Angelman syndrome (AS) is a rare neurogenetic disorder caused by UBE3A deficiency and characterized by severe developmental delay, cognitive impairment, and motor dysfunction. In the present study, ...we performed RNA-seq on hippocampal samples from both wildtype (WT) and AS male mice, with or without contextual fear memory recall. There were 281 recall-associated differentially expressed genes (DEGs) in WT mice and 268 DEGs in AS mice, with 129 shared by the two genotypes. Gene ontology analysis showed that extracellular matrix and stimulation-induced response genes were prominently enriched in recall-associated DEGs in WT mice, while nuclear acid metabolism and tissue development genes were highly enriched in those from AS mice. Further analyses showed that the 129 shared DEGs belonged to nuclear acid metabolism and tissue development genes. Unique recall DEGs in WT mice were enriched in biological processes critical for synaptic plasticity and learning and memory, including the extracellular matrix network clustered around fibronectin 1 and collagens. In contrast, AS-specific DEGs were not enriched in any known pathways. These results suggest that memory recall in AS mice, while altering the transcriptome, fails to recruit memory-associated transcriptional programs, which could be responsible for the memory impairment in AS mice.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The ubiquitin ligase, Ube3a, plays important roles in brain development and functions, since its deficiency results in Angelman Syndrome (AS) while its over-expression increases the risk for autism. ...We previously showed that the lack of Ube3a-mediated ubiquitination of the Ca
-activated small conductance potassium channel, SK2, contributes to impairment of synaptic plasticity and learning in AS mice. Synaptic SK2 levels are also regulated by protein kinase A (PKA), which phosphorylates SK2 in its C-terminal domain, facilitating its endocytosis. Here, we report that PKA activation restores theta burst stimulation (TBS)-induced long-term potentiation (LTP) in hippocampal slices from AS mice by enhancing SK2 internalization. While TBS-induced SK2 endocytosis is facilitated by PKA activation, SK2 recycling to synaptic membranes after TBS is inhibited by Ube3a. Molecular and cellular studies confirmed that phosphorylation of SK2 in the C-terminal domain increases its ubiquitination and endocytosis. Finally, PKA activation increases SK2 phosphorylation and ubiquitination in Ube3a-overexpressing mice. Our results indicate that, although both Ube3a-mediated ubiquitination and PKA-induced phosphorylation reduce synaptic SK2 levels, phosphorylation is mainly involved in TBS-induced endocytosis, while ubiquitination predominantly inhibits SK2 recycling. Understanding the complex interactions between PKA and Ube3a in the regulation of SK2 synaptic levels might provide new platforms for developing treatments for AS and various forms of autism.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Accumulating evidence indicates that the lysosomal Ragulator complex is essential for full activation of the mechanistic target of rapamycin complex 1 (mTORC1). Abnormal mTORC1 activation has been ...implicated in several developmental neurological disorders, including Angelman syndrome (AS), which is caused by maternal deficiency of the ubiquitin E3 ligase UBE3A. Here we report that Ube3a regulates mTORC1 signaling by targeting p18, a subunit of the Ragulator. Ube3a ubiquinates p18, resulting in its proteasomal degradation, and Ube3a deficiency in the hippocampus of AS mice induces increased lysosomal localization of p18 and other members of the Ragulator-Rag complex, and increased mTORC1 activity. p18 knockdown in hippocampal CA1 neurons of AS mice reduces elevated mTORC1 activity and improves dendritic spine maturation, long-term potentiation (LTP), as well as learning performance. Our results indicate that Ube3a-mediated regulation of p18 and subsequent mTORC1 signaling is critical for typical synaptic plasticity, dendritic spine development, and learning and memory.
Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by severe developmental delay, motor impairment, language and cognition deficits, and often with increased seizure activity. ...AS is caused by deficiency of UBE3A, which is both an E3 ligase and a cofactor for transcriptional regulation. We previously showed that the small conductance potassium channel protein SK2 is a UBE3A substrate, and that increased synaptic SK2 levels contribute to impairments in synaptic plasticity and fear-conditioning memory, as inhibition of SK2 channels significantly improved both synaptic plasticity and fear memory in male AS mice. In the present study, we investigated UBE3a-mediated regulation of synaptic plasticity and fear-conditioning in female AS mice. Results from both western blot and immunofluorescence analyses showed that synaptic SK2 levels were significantly increased in hippocampus of female AS mice, as compared to wild-type (WT) littermates. Like in male AS mice, long-term potentiation (LTP) was significantly reduced while long-term depression (LTD) was enhanced at hippocampal CA3-CA1 synapses of female AS mice, as compared to female WT mice. Both alterations were significantly reduced by treatment with the SK2 inhibitor, apamin. The shunting effect of SK2 channels on NMDA receptor was significantly larger in female AS mice as compared to female WT mice. Female AS mice also showed impairment in both contextual and tone memory recall, and this impairment was significantly reduced by apamin treatment. Our results indicate that like male AS mice, female AS mice showed significant impairment in both synaptic plasticity and fear-conditioning memory due to increased levels of synaptic SK2 channels. Any therapeutic strategy to reduce SK2-mediated inhibition of NMDAR should be beneficial to both male and female patients.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
•Al-2024/B4C composites have been prepared by powder metallurgy method.•Mechanical milling resulted in significant grain refinement of the Al matrix.•The compression strength of Al-2024/20wt.% B4C ...are 950 MPa.•The high strength is attributed to the refined microstructure and B4C particles.
In this work, we have evaluated the effect of high volume fraction of B4C particles (>20vol.%) on the microstructure and mechanical behavior of Al-2024 matrix composites. The composites were fabricated by mechanical milling of the matrix and the reinforcements together followed by hot extrusion. Mechanical milling resulted in significant grain refinement of the Al-2024 matrix phase (∼35.4nm), while hot extrusion provided the combined advantage of homogenous dispersion of the reinforcement in the matrix as well as clean and strong interface between the two phases. After consolidation at 823K, the grain size of the Al matrix has grown up partially, while the grains around B4C particles are still at nano-scale because of the large difference in the coefficients of thermal expansion (CTE) between the matrix and the reinforcement. The microhardness and compression strength of the composites reinforced by the B4C particles are 260 and 950MPa, respectively, which are almost twice as high as that of the matrix. The superior mechanical properties are attributed to the refined microstructure of the matrix and the homogeneous dispersion of the B4C particles.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The Chinese tradition of filial piety, which prioritized family-based care for the elderly, is transitioning and elders can no longer necessarily rely on their children. The purpose of this study was ...to identify community support for the elderly, and analyze the factors that affect which model of old-age care elderly people dwelling in communities prefer.
We used the database "Health and Social Support of Elderly Population in Community". Questionnaires were issued in 2013, covering 3 districts in Beijing. A group of 1036 people over 60 years in age were included in the study. The respondents' profile variables were organized in Andersen's Model and community healthcare resource factors were added. A multinomial logistic model was applied to analyze the factors associated with the desired aging care models.
Cohabiting with children and relying on care from family was still the primary desired aging care model for seniors (78 %), followed by living in institutions (14.8 %) and living at home independently while relying on community resources (7.2 %). The regression result indicated that predisposing, enabling and community factors were significantly associated with the aging care model preference. Specifically, compared with those who preferred to cohabit with children, those having higher education, fewer available family and friend helpers, and shorter distance to healthcare center were more likely to prefer to live independently and rely on community support. And compared with choosing to live in institutions, those having fewer available family and friend helpers and those living alone were more likely to prefer to live independently and rely on community. Need factors (health and disability condition) were not significantly associated with desired aging care models, indicating that desired aging care models were passive choices resulted from the balancing of family and social caring resources.
In Beijing, China, aging care arrangement preference is the result of balancing family care resources, economic and social status, and the accessibility of community resources. Community facilities and services supporting elderly were found to be insufficient. For China's future health system, efforts should be made to improve community capacity to provide integrated services to senior citizens.
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CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
IntroductionDeep learning techniques are gaining momentum in medical research. Evidence shows that deep learning has advantages over humans in image identification and classification, such as facial ...image analysis in detecting people’s medical conditions. While positive findings are available, little is known about the state-of-the-art of deep learning-based facial image analysis in the medical context. For the consideration of patients’ welfare and the development of the practice, a timely understanding of the challenges and opportunities faced by research on deep-learning-based facial image analysis is needed. To address this gap, we aim to conduct a systematic review to identify the characteristics and effects of deep learning-based facial image analysis in medical research. Insights gained from this systematic review will provide a much-needed understanding of the characteristics, challenges, as well as opportunities in deep learning-based facial image analysis applied in the contexts of disease detection, diagnosis and prognosis.MethodsDatabases including PubMed, PsycINFO, CINAHL, IEEEXplore and Scopus will be searched for relevant studies published in English in September, 2021. Titles, abstracts and full-text articles will be screened to identify eligible articles. A manual search of the reference lists of the included articles will also be conducted. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses framework was adopted to guide the systematic review process. Two reviewers will independently examine the citations and select studies for inclusion. Discrepancies will be resolved by group discussions till a consensus is reached. Data will be extracted based on the research objective and selection criteria adopted in this study.Ethics and disseminationAs the study is a protocol for a systematic review, ethical approval is not required. The study findings will be disseminated via peer-reviewed publications and conference presentations.PROSPERO registration numberCRD42020196473.
Gender is often neglected in health systems, yet health systems are not gender neutral. Within health systems research, gender analysis seeks to understand how gender power relations create ...inequities in access to resources, the distribution of labour and roles, social norms and values, and decision-making. This paper synthesises findings from nine studies focusing on four health systems domains, namely human resources, service delivery, governance and financing. It provides examples of how a gendered and/or intersectional gender approach can be applied by researchers in a range of low- and middle-income settings (Cambodia, Zimbabwe, Uganda, India, China, Nigeria and Tanzania) to issues across the health system and demonstrates that these types of analysis can uncover new and novel ways of viewing seemingly intractable problems.
The research used a combination of mixed, quantitative, qualitative and participatory methods, demonstrating the applicability of diverse research methods for gender and intersectional analysis. Within each study, the researchers adapted and applied a variety of gender and intersectional tools to assist with data collection and analysis, including different gender frameworks. Some researchers used participatory tools, such as photovoice and life histories, to prompt deeper and more personal reflections on gender norms from respondents, whereas others used conventional qualitative methods (in-depth interviews, focus group discussion). Findings from across the studies were reviewed and key themes were extracted and summarised.
Five core themes that cut across the different projects were identified and are reported in this paper as follows: the intersection of gender with other social stratifiers; the importance of male involvement; the influence of gendered social norms on health system structures and processes; reliance on (often female) unpaid carers within the health system; and the role of gender within policy and practice. These themes indicate the relevance of and need for gender analysis within health systems research.
The implications of the diverse examples of gender and health systems research highlighted indicate that policy-makers, health practitioners and others interested in enhancing health system research and delivery have solid grounds to advance their enquiry and that one-size-fits-all heath interventions that ignore gender and intersectionality dimensions require caution. It is essential that we build upon these insights in our efforts and commitment to move towards greater equity both locally and globally.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Aim
While previous studies have examined the association between health‐related behaviors and hypertension, comparatively little attention has been paid to the role of social participation (i.e. ...participating in community organizations). The aim of the present study was to investigate the longitudinal association between social participation and hypertension among the middle‐aged and older population (aged ≥45 years) in China where the prevalence of hypertension has been increasing rapidly in the past few decades.
Methods
Data came from the China Health and Retirement Longitudinal Study waves 2011 and 2013. Information was obtained from 5483 participants on blood pressure, social participation and covariates. A sex‐stratified Poisson regression model with a robust variance estimator was used to examine the associations.
Results
During the period between 2011 and 2013, 20.6% of men and 17.2% of women developed hypertension. A Poisson regression model showed that participating in community organizations once a week or more frequently was inversely associated with the onset of hypertension in women (incidence rate ratio 0.80, 95% confidence interval 0.67–0.95, P = 0.012). Among men, no such association was found.
Conclusion
The present study suggests that promoting social participation might help mitigate the disease burden associated with hypertension in China, particularly among women. Geriatr Gerontol Int 2018; 18: 1093–1099.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
SUMMARY
Brassinosteroids (BRs) are plant hormones that regulate wood formation in trees. Currently, little is known about the post‐transcriptional regulation of BR synthesis. Here, we show that ...during wood formation, fine‐tuning BR synthesis requires 3′UTR‐dependent decay of Populus CONSTITUTIVE PHOTOMORPHOGENIC DWARF 1 (PdCPD1). Overexpression of PdCPD1 or its 3′ UTR fragment resulted in a significant increase of BR levels and inhibited secondary growth. In contrast, transgenic poplars repressing PdCPD1 3′ UTR expression displayed moderate levels of BR and promoted wood formation. We show that the Populus GLYCINE‐RICH RNA‐BINDING PROTEIN 1 (PdGRP1) directly binds to a GU‐rich element in 3′ UTR of PdCPD1, leading to its mRNA decay. We thus provide a post‐transcriptional mechanism underlying BRs synthesis during wood formation, which may be useful for genetic manipulation of wood biomass in trees.
The RNA‐binding protein GLYCINE‐RICH RNA‐BINDING PROTEIN 1 mediates 3′ UTR‐dependent mRNA decay of Populus CONSTITUTIVE PHOTOMORPHOGENIC DWARF1, thus ensuring appropriate levels of brassinosteroids for proper wood formation in poplar stems.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
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