A common landscape for membrane‐active peptides

Three families of membrane‐active peptides are commonly found in nature and are classified according to their initial apparent activity. Antimicrobial peptides are ancient components of the innate immune system and typically act by disruption of microbial membranes leading to cell death. Amyloid peptides contribute to the pathology of diverse diseases from Alzheimer's to type II diabetes. Preamyloid states of these peptides can act as toxins by binding to and permeabilizing cellular membranes. Cell‐penetrating peptides are natural or engineered short sequences that can spontaneously translocate across a membrane. Despite these differences in classification, many similarities in sequence, structure, and activity suggest that peptides from all three classes act through a small, common set of physical principles. Namely, these peptides alter the Brownian properties of phospholipid bilayers, enhancing the sampling of intrinsic fluctuations that include membrane defects. A complete energy landscape for such systems can be described by the innate membrane properties, differential partition, and the associated kinetics of peptides dividing between surface and defect regions of the bilayer. The goal of this review is to argue that the activities of these membrane‐active families of peptides simply represent different facets of what is a shared energy landscape.     

A Conserved Role for Atlastin GTPases in Regulating Lipid Droplet Size

1. Download : Download full-size image

     

Massively Parallel Sequencing Reveals the Complex Structure of an Irradiated Human Chromosome on a Mouse Background in the Tc1 Model of Down Syndrome

Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and presents a complex phenotype that arises from abnormal dosage of genes on this chromosome. However, the individual dosage-sensitive genes underlying each phenotype remain largely unknown. To help dissect genotype – phenotype correlations in this complex syndrome, the first fully transchromosomic mouse model, the Tc1 mouse, which carries a copy of human chromosome 21 was produced in 2005. The Tc1 strain is trisomic for the majority of genes that cause phenotypes associated with DS, and this freely available mouse strain has become used widely to study DS, the effects of gene dosage abnormalities, and the effect on the basic biology of cells when a mouse carries a freely segregating human chromosome. Tc1 mice were created by a process that included irradiation microcell-mediated chromosome transfer of Hsa21 into recipient mouse embryonic stem cells. Here, the combination of next generation sequencing, array-CGH and fluorescence in situ hybridization technologies has enabled us to identify unsuspected rearrangements of Hsa21 in this mouse model; revealing one deletion, six duplications and more than 25 de novo structural rearrangements. Our study is not only essential for informing functional studies of the Tc1 mouse but also (1) presents for the first time a detailed sequence analysis of the effects of gamma radiation on an entire human chromosome, which gives some mechanistic insight into the effects of radiation damage on DNA, and (2) overcomes specific technical difficulties of assaying a human chromosome on a mouse background where highly conserved sequences may confound the analysis. Sequence data generated in this study is deposited in the ENA database, Study Accession number: ERP000439.     

Noisy Galvanic Vestibular Stimulation Modulates the Amplitude of EEG Synchrony Patterns

Noisy galvanic vestibular stimulation has been associated with numerous cognitive and behavioural effects, such as enhancement of visual memory in healthy individuals, improvement of visual deficits in stroke patients, as well as possibly improvement of motor function in Parkinson’s disease; yet, the mechanism of action is unclear. Since Parkinson’s and other neuropsychiatric diseases are characterized by maladaptive dynamics of brain rhythms, we investigated whether noisy galvanic vestibular stimulation was associated with measurable changes in EEG oscillatory rhythms within theta (4–7.5 Hz), low alpha (8–10 Hz), high alpha (10.5–12 Hz), beta (13–30 Hz) and gamma (31–50 Hz) bands. We recorded the EEG while simultaneously delivering noisy bilateral, bipolar stimulation at varying intensities of imperceptible currents – at 10, 26, 42, 58, 74 and 90% of sensory threshold – to ten neurologically healthy subjects. Using standard spectral analysis, we investigated the transient aftereffects of noisy stimulation on rhythms. Subsequently, using robust artifact rejection techniques and the Least Absolute Shrinkage Selection Operator regression and cross-validation, we assessed the combinations of channels and power spectral features within each EEG frequency band that were linearly related with stimulus intensity. We show that noisy galvanic vestibular stimulation predominantly leads to a mild suppression of gamma power in lateral regions immediately after stimulation, followed by delayed increase in beta and gamma power in frontal regions approximately 20–25 s after stimulation ceased. Ongoing changes in the power of each oscillatory band throughout frontal, central/parietal, occipital and bilateral electrodes predicted the intensity of galvanic vestibular stimulation in a stimulus-dependent manner, demonstrating linear effects of stimulation on brain rhythms. We propose that modulation of neural oscillations is a potential mechanism for the previously-described cognitive and motor effects of vestibular stimulation, and noisy galvanic vestibular stimulation may provide an additional non-invasive means for neuromodulation of functional brain networks.     

Bioelectrical Impedance Vector Analysis (BIVA) in Slovak population: application in a clinical sample

The purpose of this study is to provide new data on body composition in the Slovak population, particularly impedance vector components according to sex and age, relevant for bioelectrical impedance vector analysis (BIVA) in a clinical sample. The reference sample consisted of 1543 apparently healthy individuals (1007 females and 536 males), aged from 18 to 92 years and of 60 patients with Parkinson’s disease (PD) (26 females and 34 males), aged from 40 to 81 years. Bioelectrical parameters of resistance (R) and reactance (Xc) were measured with a monofrequency analyser (BIA 101). BIVA was used to analyse tissue electric properties in control subjects and patients with PD. The mean vector position differed significantly between PD patients and healthy controls in males of age subgroups 60–69 years and 70–79 years, respectively. These results were conterminous with significant Hotelling’s T²-test; 60–69 y T²=7.8, P=0.024 and 70–79 y T²=7.6, P=0.026. In the RXc-score graph three patients had values outside the 95% ellipse. Altered tissue electric properties were present in 23.5% of males and 15.4% of females. Distribution of impedance vector components in different age categories of healthy Slovak subjects are relevant to comparative population studies and to clinical practice.     

Ammonium Accumulation and Cell Death in a Rat 3D Brain Cell Model of Glutaric Aciduria Type I

Glutaric aciduria type I (glutaryl-CoA dehydrogenase deficiency) is an inborn error of metabolism that usually manifests in infancy by an acute encephalopathic crisis and often results in permanent motor handicap. Biochemical hallmarks of this disease are elevated levels of glutarate and 3-hydroxyglutarate in blood and urine. The neuropathology of this disease is still poorly understood, as low lysine diet and carnitine supplementation do not always prevent brain damage, even in early-treated patients. We used a 3D in vitro model of rat organotypic brain cell cultures in aggregates to mimic glutaric aciduria type I by repeated administration of 1 mM glutarate or 3-hydroxyglutarate at two time points representing different developmental stages. Both metabolites were deleterious for the developing brain cells, with 3-hydroxyglutarate being the most toxic metabolite in our model. Astrocytes were the cells most strongly affected by metabolite exposure. In culture medium, we observed an up to 11-fold increase of ammonium in the culture medium with a concomitant decrease of glutamine. We further observed an increase in lactate and a concomitant decrease in glucose. Exposure to 3-hydroxyglutarate led to a significantly increased cell death rate. Thus, we propose a three step model for brain damage in glutaric aciduria type I: (i) 3-OHGA causes the death of astrocytes, (ii) deficiency of the astrocytic enzyme glutamine synthetase leads to intracerebral ammonium accumulation, and (iii) high ammonium triggers secondary death of other brain cells. These unexpected findings need to be further investigated and verified in vivo. They suggest that intracerebral ammonium accumulation might be an important target for the development of more effective treatment strategies to prevent brain damage in patients with glutaric aciduria type I.     

Clinical Profiles Associated with Influenza Disease in the Ferret Model

Influenza A viruses continue to pose a threat to human health; thus, various vaccines and prophylaxis continue to be developed. Testing of these products requires various animal models including mice, guinea pigs, and ferrets. However, because ferrets are naturally susceptible to infection with human influenza viruses and because the disease state resembles that of human influenza, these animals have been widely used as a model to study influenza virus pathogenesis. In this report, a statistical analysis was performed to evaluate data involving 269 ferrets infected with seasonal influenza, swine influenza, and highly pathogenic avian influenza (HPAI) from 16 different studies over a five year period. The aim of the analyses was to better qualify the ferret model by identifying relationships among important animal model parameters (endpoints) and variables of interest, which include survival, time-to-death, changes in body temperature and weight, and nasal wash samples containing virus, in addition to significant changes from baseline in selected hematology and clinical chemistry parameters. The results demonstrate that a disease clinical profile, consisting of various changes in the biological parameters tested, is associated with various influenza A infections in ferrets. Additionally, the analysis yielded correlates of protection associated with HPAI disease in ferrets. In all, the results from this study further validate the use of the ferret as a model to study influenza A pathology and to evaluate product efficacy.     

Cytokine Profiling in Immigrants with Clinical Malaria after Extended Periods of Interrupted Exposure to Plasmodium falciparum

Immunity to malaria is believed to wane with time in the absence of exposure to Plasmodium falciparum infection, but immunoepidemiological data on longevity of immunity remain controversial. We quantified serum cytokines and chemokines by suspension array technology as potential biomarkers for durability of immunity in immigrants with clinical malaria after years without parasite exposure. These were compared to serum/plasma profiles in naïve adults (travelers) and semi-immune adults under continuous exposure, with malaria, along with immigrant and traveler patients without malaria. Immigrants had higher levels of IL-2, IL-5 and IL-8 compared to semi-immune adults with malaria (P≤0.0200). Time since immigration correlated with increased IL-2 (rho=0.2738P=0.0495) and IFN-γ (rho=0.3044P=0.0282). However, immigrants did not show as high IFN-γ concentrations as travelers during a first malaria episode (P<0.0001). Immigrants and travelers with malaria had higher levels of IFN-γ, IL-6, and IL-10 (P<0.0100) than patients with other diseases, and IL-8 and IL-1β were elevated in immigrants with malaria (P<0.0500). Therefore, malaria patients had a characteristic strong pro-inflammatory/Th1 signature. Upon loss of exposure, control of pro-inflammatory responses and tolerance to P. falciparum appeared to be reduced. Understanding the mechanisms to maintain non-pathogenic effector responses is important to develop new malaria control strategies.