Flavopiridol Protects Against Inflammation by Attenuating Leukocyte-Endothelial Interaction via Inhibition of Cyclin-Dependent Kinase 9

Objective: The cyclin-dependent kinase (CDK) inhibitor flavopiridol is currently being tested in clinical trials as anticancer drug. Beyond its cell death–inducing action, we hypothesized that flavopiridol affects inflammatory processes. Therefore, we elucidated the action of flavopiridol on leukocyte–endothelial cell interaction and endothelial activation in vivo and in vitro and studied the underlying molecular mechanisms. Methods and Results: Flavopiridol suppressed concanavalin A–induced hepatitis and neutrophil infiltration into liver tissue. Flavopiridol also inhibited tumor necrosis factor-α–induced leukocyte– endothelial cell interaction in the mouse cremaster muscle. Endothelial cells were found to be the major target of flavopiridol, which blocked the expression of endothelial cell adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin), as well as NF-κB-dependent transcription. Flavopiridol did not affect inhibitor of κB (IκB) kinase, the degradation and phosphorylation of IκBα, nuclear translocation of p65, or nuclear factor-κB (NF-κB) DNA-binding activity. By performing a cellular kinome array and a kinase activity panel, we found LIM domain kinase-1 (LIMK1), casein kinase 2, c-Jun N-terminal kinase (JNK), protein kinase Cθ (PKCθ), CDK4, CDK6, CDK8, and CDK9 to be influenced by flavopiridol. Using specific inhibitors, as well as RNA interference (RNAi), we revealed that only CDK9 is responsible for the action of flavopiridol. Conclusion: Our study highlights flavopiridol as a promising antiinflammatory compound and inhibition of CDK9 as a novel approach for the treatment of inflammation-associated diseases

Motilitätsstörungen des Ösophagus

Zusammenfassung: Motilitätsstörungen des Ösophagus umfassen ein heterogenes Spektrum von Erkrankungen. Primäre Fehlbildungen des Ösophagus sind heute zwar einer verbesserten chirurgischen und gastroenterologischen Therapie zugänglich, führen jedoch zu langfristig persistierender ösophagealer Dysmotilität. Die Achalasie resultiert aus einer gestörten Relaxation des gastroösophagealen Sphinkters. Systemische Erkrankungen können mit einer sekundären ösophagealen Motilitätsstörung einhergehen. Zahlreiche neuromuskuläre Erkrankungen mit viszeraler Manifestation zeigen eine ösophageale Beteiligung. Selten kann eine Aganglionose bis in den Ösophagus reichen. Die wachsende Gruppe der Myopathien schließt metabolische und mitochondriale Störungen ein, deren zunehmende Charakterisierung genetischer Defekte vereinzelt bereits therapeutische Ansätze eröffnet. Infektbedingte Ösophagitiden zeigen besonders bei immunkompromittierten Patienten eine schwere Störung der Motilität. Immunologisch vermittelte Entzündungsprozesse im und um den Ösophagus werden allmählich besser verstanden. Schließlich können seltene Tumoren und tumorartige Läsionen eine Dysmotilität des Ösophagus verursache

Answering Twitter Questions: a Model for Recommending Answerers through Social Collaboration

International audienceIn this paper, we specifically consider the challenging task of solving a question posted on Twitter. The latter generally remains unanswered and most of the replies, if any, are only from members of the questioner's neighborhood. As outlined in previous work related to community Q&A, we believe that question-answering is a collaborative process and that the relevant answer to a question post is an aggregation of answer nuggets posted by a group of relevant users. Thus, the problem of identifying the relevant answer turns into the problem of identifying the right group of users who would provide useful answers and would possibly be willing to collaborate together in the long-term. Accordingly, we present a novel method, called CRAQ, that is built on the collaboration paradigm and formulated as a group entropy optimization problem. To optimize the quality of the group, an information gain measure is used to select the most likely " informative " users according to topical and collaboration likelihood predictive features. Crowd-based experiments performed on two crisis-related Twitter datasets demonstrate the effectiveness of our collaborative-based answering approach

Surface modification of Ti-4Al-2V alloy by nitrogen implantation

Ti-4Al-2V is a new type of alpha titanium alloy that suitable for the application in high-temperature and high-pressure water/steam environment. Ti-4Al-2V can be used in marine engineering, nuclear power industry. In this paper the surface characterization of the Ti-4Al-2V implanted with 75 keV nitrogen with fluences of 3 × 10 17 and 8 × 10 17  N + /cm 2 is investigated by glancing-incidence XRD, XPS and microhardness. The results show that new phase TiN are formed after N implantation in the surface region. The nitrogen implantation increases the surface hardness up to 340 and 260% for fluence of 8 × 10 17 and 3 × 10 17  N + /cm 2 , respectively. The enhancement of hardness is related to the formation of TiN and irradiation induced hardness.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43177/1/10853_2005_Article_5365.pd

In developing hippocampal neurons, NR2B-containing N-methyl-d-aspartate receptors (NMDARs) can mediate signaling to neuronal survival and synaptic potentiation, as well as neuronal death

It has been suggested that NR2B-containing NMDA receptors have a selective tendency to promote pro-death signalling and synaptic depression, compared to the survival promoting, synapse potentiating properties of NR2A-containing NMDA receptors. A preferential localization of NR2A-containing NMDA receptors at the synapse in maturing neurons could thus explain differences in synaptic vs. extrasynaptic NMDA receptor signalling. We have investigated whether NMDA receptors can mediate signalling to survival, death, and synaptic potentiation, in neurons at a developmental stage prior to significant NR2A expression and subunit-specific differences between synaptic and extrasynaptic NMDA receptors. We show that in developing hippocampal neurons, the progressive reduction in sensitivity of NMDA receptor currents to the NR2B antagonist ifenprodil applies to both synaptic and extrasynaptic locations. However, the reduction is less acute in extrasynaptic currents, indicating that NR2A does partition preferentially, but not exclusively, into synaptic locations at DIV>12. We then studied NMDA receptor signalling at DIV10, when both synaptic and extrasynaptic NMDA receptors are both overwhelmingly and equally NR2B-dominated. To analyse pro-survival signalling we studied the influence of synaptic NMDA receptor activity on staurosporine-induced apoptosis. Blockade of spontaneous NMDAR activity with MK-801, or ifenprodil exacerbated the apoptotic insult. Furthermore, MK-801 and ifenprodil both antagonized neuroprotection promoted by enhancing synaptic activity. Pro-death signalling induced by a toxic dose of NMDA is also blocked by NR2B-specific antagonists. Using a cell culture model of synaptic NMDA receptor-dependent synaptic potentiation, we find that this is mediated exclusively by NR2B-containing NMDARs, as implicated by NR2B-specific antagonists and the use of selective vs. non-selective doses of the NR2A-preferring antagonist NVP-AAM077. Therefore, within a single neuron, NR2B-NMDA receptors are able to mediate both survival and death signalling, as well as model of NMDA receptor-dependent synaptic potentiation. In this instance, subunit differences cannot account for the dichotomous nature of NMDA receptor signalling

What’s in a Name? Use of Brand versus Generic Drug Names in United States Outpatient Practice

BACKGROUND: The use of brand rather than generic names for medications can increase health care costs. However, little is known at a national level about how often physicians refer to drugs using their brand or generic names. OBJECTIVE: To evaluate how often physicians refer to drugs using brand or generic terminology. DESIGN AND PARTICIPANTS: We used data from the 2003 National Ambulatory Medical Care Survey (NAMCS), a nationally representative survey of 25,288 community-based outpatient visits in the United States. After each visit, patient medications were recorded on a survey encounter form by the treating physician or transcribed from office notes. MEASUREMENTS: Our main outcome measure was the frequency with which medications were recorded on the encounter form using their brand or generic names. RESULTS: For 20 commonly used drugs, the median frequency of brand name use was 98% (interquartile range, 81–100%). Among 12 medications with no generic competition at the time of the survey, the median frequency of brand name use was 100% (range 92–100%). Among 8 medications with generic competition at the time of the survey (“multisource” drugs), the median frequency of brand name use was 79% (range 0–98%; P < .001 for difference between drugs with and without generic competition). CONCLUSIONS: Physicians refer to most medications by their brand names, including drugs with generic formulations. This may lead to higher health care costs by promoting the use of brand-name products when generic alternatives are available

Deregulation of Sucrose-Controlled Translation of a bZIP-Type Transcription Factor Results in Sucrose Accumulation in Leaves

Sucrose is known to repress the translation of Arabidopsis thaliana AtbZIP11 transcript which encodes a protein belonging to the group of S (S - stands for small) basic region-leucine zipper (bZIP)-type transcription factor. This repression is called sucrose-induced repression of translation (SIRT). It is mediated through the sucrose-controlled upstream open reading frame (SC-uORF) found in the AtbZIP11 transcript. The SIRT is reported for 4 other genes belonging to the group of S bZIP in Arabidopsis. Tobacco tbz17 is phylogenetically closely related to AtbZIP11 and carries a putative SC-uORF in its 5′-leader region. Here we demonstrate that tbz17 exhibits SIRT mediated by its SC-uORF in a manner similar to genes belonging to the S bZIP group of the Arabidopsis genus. Furthermore, constitutive transgenic expression of tbz17 lacking its 5′-leader region containing the SC-uORF leads to production of tobacco plants with thicker leaves composed of enlarged cells with 3–4 times higher sucrose content compared to wild type plants. Our finding provides a novel strategy to generate plants with high sucrose content

Introducing standardized field methods for fracture-focused surface process research

Rock fractures are a key contributor to a broad array of Earth surface processes due to their direct control on rock strength as well as rock porosity and permeability. However, to date, there has been no standardization for the quantification of rock fractures in surface process research. In this work, the case is made for standardization within fracture-focused research, and prior work is reviewed to identify various key datasets and methodologies. Then, a suite of standardized methods is presented as a starting “baseline” for fracture-based research in surface process studies. These methods have been shown in pre-existing work from structural geology, geotechnical engineering, and surface process disciplines to comprise best practices for the characterization of fractures in clasts and outcrops. This practical, accessible, and detailed guide can be readily employed across all fracture-focused weathering and geomorphology applications. The wide adoption of a baseline of data collected using the same methods will enable comparison and compilation of datasets among studies globally and will ultimately lead to a better understanding of the links and feedbacks between rock fracture and landscape evolution.</p

NFATc1 induction by an intronic enhancer restricts NKT γδ cell formation

In thymus, the ablation of T cell receptor (TCR)-activated transcription factor NFATc1 or its inducible isoforms during the double-negative (DN) stages of thymocyte development leads to a marked increase in γδ thymocytes whereas the development of αβ thymocytes remains mostly unaffected. These γδ thymocytes are characterized by the upregulation of the promyelocytic leukemia zinc-finger factor (PLZF), the "master regulator" of natural killer T (NKT) cell development, and the acquisition of an NKT γδ cell phenotype with higher cell survival rates. The suppressive function of NFATc1 in NKT γδ cell formation critically depends on the remote enhancer E2, which is essential for the inducible expression of NFATc1 directed by its distal promoter P1. Thus, the enhancer deciphers a strong γδ TCR signal into the expression of inducible NFATc1 isoforms resulting in high levels of NFATc1 protein that are essential to control the numbers of NKT γδ cells