Potential Disease-Modifying Effects of Lithium Carbonate in Niemann-Pick Disease, Type C1

Background: Niemann-Pick disease type C1 (NP-C1) is a rare, autosomal-recessive neurodegenerative disorder with no United States Food and Drug Administration (FDA)-approved drug. Lithium has been shown to have considerable neuroprotective effects for neurological disorders such as bipolar disorder, Alzheimer’s disease and stroke and has been tested in many clinical trials. However, the pharmacological effect of lithium on NP-C1 neurodegenerative processes has not been investigated. The aim of this study was to provide an initial evaluation of the safety and feasibility of lithium carbonate in patients with NP-C1.Methods: A total of 13 patients diagnosed with NP-C1 who met the inclusion criteria received lithium orally at doses of 300, 600, 900, or 1,200 mg daily. The dose was reduced based on tolerance or safety observations. Plasma 7-ketocholesterol (7-KC), an emerging biomarker of NP-C1, was the primary endpoint. Secondary endpoints included NPC Neurological Severity Scores (NNSS) and safety.Results: Of the 13 patients with NP-C1 (12–33 years) enrolled, three withdrew (discontinuation of follow-up outpatient visits). The last observed post-treatment values of 7-KC concentrations (128 ng/ml, SEM 20) were significantly lower than pretreatment baselines values (185 ng/ml, SEM 29; p = 0.001). The mean NNSS was improved after lithium treatment at 12 months (p = 0.005). Improvement in swallowing capacity was observed in treated patients (p = 0.014). No serious adverse events were recorded in the patients receiving lithium.Conclusion: Lithium is a potential therapeutic option for NP-C1 patients. Larger randomized and double-blind clinical trials are needed to further support this finding.Clinical Trial Registration:ClinicalTrials.gov, NCT03201627

Secondary Voltage Collaborative Control of Distributed Energy System via Multi-Agent Reinforcement Learning

In this paper, a new voltage cooperative control strategy for a distributed power generation system is proposed based on the multi-agent advantage actor-critic (MA2C) algorithm, which realizes flexible management and effective control of distributed energy. The attentional actor-critic message processor (AACMP) is extended into the MA2C method to select the important messages from all communication messages adaptively and process important messages efficiently. The cooperative control strategy trained by centralized training and decentralized execution frame will take over the responsibility of the secondary control level for voltage restoration in a distributed manner. The introduction of the attention mechanism reduces the amount of information exchanged and the requirements of the communication network. Finally, a distributed system with six energy nodes is used to verify the effectiveness of the proposed control strategy

Secondary Voltage Collaborative Control of Distributed Energy System via Multi-Agent Reinforcement Learning

In this paper, a new voltage cooperative control strategy for a distributed power generation system is proposed based on the multi-agent advantage actor-critic (MA2C) algorithm, which realizes flexible management and effective control of distributed energy. The attentional actor-critic message processor (AACMP) is extended into the MA2C method to select the important messages from all communication messages adaptively and process important messages efficiently. The cooperative control strategy trained by centralized training and decentralized execution frame will take over the responsibility of the secondary control level for voltage restoration in a distributed manner. The introduction of the attention mechanism reduces the amount of information exchanged and the requirements of the communication network. Finally, a distributed system with six energy nodes is used to verify the effectiveness of the proposed control strategy

Myeloid-specific targeting of Notch ameliorates murine renal fibrosis via reduced infiltration and activation of bone marrow-derived macrophage

Abstract Macrophages play critical roles in renal fibrosis. However, macrophages exhibit ontogenic and functional heterogeneities, and which population of macrophages contributes to renal fibrosis and the underlying mechanisms remain unclear. In this study, we genetically targeted Notch signaling by disrupting the transcription factor recombination signal binding protein-Jκ (RBP-J), to reveal its role in regulation of macrophages during the unilateral ureteral obstruction (UUO)-induced murine renal fibrosis. Myeloid-specific disruption of RBP-J attenuated renal fibrosis with reduced extracellular matrix deposition and myofibroblast activation, as well as attenuated epithelial-mesenchymal transition, likely owing to the reduced expression of TGF-β. Meanwhile, RBP-J deletion significantly hampered macrophage infiltration and activation in fibrotic kidney, although their proliferation appeared unaltered. By using macrophage clearance experiment, we found that kidney resident macrophages made negligible contribution, but bone marrow (BM)-derived macrophages played a major role in renal fibrogenesis. Further mechanistic analyses showed that Notch blockade reduced monocyte emigration from BM by down-regulating CCR2 expression. Finally, we found that myeloid-specific Notch activation aggravated renal fibrosis, which was mediated by CCR2+ macrophages infiltration. In summary, our data have unveiled that myeloid-specific targeting of Notch could ameliorate renal fibrosis by regulating BM-derived macrophages recruitment and activation, providing a novel strategy for intervention of this disease

Characterization, phylogenetic analysis, and pathogenicity of a novel genotype 2 porcine Enterovirus G

Enterovirus G belongs to the family Picornaviridae and are associated with a variety of animal diseases. We isolated and characterized a novel EV-G2 strain, CHN-SCMY2021, the first genotype 2 strain isolated in China. CHN-SCMY2021 is about 25 nm diameter with morphology typical of picornaviruses and its genome is 7341 nucleotides. Sequence alignment and phylogenetic analysis based on VP1 indicated that this isolate is a genotype 2 strain. The whole genome similarity between CHN-SCMY2021 and other EV-G genotype 2 strains is 78.3–86.4%, the greatest similarity is to EVG/Porcine/JPN/Iba26–506/2014/G2 (LC316792.1). Recombination analysis indicated that CHN-SCMY2021 resulted from recombination between 714,171/CaoLanh_VN (KT265894.2) and LP 54 (AF363455.1). Except for ST cells, CHN-SCMY2021 has a broad spectrum of cellular adaptations, which are susceptible to BHK-21, PK-15, IPEC-J2, LLC-PK and Vero cells. In piglets, CHN-SCMY2021 causes mild diarrhea and thinning of the intestinal wall. The virus was mainly distributed to intestinal tissue but was also found in heart, liver, spleen, lung, kidney, brain, and spinal cord. CHN-SCMY2021 is the first systematically characterized EV-G genotype 2 strain from China, our results enrich the information on the epidemiology, molecular evolution and pathogenicity associated with EV-G

Inhibition effect of enteropeptidase on RANKL–RANK signalling by cleavage of RANK

AbstractEnteropeptidase can cleave trypsinogen on the sequence of Asp-Asp-Asp-Asp-Lys and plays an important role in food digestion. The RANKL–RANK signalling pathway plays a pivotal role in bone remodelling. In this study, we reported that enteropeptidase can inhibit the RANKL–RANK signalling pathway through the cleavage of RANK. A surrogate peptide blocking assay indicated that enteropeptidase could specifically cleave RANK on the sequence NEEDK. Osteoclast differentiation assay and NF-κB activity assay confirmed that enteropeptidase could inhibit osteoclastogenesis in vitro through the cleavage of RANK. This is the first study to prove that the RANKL–RANK signalling pathway can be inhibited by cleavage of RANK instead of targeting RANKL.Structured summary of protein interactionsEP cleaves hRANK by cleavage assay (View interaction)EP cleaves mRANK by cleavage assay (View interaction

Porcine Deltacoronavirus (PDCoV) Entry into PK-15 Cells by Caveolae-Mediated Endocytosis

(1) Background: Porcine deltacoronavirus (PDCoV) is a newly emerged enteric virus affecting pig breeding industries worldwide, and its pathogenic mechanism remains unclear. (2) Methods: In this study, we preliminarily identified the endocytic pathway of PDCoV in PK-15 cells, using six chemical inhibitors (targeting clathrin-mediated endocytosis, caveolae-mediated endocytosis, macropinocytosis pathway and endosomal acidification), overexpression of dominant-negative (DN) mutants to treat PK-15 cells and proteins knockdown. (3) Results: The results revealed that PDCoV entry was not affected after treatment with chlorpromazine (CPZ), 5-(N-ethyl-N-isopropyl) amiloride (EIPA)or ammonium chloride (NH4Cl), indicating that the entry of PDCoV into PK-15 cells were clathrin-, micropinocytosis-, PH-independent endocytosis. Conversely, PDCoV infection was sensitive to nystatin, dynasore and methyl-β-cyclodextrin (MβCD) with reduced PDCoV internalization, indicating that entry of PDCoV into PK-15 cells was caveolae-mediated endocytosis that required dynamin and cholesterol; indirect immunofluorescence and shRNA interference further validated these results. (4) Conclusions: In conclusion, PDCoV entry into PK-15 cells depends on caveolae-mediated endocytosis, which requires cholesterol and dynamin. Our finding is the first initial identification of the endocytic pathway of PDCoV in PK-15 cells, providing a theoretical basis for an in-depth understanding of the pathogenic mechanism of PDCoV and the design of new antiviral targets