bluuebunny/crossref_metadata_2025 huggingface dataset:
Current advances in the treatment of Alzheimer's disease: focused on considerations targeting Aβ and tau
Authors: Hong-Qi Yang , Zhi-Kun Sun , Sheng-Di Chen
Published: October 2012

Alzheimer’s disease (AD) is a neurodegenerative disorder that impairs mainly the memory and cognitive function in elderly. Extracellular beta amyloid deposition and intracellular tau hyperphosphorylation are the two pathological events that are thought to cause neuronal dysfunction in AD. Since the detailed mechanisms that underlie the pathogenesis of AD are still not clear, the current treatments are those drugs that can alleviate the symptoms of AD patients. Recent studies have indicated that these symptom-reliving drugs also have the ability of regulating amyloid precursor protein processing and tau phosphorylation. Thus the pharmacological mechanism of these drugs may be too simply-evaluated. This review summarizes the current status of AD therapy and some potential preclinical considerations that target beta amyloid and tau protein are also discussed.
Transdifferentiation of MALME-3M and MCF-7 Cells toward Adipocyte-like Cells is Dependent on Clathrin-mediated Endocytosis
Authors: Carcel-Trullols Jaime , Aguilar-Gallardo Cristóbal , Garcia-Alcalde Fernando , Pardo-Cea Miguel Angel , Dopazo Joaquin , Conesa Ana , Simón Carlos
Published: October 2012

Enforced cell transdifferentiation of human cancer cells is a promising alternative to conventional chemotherapy. We previously identified albumin-associated lipid- and, more specifically, saturated fatty acid-induced transdifferentiation programs in human cancer cells (HCCLs). In this study, we further characterized the adipocyte-like cells, resulting from the transdifferentiation of human cancer cell lines MCF-7 and MALME-3M, and proposed a common mechanistic approach for these transdifferentiating programs. We showed the loss of pigmentation in MALME-3M cells treated with albumin-associated lipids, based on electron microscopic analysis, and the overexpression of perilipin 2 (PLIN2) by western blotting in MALME-3M and MCF-7 cells treated with unsaturated fatty acids. Comparing the gene expression profiles of naive melanoma MALME-3M cells and albumin-associated lipid-treated cells, based on RNA sequencing, we confirmed the transcriptional upregulation of some key adipogenic gene markers and also an alternative splicing of the adipogenic master regulator PPARG, that is probably related to the reported up regulated expression of the protein. Most importantly, these results also showed the upregulation of genes responsible for Clathrin (CLTC) and other adaptor-related proteins. An increase in CLTC expression in the transdifferentiated cells was confirmed by western blotting. Inactivation of CLTC by chlorpromazine (CHP), an inhibitor of CTLC mediated endocytosis (CME), and gene silencing by siRNAs, partially reversed the accumulation of neutral lipids observed in the transdifferentiated cells. These findings give a deeper insight into the phenotypic changes observed in HCCL to adipocyte-like transdifferentiation and point towards CME as a key pathway in distinct transdifferentiation programs.

Disclosures

Simon C and Aguilar-Gallardo C are co-inventors of the International Patent Application No. PCT/EP2011/004941 entitled “Methods for tumor treatment and adipogenesis differentiation”.
An iterative scheme for numerical solution of Volterra integral equations using collocation method and Chebyshev polynomials
Authors: Rashidinia Jalil , Najafi Esmaeil , Arzhang Asghar
Published: October 2012

When we discretize nonlinear Volterra integral equations using some numerical, such as collocation methods, the arising algebraic systems are nonlinear. Applying quasilinear technique to the nonlinear Volterra integral equations gives raise to linear Volterra integral equations. The solutions of these equations yield a functional sequence quadratically convergent to the solution. Then, we use collocation method based on Chebyshev polynomials and a modified Clenshaw-Curtis quadrature and obtain a numerical solution. Error analysis has been performed, and the method has been applied on three numerical examples.
Selective gene-expression profiling of migratory tumor cells in vivo predicts clinical outcome in breast cancer patients
Authors: Patsialou Antonia , Wang Yarong , Lin Juan , Whitney Kathleen , Goswami Sumanta , Kenny Paraic A , Condeelis John S
Published: October 2012

Introduction

Metastasis of breast cancer is the main cause of death in patients. Previous genome-wide studies have identified gene-expression patterns correlated with cancer patient outcome. However, these were derived mostly from whole tissue without respect to cell heterogeneity. In reality, only a small subpopulation of invasive cells inside the primary tumor is responsible for escaping and initiating dissemination and metastasis. When whole tissue is used for molecular profiling, the expression pattern of these cells is masked by the majority of the noninvasive tumor cells. Therefore, little information is available about the crucial early steps of the metastatic cascade: migration, invasion, and entry of tumor cells into the systemic circulation.

Methods

In the past, we developed an in vivo invasion assay that can capture specifically the highly motile tumor cells in the act of migrating inside living tumors. Here, we used this assay in orthotopic xenografts of human MDA-MB-231 breast cancer cells to isolate selectively the migratory cell subpopulation of the primary tumor for gene-expression profiling. In this way, we derived a gene signature specific to breast cancer migration and invasion, which we call the Human Invasion Signature (HIS).

Results

Unsupervised analysis of the HIS shows that the most significant upregulated gene networks in the migratory breast tumor cells include genes regulating embryonic and tissue development, cellular movement, and DNA replication and repair. We confirmed that genes involved in these functions are upregulated in the migratory tumor cells with independent biological repeats. We also demonstrate that specific genes are functionally required for in vivo invasion and hematogenous dissemination in MDA-MB-231, as well as in patient-derived breast tumors. Finally, we used statistical analysis to show that the signature can significantly predict risk of breast cancer metastasis in large patient cohorts, independent of well-established prognostic parameters.

Conclusions

Our data provide novel insights into, and reveal previously unknown mediators of, the metastatic steps of invasion and dissemination in human breast tumors in vivo. Because migration and invasion are the early steps of metastatic progression, the novel markers that we identified here might become valuable prognostic tools or therapeutic targets in breast cancer.
Vascular endothelial growth factor receptor-1 mRNA overexpression in peripheral blood as a useful prognostic marker in breast cancer
Authors: Kosaka Yoshimasa , Kataoka Akemi , Yamaguchi Hiroshi , Ueo Hiroaki , Akiyoshi Sayuri , Sengoku Norihiko , Kuranami Masaru , Ohno Shinji , Watanabe Masahiko , Mimori Koshi , Mori Masaki
Published: October 2012

Introduction

Identification of useful markers associated with poor prognosis in breast cancer patients is critically needed. We previously showed that expression of vascular endothelial growth factor receptor-1 mRNA in peripheral blood may be useful to predict distant metastasis in gastric cancer patients. However, expression of vascular endothelial growth factor receptor-1 mRNA in peripheral blood of breast cancer patients has not yet been studied.

Methods

Real-time reverse transcriptase-PCR was used to analyze vascular endothelial growth factor receptor-1 mRNA expression status with respect to various clinical parameters in 515 patients with breast cancer and 25 controls.

Results

Expression of vascular endothelial growth factor receptor-1 mRNA in peripheral blood was higher in breast cancer patients than in controls. Increased vascular endothelial growth factor receptor-1 mRNA expression was associated with large tumor size, lymph node metastasis and clinical stage. Patients with high vascular endothelial growth factor receptor-1 mRNA expression also experienced a poorer survival rate than those with low expression levels, including those patients with triple-negative type and luminal-HER2(-) type disease.

Conclusions

Expression of vascular endothelial growth factor receptor-1 mRNA in peripheral blood may be useful for prediction of poor prognosis in breast cancer, especially in patients with triple-negative type and luminal-HER2(-) type disease.
Sex hormone changes during weight loss and maintenance in overweight and obese postmenopausal African-American and non-African-American women
Authors: Stolzenberg-Solomon Rachael Z , Falk Roni T , Stanczyk Frank , Hoover Robert N , Appel Lawrence J , Ard Jamy D , Batch Bryan C , Coughlin Janelle , Han Xu , Lien Lillian F , Pinkston Christina M , Svetkey Laura P , Katki Hormuzd A
Published: October 2012

Introduction

Changes in sex hormones with weight loss might have implications for breast cancer prevention but have not been examined extensively, particularly in African-American (AA) women.

Methods

We conducted a prospective study of 278 overweight/obese postmenopausal women (38% AA) not taking hormone therapy within the Weight Loss Maintenance Trial. All participants lost at least 4 kg after a 6-month weight-loss phase and attempted to maintain weight loss during the subsequent 12 months. We evaluated the percentage changes in estrone, estradiol, free estradiol, testosterone, free testosterone, androstenedione, dehydroepiandrosterone sulfate and sex hormone-binding globulin (SHBG) using generalized estimating equations.

Results

In all study phases, AA women had higher levels of estrogen and testosterone concentrations, independent of adiposity. On average, participants lost 7.7 kg during the weight-loss phase, and concentrations of estrone (-5.7%, P = 0.006), estradiol (-9.9%, P <0.001), free estradiol (-13.4%, P <0.0001), and free testosterone (-9.9%, P <0.0001) decreased, while the SHBG concentration (16.2%, P <0.001) increased. Weight change did not significantly affect total testosterone or other androgen concentrations. Compared with non-AA women, AA women experienced less change in estrogens per kilogram of weight change (that is, per 1 kg weight loss: estrone, -0.6% vs. -1.2%, P-interaction = 0.10; estradiol, -1.1% vs. -1.9%, P-interaction = 0.04; SHBG, 0.9% vs. 1.6%, P-interaction = 0.006; free estradiol, -1.4% vs. -2.1%, P-interaction = 0.01).

Conclusion

To the best of our knowledge this is the first study to examine and compare the effects of intentional weight loss and maintenance on a panel of sex hormones in AA women and non-AA women. Although speculative, these data suggest hormonal differences may contribute to different racial patterns of breast cancer incidence and mortality and encourage further investigations to understand the long-term effects of weight loss on sex hormones in obese postmenopausal women.

Trial Registration

ClinicalTrials.gov: NCT00054925
Medical-grade honey does not reduce skin colonization at central venous catheter-insertion sites of critically ill patients: a randomized controlled trial
Authors: Kwakman Paulus H , Müller Marcella C , Binnekade Jan M , van den Akker Johannes P , de Borgie Corianne A , Schultz Marcus J , Zaat Sebastian A
Published: October 2012

Introduction

Catheter-related bloodstream infections (CRBSIs) associated with short-term central venous catheters (CVCs) in intensive care unit (ICU) patients are a major clinical problem. Bacterial colonization of the skin at the CVC insertion site is an important etiologic factor for CRBSI. The aim of this study was to assess the efficacy of medical-grade honey in reducing bacterial skin colonization at insertion sites.

Methods

A prospective, single-center, open-label randomized controlled trial was performed at the ICU of a university hospital in The Netherlands to assess the efficacy of medical-grade honey to reduce skin colonization of insertion sites. Medical-grade honey was applied in addition to standard CVC-site dressing and disinfection with 0.5% chlorhexidine in 70% alcohol. Skin colonization was assessed on a daily basis before CVC-site disinfection. The primary end point was colonization of insertion sites with >100 colony-forming units at the last sampling before removal of the CVC or transfer of the patient from the ICU. Secondary end points were quantitative levels of colonization of the insertion sites and colonization of insertion sites stratified for CVC location.

Results

Colonization of insertion sites was not affected by the use of medical-grade honey, as 44 (34%) of 129 and 36 (34%) of 106 patients in the honey and standard care groups, respectively, had a positive skin culture (P = 0.98). Median levels of skin colonization at the last sampling were 1 (0 to 2.84) and 1 (0 to 2.70) log colony-forming units (CFUs)/swab for the honey and control groups, respectively (P = 0.94). Gender, days of CVC placement, CVC location, and CVC type were predictive for a positive skin culture. Correction for these variables did not change the effect of honey on skin-culture positivity.

Conclusions

Medical-grade honey does not affect colonization of the skin at CVC insertion sites in ICU patients when applied in addition to standard disinfection with 0.5% chlorhexidine in 70% alcohol.

Trial registration

Netherlands Trial Registry, NTR1652.
Highly efficient bi-allelic mutation rates using TALENs in Xenopus tropicalis
Authors: Ishibashi Shoko , Cliffe Rebecca , Amaya Enrique
Published: October 2012

In the past decade, Xenopus tropicalis has emerged as a powerful new amphibian genetic model system, which offers all of the experimental advantages of its larger cousin, Xenopus laevis. Here we investigated the efficiency of transcription activator-like effector nucleases (TALENs) for generating targeted mutations in endogenous genes in X. tropicalis. For our analysis we targeted the tyrosinase (oculocutaneous albinism IA) (tyr) gene, which is required for the production of skin pigments, such as melanin. We injected mRNA encoding TALENs targeting the first exon of the tyr gene into two-cell-stage embryos. Surprisingly, we found that over 90% of the founder animals developed either partial or full albinism, suggesting that the TALENs induced bi-allelic mutations in the tyr gene at very high frequency in the F0 animals. Furthermore, mutations tyr gene were efficiently transmitted into the F1 progeny, as evidenced by the generation of albino offspring. These findings have far reaching implications in our quest to develop efficient reverse genetic approaches in this emerging amphibian model.
Do stroke models model stroke?
Authors: Mergenthaler Philipp , Meisel Andreas
Published: October 2012

Stroke is one of the leading causes of death worldwide and the biggest reason for long-term disability. Basic research has formed the modern understanding of stroke pathophysiology, and has revealed important molecular, cellular and systemic mechanisms. However, despite decades of research, most translational stroke trials that aim to introduce basic research findings into clinical treatment strategies – most notably in the field of neuroprotection – have failed. Among other obstacles, poor methodological and statistical standards, negative publication bias, and incomplete preclinical testing have been proposed as ‘translational roadblocks’. In this article, we introduce the models commonly used in preclinical stroke research, discuss some of the causes of failed translational success and review potential remedies. We further introduce the concept of modeling ‘care’ of stroke patients, because current preclinical research models the disorder but does not model care or state-of-the-art clinical testing. Stringent statistical methods and controlled preclinical trials have been suggested to counteract weaknesses in preclinical research. We conclude that preclinical stroke research requires (1) appropriate modeling of the disorder, (2) appropriate modeling of the care of stroke patients and (3) an approach to preclinical testing that is similar to clinical testing, including Phase 3 randomized controlled preclinical trials as necessary additional steps before new therapies enter clinical testing.
Cell culture andDrosophilamodel systems define three classes of anaplastic lymphoma kinase mutations in neuroblastoma
Authors: Chand Damini , Yamazaki Yasuo , Ruuth Kristina , Schönherr Christina , Martinsson Tommy , Kogner Per , Attiyeh Edward F. , Maris John , Morozova Olena , Marra Marco A. , Ohira Miki , Nakagawara Akira , Sandström Per-Erik , Palmer Ruth H. , Hallberg Bengt
Published: October 2012

Neuroblastoma is a childhood extracranial solid tumor which is associated with a number of genetic changes. Included in these genetic alterations are mutations in the kinase domain of the Anaplastic Lymphoma Kinase (ALK) receptor tyrosine kinase (RTK), which have been found in both somatic and familial neuroblastoma. In order to treat patients accordingly required characterisation of these mutations in terms of their response to ALK tyrosine kinase inhibitors (TKIs). Here, we report the identification and characterisation of two novel neuroblastoma ALK mutations (A1099T and 1464STOP) which we have investigated together with several previously reported but uncharacterised ALK mutations (T1087I, D1091N, T1151M, M1166R, F1174I and A1234T). In order to understand the potential role of these ALK mutations in neuroblastoma progression we have employed cell culture based systems together with the model organism Drosophila as a readout for ligand-independent activity. Mutation of ALK at position 1174 (F1174I) generates a gain-of-function receptor capable of activating intracellular targets, such as ERK (extracellular signal regulated kinase) and STAT3 (signal transducer and activator of transcription 3) in a ligand independent manner. Analysis of these previously uncharacterised ALK mutants and comparison with ALKF1174 mutants suggests that ALK mutations observed in neuroblastoma fall into three classes. These are: (i) gain-of-function ligand independent mutations such as ALKF1174, (ii) kinase-dead ALK mutants, e.g. ALKI1250T(Schonherr et al 2011a) or (iii) ALK mutations which are ligand-dependent in nature. Irrespective of the nature of the observed ALK mutants, in every case the activity of the mutant ALK receptors could be abrogated by the ALK inhibitor crizotinib (PF-02341066, Xalkori), albeit with differing levels of sensitivity.
Preclinical research in Rett syndrome: setting the foundation for translational success
Authors: Katz David M. , Berger-Sweeney Joanne E. , Eubanks James H. , Justice Monica J. , Neul Jeffrey L. , Pozzo-Miller Lucas , Blue Mary E. , Christian Diana , Crawley Jacqueline N. , Giustetto Maurizio , Guy Jacky , Howell C. James , Kron Miriam , Nelson Sacha B. , Samaco Rodney C. , Schaevitz Laura R. , St. Hillaire-Clarke Coryse , Young Juan L. , Zoghbi Huda Y. , Mamounas Laura A.
Published: October 2012

In September of 2011, the National Institute of Neurological Disorders and Stroke (NINDS), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the International Rett Syndrome Foundation (IRSF) and the Rett Syndrome Research Trust (RSRT) convened a workshop involving a broad cross-section of basic scientists, clinicians and representatives from the National Institutes of Health (NIH), the US Food and Drug Administration (FDA), the pharmaceutical industry and private foundations to assess the state of the art in animal studies of Rett syndrome (RTT). The aim of the workshop was to identify crucial knowledge gaps and to suggest scientific priorities and best practices for the use of animal models in preclinical evaluation of potential new RTT therapeutics. This review summarizes outcomes from the workshop and extensive follow-up discussions among participants, and includes: (1) a comprehensive summary of the physiological and behavioral phenotypes of RTT mouse models to date, and areas in which further phenotypic analyses are required to enhance the utility of these models for translational studies; (2) discussion of the impact of genetic differences among mouse models, and methodological differences among laboratories, on the expression and analysis, respectively, of phenotypic traits; and (3) definitions of the standards that the community of RTT researchers can implement for rigorous preclinical study design and transparent reporting to ensure that decisions to initiate costly clinical trials are grounded in reliable preclinical data.
Leukocyte migration from a fish eye's view
Authors: Deng Qing , Huttenlocher Anna
Published: October 2012

In the last five years, the zebrafish (Danio rerio) has rapidly gained popularity as a model system for studying leukocyte migration and trafficking in vivo. The optical clarity of zebrafish embryos, as well as the potential for genetic manipulation and the development of tools for live imaging, have provided new insight into how leukocytes migrate in response to directional cues in live animals. This Commentary discusses recent progress in our understanding of how leukocytes migrate in vivo, including the role of intracellular signaling through phosphatidylinositol 3-kinase (PI3K) in both random and directed migration. The importance of leukocyte reverse migration in the resolution of inflammation will also be discussed. Finally, we will highlight how zebrafish models have helped to provide new insight into leukocyte migration and the way in which migration is altered in disease.
Bioorganic Studies on the Key Natural Products from Venomous Mammals and Marine Invertebrates
Authors: Kita Masaki
Published: October 2012

The discovery of new bioactive molecules, facilitated by a deeper understanding of nature, will advance our knowledge of biological processes and lead to new strategies to treat disease. Recent technological advancements including spectroscopic analyses and genetic approaches have provided outstanding opportunities for new discoveries, even in the case of scarce, unstable, and composite compounds. This account summarizes two recent aspects of bioorganic chemistry: mammalian venoms and antitumor marine macrolides. Due to the interesting ecology of venomous mammals, we examined the constituents of mammalian venom, and identified unique neurotoxic peptides and kallikrein-like proteases in shrews and platypus. The present findings may lead to the development of valuable vasoactive or pain-relief agents, and to a deeper understanding of the biological evolution of vertebrates in relation to toxic substances. We have also established the target proteins and mode of actions of aplyronine A, a potent antitumor and apoptogenic marine macrolide. The complexity and diversity of actin-targeting natural products might enable them to achieve multiple interactions with as-yet-unidentified biomacromolecules, such as cytoskeleton proteins and focal adhesion proteins, which should offer better perspectives for the design and development of new antitumor drugs.
Piwil2 modulates the proliferation and metastasis of colon cancer via regulation of matrix metallopeptidase 9 transcriptional activity
Authors: Li Dawei , Sun Xing , Yan Dongwang , Huang Jianfeng , Luo Qiongzhen , Tang Huamei , Peng Zhihai
Published: October 2012

Piwi-like protein 2 (Piwil2) has recently emerged as a putative oncogene which is amplified in several human malignancies. However, the role of Piwil2 in colon cancer remains poorly understood. The aim of this study was to investigate the clinical and pathological significance of Piwil2, and the possible role in the proliferation and metastasis of colon cancer. Primary colon cancer paired with adjacent normal colon tissue and lymph node metastasis (LNM) lesions in 66 patients’ tissue microarrays (TMA) were used to determine the expression of Piwil2. Knocked down Piwil2 expression in SW620 and SW480 colon cancer cell lines was performed to evaluate the role of Piwil2 in cell proliferation, invasion, metastasis in vitro and tumorigenecity in vivo. The possible roles of Piwil2 in the regulation of a 2 kb matrix metallopeptidase 9 (MMP9) promoter fragment and on the regulation of apoptotic pathways were evaluated by using a luciferase reporter construct and Western blots, respectively. Significantly higher expression levels of Piwil2 were observed in primary colon cancer tissue and in LNM in comparison with normal colon mucosa. Piwil2 expression significantly correlated with more aggressive clinical and pathological parameters with poorer five-year metastasis-free survival and overall survival. Piwil2 silencing significantly reduced cancer cell proliferation, colony formation ability and increased apoptosis in vitro and inhibited tumor growth in vivo. Piwil2 knockdown also attenuated migration and invasion of colon cancer cells via modulation of MMP9 transcriptional activities. Our results indicate that Piwil2 moderates the proliferation and metastasis potential of colon cancer.
Effects of mechanical stimulation on viscoelasticity of rabbit scleral fibroblasts after posterior scleral reinforcement
Authors: Wang Guohui , Chen Weiyi
Published: October 2012

To understand the effect of mechanical stimulation on posterior scleral reinforcement (PSR), rabbit scleral fibroblasts after PSR were subjected to stretch in vitro, and the viscoelastic behavior of scleral fibroblasts was evaluated. Three-week-old rabbits were monocularly treated by eyelid suturation randomly to prepare the experimental myopia eyes. After 60 days, the experimental myopia eyes were treated by PSR. After six months, the posterior pole scleral fibroblasts (normal sclera – group A, sclera after operation – group B and fusion region of sclera and reinforcing band – group C) were isolated and cultured in vitro. The cells were subjected to cyclic stretch regimens (sine wave, 3% and 6% elongation amplitude, 0.1 Hz, 48-h duration) by an FX-4000 Tension System. The micropipette aspiration technique was used to investigate the viscoelasticity of scleral fibroblasts. The cellular viscoelasticity ( E0, E∞ and μ) of group C was significantly lower than groups A and B ( P < 0.05), and there was no significant difference between groups A and B ( P > 0.05). The results show that the viscoelasticity in different regions of sclera after PSR is different. Following a 48-h stretch, the cellular viscoelastic parameters were significantly decreased when compared with the respective static groups ( P < 0.05) in groups A and B. For group C, the viscoelasticity of the stretch group was significantly higher than the static control group ( P < 0.05). There was no difference between the 3% and 6% stretch groups in each group ( P > 0.05). The changes of viscoelasticity suggest that different regions of sclera have different responses to mechanical stimulation in the process of treating high myopia by PSR and that mechanical stimulation plays an important role in the treatment of axial myopia by regulating the viscoelasticity of scleral fibroblasts.
Serum α1β-glycoprotein and afamin ratio as potential diagnostic and prognostic markers in cholangiocarcinoma
Authors: Tolek Arthit , Wongkham Chaisiri , Proungvitaya Siriporn , Silsirivanit Atit , Roytrakul Sittiruk , Khuntikeo Narong , Wongkham Sopit
Published: October 2012

Cholangiocarcinoma (CCA) affects the intra- and extrahepatic bile ducts and is commonly burdened by a late presentation and resulting high mortality rate. Accordingly, finding non-invasive biomarkers with adequate diagnostic/prognostic values is a priority in high-risk populations. In this study, we analyzed proteomes of serum samples from six CCA cases and ten healthy subjects using two-dimensional polyacrylamide gel electrophoresis to identify CCA-associated spots. Thirty-six CCA-associated proteins found in sera were identified by mass spectrometry. α1 β-Glycoprotein (A1BG) and afamin (AFM) were detected consistently at different degrees in CCA sera compared with controls and were validated for their diagnostic and prognostic potential in a larger cohort of 64 patients with CCA, 4 with benign biliary diseases and 20 healthy subjects and compared between pre- and postsurgery serum samples from 26 CCA patients to ascertain a prognostic correlation. A single blot test developed to assess the serum A1BG/AFM ratio could detect CCA cases with 87.5% specificity, 84.4% sensitivity and the levels were significantly higher in CCA compared with controls. A high level of postoperative serum A1BG/AFM ratio was associated with worse outcomes and the infiltration of resection margins. The A1BG/AFM ratio may constitute a novel non-invasive candidate marker to diagnose CCA and its outcomes with high specificity and sensitivity. Prospective studies are awaited to demonstrate the clinical value of this observation.
Abstract folding space analysis based on helices
Authors: Huang Jiabin , Backofen Rolf , Voß Björn
Published: October 2012

RNA has many pivotal functions especially in the regulation of gene expression by ncRNAs. Identification of their structure is an important requirement for understanding their function. Structure prediction alone is often insufficient for this task, due to algorithmic problems, parameter inaccuracies, and biological peculiarities. Among the latter, there are base modifications, cotranscriptional folding leading to folding traps, and conformational switching as in the case of riboswitches. All these require more in-depth analysis of the folding space. The major drawback, which all methods have to cope with, is the exponential growth of the folding space. Therefore, methods are often limited in the sequence length they can analyze, or they make use of heuristics, sampling, or abstraction. Our approach adopts the abstraction strategy and remedies some problems of existing methods. We introduce a position-specific abstraction based on helices that we term helix index shapes, or hishapes for short. Utilizing a dynamic programming framework, we have implemented this abstraction in the program RNAHeliCes. Furthermore, we developed two hishape-based methods, one for energy barrier estimation, called HiPath, and one for abstract structure comparison, termed HiTed. We demonstrate the superior performance of HiPath compared to other existing methods and the competitive accuracy of HiTed. RNAHeliCes, together with HiPath and HiTed, are available for download at http://www.cyanolab.de/software/RNAHeliCes.htm.
Regulation of release factor expression using a translational negative feedback loop: A systems analysis
Authors: Betney Russell , de Silva Eric , Mertens Christina , Knox Yvonne , Krishnan J. , Stansfield Ian
Published: October 2012

The essential eukaryote release factor eRF1, encoded by the yeast SUP45 gene, recognizes stop codons during ribosomal translation. SUP45 nonsense alleles are, however, viable due to the establishment of feedback-regulated readthrough of the premature termination codon; reductions in full-length eRF1 promote tRNA-mediated stop codon readthrough, which, in turn, drives partial production of full-length eRF1. A deterministic mathematical model of this eRF1 feedback loop was developed using a staged increase in model complexity. Model predictions matched the experimental observation that strains carrying the mutant SUQ5 tRNA (a weak UAA suppressor) in combination with any of the tested sup45UAA nonsense alleles exhibit threefold more stop codon readthrough than that of an SUQ5 yeast strain. The model also successfully predicted that eRF1 feedback control in an SUQ5 sup45UAA mutant would resist, but not completely prevent, imposed changes in eRF1 expression. In these experiments, the introduction of a plasmid-borne SUQ5 copy into a sup45UAASUQ5 mutant directed additional readthrough and full-length eRF1 expression, despite feedback. Secondly, induction of additional sup45UAA mRNA expression in a sup45UAASUQ5 strain also directed increased full-length eRF1 expression. The autogenous sup45 control mechanism therefore acts not to precisely control eRF1 expression, but rather as a damping mechanism that only partially resists changes in release factor expression level. The validated model predicts that the degree of feedback damping (i.e., control precision) is proportional to eRF1 affinity for the premature stop codon. The validated model represents an important tool to analyze this and other translational negative feedback loops.
Explaining Risk Attitude in Framing Tasks by Regulatory Focus: A Verbal Protocol Analysis and a Simulation Using Fuzzy Logic
Authors: Kühberger Anton , Wiener Christian
Published: October 2012

We investigate the role of salient regulatory focus for risk attitude in framed gambles. In Experiment 1 we measured regulatory focus by collecting verbal protocols and found that people avoided risk under prevention focus and preferred risk under promotion focus. In Experiment 2 the same result was found when measuring people's regulatory focus with a questionnaire. Finally, the questionnaire data were used as inputs for simulating the choices of our participants by a fuzzy-logic decision generator. The findings show that regulatory focus has a strong effect on risk attitude and that risk attitude in framing tasks can be successfully modeled as some form of fuzzy processing.
ASP, The Art and Science of Practice: A Comparison of Technical and Soft Skill Requirements for Analytics and OR Professionals
Authors: Liberatore Matthew , Luo Wenhong
Published: October 2012

Analytics is having an increasing impact on decision making and performance within many organizations. To effectively compete in the analytics movement, operations research (OR) professionals need to understand the differences and similarities between analytics and OR. In this paper, we explore these differences and commonalities in terms of quantitative and soft skills. We support this discussion with the results of a survey of INFORMS members and readers of Analytics magazine. We find that the top five quantitative skills required for analytics are quite different from those required for OR professionals. However, the same set of soft skills is ranked within the top five for both fields. To better participate in the analytics revolution, OR professionals need to place added emphasis on data management and analysis skills, and strengthen their business-oriented skills in process and change management. Implications for OR professionals, academic institutions, and INFORMS are offered.
Estimating Demand for Container Freight Service at the Port of Davisville
Authors: Kroes James R. , Chen Yuwen , Mangiameli Paul
Published: October 2012

The Port of Davisville, located at Quonset Point, Rhode Island, is a former US Navy facility that was turned over to Rhode Island for commercial development when the naval base closed in 1974. Since then, a number of proposals have been put forth to expand the port’s operations to include the handling of containerized cargo. The Port of Davisville’s managing organization, the Quonset Development Corporation (QDC), partnered with this academic research team to objectively analyze the viability of three proposals: (1) a major expansion of the port to make it an international container megaport, (2) a lesser investment to make it a regional international port of entry for containers, and (3) a minor expansion to make it a short-sea shipping container port. We estimated the potential demand for each expansion option using transportation cost optimization models. QDC used our study’s demand estimation in its request for grant funds from the US Department of Transportation’s Transportation Investment Generating Economic Recovery program. As a result, QDC received $22.3 million to support the development of short-sea container freight shipping services at the Port of Davisville.
„Mein Leben gleicht einem Roman …“: Kants Schüler Friedrich August Hahnrieder und seine Geschichte
Authors: Krouglov Alexei N.
Published: October 2012

The life story of Kant’s student F. A. Hahnrieder (1765/6–1829) provides us with new examples of the application of the categorical imperative. Kant has given his opinion about that. The biography of Hahnrieder suggests that Kant has not always insisted on the uniqueness of the interpretation of the categorical imperative. He has also admitted other, “paradoxical”, “unusual”, but not “fantastic” interpretations. Kant has even respected a radical interpretation of the categorical imperative. On the base of the archive data, numerous mistakes about Hahnrieder were corrected in biographies of Kant and in the Akademie-Ausgabe.
Axonal Conduction Block as a Novel Mechanism of Prepulse Inhibition
Authors: Lee Anne H. , Megalou Evgenia V. , Wang Jean , Frost William N.
Published: October 2012

In prepulse inhibition (PPI), the startle response to a strong, unexpected stimulus is diminished if shortly preceded by the onset of a different stimulus. Because deficits in this inhibitory gating process are a hallmark feature of schizophrenia and certain other psychiatric disorders, the mechanisms underlying PPI are of significant interest. We previously used the invertebrate model systemTritonia diomedeato identify the first cellular mechanism for PPI—presynaptic inhibition of transmitter release from the afferent neurons (S-cells) mediating the startle response. Here, we report the involvement of a second, more powerful PPI mechanism inTritonia: prepulse-elicited conduction block of action potentials traveling in the startle pathway caused by identified inhibitory interneurons activated by the prepulse. This example of axo-axonic conduction block—neurons in one pathway inhibiting the propagation of action potentials in another—represents a novel and potent mechanism of sensory gating in prepulse inhibition.
Tis21Knock-Out Enhances the Frequency of Medulloblastoma in Patched1 Heterozygous Mice by Inhibiting theCxcl3-Dependent Migration of Cerebellar Neurons
Authors: Farioli-Vecchioli Stefano , Cinà Irene , Ceccarelli Manuela , Micheli Laura , Leonardi Luca , Ciotti Maria Teresa , De Bardi Marco , Di Rocco Concezio , Pallini Roberto , Cavallaro Sebastiano , Tirone Felice
Published: October 2012

A failure in the control of proliferation of cerebellar granule neuron precursor cells (GCPs), located in the external granular layer (EGL) of the cerebellum, gives rise to medulloblastoma. To investigate the process of neoplastic transformation of GCPs, we generated a new medulloblastoma model by crossingPatched1heterozygous mice, which develop medulloblastomas with low frequency, with mice lacking theTis21gene. Overexpression ofTis21is known to inhibit proliferation and trigger differentiation of GCPs; its expression decreases in human medulloblastomas. Double-knock-out mice show a striking increase in the frequency of medulloblastomas and hyperplastic EGL lesions, formed by preneoplastic GCPs.Tis21deletion does not affect the proliferation of GCPs but inhibits their differentiation and, chiefly, their intrinsic ability to migrate outside the EGL. This defect of migration may represent an important step in medulloblastoma formation, as GCPs, remaining longer in the EGL proliferative niche, may become more prone to transformation. By genome-wide analysis, we identified the chemokineCxcl3as a target ofTis21. Cxcl3is downregulated inTis21-null GCPs of EGL and lesions; addition of Cxcl3 to cerebellar slices rescues the defective migration ofTis21-null GCPs and, remarkably, reduces the area of hyperplastic lesions. AsTis21activatesCxcl3transcription, our results suggest thatTis21induces migration of GCPs throughCxcl3, which may represent a novel target for medulloblastoma therapy.
Variable Sequencing Is Actively Maintained in a Well Learned Motor Skill
Authors: Warren Timothy L. , Charlesworth Jonathan D. , Tumer Evren C. , Brainard Michael S.
Published: October 2012

Variation in sequencing of actions occurs in many natural behaviors, yet how such variation is maintained is poorly understood. We investigated maintenance of sequence variation in adult Bengalese finch song, a learned skill with rendition-to-rendition variation in the sequencing of discrete syllables (i.e., syllable “b” might transition to “c” with 70% probability and to “d” with 30% probability). We found that probabilities of transitions ordinarily remain stable but could be modified by delivering aversive noise bursts following one transition (e.g., “b→c”) but not the alternative (e.g., “b→d”). Such differential reinforcement induced gradual, adaptive decreases in probabilities of targeted transitions and compensatory increases in alternative transitions. Thus, the normal stability of transition probabilities does not reflect hardwired premotor circuitry. While all variable transitions could be modified by differential reinforcement, some were less readily modified than others; these were cases that exhibited more alternation between possible transitions than predicted by chance (i.e., “b→d ” would tend to follow “b→c ” and vice versa). These history-dependent transitions were less modifiable than more stochastic transitions. Similarly, highly stereotyped transitions (which are completely predictable) were not modifiable. This suggests that stochastically generated variability is crucial for sequence modification. Finally, we found that, when reinforcement ceased, birds gradually restored transition probabilities to their baseline values. Hence, the nervous system retains a representation of baseline probabilities and has the impetus to restore them. Together, our results indicate that variable sequencing in a motor skill can reflect an end point of learning that is stably maintained via continual self-monitoring.
Regulation of Neuronal Excitability by Interaction of Fragile X Mental Retardation Protein with Slack Potassium Channels
Authors: Zhang Yalan , Brown Maile R. , Hyland Callen , Chen Yi , Kronengold Jack , Fleming Matthew R. , Kohn Andrea B. , Moroz Leonid L. , Kaczmarek Leonard K.
Published: October 2012

Loss of the RNA-binding protein fragile X mental retardation protein (FMRP) represents the most common form of inherited intellectual disability. Studies with heterologous expression systems indicate that FMRP interacts directly with Slack Na+-activated K+channels (KNa), producing an enhancement of channel activity. We have now usedAplysiabag cell (BC) neurons, which regulate reproductive behaviors, to examine the effects of Slack and FMRP on excitability. FMRP and Slack immunoreactivity were colocalized at the periphery of isolated BC neurons, and the two proteins could be reciprocally coimmunoprecipitated. Intracellular injection of FMRP lacking its mRNA binding domain rapidly induced a biphasic outward current, with an early transient tetrodotoxin-sensitive component followed by a slowly activating sustained component. The properties of this current matched that of the native Slack potassium current, which was identified using an siRNA approach. Addition of FMRP to inside-out patches containing nativeAplysiaSlack channels increased channel opening and, in current-clamp recordings, produced narrowing of action potentials. Suppression of Slack expression did not alter the ability of BC neurons to undergo a characteristic prolonged discharge in response to synaptic stimulation, but prevented recovery from a prolonged inhibitory period that normally follows the discharge. Recovery from the inhibited period was also inhibited by the protein synthesis inhibitor anisomycin. Our studies indicate that, in BC neurons, Slack channels are required for prolonged changes in neuronal excitability that require new protein synthesis, and raise the possibility that channel–FMRP interactions may link changes in neuronal firing to changes in protein translation.
Localized Calcineurin Confers Ca2+-Dependent Inactivation on Neuronal L-Type Ca2+Channels
Authors: Oliveria Seth F. , Dittmer Philip J. , Youn Dong-ho , Dell'Acqua Mark L. , Sather William A.
Published: October 2012

Excitation-driven entry of Ca2+through L-type voltage-gated Ca2+channels controls gene expression in neurons and a variety of fundamental activities in other kinds of excitable cells. The probability of opening of CaV1.2 L-type channels is subject to pronounced enhancement by cAMP-dependent protein kinase (PKA), which is scaffolded to CaV1.2 channels by A-kinase anchoring proteins (AKAPs). CaV1.2 channels also undergo negative autoregulation via Ca2+-dependent inactivation (CDI), which strongly limits Ca2+entry. An abundance of evidence indicates that CDI relies upon binding of Ca2+/calmodulin (CaM) to an isoleucine–glutamine motif in the carboxy tail of CaV1.2 L-type channels, a molecular mechanism seemingly unrelated to phosphorylation-mediated channel enhancement. But our work reveals, in cultured hippocampal neurons and a heterologous expression system, that the Ca2+/CaM-activated phosphatase calcineurin (CaN) is scaffolded to CaV1.2 channels by the neuronal anchoring protein AKAP79/150, and that overexpression of an AKAP79/150 mutant incapable of binding CaN (ΔPIX; CaN-binding PXIXIT motif deleted) impedes CDI. Interventions that suppress CaN activity—mutation in its catalytic site, antagonism with cyclosporine A or FK506, or intracellular perfusion with a peptide mimicking the sequence of the phosphatase's autoinhibitory domain—interfere with normal CDI. In cultured hippocampal neurons from a ΔPIX knock-in mouse, CDI is absent. Results of experiments with the adenylyl cyclase stimulator forskolin and with the PKA inhibitor PKI suggest that Ca2+/CaM-activated CaN promotes CDI by reversing channel enhancement effectuated by kinases such as PKA. Hence, our investigation of AKAP79/150-anchored CaN reconciles the CaM-based model of CDI with an earlier, seemingly contradictory model based on dephosphorylation signaling.
Cerebellar Ataxia by Enhanced CaV2.1 Currents Is Alleviated by Ca2+-Dependent K+-Channel Activators inCacna1aS218LMutant Mice
Authors: Gao Zhenyu , Todorov Boyan , Barrett Curtis F. , van Dorp Stijn , Ferrari Michel D. , van den Maagdenberg Arn M.J.M. , De Zeeuw Chris I. , Hoebeek Freek E.
Published: October 2012

Mutations in theCACNA1Agene are associated with neurological disorders, such as ataxia, hemiplegic migraine, and epilepsy. These mutations affect the pore-forming α1A-subunit of CaV2.1 channels and thereby either decrease or increase neuronal Ca2+influx. A decreased CaV2.1-mediated Ca2+influx has been shown to reduce the regularity of cerebellar Purkinje cell activity and to induce episodic cerebellar ataxia. However, little is known about how ataxia can be caused byCACNA1Amutations that increase the Ca2+influx, such as the S218L missense mutation. Here, we demonstrate that the S218L mutation causes a negative shift of voltage dependence of CaV2.1 channels of mouse Purkinje cells and results in lowered thresholds for somatic action potentials and dendritic Ca2+spikes and in disrupted firing patterns. The hyperexcitability ofCacna1aS218LPurkinje cells was counteracted by application of the activators of Ca2+-dependent K+channels, 1-EBIO and chlorzoxazone (CHZ). Moreover, 1-EBIO also alleviated the irregularity of Purkinje cell firing bothin vitroandin vivo, while CHZ improved the irregularity of Purkinje cell firingin vitroas well as the motor performance ofCacna1aS218Lmutant mice. The current data suggest that abnormalities in Purkinje cell firing contributes to cerebellar ataxia induced by the S218L mutation and they advocate a general therapeutic approach in that targeting Ca2+-dependent K+channels may be beneficial for treating ataxia not only in patients suffering from a decreased Ca2+influx, but also in those suffering from an increased Ca2+influx in their Purkinje cells.