Long-term rearrangement of retinal structures in a novel mutation of X-linked retinoschisis

The aim of the present study was to report a novel mutation in the retinoschisin 1 (RS1) gene in a Caucasian family affected by X-linked juvenile retinoschisis (XLRS) and to describe the long-term modification of retinal structure. Two brothers with an early onset maculopathy were diagnosed with XLRS. Fundus photography, fluorescein angiography, spectral domain optical coherence tomography and electroretinogram analyses were performed. Their sister was also examined. All subjects were screened for mutations in the RS1 gene. XLRS patients demonstrated a marked reduction of best-corrected visual acuity. SD-OCT scans reported a cystic degeneration primarily involving the inner nuclear layer, though some cysts were detected in the outer plexiform layer and in the ganglion cell layer. During the ten-year follow-up, a progressive retinal thickening and coalescence of the cysts was observed. Genetic testing revealed a novel mutation (p.Ile212Asn) in the RS1 gene in both XLRS patients, whereas their sister was not a genetic carrier. Several mutations of the RS1 gene were recognized to be responsible for XLRS. Although the correspondence between genotype and phenotype is still under debate, is reasonable that siblings affected by XLRS could share other genetic and/or epigenetic factors capable to influence clinical course of the disease

Structure of Lipoproteins and Their Capacity for Lipid Exchange: Relevance for Development of Atherosclerosis and Its Treatment by HDL Therapy

Atherosclerosis, the largest killer in the western world, arises from build-up of plaques at the artery walls and can result in cardiovascular disease. Low- and high-density lipoproteins are involved in the disease development by depositing and removing lipids to and from macrophages at the artery wall. These processes are complex and not fully understood. Thus, determining the specific roles of the different lipoprotein fractions involved is of fundamental importance for the treatment of the disease. In this chapter, we present the state of the art in lipoprotein structure with focus on the comparison between normolipidemic and hypertriglyceridemic individuals. Then we discuss lipid transfer between lipoproteins and receptor-free cellular membranes. Although these models lack any receptor, key clinical observations are mirrored by these, including increased ability of HDL to remove lipids, in contrast to the ability of LDL to deposit them. Also effects of saturated and unsaturated lipids in the presence and absence of cholesterol are revised. These models can then be used to understand the difference in functionality of lipoproteins from individuals showing different lipid profiles and have the potential to be used also for the development of new HDL therapies

An ascorbic acid-enriched tomato genotype to fight UVA-induced oxidative stress in normal human keratinocytes

UVA radiations contribute up to 95% of the total UV exposure and are known to induce cell damage, leading to apoptosis. Since the benefic effects of ascorbic acid on human health are well known, a new tomato genotype (namedDHO4), highly rich in ascorbic acid, has been recently obtained. Here,we compared the effects of ascorbic acid and hydrophilic DHO4 extracts in protecting human keratinocytes exposed to UVA stress. Keratinocytes were pre-incubated with ascorbic acid or with extracts from the ascorbic acid enriched tomato genotype and irradiated with UVA light. Then, ROS production, intracellular GSH and lipid peroxidation levels were quantified. Western blots were carried out to evaluate mitogen-activated protein kinases cascade, activation of caspase-3 and inflammation levels. We demonstrated that ROS, GSH and lipid peroxidation levels were not altered in cell exposed to UVA stress when cellswere pre-treatedwith ascorbic acid or with tomato extracts. In addition, no evidence of apoptosis and inflammationwere observed in irradiated pre-treated cells. Altogether,we demonstrated the ability of an ascorbic acid enriched tomato genotype to counteract UVA-oxidative stress on human keratinocytes. This protective effect is due to the high concentration of vitamin C that acts as free radical scavenger. This novel tomato genotype may be used as genetic material in breeding schemes to produce improved varieties with higher antioxidant levels

Malvidin and cyanidin derivatives from açai fruit (Euterpe oleracea Mart.) counteract UV-A-induced oxidative stress in immortalized fibroblasts

UV-A radiations are known to induce cellular oxidative stress, leading to premature skin aging. Consumption of açai fruit (Euterpe oleracea Martius) is known to have many health benefits due to its high level of antioxidants. Herein, we analyzed the ability of phenolic compounds extracted from this fruit to attenuate UV-A-induced oxidative stress in immortalized fibroblast. A methanol/water açai extract was fractionated by HPLC and each fraction tested for anti-oxidant stress activity. Immortalized fibroblasts were pre-incubated with açai fractions and then exposed to UV-A radiations. Açai extract was found to be able to strongly protect cells from oxidative stress. In particular, reactive oxygen species (ROS) production, GSH depletion, lipid peroxidation and no increase in the phosphorylation levels of proteins involved in the oxidative stress pathway was observed in cells pre-incubated with the extract and then irradiated by UV-A. Mass spectrometry analyses of HPLC fractionated extract led us to the identification of malvidin and cyanidin derivatives as the most active molecules able to counteract the negative effects induced by UV-A irradiation. Our results indicate, for the first time, that açai fruit is a valuable natural source for malvidin and cyanidin to be used as anti-stress molecules and represent good candidates for dietary intervention in the prevention of age related skin damage

Insights into the interaction of the N-terminal amyloidogenic polypeptide of ApoA-I with model cellular membranes

BACKGROUND: About twenty variants of apolipoprotein A-I (ApoA-I) are associated to hereditary systemic amyloidoses. Although the molecular bases of this disease are still largely unknown, it has been hypothesized that ApoA-I proteolysis is a key event in pathogenesis, since it triggers the release of an N-terminal fragment (80-100 residue long) that misfolds to form amyloid deposits in peripheral organs and tissues. It is also known that cell membrane lipids play a key role in the fibrillogenic pathway. In the case of ApoA-I related amyloidosis caused by L174S mutation, the 93-residue N-terminal fragment of ApoA-I ([1-93]ApoA-I) was found to be the major constituent of ex vivo fibrils. METHODS: With the main goal to investigate the interaction of either [1-93]ApoA-I and ApoA-I with biomimetic membranes, we set-up an experimental system based on the Raman Tweezers methodology. We tested GUVs composed by two types of zwitterionic lipids with a different fluidity degree, i.e. dioleoylphosphatidylcholine (DOPC) and dipalmitoylphosphatidylcholine (DPPC). RESULTS: We found that [1-93]ApoA-I induces conformational disorder in an ordered lipid bilayer. When interacting with fluid phases, instead, the fragment was found to be able to penetrate the membrane bilayer inducing an alignment of lipid chains. CONCLUSIONS: The interaction features of [1-93]ApoA-I with biomimetic membranes strongly depend on the lipid phase. Full-length ApoA-I was found to have similar effects, even if significantly less pronounced. GENERAL SIGNIFICANCE: Our observations shed light on still largely unknown molecular bases of ApoA-I fibrillogenic domain interaction with membranes

Экономический анализ деятельности компании для поиска направлений повышения ее конкурентоспособности

Целью работы является проведение экономического анализа деятельности предприятия для разработки стратегии и комплекса мероприятий, направленных на повышение его конкурентоспособности.The aim of the work is to conduct an economic analysis of the enterprise to develop a strategy and a set of measures aimed at increasing its competitiveness

Adaptive OFDM-based acoustic underwater transmission: system design and experimental verification

In this paper, we present the design and implementation of a software defined orthogonal frequency division multiplexing (OFDM)-based underwater acoustic (UWA) communication system with link adaptation. Our system implementation is based on the customized versions of National Instruments Universal Software Radio Peripheral (USRP). The modified USRPs are interfaced with hydrophone front-ends for acoustic transmission. We investigate the performance of various adaptive algorithms where both modulation order/type and power on each subcarrier are selected based on channel conditions in order to maximize throughput. The experimental in-pool test results verify the superiority of adaptive transmission

Autophagy Alteration in ApoA‐I Related Systemic Amyloidosis

Amyloidoses are characterized by the accumulation and aggregation of misfolded proteins into fibrils in different organs, leading to cell death and consequent organ dysfunction. The specific substitution of Leu 75 for Pro in Apolipoprotein A-I protein sequence (ApoA-I; L75P-ApoA-I) results in late onset amyloidosis, where deposition of extracellular protein aggregates damages the normal functions of the liver. In this work, we describe that the autophagic process is inhibited in the presence of the L75P-ApoA-I amyloidogenic variant in stably transfected human hepatocyte carcinoma cells. The L75P-ApoA-I amyloidogenic variant alters the redox status of the cells, resulting into excessive mitochondrial stress and consequent cell death. Moreover, L75P-ApoA-I induces an impairment of the autophagic flux. Pharmacological induction of autophagy or transfection-enforced overexpression of the pro-autophagic transcription factor EB (TFEB) restores proficient proteostasis and reduces oxidative stress in these experimental settings, suggesting that pharmacological stimulation of autophagy could be a promising target to alleviate ApoA-I amyloidosis

Selection for background matching drives sympatric speciation in Wall Gecko

The Wall Gecko shows heterogeneous colour pattern, which may vary among individuals, depending on the time of day and on the habitat segregation. Nocturnal pale geckos live exclusively on walls. Diurnal dark geckos preferentially live on olive tree trunks, demonstrating an ability to change skin colour that is superior to that of the pale gecko and allows diurnal geckos becoming camouflaged on the diverse substrates occupied during the day. In our study, the nocturnal/pale/wall and diurnal/dark/trunk geckos could be considered the extremes of an ecological cline of morphological variation on which divergent selection may be acting. Combining the effect of balancing selection on nocturnal geckos and disruptive selection between two sympatric populations could lead to speciation. All geckos analysed here belong to the same species, as confirmed by genetic characterization, however diurnal and nocturnal gecko populations seem to be in an early stage of incipient speciation. These two different morphs still combine genes, as revealed by neutral genetic markers, yet they show complete separation according to the analyses of mtDNA coding genes. Experimental results show that diurnal and nocturnal geckos do not swap their niches, likely because the predation pressure causes severe selection for background matching. Genomic analysis of complete mtDNA suggests that nocturnal geckos seem to be under balancing selection perhaps due to the narrow niche in which they live, whereas the daytime population has more opportunity in fitting into the multiple available niches, and they experience positive selection. Here we hypothesize that the ecological segregation that we are witnessing between the nocturnal and diurnal geckos, can lead to a ecological speciation