bluuebunny/crossref_metadata_2025 huggingface dataset:
The Legal Complex
Authors: Karpik Lucien , Halliday Terence C.
Published: March 2011

The concept of the legal complex is a new addition to the lexicon of sociology and sociolegal scholarship. As a concept, the legal complex emerged from a series of interdisciplinary collaborations and primary research on the politics of lawyers and judges across the world. The review introduces this new collective actor to the political stage and elaborates its defining elements, morphology, varieties of mobilization, and repertoires of action. This review argues for a complementary methodological strategy for investigation of the politics of the legal complex, the longue durée and événements. With respect to political liberalism, it shows the contexts and resources in which the legal complex thrives, with particular emphasis on civil society, information technology, the rise of constitutionalism, and international circumstances. The essay argues, however, that the explanatory reach of this concept can extend to any policymaking issues, national or supranational, that involve law, legal institutions, and legal actors. By adopting the logic of analysis developed in this review, not only do previously discrete areas of work on lawyers, judges, or prosecutors come into creative tension, but a lively politics of the legal complex will refine and extend theory across the landscape of law and society research.
On the Future Availability of the Energy Metals
Authors: Graedel T.E.
Published: March 2011

The routine availability of metals, long assumed by materials scientists to be unworthy of concern, is now a topic of wide interest but one with little clear guidance. This review discusses availability issues from the perspective of the metals utilized in the energy industry. Although the availability of metals is a dynamic characteristic, availability of the widely used base metals appears assured in the immediate future. The same cannot be said for by-product (daughter) metals, which are increasingly vital for many carbon-free energy technologies but are produced only if recovered as part of parent metal processing. Additionally, the direct substitution of one metal for another in short supply is often difficult because the best substitutes tend to have the same availability constraints as did the original metal. Gallium, indium, and neodymium are singled out as elements of particular concern from a long-term-supply standpoint.
Crystallization Pathways in Biomineralization
Authors: Weiner Steve , Addadi Lia
Published: March 2011

A crystallization pathway describes the movement of ions from their source to the final product. Cells are intimately involved in biological crystallization pathways. In many pathways the cells utilize a unique strategy: They temporarily concentrate ions in intracellular membrane-bound vesicles in the form of a highly disordered solid phase. This phase is then transported to the final mineralization site, where it is destabilized and crystallizes. We present four case studies, each of which demonstrates specific aspects of biological crystallization pathways: seawater uptake by foraminifera, calcite spicule formation by sea urchin larvae, goethite formation in the teeth of limpets, and guanine crystal formation in fish skin and spider cuticles. Three representative crystallization pathways are described, and aspects of the different stages of crystallization are discussed. An in-depth understanding of these complex processes can lead to new ideas for synthetic crystallization processes of interest to materials science.
Deformation and Fracture Mechanisms of Bone and Nacre
Authors: Wang Rizhi , Gupta Himadri S.
Published: March 2011

Bone and nacre are the most-known biological hard tissues to materials researchers. Although highly mineralized, both bone and nacre are amazingly tough and exhibit remarkable inelasticity, properties that are still beyond the reach of many modern ceramic materials. Very interestingly, the two hard tissues seem to have adopted totally different structural strategies for achieving mechanical robustness. Starting from a true nanocomposite of the mineralized collagen fibril and following up to seven levels of hierarchical organization, bone is built on a structure with extreme complexity. In contrast, nacre possesses a structure of surprising simplicity. Polygonal mineral tablets of micrometer size are carefully cemented together into a macroscopic wonder. A comparative analysis of the structure-property relations in bone and nacre helps us to unveil the underlying mechanisms of this puzzling phenomenon. In this review, we critically compare the various levels of structures and their mechanical contributions between bone and nacre, with a focus on inelasticity and the toughening process. We demonstrate that, although nacre and bone differ from each other in many aspects, they have adopted very similar deformation and toughening mechanisms.
Electrochromic Materials
Authors: Mortimer Roger J.
Published: March 2011

Electrochromic materials have the property of a change, evocation, or bleaching of color as effected either by an electron-transfer (redox) process or by a sufficient electrochemical potential. The main classes of electrochromic materials are surveyed here, with descriptions of representative examples from the metal oxides, viologens (in solution and as adsorbed or polymeric films), conjugated conducting polymers, metal coordination complexes (as polymeric, evaporated, or sublimed films), and metal hexacyanometallates. Examples of the applications of such electrochromic materials are included. Other materials aspects important for the construction of electrochromic devices include optically transparent electrodes, electrolyte layers, and device encapsulation. Commercial successes, current trends, and future challenges in electrochromic materials research and development are summarized.
Linear and Nonlinear Rheology of Living Cells
Authors: Kollmannsberger Philip , Fabry Ben
Published: March 2011

Living cells are an active soft material with fascinating mechanical properties. Under mechanical loading, cells exhibit creep and stress relaxation behavior that follows a power-law response rather than a classical exponential response. Such a response puts cells in the context of soft colloidal glasses and other disordered metastable materials that share the same properties. In cells, however, both the power-law exponent and stiffness are related to the contractile prestress in the cytoskeleton. In addition, cells are made of a highly nonlinear material that stiffens and fluidizes under mechanical stress. They show active and adaptive mechanical behavior such as contraction and remodeling that sets them apart from any other nonliving material. Strikingly, all these observations can be linked by simple relationships with the power-law exponent as the only organizing parameter. Current theoretical models capture specific facets of cell mechanical behavior, but a comprehensive understanding is still emerging.
Plant Stems: Functional Design and Mechanics
Authors: Speck Thomas , Burgert Ingo
Published: March 2011

Plant stems are one of nature's most impressive mechanical constructs. Their sophisticated hierarchical structure and multifunctionality allow trees to grow more than 100 m tall. This review highlights the advanced mechanical design of plant stems from the integral level of stem structures down to the fiber-reinforced-composite character of the cell walls. Thereby we intend not only to provide insight into structure-function relationships at the individual levels of hierarchy but to further discuss how growth forms and habits of plant stems are closely interrelated with the peculiarities of their tissue and cell structure and mechanics. This concept is extended to a further key feature of plants, namely, adaptive growth as a reaction to mechanical perturbation and/or changing environmental conditions. These mechanical design principles of plant stems can serve as concept generators for advanced biomimetic materials and may inspire materials and engineering sciences research.
Point Defects in Oxides: Tailoring Materials Through Defect Engineering
Authors: Tuller Harry L. , Bishop Sean R.
Published: March 2011

Optimization of electrical, optical, mechanical, and other properties of many advanced, functional materials today relies on precise control of point defects. This article illustrates the progress that has been made in elucidating the often complex equilibria exhibited by many materials by examining two recently well-characterized model systems, TlBr for radiation detection and PrxCe1−xO2−δ, of potential interest in solid-oxide fuel cells. The interplay between material composition, electrical conductivity, and mechanical properties (electrochemomechanics) is discussed, and implications in these relations, for example, enhancing electrical properties through large mechanical strains, are described. The impact of space charge and strain fields at interfaces, particularly important in nanostructure materials, is also emphasized. Key experimental techniques useful in characterizing bulk and surface defects are summarized and reviewed.
General Anesthesia and Altered States of Arousal: A Systems Neuroscience Analysis
Authors: Brown Emery N. , Purdon Patrick L. , Van Dort Christa J.
Published: March 2011

Placing a patient in a state of general anesthesia is crucial for safely and humanely performing most surgical and many nonsurgical procedures. How anesthetic drugs create the state of general anesthesia is considered a major mystery of modern medicine. Unconsciousness, induced by altered arousal and/or cognition, is perhaps the most fascinating behavioral state of general anesthesia. We perform a systems neuroscience analysis of the altered arousal states induced by five classes of intravenous anesthetics by relating their behavioral and physiological features to the molecular targets and neural circuits at which these drugs are purported to act. The altered states of arousal are sedation-unconsciousness, sedation-analgesia, dissociative anesthesia, pharmacologic non-REM sleep, and neuroleptic anesthesia. Each altered arousal state results from the anesthetic drugs acting at multiple targets in the central nervous system. Our analysis shows that general anesthesia is less mysterious than currently believed.
Neural Representations for Object Perception: Structure, Category, and Adaptive Coding
Authors: Kourtzi Zoe , Connor Charles E.
Published: March 2011

Object perception is one of the most remarkable capacities of the primate brain. Owing to the large and indeterminate dimensionality of object space, the neural basis of object perception has been difficult to study and remains controversial. Recent work has provided a more precise picture of how 2D and 3D object structure is encoded in intermediate and higher-level visual cortices. Yet, other studies suggest that higher-level visual cortex represents categorical identity rather than structure. Furthermore, object responses are surprisingly adaptive to changes in environmental statistics, implying that learning through evolution, development, and also shorter-term experience during adulthood may optimize the object code. Future progress in reconciling these findings will depend on more effective sampling of the object domain and direct comparison of these competing hypotheses.
Too Many Cooks? Intrinsic and Synaptic Homeostatic Mechanisms in Cortical Circuit Refinement
Authors: Turrigiano Gina
Published: March 2011

Maintaining the proper balance between excitation and inhibition is critical for the normal function of cortical circuits. This balance is thought to be maintained by an array of homeostatic mechanisms that regulate neuronal and circuit excitability, including mechanisms that target excitatory and inhibitory synapses, and mechanisms that target intrinsic neuronal excitability. In this review, I discuss where and when these mechanisms are used in complex microcircuits, what is currently known about the signaling pathways that underlie them, and how these different ways of achieving network stability cooperate and/or compete. An important challenge for the field of homeostatic plasticity is to assemble our understanding of these individual mechanisms into a coherent view of how microcircuit stability is maintained during experience-dependent circuit refinement.
Myelin Regeneration: A Recapitulation of Development?
Authors: Fancy Stephen P.J. , Chan Jonah R. , Baranzini Sergio E. , Franklin Robin J.M. , Rowitch David H.
Published: March 2011

The developmental process of myelination and the adult regenerative process of remyelination share the common objective of investing nerve axons with myelin sheaths. A central question in myelin biology is the extent to which the mechanisms of these two processes are conserved, a concept encapsulated in the recapitulation hypothesis of remyelination. This question also has relevance for translating myelin biology into a better understanding of and eventual treatments for human myelin disorders. Here we review the current evidence for the recapitulation hypothesis and discuss recent findings in the development and regeneration of myelin in the context of human neurological disease.
Vestibular Hair Cells and Afferents: Two Channels for Head Motion Signals
Authors: Eatock Ruth Anne , Songer Jocelyn E.
Published: March 2011

Vestibular epithelia of the inner ear detect head motions over a wide range of amplitudes and frequencies. In mammals, afferent nerve fibers from central and peripheral zones of vestibular epithelia form distinct populations with different response dynamics and spike timing. Central-zone afferents are large, fast conduits for phasic signals encoded in irregular spike trains. The finer afferents from peripheral zones conduct more slowly and encode more tonic, linear signals in highly regular spike trains. The hair cells are also of two types, I and II, but the two types do not correspond directly to the two afferent populations. Zonal differences in afferent response dynamics may arise at multiple stages, including mechanoelectrical transduction, voltage-gated channels in hair cells and afferents, afferent transmission at calyceal and bouton synapses, and spike generation in regular and irregular afferents. In contrast, zonal differences in spike timing may depend more simply on the selective expression of low-voltage-activated ion channels by irregular afferents.
Neuronal Intrinsic Mechanisms of Axon Regeneration
Authors: Liu Kai , Tedeschi Andrea , Park Kevin Kyungsuk , He Zhigang
Published: March 2011

Failure of axon regeneration after central nervous system (CNS) injuries results in permanent functional deficits. Numerous studies in the past suggested that blocking extracellular inhibitory influences alone is insufficient to allow the majority of injured axons to regenerate, pointing to the importance of revisiting the hypothesis that diminished intrinsic regenerative ability critically underlies regeneration failure. Recent studies in different species and using different injury models have started to reveal important cellular and molecular mechanisms within neurons that govern axon regeneration. This review summarizes these observations and discusses possible strategies for stimulating axon regeneration and perhaps functional recovery after CNS injury.
Spatial Neglect and Attention Networks
Authors: Corbetta Maurizio , Shulman Gordon L.
Published: March 2011

Unilateral spatial neglect is a common neurological syndrome following predominantly right hemisphere injuries and is characterized by both spatial and non-spatial deficits. Core spatial deficits involve mechanisms for saliency coding, spatial attention, and short-term memory and occur in conjunction with nonspatial deficits that involve reorienting, target detection, and arousal/vigilance. We argue that neglect is better explained by the dysfunction of distributed cortical networks for the control of attention than by structural damage of specific brain regions. Ventral lesions in right parietal, temporal, and frontal cortex that cause neglect directly impair nonspatial functions partly mediated by a ventral frontoparietal attention network. Structural damage in ventral cortex also induces physiological abnormalities of task-evoked activity and functional connectivity in a dorsal frontoparietal network that controls spatial attention. The anatomy and right hemisphere dominance of neglect follow from the anatomy and laterality of the ventral regions that interact with the dorsal attention network.
Spin-Dependent Electron Scattering from Polarized Protons and Deuterons with the BLAST Experiment at MIT-Bates
Authors: Hasell Douglas K. , Milner Richard G. , Redwine Robert P. , Alarcon Ricardo , Gao Haiyan , Kohl Michael , Calarco John R.
Published: March 2011

The Bates Large Acceptance Spectrometer Toroid (BLAST) experiment was operated at the MIT-Bates Linear Accelerator Center from 2003 until 2005. The experiment was designed to exploit the power of a polarized electron beam incident on polarized targets of hydrogen and deuterium to measure, in a systematic manner, the neutron, proton, and deuteron form factors as well as other aspects of the electromagnetic interaction on few-nucleon systems. We briefly describe the experiment, and present and discuss the numerous results obtained.
Advances in Tracking Detectors
Authors: Hartmann Frank , Kaminski Jochen
Published: March 2011

Tracking detectors are of vital importance for most experiments in high-energy and nuclear physics. They are used to determine the charge, momentum, and energy of traversing particles and to allow quark-flavor identification through the reconstruction of secondary vertices. Gaseous and semiconductor detectors are the two main types of tracking detectors; other, more exotic ones are fiber or transition radiation tracking devices. These detectors originated with cloud and bubble chambers in the 1950s and wire chambers in the 1970s, which dominated the field until the 1980s, when silicon sensors were developed. Today, silicon strip and pixel sensors, time-projection chambers, gas electron multipliers, and micromegas define the field. More advanced detector types are described in this review, with an emphasis on application examples and future plans.
Chiral Dynamics of Few- and Many-Nucleon Systems
Authors: Epelbaum Evgeny , Meißner Ulf-G.
Published: March 2011

This review briefly introduces the chiral effective field theory of nuclear forces and atomic nuclei. We discuss the status of the nuclear Hamiltonian derived in this framework and some recent applications in few-nucleon systems. We also introduce nuclear lattice simulations as a new tool to address the many-body problem and present some of the first results based on that method.
Computing for the Large Hadron Collider
Authors: Bird Ian
Published: March 2011

Following the first full year of Large Hadron Collider (LHC) data taking, the Worldwide LHC Computing Grid (WLCG) computing environment built to support LHC data processing and analysis has been validated. In this review, I discuss the rationale for the design of a distributed system and describe how this environment was constructed and deployed through the use of grid computing technologies. I discuss the experience with large-scale testing and operation with real accelerator data, which shows that expectations have been met and sometimes exceeded. The computing system's key achievements are that (a) the WLCG infrastructure is distributed and makes use of all the dispersed resources, (b) the experiments' computing models are also distributed and can make excellent use of the infrastructure, and (c) the computing system has enabled physics output in a very short time. Finally, I present prospects for the future evolution of the WLCG infrastructure.
Neutrino-Nucleus Interactions
Authors: Gallagher H. , Garvey G. , Zeller G.P.
Published: March 2011

The study of neutrino oscillations has necessitated a new generation of neutrino experiments that are exploring neutrino-nuclear scattering processes. We focus in particular on charged-current quasi-elastic scattering, a particularly important channel that has been extensively investigated both in the bubble-chamber era and by current experiments. Recent results have led to theoretical reexamination of this process. We review the standard picture of quasi-elastic scattering as developed in electron scattering, review and discuss experimental results, and discuss additional nuclear effects such as exchange currents and short-range correlations that may play a significant role in neutrino-nucleus scattering.
Parity-Violating Electron Scattering and the Electric and Magnetic Strange Form Factors of the Nucleon
Authors: Armstrong D.S. , McKeown R.D.
Published: March 2011

Measurements of the neutral weak-vector form factors of the nucleon provide unique access to the strange quark content of the nucleon. These form factors can be studied by using parity-violating electron scattering. A comprehensive program of experiments has been performed at three accelerator laboratories to determine the role of strange quarks in the electromagnetic form factors of the nucleon. This article reviews the remarkable technical progress associated with this program, describes the various methods used in the different experiments, and summarizes the physics results along with recent theoretical calculations.
Physics Opportunities at the Next Generation of Precision Flavor Physics Experiments
Authors: Ciuchini Marco , Stocchi Achille
Published: March 2011

With the next-generation experiments, flavor physics is fully entering the era of precision measurements. Its focus is shifting from testing the Standard Model to finding and characterizing New Physics contributions. We review the opportunities offered by future flavor experiments and discuss the expected sensitivities of the most important measurements. We also present some examples of measurable deviations from the Standard Model in the flavor sector generated in a selection of New Physics models, which demonstrate the potentially major contribution of precision flavor physics to the effort of going beyond the Standard Model.
Rare Kaon and Pion Decays: Incisive Probes for New Physics Beyond the Standard Model
Authors: Bryman Douglas , Marciano William J. , Tschirhart Robert , Yamanaka Taku
Published: March 2011

We review the current status and future prospects of rare kaon and pion decay research programs. Our emphasis is on experimental probes of New Physics beyond the Standard Model via the theoretically pristine [Formula: see text] decays and precision tests of electron-muon universality. These studies test the Standard Model at the level of its quantum-loop predictions and have the potential to uncover new interactions beyond the O(1,000 TeV) scale.
Naturalness and the Status of Supersymmetry
Authors: Feng Jonathan L.
Published: March 2011

For decades, the unnaturalness of the weak scale has been the dominant problem motivating new particle physics, and weak-scale supersymmetry has been the dominant proposed solution. This paradigm is now being challenged by a wealth of experimental data. In this review, we begin by recalling the theoretical motivations for weak-scale supersymmetry, including the gauge hierarchy problem, grand unification, and WIMP (weakly interacting massive particle) dark matter, and their implications for superpartner masses. These are set against the leading constraints on supersymmetry from collider searches, the Higgs boson mass, and low-energy constraints on flavor and CP violation. We then critically examine attempts to quantify naturalness in supersymmetry, stressing the many subjective choices that influence the results both quantitatively and qualitatively. Finally, we survey various proposals for natural supersymmetric models, including effective supersymmetry, focus point supersymmetry, compressed supersymmetry, and R-parity-violating supersymmetry, and summarize their key features, current status, and implications for future experiments.
The Impact of Common Gene Variants on the Response of Biomarkers of Cardiovascular Disease (CVD) Risk to Increased Fish Oil Fatty Acids Intakes
Authors: Madden Jacqueline , Williams Christine M. , Calder Philip C. , Lietz Georg , Miles Elizabeth A. , Cordell Heather , Mathers John C. , Minihane Anne Marie
Published: March 2011

The cardioprotective actions of the fish oil (FO)-derived long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been demonstrated, and dose-response relationships have been defined. However, there is a substantial and well-recognized within-population heterogeneity in response to FO, the etiology of which is poorly understood. Genetic variation may influence responsiveness. Here we review the available literature relating to gene variants shown to influence tissue LC n-3 PUFA status and response to FO intervention. From this review we conclude that the available evidence is relatively limited. A number of individual genotype × LC-n3 PUFA × phenotype associations have been described, but few have been investigated in subsequent cohorts or confirmed in independent studies. In the context of a more stratified approach to the provision of dietary advice, there is a need for further research to refine current dietary EPA and DHA recommendations.
Interaction Between Obesity and the Gut Microbiota: Relevance in Nutrition
Authors: Delzenne Nathalie M. , Cani Patrice D.
Published: March 2011

This review examines mechanisms by which the bacteria present in the gut interact with nutrients and host biology to affect the risk of obesity and associated disorders, including diabetes, inflammation, and liver diseases. The bacterial metabolism of nutrients in the gut is able to drive the release of bioactive compounds (including short-chain fatty acids or lipid metabolites), which interact with host cellular targets to control energy metabolism and immunity. Animal and human data demonstrate that phylogenic changes occur in the microbiota composition in obese versus lean individuals; they suggest that the count of specific bacteria is inversely related to fat mass development, diabetes, and/or the low levels of inflammation associated with obesity. The prebiotic and probiotic approaches are presented as interesting research tools to counteract the drop in target bacteria and thereby to estimate their relevance in the improvement of host metabolism.
The Implication of Brown Adipose Tissue for Humans
Authors: Ravussin Eric , Galgani José E.
Published: March 2011

We here discuss the role of brown adipose tissue on energy homeostasis and assess its potential as a target for body weight management. Because of their high number of mitochondria and the presence of uncoupling protein 1, brown fat adipocytes can be termed as energy inefficient for adenosine-5′-triphosphate (ATP) production but energy efficient for heat production. Thus, the energy inefficiency of ATP production, despite high energy substrate oxidation, allows brown adipose tissue to generate heat for body temperature regulation. Whether such thermogenic property also plays a role in body weight regulation is still debated. The recent (re)discovery of brown adipose tissue in human adults and a better understanding of brown adipose tissue development have encouraged the quest for new alternatives to treat obesity since obese individuals seem to have less brown adipose tissue mass/activity than do their lean counterparts. In this review, we discuss the physiological relevance of brown adipose tissue on thermogenesis and its potential usefulness on body weight control in humans.
Zinc in Neurotransmission
Authors: Tóth Katalin
Published: March 2011

A subset of glutamatergic synapses in the central nervous system contains zinc; it is sequestered into the lumen of synaptic vesicles, where it colocalizes with glutamate. Extracellularly applied zinc is known to interact with various postsynaptic receptors and channels; however, the role of endogenous vesicular zinc is still an enigma. The aim of this review is to present the physiology of tonic and phasic zinc modulation of excitatory and inhibitory signals and to discuss the potential role of zinc in synaptic plasticity. Zinc homeostasis is known to be altered under pathological conditions. The importance of the careful investigation of the potential sources of zinc involved in physiological and pathological processes is highlighted.
The Pathogenesis of Mixed-Lineage Leukemia
Authors: Muntean Andrew G. , Hess Jay L.
Published: March 2011

Aggressive leukemias arise in both children and adults as a result of rearrangements to the mixed-lineage leukemia gene (MLL) located on chromosome 11q23. MLL encodes a large histone methyltransferase that directly binds DNA and positively regulates gene transcription, including homeobox (HOX) genes. MLL is involved in chromosomal translocations, partial tandem duplications, and amplifications, all of which result in hematopoietic malignancies due to sustained HOX expression and stalled differentiation. MLL lesions are associated with both acute myeloid leukemia and acute lymphoid leukemia and are usually associated with a relatively poor prognosis despite improved treatment options such as allogeneic hematopoietic stem cell transplantation, which underscores the need for new treatment regimens. Recent advances have begun to reveal the molecular mechanisms that drive MLL-associated leukemias, which, in turn, have provided opportunities for therapeutic development. Here, we discuss the etiology of MLL leukemias and potential directions for future therapy.
Pathology of Demyelinating Diseases
Authors: Popescu Bogdan F.Gh. , Lucchinetti Claudia F.
Published: March 2011

There has been significant progress in our understanding of the pathology and pathogenesis of central nervous system inflammatory demyelinating diseases. Neuropathological studies have provided fundamental new insights into the pathogenesis of these disorders and have led to major advances in our understanding of multiple sclerosis (MS) heterogeneity, the substrate of irreversible progressive disability in MS, the relationship between inflammation and neurodegeneration in MS, the neuroimaging correlates of MS lesions, and the pathogenesis of other central nervous system inflammatory disorders, including neuromyelitis optica, acute disseminated encephalomyelitis, and Balo's concentric sclerosis. Herein, we review the pathological features of these central nervous system inflammatory demyelinating disorders and discuss neuropathological studies that have yielded novel insights into potential mechanisms involved in the formation of the demyelinated lesion.
The Cell Biology of Phagocytosis
Authors: Flannagan Ronald S. , Jaumouillé Valentin , Grinstein Sergio
Published: March 2011

Engulfment and destruction of invading microorganisms by phagocytosis are critical components of the innate immune response. In addition, phagocytosis is also required for the clearance of apoptotic bodies, an essential aspect of tissue homeostasis and remodeling. Here, we summarize the current knowledge of the cellular and molecular basis of phagosome formation and maturation. We discuss the manner in which phagocytosis is subverted by certain pathogens and consider congenital disorders that affect phagocyte function.
Instantiating a Vision: Creating the New Pathology Department at Stanford Medical School
Authors: Korn David
Published: March 2011

This review represents my best effort to recreate and memorialize events that occurred 44 years ago, when I was invited to join the Stanford University faculty to create, essentially de novo, what rapidly became and remains today one of the very best and most admired departments of pathology in the world. That I was able to accomplish this challenging task I attribute to my holding fast to a somewhat inchoate vision of where the science and practice of pathology would go in future decades, a little bit to my gut instincts and innate ability to spot up-and-coming talent, but a lot to circumstances and good fortune in leading me to a small nucleus of wonderful young professionals of outstanding promise who were willing to join me in “betting the house” that, working together, we could pull off this once-in-a-lifetime opportunity—and we did.
Tuberculosis Pathogenesis and Immunity
Authors: Philips Jennifer A. , Ernst Joel D.
Published: March 2011

Despite the development of potentially curative chemotherapy, tuberculosis (TB) continues to cause increasing worldwide morbidity and is a leading cause of human mortality in the developing world. Recent advances in bacterial molecular genetics, immunology, and human genetics have yielded insight into the molecular determinants of virulence, the immune responses that are essential for restricting progressive disease, and the determinants of immunopathology in TB. Despite these advances, a large knowledge gap still exists that limits the development and testing of new interventions, including novel drugs and efficacious vaccines. This review focuses on our current knowledge of TB pathogenesis and immunity that has been derived from in vitro and in vivo studies. In addition, it highlights topics that need to be better understood to provide improved means of controlling TB worldwide.
Biology Without Walls: The Novel Endocrinology of Bone
Authors: Karsenty Gerard , Oury Franck
Published: March 2011

Classical studies of vertebrate physiology have usually been confined to a given organ or cell type. The use of mouse genetics has changed this approach and has rejuvenated the concept of a whole-body study of physiology. One physiological system that has been profoundly influenced by mouse genetics is skeletal physiology. Indeed, genetic approaches have identified several unexpected organs that affect bone physiology. These new links have begun to provide a plausible explanation for the evolutionary involvement of hormones such as leptin with bone physiology. These genetic approaches have also revealed bone as a true endocrine organ capable of regulating energy metabolism and reproduction. Collectively, the body of work discussed below illustrates a new and unconventional role for bone in mammalian physiology.
The Calyx of Held Synapse: From Model Synapse to Auditory Relay
Authors: Borst J. Gerard G. , Soria van Hoeve John
Published: March 2011

The calyx of Held is an axosomatic terminal in the auditory brainstem that has attracted anatomists because of its giant size and physiologists because of its accessibility to patch-clamp recordings. The calyx allows the principal neurons in the medial nucleus of the trapezoid body (MNTB) to provide inhibition that is both well timed and sustained to many other auditory nuclei. The special adaptations that allow the calyx to drive its principal neuron even when frequencies are high include a large number of release sites with low release probability, a large readily releasable pool, fast presynaptic calcium clearance and little delayed release, a large quantal size, and fast AMPA-type glutamate receptors. The transformation from a synapse that is unremarkable except for its giant size into a fast and reliable auditory relay happens in just a few days. In rodents this transformation is essentially ready when hearing starts.
Cell Biology and Pathology of Podocytes
Authors: Greka Anna , Mundel Peter
Published: March 2011

As an integral member of the filtration barrier in the kidney glomerulus, the podocyte is in a unique geographical position: It is exposed to chemical signals from the urinary space (Bowman's capsule), it receives and transmits chemical and mechanical signals to/from the glomerular basement membrane upon which it elaborates, and it receives chemical and mechanical signals from the vascular space with which it also communicates. As with every cell, the ability of the podocyte to receive signals from the surrounding environment and to translate them to the intracellular milieu is dependent largely on molecules residing on the cell membrane. These molecules are the first-line soldiers in the ongoing battle to sense the environment, to respond to friendly signals, and to defend against injurious foes. In this review, we take a membrane biologist's view of the podocyte, examining the many membrane receptors, channels, and other signaling molecules that have been implicated in podocyte biology. Although we attempt to be comprehensive, our goal is not to capture every membrane-mediated pathway but rather to emphasize that this approach may be fruitful in understanding the podocyte and its unique properties.
Epigenetics and Cardiovascular Development
Authors: Chang Ching-Pin , Bruneau Benoit G.
Published: March 2011

The cardiovascular system is broadly composed of the heart, which pumps blood, and the blood vessels, which carry blood to and from tissues of the body. Heart malformations are the most serious common birth defect, affecting at least 2% of newborns and leading to significant morbidity and mortality. Severe heart malformations cause heart failure in fetuses, infants, and children, whereas milder heart defects may not trigger significant heart dysfunction until early or midadulthood. Severe vasculogenesis or angiogenesis defects in embryos are incompatible with life, and anomalous arterial patterning may cause vascular aberrancies that often require surgical treatment. It is therefore important to understand the underlying mechanisms that control cardiovascular development. Understanding developmental mechanisms will also help us design better strategies to regenerate cardiovascular tissues for therapeutic purposes. An important mechanism regulating genes involves the modification of chromatin, the higher-order structure in which DNA is packaged. Recent studies have greatly expanded our understanding of the regulation of cardiovascular development at the chromatin level, including the remodeling of chromatin and the modification of histones. Chromatin-level regulation integrates multiple inputs and coordinates broad gene expression programs. Thus, understanding chromatin-level regulation will allow for a better appreciation of gene regulation as a whole and may set a fundamental basis for cardiovascular disease. This review focuses on how chromatin-remodeling and histone-modifying factors regulate gene expression to control cardiovascular development.
Genetics of Mammalian Reproduction: Modeling the End of the Germline
Authors: Matzuk Martin M. , Burns Kathleen H.
Published: March 2011

Our understanding of reproduction and early embryonic development has directly enabled our manipulation of the mouse genome for tests of gene function in vivo. In this review, we reflect on the 30 years of work that followed this singular accomplishment. We profile murine models that have given us memorable insights into fundamental processes of male and female gametogenesis and the earliest phases of embryonic life reliant on oocyte-transmitted maternal gene products. We highlight intercellular endocrine and paracrine communications essential to gamete development as well as mechanisms essential for passing the genome, with integrity and appropriate epigenetic marks, on to the next generation. Finally, we reflect on the future of reproductive biology: how advances in clinical genetics will provide special opportunities to understand which reproductive processes are affected by genetic lesions and which may allow mutations to originate.
The Control of Male Fertility by Spermatozoan Ion Channels
Authors: Lishko Polina V. , Kirichok Yuriy , Ren Dejian , Navarro Betsy , Chung Jean-Ju , Clapham David E.
Published: March 2011

Ion channels control the sperm ability to fertilize the egg by regulating sperm maturation in the female reproductive tract and by triggering key sperm physiological responses required for successful fertilization such as hyperactivated motility, chemotaxis, and the acrosome reaction. CatSper, a pH-regulated, calcium-selective ion channel, and KSper (Slo3) are core regulators of sperm tail calcium entry and sperm hyperactivated motility. Many other channels had been proposed as regulating sperm activity without direct measurements. With the development of the sperm patch-clamp technique, CatSper and KSper have been confirmed as the primary spermatozoan ion channels. In addition, the voltage-gated proton channel Hv1 has been identified in human sperm tail, and the P2X2 ion channel has been identified in the midpiece of mouse sperm. Mutations and deletions in sperm-specific ion channels affect male fertility in both mice and humans without affecting other physiological functions. The uniqueness of sperm ion channels makes them ideal pharmaceutical targets for contraception. In this review we discuss how ion channels regulate sperm physiology.
Perspectives on Kiss-and-Run: Role in Exocytosis, Endocytosis, and Neurotransmission
Authors: Alabi AbdulRasheed A. , Tsien Richard W.
Published: March 2011

Regulated exocytosis and endocytosis are critical to the function of many intercellular networks, particularly the complex neural circuits underlying mammalian behavior. Kiss-and-run (KR) is an unconventional fusion between secretory vesicles and a target membrane that releases intravesicular content through a transient, nanometer-sized fusion pore. The fusing vesicle retains its gross shape, precluding full integration into the planar membrane, and enough molecular components for rapid retrieval, reacidification, and reuse. KR makes judicious use of finite presynaptic resources, and mounting evidence suggests that it influences synaptic information transfer. Here we detail emerging perspectives on KR and its role in neurotransmission. We additionally formulate a restraining force hypothesis as a plausible mechanistic basis for KR and its physiological modulation in small nerve terminals. Clarification of the mechanism and function of KR has bearing on understanding the kinetic transitions underlying SNARE-mediated fusion, interactions between vesicles and their local environment, and the influence of release dynamics on neural information processing.
Neurotransmitter Corelease: Mechanism and Physiological Role
Authors: Hnasko Thomas S. , Edwards Robert H.
Published: March 2011

Neurotransmitter identity is a defining feature of all neurons because it constrains the type of information they convey, but many neurons release multiple transmitters. Although the physiological role for corelease has remained poorly understood, the vesicular uptake of one transmitter can regulate filling with the other by influencing expression of the H+ electrochemical driving force. In addition, the sorting of vesicular neurotransmitter transporters and other synaptic vesicle proteins into different vesicle pools suggests the potential for distinct modes of release. Corelease thus serves multiple roles in synaptic transmission.
A Conversation with Elwood Jensen
Authors: Moore David D.
Published: March 2011

VIDEO  Please visit http://www.youtube.com/watch?v=OT7HoDpJopA for a video of this interview.
Small-Conductance Ca2+-Activated K+ Channels: Form and Function
Authors: Adelman John P. , Maylie James , Sah Pankaj
Published: March 2011

Small-conductance Ca2+-activated K+ channels (SK channels) are widely expressed throughout the central nervous system. These channels are activated solely by increases in intracellular Ca2+. SK channels are stable macromolecular complexes of the ion pore–forming subunits with calmodulin, which serves as the intrinsic Ca2+ gating subunit, as well as with protein kinase CK2 and protein phosphatase 2A, which modulate Ca2+ sensitivity. Well-known for their roles in regulating somatic excitability in central neurons, SK channels are also expressed in the postsynaptic membrane of glutamatergic synapses, where their activation and regulated trafficking modulate synaptic transmission and the induction and expression of synaptic plasticity, thereby affecting learning and memory. In this review we discuss the molecular and functional properties of SK channels and their physiological roles in central neurons.
The Molecular Control of Meiotic Chromosomal Behavior: Events in Early Meiotic Prophase in Drosophila Oocytes
Authors: Lake Cathleen M. , Hawley R. Scott
Published: March 2011

We review the critical events in early meiotic prophase in Drosophila melanogaster oocytes. We focus on four aspects of this process: the formation of the synaptonemal complex (SC) and its role in maintaining homologous chromosome pairings, the critical roles of the meiosis-specific process of centromere clustering in the formation of a full-length SC, the mechanisms by which preprogrammed double-strand breaks initiate meiotic recombination, and the checkpoints that govern the progression and coordination of these processes. Central to this discussion are the roles that somatic pairing events play in establishing the necessary conditions for proper SC formation, the roles of centromere pairing in synapsis initiation, and the mechanisms by which oocytes detect failures in SC formation and/or recombination. Finally, we correlate what is known in Drosophila oocytes with our understanding of these processes in other systems.
Autophagy in Pulmonary Diseases
Authors: Ryter Stefan W. , Nakahira Kiichi , Haspel Jeffrey A. , Choi Augustine M.K.
Published: March 2011

(Macro)autophagy provides a membrane-dependent mechanism for the sequestration, transport, and lysosomal turnover of subcellular components, including proteins and organelles. In this capacity, autophagy maintains basal cellular homeostasis and healthy organelle populations such as mitochondria. During starvation, autophagy prolongs cell survival by recycling metabolic precursors from intracellular macromolecules. Furthermore, autophagy represents an inducible response to chemical and physical cellular stress. Increasing evidence suggests that autophagy, and its regulatory proteins, may critically influence vital cellular processes such as programmed cell death, cell proliferation, inflammation, and innate immune functions and thereby may play a critical role in the pathogenesis of human disease. The function of autophagy in disease pathogenesis remains unclear and may involve either impaired or accelerated autophagic activity or imbalances in the activation of autophagic proteins. This review examines the roles of autophagy in the pathogenesis of pulmonary diseases, with emphasis on pulmonary vascular disease and acute and chronic lung diseases.
Understanding the Rhythm of Breathing: So Near, Yet So Far
Authors: Feldman Jack L. , Del Negro Christopher A. , Gray Paul A.
Published: March 2011

Breathing is an essential behavior that presents a unique opportunity to understand how the nervous system functions normally, how it balances inherent robustness with a highly regulated lability, how it adapts to both rapidly and slowly changing conditions, and how particular dysfunctions result in disease. We focus on recent advancements related to two essential sites for respiratory rhythmogenesis: (a) the preBötzinger Complex (preBötC) as the site for the generation of inspiratory rhythm and (b) the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG) as the site for the generation of active expiration.
The Rhetoric of the Economy and the Polity
Authors: McCloskey Deirdre Nansen
Published: March 2011

The Great Recession is not the end of capitalism. An innovative economy makes mistakes, but that is not a good reason to regulate it out of its innovations. The innovations—not unions or regulation—have increased real income per head by a factor of 100 in the places that have adopted bourgeois liberty and dignity. An innovative economy is “rhetorical” because, if our economic lives are not frozen by tradition, we must persuade each other what is to be done. “Rhetoric,” of course, is the ancient word for unforced persuasion. Samuelsonian economics, which is the usual kind, ignores words, persuasion, rhetoric. Yet one quarter of national income in a modern economy is earned from “sweet talk.” Discovery, which Austrian economists like Schumpeter and Kirzner emphasize, depends on rhetoric, and the rhetoric depends on ethics. Realist political philosophy, and agency theory in business schools, miss the ethical foundations of our lives.