bluuebunny/crossref_metadata_2025_split huggingface dataset:
Computable cause‐and‐effect models of healthy and Alzheimer's disease states and their mechanistic differential analysis
Authors: Kodamullil Alpha Tom , Younesi Erfan , Naz Mufassra , Bagewadi Shweta , Hofmann‐Apitius Martin 
Published: April 2015

AbstractIntroductionThe discovery and development of new treatments for Alzheimer's disease (AD) requires a profound mechanistic understanding of the disease. Here, we propose a model‐driven approach supporting the systematic identification of putative disease mechanisms.MethodsWe have created a model for AD and a corresponding model for the normal physiology of neurons using biological expression language to systematically model causal and correlative relationships between biomolecules, pathways, and clinical readouts. Through model‐model comparison we identify “chains of causal relationships” that lead to new insights into putative disease mechanisms.ResultsUsing differential analysis of our models we identified a new mechanism explaining the effect of amyloid‐beta on apoptosis via both the neurotrophic tyrosine kinase receptor, type 2 and nerve growth factor receptor branches of the neurotrophin signaling pathway. We also provide the example of a model‐guided interpretation of genetic variation data for a comorbidity analysis between AD and type 2 diabetes mellitus.DiscussionThe two computable, literature‐based models introduced here provide a powerful framework for the generation and validation of rational, testable hypotheses across disease areas.
RETRACTED: Targeting MYCN IRES in MYCN‐amplified neuroblastoma with miR‐375 inhibits tumor growth and sensitizes tumor cells to radiation
Authors: Zhang Hailong , Liu Tao , Yi Sha , Gu Lubing , Zhou Muxiang 
Published: April 2015

The MYCN oncogene is amplified in 20% of neuroblastomas, leading to its overexpression at both the mRNA and protein levels. MYCN overexpression is strongly associated with advanced disease stage, rapid tumor progression and a worse prognosis. In the present study, we identified microRNA‐375 (miR‐375) as a negative regulator of MYCN: enforced expression of miR‐375 inhibited MYCN‐amplified neuroblastoma in vitro and in vivo. Upon searching the website miRbase for possible miR‐375 binding sites within the whole MYCN mRNA, we found that the MYCN 5′‐UTR had significant sequence complementarity to miR‐375, yet no complementary sequences existed within the MYCN 3′‐UTR and coding regions. Enforced overexpression of miR‐375 efficiently inhibited MYCN mRNA translation and protein synthesis, via an IRES‐dependent mechanism. In athymic nude mouse model with human MYCN‐amplified neuroblastoma, MYCN downregulation by miR‐375 led to inhibition of tumor cell growth and tumorigenicity. In particular, miR‐375‐regulated inhibition of MYCN translation was enhanced when MYCN‐amplified neuroblastoma cells were exposed to stress stimulation, such as ionizing irradiation (IR), resulting in a remarkable increase in the neuroblastoma's sensitivity to IR‐induced cell death. Our results identified a novel mechanism by which IRES‐dependent translation of MYCN is repressed by miR‐375, particularly during cellular stress, highlighting a potential anticancer strategy: the development of miR‐375 as a novel therapeutic agent to treat MYCN‐amplified neuroblastoma.
Upregulated interleukin‐6 expression contributes to erlotinib resistance in head and neck squamous cell carcinoma
Authors: Stanam Aditya , Love-Homan Laurie , Joseph Tisha S. , Espinosa-Cotton Madelyn , Simons Andrean L. 
Published: April 2015

Despite the role of epidermal growth factor receptor (EGFR) signaling in head and neck squamous cell carcinoma (HNSCC) development and progression, clinical trials involving EGFR tyrosine kinase inhibitors (TKIs) have yielded poor results in HNSCC patients. Mechanisms of acquired resistance to the EGFR TKI erlotinib was investigated by developing erlotinib‐resistant HNSCC cell lines and comparing their gene expression profiles with their parental erlotinib‐sensitive HNSCC cell lines using microarray analyses and subsequent pathway and network analyses. Erlotinib‐resistant HNSCC cells displayed a significant upregulation in immune response and inflammatory pathways compared to parental cells. Interleukin‐6 (IL‐6) was one of thirteen genes that was significantly differentially expressed in all erlotinib‐resistant HNSCC cell lines, which was validated using RT‐PCR and ELISA. Blockade of IL‐6 signaling using the IL‐6 receptor antagonist tocilizumab, was able to overcome erlotinib‐resistance in erlotinib‐resistant SQ20B tumors in vivo. Overall, erlotinib‐resistant HNSCC cells display elevated IL‐6 expression levels compared to erlotinib‐sensitive HNSCC cells and blockade of the IL‐6 signaling pathway may be an effective strategy to overcome resistance to erlotinib and possibly other EGFR TKIs for HNSCC therapy.
Preclinical validation of anti‐nuclear factor‐kappa B therapy to inhibit human vestibular schwannoma growth
Authors: Dilwali Sonam , Briët Martijn C. , Kao Shyan-Yuan , Fujita Takeshi , Landegger Lukas D. , Platt Michael P. , Stankovic Konstantina M. 
Published: April 2015

Vestibular schwannomas (VSs), the most common tumors of the cerebellopontine angle, arise from Schwann cells lining the vestibular nerve. Pharmacotherapies against VS are almost non‐existent. Although the therapeutic inhibition of inflammatory modulators has been established for other neoplasms, it has not been explored in VS. A bioinformatic network analysis of all genes reported to be differentially expressed in human VS revealed a pro‐inflammatory transcription factor nuclear factor‐kappa B (NF‐κB) as a central molecule in VS pathobiology. Assessed at the transcriptional and translational level, canonical NF‐κB complex was aberrantly activated in human VS and derived VS cultures in comparison to control nerves and Schwann cells, respectively. Cultured primary VS cells and VS‐derived human cell line HEI‐193 were treated with specific NF‐κB siRNAs, experimental NF‐κB inhibitor BAY11‐7082 (BAY11) and clinically relevant NF‐κB inhibitor curcumin. Healthy human control Schwann cells from the great auricular nerve were also treated with BAY11 and curcumin to assess toxicity. All three treatments significantly reduced proliferation in primary VS cultures and HEI‐193 cells, with siRNA, 5 μM BAY11 and 50 μM curcumin reducing average proliferation (±standard error of mean) to 62.33% ± 10.59%, 14.3 ± 9.7%, and 23.0 ± 20.9% of control primary VS cells, respectively. These treatments also induced substantial cell death. Curcumin, unlike BAY11, also affected primary Schwann cells. This work highlights NF‐κB as a key modulator in VS cell proliferation and survival and demonstrates therapeutic efficacy of directly targeting NF‐κB in VS.
The ‘logic of escalation’ in performance measurement: An analysis of the dynamics of a research evaluation system
Authors: Woelert Peter 
Published: April 2015

Abstract
This paper makes a conceptual contribution to the understanding of the ‘alternative logics’ (Pollitt) occurring in performance measurement systems in crucial public policy domains. The major focus is on what has been referred to as ‘logic of escalation’ (Pollitt) that manifests itself where performance measurement is strongly geared toward quantified performance indicators. What characterizes this logic is the unfolding of a peculiar dynamics through which performance measurement becomes increasingly expansive and technical (and hence costly), and, in political terms, control-focused. Drawing mainly on the conceptual resources of Edmund Husserl’s phenomenological philosophy, as well as on Michael Power’s work on (performance) measurement, it is shown that this sort of dynamics is linked to the constitution of quantitative performance measures as ‘abstractions from abstractions’. In addition, I highlight some of the organizational dimensions of the ‘logic of escalation’. I use the current Australian research evaluation system as a paradigmatic case to exemplify and ground my major conceptual points and observations.
On the interaction between momentum effect and size effect
Authors: Alhenawi Yasser 
Published: April 2015

AbstractThis paper uses a sample of firms listed in the NYSE, AMEX, and NASDAQ between January 1963 and December 2012 to analyze the interaction between size effect and momentum effect in cross‐sectional stock returns. Furthermore, this paper focuses on the evolution of this interaction through different market states. I report a significant shift in stock returns structure during the rising markets of the 1990s and the 2000s. First, momentum has absorbed the size effect. Second, the momentum effect has become stronger in larger, not smaller, firms. These patterns are indicative of a strong interaction between the two effects. Conceivably, in up markets, firms grow fast, and thus, the size and momentum effects stem from a common economic phenomenon: growth. The findings are robust to variations in the length of the formation period and to the use of residual return (instead of total return) to rank stocks.
Maternal age effects on Atlantic cod recruitment and implications for future population trajectories
Authors: Shelton Andrew Olaf , Hutchings Jeffrey A. , Waples Robin S. , Keith David M. , Akçakaya H. Resit , Dulvy Nicholas K. 
Published: April 2015

Abstract
Exploited fish populations frequently exhibit truncated age-structure. To address a basic question in fisheries science and conservation biology—how does age truncation affect population dynamics and productivity?—we explored the effect of age-structure on recruitment dynamics of ten stocks of Atlantic cod (Gadus morhua). Based on six alternative stock–recruitment relationships, we compared models that included and excluded maternal age-structure effects on recruitment. In all ten stocks, a recruitment model that included a maternal age-dependent effect was preferred over the standard Ricker model and in seven of the ten stocks, the preferred statistical model included a positive effect of either maternal age or mass on recruitment. Simulations comparing standard and maternal age dependent recruitment two decades into the future suggest that the inclusion of maternal age in recruitment models has little effect on projected biomasses. However, this similarity in biomass trajectory masked an increased sensitivity of populations with maternal age-dependent recruitment to stock age-structure. In particular, simulations with maternal age-dependent recruitment responded strongly to changes in fishing mortality on the oldest age classes, while simulations using standard recruitment models did not. Populations with maternal age-dependent recruitment can exhibit increased biomass catch even if fishing mortality on older individuals was reduced. Overall, simulations suggested that the influence of maternal age on population dynamics are more nuanced than suggested by previous research and indicate that careful consideration of the effects of age-structure on populations may lead to substantially different fisheries management reference points—particularly with respect to age-specific fishing mortality—than classical models. While these results suggest a link between maternal age and population productivity, future research requires the incorporation of biologically reasonable and empirically defensible mechanisms to clarify the effect of age on population dynamics.
A quantitative review of relationships between ecosystem services
Authors: Lee Heera , Lautenbach Sven 
Published: April 2015

AbstractEcosystems provide multiple ecosystem services to society. Ignoring the multi-functionality of land systems in natural resource management generates potentially trade-offs with respect to the provisioning of ecosystem services. Understanding relationships between ecosystem services can therefore help to minimize undesired trade-offs and enhance synergies. The research on relationships between ecosystem services has recently gained increasing attention in the scientific community. However, a synthesis on existing knowledge and knowledge gaps is missing so far. We analyzed 67 case studies that studied 476 pairwise combinations of ecosystem services. The relationships between these pairs of ecosystem services were classified into three categories: “trade-off”, “synergy” or “no-effect”. Most pairs of ecosystem services (74%) had a clear association with one category: the majority of case studies reported similar relationships for pairs of ecosystem services. A synergistic relationship was dominant between different regulating services and between different cultural services, whereas the relationship between regulating and provisioning services was trade-off dominated. Increases in cultural services did not influence provisioning services (”no-effect”). We further analyzed the pattern of relationships between ecosystem services across scales, land system archetypes and methods used to determine the relationship. Our analysis showed that the overall pattern of relationships between ecosystem services did not change significantly with scale and land system archetypes. However, some pairs of ecosystem services showed changes in relationships with scale. The choice of methods used to determine the relationship had an effect on the direction of the relationship: studies that employed correlation coefficients showed an increased probability to identify no-effect relationships, whereas descriptive methods had a higher probability of identifying trade-offs. The regional scale was the most commonly considered, and case studies were biased among different land system archetypes which might affect our ability to find the effect of scale or land system archetypes on the pattern of relationships. Our results provide helpful information of which services to include in ecosystem services assessments for the scientific community as well as for practitioners. Furthermore, they allow a first check if critical trade-offs have been considered in an analysis.
Isoform-level Ribosome Occupancy Estimation Guided by Transcript Abundance with Ribomap
Authors: Wang Hao , McManus Joel , Kingsford Carl 
Published: April 2015

AbstractRibosome profiling is a recently developed high-throughput sequencing technique that captures approximately 30 bp long ribosome-protected mRNA fragments during translation. Because of alternative splicing and repetitive sequences, a ribosome-protected read may map to many places in the transcriptome, leading to discarded or arbitrary mappings when standard approaches are used. We present a technique and software that addresses this problem by assigning reads to potential origins proportional to estimated transcript abundance. This yields a more accurate estimate of ribosome profiles compared with a naϊve mapping. Ribomap is available as open source athttp://www.cs.cmu.edu/∼ckingsf/software/ribomap.
Phenotypic Covariation And Morphological Diversification In The Ruminant Skull
Authors: Haber Annat 
Published: April 2015

AbstractDifferences among clades in their diversification patterns result from a combination of extrinsic and intrinsic factors. In this study I examined the role of intrinsic factors in the morphological diversification of ruminants in general, and in the differences between bovids and cervids in particular. Using skull morphology, which embodies many of the adaptations that distinguish bovids and cervids, I examined 132 of the 200 extant ruminant species. As a proxy for intrinsic constraints I quantified different aspects of the phenotypic covariation structure within species, and compared them with the among-species divergence patterns, using phylogenetic comparative methods. My results show that for most species, divergence is well aligned with their phenotypic covariance matrix, and those that are better aligned have diverged further away from their ancestor. Bovids have dispersed into a wider range of directions in morphospace than cervids, and their overall disparity is higher. This difference is best explained by the lower eccentricity of bovids’ within-species covariance matrices. These results are consistent with the role of intrinsic constraints in determining amount, range, and direction of dispersion, and demonstrate that intrinsic constraints can influence macroevolutionary patterns even as the covariance structure evolves.
Validity and reliability of bioelectrical impedance analysis to estimate body fat percentage against air displacement plethysmography and dual‐energy X‐ray absorptiometry
Authors: von Hurst Pamela R. , Walsh Daniel C.I. , Conlon Cathryn A. , Ingram Michelle , Kruger Rozanne , Stonehouse Welma 
Published: April 2015

AbstractAir displacement plethysmography (ADP) and dual‐energy X‐ray absorptiometry (DXA) are well‐regarded methods for predicting body fat percentage (BF%). Bioelectrical impedance analysis (BIA) also predicts BF% and has distinct advantages in research settings.AimTo assess the validity of BIA against ADP and DXA to measure BF%, and to test the reliability of each method.MethodsAdults (n = 166) with a wide range of body mass index (19–38 kg/m2) were tested twice during a 5‐day period. ADP was conducted in a BodPod (Life Measurement Inc, Concord, CA, USA); DXA measurements on a QDR Discovery A (Hologic) and BIA measurements used the InBody 230 (Biospace Ltd., Seoul, Korea). Agreement between measurements was analysed using t‐tests, effect size, linear regression models and method of triads (estimating true value).ResultsBIA showed excellent relative agreement to the estimated true value (ρ = 0.97 (0.96, 0.98)) and to ADP (R2 = 0.88) and DXA (R2 = 0.92), but wide limits of agreement (−4.25 to 8.37%). BIA underestimated BF% by 2%, across all values. DXA showed excellent relative agreement to the estimated true value (ρ = 0.97 (0.96, 0.98)) and with ADP (R2 = 0.92), good absolute agreement but wide limits of agreement (−6.13 to 6.91%) and under‐ and overestimation at high and low BF% levels, respectively. All methods showed excellent reliability with repeat measurements differing by less than 0.2% with very small 95% CIs.ConclusionsBIA may be a valid method in research and population samples. All three methods showed excellent reliability.
Volcanic hazards in the Mexico City metropolitan area from eruptions at Popocatépetl, Nevado de Toluca, and Jocotitlán stratovolcanoes and monogenetic scoria cones in the Sierra Chichinautzin Volcanic Field
Authors: Siebe Claus , Macías José Luis 
Published: April 2015

AbstractTephrochronological studies carried out over the past decade in the area surrounding Mexico City have yielded a wealth of new radiocarbon ages from eruptions at Popocatépetl, Nevado de Toluca, and Jocotitlán stratovolcanoes and monogenetic scoria cones in the Sierra Chichinautzin Volcanic Field. These dates allow us to constrain the frequency and types of eruptions that have affected this area during the course of the past 25,000 yr. They have important implications for archaeology as well as future hazard evaluations.Late Pleistocene and Holocene volcanic activities at the stratovolcanoes are characterized by recurrent cataclysmic Plinian eruptions of considerable magnitude. They have affected vast areas, including zones that today are occupied by large population centers at Puebla, Toluca, and Mexico City. During Holocene time, Nevado de Toluca and Jocotitlán have each experienced only one Plinian eruption, ca. 10,500 yr B.P. and 9700 yr B.P. respectively. During the same period of time, Popocatépetl had at least four such eruptions, ca. 8000, 5000, 2100, and 1100 yr B.P. Therefore, the recurrence interval for Plinian eruptions is less than 2000 yr in this region. The last two Plinian eruptions at Popocatépetl are of particular interest because they destroyed several human settlements in the Basin of Puebla. Evidence for these disasters stems from pottery shards and other artifacts covered by Plinian pumice falls, ash-flow deposits, and lahars on the plains to the east and northeast of the volcanic edifice.Several monogenetic scoria cones located within the Sierra Chichinautzin Volcanic Field at the southern margin of Mexico City were also dated by the radiocarbon method in recent years. Most previous research in this area was concentrated on Xitle scoria cone, whose lavas destroyed and buried the pre-Hispanic town of Cuicuilco ca. 1665 ± 35 yr B.P. The new dates indicate that the recurrence interval for monogenetic eruptions in the close vicinity of Mexico City is also &lt;2000 yr. The longest lava flow associated with a scoria cone was erupted by Guespalapa and reached 24 km from its source; total areas covered by lava flows from each monogenetic eruption typically range between 30 and 80 km2, and total erupted volumes range between 0.5 and 2 km3/cone. An average eruption rate for the entire Chichinautzin was estimated at ~0.5 km3/1000 yr. These findings are of great importance for archaeological as well as volcanic hazard studies in this heavily populated region.
Mountain-building theory
Authors: Mayo Dwight E. 
Published: April 2015

Abstract
Isostasy and the geosyncline are two major geological concepts that had their origins in the nineteenth century. Each is uniquely American in its origin, although a number of suggestions by Europeans triggered ideas in the minds of Americans. James Hall first published the basics of the geosyncline in 1859, although the concept was without its present name until that was provided later by James Dwight Dana. Isostasy-like generalizations began with J.F.W. Herschel in 1836, but it was not until 1889 that Clarence E. Dutton formally named the concept of isostasy. Isostasy and the geosyncline are closely related concepts in modern geological theory, and it is no surprise to find that they developed more or less concurrently and that certain individuals were involved in the development of each. Among geologists who either contributed to or critiqued the ideas, we find such familiar names as Hall, Dutton, Dana, T. Sterry Hunt, Joseph LeConte, G. K. Gilbert, William J. McGee and others. The development of isostasy and the geosyncline follows a process that is familiar in the history of science. Each was developed against the background of major philosophical arguments. Each was postulated minus much of the evidence required for a credible idea. Each attracted a number of proponents and detractors, and each had staying power sufficient to achieve general acceptance by the scientific community. At the present, against the backdrop of a major new theory system—plate tectonics—isostasy remains a useful and noncontroversial idea. The geosyncline, however, has a less solid future. Some geologists assert that it is no longer useful and should be junked, while others, by redefining the idea, continue to find it a major unifying concept.