Hydrophobic profiles of the tail anchors in SLMAP dictate subcellular targeting

<p>Abstract</p> <p>Background</p> <p>Tail anchored (TA) membrane proteins target subcellular structures via a C-terminal transmembrane domain and serve prominent roles in membrane fusion and vesicle transport. Sarcolemmal Membrane Associated Protein (SLMAP) possesses two alternatively spliced tail anchors (TA1 or TA2) but their specificity of subcellular targeting remains unknown.</p> <p>Results</p> <p>TA1 or TA2 can direct SLMAP to reticular structures including the endoplasmic reticulum (ER), whilst TA2 directs SLMAP additionally to the mitochondria. Despite the general structural similarity of SLMAP to other vesicle trafficking proteins, we found no evidence for its localization with the vesicle transport machinery or a role in vesicle transport. The predicted transmembrane region of TA2 is flanked on either side by a positively charged amino acid and is itself less hydrophobic than the transmembrane helix present in TA1. Substitution of the positively charged amino acids, in the regions flanking the transmembrane helix of TA2, with leucine did not alter its subcellular targeting. The targeting of SLMAP to the mitochondria was dependent on the hydrophobic nature of TA2 since targeting of SLMAP-TA2 was prevented by the substitution of leucine (L) for moderately hydrophobic amino acid residues within the transmembrane region. The SLMAP-TA2-4L mutant had a hydrophobic profile that was comparable to that of SLMAP-TA1 and had identical targeting properties to SLMAP-TA1.</p> <p>Conclusion</p> <p>Thus the overall hydrophobicity of the two alternatively spliced TAs in SLMAP determines its subcellular targeting and TA2 predominantly directs SLMAP to the mitochondira where it may serve roles in the function of this organelle.</p

Increased levels of hexacosanoic acid in the brain of Wistar rats: a behavioral study

Introduction: X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal metabolic disorder associated with mutations in the ATP-binding cassette sub-family D member1 (ABCD1) gene. Practically all male patients with X-ALD develop adrenocortical insufficiency during childhood and progressive myelopathy and peripheral neuropathy in adulthood. However, some male patients develop a fatal cerebral demyelinating disease named cerebral adrenoleukodystrophy. Although the exact mechanisms underlying brain damage in X-ALD are still poorly elucidated, it is known that hexacosanoic acid (C26:0) accumulation represents a hallmark in the pathogenesis of this disease. In this study, we examined whether an overload of C26:0 injected in Wistar rats was capable of causing behavioral changes in these animals.Methods: Egg lecithin in ethanol was dried under a nitrogen stream and mixed with C26:0 methyl ester. Male Wistar rats at 2–3 weeks of age were obtained from Universidade Federal do Rio Grande do Sul (UFRGS), divided into 8 groups, and submitted to an open field test. We then analyzed line crossings (locomotion and exploration), rearing (orienting and investigatory responses), grooming (anxiety manifestation), and latency to move for each animal.Results: Animals subjected to C26:0 administration presented fewer crossings and rearing episodes and a higher latency to move 45 minutes after C26:0 injection. The present work yields experimental evidence that C26:0, the main accumulated metabolite in X-ALD, can cause behavioral alterations in rats such as the impairment of locomotion and exploratory capabilities, as well as a reduction in orienting and investigatory responses.Conclusion: Although our results are preliminary, they are extremely important for future studies that investigate C26:0 accumulation and locomotor impairment in patients with X-ALD

Photobiomodulation reduces the cytokine storm syndrome associated with Covid-19 in the zebrafish model

Although the exact mechanism of the pathogenesis of COVID-19 is not fully understood, oxidative stress and the release of pro-inflammatory cytokines have been highlighted as playing a vital role in the pathogenesis of the disease. In this sense, alternative treatments are needed to reduce the inflammation caused by COVID-19. Therefore, this study aimed to investigate the potential effect of red PBM as an attractive therapy to downregulate the cytokine storm caused by COVID-19 from a zebrafish model. RT-PCR analyses and protein-protein interaction prediction among SARS-CoV-2 and Danio rerio proteins showed that rSpike was responsible for generating systemic inflammatory processes with significantly increased pro-inflammatory (il1b, il6, tnfa, and nfkbiab), oxidative stress (romo1) and energy metabolism (slc2a1a, coa1) mRNA markers, with a pattern like those observed in COVID-19 cases in humans. On the other hand, PBM treatment decreased the mRNA levels of these pro-inflammatory and oxidative stress markers compared with rSpike in various tissues, promoting an anti-inflammatory response. Conversely, PBM promotes cellular and tissue repair of injured tissues and significantly increases the survival rate of rSpike-inoculated individuals. Additionally, metabolomics analysis showed that the most impacted metabolic pathways between PBM and the rSpike-treated groups were related to steroid metabolism, immune system, and lipids metabolism. Together, our findings suggest that the inflammatory process is an incisive feature of COVID-19, and red PBM can be used as a novel therapeutic agent for COVID-19 by regulating the inflammatory response. Nevertheless, the need for more clinical trials remains, and there is a significant gap to overcome before clinical trials.publishedVersio

SPACE: the spectroscopic all-sky cosmic explorer

We describe the scientific motivations, the mission concept and the instrumentation of SPACE, a class-M mission proposed for concept study at the first call of the ESA Cosmic-Vision 2015–2025 planning cycle. SPACE aims to produce the largest three-dimensional evolutionary map of the Universe over the past 10 billion years by taking near-IR spectra and measuring redshifts for more than half a billion galaxies at 0 < z < 2 down to AB ∼ 23 over 3π sr of the sky. In addition, SPACE will also target a smaller sky field, performing a deep spectroscopic survey of millions of galaxies to AB ∼ 26 and at 2 < z < 10+. These goals are unreachable with ground-based observations due to the ≈500 times higher sky background (see e.g. Aldering, LBNL report number LBNL-51157, 2001). To achieve the main science objectives, SPACE will use a 1.5 m diameter Ritchey- Chretien telescope equipped with a set of arrays of Digital Micro-mirror Devices covering a total field of view of 0.4 deg2, and will perform large-multiplexing multi-object spectroscopy (e.g. ≈6000 targets per pointing) at a spectral resolution of R∼400 as well as diffraction-limited imaging with continuous coverage from 0.8 to 1.8 μm. Owing to the depth, redshift range, volume coverage and quality of its spectra, SPACE will reveal with unique sensitivity most of the fundamental cosmological signatures, including the power spectrum of density fluctuations and its turnover. SPACE will also place high accuracy constraints on the dark energy equation of state parameter and its evolution by measuring the baryonic acoustic oscillations imprinted when matter and radiation decoupled, the distanceluminosity relation of cosmological supernovae, the evolution of the cosmic expansion rate, the growth rate of cosmic large-scale structure, and high-z galaxy clusters. The datasets from the SPACE mission will represent a long lasting legacy for the whole astronomical community whose data will be mined for many years to come

A mathematical model of the link between growth and L-malic acid consumption for five strains of Oenococcus oeni

In winemaking, after the alcoholic fermentation of red wines and some white wines, L-malic acid must be converted into L-lactic acid to reduce the acidity. This malolactic fermentation (MLF) is usually carried out by the lactic acid bacteria Oenococcus oeni. Depending on the level of process control, selected O. oeni is inoculated or the natural microbiota of the cellar is used. This study considers the link between growth and MLF for five strains of O. oeni species. The kinetics of growth and L-malic acid consumption were followed in modified MRS medium (20 °C, pH 3.5, and 10 % ethanol) in anaerobic conditions. A large variability was found among the strains for both their growth and their consumption of L-malic acid. There was no direct link between biomass productivities and consumption of L-malic acid among strains but there was a link of proportionality between the specific growth of a strain and its specific consumption of L-malic acid. Experiments with and without malic acid clearly demonstrated that malic acid consumption improved the growth of strains. This link was quantified by a mathematical model comparing the intrinsic malic acid consumption capacity of the strains

Factors influencing terrestriality in primates of the Americas and Madagascar

Among mammals, the order Primates is exceptional in having a high taxonomic richness in which the taxa are arboreal, semiterrestrial, or terrestrial. Although habitual terrestriality is pervasive among the apes and African and Asian monkeys (catarrhines), it is largely absent among monkeys of the Americas (platyrrhines), as well as galagos, lemurs, and lorises (strepsirrhines), which are mostly arboreal. Numerous ecological drivers and species-specific factors are suggested to set the conditions for an evolutionary shift from arboreality to terrestriality, and current environmental conditions may provide analogous scenarios to those transitional periods. Therefore, we investigated predominantly arboreal, diurnal primate genera from the Americas and Madagascar that lack fully terrestrial taxa, to determine whether ecological drivers (habitat canopy cover, predation risk, maximum temperature, precipitation, primate species richness, human population density, and distance to roads) or species-specific traits (bodymass, group size, and degree of frugivory) associate with increased terrestriality. We collated 150,961 observation hours across 2,227 months from 47 species at 20 sites in Madagascar and 48 sites in the Americas. Multiple factors were associated with ground use in these otherwise arboreal species, including increased temperature, a decrease in canopy cover, a dietary shift away from frugivory, and larger group size. These factors mostly explain intraspecific differences in terrestriality. As humanity modifies habitats and causes climate change, our results suggest that species already inhabiting hot, sparsely canopied sites, and exhibiting more generalized diets, are more likely to shift toward greater ground use

Factors influencing terrestriality in primates of the Americas and Madagascar

Among mammals, the order Primates is exceptional in having a high taxonomic richness in which the taxa are arboreal, semiterrestrial, or terrestrial. Although habitual terrestriality is pervasive among the apes and African and Asian monkeys (catarrhines), it is largely absent among monkeys of the Americas (platyrrhines), as well as galagos, lemurs, and lorises (strepsirrhines), which are mostly arboreal. Numerous ecological drivers and species-specific factors are suggested to set the conditions for an evolutionary shift from arboreality to terrestriality, and current environmental conditions may provide analogous scenarios to those transitional periods. Therefore, we investigated predominantly arboreal, diurnal primate genera from the Americas and Madagascar that lack fully terrestrial taxa, to determine whether ecological drivers (habitat canopy cover, predation risk, maximum temperature, precipitation, primate species richness, human population density, and distance to roads) or species-specific traits (body mass, group size, and degree of frugivory) associate with increased terrestriality. We collated 150,961 observation hours across 2,227 months from 47 species at 20 sites in Madagascar and 48 sites in the Americas. Multiple factors were associated with ground use in these otherwise arboreal species, including increased temperature, a decrease in canopy cover, a dietary shift away from frugivory, and larger group size. These factors mostly explain intraspecific differences in terrestriality. As humanity modifies habitats and causes climate change, our results suggest that species already inhabiting hot, sparsely canopied sites, and exhibiting more generalized diets, are more likely to shift toward greater ground use

Aberrant expression of Twist1 in diseased articular cartilage and a potential role in the modulation of osteoarthritis severity.

The bHLH transcription factor Twist1 has emerged as a negative regulator of chondrogenesis in skeletal progenitor cells and as an inhibitor of maturation in growth plate chondrocytes. However, its role in articular cartilage remains obscure. Here we examine Twist1 expression during re-differentiation of expanded human articular chondrocytes, the distribution of Twist1 proteins in normal versus OA human articular cartilage, and its role in modulating OA development in mice. High levels of Twist1 transcripts were detected by qPCR analyses of expanded de-differentiated human articular chondrocytes that had acquired mesenchymal-like features. The induction of hallmark cartilage genes by Bmp-2 mediated chondrogenic differentiation was paralleled by the dramatic suppression of Twist1 in vitro. In normal human articular cartilage, Twist1-expressing chondrocytes were most abundant in the superficial zone with little to no expression in the middle and deep zones. However, our analyses revealed a higher proportion of deep zone articular chondrocytes expressing Twist1 in human OA cartilage as compared to normal articular cartilage. Moreover, Twist1 expression was prominent within proliferative cell clusters near fissure sites in more severely affected OA samples. To assess the role of Twist1 in OA pathophysiology, we subjected wild type mice and transgenic mice with gain of Twist1 function in cartilage to surgical destabilization of the medial meniscus. At 12 weeks post-surgery, micro-CT and histological analyses revealed attenuation of the OA phenotype in Twist1 transgenic mice compared to wild type mice. Collectively, the data reveal a role for Twist in articular cartilage maintenance and the attenuation of cartilage degeneration