bluuebunny/crossref_metadata_2025 huggingface dataset:
Shift happens: trailing edge contraction associated with recent warming trends threatens a distinct genetic lineage in the marine macroalga Fucus vesiculosus
Authors: Nicastro Katy R , Zardi Gerardo I , Teixeira Sara , Neiva João , Serrão Ester A , Pearson Gareth A
Published: January 2013

Background

Significant effects of recent global climate change have already been observed in a variety of ecosystems, with evidence for shifts in species ranges, but rarely have such consequences been related to the changes in the species genetic pool. The stretch of Atlantic coast between North Africa and North Iberia is ideal for studying the relationship between species distribution and climate change as it includes the distributional limits of a considerable number of both cold- and warm-water species.

We compared temporal changes in distribution of the canopy-forming alga Fucus vesiculosus with historical sea surface temperature (SST) patterns to draw links between range shifts and contemporary climate change. Moreover, we genetically characterized with microsatellite markers previously sampled extinct and extant populations in order to estimate resulting cryptic genetic erosion.

Results

Over the past 30 years, a geographic contraction of the southern range edge of this species has occurred, with a northward latitudinal shift of approximately 1,250 km. Additionally, a more restricted distributional decline was recorded in the Bay of Biscay. Coastal SST warming data over the last three decades revealed a significant increase in temperature along most of the studied coastline, averaging 0.214°C/decade. Importantly, the analysis of existing and extinct population samples clearly distinguished two genetically different groups, a northern and a southern clade. Because of the range contraction, the southern group is currently represented by very few extant populations. This southern edge range shift is thus causing the loss of a distinct component of the species genetic background.

Conclusions

We reveal a climate-correlated diversity loss below the species level, a process that could render the species more vulnerable to future environmental changes and affect its evolutionary potential. This is a remarkable case of genetic uniqueness of a vanishing cryptic genetic clade (southern clade).
Bovine neonatal pancytopenia - Comparative proteomic characterization of two BVD vaccines and the producer cell surface proteome (MDBK)
Authors: Euler Kerstin N , Hauck Stefanie M , Ueffing Marius , Deeg Cornelia A
Published: January 2013

Background

Bovine neonatal pancytopenia (BNP) is a disease syndrome in newborn calves of up to four weeks of age, first observed in southern Germany in 2006. By now, cases have been reported in several countries around the globe. Many affected calves die within days due to multiple haemorrhages, thrombocytopenia, leukocytopenia and bone marrow depletion. A certain vaccine directed against Bovine Virus Diarrhoea Virus (BVDV) was recently shown to be associated with BNP pathogenesis. Immunized cows develop alloantibodies that are transferred to newborn calves via colostrum intake. In order to further elucidate BNP pathogenesis, the purpose of this study was to characterize and compare the protein composition of the associated vaccine to another vaccine directed against BVDV not related to BNP and the cell surface proteome of MDBK (Madin-Darby Bovine Kidney) cells, the cell line used for production of the associated vaccine.

Results

By SDS-PAGE and mass spectrometry, we were able to detect several coagulation-related and immune modulatory proteins, as well as cellular and serum derived molecules being shared between the associated vaccine and MDBK cells. Furthermore, the number of proteins identified in the BNP related vaccine was almost as high as the number of surface proteins detected on MDBK cells and exceeded the amount of proteins identified in the non-BNP related vaccine over 3.5 fold. The great amount of shared cellular and serum derived proteins confirm that the BNP associated vaccine contained many molecules originating from MDBK cells and vaccine production.

Conclusions

The respective vaccine was not purified enough to prevent the development of alloantibodies. To narrow down possible candidate proteins, those most likely to represent a trigger for BNP pathogenesis are presented in this study, giving a fundament for further analysis in future research.
CpGIMethPred: computational model for predicting methylation status of CpG islands in human genome
Authors: Zheng Hao , Wu Hongwei , Li Jinping , Jiang Shi-Wen
Published: January 2013

DNA methylation is an inheritable chemical modification of cytosine, and represents one of the most important epigenetic events. Computational prediction of the DNA methylation status can be employed to speed up the genome-wide methylation profiling, and to identify the key features that are correlated with various methylation patterns. Here, we develop CpGIMethPred, the support vector machine-based models to predict the methylation status of the CpG islands in the human genome under normal conditions. The features for prediction include those that have been previously demonstrated effective (CpG island specific attributes, DNA sequence composition patterns, DNA structure patterns, distribution patterns of conserved transcription factor binding sites and conserved elements, and histone methylation status) as well as those that have not been extensively explored but are likely to contribute additional information from a biological point of view (nucleosome positioning propensities, gene functions, and histone acetylation status). Statistical tests are performed to identify the features that are significantly correlated with the methylation status of the CpG islands, and principal component analysis is then performed to decorrelate the selected features. Data from the Human Epigenome Project (HEP) are used to train, validate and test the predictive models. Specifically, the models are trained and validated by using the DNA methylation data obtained in the CD4 lymphocytes, and are then tested for generalizability using the DNA methylation data obtained in the other 11 normal tissues and cell types. Our experiments have shown that (1) an eight-dimensional feature space that is selected via the principal component analysis and that combines all categories of information is effective for predicting the CpG island methylation status, (2) by incorporating the information regarding the nucleosome positioning, gene functions, and histone acetylation, the models can achieve higher specificity and accuracy than the existing models while maintaining a comparable sensitivity measure, (3) the histone modification (methylation and acetylation) information contributes significantly to the prediction, without which the performance of the models deteriorate, and, (4) the predictive models generalize well to different tissues and cell types. The developed program CpGIMethPred is freely available at http://users.ece.gatech.edu/~hzheng7/CGIMetPred.zip.
Recursive SVM biomarker selection for early detection of breast cancer in peripheral blood
Authors: Zhang Fan , Kaufman Howard L , Deng Youping , Drabier Renee
Published: January 2013

Background

Breast cancer is worldwide the second most common type of cancer after lung cancer. Traditional mammography and Tissue Microarray has been studied for early cancer detection and cancer prediction. However, there is a need for more reliable diagnostic tools for early detection of breast cancer. This can be a challenge due to a number of factors and logistics. First, obtaining tissue biopsies can be difficult. Second, mammography may not detect small tumors, and is often unsatisfactory for younger women who typically have dense breast tissue. Lastly, breast cancer is not a single homogeneous disease but consists of multiple disease states, each arising from a distinct molecular mechanism and having a distinct clinical progression path which makes the disease difficult to detect and predict in early stages.

Results

In the paper, we present a Support Vector Machine based on Recursive Feature Elimination and Cross Validation (SVM-RFE-CV) algorithm for early detection of breast cancer in peripheral blood and show how to use SVM-RFE-CV to model the classification and prediction problem of early detection of breast cancer in peripheral blood.

The training set which consists of 32 health and 33 cancer samples and the testing set consisting of 31 health and 34 cancer samples were randomly separated from a dataset of peripheral blood of breast cancer that is downloaded from Gene Express Omnibus. First, we identified the 42 differentially expressed biomarkers between "normal" and "cancer". Then, with the SVM-RFE-CV we extracted 15 biomarkers that yield zero cross validation score. Lastly, we compared the classification and prediction performance of SVM-RFE-CV with that of SVM and SVM Recursive Feature Elimination (SVM-RFE).

Conclusions

We found that 1) the SVM-RFE-CV is suitable for analyzing noisy high-throughput microarray data, 2) it outperforms SVM-RFE in the robustness to noise and in the ability to recover informative features, and 3) it can improve the prediction performance (Area Under Curve) in the testing data set from 0.5826 to 0.7879. Further pathway analysis showed that the biomarkers are associated with Signaling, Hemostasis, Hormones, and Immune System, which are consistent with previous findings. Our prediction model can serve as a general model for biomarker discovery in early detection of other cancers. In the future, Polymerase Chain Reaction (PCR) is planned for validation of the ability of these potential biomarkers for early detection of breast cancer.
Assessment of gene order computing methods for Alzheimer's disease
Authors: Hu Benqiong , Jiang Gang , Pang Chaoyang , Wang Shipeng , Liu Qingzhong , Chen Zhongxue , Vanderburg Charles R , Rogers Jack T , Deng Youping , Huang Xudong
Published: January 2013

Background

Computational genomics of Alzheimer disease (AD), the most common form of senile dementia, is a nascent field in AD research. The field includes AD gene clustering by computing gene order which generates higher quality gene clustering patterns than most other clustering methods. However, there are few available gene order computing methods such as Genetic Algorithm (GA) and Ant Colony Optimization (ACO). Further, their performance in gene order computation using AD microarray data is not known. We thus set forth to evaluate the performances of current gene order computing methods with different distance formulas, and to identify additional features associated with gene order computation.

Methods

Using different distance formulas- Pearson distance and Euclidean distance, the squared Euclidean distance, and other conditions, gene orders were calculated by ACO and GA (including standard GA and improved GA) methods, respectively. The qualities of the gene orders were compared, and new features from the calculated gene orders were identified.

Results

Compared to the GA methods tested in this study, ACO fits the AD microarray data the best when calculating gene order. In addition, the following features were revealed: different distance formulas generated a different quality of gene order, and the commonly used Pearson distance was not the best distance formula when used with both GA and ACO methods for AD microarray data.

Conclusion

Compared with Pearson distance and Euclidean distance, the squared Euclidean distance generated the best quality gene order computed by GA and ACO methods.
Cytomegalovirus-induced salivary gland pathology: resistance to kinase inhibitors of the upregulated host cell EGFR/ERK pathway is associated with CMV-dependent stromal overexpression of IL-6 and fibronectin
Authors: Melnick Michael , Sedghizadeh Parish P , Deluca Krysta A , Jaskoll Tina
Published: January 2013

Background

Recently we identified a relationship between human cytomegalovirus (hCMV) and human salivary gland (SG) mucoepidermoid carcinoma (MEC) in over 90% of cases; tumorigenesis in these cases uniformly correlated with active hCMV protein expression and an upregulation of the EGFR → ERK pathway. Our previously characterized, novel mouse organ culture model of mouse CMV (mCMV)-induced tumorigenesis displays a number of histologic and molecular characteristics similar to human MEC.

Methods

Newborn mouse submandibular glands (SMGs) were incubated with 1 × 105 PFU/ml of lacZ-tagged mCMV RM427+ on day 0 for 24 hours and then cultured in virus-free media for a total of 6 or 12 days with or without EGFR/ERK inhibitors and/or aciclovir. SMGs were collected for histology, immunolocalization (pERK, FN, IL-6), viral distribution, or Western blot analysis (pERK).

Results

Here we report: (1) mouse SMG tumors soon exhibit an acquired resistance to EGFR/ERK pathway kinase inhibitors, alone or in combination; (2) long term tumor regression can only be sustained by concurrent inhibitor and antiviral treatment; (3) CMV-dependent, kinase inhibitor resistance is associated with overexpression of fibronectin and IL-6 proteins in abnormal stromal cells.

Conclusions

Acquired resistance to kinase inhibitors is dependent upon CMV dysregulation of alternative pathways with downstream effectors common with the targeted pathway, a phenomenon with important therapeutic implications for human MEC of salivary glands.
Human blood mDC subsets exhibit distinct TLR repertoire and responsiveness
Authors: Hémont Caroline , Neel Antoine , Heslan Michèle , Braudeau Cécile , Josien Régis
Published: January 2013

TLR repertoire and in vitro responsiveness of blood classical DC subsets.

Human blood DCs encompass pDCs and two subsets of mDCs: CD1c+ mDCs and CD141+ mDCs. The rare CD141+ DC population is thought to be the equivalent of mouse CD8α+ cDCs that play a significant role in antigen cross-presentation. Here, we analyzed by Q-PCR TLR1–10 expression in blood DC subsets. Whereas CD1c+ DCs express all TLR except TLR9, CD141+ DCs present a more restricted pattern with high expression of TLR3 and -10, expression of TLR1,-2, -6, and -8, and lack of TLR4, -5, -7, and -9. The in vitro analysis of isolated mDC subset reponsiveness to an extensive panel of TLR ligands confirmed these results, with CD141+ DCs responding only to TLR1/2, -3, and -7/8. The cytokine/chemokine production profile of isolated CD141+ DCs was also more restricted, as they produced mainly proinflammatory cytokines but no IL-12 and to a lower level, in comparison with CD1c+ DCs, except for CXCL10, CCL5, and IFN-β. In contrast, with the use of a whole blood assay, we found that CD141+ DCs produce IL-12 in response to TLR1/2, -3, and more surprisingly, -9. Finally, both mDC subsets are potent inducers of Th1 response, particularly after TLR3 triggering. Taken together, these data confirmed functional differences between blood mDC subsets. The major response of CD141+ mDCs to TLR3 ligand and their cytokine production pattern suggest a role for these cells in antiviral immunity.
Phase II Trial of Erlotinib Plus Concurrent Whole-Brain Radiation Therapy for Patients With Brain Metastases From Non–Small-Cell Lung Cancer
Authors: Welsh James W. , Komaki Ritsuko , Amini Arya , Munsell Mark F. , Unger Wyatt , Allen Pamela K. , Chang Joe Y. , Wefel Jeffrey S. , McGovern Susan L. , Garland Linda L. , Chen Su S. , Holt Jamie , Liao Zhongxing , Brown Paul , Sulman Erik , Heymach John V. , Kim Edward S. , Stea Baldassarre
Published: January 2013

Purpose

Brain metastasis (BM) is a leading cause of death from non–small-cell lung cancer (NSCLC). Reasoning that activation of the epidermal growth factor receptor (EGFR) contributes to radiation resistance, we undertook a phase II trial of the EGFR inhibitor erlotinib with whole-brain radiation therapy (WBRT) in an attempt to extend survival time for patients with BM from NSCLC. Additional end points were radiologic response and safety.

Patients and Methods

Eligible patients had BM from NSCLC, regardless of EGFR status. Erlotinib was given at 150 mg orally once per day for 1 week, then concurrently with WBRT (2.5 Gy per day 5 days per week, to 35 Gy), followed by maintenance. EGFR mutation status was tested by DNA sequencing at an accredited core facility.

Results

Forty patients were enrolled and completed erlotinib plus WBRT (median age, 59 years; median diagnosis-specific graded prognostic assessment score, 1.5). The overall response rate was 86% (n = 36). No increase in neurotoxicity was detected, and no patient experienced grade ≥ 4 toxicity, but three patients required dose reduction for grade 3 rash. At a median follow-up of 28.5 months (for living patients), median survival time was 11.8 months (95% CI, 7.4 to 19.1 months). Of 17 patients with known EGFR status, median survival time was 9.3 months for those with wild-type EGFR and 19.1 months for those with EGFR mutations.

Conclusion

Erlotinib was well tolerated in combination with WBRT, with a favorable objective response rate. The higher-than-expected rate of EGFR mutations in these unselected patients raises the possibility that EGFR-mutated tumors are prone to brain dissemination.
Overall and Cancer-Specific Survival of Patients With Breast, Colon, Kidney, and Lung Cancers With and Without Chronic Lymphocytic Leukemia: A SEER Population-Based Study
Authors: Solomon Benjamin M. , Rabe Kari G. , Slager Susan L. , Brewer Jerry D. , Cerhan James R. , Shanafelt Tait D.
Published: January 2013

Purpose

Chronic lymphocytic leukemia (CLL) is associated with an increased risk of developing second cancers. However, it is unknown whether CLL alters the disease course of these cancers once they occur.

Patients and Methods

All patients with cancers of the breast (n = 579,164), colorectum (n = 412,366), prostate (n = 631,616), lung (n = 489,053), kidney (n = 95,795), pancreas (n = 82,116), and ovary (n = 61,937) reported to the SEER program from 1990 to 2007 were identified. Overall survival (OS; death resulting from any cause) and cancer-specific survival were examined, comparing patients with and without pre-existing CLL. Cancer-specific survival was evaluated for each tumor type in a site-specific manner (eg, death resulting from breast cancer in a patient with breast cancer).

Results

Patients with cancers of the breast (hazard ratio [HR], 1.70; P < .001), colorectum (HR, 1.65; P < .001), kidney (HR, 1.54; P < .001), prostate (HR, 1.92; P < .001), or lung (HR, 1.19; P < .001) had inferior OS if they had a pre-existing diagnosis of CLL after adjusting for age, sex, race, and disease stage. These results for OS remained significant for patients with cancers of the breast, colorectum, and prostate after excluding or censoring CLL-related deaths. Cancer-specific survival was also inferior for patients with cancers of the breast (HR, 1.41; P = .005) and colorectum (HR, 1.46; P < .001) who had pre-existing CLL after adjusting for age, sex, race, and disease stage.

Conclusion

Inferior OS and cancer-specific survival was observed for several common cancers in patients with pre-existing CLL. Additional studies are needed to determine the optimal management of these malignancies in patients with CLL and whether more aggressive screening or alternative approaches to adjuvant therapy are needed.
Where Polarity Meets Fusion: Role of Par6 in Trophoblast Differentiation during Placental Development and Preeclampsia
Authors: Sivasubramaniyam Tharini , Garcia Julia , Tagliaferro Andrea , Melland-Smith Megan , Chauvin Sarah , Post Martin , Todros Tullia , Caniggia Isabella
Published: January 2013

Trophoblast cell fusion is a prerequisite for proper human placental development. Herein we examined the contribution of Par6 (Partitioning defective protein 6), a key regulator of cell polarity, to trophoblast cell fusion in human placental development. During early placentation, Par6 localized to nuclei of cytotrophoblast cells but with advancing gestation Par6 shifted its localization to the cytoplasm and apical brush border of the syncytium. Exposure of primary isolated trophoblasts to 3% O2 resulted in elevated Par6 expression, maintenance of tight junction marker ZO-1 at cell boundaries, and decreased fusogenic syncytin 1 expression compared with cells cultured at 20% O2. Treatment of choriocarcinoma BeWo cells with forskolin, a known inducer of fusion, increased syncytin 1 expression but decreased that of Par6 and ZO-1. Par6 overexpression in the presence of forskolin maintained ZO-1 at cell boundaries while decreasing syncytin 1 levels. In contrast, silencing of Par6 disrupted ZO-1 localization at cell boundaries and altered the expression and distribution of acetylated α-tubulin. Par6 expression was elevated in preeclamptic placentas relative to normotensive preterm controls and Par6 located to trophoblast cells expressing ZO-1. Together, our data indicate that Par6 negatively regulates trophoblast fusion via its roles on tight junctions and cytoskeleton dynamics and provide novel insight into the contribution of this polarity marker in altered trophoblast cell fusion typical of preeclampsia.
IGF-I Signaling Is Essential for FSH Stimulation of AKT and Steroidogenic Genes in Granulosa Cells
Authors: Zhou Ping , Baumgarten Sarah C. , Wu Yanguang , Bennett Jill , Winston Nicola , Hirshfeld-Cytron Jennifer , Stocco Carlos
Published: January 2013

FSH and IGF-I synergistically stimulate gonadal steroid production; conversely, silencing the FSH or the IGF-I genes leads to infertility and hypogonadism. To determine the molecular link between these hormones, we examined the signaling cross talk downstream of their receptors. In human and rodent granulosa cells (GCs), IGF-I potentiated the stimulatory effects of FSH and cAMP on the expression of steroidogenic genes. In contrast, inhibition of IGF-I receptor (IGF-IR) activity or expression using pharmacological, genetic, or biochemical approaches prevented the FSH- and cAMP-induced expression of steroidogenic genes and estradiol production. In vivo experiments demonstrated that IGF-IR inactivation reduces the stimulation of steroidogenic genes and follicle growth by gonadotropins. FSH or IGF-I alone stimulated protein kinase B (PKB), which is also known as AKT and in combination synergistically increased AKT phosphorylation. Remarkably, blocking IGF-IR expression or activity decreased AKT basal activity and abolished AKT activation by FSH. In GCs lacking IGF-IR activity, FSH stimulation of Cyp19 expression was rescued by overexpression of constitutively active AKT. Our findings demonstrate, for the first time, that in human, mouse, and rat GCs, the well-known stimulatory effect of FSH on Cyp19 and AKT depends on IGF-I and on the expression and activation of the IGF-IR.
Measuring the Efficiency of an FCC Spectrum Auction
Authors: Fox Jeremy T , Bajari Patrick
Published: January 2013

We propose a method to structurally estimate the deterministic component of bidder valuations in FCC spectrum auctions, and apply it to the 1995–1996 C block auction. We base estimation on a pairwise stability condition: two bidders cannot exchange two licenses in a way that increases the sum of their valuations. Pairwise stability holds in some theoretical models of simultaneous ascending auctions under intimidatory collusion and demand reduction. Pairwise stability results in a matching game approach to estimation. We find that a system of four large regional licenses would raise the allocative efficiency of the C block outcome by 48 percent. (JEL D44, D45, H82, L82)
On the Relationship between Preferential and Multilateral Trade Liberalization: The Case of Customs Unions
Authors: Saggi Kamal , Woodland Alan , Yildiz Halis Murat
Published: January 2013

This paper compares equilibrium outcomes of two games of trade liberalization. In the Bilateralism game, countries choose whether to liberalize trade preferentially via a customs union (CU), multilaterally, or not at all. The Multilateralism game is a restricted version of the Bilateralism game in that countries cannot form CUs and can only undertake non-discriminatory trade liberalization. When countries have symmetric endowments, global free trade is the only stable equilibrium of both games. Allowing for endowment asymmetry, we isolate circumstances where the option to form CUs helps further the cause of multilateral liberalization as well as where it does not. (JEL F12, F13)
Optimal Return Service Charging Policy for a Fashion Mass Customization Program
Authors: Choi Tsan-Ming
Published: January 2013

Mass customization (MC) service is a pertinent industrial practice in the fashion industry. To foster trust and enhance demand, some brands now allow dissatisfied customers to return the MC fashion product for a full refund minus a service charge. The service charge is a measure to avoid the abuse of the return right and to subsidize the operations cost (e.g., shipping) and loss from the return. Motivated by this observed industrial practice, this paper analytically examines the optimal return service charge policy. We separate the study into two cases—those of risk-neutral and those of risk-averse MC companies, respectively. For each case, we derive the closed-form expression of the optimal return service charge, and we conduct analytical sensitivity analysis to illustrate how different important parameters in the model affect the optimal return service charge. In addition, by comparing the two cases, we reveal how the MC service provider's level of risk aversion affects the optimal return service charge policy. Finally, we derive the conditions under which it is optimal to offer a zero return service charge (i.e., free return with a full refund). These conditions provide insight on the real-world practice in which some fashion companies offer free return service to their registered members but not to every customer.
Nitrofurantoin Contraindication in Patients with a Creatinine Clearance Below 60 mL/min: Looking for the Evidence
Authors: Oplinger Mandy , Andrews Carlota O
Published: January 2013

OBJECTIVE

To investigate the evidence leading to nitrofurantoin contraindication in patients with a creatinine clearance (CrCl) below 60 mL/min.

DATA SOURCES

Literature was searched in PubMed (1965-June 2012) by using the key words and MeSH terms urinary tract infections-drug therapy, chronic kidney insufficiency, kidney diseases, pharmacokinetics, safety, and efficacy, combined with nitrofurantoin. Articles were limited to the English language. References from the identified studies, Food and Drug Administration–approved product information packets, drug information resources, and pharmacology books were also reviewed.

DATA SYNTHESIS

The contraindication of nitrofurantoin in patients with a CrCl below 60 mL/min was included in the product information packets sometime between 1988 and 2003. The 1988 Macrodantin product information indicated a CrCl cutoff level of 40 mL/min, but the current contraindication of less than 60 mL/min is found in the 2003 Macrobid product information. It is unclear when and why this change occurred, but it may have followed the work of Sachs and colleagues in 1968, who reported very little drug recovery in the urine of patients with a CrCl below 60 mL/min. This and previous studies have several and severe limitations, such as the inclusion of a small number of patients, an undefined or poorly defined method to determine CrCl and renal impairment, measurement of amounts of nitrofurantoin excreted in the urine instead of urinary concentrations, and most importantly, a lack of clinical efficacy end points. More recently, a chart review on clinical cure of urinary tract infections treated with nitrofurantoin provided grounds for further investigations on the utility of this drug for patients with a CrCl of 60 mL/min or lower. Concerns of increased risks of serious adverse reactions in patients with reduced renal function have further limited the use of nitrofurantoin. However, although not completely clear, these complications seem to be linked most often to prolonged treatment, genetic variability, and predisposition to hypersensitivity.

CONCLUSIONS

Data supporting the contraindication of nitrofurantoin for patients with a CrCl less than 60 mL/min are nonexistent. Well-designed clinical trials with urinary concentration information and clinical end points on patients with various degrees of renal impairment are much needed. Until such a study becomes available, the limited data available would support considering using this drug in patients with a CrCl of 40 mL/min or higher.
Technological Innovation and Exports: Unpacking Their Reciprocal Causality
Authors: Filipescu Diana A. , Prashantham Shameen , Rialp Alex , Rialp Josep
Published: January 2013

The authors aim to advance extant understanding of the dynamics of firms operating abroad by considering the effects of innovation (research-and-development intensity, product and process innovations) on exports (breadth and depth), and vice versa. The study analyzes a panel data set of 696 Spanish manufacturing firms during 1994–2005 using Tobit and logit regressions and the Granger test of causality to offer a more complete picture of this complex relationship. They find broad support for the notion that innovation and exports have a reciprocal causal relationship, although the findings are partly nuanced by positive but nonsignificant associations between product innovation and exports and between export depth and process innovation. Furthermore, both export and innovation processes Granger-cause each other, demonstrating that there is a double causal relationship.
Soda versus Cereal and Sugar versus Fat: Drivers of Healthful Food Intake and the Impact of Diabetes Diagnosis
Authors: Ma Yu , Ailawadi Kusum L. , Grewal Dhruv
Published: January 2013

This study examines how household members’ personal characteristics and key marketing factors affect the healthfulness of food purchased for in-home consumption; it further considers how food intake changes following a diagnosis of Type 2 diabetes in the household. Using a combination of grocery purchases over four years, survey data about health status, and the nutrition content of 13 of the largest packaged food categories, this study shows that households with higher education and nutrition interest consume fewer calories, sugar, and total carbohydrates, whereas those with higher self-control consume more, because they offset their lower intake of “unhealthy” categories (e.g., soft drinks) with higher intake of “healthy” categories (e.g., cereal). The consumption of sugar and carbohydrates decreases significantly in response to a diabetes diagnosis, whereas the intake of fat and sodium increases. Education, nutrition interest, and self-control are not associated with healthier changes in response to a diagnosis, but younger and higher-income households, as well as those in which the diabetes patient is female, make healthier changes. These findings have notable implications for marketers, consumers, consumer researchers, and public health professionals.
Retinoic Acid Induces Blood–Brain Barrier Development
Authors: Mizee Mark R. , Wooldrik Desiree , Lakeman Kim A. M. , van het Hof Bert , Drexhage Joost A. R. , Geerts Dirk , Bugiani Marianna , Aronica Eleonora , Mebius Reina E. , Prat Alexandre , de Vries Helga E. , Reijerkerk Arie
Published: January 2013

The blood–brain barrier (BBB) is crucial in the maintenance of a controlled environment within the brain to safeguard optimal neuronal function. The endothelial cells (ECs) of the BBB possess specific properties that restrict the entry of cells and metabolites into the CNS. The specialized BBB endothelial phenotype is induced during neurovascular development by surrounding cells of the CNS. However, the molecular differentiation of the BBB endothelium remains poorly understood. Retinoic acid (RA) plays a crucial role in the brain during embryogenesis. Because radial glial cells supply the brain with RA during the developmental cascade and associate closely with the developing vasculature, we hypothesize that RA is important for the induction of BBB properties in brain ECs. Analysis of human postmortem fetal brain tissue shows that the enzyme mainly responsible for RA synthesis, retinaldehyde dehydrogenase, is expressed by radial glial cells. In addition, the most important receptor for RA-driven signaling in the CNS, RA-receptor β (RARβ), is markedly expressed by the developing brain vasculature. Our findings have been further corroborated byin vitroexperiments showing RA- and RARβ-dependent induction of different aspects of the brain EC barrier. Finally, pharmacologic inhibition of RAR activation during the differentiation of the murine BBB resulted in the leakage of a fluorescent tracer as well as serum proteins into the developing brain and reduced the expression levels of important BBB determinants. Together, our results point to an important role for RA in the induction of the BBB during human and mouse development.
Presenilin1 Regulates Histamine Neuron Development and Behavior in Zebrafish,Danio rerio
Authors: Sundvik Maria , Chen Yu-Chia , Panula Pertti
Published: January 2013

Modulatory neurotransmitters, including the histaminergic system, are essential in mediating cognitive functions affected in Alzheimer's disease (AD). The roles of disease genes associated with AD, most importantly thepresenilin1gene (psen1), are poorly understood. We studied the role ofpsen1in plasticity of the brain histaminergic system using a novelpsen1mutant zebrafish,Danio rerio. We found that inpsen1−/−zebrafish, the histaminergic system is altered throughout life. At 7 d postfertilization (dpf) the histamine neuron number was reduced inpsen1−/−compared with wild-type (WT) fish; at 2 months of age the histamine neuron number was at the same level as that in WT fish. In 1-year-old zebrafish, the histamine neuron number was significantly increased inpsen1−/−fish compared with WT fish. These changes in histamine neuron number were accompanied by changes in histamine-driven behaviors. Treatment with DAPT, a γ-secretase inhibitor, similarly interfered with the development of the histaminergic neurons. We also assessed the expression of γ-secretase-regulatedNotch1amRNA and β-catenin at different time points.Notch1amRNA level was reduced inpsen1−/−compared with WT fish, whereas β-catenin was slightly upregulated in the hypothalamus ofpsen1−/−compared with WT fish at 7 dpf. The results reveal a life-long brain plasticity in both the structure of the histaminergic system and its functions induced by alteredNotch1aactivity as a consequence ofpsen1mutation. The new histaminergic neurons in aging zebrafish brain may arise as a result of phenotypic plasticity or represent newly differentiated stem cells.
Receptive Field Properties of Color Opponent Neurons in the Cat Lateral Geniculate Nucleus
Authors: Buzás Péter , Kóbor Péter , Petykó Zoltán , Telkes Ildikó , Martin Paul R. , Lénárd László
Published: January 2013

Most nonprimate mammals possess dichromatic (“red–green color blind”) color vision based on short-wavelength-sensitive (S) and medium/long-wavelength-sensitive (ML) cone photoreceptor classes. However, the neural pathways carrying signals underlying the primitive “blue–yellow” axis of color vision in nonprimate mammals are largely unexplored. Here, we have characterized a population of color opponent (blue-ON) cells in recordings from the dorsal lateral geniculate nucleus of anesthetized cats. We found five points of similarity to previous descriptions of primate blue-ON cells. First, cat blue-ON cells receive ON-type excitation from S-cones, and OFF-type excitation from ML-cones. We found no blue-OFF cells. Second, the S- and ML-cone-driven receptive field regions of cat blue-ON cells are closely matched in size, consistent with specialization for detecting color contrast. Third, the receptive field center diameter of cat blue-ON cells is approximately three times larger than the center diameter of non-color opponent receptive fields at any eccentricity. Fourth, S- and ML-cones contribute weak surround inhibition to cat blue-ON cells. These data show that blue-ON receptive fields in cats are functionally very similar to blue-ON type receptive fields previously described in macaque and marmoset monkeys. Finally, cat blue-ON cells are found in the same layers as W-cells, which are thought to be homologous to the primate koniocellular system. Based on these data, we suggest that cat blue-ON cells are part of a “blue–yellow” color opponent system that is the evolutionary homolog of the blue-ON division of the koniocellular pathway in primates.
Aging-InducedNrf2-AREPathway Disruption in the Subventricular Zone Drives Neurogenic Impairment in Parkinsonian Mice viaPI3K-Wnt/β-CateninDysregulation
Authors: L'Episcopo Francesca , Tirolo Cataldo , Testa Nunzio , Caniglia Salvatore , Morale Maria C. , Impagnatiello Francesco , Pluchino Stefano , Marchetti Bianca
Published: January 2013

Aging and exposure to environmental toxins including MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) are strong risk factors for developing Parkinson's disease (PD), a common neurologic disorder characterized by selective degeneration of midbrain dopaminergic (DAergic) neurons and astrogliosis. Aging and PD impair the subventricular zone (SVZ), one of the most important brain regions for adult neurogenesis. Because inflammation and oxidative stress are the hallmarks of aging and PD, we investigated the nature, timing, and signaling mechanisms contributing to aging-induced SVZ stem/neuroprogenitor cell (NPC) inhibition in aging male mice and attempted to determine to what extent manipulation of these pathways produces a functional response in the outcome of MPTP-induced DAergic toxicity. We herein reveal an imbalance ofNrf2-driven antioxidant/anti-inflammatory genes, such asHeme oxygenase1in the SVZ niche, starting by middle age, amplified upon neurotoxin treatment and associated with an exacerbated proinflammatory SVZ microenvironment converging to dysregulate theWingless-type MMTVintegration site(Wnt)/β-cateninsignaling, a key regulatory pathway for adult NPCs.In vitroexperiments using coculture paradigms uncovered aged microglial proinflammatory mediators as critical inhibitors of NPC proliferative potential. We also found that interruption ofPI3K (phosphatidylinositol3-kinase)/Aktand theWnt/Fzd/β-cateninsignaling cascades, which switchglycogen synthase kinase 3β(GSK-3β)activation on and off, were causally related to the impairment of SVZ-NPCs. Moreover, a synergy between dysfunctional microglia of aging mice and MPTP exposure further inhibited astrocyte proneurogenic properties, including the expression of keyWntscomponents. Last, pharmacological activation/antagonism studiesin vivoandin vitrosuggest the potential that aged SVZ manipulation is associated with DAergic functional recovery.
Differential Balance of Prefrontal Synaptic Activity in Successful versus Unsuccessful Cognitive Aging
Authors: Bories Cyril , Husson Zoé , Guitton Matthieu J. , De Koninck Yves
Published: January 2013

Normal aging is associated with a variable decline in cognitive functions. Among these, executive function, decision-making, and working memory are primarily associated with the prefrontal cortex. Although a number of studies have examined the structural substrates of cognitive decline associated with aging within this cortical area, their functional correlates remain poorly understood. To fill this gap, we aimed to identify functional synaptic substrates of age-associated frontal-dependent deficits in layer 2/3 pyramidal neurons of medial prefrontal cortex of 3-, 9-, and ≥23-month-old Fischer 344 rats. We combined, in the same animals, novelty recognition and exploratory behavioral tasks with assessment of structural and functional aspects of prefrontal synaptic properties. We found that subsets of aged animals displayed stereotyped exploratory behavior or memory deficits. Despite an age-dependent dendritic spine loss, patch-clamp recording of synaptic activity revealed an increase in miniature EPSC frequency restricted to aged animals with preserved exploratory behavior. In contrast, we found a strong positive relationship between miniature IPSC frequency and the occurrence of both stereotyped exploratory behavior and novelty-related memory deficits. The enhanced miniature inhibitory tone was accompanied by a deficit in activity-driven inhibition, also suggesting an impaired dynamic range for modulation of inhibition in the aged, cognitively impaired animals. Together, our data indicate that differential changes in the balance of inhibitory to excitatory synaptic tone may underlie distinct trajectories in the evolution of cognitive performance during aging.
Declines in Drp1 and Parkin Expression Underlie DNA Damage-Induced Changes in Mitochondrial Length and Neuronal Death
Authors: Wang David B. , Garden Gwenn A. , Kinoshita Chizuru , Wyles Cody , Babazadeh Nasim , Sopher Bryce , Kinoshita Yoshito , Morrison Richard S.
Published: January 2013

Maintaining proper mitochondrial length is essential for normal mitochondrial function in neurons. Mitochondrial fragmentation has been associated with neuronal cell death caused by a variety of experimental toxic stressors. Despite the fact that oxidative stress is a hallmark of neurodegenerative conditions and aging and the resulting activation of p53 is believed to contribute to the neuropathology, little is still known regarding changes in mitochondrial morphology in p53-dependent neuronal death. Therefore, we specifically addressed the relationship between genotoxic stress, p53 activation, and the regulation of mitochondrial morphology in neurons. In cultured postnatal mouse cortical neurons, treatment with the DNA-damaging agent camptothecin (CPT) resulted in elongated mitochondria, in contrast to fragmented mitochondria observed upon staurosporine and glutamate treatment. In fibroblasts, however, CPT resulted in fragmented mitochondria. CPT treatment in neurons suppressed expression of the mitochondrial fission protein Drp1 and the E3 ubiquitin ligase parkin. The presence of elongated mitochondria and the declines in Drp1 and parkin expression occurred before the commitment point for apoptosis. The CPT-induced changes in Drp1 and parkin were not observed in p53-deficient neurons, while p53 overexpression alone was sufficient to reduce the expression of the two proteins. Elevating Drp1 or parkin expression before CPT treatment enhanced neuronal viability and restored a normal pattern of mitochondrial morphology. The present findings demonstrate that genotoxic stress in neurons results in elongated mitochondria in contrast to fission induced by other forms of stress, and p53-dependent declines in Drp1 and parkin levels contribute to altered mitochondrial morphology and cell death.
Serotonergic Neurosecretory Synapse Targeting Is Controlled by Netrin-Releasing Guidepost Neurons inCaenorhabditis elegans
Authors: Nelson Jessica C. , Colón-Ramos Daniel A.
Published: January 2013

Neurosecretory release sites lack distinct postsynaptic partners, yet target to specific circuits. This targeting specificity regulates local release of neurotransmitters and modulation of adjacent circuits. How neurosecretory release sites target to specific regions is not understood. Here we identify a molecular mechanism that governs the spatial specificity of extrasynaptic neurosecretory terminal (ENT) formation in the serotonergic neurosecretory–motor (NSM) neurons ofCaenorhabditis elegans. We show that postembryonic arborization and neurosecretory terminal targeting of theC. elegansNSM neuron is dependent on the Netrin receptor UNC-40/DCC. We observe that UNC-40 localizes to specific neurosecretory terminals at the time of axon arbor formation. This localization is dependent on UNC-6/Netrin, which is expressed by nerve ring neurons that act as guideposts to instruct local arbor and release site formation. We find that both UNC-34/Enabled and MIG-10/Lamellipodin are required downstream of UNC-40 to link the sites of ENT formation to nascent axon arbor extensions. Our findings provide a molecular link between release site development and axon arborization and introduce a novel mechanism that governs the spatial specificity of serotonergic ENTsin vivo.
Self-Inflicted Industry Wounds: Early Warning Signals and Pelican Gambits
Authors: Donaldson Thomas , Schoemaker Paul J.H.
Published: January 2013

Systemic risks arising from underlying interdependences can create havoc at an industry level and are often too formidable for any single firm to manage. The contagion effects of these risks, including the recent financial crisis, offshore oil spills, and the Japanese nuclear disaster, have upended industry practices. Sometimes they have even pulled economies apart at the seams. We recommend that leaders heed models of cooperative behavior found in nature by engaging in “Pelican Gambits,” which we define as strategic moves towards cooperation in highly competitive economic environments for the purpose of limiting risk to one's firm, the industry and society.
Low malignancy risk of thyroid follicular lesion of undetermined significance in patients from post-endemic areas
Authors: Słowińska-Klencka Dorota , Woźniak Ewa , Wojtaszek Martyna , Popowicz Bożena , Sporny Stanisław , Klencki Mariusz
Published: January 2013

Objective

New classification of the thyroid fine-needle aspiration biopsy (FNAB) results tries to stratify the risk of malignancy of thyroid follicular lesions using ‘follicular lesion of undetermined significance’ (FLUS) subcategory. Clinical significance of this category in the endemic (or post-endemic) areas has not been clearly established.

Design

The aim of the study was to determine the risk of malignancy for FLUS as well as to evaluate ultrasound (US) malignancy risk features (MRF) in such nodules in comparison with ‘suspicious for neoplasm’ (SFN) and ‘benign lesions’ (BL).

Methods

The US images and cytological diagnoses of 589 thyroid follicular lesions were analysed from January 2010 to July 2012. Cytological follow-up was assessed in 110 cases and surgical one in 100 cases.

Results

FLUS was diagnosed in 340 cases (3.8% of all cytological diagnoses and 57% of thyroid follicular lesions). Altogether, clinical and/or surgical follow-up revealed thyroid cancer in 3.2% patients with FLUS nodules. Repeat FNAB led to more specific diagnosis in 74.4% of FLUS (3.5%, papillary cancers or their suspicion; 2.3%, SFN; 68.6%, BL). The histopathological examination showed thyroid cancer in 6.4% cases of FLUS and 7.0% of SFN and follicular adenoma in 8.5% of FLUS and 11.6% of SFN (NS, FLUS vs SFN). FLUS showed MRF of intermediate values between BL and SFN; SFN more often than FLUS showed at least two MRF (53 vs 30%,P<0.0001).

Conclusions

The risk of cancer in FLUS in areas with recently corrected iodine supply is low. In such areas, repeated biopsy leads to more precise cytological diagnosis in about 3/4 cases.