It is widely believed that environmental exposures contribute to the vast majority of late-onset sporadic Parkinson's disease (PD), alone or via interactions with genetic factors. The search for ...environmental causes of PD has however been hampered by lack of understanding the prodromal phase of PD development and the difficulties in exposure assessment during this prolonged period. On the other hand, the existence of this prodromal period, along with an increasingly better understanding of PD prodromal symptoms, provides an exciting opportunity to identify environmental factors that initiate PD pathogenesis and/or modify its progression. For prevention efforts, this prodromal stage is of a major interest. Targeting factors that enter the body via the nose or gut has become even more important since the discovery of α-synuclein aggregates in the enteric and olfactory nervous systems. In this paper, we speculate about novel research hypotheses and approaches that may help us better define the role of environment in PD etiology, especially during its extended and complex prodromal phase.
N6-methyladenosine (m6A) modification is the most pervasive modification in mRNA, and has been considered as a new layer of epigenetic regulation on mRNA processing, stability and translation. ...Despite its functional significance in various physiological processes, the role of the m6A modification involved in breast cancer is yet fully understood.
We used the m6A-RNA immunoprecipitation sequencing to identify the potential targets in breast cancer. To determine the underlying mechanism for the axis of FTO-BNIP3, we performed a series of in vitro and in vivo assays in 3 breast cancer cell lines and 36 primary breast tumor tissues and 12 adjunct tissues.
We showed that FTO, a key m6A demethylase, was up-regulated in human breast cancer. High level of FTO was significantly associated with lower survival rates in patients with breast cancer. FTO promoted breast cancer cell proliferation, colony formation and metastasis in vitro and in vivo. We identified BNIP3, a pro-apoptosis gene, as a downstream target of FTO-mediated m6A modification. Epigenetically, FTO mediated m6A demethylation in the 3'UTR of BNIP3 mRNA and induced its degradation via an YTHDF2 independent mechanism. BNIP3 acts as a tumor suppressor and is negatively correlated with FTO expression in clinical breast cancer patients. BNIP3 dramatically alleviated FTO-dependent tumor growth retardation and metastasis.
Our findings demonstrate the functional significance of the m6A modification in breast cancer, and suggest that FTO may serve as a novel potential therapeutic target for breast cancer.
Various types of nanocellulose have been isolated from the cellulosic feedstock. It was expected that nanocellulose could be used to replace fossil-based plastic in certain areas because it is ...biodegradable, biocompatible, environment-friendly, and has outstanding performance. Unlike conventional plastic processing, nanocellulose is generally isolated and processed in aqueous environments. Therefore, dewatering and drying are essential unit operations for nanocellulose processing. Different drying methods for colloidal nanocellulose suspension mediated different self-assembly behaviors and thus resulted in different nanocellulose morphology and physical properties. The most utilized techniques for nanocellulose processing, such as spinning, vacuum/pressurized filtration, solvent casting and roll to roll casting, coating and roll to roll coating, and additive manufacturing are investigated. Process parameters such as temperature, pH, ion species, concentration, and external electrical field, affect the orientation and assembly behavior of nanocellulose, which in turn influence the properties of the prepared materials. Therefore, the method for assembling nanocellulose into bulk materials in a controlled way is vital for the properties of the fabricated nanocellulose composites. Here, some of the recent advances in the processing of nanocellulose for bulk materials are reviewed.
Graphic abstract
Idiopathic Parkinson's disease (PD) may take decades to develop, during which many risk or protective factors may come into play to initiate the pathogenesis or modify its progression to clinical PD. ...The lack of understanding of this prodromal phase of PD and the factors involved has been a major hurdle in the study of PD etiology and preventive strategies. Although still controversial, the Braak and dual-hit hypotheses that PD may start peripherally in the olfactory structures and/or the gut provides a theoretical platform to identify the triggers and modifiers of PD prodromal development and progression. This is particularly true for the search of environmental causes of PD as the olfactory structures and gut are the major human mucosal interfaces with the environment. In this review, we lay out our personal views about how the Braak and dual-hit hypotheses may help us search for the environmental triggers and modifiers for PD, summarize available experimental and epidemiological evidence, and discuss research gaps and strategies.
Release of immunoreactive negative regulatory factors such as immune checkpoint limits antitumor responses. PD-L1 as a significant immunosuppressive factor has been involved in resistance to ...therapies such as chemotherapy and target therapy in various cancers. Via interacting with PD-1, PD-L1 can regulate other factors or lead to immune evasion of cancer cells. Besides, immune checkpoint blockade targeting PD-1/PD-L1 has promising therapeutic efficacy in the different tumors, but a significant percentage of patients cannot benefit from this therapy due to primary and acquired resistance during treatment. In this review, we described the utility of PD-L1 expression levels for predicting poor prognosis in some tumors and present evidence for a role of PD-L1 in resistance to therapies through PD-1/PD-L1 pathway and other correlating signaling pathways. Afterwards, we elaborate the key mechanisms underlying resistance to PD-1/PD-L1 blockade in cancer immunotherapy. Furthermore, promising combination of therapeutic strategies for patients resistant to PD-1/PD-L1 blockade therapy or other therapies associated with PD-L1 expression was also summarized.
OBJECTIVES: To investigate whether indicators of obesity are associated with functional disabilities in elderly American women and men.
DESIGN: Cross‐sectional.
SETTING: National Health and Nutrition ...Examination Survey (NHANES) 1999 to 2004, United States.
PARTICIPANTS: One thousand six hundred eighty‐four elderly (aged ≥60) women and 1,611 elderly men.
MEASUREMENTS: Functional disabilities.
RESULTS: In women, body mass index (BMI) and waist circumference were each related to higher prevalence of all measures of disabilities. Compared with the lowest quartile of waist circumference, the multivariate odds ratios (ORs) of the highest quartile for having difficulties in functional domains were 2.4 (95% confidence interval (CI)=1.6–3.6) for activities of daily living, 2.3 (95% CI=1.6–3.3) for instrumental activities of daily living, 2.6 (95% CI=1.6–4.1) for leisure and social activities, 4.8 (95% CI=3.4–6.9) for lower extremity mobility, and 2.9 (95% CI=2.1–4.0) for general physical activity. In men, these associations were moderate; the corresponding ORs were 1.2 (95% CI=0.8–2.0), 1.3 (95% CI=0.9–2.1), 2.1 (95% CI=1.2–3.7), 1.8 (95% CI=1.2–2.7), and 2.1 (95% CI=1.5–2.8), respectively. Similar results were obtained for BMI. These associations could not be explained by the presence of major chronic conditions. When adjusted simultaneously, waist circumference appeared to be a better predictor than BMI of disability in women.
CONCLUSION: The results suggest that indicators of obesity are related to functional disabilities in elderly Americans.
The pathogenesis of Parkinson's disease (PD) involves the accumulation of aggregated α-synuclein, which has been suggested to begin in the gastrointestinal tract. Here, we determined the capacity of ...the appendix to modify PD risk and influence pathogenesis. In two independent epidemiological datasets, involving more than 1.6 million individuals and over 91 million person-years, we observed that removal of the appendix decades before PD onset was associated with a lower risk for PD, particularly for individuals living in rural areas, and delayed the age of PD onset. We also found that the healthy human appendix contained intraneuronal α-synuclein aggregates and an abundance of PD pathology-associated α-synuclein truncation products that are known to accumulate in Lewy bodies, the pathological hallmark of PD. Lysates of human appendix tissue induced the rapid cleavage and oligomerization of full-length recombinant α-synuclein. Together, we propose that the normal human appendix contains pathogenic forms of α-synuclein that affect the risk of developing PD.
OBJECTIVE: To investigate the relationship between diabetes and future risk of Parkinson's disease (PD) among older U.S. adults. RESEARCH DESIGN AND METHODS: A prospective study of self-reported ...diabetes in 1995 and 1996 in relation to PD diagnosed after 1995 among 288,662 participants of the National Institutes of Health-AARP Diet and Health Study. Multivariate odds ratio (OR) and 95% CI were derived from logistic regression models. RESULTS: A total of 1,565 participants with PD diagnosed after 1995 were included in the analysis. After adjustment for potential confounders, PD risk was ~40% higher (OR = 1.41 95% CI 1.20-1.66) among diabetic patients than among participants without diabetes. Further analysis showed that the risk elevation was largely limited to individuals who had diabetes for more than 10 years at the time of baseline survey (1.75 1.36-2.25). The association with diabetes was seen for both participants with PD diagnosed between 1995 and 1999 and participants with PD diagnosed after 2000. In addition, similar results were obtained after excluding participants with stroke, heart disease, cancers, or poor or fair health status and in subgroup analyses by age, sex, smoking status, and coffee consumption. CONCLUSIONS: This large study showed that diabetes was associated with a higher future risk of PD and the nature of this association warrants further investigation.
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