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Parkinson's disease (PD) is a common neurodegenerative disease characterized by motor symptoms and non-motor symptoms, and affects millions of people worldwide. Growing evidence implies β-Hydroxybutyrate (BHB), one of the ketone bodies generated by ketogenesis, plays a neuroprotective role in neurodegenerative diseases. We aimed to verify the anti-inflammatory effect of BHB on PD and further explore potential molecular mechanisms.We performed the experiments on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice model in vivo and 1-methyl-4-phenylpyridinium (MPPBHB treatment reversed motor deficits, loss of dopaminergic neurons and glial cell activation in PD mice induced by MPTP. Moreover, BHB inhibited microglia pyroptosis by negatively regulating STAT3/NLRP3/GSDMD signal pathway, resulting in downregulation of proinflammatory cytokines (IL-1β and IL-18) in vivo and vitro.These data suggested BHB supplement inhibited pyroptosis by down-regulating STAT3-mediated NLRP3 inflammasome activation for PD models in vivo and in vitro. Our findings provided novel insights and available interventions for the prevention and treatment of PD, and highlighted pyroptosis as a potential therapeutic target for PD.

Conductive scaffolds are of great value for constructing functional myocardial tissues and promoting tissue reconstruction in the treatment of myocardial infarction (MI). Here, a novel scaffold composed of silk fibroin and polypyrrole (SP50) with a typical sponge-like porous structure and electrical conductivity similar to the native myocardium is developed. An electroactive engineered cardiac patch (SP50 ECP) with a certain thickness is constructed by applying electrical stimulation (ES) to the cardiomyocytes (CMs) on the scaffold. SP50 ECP can significantly express cardiac marker protein (α-actinin, Cx-43, and cTnT) and has better contractility and electrical coupling performance. Following in vivo transplantation, SP50 ECP shows a notable therapeutic effect in repairing infarcted myocardium. Not only can SP50 ECP effectively improves left ventricular remodeling and restore cardiac functions, such as ejection function (EF), but more importantly, improves the propagation of electrical pulses and promote the synchronous contraction of CMs in the scar area with normal myocardium, effectively reducing the susceptibility of MI rats to arrhythmias. In conclusion, this study demonstrates a facile approach to constructing electroactive ECPs based on porous conductive scaffolds and proves the therapeutic effects of ECPs in repairing the infarcted heart, which may represent a promising strategy for MI treatment.

While endogenous lipids are known to exhibit rhythmic oscillations, less is known about how specific lipids modulate circadian behavior. Through a series of loss-of-function and gain-of-function experiments on ceramide phosphoethanolamine (CPE) synthase of Drosophila, we demonstrated that pan-glial-specific deficiency in membrane CPE, the structural analog of mammalian sphingomyelin (SM), leads to arrhythmic locomotor behavior and shortens lifespan, while the reverse is true for increasing CPE. Comparative proteomics uncovered dysregulated synaptic glutamate utilization and transport in CPE-deficient flies. An extensive genetic screen was conducted to verify the role of differentially expressed proteins in circadian regulation. Arrhythmic locomotion under cpes1 mutant background was rescued only by restoring endogenous CPE or SM through expressing their respective synthases. Our results underscore the essential role of CPE in maintaining synaptic glutamate homeostasis and modulating circadian behavior in Drosophila. The findings suggest that region-specific elevations of functional membrane lipids can benefit circadian regulation.

Whole organ or tissue decellularized matrices are a promising scaffold for tissue engineering because they maintain the specific memory of the original organ or tissue. A whole organ or tissue decellularized matrix contains extracellular matrix (ECM) components, and exhibits ultrastructural and mechanical properties, which could significantly regulate the fate of stem cells. To better understand the memory function of whole organ decellularized matrices, we constructed a heart decellularized matrix and seeded cross-embryonic layer stem cells - neural stem cells (NSCs) to repopulate the matrix, engineering cardiac tissue, in which a large number of NSCs differentiated into the neural lineage, but besides that, NSCs showed an obvious tendency of trans-differentiating into cardiac lineage cells. The results demonstrated that the whole heart decellularized microenvironment possesses memory function. To reveal the underlying mechanism, TMT-based quantitative proteomics analysis was used to identify the differently expressed proteins in the whole heart decellularized matrix compared with a brain decellularized matrix. 937 of the proteins changed over 1.5 fold, with 573 of the proteins downregulated and 374 of the proteins upregulated, among which integrin ligands in the ECM serve as key signals in regulating NSC fate. The findings here provide a novel insight into the memory function of tissue-specific microenvironments and pave the way for the therapeutic application of personalized tissues.

The ketogenic diet (KD) is a low-carbohydrate, high-fat and adequate-protein diet. As a diet mimicking fasting, it triggers the production of ketone bodies (KBs) and brings the body into a state of ketosis. Recent and accumulating studies on humans and animal models have shown that KD is beneficial to neurodegenerative diseases through modulating central and peripheral metabolism, mitochondrial function, inflammation, oxidative stress, autophagy, and the gut microbiome. Complicated interplay of metabolism, gut microbiome, and other mechanisms can regulate neuroinflammation in neurodegenerative diseases by activating multiple molecular and cellular pathways. In this review, we detail the physiological basis of the KD, its functions in regulating neuroinflammation, and its protective role in normal brain aging and neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). We aimed to elucidate the underlying neuroinflammatory mechanisms of KD therapies in neurodegenerative diseases and provide novel insights into their application for neurodegenerative disease prevention and treatment.

Parkinson’s disease (PD) is a common neurodegenerative disease, and the mechanism underlying PD pathogenesis is not completely understood. Increasing evidence indicates that microRNAs (miRNAs) play a critical regulatory role in the pathogenesis of PD. This study aimed to explore the miRNA-mRNA regulatory network for PD. The differentially expressed miRNAs (DEmis) and genes (DEGs) between PD patients and healthy donors were screened from the miRNA dataset GSE16658 and mRNA dataset GSE100054 downloaded from the Gene Expression Omnibus (GEO) database. Target genes of the DEmis were selected when they were predicted by three or four online databases and overlapped with DEGs from GSE100054. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were then conducted by Database for Annotation, Visualization and Integrated Discovery (DAVID) and Metascape analytic tools. The correlation between the screened genes and PD was evaluated with the online tool Comparative Toxicogenomics Database (CTD), and protein-protein interaction (PPI) networks were built by the STRING platform. We further investigated the expression of genes in the miRNA-mRNA regulatory network in blood samples collected from PD patients and healthy donors via qRT-PCR. We identified 1505 upregulated and 1302 downregulated DEGs, and 77 upregulated and 112 downregulated DEmis were preliminarily screened from the GEO database. Further functional enrichment analysis identified 10 PD-related hub genes, including RAC1, IRS2, LEPR, PPARGC1A, CAMKK2, RAB10, RAB13, RAB27B, RAB11A, and JAK2, which were mainly involved in Rab protein signaling transduction, AMPK signaling pathway, and signaling by Leptin. A miRNA-mRNA regulatory network was then constructed with 10 hub genes, and their interacting miRNAs overlapped with DEmis, including miR-30e-5p, miR-142-3p, miR-101-3p, miR-32-3p, miR-508-5p, miR-642a-5p, miR-19a-3p, and miR-21-5p. Analysis of clinical samples verified significant upregulation of LEPR and downregulation of miR-101-3p and miR-30e-5p in PD patients as compared with healthy donors. Thus, the miRNA-mRNA regulatory network was initially constructed and has the potential to provide novel insights into the pathogenesis and treatment of PD.

Objective Dementia with Lewy bodies (DLB) is a common type of neurodegenerative dementia. Molecular neuroimaging using dopamine transporter (DaT), Pittsburgh compound B (PIB), and fluorodeoxyglucose (FDG) positron emission tomography (PET) has advantages in detecting dopaminergic neuron loss, abnormal amyloid β-protein deposition, and glucose metabolism changes in patients with neurodegenerative disorders. However, the multi-modality molecular imaging features of patients with DLB have rarely been reported. Methods Five patients with a probable diagnosis of DLB were enrolled. PET/magnetic resonance imaging was performed with three tracers: 11C-β-CFT, 11C-PIB, and 18F-FDG. Clinical and imaging characteristics were analyzed. Results All patients with DLB showed reduced uptake in the bilateral putamen on DaT PET, increased uptake throughout the cerebral cortex on PIB PET, and intact metabolism of the posterior cingulate gyrus on FDG PET. Conclusion Multimodal molecular imaging is helpful for early diagnosis of DLB. Studies with larger sample sizes are needed to confirm the molecular imaging differences between DLB and Alzheimer’s disease and Parkinson’s disease dementia.

Human genetic studies support that loss-of-function mutations in theSH3 domain andankyrin repeat containing family proteins (SHANK1-3), the large synaptic scaffolding proteins enriched at the postsynaptic density of excitatory synapses, are causative for autism spectrum disorder and other neuropsychiatric disorders in humans. To better understand thein vivofunctions of Shank and facilitate dissection of neuropathology associated withSHANKmutations in human, we generated multiple mutations in theShankgene, the only member of the SHANK family inDrosophila melanogaster. Both male and femaleShanknull mutants were fully viable and fertile with no apparent morphological or developmental defects. Expression analysis revealed apparent enrichment of Shank in the neuropils of the CNS. Specifically, Shank coexpressed with another PSD scaffold protein, Homer, in the calyx of mushroom bodies in the brain. Consistent with high expression in mushroom body calyces,Shankmutants show an abnormal calyx structure and reduced olfactory acuity. These morphological and functional phenotypes were fully rescued by pan-neuronal reexpression of Shank, and only partially rescued by presynaptic but no rescue by postsynaptic reexpression of Shank. Our findings thus establish a previously unappreciated presynaptic function of Shank.SIGNIFICANCE STATEMENTMutations inSHANKfamily genes are causative for idiopathic autism spectrum disorder. To understand the neural function of Shank, a large scaffolding protein enriched at the postsynaptic densities, we examined the role ofDrosophilaShank in synapse development at the peripheral neuromuscular junctions and the central mushroom body calyx. Our results demonstrate that, in addition to its conventional postsynaptic function, Shank also acts presynaptically in synapse development in the brain. This study offers novel insights into the synaptic role of Shank.

The brain is the most metabolically active and complex organ in the human body, consisting of nearly 100 billion neurons and with over 100 trillion intricate connections. In order to maintain its intensive metabolic demands, the brain is highly vascularized, with nearly every neuron possessing its own capillary and total capillary length of nearly 400 miles. The integrity of the cerebral vascular system is accomplished through a vast vascular network of arteries, arterioles, capillaries, and veins which assure the continuous supply of oxygen and nutrients as well as provide a pathway for washing out metabolic waste products. Structural and functional integrity of blood vessels for adequate blood supply delivery is essential to maintain normal neurological function. A healthy neuronal-vascular relationship is critical for proper neurological processing, and vascular insults can consequentially initiate a cascade of molecular events which ultimately may result in neurodegeneration. Deterioration of brain functionality occurs progressively with advancing age, and an aged brain is consequently highly prone to neurodegenerative disorders. With increasing awareness of the importance of the neurovascular contribution to neurodegenerative disease, a better understanding of the contributory pathophysiological mechanisms is necessary. This chapter will cover the link between neurovascular dysfunction and neurodegeneration.

Cerebral microbleeds (CMBs) and lacunar infarcts are common manifestations of cerebral small vessel disease. However, the association between the location of CMBs and lacunar infarcts is unclear. Our study aimed to clarify the relationship between the location of CMBs and lacunar infarcts.This study retrospectively analyzed 166 patients with ischemic stroke or transient ischemic attacks admitted in the Geriatric Neurology Department of Chinese PLA General Hospital between February 2010 and December 2012. We collected clinical characteristics and risk factors of CMBs. The location of CMBs on T2*-weighted angiography was assessed by the Microbleed Anatomical Rating Scale. The number of lacunar infarcts and the severity of white matter hyperintensities were also recorded. The association between the location of CMBs and lacunar infarcts parameters was examined.CMBs were present in 77 (46.4%) patients. The presence [odds ratios (OR), 2.14; 95% confidence interval (CI), 1.02-4.48], number (OR, 1.17; 95% CI, 1.02-1.36 per lesion), severity (OR, 1.61; 95% CI, 1.07-2.42) of lacunar infarcts, and hypertension (OR, 5.76; 95% CI, 2.01-16.55) were independent risk factors for CMBs. Stratified by the location of CMBs, lobar CMBs and infratentorial CMBs did not show significant association with lacunar infarcts. Deep CMBs were significantly associated with the number (OR 1.18, 95% CI 1.03-1.36) and severity (OR 1.71, 95% CI 1.11-2.63) of lacunar infarcts. Moreover, the percentage of deep CMBs increased with the increased severity of lacunar infarcts (P = .003).Deep CMBs rather than lobar and infratentorial CMBs are associated with lacunar infarcts.

Gap junctions are widely distributed in the brains across species and play essential roles in neural information processing. However, the role of gap junctions in insect cognition remains poorly understood. Using a flight simulator paradigm and genetic tools, we found that gap junctions are present in Drosophila Kenyon cells (KCs), the major neurons of the mushroom bodies (MBs), and showed that they play an important role in visual learning and memory. Using a dye coupling approach, we determined the distribution of gap junctions in KCs. Furthermore, we identified a single pair of MB output neurons (MBONs) that possess a gap junction connection to KCs, and provide strong evidence that this connection is also required for visual learning and memory. Together, our results reveal gap junction networks in KCs and the KC-MBON circuit, and bring new insight into the synaptic network underlying fly’s visual learning and memory. DOI: http://dx.doi.org/10.7554/eLife.13238.001

Objective To investigate the clinical features of dementia with Lewy bodies (DLB) in a Chinese population. Methods Computer-based online searches through China Biology Medicine disc and China National Knowledge Infrastructure were performed to collect case reports of DLB published between 1980 and 2012. Clinical characteristics were analyzed. Results A total of 18 studies comprising 35 patients (26 males and 9 females) were included. The mean age at onset was 67.2 ± 9.8 years. Onset was characterized by memory impairment and accounted for 58.8% of all cases, followed by parkinsonism (11.8%), visual hallucinations (8.8%), and compulsive personality disorder (2.9%). The other patients (17.6%) presented two of the three core features of DLB at onset. With disease progression, parkinsonism was reported in 100% of cases, followed by visual hallucinations (97.1%), psychiatric symptoms (85.7%), severe neuroleptic sensitivity (81.8%), fluctuating cognition (68.6%), repeated falls (40.0%), sleep disorders (22.9%), and transient loss of consciousness (17.1%). 26 patients who were subjected to Mini-Mental State Examination scored ≤ 24. 10 patients presented relative preservation of hippocampus and medial temporal lobe structures on CT/MRI scan. Occipital hypometabolism occurred in 2 of 3 patients who underwent SPECT/PET perfusion scan. 12 patients showed an increasing of slow frequency activity on EEG, prominently in frontal and temporal lobes. Conclusions DLB often strikes elderly individuals. Its clinical core features are dementia, fluctuating cognition, recurrent visual hallucinations and spontaneous features of parkinsonism. Neuropsychological, neuroimaging and EEG examinations may improve the diagnostic accuracy and discriminate DLB from other dementias.

To investigate the risk factors for post-stroke pneumonia and assess the value of A(2)DS(2) score in predicting post-stroke pneumonia in elderly stroke patients.The clinical data were retrospectively collected from elderly stroke patients from January, 2007 to December, 2012. A(2)DS(2) score was then assigned using the clinical information from the medical record. The ability of the score to discriminate between patients with post-stroke pneumonia and those without was quantified using ROC analysis. The calibration of the score was analyzed using Hosmer-Lemeshow goodness-of-fit test.A total of 131 elderly male stroke patients were enrolled in this study, among whom the incidence of post-stroke pneumonia was 29.01%. The independent risk factors for post-stroke pneumonia identified included moderate (P=0.0081, OR: 5.6089; 95%CI: 1.5663-20.0854) and severe (P=0.0048, OR: 44.4827; 95%CI: 3.1847-621.3126) neurological impairment, dysphagia (P=0.0005, OR: 7.5265; 95%CI: 2.4282-23.3292), and atrial fibrillation (P=0.0226, OR: 4.1778; 95%CI: 1.2221-14.2825). The incidence of post-stroke pneumonia ranged from 2.2% in patients with a A(2)DS(2) score less than 3 to 75% in those with a score higher than 8. The C-statistic of A(2)DS(2) score for predicting post-stroke pneumonia was 0.86 (95%CI: 0.784-0.911) by the ROC analysis. The A(2)DS(2) score was well calibrated to predict post-stroke pneumonia in elderly patients by Hosmer-Lemeshow test (7.083, P=0.528).The A(2)DS(2) score can be useful for predicting post-stroke pneumonia and for routine monitoring of high-risk elderly stroke patients in the clinical setting.

Cerebral microbleeds (CMBs) and white matter hyperintensities (WMH) are the most common manifestations of small vessel disease, and often co-occur in patients with cerebral vascular disease. Hypertension is widely accepted as a risk factor for both CMBs and WMH. However, the effect of hypertension on the association between CMBs and WMH remains unclear. We hypothesized that the relationship between CMBs and WMH is determined by hypertension. One hundred forty-eight patients with acute cerebrovascular disease who were admitted to PLA general hospital in Beijing, China from February 2010 to May 2011 were recruited in this study. CMBs on T2*-weighted angiography (SWAN) were assessed using the Brain Observer Microbleed Rating Scale criteria. The severity of the WMH was separately assessed as either peri-ventricular hyperintensities (PVH) or deep white matter hyperintensities (DWMH). The association among CMBs and the severity of WMH, and hypertension were determined. CMBs were found in 65 (43.9%) patients. The frequency of CMBs was related to the severity of DWMH and PVH. CMBs were more frequently observed in patients with hypertension compared to patients without hypertension (51.3% vs. 20.0%, p = 0.001). Hypertension was an independent risk factor for CMBs (odds ratio 5.239, p = 0.001) and DWMH (odds ratio 2.373, p = 0.040). Furthermore, the relationship between the presence of CMBs and the severity of DWMH was only found in patients with hypertension (r = 0.298, p

The final goal of the paper is to establish a transient moisture equilibrium model for estimating the moisture in paper of the running oil-immersed transformer. To this end, the presented model for oil-paper insulation is improved according to the insulation structure of oil-immersed transformer. The moisture diffusion process is divided into three steps, i.e., between paper and oil, between support insulation and oil, and in oil. In order to improve the accuracy of the model, the added moisture due to ageing of paper insulation is also taken into account.