96 research outputs found

    Vascular Endothelial Dysfunction in β-Thalassemia Occurs Despite Increased eNOS Expression and Preserved Vascular Smooth Muscle Cell Reactivity to NO

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    The hereditary β-thalassemia major condition requires regular lifelong blood transfusions. Transfusion-related iron overloading has been associated with the onset of cardiovascular complications, including cardiac dysfunction and vascular anomalies. By using an untransfused murine model of β-thalassemia major, we tested the hypothesis that vascular endothelial dysfunction, alterations of arterial structure and of its mechanical properties would occur despite the absence of treatments.Vascular function and structure were evaluated ex vivo. Compared to the controls, endothelium-dependent vasodilation with acetylcholine was blunted in mesenteric resistance arteries of β-thalassemic mice while the endothelium-independent vasodilator (sodium nitroprusside) produced comparable vessel dilation, indicating endothelial cell impairment with preserved smooth muscle cell reactivity to nitric oxide (NO). While these findings suggest a decrease in NO bioavailability, Western blotting showed heightened expression of aortic endothelial NO synthase (eNOS) in β-thalassemia. Vascular remodeling of the common carotid arteries revealed increased medial elastin content. Under isobaric conditions, the carotid arteries of β-thalassemic mice exhibited decreased wall stress and softening due to structural changes of the vessel wall.A complex vasculopathy was identified in untransfused β-thalassemic mice characterized by altered carotid artery structure and endothelial dysfunction of resistance arterioles, likely attributable to reduced NO bioavailability despite enhanced vascular eNOS expression

    N-Acetylglucosamine Induces White to Opaque Switching, a Mating Prerequisite in Candida albicans

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    To mate, the fungal pathogen Candida albicans must undergo homozygosis at the mating-type locus and then switch from the white to opaque phenotype. Paradoxically, opaque cells were found to be unstable at physiological temperature, suggesting that mating had little chance of occurring in the host, the main niche of C. albicans. Recently, however, it was demonstrated that high levels of CO2, equivalent to those found in the host gastrointestinal tract and select tissues, induced the white to opaque switch at physiological temperature, providing a possible resolution to the paradox. Here, we demonstrate that a second signal, N-acetylglucosamine (GlcNAc), a monosaccharide produced primarily by gastrointestinal tract bacteria, also serves as a potent inducer of white to opaque switching and functions primarily through the Ras1/cAMP pathway and phosphorylated Wor1, the gene product of the master switch locus. Our results therefore suggest that signals produced by bacterial co-members of the gastrointestinal tract microbiota regulate switching and therefore mating of C. albicans

    The Role of Response Elements Organization in Transcription Factor Selectivity: The IFN-β Enhanceosome Example

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    What is the mechanism through which transcription factors (TFs) assemble specifically along the enhancer DNA? The IFN-β enhanceosome provides a good model system: it is small; its components' crystal structures are available; and there are biochemical and cellular data. In the IFN-β enhanceosome, there are few protein-protein interactions even though consecutive DNA response elements (REs) overlap. Our molecular dynamics (MD) simulations on different motif combinations from the enhanceosome illustrate that cooperativity is achieved via unique organization of the REs: specific binding of one TF can enhance the binding of another TF to a neighboring RE and restrict others, through overlap of REs; the order of the REs can determine which complexes will form; and the alternation of consensus and non-consensus REs can regulate binding specificity by optimizing the interactions among partners. Our observations offer an explanation of how specificity and cooperativity can be attained despite the limited interactions between neighboring TFs on the enhancer DNA. To date, when addressing selective TF binding, attention has largely focused on RE sequences. Yet, the order of the REs on the DNA and the length of the spacers between them can be a key factor in specific combinatorial assembly of the TFs on the enhancer and thus in function. Our results emphasize cooperativity via RE binding sites organization

    DNA origami-based single-molecule forcespectroscopy elucidates RNA Polymerase IIIpre-initiation complex stability

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    The TATA-binding protein (TBP) and a transcription factor (TF) IIB-like factor are important constituents of all eukaryotic initiation complexes. The reason for the emergence and strict requirement of the additional initiation factor Bdp1 in the RNA polymerase (RNAP) III system, however, remained elusive. A poorly studied aspect in this context is the effect of DNA strain arising from DNA compaction and transcriptional activity on initiation complex formation. We made use of a DNA origami-based force clamp to follow the assembly of human initiation complexes in the RNAP II and RNAP III systems at the single-molecule level under piconewton forces. We demonstrate that TBP-DNA complexes are force-sensitive and TFIIB is sufficient to stabilise TBP on a strained promoter. In contrast, Bdp1 is the pivotal component that ensures stable anchoring of initiation factors, and thus the polymerase itself, in the RNAP III system. Thereby, we offer an explanation for the crucial role of Bdp1 for the high transcriptional output of RNAP III

    Fructan and its relationship to abiotic stress tolerance in plants

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    Numerous studies have been published that attempted to correlate fructan concentrations with freezing and drought tolerance. Studies investigating the effect of fructan on liposomes indicated that a direct interaction between membranes and fructan was possible. This new area of research began to move fructan and its association with stress beyond mere correlation by confirming that fructan has the capacity to stabilize membranes during drying by inserting at least part of the polysaccharide into the lipid headgroup region of the membrane. This helps prevent leakage when water is removed from the system either during freezing or drought. When plants were transformed with the ability to synthesize fructan, a concomitant increase in drought and/or freezing tolerance was confirmed. These experiments indicate that besides an indirect effect of supplying tissues with hexose sugars, fructan has a direct protective effect that can be demonstrated by both model systems and genetic transformation

    Rehabilitation needs for older adults with stroke living at home: perceptions of four populations

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    <p>Abstract</p> <p>Background</p> <p>Many people who have suffered a stroke require rehabilitation to help them resume their previous activities and roles in their own environment, but only some of them receive inpatient or even outpatient rehabilitation services. Partial and unmet rehabilitation needs may ultimately lead to a loss of functional autonomy, which increases utilization of health services, number of hospitalizations and early institutionalization, leading to a significant psychological and financial burden on the patients, their families and the health care system. The aim of this study was to explore partially met and unmet rehabilitation needs of older adults who had suffered a stroke and who live in the community. The emphasis was put on needs that act as obstacles to social participation in terms of personal factors, environmental factors and life habits, from the point of view of four target populations.</p> <p>Methods</p> <p>Using the focus group technique, we met four types of experts living in three geographic areas of the province of Québec (Canada): older people with stroke, caregivers, health professionals and health care managers, for a total of 12 groups and 72 participants. The audio recordings of the meetings were transcribed and NVivo software was used to manage the data. The process of reducing, categorizing and analyzing the data was conducted using themes from the Disability Creation Process model.</p> <p>Results</p> <p>Rehabilitation needs persist for nine capabilities (e.g. related to behaviour or motor activities), nine factors related to the environment (e.g. type of teaching, adaptation and rehabilitation) and 11 life habits (e.g. nutrition, interpersonal relationships). The caregivers and health professionals identified more unmet needs and insisted on an individualized rehabilitation. Older people with stroke and the health care managers had a more global view of rehabilitation needs and emphasized the availability of resources.</p> <p>Conclusion</p> <p>Better knowledge of partially met or unmet rehabilitation needs expressed by the different types of people involved should lead to increased attention being paid to education for caregivers, orientation of caregivers towards resources in the community, and follow-up of patients' needs in terms of adjustment and rehabilitation, whether for improving their skills or for carrying out their activities of daily living.</p
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