bluuebunny/crossref_metadata_2025 huggingface dataset:
Basement exploration, West of Shetlands: progress in opening a new play on the UKCS
Authors: Trice Robert
Published: March 2014

Commercial production of hydrocarbon from fractured crystalline basement is well documented, with petroleum basins across the globe hosting fractured basement fields. The UK is an anomaly within this global phenomenon as, despite numerous serendipitous discoveries of basement oil in the North Sea and the West of Shetlands, there is currently no commercial field on the United Kingdom Continental Shelf (UKCS) that is reliant on oil production from fractured basement. Recognizing that this situation presented an exploration niche, Hurricane Energy plc (Hurricane) was formed to focus on UKCS basement exploration and concentrated its efforts in acquiring exploration acreage in the West of Shetlands. In 2009 Hurricane drilled the first well designed to explore the basement play on the UKCS, leading to the Lancaster Discovery with a contingent resource range (1C–3C) of 62–456 million barrels of oil equivalent (MMboe). The Lancaster Discovery is presented to summarize the challenges and processes that have been applied in the exploration and evaluation of the West of Shetlands basement play. Conclusions from this work indicate that basement hydrocarbon resource potential is of such significance that it may represent a strategic resource for the UK, with over 1154 MMboe of 2C and mean unrisked prospective resources so far identified.
Sedimentation model of piggyback basins: Cenozoic examples of San Juan Precordillera, Argentina
Authors: Suriano J. , Limarino C. O. , Tedesco A. M. , Alonso M. S.
Published: March 2014

Piggyback basins are one of the most important sediment storage systems for foredeep basins within foreland basin systems, so understanding the dynamics of sediment accumulation and allocyclic changes is essential. Three alluvial systems are proposed here to depict sediment movement along the piggyback basin: piedmont, axial and transference systems. We propose differentiation between open continental piggyback basins that include a transference system that is able to deliver sediment to the foredeep and closed piggyback basins that are isolated. Two idealized models of sedimentation in piggyback basins are proposed. For open piggyback basins we identify four stages: (a) the incision stage; (b) the confined low accommodation system tract; (c) the high accommodation system tract; and (d) the unconfined low accommodation system tract. Meanwhile two stages are proposed for closed ones: (a) the high accommodation system tract; and (b) the low accommodation system tract. To test these models, Quaternary deposits and a Miocene unit are analysed. The first one is controlled by climatic changes, and the second is related to tectonic activity in the Precordillera.
The Diversity, Biogenesis, and Activities of Endogenous Silencing Small RNAs in Arabidopsis
Authors: Bologna Nicolas G. , Voinnet Olivier
Published: March 2014

In eukaryotic RNA silencing, RNase-III classes of enzymes in the Dicer family process double-stranded RNA of cellular or exogenous origin into small-RNA (sRNA) molecules. sRNAs are then loaded into effector proteins known as ARGONAUTEs (AGOs), which, as part of RNA-induced silencing complexes, target complementary RNA or DNA for silencing. Plants have evolved a large variety of pathways over the Dicer–AGO consortium, which most likely underpins part of their phenotypic plasticity. Dicer-like proteins produce all known classes of plant silencing sRNAs, which are invariably stabilized via 2′-O-methylation mediated by HUA ENHANCER 1 (HEN1), potentially amplified by the action of several RNA-dependent RNA polymerases, and function through a variety of AGO proteins. Here, we review the known characteristics and biochemical properties of the core silencing factors found in the model plant Arabidopsis thaliana. We also describe how interactions between these core factors and more specialized proteins allow the production of a plethora of silencing sRNAs involved in a large array of biological functions. We emphasize in particular the biogenesis and activities of silencing sRNAs of endogenous origin.
The Contributions of Transposable Elements to the Structure, Function, and Evolution of Plant Genomes
Authors: Bennetzen Jeffrey L. , Wang Hao
Published: March 2014

Transposable elements (TEs) are the key players in generating genomic novelty by a combination of the chromosome rearrangements they cause and the genes that come under their regulatory sway. Genome size, gene content, gene order, centromere function, and numerous other aspects of nuclear biology are driven by TE activity. Although the origins and attitudes of TEs have the hallmarks of selfish DNA, there are numerous cases where TE components have been co-opted by the host to create new genes or modify gene regulation. In particular, epigenetic regulation has been transformed from a process to silence invading TEs and viruses into a key strategy for regulating plant genes. Most, perhaps all, of this epigenetic regulation is derived from TE insertions near genes or TE-encoded factors that act in trans. Enormous pools of genome data and new technologies for reverse genetics will lead to a powerful new era of TE analysis in plants.
Phosphate Nutrition: Improving Low-Phosphate Tolerance in Crops
Authors: López-Arredondo Damar Lizbeth , Leyva-González Marco Antonio , González-Morales Sandra Isabel , López-Bucio José , Herrera-Estrella Luis
Published: March 2014

Phosphorus is an essential nutrient that is required for all major developmental processes and reproduction in plants. It is also a major constituent of the fertilizers required to sustain high-yield agriculture. Levels of phosphate—the only form of phosphorus that can be assimilated by plants—are suboptimal in most natural and agricultural ecosystems, and when phosphate is applied as fertilizer in soils, it is rapidly immobilized owing to fixation and microbial activity. Thus, cultivated plants use only approximately 20–30% of the applied phosphate, and the rest is lost, eventually causing water eutrophication. Recent advances in the understanding of mechanisms by which wild and cultivated species adapt to low-phosphate stress and the implementation of alternative bacterial pathways for phosphorus metabolism have started to allow the design of more effective breeding and genetic engineering strategies to produce highly phosphate-efficient crops, optimize fertilizer use, and reach agricultural sustainability with a lower environmental cost. In this review, we outline the current advances in research on the complex network of plant responses to low-phosphorus stress and discuss some strategies used to manipulate genes involved in phosphate uptake, remobilization, and metabolism to develop low-phosphate-tolerant crops, which could help in designing more efficient crops.
Cyanogenic Glycosides: Synthesis, Physiology, and Phenotypic Plasticity
Authors: Gleadow Roslyn M. , Møller Birger Lindberg
Published: March 2014

Cyanogenic glycosides (CNglcs) are bioactive plant products derived from amino acids. Structurally, these specialized plant compounds are characterized as α-hydroxynitriles (cyanohydrins) that are stabilized by glucosylation. In recent years, improved tools within analytical chemistry have greatly increased the number of known CNglcs by enabling the discovery of less abundant CNglcs formed by additional hydroxylation, glycosylation, and acylation reactions. Cyanogenesis—the release of toxic hydrogen cyanide from endogenous CNglcs—is an effective defense against generalist herbivores but less effective against fungal pathogens. In the course of evolution, CNglcs have acquired additional roles to improve plant plasticity, i.e., establishment, robustness, and viability in response to environmental challenges. CNglc concentration is usually higher in young plants, when nitrogen is in ready supply, or when growth is constrained by nonoptimal growth conditions. Efforts are under way to engineer CNglcs into some crops as a pest control measure, whereas in other crops efforts are directed toward their removal to improve food safety. Given that many food crops are cyanogenic, it is important to understand the molecular mechanisms regulating cyanogenesis so that the impact of future environmental challenges can be anticipated.
Genetically Engineered Crops: From Idea to Product
Authors: Prado Jose Rafael , Segers Gerrit , Voelker Toni , Carson Dave , Dobert Raymond , Phillips Jonathan , Cook Kevin , Cornejo Camilo , Monken Josh , Grapes Laura , Reynolds Tracey , Martino-Catt Susan
Published: March 2014

Genetically engineered crops were first commercialized in 1994 and since then have been rapidly adopted, enabling growers to more effectively manage pests and increase crop productivity while ensuring food, feed, and environmental safety. The development of these crops is complex and based on rigorous science that must be well coordinated to create a plant with desired beneficial phenotypes. This article describes the general process by which a genetically engineered crop is developed from an initial concept to a commercialized product.
The Cell Biology of Cellulose Synthesis
Authors: McFarlane Heather E. , Döring Anett , Persson Staffan
Published: March 2014

Plant stature and development are governed by cell proliferation and directed cell growth. These parameters are determined largely by cell wall characteristics. Cellulose microfibrils, composed of hydrogen-bonded β-1,4 glucans, are key components for anisotropic growth in plants. Cellulose is synthesized by plasma membrane–localized cellulose synthase complexes. In higher plants, these complexes are assembled into hexameric rosettes in intracellular compartments and secreted to the plasma membrane. Here, the complexes typically track along cortical microtubules, which may guide cellulose synthesis, until the complexes are inactivated and/or internalized. Determining the regulatory aspects that control the behavior of cellulose synthase complexes is vital to understanding directed cell and plant growth and to tailoring cell wall content for industrial products, including paper, textiles, and fuel. In this review, we summarize and discuss cellulose synthesis and regulatory aspects of the cellulose synthase complex, focusing on Arabidopsis thaliana.
Manipulating Crystallization with Molecular Additives
Authors: Shtukenberg Alexander G. , Lee Stephanie S. , Kahr Bart , Ward Michael D.
Published: March 2014

Given the importance of organic crystals in a wide range of industrial applications, the chemistry, biology, materials science, and chemical engineering communities have focused considerable attention on developing methods to control crystal structure, size, shape, and orientation. Tailored additives have been used to control crystallization to great effect, presumably by selectively binding to particular crystallographic surfaces and sites. However, substantial knowledge gaps still exist in the fundamental mechanisms that govern the formation and growth of organic crystals in both the absence and presence of additives. In this review, we highlight research discoveries that reveal the role of additives, either introduced by design or present adventitiously, on various stages of formation and growth of organic crystals, including nucleation, dislocation spiral growth mechanisms, growth inhibition, and nonclassical crystal morphologies. The insights from these investigations and others of their kind are likely to guide the development of innovative methods to manipulate crystallization for a wide range of materials and applications.
Mercury Isotopes in Earth and Environmental Sciences
Authors: Blum Joel D. , Sherman Laura S. , Johnson Marcus W.
Published: March 2014

Virtually all biotic, dark abiotic, and photochemical transformations of mercury (Hg) produce Hg isotope fractionation, which can be either mass dependent (MDF) or mass independent (MIF). The largest range in MDF is observed among geological materials and rainfall impacted by anthropogenic sources. The largest positive MIF of Hg isotopes (odd-mass excess) is caused by photochemical degradation of methylmercury in water. This signature is retained through the food web and measured in all freshwater and marine fish. The largest negative MIF of Hg isotopes (odd-mass deficit) is caused by photochemical reduction of inorganic Hg and has been observed in Arctic snow and plant foliage. Ratios of MDF to MIF and ratios of 199Hg MIF to 201Hg MIF are often diagnostic of biogeochemical reaction pathways. More than a decade of research demonstrates that Hg isotopes can be used to trace sources, biogeochemical cycling, and reactions involving Hg in the environment.
Investigating Microbe-Mineral Interactions: Recent Advances in X-Ray and Electron Microscopy and Redox-Sensitive Methods
Authors: Miot Jennyfer , Benzerara Karim , Kappler Andreas
Published: March 2014

Microbe-mineral interactions occur in diverse modern environments, from the deep sea and subsurface rocks to soils and surface aquatic environments. They may have played a central role in the geochemical cycling of major (e.g., C, Fe, Ca, Mn, S, P) and trace (e.g., Ni, Mo, As, Cr) elements over Earth's history. Such interactions include electron transfer at the microbe-mineral interface that left traces in the rock record. Geomicrobiology consists in studying interactions at these organic-mineral interfaces in modern samples and looking for traces of past microbe-mineral interactions recorded in ancient rocks. Specific tools are required to probe these interfaces and to understand the mechanisms of interaction between microbes and minerals from the scale of the biofilm to the nanometer scale. In this review, we focus on recent advances in electron microscopy, in particular in cryoelectron microscopy, and on a panel of electrochemical and synchrotron-based methods that have recently provided new understanding and imaging of the microbe-mineral interface, ultimately opening new fields to be explored.
The Uses of Dynamic Earthquake Triggering
Authors: Brodsky Emily E. , van der Elst Nicholas J.
Published: March 2014

Dynamic triggering of earthquakes by seismic waves is a robustly observed phenomenon with well-documented examples from over 30 major earthquakes. We are now in a position to use dynamic triggering as a natural experiment to probe the reaction of faults to the known stresses from seismic waves. We show here that dynamic triggering can be used to investigate the distribution of stresses required for failure on faults. In some regions, faults appear to be uniformly distributed over their loading cycles with equal numbers at all possible stresses from failure. Regions under tectonic extension, at the interface between locked and creeping faults, or subject to anthropogenic forcing are most prone to triggered failure. Predictions of future seismicity rates based on seismic wave amplitudes are theoretically possible and may provide similar results to purely stochastic prediction schemes. The underlying mechanisms of dynamic triggering are still unknown. The prolonged triggered sequences require a multistage process such as shear failure from rate-state friction coupled to aseismic creep or continued triggering through a secondary cascade. Permeability enhancement leading to drainage or pore pressure redistribution on faults is an alternative possibility.
Short-Lived Climate Pollution
Authors: Pierrehumbert R.T.
Published: March 2014

Although carbon dioxide emissions are by far the most important mediator of anthropogenic climate disruption, a number of shorter-lived substances with atmospheric lifetimes of under a few decades also contribute significantly to the radiative forcing that drives climate change. In recent years, the argument that early and aggressive mitigation of the emission of these substances or their precursors forms an essential part of any climate protection strategy has gained a considerable following. There is often an implication that such control can in some way make up for the current inaction on carbon dioxide emissions. The prime targets for mitigation, known collectively as short-lived climate pollution (SLCP), are methane, hydrofluo-rocarbons, black carbon, and ozone. A re-examination of the issues shows that the benefits of early SLCP mitigation have been greatly exaggerated, largely because of inadequacies in the methodologies used to compare the climate effects of short-lived substances with those of CO2, which causes nearly irreversible climate change persisting millennia after emissions cease. Eventual mitigation of SLCP can make a useful contribution to climate protection, but there is little to be gained by implementing SLCP mitigation before stringent carbon dioxide controls are in place and have caused annual emissions to approach zero. Any earlier implementation of SLCP mitigation that substitutes to any significant extent for carbon dioxide mitigation will lead to a climate irreversibly warmer than will a strategy with delayed SLCP mitigation. SLCP mitigation does not buy time for implementation of stringent controls on CO2 emissions.
Mineralogy of the Martian Surface
Authors: Ehlmann Bethany L. , Edwards Christopher S.
Published: March 2014

The past fifteen years of orbital infrared spectroscopy and in situ exploration have led to a new understanding of the composition and history of Mars. Globally, Mars has a basaltic upper crust with regionally variable quantities of plagioclase, pyroxene, and olivine associated with distinctive terrains. Enrichments in olivine (>20%) are found around the largest basins and within late Noachian–early Hesperian lavas. Alkali volcanics are also locally present, pointing to regional differences in igneous processes. Many materials from ancient Mars bear the mineralogic fingerprints of interaction with water. Clay minerals, found in exposures of Noachian crust across the globe, preserve widespread evidence for early weathering, hydrothermal, and diagenetic aqueous environments. Noachian and Hesperian sediments include paleolake deposits with clays, carbonates, sulfates, and chlorides that are more localized in extent. The late Hesperian to Amazonian mineralogic record of water is sparser, though sulfates and silica in some locations indicate local availability of ground and surface waters even in the most recent geologic epoch.
China’s Great Convergence and Beyond
Authors: Storesletten Kjetil , Zilibotti Fabrizio
Published: March 2014

A recent wave of economic research has studied the transformation of China from a poor country in the 1970s to a middle-income economy today. Based on this literature, we discuss the factors driving China’s development process. We provide a historical account of China’s rise, fall, and resurgence. We then discuss the stylized facts associated with China’s growth process and review a comprehensive theory of its economic transition. Finally, we discuss China’s future. In particular, we review some recent studies about technological and politico-economic factors that may foster or hinder its future economic performance.
Dynamics and Control in Complex Transition Metal Oxides
Authors: Zhang J. , Averitt R.D.
Published: March 2014

Advances in the synthesis, growth, and characterization of complex transition metal oxides coupled with new experimental techniques in ultrafast optical spectroscopy have ushered in an exciting era of dynamics and control in these materials. Experiments utilizing femtosecond optical pulses can initiate and probe dynamics of the spin, lattice, orbital, and charge degrees of freedom. Major goals include (a) determining how interaction and competition between the relevant degrees of freedom determine macroscopic functionality in transition metal oxides (TMOs) and (b) searching for hidden phases in TMOs by controlling dynamic trajectories in a complex and pliable energy landscape. Advances in creating intense pulses from the far-IR spectrum through the visible spectrum enable mode-selective excitation to facilitate exploration of these possibilities. This review covers recent developments in this emerging field and presents examples that include the cuprates, manganites, and vanadates.
Chemical Expansion: Implications for Electrochemical Energy Storage and Conversion Devices
Authors: Bishop S.R. , Marrocchelli D. , Chatzichristodoulou C. , Perry N.H. , Mogensen M.B. , Tuller H.L. , Wachsman E.D.
Published: March 2014

Many energy-related materials rely on the uptake and release of large quantities of ions, for example, Li+in batteries, H+in hydrogen storage materials, and O2−in solid-oxide fuel cell and related materials. These compositional changes often result in large volumetric dilation of the material, commonly referred to as chemical expansion. This article reviews the current knowledge of chemical expansion and aspires to facilitate and promote future research in this field by providing a taxonomy for its sources, along with recent atomistic insights of its origin, aided by recent computational modeling and an overview of factors impacting chemical expansion. We discuss the implications of chemical expansion for mechanical stability and functionality in the energy applications above, as well as in other oxide-based systems. The use of chemical expansion as a new means to probe other materials properties, as well as its contribution to recently investigated electromechanical coupling, is also highlighted.
Does Transparency Improve Governance?
Authors: Kosack Stephen , Fung Archon
Published: March 2014

In recent years, there has been increasing interest in the potential of transparency—the provision of information to the public—to improve governance in both developed and developing societies. In this article, we characterize and assess the evolution of transparency from an end in itself to a tool for resolving increasingly practical concerns of governance and government performance. After delineating four distinct varieties of transparency, we focus on the type that has received the most rigorous empirical scrutiny from social scientists—so-called “transparency and accountability” (T/A) interventions intended to improve the quality of public services and governance in developing countries. T/A interventions have yielded mixed results: some are highly successful; others appear to have little impact. We develop a rubric of five ideal-typical “worlds” facing transparency that helps to account for this variation in outcomes. Reform based on transparency can face obstacles of collective action, political resistance, and long implementation chains. T/A interventions are more likely to succeed in contextual “worlds” with fewer of these obstacles. We find that 16 experimental evaluations of T/A interventions are largely consistent with the theoretical predictions of our five-worlds rubric.
Inequality and Institutions: The Case of Economic Coordination
Authors: Beramendi Pablo , Rueda David
Published: March 2014

The understanding of observable associations between institutions and inequality today requires a better grasp of the process driving the selection of economic institutions, in particular wage bargaining centralization agreements, as the outcome of a distributive conflict in which inequality itself plays a prominent role. Low levels of inequality facilitated the adoption of encompassing wage centralization agreements during the early twentieth century in Europe, thereby creating a long-term association between low inequality and high centralization that, for a large subset of cases, remained stable throughout the century. We develop a theoretical argument as to why inequality should lead to lower levels of coordination and test it against competing hypotheses on the basis of a database on 11 OECD nations between the 1910s and the 1950s.
When and Why Minority Legislators Matter
Authors: Griffin John D.
Published: March 2014

This review examines how legislators' race and ethnicity affect the representation of racial and ethnic minorities' interests and priorities in the mass public, how these legislators affect the political participation of these groups, how the presence of these candidates affects voter decision making, and how their prevalence impacts the composition of the parties and the nature of public policy. It also points to new directions and opportunities for scholarship on why minority legislators matter for American politics.
Field Experimental Work on Political Institutions
Authors: Grose Christian R.
Published: March 2014

A nascent but growing research area examines political institutions through the use of field experiments. I consider why field experimentation has been used infrequently in the study of political institutions and note that some research questions are not amenable to field experimentation. I review areas of research inquiry where field experimentation has enhanced scholarly knowledge about political institutions and representation. These areas include the study of race, representation, and bias in legislatures and courts; and policy responsiveness and legislative accountability. I synthesize this research by examining puzzles that emerge between the field experimental and observational work. I conclude with suggestions for promising research avenues, including the use of field experiments to study the bureaucracy. The discipline's understanding of political institutions could be improved with a greater emphasis on field experimental work.
Advancing the Empirical Research on Lobbying
Authors: de Figueiredo John M. , Richter Brian Kelleher
Published: March 2014

This review identifies empirical facts about lobbying that are generally agreed upon in the literature. It then discusses challenges to empirical research in lobbying and provides examples of empirical methods that can be employed to overcome these challenges—with an emphasis on statistical measurement, identification, and casual inference. The article then discusses the advantages, disadvantages, and effective use of the main types of data available for research in lobbying. It closes with a number of open questions for researchers in the field and avenues for future work to advance empirical research on lobbying.
The immune system in hypertension
Authors: Trott Daniel W. , Harrison David G.
Published: March 2014

While hypertension has predominantly been attributed to perturbations of the vasculature, kidney, and central nervous system, research for almost 50 yr has shown that the immune system also contributes to this disease. Inflammatory cells accumulate in the kidneys and vasculature of humans and experimental animals with hypertension and likely contribute to end-organ damage. We and others have shown that mice lacking adaptive immune cells, including recombinase-activating gene-deficient mice and rats and mice with severe combined immunodeficiency have blunted hypertension to stimuli such as ANG II, high salt, and norepinephrine. Adoptive transfer of T cells restores the blood pressure response to these stimuli. Agonistic antibodies to the ANG II receptor, produced by B cells, contribute to hypertension in experimental models of preeclampsia. The central nervous system seems important in immune cell activation, because lesions in the anteroventral third ventricle block hypertension and T cell activation in response to ANG II. Likewise, genetic manipulation of reactive oxygen species in the subfornical organ modulates both hypertension and immune cell activation. Current evidence indicates that the production of cytokines, including tumor necrosis factor-α, interleukin-17, and interleukin-6, contribute to hypertension, likely via effects on both the kidney and vasculature. In addition, the innate immune system also appears to contribute to hypertension. We propose a working hypothesis linking the sympathetic nervous system, immune cells, production of cytokines, and, ultimately, vascular and renal dysfunction, leading to the augmentation of hypertension. Studies of immune cell activation will clearly be useful in understanding this common yet complex disease.
Interactive computer-assisted instruction in acid-base physiology for mobile computer platforms
Authors: Longmuir Kenneth J.
Published: March 2014

In this project, the traditional lecture hall presentation of acid-base physiology in the first-year medical school curriculum was replaced by interactive, computer-assisted instruction designed primarily for the iPad and other mobile computer platforms. Three learning modules were developed, each with ∼20 screens of information, on the subjects of the CO2-bicarbonate buffer system, other body buffer systems, and acid-base disorders. Five clinical case modules were also developed. For the learning modules, the interactive, active learning activities were primarily step-by-step learner control of explanations of complex physiological concepts, usually presented graphically. For the clinical cases, the active learning activities were primarily question-and-answer exercises that related clinical findings to the relevant basic science concepts. The student response was remarkably positive, with the interactive, active learning aspect of the instruction cited as the most important feature. Also, students cited the self-paced instruction, extensive use of interactive graphics, and side-by-side presentation of text and graphics as positive features. Most students reported that it took less time to study the subject matter with this online instruction compared with subject matter presented in the lecture hall. However, the approach to learning was highly examination driven, with most students delaying the study of the subject matter until a few days before the scheduled examination. Wider implementation of active learning computer-assisted instruction will require that instructors present subject matter interactively, that students fully embrace the responsibilities of independent learning, and that institutional administrations measure instructional effort by criteria other than scheduled hours of instruction.
The summer premedical program for matriculating medical students: a student-led initiative
Authors: Awad Ayman M. , AlAmodi Abdulhadi A. , Shareef Mohammad A. , Alsheikh Ammar J. , Mahmod Asim I. , Daghistany Asem O. , Hijazi Mohammed M. , Abu-Zaid Ahmed , Alsadoon Mohamed , Shabllout Mohamed , Rasool Abduljabar , Yaqinuddin Ahmed
Published: March 2014

The freshman academic year is one of the most difficult years that a medical student experiences in his/her academic life at a medical school. Freshmen are frequently faced with several challenges, such as adaptation to a new academic environment and its associated different methods of teaching, learning, skills, and assessment. The aim of this study was to describe a 4-wk innovative summer premedical program developed by senior medical students at the College of Medicine, Alfaisal University, in an attempt to improve/smooth the experience(s) of prospective freshmen. This report describes the objectives/strategies/methodologies used to tackle the top three identified freshman challenges, namely, 1) advancement of the academic/scholastic/educational background, 2) the development of college-required skills to succeed and excel in the freshman year, and 3) adaption to the college environment. At the end of the program, a survey was conducted to evaluate the effectiveness of the summer premedical program. Seventy-two students attended this program over the past three summers from 2010 to 2012, and twenty-nine students answered the survey with a response rate of 74.7%. Overall, >90% of the survey respondents reported an improvement in their understanding of basic medical science, integration, presentation skills, medical terminology, and junior-senior relationships. Furthermore, the survey highlighted the need for more focus on skills such as time management, participation in large-group discussions, and use of electronic resources, as >50% of respondents reported no improvement in these areas. In conclusion, this is the first report, to our knowledge, that describes a program developed by senior medical students to improve the experience of freshmen.
The sympathetic release test: a test used to assess thermoregulation and autonomic control of blood flow
Authors: Tansey E. A. , Roe S. M. , Johnson C. D.
Published: March 2014

When a subject is heated, the stimulation of temperature-sensitive nerve endings in the skin, and the raising of the central body temperature, results in the reflex release of sympathetic vasoconstrictor tone in the skin of the extremities, causing a measurable temperature increase at the site of release. In the sympathetic release test, the subject is gently heated by placing the feet and calves in a commercially available foot warming pouch or immersing the feet and calves in warm water and wrapping the subject in blankets. Skin blood flow is estimated from measurements of skin temperature in the fingers. Normally skin temperature of the fingers is 65–75°F in cool conditions (environmental temperature: 59–68°F) and rises to 85–95°F during body heating. Deviations in this pattern may mean that there is abnormal sympathetic vasoconstrictor control of skin blood flow. Abnormal skin blood flow can substantially impair an individual's ability to thermoregulate and has important clinical implications. During whole body heating, the skin temperature from three different skin sites is monitored and oral temperature is monitored as an index of core temperature. Students determine the fingertip temperature at which the reflex release of sympathetic activity occurs and its maximal attainment, which reflects the vasodilating capacity of this cutaneous vascular bed. Students should interpret typical sample data for certain clinical conditions (Raynaud's disease, peripheral vascular disease, and postsympathectomy) and explain why there may be altered skin blood flow in these disorders.
Making students do the thinking: team-based learning in a laboratory course
Authors: Simonson Shawn R.
Published: March 2014

Team-based learning (TBL) is a teaching pedagogy for flipping the classroom that moves the focus of the classroom from the instructor conveying course concepts via lecture to the application of concepts by student teams. It has been used extensively in lecture courses; however, there is little evidence of its use in laboratory courses. The purpose of this report is to describe the implementation of TBL in a graduate exercise physiology laboratory course. Using TBL in a graduate laboratory course was very successful and well received by both the students and instructor. Students reported increased content learning, skill development, and retention. They took on the responsibility for learning and were more accountable. The learners drove the process and were guided by the instructor rather than through instructor-centered delivery.
The University of California Institute of Environmental Stress marathon field studies
Authors: Maron Michael B.
Published: March 2014

In 1973, the Institute of Environmental Stress of the University of California-Santa Barbara, under the direction of Steven M. Horvath, began a series of field and laboratory studies of marathon runners during competition. As one of Horvath's graduate students, many of these studies became part of my doctoral dissertation. The rationale for studying runners under race conditions was based on my belief as a marathoner that runners would push themselves much harder while competing than under simulated conditions in the laboratory. Horvath's ready support of the studies likely had its roots in his graduate training at the Harvard Fatigue Laboratory, a laboratory well known for its field studies of individuals working in extreme environments. This report describes the studies of 1973–1975, focusing on how the measurements were made and detailing the learning experiences of a new graduate student. In 1973, blood chemistry and fluid shifts were studied in six runners before and for 3 days after a race. This was the first modern study to systematically examine the recovery process. In 1974, oxygen consumption was measured every 3 mi. in two runners during the race. In 1975, rectal temperature and five skin temperatures were evaluated in the same two runners every 1.4 mi. of the race. The latter two studies were the first to make such measurements under race conditions. The Institute of Environmental Stress marathon studies demonstrated the possibility of making measurements during competition without disrupting performance, enhanced our understanding of human exercise capacity under competitive conditions, and provided new insight into the postrace recovery process.
Stromal interaction molecule 1 is essential for normal cardiac homeostasis through modulation of ER and mitochondrial function
Authors: Collins Helen E. , He Lan , Zou Luyun , Qu Jing , Zhou Lufang , Litovsky Silvio H. , Yang Qinglin , Young Martin E. , Marchase Richard B. , Chatham John C.
Published: March 2014

The endoplasmic reticulum (ER) Ca2+ sensor stromal interaction molecule 1 (STIM1) has been implicated as a key mediator of store-dependent and store-independent Ca2+ entry pathways and maintenance of ER structure. STIM1 is present in embryonic, neonatal, and adult cardiomyocytes and has been strongly implicated in hypertrophic signaling; however, the physiological role of STIM1 in the adult heart remains unknown. We, therefore, developed a novel cardiomyocyte-restricted STIM1 knockout (crSTIM1-KO) mouse. In cardiomyocytes isolated from crSTIM1-KO mice, STIM1 expression was reduced by ∼92% with no change in the expression of related store-operated Ca2+ entry proteins, STIM2, and Orai1. Immunoblot analyses revealed that crSTIM1-KO hearts exhibited increased ER stress from 12 wk, as indicated by increased levels of the transcription factor C/EBP homologous protein (CHOP), one of the terminal markers of ER stress. Transmission electron microscopy revealed ER dilatation, mitochondrial disorganization, and increased numbers of smaller mitochondria in crSTIM1-KO hearts, which was associated with increased mitochondrial fission. Using serial echocardiography and histological analyses, we observed a progressive decline in cardiac function in crSTIM1-KO mice, starting at 20 wk of age, which was associated with marked left ventricular dilatation by 36 wk. In addition, we observed the presence of an inflammatory infiltrate and evidence of cardiac fibrosis from 20 wk in crSTIM1-KO mice, which progressively worsened by 36 wk. These data demonstrate for the first time that STIM1 plays an essential role in normal cardiac function in the adult heart, which may be important for the regulation of ER and mitochondrial function.
Automated analysis of contractile force and Ca2+transients in engineered heart tissue
Authors: Stoehr Andrea , Neuber Christiane , Baldauf Christina , Vollert Ingra , Friedrich Felix W. , Flenner Frederik , Carrier Lucie , Eder Alexandra , Schaaf Sebastian , Hirt Marc N. , Aksehirlioglu Bülent , Tong Carl W. , Moretti Alessandra , Eschenhagen Thomas , Hansen Arne
Published: March 2014

Contraction and relaxation are fundamental aspects of cardiomyocyte functional biology. They reflect the response of the contractile machinery to the systolic increase and diastolic decrease of the cytoplasmic Ca2+concentration. The analysis of contractile function and Ca2+transients is therefore important to discriminate between myofilament responsiveness and changes in Ca2+homeostasis. This article describes an automated technology to perform sequential analysis of contractile force and Ca2+transients in up to 11 strip-format, fibrin-based rat, mouse, and human fura-2-loaded engineered heart tissues (EHTs) under perfusion and electrical stimulation. Measurements in EHTs under increasing concentrations of extracellular Ca2+and responses to isoprenaline and carbachol demonstrate that EHTs recapitulate basic principles of heart tissue functional biology. Ca2+concentration-response curves in rat, mouse, and human EHTs indicated different maximal twitch forces (0.22, 0.05, and 0.08 mN in rat, mouse, and human, respectively; P < 0.001) and different sensitivity to external Ca2+(EC50: 0.15, 0.39, and 1.05 mM Ca2+in rat, mouse, and human, respectively; P < 0.001) in the three groups. In contrast, no difference in myofilament Ca2+sensitivity was detected between skinned rat and human EHTs, suggesting that the difference in sensitivity to external Ca2+concentration is due to changes in Ca2+handling proteins. Finally, this study confirms that fura-2 has Ca2+buffering effects and is thereby changing the force response to extracellular Ca2+.
Bleomycin delivery by osmotic minipump: similarity to human scleroderma interstitial lung disease
Authors: Lee Rebecca , Reese Charles , Bonner Michael , Tourkina Elena , Hajdu Zoltan , Riemer Ellen C. , Silver Richard M. , Visconti Richard P. , Hoffman Stanley
Published: March 2014

The interstitial lung diseases (ILD) include a large number of chronic, progressive, irreversible respiratory disorders involving pulmonary fibrosis, the most common of which are idiopathic pulmonary fibrosis and scleroderma lung disease (SSc ILD). Because bleomycin causes lung fibrosis when used in cancer chemotherapy, it is used to model human ILD in rodents. In most studies, bleomycin has been delivered directly into the lung by intratracheal or intraoral administration. Here we have compared the effects in mice of bleomycin delivered directly into the lungs (direct model) or systemically using osmotic minipumps (pump model) to determine which more closely resembles human ILD. The pump model is more similar to human SSc ILD in that: 1) lung injury/fibrosis is limited to the subpleural portion of the lung in the pump model and in SSc ILD, whereas the entire lung is affected in the direct model; 2) conversely, there is massive inflammation throughout the lung in the direct model, whereas inflammation is limited in the pump model and in SSc ILD; 3) hypertrophic type II alveolar epithelial cells are present at high levels in SSc ILD and in the pump model but not in the direct model; and 4) lung fibrosis is accompanied by dermal fibrosis. The pump model is also move convenient and humane than the direct model because there is less weight loss and mortality.
c-Kit immunoexpression delineates a putative endothelial progenitor cell population in developing human lungs
Authors: Suzuki Takaya , Suzuki Satoshi , Fujino Naoya , Ota Chiharu , Yamada Mitsuhiro , Suzuki Takashi , Yamaya Mutsuo , Kondo Takashi , Kubo Hiroshi
Published: March 2014

Expression of c-Kit and its ligand, stem cell factor (SCF), in developing human lung tissue was investigated by immunohistochemistry. Twenty-eight human fetal lungs [age range 13 to 38 gestational wk (GW)] and 12 postnatal lungs (age range 1–79 yr) were evaluated. We identified c-Kit+cells in the lung mesenchyme as early as 13 GW. These mesenchymal c-Kit+cells in the lung did not express mast cell tryptase or α-smooth muscle actin. However, these cells did express CD34, VEGFR2, and Tie-2, indicating their endothelial lineage. Three-dimensional reconstructions of confocal laser scanning images revealed that c-Kit+cells displayed a closed-end tube formation that did not contain hematopoietic cells. From the pseudoglandular phase to the canalicular phase, c-Kit+cells appeared to continuously proliferate, to connect with central pulmonary vessels, and finally, to develop the lung capillary plexus. The spatial distribution of c-Kit- and SCF-positive cells was also demonstrated, and these cells were shown to be in close association. Our results suggest that c-Kit expression in early fetal lungs marks a progenitor population that is restricted to endothelial lineage. This study also suggests the potential involvement of c-Kit signaling in lung vascular development.
GLP-1-Based Strategies: A Physiological Analysis of Differential Mode of Action
Authors: Burcelin Rémy , Gourdy Pierre , Dalle Stéphane
Published: March 2014

DPP4 inhibitors and GLP-1 receptor agonists used in incretin-based strategies treat Type 2 diabetes with different modes of action. The pharmacological blood GLP-1R agonist concentration targets pancreatic and some extrapancreatic GLP-1R, whereas DPP4i favors the physiological activation of the gut-brain-periphery axis that could allow clinicians to adapt the management of Type 2 diabetes, according to the patient's pathophysiological characteristics.
Phosphodiesterases Maintain Signaling Fidelity via Compartmentalization of Cyclic Nucleotides
Authors: Lomas Oliver , Zaccolo Manuela
Published: March 2014

Novel technological advances have improved our understanding of how cyclic nucleotides are able to convey signals faithfully between cellular compartments. Phosphodiesterases play a crucial role in shaping these signals in health and disease. The concept of compartmentalization is guiding the search for therapies that have the potential to offer greater efficacy and tolerability compared with current treatments.
Sex Differences in the Developmental Origins of Cardiovascular Disease
Authors: Intapad Suttira , Ojeda Norma B. , Dasinger John Henry , Alexander Barbara T.
Published: March 2014

The Developmental Origins of Health and Disease (DOHaD) proposes that adverse events during early life program an increased risk for cardiovascular disease. Experimental models provide proof of concept but also indicate that insults during early life program sex differences in adult blood pressure and cardiovascular risk. This review will highlight the potential mechanisms that contribute to the etiology of sex differences in the developmental programming of cardiovascular disease.
AMPK: Regulating Energy Balance at the Cellular and Whole Body Levels
Authors: Hardie D. Grahame , Ashford Michael L. J.
Published: March 2014

AMP-activated protein kinase appears to have evolved in single-celled eukaryotes as an adenine nucleotide sensor that maintains energy homeostasis at the cellular level. However, during evolution of more complex multicellular organisms, the system has adapted to interact with hormones so that it also plays a key role in balancing energy intake and expenditure at the whole body level.
Preclinical and Early Clinical Evaluation of the Oral AKT Inhibitor, MK-2206, for the Treatment of Acute Myelogenous Leukemia
Authors: Konopleva Marina Y. , Walter Roland B. , Faderl Stefan H. , Jabbour Elias J. , Zeng Zhihong , Borthakur Gautam , Huang Xuelin , Kadia Tapan M. , Ruvolo Peter P. , Feliu Jennie B. , Lu Hongbo , Debose LaKiesha , Burger Jan A. , Andreeff Michael , Liu Wenbin , Baggerly Keith A. , Kornblau Steven M. , Doyle L. Austin , Estey Elihu H. , Kantarjian Hagop M.
Published: March 2014

Purpose: Recent studies suggested that AKT activation might confer poor prognosis in acute myelogenous leukemia (AML), providing the rationale for therapeutic targeting of this signaling pathway. We, therefore, explored the preclinical and clinical anti-AML activity of an oral AKT inhibitor, MK-2206.

Experimental Methods: We first studied the effects of MK-2206 in human AML cell lines and primary AML specimens in vitro. Subsequently, we conducted a phase II trial of MK-2206 (200 mg weekly) in adults requiring second salvage therapy for relapsed/refractory AML, and assessed target inhibition via reverse phase protein array (RPPA).

Results: In preclinical studies, MK-2206 dose-dependently inhibited growth and induced apoptosis in AML cell lines and primary AML blasts. We then treated 19 patients with MK-2206 but, among 18 evaluable participants, observed only 1 (95% confidence interval, 0%–17%) response (complete remission with incomplete platelet count recovery), leading to early study termination. The most common grade 3/4 drug-related toxicity was a pruritic rash in 6 of 18 patients. Nevertheless, despite the use of MK-2206 at maximum tolerated doses, RPPA analyses indicated only modest decreases in Ser473 AKT (median 28%; range, 12%–45%) and limited inhibition of downstream targets.

Conclusions: Although preclinical activity of MK-2206 can be demonstrated, this inhibitor has insufficient clinical antileukemia activity when given alone at tolerated doses, and alternative approaches to block AKT signaling should be explored. Clin Cancer Res; 20(8); 2226–35. ©2014 AACR.