Lessons from LIMK1 enzymology and their impact on inhibitor design

LIM domain kinase 1 (LIMK1) is a key regulator of actin dynamics. It is thereby a potential therapeutic target for the prevention of fragile X syndrome and amyotrophic lateral sclerosis. Herein, we use X-ray crystallography and activity assays to describe how LIMK1 accomplishes substrate specificity, to suggest a unique ‘rock-and-poke’ mechanism of catalysis and to explore the regulation of the kinase by activation loop phosphorylation. Based on these findings, a differential scanning fluorimetry assay and a RapidFire mass spectrometry activity assay were established, leading to the discovery and confirmation of a set of small-molecule LIMK1 inhibitors. Interestingly, several of the inhibitors were inactive towards the closely related isoform LIMK2. Finally, crystal structures of the LIMK1 kinase domain in complex with inhibitors (PF-477736 and staurosporine, respectively) are presented, providing insights into LIMK1 plasticity upon inhibitor binding

Active Mass Under Pressure

After a historical introduction to Poisson's equation for Newtonian gravity, its analog for static gravitational fields in Einstein's theory is reviewed. It appears that the pressure contribution to the active mass density in Einstein's theory might also be noticeable at the Newtonian level. A form of its surprising appearance, first noticed by Richard Chase Tolman, was discussed half a century ago in the Hamburg Relativity Seminar and is resolved here.Comment: 28 pages, 4 figure

Traditional and emerging biomarkers in asymptomatic left ventricular dysfunction\u2014promising non-coding rnas and exosomes as biomarkers in early phases of cardiac damage

Heart failure (HF) is one of the major causes of morbidity and mortality worldwide and represents an escalating problem for healthcare systems. The identification of asymptomatic patients with underlying cardiac subclinical disease would create an opportunity for early intervention and prevention of symptomatic HF. Traditional biomarkers are very useful as diagnostic and prognostic tools in the cardiovascular field; however, their application is usually limited to overt cardiac disease. On the other hand, a growing number of studies is investigating the diagnostic and prognostic potential of new biomarkers, such as micro-RNAs (miRNA), long non-coding RNAs, and exosome cargo, because of their involvement in the early phases of cardiac dysfunction. Unfor-tunately, their use in asymptomatic phases remains a distant goal. The aim of this review is to gather the current knowledge of old and novel biomarkers in the early diagnosis of cardiac dysfunction in asymptomatic individuals

What the cardiologist needs to consider in the management of oncologic patients with stemi-like syndrome; A case report and literature review

In pre-hospital care, an accurate and quick diagnosis of ST-segment elevation myocardial infarction (STEMI) is imperative to promptly kick-off the STEMI network with a direct transfer to the cardiac catheterization laboratory (cath lab) in order to reduce myocardial infarction size and mortality. Aa atherosclerotic plaque rupture is the main mechanism responsible for STEMI. However, in a small percentage of patients, emergency coronarography does not reveal any significant coronary stenosis. The fluoropyrimidine agents such as 5-Fluorouracil (5-FU) and capecitabine, widely used to treat gastrointestinal, breast, head and neck cancers, either as a single agent or in combination with other chemotherapies, can cause potentially lethal cardiac side effects. Here, we present the case of a patient with 5-FU cardiotoxicity resulting in an acute coronary syndrome (ACS) with recurrent episodes of chest pain and ST-segment elevation.. Our case report highlights the importance of widening the knowledge among cardiologists of the side effects of chemotherapeutic drugs, especially considering the rising number of cancer patients around the world and that fluoropyrimidines are the main treatment for many types of cancer, both in adjuvant and advanced settings

COVID-19-Related Myocarditis: Are We There Yet? A Case Report of COVID-19-Related Fulminant Myocarditis

There is increasing evidence of cardiac involvement in COVID-19 cases, with a broad range of clinical manifestations spanning from acute life-threatening conditions such as ventricular dysrhythmias, myocarditis, acute myocardial ischemia and pulmonary thromboembolism to long-term cardiovascular sequelae. In particular, acute myocarditis represents an uncommon but frightening complication of SARS-CoV-2 infection. Even if many reports of SARS CoV-2 myocarditis are present in the literature, the majority of them lacks histological confirmation of cardiac injury. Here, we report a case of a young lady, who died suddenly a few days after testing positive for SARS-CoV-2, whose microscopic and genetics features suggested a direct cardiac involvement compatible with fulminant myocarditis

Evidences for a Nutritional Role of Iodine in Plants

Little is known about the role of iodine in plant physiology. We evaluated the impact of low concentrations of iodine on the phenotype, transcriptome and proteome of Arabidopsis thaliana. Our experiments showed that removal of iodine from the nutrition solution compromises plant growth, and restoring it in micromolar concentrations is beneficial for biomass accumulation and leads to early flowering. In addition, iodine treatments specifically regulate the expression of several genes, mostly involved in the plant defence response, suggesting that iodine may protect against both biotic and abiotic stress. Finally, we demonstrated iodine organification in proteins. Our bioinformatic analysis of proteomic data revealed that iodinated proteins identified in the shoots are mainly associated with the chloroplast and are functionally involved in photosynthetic processes, whereas those in the roots mostly belong and/or are related to the action of various peroxidases. These results suggest the functional involvement of iodine in plant nutrition