19 research outputs found
Notch1 signaling is mediated by importins alpha 3, 4, and 7
The Notch signaling pathway is an important regulation system for the development and self-renewal of different tissues. A specific feature of this signaling cascade is the function of Notch as a surface receptor and regulator of gene expression. Hence, Notch activation and signal transduction requires the proteolytic release of the Notch intracellular domain (NICD), which activates the transcription of cell-specific genes after its transport into the nucleus. To date, little is known about the mechanisms that mediate NICD nuclear import. We here show that transport of NICD into the nucleus is mediated by the canonical importin Ī±/Ī²1 pathway. GST pull-down experiments revealed that NICD binds via one of its four potential nuclear localization signals to importins Ī±3, Ī±4, and Ī±7, but not to Ī±1 and Ī±5. siRNA-mediated knockdown experiments showed that importins Ī±3, Ī±4 (and to a lesser extent, Ī±7) mediate nuclear import of NICD and thus are directly involved in Notch signaling
Treatment with etanercept and low monocyte concentration contribute to the risk of invasive aspergillosis in patients post allogeneic stem cell transplantation
Invasive aspergillosis (IA) is a life-threatening complication among allogeneic hematopoietic stem cell transplant (alloSCT) recipients. Despite well known risk factors and different available assays, diagnosis of invasive aspergillosis remains challenging. 103 clinical variables from patients with hematological malignancies and subsequent alloSCT were collected. Associations between collected variables and patients with (n = 36) and without IA (n = 36) were investigated by applying univariate and multivariable logistic regression. The predictive power of the final model was tested in an independent patient cohort (23 IA cases and 25 control patients). Findings were investigated further by in vitro studies, which analysed the effect of etanercept on A. fumigatus-stimulated macrophages at the gene expression and cytokine secretion. Additionally, the release of C-X-C motif chemokine ligand 10 (CXCL10) in patient sera was studied. Low monocyte concentration (p = 4.8 Ć 10ā06), severe GvHD of the gut (grade 2ā4) (p = 1.08 Ć 10ā02) and etanercept treatment of GvHD (p = 3.5 Ć 10ā03) were significantly associated with IA. Our studies showed that etanercept lowers CXCL10 concentrations in vitro and ex vivo and downregulates genes involved in immune responses and TNF-alpha signaling. Our study offers clinicians new information regarding risk factors for IA including low monocyte counts and administration of etanercept. After necessary validation, such information may be used for decision making regarding antifungal prophylaxis or closely monitoring patients at risk
Diversification of importin-Ī± isoforms in cellular trafficking and disease states.
The human genome encodes seven isoforms of importin Ī± which are grouped into three subfamilies known as Ī±1, Ī±2 and Ī±3. All isoforms share a fundamentally conserved architecture that consists of an N-terminal, autoinhibitory, importin-Ī²-binding (IBB) domain and a C-terminal Arm (Armadillo)-core that associates with nuclear localization signal (NLS) cargoes. Despite striking similarity in amino acid sequence and 3D structure, importin-Ī± isoforms display remarkable substrate specificity in vivo. In the present review, we look at key differences among importin-Ī± isoforms and provide a comprehensive inventory of known viral and cellular cargoes that have been shown to associate preferentially with specific isoforms. We illustrate how the diversification of the adaptor importin Ī± into seven isoforms expands the dynamic range and regulatory control of nucleocytoplasmic transport, offering unexpected opportunities for pharmacological intervention. The emerging view of importin Ī± is that of a key signalling molecule, with isoforms that confer preferential nuclear entry and spatiotemporal specificity on viral and cellular cargoes directly linked to human diseases
Preventable patient harm: A multidisciplinary, bundled approach to reducing clostridium difficile infections while using a glutamate dehydrogenase/toxin immunochromatographic assay/nucleic acid amplification test diagnostic algorithm
Health care facility-onset Clostridium difficile infections (HO-CDI) are an important national problem, causing increased morbidity and mortality. HO-CDI is an important metric for the Center for Medicare and Medicaid Serviceās (CMS) performance measures. Hospitals that fall into the worst-performing quartile in preventing hospital-acquired infections, including HO-CDI, may lose millions of dollars in reimbursement. Under pressure to reduce CDI and without a clear optimal method for C. difficile detection, health care facilities are questioning how best to use highly sensitive nucleic acid amplification tests (NAATs) to aid in the diagnosis of CDI. Our institution has used a two-step glutamate dehydrogenase (GDH)/toxin immunochromatographic assay/NAAT algorithm since 2009. In 2016, our institution set an organizational goal to reduce our CDI rates by 10% by July 2017. We achieved a statistically significant reduction of 42.7% in our HO-CDI rate by forming a multidisciplinary group to implement and monitor eight key categories of infection prevention interventions over a period of 13 months. Notably, we achieved this reduction without modifying our laboratory algorithm. Significant reductions in CDI rates can be achieved without altering sensitive laboratory testing methods
Systematic interactome mapping of acute lymphoblastic leukemia cancer gene products reveals EXT-1 tumor suppressor as a Notch1 and FBWX7 common interactor
Direct Experimental Evidence of Non-first Order Degradation Kinetics and Sorption-Induced Isotopic Fractionation in a Mesoscale Aquifer: <sup>13</sup>C/<sup>12</sup>C Analysis of a Transient Toluene Pulse
The
injection of a mixed toluene and D<sub>2</sub>O (conservative
tracer) pulse into a pristine mesoscale aquifer enabled a first direct
experimental comparison of contaminant-specific isotopic fractionation
from sorption versus biodegradation and transverse dispersion on a
relevant scale. Water samples were taken from two vertically resolved
sampling ports at 4.2 m distance. Analysis of deuterium and toluene
concentrations allowed quantifying the extent of sorption (<i>R</i> = 1.25) and biodegradation (37% and 44% of initial toluene
at the two sampling ports). Sorption and biodegradation were found
to directly affect toluene <sup>13</sup>C/<sup>12</sup>C breakthrough
curves. In particular, isotope trends demonstrated that biodegradation
underwent MichaelisāMenten kinetics rather than first-order
kinetics. Carbon isotope enrichment factors obtained from an optimized
reactive transport model (Eckert et al., this issue) including a possible
isotope fractionation of transverse dispersion were Īµ<sup>equ</sup><sub>sorption</sub> = ā0.31 ā°, Īµ<sup>kin</sup><sub>transverseādispersion</sub> = ā0.82 ā°,
and Īµ<sup>kin</sup><sub>biodegradation</sub> = ā2.15
ā°. Extrapolation of our results to the scenario of a continuous
injection predicted that (i) the bias in isotope fractionation from
sorption, but not transverse dispersion, may be avoided when the plume
reaches steady-state; and (ii) the relevance from both processes is
expected to decrease at longer flow distances when isotope fractionation
of degradation increasingly dominates
Targeting the cell wall: Preparation of monoclonal antibody for accurate identification of Alicyclobacillus acidoterrestris in apple juice
The Drosophila Importin-Ī±3 Is Required for Nuclear Import of Notch In Vivo and It Displays Synergistic Effects with Notch Receptor on Cell Proliferation
Notch signaling in response to excitotoxicity induces neurodegeneration via erroneous cell cycle reentry
Neurological disorders such as Alzheimerās disease, stroke and epilepsy are currently marred by the lack of effective treatments to prevent neuronal death. Erroneous cell cycle reentry (CCR) is hypothesized to have a causative role in neurodegeneration. We show that forcing S-phase reentry in cultured hippocampal neurons is sufficient to induce neurodegeneration. We found that kainic-acid treatment in vivo induces erroneous CCR and neuronal death through a Notch-dependent mechanism. Ablating Notch signaling in neurons provides neuroprotection against kainic acid-induced neuronal death. We further show that kainic-acid treatment activates Notch signaling, which increases the bioavailability of CyclinD1 through Akt/GSK3Ī² pathway, leading to aberrant CCR via activation of CyclinD1-Rb-E2F1 axis. In addition, pharmacological blockade of this pathway at critical steps is sufficient to confer resistance to kainic acid-induced neurotoxicity in mice. Taken together, our results demonstrate that excitotoxicity leads to neuronal death in a Notch-dependent manner through erroneous CCR