bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stat1 stimulates cap-independent mRNA translation to inhibit cell proliferation and promote survival in response to antitumor drugs
Authors: Wang Shuo , Patsis Christos , Koromilas Antonis E. 
Published: April 2015

Significance
Stat1 functions as a tumor suppressor by inhibiting cell proliferation and mediating antitumor immune responses. Thus, Stat1 is thought to be a suitable target for the implementation of effective antitumor therapies. However, recent findings have shown that Stat1 can mediate resistance to antitumor drugs through mechanisms that are not well understood. Herein, we demonstrate the ability of Stat1 to induce phosphoinositide 3-kinase γ (PI3Kγ) signaling and inhibit general protein synthesis, which results in the translation of select mRNAs encoding for proteins that inhibit cell proliferation or render cells increasingly resistant to antitumor drugs. Our work may result in the design of therapies that disarm the prosurvival function of Stat1 in tumors without compromising its ability to mount an effective antitumor immune response.
Inhibition of TLR2 signaling by small molecule inhibitors targeting a pocket within the TLR2 TIR domain
Authors: Mistry Pragnesh , Laird Michelle H. W. , Schwarz Ryan S. , Greene Shannon , Dyson Tristan , Snyder Greg A. , Xiao Tsan Sam , Chauhan Jay , Fletcher Steven , Toshchakov Vladimir Y. , MacKerell Alexander D. , Vogel Stefanie N. 
Published: April 2015

SignificanceExcess Toll-like receptor 2 (TLR2) signaling has been implicated in numerous inflammatory diseases, yet there is no TLR2 inhibitor licensed for human use. Using computer-aided drug design (CADD), we identified a compound, C16H15NO4(C29), and a derivative,ortho-vanillin, that inhibit TLR2 signaling in vitro and in vivo. Our findings also revealed unexpected differences between TLR2/1 and TLR2/6 signaling in mice vs. humans. Importantly, our data provide proof of principle that the CADD-targeted BB loop pocket residues are critical for TLR2 signaling and may be targeted therapeutically.
Nanoparticle self-assembly at the interface of liquid crystal droplets
Authors: Rahimi Mohammad , Roberts Tyler F. , Armas-Pérez Julio C. , Wang Xiaoguang , Bukusoglu Emre , Abbott Nicholas L. , de Pablo Juan J. 
Published: April 2015

Significance
Controlled assembly of nanoparticles at liquid crystal interfaces could lead to easily manufacturable building blocks for assembly of materials with tunable mechanical, optical, and electronic properties. Past work has examined nanoparticle assembly at planar liquid crystal interfaces. In this work, we show that nanoparticle assembly on curved interfaces is drastically different and arises for conditions under which assembly is too weak to occur on planar interfaces. We also demonstrate that liquid crystal-mediated nanoparticle interactions are strong, are remarkably sensitive to surface anchoring, and lead to hexagonal arrangements that do not arise in bulk systems. All of these elements form the basis for a highly tunable, predictable, and versatile platform for hierarchical materials assembly.
Cryo-EM structure of the tetracycline resistance protein TetM in complex with a translating ribosome at 3.9-Å resolution
Authors: Arenz Stefan , Nguyen Fabian , Beckmann Roland , Wilson Daniel N. 
Published: April 2015

Significance
The ribosome, the protein-synthesizing machine in the cell, is a major target for antibiotics, such as tetracyclines. The widespread usage of tetracyclines has led to an increase in tetracycline resistance amongst medically relevant pathogenic bacteria, limiting their utility. Many bacteria obtain tetracycline resistance via ribosome protection proteins, such as TetM and TetO, that bind to the ribosome and chase tetracycline from its binding site. We have determined a structure of TetM bound to a translating ribosome at 3.9 Å, providing molecular insight into how TetM interacts with the ribosome to dislodge the drug from its binding site.
Digital diffraction analysis enables low-cost molecular diagnostics on a smartphone
Authors: Im Hyungsoon , Castro Cesar M. , Shao Huilin , Liong Monty , Song Jun , Pathania Divya , Fexon Lioubov , Min Changwook , Avila-Wallace Maria , Zurkiya Omar , Rho Junsung , Magaoay Brady , Tambouret Rosemary H. , Pivovarov Misha , Weissleder Ralph , Lee Hakho 
Published: April 2015

Significance
Smartphones and wearable electronics have advanced tremendously over the last several years but fall short of allowing their use for molecular diagnostics. We herein report a generic approach to enable molecular diagnostics on smartphones. The method utilizes molecular-specific microbeads to generate unique diffraction patterns of “blurry beads” which can be recorded and deconvoluted by digital processing. We applied the system to resolve individual precancerous and cancerous cells as well as to detect cancer-associated DNA targets. Because the system is compact, easy to operate, and readily integrated with the standard, portable smartphone, this approach could enable medical diagnostics in geographically and/or socioeconomically limited settings with pathology bottlenecks.
Neuronal medium that supports basic synaptic functions and activity of human neurons in vitro
Authors: Bardy Cedric , van den Hurk Mark , Eames Tameji , Marchand Cynthia , Hernandez Ruben V. , Kellogg Mariko , Gorris Mark , Galet Ben , Palomares Vanessa , Brown Joshua , Bang Anne G. , Mertens Jerome , Böhnke Lena , Boyer Leah , Simon Suzanne , Gage Fred H. 
Published: April 2015

SignificanceNeuronal cultures are very valuable to learn about basic principles of the nervous system. In vivo, neural electrical activity is the essence of nervous system function, controlling emotion, memory, sensory modalities, and behavior. In this study, we discovered that many crucial neurophysiological properties were strongly altered in classic culture media that are widely used by the research community. To overcome this problem, we designed and tested a new tissue culture neuromedium that adequately supports in vitro neuronal activity. The improvements made in this medium reduce the gap between in vivo brain physiological conditions and neuronal models in vitro. Improving physiological conditions in vitro may lead to more successful translation from bench to clinics.
Increased size and cellularity of advanced atherosclerotic lesions in mice with endothelial overexpression of the human TRPC3 channel
Authors: Smedlund Kathryn B. , Birnbaumer Lutz , Vazquez Guillermo 
Published: April 2015

SignificanceAtherosclerosis is a chronic disease of the arterial wall with a dominant inflammatory component. Endothelial cell inflammation and recruitment of circulating monocytes are critical processes during atherosclerotic lesion progression. In this manuscript, we generated a mouse model of atherosclerosis with endothelial-specific overexpression of TRPC3, a calcium permeable channel, and provide evidence indicating that augmented expression/function of TRPC3 supports, in vivo, endothelial inflammation and increased macrophage infiltration, resulting in atherosclerotic lesions of bigger size and complexity. These findings support the notion that endothelial TRPC3 channels may represent attractive targets for development of novel therapeutic strategies in the treatment of atherosclerosis.
Multifunctional bioscaffolds for 3D culture of melanoma cells reveal increased MMP activity and migration with BRAF kinase inhibition
Authors: Leight Jennifer L. , Tokuda Emi Y. , Jones Caitlin E. , Lin Austin J. , Anseth Kristi S. 
Published: April 2015

Significance
Matrix metalloproteinases (MMPs) are a family of enzymes that enable cell-mediated remodeling of the local environment. Because of their ability to degrade the extracellular matrix, MMPs are an important component of the metastatic cascade. However, the effect of cancer drug treatment on MMP activity is not well-established. This study reveals that treatment with a clinically relevant BRAF protein kinase inhibitor (PLX4032) correlates with increases in melanoma MMP activity in 3D culture, which consequently leads to increased cell migration. Although PLX4032 initially causes significant tumor shrinkage, patients typically relapse due to metastatic lesions. This work may contribute to our understanding of how initially promising therapeutics ultimately lead to poor patient outcome through drug-induced effects on MMP activity and cell motility.
Assaying the kinetics of protein denaturation catalyzed by AAA+ unfolding machines and proteases
Authors: Baytshtok Vladimir , Baker Tania A. , Sauer Robert T. 
Published: April 2015

Significance
Protein unfolding by ATP-powered enzymes is an essential aspect of many biological reactions, including degradation by AAA+ proteases such as ClpXP and ClpAP, but there have been no robust methods to assay the steady-state kinetics of these reactions. Here, we show that the kinetics of enzymatic unfolding can be monitored by the rate at which a mixture of donor-labeled and acceptor-labeled homodimers is converted into heterodimers and use this assay to characterize the activities of the AAA+ ClpX and ClpA unfoldases with and without ClpP, their proteolytic partner. Our results show differences in intrinsic unfolding activity and in ClpP stimulation and indicate that this assay should be broadly applicable for studying the mechanisms of related AAA+ enzymes and remodeling chaperones.
Spatial Structure of Morphological and Neutral Genetic Variation in Brook Trout
Authors: Kazyak David C. , Hilderbrand Robert H. , Keller Stephen R. , Colaw Mark C. , Holloway Amanda E. , Morgan Raymond P. , King Tim L. 
Published: April 2015

AbstractBrook Trout Salvelinus fontinalis exhibit exceptional levels of life history variation, remarkable genetic variability, and fine‐scale population structure. In many cases, neighboring populations may be highly differentiated from one another to an extent that is comparable with species‐level distinctions in other taxa. Although genetic samples have been collected from hundreds of populations and tens of thousands of individuals, little is known about whether differentiation at neutral markers reflects phenotypic differences among Brook Trout populations. We compared differentiation in morphology and neutral molecular markers among populations from four geographically proximate locations (all within 24 km) to examine how genetic diversity covaries with morphology. We found significant differences among and/or within streams for all three morphological axes examined and identified the source stream of many individuals based on morphology (52.3% classification efficiency). Although molecular and morphological differentiation among streams ranged considerably (mean pairwise FST: 0.023–0.264; pairwise PST: 0.000–0.339), the two measures were not significantly correlated. While in some cases morphological characters appear to have diverged to a greater extent than expected by neutral genetic drift, many traits were conserved to a greater extent than were neutral genetic markers. Thus, while Brook Trout exhibit fine‐scale spatial patterns in both morphology and neutral genetic diversity, these types of biological variabilities are being structured by different ecological and evolutionary processes. The relative influences of genetic drift versus selection and phenotypic plasticity in shaping morphology appear to vary among populations occupying nearby streams.
Diel Cycle and Effects of Water Flow on Activity and Use of Depth by Common Carp
Authors: Benito Josep , Benejam Lluís , Zamora Lluís , García‐Berthou Emili 
Published: April 2015

AbstractCommon Carp Cyprinus carpio is among the most popular and commercially important fishes globally. For this reason, it has been introduced worldwide and is invasive in many regions, with well‐known ecosystems impacts. Like many other freshwater invaders it is thought not to tolerate strong flows well, but knowledge of the effects of flow on their activity, habitat use, and diel cycles are limited, despite this being crucial information for management and control. By means of ultrasonic telemetry we investigated depth use and activity of Common Carp in a small reservoir with a very low water residence time on the main stem of the Ebro River, the largest river by discharge in the Iberian Peninsula, over a 19‐month period. The activity of carp and their use of depth displayed low seasonality compared with abiotic factors. However, carp exhibited diel vertical migration patterns, mostly in the warm season, shifting from deep positions near the reservoir bottom during the night (with decreased activity) to shallow waters during the day. This pattern included extensive use of hypoxic waters (<1.1 mg/L dissolved oxygen) and occurred largely at night. Activity and habitat use also varied among individuals and were significantly related to water flow; carp were less active and used shallower water during increased flows. The individual variability, the behavioral adaptation to refuge from high floods flows, and the extraordinary resistance to hypoxic waters might help explain why Common Carp is one of the most successful invasive freshwater fish species.
Dynamics of Endangered Eastern Cape Breton Atlantic Salmon Populations
Authors: Gibson A. Jamie F. , Bowlby Heather D. , Levy Alex L. 
Published: April 2015

Abstract
The eastern Cape Breton (ECB) designable unit (DU) of Atlantic Salmon Salmo salar comprises populations in 46 or more rivers in the eastern portion of Cape Breton Island, Nova Scotia, Canada. In 2010, the Committee on the Status of Endangered Wildlife in Canada classified the ECB DU as endangered. In support of recovery planning processes, we developed an integrated, statistical, life history-based model for evaluating the dynamics of populations belonging to this DU. Using maximum likelihood, the model was fitted to recreational fishery catch and effort data, fish counts by divers, intermittent mark–recapture data, and sparse age composition data for two populations in the DU. The model output included estimates of maximum lifetime reproductive rate (αˆ) and equilibrium population size—parameters that are important for determining extinction risk. The αˆ for the Middle River population (2.82 spawners/spawner) was double that of the Baddeck River population (1.39 spawners/spawner). These αˆ values would be considered low for Atlantic Salmon populations in general but are higher than those of populations in a neighboring endangered DU to the south. Slightly negative trends in recruitment deviates may indicate declining productivity in the two ECB populations; based on equilibrium analyses, neither population is expected to achieve the proposed recovery targets without an increase in productivity, survival, or both. Atlantic Salmon populations and habitat characteristics in ECB exhibit considerable diversity. Therefore, the dynamics of the Middle River and Baddeck River populations are unlikely to be representative of all populations in the ECB DU. Based on recent trends in recreational fishery catches, these two populations are likely among the healthier populations within the DU.
Received July 8, 2014; accepted December 17, 2014
Normalization of relative and incomplete temporal expressions in clinical narratives
Authors: Sun Weiyi , Rumshisky Anna , Uzuner Ozlem 
Published: April 2015

Abstract
Objective To improve the normalization of relative and incomplete temporal expressions (RI-TIMEXes) in clinical narratives.
Methods We analyzed the RI-TIMEXes in temporally annotated corpora and propose two hypotheses regarding the normalization of RI-TIMEXes in the clinical narrative domain: the anchor point hypothesis and the anchor relation hypothesis. We annotated the RI-TIMEXes in three corpora to study the characteristics of RI-TMEXes in different domains. This informed the design of our RI-TIMEX normalization system for the clinical domain, which consists of an anchor point classifier, an anchor relation classifier, and a rule-based RI-TIMEX text span parser. We experimented with different feature sets and performed an error analysis for each system component.
Results The annotation confirmed the hypotheses that we can simplify the RI-TIMEXes normalization task using two multi-label classifiers. Our system achieves anchor point classification, anchor relation classification, and rule-based parsing accuracy of 74.68%, 87.71%, and 57.2% (82.09% under relaxed matching criteria), respectively, on the held-out test set of the 2012 i2b2 temporal relation challenge.
Discussion Experiments with feature sets reveal some interesting findings, such as: the verbal tense feature does not inform the anchor relation classification in clinical narratives as much as the tokens near the RI-TIMEX. Error analysis showed that underrepresented anchor point and anchor relation classes are difficult to detect.
Conclusions We formulate the RI-TIMEX normalization problem as a pair of multi-label classification problems. Considering only RI-TIMEX extraction and normalization, the system achieves statistically significant improvement over the RI-TIMEX results of the best systems in the 2012 i2b2 challenge.
Numbers Count
Authors: Dowrick Nick 
Published: April 2015

Abstract
Young children who find mathematics very difficult are likely to encounter profound problems later on. Previous small-scale studies have indicated that early intervention can help them, but have provided insubstantial evidence. This chapter discusses the key features of a new mathematics intervention in England, Numbers Count, and analyzes the findings of a large-scale impact study of 8000 low-achieving 6- and 7-year-old children. After an average of 43 half-hour, one-to-one lessons in 3 months, their number age test scores had risen by 14 months with an effect size of .85. Their attitudes towards learning mathematics also improved substantially, with an effect size of .7. Children made strong progress irrespective of their background characteristics. It is suggested that the success of the intervention was due to its design, to its teachers’ professional development program, and to rigorous quality assurance. Subsequent changes are discussed.
Fast ventral stream neural activity enables rapid visual categorization
Authors: Cauchoix Maxime , Crouzet Sébastien M. , Fize Denis , Serre Thomas 
Published: April 2015

AbstractPrimates can recognize objects embedded in complex natural scenes in a glimpse. Rapid categorization paradigms have been extensively used to study our core perceptual abilities when the visual system is forced to operate under strong time constraints. However, the neural underpinning of rapid categorization remains to be understood, and the incredible speed of sight has yet to be reconciled with modern ventral stream cortical theories of shape processing.Here we recorded multichannel subdural electrocorticogram (ECoG) signals from intermediate areas (V4/PIT) of the ventral stream of the visual cortex while monkeys were actively engaged in detecting the presence or absence of animal targets in natural scenes. Using multivariate pattern analysis (MVPA) techniques, we quantified at millisecond precision task-relevant signals conveyed by ECoG data. Reliable neural decoding was possible shortly after stimulus onset from single trials with a degree of generalization to experimental manipulations closely mimicking monkeys’ accuracy and reaction time.Together, the present study suggests that rapid ventral stream neural activity induces a selective task-relevant signal subsequently used to drive visual categorization.ClassificationBiological sciences / Neuroscience
Concurrent origins of the genetic code and the homochirality of life, and the origin and evolution of biodiversity. Part I: Observations and explanations
Authors: Li Dirson Jian 
Published: April 2015

AbstractThe post-genomic era has brought opportunities to bridge traditionally separate fields on early history of life. New methods promote a deeper understanding of the origin of biodiversity. Relative stabilities of base triplexes are able to regulate base substitutions in triplex DNAs. We constructed a roadmap based on such a regulation to explain concurrent origins of the genetic code and the homochirality of life. Based on the recruitment order of codons in the roadmap and the complete genome sequences, we reconstructed the three-domain tree of life. The Phanerozoic biodiversity curve has been reconstructed based on genomic, climatic and eustatic data; this result supports tectonic cause of mass extinctions. Our results indicate that chirality played a crucial role in the origin and evolution of life. Here is Part I of my two-part series paper; technical details are in Part II of this paper (see “Concurrent origins of the genetic code and the homochirality of life, and the origin and evolution of biodiversity. Part II: Technical appendix” on bioRxiv).
An integrative approach to identifying factors related to long-term career commitments
Authors: Jordan Mark H. , Gabriel T.J. , Teasley Russell , Walker Wendy J. , Schraeder Mike 
Published: April 2015

Purpose
– The purpose of this paper is to examine an initial set of characteristics and traits that may reduce officer recruitment turnover by increasing a cadet’s decision to contract vs those that do not contract (contracting represents a written commitment to commission into an US Armed Services Organization after graduation). This paper is the first of a larger, long-term project. The factors of particular interest in this initial study are generalized self-efficacy, grit, and perceived organizational support (POS).

Design/methodology/approach
– Computer-based surveys containing variables of interest were administered to a random sample of freshmen, sophomore, junior, and senior cadets over a period of three years. Data for 517 cadets responding to the survey were analyzed using logistical regression to test hypotheses examining whether or not self-efficacy, grit, and POS were positively related to cadets’ decisions to contract.

Findings
– Logistical regression results indicated that self-efficacy and grit were not significantly related to contracting decisions. However, cadets’ decisions to contract were significantly related to POS.

Research limitations/implications
– A significant limitation of this study is the fact that data were collected using a self-report, single survey methodology. However, there were no patterns of significant correlations between self-report variables that seemed to indicate that this was a major issue in the current study. The primary implication of this study is that cadets’ perceptions of support (i.e. POS) provided by the organization do seem to influence their decisions to contract, with this influence being particularly notable in their freshmen year.

Originality/value
– The current study represents a unique context where individuals are making decisions to commit to an organization for a minimum of four years after graduation. Further, the commitment is being made to a military organization. The initial findings of this analysis provided the organization in this study with keen insight regarding possible factors to address or be aware of in relation to cadets’ decisions to contract. This approach and these findings can be extended to other organizations in understanding factors impacting decisions related to long-term commitments of individuals.