Advancing EEG/MEG Source Imaging with Geometric-Informed Basis Functions

Electroencephalography (EEG) and Magnetoencephalography (MEG) are pivotal in understanding brain activity but are limited by their poor spatial resolution. EEG/MEG source imaging (ESI) infers the high-resolution electric field distribution in the brain based on the low-resolution scalp EEG/MEG observations. However, the ESI problem is ill-posed, and how to bring neuroscience priors into ESI method is the key. Here, we present a novel method which utilizes the Brain Geometric-informed Basis Functions (GBFs) as priors to enhance EEG/MEG source imaging. Through comprehensive experiments on both synthetic data and real task EEG data, we demonstrate the superiority of GBFs over traditional spatial basis functions (e.g., Harmonic and MSP), as well as existing ESI methods (e.g., dSPM, MNE, sLORETA, eLORETA). GBFs provide robust ESI results under different noise levels, and result in biologically interpretable EEG sources. We believe the high-resolution EEG source imaging from GBFs will greatly advance neuroscience research

Regulation of the stability and transcriptional activity of NFATc4 by ubiquitination

AbstractNuclear factor of activated T cells (NFATc4) has been implicated as a critical regulator of the cardiac development and hypertrophy. However, the mechanisms for regulating NFATc4 stability and transactivation remain unclear. We showed that NFATc4 protein was predominantly ubiquitinated through the formation of Lysine 48-linked polyubiquitin chains, and this modification decreased NFATc4 protein levels and its transcriptional activity. Furthermore, activation of GSK3β markedly enhanced NFATc4 ubiquitination and decreased its transactivation, whereas inhibition of GSK3β had opposite effects. Importantly, ubiquitination and phosphorylation induced by GSK3β repressed NFATc4-dependent cardiac-specific gene expression. These results demonstrate that the ubiquitin–proteasome system plays an important role in regulating NFATc4 stability and transactivation.Structured summaryMINT-6798349:NFATc4 (uniprotkb:Q14934) physically interacts (MI:0218) with Ubiquitin (uniprotkb:P62988) by anti bait coimmunoprecipitation (MI:0006)MINT-6798334:NFATc4 (uniprotkb:Q14934) physically interacts (MI:0218) with Ubiquitin (uniprotkb:P62988) by anti tag coimmunoprecipitation (MI:0007)MINT-6798321:Ubiquitin (uniprotkb:P62988) physically interacts (MI:0218) with NFATc4 (uniprotkb:Q14934) by pull down (MI:0096

Proteases and Protease Inhibitors of Urinary Extracellular Vesicles in Diabetic Nephropathy

Diabetic nephropathy (DN) is one of the major complications of diabetes mellitus (DM), leads to chronic kidney disease (CKD), and, ultimately, is the main cause for end-stage kidney disease (ESKD). Beyond urinary albumin, no reliable biomarkers are available for accurate early diagnostics. Urinary extracellular vesicles (UEVs) have recently emerged as an interesting source of diagnostic and prognostic disease biomarkers. Here we used a protease and respective protease inhibitor array to profile urines of type 1 diabetes patients at different stages of kidney involvement. Urine samples were divided into groups based on the level of albuminuria and UEVs isolated by hydrostatic dialysis and screened for relative changes of 34 different proteases and 32 protease inhibitors, respectively. Interestingly, myeloblastin and its natural inhibitor elafin showed an increase in the normo- and microalbuminuric groups. Similarly, a characteristic pattern was observed in the array of protease inhibitors, with a marked increase of cystatin B, natural inhibitor of cathepsins L, H, and B as well as of neutrophil gelatinase-associated Lipocalin (NGAL) in the normoalbuminuric group. This study shows for the first time the distinctive alterations in comprehensive protease profiles of UEVs in diabetic nephropathy and uncovers intriguing mechanistic, prognostic, and diagnostic features of kidney damage in diabetes.Peer reviewe

Aggregate blood pressure responses to serial dietary sodium and potassium intervention: Defining responses using independent component analysis

BACKGROUND: Hypertension is a complex trait that often co-occurs with other conditions such as obesity and is affected by genetic and environmental factors. Aggregate indices such as principal components among these variables and their responses to environmental interventions may represent novel information that is potentially useful for genetic studies. RESULTS: In this study of families participating in the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) Study, blood pressure (BP) responses to dietary sodium interventions are explored. Independent component analysis (ICA) was applied to 20 variables indexing obesity and BP measured at baseline and during low sodium, high sodium and high sodium plus potassium dietary intervention periods. A “heat map” protocol that classifies subjects based on risk for hypertension is used to interpret the extracted components. ICA and heat map suggest four components best describe the data: (1) systolic hypertension, (2) general hypertension, (3) response to sodium intervention and (4) obesity. The largest heritabilities are for the systolic (64 %) and general hypertension (56 %) components. There is a pattern of higher heritability for the component response to intervention (40–42 %) as compared to those for the traditional intervention responses computed as delta scores (24 %–40 %). CONCLUSIONS: In summary, the present study provides intermediate phenotypes that are heritable. Using these derived components may prove useful in gene discovery applications. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12863-015-0226-8) contains supplementary material, which is available to authorized users

Linkage and linkage disequilibrium analysis of the lipoprotein lipase gene with lipid profiles in Chinese hypertensive families

A B S T R A C T Elevated TG [triacylglycerol (triglyceride)] is a significant independent risk factor for cardiovascular disease. LPL (lipoprotein lipase) is one of the key enzymes in the metabolism of the TG-rich lipoproteins which hydrolyses TG from the chylomicrons and very-LDL (low-density lipoprotein). To investigate the relationship between the LPL gene and lipid profiles, especially TG, in 148 hypertensive families, we have chosen seven flanking microsatellite markers and four internal markers of the LPL gene and conducted linkage analysis by SOLAR and S.A.G.E. (statistical analysis for genetic epidemiology)/SIBPAL 2 programs, and linkage disequilibrium analysis by QTDT (quantitative transmission/disequilibrium test) and GOLD (graphical overview of linkage disequilibrium). There were statistically significant differences in lipid levels between subjects without and with hypertension within families. A maximum LOD score of 1.3 with TG at the marker D8S261 was observed by SOLAR. Using S.A.G.E./SIBPAL 2, we identified a linkage with TG at the marker 'ATTT' located within intron 6 of the LPL gene (P = 0.0095). Two SNPs (single nucleotide polymorphisms), HindIII and HinfI, were found in linkage disequilibrium with LDLcholesterol levels (P = 0.0178 and P = 0.0088 respectively). A strong linkage disequilibrium was observed between the HindIII in intron 8 and HinfI in the exon 9 (P < 0.00001, D = 0.895). Linkage disequilibrium was also found between the 'ATTT' polymorphism in intron 6 and two SNPs (P = 0.0021 and D = 0.611 for HindIII; and P = 0.00004, D = 0.459 for HinfI). The present study in the Chinese families with hypertension suggested that the LPL gene might influence lipid levels, especially TG metabolism. Replication studies both in Chinese and other populations are warranted to confirm these results

Diabetes with kidney injury may change the abundance and cargo of urinary extracellular vesicles

BackgroundUrinary extracellular vesicles (uEVs) are derived from epithelia facing the renal tubule lumen in the kidney and urogenital tract; they may carry protein biomarkers of renal dysfunction and structural injury. However, there are scarce studies focusing on uEVs in diabetes with kidney injury.Materials and methodsA community-based epidemiological survey was performed, and the participants were randomly selected for our study. uEVs were enriched by dehydrated dialysis method, quantified by Coomassie Bradford protein assay, and adjusted by urinary creatinine (UCr). Then, they identified by transmission electron microscopy (TEM), nanoparticle track analysis (NTA), and western blot of tumor susceptibility gene 101.ResultsDecent uEVs with a homogeneous distribution were finally obtained, presenting a membrane-encapsulated structure like cup-shaped or roundish under TEM, having active Brownian motion, and presenting the main peak between 55 and 110 nm under NTA. The Bradford protein assay showed that the protein concentrations of uEVs were 0.02 ± 0.02, 0.04 ± 0.05, 0.05 ± 0.04, 0.07 ± 0.08, and 0.11 ± 0.15 μg/mg UCr, respectively, in normal controls and in prediabetes, diabetes with normal proteinuria, diabetes with microalbuminuria, and diabetes with macroproteinuria groups after adjusting the protein concentration with UCr by calculating the vesicles-to-creatinine ratio.ConclusionThe protein concentration of uEVs in diabetes with kidney injury increased significantly than the normal controls before and after adjusting the UCr. Therefore, diabetes with kidney injury may change the abundance and cargo of uEVs, which may be involved in the physiological and pathological changes of diabetes

C Terminus of Hsc70-interacting Protein Promotes Smooth Muscle Cell Proliferation and Survival through Ubiquitin-mediated Degradation of FoxO1

Forkhead transcription factors (FoxOs) play a pivotal role in controlling cellular proliferation and survival. The cellular level of these factors is tightly regulated through the phosphoinositide 3-kinase/Akt and ubiquitin-mediated degradation. However, the ubiquitin ligases responsible for the degradation of FoxO1 and the relevance of this regulation to smooth muscle cell (SMC) proliferation and survival have not been fully identified. Here we showed that overexpression of C terminus of Hsc70-interacting protein (CHIP) promoted ubiquitination and degradation of FoxO1 in SMCs in response to tumor necrosis factor-α. Both the U-box (containing ubiquitin ligase activity) and the charged (essential for FoxO1 binding) domains within CHIP were required for CHIP-mediated FoxO1 down-regulation. Moreover, interaction and ubiquitination of FoxO1 by CHIP depended on phos pho ryl a tion of FoxO1 at Ser-256. Furthermore, overexpression of CHIP repressed FoxO1-mediated transactivation and its proapo pto tic function following tumor necrosis factor-α treatment. In contrast, knockdown of CHIP by small interfering RNA enhanced FoxO1-mediated transactivation and its effect on SMC proliferation and survival. Taken together, our data indicate that CHIP is a negative regulator of FoxO1 activity through ubiquitin-mediated degradation, and inhibition of CHIP may serve as a potential therapeutic target for reducing proliferative arterial diseases

Yeast peptides alleviate lipopolysaccharide-induced intestinal barrier damage in rabbits involving Toll-like receptor signaling pathway modulation and gut microbiota regulation

IntroductionYeast peptides have garnered attention as valuable nutritional modifiers due to their potential health benefits. However, the precise mechanisms underlying their effects remain elusive. This study aims to explore the potential of yeast peptides, when added to diets, to mitigate lipopolysaccharide (LPS)-induced intestinal damage and microbiota alterations in rabbits.MethodsA total of 160 35-day-old Hyla line rabbits (0.96 ± 0.06 kg) were randomly assigned to 4 groups. These groups constituted a 2 × 2 factorial arrangement: basal diet (CON), 100 mg/kg yeast peptide diet (YP), LPS challenge + basal diet (LPS), LPS challenge +100 mg/kg yeast peptide diet (L-YP). The experiment spanned 35 days, encompassing a 7-day pre-feeding period and a 28-day formal trial.ResultsThe results indicated that yeast peptides mitigated the intestinal barrier damage induced by LPS, as evidenced by a significant reduction in serum Diamine oxidase and D-lactic acid levels in rabbits in the L-YP group compared to the LPS group (p < 0.05). Furthermore, in the jejunum, the L-YP group exhibited a significantly higher villus height compared to the LPS group (p < 0.05). In comparison to the LPS group, the L-YP rabbits significantly upregulated the expression of Claudin-1, Occludin-1 and ZO-1 in the jejunum (p < 0.05). Compared with the CON group, the YP group significantly reduced the levels of rabbit jejunal inflammatory cytokines (TNF-α, IL-1β and IL-6) and decreased the relative mRNA expression of jejunal signaling pathway-associated inflammatory factors such as TLR4, MyD88, NF-κB and IL-1β (p < 0.05). Additionally, notable changes in the hindgut also included the concentration of short-chain fatty acids (SCFA) of the YP group was significantly higher than that of the CON group (p < 0.05). 16S RNA sequencing revealed a substantial impact of yeast peptides on the composition of the cecal microbiota. Correlation analyses indicated potential associations of specific gut microbiota with jejunal inflammatory factors, tight junction proteins, and SCFA.ConclusionIn conclusion, yeast peptides have shown promise in mitigating LPS-induced intestinal barrier damage in rabbits through their anti-inflammatory effects, modulation of the gut microbiota, and maintenance of intestinal tight junctions

The future impact of population growth and aging on coronary heart disease in China: projections from the Coronary Heart Disease Policy Model-China

Background: China will experience an overall growth and aging of its adult population in coming decades. We used a computer model to forecast the future impact of these demographic changes on coronary heart disease (CHD) in China. Methods: The CHD Policy Model is a validated state-transition, computer simulation of CHD on a national scale. China-specific CHD risk factor, incidence, case-fatality, and prevalence data were incorporated, and a CHD prediction model was generated from a Chinese cohort study and calibrated to age-specific Chinese mortality rates. Disability-adjusted life years (DALYs) due to CHD were calculated using standard methods. The projected population of China aged 35–84 years was entered, and CHD events, deaths, and DALYs were simulated over 2000–2029. CHD risk factors other than age and case-fatality were held at year 2000 levels. Sensitivity analyses tested uncertainty regarding CHD mortality coding, the proportion of total deaths attributable to CHD, and case-fatality. Results: We predicted 7.8 million excess CHD events (a 69% increase) and 3.4 million excess CHD deaths (a 64% increase) in the decade 2020–2029 compared with 2000–2009. For 2030, we predicted 71% of almost one million annual CHD deaths will occur in persons ≥ 65 years old, while 67% of the growing annual burden of CHD death and disability will weigh on adults < 65 years old. Substituting alternate CHD mortality assumptions led to 17–20% more predicted CHD deaths over 2000–2029, though the pattern of increases in CHD events and deaths over time remained. Conclusion: We forecast that absolute numbers of CHD events and deaths will increase dramatically in China over 2010–2029, due to a growing and aging population alone. Recent data suggest CHD risk factor levels are increasing, so our projections may underestimate the extent of the potential CHD epidemic in China