Downregulation of Protease Cathepsin D and Upregulation of Pathologic α-Synuclein Mediate Paucity of DNAJC6-Induced Degeneration of Dopaminergic Neurons.

A homozygous mutation of the DNAJC6 gene causes autosomal recessive familial type 19 of Parkinson's disease (PARK19). To test the hypothesis that PARK19 DNAJC6 mutations induce the neurodegeneration of dopaminergic cells by reducing the protein expression of functional DNAJC6 and causing DNAJC6 paucity, an in vitro PARK19 model was constructed by using shRNA-mediated gene silencing of endogenous DANJC6 in differentiated human SH-SY5Y dopaminergic neurons. shRNA targeting DNAJC6 induced the neurodegeneration of dopaminergic cells. DNAJC6 paucity reduced the level of cytosolic clathrin heavy chain and the number of lysosomes in dopaminergic neurons. A DNAJC6 paucity-induced reduction in the lysosomal number downregulated the protein level of lysosomal protease cathepsin D and impaired macroautophagy, resulting in the upregulation of pathologic α-synuclein or phospho-α-synucleinSer129 in the endoplasmic reticulum (ER) and mitochondria. The expression of α-synuclein shRNA or cathepsin D blocked the DNAJC6 deficiency-evoked degeneration of dopaminergic cells. An increase in ER α-synuclein or phospho-α-synucleinSer129 caused by DNAJC6 paucity activated ER stress, the unfolded protein response and ER stress-triggered apoptotic signaling. The lack of DNAJC6-induced upregulation of mitochondrial α-synuclein depolarized the mitochondrial membrane potential and elevated the mitochondrial level of superoxide. The DNAJC6 paucity-evoked ER stress-related apoptotic cascade, mitochondrial malfunction and oxidative stress induced the degeneration of dopaminergic neurons via activating mitochondrial pro-apoptotic signaling. In contrast with the neuroprotective function of WT DNAJC6, the PARK19 DNAJC6 mutants (Q789X or R927G) failed to attenuate the tunicamycin- or rotenone-induced upregulation of pathologic α-synuclein and stimulation of apoptotic signaling. Our data suggest that PARK19 mutation-induced DNAJC6 paucity causes the degeneration of dopaminergic neurons via downregulating protease cathepsin D and upregulating neurotoxic α-synuclein. Our results also indicate that PARK19 mutation (Q789X or R927G) impairs the DNAJC6-mediated neuroprotective function.

Effects of urban functional fragmentation on nitrogen dioxide (NO2) variation with anthropogenic-emission restriction in China.

Urban functional fragmentation plays an important role in assessing Nitrogen Dioxide (NO2) emissions and variations. While the mediated impact of anthropogenic-emission restriction has not been comprehensively discussed, the lockdown response to the novel coronavirus disease 2019 (COVID-19) provides an unprecedented opportunity to meet this goal. This study proposes a new idea to explore the effects of urban functional fragmentation on NO2 variation with anthropogenic-emission restriction in China. First, NO2 variations are quantified by an Autoregressive Integrated Moving Average with external variables-Dynamic Time Warping (SARIMAX-DTW)-based model. Then, urban functional fragmentation indices including industrial/public Edge Density (ED) and Landscape Shape Index (LSI), urban functional Aggregation Index (AI) and Number of Patches (NP) are developed. Finally, the mediated impacts of anthropogenic-emission restriction are assessed by evaluating the fragmentation-NO2 variation association before and during the lockdown during COVID-19. The findings reveal negative effects of industrial ED, public LSI, urban functional AI and NP and positive effects of public ED and industrial LSI on NO2 variation based on the restricted anthropogenic emissions. By comparing the association analysis before and during lockdown, the mediated impact of anthropogenic-emission restriction is revealed to partially increase the effect of industrial ED, industrial LSI, public LSI, urban functional AI and NP and decrease the effect of public ED on NO2 variation. This study provides scientific findings for redesigning the urban environment in related to the urban functional configuration to mitigating the air pollution, ultimately developing sustainable societies.

Spatial analysis of the impact of urban geometry and socio-demographic characteristics on COVID-19, a study in Hong Kong.

The World Health Organization considered the wide spread of COVID-19 over the world as a pandemic. There is still a lack of understanding of its origin, transmission, and treatment methods. Understanding the influencing factors of COVID-19 can help mitigate its spread, but little research on the spatial factors has been conducted. Therefore, this study explores the effects of urban geometry and socio-demographic factors on the COVID-19 cases in Hong Kong. For each patient, the places they visited during the incubation period before going to hospital were identified, and matched with corresponding attributes of urban geometry (i.e., building geometry, road network and greenspace) and socio-demographic factors (i.e., demographic, educational, economic, household and housing characteristics) based on the coordinates. The local cases were then compared with the imported cases using stepwise logistic regression, logistic regression with case-control of time, and least absolute shrinkage and selection operator regression to identify factors influencing local disease transmission. Results show that the building geometry, road network and certain socio-economic characteristics are significantly associated with COVID-19 cases. In addition, the results indicate that urban geometry is playing a more important role than socio-demographic characteristics in affecting COVID-19 incidence. These findings provide a useful reference to the government and the general public as to the spatial vulnerability of COVID-19 transmission and to take appropriate preventive measures in high-risk areas.

Mechanical ventilation promotes lung metastasis in experimental 4T1 breast cancer lung-metastasized models.

BACKGROUND/PURPOSE: The aim of this study was to test the hypothesis that mechanical ventilation (MV) during cancer surgery induces lung stroma/tissue milieu changes, creating a favorable microenvironment for postoperative lung metastatic tumor establishment. MATERIALS AND METHODS: In Protocol A, female BALB/c mice were divided into an MV group and a control (no MV) group, both of which were anesthetized and subjected to intravenous injection of green fluorescent protein (GFP)-labeled mouse mammary carcinoma cell line (4T1) cells. After 24 h, the lung tissue was removed and the number of GFP-labeled 4T1 cells was calculated. In Protocol B, the clinically relevant mouse model of spontaneous breast cancer lung metastasis was used with surgical resection of the primary tumor to investigate the MV event that dictates postoperative lung metastasis. Female BALB/c mice were inoculated in the mammary fat pad with 4T1 cells. After 14-d growth, mice were anesthetized and divided into an MV group and a control (no MV) group during surgical procedures (mastectomy). Metastatic tumor burden was assessed two weeks after mastectomy by both macroscopic metastatic nodule count, hematoxylin-eosin histology, immunohistochemistry for the macrophage marker (CD68), and epithelial cell adhesion molecule (EpCAM). RESULTS: MV was associated with a significant increase in the number of circulating breast tumor cells (GFP-labeled 4T1 cells) remaining in the microvasculature of the lung (P<0.01). Immunohistochemical results showed increased infiltration of CD68-positive macrophages within injured lung parenchyma and metastatic tumor as well as increased expression of EpCAM in metastatic nodules. Postoperative metastases were more prevalent in the mechanically ventilated mice group compared to the non-ventilated group (P<0.05). CONCLUSION: MV-induced lung metastasis occurs by attracting circulating tumor cells to the site of the lung injury and by accelerating the proliferation of preexisting micro-metastases in the lung. These observations indicate that the metastasis-enhancing effect of MV should be considered in general anesthesia during cancer surgery.

Animal research, non-vegetarianism, and the moral status of animals--understanding the impasse of the animal rights problem.

I offer some reasons for the theory that, compared with human beings, non-human animals have some but lesser intrinsic value. On the basis of this theory, I first argue that we do not know how to compare an animal's claim to be free from a more serious type of harm (e.g., death), and a human's claim to be free from some lesser type of harm (e.g., non-fatal morbidity). For we need to take account of these parties' intrinsic value, and their competing types of claim. Yet, there exists no known way for making such comparison, when a human's intrinsic value is higher than that of an animal, whereas the type of claim an animal has is morally weightier than the type of claim a human has. Second, I explain why utilitarianism is unhelpful in making such comparison. Third, in the case where some animals can be sacrificed for saving a larger number of humans, it is crucial to ask whether animals have the right to life, and I argue that this question is more perplexing than we might think. My conclusion is that the various difficulties mentioned above have a deeper source than we have so far acknowledged, and that this reflects that the moral reality is less tidy and more complex than many theories portray.