Clinical features of NOTCH2NLC-related neuronal intranuclear inclusion disease.

BACKGROUND: Abnormal expanded GGC repeats within the NOTCH2HLC gene has been confirmed as the genetic mechanism for most Asian patients with neuronal intranuclear inclusion disease (NIID). This cross-sectional observational study aimed to characterise the clinical features of NOTCH2NLC-related NIID in China. METHODS: Patients with NOTCH2NLC-related NIID underwent an evaluation of clinical symptoms, a neuropsychological assessment, electrophysiological examination, MRI and skin biopsy. RESULTS: In the 247 patients with NOTCH2NLC-related NIID, 149 cases were sporadic, while 98 had a positive family history. The most common manifestations were paroxysmal symptoms (66.8%), autonomic dysfunction (64.0%), movement disorders (50.2%), cognitive impairment (49.4%) and muscle weakness (30.8%). Based on the initial presentation and main symptomology, NIID was divided into four subgroups: dementia dominant (n=94), movement disorder dominant (n=63), paroxysmal symptom dominant (n=61) and muscle weakness dominant (n=29). Clinical (42.7%) and subclinical (49.1%) peripheral neuropathies were common in all types. Typical diffusion-weighted imaging subcortical lace signs were more frequent in patients with dementia (93.9%) and paroxysmal symptoms types (94.9%) than in those with muscle weakness (50.0%) and movement disorders types (86.4%). GGC repeat sizes were negatively correlated with age of onset (r=-0.196, p<0.05), and in the muscle weakness-dominant type (median 155.00), the number of repeats was much higher than in the other three groups (p<0.05). In NIID pedigrees, significant genetic anticipation was observed (p<0.05) without repeat instability (p=0.454) during transmission. CONCLUSIONS: NIID is not rare; however, it is usually misdiagnosed as other diseases. Our results help to extend the known clinical spectrum of NOTCH2NLC-related NIID.

Mechanistic Insights Into Inflammation-Induced Arrhythmias: A Simulation Study.

Cardiovascular diseases are the primary cause of death of humans, and among these, ventricular arrhythmias are the most common cause of death. There is plausible evidence implicating inflammation in the etiology of ventricular fibrillation (VF). In the case of systemic inflammation caused by an overactive immune response, the induced inflammatory cytokines directly affect the function of ion channels in cardiomyocytes, leading to a prolonged action potential duration (APD). However, the mechanistic links between inflammatory cytokine-induced molecular and cellular influences and inflammation-associated ventricular arrhythmias need to be elucidated. The present study aimed to determine the potential impact of systemic inflammation on ventricular electrophysiology by means of multiscale virtual heart models. The experimental data on the ionic current of three major cytokines [i.e., tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1ß), and interleukin-6 (IL-6)] were incorporated into the cell model, and the effects of each cytokine and their combined effect on the cell action potential (AP) were evaluated. Moreover, the integral effect of these cytokines on the conduction of excitation waves was also investigated in a tissue model. The simulation results suggested that inflammatory cytokines significantly prolonged APD, enhanced the transmural and regional repolarization heterogeneities that predispose to arrhythmias, and reduced the adaptability of ventricular tissue to fast heart rates. In addition, simulated pseudo-ECGs showed a prolonged QT interval-a manifestation consistent with clinical observations. In summary, the present study provides new insights into ventricular arrhythmias associated with inflammation.

A Multi-Scale Computational Model for the Rat Ventricle: Construction, Parallelization, and Applications.

BACKGROUND: Cardiovascular diseases are the top killer of human beings. The ventricular arrhythmia, as a type of malignant cardiac arrhythmias, typically leads to death if not treated within minutes. The multi-scale virtual heart provides an idealized tool for exploring the underlying mechanisms, by means of incorporating abundant experimental data at the level of ion channels and analyzing the subsequent pathological changes at organ levels. However, there are few studies on building a virtual heart model for rats-a species most widely used in experiments. OBJECTIVE: To build a multi-scale computational model for rats, with detailed methodology for the model construction, computational optimization, and its applications. METHODS: First, approaches for building multi-scale models ranging from cellular to 3-D organ levels are introduced, with detailed descriptions of handling the ventricular myocardium heterogeneity, geometry processing, and boundary conditions, etc. Next, for dealing with the expensive computational costs of 3-D models, optimization approaches including an optimized representation and a GPU-based parallelization method are introduced. Finally, methods for reproducing of some key phenomenon (e.g., electrocardiograph, spiral/scroll waves) are demonstrated. RESULTS: Three types of heterogeneity, including the transmural heterogeneity, the interventricular heterogeneity, and the base-apex heterogeneity are incorporated into the model. The normal and reentrant excitation waves, as well as the corresponding pseudo-ECGs are reproduced by the constructed ventricle model. In addition, the temporal and spatial vulnerability to reentry arrhythmias are quantified based on the evaluation experiments of vulnerable window and the critical length. CONCLUSIONS: The constructed multi-scale rat ventricle model is able to reproduce both the physiological and the pathological phenomenon in different scales. Evaluation experiments suggest that the apex is the most susceptible area to arrhythmias. The model can be a promising tool for the investigation of arrhythmogenesis and the screening of anti-arrhythmic drugs.

Neuroprotective effect of angiotensin-(1-7) against rotenone-induced oxidative damage in CATH.a neurons.

There is evidence to support that ROSs are increased in Parkinson's disease (PD). Our recent research showed that angiotensin II (Ang II) participated in the pathogenesis of PD by triggering oxidative stress. Angiotensin-(1-7)[Ang-(1-7)] has been shown to moderate the adverse effects of the Ang II in many diseases. The purpose of the present study was to determine whether the Ang-(1-7) could have similar effects in CATH.a neurons. We used rotenone-induced neuron injury models to evaluate changes in cultured CATH.a cell lines levels of SOD, GSH and ROS. We also evaluated the expression of AT1, AT2, Mas receptors and Nox1, Nox2, P47phox, Hsp70 in treated with PBS, rotenone, Ang-(1-7), or Mas receptor antagonist A-779, alone and combined. The qRT-PCR and western blot were used to detect mRNA and protein levels of the AT1, AT2, Mas receptors and Nox1, Nox2, P47phox, Hsp70. The levels of SOD and GSH were determined by using commercial kits. The ROS generation was measured by the fluorescent probe assay. Ang-(1-7) in our current study significantly decreased rotenone-induced oxidative damage and increased the SOD and GSH generation. In addition, Ang-(1-7) significantly elevated Mas receptor expression and reduced NADPH oxidase activation, and these effects were completely eliminated by the A-779. Our findings suggest that Ang-(1-7) attenuates rotenone-induced oxidative damage in CATH.a neurons by activating the Mas receptor expression and inhibiting NADPH oxidase.

Modeling and Optimizing the Synthesis of Urea-formaldehyde Fertilizers and Analyses of Factors Affecting these Processes.

Previous research into the synthesis of urea-formaldehyde fertilizers was mostly based on orthogonal experimental designs or single factor tests; this led to low precision for synthesis and relatively large ranges of parameters for these processes. To obtain mathematical response models for the synthesis of urea-formaldehyde fertilizers with different nitrogen release properties, a central composite design (CCD) of response surface methodology was used in our research to examine the effects of different reaction times, temperatures, and molar ratios on nitrogen insoluble in either hot or cold water. Our results showed that nitrogen insoluble in cold or hot water from urea-formaldehyde fertilizers were mainly affected by urea: formaldehyde molar ratios. Also, quadratic polynomial mathematical models were established for urea-formaldehyde. According to the models, the optimal process parameters which maximize cold-water-insoluble nitrogen and minimize hot-water-insoluble nitrogen for the synthesis of urea formaldehyde were as follows urea: formaldehyde molar ratio was 1.33, reaction temperature was 43.5 °C, and reaction time was 1.64 h. Under these conditions, the content of cold-water-insoluble nitrogen was 22.14%, and hot-water-insoluble nitrogen was 9.87%. The model could be an effective tool for predicting properties of urea-formaldehyde slow release fertilizers if the experimental conditions were held within the design limits.

The expression of angiotensin-converting enzyme 2-angiotensin-(1-7)-Mas receptor axis are upregulated after acute cerebral ischemic stroke in rats.

There is now unequivocal evidence that the angiotensin-converting enzyme 2(ACE2)-Ang-(1-7)-Mas axis is a key component of the renin-angiotensin system (RAS) cascade, which is closely correlated with ischemic insult occurrence. Our previous studies demonstrated that the Ang-(1-7), was an active member of the brain RAS. However, the ACE2-Ang-(1-7)-Mas axis expression after cerebral ischemic injury are currently unclear. In the present study, we investigated the time course of ACE2-Ang-(1-7) and Mas receptor expression in the acute stage of cerebral ischemic stroke. The content of Ang-(1-7) in ischemic tissues and blood serum was measured by specific EIA kits. Real-time PCR and western blot were used to determine messenger RNA (mRNA) and protein levels of the ACE2 and Mas. The cerebral ischemic lesion resulted in a significant increase of regional cerebral and circulating Ang-(1-7) at 6-48 h compared with sham operation group following focal ischemic stroke (12h: 7.276±0.320 ng/ml vs. 2.466±0.410 ng/ml, serum; 1.024±0.056 ng/mg vs. 0.499±0.032, brain) (P<0.05). Both ACE2 and Mas expression were markedly enhanced compared to the control in the ischemic tissues (P<0.05). Mas immunopositive neurons were also seen stronger expression in the ischemic cortex (19.167±2.858 vs. 7.833±2.483) (P<0.05). The evidence collected in our present study will indicate that, ACE2-Ang-(1-7)-Mas axis are upregulated after acute ischemic stroke and would play a pivotal role in the regulation of acute neuron injury in ischemic cerebrovascular diseases.

Indirubin-3'-monoxime inhibits beta-amyloid-induced neurotoxicity in neuroblastoma SH-SY5Y cells.

Increasing evidence suggests that the inappropriate activation of cyclin-dependent kinases (CDKs) could induce neuronal apoptosis in Alzheimer's disease (AD), which means that the pharmacological inhibitors of cell-cycle progression may effectively impede the development or progression of AD. Indirubin-3'-monoxime (IMX), a known effective inhibitor of CDKs, has been shown to have therapeutic effects on learning and memory deficits induced by beta-amyloid (Abeta) intracerebroventricular infusion in rats. In the present study, we investigated the neuroprotective effects of IMX on Abeta(25-35)-induced neuronal apoptosis and its potential mechanisms in human neuroblastoma SH-SY5Y cells. Abeta(25-35)-induced apoptosis, characterized by decreased cell viability, neuronal DNA condensation, and fragmentation, was associated with an increase in tau protein hyperphosphorylation. IMX, however, attenuated Abeta(25-35)-induced cell death in a dose-dependent manner. Furthermore, expression of hyperphosphorylation tau protein was significantly decreased with IMX treatment. Our study suggests that IMX may usefully prevent or delay the neuronal loss of AD.

Self-assembling short oligopeptides and the promotion of angiogenesis.

Because an adequate blood supply to and within tissues is an essential factor for successful tissue regeneration, promoting a functional microvasculature is a crucial factor for biomaterials. In this study, we demonstrate that short self-assembling peptides form scaffolds that provide an angiogenic environment promoting long-term cell survival and capillary-like network formation in three-dimensional cultures of human microvascular endothelial cells. Our data show that, in contrast to collagen type I, the peptide scaffold inhibits endothelial cell apoptosis in the absence of added angiogenic factors, accompanied by enhanced gene expression of the angiogenic factor VEGF. In addition, our results suggest that the process of capillary-like network formation and the size and spatial organization of cell networks may be controlled through manipulation of the scaffold properties, with a more rigid scaffold promoting extended structures with a larger inter-structure distance, as compared with more dense structures of smaller size observed in a more compliant scaffold. These findings indicate that self-assembling peptide scaffolds have potential for engineering vascularized tissues with control over angiogenic processes. Since these peptides can be modified in many ways, they may be uniquely valuable in regeneration of vascularized tissues.