Parrishandersen6808

Loss of the outer hair cells, combined with the aberrant ribbon synapse distribution, may lead to the observed auditory impairment. Together, these results suggest a novel function for striatin in the mammalian auditory system.Diabetes significantly induces cognitive dysfunction. Neuronal apoptosis is the main cause of diabetes-induced cognitive decline (DICD). Apoptosis signal-regulating kinase 1 (ASK1) and endoplasmic reticulum (ER) stress are remarkably activated by diabetes. The role and relationship of ASK1-JNK1/2 signaling and ER stress in DICD have not yet been elucidated. In this study, we used db/db mice as the DICD animal model and confirmed that db/db mice displayed cognitive decline with inferior learning and memory function. Diabetes significantly induced morphological and structural changes, excessive neuronal apoptosis, Aβ1-42 large deposition, and synaptic dysfunction in the hippocampus. Mechanistic studies found that diabetes significantly triggered ASK1-JNK1/2 signaling activation and increased ER stress in the hippocampus. Moreover, diabetes enhanced the formation of the IRE1α-TRAF2-ASK1 complex, which promotes the crosstalk of ER stress and the ASK1-JNK1/2 pathway during DICD. Furthermore, 4-PBA treatment blocked high glucose (HG)-induced ASK1-JNK1/2 signaling activation, and excessive apoptosis in vitro. Inhibiting ASK1 via siRNA remarkably ameliorated the HG-induced increase in p-IRE1α and associated apoptosis in SH-SY5Y cells, suggesting that ASK1 is essential for the assembly and function of the proapoptotic kinase activity of the IRE1α signalosome. In summary, ER stress and ASK1-JNK1/2 signaling play causal roles in DICD development, which has crosstalk through the formation of the IRE1α-TRAF2-ASK1 complex.Autophagy is a process of intracellular self-recycling and degradation that plays an important role in maintaining cell homeostasis. However, the molecular mechanism of autophagy remains to be further studied. Mitochondria-associated endoplasmic reticulum membranes (MAMs) are the region of the ER that mediate communication between the ER and mitochondria. MAMs have been demonstrated to be involved in autophagy, Ca2+ transport and lipid metabolism. Here, we discuss the composition and function of MAMs, more specifically, to emphasize the role of MAMs in regulating autophagy. Finally, some key information that may be useful for future research is summarized.The architecture of the lipid matrix of the outer membrane of Gram-negative bacteria is extremely asymmetric Whereas the inner leaflet is composed of a phospholipid mixture, the outer leaflet is built up by glycolipids. For most Gram-negative species, these glycolipids are lipopolysaccharides (LPS), for a few species, however, glycosphingolipids. selleckchem We demonstrate experimental approaches for the reconstitution of these asymmetric membranes as (i) solid supported membranes prepared by the Langmuir-Blodgett technique, (ii) planar lipid bilayers prepared by the Montal-Mueller technique, and (iii) giant unilamellar vesicles (GUVs) prepared by the phase transfer method. The asymmetric GUVs (aGUVs) composed of LPS on one leaflet are shown for the first time. They are characterized with respect to their phase behavior, flip-flop of lipids and their usability to investigate the interaction with membrane active peptides or proteins. For the antimicrobial peptide LL-32 and for the bacterial porin OmpF the specificity of the interaction with asymmetric membranes is shown. The three reconstitution systems are compared with respect to their usability to investigate domain formation and interactions with peptides and proteins.Runting and stunting syndrome (RSS), which is characterized by low body weight, generally occurs early in life and leads to considerable economic losses in the commercial broiler industry. Our previous study has suggested that RSS is associated with mitochondria dysfunction in sex-linked dwarf (SLD) chickens. However, the molecular mechanism of RSS remains unknown. Based on the molecular diagnostics of mitochondrial diseases, we identified a recessive mutation c. 409G > A (p. Ala137Thr) of Twinkle mitochondrial DNA helicase (TWNK) gene and mitochondrial DNA (mtDNA) depletion in RSS chickens' livers from strain N301. Bioinformatics investigations supported the pathogenicity of the TWNK mutation that is located on the extended peptide linker of Twinkle primase domain and might further lead to mtDNA depletion in chicken. Furthermore, overexpression of wild-type TWNK increases mtDNA copy number, whereas overexpression of TWNK A137T causes mtDNA depletion in vitro. Additionally, the TWNK c. 409G > A mutation showed significant associations with body weight, daily gain, pectoralis weight, crureus weight, and abdominal fat weight. Taken together, we corroborated that the recessive TWNK c. 409G > A (p. Ala137Thr) mutation is associated with RSS characterized by mtDNA depletion in SLD chicken.Although genetic variants in autophagy pathway genes were associated with the risk of oral cancers and early development in embryos, their associations with non-syndromic cleft lip with or without cleft palate (NSCL/P) risk remained unclear. A two-stage case-control study (2,027 NSCL/P cases and 1,843 controls) was performed to investigate the associations between single nucleotide polymorphisms (SNPs) in 23 autophagy pathway genes and NSCL/P susceptibility. The logistic regression model was used to calculate effects of SNPs on NSCL/P susceptibility. Gene-based analysis was performed via the sequence kernel association test (SKAT) and multi-marker analysis of genomic annotation (MAGMA) methods. Expression quantitative trait loci (eQTL) analysis was conducted using NSCL/P lip tissue samples. Gene expression during embryonic development was evaluated using RNA-Seq. Functional roles were explored by luciferase activity assay, cell apoptosis, proliferation, and cycle in vitro. Rs2301104 in HIF1A was significantly associated with NSCL/P susceptibility in the combined analysis (OR 1.29, 95% CI 1.09-1.29, P = 3.39 × 10-03), and showed strong evidence of association heterogeneity (P = 9.06 × 10-03) with obvious association in the female (OR 1.80; 95% CI 1.32-2.45; P = 1.79 × 10-04). The G allele of rs2301104 was associated with enhanced transcription activity and high expression of HIF1A compared with that of C allele. Moreover, rs2301104 exhibited an eQTL effect for HIF1A with its GC/CC genotypes associated with decreased HIF1A expression compared with those with GG genotypes (P = 3.1 × 10-2). Knockdown of HIF1A induced cell apoptosis and inhibited cell proliferation in human embryonic palate mesenchyme (HEPM) and human oral epithelium cells (HOEC). This study demonstrated that rs2301104 in autophagy pathway gene HIF1A was associated with susceptibility of NSCL/P.