bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of ERK Docking Domain Inhibitors that Induce Apoptosis by Targeting Rsk-1 and Caspase-9
Authors: Boston Sarice R , Deshmukh Rahul , Strome Scott , Priyakumar U Deva , MacKerell Alexander D , Shapiro Paul 
Published: January 2011

Abstract

Background
The extracellular signal-regulated kinase-1 and 2 (ERK1/2) proteins play an important role in cancer cell proliferation and survival. ERK1/2 proteins also are important for normal cell functions. Thus, anti-cancer therapies that block all ERK1/2 signaling may result in undesirable toxicity to normal cells. As an alternative, we have used computational and biological approaches to identify low-molecular weight compounds that have the potential to interact with unique ERK1/2 docking sites and selectively inhibit interactions with substrates involved in promoting cell proliferation.

Methods
Colony formation and water soluble tetrazolium salt (WST) assays were used to determine the effects of test compounds on cell proliferation. Changes in phosphorylation and protein expression in response to test compound treatment were examined by immunoblotting and in vitro kinase assays. Apoptosis was determined with immunoblotting and caspase activity assays.

Results

In silico modeling was used to identify compounds that were structurally similar to a previously identified parent compound, called 76. From this screen, several compounds, termed 76.2, 76.3, and 76.4 sharing a common thiazolidinedione core with an aminoethyl side group, inhibited proliferation and induced apoptosis of HeLa cells. However, the active compounds were less effective in inhibiting proliferation or inducing apoptosis in non-transformed epithelial cells. Induction of HeLa cell apoptosis appeared to be through intrinsic mechanisms involving caspase-9 activation and decreased phosphorylation of the pro-apoptotic Bad protein. Cell-based and in vitro kinase assays indicated that compounds 76.3 and 76.4 directly inhibited ERK-mediated phosphorylation of caspase-9 and the p90Rsk-1 kinase, which phosphorylates and inhibits Bad, more effectively than the parent compound 76. Further examination of the test compound's mechanism of action showed little effects on related MAP kinases or other cell survival proteins.

Conclusion
These findings support the identification of a class of ERK-targeted molecules that can induce apoptosis in transformed cells by inhibiting ERK-mediated phosphorylation and inactivation of pro-apoptotic proteins.
SciReader enables reading of medical content with instantaneous definitions
Authors: Gradie Patrick R , Litster Megan , Thomas Rinu , Vyas Jay , Schiller Martin R 
Published: January 2011

Abstract

Background
A major problem patients encounter when reading about health related issues is document interpretation, which limits reading comprehension and therefore negatively impacts health care. Currently, searching for medical definitions from an external source is time consuming, distracting, and negatively impacts reading comprehension and memory of the material.

Methods

SciReader was built as a Java application with a Flex-based front-end client. The dictionary used by SciReader was built by consolidating data from several sources and generating new definitions with a standardized syntax. The application was evaluated by measuring the percentage of words defined in different documents. A survey was used to test the perceived effect of SciReader on reading time and comprehension.

Results
We present SciReader, a web-application that simplifies document interpretation by allowing users to instantaneously view medical, English, and scientific definitions as they read any document. This tool reveals the definitions of any selected word in a small frame at the top of the application. SciReader relies on a dictionary of ~750,000 unique Biomedical and English word definitions. Evaluation of the application shows that it maps ~98% of words in several different types of documents and that most users tested in a survey indicate that the application decreases reading time and increases comprehension.

Conclusions

SciReader is a web application useful for reading medical and scientific documents. The program makes jargon-laden content more accessible to patients, educators, health care professionals, and the general public.
Evaluation of a large scale implementation of disease management programmes in various Dutch regions: a study protocol
Authors: Lemmens Karin MM , Rutten-Van Mölken Maureen PMH , Cramm Jane M , Huijsman Robbert , Bal Roland A , Nieboer Anna P 
Published: January 2011

Abstract

Background
Disease management programmes (DMPs) have been developed to improve effectiveness and economic efficiency within chronic care delivery by combining patient-related, professional-directed, and organisational interventions. The benefits of DMPs within different settings, patient groups, and versions remain unclear. In this article we propose a protocol to evaluate a range of current DMPs by capturing them in a single conceptual framework, employing comparable structure, process, and outcome measures, and combining qualitative and quantitative research methods.

Methods
To assess DMP effectiveness a practical clinical trial will be conducted. Twenty-two disease management experiments will be studied in various Dutch regions consisting of a variety of collaborations between organisations and/or professionals. Patient cohorts include those with cardiovascular diseases, chronic obstructive pulmonary disease, diabetes, stroke, depression, psychotic diseases, and eating disorders. Our methodological approach combines qualitative and quantitative research methods to enable a comprehensive evaluation of complex programmes. Process indicators will be collected from health care providers' data registries and measured via physician and staff questionnaires. Patient questionnaires include health care experiences, health care utilisation, and quality of life. Qualitative data will be gathered by means of interviews and document analysis for an in depth description of project interventions and the contexts in which DMPs are embedded, and an ethnographic process evaluation in five DMPs. Such a design will provide insight into ongoing DMPs and demonstrate which elements of the intervention are potentially (cost)-effective for which patient populations. It will also enable sound comparison of the results of the different programmes.

Discussion
The study will lead to a better understanding of (1) the mechanisms of disease management, (2) the feasibility, and cost-effectiveness of a disease management approach to improving health care, and (3) the factors that determine success and failure of DMPs. Our study results will be relevant to decision makers and managers who confront the challenge of implementing and integrating DMPs into the health care system. Moreover, it will contribute to the search for methods to evaluate complex healthcare interventions.
Metabolic pathway engineering based on metabolomics confers acetic and formic acid tolerance to a recombinant xylose-fermenting strain of Saccharomyces cerevisiae
Authors: Hasunuma Tomohisa , Sanda Tomoya , Yamada Ryosuke , Yoshimura Kazuya , Ishii Jun , Kondo Akihiko 
Published: January 2011

Abstract

Background
The development of novel yeast strains with increased tolerance toward inhibitors in lignocellulosic hydrolysates is highly desirable for the production of bio-ethanol. Weak organic acids such as acetic and formic acids are necessarily released during the pretreatment (i.e. solubilization and hydrolysis) of lignocelluloses, which negatively affect microbial growth and ethanol production. However, since the mode of toxicity is complicated, genetic engineering strategies addressing yeast tolerance to weak organic acids have been rare. Thus, enhanced basic research is expected to identify target genes for improved weak acid tolerance.

Results
In this study, the effect of acetic acid on xylose fermentation was analyzed by examining metabolite profiles in a recombinant xylose-fermenting strain of Saccharomyces cerevisiae. Metabolome analysis revealed that metabolites involved in the non-oxidative pentose phosphate pathway (PPP) [e.g. sedoheptulose-7-phosphate, ribulose-5-phosphate, ribose-5-phosphate and erythrose-4-phosphate] were significantly accumulated by the addition of acetate, indicating the possibility that acetic acid slows down the flux of the pathway. Accordingly, a gene encoding a PPP-related enzyme, transaldolase or transketolase, was overexpressed in the xylose-fermenting yeast, which successfully conferred increased ethanol productivity in the presence of acetic and formic acid.

Conclusions
Our metabolomic approach revealed one of the molecular events underlying the response to acetic acid and focuses attention on the non-oxidative PPP as a target for metabolic engineering. An important challenge for metabolic engineering is identification of gene targets that have material importance. This study has demonstrated that metabolomics is a powerful tool to develop rational strategies to confer tolerance to stress through genetic engineering.
A graphical simulation software for instruction in cardiovascular mechanics physiology
Authors: Wildhaber Reto A , Verrey François , Wenger Roland H 
Published: January 2011

Abstract

Background
Computer supported, interactive e-learning systems are widely used in the teaching of physiology. However, the currently available complimentary software tools in the field of the physiology of cardiovascular mechanics have not yet been adapted to the latest systems software. Therefore, a simple-to-use replacement for undergraduate and graduate students' education was needed, including an up-to-date graphical software that is validated and field-tested.

Methods
Software compatible to Windows, based on modified versions of existing mathematical algorithms, has been newly developed. Testing was performed during a full term of physiological lecturing to medical and biology students.

Results
The newly developed CLabUZH software models a reduced human cardiovascular loop containing all basic compartments: an isolated heart including an artificial electrical stimulator, main vessels and the peripheral resistive components. Students can alter several physiological parameters interactively. The resulting output variables are printed in x-y diagrams and in addition shown in an animated, graphical model. CLabUZH offers insight into the relations of volume, pressure and time dependency in the circulation and their correlation to the electrocardiogram (ECG). Established mechanisms such as the Frank-Starling Law or the Windkessel Effect are considered in this model. The CLabUZH software is self-contained with no extra installation required and runs on most of today's personal computer systems.

Conclusions
CLabUZH is a user-friendly interactive computer programme that has proved to be useful in teaching the basic physiological principles of heart mechanics.
Fructose impairs glucose-induced hepatic triglyceride synthesis
Authors: Huang Danshan , Dhawan Tania , Young Stephen , Yong William H , Boros Laszlo G , Heaney Anthony P 
Published: January 2011

AbstractObesity, type 2 diabetes and hyperlipidemia frequently coexist and are associated with significantly increased morbidity and mortality. Consumption of refined carbohydrate and particularly fructose has increased significantly in recent years and has paralled the increased incidence of obesity and diabetes. Human and animal studies have demonstrated that high dietary fructose intake positively correlates with increased dyslipidemia, insulin resistance, and hypertension. Metabolism of fructose occurs primarily in the liver and high fructose flux leads to enhanced hepatic triglyceride accumulation (hepatic steatosis). This results in impaired glucose and lipid metabolism and increased proinflammatory cytokine expression. Here we demonstrate that fructose alters glucose-stimulated expression of activated acetyl CoA carboxylase (ACC), pSer hormone sensitive lipase (pSerHSL) and adipose triglyceride lipase (ATGL) in hepatic HepG2 or primary hepatic cell culturesin vitro. This was associated with increased de novo triglyceride synthesisin vitroand hepatic steatosisin vivoin fructose- versus glucose-fed and standard-diet fed mice. These studies provide novel insight into the mechanisms involved in fructose-mediated hepatic hypertriglyceridemia and identify fructose-uptake as a new potential therapeutic target for lipid-associated diseases.
Analysis of machine perfusion benefits in kidney grafts: a preclinical study
Authors: Vaziri Nader , Thuillier Raphaël , Favreau Frederic D , Eugene Michel , Milin Serge , Chatauret Nicolas P , Hauet Thierry , Barrou Benoit 
Published: January 2011

Abstract

Background
Machine perfusion (MP) has potential benefits for marginal organs such as from deceased from cardiac death donors (DCD). However, there is still no consensus on MP benefits. We aimed to determine machine perfusion benefits on kidney grafts.

Methods
We evaluated kidney grafts preserved in ViaspanUW or KPS solutions either by CS or MP, in a DCD pig model (60 min warm ischemia + 24 h hypothermic preservation). Endpoints were: function recovery, quality of function during follow up (3 month), inflammation, fibrosis, animal survival.

Results
ViaspanUW-CS animals did not recover function, while in other groups early follow up showed similar values for kidney function. Alanine peptidase and β-NAG activities in the urine were higher in CS than in MP groups. Oxydative stress was lower in KPS-MP animals. Histology was improved by MP over CS. Survival was 0% in ViaspanUW-CS and 60% in other groups. Chronic inflammation, epithelial-to-mesenchymal transition and fibrosis were lowest in KPS-MP, followed by KPS-CS and ViaspanUW-MP.

Conclusions
With ViaspanUW, effects of MP are obvious as only MP kidney recovered function and allowed survival. With KPS, the benefits of MP over CS are not directly obvious in the early follow up period and only histological analysis, urinary tubular enzymes and red/ox status was discriminating. Chronic follow-up was more conclusive, with a clear superiority of MP over CS, independently of the solution used. KPS was proven superior to ViaspanUW in each preservation method in terms of function and outcome. In our pre-clinical animal model of DCD transplantation, MP offers critical benefits.
Nanofluid bioconvection in water-based suspensions containing nanoparticles and oxytactic microorganisms: oscillatory instability
Authors: Kuznetsov Andrey V 
Published: January 2011

AbstractThe aim of this article is to propose a novel type of a nanofluid that contains both nanoparticles and motile (oxytactic) microorganisms. The benefits of adding motile microorganisms to the suspension include enhanced mass transfer, microscale mixing, and anticipated improved stability of the nanofluid. In order to understand the behavior of such a suspension at the fundamental level, this article investigates its stability when it occupies a shallow horizontal layer. The oscillatory mode of nanofluid bioconvection may be induced by the interaction of three competing agencies: oxytactic microorganisms, heating or cooling from the bottom, and top or bottom-heavy nanoparticle distribution. The model includes equations expressing conservation of total mass, momentum, thermal energy, nanoparticles, microorganisms, and oxygen. Physical mechanisms responsible for the slip velocity between the nanoparticles and the base fluid, such as Brownian motion and thermophoresis, are accounted for in the model. An approximate analytical solution of the eigenvalue problem is obtained using the Galerkin method. The obtained solution provides important physical insights into the behavior of this system; it also explains when the oscillatory mode of instability is possible in such system.
Inhibition of spinal astrocytic c-Jun N-terminal kinase (JNK) activation correlates with the analgesic effects of ketamine in neuropathic pain
Authors: Mei Xiao-Peng , Zhang Hui , Wang Wei , Wei Yan-Yan , Zhai Ming-Zhu , Wang Wen , Xu Li-Xian , Li Yun-Qing 
Published: January 2011

Abstract

Background
We have previously reported that inhibition of astrocytic activation contributes to the analgesic effects of intrathecal ketamine on spinal nerve ligation (SNL)-induced neuropathic pain. However, the underlying mechanisms are still unclear. c-Jun N-terminal kinase (JNK), a member of mitogen-activated protein kinase (MAPK) family, has been reported to be critical for spinal astrocytic activation and neuropathic pain development after SNL. Ketamine can decrease lipopolysaccharide (LPS)-induced phosphorylated JNK (pJNK) expression and could thus exert its anti-inflammatory effect. We hypothesized that inhibition of astrocytic JNK activation might be involved in the suppressive effect of ketamine on SNL-induced spinal astrocytic activation.

Methods
Immunofluorescence histochemical staining was used to detect SNL-induced spinal pJNK expression and localization. The effects of ketamine on SNL-induced mechanical allodynia were confirmed by behavioral testing. Immunofluorescence histochemistry and Western blot were used to quantify the SNL-induced spinal pJNK expression after ketamine administration.

Results
The present study showed that SNL induced ipsilateral pJNK up-regulation in astrocytes but not microglia or neurons within the spinal dorsal horn. Intrathecal ketamine relieved SNL-induced mechanical allodynia without interfering with motor performance. Additionally, intrathecal administration of ketamine attenuated SNL-induced spinal astrocytic JNK activation in a dose-dependent manner, but not JNK protein expression.

Conclusions
The present results suggest that inhibition of JNK activation may be involved in the suppressive effects of ketamine on SNL-induced spinal astrocyte activation. Therefore, inhibition of spinal JNK activation may be involved in the analgesic effects of ketamine on SNL-induced neuropathic pain.
Development of an in situ assay for simultaneous detection of the genomic and replicative form of PCV2 using padlock probes and rolling circle amplification
Authors: Henriksson Sara , Blomström Anne-Lie , Fuxler Lisbeth , Fossum Caroline , Berg Mikael , Nilsson Mats 
Published: January 2011

Abstract

Background
In this study we utilized padlock probes and rolling circle amplification as a mean to detect and study the replication of porcine circovirus type 2 (PCV2) in cultured cells and in infected tissue. Porcine circovirus type 2 is a single-stranded circular DNA virus associated with several severe diseases, porcine circovirus diseases (PCVD) in pigs, such as postweaning multisystemic wasting syndrome. The exact reason and mechanisms behind the trigger of PCV2 replication that is associated with these diseases is not well-known. The virus replicates with rolling circle replication and thus also exists as a double-stranded replicative form.

Results
By applying padlock probes and rolling circle amplification we could not only visualise the viral genome but also discriminate between the genomic and the replicative strand in situ. The genomic strand existed in higher numbers than the replicative strand. The virus accumulated in certain nuclei but also spread into the cytoplasm of cells in the surrounding tissue. In cultured cells the average number of signals increased with time after infection.

Conclusions
We have developed a method for detection of both strands of PCV2 in situ that can be useful for studies of replication and in situ detection of PCV2 as well as of DNA viruses in general.
A rapid method to screen putative mRNA targets of any known microRNA
Authors: Huang Yujing , Qi Ying , Ruan Qiang , Ma Yanping , He Rong , Ji Yaohua , Sun Zhengrong 
Published: January 2011

Abstract

Background
microRNAs (miRNAs) are a group of regulatory RNAs that regulate gene expression by binding to specific sequences on target mRNAs. However, functional identification of mRNA targets is usually difficult and time consuming. Here we report hybrid-PCR as a new and rapid approach to screen putative mRNA targets in vitro.

Results
Fifteen putative target mRNAs for human cytomegalovirus (HCMV) miR-UL112-1, including previously confirmed HCMV IE72, were identified from mRNA-derived cDNAs using hybrid-PCR. Moreover, we randomly validated six different target candidates by luciferase reporter assays, and confirmed that their luciferase activities were down-regulated with co-transfection of HCMV miR-UL112-1.

Conclusions
Our study demonstrated that hybrid-PCR is an effective and rapid approach for screening putative miRNA targets, with much more advantage of simplicity, low cost, and ease of implementation.
Transient Inflammation-Induced Ongoing Pain is Driven by TRPV1 Sensitive Afferents
Authors: Okun Alec , DeFelice Milena , Eyde Nathan , Ren Jiyang , Mercado Ramon , King Tamara , Porreca Frank 
Published: January 2011

Background: Tissue injury elicits both hypersensitivity to evoked stimuli and ongoing, stimulus-independent pain. We previously demonstrated that pain relief elicits reward in nerve-injured rats. This approach was used to evaluate the temporal and mechanistic features of inflammation-induced ongoing pain. Results: Intraplantar Complete Freund's Adjuvant (CFA) produced thermal hyperalgesia and guarding behavior that was reliably observed within 24 hrs and maintained, albeit diminished, 4 days post-administration. Spinal clonidine produced robust conditioned place preference (CPP) in CFA treated rats 1 day, but not 4 days following CFA administration. However, spinal clonidine blocked CFA-induced thermal hyperalgesia at both post-CFA days 1 and 4, indicating different time-courses of ongoing and evoked pain. Peripheral nerve block by lidocaine administration into the popliteal fossa 1 day following intraplantar CFA produced a robust preference for the lidocaine paired chamber, indicating that injury-induced ongoing pain is driven by afferent fibers innervating the site of injury. Pretreatment with resiniferatoxin (RTX), an ultrapotent capsaicin analogue known to produce long-lasting desensitization of TRPV1 positive afferents, fully blocked CFA-induced thermal hypersensitivity and abolished the CPP elicited by administration of popliteal fossa lidocaine 24 hrs post-CFA. In addition, RTX pretreatment blocked guarding behavior observed 1 day following intraplantar CFA. In contrast, administration of the selective TRPV1 receptor antagonist, AMG9810, at a dose that reversed CFA-induced thermal hyperalgesia failed to reduce CFA-induced ongoing pain or guarding behavior. Conclusions: These data demonstrate that inflammation induces both ongoing pain and evoked hypersensitivity that can be differentiated on the basis of time course. Ongoing pain (a) is transient, (b) driven by peripheral input resulting from the injury, (c) dependent on TRPV1 positive fibers and (d) not blocked by TRPV1 receptor antagonism. Mechanisms underlying excitation of these afferent fibers in the early post-injury period will offer insights for development of novel pain relieving strategies in the early post-traumatic period.