Mutations in PARK2 (parkin), which encodes Parkin protein, an E3 ubiquitin ligase, are associated with autosomal recessive early-onset Parkinson's disease (PD). While several studies implicated ...Parkin in the regulation of mitophagy and proteasomal degradation, the precise mechanism leading to neurodegeneration upon Parkin loss of function remains incompletely understood. In this study, we found that Parkin modulates the endocytic pathway through the regulation of endosomal structure and function. We showed that loss of Parkin function led to decreased endosomal tubulation and membrane association of vesicle protein sorting 35 (VPS35) and sorting nexin 1 (SNX1), as well as decreased mannose 6 phosphate receptor (M6PR), suggesting the impairment of retromer pathway in Parkin-deficient cells. We also found increased formation of intraluminal vesicles coupled with enhanced release of exosomes in the presence of mutant Parkin. To elucidate the molecular mechanism of these alterations in the endocytic pathway in Parkin-deficient cells, we found that Parkin regulates the levels and activity of Rab7 by promoting its ubiquitination on lysine 38 residue. Both endogenous Rab7 in Parkin-deficient cells and overexpressed K38 R-Rab7 mutant displayed decreased effector binding and membrane association. Furthermore, overexpression of K38R-Rab7 in HEK293 cells phenocopied the increased secretion of exosomes observed in Parkin-deficient cells, suggesting that Rab7 deregulation may be at least partially responsible for the endocytic phenotype observed in Parkin-deficient cells. These findings establish a role for Parkin in regulating the endo-lysosomal pathway and retromer function and raise the possibility that alterations in these pathways contribute to the development of pathology in Parkin-linked Parkinson's disease.
The design of nanocatalysts by controlling pore size and particle characteristics is crucial to enhance the selectivity and activity of the catalysts. Thus, we have successfully demonstrated the ...synthesis of binary PdPb alloy nanocubes (PdPb NCs) by controlling pore size and particle characteristics. In addition, the as-obtained binary PdPb NCs exhibited superior electrocatalytic activity of 4.06 A mg–1 and 16.8 mA cm–2 toward ethylene glycol oxidation reaction and 2.22 A mg–1 and 9.2 mA cm–2 toward glycerol oxidation reaction when compared to the commercial Pd/C. These astonishing characteristics are attributed to the attractive nanocube structures as well as the large number of exposed active areas. Furthermore, the bifunctional effects originated from Pd and Pb interactions help to display high endurance with less activity decay after 500 cycles, showing a great potential in fuel cell applications.
Gastric cancer (GC) is one of the most common types of malignancy. Its potential molecular mechanism has not been clarified. In this study, we aimed to explore potential biomarkers and ...prognosis-related hub genes associated with GC. The gene chip dataset GSE79973 was downloaded from the GEO datasets and limma package was used to identify the differentially expressed genes (DEGs). A total of 1269 up-regulated and 330 down-regulated genes were identified. The protein-protein interactions (PPI) network of DEGs was constructed by STRING V11 database, and 11 hub genes were selected through intersection of 11 topological analysis methods of CytoHubba in Cytoscape plug-in. All the 11 selected hub genes were found in the module with the highest score from PPI network of all DEGs by the molecular complex detection (MCODE) clustering algorithm. In order to explore the role of the 11 hub genes, we performed GO function and KEGG pathway analysis for them and found that the genes were enriched in a variety of functions and pathways among which cellular senescence, cell cycle, viral carcinogenesis and p53 signaling pathway were the most associated with GC. Kaplan-Meier analysis revealed that 10 out of the 11 hub genes were related to the overall survival of GC patients. Further, seven of the 11 selected hub genes were verified significantly correlated with GC by uni- or multivariable Cox model and LASSO regression analysis including C3, CDK1, FN1, CCNB1, CDC20, BUB1B and MAD2L1. C3, CDK1, FN1, CCNB1, CDC20, BUB1B and MAD2L1 may serve as potential prognostic biomarkers and therapeutic targets for GC.
Bimetallic one-dimensional (1D) nanostructures such as nanowires (NWs) and nanorods (NRs), serving as high-efficiency anode electrocatalysts, have attracted extensive attention in the past decade. ...However, the precise design and synthesis of 1D Pt-based nanocrystals with tunable morphology and size still remain an arduous challenge. Driven by this, we report a facile yet efficient strategy for the first time to prepare PtNi ultrafine NWs (UNWs), sinuous NWs (SNWs) and ultrashort NRs (UNRs) by adjusting the amount of citric acid, ascorbic acid and glucose. Detailed analysis of their electrocatalytic properties has indicated that the as-obtained PtNi SNWs exhibit the most outstanding electrocatalytic activity toward ethylene glycol oxidation reaction (EGOR) and glycerol oxidation (GOR), 4.5 and 4.3 times higher in mass activity as well as 4.3 and 3.9 times higher in specific activity compared with the commercial Pt/C catalyst. The as-prepared PtNi SNWs are also more stable than the commercial Pt/C catalyst after successive durability tests. The proposed method provides insight into more rational designs of bimetallic nanocatalysts with 1D architectures and the as-synthesized PtNi catalysts with improved electrocatalytic performance assist in promoting the further development of direct alcohol fuel cells (DAFCs).
Abstract
Background
The problem-based learning (PBL) model has been widely carried out in many fields of medical colleges and universities. Immunochemistry as a cross-disciplinary science plays a ...vital role in preventing the occurrence of diseases and bridging the development of Life Science and Medicine. But now the Immunochemistry course still lacks the teaching practice in PBL. To explore the significance of PBL applied in the Immunochemistry course, the effect of the PBL model on the learning of undergraduates majoring in Chemicobiology was systematically evaluated.
Methods
The teaching objects were the undergraduates majoring in Chemicobiology from Guizhou Medical University. The PBL model was applied in the Immunochemistry course. 62 undergraduates in Grade 2018 were set as the control group and adopted the traditional expository model. 93 undergraduates in Grades 2019–2020 were separately set as the experimental groups, which adopted the PBL model based on traditional lecture-based learning. In the PBL model, six cases related to course contents were designed for the students to complete. The final exams of the undergraduates in Grades 2018–2020 were analyzed by the score ranges (< 60 points, 60–69 points, 70–79 points, and ≥ 80 points) and nonparametric test. Finally, the questionnaire survey about the teaching evaluation was performed in Grades 2019–2020.
Results
In Grades 2019 and 2020, the excellent rates (≥ 80 points), pass rates (≥ 60 points), fail rates (< 60 points), and average scores of the undergraduates were separately about 29%, 91.11% and 93.75%, 6.25%, and 8.89%, and 72.55 and 74.45 points. But in Grade 2018, the excellent rate, pass rate, failure rate, and average score of the undergraduates were separately 9.68%, 59.68%, 40.32%, and 62.55 points. By the statistical analysis, it was found that the excellent rates (χ
2
= 8.317,
P
< 0.005) and pass rates (χ
2
= 24.52,
P
< 0.0001) in Grades 2018–2020 were different, of which Grade 2020were the highest (29.17%, 93.75%) and Grade 2018 was the lowest (9.68%, 59.68%). The average score, excellent rate, and pass rate in Grade 2018 had significant differences with Grade 2019 (
P
< 0.0001,
P
< 0.0167) and Grade 2020 (
P
< 0.001,
P
< 0.0167). The questionnaire survey also showed that the student’s learning interests, independent problem-solving ability, knowledge structure system, and scientific thought and teamwork awareness were enhanced. In Grades 2019 and 2020, the ICC (95% CI) of criterion validity and inter-rater reliability were separately 0.42/0.34 and 0.81/0.80 (
P
< 0.0001).
Conclusion
The combination of PBL and traditional expository models played positive roles in the student’s learning in the Immunochemistry course.
Mitochondrial and lysosomal dysfunction have been implicated in substantia nigra dopaminergic neurodegeneration in Parkinson’s disease (PD), but how these pathways are linked in human neurons remains ...unclear. Here we studied dopaminergic neurons derived from patients with idiopathic and familial PD. We identified a time-dependent pathological cascade beginning with mitochondrial oxidant stress leading to oxidized dopamine accumulation and ultimately resulting in reduced glucocerebrosidase enzymatic activity, lysosomal dysfunction, and α-synuclein accumulation. This toxic cascade was observed in human, but not in mouse, PD neurons at least in part because of species-specific differences in dopamine metabolism. Increasing dopamine synthesis or α-synuclein amounts in mouse midbrain neurons recapitulated pathological phenotypes observed in human neurons. Thus, dopamine oxidation represents an important link between mitochondrial and lysosomal dysfunction in PD pathogenesis.
The tailoring and design of electrocatalysts, such as Pt-based nanocubes (NCs) covered by {100} facets, have received extensive attention in the past decade; however, studies on the facile yet ...precise synthesis of PtRh NCs with different sizes have rarely been reported up till now. Herein, a reliable method is reported for the first time to synthesize PtRh-small (PtRh-S) and PtRh-large (PtRh-L) NCs with the different sizes of 5.5 and 10.5 nm by introducing rhodium acetate and rhodium chloride, respectively. In particular, to the best of our knowledge, the PtRh-S NCs are the smallest synthesized PtRh NCs reported to date. We demonstrated that the {100} facet-covered PtRh NCs showed much better catalytic activity and stability than the {100}-terminated pure Pt NCs towards the ethylene glycol oxidation reaction (EGOR). Specifically, the size-optimized PtRh-S NCs show a much higher mass and specific activity (5125.0 mA mg −1 and 11.6 mA cm −2 ) for EGOR, which are 4.2 and 2.0 and 4.7 and 6.4-fold higher than those of the Pt NCs and Pt/C catalysts, respectively. The monodisperse nanocubic structure, ultra-small size and alloy effect led to the enhanced electrocatalytic behaviors. The present study describes the rational synthesis of size-controlled PtRh NCs and further provides a promising reference for the effective manipulation of other cubic nanocatalysts for applications in fuel cells and so forth.
Uridine diphosphate glycosyltransferases (UGTs) are multifunctional detoxification enzymes, which are involved in metabolizing various chemicals and contribute to the development of insecticide ...resistance. However, the possible roles of UGTs in chlorantraniliprole resistance in
have rarely been studied in detail. Based on genome data, 24 UGT genes in
belonging to 11 families were identified, which were designated by the UGT nomenclature committee. Synergism assay data suggested that UGTs are potentially involved in chlorantraniliprole resistance in
and
were significantly overexpressed in the chlorantraniliprole resistant strain (12.36- and 5.34-fold, respectively). The two UGTs were highly expressed in the larval Malpighian tubules, fat body, and midgut; however, expression was lowest in the head. Injection of individual dsRNAs reduced the expression of the two target genes (by 69.34% and 48.74%, respectively) and caused significant higher larval mortality (81.33% and 54.67%, respectively). Overexpression of
and
was potentially involved in chlorantraniliprole resistance in
as confirmed by the RNAi assay. Our findings suggest that overexpression of UGTs may contribute to chlorantraniliprole resistance in
.
Accumulating evidence has shown that dysfunctional mitochondria can be selectively removed by mitophagy. Dysregulation of mitophagy is implicated in the development of neurodegenerative disease and ...metabolic disorders. How individual mitochondria are recognized for removal and how this process is regulated remain poorly understood. Here we report that FUNDC1, an integral mitochondrial outer-membrane protein, is a receptor for hypoxia-induced mitophagy. FUNDC1 interacted with LC3 through its typical LC3-binding motif Y(18)xxL(21), and mutation of the LC3-interaction region impaired its interaction with LC3 and the subsequent induction of mitophagy. Knockdown of endogenous FUNDC1 significantly prevented hypoxia-induced mitophagy, which could be reversed by the expression of wild-type FUNDC1, but not LC3-interaction-deficient FUNDC1 mutants. Mechanistic studies further revealed that hypoxia induced dephosphorylation of FUNDC1 and enhanced its interaction with LC3 for selective mitophagy. Our findings thus offer insights into mitochondrial quality control in mammalian cells.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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