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Stanford, CA, United States

Leland Stanford Junior University, or more commonly Stanford University, is a private research university in Stanford, California, and one of the world's most prestigious institutions, with the highest undergraduate selectivity and the top position in numerous surveys and measures in the United States.Stanford was founded in 1885 by Leland Stanford, former governor of and U.S. senator from California and leading railroad tycoon, and his wife, Jane Lathrop Stanford, in memory of their only child, Leland Stanford, Jr., who had died of typhoid fever at age 15 the previous year. Stanford was opened on October 1, 1891 as a coeducational and non-denominational institution. Tuition was free until 1920. The university struggled financially after Leland Stanford's 1893 death and after much of the campus was damaged by the 1906 San Francisco earthquake. Following World War II, Provost Frederick Terman supported faculty and graduates' entrepreneurialism to build self-sufficient local industry in what would later be known as Silicon Valley. By 1970, Stanford was home to a linear accelerator, and was one of the original four ARPANET nodes .Stanford is located in northern Silicon Valley near Palo Alto, California. The University's academic departments are organized into seven schools, with several other holdings, such as laboratories and nature reserves, located outside the main campus. Its 8,180-acre campus is one of the largest in the United States. The University is also one of the top fundraising institutions in the country, becoming the first school to raise more than a billion dollars in a year.Stanford's undergraduate program is the most selective in the country with an acceptance rate of 5.07% for the 2018 Class. Students compete in 36 varsity sports, and the University is one of two private institutions in the Division I FBS Pacific-12 Conference. It has gained 105 NCAA team championships, the second-most for a university, 465 individual championships, the most in Division I, and has won the NACDA Directors' Cup, recognizing the university with the best overall athletic team achievement, every year since 1994-1995.Stanford faculty and alumni have founded many companies including Google, Hewlett-Packard, Nike, Sun Microsystems, and Yahoo!, and companies founded by Stanford alumni generate more than $2.7 trillion in annual revenue, equivalent to the 10th-largest economy in the world. Fifty-nine Nobel laureates have been affiliated with the University, and it is the alma mater of 30 living billionaires and 17 astronauts. Stanford has produced a total of 18 Turing Award laureates, the highest in the world for any one institution. It is also one of the leading producers of members of the United States Congress. Wikipedia.


Ryu S.,University of Illinois at Urbana - Champaign | Zhang S.-C.,Stanford University
Physical Review B - Condensed Matter and Materials Physics | Year: 2012

We discuss (2+1)-dimensional topological superconductors with N f left- and right-moving Majorana edge modes and a Z 2×Z 2 symmetry. In the absence of interactions, these phases are distinguished by an integral topological invariant N f. With interactions, the edge state in the case of N f=8 is unstable against interactions, and a Z 2×Z 2 invariant mass gap can be generated dynamically. We show that this phenomenon is closely related to the modular invariance of type II superstring theory. More generally, we show that the global gravitational anomaly of the nonchiral Majorana edge states is the physical manifestation of the bulk topological superconductors classified by Z 8. © 2012 American Physical Society.


We present the fundamentals of multiple-input, multiple-output (MIMO) signal processing for mode-division multiplexing (MDM) in multimode fiber (MMF). As an introduction, we review current long-haul optical transmission systems and how continued traffic growth motivates study of new methods to increase transmission capacity per fiber. We describe the key characteristics of MIMO channels in MMF, contrasting these with wireless MIMO channels. We review MMF channel models, the statistics derived from them, and their implications for MDM system performance and complexity. We show that optimizing performance and complexity requires management of channel parameters-particularly group delay (GD) spread and mode-dependent loss and gain-by design of transmission fibers and optical amplifiers, and by control of mode coupling along the link. We describe a family of fibers optimized for low GD spread, which decreases with an increasing number of modes. We compare the performance and complexity of candidate MIMO signal processing architectures in a representative long-haul system design, and show that programmable frequency-domain equalization (FDE) of chromatic dispersion (CD) and adaptive FDE of modal dispersion (MD) is an attractive combination. We review two major algorithms for adaptive FDE of MD-least mean squares (LMS) and recursive least squares (RLS)-and analyze their complexity, throughput efficiency, and convergence time. We demonstrate that, with careful physical link design and judicious choice of signal processing architectures, it is possible to overcome MIMO signal processing challenges in MDM systems. © 1991-2012 IEEE.


Spahn D.R.,University of Zurich | Goodnough L.T.,Stanford University
The Lancet | Year: 2013

The use of alternatives to allogeneic blood continues to rest on the principles that blood transfusions have inherent risks, associated costs, and affect the blood inventory available for health-care delivery. Increasing evidence exists of a fall in the use of blood because of associated costs and adverse outcomes, and suggests that the challenge for the use of alternatives to blood components will similarly be driven by costs and patient outcomes. Additionally, the risk-benefit profiles of alternatives to blood transfusion such as autologous blood procurement, erythropoiesis-stimulating agents, and haemostatic agents are under investigation. Nevertheless, the inherent risks of blood, along with the continued rise in blood costs are likely to favour the continued development and use of alternatives to blood transfusion. We summarise the current roles of alternatives to blood in the management of medical and surgical anaemias.


Ebitz R.B.,Stanford University | Ebitz R.B.,Duke University | Platt M.L.,Duke University
Neuron | Year: 2015

Whether driving a car, shopping for food, or paying attention in a classroom of boisterous teenagers, it's often hard to maintain focus on goals in theface of distraction. Brain imaging studies in humans implicate the dorsal anterior cingulate cortex (dACC) in regulating the conflict between goals and distractors. Here we show that single dACC neurons signal conflict between task goals and distractors in the rhesus macaque, particularly for biologically relevant social stimuli. For some neurons, task conflict signals predicted subsequent changes in pupil size-a peripheral index of arousal linked to noradrenergic tone-associated with reduced distractor interference. dACC neurons also responded to errors, and these signals predicted adjustments in pupil size. These findings provide the first neurophysiological endorsement of the hypothesis that dACC regulates conflict, in part, via modulation of pupil-linked processes such as arousal. © 2015 Elsevier Inc.


Popp R.L.,Stanford University
Journal of the American College of Cardiology | Year: 2013

Cardiac troponin (cTn) is a biomarker of myocardial damage. New generations of high-sensitivity assays find circulating cTn in virtually all subjects. Multiple studies in various populations and patient groups have found higher levels of cTn to be predictive of future heart failure. The author proposes that initial myocardial damage from various mechanisms may lead to anti-cTn antibodies that participate in ongoing myocardial damage that eventually results in heart failure. © 2013 American College of Cardiology Foundation.


Reed E.J.,Stanford University
Journal of Physical Chemistry C | Year: 2012

The magnitude and role of electronic excitations in shocked energetic materials are studied theoretically using quantum molecular dynamics simulations. Focusing on the detonating primary explosive HN 3 (hydrazoic acid), this work finds that the material transiently exhibits a high level of electronic excitation characterized by carrier densities in excess of 10 21 cm -3, or one electronic excitation for every eight molecules. Electronic excitations enhance the kinetics of chemical decomposition by ∼30%. The electronic heat capacity has a minor impact on the temperatures exhibited, on the order of 100 K. These simulations are performed using the self-consistent charge density functional tight-binding method (SCC-DFTB) combined with a new modification of a multiscale computational scheme for simulation of the coupling between electrons and ions in shocked matter. © 2012 American Chemical Society.


Ingrande J.,Stanford University
British journal of anaesthesia | Year: 2010

Anaesthesiologists must be prepared to deal with pharmacokinetic and pharmacodynamic (PD) differences in morbidly obese individuals. As drug administration based on total body weight can result in overdose, weight-based dosing scalars must be considered. Conversely, administration of drugs based on ideal body weight can result in a sub-therapeutic dose. Changes in cardiac output and alterations in body composition affect the distribution of numerous anaesthetic drugs. With the exception of neuromuscular antagonists, lean body weight is the optimal dosing scalar for most drugs used in anaesthesia including opioids and anaesthetic induction agents. The increased incidence of obstructive sleep apnoea and fat deposition in the pharynx and chest wall places the morbidly obese at increased risk for adverse respiratory events secondary to anaesthetic agents, thus altering the PD properties of these drugs. Awareness of the pharmacology of the commonly used anaesthetic agents including induction agents, opioids, inhalation agents and neuromuscular blockers is necessary for safe and effective care of morbidly obese patients.


Boyko A.R.,Stanford University
PLoS biology | Year: 2010

Domestic dogs exhibit tremendous phenotypic diversity, including a greater variation in body size than any other terrestrial mammal. Here, we generate a high density map of canine genetic variation by genotyping 915 dogs from 80 domestic dog breeds, 83 wild canids, and 10 outbred African shelter dogs across 60,968 single-nucleotide polymorphisms (SNPs). Coupling this genomic resource with external measurements from breed standards and individuals as well as skeletal measurements from museum specimens, we identify 51 regions of the dog genome associated with phenotypic variation among breeds in 57 traits. The complex traits include average breed body size and external body dimensions and cranial, dental, and long bone shape and size with and without allometric scaling. In contrast to the results from association mapping of quantitative traits in humans and domesticated plants, we find that across dog breeds, a small number of quantitative trait loci (< or = 3) explain the majority of phenotypic variation for most of the traits we studied. In addition, many genomic regions show signatures of recent selection, with most of the highly differentiated regions being associated with breed-defining traits such as body size, coat characteristics, and ear floppiness. Our results demonstrate the efficacy of mapping multiple traits in the domestic dog using a database of genotyped individuals and highlight the important role human-directed selection has played in altering the genetic architecture of key traits in this important species.


Karasov T.,Stanford University
PLoS genetics | Year: 2010

Adaptation in eukaryotes is generally assumed to be mutation-limited because of small effective population sizes. This view is difficult to reconcile, however, with the observation that adaptation to anthropogenic changes, such as the introduction of pesticides, can occur very rapidly. Here we investigate adaptation at a key insecticide resistance locus (Ace) in Drosophila melanogaster and show that multiple simple and complex resistance alleles evolved quickly and repeatedly within individual populations. Our results imply that the current effective population size of modern D. melanogaster populations is likely to be substantially larger (> or = 100-fold) than commonly believed. This discrepancy arises because estimates of the effective population size are generally derived from levels of standing variation and thus reveal long-term population dynamics dominated by sharp--even if infrequent--bottlenecks. The short-term effective population sizes relevant for strong adaptation, on the other hand, might be much closer to census population sizes. Adaptation in Drosophila may therefore not be limited by waiting for mutations at single sites, and complex adaptive alleles can be generated quickly without fixation of intermediate states. Adaptive events should also commonly involve the simultaneous rise in frequency of independently generated adaptive mutations. These so-called soft sweeps have very distinct effects on the linked neutral polymorphisms compared to the standard hard sweeps in mutation-limited scenarios. Methods for the mapping of adaptive mutations or association mapping of evolutionarily relevant mutations may thus need to be reconsidered.


Anninos D.,Stanford University
International Journal of Modern Physics A | Year: 2012

We discuss some of the issues arising when considering asymptotically de Sitter spacetimes and attempts to address them. Our development begins at the classical level where several initial value problems are discussed and ends with several proposals for holography in asymptotically de Sitter space-times. Throughout the paper we give a review of some basic notions such as the geometry of Schwarzschild-de Sitter black hole, the Nariai limit and quantum field theory in a fixed de Sitter background. We also briefly discuss some semiclassical aspects such as the nucleation of black holes and the Hartle-Hawking wavefunctional. We end by giving an overview of some open questions. An emphasis is placed on the differences between a static patch observer confined to live in a thermal cavity and the metaobserver who has access to a finite region of the future boundary. © 2012 World Scientific Publishing Company.


Storm B.C.,University of Illinois at Chicago | Levy B.J.,Stanford University
Memory and Cognition | Year: 2012

Remembering and forgetting reflect fundamentally interdependent processes in human memory (Bjork, 2011). This interdependency is particularly apparent in research on retrieval-induced forgetting, which has shown that retrieving a subset of information can cause the forgetting of other information (Anderson et al. Journal of Experimental Psychology: Learning, Memory, & Cognition 20:1063-1087, 1994). According to one prominent theoretical account, retrieval-induced forgetting is caused by an inhibitory process that acts to resolve competition during retrieval. Specifically, when cues activate competing, contextually inappropriate responses, those responses are claimed to be inhibited in order to facilitate the retrieval of target responses (Anderson Journal of Memory and Language 49: 415-445, 2003; Levy & Anderson Trends in Cognitive Sciences 6: 299-305, 2002; Storm, 2011b). Interest in retrieval-induced forgetting has grown steadily over the past two decades. In fact, a search of the abstracts at the 5th International Conference on Memory (ICOM, York University, 2011) revealed 40 presentations specifically mentioning "retrieval-induced forgetting," and nearly twice that number referring to the concept of inhibition. Clearly, researchers are interested in the empirical phenomenon of retrieval-induced forgetting, and inhibition is gaining increasing attention as a mechanism involved in memory. The goal of the present progress report is to critically review the inhibitory account of retrieval-induced forgetting and to provide direction so that future research can have a more meaningful impact on our understanding of human memory. © 2012 Psychonomic Society, Inc.


Kane D.M.,Stanford University
Proceedings - Annual IEEE Symposium on Foundations of Computer Science, FOCS | Year: 2012

We prove a structural result for degree-d polynomials. In particular, we show that any degree-d polynomial, p can be approximated by another polynomial, p0, which can be decomposed as some function of polynomials q 1,..., qm with qi normalized and m = O d(1), so that if X is a Gaussian random variable, the probability distribution on (q1(X),..., qm(X)) does not have too much mass in any small box. Using this result, we prove improved versions of a number of results about polynomial threshold functions, including producing better pseudorandom generators, obtaining a better invariance principle, and proving improved bounds on noise sensitivity. © 2012 IEEE.


Long intergenic noncoding RNAs (lincRNAs) are derived from thousands of loci in mammalian genomes and are frequently enriched in transposable elements (TEs). Although families of TE-derived lincRNAs have recently been implicated in the regulation of pluripotency, little is known of the specific functions of individual family members. Here we characterize three new individual TE-derived human lincRNAs, human pluripotency-associated transcripts 2, 3 and 5 (HPAT2, HPAT3 and HPAT5). Loss-of-function experiments indicate that HPAT2, HPAT3 and HPAT5 function in preimplantation embryo development to modulate the acquisition of pluripotency and the formation of the inner cell mass. CRISPR-mediated disruption of the genes for these lincRNAs in pluripotent stem cells, followed by whole-transcriptome analysis, identifies HPAT5 as a key component of the pluripotency network. Protein binding and reporter-based assays further demonstrate that HPAT5 interacts with the let-7 microRNA family. Our results indicate that unique individual members of large primate-specific lincRNA families modulate gene expression during development and differentiation to reinforce cell fate. © 2015 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.


Craig H.A.,Stanford University
Astrophysical Journal | Year: 2014

The traditional, geometrical rotating vector model (RVM) has proved particularly poor at capturing the polarization sweeps of the young energetic and millisecond pulsars detected by Fermi. We augment this model by including finite altitude effects using a swept back vacuum dipole geometry. By further including the effects of orthogonal mode jumps, multiple emission altitudes, open zone growth via y-point lowering, and interstellar scattering, we show that a wide range of departures from RVM can be modeled well while retaining a geometrical picture. We illustrate these effects by fitting six Fermi-detected pulsars (J0023+0923, J1024-0719, J1744-1134, J1057-5226, J1420-6048, and J2124-3358) and we describe how such modeling can improve our understanding of their emission geometry. © 2014. The American Astronomical Society. All rights reserved..


Memoli F.,Stanford University
Foundations of Computational Mathematics | Year: 2011

This paper discusses certain modifications of the ideas concerning the Gromov-Hausdorff distance which have the goal of modeling and tackling the practical problems of object matching and comparison. Objects are viewed as metric measure spaces, and based on ideas from mass transportation, a Gromov-Wasserstein type of distance between objects is defined. This reformulation yields a distance between objects which is more amenable to practical computations but retains all the desirable theoretical underpinnings. The theoretical properties of this new notion of distance are studied, and it is established that it provides a strict metric on the collection of isomorphism classes of metric measure spaces. Furthermore, the topology generated by this metric is studied, and sufficient conditions for the pre-compactness of families of metric measure spaces are identified. A second goal of this paper is to establish links to several other practical methods proposed in the literature for comparing/matching shapes in precise terms. This is done by proving explicit lower bounds for the proposed distance that involve many of the invariants previously reported by researchers. These lower bounds can be computed in polynomial time. The numerical implementations of the ideas are discussed and computational examples are presented. © 2011 SFoCM.


Pande V.S.,Stanford University
Physical Review Letters | Year: 2010

We present a simple model of protein folding dynamics that captures key qualitative elements recently seen in all-atom simulations. The goals of this theory are to serve as a simple formalism for gaining deeper insight into the physical properties seen in detailed simulations as well as to serve as a model to easily compare why these simulations suggest a different kinetic mechanism than previous simple models. Specifically, we find that non-native contacts play a key role in determining the mechanism, which can shift dramatically as the energetic strength of non-native interactions is changed. For proteinlike non-native interactions, our model finds that the native state is a kinetic hub, connecting the strength of relevant interactions directly to the nature of folding kinetics. © 2010 The American Physical Society.


Cambier C.J.,University of Washington | Falkow S.,Stanford University | Ramakrishnan L.,University of Washington | Ramakrishnan L.,University of Cambridge
Cell | Year: 2014

Tuberculosis, an ancient disease of mankind, remains one of the major infectious causes of human death. We examine newly discovered facets of tuberculosis pathogenesis and explore the evolution of its causative organism Mycobacterium tuberculosis from soil dweller to human pathogen. M. tuberculosis has coevolved with the human host to evade and exploit host macrophages and other immune cells in multiple ways. Though the host can often clear infection, the organism can cause transmissible disease in enough individuals to sustain itself. Tuberculosis is a near-perfect paradigm of a host-pathogen relationship, and that may be the challenge to the development of new therapies for its eradication. © 2014 Elsevier Inc. All rights reserved.


Denny M.,Stanford University | Benedetti-Cecchi L.,University of Pisa
Annual Review of Ecology, Evolution, and Systematics | Year: 2012

Ecologists have long grappled with the problem of scaling up from tractable, small-scale observations and experiments to the prediction of large-scale patterns. Although there are multiple approaches to this formidable task, there is a common underpinning in the formulation, testing, and use of mechanistic response functions to describe how phenomena interact across scales. Here, we review the principles of response functions to illustrate how they provide a means to guide research, extrapolate beyond measured data, and simplify our conceptual grasp of reality. We illustrate these principles with examples of mechanistic approaches ranging from explorations of the ecological niche, random walks, and macrophysiology to theories dealing with scale transition, self-organization, and the prediction of extremes. © 2012 by Annual Reviews. All rights reserved.


Williams V.V.,University of California at Berkeley | Williams V.V.,Stanford University
Proceedings of the Annual ACM Symposium on Theory of Computing | Year: 2012

We develop an automated approach for designing matrix multiplication algorithms based on constructions similar to the Coppersmith-Winograd construction. Using this approach we obtain a new improved bound on the matrix multiplication exponent ω < 2.3727. © 2012 ACM.


Henriksen L.,Stanford University
Tobacco Control | Year: 2012

Evidence of the causal role of marketing in the tobacco epidemic and the advent of the WHO Framework Convention on Tobacco Control have inspired more than half the countries in the world to ban some forms of tobacco marketing. This paper briefly describes the ways in which cigarette marketing is restricted and the tobacco industry's efforts to subvert restrictions. It reviews what is known about the impact of marketing regulations on smoking by adults and adolescents. It also addresses what little is known about the impact of marketing bans in relation to concurrent population-level interventions, such as price controls, anti-tobacco media campaigns and smoke-free laws. Point of sale is the least regulated channel and research is needed to address the immediate and long-term consequences of policies to ban retail advertising and pack displays. Comprehensive marketing restrictions require a global ban on all forms of promotion, elimination of packaging and price as marketing tools, and limitations on the quantity, type and location of tobacco retailers.


Roughgarden T.,Stanford University
Proceedings of the ACM Conference on Electronic Commerce | Year: 2012

We define smooth games of incomplete information. We prove an "extension theorem" for such games: price of anarchy bounds for pure Nash equilibria for all induced full-information games extend automatically, without quantitative degradation, to all mixed-strategy Bayes-Nash equilibria with respect to a product prior distribution over players' preferences. We also note that, for Bayes-Nash equilibria in games with correlated player preferences, there is no general extension theorem for smooth games. We give several applications of our definition and extension theorem. First, we show that many games of incomplete information for which the price of anarchy has been studied are smooth in our sense. Thus our extension theorem unifies much of the known work on the price of anarchy in games of incomplete information. Second, we use our extension theorem to prove new bounds on the price of anarchy of Bayes-Nash equilibria in congestion games with incomplete information. © 2012 ACM.


Zhandry M.,Stanford University
Proceedings - Annual IEEE Symposium on Foundations of Computer Science, FOCS | Year: 2012

In the presence of a quantum adversary, there are two possible definitions of security for a pseudorandom function. The first, which we call standard-security, allows the adversary to be quantum, but requires queries to the function to be classical. The second, quantum-security, allows the adversary to query the function on a quantum superposition of inputs, thereby giving the adversary a superposition of the values of the function at many inputs at once. Existing techniques for proving the security of pseudorandom functions fail when the adversary can make quantum queries. We give the first quantum-security proofs for pseudorandom functions by showing that some classical constructions of pseudorandom functions are quantum-secure. Namely, we show that the standard constructions of pseudorandom functions from pseudorandom generators or pseudorandom synthesizers are secure, even when the adversary can make quantum queries. We also show that a direct construction from lattices is quantum-secure. To prove security, we develop new tools to prove the indistinguishability of distributions under quantum queries. In light of these positive results, one might hope that all standard-secure pseudorandom functions are quantum-secure. To the contrary, we show a separation: under the assumption that standard-secure pseudorandom functions exist, there are pseudorandom functions secure against quantum adversaries making classical queries, but insecure once the adversary can make quantum queries. © 2012 IEEE.


Greenberg P.L.,Stanford University
JNCCN Journal of the National Comprehensive Cancer Network | Year: 2013

The myelodysplastic syndromes (MDS) consist of a heterogeneous spectrum of myeloid clonal hemopathies. The Revised International Prognostic Scoring System (IPSS-R) provides a recently refined method for clinically evaluating the prognosis of patients with MDS. Molecular profiling has recently generated extensive data describing critical hematopoietic molecular and biologic derangements contributing to clinical phenotypes. Current molecular insights have demonstrated roles of specific somatic gene mutations in the development and clinical outcomes of MDS, including their propensity to progress to more aggressive stages, such as acute myeloid leukemia. This article focuses on these recently reported clinical and underlying pathogenetic findings. The discussion provides a synthesis of the prognostic clinical, molecular, and biologic abnormalities intrinsic to the aberrant marrow hematopoietic and microenvironmental influences in MDS. Copyright © 2013 by the National Comprehensive Cancer Network. All rights reserved.


Prober C.G.,Stanford University | Khan S.,Khan Academy
Academic Medicine | Year: 2013

The authors propose a new model for medical education based on the flipped classroom design. In this model, students would access brief (~10 minute) online videos to learn new concepts on their own time. The content could be viewed by the students as many times as necessary to master the knowledge in preparation for classroom time facilitated by expert faculty leading dynamic, interactive sessions where students can apply their newly mastered knowledge.The authors argue that the modern digitally empowered learner, the unremitting expansion of biomedical knowledge, and the increasing specialization within the practice of medicine drive the need to reimagine medical education. The changes that they propose emphasize the need to define a core curriculum that can meet learners where they are in a digitally oriented world, enhance the relevance and retention of knowledge through rich interactive exercises, and facilitate in-depth learning fueled by individual students' aptitude and passion. The creation and adoption of this model would be meaningfully enhanced by cooperative efforts across medical schools.


Fisher R.S.,Stanford University
Annals of Neurology | Year: 2012

Therapeutic devices provide new options for treating drug-resistant epilepsy. These devices act by a variety of mechanisms to modulate neuronal activity. Only vagus nerve stimulation (VNS), which continues to develop new technology, is approved for use in the United States. Deep brain stimulation of anterior thalamus for partial epilepsy recently was approved in Europe and several other countries. Responsive neurostimulation, which delivers stimuli to 1 or 2 seizure foci in response to a detected seizure, recently completed a successful multicenter trial. Several other trials of brain stimulation are in planning or underway. Transcutaneous magnetic stimulation (TMS) may provide a noninvasive method to stimulate cortex. Controlled studies of TMS are split on efficacy, which may depend on whether a seizure focus is near a possible region for stimulation. Seizure detection devices in the form of shake detectors via portable accelerometers can provide notification of an ongoing tonic-clonic seizure, or peace of mind in the absence of notification. Prediction of seizures from various aspects of electroencephalography (EEG) is in early stages. Prediction appears to be possible in a subpopulation of people with refractory seizures, and a clinical trial of an implantable prediction device is underway. Cooling of neocortex or hippocampus reversibly can attenuate epileptiform EEG activity and seizures, but engineering problems remain in its implementation. Optogenetics is a new technique that can control excitability of specific populations of neurons with light. Inhibition of epileptiform activity has been demonstrated in hippocampal slices, but use in humans will require more work. In general, devices provide useful palliation for otherwise uncontrollable seizures, but with a different risk profile than with most drugs. Optimizing the place of devices in therapy for epilepsy will require further development and clinical experience. Copyright © 2011 American Neurological Association.


Paro J.A.M.,Stanford University
Annals of Plastic Surgery | Year: 2015

INTRODUCTION: Professionals in a variety of specialties use video-based review as a method of constant self-evaluation. We believe critical self-reflection will allow a surgical trainee to identify methods for improvement throughout residency and beyond. We have used 2 new popular technologies to evaluate their role in accomplishing the previously mentioned objectives.METHODS: Our group investigated Google Glass and GoPro cameras. Medical students, residents, and faculty were invited to wear each of the devices during a scheduled operation. After the case, each participant was asked to comment on a number of features of the device including comfort, level of distraction/interference with operating, ease of video acquisition, and battery life. Software and hardware specifications were compiled and compared by the authors. A “proof-of-concept” was also performed using the video-conferencing abilities of Google Glass to perform a simulated flap check.RESULTS: The technical specifications of the 2 cameras favor GoPro over Google Glass. Glass records in 720p with 5-MP still shots, and the GoPro records in 1080p with 12-MP still shots. Our tests of battery life showed more than 2 hours of continuous video with GoPro, and less than 1 hour for Glass. Favorable features of Google Glass included comfort and relative ease of use; they could not comfortably wear loupes while operating, and would have preferred longer hands-free video recording. The GoPro was slightly more cumbersome and required a nonsterile team member to activate all pictures or video; however, loupes could be worn. Google Glass was successfully used in the hospital for a simulated flap check, with overall audio and video being transmitted—fine detail was lost, however.CONCLUSIONS: There are benefits and limitations to each of the devices tested. Google Glass is in its infancy and may gain a larger intraoperative role in the future. We plan to use Glass as a way for trainees to easily acquire intraoperative footage as a means to “review tape” and will use the GoPro to amass a video library of commonly performed operations. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.


Tetrodotoxin (TTX) is widely distributed in marine taxa, however in terrestrial taxa it is limited to a single class of vertebrates (Amphibia). Tetrodotoxin present in the skin and eggs of TTX-bearing amphibians primarily serves as an antipredator defense and these taxa have provided excellent models for the study of the evolution and chemical ecology of TTX toxicity. The origin of TTX present in terrestrial vertebrates is controversial. In marine organisms the accepted hypothesis is that the TTX present in metazoans results from either dietary uptake of bacterially produced TTX or symbiosis with TTX producing bacteria, but this hypothesis may not be applicable to TTX-bearing amphibians. Here I review the taxonomic distribution and evolutionary ecology of TTX in amphibians with some attention to the origin of TTX present in these taxa. © 2010 by the authors; licensee Molecular Diversity Preservation International.


Shrager J.B.,Stanford University
Annals of Thoracic Surgery | Year: 2010

Endobronchial ultrasound (EBUS-TBNA) is emerging as an alternative to mediastinoscopy for mediastinal lymph node evaluation in non-small cell lung cancer. It remains controversial whether EBUS-TBNA is as accurate as mediastinoscopy. Sensitivity appears similar to mediastinoscopy with enlarged nodes, but lower with normal-sized nodes. The false negative rate appears higher than with mediastinoscopy, so nonmalignant EBUS results may be unreliable. Two flawed studies examining costs identify a very small cost benefit to EBUS, which we will question herein. There are scenarios in which EBUS is preferable to mediastinoscopy. However, for routine staging of the upper mediastinum in non-small cell lung cancer, the benefits of EBUS over mediastinoscopy remain unproven. © 2010 The Society of Thoracic Surgeons.


Makridis C.,Stanford University
Environmental Science and Policy | Year: 2013

In the absence of structural incentives that price negative externalities, renewable energies rely primarily on investors' expectations of future performance to succeed in the marketplace. While there have been many disparate regional analyses of the prospects for clean energy, in particular wind, there is yet a cohesive framework for thinking about global interactions. Using data from the National Renewable Energy Laboratory (NREL), the article addresses three shortcomings in empirical renewable policy literature. First, the article briefly synthesizes the current state of the offshore wind literature. Second, the article develops a linear programming model to assess the relative prospects of offshore wind energy throughout seven world regions: Organization for Economic Co-operation and Development (OECD) North America, OECD Europe, OECD Asia and Eurasia, Non-OECD Europe and Eurasia, Non-OECD Asia, Africa, and Central & South America. Third, the article applies the Interactive Agency Model (IAM) as a systems-level framework for thinking about offshore wind development in the presence of social, economic, and institutional attributes. Results suggest that OECD Asia and Eurasia, OECD Europe, and non-OECD Europe and Eurasia, respectively, have the highest potential for offshore wind sector performance. Despite simplifying assumptions, this article presents one of the first evaluations of global offshore wind energy potential for policymakers and industry to consider in crafting future renewable energy investment decisions. © 2013 Elsevier Ltd.


Jacobson M.Z.,Stanford University | Delucchi M.A.,University of California at Davis
Energy Policy | Year: 2011

Climate change, pollution, and energy insecurity are among the greatest problems of our time. Addressing them requires major changes in our energy infrastructure. Here, we analyze the feasibility of providing worldwide energy for all purposes (electric power, transportation, heating/cooling, etc.) from wind, water, and sunlight (WWS). In Part I, we discuss WWS energy system characteristics, current and future energy demand, availability of WWS resources, numbers of WWS devices, and area and material requirements. In Part II, we address variability, economics, and policy of WWS energy. We estimate that ~3,800,000 5 MW wind turbines, ~49,000 300. MW concentrated solar plants, ~40,000 300. MW solar PV power plants, ~1.7 billion 3 kW rooftop PV systems, ~5350 100. MW geothermal power plants, ~270 new 1300. MW hydroelectric power plants, ~720,000 0.75. MW wave devices, and ~490,000 1. MW tidal turbines can power a 2030 WWS world that uses electricity and electrolytic hydrogen for all purposes. Such a WWS infrastructure reduces world power demand by 30% and requires only ~0.41% and ~0.59% more of the world's land for footprint and spacing, respectively. We suggest producing all new energy with WWS by 2030 and replacing the pre-existing energy by 2050. Barriers to the plan are primarily social and political, not technological or economic. The energy cost in a WWS world should be similar to that today. © 2010 Elsevier Ltd.


Benitz W.E.,Stanford University
Clinics in Perinatology | Year: 2010

Early-onset sepsis remains a major diagnostic problem in neonatal medicine. Definitive diagnosis depends on cultures of blood or other normally sterile body fluids. Abnormal hematological counts, acute-phase reactants, and inflammatory cytokines are neither sensitive nor specific, especially at the onset of illness. Combinations of measurements improve diagnostic test performance, but the optimal selection of analytes has not been determined. The best-established use of these laboratory tests is for retrospective determination that an infant was not infected, based on failure to mount an acute-phase response over the following 24 to 48 hours. © 2010 Elsevier Inc.


Kitanidis P.K.,Stanford University
Advances in Water Resources | Year: 2012

Inverse problems, when only hard data are considered, are mathematically ill-posed because they have multiple solutions and are sensitive to small changes in the data. An example is the determination of hydraulic conductivity from head data. Bayesian methods provide a general stochastic framework within which one can solve such problems. The approach allows one to combine hard data with other information in order to explore the range of possible solutions. We consider the role of generalized (also known as improper) probability distributions within this framework. These distributions are very useful because they represent information parsimoniously (with simple equations and few parameters) and are ideal in terms of representing situations with limited information. They are particularly useful in introducing prior information about the dependent variables of the inverse problem and structural parameters that describe the degree of continuity or smoothness of dependent variables. Additionally, they are very useful from a computational perspective because they can lead to formulations with special structure, such as with high degree of sparsity or structure that can be exploited through high performance computing algorithms. We examine in the context of a simple example some of the consequences of using different generalized priors. © 2011 Elsevier Ltd.


Membrane fusion is essential to both cellular vesicle trafficking and infection by enveloped viruses. While the fusion protein assemblies that catalyze fusion are readily identifiable, the specific activities of the proteins involved and nature of the membrane changes they induce remain unknown. Here, we use many atomic-resolution simulations of vesicle fusion to examine the molecular mechanisms for fusion in detail. We employ committor analysis for these million-atom vesicle fusion simulations to identify a transition state for fusion stalk formation. In our simulations, this transition state occurs when the bulk properties of each lipid bilayer remain in a lamellar state but a few hydrophobic tails bulge into the hydrophilic interface layer and make contact to nucleate a stalk. Additional simulations of influenza fusion peptides in lipid bilayers show that the peptides promote similar local protrusion of lipid tails. Comparing these two sets of simulations, we obtain a common set of structural changes between the transition state for stalk formation and the local environment of peptides known to catalyze fusion. Our results thus suggest that the specific molecular properties of individual lipids are highly important to vesicle fusion and yield an explicit structural model that could help explain the mechanism of catalysis by fusion proteins.


Pinsky P.M.,Stanford University
Investigative Ophthalmology and Visual Science | Year: 2014

Purpose. Intrastromal inlays for refractive correction of presbyopia are being adopted into clinical practice. An important concern is the effect of the inlay on the long-term health of the cornea due to disturbances in the concentration profiles of metabolic species. A three-dimensional metabolic model for the cornea is employed to investigate oxygen, glucose, and lactate ion transport in the cornea and to estimate changes in species concentrations induced by the introduction of a hydrogel inlay. Methods. A reaction-diffusion metabolic model, appropriate for highly oxygen-permeable hydrogel inlays, is used to describe cellular consumption of oxygen and glucose and production of lactic acid. A three-layer corneal geometry (epithelium, stroma, endothelium is employed with a hydrogel inlay placed under a lamellar flap. The model is solved numerically by the finite element method. Results. For a commercially available hydrogel material with a relative inlay diffusivity of 43.5%, maximum glucose depletion and lactate ion accumulation occur anterior to the inlay and both are less than 3%. Below 20% relative diffusivity, glucose depletion and lactate ion accumulation increase exponentially. Glucose depletion increases slightly with increasing depth of inlay placement. Conclusions. The flux of metabolic species is modified by an inlay, depending on the inlay relative diffusivity. For commercially available hydrogel materials and a typical inlay design, predicted changes in species concentrations are small when compared to the variation of concentrations across the normal cornea. In general, glucose depletion and lactate ion accumulation are highly sensitive to inlay diffusivity and somewhat insensitive to inlay depth. © 2014 The Association for Research in Vision and Ophthalmology, Inc.


Haber S.N.,University of Rochester | Knutson B.,Stanford University
Neuropsychopharmacology | Year: 2010

Although cells in many brain regions respond to reward, the cortical-basal ganglia circuit is at the heart of the reward system. The key structures in this network are the anterior cingulate cortex, the orbital prefrontal cortex, the ventral striatum, the ventral pallidum, and the midbrain dopamine neurons. In addition, other structures, including the dorsal prefrontal cortex, amygdala, hippocampus, thalamus, and lateral habenular nucleus, and specific brainstem structures such as the pedunculopontine nucleus, and the raphe nucleus, are key components in regulating the reward circuit. Connectivity between these areas forms a complex neural network that mediates different aspects of reward processing. Advances in neuroimaging techniques allow better spatial and temporal resolution. These studies now demonstrate that human functional and structural imaging results map increasingly close to primate anatomy. © 2010 Nature Publishing Group All rights reserved.


We present a method for rapid, sequence-specific detection of multiple DNA fragments by integrating isotachophoresis (ITP) based DNA hybridization and capillary zone electrophoresis (CZE) using bidirectional ITP. Our method leverages the high preconcentration ability of ITP to accelerate slow, second-order DNA hybridization kinetics, and the high resolving power of CZE to separate and identify reaction products. We demonstrate the speed and sensitivity of our assay by detecting 5 pM, 39 nt ssDNA target within 3 min, using a molecular beacon probe. We also demonstrate the feasibility of our assay for multiplexed detection of multiple-length ssDNA targets by simultaneously detecting 39 and 90 nt ssDNA targets.


Van Den Bedem H.,Stanford University | Van Den Bedem H.,SLAC | Fraser J.S.,University of California at San Francisco
Nature Methods | Year: 2015

Biomolecules adopt a dynamic ensemble of conformations, each with the potential to interact with binding partners or perform the chemical reactions required for a multitude of cellular functions. Recent advances in X-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy and other techniques are helping us realize the dream of seeing - in atomic detail - how different parts of biomolecules shift between functional substates using concerted motions. Integrative structural biology has advanced our understanding of the formation of large macromolecular complexes and how their components interact in assemblies by leveraging data from many low-resolution methods. Here, we review the growing opportunities for integrative, dynamic structural biology at the atomic scale, contending there is increasing synergistic potential between X-ray crystallography, NMR and computer simulations to reveal a structural basis for protein conformational dynamics at high resolution.


Chang K.D.,Stanford University
The Journal of clinical psychiatry | Year: 2010

The presentation of bipolar disorder in children and adolescents may vary from its presentation in adults. Rage, irritability, and long episodes are common manifestations of mania in young people with bipolar disorder. Frequent comorbid disorders in young patients include ADHD and anxiety disorders. Prodromal and subsyndromal states of bipolar disorder, such as bipolar disorder NOS, present opportunities for early intervention and prevention. Early recognition and intervention are crucial, because untreated pediatric bipolar disorder becomes chronic, has a high incidence of relapse, and has a poor prognosis. Copyright 2010 Physicians Postgraduate Press, Inc.


Kesler S.R.,Stanford University
Neurobiology of Aging | Year: 2014

Chronic medical conditions and/or their treatments may interact with aging to alter or even accelerate brain senescence. Adult onset cancer, for example, is a disease associated with advanced aging and emerging evidence suggests a profile of subtle but diffuse brain injury following cancer chemotherapy. Breast cancer is currently the primary model for studying these "chemobrain" effects. Given the widespread changes to brain structure and function as well as the common impairment of integrated cognitive skills observed following breast cancer chemotherapy, it is likely that large-scale brain networks are involved. Default mode network (DMN) is a strong candidate considering its preferential vulnerability to aging and sensitivity to toxicity and disease states. Additionally, chemotherapy is associated with several physiological effects including increased inflammation and oxidative stress that are believed to elevate toxicity in the DMN. Biomarkers of DMN connectivity could aid in the development of treatments for chemotherapy-related cognitive decline. © 2014 Elsevier Inc.


Motter A.E.,Northwestern University | Myers S.A.,Stanford University | Anghel M.,Los Alamos National Laboratory | Nishikawa T.,Northwestern University
Nature Physics | Year: 2013

An imperative condition for the functioning of a power-grid network is that its power generators remain synchronized. Disturbances can prompt desynchronization, which is a process that has been involved in large power outages. Here we derive a condition under which the desired synchronous state of a power grid is stable, and use this condition to identify tunable parameters of the generators that are determinants of spontaneous synchronization. Our analysis gives rise to an approach to specify parameter assignments that can enhance synchronization of any given network, which we demonstrate for a selection of both test systems and real power grids. These findings may be used to optimize stability and help devise new control schemes, thus offering an additional layer of protection and contributing to the development of smart grids that can recover from failures in real time. © 2013 Macmillan Publishers Limited. All rights reserved.


Lembke A.,Stanford University
American Journal of Drug and Alcohol Abuse | Year: 2012

Background: The Self-Medication Hypothesis (SMH) of addictive disorders as articulated by Edward Khantzian in his seminal 1985 paper postulates that individuals with psychiatric disorders use substances to relieve psychiatric symptoms and that this pattern of usage predisposes them to addiction. Khantzian's SMH also postulates that the preferred substance is not random, but is based on the unique pharmacological properties of the substance. For example, an individual with attention deficit disorder would prefer amphetamines to alcohol, due to its stimulating properties, whereas an individual with anxiety would prefer alcohol to amphetamines, due to its anxiolytic properties. Finally, Khantzian's SMH implies that treating the underlying psychiatric disorder will improve or resolve the problems of addiction. Aims and Results: A review of the scientific literature demonstrates a striking lack of robust evidence in support of the SMH as put forth by Khantzian. Conclusions and Scientific Significance: Nonetheless, the SMH has had a profound influence on medical and lay culture, as well as clinical care. Although originally formulated as a compassionate explanation for addiction in those with psychiatric disorders, the SMH does not provide, as originally intended, a "useful rationale" for guiding treatment and instead has led to under-recognition and under-treatment of substance use disorders. © 2012 Informa Healthcare USA, Inc.


Comiter C.V.,Stanford University
Current Opinion in Urology | Year: 2010

PURPOSE OF REVIEW: Surgery is the mainstay for treating postprostatectomy stress urinary incontinence. Although the artificial urinary sphincter (AUS) remains a popular treatment option, a decade worth of innovations have expanded the role of male sling surgery. RECENT FINDINGS: AUS surgery has an approximately 80-85% success rate, regardless of the degree of incontinence. The bone-anchored male sling has a similar success rate in men with mild-to-moderate leakage, but is less efficacious in those with severe incontinence. A transobturator approach has simplified the procedure, but appears best suited for men with milder degrees of incontinence. A new quadratically fixed sling that achieves a broader area of urethral compression by combining a transobturator and suprapubic approach has recently been introduced, with the aim of greater efficacy, while maintaining the low morbidity of sling surgery. SUMMARY: The male sling and AUS are equally efficacious for the treatment of mild-to-moderate stress urinary incontinence. The sling appears to have a lower risk of infection, erosion, and urethral atrophy. The AUS remains the most efficacious treatment for severe stress urinary incontinence and for radiated patients. Recent changes in male sling surgery may improve efficacy in men with more severe incontinence. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Buchwald C.,Woods Hole Oceanographic Institution | Casciotti K.L.,Stanford University
Nature Geoscience | Year: 2013

Nitrite is a central intermediate in the marine nitrogen cycle, and is generally found at low concentrations in the ocean. However, nitrite accumulates at the base of the sunlit surface ocean. The origin of this ubiquitous feature, known as the primary nitrite maximum, is debated and has been difficult to resolve through short-term isotope tracer incubations. Here, we use measurements of the dual isotopic composition of nitrite to evaluate the sources, sinks and average rates of nitrite turnover in the primary nitrite maximum in the Arabian Sea. We determined the rate of abiotic oxygen isotope exchange between nitrite and water, as well as equilibrium isotope effects, under a variety of conditions in a series of laboratory experiments. We used these data to model nitrite isotope data from several sites in the Arabian Sea. The results suggest that ammonia oxidation is the primary source of nitrite at most sites. Steady-state nitrite turnover times of 33-178 days correspond to ammonia oxidation rates of 9-30 nM per day at these sites. We suggest that a similar approach could be used to determine the rates of nitrite turnover in other environments, including the secondary nitrite maximum in low-oxygen regions. © 2013 Macmillan Publishers Limited. All rights reserved.


Spiegel D.,Stanford University
Psycho-Oncology | Year: 2012

Objective The very name "psycho-oncology" implies interaction between brain and body. One of the most intriguing scientific questions for the field is whether or not living better may also mean living longer. Methods Randomized intervention trials examining this question will be reviewed. Results The majority show a survival advantage for patients randomized to psychologically effective interventions for individuals with a variety of cancers, including breast, melanoma, gastrointestinal, lymphoma, and lung cancers. Importantly, for breast and other cancers, when aggressive anti-tumor treatments are less effective, supportive approaches appear to become more useful. This is highlighted by a recent randomized clinical trial of palliative care for non-small cell lung cancer patients.There is growing evidence that disruption of circadian rhythms, including rest-activity patterns and hypothalamic-pituitary-adrenal (HPA) axis function, affects cancer risk and progression. Women with metastatic breast cancer have flatter diurnal cortisol patterns than normal, and the degree of loss of daily variation in cortisol predicts earlier mortality. Mechanisms by which abnormal cortisol patterns affect metabolism, gene expression, and immune function are reviewed. The HPA hyperactivity associated with depression can produce elevated levels of cytokines that affect the brain. Tumor cells can, in turn, co-opt certain mediators of inflammation such as NFkB, interleukin-6, and angiogenic factors to promote metastasis. Also, exposure to elevated levels of norepinephrine triggers release of vascular endothelial growth factor, which facilitates tumor growth. Conclusions Therefore, the stress of advancing cancer and management of it is associated with endocrine, immune, and autonomic dysfunction that has consequences for host resistance to cancer progression. Copyright © 2012 John Wiley & Sons, Ltd.


Bandura A.,Stanford University
Behavioral and Brain Sciences | Year: 2011

A major challenge to von Hippel & Trivers's evolutionary analysis of self-deception is the paradox that one cannot deceive oneself into believing something while simultaneously knowing it to be false. The authors use biased information seeking and processing as evidence that individuals knowingly convince themselves of the truth of their falsehood. Acting in ways that keep one uninformed about unwanted information is self-deception. Acting in selectively biasing and misinforming ways is self-bias. © 2011 Cambridge University Press.


Gotlib J.,Stanford University
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2013

The discovery of the JAK2 V617F mutation in the classic BCR-ABL1-negative myeloproliferative neoplasms in 2005 catalyzed a burst of research efforts that have culminated in substantial dividends for patients. Beyond JAK2 V617F, a more detailed picture of the pathobiologic basis for activated JAK-STAT signaling has emerged. In some patients with myelofibrosis (MF), next-generation sequencing technologies have revealed a complex clonal architecture affecting both genetic and epigenetic regulators of cell growth and differentiation. Although these bench-top findings have informed the clinical development of JAK inhibitors in MF, they have also provided scientific context for some of their limitations. The JAK1/JAK2 inhibitor ruxolitinib is approved for treatment of MF in North America and Europe and other lead JAK inhibitors discussed herein (fedratinib [SAR302503], momelotinib [CYT387], and pacritinib [SB1518]), have entered advanced phases of trial investigation. Uniformly, these agents share the ability to reduce spleen size and symptom burden. A major challenge for practitioners is how to optimize dosing of these agents to secure clinically relevant and durable benefits while minimizing myelosuppression. Suboptimal responses have spurred a "return to the bench" to characterize the basis for disease persistence and to inform new avenues of drug therapy.


Hekler E.B.,Stanford University
Journal of physical activity & health | Year: 2012

Recent research highlights the potential value of differentiating between categories of physical activity intensities as predictors of health and well-being. This study sought to assess reliability and concurrent validity of sedentary (ie, 1 METs), low-light (ie, >1 and ≤2 METs; eg, playing cards), high-light (ie, >2 and <3 METs; eg, light walking), moderate-to-vigorous physical activity (MVPA, ≥3 METs), and "total activity" (≥2 METs) from the CHAMPS survey. Further, this study explored over-reporting and double-reporting. CHAMPS data were gathered from the Seniors Neighborhood Quality of Life Study, an observational study of adults aged 65+ years conducted in 2 US regions. Participants (N = 870) were 75.3 ± 6.8 years old, with 56% women and 71% white. The CHAMPS sedentary, low-light, high-light, total activity, and MVPA variables had acceptable test-retest reliability (ICCs 0.56-0.70). The CHAMPS high-light (ρ = 0.27), total activity (ρ = 0.34), and MVPA (ρ = 0.37) duration scales were moderately associated with accelerometry minutes of corresponding intensity, and the sedentary scale (ρ = 0.12) had a lower, but significant correlation. Results suggested that several CHAMPS items may be susceptible to over-reporting (eg, walking, housework). CHAMPS items effectively measured high-light, total activity, and MVPA in seniors, but further refinement is needed for sedentary and low-light activity.


Banerjee S.,Stanford University
Physical Review Letters | Year: 2012

In this Letter, we consider the variation of the entanglement entropy of a region as the shape of the entangling surface is changed. We show that the variation satisfies a Wess-Zumino-like integrability condition in field theories which can be consistently coupled to gravity. In this case, the "anomaly" is localized on the entangling surface. The solution of the integrability condition should give all the nontrivial finite local terms which can appear in the variation of the entanglement entropy. The answers depend on the intrinsic and extrinsic geometry of the entangling surface, but the form does not depend on the details of the field theory. The coefficients, which multiply the purely geometric contributions, will depend on the particular details of the field theory. © 2012 American Physical Society.


Miller D.A.B.,Stanford University
Optics Express | Year: 2012

We analyze energy consumption in optical modulators operated in depletion and intended for low-power interconnect applications. We include dynamic dissipation from charging modulator capacitance and net energy consumption from absorption and photocurrent, both in reverse and small forward bias. We show that dynamic dissipation can be independent of static bias, though only with specific kinds of bias circuits. We derive simple expressions for the effects of photocurrent on energy consumption, valid in both reverse and small forward bias. Though electroabsorption modulators with large reverse bias have substantial energy penalties from photocurrent dissipation, we argue that modulator diodes with thin depletion regions and operating in small reverse and/or forward bias could have little or no such photocurrent energy penalty, even conceivably being more energy-efficient than an ideal loss-less modulator. © 2012 Optical Society of America.


Aguzzi A.,University of Zurich | Gitler A.D.,Stanford University
Cell | Year: 2013

Alzheimer's disease (AD) is associated with the deposition of β-amyloid (Aβ) plaques in the brain. In this issue, by cleverly processing patient samples, Lu et al. define a novel structural model of Aβ fibrils from AD brain, revealing surprising differences from in vitro fibrils. These findings may lead to structure-specific inhibitors and more selective amyloid-imaging methods. © 2013 Elsevier Inc.


Vitousek P.M.,Stanford University
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2013

New techniques have identified a wide range of organisms with the capacity to carry out biological nitrogen fixation (BNF)-greatly expanding our appreciation of the diversity and ubiquity of N fixers-but our understanding of the rates and controls of BNF at ecosystem and global scales has not advanced at the same pace. Nevertheless, determining rates and controls of BNF is crucial to placing anthropogenic changes to the N cycle in context, and to understanding, predicting and managing many aspects of global environmental change. Here, we estimate terrestrial BNF for a pre-industrial world by combining information on N fluxes with (15)N relative abundance data for terrestrial ecosystems. Our estimate is that pre-industrial N fixation was 58 (range of 40-100) Tg N fixed yr(-1); adding conservative assumptions for geological N reduces our best estimate to 44 Tg N yr(-1). This approach yields substantially lower estimates than most recent calculations; it suggests that the magnitude of human alternation of the N cycle is substantially larger than has been assumed.


Meador K.J.,Stanford University | Loring D.W.,Emory University
Neurology | Year: 2016

Antiepileptic drugs (AEDs) are among the most common teratogenic drugs prescribed to women of childbearing age. AEDs can induce both anatomical (malformations) and behavioral (cognitive/ behavioral deficits) teratogenicity. Only in the last decade have we begun to truly discriminate differential AED developmental effects. Fetal valproate exposure carries a special risk for both anatomical and behavioral teratogenic abnormalities, but the mechanisms and reasons for individual variability are unknown. Intermediate anatomical risks exist for phenobarbital and topiramate. Several AEDs (e.g., lamotrigine and levetiracetam) appear to possess low risks for both anatomical and behavioral teratogenesis. Despite advances in the past decade, our knowledge of the teratogenic risks for most AEDs and the underlying mechanisms remain inadequate. Further, the long-term effects of AEDs in neonates and older children remain uncertain. The pace of progress is slow given the lifelong consequences of diminished developmental outcomes, exposing children unnecessarily to potential adverse effects. It is imperative that new approaches be employed to determine risks more expediently. Our recommendations include a national reporting system for congenital malformations, federal funding of the North American AED Pregnancy Registry, routine meta-analyses of cohort studies to detect teratogenic signals, monitoring of AED prescription practices for women, routine preclinical testing of all new AEDs for neurodevelopmental effects, more specific Food and Drug Administration requirements to establish differential AED cognitive effects in children, and improved funding of basic and clinical research to fully delineate risks and underlying mechanisms for AED-induced anatomical and behavioral teratogenesis. © 2015 American Academy of Neurology.


Hallenbeck J.,Stanford University
Journal of Palliative Medicine | Year: 2012

We seem to have become so acculturated to our concern about the respiratory depressive effects of opioids that we may have overlooked the possibility that more common threats to survival from an evolutionary perspective might be grave debilitation at one extreme or catastrophic respiratory failure at the other, both of which would have the same lethal outcome, death. Modulation between such extremes seems highly advantageous. Researchers have not teased apart the discrete roles of opioids in modulating dyspnea in advanced illness. However, it seems at least plausible that metaphorically speaking opioids may allow patients to "ease up on the gas pedal,"when still trying to climbsteep hills. They may get to their destinations a bit more slowly, but at least they get there. Relief of suffering is a secondary, albeit far from trivial, side benefit. Our current understanding of the physiologic mechanisms of dyspnea and mechanisms of therapeutic action for many agents remains remarkably primitive. The discussion above is offered less as a definitive explanation of these mechanisms than an invitation and challenge to others to expand, refine, or refute this understanding. In the meantime, the practicing clinician is advised to consider what physiologic mechanisms may be a work in tailoring patient-specific therapeutic plans. © Copyright 2012, Mary Ann Liebert, Inc.


Yan Q.,Stanford University
Proceedings of the Annual ACM-SIAM Symposium on Discrete Algorithms | Year: 2011

For revenue and welfare maximization in single-dimensional Bayesian settings, Chawla et al. (STOC10) recently showed that sequential posted-price mechanisms (SPMs), though simple in form, can perform surprisingly well compared to the optimal mechanisms. In this paper, we give a theoretical explanation of this fact, based on a connection to the notion of correlation gap. Loosely speaking, for auction environments with matroid constraints, we can relate the performance of a mechanism to the expectation of a monotone submodular function over a random set. This random set corresponds to the winner set for the optimal mechanism, which is highly correlated, and corresponds to certain demand set for SPMs, which is independent. The notion of correlation gap of Agrawal et al. (SODAl0) quantifies how much we "lose" in the expectation of the function by ignoring correlation in the random set, and hence bounds our loss in using certain SPM instead of the optimal mechanism. Furthermore, the correlation gap of a monotone and submodular function is known to be small, and it follows that certain SPM can approximate the optimal mechanism by a good constant factor. Exploiting this connection, we give tight analysis of a greedy-based SPM of Chawla et al. for several environments. In particular, we show that it gives an e/(e - 1)-approximation for matroid environments, gives asymptotically a 1/(1 - 1 /√2πk)-approximation for the important sub-case of k-unit auctions, and gives a (p + l)-approximation for environments with p-independent set system constraints.


Beroza G.C.,Stanford University | Ide S.,University of Tokyo
Annual Review of Earth and Planetary Sciences | Year: 2011

Nonvolcanic tremor is observed in close association with geodetically observed slow-slip events in subduction zones. Accumulating evidence points to these events as members of a family of slow earthquakes that occur as shear slip on the downdip extensions of fault zones in a regime that is transitional between a frictionally locked region above and a freely slipping region below. By virtue of their locations and their properties, slow earthquakes are certain to provide new insights into the behavior of earthquakes and faulting and into the hazard they embody. Copyright © 2011 by Annual Reviews. All rights reserved.


Dionne J.A.,Stanford University
Nature Materials | Year: 2013

Two-photon luminescence (TPL) in metallic nanostructures provides a unique signature of the number of plasmonic modes per unit energy and volume, paving the way for more efficient plasmonic sources, detectors and sensors. Arbouet, Dujardin and co-workers explore TPL in single-crystalline, micrometre-scale gold prisms made by colloidal synthesis. The researchers use a focused infrared laser to locally excite surface plasmons in the prisms, then detect the visible TPL signal from the sample. By scanning the laser over different regions of the prisms, the researchers can generate spatial maps of TPL intensities for various illumination wavelengths and polarizations. As the incident wavelength is increased, the TPL signal becomes stronger along the prism edge parallel to the laser polarization. Combining their experimental tools and theoretical formalism, Arbouet, Dujardin and co-workers extend their work to coupled nanostructures.


Maher K.,Stanford University
Earth and Planetary Science Letters | Year: 2011

The role of fluid residence time and catchment length scales in controlling the chemical composition of rivers is evaluated by comparing numerical simulations and scaling arguments to concentration-discharge data from small catchments. The analysis suggests that poorly-crystalline aluminosilicates are an important control on the composition of stream waters and therefore chemical equilibrium between the dissolving and precipitating phases determines the maximum concentration and the maximum silicate weathering flux. The modeling results suggest that the residence time of fluid relative to the residence time required to approach chemical equilibrium can be used to assess the controls on solute fluxes in small catchments, and possibly larger rivers. Catchments that show little variability in concentration with discharge (or "chemostatic behavior") likely have average fluid residence times that exceed the time required to reach chemical equilibrium. Conversely, decreases in concentration with increasing discharge are explained by average residence times shorter than required to approach chemical equilibrium, resulting in dilution. Solute fluxes are also strongly impacted by the distribution of fluid residence times in a basin. The fluid residence time model provides an alternative framework for assessing both the relationship between discharge and concentration observed for individual catchments, and controls on the solute fluxes of rivers. If fluid residence times are a dominant control on weathering fluxes, the chemistry of different rivers could vary entirely as a function of the nature subsurface flow paths and the composition of the system at equilibrium, which is complex to predict and strongly coupled to biological processes, temperature and the composition of the system. As a result of thermodynamic and hydrologic restrictions on the amount of weathering, global solute fluxes may depend more strongly on the geometry, relief, runoff and permeability of basins then on temperature and rates of erosion. © 2011 Elsevier B.V.


Sussillo D.,Stanford University
Current Opinion in Neurobiology | Year: 2014

Many recent studies of neurons recorded from cortex reveal complex temporal dynamics. How such dynamics embody the computations that ultimately lead to behavior remains a mystery. Approaching this issue requires developing plausible hypotheses couched in terms of neural dynamics. A tool ideally suited to aid in this question is the recurrent neural network (RNN). RNNs straddle the fields of nonlinear dynamical systems and machine learning and have recently seen great advances in both theory and application. I summarize recent theoretical and technological advances and highlight an example of how RNNs helped to explain perplexing high-dimensional neurophysiological data in the prefrontal cortex. © 2014 Elsevier Ltd.


Michener J.K.,California Institute of Technology | Smolke C.D.,Stanford University
Metabolic Engineering | Year: 2012

Metabolic engineering can produce a wide range of bulk and fine chemicals using renewable resources. These approaches frequently require high levels of activity from multiple heterologous enzymes. Directed evolution techniques have been used to improve the activity of a wide range of enzymes but can be difficult to apply when the enzyme is used in whole cells. To address this limitation, we developed generalizable in vivo biosensors using engineered RNA switches to link metabolite concentrations and GFP expression levels in living cells. Using such a sensor, we quantitatively screened large enzyme libraries in high throughput based on fluorescence, either in clonal cultures or in single cells by fluorescence activated cell sorting (FACS). By iteratively screening libraries of a caffeine demethylase, we identified beneficial mutations that ultimately increased the enzyme activity in vivo by 33 fold and the product selectivity by 22 fold. As aptamer selection strategies allow RNA switches to be readily adapted to recognize new small molecules, these RNA-based screening techniques are applicable to a broad range of enzymes and metabolic pathways. © 2012 Elsevier Inc.


Gourdji S.M.,Stanford University
Proceedings. Biological sciences / The Royal Society | Year: 2013

Genetic improvements in heat tolerance of wheat provide a potential adaptation response to long-term warming trends, and may also boost yields in wheat-growing areas already subject to heat stress. Yet there have been few assessments of recent progress in breeding wheat for hot environments. Here, data from 25 years of wheat trials in 76 countries from the International Maize and Wheat Improvement Center (CIMMYT) are used to empirically model the response of wheat to environmental variation and assess the genetic gains over time in different environments and for different breeding strategies. Wheat yields exhibited the most sensitivity to warming during the grain-filling stage, typically the hottest part of the season. Sites with high vapour pressure deficit (VPD) exhibited a less negative response to temperatures during this period, probably associated with increased transpirational cooling. Genetic improvements were assessed by using the empirical model to correct observed yield growth for changes in environmental conditions and management over time. These 'climate-corrected' yield trends showed that most of the genetic gains in the high-yield-potential Elite Spring Wheat Yield Trial (ESWYT) were made at cooler temperatures, close to the physiological optimum, with no evidence for genetic gains at the hottest temperatures. In contrast, the Semi-Arid Wheat Yield Trial (SAWYT), a lower-yielding nursery targeted at maintaining yields under stressed conditions, showed the strongest genetic gains at the hottest temperatures. These results imply that targeted breeding efforts help us to ensure progress in building heat tolerance, and that intensified (and possibly new) approaches are needed to improve the yield potential of wheat in hot environments in order to maintain global food security in a warmer climate.


Goodman S.B.,Stanford University
Instructional course lectures | Year: 2013

Total joint arthroplasty has revolutionized the treatment of arthritic and degenerative conditions for many joints in the body; however, wear debris is continuously generated with day-to-day use of an artificial joint. Excessive production of wear by-products induces a foreign body and chronic inflammatory reaction that accelerates periprosthetic bone destruction and inhibits bone formation. The specific biologic reaction is dependent on the type, amount, and characteristics of the by-products of wear, along with individual genetic variations. For polymeric and ceramic particles, the inflammatory reaction is generally nonspecific and nonimmune; however, with metallic by-products, a type IV, T lymphocyte-mediated, antigen-dependent immune reaction can occur in some patients. The production of proinflammatory cytokines, chemokines, reactive oxygen species, and other mediators is upregulated by wear particles. Animal models have shown that the biologic reaction to wear particles is systemic in nature, not a localized event. Mechanical stimuli and the presence of endotoxin also appear to be important. Efficacious biologic treatments of periprosthetic osteolysis are not yet available. Research continues with the hope that viable strategies for preventing and treating particle-induced osteolysis will be introduced in the future, thus mitigating the need for revision surgery.


Observational constraints of the relativistic jets from black holes have largely come from the most powerful and extended jets, leaving the nature of the low-luminosity jets a mystery. M81* is one of the nearest low-luminosity jets and it emitted an extremely large radio flare in 2011, allowing us to study compact core emission with unprecedented sensitivity and linear resolution. Using a multiwavelength campaign, we were able to track the flare as it re-brightened and became optically thick. Simultaneous X-ray observations indicated that the radio re-brightening was preceded by a low-energy X-ray flare at least 12 days earlier. Associating the time delay (tdelay) between the two bands with the cooling time in a synchrotron flare, we find that the magnetic field strength was 1.9 < B < 9.2 G, which is consistent with magnetic field estimate from spectral energy distribution modelling, B < 10.2 G. In addition, Very Long Baseline Array observations at 23 GHz clearly illustrate a discrete knot moving at a low relativistic speed of vapp/c = 0.51 ± 0.17 associated with the initial radio flare. The observations indicate radial jet motions for the first time in M81*. This has profound implications for jet production, as it means radial motion can be observed in even the lowest-luminosity AGN, but at slower velocities and smaller radial extents (≍104 RG). © 2016 Nature Publishing Group


Fraser H.B.,Stanford University
Genome Biology | Year: 2013

Background: Eukaryotic DNA replication follows a specific temporal program, with some genomic regions consistently replicating earlier than others, yet what determines this program is largely unknown. Highly transcribed regions have been observed to replicate in early S-phase in all plant and animal species studied to date, but this relationship is thought to be absent from both budding yeast and fission yeast. No association between cell-cycle regulated transcription and replication timing has been reported for any species.Results: Here I show that in budding yeast, fission yeast, and human, the genes most highly transcribed during S-phase replicate early, whereas those repressed in S-phase replicate late. Transcription during other cell-cycle phases shows either the opposite correlation with replication timing, or no relation. The relationship is strongest near late-firing origins of replication, which is not consistent with a previously proposed model-that replication timing may affect transcription-and instead suggests a potential mechanism involving the recruitment of limiting replication initiation factors during S-phase.Conclusions: These results suggest that S-phase transcription may be an important determinant of DNA replication timing across eukaryotes, which may explain the well-established association between transcription and replication timing. © 2013 Fraser; licensee BioMed Central Ltd.


Li Y.,Soochow University of China | Dai H.,Stanford University
Chemical Society Reviews | Year: 2014

Zinc-air is a century-old battery technology but has attracted revived interest recently. With larger storage capacity at a fraction of the cost compared to lithium-ion, zinc-air batteries clearly represent one of the most viable future options to powering electric vehicles. However, some technical problems associated with them have yet to be resolved. In this review, we present the fundamentals, challenges and latest exciting advances related to zinc-air research. Detailed discussion will be organized around the individual components of the system-from zinc electrodes, electrolytes, and separators to air electrodes and oxygen electrocatalysts in sequential order for both primary and electrically/mechanically rechargeable types. The detrimental effect of CO2 on battery performance is also emphasized, and possible solutions summarized. Finally, other metal-air batteries are briefly overviewed and compared in favor of zinc-air. This journal is © the Partner Organisations 2014.


Casper R.C.,Stanford University
Journal of Nervous and Mental Disease | Year: 2015

The paper by Robinson posits that risks fromprenatal exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants are not different from the risks encountered in the general population and that untoward effects of SSRIs are difficult to distinguish from those of the mood disorder. Indeed, maternal depression and anxiety can have negative consequences for fetal and postnatal development. Fortunately, experimental evidence suggests thatmood and anxiety disorder symptoms often respond to psychosocial interventions. If pharmacotherapy becomes necessary, it is, however, important to know that even if SSRI drugs have been shown to be safe overall, research has shown that fetal development can be adversely affected by in utero exposure to SSRIs in a subgroup of neonates. Examples would be the transient neonatal adaptation syndrome, an increased risk of persistent pulmonary hypertension of the newborn, and small, albeit measurable, changes in motor and social adaptability in infancy and childhood. © 2015 Wolters Kluwer Health, Inc. All rights reserved.


Boyko A.R.,Stanford University
Genome Biology | Year: 2011

The domestic dog genome - shaped by domestication, adaptation to human-dominated environments and artificial selection - encodes tremendous phenotypic diversity. Recent developments have improved our understanding of the genetics underlying this diversity, unleashing the dog as an important model organism for complex-trait analysis. © 2011 BioMed Central Ltd.


Krishnan E.,Stanford University
Rheumatology | Year: 2010

For many years, the relationship between cardiovascular disease risk and gout, though strong and consistent, was suspected of being coincidental rather than causative. In recent years, compelling epidemiological and clinical data have increasingly favoured an aetiological connection. However, that connection is notably complex, involving a multifaceted model that includes interactions between inflammatory processes, oxidative stress and potential genetic influences, as well as cardiovascular and renal components that remain only partly explained. Urate appears to be able to activate the immune response, and in that context has a mediating role in the inflammatory process via the inflammasome. This interaction of urate and inflammation is central to the inflammatory cascade associated with gout flares. In the arena of oxidative stress, urate has both antioxidant and pro-oxidant properties, and while potentially beneficial in scavenging free radicals, it can also impair endothelial function and thereby give rise to atherosclerotic risk. Human and animal studies have revealed associations between hyperuricaemia and a host of atherosclerotic risk factors, whereas a reduction in urate levels is frequently associated with improvement or even resolution of such risk factors. The degree to which reduction of serum urate can reliably improve cardiovascular risk remains uncertain. It is hoped that the introduction of newer urate-lowering agents may help to clarify this picture and improve treatment options for both gout and atherosclerosis. © The Author 2010. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org.


Jay D.C.,Stanford University
Current allergy and asthma reports | Year: 2014

Sublingual immunotherapy (SLIT) is a well-established allergen-specific immunotherapy and a safe and effective strategy to reorient inappropriate immune responses in allergic patients. SLIT takes advantage of the tolerogenic environment of the oral mucosa to promote tolerance to the allergen. Several clinical studies have investigated the complex interplay of innate and adaptive immune responses that SLIT exploits. The oral immune system is composed of tolerogenic dendritic cells that, following uptake of allergen during SLIT, support the differentiation of T helper cell type 1 (Th1) and the induction of IL-10-producing regulatory T cells. Following SLIT, allergic disease-promoting T helper cell type 2 (Th2) responses shift to a Th1 inflammatory response, and IL-10 and transforming growth factor (TGF)-β production by regulatory T cells and tolerogenic dendritic cells suppress allergen-specific T cell responses. These immune changes occur both in the sublingual mucosa and in the periphery of a patient following SLIT. SLIT also promotes the synthesis of allergen-specific IgG and IgA antibodies that block allergen-IgE complex formation and binding to inflammatory cells, thus encouraging an anti-inflammatory environment. Several of these revealing findings have also paved the way for the identification of biomarkers of the clinical efficacy of SLIT. This review presents the emerging elucidation of the immune mechanisms mediated by SLIT.


Henderson V.W.,Stanford University
Biochimica et Biophysica Acta - General Subjects | Year: 2010

Background: Menopause is associated with sharp declines in concentrations of circulating estrogens. This change in hormone milieu has the potential to affect brain functions relevant to dementia and cognitive aging. Scope of review: Focused review of published results of randomized clinical trials of estrogen-containing hormone therapy for Alzheimer's disease treatment and dementia prevention, observational research on cognition across the menopause transition, and observational research on the association of hormone therapy and Alzheimer's disease risk. Major conclusions: Clinical trial evidence supports conclusions that estrogen therapy does not improve dementia symptoms in women with Alzheimer's disease and that estrogen-containing hormone therapy initiated after about age 65 years increases dementia risk. Hormone therapy begun in this older postmenopausal group does not ameliorate cognitive aging. Cognitive outcomes of midlife hormone exposures are less well studied. There is no strong indication of short-term cognitive benefit of hormone use after natural menopause, but clinical trial data are sparse. Little research addresses midlife estrogen use after surgical menopause; limited clinical trial data imply short-term benefit of prompt initiation at the time of oophorectomy. Whether exogenous estrogen exposures in the early postmenopause affect Alzheimer risk or cognitive aging much later in life is unanswered by available data. Observational results raise the possibility of long-term cognitive benefit, but bias is a concern in interpreting these findings. General significance: Estrogen-containing hormone therapy should not be initiated after age 65 to prevent dementia or remediate cognitive aging. Further research is needed to understand short-term and long-term cognitive effects of estrogen exposures closer to the age of menopause. © 2009 Elsevier B.V.


Subduction generated a NW-trending Andean arc along the Californian margin beginning at ∼175 Ma. Coeval high-pressure (HP) transformation of oceanic crust in an east-dipping, subduction zone probably accompanied plate convergence, but recovered Franciscan eclogite and garnet blueschist blocks chiefly possess younger recrystallization ages of ∼165-150 Ma. These Jurassic HP metamafic rocks were sequestered in a low-temperature environment well into Cretaceous time. Fragments of actinolitic rinds partially surround many such high-grade blocks. Only slightly younger than the HP metamorphism, these rinds reflect metasomatic exchange between metabasalt and serpentinized harzburgite along the dynamic oceanic crust-mantle hanging wall during storage of the mafic rocks at moderate depth. High-grade tectonic blocks later were brought toward the surface in circulating, low-density, sheared mud-matrix mélange and/or in buoyant serpentinite bodies. Most exotic HP metamafic blocks occur in mélanges of the Franciscan Central Belt, reflecting tectonic insertion within the subduction zone - not near-surface additions to the clastic section. However, rare, high-grade clasts in feebly recrystallized Franciscan conglomerates suggest erosion and sedimentary deposition for some HP blocks. The addition of dense metabasaltic olistoliths to the mid- and Upper Cretaceous section requires that these HP material were carried surfaceward first as tectonic fragments, perhaps immersed in low-density serpentinite or mud-matrix mélange, then eroded and transported into the trench. HP rocks are conspicuously lacking in coeval Great Valley strata. Whatever the origin of particular high-grade rocks, widespread post-depositional shearing has largely obliterated their original natures, but all dense metamafic blocks of Jurassic recrystallization age must have been supplied to the Cretaceous Franciscan accretionary complex by entrainment in a low-density, circulating muddy matrix or serpentinite body. The vast majority of exotic HP blocks resides in Central Belt mélanges, and appears to be tectonic rather than olistostromal in origin. © 2015, Walter de Gruyter GmbH. All rights reserved.


Shen A.,Stanford University
Molecular BioSystems | Year: 2010

Proteases regulate a plethora of biological processes. Because they irreversibly cleave peptide bonds, the activity of proteases is strictly controlled. While there are many ways to regulate protease activity, an emergent mechanism is the modulation of protease function by small molecules acting at allosteric sites. This mode of regulation holds the potential to allow for the specific and temporal control of a given biological process using small molecules. These compounds also serve as useful tools for studying protein dynamics and function. This review highlights recent advances in identifying and characterizing natural and synthetic small molecule allosteric regulators of proteases and discusses their utility in studies of protease function, drug discovery and protein engineering. © The Royal Society of Chemistry 2010.


Pestilli F.,Stanford University
Nature Methods | Year: 2014

Diffusion-weighted imaging coupled with tractography is currently the only method for in vivo mapping of human white-matter fascicles. Tractography takes diffusion measurements as input and produces the connectome, a large collection of white-matter fascicles, as output. We introduce a method to evaluate the evidence supporting connectomes. Linear fascicle evaluation (LiFE) takes any connectome as input and predicts diffusion measurements as output, using the difference between the measured and predicted diffusion signals to quantify the prediction error. We use the prediction error to evaluate the evidence that supports the properties of the connectome, to compare tractography algorithms and to test hypotheses about tracts and connections.


Krahenbuhl P.,Stanford University
Proceedings of the IEEE Computer Society Conference on Computer Vision and Pattern Recognition | Year: 2012

Saliency estimation has become a valuable tool in image processing. Yet, existing approaches exhibit considerable variation in methodology, and it is often difficult to attribute improvements in result quality to specific algorithm properties. In this paper we reconsider some of the design choices of previous methods and propose a conceptually clear and intuitive algorithm for contrast-based saliency estimation. Our algorithm consists of four basic steps. First, our method decomposes a given image into compact, perceptually homogeneous elements that abstract unnecessary detail. Based on this abstraction we compute two measures of contrast that rate the uniqueness and the spatial distribution of these elements. From the element contrast we then derive a saliency measure that produces a pixel-accurate saliency map which uniformly covers the objects of interest and consistently separates fore- and background. We show that the complete contrast and saliency estimation can be formulated in a unified way using high-dimensional Gaussian filters. This contributes to the conceptual simplicity of our method and lends itself to a highly efficient implementation with linear complexity. In a detailed experimental evaluation we analyze the contribution of each individual feature and show that our method outperforms all state-of-the-art approaches. © 2012 IEEE.


Supported lipid bilayers (SLBs) mimic biological membranes and are a versatile platform for a wide range of biophysical research fields including lipid-protein interactions, protein-protein interactions and membrane-based biosensors. The quartz crystal microbalance with dissipation monitoring (QCM-D) has had a pivotal role in understanding SLB formation on various substrates. As shown by its real-time kinetic monitoring of SLB formation, QCM-D can probe the dynamics of biomacromolecular interactions. We present a protocol for constructing zwitterionic SLBs supported on silicon oxide and titanium oxide, and discuss technical issues that need to be considered when working with charged lipid compositions. Furthermore, we explain a recently developed strategy that uses an amphipathic, alpha-helical (AH) peptide to form SLBs on gold and titanium oxide substrates. The protocols can be completed in less than 3 h.


David S.P.,Stanford University
The Cochrane database of systematic reviews | Year: 2013

The reinforcing properties of nicotine may be mediated through release of various neurotransmitters both centrally and systemically. People who smoke report positive effects such as pleasure, arousal, and relaxation as well as relief of negative affect, tension, and anxiety. Opioid (narcotic) antagonists are of particular interest to investigators as potential agents to attenuate the rewarding effects of cigarette smoking. To evaluate the efficacy of opioid antagonists in promoting long-term smoking cessation. The drugs include naloxone and the longer-acting opioid antagonist naltrexone. We searched the Cochrane Tobacco Addiction Group Specialised Register for trials of naloxone, naltrexone and other opioid antagonists and conducted an additional search of MEDLINE using 'Narcotic antagonists' and smoking terms in April 2013. We also contacted investigators, when possible, for information on unpublished studies. We considered randomised controlled trials comparing opioid antagonists to placebo or an alternative therapeutic control for smoking cessation. We included in the meta-analysis only those trials which reported data on abstinence for a minimum of six months. We also reviewed, for descriptive purposes, results from short-term laboratory-based studies of opioid antagonists designed to evaluate psycho-biological mediating variables associated with nicotine dependence. We extracted data in duplicate on the study population, the nature of the drug therapy, the outcome measures, method of randomisation, and completeness of follow-up. The main outcome measure was abstinence from smoking after at least six months follow-up in patients smoking at baseline. Abstinence at end of treatment was a secondary outcome. We extracted cotinine- or carbon monoxide-verified abstinence where available. Where appropriate, we performed meta-analysis, pooling risk ratios using a Mantel-Haenszel fixed-effect model. Eight trials of naltrexone met inclusion criteria for meta-analysis of long-term cessation. One trial used a factorial design so five trials compared naltrexone versus placebo and four trials compared naltrexone plus nicotine replacement therapy (NRT) versus placebo plus NRT. Results from 250 participants in one long-term trial remain unpublished. No significant difference was detected between naltrexone and placebo (risk ratio (RR) 1.00; 95% confidence interval (CI) 0.66 to 1.51, 445 participants), or between naltrexone and placebo as an adjunct to NRT (RR 0.95; 95% CI 0.70 to 1.30, 768 participants). The estimate was similar when all eight trials were pooled (RR 0.97; 95% CI 0.76 to 1.24, 1213 participants). In a secondary analysis of abstinence at end of treatment, there was also no evidence of any early treatment effect, (RR 1.03; 95% CI 0.88 to 1.22, 1213 participants). No trials of naloxone or buprenorphine reported abstinence outcomes. Based on data from eight trials and over 1200 individuals, there was no evidence of an effect of naltrexone alone or as an adjunct to NRT on long-term smoking abstinence, with a point estimate strongly suggesting no effect and confidence intervals that make a clinically important effect of treatment unlikely. Although further trials might narrow the confidence intervals they are unlikely to be a good use of resources.


Mignot E.J.M.,Stanford University
Neurotherapeutics | Year: 2012

Summary: Narcolepsy and other syndromes associated with excessive daytime sleepiness can be challenging to treat. New classifications now distinguish narcolepsy/hypocretin deficiency (also called type 1 narcolepsy), a lifelong disorder with well-established diagnostic procedures and etiology, from other syndromes with hypersomnolence of unknown causes. Klein-Levin Syndrome, a periodic hypersomnia associated with cognitive and behavioral abnormalities, is also considered a separate entity with separate therapeutic protocols. Non hypocretin-related hypersomnia syndromes are diagnoses of exclusion. These diagnoses are only made after eliminating sleep deprivation, sleep apnea, disturbed nocturnal sleep, and psychiatric comorbidities as the primary cause of daytime sleepiness. The treatment of narcolepsy/hypocretin deficiency is well-codified, and involves pharmacotherapies using sodium oxybate, stimulants, and/or antidepressants, plus behavioral modifications. These therapies are almost always needed, and the risk-to-benefit ratio is clear, notably in children. Detailed knowledge of the pharmacological profile of each compound is needed to optimize use. Treatment for other syndromes with hypersomnolence is more challenging and less codified. Preferably, therapy should be conservative (such as modafinil, atomoxetine, behavioral modifications), but it may have to be more aggressive (high-dose stimulants, sodium oxybate, etc.) on a case-by-case, empirical trial basis. As cause and evolution are unknown in these conditions, it is important to challenge diagnosis and therapy over time, keeping in mind the possibility of tolerance and the development of stimulant addiction. Kleine-Levin Syndrome is usually best left untreated, although lithium can be considered in severe cases with frequent episodes. Guidelines are provided based on the literature and personal experience of the author. © 2012 The Author(s).


Breslow D.K.,Stanford University
Cold Spring Harbor Perspectives in Biology | Year: 2013

Sphingolipids are a diverse group of lipids that have essential cellular roles as structural components of membranes and as potent signaling molecules. In recent years, a detailed picture has emerged of the basic biochemistry of sphingolipids-from their initial synthesis in the endoplasmic reticulum (ER), to their elaboration into complex glycosphingolipids, to their turnover and degradation. However, our understanding of how sphingolipid metabolism is regulated in response to metabolic demand and physiologic cues remains incomplete. Here I discuss new insights into the mechanisms that ensure sphingolipid homeostasis, with an emphasis on the ER as a critical regulatory site in sphingolipid metabolism. In particular, Orm family proteins have recently emerged as key ER-localized mediators of sphingolipid homeostasis. A detailed understanding of how cells sense and control sphingolipid production promises to provide key insights into membrane function in health and disease. © 2013 Cold Spring Harbor Laboratory Press; all rights reserved.


Fleischmann D.,Stanford University
Radiologic clinics of North America | Year: 2010

CT scanner technology is continuously evolving, with scan times becoming shorter with each scanner generation. Achieving adequate arterial opacification synchronized with CT data acquisition is becoming increasingly difficult. A fundamental understanding of early arterial contrast medium dynamics is thus of utmost importance for the design of CT scanning and injection protocols for current and future cardiovascular CT applications. Arterial enhancement is primarily controlled by the iodine flux (injection flow rate) and the injection duration versus a patient's cardiac output and local downstream physiology. The technical capabilities of modern CT equipment require precise scan timing. Together with automated tube current modulation and weight-based injection protocols, both radiation exposure and contrast medium enhancement can be individualized. Copyright 2010. Published by Elsevier Inc.


Reynolds P.,Cancer Prevention Institute of California | Reynolds P.,Stanford University
Journal of Mammary Gland Biology and Neoplasia | Year: 2013

The potential role of smoking in breast cancer risk has been the subject of over 100 publications, numerous scientific reviews, and animated debate. Tobacco exposure is a well-established cause of lung cancer, and is thought to account for nearly one third of all cancer deaths. Tobacco smoke contains thousands of chemicals, many of which are known to be mammary carcinogens. Although not initially thought to be a tobacco-related cancer, over the last several decades evidence has been accumulating on the role of both active smoking and secondhand smoking in the etiology of breast cancer. The human health evidence has been systematically evaluated not only by several independent researchers but also by several expert agency panels including those of the U.S. Surgeon General, the International Agency for Research on Cancer, the California Environmental Protection Agency, and a coalition of Canadian health agencies. Although the assessments have varied with time and across reviewers, the most recent weight of the evidence has suggested a potentially casual role for active smoking and breast cancer, particularly for long-term heavy smoking and smoking initiation at an early age. The role of secondhand smoking and breast cancer is less clear, although there has been some suggestion for an increased risk for premenopausal breast cancer. Recent studies evaluating the possible modifying role of polymorphisms in genes involved in the metabolism of tobacco products, particularly NAT2, have contributed another dimension to these assessments, although to date that evidence remains equivocal. © 2012 Springer Science+Business Media New York.


Pasricha P.J.,Stanford University
Nature Reviews Gastroenterology and Hepatology | Year: 2012

Chronic pancreatitis is typically a painful condition and it can be associated with a severe burden of disease. The pathogenesis of pain in this disorder is poorly understood and its treatment has been largely empirical, often consisting of surgical or other invasive methods, with an outcome that is variable and frequently unsatisfactory. Human and experimental studies have indicated a critical role for neuronal mechanisms that result in peripheral and central sensitization. The pancreatic nociceptor seems to be significantly affected in this condition, with increased excitability associated with downregulation of potassium currents. Some of the specific molecules implicated in this process include the vanilloid receptor, TRPV1, nerve growth factor, the protease activated receptor 2 and a variety of others that are discussed in this Review. Studies have also indicated novel therapeutic targets for this condition. © 2012 Macmillan Publishers Limited. All rights reserved.


The Stenting and Aggressive Medical Management for Preventing Recurrent Stroke and Intracranial Stenosis (SAMMPRIS) trial, a randomized clinical trial comparing aggressive medical management to stenting with aggressive medical management for symptomatic intracranial stenosis, was prematurely halted when a high rate of periprocedural events was found in the stent arm. The trial also demonstrated a high rate of stroke with medical management. This article explores possible reasons for these outcomes and discusses some weaknesses of the trial. Against this background endovascular therapy should continue to be explored in the treatment of this disease. © 2011 American Heart Association, Inc.


Chen B.,Stanford University
Cold Spring Harbor perspectives in biology | Year: 2011

Eukaryotic cells must contend with a continuous stream of misfolded proteins that compromise the cellular protein homeostasis balance and jeopardize cell viability. An elaborate network of molecular chaperones and protein degradation factors continually monitor and maintain the integrity of the proteome. Cellular protein quality control relies on three distinct yet interconnected strategies whereby misfolded proteins can either be refolded, degraded, or delivered to distinct quality control compartments that sequester potentially harmful misfolded species. Molecular chaperones play a critical role in determining the fate of misfolded proteins in the cell. Here, we discuss the spatial and temporal organization of cellular quality control strategies and their implications for human diseases linked to protein misfolding and aggregation.


Ernst W.G.,Stanford University
Gondwana Research | Year: 2010

At the dawn of the age of plate tectonics, Akiho Miyashiro published a seminal paper in which he drew attention to significant differences in regional metamorphic phase assemblages, described contrasting geologic occurrences, and inferred their characteristic ranges of physical conditions. He advanced the paired metamorphic belt concept, involving an oceanward, narrow, high-P/low-T blueschist zone intimately intermixed with ophiolites, and a landward, broad, low-P/high-T realm associated with arc volcanic-plutonic rocks. More recent studies have illuminated the following: (1) Two main types of convergent plate junction can be distinguished, Pacific underflow of thousands of km of oceanic lithosphere, and Alpine closure of an intervening oceanic basin leading to continental collision. (2) Plate descent carries mafic + felsic lithologies to depths of ~ 35-120 km or more at relatively low temperatures, producing high-pressure (HP) Pacific-type and ultrahigh-pressure (UHP) Alpine-type metamorphic terranes, respectively. (3) Exhumed HP-UHP complexes display low-aggregate bulk densities, reflecting chiefly buoyancy-driven ascent of quartzofeldspathic allochthons. (4) At a depth of ~ 35 km in a warm-lithosphere subduction zone, sialic crust should melt if an aqueous fluid were abundant; it does not, hence the activity of H2O must be low at such depths. (5) Global observations indicate that volcanic-plutonic arcs are sited 100 ± 20 km above subducting oceanic plates; devolatilization of sinking, hydrated oceanic crust ± mantle promotes the generation of calc-alkaline arc melts in this magmagenic zone. (6) Pacific-type underflow of basaltic crust-capped plates produces new and recycled continental crust, whereas Alpine-type convergence reshuffles collided terranes but does not generate juvenile sialic crust. © 2009 International Association for Gondwana Research.


Lavaei J.,Stanford University
IEEE Transactions on Automatic Control | Year: 2012

Given a centralized controller associated with a linear time-invariant (LTI) interconnected system, this paper is concerned with designing a parameterized decentralized controller in such a way that the state and input of the system under the obtained decentralized controller can become arbitrarily close to those of the system under the given centralized controller, by tuning the controller's parameters. To this end, a two-level decentralized controller is designed, where the upper level captures the dynamics of the centralized closed-loop system, and the lower level is an observed-based subcontroller designed based on the new notion of structural initial value observability. The proposed method can decentralize every generic centralized controller, provided the interconnected system satisfies very mild conditions. © 2012 IEEE.


Hanson R.K.,Stanford University
Proceedings of the Combustion Institute | Year: 2011

Laser diagnostic techniques play a large and growing role in combustion research and development. Here we highlight three areas where quantitative sensing based on laser absorption has had strong influence: chemical kinetics, propulsion, and practical energy systems. In the area of chemical kinetics, measurements in shock tubes of high-temperature reaction rate coefficients using species-specific laser absorption techniques have provided new and accurate answers to questions about combustion chemical processes. In the area of propulsion, wide-bandwidth measurements of flow temperatures, species concentrations, and velocity have provided engine designers with the necessary information to improve operation and performance. In the area of practical energy systems, real-time measurements of combustor operating conditions and emissions have enabled needed incremental improvements in large power plants and improved safety of operation. Yet, there is still more to be done, and opportunities for new applications will grow as laser sensors evolve. This review seeks to provide an overview of the current power and future potential of these modern diagnostic tools. © 2010 Published by Elsevier Inc. on behalf of The Combustion Institute. All rights reserved.


Ketter T.A.,Stanford University
The Journal of clinical psychiatry | Year: 2010

Bipolar disorder shares depressive symptoms with unipolar major depressive disorder but is defined by episodes of mania or hypomania. Bipolar disorder in its broadest sense has a community lifetime prevalence of 4% and is a severely impairing illness that impacts several aspects of patients' lives. Race, ethnicity, and gender have no effect on prevalence rates, but women are more likely to experience rapid cycling, mixed states, depressive episodes, and bipolar II disorder than men. Patients with bipolar disorder have high rates of disability and higher rates of mortality than individuals without bipolar disorder. Natural causes such as cardiovascular disease and diabetes, as well as suicide and other "unnatural" causes are key contributors to the high mortality rate. The costs associated with bipolar disorder include not only the direct costs of treatment, but also the much greater indirect costs of decreased productivity, excess unemployment, and excess mortality. 2010 Physicians Postgraduate Press, Inc.


Krishnan E.,Stanford University
PLoS ONE | Year: 2012

Background: The renal tubule is a major route of clearance of uric acid, a product of purine metabolism. The links between reduced glomerular filtration rate (GFR), hyperuricemia, and gout in the general population are not well understood. The objective of the present study was to estimate prevalence of gout and hyperuricemia among people with impaired GFR in the US general population. Study Design: Cross-sectional, survey-weighted analyses of data on adults (age>20 years) in the 2009-10 cycle of the US National Health and Nutrition Examination Surveys (n = 5,589). Associations between self-reported physician diagnosis of gout and degrees of renal impairment were the primary focus of the present analyses. Results: In the 2009-2010 period, there was an estimated 7.5 million people with gout in the US. There were 1.25 million men and 0.78 million women with moderate or severe renal impairment and gout. The age standardized prevalence of gout was 2.9% among those with normal GFR compared to 24% among those with GFR<60 ml/min/1.73 m2.In multivariable logistic regression analyses that adjusted for age, gender, body mass index, hypertension, diabetes, hypertension medications, including diuretics, blood lead levels, and hyperlipidemia, the odds ratios of gout and hyperuricemia were 5.9 (2.2, 15.7) and 9.58 (4.3, 22.0) respectively among those with severe renal impairment compared to those with no renal impairment. Approximately 2-3 fold increase in prevalence of gout was observed for each 30 ml/min/1.73 m2 decrease in GFR, after accounting for the above factors. Conclusions: Renal glomerular function is an important risk factor for gout. The prevalence of hyperuricemia and gout increases with decreasing glomerular function independent of other factors. This association is non-linear and an eGFR of 60 ml/min/1.73 m2 appears to be a threshold for the dramatic increase in the prevalence of gout. © 2012 Eswar Krishnan.


Jacobson M.Z.,Stanford University
Journal of Geophysical Research: Atmospheres | Year: 2010

This study examines the short-term (∼15 year) effects of controlling fossil-fuel soot (FS) (black carbon (BC), primary organic matter (POM), and S(IV) (H2SO4(aq), HSO4 -, and SO 4 2-)), solid-biofuel soot and gases (BSG) (BC, POM, S(IV), K+, Na+, Ca2+, Mg2+, NH 4 +, NO3 -, Cl- and several dozen gases, including CO2 and CH4), and methane on global and Arctic temperatures, cloudiness, precipitation, and atmospheric composition. Climate response simulations were run with GATOR-GCMOM, accounting for both microphysical (indirect) and radiative effects of aerosols on clouds and precipitation. The model treated discrete size-resolved aging and internal mixing of aerosol soot, discrete size-resolved evolution of clouds/precipitation from externally and internally mixed aerosol particles, and soot absorption in aerosols, clouds/precipitation, and snow/sea ice. Eliminating FS, FS+BSG (FSBSG), and CH4 in isolation were found to reduce global surface air temperatures by a statistically significant 0.3-0.5 K, 0.4-0.7 K, and 0.2-0.4 K, respectively, averaged over 15 years. As net global warming (0.7-0.8 K) is due mostly to gross pollutant warming from fossil-fuel greenhouse gases (2-2.4 K), and FSBSG (0.4-0.7 K) offset by cooling due to non-FSBSG aerosol particles (-1.7 to -2.3 K), removing FS and FSBSG may reduce 13-16% and 17-23%, respectively, of gross warming to date. Reducing FS, FSBSG, and CH4 in isolation may reduce warming above the Arctic Circle by up to ∼1.2 K, ∼1.7 K, and ∼0.9 K, respectively. Both FS and BSG contribute to warming, but FS is a stronger contributor per unit mass emission. However, BSG may cause 8 times more mortality than FS. The global e-folding lifetime of emitted BC (from all fossil sources) against internal mixing by coagulation was ∼3 h, similar to data, and that of all BC against dry plus wet removal was ∼4.7 days. About 90% of emitted FS BC mass was lost to internal mixing by coagulation, ∼7% to wet removal, ∼3% to dry removal, and a residual remaining airborne. Of all emitted plus internally mixed BC, ∼92% was wet removed and ∼8% dry removed, with a residual remaining airborne. The 20 and 100 year surface temperature response per unit continuous emissions (STRE) (similar to global warming potentials (GWPs)) of BC in FS were 4500-7200 and 2900-4600, respectively; those of BC in BSG were 2100-4000 and 1060-2020, respectively; and those of CH4 were 52-92 and 29-63, respectively. Thus, FSBSG may be the second leading cause of warming after CO2. Controlling FS and BSG may be a faster method of reducing Arctic ice loss and global warming than other options, including controlling CH4 or CO2, although all controls are needed. Copyright 2010 by the American Geophysical Union.


Miller D.A.B.,Stanford University
Applied Optics | Year: 2010

Optical interconnects are progressively replacing wires at shorter and shorter distances in information processing machines. This paper summarizes the progress toward and prospects for the penetration of optics all the way to the silicon chip. © 2010 Optical Society of America.


Boroditsky L.,Stanford University
Psychological science : a journal of the American Psychological Society / APS | Year: 2010

How do people think about time? Here we describe representations of time in Pormpuraaw, a remote Australian Aboriginal community. Pormpuraawans' representations of time differ strikingly from all others documented to date. Previously, people have been shown to represent time spatially from left to right or right to left, or from front to back or back to front. All of these representations are with respect to the body. Pormpuraawans instead arrange time according to cardinal directions: east to west. That is, time flows from left to right when one is facing south, from right to left when one is facing north, toward the body when one is facing east, and away from the body when one is facing west. These findings reveal a qualitatively different set of representations of time, with time organized in a coordinate frame that is independent from others reported previously. The results demonstrate that conceptions of even such fundamental domains as time can differ dramatically across cultures.


Fayer M.D.,Stanford University
Physiology | Year: 2011

In many situations, form biology to geology, water occurs not as the pure bulk liquid but rather in nanoscopic environments, in contact with interfaces, interacting with ionic species, and interacting with large organic molecules. In such situations, water does not behave in the same manner as it does in the pure bulk liquid. Water dynamics are fundamental to many processes such as protein folding and proton transport. Such processes depend on the dynamics of water's hydrogen bonding network. Here, the results of ultrafast infrared experiments are described that shed light on the influences of nanoconfinement, interfaces, ions, and organic molecules on water hydrogen bond dynamics. © 2011 Int. Union Physiol. Sci./Am. Physiol. Soc.


Morton J.M.,Stanford University
Diabetes Care | Year: 2016

Obesity and diabetes represent twin health concerns in the developed world. Metabolic surgery has emerged as an established and enduring treatment for both obesity and diabetes. As the burden of obesity and diabetes varies upon the basis of ethnicity, it is also apparent that there may be differences for indications and outcomes for different ethnic groups after metabolic surgery. Whereas there appears to be evidence for variation in weight loss and complications for different ethnic groups, comorbidity remission particularly for diabetes appears to be free of ethnic disparity after metabolic surgery. The impacts of access, biology, culture, genetics, procedure, and socioeconomic status upon metabolic surgery outcomes are examined. Further refinement of the influence of ethnicity upon metabolic surgery outcomes is likely imminent. © 2016 by the American Diabetes Association.


Kambham N.,Stanford University
Advances in Anatomic Pathology | Year: 2012

Crescentic glomerulonephritis (GN) in a renal biopsy is a widely accepted "critical diagnosis" in Anatomic Pathology practice. Prompt biopsy evaluation and notification of the referring physician is essential to facilitate rapid therapeutic intervention. The differential diagnostic categories of crescentic GN include pauci-immune GN, anti-glomerular basement membrane (GBM) nephritis and immune complex-mediated GN, distinguished from one another by immunofluorescence and electron microscopic study of the renal biopsy. Immune complex-mediated GN is characterized by abundant glomerular deposits and encompasses several diseases including but not limited to lupus nephritis, cryoglobulinemic GN and immunoglobulin A nephropathy. Pauci-immune GN, with paucity of deposits, correlates closely with antineutrophil cytoplasmic antibody disease due to the identifiable circulating pathogenic antineutrophil cytoplasmic antibody in most patients. Recent studies have identified other antibodies in pauci-immune GN and implicated infectious organisms in triggering autoimmunity in a susceptible host by molecular mimicry of host antigens. Anti-GBM nephritis is a rare but potentially life-threatening autoimmune disease with circulating antibodies against GBM epitopes in α3 chain of type IV collagen. It is characterized by a linear immunoglobulin G deposition along GBM on immunofluorescence microscopy. Environmental triggers including infections and solvent exposure seem to change the tertiary structure of the type IV collagen α345 hexamer in GBM, expose neoepitopes, and initiate autoimmunity. Even in light of advances in understanding of pathophysiology and serologic testing, renal biopsy remains the mainstay of diagnosis of crescentic GN. Copyright © 2012 by Lippincott Williams &Wilkins.


Lobell D.B.,Stanford University
Global Food Security | Year: 2014

A primary goal of studying climate change adaptation is to estimate the net impacts of climate change. Many potential changes in agricultural management and technology, including shifts in crop phenology and improved drought and heat tolerance, would help to improve crop productivity but do not necessarily represent true adaptations. Here the importance of retaining a strict definition of adaptation - as an action that reduces negative or enhances positive impacts of climate change - is discussed, as are common ways in which studies misinterpret the adaptation benefits of various changes. These "adaptation illusions" arise from a combination of faulty logic, model errors, and management assumptions that ignore the tendency for farmers to maximize profits for a given technology. More consistent treatment of adaptation is needed to better inform synthetic assessments of climate change impacts, and to more easily identify innovations in agriculture that are truly more effective in future climates than in current or past ones. Of course, some of the best innovations in agriculture in coming decades may have no adaptation benefits, and that makes them no less worthy of attention. © 2014 Elsevier B.V.


MicroRNA (miRNA) genes produce three major RNA products; primary (pri-), precursor (pre-), and mature miRNAs. Each product includes sequences complementary to cognate targets, thus they all can in principle interact with the targets. In a recent study we showed that pri-miRNAs play a direct role in target recognition and repression in the absence of functional mature miRNAs. Here we examined the functional contribution of pri-miRNAs in target regulation when full-length functional miRNAs are present. We found that pri-let-7 loop nucleotides control the production of the 5' end of mature miRNAs and modulate the activity of the miRNA gene. This insight enabled us to modulate biogenesis of functional mature miRNAs and dissect the causal relationships between mature miRNA biogenesis and target repression. We demonstrate that both pri- and mature miRNAs can contribute to target repression and that their contributions can be distinguished by the differences between the pri- and mature miRNAs' sensitivity to bind to the first seed nucleotide. Our results demonstrate that the regulatory information encoded in the pri-/pre-miRNA loop nucleotides controls the activities of pri-miRNAs and mature let-7 by influencing pri-miRNA and target complex formation and the fidelity of mature miRNA seed generation.


Donos A.,Imperial College London | Hartnoll S.A.,Stanford University
Nature Physics | Year: 2013

Interaction-driven charge localization across a quantum phase transition involves a fundamental rearrangement of the low-energy degrees of freedom. This fact challenges weakly interacting quasiparticle descriptions of the physics. The canonical example of such localization is the Mott transition. Here, we present a localization mechanism distinct from 'Mottness', which employs strong interactions in an essential way. Our mechanism allows anisotropic localization: phases can arise that are insulating in some directions and metallic in others. The central observation is that localization occurs if an operator that breaks translation invariance, a 'generalized Umklapp' operator, becomes relevant in the effective low-energy theory. This does not occur at weak coupling. We realize such localization in a strongly interacting theory described by means of the holographic correspondence. Our model captures key features of metal-insulator transitions including major spectral weight transfer and bad (incoherent) metallic behaviour in the vicinity of the transition. The localized phase has a power law gap in the optical conductivity. © 2013 Macmillan Publishers Limited.


Cohen D.J.,University of California at Berkeley | Nelson W.J.,Stanford University | Maharbiz M.M.,University of California at Berkeley
Nature Materials | Year: 2014

Many normal and pathological biological processes involve the migration of epithelial cell sheets. This arises from complex emergent behaviour resulting from the interplay between cellular signalling networks and the forces that physically couple the cells. Here, we demonstrate that collective migration of an epithelium can be interactively guided by applying electric fields that bias the underlying signalling networks. We show that complex, spatiotemporal cues are locally interpreted by the epithelium, resulting in rapid, coordinated responses such as a collective U-turn, divergent migration, and unchecked migration against an obstacle. We observed that the degree of external control depends on the size and shape of the cell population, and on the existence of physical coupling between cells. Together, our results offer design and engineering principles for the rational manipulation of the collective behaviour and material properties of a tissue. © 2014 Macmillan Publishers Limited. All rights reserved.


Zare R.N.,Stanford University | Kim S.,Pohang University of Science and Technology
Annual Review of Biomedical Engineering | Year: 2010

Microfluidics, the study and control of the fluidic behavior in microstructures, has emerged as an important enabling tool for single-cell chemical analysis. The complex procedures for chemical cytometry experiments can be integrated into a single microfabricated device. The capability of handling a volume of liquid as small as picoliters can be utilized to manipulate cells, perform controlled cell lysis and chemical reactions, and efficiently minimize sample dilution after lysis. The separation modalities such as chromatography and electrophoresis within microchannels are incorporated to analyze various types of intracellular components quantitatively. The microfluidic approach offers a rapid, accurate, and cost-effective tool for single-cell biology. We present an overview of the recent developments in microfluidic technology for chemical-content analysis of individual cells. © 2010 by Annual Reviews. All rights reserved.


Moser S.C.,Susanne Moser Research and Consulting | Moser S.C.,Stanford University
Wiley Interdisciplinary Reviews: Climate Change | Year: 2014

This article synthesizes relevant literature and examples from practice to examine what is known to date about communicating climate change adaptation. It explores the language used to discuss adaptation, what is known about resonant frames, drawing on adaptation discourses in policy, practice, and the media. Identifying trends and widely applicable insights is made challenging not only by the variety of words used to speak of adaptation, but by the fact that 'adaptation' language is often not used at all. A broad literature on perceptions and experiences of climate change impacts and how these experiences affect people's valuations and emotional responses to climate change offers crucial insights to the challenges and opportunities in communicating adaptation. It reveals much about people's interest in and acceptability and knowledge of adaptation, about preferred timing and who is thought to be responsible for enacting adaptive actions. Insights from the literature on place attachment and place identity are of particular relevance to public engagement on adaptation as it goes a long way toward explaining the quality of the adaptation debate to date while offering promising opportunities for dialogue. Suggestions for improved adaptation communication practice and critical research gaps are offered. For further resources related to this article, please visit the WIREs website. Conflict of interest: The author has declared no conflicts of interest for this article. Additional Supporting Information may be found in the online version of this article. © 2014 John Wiley & Sons, Ltd.


Benitez C.M.,Stanford University
Cold Spring Harbor perspectives in biology | Year: 2012

The relentless nature and increasing prevalence of human pancreatic diseases, in particular, diabetes mellitus and adenocarcinoma, has motivated further understanding of pancreas organogenesis. The pancreas is a multifunctional organ whose epithelial cells govern a diversity of physiologically vital endocrine and exocrine functions. The mechanisms governing the birth, differentiation, morphogenesis, growth, maturation, and maintenance of the endocrine and exocrine components in the pancreas have been discovered recently with increasing tempo. This includes recent studies unveiling mechanisms permitting unexpected flexibility in the developmental potential of immature and mature pancreatic cell subsets, including the ability to interconvert fates. In this article, we describe how classical cell biology, genetic analysis, lineage tracing, and embryological investigations are being complemented by powerful modern methods including epigenetic analysis, time-lapse imaging, and flow cytometry-based cell purification to dissect fundamental processes of pancreas development.


Smolke C.D.,Stanford University | Silver P.A.,Wyss Institute for Biologically Inspired Engineering
Cell | Year: 2011

Synthetic biology aims to make the engineering of biology faster and more predictable. In contrast, systems biology focuses on the interaction of myriad components and how these give rise to the dynamic and complex behavior of biological systems. Here, we examine the synergies between these two fields. © 2011 Elsevier Inc.


Henderson V.W.,Stanford University
Climacteric | Year: 2014

The slow, progressive accumulation of pathology characteristic of Alzheimer's disease is the principal determinant of cognitive decline leading to dementia. Risk-reduction strategies during midlife focus on raising the clinical threshold for the appearance of cognitive symptoms and on reducing the extent of Alzheimer pathology. Best available evidence suggests an approach based on three, conceptually distinct strategies. (1) Raise the threshold for cognitive symptoms by improving brain health. To achieve this goal, the tactic is to reduce cerebrovascular risks mediated by hypertension, diabetes, cigarette smoking, and hyperlipidemia. (2) Raise the threshold for cognitive symptoms by enhancing cognitive reserve. Here, tactics focus on mental stimulation associated with occupation, leisure activities and social engagement. (3) Reduce the burden of Alzheimer pathology. The most promising tactic toward this end is regular aerobic exercise. Tactics in support of strategies to reduce cognitive impairment due to Alzheimer pathology are not yet substantiated by robust, consistent clinical trial evidence. There is pressing need for well-designed pragmatic trials to provide stronger evidence on preventive strategies for late-life cognitive decline and dementia. © 2014 International Menopause Society.


Roy-Chaudhuri B.,Stanford University
Nature Structural and Molecular Biology | Year: 2014

Processing of microRNAs (miRNAs) from their precursors to their biologically active mature forms is regulated during development and cancer. We show that mouse pri- or pre-miR-151 can bind to and compete with mature miR-151-5p and miR-151-3p for binding sites contained within the complementary regions of the E2f6 mRNA 3′ untranslated region (UTR). E2f6 mRNA levels were directly regulated by pri- or pre-miR-151. Conversely, miR-151-mediated repression of ARHGDIA mRNA was dependent on the level of mature miR-151 because only the mature miRNA binds the 3′ UTR. Thus, processing of miR-151 can have different effects on separate mRNA targets within a cell. A bioinformatics pipeline revealed additional candidate regions where precursor miRNAs can compete with their mature miRNA counterparts. We validated this experimentally for miR-124 and the SNAI2 3′ UTR. Hence, miRNA precursors can serve as post-transcriptional regulators of miRNA activity and are not mere biogenesis intermediates.


Romani R.W.,Stanford University
Astrophysical Journal Letters | Year: 2015

We have identified an optical/X-ray binary with an orbital period of Pb = 5.47 hr as the likely counterpart of the Fermi source 2FGL J2039.6-5620. GROND, SOAR, and DES observations provide an accurate orbital period and allow us to compare to the light curve of an archival XMM exposure. Like many short-period optical/X-ray binaries associated with Large Area Telescope sources, this may be an interacting (black widow/redback) millisecond pulsar binary. The X-ray light curve is consistent with the emission associated with an intrabinary shock. The optical light curve shows evidence of companion heating, but has a peculiar asymmetric double peak. The nature of this optical structure is not yet clear; additional optical studies and, in particular, detection of an orbital modulation in a γ-ray pulsar are needed to elucidate the nature of this peculiar source. © 2015. The American Astronomical Society. All rights reserved..


There are at least three motivations for government intervention in GHG mitigation: (1) inducing the private sector to reduce GHG emissions directly by setting a price on emissions, (2) increasing the amount of innovative activity in GHG mitigation technology development, and (3) educating the public regarding GHG-reducing investment opportunities, allowing consumers to make better private decisions. This paper discusses the pros and cons of policy instruments that might be used to respond to these motivations and makes recommendations for an appropriate mix of policy instruments over time given both economic and policital/instituional considerations. © 2010 Elsevier B.V.


Chang K.W.,Stanford University | Chinosornvatana N.,Columbia University
Journal of Clinical Oncology | Year: 2010

Purpose: We present a new ototoxicity grading system that has clearly defined and frequency-specific audiometric criteria. The purpose of this study was to validate this grading system by assessing its correspondence to audiology treatment recommendations and comparing it with the currently utilized Common Terminology Criteria for Adverse Events (CTCAE). Patients and Methods: A retrospective chart review was conducted using audiologic, demographic, and clinical data from 134 children receiving 149 courses of chemotherapy consisting of cisplatin and/or carboplatin. Pure-tone audiograms were evaluated using both our proposed grading criteria and the CTCAE criteria. The resulting grades were then compared with charted audiologic interventions and a number of clinical parameters to assess the clinical validity of the grading scale. Results: Chang grade 2a or higher predicted audiologic intervention. Although both the Chang and CTCAE ototoxicity grades were significantly related to audiologist recommendations for assistive devices such as hearing aids and/or frequency modulated systems (P < .0001), the Chang scale was more specific, with the CTCAE scale diverging from clinical recommendation at higher grades. As expected, patients receiving cisplatin had more severe hearing loss with concurrent carboplatin administration, radiation therapy exposure, younger age, smaller body-surface area, longer treatment exposure, and more severe disease. Conclusion: This grading system provides robust and clinically useful criteria to represent clinical hearing loss induced by ototoxicity with regard to the impact on speech and language and the need for assistive hearing devices. It is both more specific and more sensitive than the traditional CTCAE criteria for identifying clinically significant ototoxicity. © 2010 by American Society of Clinical Oncology.


Petrov A.,Stanford University
Cold Spring Harbor perspectives in biology | Year: 2012

Decades of extensive biochemical and biophysical research have outlined the mechanism of translation. Rich structural studies have provided detailed snapshots of the translational machinery at all phases of the translation cycle. However, the relationship between structural dynamics, composition, and function remains unknown. The multistep nature of each stage of the translation cycle results in rapid desynchronization of individual ribosomes, thus hindering elucidation of the underlying mechanisms by conventional bulk biophysical and biochemical methods. Single-molecule approaches unsusceptible to these complications have led to the first glances at both compositional and conformational dynamics on the ribosome and their impact on translational control. These experiments provide the necessary link between static structure and mechanism, often providing new perspectives. Here we review recent advances in the field and their relationship to structural and biochemical data.


Mossy cells are likely to contribute to normal hippocampal function and to the pathogenesis of neurologic disorders that involve the hippocampus, including epilepsy. Mossy cells are the least well-characterized excitatory neurons in the hippocampus. Their somatic and dendritic morphology has been described qualitatively but not quantitatively. In the present study rat mossy cells were labeled intracellularly with biocytin in vivo. Somatic and dendritic structure was reconstructed three-dimensionally. For comparison, granule cells, CA3 pyramidal cells, and CA1 pyramidal cells were labeled and analyzed using the same approach. Among the four types of hippocampal neurons, granule cells had the smallest somata, fewest primary dendrites and dendritic branches, and shortest total dendritic length. CA1 pyramidal cells had the most dendritic branches and longest total dendritic length. Mossy cells and CA3 pyramidal cells both had large somata and similar total dendritic lengths. However, mossy cell dendrites branched less than CA3 pyramidal cells, especially close to the soma. These findings suggest that mossy cells have dendritic features that are not identical to any other type of hippocampal neuron. Therefore, electrotonic properties that depend on soma-dendritic structure are likely to be distinct in mossy cells compared to other neurons. © 2012 International League Against Epilepsy.


Horowitz M.,Stanford University
Digest of Technical Papers - IEEE International Solid-State Circuits Conference | Year: 2014

Technology scaling has decreased the cost of computing to the point where it can be included in almost anything. As a result, we now live in a world surrounded by computing devices. They power our searches on Google, connect to our friends on Facebook, answer our questions to Siri, and serve us our entertainment on Youtube; they are in our homes everywhere, in all our appliances (I recently had to reboot my refrigerator), cars, workplaces, and even in the cards we send to each other. We have become so accustomed to computing becoming faster, cheaper, and lower power, we simply assume it will continue. Already, smartphone capabilities are being embedded in eye glasses [1] and smart watches [2]. © 2014 IEEE.


Lewis R.S.,Stanford University
Cold Spring Harbor Perspectives in Biology | Year: 2011

Store-operated calcium channels (SOCs) are a nearly ubiquitous Ca2+ entry pathway stimulated by numerous cell surface receptors via the reduction of Ca2+ concentration in the ER. The discovery of STIM proteins as ER Ca2+ sensors and Orai proteins as structural components of the Ca2+ release-activated Ca2+ (CRAC) channel, a prototypic SOC, opened the floodgates for exploring the molecular mechanism of this pathway and its functions. This review focuses on recent advances made possible by the use of STIM and Orai as molecular tools. I will describe our current understanding of the store-operated Ca2+ entry mechanism and its emerging roles in physiology and disease, areas of uncertainty in which further progress is needed, and recent findings that are opening new directions for research in this rapidly growing field. © 2011 Cold Spring Harbor Laboratory Press. all rights reserved.


Lock J.,Stanford University
Current Opinion in Psychiatry | Year: 2011

Purpose of review: Interest in the effectiveness of family interventions for eating disorders has increased over the past 5 years. This review considers the theoretical justification and current evidence base for the use of family treatments for eating disorders in children and adolescents. Recent findings: Family-based treatment is the best studied treatment. It has the strongest evidence base for effectiveness for anorexia nervosa in adolescents. Family-based treatment can be delivered in several formats and doses, and preliminary data suggest it can be disseminated by training and manuals. There is a more limited evidence base demonstrating the usefulness of family interventions for bulimia nervosa in adolescents. Summary: The implications of the findings of this review are that family interventions are the current first-line treatment for adolescent anorexia nervosa and promising for adolescent bulimia nervosa. Pilot studies suggest that family interventions can be disseminated in diverse clinical settings. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Pfeffer S.R.,Stanford University
Cell | Year: 2013

The 2013 Nobel Prize in Physiology or Medicine has been awarded to James Rothman, Randy Schekman, and Thomas Südhof "for their discoveries of machinery regulating vesicle traffic, a major transport system in our cells". I present a personal view of the membrane trafficking field, highlighting the contributions of these three Nobel laureates in a historical context. © 2013 Elsevier Inc.


Melles R.B.,Kaiser Permanente | Marmor M.F.,Stanford University
Ophthalmology | Year: 2015

Purpose: To describe patterns of hydroxychloroquine retinopathy distinct from the classic parafoveal (bull's eye) maculopathy. Design: Retrospective case series. Participants: Patients from a large multi-provider group practice and a smaller university referral practice diagnosed with hydroxychloroquine retinopathy. Patients with widespread or "end-stage" retinopathy were excluded. Methods: Review of ophthalmic studies (fundus photography, spectral-domain optical coherence tomography, fundus autofluorescence, multifocal electroretinography, visual fields) and classification of retinopathy into 1 of 3 patterns: parafoveal (retinal changes 2°-6° from the fovea), pericentral (retinal changes ≥8° from the fovea), or mixed (retinal changes in both parafoveal and pericentral areas). Main Outcome Measures: Relative frequency of different patterns of hydroxychloroquine retinopathy and comparison of risk factors. Results: Of 201 total patients (18% Asian) with hydroxychloroquine retinopathy, 153 (76%) had typical parafoveal changes, 24 (12%) also had a zone of pericentral damage, and 24 (12%) had pericentral retinopathy without any parafoveal damage. Pericentral retinopathy alone was seen in 50% of Asian patients but only in 2% of white patients. Patients with the pericentral pattern were taking hydroxychloroquine for a somewhat longer duration (19.5 vs. 15.0 years, P < 0.01) and took a larger cumulative dose (2186 vs. 1813 g, P = 0.02) than patients with the parafoveal pattern, but they were diagnosed at a more severe stage of toxicity. Conclusions: Hydroxychloroquine retinopathy does not always develop in a parafoveal (bull's eye) pattern, and a pericentral pattern of damage is especially prevalent among Asian patients. Screening practices may need to be adjusted to recognize pericentral and parafoveal hydroxychloroquine retinopathy. © 2015 by the American Academy of Ophthalmology.


Denny M.W.,Stanford University | Gaylord B.,University of California at Davis
Annual Review of Marine Science | Year: 2010

The emerging field of marine ecomechanics provides an explicit physical framework for exploring interactions among marine organisms and between these organisms and their environments. It exhibits particular utility through its construction of predictive, mechanistic models, a number of which address responses to changing climatic conditions. Examples include predictions of (a) the change in relative abundance of corals as a function of colony morphology, ocean acidity, and storm intensity; (b) the rate of disturbance and patch formation in beds of mussels, a competitive dominant on many intertidal shores; (c) the dispersal and recruitment patterns of giant kelps, an important nearshore foundation species; (d) the effects of turbulence on external fertilization, a widespread method of reproduction in the sea; and (e) the long-term incidence of extreme ecological events. These diverse examples emphasize the breadth of marine ecomechanics. Indeed, its principles can be applied to any ecological system. © 2010 by Annual Reviews.


Maher K.,Stanford University
Earth and Planetary Science Letters | Year: 2010

In order to evaluate the importance of hydrologic processes in controlling chemical weathering rates, a reactive transport analysis is used to interpret chemical weathering rate data for a range of systems. An analysis of weathering rates for granitic material shows that weathering rates depend most strongly on fluid residence times and fluid flow rates, and depend very weakly on material age. Over moderate fluid residence times from 5. days to 10. yr, characteristic of soils and some aquifers, transport-controlled weathering explains the orders of magnitude variation in weathering rates to a better extent than material age. For fluid residence times greater than 10. yr, characteristic of some aquifers, saprolites, and most marine sediments, a purely thermodynamic-control on chemical weathering rates sustains chemical weathering-this control may be due to clay precipitation, which can drive weathering of primary minerals, or microbial processes which alter the fluid chemistry via the oxidation of organic matter. In addition, this analysis suggests that the apparent time dependence of chemical weathering rates commonly used to model the evolution of Earth's landforms may be attributable to transport-controlled weathering and the evolution of hydrologic properties over time. If hydrologic processes are the primary control on chemical weathering rates, the nature of the temperature dependence of chemical weathering rates is also altered. © 2010 Elsevier B.V.


Hargreaves B.,Stanford University
Journal of Magnetic Resonance Imaging | Year: 2012

Gradient-echo sequences are widely used in magnetic resonance imaging (MRI) for numerous applications ranging from angiography to perfusion to functional MRI. Compared with spin-echo techniques, the very short repetition times of gradient-echo methods enable very rapid 2D and 3D imaging, but also lead to complicated "steady states." Signal and contrast behavior can be described graphically and mathematically, and depends strongly on the type of spoiling: fully balanced (no spoiling), gradient spoiling, or radiofrequency (RF)-spoiling. These spoiling options trade off between high signal and pure T1 contrast, while the flip angle also affects image contrast in all cases, both of which can be demonstrated theoretically and in image examples. As with spin-echo sequences, magnetization preparation can be added to gradient-echo sequences to alter image contrast. Gradient-echo sequences are widely used for numerous applications such as 3D perfusion imaging, functional MRI, cardiac imaging, and MR angiography. © 2012 Wiley-Liss, Inc.


Steinman L.,Stanford University
Journal of Internal Medicine | Year: 2010

Steinman L (Stanford University, Stanford, CA, USA). Inverse vaccination, the opposite of Jenner's concept, for therapy of autoimmunity (foresight). J Intern Med 2010: 267: 441-451. DNA-based vaccines to induce antigen-specific inhibition of immune responses in human autoimmune diseases represent the inverse of what Jenner intended when he invented vaccination. Jenner's vaccine induced antigen-specific immunity to small pox. DNA vaccines for autoimmunity have been developed in preclinical settings, and now tested in human trials. The first two clinical trials, one in relapsing remitting multiple sclerosis, and the other in type 1 diabetes indicate that specific inhibition of antigen-specific antibody and T-cell responses is attainable in humans. Further development of this approach is ongoing. This new version of immunization termed 'inverse vaccination' when applied to autoimmune diseases, may allow targeted reduction of unwanted antibody and T-cell responses to autoantigens, while leaving the remainder of the immune system intact. The method of specifically reducing a pathological adaptive autoimmune response is termed inverse vaccination. © 2010 Blackwell Publishing Ltd.


Women who do not have a documented germline mutation or who do not have a strong family history suspicious for a germline mutation are considered to be at average risk of ovarian cancer. Women who have confirmed deleterious BRCA1 and BRCA2 germline mutations are high risk of ovarian cancer. In addition, women who have a strong family history of either ovarian or breast cancer may carry a deleterious mutation and must be presumed to be at higher-than-average risk, even if they have not been tested, because there could be other mutations that are either untested or yet undiscovered that confirm higher-than-average risk of these diseases. We reviewed studies pertaining to prophylactic bilateral salpingo-oophorectomy in women at average risk of ovarian cancer who are undergoing hysterectomy for benign disease. We also reviewed the role of prophylactic bilateral salpingo-oophorectomy in preventing ovarian cancer based on the level of risk of the patient. For women at average risk of ovarian cancer who are undergoing a hysterectomy for benign conditions, the decision to perform prophylactic bilateral salpingo-oophorectomy should be individualized after appropriate informed consent, including a careful analysis of personal risk factors. Several studies suggest an overall negative health effect when prophylactic bilateral salpingo-oophorectomy is performed before the age of menopause. Ovarian conservation before menopause may be especially important in patients with a personal or strong family history of cardiovascular or neurological disease. Conversely, women at high risk of ovarian cancer should undergo risk-reducing bilateral salpingo-oophorectomy. © 2010 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams &Wilkins.


Sullivan S.S.,Stanford University
Neurotherapeutics | Year: 2012

While pediatric sleep disorders are relatively common, treatments are often not straightforward. There is often a paucity of gold standard studies and data available to guide clinicians, treatments may yield arguably incomplete results, interventions may require chronic use, and/ or involve multiple modalities including behavioral interventions that require high parental and family commitment. This review points out diagnostic differences compared to adults and focuses on current therapy for selected common pediatric sleep disorders including sleep disordered breathing/ obstructive sleep apnea, narcolepsy, and restless legs syndrome. Other common pediatric sleep disorders, such as insomnia and parasomnias, are not covered. © 2012 The American Society for Experimental NeuroTherapeutics, Inc.


Youyou W.,University of Cambridge | Kosinski M.,Stanford University | Stillwell D.,University of Cambridge
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

Judging others' personalities is an essential skill in successful social living, as personality is a key driver behind people's interactions, behaviors, and emotions. Although accurate personality judgments stem from social-cognitive skills, developments in machine learning show that computer models can also make valid judgments. This study compares the accuracy of human and com-puter- based personality judgments, using a sample of 86,220 volunteers who completed a 100-item personality questionnaire. We show that (i) computer predictions based on a generic digital footprint (Facebook Likes) are more accurate (r = 0.56) than those made by the participants' Facebook friends using a personality questionnaire (r = 0.49); (ii) computer models show higher interjudge agreement; and (iii) computer personality judgments have higher external validity when predicting life outcomes such as substance use, political attitudes, and physical health; for some outcomes, they even outperform the self-rated personality scores. Computers outpacing humans in personality judgment presents significant opportunities and challenges in the areas of psychological assessment, marketing, and privacy.


DiGiulio D.B.,Stanford University
Seminars in Fetal and Neonatal Medicine | Year: 2012

Recent polymerase chain reaction (PCR)-based studies estimate the prevalence of microbial invasion of the amniotic cavity (MIAC) to be ≥30-50% higher than that detected by cultivation-based methods. Some species that have been long implicated in causing MIAC remain among the common invaders (e.g. Ureaplasma spp., Mycoplasma spp., Fusobacterium spp. Streptococcus spp., Bacteroides spp. and Prevotella spp.). Yet we now know from studies based on PCR of the 16S ribosomal DNA that cultivation-resistant anaerobes belonging to the family Fusobacteriaceae (particularly Sneathia sanguinegens, and Leptotrichia spp.) are also commonly found in amniotic fluid. Other diverse microbes detected by PCR of amniotic fluid include as-yet uncultivated and uncharacterized species. The presence of some microbial taxa is associated with specific host factors (e.g. Candida spp. and an indwelling intrauterine device). It appears that MIAC is polymicrobial in 24-67% of cases, but the potential role of pathogen synergy is poorly understood. A causal relationship between diverse microbes, as detected by PCR, and preterm birth is supported by types of association (e.g. space, time and dose) proposed as alternatives to Koch's postulates for inferring causality from molecular findings. The microbial census of the amniotic cavity remains unfinished. A more complete understanding may inform future research directions leading to improved strategies for preventing, diagnosing and treating MIAC. © 2011.


Balakrishnan R.,Stanford University
Database : the journal of biological databases and curation | Year: 2013

The Gene Ontology Consortium (GOC) is a community-based bioinformatics project that classifies gene product function through the use of structured controlled vocabularies. A fundamental application of the Gene Ontology (GO) is in the creation of gene product annotations, evidence-based associations between GO definitions and experimental or sequence-based analysis. Currently, the GOC disseminates 126 million annotations covering >374,000 species including all the kingdoms of life. This number includes two classes of GO annotations: those created manually by experienced biocurators reviewing the literature or by examination of biological data (1.1 million annotations covering 2226 species) and those generated computationally via automated methods. As manual annotations are often used to propagate functional predictions between related proteins within and between genomes, it is critical to provide accurate consistent manual annotations. Toward this goal, we present here the conventions defined by the GOC for the creation of manual annotation. This guide represents the best practices for manual annotation as established by the GOC project over the past 12 years. We hope this guide will encourage research communities to annotate gene products of their interest to enhance the corpus of GO annotations available to all. DATABASE URL: http://www.geneontology.org.


Lehmann L.,Stanford University
American Naturalist | Year: 2010

Genes affect not only the behavior and fitness of their carriers but also that of other individuals. According to Hamilton's rule, whether a mutant gene will spread in the gene pool depends on the effects of its carrier on the fitness of all individuals in the population, each weighted by its relatedness to the carrier. However, social behaviors may affect not only recipients living in the generation of the actor but also individuals living in subsequent generations. In this note, I evaluate space-time relatedness coefficients for localized dispersal. These relatedness coefficients weight the selection pressures on long-lasting behaviors, which stem from a multigenerational gap between phenotypic expression by actors and the resulting environmental feedback on the fitness of recipients. Explicit values of space-time relatedness coefficients reveal that they can be surprisingly large for typical dispersal rates, even for hundreds of generations in the future. © 2009 by The University of Chicago.


Kroger T.,Stanford University
IEEE Transactions on Robotics | Year: 2011

A concept of online trajectory generation for robot motion control systems that enables instantaneous reactions to unforeseen sensor events was introduced in a former publication. This concept is now extended with the important feature of homothety. Homothetic trajectories are 1-D straight lines in a multidimensional space and are relevant for all straight-line motion operations in robotics. This paper clarifies 1) how online concepts can be used to generate homothetic trajectories and 2) how we can instantaneously react to (sensor) events with homothetic trajectories. To underline the practical relevance, real-world experimental results with a seven-degree-of-freedom (DOF) robot arm are shown. © 2011 IEEE.


Chang T.C.,Stanford University
Journal of endourology / Endourological Society | Year: 2013

Emerging optical imaging technologies such as confocal laser endomicroscopy (CLE) hold promise in improving bladder cancer diagnosis. The purpose of this study was to determine the interobserver agreement of image interpretation using CLE for bladder cancer. Experienced CLE urologists (n=2), novice CLE urologists (n=6), pathologists (n=4), and nonclinical researchers (n=5) were recruited to participate in a 2-hour computer-based training consisting of a teaching and validation set of intraoperative white light cystoscopy (WLC) and CLE video sequences from patients undergoing transurethral resection of bladder tumor. Interobserver agreement was determined using the κ statistic. Of the 31 bladder regions analyzed, 19 were cancer and 12 were benign. For cancer diagnosis, experienced CLE urologists had substantial agreement for both CLE and WLC+CLE (90%, κ 0.80) compared with moderate agreement for WLC alone (74%, κ 0.46), while novice CLE urologists had moderate agreement for CLE (77%, κ 0.55), WLC (78%, κ 0.54), and WLC+CLE (80%, κ 0.59). Pathologists had substantial agreement for CLE (81%, κ 0.61), and nonclinical researchers had moderate agreement (77%, κ 0.49) in cancer diagnosis. For cancer grading, experienced CLE urologists had fair to moderate agreement for CLE (68%, κ 0.64), WLC (74%, κ 0.67), and WLC+CLE (53%, κ 0.33), as did novice CLE urologists for CLE (53%, κ 0.39), WLC (66%, κ 0.50), and WLC+CLE (61%, κ 0.49). Pathologists (65%, κ 0.55) and nonclinical researchers (61%, κ 0.56) both had moderate agreement for CLE in cancer grading. CLE is an adoptable technology for cancer diagnosis in novice CLE observers after a short training with moderate interobserver agreement and diagnostic accuracy similar to WLC alone. Experienced CLE observers may be capable of achieving substantial levels of agreement for cancer diagnosis that is higher than with WLC alone.


Mursula et al. (2011, hereafter MTL11) suggest that there is a 22-year variation in solar wind activity that coupled with the variation in heliographic latitude of the Earth during the year, gives rise to an apparent semiannual variation of geomagnetic activity in averages obtained over several solar cycles. They suggest that the observed semiannual variation is seriously overestimated and is largely an artifact of this inferred 22-year variation. We show: (1) that there is no systematically alternating annual variation of geomagnetic activity or of the solar driver, changing with the polarity of the solar polar fields, (2) that the universal time variation of geomagnetic activity at all times has the characteristic imprint of the equinoctial hypothesis rather than that of the axial hypothesis required by the suggestion of MTL11, and (3) that the semiannual variation is not an artifact, is not overestimated, and does not need revision. Copyright 2011 by the American Geophysical Union.


Monack D.M.,Stanford University
Current Opinion in Microbiology | Year: 2012

Host-adapted strains of Salmonella enterica cause systemic infections and have the ability to persist systemically for long periods of time and pose significant public-health problems. Multidrug-resistant Salmonella enteric serovar Typhi (S. Typhi) and non-Typhoidal Salmonella (NTS) are on the increase, and are often associated with HIV infection. Chronically infected hosts are often asymptomatic and transmit disease to naïve hosts via fecal shedding of bacteria, thereby serving as a critical reservoir for disease. Salmonella utilizes multiple strategies to evade and modulate host innate and adaptive immune responses in order to persist in the presence of a robust immune response. In addition, the intestinal microbiota plays a critical role in controlling Salmonella infection, disease, and transmissibility. © 2011 Elsevier Ltd.


Dong X.,Stanford University
Journal of High Energy Physics | Year: 2014

We propose a general formula for calculating the entanglement entropy in theories dual to higher derivative gravity where the Lagrangian is a contraction of Riemann tensors. Our formula consists of Wald's formula for the black hole entropy, as well as corrections involving the extrinsic curvature. We derive these corrections by noting that they arise from naively higher order contributions to the action which are enhanced due to would-be logarithmic divergences. Our formula reproduces the Jacobson-Myers entropy in the context of Lovelock gravity, and agrees with existing results for general four-derivative gravity. We emphasize that the formula should be evaluated on a particular bulk surface whose location can in principle be determined by solving the equations of motion with conical boundary conditions. This may be difficult in practice, and an alternative method is desirable. A natural prescription is simply minimizing our formula, analogous to the Ryu-Takayanagi prescription for Einstein gravity. We show that this is correct in several examples including Lovelock and general four-derivative gravity. © 2014 SISSA.


Kircher M.F.,Sloan Kettering Cancer Center | Willmann J.K.,Stanford University
Radiology | Year: 2012

Molecular imaging, generally defined as noninvasive imaging of cellular and subcellular events, has gained tremendous depth and breadth as a research and clinical discipline in recent years. The coalescence of major advances in engineering, molecular biology, chemistry, immunology, and genetics has fueled multi- and interdisciplinary innovations with the goal of driving clinical noninvasive imaging strategies that will ultimately allow disease identification, risk stratification, and monitoring of therapy effects with unparalleled sensitivity and specificity. Techniques that allow imaging of molecular and cellular events facilitate and go hand in hand with the development of molecular therapies, offering promise for successfully combining imaging with therapy. While traditionally nuclear medicine imaging techniques, in particular positron emission tomography (PET), PET combined with computed tomography (CT), and single photon emission computed tomography, have been the molecular imaging methods most familiar to clinicians, great advances have recently been made in developing imaging techniques that utilize magnetic resonance (MR), optical, CT, and ultrasonographic (US) imaging. In the first part of this review series, we present an overview of the principles of MR imaging-, CT-, and US-based molecular imaging strategies. © RSNA, 2012.


Meador K.J.,Stanford University
Neurology | Year: 2015

Marked changes in US medical school funding began in the 1960s with progressively increasing revenues from clinical services. The growth of clinical revenues slowed in the mid-1990s, creating a funding crisis for US academic health care centers, who responded by having their faculty increase their clinical duties at the expense of research activities. Surveys document the resultant stresses on the academic clinician researcher. The NIH provides greater funding for basic and translational research than for clinical research, and the new Patient-Centered Outcomes Research Institute is inadequately funded to address the scope of needed clinical research. An increasing portion of clinical research is funded by industry, which leaves many important clinical issues unaddressed. There is an inadequate supply of skilled clinical researchers and a lack of external support for clinical research. The impact on the academic environment in university medical centers is especially severe on young faculty, who have a shrinking potential to achieve successful academic careers. National health care research funding policies should encourage the right balance of life-science investigations. Medical universities need to improve and highlight education on clinical research for students, residents, fellows, and young faculty. Medical universities also need to provide appropriate incentives for clinical research. Without training to ensure an adequate supply of skilled clinical researchers and a method to adequately fund clinical research, discoveries from basic and translational research cannot be clinically tested and affect patient care. Thus, many clinical problems will continue to be evaluated and treated with inadequate or even absent evidence-based knowledge. © 2015 American Academy of Neurology.


Huda A.,Stanford University
Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society | Year: 2012

The goal of liver transplantation (LT) is to maximize the length and quality of a patient's life and facilitate his or her return to full productivity. The aims of this study were (1) to use the United Network for Organ Sharing (UNOS) data set to determine the proportions of recipients who were employed and unemployed within 24 months after LT between 2002 and 2008 and (2) to examine the factors associated with a return to employment. UNOS data that were collected since the adoption of the Model for End-Stage Liver Disease scoring system on February 27, 2002 were analyzed. There were 21,942 transplant recipients who met the inclusion criteria. The employment status of the recipients was analyzed within a 60-day window at the following times after transplantation: 6, 12, and 24 months. Approximately one-quarter of the LT recipients (5360 or 24.4%) were employed within 24 months after transplantation, and the remaining recipients had not returned to work. The demographic variables that were independently associated with posttransplant employment included an age of 18 to 40 years, male sex, a college degree, Caucasian race, and pretransplant employment. Patients with alcoholic liver disease had a significantly lower rate of employment than patients with other etiologies of liver disease. The recipients who were employed after transplantation had significantly better functional status than those who were not employed. In conclusion, the employment rate after LT is low, with only one-quarter of LT recipients employed. New national and individual transplant program policies are needed to assess the root causes of unemployment in recipients who wish to work after LT. Copyright © 2011 American Association for the Study of Liver Diseases.


Objectives. This Anna Monika Award Lecture updates the role of the hypothalamic-pituitary-adrenal (HPA) axis in the pathogenesis and treatment of psychotic major depression (PMD). Methods. Published reports from our group and others on the clinical phenomenology (including cognition), HPA axis activity, and genetics of PMD are reviewed as are published trials of the GR antagonist, mifepristone. Results. Current prevalence of PMD is 0.4%. PMD patients demonstrate significant elevations in HPA activity (e.g., particularly high rates of dexamethasone non-suppression, high post-dexamethasone cortisol, etc.) as well as significant impairment in cognition (attention, executive function/response inhibition and verbal and visual memory). High cortisol levels correlate with a number of cognitive deficits (e.g., verbal memory). Allelic variants of the glucocorticoid receptor (GR) gene contribute significantly to both cortisol levels and to measures of psychosis; corticotropin-releasing hormone receptor 1 variants contribute to measures of depression and psychosis. GR antagonists have produced rapid improvement in psychotic symptoms, although failed trials indicate a therapeutic blood level that may require a dose of 1,200 mg/day that is much higher than the commonly tested 600 mg/day. Conclusions. HPA axis over-activity appears to play a major role in the pathogenesis of PMD and is a target of drug development. © 2015 Informa Healthcare.


Katznelson L.,Stanford University
Journal of Clinical Endocrinology and Metabolism | Year: 2010

The approach to a patient with acromegaly and persistent disease after surgery requires a complex diagnostic assessment. Acromegaly is a chronic and insidious disease that is associated with multisystem comorbidities, including cardiovascular disease, hypertension, sleep apnea syndrome, colon polyposis, arthropathy, and metabolic complications including glucose intolerance and type 2 diabetes mellitus. Patients also have a variety of signs and symptoms, including headache, arthralgias, carpal tunnel syndrome, sweating, fatigue, and psychological issues that impact significantly on quality of life. The recommended approach to the evaluation of the postoperative patient includes a biochemical assessment, with measurement of serum IGF-I along with a glucose-suppressed GH value, radiological assessment to determine location of residual tumor and presence of mass effects, a physical examination for evidence of skeletal and soft tissue overgrowth and related signs of acromegaly, and a thorough clinical assessment for the presence of comorbidities. Repeat surgery is indicated if there is residual tumor that is surgically accessible and there may be a chance for surgical cure, or if there are persistent mass effects upon the optic chiasm. Otherwise, medical therapy is indicated, utilizing somatostatin analogs, dopamine agonists, and pegvisomant, a GH receptor antagonist. Radiation therapy is usually relegated to situations where medical therapy is ineffective or poorly tolerated or where patients would prefer not to sustain the cost of long-term medical therapy. The choice of therapy requires close dialog among endocrinologists, neurosurgeons, radiation therapists, and neuroophthalmologists for optimal care of patients. Copyright © 2010 by The Endocrine Society.


Lobell D.B.,Stanford University
Field Crops Research | Year: 2013

Field experiments and simulation models are useful tools for understanding crop yield gaps, but scaling up these approaches to understand entire regions over time has remained a considerable challenge. Satellite data have repeatedly been shown to provide information that, by themselves or in combination with other data and models, can accurately measure crop yields in farmers' fields. The resulting yield maps provide a unique opportunity to overcome both spatial and temporal scaling challenges and thus improve understanding of crop yield gaps. This review discusses the use of remote sensing to measure the magnitude and causes of yield gaps. Examples from previous work demonstrate the utility of remote sensing, but many areas of possible application remain unexplored. Two simple yet useful approaches are presented that measure the persistence of yield differences between fields, which in combination with maps of average yields can be used to direct further study of specific factors. Whereas the use of remote sensing may have historically been restricted by the cost and availability of fine resolution data, this impediment is rapidly receding. © 2012 Elsevier B.V.


Wagoner R.V.,Stanford University
Astrophysical Journal Letters | Year: 2012

We compare the determinations of the angular momentum of stellar mass black holes via the continuum and line methods with those from diskoseismology. The assumption that is being tested is that one of the quasi-periodic oscillations (QPOs) in each binary X-ray source is produced by the fundamental g-mode. This should be the most robust and visible normal mode of oscillation of the accretion disk, and therefore its absence should rule out diskoseismology as the origin of QPOs. The comparisons are consistent with the second highest frequency QPO being produced by this g-mode, but are not consistent with models in which one QPO frequency is that of the innermost stable circular orbit. © 2012. The American Astronomical Society. All rights reserved..


Williams L.M.,Stanford University
The Lancet Psychiatry | Year: 2016

Although there have been tremendous advances in the understanding of human dysfunctions in the brain circuitry for self-reflection, emotion, and cognitive control, a brain-based taxonomy for mental disease is still lacking. As a result, these advances have not been translated into actionable clinical tools, and the language of brain circuits has not been incorporated into training programmes. To address this gap, I present this synthesis of published work, with a focus on functional imaging of circuit dysfunctions across the spectrum of mood and anxiety disorders. This synthesis provides the foundation for a taxonomy of putative types of dysfunction, which cuts across traditional diagnostic boundaries for depression and anxiety and includes instead distinct types of neural circuit dysfunction that together reflect the heterogeneity of depression and anxiety. This taxonomy is suited to specifying symptoms in terms of underlying neural dysfunction at the individual level and is intended as the foundation for building mechanistic research and ultimately guiding clinical practice. © 2016 Elsevier Ltd.


Romani R.W.,Stanford University
Astrophysical Journal Letters | Year: 2012

We have found an optical/X-ray counterpart candidate for the bright, but presently unidentified, Fermi source 2FGL J1311.7-3429. This counterpart undergoes large-amplitude quasi-sinusoidal optical modulation with a 1.56 hr (5626s) period. The modulated flux is blue at peak, with T eff 14, 000 K, and redder at minimum. Superimposed on this variation are dramatic optical flares. Archival X-ray data suggest modest binary modulation, but no eclipse. With the γ-ray properties, this appears to be another black-widow-type millisecond pulsar. If confirmation pulses can be found in the GeV data, this binary will have the shortest orbital period of any known spin-powered pulsar. The flares may be magnetic events on the rapidly rotating companion or shocks in the companion-stripping wind. While this may be a radio-quiet millisecond pulsar, we show that such objects are a small subset of the γ-ray pulsar population. © 2012. The American Astronomical Society. All rights reserved..


Luscher C.,University of Geneva | Malenka R.C.,Stanford University
Cold Spring Harbor Perspectives in Biology | Year: 2012

Long-term potentiation and long-term depression (LTP/LTD) can be elicited by activating N-methyl-D-aspartate (NMDA)-type glutamate receptors, typically by the coincident activity of pre- and postsynaptic neurons. The early phases of expression are mediated by a redistribution of AMPA-type glutamate receptors: More receptors are added to potentiate the synapse or receptors are removed to weaken synapses. With time, structural changes become apparent, which in general require the synthesis of new proteins. The investigation of the molecular and cellular mechanisms underlying these forms of synaptic plasticity has received much attention, because NMDA receptor-dependent LTP and LTD may constitute cellular substrates of learning and memory. © 2012 Cold Spring Harbor Laboratory Press; all rights reserved.


Gravel S.,Stanford University
Genetics | Year: 2012

Migrations have played an important role in shaping the genetic diversity of human populations. Understanding genomic data thus requires careful modeling of historical gene flow. Here we consider the effect of relatively recent population structure and gene flow and interpret genomes of individuals that have ancestry from multiple source populations as mosaics of segments originating from each population. This article describes general and tractable models for local ancestry patterns with a focus on the length distribution of continuous ancestry tracts and the variance in total ancestry proportions among individuals. The models offer improved agreement with Wright-Fisher simulation data when compared to the state-of-the art and can be used to infer timedependent migration rates from multiple populations. Considering HapMap African-American (ASW) data, we find that a model with two distinct phases of "European" gene flow significantly improves the modeling of both tract lengths and ancestry variances. © 2012 by the Genetics Society of America.


Whittemore A.S.,Stanford University
Statistics in Medicine | Year: 2010

Interest in targeted disease prevention has stimulated development of models that assign risks to individuals, using their personal covariates. We need to evaluate these models and quantify the gains achieved by expanding a model to include additional covariates. This paper reviews several performance measures and shows how they are related. Examples are used to show that appropriate performance criteria for a risk model depend upon how the model is used. Application of the performance measures to risk models for hypothetical populations and for US women at risk of breast cancer illustrate two additional points. First, model performance is constrained by the distribution of risk-determining covariates in the population. This complicates the comparison of two models when applied to populations with different covariate distributions. Second, all summary performance measures obscure model features of relevance to its utility for the application at hand, such as performance in specific subgroups of the population. In particular, the precision gained by adding covariates to a model can be small overall, but large in certain subgroups. We propose new ways to identify these subgroups and to quantify how much they gain by measuring the additional covariates. Those with largest gains could be targeted for cost-efficient covariate assessment. © 2010 John Wiley & Sons, Ltd.


Karzmark P.,Stanford University
Neurosurgery | Year: 2012

Adults with moyamoya disease (MMD) have been shown to manifest cognitive impairment, but it is unclear whether this is the result of ischemic stroke. To determine whether adults with MMD but without stroke have cognitive impairment. We performed detailed neuropsychological assessments in 30 adults with angiographically confirmed MMD without magnetic resonance imaging (MRI) evidence of stroke. Twenty patients (67%) exhibited small T2 hyperintensities in the cerebral subcortical white matter on brain MRI but no evidence of gray matter damage. Significant cognitive impairment, defined as half of test scores ≥ 1 SD below the normal mean, was present in 7 patients (23%). Executive functioning, mental efficiency, and word finding were the ability areas most frequently impaired, whereas memory was relatively intact. Clinically significant emotional distress (depression and/or anxiety) was present in 11 patients (37%). Comparable cognitive findings were also observed in the subset of 10 patients (33%) with completely normal static brain MRI. Cognitive impairment in MMD can occur in the absence of ischemic stroke as manifested on MRI.


Nielsen T.O.,University of British Columbia | West R.B.,Stanford University
Journal of Clinical Oncology | Year: 2010

Whereas most solid tumors are characterized by considerable genetic instability and molecular heterogeneity, sarcomas include many subtypes with very specific underlying molecular events driving oncogenesis. Gene expression profiling and other modern techniques have consequently had particular success in identifying the critical biologic pathways active in specific sarcomas, yielding insights which can be translated into useful diagnostic biomarkers. Public availability of data sets and new sequencing-based technologies will accelerate this process. Molecular studies have also identified oncogenic pathways of particular importance in sarcomas which can be targeted by investigational drugs. Examples include histone deacetylases in translocation-associated sarcomas of young adults, Akt/mammalian target of rapamycin in pleomorphic sarcomas, and macrophage colony-stimulating factor in tenosynovial giant cell tumor. Despite challenges in organization and accrual, future clinical trials of sarcomas need to be designed that take into account specific molecular subtypes as distinct diseases. © 2010 by American Society of Clinical Oncology.


Giaccia A.J.,Stanford University
Current Opinion in Cell Biology | Year: 2010

Autophagy is a cellular degradation process in which portions of the cell's cytoplasm and organelles are sequestered in a double-membrane bound vesicle called an autophagosome. Fusion of autophagosomes with lysosomes results in the formation of autolysosomes, where the proteins and organelles are degraded. This degradation pathway is induced under nutrient deprivation, metabolic stress or microenvironmental conditions to ensure energy balance, clearance of damaged proteins and adaptation to stress. Disruption of autophagy is involved in diverse human diseases including cancer. In particular, the regulation of autophagy in cancer cells is complex since it can enhance tumor cell survival in response to certain stresses, yet it can also act to suppress the initiation of tumor growth. Understanding the signaling pathways involved in the regulation of autophagy as well as the autophagy process itself represents new directions in the development of anticancer therapies. In this review, we discuss recent advances in our understanding the complexity of the autophagy process and the development of targeted therapies that modulate autophagy in cancer cells in the clinic. © 2009.


Philip A.G.S.,Stanford University
Neonatology | Year: 2012

When bronchopulmonary dysplasia (BPD) was first described in 1967, the use of assisted ventilation in neonates was in its infancy. High concentrations of oxygen were implicated, and BPD was equated with 'pulmonary oxygen toxicity'. The etiologic role of not only oxygen but also peak inspiratory pressures and the duration of exposure to both was emphasized in the 1970s, but BPD remained a dreaded complication of managing respiratory distress syndrome in the 1980s. It was only after exogenous surfactant became commercially available for endotracheal administration that 'classical' BPD began to disappear and was replaced by the 'new' BPD. 'Classical' BPD was seen in more mature preterm infants (>28 weeks' gestational age) and in its severe form was characterized radiographically by micro- and macrocysts of the lung, lung hyperinflation and flattening of the diaphragms. In contrast, 'new' BPD is seen in less mature infants (<28 weeks' gestational age), has comparatively mild radiographic abnormalities and has been defined as continued oxygen requirement at 36 weeks' postmenstrual age. Pathologically, 'classical' BPD frequently revealed obstructive bronchiolitis and fibrosis of lung parenchyma, whereas 'new' BPD demonstrates minimal fibrosis but uniform arrest of development. Herein, factors which may contribute to the etiology of BPD are described, as well as possible preventative and therapeutic strategies. Copyright © 2012 S. Karger AG, Basel..


Gans H.A.,Stanford University
Vaccine | Year: 2013

The need for neonatal vaccines is supported by the high disease burden during the first year of life particularly in the first month. Two-thirds of childhood deaths are attributable to infectious diseases of which viruses represent key pathogens. Many infectious diseases have the highest incidence, severity and mortality in the first months of life, and therefore early life vaccination would provide significant protection and life savings. For some childhood viral diseases successful vaccines exist, such as against measles, mumps, rubella, varicella, influenza poliovirus, and rotavirus, but their use in the first year particularly at birth is not yet practiced. Vaccines against other key pathogens continue to elude scientists such as against respiratory syncytial virus. The obstacles for early and neonatal vaccination are complex and include host factors, such as a developing immune system and the interference of passively acquired antibodies, as well vaccine-specific issues, such as optimal route of administration, titer and dosing requirements. Importantly, additional host and infrastructure barriers also present obstacles to neonatal vaccination in the developing world where morbidity and mortality rates are highest. This review will highlight the current live viral vaccines and their use in the first year of life, focusing on efficacy and entertaining the barriers that exist. It is important to understand the successes of current vaccines and use this knowledge to determine strategies that are successful in young infants and for the development of new vaccines for use in early life. © 2012 Elsevier Ltd.


Delage E.,HEC Montreal | Ye Y.,Stanford University
Operations Research | Year: 2010

We propose a robust optimization approach to address a multiperiod inventory control problem under ambiguous demands,that is, only limited information of the demand distributions such as mean, support, and some measures of deviations. Our framework extends to correlated demands and is developed around a factor-based model, which has the ability to incorporate business factors as well as time-series forecast effects of trend, seasonality, and cyclic variations. We can obtain the parameters of the replenishment policies by solving a tractable deterministic optimization problem in the form of a second-order cone optimization problem (SOCP), with solution time; unlike dynamic programming approaches, it is polynomial and independent on parameters such as replenishment lead time, demand variability, and correlations. Theproposed truncated linear replenishment policy (TLRP), which is piecewise linear with respect to demand history, improves upon static and linear policies, and achieves objective values that are reasonably close to optimal. © 2010 INFORMS.


Alloreactivity of donor lymphocytes leads to graft-versus-host disease (GVHD) contributing to significant morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Within the past decade, significant progress has been made in elucidating the mechanisms underlying the immunologic dysregulation characteristic of GVHD. The recent discoveries of different cell subpopulations with immune regulatory function has led to a number of studies aimed at understanding their role in allogeneic HCT and possible application for the prevention and treatment of GVHD and a host of other immune-mediated diseases. Preclinical animal modeling has helped define the potential roles of distinct populations of regulatory cells that have progressed to clinical translation with promising early results.


Pfeffer S.R.,Stanford University
Biochemical Society Transactions | Year: 2012

Rab GTPases are master regulators of membrane traffic. By binding to distinct sets of effector proteins, Rabs catalyse the formation of function-specifying membrane microdomains. They are delivered to membranes by a protein named GDI (guanine-nucleotide-dissociation inhibitor) and are stabilized there after nucleotide exchange by effector binding. In the present mini-review, I discuss what we know about how Rab GTPases are delivered to the correct membrane-bound compartments and how Rab GTPase cascades order Rabs within the secretory and endocytic pathways. Finally, I describe how Rab cascades may establish the distinct compartments of the Golgi complex to permit ordered processing, sorting and secretion of secretory cargoes. ©The Authors Journal compilation ©2012 Biochemical Society.


Wood C.L.,Stanford University | Lafferty K.D.,U.S. Geological Survey
Trends in Ecology and Evolution | Year: 2013

Recent reviews have argued that disease control is among the ecosystem services yielded by biodiversity. Lyme disease (LD) is commonly cited as the best example of the 'diluting' effect of biodiversity on disease transmission, but many studies document the opposite relationship, showing that human LD risk can increase with forestation. Here, we unify these divergent perspectives and find strong evidence for a positive link between biodiversity and LD at broad spatial scales (urban to suburban to rural) and equivocal evidence for a negative link between biodiversity and LD at varying levels of biodiversity within forests. This finding suggests that, across zoonotic disease agents, the biodiversity-disease relationship is scale dependent and complex. © 2012 Elsevier Ltd.


Boyd S.D.,Stanford University
Annual Review of Pathology: Mechanisms of Disease | Year: 2013

Advances in DNA sequencing technology have allowed comprehensive investigation of the genetics of human beings and human diseases. Insights from sequencing the genomes, exomes, or transcriptomes of healthy and diseased cells in patients are already enabling improved diagnostic classification, prognostication, and therapy selection for many diseases. Understanding the data obtained using new high-throughput DNA sequencing methods, choices made in sequencing strategies, and common challenges in data analysis and genotype-phenotype correlation is essential if pathologists, geneticists, and clinicians are to interpret the growing scientific literature in this area. This review highlights some of the major results and discoveries stemming from high-throughput DNA sequencing research in our understanding of Mendelian genetic disorders, hematologic cancer biology, infectious diseases, the immune system, transplant biology, and prenatal diagnostics. Transition of new DNA sequencing methodologies to the clinical laboratory is under way and is likely to have a major impact on all areas of medicine. © 2013 by Annual Reviews. All rights reserved.


Feng L.,Stanford University | Frommer W.B.,Carnegie Institution for Science
Trends in Biochemical Sciences | Year: 2015

SemiSWEETs and SWEETs have emerged as unique sugar transporters. First discovered in plants with the help of fluorescent biosensors, homologs exist in all kingdoms of life. Bacterial and plant homologs transport hexoses and sucrose, whereas animal SWEETs transport glucose. Prokaryotic SemiSWEETs are small and comprise a parallel homodimer of an approximately 100 amino acid-long triple helix bundle (THB). Duplicated THBs are fused to create eukaryotic SWEETs in a parallel orientation via an inversion linker helix, producing a similar configuration to that of SemiSWEET dimers. Structures of four SemiSWEETs have been resolved in three states: open outside, occluded, and open inside, indicating alternating access. As we discuss here, these atomic structures provide a basis for exploring the evolution of structure-function relations in this new class of transporters. © 2015 Elsevier Ltd.


Hanawalt P.C.,Stanford University
Frontiers in Microbiology | Year: 2015

The early history of the esoteric phenomenon of thymineless death (TLD) is recounted, from the pioneering discovery by Seymour Cohen and Hazel Barner, through my graduate studies at Yale and postdoctoral research in Copenhagen. My principal contribution was the discovery that restricted synthesis of protein and RNA permits cultures of Escherichia coli to complete their DNA replication cycles without initiating new ones, and that cells held in this physiological state are immune to the lethality of thymine deprivation; unbalanced growth is not the fundamental cause of TLD. The successful synchronization of the DNA replication cycle contributed to formulation of the replicon concept. Studies at Stanford revealed a specific requirement for transcription and led to the discovery of a TLD-resistant mutant in a new gene, termed recQ, with important homologs in humans and most other organisms. The lessons learned from research on TLD underscore the value of basic research in bacterial systems that can have profound implications for human health. © 2015 Hanawalt.


Individuals affected with narcolepsy represent a vulnerable segment of the population. However, we only have a partial understanding of this vulnerability. Our study aims to examine psychiatric disorders and medical conditions associated with narcolepsy. A total of 320 narcoleptic participants were interviewed regarding sleeping habits, health, medication consumption, medical conditions (International Statistical Classification of Diseases and Related Health Problems, 10th edition), sleep disorders (International Classification of Sleep Disorders, second edition [ICSD-2]) and mental disorders (Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision [DSM-IV-TR]) using Sleep-EVAL. A general population comparison sample (N=1464) matched for age, sex, and body mass index (BMI) and interviewed with the same instrument was used to estimate odds ratios (OR). Five diseases were more frequently observed among narcoleptic participants, including hypercholesterolemia (OR, 1.51), diseases of the digestive system (OR, 3.27), heart diseases (OR, 2.07), upper respiratory tract diseases (OR, 2.52), and hypertension (OR, 1.32). Most frequent psychiatric disorders among the narcolepsy group were major depressive disorder (MDD) (OR, 2.67) and social anxiety disorder (OR, 2.43), both affecting nearly 20% of narcoleptic individuals. However, most mood and anxiety disorders were more prevalent among the narcoleptic group. Alcohol abuse or alcohol dependence was comparable between groups. Narcolepsy is associated with a high comorbidity of both medical conditions and psychiatric disorders that need to be addressed when developing a treatment plan. Copyright © 2013 Elsevier B.V. All rights reserved.


Koza J.R.,Stanford University
Genetic Programming and Evolvable Machines | Year: 2010

Genetic programming has now been used to produce at least 76 instances of results that are competitive with human-produced results. These human-competitive results come from a wide variety of fields, including quantum computing circuits, analog electrical circuits, antennas, mechanical systems, controllers, game playing, finite algebras, photonic systems, image recognition, optical lens systems, mathematical algorithms, cellular automata rules, bioinformatics, sorting networks, robotics, assembly code generation, software repair, scheduling, communication protocols, symbolic regression, reverse engineering, and empirical model discovery. This paper observes that, despite considerable variation in the techniques employed by the various researchers and research groups that produced these human-competitive results, many of the results share several common features. Many of the results were achieved by using a developmental process and by using native representations regularly used by engineers in the fields involved. The best individual in the initial generation of the run of genetic programming often contains only a small number of operative parts. Most of the results that duplicated the functionality of previously issued patents were novel solutions, not infringing solutions. In addition, the production of human-competitive results, as well as the increased intricacy of the results, are broadly correlated to increased availability of computing power tracked by Moore's law. The paper ends by predicting that the increased availability of computing power (through both parallel computing and Moore's law) should result in the production, in the future, of an increasing flow of human-competitive results, as well as more intricate and impressive results. © Springer Science+Business Media, LLC 2010.


Ioannidis J.P.A.,Foundation for Research and Technology Hellas | Ioannidis J.P.A.,Tufts University | Ioannidis J.P.A.,Stanford University
Archives of General Psychiatry | Year: 2011

Context: Many studies report volume abnormalities in diverse brain structures in patients with various mental health conditions. Objective: To evaluate whether there is evidence for an excess number of statistically significant results in studies of brain volume abnormalities that suggest the presence of bias in the literature. Data Sources: PubMed (articles published from January 2006 to December 2009). Study Selection: Recent meta-analyses of brain volume abnormalities in participants with various mental health conditions vs control participants with 6 or more data sets included, excluding voxel-based morphometry. Data Extraction: Standardized effect sizes were extracted in each data set, and it was noted whether the results were "positive" (P<.05) or not. For each data set in each meta-analysis, I estimated the power to detect at α=.05 an effect equal to the summary effect of the respective meta-analysis. The sum of the power estimates gives the number of expected positive data sets. The expected number of positive data sets can then be compared against the observed number. Data Synthesis: From 8 articles, 41 meta-analyses with 461 data sets were evaluated (median, 10 data sets per meta-analysis) pertaining to 7 conditions. Twenty-one of the 41 meta-analyses had found statistically significant associations, and 142 of 461 (31%) data sets had positive results. Even if the summary effect sizes of the metaanalyses were unbiased, the expected number of positive results would have been only 78.5 compared with the observed number of 142 (P<.001). Conclusion: There are too many studies with statistically significant results in the literature on brain volume abnormalities. This pattern suggests strong biases in the literature, with selective outcome reporting and selective analyses reporting being possible explanations. ©2011 American Medical Association. All rights reserved.


Kosovichev A.G.,Stanford University
Astrophysical Journal Letters | Year: 2011

The X2.2-class solar flare of 2011 February 15 produced a powerful "sunquake" event, representing a helioseismic response to the flare impact in the solar photosphere, which was observed with the Helioseismic and Magnetic Imager (HMI) instrument on board the Solar Dynamics Observatory (SDO). The impulsively excited acoustic waves formed a compact wave packet traveling through the solar interior and appearing on the surface as expanding wave ripples. The initial flare impacts were observed in the form of compact and rapid variations of the Doppler velocity, line-of-sight magnetic field, and continuum intensity. These variations formed a typical two-ribbon flare structure, and are believed to be associated with thermal and hydrodynamic effects of high-energy particles heating the lower atmosphere. The analysis of the SDO/HMI and X-ray data from RHESSI shows that the helioseismic waves were initiated by the photospheric impact in the early impulsive phase, observed prior to the hard X-ray (50-100keV) impulse, and were probably associated with atmospheric heating by relatively low-energy electrons (6-50keV) and heat flux transport. The impact caused a short motion in the sunspot penumbra prior to the appearance of the helioseismic wave. It is found that the helioseismic wave front traveling through a sunspot had a lower amplitude and was significantly delayed relative to the front traveling outside the spot. These observations open new perspectives for studying the flare photospheric impacts and for using the flare-excited waves for sunspot seismology. © 2011. The American Astronomical Society. All rights reserved.


Beasley M.R.,Stanford University
MRS Bulletin | Year: 2011

In this article, we review the reasons why high-temperature cuprate superconductors are inadequate for electric power applications, above liquid nitrogen temperatures, and examine the underlying causes. The most important reason is their low superconducting Cooper pair density, which for thermodynamic reasons reduces the theoretical maximum critical current density. We also discuss how low pair density (and high anisotropy) increase thermodynamic phase fluctuations of the macroscopic quantum pair wave function, which in turn leads to a limitation on the transition temperature itself. Finally, we discuss how, in highly correlated superconductors, there may be a conflict between the conditions necessary to achieve high transition temperatures in the face of phase fluctuations and the conditions necessary to produce strong pairing interactions. © 2011 Materials Research Society.


Stephens N.M.,Northwestern University | Hamedani M.G.,Stanford University | Destin M.,Northwestern University
Psychological Science | Year: 2014

College students who do not have parents with 4-year degrees (first-generation students) earn lower grades and encounter more obstacles to success than do students who have at least one parent with a 4-year degree (continuing-generation students). In the study reported here, we tested a novel intervention designed to reduce this social-class achievement gap with a randomized controlled trial (N = 168). Using senior college students' real-life stories, we conducted a difference-education intervention with incoming students about how their diverse backgrounds can shape what they experience in college. Compared with a standard intervention that provided similar stories of college adjustment without highlighting students' different backgrounds, the difference-education intervention eliminated the social-class achievement gap by increasing first-generation students' tendency to seek out college resources (e.g., meeting with professors) and, in turn, improving their end-of-year grade point averages. The difference-education intervention also improved the college transition for all students on numerous psychosocial outcomes (e.g., mental health and engagement). © The Author(s) 2014.


Moss R.B.,Stanford University
Annals of the New York Academy of Sciences | Year: 2012

Allergic bronchopulmonary aspergillosis (ABPA) is a virulent manifestation of the Th2 asthma endotype that includes asthma with fungal sensitization, raising the feasibility of biological therapies targeting Th2 pathway molecules or cells. The first molecule amenable to clinical intervention with a biological was IgE. Omalizumab, a humanized monoclonal antibody (Mab), targets the same epitope on the IgE CH3 region that binds to and crosslinks high-affinity receptors on mast cells and basophils, thereby initiating the allergic inflammatory cascade. Omalizumab is licensed for allergic asthma and has been beneficial in uncontrolled studies of ABPA, reducing exacerbations and steroid requirements. Trials of several Mabs directed against the Th2 cytokine IL-5 show clinical benefit in patients with a severe refractory eosinophilic asthma phenotype, while a Mab against IL-13 is effective in asthma patients with a Th2-high endotype. Immunodulation is also feasible with small molecule biologicals, such as antisense oligodeoxynucleotides and cholecalciferol. Controlled trials of Th2-inhibiting biologicals in patients with ABPA and severe asthma with fungal sensitization appear warranted. © 2012 New York Academy of Sciences.


Fendorf S.,Stanford University | Michael H.A.,University of Delaware | Van Geen A.,Lamont Doherty Earth Observatory
Science | Year: 2010

Over the past few decades, groundwater wells installed in rural areas throughout the major river basins draining the Himalayas have become the main source of drinking water for tens of millions of people. Groundwater in this region is much less likely to contain microbial pathogens than surface water but often contains hazardous amounts of arsenic - a known carcinogen. Arsenic enters groundwater naturally from rocks and sediment by coupled biogeochemical and hydrologic processes, some of which are presently affected by human activity. Mitigation of the resulting health crisis in South and Southeast Asia requires an understanding of the transport of arsenic and key reactants such as organic carbon that could trigger release in zones with presently low groundwater arsenic levels.


Klippenstein S.J.,Argonne National Laboratory | Pande V.S.,Stanford University | Truhlar D.G.,University of Minnesota
Journal of the American Chemical Society | Year: 2014

This Perspective presents a personal overview of the current status of the theory of chemical kinetics and mechanisms for complex processes. We attempt to assess the status of the field for reactions in the gas phase, at gas-solid interfaces, in liquid solutions, in enzymes, and for protein folding. Some unifying concepts such as potential energy surfaces, free energy, master equations, and reaction coordinates occur in more than one area. We hope this Perspective will be useful for highlighting recent advances and for identifying important areas for future research. © 2013 American Chemical Society.


Friederici A.D.,Max Planck Institute | Friederici A.D.,Stanford University
Physiological Reviews | Year: 2011

Language processing is a trait of human species. The knowledge about its neurobiological basis has been increased considerably over the past decades. Different brain regions in the left and right hemisphere have been identified to support particular language functions. Networks involving the temporal cortex and the inferior frontal cortex with a clear left lateralization were shown to support syntactic processes, whereas less lateralized temporo-frontal networks subserve semantic processes. These networks have been substantiated both by functional as well as by structural connectivity data. Electrophysiological measures indicate that within these networks syntactic processes of local structure building precede the assignment of grammatical and semantic relations in a sentence. Suprasegmental prosodic information overtly available in the acoustic language input is processed predominantly in a temporo-frontal network in the right hemisphere associated with a clear electrophysiological marker. Studies with patients suffering from lesions in the corpus callosum reveal that the posterior portion of this structure plays a crucial role in the interaction of syntactic and prosodic information during language processing. © 2011 by the American Physiological Society.


Samanez-Larkin G.R.,Yale University | Knutson B.,Stanford University
Nature Reviews Neuroscience | Year: 2015

As the global population ages, older decision makers will be required to take greater responsibility for their own physical, psychological and financial well-being. With this in mind, researchers have begun to examine the effects of ageing on decision making and associated neural circuits. A new 'affect-integration-motivation' (AIM) framework may help to clarify how affective and motivational circuits support decision making. Recent research has shed light on whether and how ageing influences these circuits, providing an interdisciplinary account of how ageing can alter decision making. © 2015 Macmillan Publishers Limited. All rights reserved.


Clark K.L.,Stanford University
Proceedings. Biological sciences / The Royal Society | Year: 2011

Since the discovery of the nervous system's electrical excitability more than 200 years ago, neuroscientists have used electrical stimulation to manipulate brain activity in order to study its function. Microstimulation has been a valuable technique for probing neural circuitry and identifying networks of neurons that underlie perception, movement and cognition. In this review, we focus on the use of stimulation in behaving primates, an experimental system that permits causal inferences to be made about the effect of stimulation-induced activity on the resulting behaviour or neural signals elsewhere in the brain.


Zhao H.,Stanford University
Translational Stroke Research | Year: 2013

Ischemic postconditioning has been established for its protective effects against stroke in animal models. It is performed after post-stroke reperfusion and refers to a series of induced ischemia or a single brief one. This review article addresses major hurdles in clinical translation of ischemic postconditioning to stroke patients, including potential hazards, the lack of well-defined protective paradigms, and the paucity of deeply understood protective mechanisms. A hormetic model, often used in toxicology to describe a dose-dependent response to a toxic agent, is suggested to study both beneficial and detrimental effects of ischemic postconditioning. Experimental strategies are discussed, including how to define the hazards of ischemic (homologous) postconditioning and the possibility of employing non-ischemic (heterologous) postconditioning to facilitate clinical translation. This review concludes that a more detailed assessment of ischemic postconditioning and studies of a broad range of heterologous postconditioning models are warranted for future clinical translation. © 2013 Springer Science+Business Media New York.


Sagan S.M.,McGill University | Sarnow P.,Stanford University
Science | Year: 2013

No longer elusive, mammalian antiviral RNA interference is now confirmed.


Jones D.L.,Salk Institute for Biological Studies | Rando T.A.,Stanford University
Nature Cell Biology | Year: 2011

Ageing is accompanied by a progressive decline in stem cell function, resulting in less effective tissue homeostasis and repair. Here we discuss emerging invertebrate models that provide insights into molecular pathways of age-related stem cell dysfunction in mammals, and we present various paradigms of how stem cell functionality changes with age, including impaired self-renewal and aberrant differentiation potential. © 2011 Macmillan Publishers Limited. All rights reserved.


Background: Individuals affected with narcolepsy represent a vulnerable segment of the population. However, we only have a partial understanding of this vulnerability. Our study aims to examine psychiatric disorders and medical conditions associated with narcolepsy. Methods: A total of 320 narcoleptic participants were interviewed regarding sleeping habits, health, medication consumption, medical conditions (International Statistical Classification of Diseases and Related Health Problems, 10th edition), sleep disorders (International Classification of Sleep Disorders, second edition [ICSD-2]) and mental disorders (Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision [DSM-IV-TR]) using Sleep-EVAL. A general population comparison sample (N = 1464) matched for age, sex, and body mass index (BMI) and interviewed with the same instrument was used to estimate odds ratios (OR). Results: Five diseases were more frequently observed among narcoleptic participants, including hypercholesterolemia (OR, 1.51), diseases of the digestive system (OR, 3.27), heart diseases (OR, 2.07), upper respiratory tract diseases (OR, 2.52), and hypertension (OR, 1.32). Most frequent psychiatric disorders among the narcolepsy group were major depressive disorder (MDD) (OR, 2.67) and social anxiety disorder (OR, 2.43), both affecting nearly 20% of narcoleptic individuals. However, most mood and anxiety disorders were more prevalent among the narcoleptic group. Alcohol abuse or alcohol dependence was comparable between groups. Conclusions: Narcolepsy is associated with a high comorbidity of both medical conditions and psychiatric disorders that need to be addressed when developing a treatment plan. © 2013 Elsevier B.V. All rights reserved.


Sehgal A.,Howard Hughes Medical Institute | Mignot E.,Stanford University
Cell | Year: 2011

Sleep remains one of the least understood phenomena in biology - even its role in synaptic plasticity remains debatable. Since sleep was recognized to be regulated genetically, intense research has launched on two fronts: the development of model organisms for deciphering the molecular mechanisms of sleep and attempts to identify genetic underpinnings of human sleep disorders. In this Review, we describe how unbiased, high-throughput screens in model organisms are uncovering sleep regulatory mechanisms and how pathways, such as the circadian clock network and specific neurotransmitter signals, have conserved effects on sleep from Drosophila to humans. At the same time, genome-wide association studies (GWAS) have uncovered ∼14 loci increasing susceptibility to sleep disorders, such as narcolepsy and restless leg syndrome. To conclude, we discuss how these different strategies will be critical to unambiguously defining the function of sleep. © 2011 Elsevier Inc.


Haigis K.M.,Harvard University | Sweet-Cordero A.,Stanford University
Nature Genetics | Year: 2011

Expression of oncogenes in otherwise normal cells often leads to the activation of anti-oncogenic pathways through a poorly understood process described as 'oncogenic stress'. A new study implicates the Jnk pathway signaling in the activation of p53 in response to both K-Ras and Neu oncogene expression. © 2011 Nature America, Inc. All rights reserved.


Steyaert J.,Vrije Universiteit Brussel | Kobilka B.K.,Stanford University
Current Opinion in Structural Biology | Year: 2011

Remarkable progress has been made in the field of G protein-coupled receptor (GPCR) structural biology during the past four years. Several obstacles to generating diffraction quality crystals of GPCRs have been overcome by combining innovative methods ranging from protein engineering to lipid-based screens and microdiffraction technology. The initial GPCR structures represent energetically stable inactive-state conformations. However, GPCRs signal through different G protein isoforms or G protein-independent effectors upon ligand binding suggesting the existence of multiple ligand-specific active states. These active-state conformations are unstable in the absence of specific cytosolic signaling partners representing new challenges for structural biology. Camelid single chain antibody fragments (nanobodies) show promise for stabilizing active GPCR conformations and as chaperones for crystallogenesis. © 2011 Elsevier Ltd.


Krishnan E.,Stanford University
American journal of epidemiology | Year: 2012

The objective of this study was to assess the utility of hyperuricemia as a marker for diabetes and prediabetes (impaired fasting glucose) and insulin resistance in young adults. Using Cox proportional hazards regression models, the authors analyzed 15-year follow-up data on 5,012 persons in 4 US cities who were aged 18-30 years and diabetes-free at the time of enrollment. At baseline (1986), 88% of participants had a body mass index (weight (kg)/height (m)(2)) less than 30. During the follow-up period (through 2001), the incidence rates of diabetes and prediabetes (insulin resistance and impaired fasting glucose) were higher among persons with greater serum urate concentrations. In multivariable Cox regression analyses that adjusted for age, gender, race, body mass index, family history of diabetes, diastolic blood pressure, total cholesterol, smoking, and alcohol use, the hazard ratios for diabetes, insulin resistance, and prediabetes among persons with hyperuricemia (serum urate level >7 mg/dL vs. ≤7.0 mg/dL) were 1.87 (95% confidence interval (CI): 1.33, 2.62), 1.36 (95% CI: 1.23, 1.51), and 1.25 (95% CI: 1.04, 1.52), respectively. This observation was generally consistent across subgroups. The authors conclude that hyperuricemia in the midtwenties is an independent marker for predicting diabetes and prediabetes among young adults in the subsequent 15 years.


Baker J.W.,Stanford University
Earthquake Spectra | Year: 2015

Estimation of fragility functions using dynamic structural analysis is an important step in a number of seismic assessment procedures. This paper discusses the applicability of statistical inference concepts for fragility function estimation, describes appropriate fitting approaches for use with various structural analysis strategies, and studies how to fit fragility functions while minimizing the required number of structural analyses. Illustrative results show that multiple stripe analysis produces more efficient fragility estimates than incremental dynamic analysis for a given number of structural analyses, provided that some knowledge of the building's capacity is available prior to analysis so that relevant portions of the fragility curve can be approximately identified. This finding has other benefits, given that the multiple stripe analysis approach allows for different ground motions to be used for analyses at varying intensity levels, to represent the differing characteristics of low-intensity and high-intensity shaking. The proposed assessment approach also provides a framework for evaluating alternate analysis procedures that may arise in the future. © 2015, Earthquake Engineering Research Institute.


Newman B.,Stanford University
Radiologic Clinics of North America | Year: 2011

This article presents an overview of the benign and malignant neoplasms that affect the chest in children and their imaging characteristics. The relative roles of plain film, fluoroscopy, ultrasound, CT, MR imaging, and nuclear imaging in assessing these lesions are reviewed. Areas covered include the mediastinum, heart, lungs, airway, pleura, and chest wall. © 2011 Elsevier Inc.


Cornfield D.N.,Stanford University
Current Opinion in Pediatrics | Year: 2013

Purpose of review: The present review seeks to review the pathophysiologic processes that underlie the development of acute respiratory distress syndrome (ARDS) in children. The review intends to provide the physiologic foundation for the treatment strategies that are associated with the most optimal outcome. Recent findings: In infants and children, ARDS remains a significant cause of morbidity and mortality. Although any infant or child can develop ARDS, children who have experienced trauma, pneumonia, aspiration, or immune compromise are at increased risk. Data indicate that adoption of an open-lung ventilation strategy, characterized by sufficient positive end-expiratory pressure to avoid atelectasis, a tidal volume that is limited to less than 5-7 cc/kg per breath and a plateau pressure of 30 cm of water or less provides the greatest likelihood of survival and minimizes lung injury. The relative benefits of strategies such as high frequency oscillatory ventilation, surfactant replacement therapy and inhaled nitric oxide are considered. Summary: ARDS remains a cause of significant mortality and morbidity in children. By employing sound physiologic principles, clinical outcomes can be optimized. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Fisher R.S.,Stanford University | Velasco A.L.,Clinica de Epilepsia
Nature Reviews Neurology | Year: 2014

Neurostimulation enables adjustable and reversible modulation of disease symptoms, including those of epilepsy. Two types of brain neuromodulation, comprising anterior thalamic deep brain stimulation and responsive neurostimulation at seizure foci, are supported by Class I evidence of effectiveness, and many other sites in the brain have been targeted in small trials of neurostimulation therapy for seizures. Animal studies have mainly assisted in the identification of potential neurostimulation sites and parameters, but much of the clinical work is only loosely based on fundamental principles derived from the laboratory, and the mechanisms by which brain neurostimulation reduces seizures remain poorly understood. The benefits of stimulation tend to increase over time, with maximal effect seen typically 1-2 years after implantation. Typical reductions of seizure frequency are approximately 40% acutely, and 50-69% after several years. Seizure intensity might also be reduced. Complications from brain neurostimulation are mainly associated with the implantation procedure and hardware, including stimulation-related paraesthesias, stimulation-site infections, electrode mistargeting and, in some patients, triggered seizures or even status epilepticus. Further preclinical and clinical experience with brain stimulation surgery should lead to improved outcomes by increasing our understanding of the optimal surgical candidates, sites and parameters. © 2014 Macmillan Publishers Limited.


Chang A.L.S.,Stanford University
Journal of Investigative Dermatology | Year: 2015

Rosacea is a common, chronic skin disease that is currently incurable. Although environmental factors influence rosacea, the genetic basis of rosacea is not established. In this genome-wide association study, a discovery group of 22,952 individuals (2,618 rosacea cases and 20,334 controls) was analyzed, leading to identification of two significant single-nucleotide polymorphisms (SNPs) associated with rosacea, one of which replicated in a new group of 29,481 individuals (3,205 rosacea cases and 26,262 controls). The confirmed SNP, rs763035 (P=8.0 × 10-11 discovery group; P=0.00031 replication group), is intergenic between HLA-DRA and BTNL2. Exploratory immunohistochemical analysis of HLA-DRA and BTNL2 expression in papulopustular rosacea lesions from six individuals, including one with the rs763035 variant, revealed staining in the perifollicular inflammatory infiltrate of rosacea for both proteins. In addition, three HLA alleles, all MHC class II proteins, were significantly associated with rosacea in the discovery group and confirmed in the replication group: HLA-DRB1*03:01 (P=1.0 × 10-8 discovery group; P=4.4 × 10-6 replication group), HLA-DQB1*02:01 (P=1.3 × 10-8 discovery group; P=7.2 × 10-6 replication group), and HLA-DQA1*05:01 (P=1.4 × 10-8 discovery group; P=7.6 × 10-6 replication group). Collectively, the gene variants identified in this study support the concept of a genetic component for rosacea, and provide candidate targets for future studies to better understand and treat rosacea.Journal of Investigative Dermatology advance online publication, 12 March 2015; doi:10.1038/jid.2015.53. © 2015 The Society for Investigative Dermatology, Inc


Steinman L.,Stanford University
Annual Review of Immunology | Year: 2014

Eighty percent of individuals with multiple sclerosis (MS) initially develop a clinical pattern with periodic relapses followed by remissions, called relapsing-remitting MS (RRMS). This period of fluctuating disease may last for a decade or more. Clinical relapses reflect acute inflammation in the central nervous system (CNS), composed of the brain and spinal cord. Often, different anatomic areas in the CNS are involved each time a relapse occurs, resulting in varied clinical manifestations in each instance. Relapses are nearly always followed by some degree of remission, though recovery to baseline status before the flare is often incomplete. There are nine approved drugs for treatment of RRMS. The most potent drug for inhibiting relapses, the humanized anti-α4 integrin antibody known as Natalizumab, blocks homing of mononuclear cells to the CNS. The mechanisms of action of the approved drugs for RRMS provide a strong foundation for understanding the pathobiology of the relapse. Despite substantial progress in controlling relapses with the current armamentarium of medications, there is much to learn and ever more effective and safe therapies to develop. © 2014 by Annual Reviews. All rights reserved.


Strober S.,Stanford University
Immunologic Research | Year: 2014

Although organ and bone marrow transplantations are life-saving procedures for patients with terminal diseases, the requirement for the lifelong use of immunosuppressive drugs to prevent organ graft rejection and the development of graft versus host disease (GVHD) remain important problems. Experimental approaches to solve these problems, first in preclinical models and then in clinical studies, developed at Stanford during the past 40 years are summarized in this article. The approaches use fractionated radiation of the lymphoid tissues, a procedure initially developed to treat Hodgkin's disease, to alter the immune system such that tolerance to organ transplants can be achieved and GVHD can be prevented after the establishment of chimerism. In both instances, the desired goal was achieved when the balance of immune cells was changed to favor regulatory innate and adaptive immune cells that suppress the conventional immune cells that ordinarily promote inflammation and tissue injury. © Springer Science+Business Media 2014.


Osborne J.,Stanford University
Science | Year: 2010

Argument and debate are common in science, yet they are virtually absent from science education. Recent research shows, however, that opportunities for students to engage in collaborative discourse and argumentation offer a means of enhancing student conceptual understanding and students' skills and capabilities with scientific reasoning. As one of the hallmarks of the scientist is critical, rational skepticism, the lack of opportunities to develop the ability to reason and argue scientifically would appear to be a significant weakness in contemporary educational practice. In short, knowing what is wrong matters as much as knowing what is right. This paper presents a summary of the main features of this body of research and discusses its implications for the teaching and learning of science.


Pfeffer S.R.,Stanford University
Cold Spring Harbor perspectives in biology | Year: 2011

The trans-Golgi network (TGN) receives a select set of proteins from the endocytic pathway-about 5% of total plasma membrane glycoproteins (Duncan and Kornfeld 1988). Proteins that are delivered include mannose 6-phosphate receptors (MPRs), TGN46, sortilin, and various toxins that hitchhike a ride backward through the secretory pathway to intoxicate cells after they exit into the cytoplasm from the endoplasmic reticulum (ER). This article will review work on the molecular players that drive protein transport from the endocytic pathway to the TGN. Distinct requirements have revealed multiple routes for retrograde transport; in addition, the existence of multiple, potential coat proteins and/or cargo adaptors imply that multiple vesicular transfers are likely involved. Several comprehensive reviews have appeared recently and should be sought for additional details (Bonifacino and Rojas 2006; Johannes and Popoff 2008).


Nachury M.V.,Stanford University
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2014

Cilia and flagella are closely related centriole-nucleated protrusions of the cell with roles in motility and signal transduction. Two of the best-studied signalling pathways organized by cilia are the transduction cascade for the morphogen Hedgehog in vertebrates and the mating pathway that initiates gamete fusion in the unicellular green alga Chlamydomonas reinhardtii. What is the role of cilia in these signalling transduction cascades? In both Hedgehog and mating pathways, all signalling intermediates have been found to localize to cilia, and, for some signalling factors, ciliary localization is regulated by pathway activation. Given a concentration factor of three orders of magnitude provided by translocating a protein into the cilium, the compartment model proposes that cilia act as miniaturized reaction tubes bringing signalling factors and processing enzymes in close proximity. On the other hand, the scaffolding model views the intraflagellar transport machinery, whose primary function is to build cilia and flagella, as a molecular scaffold for the mating transduction cascade at the flagellar membrane. While these models may coexist, it is hoped that a precise understanding of the mechanisms that govern signalling inside cilia will provide a satisfying answer to the question 'how do cilia organize signalling?'. This review covers the evidence supporting each model of signalling and outlines future directions that may address which model applies in given biological settings. © 2014 The Author(s) Published by the Royal Society.


Knope M.L.,Stanford University
Molecular Phylogenetics and Evolution | Year: 2013

With 92 species along the North American Pacific Coast, marine sculpins represent the most species-rich radiation of fishes in this region. I used the mitochondrial cytochrome b gene and the nuclear ribosomal S7 intron for 99 species (76 North American, 19 Asian, and four North Atlantic) to produce the most complete phylogenetic hypothesis yet generated for this assemblage. Maximum likelihood and Bayesian analyses produced highly similar tree topologies. While many previously proposed groupings based on morphology are recovered, the molecular data suggest that a number of genera are para- or polyphyletic. However, this analysis supports the monophyly of one large clade that is found exclusively along the North American Pacific Coast (Chitonotous-Ruscarius-Artedius-Orthonopius-Clinocottus-Leiocottus-Oligocottus). Some sibling species have disjunct ranges, suggesting allopatric speciation. However, many other sibling species have largely overlapping ranges, and repeated habitat shifts appear to have facilitated diversification. © 2012 Elsevier Inc.


Barnes P.D.,Stanford University
Radiologic Clinics of North America | Year: 2011

Because of the controversy involving the determination of child abuse, or nonaccidental injury (NAI), radiologists must be familiar with the issues, literature, and principles of evidence-based medicine to understand the role of imaging. Children with suspected NAI must receive protective evaluation along with a timely and complete clinical and imaging work-up. Imaging findings cannot stand alone and must be correlated with clinical findings, laboratory testing, and pathologic and forensic examinations. Only the child protection investigation may provide the basis for inflicted injury in the context of supportive clinical, imaging, biomechanical, or pathology findings. © 2011 Elsevier Inc.


Moerner W.E.,Stanford University
Journal of Microscopy | Year: 2012

In this short review, the general principles are described for obtaining microscopic images with resolution beyond the optical diffraction limit with single molecules. Although it has been known for several decades that single-molecule emitters can blink or turn on and off, in recent work the addition of on/off control of molecular emission to maintain concentrations at very low levels in each imaging frame combined with sequential imaging of sparse subsets has enabled the reconstruction of images with resolution far below the optical diffraction limit. Single-molecule active control microscopy provides a powerful window into information about nanoscale structures that was previously unavailable. © 2012 The Authors Journal of Microscopy © 2012 Wadsworth Center, New York State Department of Health.


Lowe D.R.,Stanford University
Bulletin of the Geological Society of America | Year: 2013

The ca. 3260 Ma contact between the largely volcanic Onverwacht Group and overlying largely sedimentary Fig Tree Group in the Barberton greenstone belt, South Africa, is widely marked by chert dikes that extend downward for up to 100 m into underlying sedimentary and volcanic rocks of the Mendon Formation (Onverwacht Group). In the Barite Valley area, these dikes formed as open fractures that were filled by both precipitative fill and the downward flowage of liquefied carbonaceous sediments and ash at the top of the Mendon Formation. Spherules that formed during a large meteorite or asteroid impact event occur in a wave- and/or current-deposited unit, spherule bed S2, which widely marks the Onverwacht-Fig Tree contact, and as loose grains and masses within some chert dikes up to 50 m below the contact. Four main types of chert dikes and veins are recognized: (Type 1) irregular dikes up to 8 m wide that extend downward across as much as 100 m of stratigraphy; (Type 2) small vertical dikes, most <1 m wide, which are restricted to the lower half of the Mendon chert section; (Type 3) small crosscutting veins, most <50 cm across, filled with precipitative silica; and (Type 4) small irregular to bedding-parallel to irregular veins, mostly <10 cm wide, filled with translucent precipitative silica. Type 2 dikes formed first and reflect a short-lived seismic event that locally decoupled the sedimentary section at the top of the Mendon Formation from underlying volcanic rocks and opened narrow vertical tension fractures in the lower, lithified part of the sedimentary section. Later seismic events triggered formation of the larger type 1 fractures throughout the sedimentary and upper volcanic section, widespread liquefaction of soft, uppermost Mendon sediments, andflowage of the liquefied sediments and loose impact-generated spherules into the open fractures. Late-stage tsunamis everywhere eroded and reworked the spherule layer. The coincidence of crustal disruption, dike formation, spherule deposition, and tsunami activity suggests that all were related to the S2 impact or impact cluster. Crustal disruption at this time also formed local relief that provided clastic sediment to the postimpact Fig Tree Group, including a small conglomeratic fan delta in the Barite Valley area. Remobilization and further movement of debris in the subsurface continued for some time. Locally, the deposition of dense baritic sediments over soft dike materials induced remobilization of material in the dike, causing foundering of S2 and ~1-2 m of overlying baritic sediments into the dike. Spherule beds occur at the base of the Fig Tree Group over wide areas of the Barberton belt, marking the abrupt change from ~300 m.y. of predominantly anorogenic, mafic, and komatiitic volcanism of the Onverwacht Group to orogenic clastic sedimentation and associated felsic volcanism of the Fig Tree Group. This area never again returned to Onverwachtstyle mafic and ultramafic volcanism but evolved ~100 m.y. later into the Kaapvaal craton. These results indicate that this major transition in crustal evolution coincided with and was perhaps triggered by major impact events ca. 3260-3240 Ma. © 2013 Geological Society of America.


DeVeale B.,University of Toronto | van der Kooy D.,University of Toronto | Babak T.,Stanford University
PLoS Genetics | Year: 2012

In contrast to existing estimates of approximately 200 murine imprinted genes, recent work based on transcriptome sequencing uncovered parent-of-origin allelic effects at more than 1,300 loci in the developing brain and two adult brain regions, including hundreds present in only males or females. Our independent replication of the embryonic brain stage, where the majority of novel imprinted genes were discovered and the majority of previously known imprinted genes confirmed, resulted in only 12.9% concordance among the novel imprinted loci. Further analysis and pyrosequencing-based validation revealed that the vast majority of the novel reported imprinted loci are false-positives explained by technical and biological variation of the experimental approach. We show that allele-specific expression (ASE) measured with RNA-Seq is not accurately modeled with statistical methods that assume random independent sampling and that systematic error must be accounted for to enable accurate identification of imprinted expression. Application of a robust approach that accounts for these effects revealed 50 candidate genes where allelic bias was predicted to be parent-of-origin-dependent. However, 11 independent validation attempts through a range of allelic expression biases confirmed only 6 of these novel cases. The results emphasize the importance of independent validation and suggest that the number of imprinted genes is much closer to the initial estimates. © 2012 DeVeale et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Tahmasebi P.,Stanford University | Sahimi M.,University of Southern California
Physical Review Letters | Year: 2013

Porous media, heterogeneous materials, and biological tissues are examples of ubiquitous disordered systems, the understanding of which and any physical phenomenon in them entails having an accurate model. We show that a new reconstruction method based on a cross-correlation function and a one-dimensional raster path provides an accurate description of a wide variety of such materials and media. The reconstruction uses a single 2D slice of data to reconstruct an entire 3D medium. Seventeen examples are reconstructed accurately, as indicated by two connectivity functions that we compute for them. The reconstruction method may be used for both unconditioned and conditioned problems, and is highly efficient computationally. © 2013 American Physical Society.


Linde A.,Stanford University
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2013

We describe a simple model of chaotic inflation in supergravity where one can easily tune not only the basic cosmological parameters such as n s, r, and fNL but also a possible (subdominant) cosmic string contribution to the cosmic microwave background anisotropy. © 2013 American Physical Society.


Bertoli C.,University College London | Skotheim J.M.,Stanford University | De Bruin R.A.M.,University College London
Nature Reviews Molecular Cell Biology | Year: 2013

The accurate transition from G1 phase of the cell cycle to S phase is crucial for the control of eukaryotic cell proliferation, and its misregulation promotes oncogenesis. During G1 phase, growth-dependent cyclin-dependent kinase (CDK) activity promotes DNA replication and initiates G1-to-S phase transition. CDK activation initiates a positive feedback loop that further increases CDK activity, and this commits the cell to division by inducing genome-wide transcriptional changes. G1-S transcripts encode proteins that regulate downstream cell cycle events. Recent work is beginning to reveal the complex molecular mechanisms that control the temporal order of transcriptional activation and inactivation, determine distinct functional subgroups of genes and link cell cycle-dependent transcription to DNA replication stress in yeast and mammals. © 2013 Macmillan Publishers Limited. All rights reserved.


Rabello-Soares M.C.,Stanford University
Astrophysical Journal | Year: 2012

We present evidence that the sound-speed variation with solar activity has a two-layer configuration, similar to the one observed below an active region, which consists of a negative layer near the solar surface and a positive one in the layer immediately below the first one. Frequency differences between the activity minimum and maximum of solar cycle 23, obtained applying global helioseismology to the Michelson Doppler Imager on board the Solar and Heliospheric Observatory, is used to determine the sound-speed variation from below the base of the convection zone to a fewMm below the solar surface. We find that the sound speed at solar maximum is smaller than at solar minimum at the limit of our determination (5.5Mm). The min-to-max difference decreases in absolute values until ∼7Mm. At larger depths, the sound speed at solar maximum is larger than at solar minimum and the difference increases with depth until ∼10Mm. At this depth, the relative difference (δc 2/c 2) is less than half of the value observed at the lowest depth determination. At deeper layers, it slowly decreases with depth until there is no difference between maximum and minimum activity. © 2012. The American Astronomical Society. All rights reserved.


Toro E.,Stanford University
Cold Spring Harbor perspectives in biology | Year: 2010

Bacterial chromosomes are generally approximately 1000 times longer than the cells in which they reside, and concurrent replication, segregation, and transcription/translation of this crowded mass of DNA poses a challenging organizational problem. Recent advances in cell-imaging technology with subdiffraction resolution have revealed that the bacterial nucleoid is reliably oriented and highly organized within the cell. Such organization is transmitted from one generation to the next by progressive segregation of daughter chromosomes and anchoring of DNA to the cell envelope. Active segregation by a mitotic machinery appears to be common; however, the mode of chromosome segregation varies significantly from species to species.


Sleep N.H.,Stanford University
Cold Spring Harbor perspectives in biology | Year: 2010

A sparse geological record combined with physics and molecular phylogeny constrains the environmental conditions on the early Earth. The Earth began hot after the moon-forming impact and cooled to the point where liquid water was present in approximately 10 million years. Subsequently, a few asteroid impacts may have briefly heated surface environments, leaving only thermophile survivors in kilometer-deep rocks. A warm 500 K, 100 bar CO(2) greenhouse persisted until subducted oceanic crust sequestered CO(2) into the mantle. It is not known whether the Earth's surface lingered in a approximately 70 degrees C thermophile environment well into the Archaean or cooled to clement or freezing conditions in the Hadean. Recently discovered approximately 4.3 Ga rocks near Hudson Bay may have formed during the warm greenhouse. Alkalic rocks in India indicate carbonate subduction by 4.26 Ga. The presence of 3.8 Ga black shales in Greenland indicates that S-based photosynthesis had evolved in the oceans and likely Fe-based photosynthesis and efficient chemical weathering on land. Overall, mantle derived rocks, especially kimberlites and similar CO(2)-rich magmas, preserve evidence of subducted upper oceanic crust, ancient surface environments, and biosignatures of photosynthesis.


A 4-parameter Fermi-liquid calculation of the high-Tc cuprate phase diagram is reported. Simultaneously accounted for are the special doping densities of 5% and 16%, the d-wave functional form of the (orbital antiferromagnetic) pseudogap, the measured Tc, superconducting gap, pseudogap and superfluid density as a function of doping, the particle-hole doping asymmetry and the half-filling spin wave velocity. © 2014 American Physical Society.


Kaiser D.,Stanford University
Cold Spring Harbor perspectives in biology | Year: 2010

Myxobacteria are renowned for the ability to sporulate within fruiting bodies whose shapes are species-specific. The capacity to build those multicellular structures arises from the ability of M. xanthus to organize high cell-density swarms, in which the cells tend to be aligned with each other while constantly in motion. The intrinsic polarity of rod-shaped cells lays the foundation, and each cell uses two polar engines for gliding on surfaces. It sprouts retractile type IV pili from the leading cell pole and secretes capsular polysaccharide through nozzles from the trailing pole. Regularly periodic reversal of the gliding direction was found to be required for swarming. Those reversals are generated by a G-protein switch which is driven by a sharply tuned oscillator. Starvation induces fruiting body development, and systematic reductions in the reversal frequency are necessary for the cells to aggregate rather than continue to swarm. Developmental gene expression is regulated by a network that is connected to the suppression of reversals.


Daneshjou R.,Stanford University
BMC genomics | Year: 2013

Many genome-wide association studies focus on associating single loci with target phenotypes. However, in the setting of rare variation, accumulating sufficient samples to assess these associations can be difficult. Moreover, multiple variations in a gene or a set of genes within a pathway may all contribute to the phenotype, suggesting that the aggregation of variations found over the gene or pathway may be useful for improving the power to detect associations. Here, we present a method for aggregating single nucleotide polymorphisms (SNPs) along biologically relevant pathways in order to seek genetic associations with phenotypes. Our method uses all available genetic variants and does not remove those in linkage disequilibrium (LD). Instead, it uses a novel SNP weighting scheme to down-weight the contributions of correlated SNPs. We apply our method to three cohorts of patients taking warfarin: two European descent cohorts and an African American cohort. Although the clinical covariates and key pharmacogenetic loci for warfarin have been characterized, our association metric identifies a significant association with mutations distributed throughout the pathway of warfarin metabolism. We improve dose prediction after using all known clinical covariates and pharmacogenetic variants in VKORC1 and CYP2C9. In particular, we find that at least 1% of the missing heritability in warfarin dose may be due to the aggregated effects of variations in the warfarin metabolic pathway, even though the SNPs do not individually show a significant association. Our method allows researchers to study aggregative SNP effects in an unbiased manner by not preselecting SNPs. It retains all the available information by accounting for LD-structure through weighting, which eliminates the need for LD pruning.


Tang J.Y.,Stanford University
Journal of the American Academy of Dermatology | Year: 2012

Skin cancer is the most common cancer in the United States. Exposure to ultraviolet radiation is a known risk factor for skin cancer but is also the principal means by which the body obtains vitamin D. Several studies have suggested that vitamin D plays a protective role in a variety of internal malignancies. With regard to skin cancer, epidemiologic and laboratory studies suggest that vitamin D and its metabolites may have a similar protective effect. These noncalcemic actions of vitamin D have called into question whether the current recommended intake of vitamin D is too low for optimal health and cancer prevention. Part I will review the role of vitamin D in the epidermis; part II will review the role of vitamin D in keratinocyte-derived tumors to help frame the discussion on the possible role of vitamin D in the prevention of skin cancer. Copyright © 2012 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.


Ehrlich P.R.,Stanford University
Proceedings. Biological sciences / The Royal Society | Year: 2013

Environmental problems have contributed to numerous collapses of civilizations in the past. Now, for the first time, a global collapse appears likely. Overpopulation, overconsumption by the rich and poor choices of technologies are major drivers; dramatic cultural change provides the main hope of averting calamity.


Dunn B.J.,Stanford University
Journal of the Royal Society, Interface / the Royal Society | Year: 2013

Polyketide natural products act as a broad range of therapeutics, including antibiotics, immunosuppressants and anti-cancer agents. This therapeutic diversity stems from the structural diversity of these small molecules, many of which are produced in an assembly line manner by modular polyketide synthases. The acyltransferase (AT) domains of these megasynthases are responsible for selection and incorporation of simple monomeric building blocks, and are thus responsible for a large amount of the resulting polyketide structural diversity. The substrate specificity of these domains is often targeted for engineering in the generation of novel, therapeutically active natural products. This review outlines recent developments that can be used in the successful engineering of these domains, including AT sequence and structural data, mechanistic insights and the production of a diverse pool of extender units. It also provides an overview of previous AT domain engineering attempts, and concludes with proposed engineering approaches that take advantage of current knowledge. These approaches may lead to successful production of biologically active 'unnatural' natural products.


Fernald R.D.,Stanford University
Animal Behaviour | Year: 2015

Dominance hierarchies are ubiquitous in social species. Social status is established initially through physical conflict between individuals and then communicated directly by a variety of signals. Social interactions depend critically on the relative social status of those interacting. But how do individuals acquire the information they need to modulate their behaviour and how do they use that information to decide what to do? What brain mechanisms might underlie such animal cognition? Using a particularly suitable fish model system that depends on complex social interactions, we report how the social context of behaviour shapes the brain and, in turn, alters the behaviour of animals as they interact. Animals observe social interactions carefully to gather information vicariously that then guides their future behaviour. Social opportunities produce rapid changes in gene expression in key nuclei in the brain and these genomic responses may prepare the individual to modify its behaviour to move into a different social niche. Both social success and failure produce changes in neuronal cell size and connectivity in key nuclei. Understanding mechanisms through which social information is transduced into cellular and molecular changes will provide a deeper understanding of the brain systems responsible for animal cognition. © 2015 The Association for the Study of Animal Behaviour.


Edgington L.E.,Stanford University
Current opinion in chemical biology | Year: 2011

Proteases are enzymes that cleave peptide bonds in protein substrates. This process can be important for regulated turnover of a target protein but it can also produce protein fragments that then perform other functions. Because the last few decades of protease research have confirmed that proteolysis is an essential regulatory process in both normal physiology and in multiple disease-associated conditions, there has been an increasing interest in developing methods to image protease activity. Proteases are also considered to be one of the few 'druggable' classes of proteins and therefore a large number of small molecule based inhibitors of proteases have been reported. These compounds serve as a starting point for the design of probes that can be used to target active proteases for imaging applications. Currently, several classes of fluorescent probes have been developed to visualize protease activity in live cells and even whole organisms. The two primary classes of protease probes make use of either peptide/protein substrates or covalent inhibitors that produce a fluorescent signal when bound to an active protease target. This review outlines some of the most recent advances in the design of imaging probes for proteases. In particular, it highlights the strengths and weaknesses of both substrate-based and activity-based probes and their applications for imaging cysteine proteases that are important biomarkers for multiple human diseases. Copyright © 2011 Elsevier Ltd. All rights reserved.


Jacobson M.Z.,Stanford University
Environmental Science and Technology | Year: 2010

Data suggest that domes of high CO2 levels form over cities. Despite our knowledge of these domes for over a decade, no study has contemplated their effects on air pollution or health. in fact, all air pollution regulations worldwide assume arbitrarilythatsuch domes have no local health impact, and carbon policy proposals, such as "cap and trade", implicitly assume that CO2 impacts are the same regardless of where emissions occur. Here, it is found through data-evaluated numerical modeling with telescoping domains from the globe to the U.S., California, and Los Angeles, that local CO2 emissions in isolation may increase local ozone and particulate matter. Although health impacts of such changes are uncertain, they are of concern, and it is estimated that that local CO 2 emissions may increase premature mortality by 50-100 and 300-1000/yr in California and the U.S., respectively. As such, reducing locally emitted CO2 may reduce local air pollution mortality even if CO 2 in adjacent regions is not controlled. If correct, this result contradicts the basis for air pollution regulations worldwide, none of which considers controlling local CO2 based on its local health impacts. It also suggests that a "cap and trade" policy should considerthe location of CO2 emissions, as the underlying assumption of the policy is incorrect. © 2010 American Chemical Society.


Zare R.N.,Stanford University
Annual Review of Analytical Chemistry | Year: 2012

Laser-induced fluorescence (LIF) is a spectroscopic technique that involves the excitation of a molecular target by a beam of laser radiation followed by the detection of the subsequent emission of radiation from the target. LIF detection has several advantages over absorption spectroscopy. First, LIF has excellent detection sensitivity because a signal is observed against a dark background. Second, the emitted radiation can be collected at various angles with respect to the incoming laser beam, making it possible to obtain two- and three-dimensional images because the fluorescence is emitted in all directions. Third, by dispersing the fluorescence, it is also possible to learn about the transitions from the state excited to the various lower levels of the target species. Finally, because of the delay between the excitation and detection events, it is also possible to learn about what processes the excited target undergoes in the intervening time. Copyright © 2012 by Annual Reviews. All rights reserved.


Bailey S.R.,Stanford University
Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco | Year: 2011

The factors that influence the initial phase of quitting smoking have been understudied. Although maintenance of change is the ultimate test of the efficacy of treatment, maintenance is a nonissue for those who fail to manage even brief periods of abstinence. We examined factors associated with smokers' ability to achieve a targeted 24-hr quit during a smoking cessation program. As a comparison, we also examine whether predictors of an initial quit are different from factors that predict smoking abstinence at 52-week follow-up. Using baseline data from a randomized clinical trial to examine the efficacy of selegiline for cigarette smoking cessation (n = 280), we conducted univariate analyses (analysis of variance or chi-square) to determine statistically significant predictors of a successful quit attempt (SQA) versus unsuccessful quit attempt. Multiple logistic regression was performed with significant predictors from the univariate analyses to determine main effects and interactions in a multivariate model. The same factors and analyses were used to examine predictors of 52-week point prevalence abstinence. Lower nicotine dependence (modified Fagerström Tolerance Questionnaire [mFTQ]), higher Behavioral Inhibition System score, and lower baseline heart rate were predictive of SQA in both the univariate and the multivariate models. Gender was the only predictor of 52-week smoking abstinence. Predictors of initial induction of change were not predictors of abstinence at the 1-year follow-up, suggesting that different factors mediate the different subprocesses of behavior change. Knowledge of these pretreatment factors that moderate a SQA could help clinicians target smokers who need more intensive therapy during the initial induction of cessation.


Rando T.A.,Stanford University
Annual Review of Physiology | Year: 2013

As a nod to the oft-quoted evolutionary theorist George Williams, "It is remarkable that after a seemingly miraculous feat of morphogenesis, a complex metazoan should be unable to perform the much simpler task of merely maintaining what is already formed" (1). How and why we age are mysteries of the ages (2, 3). The "how" of this mystery is the purview of experimental biologists who try to understand the basic processes that lead to system maintenance failure-from the level of molecules to that of entire organisms-that we term "aging". The "why" of this mystery is the purview of evolutionary theorists whose ideas shape the questions that biogerontologists pose, on the basis of the premise put forth by another preeminent geneticist and evolutionary biologist, Theodosius Dobzhansky, that "[n]othing in biology makes sense except in the light of evolution" (4). These experimental and evolutionary perspectives converge in the modern science of aging, and its curious cousin "longevity", in an attempt to unify extensive findings from diverse areas of biology (5). Copyright © 2013 by Annual Reviews. All rights reserved.


Andriacchi T.P.,Stanford University
Nature Reviews Rheumatology | Year: 2012

Systems level analysis using stimulus-response modelling could increase our understanding of the interplay between biochemical, structural and functional variables that influence the development and manifestation of osteoarthritis. Furthermore, surrogate markers of clinical responses identified might enable early diagnosis, improve therapy, and facilitate development of new treatments and end points. © 2012 Macmillan Publishers Limited. All rights reserved.


Although Late Triassic igneous rocks are present, the Sierra Nevada-Klamath calc-alkaline arc began massive construction along the continental margin at ca. 170 Ma during oblique underfl ow of paleo-Pacifi c oceanic lithosphere; intense activity continued throughout the volcanic-plutonic belt until at least ca. 140 Ma. This volcanic-plutonic arc supplied detritus to the Mariposa-Galice proximal clastic sequence starting by ca. 165-160 Ma. After onset of uppermost Jurassic Myrtle overlap sedimentation on the western fl ank of the Klamath Mountains, but before Hornbrook and Valanginian Great Valley Group overlap deposition on the eastern and southeastern sides, the Klamath Mountains salient was displaced ̃200 km westward relative to the igneous arc. The orogen thus moved off the deep-seated magmagenic zone underlying the arc and did not participate in the massive Sierra Nevada igneous fl are-up between ca. 125 and ca. 85 Ma. I suggest that, beginning at ca. 140 Ma, underfl ow of a young, thin oceanic slab beneath the Klamath Mountains slid beneath the gently east-dipping stack of thrust sheets without disturbing their inclinations. Subduction and collision of much thicker oceanic lithosphere on both the north and south caused contraction, eastward relative displacement of the continental margin arc, and ductility-enhanced rotation of the superjacent stack of allochthons into near-vertical dips. After a magmatic lull, heightened igneous activity in the Sierra Nevada recommenced at ca. 125 Ma. The earliest Cretaceous oceanward plate junction rollback lay directly offshore the Klamath imbricate orogen, but to the south trapped the ca. 165 Ma Coast Range ophiolite on the North American side of the suture. After ca. 140 Ma, fi rst-cycle arc detritus began to accumulate on the mafi c igneous basement fl ooring the Great Valley forearc, and turbiditic clastic material also was carried oceanward across the forearc into the coeval Franciscan trench. © 2013 Geological Society of America.


We propose a systematical approach to construct generic fractional quantum anomalous Hall states, which are generalizations of the fractional quantum Hall states to lattice models with zero net magnetic field and full lattice translation symmetry. Local and translationally invariant Hamiltonians can also be constructed, for which the proposed states are unique ground states. Our result demonstrates that generic chiral topologically ordered states can be realized in lattice models, without requiring magnetic translation symmetry and Landau level structure. We further generalize our approach to fractional topological insulators, and provide the first explicit wave-function description of fractional topological insulators in the absence of spin conservation. © 2011 American Physical Society.


Biteen J.S.,Stanford University
Cold Spring Harbor perspectives in biology | Year: 2010

Single-molecule imaging enables biophysical measurements devoid of ensemble averaging, gives enhanced spatial resolution beyond the diffraction limit, and permits superresolution reconstructions. Here, single-molecule and superresolution imaging are applied to the study of proteins in live Caulobacter crescentus cells to illustrate the power of these methods in bacterial imaging. Based on these techniques, the diffusion coefficient and dynamics of the histidine protein kinase PleC, the localization behavior of the polar protein PopZ, and the treadmilling behavior and protein superstructure of the structural protein MreB are investigated with sub-40-nm spatial resolution, all in live cells.


Listeria monocytogenes (Lm) uses InlA to invade the tips of the intestinal villi, a location at which cell extrusion generates a transient defect in epithelial polarity that exposes the receptor for InlA, E-cadherin, on the cell surface. As the dying cell is removed from the epithelium, the surrounding cells reorganize to form a multicellular junction (MCJ) that Lm exploits to find its basolateral receptor and invade. By examining individual infected villi using 3D-confocal imaging, we uncovered a novel role for the second major invasin, InlB, during invasion of the intestine. We infected mice intragastrically with isogenic strains of Lm that express or lack InlB and that have a modified InlA capable of binding murine E-cadherin and found that Lm lacking InlB invade the same number of villi but have decreased numbers of bacteria within each infected villus tip. We studied the mechanism of InlB action at the MCJs of polarized MDCK monolayers and find that InlB does not act as an adhesin, but instead accelerates bacterial internalization after attachment. InlB locally activates its receptor, c-Met, and increases endocytosis of junctional components, including E-cadherin. We show that MCJs are naturally more endocytic than other sites of the apical membrane, that endocytosis and Lm invasion of MCJs depends on functional dynamin, and that c-Met activation by soluble InlB or hepatocyte growth factor (HGF) increases MCJ endocytosis. Also, in vivo, InlB applied through the intestinal lumen increases endocytosis at the villus tips. Our findings demonstrate a two-step mechanism of synergy between Lm's invasins: InlA provides the specificity of Lm adhesion to MCJs at the villus tips and InlB locally activates c-Met to accelerate junctional endocytosis and bacterial invasion of the intestine.


McClosky D.,Stanford University
BMC bioinformatics | Year: 2012

We explore techniques for performing model combination between the UMass and Stanford biomedical event extraction systems. Both sub-components address event extraction as a structured prediction problem, and use dual decomposition (UMass) and parsing algorithms (Stanford) to find the best scoring event structure. Our primary focus is on stacking where the predictions from the Stanford system are used as features in the UMass system. For comparison, we look at simpler model combination techniques such as intersection and union which require only the outputs from each system and combine them directly. First, we find that stacking substantially improves performance while intersection and union provide no significant benefits. Second, we investigate the graph properties of event structures and their impact on the combination of our systems. Finally, we trace the origins of events proposed by the stacked model to determine the role each system plays in different components of the output. We learn that, while stacking can propose novel event structures not seen in either base model, these events have extremely low precision. Removing these novel events improves our already state-of-the-art F1 to 56.6% on the test set of Genia (Task 1). Overall, the combined system formed via stacking ("FAUST") performed well in the BioNLP 2011 shared task. The FAUST system obtained 1st place in three out of four tasks: 1st place in Genia Task 1 (56.0% F1) and Task 2 (53.9%), 2nd place in the Epigenetics and Post-translational Modifications track (35.0%), and 1st place in the Infectious Diseases track (55.6%). We present a state-of-the-art event extraction system that relies on the strengths of structured prediction and model combination through stacking. Akin to results on other tasks, stacking outperforms intersection and union and leads to very strong results. The utility of model combination hinges on complementary views of the data, and we show that our sub-systems capture different graph properties of event structures. Finally, by removing low precision novel events, we show that performance from stacking can be further improved.


Schatzberg A.F.,Stanford University
Annals of the New York Academy of Sciences | Year: 2015

The development of new antidepressants has had mixed results over the past decade, with several notable failures. This paper reviews a number of major initiatives in the development of new antidepressant agents. Traditional strategies to build on agents that have monoaminergic effects at the synapse (e.g., vilazodone and ketamine) have been complemented with efforts that have emphasized devices and brain circuits (e.g., deep brain stimulation and transcranial magnetic stimulation) or chemical agents that modulate neuroendocrine systems (e.g., glucocorticoid antagonists, mixed melatonin agonists/serotonin type-2 receptor antagonists). Interestingly, chemical agents, such as onabotulinumtoxin A, may affect brain circuits as well. We present data from recent studies in drug and device development-reviewing progress made, stumbling blocks encountered, and issues that need to be addressed in future studies. © 2015 The New York Academy of Sciences.


Purpose: Previous studies suggest that some common medications alter prostate-specific antigen (PSA) levels. It remains unclear whether these reported medication effects are due to clinicodemographic factors or concurrent use of other medications. We investigated the impact of individual and combinations of common medications on PSA in a large cross-sectional study of the United States population. Patients and Methods: The study included men ≥ 40 years old without prostate cancer from the 2003 to 2004 and 2005 to 2006 cycles of the National Health and Nutrition Examination Survey (NHANES). Men with recent prostate manipulation, prostatitis, and those on hormone therapy were excluded. Weighted multivariate linear regression was performed on log-transformed total PSA to determine the effect of the 10 most commonly prescribed medication classes, adjusting for potential confounders including demographics, clinical characteristics, physical examination, laboratory studies, and duration of medication use. Results: In total, 1,864 men met inclusion criteria. Nonsteroidal anti-inflammatory drug (NSAID; P = .03), statin (P = .01), and thiazide diuretic (P = .025) intake was inversely related to PSA levels. Five years of NSAID, statin, and thiazide diuretic use was associated with PSA levels lower by 6%, 13%, and 26%, respectively. The combination of statins and thiazide diuretics showed the greatest reduction in PSA levels: 36% after 5 years. Concurrent calcium channel blocker use minimizes or negates the inverse relationship of statin use and PSA level. Conclusion: We found that men using NSAIDs, statins, and thiazide diuretics have reduced PSA levels by clinically relevant amounts. The impact of regularly consuming these common medications on prostate cancer screening is unknown. © 2010 by American Society of Clinical Oncology.


Frank M.C.,Stanford University
Science | Year: 2016

Berkowitz et al. (Reports, 9 October 2015, p. 196) described a randomized field experiment testing whether a math app designed to increase parent-child interaction could also bring academic benefits. A reanalysis of the data suggests that this well-designed trial failed to find strong evidence for the efficacy of the intervention. In particular, there was no significant effect of the intervention on math performance.


Sanacora G.,Yale University | Schatzberg A.F.,Stanford University
Neuropsychopharmacology | Year: 2015

Large 'real world' studies demonstrating the limited effectiveness and slow onset of clinical response associated with our existing antidepressant medications has highlighted the need for the development of new therapeutic strategies for major depression and other mood disorders. Yet, despite intense research efforts, the field has had little success in developing antidepressant treatments with fundamentally novel mechanisms of action over the past six decades, leaving the field wary and skeptical about any new developments. However, a series of relatively small proof-of-concept studies conducted over the last 15 years has gradually gained great interest by providing strong evidence that a unique, rapid onset of sustained, but still temporally limited, antidepressant effects can be achieved with a single administration of ketamine. We are now left with several questions regarding the true clinical meaningfulness of the findings and the mechanisms underlying the antidepressant action. In this Circumspectives piece, Dr Sanacora and Dr Schatzberg share their opinions on these issues and discuss paths to move the field forward.


Lau O.S.,Yale University | Lau O.S.,Stanford University | Deng X.W.,Yale University
Trends in Plant Science | Year: 2012

COP1 and DET1 are among the first repressors of photomorphogenesis to be identified, more than 20 years ago. Discovery of these repressors as conserved regulators of the ubiquitin-proteasome system has established protein degradation as a central theme in light signal transduction. COP1 is a RING E3 ubiquitin ligase that targets key regulators for degradation, and DET1 complexes with COP10 and DDB1, which is proposed to aid in COP1-mediated degradation. Recent studies have strengthened the role of COP1 as a major signaling center. DET1 is also emerging as a chromatin regulator in repressing gene expression. Here, we review current understanding on COP1 and DET1, with a focus on their role as part of two distinct, multimeric CUL4-based E3 ligases. © 2012 Elsevier Ltd.


Rylander J.H.,Stanford University
The American journal of sports medicine | Year: 2011

Femoroacetabular impingement (FAI) has been linked to osteoarthritis. Treatment options range from nonoperative to operative, and current outcome measures are generally subjective or not conducted under actual activities of daily living. Thus, there is a need for the use of motion capture techniques to quantitatively assess the outcome of surgical intervention for those treated for FAI. The gait of FAI patients 1 year after operative treatment (arthroscopic hip reshaping) will be significantly closer to the normal range and pattern of hip flexion motion, relative to pretreatment. Case series; Level of evidence, 4. Eleven patients between 18 and 44 years of age with diagnosed FAI were enrolled in this study. Kinematics and kinetics for this group of patients were collected using motion capture techniques before arthroscopic bone-reshaping surgery and again 1 year after surgery. Pain and perceived activity level (Tegner scale) were also collected. All collected data were compared using a paired t test. Overall hip sagittal plane range of motion increased on the affected side from 27.6° ± 5.0° to 30.7° ± 4.3° (P = .02). The presence of abnormal reversals (second-order change in the slope in the hip flexion/extension curve) that was present in 5 patients preoperatively disappeared or was reduced in prevalence and magnitude in 4 of the patients postoperatively. Additionally, pain decreased and activity level increased postoperatively. The results supported the hypothesis that surgical intervention for FAI restores more normal patterns of gait and provides objective support that the surgical procedure is useful. The results help establish motion capture as a potential method for quantitatively assessing the outcome in FAI surgical interventions. The presence of abnormal reversals in hip flexion has been reported in end-stage hip osteoarthritis, and the presence of these reversals in FAI patients reinforces the idea of FAI being a precursor to hip osteoarthritis.


Steinman L.,Stanford University
Science Signaling | Year: 2013

When considering the hierarchical organization of pathological signaling cascades in immunological disorders of the brain, certain cytokines might be considered pinnacles of pathophysiological importance, with their presence determining the appearance or the course of a particular disease. Interleukin-1 (IL-1), IL-6, IL-17, and tumor necrosis factor are critical for the pathogenesis of inflammation in specifi c brain disorders. Targeting these cytokines or their receptors can alter the course of several neurological diseases, but the effects may be benefi cial or harmful. © 2013 American Association for the Advancement of Science.


With the advent of technologies to obtain the complete sequence of the human genome in a cost-effective manner, this decade and those to come will see an exponential increase in our understanding of the underlying genetics that lead to human disease. And where we have a deep understanding of the biochemical and biophysical basis of the machineries and pathways involved in those genetic changes, there are great hopes for the development of modern therapeutics that specifically target the actual machinery and pathways altered by individual mutations. Prime examples of such a genetic disease are those classes of hypertrophic and dilated cardiomyopathy that result from single amino-acid substitutions in one of several of the proteins that make up the cardiac sarcomere or from the truncation of myosin binding protein C. Hypertrophic cardiomyopathy alone affects ∼1 in 500 individuals, and it is the leading cause of sudden cardiac death in young adults. Here I describe approaches to understand the molecular basis of the alterations in power output that result from these mutations. Small molecules binding to the mutant sarcomeric protein complex should be able to mitigate the effects of hypertrophic and dilated cardiomyopathy mutations at their sources, leading to possible new therapeutic approaches for these genetic diseases. © 2014 The Authors.


Frumkin L.R.,Stanford University
Pharmacological Reviews | Year: 2012

Pulmonary arterial hypertension (PAH) is a life-threatening and progressive disease of various origins characterized by pulmonary vascular remodeling that leads to increased pulmonary vascular resistance and pulmonary arterial pressure, most often resulting in right-sided heart failure. The most common symptom at presentation is breathlessness, with impaired exercise capacity as a hallmark of the disease. Advances in understanding the pathobiology over the last 2 decades have led to therapies (endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclins or analogs) initially directed at reversing the pulmonary vasoconstriction and more recently directed toward reversing endothelial cell dysfunction and smooth muscle cell proliferation. Despite these advances, disease progression is common even with use of combination regimens targeting multiple mechanistic pathways. Overall 5-year survival for PAH has increased significantly from approximately 30% in the 1980s to approximately 60% at present, yet remains abysmal. This review summarizes the mechanisms of action, clinical data, and regulatory histories of approved PAH therapies and describes the latest agents in late-stage clinical development. © 2012 by The American Society for Pharmacology and Experimental Therapeutics.


Pfeffer S.R.,Stanford University
Current Opinion in Cell Biology | Year: 2013

A fundamental question in cell biology is how cells determine membrane compartment identity and the directionality with which cargoes pass through the secretory and endocytic pathways. The discovery of so-called 'Rab cascades' provides a satisfying molecular mechanism that helps to resolve this paradox. One Rab GTPase has the ability to template the localization of the subsequent acting Rab GTPase along a given transport pathway. Thus, in addition to determining compartment identity and functionality, Rab GTPases are likely able to order the events of membrane trafficking. This review will highlight recent advances in our understanding of Rabs and Rab cascades. © 2013 Elsevier Ltd.


Salinger M.J.,Stanford University
Climatic Change | Year: 2013

Climatic variability has profound effects on the distribution, abundance and catch of oceanic fish species around the world. The major modes of this climate variability include the El Niño-Southern Oscillation (ENSO) events, the Pacific Decadal Oscillation (PDO) also referred to as the Interdecadal Pacific Oscillation (IPO), the Indian Ocean Dipole (IOD), the Southern Annular Mode (SAM) and the North Atlantic Oscillation (NAO). Other modes of climate variability include the North Pacific Gyre Oscillation (NPGO), the Atlantic Multidecadal Oscillation (AMO) and the Arctic Oscillation (AO). ENSO events are the principle source of interannual global climate variability, centred in the ocean-atmosphere circulations of the tropical Pacific Ocean and operating on seasonal to interannual time scales. ENSO and the strength of its climate teleconnections are modulated on decadal timescales by the IPO. The time scale of the IOD is seasonal to interannual. The SAM in the mid to high latitudes of the Southern Hemisphere operates in the range of 50-60 days. A prominent teleconnection pattern throughout the year in the Northern Hemisphere is the North Atlantic Oscillation (NAO) which modulates the strength of the westerlies across the North Atlantic in winter, has an impact on the catches of marine fisheries. ENSO events affect the distribution of tuna species in the equatorial Pacific, especially skipjack tuna as well as the abundance and distribution of fish along the western coasts of the Americas. The IOD modulates the distribution of tuna populations and catches in the Indian Ocean, whilst the NAO affects cod stocks heavily exploited in the Atlantic Ocean. The SAM, and its effects on sea surface temperatures influence krill biomass and fisheries catches in the Southern Ocean. The response of oceanic fish stocks to these sources of climatic variability can be used as a guide to the likely effects of climate change on these valuable resources. © 2013 Springer Science+Business Media Dordrecht.


Baldwin R.L.,Stanford University | Rose G.D.,Johns Hopkins University
Current Opinion in Structural Biology | Year: 2013

The exquisite side chain close-packing in the protein core and at binding interfaces has prompted a conviction that packing selectivity is the primary mechanism for molecular recognition in folding and/or binding reactions. Contrary to this view, molten globule proteins can adopt native topology and bind targets tightly and specifically in the absence of side chain close-packing. The molten globule is a highly dynamic form with native-like secondary structure and a loose protein core that admits solvent. The related (but still controversial) dry molten globule is an expanded form of the native protein with largely intact topology but a tighter protein core that excludes solvent. Neither form retains side chain close-packing, and therefore both structure and function must result from other factors, assuming that the reality of the dry molten globule is accepted. This simplifying realization calls for a re-evaluation of established models. © 2012 Elsevier Ltd.


Faix J.D.,Stanford University
Critical Reviews in Clinical Laboratory Sciences | Year: 2013

Sepsis is an unusual systemic reaction to what is sometimes an otherwise ordinary infection, and it probably represents a pattern of response by the immune system to injury. A hyper-inflammatory response is followed by an immunosuppressive phase during which multiple organ dysfunction is present and the patient is susceptible to nosocomial infection. Biomarkers to diagnose sepsis may allow early intervention which, although primarily supportive, can reduce the risk of death. Although lactate is currently the most commonly used biomarker to identify sepsis, other biomarkers may help to enhance lactate's effectiveness; these include markers of the hyper-inflammatory phase of sepsis, such as pro-inflammatory cytokines and chemokines; proteins such as C-reactive protein and procalcitonin which are synthesized in response to infection and inflammation; and markers of neutrophil and monocyte activation. Recently, markers of the immunosuppressive phase of sepsis, such as anti-inflammatory cytokines, and alterations of the cell surface markers of monocytes and lymphocytes have been examined. Combinations of pro- and anti-inflammatory biomarkers in a multi-marker panel may help identify patients who are developing severe sepsis before organ dysfunction has advanced too far. Combined with innovative approaches to treatment that target the immunosuppressive phase, these biomarkers may help to reduce the mortality rate associated with severe sepsis which, despite advances in supportive measures, remains high. © 2013 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.


Relman D.A.,Stanford University
Nutrition Reviews | Year: 2012

Given the importance of the microbiome for human health, both the stability and the response to disturbance of this microbial ecosystem are crucial issues. Yet, the current understanding of these factors is insufficient. Early data suggest there is relative stability in the microbiome of adults in the absence of gross perturbation, and that long-term stability of the human indigenous microbial communities is maintained not by inertia but by the action of restorative forces within a dynamic system. After brief exposures to some antibiotics, there is an immediate and substantial perturbation and at least a partial recovery of taxonomic composition. Responses to antibiotics are individualized and are influenced by prior experience with the same antibiotic. These findings suggest that the human microbiome has properties of resilience. Besides serving to reveal critical underlying functional attributes, microbial interactions, and keystone species within the indigenous microbiota, the response to disturbance may have value in predicting future instability and disease and in managing the human microbial ecosystem. © 2012 International Life Sciences Institute.


Context: Nelson's syndrome refers to aggressive pituitary corticotroph adenoma growth after bilateral adrenalectomy for treatment of Cushing's disease (CD). Pasireotide, a novel somatostatin analog, has been effective in treating CD. Here, the first case report of a patient with Nelson's syndrome treated with pasireotide is presented. Case Presentation: A 55-year-old female was diagnosed with CD in 1973 at age 15 years and underwent bilateral adrenalectomy 1 year later. She subsequently developed Nelson's syndrome and underwent multiple surgeries and radiotherapy for adenoma growth. After presentation with ocular pain, third cranial nerve palsy, and a finding of suprasellar tumor enlargement with hemorrhage, she began pasireotide long-acting release 60 mg/28 days im. At baseline, fasting plasma ACTH was 42 710 pg/mL (normal, 5-27 pg/mL), and fasting plasma glucose was 98 mg/dL. After 1 month, ACTH declined to 4272 pg/mL, and it has remained stable over 19 months of follow-up. Hyperpigmentation progressively improved. Magnetic resonance imaging scans show reduction in the suprasellar component. Fasting plasma glucose increased to 124 mg/dL, and the patient underwent diabetes management. Evidence Acquisition and Synthesis: In this clinical case seminar, the current understanding of the treatment of Nelson's syndrome and the use of pasireotide in CD are summarized. Conclusion: A case of Nelson's syndrome with clinically significant and dramatic biochemical and clinical responses to pasireotide administration is reported. Hyperglycemia was noted after pasireotide administration. Pasireotide may represent a useful tool in the medical management of Nelson's syndrome. Further study of the potential benefits and risks of pasireotide in this population is necessary. Copyright © 2013 by The Endocrine Society.


Jones C.,Stanford University
Physical Review A - Atomic, Molecular, and Optical Physics | Year: 2013

We develop a procedure for distilling magic states used in universal quantum computing that requires substantially fewer initial resources than prior schemes. Our distillation circuit is based on a family of concatenated quantum codes that possess a transversal Hadamard operation, enabling each of these codes to distill the eigenstate of the Hadamard operator. A crucial result of this design is that low-fidelity magic states can be consumed to purify other high-fidelity magic states to even higher fidelity, which we call multilevel distillation. When distilling in the asymptotic regime of infidelity ε→0 for each input magic state, the number of input magic states consumed on average to yield an output state with infidelity O(ε2r) approaches 2r+1, which comes close to saturating the conjectured bound in another investigation. We show numerically that there exist multilevel protocols such that the average number of magic states consumed to distill from error rate εin=0.01 to εout in the range 10 -5-10-40 is about 14log10(1/ε out)-40; the efficiency of multilevel distillation dominates all other reported protocols when distilling Hadamard magic states from initial infidelity 0.01 to any final infidelity below 10-7. These methods are an important advance for magic-state distillation circuits in high-performance quantum computing and provide insight into the limitations of nearly resource-optimal quantum error correction. © 2013 American Physical Society.


Chemissanya W.,Stanford University | Papadimitriou I.,Autonomous University of Madrid
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2014

We present a general algorithm for constructing the holographic dictionary for Lifshitz and hyperscaling violating Lifshitz backgrounds for any value of the dynamical exponent zand any value of the hyperscaling violation parameter θ compatible with the null energy condition. The objective of the algorithm is the construction of the general asymptotic solution of the radial Hamilton-Jacobi equation subject to the desired boundary conditions, from which the full dictionary can be subsequently derived. Contrary to the relativistic case, we find that a fully covariant construction of the asymptotic solution for running non-relativistic theories necessitates an expansion in the eigenfunctions of two commuting operators instead of one. This provides a covariant but non-relativistic grading of the expansion, according to the number of time derivatives. © 2014 The Authors.


Jones C.,Stanford University
Physical Review A - Atomic, Molecular, and Optical Physics | Year: 2013

We introduce a fault-tolerant construction to implement a composite quantum operation of four overlapping Toffoli gates. The same construction can produce two independent Toffoli gates. This result lowers resource overheads in designs for quantum computers by more than an order of magnitude. The procedure uses Clifford operations and 64 copies of the non-Clifford gate T=exp[iπ(I- σz)/8]. Quantum codes detect errors in the circuit. When the dominant source of error is T-gate failure with probability p, then the composite Toffoli circuit has a postselected failure rate of 3072p4 to lowest order. © 2013 American Physical Society.


Fayer M.D.,Stanford University
Accounts of Chemical Research | Year: 2012

Water is a critical component of many chemical processes, in fields as diverse as biology and geology. Water in chemical, biological, and other systems frequently occurs in very crowded situations: the confined water must interact with a variety of interfaces and molecular groups, often on a characteristic length scale of nanometers. Water's behavior in diverse environments is an important contributor to the functioning of chemical systems. In biology, water is found in cells, where it hydrates membranes and large biomolecules. In geology, interfacial water molecules can control ion adsorption and mineral dissolution. Embedded water molecules can change the structure of zeolites. In chemistry, water is an important polar solvent that is often in contact with interfaces, for example, in ion-exchange resin systems.Water is a very small molecule; its unusual properties for its size are attributable to the formation of extended hydrogen bond networks. A water molecule is similar in mass and volume to methane, but methane is a gas at room temperature, with melting and boiling points of 91 and 112 K, respectively. This is in contrast to water, with melting and boiling points of 273 and 373 K, respectively. The difference is that water forms up to four hydrogen bonds with approximately tetrahedral geometry. Water's hydrogen bond network is not static. Hydrogen bonds are constantly forming and breaking. In bulk water, the time scale for hydrogen bond randomization through concerted formation and dissociation of hydrogen bonds is approximately 2 ps. Water's rapid hydrogen bond rearrangement makes possible many of the processes that occur in water, such as protein folding and ion solvation. However, many processes involving water do not take place in pure bulk water, and water's hydrogen bond structural dynamics can be substantially influenced by the presence of, for example, interfaces, ions, and large molecules. In this Account, spectroscopic studies that have been used to explore the details of these influences are discussed.Because rearrangements of water molecules occur so quickly, ultrafast infrared experiments that probe water's hydroxyl stretching mode are useful in providing direct information about water dynamics on the appropriate time scales. Infrared polarization-selective pump-probe experiments and two-dimensional infrared (2D IR) vibrational echo experiments have been used to study the hydrogen bond dynamics of water. Water orientational relaxation, which requires hydrogen bond rearrangements, has been studied at spherical interfaces of ionic reverse micelles and compared with planar interfaces of lamellar structures composed of the same surfactants. Water orientational relaxation slows considerably at interfaces. It is found that the geometry of the interface is less important than the presence of the interface. The influence of ions is shown to slow hydrogen bond rearrangements. However, comparing an ionic interface to a neutral interface demonstrates that the chemical nature of the interface is less important than the presence of the interface. Finally, it is found that the dynamics of water at an organic interface is very similar to water molecules interacting with a large polyether. © 2011 American Chemical Society.


Objective: In 2013, the American College of Critical Care Medicine published a revised version of the pain, agitation, and delirium guidelines. The guidelines included an ICU pain, agitation, and delirium care bundle designed to facilitate implementation of the pain, agitation, and delirium guidelines. Design: Review article. Setting: Multispecialty critical care units. Patients: Adult ICU patients. Interventions: This article describes: 1) the ICU pain, agitation, and delirium care bundle in more detail, linking pain, sedation/agitation, and delirium management in an integrated and interdisciplinary fashion; 2) pain, agitation, and delirium implementation strategies; and 3) the potential synergistic benefits of linking pain, agitation, and delirium management strategies to other evidence-based ICU practices, including spontaneous breathing trials, ICU early mobility programs, and ICU sleep hygiene programs, in order to improve ICU patient outcomes and to reduce costs of care. Results: Linking the ICU pain, agitation, and delirium management strategies with spontaneous awakening trials, spontaneous breathing trials, and early mobility and sleep hygiene programs is associated with significant improvements in ICU patient outcomes and reductions in their costs of care. Conclusions: The 2013 ICU pain, agitation, and delirium guidelines provide critical care providers with an evidence-based, integrated, and interdisciplinary approach to managing pain, agitation/sedation, and delirium. The ICU pain, agitation, and delirium care bundle provides a framework for facilitating implementation of the pain, agitation, and delirium guidelines. Widespread implementation of the ICU pain, agitation, and delirium care bundle is likely to result in large-scale improvements in ICU patient outcomes and significant reductions in costs. © 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.


Chen D.,Stanford University | Chen D.,Genentech | Mellman I.,University of California at San Francisco | Mellman I.,Genentech
Immunity | Year: 2013

The genetic and cellular alterations that define cancer provide the immune system with the means to generate Tcell responses that recognize and eradicate cancer cells. However, elimination of cancer by Tcells is only one step in the Cancer-Immunity Cycle, which manages the delicate balance between the recognition of nonself and the prevention of autoimmunity. Identification of cancer cell Tcell inhibitory signals, including PD-L1, has prompted the development of a new class of cancer immunotherapy that specifically hinders immune effector inhibition, reinvigorating and potentially expanding preexisting anticancer immune responses. The presence of suppressive factors in the tumor microenvironment may explain the limited activity observed with previous immune-based therapies and why these therapies may be more effective in combination with agents that target other steps of the cycle. Emerging clinical data suggest that cancer immunotherapy is likely to become a key part of the clinical management of cancer. © 2013 Elsevier Inc.


Erickson D.,Stanford University
HotSDN 2013 - Proceedings of the 2013 ACM SIGCOMM Workshop on Hot Topics in Software Defined Networking | Year: 2013

Beacon is a Java-based open source OpenFlow controller created in 2010. It has been widely used for teaching, research, and as the basis of Floodlight. This paper describes the architectural decisions and implementation that achieves three of Beacon's goals: to improve developer productivity, to provide the runtime ability to start and stop existing and new applications, and to be high performance. © 2013 ACM.


Schreur P.E.,Stanford University
Library Resources and Technical Services | Year: 2012

Linked data has the potential to revolutionize the academic world of information creation and exchange. Basic tenets of what libraries collect, how they collect, how they organize, and how they provide information will be questioned and rethought. Limited pools of bibliographic records for information resources will be enhanced by data captured at creation. By harvesting the entire output of the academy, an immensely rich web of data will be created that will liberate research and teaching from the limited, disconnected silos of information that they are dependent on today.


Rosenberg N.A.,Stanford University
Molecular Biology and Evolution | Year: 2013

A labeled gene tree topology that disagrees with a labeled species tree topology is said to be anomalous if it is more probable under a coalescent model for gene lineage evolution than the labeled gene tree topology that matches the species tree. It has previously been shown that as a consequence of short internal branches of the species tree, for every labeled species tree topology with five or more taxa, and for asymmetric four-taxon species tree topologies, an assignment of species tree branch lengths can be made which gives rise to anomalous gene trees (AGTs). Here, I offer an alternative characterization of this result-a labeled species tree topology produces AGTs if and only if it contains two consecutive internal branches in an ancestor-descendant relationship-and I provide a proof that follows from the change in perspective. The reformulation and alternative proof of the existence result for AGTs provide the insight that it is not merely short internal branches that generate AGTs, but instead, short internal branches that are arranged consecutively. © 2013 The Author.


Kerchner G.A.,Stanford University
Journal of Alzheimer's Disease | Year: 2011

Ultra-high field 7T MRI offers superior signal-to-noise and spatial resolution relative to any other noninvasive imaging technique. By revealing fine anatomical details of the living brain, 7T MRI allows neuroimaging researchers the opportunity to observe in patients disease-related structural changes previously apparent only on postmortem tissue analysis. Alzheimers disease (AD) is a natural subject for this technology, and I review here two AD-related applications of 7T MRI: direct visualization of cortical plaques, and high resolution hippocampal imaging. I also discuss limitations of this technology as well as expected advances that are likely to establish 7T MRI as an increasingly important tool for the diagnosis and tracking of AD. © 2011 IOS Press and the authors. All rights reserved.


Cooper E.A.,Stanford University
Journal of vision | Year: 2013

Vision researchers rely on visual display technology for the presentation of stimuli to human and nonhuman observers. Verifying that the desired and displayed visual patterns match along dimensions such as luminance, spectrum, and spatial and temporal frequency is an essential part of developing controlled experiments. With cathode-ray tubes (CRTs) becoming virtually unavailable on the commercial market, it is useful to determine the characteristics of newly available displays based on organic light emitting diode (OLED) panels to determine how well they may serve to produce visual stimuli. This report describes a series of measurements summarizing the properties of images displayed on two commercially available OLED displays: the Sony Trimaster EL BVM-F250 and PVM-2541. The results show that the OLED displays have large contrast ratios, wide color gamuts, and precise, well-behaved temporal responses. Correct adjustment of the settings on both models produced luminance nonlinearities that were well predicted by a power function ("gamma correction"). Both displays have adjustable pixel independence and can be set to have little to no spatial pixel interactions. OLED displays appear to be a suitable, or even preferable, option for many vision research applications.


Goergen C.J.,Stanford University
Journal of magnetic resonance imaging : JMRI | Year: 2010

To develop methods to quantify cyclic strain, motion, and curvature of the murine abdominal aorta in vivo. C57BL/6J and apoE(-/-) mice underwent three-dimensional (3D) time-of-flight MR angiography to position cardiac-gated 2D slices at four locations along the abdominal aorta where circumferential cyclic strain and lumen centroid motion were calculated. From the 3D data, a centerline through the aorta was created to quantify geometric curvature at 0.1-mm intervals. Medial elastin content was quantified with histology postmortem. The location and shape of abdominal aortic aneurysms (AAAs), created from angiotensin II infusion, were evaluated qualitatively. Strain waveforms were similar at all locations and between groups. Centroid motion was significantly larger and more leftward above the renal vessels than below (P < 0.05). Maximum geometric curvature occurred slightly proximal to the right renal artery. Elastin content was similar around the circumference of the vessel. AAAs developed in the same location as the maximum curvature and grew in the same direction as vessel curvature and motion. The methods presented provide temporally and spatially resolved data quantifying murine aortic motion and curvature in vivo. This noninvasive methodology will allow serial quantification of how these parameters influence the location and direction of AAA growth.


Mahoney M.W.,Stanford University
Foundations and Trends in Machine Learning | Year: 2010

Randomized algorithms for very large matrix problems have received a great deal of attention in recent years. Much of this work was motivated by problems in large-scale data analysis, largely since matrices are popular structures with which to model data drawn from a wide range of application domains, and this work was performed by individuals from many different research communities. While the most obvious benefit of randomization is that it can lead to faster algorithms, either in worst-case asymptotic theory and/or numerical implementation, there are numerous other benefits that are at least as important. For example, the use of randomization can lead to simpler algorithms that are easier to analyze or reason about when applied in counterintuitive settings; it can lead to algorithms with more interpretable output, which is of interest in applications where analyst time rather than just computational time is of interest; it can lead implicitly to regularization and more robust output; and randomized algorithms can often be organized to exploit modern computational architectures better than classical numerical methods. © 2011 M. W. Mahoney.


Logan A.C.,Stanford University
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2010

Recombinant human factor VIIa (rFVIIa) is approved by the US Food and Drug Administration for use in the setting of hemorrhage associated with factor VIII or factor IX inhibitors in patients with congenital or acquired hemophilia. This indication represents only a small number of bleeding conditions. Since it became available, rFVIIa has been increasingly used in the management of off-label indications, ranging from emergent hemostasis in traumatic hemorrhage to prophylactic hemostasis in patients undergoing major surgery. Prominent off-label indications include the management of patients with coagulopathies, such as occurs in trauma patients experiencing massive and uncontrolled hemorrhage, and in patients undergoing cardiovascular surgery with cardiopulmonary bypass. Other occasions for use occur in patients with intact coagulation systems, with nontraumatic intracranial hemorrhage being the most common in this group. Uncertainties regarding the efficacy and safety associated with use of rFVIIa in these off-label scenarios have led to evidence-based assessments of patient outcomes, including mortality, the rate of thromboembolic adverse events, and posttreatment functional status. We review the evidence regarding the efficacy and safety of this important, but controversial, hemostatic agent in the off-label setting.


Marmor M.F.,Stanford University | Melles R.B.,Kaiser Permanente
Ophthalmology | Year: 2014

Purpose American Academy of Ophthalmology recommendations for screening for hydroxychloroquine (HCQ) retinopathy advise objective measures, such as spectral-domain optical coherence tomography (SD-OCT) and multifocal electroretinography (mfERG) along with visual fields. However, the relative sensitivity and specificity of screening tests have not been fully resolved. We characterize a subset of patients with toxicity who show unusual disparity between fields and SD-OCT and thus have implications for screening practice. Design Review of charts and clinical data. Participants Patients at Stanford and Kaiser Permanente who had used HCQ with greater than 1000 g cumulative exposure. There were more than 2000 such individuals, among whom 150 had clear evidence of toxicity. Methods Patients were evaluated by visual fields (10-2 white Swedish Interactive Threshold Algorithm pattern deviation plots), SD-OCT, and sometimes mfERG or fundus autofluorescence. Main Outcome Measures Relative findings on visual fields in comparison with SD-OCT. Results There were 11 patients among those with HCQ toxicity who had parafoveal ring scotomas but a normal-appearing SD-OCT. None had a history of macular disease or evidence for any other cause of bull's eye maculopathy. Conversely, all cases with a clear degree of parafoveal damage on SD-OCT showed at least some focal spots of parafoveal field loss. Conclusions Approximately 10% of patients with early HCQ toxicity showed prominent ring scotomas on field testing without obvious SD-OCT abnormality. This should encourage the inclusion of visual fields as a key screening tool, even when SD-OCT (a more specific and objective test) also is performed. The combination of visual fields and SD-OCT gives both sensitivity and specificity while avoiding unnecessary stoppage of the drug. © 2014 by the American Academy of Ophthalmology.


Khan M.A.,Stanford University
Advances in experimental medicine and biology | Year: 2013

Microvascular loss may be an unappreciated root cause of chronic rejection for all solid organ transplants. As the only solid organ transplant that does not undergo primary systemic arterial revascularization at the time of surgery, lung transplants rely on the establishment of a microcirculation and are especially vulnerable to the effects of microvascular loss. Microangiopathy, with its attendant ischemia, can lead to tissue infarction and airway fibrosis. Maintaining healthy vasculature in lung allografts may be critical for preventing terminal airway fibrosis, also known as the bronchiolitis obliterans syndrome (BOS). BOS is the major obstacle to lung transplant success and affects up to 60% of patients surviving 5 years. The role of complement in causing acute microvascular loss and ischemia during rejection has recently been examined using the mouse orthotopic tracheal transplantation; this is an ideal model for parsing the role of airway vasculature in rejection. Prior to the development of airway fibrosis in rejecting tracheal allografts, C3 deposits on the vascular endothelium just as tissue hypoxia is first detected. With the eventual destruction of vessels, microvascular blood flow to the graft stops altogether for several days. Complement deficiency and complement inhibition lead to markedly improved tissue oxygenation in transplants, diminished airway remodeling, and accelerated vascular repair. CD4+ T cells and antibody-dependent complement activity independently mediate vascular destruction and sustained tissue ischemia during acute rejection. Consequently, interceding against complement-mediated microvascular injury with adjunctive therapy during acute rejection episodes, in addition to standard immunosuppression which targets CD4+ T cells, may help prevent the subsequent development of chronic rejection.


Mabuchi H.,Stanford University
Physical Review A - Atomic, Molecular, and Optical Physics | Year: 2012

Many proposals for solid-state photonic implementations of quantum information processing utilize high-quality optical resonators to achieve strong coupling between guided fields and heterogeneously incorporated qubits. Given the practical difficulty of accurately placing quantum dots, vacancy centers, or other such atomlike emitters throughout a complex nanophotonic circuit, it would be natural to consider whether high-quality resonators could be used in conjunction with bulk optical nonlinearities to create optically coupled qubit degrees of freedom via lithographic patterning of a homogeneous medium. A recent limit theorem for quantum stochastic differential equations can be used to prove rigorously that this should be possible, in principle, using resonators incorporating a strongly Kerr-nonlinear, χ (2 )- nonlinear, or two-photon-absorbing material with very low loss at the fundamental optical wavelength. Published by the American Physical Society under the terms of the Creative Commons Attribution 3.0 License. Further distribution of this work must maintain attribution to the author(s) and the published article's title, journal citation, and DOI.


Kallosh R.,Stanford University
Journal of High Energy Physics | Year: 2012

We study N = 8 supergravity deformed by the presence of the candidate counterterms. We show that even though they are invariant under undeformed E 7(7), all of the candidate counterterms violate the deformed E 7(7) current conservation. The same conclusion follows from the uniqueness of the Lorentz and SU(8) covariant, E 7(7) invariant unitarity constraint expressing the 56-dimensional E 7(7) doublet via 28 independent vectors, in agreement with the E 7(7)/SU(8) coset space geometry. Therefore E 7(7) duality predicts the allloop UV finiteness of perturbative N = 8 supergravity. © 2012 SISSA.


Dolmetsch R.,Stanford University | Geschwind D.H.,Psychiatry and Human Genetics
Cell | Year: 2011

Induced pluripotent stem cell-derived neurons from patients promise to fill an important niche between studies in humans and model organisms in deciphering mechanisms and identifying therapeutic avenues for neurologic and psychiatric diseases. Recent work begins to tap this potential and also highlights challenges that must be overcome to be fully realized. © 2011 Elsevier Inc. All Rights Reserved.


O'Brien L.E.,Stanford University | Bilder D.,University of California at Berkeley
Annual Review of Cell and Developmental Biology | Year: 2013

Adult animals rely on populations of stem cells to ensure organ function throughout their lifetime. Stem cells are governed by signals from stem cell niches, and much is known about how single niches promote stemness and direct stem cell behavior. However, most organs contain a multitude of stem cell-niche units, which are often distributed across the entire expanse of the tissue. Beyond the biology of individual stem cell-niche interactions, the next challenge is to uncover the tissue-level processes that orchestrate spatial control of stem-based renewal, repair, and remodeling throughout a whole organ. Here we examine what is known about higher order mechanisms for interniche coordination in epithelial organs, whose simple geometry offers a promising entry point for understanding the regulation of niche number, distribution, and activity. We also consider the potential existence of stem cell territories and how tissue architecture may influence niche coordination. © 2013 by Annual Reviews. All rights reserved.


Harris B.,Stanford University
Tobacco Control | Year: 2011

Background When lung cancer fears emerged in the 1950s, cigarette companies initiated a shift in cigarette design from unfiltered to filtered cigarettes. Both the ineffectiveness of cigarette filters and the tobacco industry's misleading marketing of the benefits of filtered cigarettes have been well documented. However, during the 1950s and 1960s, American cigarette companies spent millions of dollars to solve what the industry identified as the 'filter problem'. These extensive filter research and development efforts suggest a phase of genuine optimism among cigarette designers that cigarette filters could be engineered to mitigate the health hazards of smoking. Objective This paper explores the early history of cigarette filter research and development in order to elucidate why and when seemingly sincere filter engineering efforts devolved into manipulations in cigarette design to sustain cigarette marketing and mitigate consumers' concerns about the health consequences of smoking. Methods Relevant word and phrase searches were conducted in the Legacy Tobacco Documents Library online database, Google Patents, and media and medical databases including ProQuest, JSTOR, Medline and PubMed. Results 13 tobacco industry documents were identified that track prominent developments involved in what the industry referred to as the 'filter problem'. These reveal a period of intense focus on the 'filter problem' that persisted from the mid-1950s to the mid-1960s, featuring collaborations between cigarette producers and large American chemical and textile companies to develop effective filters. In addition, the documents reveal how cigarette filter researchers' growing scientific knowledge of smoke chemistry led to increasing recognition that filters were unlikely to offer significant health protection. One of the primary concerns of cigarette producers was to design cigarette filters that could be economically incorporated into the massive scale of cigarette production. The synthetic plastic cellulose acetate became the fundamental cigarette filter material. By the mid-1960s, the meaning of the phrase 'filter problem' changed, such that the effort to develop effective filters became a campaign to market cigarette designs that would sustain the myth of cigarette filter efficacy. Conclusions This study indicates that cigarette designers at Philip Morris, British-American Tobacco, Lorillard and other companies believed for a time that they might be able to reduce some of the most dangerous substances in mainstream smoke through advanced engineering of filter tips. In their attempts to accomplish this, they developed the now ubiquitous cellulose acetate cigarette filter. By the mid-1960s cigarette designers realised that the intractability of the 'filter problem' derived from a simple fact: that which is harmful in mainstream smoke and that which provides the smoker with 'satisfaction' are essentially one and the same. Only in the wake of this realisation did the agenda of cigarette designers appear to transition away from mitigating the health hazards of smoking and towards the perpetuation of the notion that cigarette filters are effective in reducing these hazards. Filters became a marketing tool, designed to keep and recruit smokers as consumers of these hazardous products.


Petrosian V.,Stanford University
Space Science Reviews | Year: 2012

The subject of this paper is stochastic acceleration by plasma turbulence, a process akin to the original model proposed by Fermi. We review the relative merits of different acceleration models, in particular the so called first order Fermi acceleration by shocks and second order Fermi by stochastic processes, and point out that plasma waves or turbulence play an important role in all mechanisms of acceleration. Thus, stochastic acceleration by turbulence is active in most situations. We also show that it is the most efficient mechanism of acceleration of relatively cool non relativistic thermal background magnetized plasma particles. In addition, it can preferentially accelerate electrons relative to protons as is needed in many astrophysical radiating sources, where usually there are no indications of presence of shocks. We also point out that a hybrid acceleration mechanism consisting of initial acceleration by turbulence of background particles followed by a second stage acceleration by a shock has many attractive features. It is demonstrated that the above scenarios can account for many signatures of the accelerated electrons, protons and other ions, in particular 3He and 4He, seen directly as Solar Energetic Particles and through the radiation they produce in solar flares. © 2012 Springer Science+Business Media B.V.


The retinoblastoma tumor suppressor (Rb) is a potent and ubiquitously expressed cell cycle regulator, but patients with a germline Rb mutation develop a very specific tumor spectrum. This surprising observation raises the possibility that mechanisms that compensate for loss of Rb function are present or activated in many cell types. In particular, p107, a protein related to Rb, has been shown to functionally overlap for loss of Rb in several cellular contexts. To investigate the mechanisms underlying this functional redundancy between Rb and p107 in vivo, we used gene targeting in embryonic stem cells to engineer point mutations in two consensus E2F binding sites in the endogenous p107 promoter. Analysis of normal and mutant cells by gene expression and chromatin immunoprecipitation assays showed that members of the Rb and E2F families directly bound these two sites. Furthermore, we found that these two E2F sites controlled both the repression of p107 in quiescent cells and also its activation in cycling cells, as well as in Rb mutant cells. Cell cycle assays further indicated that activation of p107 transcription during S phase through the two E2F binding sites was critical for controlled cell cycle progression, uncovering a specific role for p107 to slow proliferation in mammalian cells. Direct transcriptional repression of p107 by Rb and E2F family members provides a molecular mechanism for a critical negative feedback loop during cell cycle progression and tumorigenesis. These experiments also suggest novel therapeutic strategies to increase the p107 levels in tumor cells.


Two images, "black swans" and "perfect storms," have struck the public's imagination and are used-at times indiscriminately-to describe the unthinkable or the extremely unlikely. These metaphors have been used as excuses to wait for an accident to happen before taking risk management measures, both in industry and government. These two images represent two distinct types of uncertainties (epistemic and aleatory). Existing statistics are often insufficient to support risk management because the sample may be too small and the system may have changed. Rationality as defined by the von Neumann axioms leads to a combination of both types of uncertainties into a single probability measure-Bayesian probability-and accounts only for risk aversion. Yet, the decisionmaker may also want to be ambiguity averse. This article presents an engineering risk analysis perspective on the problem, using all available information in support of proactive risk management decisions and considering both types of uncertainty. These measures involve monitoring of signals, precursors, and near-misses, as well as reinforcement of the system and a thoughtful response strategy. It also involves careful examination of organizational factors such as the incentive system, which shape human performance and affect the risk of errors. In all cases, including rare events, risk quantification does not allow "prediction" of accidents and catastrophes. Instead, it is meant to support effective risk management rather than simply reacting to the latest events and headlines. © 2012 Society for Risk Analysis.


Fu M.-M.,University of Pennsylvania | Fu M.-M.,Stanford University | Holzbaur E.L.F.,University of Pennsylvania
Trends in Cell Biology | Year: 2014

Intracellular trafficking pathways, including endocytosis, autophagy, and secretion, rely on directed organelle transport driven by the opposing microtubule motor proteins kinesin and dynein. Precise spatial and temporal targeting of vesicles and organelles requires the integrated regulation of these opposing motors, which are often bound simultaneously to the same cargo. Recent progress demonstrates that organelle-associated scaffol