On the relevance of thrombomodulin variants in atypical hemolytic uremic syndrome

Atypical hemolytic uremic syndrome; Genetic analysis; ThrombomodulinSíndrome hemolítica urèmica atípica; Anàlisi genètica; TrombomodulinaSíndrome hemolítico urémico atípico; Análisis genético; TrombomodulinaThis project was funded by the Instituto de Salud Carlos III: REDinREN (RD016/009/009) and Instituto de Investigacion Puerta de Hierro-Segovia Arana (IDIPHISA) to AH and by grants from the Spanish Ministerio de Economía y Competitividad–FEDER (European Regional Development Fund) (PID2019-104912RB-I00) and the Autonomous Region of Madrid (S2017/BMD-3673 and S2022/BMD-7278) to SRdC. TC was supported by a grant from National Health Institute Carlos III (RETIC ISCIII RD21/0005; RICORS), This work was developed under the supervision of the Spanish Registry of the Atypical Hemolytic Uremic Syndrome and C3 Glomerulopathy (aHUS/C3G) registry

Age effect on retina and optic disc normal values

Purpose: To investigate retinal thickness and optic disc parameters by the Retinal Thickness Analyzer (RTA) glaucoma program in older normal subjects and to determine any age effect. Methods: Subjects over 40 years of age without any prior history of eye diseases were recruited. Only subjects completely normal on clinical ophthalmologic examination and on visual field testing by Humphrey Field Analyzer (HFA) using the SITA 24-2 program were included. A total of 74 eyes from 74 subjects with even age distribution over the decades were enrolled and underwent topographic measurements of the posterior pole and of the optic disc by RTA. The `glaucoma full' program in software version 4.11B was applied. Results: Mean patient age was 59.9 +/- 10.3 years with a range from 40 to 80 years. The only parameter intraocular pressure (IOP) correlated with was retinal posterior pole asymmetry (r=0.27, p=0.02). IOP itself increased significantly with age (r=0.341, p=0.003). Mean defect and pattern standard deviation of the HFA did not correlate with any of the retinal or optic disc measurements. Increasing age correlated significantly with some of the morphologic measurements of the RTA: decreasing perifoveal minimum thickness (r=-0.258, p=0.026), increased cup-to-disc area ratio (r=0.302, p=0.016) and increased cup area (r=0.338 p=0.007). Conclusions: An age effect exists for some of the retina and optic disc measurements obtained by the RTA. Copyright (C) 2005 S. Karger AG, Basel

Mutations and Deregulation of Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Cascades Which Alter Therapy Response

The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Certain components of these pathways, RAS, NF1, BRAF, MEK1, DUSP5, PP2A, PIK3CA, PIK3R1, PIK3R4, PIK3R5, IRS4, AKT, NFKB1, MTOR, PTEN, TSC1, and TSC2 may also be activated/inactivated by mutations or epigenetic silencing. Upstream mutations in one signaling pathway or even in downstream components of the same pathway can alter the sensitivity of the cells to certain small molecule inhibitors. These pathways have profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of components of these cascades can contribute to: resistance to other pathway inhibitors, chemotherapeutic drug resistance, premature aging as well as other diseases. This review will first describe these pathways and discuss how genetic mutations and epigenetic alterations can result in resistance to various inhibitors

Matrix metalloproteinase 12 silencing: A therapeutic approach to treat pathological lung tissue remodeling?

peer reviewedAmong the large matrix metalloproteinases (MMPs) family, MMP-12, also referred to as macrophage elastase, plays a significant role in chronic pulmonary pathologies characterized by an intense tissue remodeling such as asthma and COPD. This review will summarize knowledge about MMP-12 structure, functions and mechanisms of activation and regulation, including potential MMP-12 modulation by microRNA. As MMP-12 is involved in many tissue remodeling diseases, efforts have been made to develop specific synthetic inhibitors. However, at this time, very few chemical inhibitors have proved to be efficient and specific to a particular MMP. The relevance of silencing MMP-12 by RNA interference is highlighted. The specificity of this approach using siRNA or shRNA and the strategies to deliver these molecules in the lung are discussed

Efficient I/O joining and reliable data publication in energy harvested ISA100.11a network

Energy harvesting technologies have brought a paradigm shift in the industrial automation sector by procreating self-powered wireless input/output (I/O) devices. Unfortunately, current wireless technologies for industrial applications, such as ISA100.11a and WirelessHART, are yet far from supporting harvester powered I/O devices. Although several works have been conducted to address the requirements of energy harvested I/O devices, most of those have focused on minimizing the I/O energy consumption during the steady-state phase of the network. However, a very important aspect, the energy consumption during network joining that consumes a significant amount of energy, is overlooked in these works. In this paper, we therefore analyze the I/O energy consumption in ISA100.11a network during the joining phase in addition to that in normal operation to better understand the challenges of energy harvesting communications. Then, we propose an energy efficient network joining scheme to support harvester powered I/O devices in ISA100.11a network. The proposed scheme significantly reduces the joining delay when compared with the traditional ISA100.11a joining scheme. We also propose a reliable data transmission scheme for energy harvested I/O devices by utilizing spatial diversity that can outperform ISA100.11a data publication through significant improvement in packet reception

Therapeutic effects of cell-permeant peptides that activate G proteins downstream of growth factors

In eukaryotes, receptor tyrosine kinases (RTKs) and trimeric G proteins are two major signaling hubs. Signal transduction via trimeric G proteins has long been believed to be triggered exclusively by G protein-coupled receptors (GPCRs). This paradigm has recently been challenged by several studies on a multimodular signal transducer, Gα-Interacting Vesicle associated protein (GIV/Girdin). We recently demonstrated that GIV’s C terminus (CT) serves as a platform for dynamic association of ligand-activated RTKs with Gαi, and for noncanonical transactivation of G proteins. However, exogenous manipulation of this platform has remained beyond reach. Here we developed cell-permeable GIV-CT peptides by fusing a TAT-peptide transduction domain (TAT-PTD) to the minimal modular elements of GIV that are necessary and sufficient for activation of Gi downstream of RTKs, and used them to engineer signaling networks and alter cell behavior. In the presence of an intact GEF motif, TAT-GIV-CT peptides enhanced diverse processes in which GIV’s GEF function has previously been implicated, e.g., 2D cell migration after scratch-wounding, invasion of cancer cells, and finally, myofibroblast activation and collagen production. Furthermore, topical application of TAT-GIV-CT peptides enhanced the complex, multireceptor-driven process of wound repair in mice in a GEF-dependent manner. Thus, TAT-GIV peptides provide a novel and versatile tool to manipulate Gαi activation downstream of growth factors in a diverse array of pathophysiologic conditions

Therapeutic effects of cell-permeant peptides that activate G proteins downstream of growth factors

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Mucin-mimetic glycan arrays integrating machine learning for analyzing receptor pattern recognition by influenza A viruses.

Influenza A viruses (IAVs) exploit host glycans in airway mucosa for entry and infection. Detection of changes in IAV glycan-binding phenotype can provide early indication of transmissibility and infection potential. While zoonotic viruses are monitored for mutations, the influence of host glycan presentation on viral specificity remains obscured. Here, we describe an array platform which uses synthetic mimetics of mucin glycoproteins to model how receptor presentation and density in the mucinous glycocalyx may impact IAV recognition. H1N1 and H3N2 binding in arrays of α2,3- and α2,6-sialyllactose receptors confirmed their known sialic acid-binding specificities and revealed their different sensitivities to receptor presentation. Further, the transition of H1N1 from avian to mammalian cell culture improved the ability of the virus to recognize mucin-like displays of α2,6-sialic acid receptors. Support vector machine (SVM) learning efficiently characterized this shift in binding preference and may prove useful to study viral evolution to a new host

Mucin-mimetic glycan arrays integrating machine learning for analyzing receptor pattern recognition by influenza A viruses

Influenza A viruses (IAVs) exploit host glycans in airway mucosa for entry and infection. Detection of changes in IAV glycan-binding phenotype can provide early indication of transmissibility and infection potential. While zoonotic viruses are monitored for mutations, the influence of host glycan presentation on viral specificity remains obscured. Here, we describe an array platform which uses synthetic mimetics of mucin glycoproteins to model how receptor presentation and density in the mucinous glycocalyx may impact IAV recognition. H1N1 and H3N2 binding in arrays of α2,3- and α2,6-sialyllactose receptors confirmed their known sialic acid-binding specificities and revealed their different sensitivities to receptor presentation. Further, the transition of H1N1 from avian to mammalian cell culture improved the ability of the virus to recognize mucin-like displays of α2,6-sialic acid receptors. Support vector machine (SVM) learning efficiently characterized this shift in binding preference and may prove useful to study viral evolution to a new host

Deep Sclerectomy With Intrascleral Versus Suprachoroidal Collagen Implant: A Randomized Control Trial

Deep sclerectomy with intrascleral collagen implant (DSCI) was less effective in lowering intraocular pressure (IOP) than with suprachoroidal implantation. Further studies are needed to establish the potency and safety of deep sclerectomy with suprachoroidal collagen implant (DSSCI)