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

Glioma Associated Stem Cells (GASCs) Isolation and Culture.

Glioma Associated Stem Cells (GASCs) represent a population of nontumorigenic multipotent stem cells hosted in the microenvironment of human gliomas. In vitro, these cells are able, through the release of exosomes, to increase the biological aggressiveness of glioma-initiating cells. The clinical importance of this finding is supported by the strong prognostic value associated with the GASCs surface immunophenotype thus suggesting that this patient-based approach can provide a groundbreaking method to predict prognosis and to exploit novel strategies that target the tumor strom

Biological Prosthesis (Hollow 3D-Printed Titanium Custom-Made Prosthesis and Bone Graft) for Humeral Reconstruction in Pediatric Oncologic Patients: Surgical Indications and Results

This study presents the mid-term outcomes of a novel “biological prosthesis” for pediatric humerus reconstruction after major bone tumor removal. This approach involves a hollow 3D-printed titanium custom-made prosthesis combined with bone grafting. The primary aim was to preserve and revitalize the unaffected autologous proximal or distal humeral stump. Between 2017 and 2021, we treated five pediatric patients (mean age 11.2 years; range 7–17) with humeral bone sarcomas. A one-stage surgical procedure involved tumor resection and implanting a hollow 3D-printed custom-made prosthesis. In two cases, we preserved the proximal humerus; in two, the distal part; and in one, both. Graft materials included homologous bone chips in three cases and free vascularized fibular grafts in two cases. All patients were clinically and radiographically assessed after a mean follow-up of 32.2 months (range of 14–68). No significant complications were observed, and no implant revisions were needed. Osseointegration was evident in all cases within eight months post-surgery; vascular support for the remaining autologous stump was demonstrated in all cases. Our hollow 3D-printed custom-made prosthesis and bone grafting offer the potential for partial or complete articular surface preservation. This approach encourages revascularization of the epiphysis, leading to satisfactory outcomes in humerus reconstruction within the pediatric population

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

5.7 The Input of Home Telemonitoring for the Treatment of Chronic Heart Failure in Old People at High Risk

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Gradient catastrophe and flutter in vortex filament dynamics

Gradient catastrophe and flutter instability in the motion of vortex filament within the localized induction approximation are analyzed. It is shown that the origin if this phenomenon is in the gradient catastrophe for the dispersionless Da Rios system which describes motion of filament with slow varying curvature and torsion. Geometrically this catastrophe manifests as a rapid oscillation of a filament curve in a point that resembles the flutter of airfoils. Analytically it is the elliptic umbilic singularity in the terminology of the catastrophe theory. It is demonstrated that its double scaling regularization is governed by the Painlev\'e-I equation.Comment: 11 pages, 3 figures, typos corrected, references adde

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