Prior myocardial infarction, coronary artery disease extent, diabetes mellitus, and CERT2 score for risk stratification in stable coronary artery disease

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Lipidomics: A Tool for Studies of Atherosclerosis

Lipids, abundant constituents of both the vascular plaque and lipoproteins, play a pivotal role in atherosclerosis. Mass spectrometry-based analysis of lipids, called lipidomics, presents a number of opportunities not only for understanding the cellular processes in health and disease but also in enabling personalized medicine. Lipidomics in its most advanced form is able to quantify hundreds of different molecular lipid species with various structural and functional roles. Unraveling this complexity will improve our understanding of diseases such as atherosclerosis at a level of detail not attainable with classical analytical methods. Improved patient selection, biomarkers for gauging treatment efficacy and safety, and translational models will be facilitated by the lipidomic deliverables. Importantly, lipid-based biomarkers and targets should lead the way as we progress toward more specialized therapeutics

Plasma ceramides predict cardiovascular death in patients with stable coronary artery disease and acute coronary syndromes beyond LDL-cholesterol

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Studies on the coiled-coil protein TlpA in salmonella : A thermosensing transcription autoregulator

Studies on the Coiled-Coil Protein TlpA in Salmonella: A Thermosensing Transcription Autoregulator The coiled-coil motif is composed of amino acid heptad repeats with hydrophobic or apolar residues at conserved positions. Such repeats are responsible for the apolar stripe that is buried inside the coiled-coil structure formed upon coiling of two (or more) alpha-helical chains about each other. The Salmonella typhimurium virulence plasmid carries the tlpA gene which encodes a protein with an extensive coiled-coil domain. TlpA was shown to be a sequence-specific DNA-binding protein. The DNA-binding domain is situated at the N- terminus and attached to it is the elongated coiled-coil domain extending all the way to the C-terminus. TlpA acts at the tlpA promoter as a transcription repressor. TlpA structure is governed by a monomer to coiled-coil equilibrium. Therefore the fully folded coiled-coil in TlpA is inherently concentration and temperature dependent. Shifting exponentially growing Salmonella to temperatures ranging from 37 °C to 45 °C leads to increasing derepression of the tlpA promoter. Interestingly this is the temperature range met by an invading bacterial pathogen in the host organism. It was demonstrated that the regulation of tlpA transcription is exerted by the TlpA repressor protein only. In vitro DNA-binding tested with highly purified TlpA was also temperature dependent. Control experiments ruled out the involvement of supercoiling and temperature induced changes in DNA topology and dependence on heat shock response. The thermoregulatory capacity of TlpA is due to its monomer to coiled-coil equilibrium which is pushed more to the monomer side (monomers being unfolded and nonfunctional) at elevated temperatures leading to subsequent derepression of tlpA and increased transcription. Studies on TlpA are unique in that they demonstrate for the first time that a single protein can regulate transcription according to sensed temperature cues. TlpA also represents a novel utilization of the dynamic coiled-coil structure for regulation of function. Key words: coiled-coil/gene regulation/repressor/thermoregulation/Salmonella ISBN 9 1-628-2304-

A Proteinaceous Gene Regulatory Thermometer in Salmonella

AbstractNovel utilization of the coiled-coil motif is presented that enables TlpA, an autoregulatory repressor protein in Salmonella, to sense temperature shifts directly and thereby to modulate the extent of transcription repression. Salmonella cells shifted to higher temperatures, such as those encountered at host entry, showed derepressed tlpA activity. tlpA::lacZ fusions indicated that the promoter itself is insensitive to thermal shifts and that transcription control was exerted by the autorepressor TlpA only. In vitro studies with highly purified TlpA showed concentration and temperature dependence for both fully folded conformation and function, indicating that the thermosensing in TlpA is based on monomer-to-coiled-coil equilibrium

Ceramides and Ceramide Scores : Clinical Applications for Cardiometabolic Risk Stratification

Ceramides are bioactive lipids that have an important role in many cellular functions such as apoptosis and inflammation. During the past decade emerging clinical data have shown that ceramides are not only of great biochemical interest but may also have diagnostic utility. Ceramides have shown independent predictive value for negative cardiovascular outcomes as well as for the onset of type 2 diabetes. Based on abundant published data, risk score using the concentrations of circulating ceramides have been developed and adapted for routine clinical practice. Currently serum ceramides are used clinically as efficient risk stratifiers for primary and secondary prevention of atherosclerotic cardiovascular disease (CVD). A direct cause-effect relationship between CVD and ceramide has not been established to date. As ceramide-specific medications are being developed, conventional strategies such as lipid lowering agents and lifestyle interventions can be used to reduce overall risk. Ceramides can identify a very high-risk coronary heart disease category of patients in need for more intense medical attention, specifically those patients at higher risk as highlighted in the 2019 European Society of Cardiology guidelines for stable chronic coronary syndrome patients. In addition, the ceramide risk score may be used as a decision-making tool in primary prevention patients with moderate CVD risk. Finally, the ceramide risk score may have a unique utility as a motivational tool to increase patient's adherence to medical therapy and lifestyle changes.publishedVersionPeer reviewe

A role for alpha-and beta-catenins in bacterial uptake.

International audienceInteraction of internalin with E-cadherin promotes entry of Listeria monocytogenes into human epithelial cells. This process requires actin cytoskeleton rearrangements. Here we show, by using a series of stably transfected cell lines expressing E-cadherin variants, that the ectodomain of E-cadherin is sufficient for bacterial adherence and that the intracytoplasmic domain is required for entry. The critical cytoplasmic region was further mapped to the beta-catenin binding domain. Because beta-catenin is known to interact with alpha-catenin, which binds to actin, we generated a fusion molecule consisting of the ectodomain of E-cadherin and the actin binding site of alpha-catenin. Cells expressing this chimera were as permissive as E-cadherin-expressing cells. In agreement with these data, alpha- and beta-catenins as well as E-cadherin clustered and colocalized at the entry site, where F-actin then accumulated. Taken together, these results reveal that E-cadherin, via beta- and alpha-catenins, can trigger dynamic events of actin polymerization and membrane extensions culminating in bacterial uptake