GDF11 slows excitatory neuronal senescence and brain ageing by repressing p21.

As a major neuron type in the brain, the excitatory neuron (EN) regulates the lifespan in C. elegans. How the EN acquires senescence, however, is unknown. Here, we show that growth differentiation factor 11 (GDF11) is predominantly expressed in the EN in the adult mouse, marmoset and human brain. In mice, selective knock-out of GDF11 in the post-mitotic EN shapes the brain ageing-related transcriptional profile, induces EN senescence and hyperexcitability, prunes their dendrites, impedes their synaptic input, impairs object recognition memory and shortens the lifespan, establishing a functional link between GDF11, brain ageing and cognition. In vitro GDF11 deletion causes cellular senescence in Neuro-2a cells. Mechanistically, GDF11 deletion induces neuronal senescence via Smad2-induced transcription of the pro-senescence factor p21. This work indicates that endogenous GDF11 acts as a brake on EN senescence and brain ageing.

Inhibition of RIPK1 by ZJU-37 promotes oligodendrocyte progenitor proliferation and remyelination via NF-κB pathway.

Receptor interacting serine/threonine protein kinase 1 (RIPK1) activation and necroptosis have been genetically and mechanistically linked with human multiple sclerosis and neurodegenerative diseases for which demyelination is a common key pathology. Demyelination can be healed through remyelination which is mediated by new oligodendrocytes derived from the adult oligodendrocyte progenitor cells (OPCs). Unfortunately, the efficiency of remyelination declines with progressive aging partially due to the depletion of OPCs following chronic or repeated demyelination. However, to our knowledge, so far there is no drug which enhances proliferation of OPCs, and it is unknown whether inhibiting RIPK1 activity directly affect OPCs, the central player of remyelination. Using TNFα induced RIPK1-dependent necroptosis in Jurkat FADD-/- cells as a cell death assay, we screened from 2112 FDA-approved drugs and the drug candidates of new RIPK1 inhibitors selected by ourselves, and identified ZJU-37, a small molecule modified by introducing an amide bond to Nec-1s, is a new RIPK1 kinase inhibitor with higher potency than Nec-1s which has the best reported potency. We unveil in addition to protecting myelin from demyelination and axons from degeneration, ZJU-37 exhibits a new role on promoting proliferation of OPCs and enhancing remyelination by inhibiting RIPK1 kinase activity with higher potency than Nec-1s. Mechanistically, ZJU-37 promotes proliferation of OPCs by enhancing the transcription of platelet derived growth factor receptor alpha via NF-κB pathway. This work identifies ZJU-37 as a new drug candidate which enhances remyelination by promoting proliferation of OPCs, paving the way for a potential drug to enhance myelin repair.

Impaired metabolism of oligodendrocyte progenitor cells and axons in demyelinated lesion and in the aged CNS.

The key pathology of multiple sclerosis (MS) comprises demyelination, axonal damage, and neuronal loss, and when MS develops into the progressive phase it is essentially untreatable. Identifying new targets in both axons and oligodendrocyte progenitor cells (OPCs) and rejuvenating the aged OPCs holds promise for this unmet medical need. We summarize here the recent evidence showing that mitochondria in both axons and OPCs are impaired, and lipid metabolism of OPCs within demyelinated lesion and in the aged CNS is disturbed. Given that emerging evidence shows that rewiring cellular metabolism regulates stem cell aging, to protect axons from degeneration and promote differentiation of OPCs, we propose that restoring the impaired metabolism of both OPCs and axons in the aged CNS in a synergistic way could be a promising strategy to enhance remyelination in the aged CNS, leading to novel drug-based approaches to treat the progressive phase of MS.

Restoring nuclear entry of Sirtuin 2 in oligodendrocyte progenitor cells promotes remyelination during ageing.

The age-dependent decline in remyelination potential of the central nervous system during ageing is associated with a declined differentiation capacity of oligodendrocyte progenitor cells (OPCs). The molecular players that can enhance OPC differentiation or rejuvenate OPCs are unclear. Here we show that, in mouse OPCs, nuclear entry of SIRT2 is impaired and NAD+ levels are reduced during ageing. When we supplement ß-nicotinamide mononucleotide (ß-NMN), an NAD+ precursor, nuclear entry of SIRT2 in OPCs, OPC differentiation, and remyelination were rescued in aged animals. We show that the effects on myelination are mediated via the NAD+-SIRT2-H3K18Ac-ID4 axis, and SIRT2 is required for rejuvenating OPCs. Our results show that SIRT2 and NAD+ levels rescue the aged OPC differentiation potential to levels comparable to young age, providing potential targets to enhance remyelination during ageing.

Neutralization of Hv1/HVCN1 With Antibody Enhances Microglia/Macrophages Myelin Clearance by Promoting Their Migration in the Brain.

Microglia dynamically monitor the microenvironment of the central nervous system (CNS) by constantly extending and retracting their processes in physiological conditions, and microglia/macrophages rapidly migrate into lesion sites in response to injuries or diseases in the CNS. Consequently, their migration ability is fundamentally important for their proper functioning. However, the mechanisms underlying their migration have not been fully understood. We wonder whether the voltage-gated proton channel HVCN1 in microglia/macrophages in the brain plays a role in their migration. We show in this study that in physiological conditions, microglia and bone marrow derived macrophage (BMDM) express HVCN1 with the highest level among glial cells, and upregulation of HVCN1 in microglia/macrophages is presented in multiple injuries and diseases of the CNS, reflecting the overactivation of HVCN1. In parallel, myelin debris accumulation occurs in both the focal lesion and the site where neurodegeneration takes place. Importantly, both genetic deletion of the HVCN1 gene in cells in vitro and neutralization of HVCN1 with antibody in the brain in vivo promotes migration of microglia/macrophages. Furthermore, neutralization of HVCN1 with antibody in the brain in vivo promotes myelin debris clearance by microglia/macrophages. This study uncovers a new role of HVCN1 in microglia/macrophages, coupling the proton channel HVCN1 to the migration of microglia/macrophages for the first time.

Loss of Growth Differentiation Factor 11 Shortens Telomere Length by Downregulating Telomerase Activity.

Maintenance of telomere length is essential to delay replicative cellular senescence. It is controversial on whether growth differentiation factor 11 (GDF11) can reverse cellular senescence, and this work aims to establish the causality between GDF11 and the telomere maintenance unequivocally. Using CRISPR/Cas9 technique and a long-term in vitro culture model of cellular senescence, we show here that in vitro genetic deletion of GDF11 causes shortening of telomere length, downregulation of telomeric reverse transcriptase (TERT) and telomeric RNA component (TERC), the key enzyme and the RNA component for extension of the telomere, and reduction of telomerase activity. In contrast, both recombinant and overexpressed GDF11 restore the transcription of TERT in GDF11KO cells to the wild-type level. Furthermore, loss of GDF11-induced telomere shortening is likely caused by enhancing the nuclear entry of SMAD2 which inhibits the transcription of TERT and TERC. Our results provide the first proof-of-cause-and-effect evidence that endogenous GDF11 plays a causal role for proliferative cells to maintain telomere length, paving the way for potential rejuvenation of the proliferative cells, tissues, and organs.

Dataset for NiO/ZnO biomorphic nanocomposite using a poplar tree leaf template to generate an enhanced gas sensing platform to detect n-butanol.

The SEM image data presented in this article was collected by the Scanning electron microscopy (SEM) performed on an XL-30 ESEM FEG scanning electron microscopy. The diameter stastics data was collected and calculated by the Image-Pro Plus software system. The UV-Vis Res spectrum was collected by solid state UV diffuse reflector Shimadzu UV-4100 at wavelength 200-800 nm. The SEM image data showed more details of the poplar tree leave template(PTLT). The diameter stastics data show the diameter averagely distributed in the material. The UV-Vis Res spectrum reflected the physical property of PTLT NiO/ZnO. Interpretation of this data can be found in a research article titled "One-step facile synthesis of a NiO/ZnO biomorphic nanocomposite using a poplar tree leaf template to generate an enhanced gas sensing platform to detect n-butanol" (Qingrui Zeng et al., 2019) [1], Research Article DOI: 10.1016/j.jallcom.2019.05.018•The SEM image provide the more details about the distinction of the PTLT ZnO and conventional ZnO, further present more morphology information of the PTLT biotemplate. Exhibiting a facile and green way for synthesising ZnO and narrow down the size of ZnO crystal, present the advantage of PTLT ZnO in morphology control. Motivating gas sensor researcher to fabricate ZnO by a biotemplate method, which owned biomorphic and extraordinary gas sensing properties.•The UV-Vis Res spectrum present more detail of the energy band information of PTLT ZnO and PTLT NiO/ZnO, which is use for the gas sensing mechanism analysis. Inspiring researcher forcus on the construction on p-n heterojunction type gas sensor to enhance the gas sensing properties.•The material researchers work on the morphic investigation, gas sensor, and application of semiconductor.•These data are benefit for the application of biotemplate method for material fabrication and material application.

Integrated transcriptomic analysis reveals hub genes involved in diagnosis and prognosis of pancreatic cancer.

BACKGROUND: The hunt for the molecular markers with specificity and sensitivity has been a hot area for the tumor treatment. Due to the poor diagnosis and prognosis of pancreatic cancer (PC), the excision rate is often low, which makes it more urgent to find the ideal tumor markers. METHODS: Robust Rank Aggreg (RRA) methods was firstly applied to identify the differentially expressed genes (DEGs) between PC tissues and normal tissues from GSE28735, GSE15471, GSE16515, and GSE101448. Among these DEGs, the highly correlated genes were clustered using WGCNA analysis. The co-expression networks and molecular complex detection (MCODE) Cytoscape app were then performed to find the sub-clusters and confirm 35 candidate genes. For these genes, least absolute shrinkage and selection operator (lasso) regression model was applied and validated to build a diagnostic risk score model. Cox proportional hazard regression analysis was used and validated to build a prognostic model. RESULTS: Based on integrated transcriptomic analysis, we identified a 19 gene module (SYCN, PNLIPRP1, CAP2, GNMT, MAT1A, ABAT, GPT2, ADHFE1, PHGDH, PSAT1, ERP27, PDIA2, MT1H, COMP, COL5A2, FN1, COL1A2, FAP and POSTN) as a specific predictive signature for the diagnosis of PC. Based on the two consideration, accuracy and feasibility, we simplified the diagnostic risk model as a four-gene model: 0.3034*log2(MAT1A)-0.1526*log2(MT1H) + 0.4645*log2(FN1) -0.2244*log2(FAP), log2(gene count). Besides, a four-hub gene module was also identified as prognostic model = - 1.400*log2(CEL) + 1.321*log2(CPA1) + 0.454*log2(POSTN) + 1.011*log2(PM20D1), log2(gene count). CONCLUSION: Integrated transcriptomic analysis identifies two four-hub gene modules as specific predictive signatures for the diagnosis and prognosis of PC, which may bring new sight for the clinical practice of PC.

[Development of medical emergency response system for accidents due to chemicals in Chongqing municipality].

OBJECTIVE: To plan and develop a Chongqing chemical accident rescue command system. METHODS: Based on the modes of leakage and diffusion of various poisonous gases and chemicals, different modes of injuries produced, and their appropriate rescue and treatments, also taking the following factors such as the condition of storage of chemicals, meteorological and geographic conditions, medical institutions and equipment, and their rescuing capacity into consideration, a plan was drafted to establish the rescue system. Real-time simulation technology, data analysis, evaluation technology and database technology were employed in the planning. Using Visual Studio 6.0 as the software development platform, this project aimed to design the software of an emergency command system for chemical accidents in Chongqing which could be operated with the Windows 2000/XP operating system. RESULTS: This system provided a dynamic scope of the endangered area, casualty number estimates, and recommendation of measures and a rescue plan for various chemical accidents. Furthermore, the system helped retrieve comprehensive information regarding the physical and chemical characteristics of more than 4 200 dangerous poisonous chemicals and their appropriate treatment modalities. CONCLUSION: This system is easy to operate with a friendly interface, functions rapidly and can provide real-time analysis with comparatively precise results. This system could satisfy the requirements of executing the command and the rescue of a chemical accident with good prospects of application.