43 research outputs found
Calmodulin-dependent kinase IV links Toll-like receptor 4 signaling with survival pathway of activated dendritic cells.
Microbial products, including lipopolysaccharide (LPS), an agonist of Toll-like receptor 4 (TLR4), regulate the lifespan of dendritic cells (DCs) by largely undefined mechanisms. Here, we identify a role for calcium-calmodulinâdependent kinase IV (CaMKIV) in this survival program. The pharmacologic inhibition of CaMKs as well as ectopic expression of kinase-inactive CaMKIV decrease the viability of monocyte-derived DCs exposed to bacterial LPS. The defect in TLR4 signaling includes a failure to accumulate the phosphorylated form of the cAMP response element-binding protein (pCREB), Bcl-2, and Bcl-xL. CaMKIV null mice have a decreased number of DCs in lymphoid tissues and fail to accumulate mature DCs in spleen on in vivo exposure to LPS. Although isolated Camk4(â/â) DCs are able to acquire the phenotype typical of mature cells and release normal amounts of cytokines in response to LPS, they fail to accumulate pCREB, Bcl-2, and Bcl-xL and therefore do not survive. The transgenic expression of Bcl-2 in CaMKIV null mice results in full recovery of DC survival in response to LPS. These results reveal a novel link between TLR4 and a calcium-dependent signaling cascade comprising CaMKIV-CREB-Bcl-2 that is essential for DC survival
Prediction of early recurrent thromboembolic event and major bleeding in patients with acute stroke and atrial fibrillation by a risk stratification schema: the ALESSA score study
Background and PurposesâThis study was designed to derive and validate a score to predict early ischemic events and major bleedings after an acute ischemic stroke in patients with atrial fibrillation.
MethodsâThe derivation cohort consisted of 854 patients with acute ischemic stroke and atrial fibrillation included in prospective series between January 2012 and March 2014. Older age (hazard ratio 1.06 for each additional year; 95% confidence interval, 1.00â1.11) and severe atrial enlargement (hazard ratio, 2.05; 95% confidence interval, 1.08â2.87) were predictors for ischemic outcome events (stroke, transient ischemic attack, and systemic embolism) at 90 days from acute stroke. Small lesions (â€1.5 cm) were inversely correlated with both major bleeding (hazard ratio, 0.39; P=0.03) and ischemic outcome events (hazard ratio, 0.55; 95% confidence interval, 0.30â1.00). We assigned to age â„80 years 2 points and between 70 and 79 years 1 point; ischemic index lesion >1.5 cm, 1 point; severe atrial enlargement, 1 point (ALESSA score). A logistic regression with the receiver-operating characteristic graph procedure (C statistic) showed an area under the curve of 0.697 (0.632â0.763; P=0.0001) for ischemic outcome events and 0.585 (0.493â0.678; P=0.10) for major bleedings.
ResultsâThe validation cohort consisted of 994 patients included in prospective series between April 2014 and June 2016. Logistic regression with the receiver-operating characteristic graph procedure showed an area under the curve of 0.646 (0.529â0.763; P=0.009) for ischemic outcome events and 0.407 (0.275â0.540; P=0.14) for hemorrhagic outcome events.
ConclusionsâIn acute stroke patients with atrial fibrillation, high ALESSA scores were associated with a high risk of ischemic events but not of major bleedings
Bicaudal D2, Dynein, and Kinesin-1 Associate with Nuclear Pore Complexes and Regulate Centrosome and Nuclear Positioning during Mitotic Entry
Mammalian Bicaudal D2 is the missing molecular link between cytoplasmic motor proteins and the nucleus during nuclear positioning prior to the onset of mitosis
Common Limitations of Image Processing Metrics:A Picture Story
While the importance of automatic image analysis is continuously increasing,
recent meta-research revealed major flaws with respect to algorithm validation.
Performance metrics are particularly key for meaningful, objective, and
transparent performance assessment and validation of the used automatic
algorithms, but relatively little attention has been given to the practical
pitfalls when using specific metrics for a given image analysis task. These are
typically related to (1) the disregard of inherent metric properties, such as
the behaviour in the presence of class imbalance or small target structures,
(2) the disregard of inherent data set properties, such as the non-independence
of the test cases, and (3) the disregard of the actual biomedical domain
interest that the metrics should reflect. This living dynamically document has
the purpose to illustrate important limitations of performance metrics commonly
applied in the field of image analysis. In this context, it focuses on
biomedical image analysis problems that can be phrased as image-level
classification, semantic segmentation, instance segmentation, or object
detection task. The current version is based on a Delphi process on metrics
conducted by an international consortium of image analysis experts from more
than 60 institutions worldwide.Comment: This is a dynamic paper on limitations of commonly used metrics. The
current version discusses metrics for image-level classification, semantic
segmentation, object detection and instance segmentation. For missing use
cases, comments or questions, please contact [email protected] or
[email protected]. Substantial contributions to this document will be
acknowledged with a co-authorshi
Understanding metric-related pitfalls in image analysis validation
Validation metrics are key for the reliable tracking of scientific progress
and for bridging the current chasm between artificial intelligence (AI)
research and its translation into practice. However, increasing evidence shows
that particularly in image analysis, metrics are often chosen inadequately in
relation to the underlying research problem. This could be attributed to a lack
of accessibility of metric-related knowledge: While taking into account the
individual strengths, weaknesses, and limitations of validation metrics is a
critical prerequisite to making educated choices, the relevant knowledge is
currently scattered and poorly accessible to individual researchers. Based on a
multi-stage Delphi process conducted by a multidisciplinary expert consortium
as well as extensive community feedback, the present work provides the first
reliable and comprehensive common point of access to information on pitfalls
related to validation metrics in image analysis. Focusing on biomedical image
analysis but with the potential of transfer to other fields, the addressed
pitfalls generalize across application domains and are categorized according to
a newly created, domain-agnostic taxonomy. To facilitate comprehension,
illustrations and specific examples accompany each pitfall. As a structured
body of information accessible to researchers of all levels of expertise, this
work enhances global comprehension of a key topic in image analysis validation.Comment: Shared first authors: Annika Reinke, Minu D. Tizabi; shared senior
authors: Paul F. J\"ager, Lena Maier-Hei
PPAR-Îł Agonist GW1929 But Not Antagonist GW9662 Reduces TBBPA-Induced Neurotoxicity in Primary Neocortical Cells
Anticoagulation After Stroke in Patients With Atrial Fibrillation : To Bridge or Not With Low-Molecular-Weight Heparin?
Background and Purpose- Bridging therapy with low-molecular-weight heparin reportedly leads to a worse outcome for acute cardioembolic stroke patients because of a higher incidence of intracerebral bleeding. However, this practice is common in clinical settings. This observational study aimed to compare (1) the clinical profiles of patients receiving and not receiving bridging therapy, (2) overall group outcomes, and (3) outcomes according to the type of anticoagulant prescribed. Methods- We analyzed data of patients from the prospective RAF and RAF-NOACs studies. The primary outcome was defined as the composite of ischemic stroke, transient ischemic attack, systemic embolism, symptomatic cerebral bleeding, and major extracerebral bleeding observed at 90 days after the acute stroke. Results- Of 1810 patients who initiated oral anticoagulant therapy, 371 (20%) underwent bridging therapy with full-dose low-molecular-weight heparin. Older age and the presence of leukoaraiosis were inversely correlated with the use of bridging therapy. Forty-two bridged patients (11.3%) reached the combined outcome versus 72 (5.0%) of the nonbridged patients (P=0.0001). At multivariable analysis, bridging therapy was associated with the composite end point (odds ratio, 2.3; 95% CI, 1.4-3.7; P Conclusions- Our findings suggest that patients receiving low-molecular-weight heparin have a higher risk of early ischemic recurrence and hemorrhagic transformation compared with nonbridged patients.Peer reviewe