18:1) signaling in metabolic disorders including obesity

Expression of SET Protein in the Ovaries of Patients with Polycystic Ovary Syndrome

Background. We previously found that expression of SET gene was up-regulated in polycystic ovaries by using microarray. It suggested that SET may be an attractive candidate regulator involved in the pathophysiology of polycystic ovary syndrome (PCOS). In this study, expression and cellular localization of SET protein were investigated in human polycystic and normal ovaries. Method. Ovarian tissues, six normal ovaries and six polycystic ovaries, were collected during transsexual operation and surgical treatment with the signed consent form. The cellular localization of SET protein was observed by immunohistochemistry. The expression levels of SET protein were analyzed by Western Blot. Result. SET protein was expressed predominantly in the theca cells and oocytes of human ovarian follicles in both PCOS ovarian tissues and normal ovarian tissues. The level of SET protein expression in polycystic ovaries was triple higher than that in normal ovaries (P<0.05). Conclusion. SET was overexpressed in polycystic ovaries more than that in normal ovaries. Combined with its localization in theca cells, SET may participate in regulating ovarian androgen biosynthesis and the pathophysiology of hyperandrogenism in PCOS

Dosiomics: Extracting 3D Spatial Features From Dose Distribution to Predict Incidence of Radiation Pneumonitis

Radiation pneumonitis (RP) is one of the major toxicities of thoracic radiation therapy. RP incidence has been proven to be closely associated with the dosimetric factors and normal tissue control possibility (NTCP) factors. However, because these factors only utilize limited information of the dose distribution, the prediction abilities of these factors are modest. We adopted the dosiomics method for RP prediction. The dosiomics method first extracts spatial features of the dose distribution within ipsilateral, contralateral, and total lungs, and then uses these extracted features to construct prediction model via univariate and multivariate logistic regression (LR). The dosiomics method is validated using 70 non-small cell lung cancer (NSCLC) patients treated with volumetric modulated arc therapy (VMAT) radiotherapy. Dosimetric and NTCP factors based prediction models are also constructed to compare with the dosiomics features based prediction model. For the dosimetric, NTCP and dosiomics factors/features, the most significant single factors/features are the mean dose, parallel/serial (PS) NTCP and gray level co-occurrence matrix (GLCM) contrast of ipsilateral lung, respectively. And the area under curve (AUC) of univariate LR is 0.665, 0.710 and 0.709, respectively. The second significant factors are V5 of contralateral lung, equivalent uniform dose (EUD) derived from PS NTCP of contralateral lung and the low gray level run emphasis of gray level run length matrix (GLRLM) of total lungs. The AUC of multivariate LR is improved to 0.676, 0.744, and 0.782, respectively. The results demonstrate that the univariate LR of dosiomics features has approximate predictive ability with NTCP factors, and the multivariate LR outperforms both the dosimetric and NTCP factors. In conclusion, the spatial features of dose distribution extracted by the dosiomics method effectively improves the prediction ability

Microglia Mediate Synaptic Material Clearance at the Early Stage of Rats With Retinitis Pigmentosa

Resident microglia are the main immune cells in the retina and play a key role in the pathogenesis of retinitis pigmentosa (RP). Many previous studies on the roles of microglia mainly focused on the neurotoxicity or neuroprotection of photoreceptors, while their contributions to synaptic remodeling of neuronal circuits in the retina of early RP remained unclarified. In the present study, we used Royal College of Surgeons (RCS) rats, a classic RP model characterized by progressive microglia activation and synapse loss, to investigate the constitutive effects of microglia on the synaptic lesions and ectopic neuritogenesis. Rod degeneration resulted in synapse disruption and loss in the outer plexiform layer (OPL) at the early stage of RP. Coincidentally, the resident microglia in the OPL increased phagocytosis and mainly engaged in phagocytic engulfment of postsynaptic mGluR6 of rod bipolar cells (RBCs). Complement pathway might be involved in clearance of postsynaptic elements of RBCs by microglia. We pharmacologically deleted microglia using a CSF1 receptor (CSF1R) inhibitor to confirm this finding, and found that it caused the accumulation of postsynaptic mGluR6 levels and increased the number and length of ectopic dendrites in the RBCs. Interestingly, the numbers of presynaptic sites expressing CtBP2 and colocalized puncta in the OPL of RCS rats were not affected by microglia elimination. However, sustained microglial depletion led to progressive functional deterioration in the retinal responses to light in RCS rats. Based on our results, microglia mediated the remodeling of RBCs by phagocytosing postsynaptic materials and inhibiting ectopic neuritogenesis, contributing to delay the deterioration of vision at the early stage of RP