Network-selective vulnerability of the human cerebellum to Alzheimer’s disease and frontotemporal dementia

Neurodegenerative diseases are associated with distinct and distributed patterns of atrophy in the cerebral cortex. Emerging evidence suggests that these atrophy patterns resemble intrinsic connectivity networks in the healthy brain, supporting the network-based degeneration framework where neuropathology spreads across connectivity networks. An intriguing yet untested possibility is that the cerebellar circuits, which share extensive connections with the cerebral cortex, could be selectively targeted by major neurodegenerative diseases. Here we examined the structural atrophy in the cerebellum across common types of neurodegenerative diseases, and characterized the functional connectivity patterns of these cerebellar atrophy regions. Our results showed that Alzheimer’s disease and frontotemporal dementia are associated with distinct and circumscribed atrophy in the cerebellum. These cerebellar atrophied regions share robust and selective intrinsic connectivity with the atrophied regions in the cerebral cortex. These findings for the first time demonstrated the selective vulnerability of the cerebellum to common neurodegenerative disease, extending the network-based degeneration framework to the cerebellum. Our work also has direct implications on the cerebellar contribution to the cognitive and affective processes that are compromised in neurodegeneration as well as the practice of using the cerebellum as reference region for ligand neuroimaging studies

The VHL/HIF Axis in the Development and Treatment of Pheochromocytoma/Paraganglioma

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors originating from chromaffin cells in the adrenal medulla (PCCs) or extra-adrenal sympathetic or parasympathetic paraganglia (PGLs). About 40% of PPGLs result from germline mutations and therefore they are highly inheritable. Although dysfunction of any one of a panel of more than 20 genes can lead to PPGLs, mutations in genes involved in the VHL/HIF axis includin

Germline Mutations in Patients With Early-Onset Prostate Cancer.

Objective: To investigate the inherited mutations and their association with clinical features and treatment response in young-onset prostate cancer patients. Method: Targeted gene sequencing on 139 tumor susceptibility genes was conducted with a total of 24 patients diagnosed with PCa under the age of 63 years old. Meanwhile, the related clinical information of those patients is collected and analyzed. Results: Sixty-two germline mutations in 45 genes were verified in 22 patients. Conclusion: Mutations in DRGs are more prevalent in early-onset PCa with advanced clinical stages, and these patients had shorter progression-free survival. ADT Combined with either radiotherapy or chemotherapy may be effective in treating PCa caused by HRR-related gene mutations

PHF8-GLUL axis in lipid deposition and tumor growth of clear cell renal cell carcinoma.

For clear cell renal cell carcinoma (ccRCC), lipid deposition plays important roles in the development, metastasis, and drug resistance. However, the molecular mechanisms underlying lipid deposition in ccRCC remain largely unknown. By conducting an unbiased CRISPR-Cas9 screening, we identified the epigenetic regulator plant homeodomain finger protein 8 (PHF8) as an important regulator in ccRCC lipid deposition. Moreover, PHF8 is regulated by von Hippel-Lindau (VHL)/hypoxia-inducible factor (HIF) axis and essential for VHL deficiency-induced lipid deposition. PHF8 transcriptionally up-regulates glutamate-ammonia ligase (GLUL), which promotes the lipid deposition and ccRCC progression. Mechanistically, by forming a complex with c-MYC, PHF8 up-regulates TEA domain transcription factor 1 (TEAD1) in a histone demethylation-dependent manner. Subsequently, TEAD1 up-regulates GLUL transcriptionally. Pharmacological inhibition of GLUL by l-methionine sulfoximine not only repressed ccRCC lipid deposition and tumor growth but also enhanced the anticancer effects of everolimus. Thus, the PHF8-GLUL axis represents a potential therapeutic target for ccRCC treatment

Comprehensive Benefit Evaluation of Hybrid Pumped-Storage Power Stations Based on Improved Rank Correlation-Entropy Weight Method

Over the past decade, the growth of new power plants has become a trend, with new energy stations growing particularly fast. In order to solve the problem of electricity consumption, the development of hybrid pumped storage based on hydropower stations has become a focus, so it is necessary to evaluate and analyze its technical and economic characteristics. Based on the characteristics of pumped-storage power stations, this paper proposes a comprehensive benefit evaluation model for the functional, financial, and environmental benefits. The model uses the fuzzy Delphi method to improve the rank correlation analysis method and introduces the entropy weighting method, calculating the comprehensive weight of indicators by the subjective and objective combination weighting method. The fuzzy comprehensive evaluation method is used to establish a comprehensive evaluation model and calculate the comprehensive benefit evaluation grade of hybrid pumped-storage power plants. Finally, the practicality and validity of the evaluation model are verified through case studies, and the technical and economic characteristics and superiority of the hybrid pumped-storage power plants are analyzed based on the evaluation results

Comprehensive Benefit Evaluation of Hybrid Pumped-Storage Power Stations Based on Improved Rank Correlation-Entropy Weight Method

Over the past decade, the growth of new power plants has become a trend, with new energy stations growing particularly fast. In order to solve the problem of electricity consumption, the development of hybrid pumped storage based on hydropower stations has become a focus, so it is necessary to evaluate and analyze its technical and economic characteristics. Based on the characteristics of pumped-storage power stations, this paper proposes a comprehensive benefit evaluation model for the functional, financial, and environmental benefits. The model uses the fuzzy Delphi method to improve the rank correlation analysis method and introduces the entropy weighting method, calculating the comprehensive weight of indicators by the subjective and objective combination weighting method. The fuzzy comprehensive evaluation method is used to establish a comprehensive evaluation model and calculate the comprehensive benefit evaluation grade of hybrid pumped-storage power plants. Finally, the practicality and validity of the evaluation model are verified through case studies, and the technical and economic characteristics and superiority of the hybrid pumped-storage power plants are analyzed based on the evaluation results

Allele-specific binding of RNA-binding proteins reveals functional genetic variants in the RNA.

Allele-specific protein-RNA binding is an essential aspect that may reveal functional genetic variants (GVs) mediating post-transcriptional regulation. Recently, genome-wide detection of in vivo binding of RNA-binding proteins is greatly facilitated by the enhanced crosslinking and immunoprecipitation (eCLIP) method. We developed a new computational approach, called BEAPR, to identify allele-specific binding (ASB) events in eCLIP-Seq data. BEAPR takes into account crosslinking-induced sequence propensity and variations between replicated experiments. Using simulated and actual data, we show that BEAPR largely outperforms often-used count analysis methods. Importantly, BEAPR overcomes the inherent overdispersion problem of these methods. Complemented by experimental validations, we demonstrate that the application of BEAPR to ENCODE eCLIP-Seq data of 154 proteins helps to predict functional GVs that alter splicing or mRNA abundance. Moreover, many GVs with ASB patterns have known disease relevance. Overall, BEAPR is an effective method that helps to address the outstanding challenge of functional interpretation of GVs

Allele-specific binding of RNA-binding proteins reveals functional genetic variants in the RNA

Differential binding of RNA-binding proteins mediated by genetic variants (GVs) can influence posttranscriptional regulation. Here, the authors develop BEAPR, a computational approach to identify allele-specific binding events in eCLIP-Seq data