Rosenhandberg0706

Niemann-Pick type C (NPC) disease is a fatal neurodegenerative disorder caused by mutations in NPC1 and NPC2 genes that result in an accumulation of cholesterol in lysosomes. The majority of children with NPC die in adolescence. Currently, no FDA-approved therapies exist for NPC and the mechanisms of NPC disease are not fully understood. Our recent study and the reports from other laboratories showed that 2-hydroxypropyl-γ-cyclodextrin (HPγCD) alleviates cholesterol accumulation in NPC1-deficient cells in spite of its low binding affinity for cholesterol. In this study, we explored the cellular changes that are induced upon HPγCD treatment in NPC1 patient-derived fibroblasts. We show that HPγCD treatment increases lysosome-ER association and enhances autophagic activity. Our study indicates that HPγCD induces an activation of the transcription factor EB (TFEB), a master regulator of lysosomal functions and autophagy. Lysosome-ER association could potentially function as conduits for cholesterol transport from lysosomes to the ER. Accumulating evidence suggests a role for autophagy in rescuing the cholesterol accumulation in NPC and other degenerative diseases. Collectively, our findings suggest that HPγCD restores cellular homeostasis in NPC1-deficient cells via enhancing lysosomal dynamics and functions. Understanding the mechanisms of HPγCD-induced cellular pathways could contribute to effective NPC therapies.Generalized attitudes toward authority and justice are often conceptualized as individual differences that are resistant to enduring change. However, across two field experiments with Chinese factory workers and American university staff, small adjustments to people's experience of participation in the workplace shifted these attitudes one month later. Both experiments randomly assigned work groups to a 20-minute participatory meeting once per week for six weeks, in which the supervisor stepped aside and workers discussed problems, ideas, and goals regarding their work (vs. a status quo meeting). Across 97 work groups and 1,924 workers, participatory meetings led workers to be less authoritarian and more critical about societal authority and justice, and to be more willing to participate in political, social, and familial decision-making. These findings provide rare experimental evidence of the theoretical predictions regarding participatory democracy that local participatory experiences can influence broader democratic attitudes and empowerment.Maturation of dendritic cells (DCs) initiates adaptive immune responses and thereby provokes allograft rejection. Here, this study aimed to explore the effect of Methyltransferase-like protein 3 (METTL3) silencing on DC function and the role of METTL3-silencing donor DCs in the immune response after mouse heart transplantation. Bone marrow-derived DCs from donor BALB/c mice were infected with lentiviruses expressing METTL3-specific short hairpin RNA (LV-METTL3 shRNA) to silence METTL3. Then METTL3-silencing DCs were treated with lipopolysaccharide (LPS) for another 48 h to induce DC maturation. Recipient C57BL/6 mice were injected with phosphate-buffered saline (PBS), immature DCs, and METTL3 shRNA-DCs prior to the cardiac transplantation involving the transfer of hearts from donor BALB/c mice to recipient C57BL/6 mice. In vitro we demonstrated that METTL3-silencing DCs had lower expression of MHCII, costimulatory molecules (CD80, CD86), and DC-related cytokines (IFN-γ, IL-12) as well as lower ability to activate T-cell proliferation, which were consistent with the characteristics of tolerogenic DCs. In vivo we found that METTL3-silencing donor DCs induced immune tolerance after mouse heart transplantation and prolonged the allograft survival, which might be associated with Th1/Th2 immune deviation. In summary, METTL3-silencing DCs exhibit immature properties and prolong allograft survival.Snow depth may have a complex influence on carbon cycling in winter. Here we set up a field experiment to investigate how different snow depths (0 cm, 60 cm, 90 cm) influenced carbon dioxide (CO2) in a wetland. The mean ± standard error of CO2 emissions under snow addition treatments (60 cm and 90 cm snow depths) were 0.92 ± 0.16 g·cm-2·s-1 and 0.53 ± 0.16 g·cm-2·s-1, respectively, compared with snow removal treatment (0 cm snow depth), 0.11 ± 0.05 g·cm-2·s-1. In general, snow addition increased CO2 fluxes significantly. As snow depths increased, microbial biomass carbon (MBC) and bacterial diversities increased drastically. More important, the community of bacteria differed under different treatments. Firmicutes, which can resist dehydration and extremely low temperatures, was widely distributed in the snow removal treatment, where it sustained soil biochemical processes. Overall, our study indicates that snow cover counteracts the negative effects on soil microbial activities caused by low temperatures and could play a critical role in winter carbon cycling in wetlands.An amendment to this paper has been published and can be accessed via a link at the top of the paper.The significance of activated microglia around motoneurons axotomized after nerve injuries has been intensely debated. In particular, whether microglia become phagocytic is controversial. To resolve these issues we directly observed microglia behaviors with two-photon microscopy in ex vivo spinal cord slices from CX3CR1-GFP mice complemented with confocal analyses of CD68 protein. Axotomized motoneurons were retrogradely-labeled from muscle before nerve injuries. Microglia behaviors close to axotomized motoneurons greatly differ from those within uninjured motor pools. They develop a phagocytic phenotype as early as 3 days after injury, characterized by frequent phagocytic cups, high phagosome content and CD68 upregulation. Interactions between microglia and motoneurons changed with time after axotomy. Microglia first extend processes that end in phagocytic cups at the motoneuron surface, then they closely attach to the motoneuron while extending filopodia over the cell body. Confocal 3D analyses revealed increased microglia coverage of the motoneuron cell body surface with time after injury and the presence of CD68 granules in microglia surfaces opposed to motoneurons. Some microglia formed macroclusters associated with dying motoneurons. Nutlin-3 mw Microglia in these clusters display the highest CD68 expression and associate with cytotoxic T-cells. These observations are discussed in relation to current theories on microglia function around axotomized motoneurons.