bluuebunny/crossref_metadata_2025 huggingface dataset:
Elastic and Mechanical Properties of the MAX Phases
Authors: Barsoum Michel W. , Radovic Miladin
Published: March 2011

The more than 60 ternary carbides and nitrides, with the general formula Mn+1AXn—where n = 1, 2, or 3; M is an early transition metal; A is an A-group element (a subset of groups 13–16); and X is C and/or N—represent a new class of layered solids, where Mn+1Xnlayers are interleaved with pure A-group element layers. The growing interest in the Mn+1AXnphases lies in their unusual, and sometimes unique, set of properties that can be traced back to their layered nature and the fact that basal dislocations multiply and are mobile at room temperature. Because of their chemical and structural similarities, the MAX phases and their corresponding MX phases share many physical and chemical properties. In this paper we review our current understanding of the elastic and mechanical properties of bulk MAX phases where they differ significantly from their MX counterparts. Elastically the MAX phases are in general quite stiff and elastically isotropic. The MAX phases are relatively soft (2–8 GPa), are most readily machinable, and are damage tolerant. Some of them are also lightweight and resistant to thermal shock, oxidation, fatigue, and creep. In addition, they behave as nonlinear elastic solids, dissipating 25% of the mechanical energy during compressive cycling loading of up to 1 GPa at room temperature. At higher temperatures, they undergo a brittle-to-plastic transition, and their mechanical behavior is a strong function of deformation rate.
Thermoelectric Phenomena, Materials, and Applications
Authors: Tritt Terry M.
Published: March 2011

Over the past 10–15 years, there have been significant advances in the scientific understanding as well as in the performance of thermoelectric (TE) materials. TE materials can be incorporated into power generation devices that are designed to convert waste heat into useful electrical energy. These TE materials can also be used in solid-state refrigeration devices for cooling applications. The conversion of waste heat into electrical energy will certainly play a role in our current challenge for alternative energy technologies to reduce our dependence on fossil fuels and to reduce greenhouse gas emissions. This article provides an overview of the various TE phenomena and discusses some of the primary TE materials that are currently being investigated. Several of the key parameters and terminology are defined and discussed along with an overview of some of the current and emerging technologies. The phonon glass–electron crystal approach to new TE materials for developing new materials is presented along with the role of solid-state crystal chemistry and the criteria for higher-performance TE materials. This article discusses TE phenomena, the selection criteria for higher-performance materials, and a few key materials.
Biologically Inspired Mushroom-Shaped Adhesive Microstructures
Authors: Heepe Lars , Gorb Stanislav N.
Published: March 2011

Adhesion is a fundamental phenomenon with great importance in technology, in our everyday life, and in nature. In this article, we review physical interactions that resist the separation of two solids in contact. By using examples of biological attachment systems, we summarize and categorize various principles that contribute to the so-called gecko effect. Emphasis is placed on the contact geometry and in particular on the mushroom-shaped geometry, which is observed in long-term biological adhesive systems. Furthermore, we report on artificial model systems with this bio-inspired geometry and demonstrate that surface microstructures with this geometry are promising candidates for technical applications, in which repeatable, reversible, and residue-free adhesion under different environmental conditions—such as air, fluid, and vacuum—is required. Various applications in robotic systems and in industrial pick-and-place processes are discussed.
Amyloid Precursor Protein Processing and Alzheimer's Disease
Authors: O'Brien Richard J. , Wong Philip C.
Published: March 2011

Alzheimer's disease (AD), the leading cause of dementia worldwide, is characterized by the accumulation of the β-amyloid peptide (Aβ) within the brain along with hyperphosphorylated and cleaved forms of the microtubule-associated protein tau. Genetic, biochemical, and behavioral research suggest that physiologic generation of the neurotoxic Aβ peptide from sequential amyloid precursor protein (APP) proteolysis is the crucial step in the development of AD. APP is a single-pass transmembrane protein expressed at high levels in the brain and metabolized in a rapid and highly complex fashion by a series of sequential proteases, including the intramembranous γ-secretase complex, which also process other key regulatory molecules. Why Aβ accumulates in the brains of elderly individuals is unclear but could relate to changes in APP metabolism or Aβ elimination. Lessons learned from biochemical and genetic studies of APP processing will be crucial to the development of therapeutic targets to treat AD.
Collision Detection as a Model for Sensory-Motor Integration
Authors: Fotowat Haleh , Gabbiani Fabrizio
Published: March 2011

Visually guided collision avoidance is critical for the survival of many animals. The execution of successful collision-avoidance behaviors requires accurate processing of approaching threats by the visual system and signaling of threat characteristics to motor circuits to execute appropriate motor programs in a timely manner. Consequently, visually guided collision avoidance offers an excellent model with which to study the neural mechanisms of sensory-motor integration in the context of a natural behavior. Neurons that selectively respond to approaching threats and brain areas processing them have been characterized across many species. In locusts in particular, the underlying sensory and motor processes have been analyzed in great detail: These animals possess an identified neuron, called the LGMD, that responds selectively to approaching threats and conveys that information through a second identified neuron, the DCMD, to motor centers, generating escape jumps. A combination of behavioral and in vivo electrophysiological experiments has unraveled many of the cellular and network mechanisms underlying this behavior.
Modulation of Striatal Projection Systems by Dopamine
Authors: Gerfen Charles R. , Surmeier D. James
Published: March 2011

The basal ganglia are a chain of subcortical nuclei that facilitate action selection. Two striatal projection systems—so-called direct and indirect pathways—form the functional backbone of the basal ganglia circuit. Twenty years ago, investigators proposed that the striatum's ability to use dopamine (DA) rise and fall to control action selection was due to the segregation of D1 and D2 DA receptors in direct- and indirect-pathway spiny projection neurons. Although this hypothesis sparked a debate, the evidence that has accumulated since then clearly supports this model. Recent advances in the means of marking neural circuits with optical or molecular reporters have revealed a clear-cut dichotomy between these two cell types at the molecular, anatomical, and physiological levels. The contrast provided by these studies has provided new insights into how the striatum responds to fluctuations in DA signaling and how diseases that alter this signaling change striatal function.
Neurobiology of Economic Choice: A Good-Based Model
Authors: Padoa-Schioppa Camillo
Published: March 2011

Traditionally the object of economic theory and experimental psychology, economic choice recently became a lively research focus in systems neuroscience. Here I summarize the emerging results and propose a unifying model of how economic choice might function at the neural level. Economic choice entails comparing options that vary on multiple dimensions. Hence, while choosing, individuals integrate different determinants into a subjective value; decisions are then made by comparing values. According to the good-based model, the values of different goods are computed independently of one another, which implies transitivity. Values are not learned as such, but rather computed at the time of choice. Most importantly, values are compared within the space of goods, independent of the sensorimotor contingencies of choice. Evidence from neurophysiology, imaging, and lesion studies indicates that abstract representations of value exist in the orbitofrontal and ventromedial prefrontal cortices. The computation and comparison of values may thus take place within these regions.
Gender Development and the Human Brain
Authors: Hines Melissa
Published: March 2011

Convincing evidence indicates that prenatal exposure to the gonadal hormone, testosterone, influences the development of children's sex-typical toy and activity interests. In addition, growing evidence shows that testosterone exposure contributes similarly to the development of other human behaviors that show sex differences, including sexual orientation, core gender identity, and some, though not all, sex-related cognitive and personality characteristics. In addition to these prenatal hormonal influences, early infancy and puberty may provide additional critical periods when hormones influence human neurobehavioral organization. Sex-linked genes could also contribute to human gender development, and most sex-related characteristics are influenced by socialization and other aspects of postnatal experience, as well. Neural mechanisms underlying the influences of gonadal hormones on human behavior are beginning to be identified. Although the neural mechanisms underlying experiential influences remain largely uninvestigated, they could involve the same neural circuitry as that affected by hormones.
Mechanisms of Inhibition within the Telencephalon: “Where the Wild Things Are”
Authors: Fishell Gord , Rudy Bernardo
Published: March 2011

In this review, we first provide a historical perspective of inhibitory signaling from the discovery of inhibition through to our present understanding of the diversity and mechanisms by which GABAergic interneuron populations function in different parts of the telencephalon. This is followed by a summary of the mechanisms of inhibition in the CNS. With this as a starting point, we provide an overview describing the variations in the subtypes and origins of inhibitory interneurons within the pallial and subpallial divisions of the telencephalon, with a focus on the hippocampus, somatosensory, paleo/piriform cortex, striatum, and various amygdala nuclei. Strikingly, we observe that marked variations exist in the origin and numerical balance between GABAergic interneurons and the principal cell populations in distinct regions of the telencephalon. Finally we speculate regarding the attractiveness and challenges of establishing a unifying nomenclature to describe inhibitory neuron diversity throughout the telencephalon.
The Cognitive Neuroscience of Human Memory Since H.M.
Authors: Squire Larry R. , Wixted John T.
Published: March 2011

Work with patient H.M., beginning in the 1950s, established key principles about the organization of memory that inspired decades of experimental work. Since H.M., the study of human memory and its disorders has continued to yield new insights and to improve understanding of the structure and organization of memory. Here we review this work with emphasis on the neuroanatomy of medial temporal lobe and diencephalic structures important for memory, multiple memory systems, visual perception, immediate memory, memory consolidation, the locus of long-term memory storage, the concepts of recollection and familiarity, and the question of how different medial temporal lobe structures may contribute differently to memory functions.
Motor Functions of the Superior Colliculus
Authors: Gandhi Neeraj J. , Katnani Husam A.
Published: March 2011

The mammalian superior colliculus (SC) and its nonmammalian homolog, the optic tectum, constitute a major node in processing sensory information, incorporating cognitive factors, and issuing motor commands. The resulting action—to orient toward or away from a stimulus—can be accomplished as an integrated movement across oculomotor, cephalomotor, and skeletomotor effectors. The SC also participates in preserving fixation during intersaccadic intervals. This review highlights the repertoire of movements attributed to SC function and analyzes the significance of results obtained from causality-based experiments (microstimulation and inactivation). The mechanisms potentially used to decode the population activity in the SC into an appropriate movement command are also discussed.
The Development and Application of Optogenetics
Authors: Fenno Lief , Yizhar Ofer , Deisseroth Karl
Published: March 2011

Genetically encoded, single-component optogenetic tools have made a significant impact on neuroscience, enabling specific modulation of selected cells within complex neural tissues. As the optogenetic toolbox contents grow and diversify, the opportunities for neuroscience continue to grow. In this review, we outline the development of currently available single-component optogenetic tools and summarize the application of various optogenetic tools in diverse model organisms.
The Extraction of 3D Shape in the Visual System of Human and Nonhuman Primates
Authors: Orban Guy A.
Published: March 2011

Depth structure, the third dimension of object shape, is extracted from disparity, motion, texture, and shading in the optic array. Gradient-selective neurons play a key role in this process. Such neurons occur in CIP, AIP, TEs, and F5 (for first- or second-order disparity gradients), in MT/V5, in FST (for speed gradients), and in CIP and TEs (for texture gradients). Most of these regions are activated during magnetic resonance scanning in alert monkeys by comparing 3D conditions with the 2D controls for the different cues. Similarities in activation patterns of monkeys and humans tested with identical paradigms suggest that like gradient-selective neurons are found in corresponding human cortical areas. This view gains credence as the homologies between such areas become more evident. Furthermore, 3D shape-processing networks are similar in the two species, with the exception of the greater involvement of human posterior parietal cortex in the extraction of 3D shape from motion. Thus we can begin to understand how depth structure is extracted from motion, disparity, and texture in the primate brain, but the extraction of depth structure from shading and that of wire-like objects requires further scrutiny.
Diboson Production at Colliders
Authors: Neubauer Mark S.
Published: March 2011

This article is devoted to the physics of pairs of electroweak gauge bosons (dibosons) produced at high-energy particle colliders. Particular emphasis is placed on published results on diboson production from the CDF and DØ experiments at the Fermilab Tevatron and the CMS and ATLAS experiments at the CERN Large Hadron Collider (LHC). The study of diboson production at colliders plays an important role in tests of electroweak theory and searches for new phenomena at the TeV-energy scale and beyond. The diboson physics program has been a highlight of Run II at the Fermilab Tevatron. The progress made on analysis methods through the study of Standard Model diboson signals has had a direct and positive impact on the sensitivity of Higgs boson and New Physics searches in the Tevatron experiments. It is anticipated that diboson physics will play an even bigger role in the TeV-scale exploration now under way at the LHC.
Higgs Boson Searches at the Tevatron
Authors: Herndon Matthew
Published: March 2011

The Tevatron experiments are currently the world's most sensitive experiments for searching for the Higgs boson. They are sensitive enough to find evidence of the Standard Model Higgs boson, if it has a large mass, and are nearly sensitive enough to find evidence at lower mass or to exclude the Standard Model Higgs boson at all masses, if it does not exist. This review describes the recent experimental progress achieved at the Tevatron at a time when the discovery of the Higgs boson is considered imminent.
M-Theory and Maximally Supersymmetric Gauge Theories
Authors: Lambert Neil
Published: March 2011

In this informal review for nonspecialists, we discuss the construction of maximally supersymmetric gauge theories that arise on the world-volume branes in string theory and M-theory. We focus on the relatively recent construction of M2-brane world-volume theories. In a formal sense, the existence of these quantum field theories can be viewed as predictions of M-theory. Their construction is therefore a reinforcement of the ideas underlying string theory and M-theory. We also briefly discuss the six-dimensional conformal field theory that is expected to arise on M5-branes. The construction of this theory is not only an important open problem for M-theory but also a significant challenge to our current understanding of quantum field theory more generally.
Supernova Cosmology: Legacy and Future
Authors: Goobar Ariel , Leibundgut Bruno
Published: March 2011

The discovery of dark energy by the first generation of high-redshift supernova surveys has generated enormous interest beyond cosmology and has dramatic implications for fundamental physics. Distance measurements using supernova explosions are the most direct probes of the expansion history of the universe, making them extremely useful tools with which to study the cosmic fabric and the properties of gravity at the largest scales. The past decade has seen confirmation of the original results. Type Ia supernovae are among the leading techniques to obtain high-precision measurements of the dark energy equation-of-state parameter and, in the near future, its time dependence. The success of these efforts depends on our ability to understand a large number of effects, mostly of an astrophysical nature, that influence the observed flux at Earth. The frontier now lies in understanding whether the observed phenomenon is due to vacuum energy, despite its unnatural density, or some exotic new physics. Future surveys will address the systematic effects with improved calibration procedures and will provide thousands of supernovae for detailed studies.
Associated Production of W/Z Gauge Bosons and Jets in Hadronic Collisions
Authors: Campbell John , Mangano Michelangelo
Published: March 2011

Most new particles predicted by theories beyond the Standard Model of particle physics decay to jets and electroweak gauge bosons, W and Z. The search and study of these particles therefore require a solid understanding of the associated production of W/Z and jets. This review provides an introduction to the theoretical and experimental aspects of these processes in the context of the Standard Model. First, we introduce the challenges presented by the calculation of the production properties of W/Z plus jets in hadronic collisions and review the tools developed to quantitatively characterize such final states. Then, we summarize the current experimental results at the Tevatron and LHC colliders and discuss the comparison between the available data and the theoretical predictions.
Mechanisms of Membrane Transport of Folates into Cells and Across Epithelia
Authors: Zhao Rongbao , Diop-Bove Ndeye , Visentin Michele , Goldman I. David
Published: March 2011

Until recently, the transport of folates into cells and across epithelia has been interpreted primarily within the context of two transporters with high affinity and specificity for folates, the reduced folate carrier and the folate receptors. However, there were discrepancies between the properties of these transporters and characteristics of folate transport in many tissues, most notably the intestinal absorption of folates, in terms of pH dependency and substrate specificity. With the recent cloning of the proton-coupled folate transporter (PCFT) and the demonstration that this transporter is mutated in hereditary folate malabsorption, an autosomal recessive disorder, the molecular basis for this low-pH transport activity is now understood. This review focuses on the properties of PCFT and briefly addresses the two other folate-specific transporters along with other facilitative and ATP-binding cassette (ABC) transporters with folate transport activities. The role of these transporters in the vectorial transport of folates across epithelia is considered.
How Is Maternal Nutrition Related to Preterm Birth?
Authors: Bloomfield Frank H.
Published: March 2011

The incidence of preterm birth in developed countries is increasing, and in some countries, including the United States, it is almost as high as in developing countries. Demographic changes in women becoming pregnant can account for only a relatively small proportion of the increase. A significant proportion of spontaneous preterm birth continues to be of unknown cause. Experimental data from animal studies suggesting that maternal undernutrition may play a role in spontaneous, noninfectious, preterm birth are supported by observational data in human populations, which support a role for maternal prepregnancy nutritional status in determining gestation length. In addition, intakes or lack of specific nutrients during pregnancy may influence gestation length and thus the risk of preterm birth. As yet, the role of paternal nutrition in contributing to gestation length is unexplored.
Potential Mechanisms by Which Polyphenol-Rich Grapes Prevent Obesity-Mediated Inflammation and Metabolic Diseases
Authors: Chuang Chia-Chi , McIntosh Michael K.
Published: March 2011

Obesity and metabolic disease–related health problems (e.g., type 2 diabetes, atherosclerosis, and hypertension) are the most prevalent nutrition-related issues in the United States. An emerging feature of obesity and type 2 diabetes is their linkage with chronic inflammation that begins in white adipose tissue and eventually becomes systemic. One potential strategy to reduce inflammation and insulin resistance is consumption of polyphenol-rich foods like grapes or their by-products, which have anti-inflammatory properties. Polyphenols commonly found in grape products have been reported to reduce inflammation by (a) acting as an antioxidant or increasing antioxidant gene or protein expression, (b) attenuating endoplasmic reticulum stress signaling, (c) blocking proinflammatory cytokines or endotoxin-mediated kinases and transcription factors involved in metabolic disease, (d) suppressing inflammatory- or inducing metabolic-gene expression via increasing histone deacetylase activity, or (e) activating transcription factors that antagonize chronic inflammation. Thus, polyphenol-rich grape products may reduce obesity-mediated chronic inflammation by multiple mechanisms, thereby preventing metabolic diseases.
What Are the Risks and Benefits to Increasing Dietary Bone Minerals and Vitamin D Intake in Infants and Small Children?
Authors: Abrams Steven A.
Published: March 2011

Bone minerals and vitamin D are crucial for infants and small children. Human milk has little vitamin D, and supplemental vitamin D must be given to all infants either via drops or as contained in infant formula or foods. The calcium and phosphorus in human milk are adequate for infants in the first six months of life, with supplemental minerals coming from weaning foods after six months. Long-term benefits to providing bone minerals at greater levels than in human milk have not been shown. There is no evidence to support high-dose bone mineral supplementation or high-dose vitamin D supplementation in infancy, and controlled trials are needed before these can be advocated.
How Many People Are Malnourished?
Authors: Svedberg Peter
Published: March 2011

The present article reviews the strengths and weaknesses of the three main methods for estimating the prevalence of malnutrition in populations: self-reported hunger, estimates based on food supplies, and anthropometrics. Although far from flawless, anthropometrics is found to be the most reliable method and also the most useful for directing policy. The main form of malnutrition among adults is overweight, not only in developed countries, but also in almost all developing countries. Only in a few developing countries is adult underweight more prevalent. By the conventional anthropometric indicators, about one-quarter of all children below the age of 5 in the developing countries are stunted or underweight, and about 10% are wasted. The total burden of malnutrition among young children, as measured by the Composite Index of Anthropometric Failure, is considerably higher, about 60% in India, the country with the largest child population in the world.
Energy Intake and Response to Infection with Influenza
Authors: Gardner Elizabeth M. , Beli Eleni , Clinthorne Jonathan F. , Duriancik David M.
Published: March 2011

Influenza is a worldwide public health concern, particularly with emerging new strains of influenza to which vaccines are ineffective, limited, or unavailable. In addition, the relationship between adequate nutrition and immune function has been repeatedly demonstrated. Mouse models provide strong evidence that energy extremes, including energy restriction (ER) and diet-induced obesity (DIO), have deleterious effects on the immune response to influenza infection. Both ER and DIO mice demonstrate increased susceptibility and mortality to influenza infection. The effects of ER are more pronounced during innate responses to influenza infection, whereas the effects of DIO are evidenced during innate and adaptive responses to both primary and secondary infection. There are striking similarities between ER and DIO during influenza infection, including impaired natural killer cell function and altered inflammation. Future studies must develop effective nutritional paradigms to offset the effects of these energy extremes on the immune response to an acute infection.
Mechanisms of Function and Disease of Natural and Replacement Heart Valves
Authors: Schoen Frederick J.
Published: March 2011

Over the past several decades, there has been substantial progress toward understanding the mechanisms of heart valve function and dysfunction. This review summarizes an evolving conceptual framework of heart valve functional structure, developmental biology, and pathobiology and explores the implications of key insights. I emphasize: (a) valve cell and extracellular matrix biology and the impact of biomechanical factors on function, homeostasis, environmental adaptation, and key pathological processes; (b) the role of developmental processes, valvular cell behavior, and extracellular matrix remodeling in congenital and acquired valve abnormalities; and (c) the cell/matrix biology of degeneration in replacement tissue valves. I also summarize how these considerations may ultimately inform the potential for prevention and treatment of major diseases and potentially therapeutic regeneration of the cardiac valves. Recent advances and opportunities for research and clinical translation are highlighted.
RNA Dysregulation in Diseases of Motor Neurons
Authors: Ibrahim Fadia , Nakaya Tadashi , Mourelatos Zissimos
Published: March 2011

Motor neuron diseases (MNDs) are neurodegenerative disorders that lead to paralysis and typically carry a dismal prognosis. In children, inherited spinal muscular atrophies are the predominant diseases that affect motor neurons, whereas in adults, amyotrophic lateral sclerosis, which is inherited but mostly sporadic, is the most common MND. In recent years, we have witnessed a revolution in this field, sparked by the discovery of the genes that cause MNDs. Remarkably, at least 10 genes, whose products are either RNA-binding proteins or proteins that function in RNA processing and regulation, cause MNDs and place the dysregulation of RNA pathways at the center of motor neuron degeneration pathogenesis.
Glioblastoma: From Molecular Pathology to Targeted Treatment
Authors: Cloughesy Timothy F. , Cavenee Webster K. , Mischel Paul S.
Published: March 2011

Glioblastoma (GBM) is one of the most lethal human cancers. Genomic analyses are defining the molecular architecture of GBM, uncovering relevant subsets of patients whose disease may require different treatments. Many pharmacological targets have been revealed, promising to transform patient care through targeted therapies. However, for most patients, clinical responses to targeted inhibitors are either not apparent or not durable. In this review, we address the challenge of developing more effective, molecularly guided approaches for the treatment of GBM patients. We summarize the current state of knowledge regarding molecular classifiers and examine their benefit for stratifying patients for treatment. We survey the molecular landscape of the disease, discussing the challenges raised by acquired drug resistance. Furthermore, we analyze the biochemical features of GBM, suggesting a next generation of drug targets, and we examine the contribution of tumor heterogeneity and its implications. We conclude with an analysis of the experimental approaches and their potential benefit to patients.
Caveolin-1 and Cancer Metabolism in the Tumor Microenvironment: Markers, Models, and Mechanisms
Authors: Sotgia Federica , Martinez-Outschoorn Ubaldo E. , Howell Anthony , Pestell Richard G. , Pavlides Stephanos , Lisanti Michael P.
Published: March 2011

Caveolins are a family of membrane-bound scaffolding proteins that compartmentalize and negatively regulate signal transduction. Recent studies have implicated a loss of caveolin-1 (Cav-1) expression in the pathogenesis of human cancers. Loss of Cav-1 expression in cancer-associated fibroblasts results in an activated tumor microenvironment, thereby driving early tumor recurrence, metastasis, and poor clinical outcome in breast and prostate cancers. We describe various paracrine signaling mechanism(s) by which the loss of stromal Cav-1 promotes tumor progression, including fibrosis, extracellular matrix remodeling, and the metabolic/catabolic reprogramming of cancer-associated fibroblast, to fuel the growth of adjacent tumor cells. It appears that oxidative stress is the root cause of initiation of the loss of stromal Cav-1 via autophagy, which provides further impetus for the use of antioxidants in anticancer therapy. Finally, we discuss the functional role of Cav-1 in epithelial cancer cells.
Digital Imaging in Pathology: Whole-Slide Imaging and Beyond
Authors: Ghaznavi Farzad , Evans Andrew , Madabhushi Anant , Feldman Michael
Published: March 2011

Digital imaging in pathology has undergone an exponential period of growth and expansion catalyzed by changes in imaging hardware and gains in computational processing. Today, digitization of entire glass slides at near the optical resolution limits of light can occur in 60 s. Whole slides can be imaged in fluorescence or by use of multispectral imaging systems. Computational algorithms have been developed for cytometric analysis of cells and proteins in subcellular locations by use of multiplexed antibody staining protocols. Digital imaging is unlocking the potential to integrate primary image features into high-dimensional genomic assays by moving microscopic analysis into the digital age. This review highlights the emerging field of digital pathology and explores the methods and analytic approaches being developed for the application and use of these methods in clinical care and research settings.
The Life and Death of Epithelia During Inflammation: Lessons Learned from the Gut
Authors: Koch Stefan , Nusrat Asma
Published: March 2011

Epithelial cells form protective barriers that physically separate an organism from the outside world. Rather than being merely static, impregnable shields, epithelia are highly dynamic structures that can adjust their proliferation, differentiation, and death in response to intrinsic and extrinsic signals. The advantages as well as pitfalls of this flexibility are highlighted in inflammatory disorders such as inflammatory bowel diseases and psoriasis, which are characterized by a chronically dysregulated homeostasis of the epithelium. In recent years, it has become increasingly apparent that epithelial cells communicate with their surroundings through converging, integrated signaling cascades and that even minor alterations in these pathways can have dramatic pathologic consequences. In this review, we discuss how inflammatory cytokines and other signaling molecules, directly or through cross talk, regulate epithelial homeostasis in the intestine, and we highlight parallels and differences in a few other organs.
Human Microbiome in Health and Disease
Authors: Pflughoeft Kathryn J. , Versalovic James
Published: March 2011

Mammals are complex assemblages of mammalian and bacterial cells organized into functional organs, tissues, and cellular communities. Human biology can no longer concern itself only with human cells: Microbiomes at different body sites and functional metagenomics must be considered part of systems biology. The emergence of metagenomics has resulted in the generation of vast data sets of microbial genes and pathways present in different body habitats. The profound differences between microbiomes in various body sites reveal how metagenomes contribute to tissue and organ function. As next-generation DNA-sequencing methods provide whole-metagenome data in addition to gene-expression profiling, metaproteomics, and metabonomics, differences in microbial composition and function are being linked to health and disease states in different organs and tissues. Global parameters of microbial communities may provide valuable information regarding human health status and disease predisposition. More detailed knowledge of the human microbiome will yield next-generation diagnostics and therapeutics for various acute, chronic, localized, and systemic human diseases.
Pathogenesis of NUT Midline Carcinoma
Authors: French Christopher A.
Published: March 2011

NUT midline carcinoma (NMC), an aggressive form of squamous cell carcinoma, is defined by the presence of acquired chromosomal rearrangements involving NUT, usually BRD4-NUT fusion genes and, less commonly, NUT-variant fusion genes involving BRD3 or still-uncharacterized genes. Improved diagnostic tests reveal that although rare, NMCs occur in people of any age and may be indistinguishable from more common squamous cell carcinomas of adulthood. NMCs have simple karyotypes whose hallmark is genomic instability, suggesting that NMC arises through a distinct pathogenic pathway representing a genetic shortcut to the phenotype of squamous cell carcinoma. Mechanistically, BRD-NUT fusion proteins appear to act by blocking differentiation, possibly by sequestering histone acetyltransferase activity. Accordingly, histone deacetylase inhibitors or BET inhibitors, the latter of which inhibit binding of BRD-NUT proteins to chromatin, induce terminal differentiation of NMC cells. These insights provide a rationale for targeted therapy of NMC, which is almost uniformly refractory to conventional chemotherapy and radiotherapy.
Pathogenesis of Plexiform Neurofibroma: Tumor-Stromal/Hematopoietic Interactions in Tumor Progression
Authors: Staser Karl , Yang Feng-Chun , Clapp D. Wade
Published: March 2011

Neurofibromatosis type 1 (NF1) is a genetic disease that results from either heritable or spontaneous autosomal dominant mutations in the NF1 gene. A second-hit mutation precedes the predominant NF1 neoplasms, which include myeloid leukemia, optic glioma, and plexiform neurofibroma. Despite this requisite NF1 loss of heterozygosity in the tumor cell of origin, nontumorigenic cells contribute to both generalized and specific disease manifestations. In mouse models of plexiform neurofibroma formation, Nf1 haploinsufficient mast cells promote inflammation, accelerating tumor formation and growth. These recruited mast cells, hematopoietic effector cells long known to permeate neurofibroma tissue, mediate key mitogenic signals that contribute to vascular ingrowth, collagen deposition, and tumor growth. Thus, the plexiform neurofibroma microenvironment involves a tumor/stromal interaction with the hematopoietic system that depends, at the molecular level, on a stem cell factor/c-kit-mediated signaling axis. These observations parallel findings in other NF1 disease manifestations and are clearly relevant to medical management of these neurofibromas.
Psoriasis
Authors: Perera Gayathri K. , Di Meglio Paola , Nestle Frank O.
Published: March 2011

Psoriasis is a common relapsing and remitting immune-mediated inflammatory disease that affects the skin and joints. This review focuses on current immunogenetic concepts, key cellular players, and axes of cytokines that are thought to contribute to disease pathogenesis. We highlight potential therapeutic targets and give an overview of the currently used immune-targeted therapies.
Pathogenesis of Antineutrophil Cytoplasmic Autoantibody–Associated Small-Vessel Vasculitis
Authors: Jennette J. Charles , Falk Ronald J. , Hu Peiqi , Xiao Hong
Published: March 2011

Clinical, in vitro, and experimental animal observations indicate that antineutrophil cytoplasmic autoantibodies (ANCA) are pathogenic. The genesis of the ANCA autoimmune response is a multifactorial process that includes genetic predisposition, environmental adjuvant factors, an initiating antigen, and failure of T cell regulation. ANCA activate primed neutrophils (and monocytes) by binding to certain antigens expressed on the surface of neutrophils in specific inflammatory microenvironments. ANCA-activated neutrophils activate the alternative complement pathway, establishing an inflammatory amplification loop. The acute injury elicits an innate inflammatory response that recruits monocytes and T lymphocytes, which replace the neutrophils that have undergone karyorrhexis during acute inflammation. Extravascular granulomatous inflammation may be initiated by ANCA-induced activation of extravascular neutrophils, causing tissue necrosis and fibrin formation, which would elicit an influx of monocytes that transform into macrophages and multinucleated giant cells. Over time, the neutrophil-rich acute necrotizing lesions cause the accumulation of more lymphocytes, monocytes, and macrophages and produce typical granulomatous inflammation.
ATM and the Molecular Pathogenesis of Ataxia Telangiectasia
Authors: McKinnon Peter J.
Published: March 2011

Ataxia telangiectasia (A-T) results from inactivation of the ATM protein kinase. DNA-damage signaling is a prime function of this kinase, although other roles have been ascribed to ATM. Identifying the primary ATM function(s) for tissue homeostasis is key to understanding how these functions contribute to the prevention of A-T-related pathology. In this regard, because A-T is primarily a neurodegenerative disease, it is essential to understand how ATM loss results in degenerative effects on the nervous system. In addition to delineating the biochemistry and cell biology of ATM, important insights into the molecular basis for neurodegeneration in A-T come from a spectrum of phenotypically related neurodegenerative diseases that directly result from DNA-repair deficiency. Together with A-T, these syndromes indicate that neurodegeneration can be caused by the failure to appropriately respond to DNA damage. This review focuses on defective DNA-damage signaling as the underlying cause of A-T.
Epigenetic Control of Smooth Muscle Cell Differentiation and Phenotypic Switching in Vascular Development and Disease
Authors: Alexander Matthew R. , Owens Gary K.
Published: March 2011

The vascular smooth muscle cell (SMC) in adult animals is a highly specialized cell whose principal function is contraction. However, this cell displays remarkable plasticity and can undergo profound changes in phenotype during repair of vascular injury, during remodeling in response to altered blood flow, or in various disease states. There has been extensive progress in recent years in our understanding of the complex mechanisms that control SMC differentiation and phenotypic plasticity, including the demonstration that epigenetic mechanisms play a critical role. In addition, recent evidence indicates that SMC phenotypic switching in adult animals involves the reactivation of embryonic stem cell pluripotency genes and that mesenchymal stem cells may be derived from SMC and/or pericytes. This review summarizes the current state of our knowledge in this field and identifies some of the key unresolved challenges and questions that we feel require further study.
Lysosomal Acidification Mechanisms
Authors: Mindell Joseph A.
Published: March 2011

Lysosomes, the terminal organelles on the endocytic pathway, digest macromolecules and make their components available to the cell as nutrients. Hydrolytic enzymes specific to a wide range of targets reside within the lysosome; these enzymes are activated by the highly acidic pH (between 4.5 and 5.0) in the organelles' interior. Lysosomes generate and maintain their pH gradients by using the activity of a proton-pumping V-type ATPase, which uses metabolic energy in the form of ATP to pump protons into the lysosome lumen. Because this activity separates electric charge and generates a transmembrane voltage, another ion must move to dissipate this voltage for net pumping to occur. This so-called counterion may be either a cation (moving out of the lysosome) or an anion (moving into the lysosome). Recent data support the involvement of ClC-7, a Cl−/H+ antiporter, in this process, although many open questions remain as to this transporter's involvement. Although functional results also point to a cation transporter, its molecular identity remains uncertain. Both the V-ATPase and the counterion transporter are likely to be important players in the mechanisms determining the steady-state pH of the lysosome interior. Exciting new results suggest that lysosomal pH may be dynamically regulated in some cell types.
A New Look at Electrolyte Transport in the Distal Tubule
Authors: Eladari Dominique , Chambrey Régine , Peti-Peterdi Janos
Published: March 2011

The distal nephron plays a critical role in the renal control of homeostasis. Until very recently most studies focused on the control of Na+, K+, and water balance by principal cells of the collecting duct and the regulation of solute and water by hormones from the renin-angiotensin-aldosterone system and by antidiuretic hormone. However, recent studies have revealed the unexpected importance of renal intercalated cells, a subtype of cells present in the connecting tubule and collecting ducts. Such cells were thought initially to be involved exclusively in acid-base regulation. However, it is clear now that intercalated cells absorb NaCl and K+ and hence may participate in the regulation of blood pressure and potassium balance. The second paradigm-challenging concept we highlight is the emerging importance of local paracrine factors that play a critical role in the renal control of water and electrolyte balance.
Adenosine and Hypoxia-Inducible Factor Signaling in Intestinal Injury and Recovery
Authors: Colgan Sean P. , Eltzschig Holger K.
Published: March 2011

The gastrointestinal mucosa has proven to be an interesting tissue in which to investigate disease-related metabolism. In this review, we outline some of the evidence that implicates hypoxia-mediated adenosine signaling as an important signature within both healthy and diseased mucosa. Studies derived from cultured cell systems, animal models, and human patients have revealed that hypoxia is a significant component of the inflammatory microenvironment. These studies have revealed a prominent role for hypoxia-induced factor (HIF) and hypoxia signaling at several steps along the adenine nucleotide metabolism and adenosine receptor signaling pathways. Likewise, studies to date in animal models of intestinal inflammation have demonstrated an almost uniformly beneficial influence of HIF stabilization on disease outcomes. Ongoing studies to define potential similarities with and differences between innate and adaptive immune responses will continue to teach us important lessons about the complexity of the gastrointestinal tract. Such information has provided new insights into disease pathogenesis and, importantly, will provide insights into new therapeutic targets.
Fetal Programming and Metabolic Syndrome
Authors: Rinaudo Paolo , Wang Erica
Published: March 2011

Metabolic syndrome is reaching epidemic proportions, particularly in developing countries. In this review, we explore the concept—based on the developmental-origin-of-health-and-disease hypothesis—that reprogramming during critical times of fetal life can lead to metabolic syndrome in adulthood. Specifically, we summarize the epidemiological evidence linking prenatal stress, manifested by low birth weight, to metabolic syndrome and its individual components. We also review animal studies that suggest potential mechanisms for the long-term effects of fetal reprogramming, including the cellular response to stress and both organ- and hormone-specific alterations induced by stress. Although metabolic syndrome in adulthood is undoubtedly caused by multiple factors, including modifiable behavior, fetal life may provide a critical window in which individuals are predisposed to metabolic syndrome later in life.
Cardiac Sarcoplasmic Reticulum Calcium Leak: Basis and Roles in Cardiac Dysfunction
Authors: Bers Donald M.
Published: March 2011

Synchronized SR calcium (Ca) release is critical to normal cardiac myocyte excitation-contraction coupling, and ideally this release shuts off completely between heartbeats. However, other SR Ca release events are referred to collectively as SR Ca leak (which includes Ca sparks and waves as well as smaller events not detectable as Ca sparks). Much, but not all, of the SR Ca leak occurs via ryanodine receptors and can be exacerbated in pathological states such as heart failure. The extent of SR Ca leak is important because it can (a) reduce SR Ca available for release, causing systolic dysfunction; (b) elevate diastolic [Ca]i, contributing to diastolic dysfunction; (c) cause triggered arrhythmias; and (d) be energetically costly because of extra ATP used to repump Ca. This review addresses quantitative aspects and manifestations of SR Ca leak and its measurement, and how leak is modulated by Ca, associated proteins, and posttranslational modifications in health and disease.
Renal Function in Diabetic Disease Models: The Tubular System in the Pathophysiology of the Diabetic Kidney
Authors: Vallon Volker , Thomson Scott C.
Published: March 2011

Diabetes mellitus affects the kidney in stages. At the onset of diabetes mellitus, in a subset of diabetic patients the kidneys grow large, and glomerular filtration rate (GFR) becomes supranormal, which are risk factors for developing diabetic nephropathy later in life. This review outlines a pathophysiological concept that focuses on the tubular system to explain these changes. The concept includes the tubular hypothesis of glomerular filtration, which states that early tubular growth and sodium-glucose cotransport enhance proximal tubule reabsorption and make the GFR supranormal through the physiology of tubuloglomerular feedback. The diabetic milieu triggers early tubular cell proliferation, but the induction of TGF-β and cyclin-dependent kinase inhibitors causes a cell cycle arrest and a switch to tubular hypertrophy and a senescence-like phenotype. Although this growth phenotype explains unusual responses like the salt paradox of the early diabetic kidney, the activated molecular pathways may set the stage for tubulointerstitial injury and diabetic nephropathy.