Autophagy Inhibitor LRPPRC Suppresses Mitophagy through Interaction with Mitophagy Initiator Parkin

Autophagy plays an important role in tumorigenesis. Mitochondrion-associated protein LRPPRC interacts with MAP1S that interacts with LC3 and bridges autophagy components with microtubules and mitochondria to affect autophagy flux. Dysfunction of LRPPRC and MAP1S is associated with poor survival of ovarian cancer patients. Furthermore, elevated levels of LRPPRC predict shorter overall survival in patients with prostate adenocarcinomas or gastric cancer. To understand the role of LRPPRC in tumor development, previously we reported that LRPPRC forms a ternary complex with Beclin 1 and Bcl-2 to inhibit autophagy. Here we further show that LRPPRC maintains the stability of Parkin that mono-ubiquitinates Bcl-2 to increase Bcl-2 stability to inhibit autophagy. Under mitophagy stress, Parkin translocates to mitochondria to cause rupture of outer mitochondrial membrane and bind with exposed LRPPRC. Consequently, LRPPRC and Parkin help mitochondria being engulfed in autophagosomes to be degraded. In cells under long-term mitophagy stress, both LRPPRC and Parkin become depleted coincident with disappearance of mitochondria and final autophagy inactivation due to depletion of ATG5-ATG12 conjugates. LRPPRC functions as a checkpoint protein that prevents mitochondria from autophagy degradation and impact tumorigenesis

Contrasting P-T-t-d paths of the polycyclic Palaeozoic tectono-metamorphic event in the Southern Chinese Altai: an example from Kalasu area

To understand the polycyclic Palaeozoic tectono-metamorphic evolution of the Southern Chinese Altai, petrological and structural studies together with thermodynamic modelling and dating were carried out in the Cambro-Ordovician metapelitic sequence of the Kalasu area. The sequence is divided into upper, middle and lower crustal orogenic levels according to their metamorphic grade and structural patterns. Metamorphism increases from low to high-grade towards the deeper crustal levels with garnet-biotite schists in the upper crustal level, sillimanite-garnet and staurolite-garnet-sillimanite schists and gneisses in the middle crustal level, and cordierite-sillimanite-K-feldspar migmatites in the lower crustal level. Structural succession involves a subhorizontal S1 foliation folded by NE-SW open to tight and upright F2 folds (with no metamorphism associated), reworking by an orthogonal D3 deformation, characterized by NW-SE open to close F3 folds with moderately plunging axes, steeply dipping S3 axial planes and S3 cleavage. Early Devonian calc-alkaline granitoids intruded the sequence parallel to S1 foliation, whereas Permian undeformed gabbroic bodies were emplaced in the lower crust and granites in the upper crust coevally with D3. The P-T-t-d paths indicate that the crystalline rocks underwent a clockwise evolution marked by Early Devonian burial associated with heating, followed by Permian decompression, in agreement with studies from other parts of the Chinese Altai. The burial is recorded in the middle and lower levels by the presence of g-st-ky-ru relics within the S1 fabric. This stage is related to crustal thickening, whereas heating is related to intrusions of Devonian granite sheets during an extensional setting. A subsequent decompression (around 3-5 kbar) is recorded in all crustal levels, associated with intrusions of gabbro and granite along the southern border of the Chinese Altai and coeval with the last Permian deformation. This last stage is related to the collision between the Junggar arc system and the Chinese Altai orogenic belt

Magnesium isoglycyrrhizinate reduces hepatic lipotoxicity through regulating metabolic abnormalities

The excessive accumulation of lipids in hepatocytes induces a type of cytotoxicity called hepatic lipotoxicity, which is a fundamental contributor to liver metabolic diseases (such as NAFLD). Magnesium isoglycyrrhizinate (MGIG), a magnesium salt of the stereoisomer of natural glycyrrhizic acid, is widely used as a safe and effective liver protectant. However, the mechanism by which MGIG protects against NAFLD remains unknown. Based on the significant correlation between NAFLD and the reprogramming of liver metabolism, we aimed to explore the beneficial effects of MGIG from a metabolic viewpoint in this paper. We treated HepaRG cells with palmitic acid (PA, a saturated fatty acid of C16:0) to induce lipotoxicity and then evaluated the antagonistic effect of MGIG on lipotoxicity by investigating the cell survival rate, DNA proliferation rate, organelle damage, and endoplasmic reticulum stress (ERS). Metabolomics, lipidomics, and isotope tracing were used to investigate changes in the metabolite profile, lipid profile, and lipid flux in HepaRG cells under different intervention conditions. The results showed that MGIG can indeed protect hepatocytes against PA-induced cytotoxicity and ERS. In response to the metabolic abnormality of lipotoxicity, MGIG curtailed the metabolic activation of lipids induced by PA. The content of total lipids and saturated lipids containing C16:0 chains increased significantly after PA stimulation and then decreased significantly or even returned to normal levels after MGIG intervention. Lipidomic data show that glycerides and glycerophospholipids were the two most affected lipids. For excessive lipid accumulation in hepatocytes, MGIG can downregulate the expression of the metabolic enzymes (GPATs and DAGTs) involved in triglyceride biosynthesis. In conclusion, MGIG has a positive regulatory effect on the metabolic disorders that occur in hepatocytes under lipotoxicity, and the main mechanisms of this effect are in lipid metabolism, including reducing the total lipid content, reducing lipid saturation, inhibiting glyceride and glycerophospholipid metabolism, and downregulating the expression of metabolic enzymes in lipid synthesis

Analyses of MicroRNA and mRNA Expression Profiles Reveal the Crucial Interaction Networks and Pathways for Regulation of Chicken Breast Muscle Development

There is a lack of understanding surrounding the molecular mechanisms involved in the development of chicken skeletal muscle in the late postnatal stage, especially in the regulation of breast muscle development related genes, pathways, miRNAs and other factors. In this study, 12 cDNA libraries and 4 small RNA libraries were constructed from Gushi chicken breast muscle samples from 6, 14, 22, and 30 weeks. A total of 15,508 known transcripts, 25,718 novel transcripts, 388 known miRNAs and 31 novel miRNAs were identified by RNA-seq in breast muscle at the four developmental stages. Through correlation analysis of miRNA and mRNA expression profiles, it was found that 417, 370, 240, 1,418, 496, and 363 negatively correlated miRNA–mRNA pairs of W14 vs. W6, W22 vs. W6, W22 vs. W14, W30 vs. W6, W30 vs. W14, and W30 vs. W22 comparisons, respectively. Based on the annotation analysis of these miRNA–mRNA pairs, we constructed the miRNA–mRNA interaction network related to biological processes, such as muscle cell differentiation, striated muscle tissue development and skeletal muscle cell differentiation. The interaction networks for signaling pathways related to five KEGG pathways (the focal adhesion, ECM-receptor interaction, FoxO signaling, cell cycle, and p53 signaling pathways) and PPI networks were also constructed. We found that ANKRD1, EYA2, JSC, AGT, MYBPC3, MYH11, ACTC1, FHL2, RCAN1, FOS, EGR1, and FOXO3, PTEN, AKT1, GADD45, PLK1, CCNB2, CCNB3 and other genes were the key core nodes of these networks, most of which are targets of miRNAs. The FoxO signaling pathway was in the center of the five pathway-related networks. In the PPI network, there was a clear interaction among PLK1 and CDK1, CCNB2, CDK1, and GADD45B, and CDC45, ORC1 and MCM3 genes. These results increase the understanding for the molecular mechanisms of chicken breast muscle development, and also provide a basis for studying the interactions between genes and miRNAs, as well as the functions of the pathways involved in postnatal developmental regulation of chicken breast muscle

Disc Thickness and Spacing Distance Impacts on Flow Characteristics of Multichannel Tesla Turbines

Tesla turbines are a kind of unconventional bladeless turbines, which utilize the viscosity of working fluid to rotate the rotor and realize energy conversion. They offer an attractive substitution for small and micro conventional bladed turbines due to two major advantages. In this study, the effects of two influential geometrical parameters, disc thickness and disc spacing distance, on the aerodynamic performance and flow characteristics for two kinds of multichannel Tesla turbines (one-to-one turbine and one-to-many turbine) were investigated and analyzed numerically. The results show that, with increasing disc thickness, the isentropic efficiency of the one-to-one turbine decreases a little and that of the one-to-many turbine reduces significantly. For example, for turbine cases with 0.5 mm disc spacing distance, the former drops less than 7% and the latter decreases by about 45% of their original values as disc thickness increases from 1 mm to 2 mm. With increasing disc spacing distance, the isentropic efficiency of both kinds of turbines increases first and then decreases, and an optimal value and a high efficiency range exist to make the isentropic efficiency reach its maximum and maintain at a high level, respectively. The optimal disc spacing distance for the one-to-one turbine is less than that for the one-to-many turbine (0.5 mm and 1 mm, respectively, for turbine cases with disc thickness of 1 mm). To sum up, for designing a multichannel Tesla turbine, the disc spacing distance should be among its high efficiency range, and the determination of disc thickness should be balanced between its impacts on the aerodynamic performance and mechanical stress

Are The Chinese Altai 'terranes' the result of juxtaposition of different crustal levels during Late Devonian and Permian orogenesis?

The general structure of the Chinese Altai has been traditionally regarded as being formed by five tectono- stratigraphic 'terranes' bounded by large-scale faults. However, numerous detrital zircon studies of the Paleozoic volcano-sedimentary sequences shown that the variably metamorphosed Cambro-Ordovician sequence, known as the Habahe Group, is present at least in four 'terranes'. It structurally represents deepest rocks unconformably covered by Devonian and Carboniferous sedimentary and volcanic rocks. Calc-alkaline, mostly Devonian, granitoids that intruded all the terranes revealed their syn-subduction related setting. Geochemistry and isotope features of the syn-subduction granitoids have shown that they originated mainly from the melting of youthful sediments de- rived from an eroded Ordovician arc further north. In contrast, Permian alkaline granitoids, mostly located in the southern part of the Chinese Altai, reflect a post-subduction intraplate setting. The metamorphic evolution of the metasedimentary sequences shows an early MP-MT Barrovian event, followed by two Buchan events: LP-HT mid-Devonian (ca. 400-380 Ma) and UHT-HT Permian (ca. 300-270 Ma) cycles. The Barrovian metamorphism is linked to the formation of a regional sub-horizontal possibly Early Devonian fabric and the burial of the Cambro- Ordovician sequence. The Middle Devonian Buchan type event is related to intrusions of the syn-subduction granitoids during an extensional setting and followed by Late Devonian-Early Carboniferous NE-SW trending upright folding and crustal scale doming during a general NW-SE shortening, responsible for the exhumation of the hot lower crust. The last Permian deformation formed NW-SE trending upright folds and vertical zones of deformation related to the extrusion of migmatites, anatectic granitoids and granulite rocks, and to the intrusions of gabbros and granites along the southern border of the Chinese Altai. Finally, the Permo-Triassic cooling and thrust systems affected the whole mountain range from ca. 265 to 230 Ma. In conclusion, the Chinese Altai represents different crustal levels of the lower, middle and upper orogenic crust of a single Cambro-Ordovician accretionary wedge, heterogeneously affected by the Devonian polyphase metamorphism and deformation followed by the Permian tectono-thermal reworking event related to the collision with the Junggar arc. It is the interference of Devonian and Permian upright folding events that formed vertical boundaries surrounding the variously exhumed and eroded crustal segments. Consequently, these crustal segments should not be regarded as individual suspect terranes

FIP200 Methylation by SETD2 Prevents Trim21-Induced Degradation and Preserves Autophagy Initiation

FIP200, also known as RB1CC1, is a protein that assembles the autophagy initiation complex. Its post-translational modifications and degradation mechanisms are unclear. Upon autophagy activation, we find that FIP200 is methylated at lysine1133 (K1133) by methyltransferase SETD2. We identify the E3 ligase Trim21 to be responsible for FIP200 ubiquitination by targeting K1133, resulting in FIP200 degradation through the ubiquitin–proteasome system. SETD2-induced methylation blocks Trim21-mediated ubiquitination and degradation, preserving autophagy activity. SETD2 and Trim21 orchestrate FIP200 protein stability to achieve dynamic and precise control of autophagy flux

Polycyclic Palaeozoic evolution of accretionary orogenic wedge in the southern Chinese Altai: Evidence from structural relationships and U-Pb geochronology.

Structural analysis and U-Pb geochronological study on zircons from the southern Chinese Altai (the Kalasu area, SE of the Altai city) show that the Cambro-Ordovician accretionary wedge (ca. 520-492 Ma) underwent four major geological events: 1) emplacement of Early Devonian magmas (ca. 410-400) associated with formation of a volcano-sedimentary cover, 2) major Middle Devonian (ca. 390-374 Ma) tectono-metamorphic event, 3) Late Devonian-Early Carboniferous folding without apparent metamorphism, and 4) a regional folding with localized Early Permian high- to ultrahigh-temperature reworking (ca. 300-280 Ma). The Early Devonian magmatism is characterized by emplacement of mafic rocks and granitoids in the centre of the NE-SW profile, coevally with granitoid magmatism and rhyolite volcanism in the southwest and northeast, respectively. The whole volcano-sedimentary and magmatic edifice was transposed by sub-horizontal metamorphic fabric associated with variable metamorphic degrees in different areas ranging from greenschist facies in the northeast (mu + bi±g) to amphibolite facies in the southwest (st + g ± sill) and granulite facies in the centre (g + sill+kfs). This metamorphic architecture, distribution of magmatism and character of metamorphic zircon populations allow to correlate these areas with upper, middle and lower orogenic crust that developed during important vertical shortening and horizontal flow in Middle Devonian. Subsequently, the whole edifice was affected by regional NE-SW trending upright (possibly Late Devonian-Early Carboniferous) folding. Finally, Early Permian shortening produced NW-SE trending regional upright folds in the southwest and northeast and a crustal-scale vertical, tabular deformation zone in the centre. The Permian deformation is accompanied by granulite facies (kfs + cd + sill+g) metamorphism and anatexis reworking the Devonian lower orogenic crust, with extensive resetting and growth of new zircons and with intrusions of Permian granites and gabbros. This study suggests that the Early Permian event was related to massive perturbation of thermal structure of the mantle lithosphere due to the collision of the Junggar arc with the Chinese Altai terrane

Ca3Be6B5O16F: the first alkaline-earth beryllium borate with fluorine anions

The first all-alkaline-earth beryllium borate with fluorine anions, Ca3Be6B5O16F, was synthesized by a spontaneous crystallization flux method using LiF–B2O3as the flux.</p