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Columbia University in the City of New York, or simply Columbia University, is an American private Ivy League research university located in the Morningside Heights neighborhood of Upper Manhattan in New York City. It is the oldest institution of higher learning in the State of New York, the fifth oldest in the United States, and one of the country's nine Colonial Colleges founded before the American Revolution. Today the university operates Columbia Global Centers overseas in Amman, Beijing, Istanbul, Paris, Mumbai, Rio de Janeiro, Santiago and Nairobi.The university was founded in 1754 as King's College by royal charter of George II of Great Britain. After the American Revolutionary War, King's College briefly became a state entity, and was renamed Columbia College in 1784. The University now operates under a 1787 charter that places the institution under a private board of trustees, and in 1896 it was further renamed Columbia University. That same year, the university's campus was moved from Madison Avenue to its current location in Morningside Heights, where it occupies more than six city blocks, or 32 acres .The university encompasses twenty schools and is affiliated with numerous institutions, including Teachers College , Barnard College, and the Union Theological Seminary, with joint undergraduate programs available through the Jewish Theological Seminary of America as well as the Juilliard School.Columbia annually administers the Pulitzer Prize. 101 Nobel Prize laureates have been affiliated with the university as students, faculty, or staff, the second most of any institution in the world. Columbia is one of the fourteen founding members of the Association of American Universities, and was the first school in the United States to grant the M.D. degree. Notable alumni and former students of the university and its predecessor, King's College, include five Founding Fathers of the United States; nine Justices of the United States Supreme Court; 43 Nobel Prize laureates; 20 living billionaires; 28 Academy Award winners; and 29 heads of state, including three United States Presidents. Wikipedia.


Lelli K.M.,Columbia University | Slattery M.,University of Chicago | Mann R.S.,Columbia University
Annual Review of Genetics | Year: 2012

Regulation of gene expression in eukaryotes is an extremely complex process. In this review, we break down several critical steps, emphasizing new data and techniques that have expanded current gene regulatory models. We begin at the level of DNA sequence where cis-regulatory modules (CRMs) provide important regulatory information in the form of transcription factor (TF) binding sites. In this respect, CRMs function as instructional platforms for the assembly of gene regulatory complexes. We discuss multiple mechanisms controlling complex assembly, including cooperative DNA binding, combinatorial codes, and CRM architecture. The second section of this review places CRM assembly in the context of nucleosomes and condensed chromatin. We discuss how DNA accessibility and histone modifications contribute to TF function. Lastly, new advances in chromosomal mapping techniques have provided increased understanding of intra- and interchromosomal interactions. We discuss how these topological maps influence gene regulatory models. © 2012 by Annual Reviews. Source


Petukhova L.,Columbia University
The journal of investigative dermatology. Symposium proceedings / the Society for Investigative Dermatology, Inc. [and] European Society for Dermatological Research | Year: 2013

A major impetus to initiating the Human Genome Project was the belief that information encoded in the human genome would "accelerate progress in understanding disease pathogenesis and in developing new approaches to diagnosis, treatment, and prevention in many areas of medicine". Alopecia areata (AA) is a notable example of how understanding the genetic basis of a disease can have an impact on the care of patients in a relatively short time. Our first genome-wide association study in AA identified an initial set of common variants that increase risk of AA, some of which are shared with other autoimmune diseases. Thus, there has already been rapid progress in the translation of this information into new therapeutic strategies for patients, as drugs are already on the market for some of these disorders that can now be tested in AA. Informed by the progress achieved with genetic studies for mechanistically aligned autoimmune diseases, we are poised to carry this work forward and interrogate the underlying disease mechanisms in AA. Importantly, future genetic studies aimed at identifying additional susceptibility genes will further establish the foundation for the application of precision medicine in the care of AA patients. Source


Aprile E.,Columbia University | Doke T.,Waseda University
Reviews of Modern Physics | Year: 2010

This article reviews the progress made over the last 20 years in the development and applications of liquid xenon detectors in particle physics, astrophysics, and medical imaging experiments. A summary of the fundamental properties of liquid xenon as radiation detection medium, in light of the most current theoretical and experimental information is first provided. After an introduction of the different type of liquid xenon detectors, a review of past, current, and future experiments using liquid xenon to search for rare processes and to image radiation in space and in medicine is given. Each application is introduced with a survey of the underlying scientific motivation and experimental requirements before reviewing the basic characteristics and expected performance of each experiment. Within this decade it appears likely that large volume liquid xenon detectors operated in different modes will contribute to answering some of the most fundamental questions in particle physics, astrophysics, and cosmology, fulfilling the most demanding detection challenges. From detectors based solely on liquid xenon (LXe) scintillation, such as in the MEG experiment for the search of the rare " μ→eγ " decay, currently the largest liquid xenon detector in operation, and in the XMASS experiment for dark matter detection, to the class of time projection chambers which exploit both scintillation and ionization of LXe, such as in the XENON dark matter search experiment and in the Enriched Xenon Observatory for neutrinoless double beta decay, unrivaled performance and important contributions to physics in the next few years are anticipated. © 2010 The American Physical Society. Source


Mitsumoto H.,Columbia University | Brooks B.R.,University of North Carolina at Charlotte | Silani V.,University of Milan
The Lancet Neurology | Year: 2014

Amyotrophic lateral sclerosis (ALS) is one of the most rapidly progressive neurodegenerative diseases of unknown cause. Riluzole is the only drug that slows disease progression. More than 50 randomised controlled trials (RCTs) of proposed disease-modifying drugs have failed to show positive results in the past half-century. In the past decade, at least 18 drugs have been tested in large phase 2 or 3 RCTs, including lithium, which was tested in several RCTs. Potential reasons for the negative results can be classified into three categories: first, issues regarding trial rationale and preclinical study results; second, pharmacological issues; and third, clinical trial design and methodology issues. Clinical trials for stem cell therapy and RCTs targeting pharmacological or non-pharmacological symptomatic treatment in ALS are examples of areas that need novel design strategies. Only through critical analyses of the failed trials can new and important suggestions be identified for the future success of clinical trials in ALS. © 2014 Elsevier Ltd. Source


Moore K.J.,New York University | Tabas I.,Columbia University
Cell | Year: 2011

In atherosclerosis, the accumulation of apolipoprotein B-lipoproteins in the matrix beneath the endothelial cell layer of blood vessels leads to the recruitment of monocytes, the cells of the immune system that give rise to macrophages and dendritic cells. Macrophages derived from these recruited monocytes participate in a maladaptive, nonresolving inflammatory response that expands the subendothelial layer due to the accumulation of cells, lipid, and matrix. Some lesions subsequently form a necrotic core, triggering acute thrombotic vascular disease, including myocardial infarction, stroke, and sudden cardiac death. This Review discusses the central roles of macrophages in each of these stages of disease pathogenesis. © 2011 Elsevier Inc. Source


Chesin M.,Columbia University
Bipolar disorders | Year: 2013

Suicide is a leading cause of death in the USA. Although factors elevating long-term risk for suicide are known and include bipolar disorder, signs of imminent suicide risk are difficult to study and not well specified. Acute risk determinations must be made to determine the appropriate level of care to safeguard patients. To increase safety among at-risk patients in the short term and to decrease risk over time, psychosocial interventions to prevent suicide have been developed and tested in acute care and outpatient settings. A narrative review of studies of imminent risk factors for suicide, suicide risk decision-making, and psychosocial suicide prevention interventions was conducted. Although some long-term risk factors of suicide have been established, accurate identification of individuals at imminent risk for suicide is difficult. Therefore, prevention efforts targeting individuals at high suicide behavior risk discharging from acute care settings tend to be generic and focus on psychoeducation and supportive follow-up contact. Data regarding the effectiveness of brief interventions (i.e., those not requiring more than one individualized treatment session) are mixed, showing better outcomes in the shorter term and when the incidence of suicidal behavior or ideation is the outcome. With respect to longer-term suicide prevention interventions (i.e., those with a minimum of ten sessions), Dialectical Behavior Therapy has the largest evidence base. To improve suicide prevention efforts, more rigorous study of imminent risk factors and psychosocial interventions is needed. Adaptations specific to individuals with bipolar disorder are possible and needed. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Source


Beckerman R.,Columbia University
Cold Spring Harbor perspectives in biology | Year: 2010

Inactivation of p53 is critical for the formation of most tumors. Illumination of the key function(s) of p53 protein in protecting cells from becoming cancerous is therefore a worthy goal. Arguably p53's most important function is to act as a transcription factor that directly regulates perhaps several hundred of the cell's RNA polymerase II (RNAP II)-transcribed genes, and indirectly regulates thousands of others. Indeed p53 is the most well studied mammalian transcription factor. The p53 tetramer binds to its response element where it can recruit diverse transcriptional coregulators such as histone modifying enzymes, chromatin remodeling factors, subunits of the mediator complex, and components of general transcription machinery and preinitiation complex (PIC) to modulate RNAPII activity at target loci (Laptenko and Prives 2006). The p53 transcriptional program is regulated in a stimulus-specific fashion (Murray-Zmijewski et al. 2008; Vousden and Prives 2009), whereby distinct subsets of p53 target genes are induced in response to different p53-activating agents, likely allowing cells to tailor their response to different types of stress. How p53 is able to discriminate between these different loci is the subject of intense research. Here, we describe key aspects of the fundamentals of p53-mediated transcriptional regulation and target gene promoter selectivity. Source


MacGregor J.L.,Columbia University
Seminars in cutaneous medicine and surgery | Year: 2013

The demand for noninvasive skin tightening procedures is increasing as patients seek safe and effective alternatives to aesthetic surgical procedures of the face, neck, and body. Over the past decade, radiofrequency and infrared laser devices have been popularized owing to their ability to deliver controlled heat to the dermis, stimulate neocollagenesis, and effect modest tissue tightening with minimal recovery. However, these less invasive approaches are historically associated with inferior efficacy so that surgery still remains the treatment of choice to address moderate to severe tissue laxity. Microfocused ultrasound was recently introduced as a novel energy modality for transcutaneous heat delivery that reaches the deeper subdermal connective tissue in tightly focused zones at consistent programmed depths. The goal is to produce a deeper wound healing response at multiple levels with robust collagen remodeling and a more durable clinical response. The Ulthera device (Ulthera, Inc, Meza, AZ), with refined microfocused ultrasound technology, has been adapted specifically for skin tightening and lifting with little recovery or risk of complications since its introduction in 2009. As clinical parameters are studied and optimized, enhanced efficacy and consistency of clinical improvement is expected. Source


Levav J.,Columbia University
Psychological science : a journal of the American Psychological Society / APS | Year: 2010

We show that minimal physical contact can increase people's sense of security and consequently lead them to increased risk-taking behavior. In three experiments, with both hypothetical and real payoffs, a female experimenter's light, comforting pat on the shoulder led participants to greater financial risk taking. Further, this effect was both mediated and moderated by feelings of security in both male and female participants. Finally, we established the boundary conditions for the impact of physical contact on risk-taking behaviors by demonstrating that the effect does not occur when the touching is performed by a male and is attenuated when the touch consists of a handshake. The results suggest that subtle physical contact can be strongly influential in decision making and the willingness to accept risk. Source


Marrero V.A.,Columbia University
PLoS genetics | Year: 2010

Homology-dependent repair of DNA double-strand breaks (DSBs) by gene conversion involves short tracts of DNA synthesis and limited loss of heterozygosity (LOH). For DSBs that present only one end, repair occurs by invasion into a homologous sequence followed by replication to the end of the chromosome resulting in extensive LOH, a process called break-induced replication (BIR). We developed a BIR assay in Saccharomyces cerevisiae consisting of a plasmid with a telomere seeding sequence separated from sequence homologous to chromosome III by an I-SceI endonuclease recognition site. Following cleavage of the plasmid by I-SceI in vivo, de novo telomere synthesis occurs at one end of the vector, and the other end invades at the homologous sequence on chromosome III and initiates replication to the end of the chromosome to generate a stable chromosome fragment (CF). BIR was infrequent in wild-type cells due to degradation of the linearized vector. However, in the exo1Delta sgs1Delta mutant, which is defective in the 5'-3' resection of DSBs, the frequency of BIR was increased by 39-fold. Extension of the invading end of the plasmid was detected by physical analysis two hours after induction of the I-SceI endonuclease in the wild-type exo1Delta, sgs1Delta, and exo1Delta sgs1Delta mutants, but fully repaired products were only visible in the exo1Delta sgs1Delta mutant. The inhibitory effect of resection was less in a plasmid-chromosome gene conversion assay, compared to BIR, and products were detected by physical assay in the wild-type strain. The rare chromosome rearrangements due to BIR template switching at repeated sequences were increased in the exo1Delta sgs1Delta mutant, suggesting that reduced resection can decrease the fidelity of homologous recombination. Source


A method of delivering an oligonucleotide or a plasmid expressing an oligonucleotide into a target cell comprises introducing an oligonucleotide into a donor cell, particularly a stem cell, and contacting the target cell with the donor cell under conditions permitting the donor cell to form a gap junction with the target cell, whereby the oligonucleotide or a product of the oligonucleotide is delivered into the target cell from the donor cell.


Patent
Columbia University and New York University | Date: 2011-05-17

A method of creating an atrioventricular bypass tract for a heart comprises growing mesenchymal stem cells into a strip with two ends, attaching one end of the strip onto the atrium of the heart, and attaching the other end of the strip to the ventricle of the heart, to create a tract connecting the atrium to the ventricle to provide a path for electrical signals generated by the sinus node to propagate across the tract and excite the ventricle.


The present invention relates to methods and compositions for modulating the activity of two-pore domain K+ channels (K


Liu X.,Columbia University
Statistics in Medicine | Year: 2012

In biomedical research and practice, quantitative tests or biomarkers are often used for diagnostic or screening purposes, with a cut point established on the quantitative measurement to aid binary classification. This paper introduces an alternative to the traditional methods based on the Youden index and the closest-to-(0, 1) criterion for threshold selection. A concordance probability evaluating the classification accuracy of a dichotomized measure is defined as an objective function of the possible cut point. A nonparametric approach is used to search for the optimal cut point maximizing the objective function. The procedure is shown to perform well in a simulation study. Using data from a real-world study of arsenic-induced skin lesions, we apply the method to a measure of blood arsenic levels, selecting a cut point to be used as a warning threshold. © 2012 John Wiley & Sons, Ltd. Source


Dempster D.W.,Columbia University
The American journal of managed care | Year: 2011

Osteoporosis is responsible for approximately 2 million fractures annually, including hip, vertebral (spinal), wrist, and other fractures. Osteoporosis-related fractures may lead to diminished quality of life, disability, and even death. In addition, the direct and indirect costs of osteoporosis and its associated fractures are tremendous. Given the aging population, by 2025, annual direct costs from osteoporosis are expected to reach approximately $25.3 billion. Thus, osteoporosis has significant physical, emotional, and financial consequences. With appropriate screening, healthcare providers can implement effective interventions before fractures occur and ultimately improve quality of life, as well as help curb looming osteoporosis-related costs. Source


Basch C.E.,Columbia University
Journal of School Health | Year: 2011

Objectives: This article provides an introduction to the October 2011 special issue of the Journal of School Health on "Healthier Students Are Better Learners." Methods: Literature was reviewed and synthesized to identify health problems affecting school-aged youth that are highly prevalent, disproportionately affect urban minority youth, directly and indirectly causally affect academic achievement, and can be feasibly and effectively addressed through school health programs and services. Results: Based on these criteria, 7 educationally relevant health disparities were selected as strategic priorities to help close the achievement gap: (1) vision, (2) asthma, (3) teen pregnancy, (4) aggression and violence, (5) physical activity, (6) breakfast, and (7) inattention and hyperactivity. Research clearly shows that these health problems influence students' motivation and ability to learn. Disparities among urban minority youth are outlined, along with the causal pathways through which each adversely affects academic achievement, including sensory perceptions, cognition, school connectedness, absenteeism, and dropping out. Evidence-based approaches that schools can implement to address these problems are presented. These health problems and the causal pathways they influence have interactive and a synergistic effect, which is why they must be addressed collectively using a coordinated approach. Conclusions: No matter how well teachers are prepared to teach, no matter what accountability measures are put in place, no matter what governing structures are established for schools, educational progress will be profoundly limited if students are not motivated and able to learn. Particular health problems play a major role in limiting the motivation and ability to learn of urban minority youth. This is why reducing these disparities through a coordinated approach warrants validation as a cohesive school improvement initiative to close the achievement gap. Local, state, and national policies for implementing this recommendation are suggested. © 2011, American School Health Association. Source


Champagne F.A.,Columbia University
Advances in Genetics | Year: 2012

Social experiences can have a persistent effect on biological processes leading to phenotypic diversity. Variation in gene regulation has emerged as a mechanism through which the interplay between DNA and environments leads to the biological encoding of these experiences. Epigenetic modifications-molecular pathways through which transcription is altered without altering the underlying DNA sequence-play a critical role in the normal process of development and are being increasingly explored as a mechanism linking environmental experiences to long-term biobehavioral outcomes. In this review, evidence implicating epigenetic factors, such as DNA methylation and histone modifications, in the link between social experiences occurring during the postnatal period and in adulthood and altered neuroendocrine and behavioral outcomes will be highlighted. In addition, the role of epigenetic mechanisms in shaping variation in social behavior and the implications of epigenetics for our understanding of the transmission of traits across generations will be discussed. © 2012 Elsevier Inc. Source


Background: Essential tremor (ET) is amongst the most commonly misdiagnosed neurological diseases. The current aim was to provide observational data on a basic characteristic of ET, namely, the relative severity of postural to kinetic tremor. Methods: A total of 369 ET cases were enrolled in a cross-sectional study. Postural tremor scores (0-3) and kinetic tremor scores (0-3) were assigned during a standardized neurological examination. Results: In the vast bulk of cases (~95%), kinetic tremor was more severe than postural tremor. In nearly one-in-three cases (32.8%), the kinetic tremor score was ≥1 points higher than the postural tremor score. Conversely, in only a few cases (~5%) was postural tremor even marginally (<1 point) more severe than kinetic tremor, and in no case was the postural tremor score ≥1 point higher than the kinetic tremor score. At each postural tremor score, nearly all cases had that amount of kinetic tremor or more. Conclusion: The primary type of tremor in ET is kinetic rather than postural. Recognition of the simple, empirical features of tremor phenomenology has potential diagnostic value for practicing clinicians. © 2012 The Author(s). European Journal of Neurology © 2012 EFNS. Source


Sulzer D.,Columbia University
Movement Disorders | Year: 2010

Alpha-synuclein (α-syn) appears to normally regulate neurotransmitter release, possibly via calcium-dependent binding and dissociation from lipid domains on secretory vesicles. The pathogenic effects of α-syn leading to Parkinson's disease (PD) appear to result from alternate toxic effects on lipid membrane. A variety of findings indicate that overexpression of wild-type α-syn, pathogenic mutations of α-syn, and dopamine-modified-α-syn promote toxic interaction between α-syn oligomers and lipids. These may disrupt transmembrane concentration gradients across secretory vesicles and other organelles and interfere with normal lysosomal or ubiqutin/proteasome mediated protein degradation or mitochondrial function. Additional causes of PD may interfere at other points with normal handling and degradation of α-syn, providing a variety of entry points to a converging neurodegenerative path underlying the disease. © 2010 Movement Disorder Society. Source


Brus L.,Columbia University
Accounts of Chemical Research | Year: 2014

ConspectusIn electronic structure theory, electron-electron repulsion is normally considered only in an average (or mean field) sense, for example, in a single Hartree-Fock determinant. This is the simple molecular orbital model, which is often a good approximation for molecules. In infinite systems, this averaging treatment leads to delocalized electronic bands, an excellent description of bulk 3D sp3 semiconductors. However, in reality electrons try to instantaneously avoid each other; their relative motion is correlated. Strong electron-electron repulsion and correlation create new collective states and cause new femtosecond kinetic processes. This is especially true in 1D and 2D systems. The quantum size effect, a single electron property, is widely known: the band gap increases with decreasing size. This Account focuses on the experimental consequences of strong correlation. We first describe π-π∗ excited states in carbon nanotubes (CNTs). To obtain the spectra of individual CNTs, we developed a white-light, right-angle resonant Rayleigh scattering method. Discrete exciton transitions dominate the optical absorption spectra of both semiconducting and metallic tubes. Excitons are bound neutral excited states in which the electron and hole tightly orbit each other due to their mutual Coulomb attraction. We then describe more generally the independent roles of size and dimensionality in nanoelectronic structure, using additional examples from graphene, trans-polyacetylene chains, transition metal dichalcogenides, organic/inorganic Pb iodide perovskites, quantum dots, and pentacene van der Waals crystals. In 1D and 2D chemical systems, the electronic band structure diagram can be a poor predictor of properties if explicit correlation is not considered. One- and two-dimensional systems show quantum confinement and especially strong correlation as compared with their 3D parent systems. The Coulomb interaction is enhanced because the electrons are on the surface. One- and two-dimensional systems can exhibit essentially molecular properties even though they are infinite in size. Zero-dimensional Qdots show quantum confinement and modest electron correlation. Correlation is weak in 3D bulk semiconductors. Strongly correlated electronic states can behave as if they have fractional charge and effectively separate the spin and charge of the electron. This is apparent in the "soliton" state of polyacetylene, the fractional charge quantum Hall state of graphene, and the Luttinger electrical conductivity of metallic CNTs. © 2014 American Chemical Society. Source


Beloborodov A.M.,Columbia University
Monthly Notices of the Royal Astronomical Society | Year: 2014

Merger of a white dwarf binary creates a differentially rotating object which is expected to generate strong magnetic fields. Kinetic energy stored in differential rotation is partially dissipated in the magnetically dominated corona, which forms a hot variable outflow with ejection velocity comparable to 109 cm s-1. The outflow should carry significant mass and energy for hours to days, creating an expanding fireball with the following features. (i) The fireball is initially opaque and its internal energy is dominated by the trapped thermal radiation. The stored heat is partially converted to kinetic energy of the flow (through adiabatic cooling) and partially radiated away. (ii) Internal shocks develop in the fireball and increase its radiative output. (iii) A significant fraction of the emitted energy is in the optical band. As a result, a bright optical transient with luminosity L ∼ 1041-1042 erg s-1 and a characteristic peak duration comparable to 1 d may be expected from the merger. In contrast to classical novae or supernovae, the transient does not involve nuclear energy. The decay after its peak reflects the damping of differential rotation in the merger remnant. Such outbursts may be detected in the local Universe with current and upcoming optical surveys. © 2013 The Author Published by Oxford University Press on behalf of the Royal Astronomical Society. Source


Simpson L.L.,Society for Maternal Fetal Medicine Publications Committee | Simpson L.L.,Columbia University
American Journal of Obstetrics and Gynecology | Year: 2013

Objective: We sought to review the natural history, pathophysiology, diagnosis, and treatment options for twin-twin transfusion syndrome (TTTS). Methods: A systematic review was performed using MEDLINE database, PubMed, EMBASE, and Cochrane Library. The search was restricted to English-language articles published from 1966 through July 2012. Priority was given to articles reporting original research, in particular randomized controlled trials, although review articles and commentaries also were consulted. Abstracts of research presented at symposia and scientific conferences were not considered adequate for inclusion in this document. Evidence reports and guidelines published by organizations or institutions such as the National Institutes of Health, Agency for Health Research and Quality, American College of Obstetricians and Gynecologists, and Society for Maternal-Fetal Medicine were also reviewed, and additional studies were located by reviewing bibliographies of identified articles. Consistent with US Preventive Task Force guidelines, references were evaluated for quality based on the highest level of evidence, and recommendations were graded accordingly. Results and Recommendations: TTTS is a serious condition that can complicate 8-10% of twin pregnancies with monochorionic diamniotic (MCDA) placentation. The diagnosis of TTTS requires 2 criteria: (1) the presence of a MCDA pregnancy; and (2) the presence of oligohydramnios (defined as a maximal vertical pocket of <2 cm) in one sac, and of polyhydramnios (a maximal vertical pocket of >8 cm) in the other sac. The Quintero staging system appears to be a useful tool for describing the severity of TTTS in a standardized fashion. Serial sonographic evaluation should be considered for all twins with MCDA placentation, usually beginning at around 16 weeks and continuing about every 2 weeks until delivery. Screening for congenital heart disease is warranted in all monochorionic twins, in particular those complicated by TTTS. Extensive counseling should be provided to patients with pregnancies complicated by TTTS including natural history of the disease, as well as management options and their risks and benefits. The natural history of stage I TTTS is that more than three-fourths of cases remain stable or regress without invasive intervention, with perinatal survival of about 86%. Therefore, many patients with stage I TTTS may often be managed expectantly. The natural history of advanced (eg, stage ≥III) TTTS is bleak, with a reported perinatal loss rate of 70-100%, particularly when it presents <26 weeks. Fetoscopic laser photocoagulation of placental anastomoses is considered by most experts to be the best available approach for stages II, III, and IV TTTS in continuing pregnancies at <26 weeks, but the metaanalysis data show no significant survival benefit, and the long-term neurologic outcomes in the Eurofetus trial were not different than in nonlaser-treated controls. Even laser-treated TTTS is associated with a perinatal mortality rate of 30-50%, and a 5-20% chance of long-term neurologic handicap. Steroids for fetal maturation should be considered at 24 0/7 to 33 6/7 weeks, particularly in pregnancies complicated by stage ≥III TTTS, and those undergoing invasive interventions. © 2013 Mosby, Inc. Source


Jebara T.,Columbia University
Journal of Machine Learning Research | Year: 2011

A multitask learning framework is developed for discriminative classification and regression where multiple large-margin linear classifiers are estimated for different prediction problems. These classifiers operate in a common input space but are coupled as they recover an unknown shared representation. A maximum entropy discrimination (MED) framework is used to derive the multitask algorithm which involves only convex optimization problems that are straightforward to implement. Three multitask scenarios are described. The first multitask method produces multiple support vector machines that learn a shared sparse feature selection over the input space. The second multitask method produces multiple support vector machines that learn a shared conic kernel combination. The third multitask method produces a pooled classifier as well as adaptively specialized individual classifiers. Furthermore, extensions to regression, graphical model structure estimation and other sparse methods are discussed. The maximum entropy optimization problems are implemented via a sequential quadratic programming method which leverages recent progress in fast SVM solvers. Fast monotonic convergence bounds are provided by bounding the MED sparsifying cost function with a quadratic function and ensuring only a constant factor runtime increase above standard independent SVM solvers. Results are shown on multitask data sets and favor multitask learning over single-task or tabula rasa methods. © 2011 Tony Jebara. Source


Shear M.K.,Columbia University
Dialogues in Clinical Neuroscience | Year: 2012

Complicated grief is a recently recognized condition that occurs in about 7% of bereaved people. People with this condition are caught up in rumination about the circumstances of the death, worry about its consequences, or excessive avoidance of reminders of the loss. Unable to comprehend the finality and consequences of the loss, they resort to excessive avoidance of reminders of the loss as they are tossed helplessly on waves of intense emotion. People with complicated grief need help, and clinicians need to know how to recognize the symptoms and how to provide help. This paper provides a framework to help clinicans understand bereavement, grief, and mourning. Evidence-based diagnostic criteria are provided to help clinicians recognize complicated grief, and differentiate it from depression as well as anxiety disorder. We provide an overview of risk factors and basic assumptions and principles that can guide treatment. © 2012, LLS SAS. Source


Dworkin J.,Columbia University
Annual Review of Microbiology | Year: 2014

Peptidoglycan serves as a key structure of the bacterial cell by determining cell shape and providing resistance to internal turgor pressure. However, in addition to these essential and well-studied functions, bacterial signaling by peptidoglycan fragments, or muropeptides, has been demonstrated by recent work. Actively growing bacteria release muropeptides as a consequence of cell wall remodeling during elongation and division. Therefore, the presence of muropeptide synthesis is indicative of growth-promoting conditions and may serve as a broadly conserved signal for nongrowing cells to reinitiate growth. In addition, muropeptides serve as signals between bacteria and eukaryotic organisms during both pathogenic and symbiotic interactions. The increasingly appreciated role of the microbiota in metazoan organisms suggests that muropeptide signaling likely has important implications for homeostatic mammalian physiology. Copyright © 2014 by Annual Reviews. All rights reserved. Source


de Sherbinin A.,Columbia University
Climatic Change | Year: 2014

In the past 5 years there has been a proliferation of efforts to map climate change "hotspots" - regions that are particularly vulnerable to current or future climate impacts, and where human security may be at risk. While some are academic exercises, many are produced with the goal of drawing policy maker attention to regions that are particularly susceptible to climate impacts, either to mitigate the risk of humanitarian crises or conflicts or to target adaptation assistance. Hotspots mapping efforts address a range of issues and sectors such as vulnerable populations, humanitarian crises, conflict, agriculture and food security, and water resources. This paper offers a timely assessment of the strengths and weaknesses of current hotspots mapping approaches with the goal of improving future efforts. It also highlights regions that are anticipated, based on combinations of high exposure, high sensitivity and low adaptive capacity, to suffer significant impacts from climate change. © 2013 Springer Science+Business Media Dordrecht. Source


Pozueta J.,Columbia University
Nature communications | Year: 2013

Caspases have critical roles in Alzheimer's disease pathogenesis. Here we show that caspase-2 is required for the cognitive decline seen in human amyloid precursor protein transgenic mice (J20). The age-related changes in behaviour and dendritic spine density observed in these mice are absent when they lack caspase-2, in spite of similar levels of amyloid beta (Aβ) deposition and inflammation. A similar degree of protection is observed in cultured hippocampal neurons lacking caspase-2, which are immune to the synaptotoxic effects of Aβ. Our studies suggest that caspase-2 is a critical mediator in the activation of the RhoA/ROCK-II signalling pathway, leading to the collapse of dendritic spines. We propose that this is controlled by an inactive caspase-2/RhoA/ROCK-II complex localized in dendrites, which dissociates in the presence of Aβ, allowing for their activation and entry in the spine. These findings directly implicate caspase-2 as key driver of synaptic dysfunction in Alzheimer's disease and offer novel therapeutic targets. Source


Hornig M.,Columbia University
Current Opinion in Rheumatology | Year: 2013

PURPOSE OF REVIEW: To illustrate how microbes might participate in the pathogenesis of neuropsychiatric illness by triggering the production of autoantibodies that bind to brain targets. RECENT FINDINGS: Some studies link exposure to infectious agents to development of brain disorders; others have identified autoantibodies in individuals with these conditions without finding evidence of pathogens. Neither line of work demonstrates consistent associations between a specific neuropsychiatric disease and a particular environmental trigger or immune marker. Growing evidence suggests that the microbiome conditions host immunity to microbes and xenobiotics, and regulates autoimmune responses that can affect the central nervous system (CNS). The presence of CNS receptors for cytokines and other immune molecules underscores the importance of brain-immune crosstalk in maintaining normal function. An increased prevalence of familial autoimmunity, exposure to pathogens prenatally and postnatally, and findings of antibrain antibodies is common in disorders as diverse as schizophrenia, obsessive-compulsive disorder and autism, and suggests that differences in exposure timing and genetic vulnerability toward autoimmunity are important determinants of neuropsychiatric outcomes. SUMMARY: Microbes, both pathogenic and commensal, can induce autoantibodies that bind to brain and affect behavior in susceptible hosts. Interventions that correct the microbial balance or diminish autoantibody binding may be effective in diverse neuropsychiatric conditions mediated by autoimmunity. © 2013 Wolters Kluwer Health / Lippincott Williams & Wilkins. Source


Javitt D.C.,Columbia University
Schizophrenia Bulletin | Year: 2012

At present, all medications for schizophrenia function primarily by blocking dopamine D2 receptors. Over 50 years ago, the first observations were made that subsequently led to development of alternative, glutamatergic conceptualizations. This special issue traces the historic development of the phencyclidine (PCP) model of schizophrenia from the initial description of the psychotomimetic effects of PCP in the early 1960s, through discovery of the link to N-methyl-D-aspartate-type glutamate receptors (NMDAR) in the 1980s, and finally to the development of NMDA-based treatment strategies starting in the 1990s. NMDAR antagonists uniquely reproduce both positive and negative symptoms of schizophrenia, and induce schizophrenia-like cognitive deficits and neurophysiological dysfunction. At present, there remain several hypotheses concerning mechanisms by which NMDAR dysfunction leads to symptoms/deficits, and several theories regarding ideal NMDAR-based treatment approaches as outlined in the issue. Several classes of agent, including metabotropic glutamate agonists, glycine transport inhibitors, and D-serine-based compounds are currently in late-stage clinical development and may provide long-sought treatments for persistent positive and negative symptoms and cognitive dysfunction in schizophrenia. © 2012 The Author. Source


Yang T.,Columbia University
Nature communications | Year: 2013

Ca(2+) influx via voltage-dependent CaV1/CaV2 channels couples electrical signals to biological responses in excitable cells. CaV1/CaV2 channel blockers have broad biotechnological and therapeutic applications. Here we report a general method for developing novel genetically encoded calcium channel blockers inspired by Rem, a small G-protein that constitutively inhibits CaV1/CaV2 channels. We show that diverse cytosolic proteins (CaVβ, 14-3-3, calmodulin and CaMKII) that bind pore-forming α1-subunits can be converted into calcium channel blockers with tunable selectivity, kinetics and potency, simply by anchoring them to the plasma membrane. We term this method 'channel inactivation induced by membrane-tethering of an associated protein' (ChIMP). ChIMP is potentially extendable to small-molecule drug discovery, as engineering FK506-binding protein into intracellular sites within CaV1.2-α1C permits heterodimerization-initiated channel inhibition with rapamycin. The results reveal a universal method for developing novel calcium channel blockers that may be extended to develop probes for a broad cohort of unrelated ion channels. Source


Smolak A.,Columbia University
AIDS Care - Psychological and Socio-Medical Aspects of AIDS/HIV | Year: 2014

With HIV prevalence levels up to 30%, fishermen as a group have a comparable prevalence to at-risk populations such as female sex workers (FSWs), truck drivers, military personnel, and prisoners. This study examines sexual risk behavior among fishermen, primarily in Africa and Asia. A meta-analysis embedded within a systematic review is utilized for this study. This study included 44 peer-reviewed articles and gray literature from 1992 to 2012. The study found that 42% of fishermen engaged in transactional sex, 48% of whom reported not using a condom with FSWs. Ninety percent of the fishermen reported having partners outside of their regular partner, but only 7% reported using a condom with their regular partner. Mobility, peer norms, and alcohol were found to be contextual risks for HIV infection. The findings have important implications for HIV prevention, targeting fishermen, and their sexual networks. Prevention strategies are needed to address HIV risk among this population. © 2013 Taylor & Francis. Source


Weiss S.A.,Columbia University
Brain : a journal of neurology | Year: 2013

High frequency oscillations have been proposed as a clinically useful biomarker of seizure generating sites. We used a unique set of human microelectrode array recordings (four patients, 10 seizures), in which propagating seizure wavefronts could be readily identified, to investigate the basis of ictal high frequency activity at the cortical (subdural) surface. Sustained, repetitive transient increases in high gamma (80-150 Hz) amplitude, phase-locked to the low-frequency (1-25 Hz) ictal rhythm, correlated with strong multi-unit firing bursts synchronized across the core territory of the seizure. These repetitive high frequency oscillations were seen in recordings from subdural electrodes adjacent to the microelectrode array several seconds after seizure onset, following ictal wavefront passage. Conversely, microelectrode recordings demonstrating only low-level, heterogeneous neural firing correlated with a lack of high frequency oscillations in adjacent subdural recording sites, despite the presence of a strong low-frequency signature. Previously, we reported that this pattern indicates a failure of the seizure to invade the area, because of a feedforward inhibitory veto mechanism. Because multi-unit firing rate and high gamma amplitude are closely related, high frequency oscillations can be used as a surrogate marker to distinguish the core seizure territory from the surrounding penumbra. We developed an efficient measure to detect delayed-onset, sustained ictal high frequency oscillations based on cross-frequency coupling between high gamma amplitude and the low-frequency (1-25 Hz) ictal rhythm. When applied to the broader subdural recording, this measure consistently predicted the timing or failure of ictal invasion, and revealed a surprisingly small and slowly spreading seizure core surrounded by a far larger penumbral territory. Our findings thus establish an underlying neural mechanism for delayed-onset, sustained ictal high frequency oscillations, and provide a practical, efficient method for using them to identify the small ictal core regions. Our observations suggest that it may be possible to reduce substantially the extent of cortical resections in epilepsy surgery procedures without compromising seizure control. Source


Galea S.,Columbia University
American Journal of Epidemiology | Year: 2013

Epidemiology is the study of the causes and distributions of diseases in human populations so that we may identify ways to prevent and control disease. Although this definition broadly serves us well, I suggest that in recent decades, our discipline's robust interest in identifying causes has come at the expense of a more rigorous engagement with the second part of our vision for ourselves-the intent for us to intervene-and that this approach threatens to diminish our field's relevance. I argue here for a consequentialist epidemiology, a formalization and recalibration of the philosophical foundations of our discipline. I discuss how epidemiology is, at its core, more comfortably a consequentialist, as opposed to a deontological, discipline. A more consequentialist approach to epidemiology has several implications. It clarifies our research priorities, offers a perspective on the place of novel epidemiologic approaches and a metric to evaluate the utility of new methods, elevates the importance of global health and considerations about equity to the discipline, brings into sharp focus our engagement in implementation and translational science, and has implications for how we teach our students. I intend this article to be a provocation that can help clarify our disciplinary intentions. © 2013 The Author. Source


Ford B.,Columbia University
Movement Disorders | Year: 2010

Parkinson's disease is characterized primarily as a neurodegenerative disorder that leads to disabling motor and cognitive impairment. PD is less widely appreciated as a disease causing a substantial variety of pain syndromes, although the prevalence of pain in PD is approximately 40%. In a minority of patients, pain is so severe and intractable that it overshadows the motor symptoms of the disorder. In recent years, descriptive surveys of non-motor symptoms in PD have led to a classification of painful sensations into one or more of several categories: musculoskeletal pain, radicular or neuropathic pain, dystonia-related pain, akathitic discomfort, and primary, central parkinsonian pain. A framework for diagnosing and treating painful PD is described in this review, together with recent insignts into the neurophysiological mechanisms and substrates of pain in PD. © 2010 Movement Disorder Society. Source


Elkind M.S.V.,Columbia University
Stroke | Year: 2010

Basic and clinical research provides evidence that inflammatory mechanisms play a central role in the pathogenesis and progression of atherosclerosis, plaque rupture, thrombosis, and stroke. Inflammatory biomarkers such as high-sensitivity C-reactive protein have been identified as predictors of first stroke and prognosis after stroke. The value of high-sensitivity C-reactive protein and other markers may depend on the characteristics of the study population; their utility may be less among populations with high vascular risk. A recent randomized, clinical trial suggests that the use of rosuvastatin therapy in otherwise healthy patients with high-sensitivity C-reactive protein >2 mg/dL can reduce the risk of a first stroke by 50%. The prognostic role of high-sensitivity C-reactive protein among patients after stroke, however, is less clear, and other biomarkers, including lipoprotein-associated phospholipase A2, may provide complementary information about the risk of stroke recurrence. Infections, moreover, may contribute to inflammation and stroke risk. Although no single infectious organism is likely to be identified as the direct cause of atherosclerosis, summary measures of multiple chronic infectious exposures, or "infectious burden," have been associated with the risk of stroke and atherosclerosis affecting the carotid arteries. Acute infections have also been found to serve as stroke triggers in epidemiologic studies. Recommendations to vaccinate patients with cardiovascular disease against influenza represent the first specific anti-infective strategy to be used in vascular prophylaxis. Further studies are needed to determine the role of treatment of inflammation and infection in stroke prevention. © 2010 American Heart Association, Inc. Source


Ager A.,Columbia University
Journal of Child Psychology and Psychiatry and Allied Disciplines | Year: 2013

Background: There has been an 8-fold increase in use of the term resilience within scientific and scholar literature over the last twenty years. The arena of public policy has also seen increasing use made of the concept, both with respect to child well-being and development and wider issues. Method: A focal sample of literature comprising 108 papers addressing public policy implications of work on child resilience was identified by a structured bibliographic search. Results: This literature suggests that current work: is characterized by a breadth of sectoral engagement across the fields of education, social work, and health; demonstrates diversity with regard to the systemic levels - individual (biological and psychological), communal (including systems of faith and cultural identity), institutional and societal - with which it engages; but is based more upon conceptual rather than empirical analysis. Major themes of policy recommendation target strengthened family dynamics, increased capacity for counseling and mental health services, supportive school environments, development of community programs, promotion of socioeconomic improvement and adoption of a more comprehensive conception of resilience. Evaluations of resiliency-informed policy initiatives are limited in number, with greatest rigor in design associated with more discrete programmatic interventions. Conclusion: A number of strategies to strengthen research-policy linkages are identified. These include greater commitment to operationalize indicators of resilience at all levels of analysis; more coherent engagement with the policy making process through explicit knowledge translation initiatives; and developing complex adaptive systems models amenable to exploring policy scenarios. © 2013 The Author. Journal of Child Psychology and Psychiatry © 2013 Association for Child and Adolescent Mental Health. Source


Brickman A.M.,Columbia University
Current Neurology and Neuroscience Reports | Year: 2013

As the older adult segment of the population increases, Alzheimer's disease (AD) has emerged as a significant public health epidemic. Over the past 3 decades, advances in the understanding of the biology of AD have led to a somewhat unified hypothesis of disease pathogenesis that emphasizes the precipitating role of beta amyloid protein. However, several lines of evidence suggest that multiple pathologies are necessary for clinical manifestation of the disease. Our focus over the past several years has been on the contribution of small vessel cerebrovascular disease, visualized as white matter hyperintensities (WMH) on magnetic resonance imaging, to AD. White matter hyperintensity volume, particularly in parietal regions, is elevated among individuals with and at risk for AD, predicts future diagnosis of AD, predicts the rate of progression of cognitive symptoms among individuals with AD, and increases over time among individuals destined to develop AD. White matter hyperintensities may represent an independent source of impairment and/or may interact more fundamentally with "primary" AD pathology. Future work should focus on more inclusive models of that better define "normal" vs "pathological" aging. © 2013 Springer Science+Business Media New York. Source


Kornfeld D.S.,Columbia University
Academic Medicine | Year: 2012

Research misconduct-fabrication, falsification, and plagiarism-is an insidious problem in the scientific community today with the capacity to harm science, scientists, and the public. Federal agencies require that research trainees complete a course designed to deter such behavior, but the author could find no evidence to suggest that this effort has been effective. In fact, research shows that most cases of misconduct continue to go unreported.The author conducted a detailed examination of 146 individual Office of Research Integrity reports from 1992 to 2003 and determined that these acts of misconduct were the results of individual psychological traits and the circumstances in which the researchers found themselves. Therefore, a course in research misconduct, such as is now federally mandated, should not be expected to have a significant effect. However, a course developed specifically for support staff, who currently do not receive such training, might prove effective.Improving the quality of mentoring is essential to meaningfully deal with this issue. Therefore, the quality of mentorship should be a factor in the evaluation of training grants for funding. In addition, mentors should share responsibility for their trainees' published work. The whistleblower can also play a significant role in this effort. However, the potential whistleblower is deterred by a realistic fear of retaliation. Therefore, institutions must establish policies that acknowledge the whistleblower's contribution to the integrity of science and provide truly effective protection from retaliation. An increase in whistleblowing activity would provide greater, earlier exposure of misconduct and serve as a deterrent. Source


Pescitelli G.,University of Pisa | Di Bari L.,University of Pisa | Berova N.,Columbia University
Chemical Society Reviews | Year: 2014

Chiral supramolecular architectures constitute crucial structural and functional elements in living systems and have been long mimicked by chemists to synthesize new artificial systems endowed with desired properties and functions. Among several techniques to study noncovalent chiral assemblies or aggregates, electronic circular dichroism (ECD) plays a key role because many mechanisms responsible for the appearance of ECD bands occur through space, and therefore are intrinsically sensitive to intermolecular interactions, from short to long-range. The aim of this tutorial review is to emphasize the different kinds of information which can be obtained specifically when chiral supramolecular species are characterized by means of ECD spectroscopy. We will survey several typical applications of ECD in the context of supramolecular chemistry, ranging from the simple detection of chiral aggregates or complexes, to the definition of stoichiometric ratios between the partners, the derivation of thermodynamic and kinetic parameters such as binding and rate constants, and ultimately to the refinement of the most plausible structure of the supramolecular species. This journal is © the Partner Organisations 2014. Source


Ulbricht R.,FOM Institute for Atomic and Molecular Physics | Hendry E.,University of Exeter | Shan J.,Case Western Reserve University | Heinz T.F.,Columbia University | Bonn M.,FOM Institute for Atomic and Molecular Physics
Reviews of Modern Physics | Year: 2011

Time-resolved, pulsed terahertz spectroscopy has developed into a powerful tool to study charge carrier dynamics in semiconductors and semiconductor structures over the past decades. Covering the energy range from a few to about 100 meV, terahertz radiation is sensitive to the response of charge quasiparticles, e.g., free carriers, polarons, and excitons. The distinct spectral signatures of these different quasiparticles in the THz range allow their discrimination and characterization using pulsed THz radiation. This frequency region is also well suited for the study of phonon resonances and intraband transitions in low-dimensional systems. Moreover, using a pump-probe scheme, it is possible to monitor the nonequilibrium time evolution of carriers and low-energy excitations with sub-ps time resolution. Being an all-optical technique, terahertz time-domain spectroscopy is contact-free and noninvasive and hence suited to probe the conductivity of, particularly, nanostructured materials that are difficult or impossible to access with other methods. The latest developments in the application of terahertz time-domain spectroscopy to bulk and nanostructured semiconductors are reviewed. © 2011 American Physical Society. Source


Breslow R.,Columbia University
Journal of the American Chemical Society | Year: 2012

Over the past century, the origin of terrestrial prebiotic homochirality has been the subject of much speculation. For life to start on Earth and elsewhere, it is critical that the building blocks of amino acids, sugars, and nucleosides be created in predominant homochiral form. Recent findings of a modest excess l chirality of α-methyl amino acids in some meteorites that landed on Earth have furnished an important piece of evidence. We have shown how these meteoritic components can furnish normal l-amino acids, and therefrom d-sugars and d-nucleosides, in high chiral excess under sensible prebiotic conditions. Some important remaining goals are also described. © 2012 American Chemical Society. Source


First M.B.,Columbia University
Current Opinion in Psychiatry | Year: 2011

Purpose of Review: The Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 revision is underway. The review examines draft proposals for changes in mood disorders (posted February 2010 on DSM-5 web site), explains their rationale, and considers relative costs vs. benefits. Recent Findings: Proposals covered include recommendation for a comorbid anxiety dimension; addition of a new disorder, mixed anxiety depression; replacement of mixed manic episodes with a 'mixed features' specifier applicable to manic, hypomanic, and major depressive episodes; addition of severity dimensions for manic and major depressive episodes; and removal of the bereavement exclusion in major depressive episode. Although some proposals (particularly the anxiety dimension and the use of Patient Health Questionnaire-9 (PHQ-9) as depression severity dimension) may improve clinical and research utility, others have a high potential for false positives (e.g., addition of mixed anxiety depression, removal of bereavement exclusion), unclear clinical utility (e.g., mixed features specifier for depressive episodes), or problematic implementation (e.g., use of Clinical Global Impression (CGI), which requires prior experience of treating bipolar patients, for rating manic episode severity). Summary: A cost-benefit analysis of mood proposals yields mixed results, with some having significant benefits and others carrying the risk of significant problems. Only proposals in which benefits outweigh costs should be included in the final DSM-5. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source


Manganese (Mn) is an essential metal and has important physiological functions for human health. However, exposure to excess levels of Mn in occupational settings or from environmental sources has been associated with a neurological syndrome comprising cognitive deficits, neuropsychological abnormalities and parkinsonism. Historically, studies on the effects of Mn in humans and experimental animals have been concerned with effects on the basal ganglia and the dopaminergic system as it relates to movement abnormalities. However, emerging studies are beginning to provide significant evidence of Mn effects on cortical structures and cognitive function at lower levels than previously recognized. This review advances new knowledge of putative mechanisms by which exposure to excess levels of Mn alters neurobiological systems and produces neurological deficits not only in the basal ganglia but also in the cerebral cortex. The emerging evidence suggests that working memory is significantly affected by chronic Mn exposure and this may be mediated by alterations in brain structures associated with the working memory network including the caudate nucleus in the striatum, frontal cortex and parietal cortex. Dysregulation of the dopaminergic system may play an important role in both the movement abnormalities as well as the neuropsychiatric and cognitive function deficits that have been described in humans and non-human primates exposed to Mn. © 2013 Guilarte. Source


Dworkin J.,Columbia University
Current Opinion in Microbiology | Year: 2015

This review will discuss some recent work describing the role of Ser/Thr phosphorylation as a post-translational mechanism of regulation in bacteria. I will discuss the interaction between bacterial eukaryotic-like Ser/Thr kinases (eSTKs) and two-component systems as well as hints as to physiological function of eSTKs and their cognate eukaryotic-like phosphatases (eSTPs). In particular, I will highlight the role of eSTKs and eSTPs in the regulation of peptidoglycan metabolism and protein synthesis. In addition, I will discuss how data from phosphoproteomic surveys suggest that Ser/Thr phosphorylation plays a much more significant physiological role than would be predicted simply based on in vivo and in vitro analyses of individual kinases. © 2015 Elsevier Ltd. Source


Wright J.D.,Columbia University
Obstetrics and gynecology | Year: 2013

To examine the use of inpatient hysterectomy and explore changes in the use of various routes of hysterectomy and patterns of referral. The Nationwide Inpatient Sample was used to identify all women aged 18 years or older who underwent inpatient hysterectomy between 1998 and 2010. Weighted estimates of national trends were calculated and the number of procedures performed estimated. Trends in hospital volume and across hospital characteristics were examined. After weighting, we identified a total 7,438,452 women who underwent inpatient hysterectomy between 1998 and 2010. The number of hysterectomies performed annually rose from 543,812 in 1998 to a peak of 681,234 in 2002; it then declined consistently annually and reached 433,621 cases in 2010. Overall, 247,973 (36.4%) fewer hysterectomies were performed in 2010 compared with 2002. From 2002 to 2010 the number of hysterectomies performed for each of the following indications declined: leiomyoma (-47.6%), abnormal bleeding (-28.9%), benign ovarian mass (-63.1%), endometriosis (-65.3%), and pelvic organ prolapse (-39.4%). The median hospital case volume decreased from 83 procedures per year in 2002 to 50 cases per year in 2010 (P<.001). The number of inpatient hysterectomies performed in the United States has declined substantially over the past decade. The median number of hysterectomies per hospital has declined likewise by more than 40%. III. Source


Chudnovsky M.,Columbia University
Journal of Combinatorial Theory. Series B | Year: 2012

The bull is the graph consisting of a triangle and two disjoint pendant edges. A graph is called bull-free if no induced subgraph of it is a bull. This is the first paper in a series of three. The goal of the series is to explicitly describe the structure of all bull-free graphs. In this paper we study the structure of bull-free graphs that contain as induced subgraphs three-edge-paths P and Q, and vertices c∉ V(P) and a∉ V(Q), such that c is adjacent to every vertex of V(P) and a has no neighbor in V(Q). One of the theorems in this paper, namely 1.2, is used in Chudnovsky and Safra (2008) [9] in order to prove that every bull-free graph on n vertices contains either a clique or a stable set of size n14, thus settling the Erdös-Hajnal conjecture (Erdös and Hajnal, 1989) [17] for the bull. © 2011 Elsevier Inc. Source


Chudnovsky M.,Columbia University
Journal of Combinatorial Theory. Series B | Year: 2012

The bull is a graph consisting of a triangle and two pendant edges. A graph is called bull-free if no induced subgraph of it is a bull. This is a summary of the last two papers [2,3] in a series [1-3] (Chudnovsky, 2012). The goal of the series is to give a complete description of all bull-free graphs. We call a bull-free graph elementary if it does not contain an induced three-edge-path P such that some vertex c∉ V(P) is complete to V(P), and some vertex a∉ V(P) is anticomplete to V(P). Here we prove that every elementary graph either belongs to one of a few basic classes, or admits a certain decomposition, and then uses this result together with the results of [1] (this issue) to give an explicit description of the structure of all bull-free graphs. © 2011 Elsevier Inc. Source


Lipkin W.I.,Columbia University
Microbiology and Molecular Biology Reviews | Year: 2010

Platforms for pathogen discovery have improved since the days of Koch and Pasteur; nonetheless, the challenges of proving causation are at least as daunting as they were in the late 1800s. Although we will almost certainly continue to accumulate low-hanging fruit, where simple relationships will be found between the presence of a cultivatable agent and a disease, these successes will be increasingly infrequent. The future of the field rests instead in our ability to follow footprints of infectious agents that cannot be characterized using classical microbiological techniques and to develop the laboratory and computational infrastructure required to dissect complex host-microbe interactions. I have tried to refine the criteria used by Koch and successors to prove linkage to disease. These refinements are working constructs that will continue to evolve in light of new technologies, new models, and new insights. What will endure is the excitement of the chase. Happy hunting! Copyright © 2010, American Society for Microbiology. All Rights Reserved. Source


Giannini A.,Columbia University
Journal of Climate | Year: 2010

Application of the moist static energy framework to analyses of vertical stability and net energy in the Sahel sheds light on the divergence of projections of climate change. Two distinct mechanisms are sketched. In one, anthropogenic warming changes continental climate indirectly: warming of the oceans increases moist static energy at upper levels, affecting vertical stability globally, from the top down, and driving drying over the Sahel, in a way analogous to the impact of El Niño-Southern Oscillation on the global tropical atmosphere. In the other, the increase in anthropogenic greenhouse gases drives a direct continental change: the increase in net terrestrial radiation at the surface increases evaporation, favoring vertical instability and near-surface convergence from the bottom up. In both cases the surface warms, but in the first precipitation and evaporation decrease, while in the second they increase. In the first case, land surface warming is brought about by the remotely forced decrease in precipitation and consequent decrease in evaporation and increase in net solar radiation at the surface. In the second, it is brought about by the increase in net terrestrial radiation at the surface, amplified by the water vapor feedback associated with an increase in near-surface humidity. © 2010 American Meteorological Society. Source


Hendrickson W.A.,Columbia University
Acta Crystallographica Section A: Foundations of Crystallography | Year: 2013

The discovery of X-ray diffraction in 1912 by Laue and co-workers had important implications for the physics of diffraction, for the nature of X-radiation and for the structure of matter. Lawrence Bragg made important contributions to early developments in each of these areas, but the most pregnant of his innovations was in structure determination from X-ray diffraction data. He continued to make highly significant contributions to structure determination right on to the first crystal structures of proteins. Crystallography has made substantial contributions to chemistry and biology, and notably so for biological macromolecules. Source


Iskratsch T.,Columbia University
Nature Reviews Molecular Cell Biology | Year: 2014

Although the shapes of organisms are encoded in their genome, the developmental processes that lead to the final form of vertebrates involve a constant feedback between dynamic mechanical forces, and cell growth and motility. Mechanobiology has emerged as a discipline dedicated to the study of the effects of mechanical forces and geometry on cell growth and motility — for example, during cell–matrix adhesion development — through the signalling process of mechanotransduction. © 2014 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. Source


Charon R.,Columbia University
Academic Medicine | Year: 2012

Recognizing clinical medicine as a narrative undertaking fortified by learnable skills in understanding stories has helped doctors and teachers to face otherwise vexing problems in medical practice and education in the areas of professionalism, medical interviewing, reflective practice, patient-centered care, and self-awareness. The emerging practices of narrative medicine give clinicians fresh Methods with which to make contact with patients and to come to understand their points of view. This essay provides a brief review of narrative theory regarding the structure of stories, suggesting that clinical texts contain and can reveal information in excess of their plots. Through close reading of the form and content of two clinical texts-an excerpt from a medical chart and a portion of an audiotaped interview with a medical student-and a reflection on a short section of a modernist novel, the author suggests ways to expand conventional medical routines of recognizing the meanings of patients' situations. The contributions of close reading and reflective writing to clinical practice may occur by increasing the capacities to perceive and then to represent the perceived, thereby making available to a writer that which otherwise might remain out of awareness. A clinical case is given to exemplify the consequences in practice of adopting the Methods of narrative medicine. A metaphor of the activated cellular membrane is proposed as a figure for the effective clinician/patient contact. © 2012 Association American Medical Colleges. Unauthorized reproduction of the artical is prohibited. Source


Champagne F.A.,Columbia University
Developmental Psychobiology | Year: 2013

Plasticity is a typical feature of development and can lead to divergent phenotypes. There is increasing evidence that epigenetic mechanisms, such as DNA methylation, are present across species, are modifiable by the environment, and are involved in developmental plasticity. Thus, in the context of the concept of developmental homology, epigenetic mechanisms may serve to create a process homology between species by providing a common molecular pathway through which environmental experiences shape development, ultimately leading to phenotypic diversity. This article will highlight evidence derived from across-species investigations of epigenetics, development, and plasticity which may contribute to our understanding of the homology that exists between species and between ancestors and descendants. © 2012 Wiley Periodicals, Inc. Source


Menou K.,Columbia University
Astrophysical Journal Letters | Year: 2012

The exoplanet GJ1214b presents an interesting example of compositional degeneracy for low-mass planets. Its atmosphere may be composed of water, super-solar or solar metallicity material. We present atmospheric circulation models of GJ1214b for these three compositions, with explicit gray radiative transfer and an optional treatment of MHD bottom drag. All models develop strong, superrotating zonal winds (∼1-2 kms-1). The degree of eastward heat advection, which can be inferred from secondary eclipse and thermal phase curve measurements, varies greatly between the models. These differences are understood as resulting from variations in the radiative times at the thermal photosphere, caused by separate molecular weight and opacity effects. Our GJ1214b models illustrate how atmospheric circulation can be used as a probe of composition for similar tidally locked exoplanets in the mini-Neptune/waterworld class. © 2012. The American Astronomical Society. All rights reserved. Source


Zhu X.-Y.,Columbia University
Journal of Physical Chemistry Letters | Year: 2014

Emerging photovoltaic devices based on molecular and nanomaterials are mostly excitonic in nature. The initial absorption of a photon in these materials creates an exciton that can subsequently dissociate in each material or at their interfaces to give charge carriers. Any attempt at mechanistic understanding of excitonic solar cells must start with drawing energy level diagrams. This seemingly elementary exercise, which is described in textbooks for inorganic solar cells, has turned out to be a difficult subject in the literature. The problem stems from conceptual confusion of single-particle energy with quasi-particle energy and the misleading practice of mixing the two on the same energy level diagram. Here, I discuss how to draw physically accurate energy diagrams in excitonic solar cells using only single-particle energies (ionization potentials and electron affinities) of both ground and optically excited states. I will briefly discuss current understanding on the electronic energy landscape responsible for efficient charge separation in excitonic solar cells. © 2014 American Chemical Society. Source


Kandel E.,Columbia University
Cell | Year: 2014

The 2014 Nobel Prize in Physiology or Medicine, awarded to John O'Keefe, May-Britt Moser, and Edvard I. Moser, recognizes the first deep-brain insights into a cognitive function. Their insights established a new view for how the brain represents spatial location. Copyright © 2014 Elsevier Inc. All rights reserved. Source


Repeated drug consumption may progress to problematic use by triggering neuroplastic adaptations that attenuate sensitivity to natural rewards while increasing reactivity to craving and drug cues. Converging evidence suggests a single sub-anesthetic dose of the N-methyl-D-aspartate receptor antagonist ketamine may work to correct these neuroadaptations and restore motivation for non-drug rewards. Using an established laboratory model aimed at evaluating behavioral shifts in the salience of cocaine now vs money later, we found that ketamine, as compared to the control, significantly decreased cocaine self-administration by 67% relative to baseline at greater than 24 h post-infusion, the most robust reduction observed to date in human cocaine users and the first to involve mechanisms other than stimulant or dopamine agonist effects. These findings signal new directions in medication development for substance use disorders.Molecular Psychiatry advance online publication, 19 April 2016; doi:10.1038/mp.2016.39. © 2016 Macmillan Publishers Limited Source


Lu H.H.,Columbia University | Thomopoulos S.,University of Washington
Annual Review of Biomedical Engineering | Year: 2013

Connective tissues such as tendons or ligaments attach to bone across a multitissue interface with spatial gradients in composition, structure, and mechanical properties. These gradients minimize stress concentrations and mediate load transfer between the soft and hard tissues. Given the high incidence of tendon and ligament injuries and the lack of integrative solutions for their repair, interface regeneration remains a significant clinical challenge. This review begins with a description of the developmental processes and the resultant structure-function relationships that translate into the functional grading necessary for stress transfer between soft tissue and bone. It then discusses the interface healing response, with a focus on the luence of mechanical loading and the role of cell-cell interactions. The review continues with a description of current efforts in interface tissue engineering, highlighting key strategies for the regeneration of the soft tissue-to-bone interface, and concludes with a summary of challenges and future directions. Copyright © 2013 by Annual Reviews. Source


Gershon M.D.,Columbia University
Current Opinion in Endocrinology, Diabetes and Obesity | Year: 2013

PURPOSE OF REVIEW: Although the gut contains most of the bodys 5-hydroxytryptamine (5-HT), many of its most important functions have recently been discovered. This review summarizes and directs attention to this new burst of knowledge. RECENT FINDINGS: Enteroendocrine cells have classically been regarded as pressure sensors, which secrete 5-HT to initiate peristaltic reflexes; nevertheless, recent data obtained from studies of mice that selectively lack 5-HT either in enterochromaffin cells (deletion of tryptophan hydroxylase 1 knockout; TPH1KO) or neurons (TPH2KO) imply that neuronal 5-HT is more important for constitutive gastrointestinal transit than that of enteroendocrine cells. The enteric nervous system of TPH2KO mice, however, also lacks a full complement of neurons; therefore, it is not clear whether slow transit in TPH2KO animals is due to their neuronal deficiency or absence of serotonergic neurotransmission. Neuronal 5-HT promotes the growth/maintenance of the mucosa as well as neurogenesis. Enteroendocrine cell derived 5-HT is an essential component of the gastrointestinal inflammatory response; thus, deletion of the serotonin transporter increases, whereas TPH1KO decreases the severity of intestinal inflammation. Enteroendocrine cell derived 5-HT, moreover, is also a hormone, which inhibits osteoblast proliferation and promotes hepatic regeneration. SUMMARY: New studies show that enteric 5-HT is a polyfunctional signalling molecule, acting both in developing and mature animals as a neurotransmitter paracrine factor, endocrine hormone and growth factor. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source


Bhattacharya J.,Columbia University | Matthay M.A.,University of California at San Francisco
Annual Review of Physiology | Year: 2013

Considerable progress has been made in understanding the basic mechanisms that regulate fluid and protein exchange across the endothelial and epithelial barriers of the lung under both normal and pathological conditions. Clinically relevant lung injury occurs most commonly from severe viral and bacterial infections, aspiration syndromes, and severe shock. The mechanisms of lung injury have been identified in both experimental and clinical studies. Recovery from lung injury requires the reestablishment of an intact endothelial barrier and a functional alveolar epithelial barrier capable of secreting surfactant and removing alveolar edema fluid. Repair mechanisms include the participation of endogenous progenitor cells in strategically located niches in the lung. Novel treatment strategies include the possibility of cell-based therapy that may reduce the severity of lung injury and enhance lung repair. Copyright © 2013 by Annual Reviews. All rights reserved. Source


Meyer-Bahlburg H.F.L.,Columbia University
Endocrinology and Metabolism Clinics of North America | Year: 2013

This article summarizes for the practicing endocrinologist the current literature on the psychobiology of the development of gender identity and its variants in individuals with disorders of sex development (DSD) or with non-DSD transgenderism. Gender reassignment remains the treatment of choice for strong and persistent gender dysphoria in both categories, but more research is needed on the short-term and long-term effects of puberty-suppressing medications and cross-sex hormones on brain and behavior. © 2013 Elsevier Inc. Source


Jasin M.,Sloan Kettering Cancer Center | Rothstein R.,Columbia University
Cold Spring Harbor Perspectives in Biology | Year: 2013

In this review, we discuss the repair of DNA double-strand breaks (DSBs) using a homologous DNA sequence (i.e., homologous recombination [HR]), focusing mainly on yeast and mammals. We provide a historical context for the current view of HR and describe how DSBs are processed during HR as well as interactions with other DSB repair pathways. We discuss the enzymology of the process, followed by studies on DSB repair in living cells. Whenever possible, we cite both original articles and reviews to aid the reader for further studies. © 2013 Cold Spring Harbor Laboratory Press; all rights reserved. Source


Woolley S.M.N.,Columbia University
Developmental Psychobiology | Year: 2012

Songbirds, like humans, are highly accomplished vocal learners. The many parallels between speech and birdsong and conserved features of mammalian and avian auditory systems have led to the emergence of the songbird as a model system for studying the perceptual mechanisms of vocal communication. Laboratory research on songbirds allows the careful control of early life experience and high-resolution analysis of brain function during vocal learning, production, and perception. Here, I review what songbird studies have revealed about the role of early experience in the development of vocal behavior, auditory perception, and the processing of learned vocalizations by auditory neurons. The findings of these studies suggest general principles for how exposure to vocalizations during development and into adulthood influences the perception of learned vocal signals. © 2012 Wiley Periodicals, Inc. Source


Shi Y.,University of California at Irvine | Manley J.L.,Columbia University
Genes and Development | Year: 2015

The key RNA sequence elements and protein factors necessary for 3′ processing of polyadenylated mRNA precursors are well known. Recent studies, however, have significantly reshaped current models for the protein– RNA interactions involved in poly(A) site recognition, painting a picture more complex than previously envisioned and also providing new insights into regulation of this important step in gene expression. Here we review the recent advances in this area and provide a perspective for future studies. © 2015 Shi and Manley Source


Wexler N.S.,Columbia University
Annual Review of Medicine | Year: 2012

My mother, Leonore, was diagnosed with Huntington's disease (HD) in 1968 at age 53. I was 23, my sister Alice 26, and our father, Milton Wexler, 60 years old. The same year, our father created the Hereditary Disease Foundation (HDF), dedicated to finding treatments and cures for HD. HD is an autosomal dominant, neurodegenerative disorder. Alice and I each have a 50% chance of inheriting and dying from the disorder. Over the past 43 years, we have been proud to change the face of science. Through Milton Wexler Interdisciplinary Workshops, judicious funding, and focusing on innovation and creativity, the HDF is an integral partner in key discoveries. The HDF recruited and supported >100 scientists worldwide who worked together as the Huntington's Disease Collaborative Research Group in a successful ten-year search for the HD gene. We found a DNA marker for the HD gene in 1983the first marker to be found when the chromosomal location was unknown. We isolated the HD gene itself a decade later. These breakthroughs helped launch the Human Genome Project. We supported creating the first mouse model of HD and many other model systems. Currently, we focus on gene silencing, among other approaches, to create new treatments and cures. © 2012 by Annual Reviews. All rights reserved. Source


Champagne F.A.,Columbia University
Developmental Psychobiology | Year: 2010

The critical role of social interactions in driving phenotypic variation has long been inferred from the association between early social deprivation and adverse neurodevelopmental outcomes. Recent evidence has implicated molecular pathways involved in the regulation of gene expression as one possible route through which these long-term outcomes are achieved. These epigenetic effects, though not exclusive to social experiences, may be a mechanism through which the quality of the social environment becomes embedded at a biological level. Moreover, there is increasing evidence for the transgenerational impact of these early experiences mediated through changes in social and reproductive behavior exhibited in adulthood. In this review, recent studies which highlight the epigenetic effects of parent-offspring, peer and adult social interactions both with and across generations will be discussed and the implications of this research for understanding the developmental origins of individual differences in brain and behavior will be explored. © 2010 Wiley Periodicals, Inc. Source


Kousteni S.,Columbia University
Journal of Bone and Mineral Research | Year: 2011

The FoxO family of forkhead transcription factors is at the crossroads of many signal transduction pathways that are evolutionarily conserved. Such pathways have been co-opted in differentiated tissues for a variety of vital and specialized functions, such as differentiation, proliferation, and survival in cells as diverse as adipocytes, hepatocytes, β-cells, myoblasts, thymocytes, and cancer cells. FoxO metabolic functions are relevant to glucose metabolism, tumor suppression, hematopoiesis, angiogenesis, and antioxidant defense. Among the FoxO isoforms, FoxO1 is a main target of insulin signaling and regulates metabolic homeostasis and organismal survival at many different levels. FoxO1 entered into the field of skeletal biology by a property that is unique among its functions in other organs. With the osteoblast as its target cell, FoxO1 not only acts on it to regulate bone homeostasis but also through it as a transcriptional modulator of the endocrine function of the skeleton in regulating glucose metabolism. Through its direct skeletal actions, FoxO1 promotes osteoblast proliferation by maintaining protein synthesis and redox balance. Through its endocrine actions on target tissues of insulin, FoxO1 acts by way of osteocalcin to suppress glucose production by pancreatic beta cells and hepatocytes and to decrease insulin production and sensitivity. These two parallel but opposing actions, one in favor of the skeleton and the other in disadvantage of glucose-regulating tissues, may signify an adaptive mechanism that integrates responses between different organs and is beneficial for whole-body physiology during stress and aging. © 2011 American Society for Bone and Mineral Research. Source


D'Alton M.E.,Columbia University
Obstetrics and Gynecology | Year: 2010

In contrast to the generally encouraging trend regarding global maternal mortality, there has been an apparent increase in the maternal mortality ratio in the United States. Although maternal death remains a relatively rare adverse event in this country, programs to reduce maternal mortality also will result in a reduction in maternal morbidity, which is a far more prevalent problem. Progress in the field of maternal-fetal medicine over the past several decades has been largely attributable to improvements in fetal and neonatal medicine. We need to develop an organized, national approach focused on reducing maternal mortality and morbidity. The goal will be to outline a specific plan for clinical, educational, and research initiatives to put the "M" back in maternal-fetal medicine. © 2010 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. Source


Phelan J.C.,Columbia University
Journal of health and social behavior | Year: 2010

Link and Phelan (1995) developed the theory of fundamental causes to explain why the association between socioeconomic status (SES) and mortality has persisted despite radical changes in the diseases and risk factors that are presumed to explain it. They proposed that the enduring association results because SES embodies an array of resources, such as money, knowledge, prestige, power, and beneficial social connections that protect health no matter what mechanisms are relevant at any given time. In this article, we explicate the theory, review key findings, discuss refinements and limits to the theory, and discuss implications for health policies that might reduce health inequalities. We advocate policies that encourage medical and other health-promoting advances while at the same time breaking or weakening the link between these advances and socioeconomic resources. This can be accomplished either by reducing disparities in socioeconomic resources themselves or by developing interventions that, by their nature, are more equally distributed across SES groups. Source


Miller E.A.,Columbia University
Current Opinion in Cell Biology | Year: 2010

The small GTPase Sar1 resides at the core of a regulatory cycle that controls protein export from the ER in COPII vesicles. Recent advances in minimally reconstituted systems indicate continual flux of Sar1 through GTPase cycles facilitates cargo concentration into forming vesicles that ultimately bud from membranes. During export from ER membranes, this GTPase cycle is harnessed through the combinatorial power of multiple coat subunits and cargo adaptors to sort an expanding array of proteins into ER-derived vesicles. The COPII budding machinery is further organized into higher-order structures at transitional zones on the ER surface where the large multi-domain Sec16 protein appears to perform a central function. © 2010 Elsevier Ltd. Source


Santulli G.,Columbia University
Journal of Cardiovascular Disease Research | Year: 2013

According to updated statistics, cardiovascular disease is the first cause of death both in United States (source: American Heart Association, 2013) and worldwide (data of the World Health Organization, 2013). In this special short report the current epidemiological data concerning cardiovascular disease, diabetes and stroke are presented. Cardiovascular disorders represent the foremost cause of preventable death globally. Indeed, efforts to improve lifestyles, controlling lifestyle-related major cardiovascular risk factors, will definitely contribute to cardiovascular disease prevention. Source


Di Tullio M.R.,Columbia University
Journal of the American Society of Echocardiography | Year: 2010

This article reviews the main clinical aspects of patent foramen ovale (PFO), such as its prevalence in the population, the diagnostic techniques to detect its presence, its role as a risk factor for ischemic stroke of otherwise unexplained origin, and its controversial association with migraine. Some cofactors possibly involved in the association between PFO and stroke are discussed, along with the various therapeutic options to prevent recurrent cerebral ischemic events in stroke patients with a PFO. © 2010 American Society of Echocardiography. Source


Kandel E.R.,Columbia University
Molecular Brain | Year: 2012

The analysis of the contributions to synaptic plasticity and memory of cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB has recruited the efforts of many laboratories all over the world. These are six key steps in the molecular biological delineation of short-term memory and its conversion to long-term memory for both implicit (procedural) and explicit (declarative) memory. I here first trace the background for the clinical and behavioral studies of implicit memory that made a molecular biology of memory storage possible, and then detail the discovery and early history of these six molecular steps and their roles in explicit memory. © 2012 Kandel; licensee BioMed Central Ltd. Source


Simpson L.L.,Columbia University
Obstetrics and Gynecology | Year: 2012

Heart disease complicates more than 1% of pregnancies and is now the leading cause of indirect maternal deaths. The spectrum and severity of heart disease observed in reproductive-aged women is changing. Today, congenital heart disease accounts for more than half of cardiac disease in pregnancy, and ischemic heart disease is on the rise as a result of obesity, hypertension, diabetes, and delayed childbearing. Pregnancy is still contraindicated in women with pulmonary hypertension, severe systemic ventricular dysfunction, dilated aortopathy, and severe left-sided obstructive lesions, but advances in medical and surgical management have resulted in an increasing number of patients with congenital heart defects reaching childbearing age who are interested in pregnancy. A multidisciplinary approach can best determine whether acceptable outcomes can be expected and what management strategies may improve the prognosis for pregnant women with heart disease. © 2012 by The American College of Obstetricians and Gynecologists. Source


Spitalnik S.L.,Columbia University
Transfusion | Year: 2014

Emily Cooley was a highly regarded medical technologist and morphologist. The "Emily Cooley Lectureship and Award" was established to honor her, in particular, and medical technologists, in general. This article reviews some basic concepts about the "life of a red blood cell" (RBC) and uses these to discuss the actual and potential consequences that occur in patients after clearance of transfused refrigerator storage-damaged RBCs by extravascular hemolysis. Source


Simpson L.L.,Columbia University
Seminars in Perinatology | Year: 2013

The objective of this review is to assess the evidence that supports the use of ultrasound in twin pregnancies. Although many of the indications for obstetric ultrasound are the same in both singleton and multiple gestations, there are special considerations as well as unique conditions in twins that require additional imaging studies. The reasons for ultrasound in twins include pregnancy dating, determination of chorionicity, nuchal translucency assessment, anatomical survey, placental evaluation, cervical length assessment, routine fetal growth, and serial surveillance of pregnancies complicated by anomalies, cervical shortening, fetal growth disturbances, and amniotic fluid abnormalities. Twins with monochorionic placentation require heightened scrutiny for monoamnionicity, conjoined twins, twin reversed arterial perfusion (TRAP) syndrome, twin-twin transfusion syndrome, unequal placental sharing with discordant twin growth or selective intrauterine fetal growth restriction (IUGR), twin anemia-polycythemia sequence (TAPS), and single fetal demise. Ultrasound is essential for the detection and management of conditions that can complicate dichorionic and monochorionic twin pregnancies. © 2013 Elsevier Inc. Source


Frimpong J.A.,Columbia University
American Journal of Public Health | Year: 2013

HCV has surpassed HIV as a cause of death in the United States and is particularly prevalent among injection drug users. I examined the availability of on-site HCV testing in a nationally representative sample of opioid treatment programs. Nearly 68% of these programs had the staff required for HCV testing, but only 34% offered on-site testing. Availability of on-site testing increased only slightly with the proportion of injection drug users among clients. The limited HCV testing services in opioid treatment programs is a key challenge to reducing HCV in the US population. Source


Cao S.S.,Columbia University
Inflammatory Bowel Diseases | Year: 2015

In eukaryotic cells, protein folding and modification in the endoplasmic reticulum (ER) is highly sensitive to disturbances of homeostasis. The accumulation of unfolded and misfolded proteins in the ER lumen, termed ER stress, activates intracellular signaling pathways to resolve the protein-folding defect. This unfolded protein response (UPR) increases the capacity of ER protein folding, reduces global protein synthesis, and activates ER-associated protein degradation. If ER stress is too severe or chronic, or the UPR is compromised and not able to restore ER protein-folding homeostasis, numerous apoptotic signaling pathways are activated. Preclinical and clinical studies in the past decade indicate that ER stress and the UPR have a significant impact on the pathogenesis of inflammatory bowel disease. Paneth and goblet cells, 2 epithelial cell populations in the gut, rely on a robust ER function for protein folding and secretion. Several immune cells are orchestrated by ER stress and the UPR for differentiation, activation, migration, and survival. In addition, a variety of exogenous and endogenous molecules in the intestinal lumen affect ER function, making ER stress and the UPR relevant cellular signals in intestinal homeostasis. Recent studies demonstrated that unresolved ER stress and/or dysregulated UPR may cause inflammatory bowel disease by inducing epithelial cell death, impairing mucosal barrier function, and activating proinflammatory response in the gut. With our increased understanding of ER stress in inflammatory bowel disease pathogenesis, it is now possible to develop novel therapies to improve ER protein-folding homeostasis and target-specific UPR pathways in cells residing in the intestinal mucosa. Copyright © 2015 Crohn's & Colitis Foundation of America, Inc. Source


Abi-Dargham A.,Columbia University
The Journal of clinical psychiatry | Year: 2014

Schizophrenia is a chronic, often disabling illness that affects approximately 24 million people worldwide. Unfortunately, while the majority of first-episode schizophrenia patients respond well to initial antipsychotic treatment, less than 1 in 5 will maintain recovery over 2 to 5 years, and most will experience at least 1 relapse. Dopamine dysfunction helps to explain the positive symptoms experienced by patients with schizophrenia, and targeting these pathways has made current antipsychotics effective treatments for this condition. However, these agents primarily manage the positive symptoms of the disorder, while negative and cognitive symptoms can persist. More treatments are needed that comprehensively address all presentations of the disorder. © Copyright 2014 Physicians Postgraduate Press, Inc. Source


Bian L.,Columbia University
The American journal of sports medicine | Year: 2010

Intact articular cartilage tissue is used clinically in the form of osteochondral allografts and experimentally as explants in modeling the physiologic behavior of chondrocytes in their native extracellular matrix. Long-term maintenance of allograft tissue is challenging. By carefully modulating the preservation environment, it may be possible to preserve osteochondral allograft tissue over the long term while maintaining its original mechanical and biochemical properties. Controlled laboratory study. In this study, juvenile bovine, mature bovine, and canine cartilage explants were cultured in chemically defined media with or without supplementation of dexamethasone for up to 4 weeks. The mechanical properties and biochemical content of juvenile bovine explants cultured in the presence of dexamethasone were significantly enhanced after 2 weeks in culture and remained stable with sustained cell viability thereafter. In contrast, the mechanical properties and biochemical content of juvenile bovine explants cultured in the absence of the dexamethasone significantly decreased after 2 weeks of culture. The mechanical and biochemical content of mature bovine and canine explants were not significantly affected by the presence of dexamethasone and maintained initial (day 0) mechanical and biochemical properties throughout the entire culture period with or without supplementation of dexamethasone. These results suggest that juvenile and mature cartilage explants respond differently to dexamethasone. The functional properties of juvenile cartilage explants can be maintained in vitro through the addition of dexamethasone to culture media. Functional properties of mature cartilage can be preserved for at least 4 weeks in culture regardless of the presence of dexamethasone. Biochemical and biomechanical properties of osteochondral allograft tissue may be enhanced by the addition of dexamethasone to culture media. These findings may translate to longer shelf life of preserved osteochondral allograft transplantation tissue and increased clinical availability of grafts. Source


Al-Awqati Q.,Columbia University
Annual Review of Physiology | Year: 2011

Epithelia, the most abundant cell type, differentiate to protoepithelia from stem cells by developing apical and basolateral membrane domains and form sheets of cells connected by junctions. Following this differentiation step, the cells undergo a second step (terminal differentiation), during which they acquire a mature phenotype, which unlike the protoepithelial one is tissue and organ specific. An extracellular matrix (ECM) protein termed hensin (DMBT1) mediates this differentiation step in the kidney intercalated cells. Although hensin is secreted as a soluble monomer, it requires polymerization and deposition in the ECM to become active. The polymerization step is mediated by the activation of inside-out signaling by integrins and by the secretion of two proteins: cypA (a cis-trans prolyl isomerase) and galectin 3. © 2011 by Annual Reviews. All rights reserved. Source


Oury F.,Columbia University
Annals of the New York Academy of Sciences | Year: 2012

The sex steroid hormones testosterone and estrogen are essential determinants not only of reproductive functions but also for bone growth and the maintenance of skeletal integrity. The importance of this latter form of regulation is best exemplified by the fact that gonadal failure triggers bone loss in both genders and causes osteoporosis in postmenauposal women. Traditionally, bone physiology is studied with the view that the skeleton is simply a recipient of hormonal inputs. However, a richer picture of bone physiology has recently emerged, and it is now clear that the skeleton is an endocrine organ itself. This is particularly relevant to the interplay between bone and gonads because genetics and biochemical evidence have established that bone, via the osteoblast-derived hormone osteocalcin, promotes testosterone biosynthesis. This review will present the mechanism of action of osteocalcin and will discuss the implications of this novel regulation. © 2012 New York Academy of Sciences. Source


Karsenty G.,Columbia University
Journal of Endocrinology | Year: 2012

It has long been known that sex steroid hormones regulate bone mass accrual. This observation raises the testable hypothesis that bone may in turn regulate the synthesis and secretion of sex steroid hormones in one or both genders. This hypothesis is comprised within a more general hypothesis that bone mass, energy metabolism, and reproduction are regulated coordinately. The identification of osteocalcin as an osteoblast-specific secretedmolecule allows us to address this question inmolecular terms. This reviewdetails howthe regulation ofmale fertility by osteocalcin was unraveled, and how osteocalcin signaling in Leydig cells of the testis occurs. It also discusses the implication of this novel mode of regulation of testosterone synthesis observed in males but not in females. © 2012 Society for Endocrinology. Source


Brickman A.M.,Columbia University
Acta neuropathologica communications | Year: 2014

Alzheimer's disease (AD) is the most common neurodegenerative disease and the leading cause of dementia. In addition to grey matter pathology, white matter changes are now recognized as an important pathological feature in the emergence of the disease. Despite growing recognition of the importance of white matter abnormalities in the pathogenesis of AD, the causes of white matter degeneration are still unknown. While multiple studies propose Wallerian-like degeneration as the source of white matter change, others suggest that primary white matter pathology may be due, at least in part, to other mechanisms, including local effects of toxic Aβ peptides. In the current study, we investigated levels of soluble amyloid-beta (Aβ) in white matter of AD patients (n=12) compared with controls (n=10). Fresh frozen white matter samples were obtained from anterior (Brodmann area 9) and posterior (Brodmann area 1, 2 and 3) areas of post-mortem AD and control brains. ELISA was used to examine levels of soluble Aβ -42 and Aβ -40. Total cortical neuritic plaque severity rating was derived from individual ratings in the following areas of cortex: mid-frontal, superior temporal, pre-central, inferior parietal, hippocampus (CA1), subiculum, entorhinal cortex, transentorhinal cortex, inferior temporal, amygdala and basal forebrain. Compared with controls, AD samples had higher white matter levels of both soluble Aβ -42 and Aβ -40. While no regional white matter differences were found in Aβ -40, Aβ -42 levels were higher in anterior regions than in posterior regions across both groups. After statistically controlling for total cortical neuritic plaque severity, differences in both soluble Aβ -42 and Aβ -40 between the groups remained, suggesting that white matter Aβ peptides accumulate independent of overall grey matter fibrillar amyloid pathology and are not simply a reflection of overall amyloid burden. These results shed light on one potential mechanism through which white matter degeneration may occur in AD. Given that white matter degeneration may be an early marker of disease, preceding grey matter atrophy, understanding the mechanisms and risk factors that may lead to white matter loss could help to identify those at high risk and to intervene earlier in the pathogenic process. Source


Goodwin R.D.,Columbia University
Journal of Psychiatric Research | Year: 2011

Background: The goal of this study is to examine the relationship between chronic obstructive pulmonary disease (COPD) and suicidal ideation and suicide attempt among adults in the United States. Methods: Data were drawn from the National Comorbidity Study-Replication (NCS-R), a household probability sample of adults ages 18 and older in the United States. Results: COPD is associated with significantly increased odds of suicidal ideation and suicide attempt, compared with those without COPD. The association between COPD and suicide attempt remained statistically significant after adjusting for demographics, depression, panic disorder, substance use and nicotine dependence. The association between COPD and suicidal ideation was no longer significant after adjusting for nicotine dependence. Conclusions: Our findings provide initial evidence that there is a relationship between COPD and suicidal behavior among adults in the community. Future studies that can examine the relationship between COPD and completed suicide, as well as replication of these results, would improve our understanding of whether and to what degree COPD confers an increased vulnerability for suicide behavior. © 2011. Source


Wright J.D.,Columbia University
Obstetrics and Gynecology | Year: 2010

Objective: To estimate the effect of surgical volume on outcomes and resource use in women undergoing vaginal hysterectomy. Methods: Women who underwent total vaginal hysterectomy and were registered in the Perspective database were examined. Perspective is a nationwide database developed to measure quality and resource use. Procedure-associated intraoperative, perioperative, and postoperative medical complications as well as hospital readmission, length of stay, intensive care unit (ICU) use, operating time, and cost were analyzed. Based on the overall gynecologic surgical volume and vaginal surgical volume of their surgeons, patients were stratified into tertiles. Complications were compared using adjusted generalized estimating equations and reported as odds ratios (ORs). Results: A total of 77,109 patients operated on by 6,195 gynecologic surgeons were identified. After adjustment for the effects of other demographic variables and concomitant procedures, patients operated on by high-volume vaginal surgeons were 31% (OR 0.69; 95% confidence interval [CI] 0.59-0.80) less likely to experience an operative injury, whereas perioperative complications were reduced by 19% (OR 0.81; 95% CI 0.72-0.92), medical complications decreased by 24% (OR 0.76; 95% CI 0.67-0.86), ICU admission reduced by 46% (OR 0.56; 95% CI 0.43-0.73), and the transfusion rate decreased by 28% (OR 0.72; 95% CI 0.61-0.85) in patients treated by high-volume vaginal surgeons, whereas rates of readmission were higher (OR 1.24; 95% CI 1.04-1.47) in patients treated by high-volume surgeons. Operative times were lower in patients operated on by high-volume surgeons (P<.001). Although total gynecologic surgical volume had no effect on cost, patients treated by high-volume vaginal surgeons had lower costs (P<.001). Conclusion: Perioperative morbidity and resource use are lower in women undergoing vaginal hysterectomy when the procedure is performed by high-volume vaginal surgeons. © 2010 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. Source


Min W.,Columbia University
Current opinion in chemical biology | Year: 2011

Imaging contrasts other than fluorescence are highly desirable for label-free detection and interrogation of nonfluorescent molecular species inside live cells, tissues, and organisms. The recently developed stimulated Raman scattering (SRS) and stimulated emission microscopy techniques provide sensitive and specific contrast mechanisms for nonfluorescent species, by employing the light amplification aspect of stimulated radiation. Compared to their spontaneous counterparts, stimulated radiation can enhance the imaging performance significantly, making the previously 'dark' molecules observable. Here we review and summarize the underlying principles of this emerging class of molecular imaging techniques. Copyright © 2011 Elsevier Ltd. All rights reserved. Source


Rubenstein D.R.,Columbia University
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2012

Males figured more prominently than females in Darwin's view of sexual selection. He considered female choice of secondary importance to male-male competition as a mechanism to explain the evolution of male ornaments and armaments. Fisher later demonstrated the importance of female choice in driving male trait evolution, but his ideas were largely ignored for decades. As sexual selection came to embrace the notions of parent-offspring and sexual conflict, and experimental tests of female choice showed promise, females began to feature more prominently in the framework of sexual selection theory. Recent debate over this theory has centred around the role of females, not only over the question of choice, but also over female-female competition. Whereas some have called for expanding the sexual selection framework to encompass all forms of female-female competition, others have called for subsuming sexual selection within a broader framework of social selection, or replacing it altogether. Still others have argued for linking sexual selection more clearly to other evolutionary theories such as kin selection. Rather than simply debating terminology, we must take a broader view of the general processes that lead to trait evolution in both sexes by clearly defining the roles that females play in the process, and by focusing on intra-and inter-sexual interactions in males and females. © 2012 The Royal Society. Source


Xu X.,University of Washington | Yao W.,University of Hong Kong | Xiao D.,Carnegie Mellon University | Heinz T.F.,Columbia University
Nature Physics | Year: 2014

The recent emergence of two-dimensional layered materials-in particular the transition metal dichalcogenides-provides a new laboratory for exploring the internal quantum degrees of freedom of electrons and their potential for new electronics. These degrees of freedom are the real electron spin, the layer pseudospin, and the valley pseudospin. New methods for the quantum control of the spin and these pseudospins arise from the existence of Berry phase-related physical properties and strong spin-orbit coupling. The former leads to the versatile control of the valley pseudospin, whereas the latter gives rise to an interplay between the spin and the pseudospins. Here, we provide a brief review of both theoretical and experimental advances in this field. © 2014 Macmillan Publishers Limited. Source


Dimaggio C.,Columbia University
Epidemiology | Year: 2015

Background: This study quantifies the spatiotemporal risk of pedestrian and bicyclist injury in New York City at the census tract level over a recent 10-year period, identifies areas of increased risk, and evaluates the role of socioeconomic and traffic-related variables in injury risk.Methods: Crash data on 140,835 pedestrian and bicyclist injuries in 1908 census tracts from 2001 to 2010 were obtained from the New York City Department of Transportation. We analyzed injury counts within census tracts with Bayesian hierarchical spatial models using integrated nested Laplace approximations. The model included variables for social fragmentation, median household income, and average vehicle speed and traffic density, as well as a spatially unstructured random effect term, a spatially structured conditional autoregression term, a first-order random walk-correlated time variable, and an interaction term for time and place. Incidence density ratios, credible intervals, and probability exceedances were calculated and mapped.Results: The yearly rate of crashes involving injuries to "pedestrians" (including bicyclists) decreased 16.2% over the study period, from 23.7 per 10,000 population to 16.2 per 10,000. The temporal term in the spatiotemporal model indicated that much of the decrease over the study period occurred during the first 4 years of the study period. Despite an overall decrease, the model identified census tracts that were at persistently high risk of pedestrian injury throughout the study period, as well as areas that experienced sporadic annual increases in risk. Aggregate social, economic, and traffic-related measures were associated with pedestrian injury risk at the ecologic level. Every 1-unit increase in a standardized social fragmentation index was associated with a 19% increase in pedestrian injury risk (incidence density ratio = 1.19 [95% credible interval = 1.16 - 1.23]), and every 1 standardized unit increase in traffic density was associated with a 20% increase in pedestrian injury risk (1.20 [1.15 - 1.26]). Each 10-mile-per-hour increase in average traffic speed in a census tract was associated with a 24% decrease in pedestrian injury risk (0.76 [0.69 - 0.83]).Conclusions: The risk of a pedestrian or bicyclist being struck by a motor vehicle in New York City decreased from 2001 to 2004 and held fairly steady thereafter. Some census tracts in the city did not benefit from overall reductions or experienced sporadic years of increased risk compared with the city as a whole. Injury risk at the census tract level was associated with social, economic, and trafficrelated factors. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Source


Bernstein A.,Columbia University
Proceedings of the Annual ACM Symposium on Theory of Computing | Year: 2013

We present an improved algorithm for maintaining all-pairs (1 + ε) approximate shortest paths under deletions and weight-increases. The previous state of the art for this problem was total update time O ̃(n 2√m/ε) for directed, unweighted graphs [2], and Õ(mn=ε) for undirected, unweighted graphs [12]. Both algorithms were randomized and had constant query time. Note that Õ(mn) is a natural bar- rier because even with a (1 + ε) approximation, there is no o(mn) combinatorial algorithm for the static all-pairs short- est path problem. Our algorithm works on directed, weighted graphs and has total (randomized) update time Õ(mnlog(R)=ε) where R is the ratio of the largest edge weight ever seen in the graph, to the smallest such weight (our query time is constant). Note that log(R) = O(log(n)) as long as weights are poly- nomial in n. Although Õ(mnlog(R)=ε) is the total time over all updates, our algorithm also requires a clearly unavoid- able constant time per update. Thus, we effectively expand the Õ (mn) total update time bound from undirected, un- weighted graphs to directed graphs with polynomial weights. This is in fact the first non-trivial algorithm for decremental all-pairs shortest paths that works on weighted graphs (pre- vious algorithms could only handle small integer weights). By a well known reduction from decremental algorithms to fully dynamic ones [9], our improved decremental algorithm leads to improved query-update tradeoffs for fully dynamic (1 + ε) approximate APSP algorithm in directed graphs. Copyright 2013 ACM. Source


Pasqualucci L.,Columbia University
Current Opinion in Hematology | Year: 2013

Purpose of Review: Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease featuring heterogeneous genetic, phenotypic, and clinical characteristics. Understanding the basis for this heterogeneity represents a critical step toward further progress in the management of this disease, which remains a clinical challenge in approximately one-third of patients. This review summarizes current knowledge about the molecular pathogenesis of DLBCL, and describes how recent advances in the genomic characterization of this cancer have provided new insights into its biology, revealing several potential targets for improved diagnosis and therapy. RECENT FINDINGS: In the past few years, the development of high-resolution technologies has provided significant help in identifying genetic lesions and/or disrupted signaling pathways that are required for DLBCL initiation and progression. These studies uncovered the involvement of cellular programs that had not been previously appreciated, including histone/chromatin remodeling and immune recognition. Alterations in these pathways could favor epigenetic reprogramming and escape from cellular immunity. SUMMARY: The identification of genetic alterations that contribute to the malignant transformation of a B cell into a DLBCL is helping to better understand the biology of this disease and to identify critical nodes driving tumor progression or resistance to therapy. The rapid pace at which these discoveries are taking place is poised to have significant impact for patient stratification based on molecular predictors and for the development of rational targeted therapies. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source


Glade Bender J.L.,Columbia University
Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2013

Pazopanib, an oral multikinase angiogenesis inhibitor, prolongs progression-free survival in adults with soft tissue sarcoma (STS). A phase I pharmacokinetic and pharmacodynamic study of two formulations of pazopanib was performed in children with STS or other refractory solid tumors. Pazopanib (tablet formulation) was administered once daily in 28-day cycles at four dose levels (275 to 600 mg/m(2)) using the rolling-six design. Dose determination for a powder suspension was initiated at 50% of the maximum-tolerated dose (MTD) for the intact tablet. Ten patients with STS underwent dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) scanning at baseline and 15 ± 2 days after initiation of pazopanib at the tablet MTD. Fifty-three patients were enrolled; 51 were eligible (26 males; median age, 12.9 years; range, 3.8 to 23.9 years). Hematologic and nonhematologic toxicities were generally mild, with dose-limiting lipase, amylase, and ALT elevation, proteinuria, and hypertension. One patient with occult brain metastasis had grade 4 intracranial hemorrhage. The MTD was 450 mg/m(2) for tablet and 160 mg/m(2) for suspension. Steady-state trough concentrations were reached by day 15 and did not seem to be dose dependent. One patient each with hepatoblastoma or desmoplastic small round cell tumor achieved a partial response; eight patients had stable disease for ≥ six cycles, seven of whom had sarcoma. All patients with evaluable DCE-MRI (n = 8) experienced decreases in tumor blood volume and permeability (P < .01). Placental growth factor increased, whereas endoglin and soluble vascular endothelial growth factor receptor-2 decreased (P < .01; n = 41). Pazopanib is well tolerated in children, with evidence of antiangiogenic effect and potential clinical benefit in pediatric sarcoma. Source


Keyes K.M.,Columbia University
Psychological medicine | Year: 2013

Dimensional models of co-morbidity have the potential to improve the conceptualization of mental disorders in research and clinical work, yet little is known about how relatively uncommon disorders may fit with more common disorders. The present study estimated the meta-structure of psychopathology in the US general population focusing on the placement of five under-studied disorders sharing features of thought disorder: paranoid, schizoid, avoidant and schizotypal personality disorders, and manic episodes as well as bipolar disorder. Data were drawn from the National Epidemiologic Survey on Alcohol and Related Conditions, a face-to-face interview of 34 653 non-institutionalized adults in the US general population. The meta-structure of 16 DSM-IV Axis I and Axis II psychiatric disorders, as assessed by the Alcohol Use Disorder and Associated Disabilities Interview Schedule DSM-IV version (AUDADIS-IV), was examined using exploratory and confirmatory factor analysis. We document an empirically derived thought disorder factor that is a subdomain of the internalizing dimension, characterized by schizoid, paranoid, schizotypal and avoidant personality disorders as well as manic episodes. Manic episodes exhibit notable associations with both the distress subdomain of the internalizing dimension as well as the thought disorder subdomain. The structure was replicated for bipolar disorder (I or II) in place of manic episodes. As our understanding of psychopathological meta-structure expands, incorporation of disorders characterized by detachment and psychoticism grows increasingly important. Disorders characterized by detachment and psychoticism may be well conceptualized, organized and measured as a subdimension of the internalizing spectrum of disorders. Manic episodes and bipolar disorder exhibit substantial co-morbidity across both distress and thought disorder domains of the internalizing dimension. Clinically, these results underscore the potential utility of conceptualizing patient treatment needs using an approach targeting psychopathological systems underlying meta-structural classification rubrics. Source


Hauser A.,Columbia University
Epilepsia | Year: 2014

The report by Fisher and colleagues is an excellent first step to provide operational definitions of epilepsy but there is considerably more to be accomplished. In the past absence of data expert opinion had a place in establishing definitions. When data is available, evidence based systematic review seems more appropriate14. Definition 1 is evidence based. For epilepsy definition 2, systematic reviews could be undertaken to provide definitive risk estimates to define epilepsy in association with putative clinical scenarios using as a baseline risk for further seizures in those with two unprovoked seizures and identify areas where further work is necessary. To define resolved epilepsy,a level of risk should be set (for example 1% per year) rather than using an arbitrary time of seizure freedom. A systematic assessment of data could then be undertaken to determine when this risk is attained. In successful surgical cases for example, the point at which seizure recurrence risk reaches 1% may be less than a 10 years of seizure freedom. It remains to be seen how the proposed definitions will influence the clinical course of epilepsy. Let's hope that these modified definitions lead to both improved patient function and outcomes and act as a stimulus to further clinical research. Source


Tian B.,The New School | Manley J.L.,Columbia University
Trends in Biochemical Sciences | Year: 2013

Cleavage and polyadenylation (C/P) of nascent transcripts is essential for maturation of the 3' ends of most eukaryotic mRNAs. Over the past three decades, biochemical studies have elucidated the machinery responsible for the seemingly simple C/P reaction. Recent genomic analyses have indicated that most eukaryotic genes have multiple cleavage and polyadenylation sites (pAs), leading to transcript isoforms with different coding potentials and/or variable 3' untranslated regions (UTRs). As such, alternative cleavage and polyadenylation (APA) is an important layer of gene regulation impacting mRNA metabolism. Here, we review our current understanding of APA and recent progress in this field. © 2013 Elsevier Ltd. Source


This paper provides a review of atmospheric circulation and sea surface temperature (SST) conditions that are associated with meteorological drought on the seasonal time scale in the Greater Horn of Africa (the region 10°S-15°N, 30°-528°). New findings regarding a post-1998 increase in drought frequency during the March-May (MAM) "long rains" are also reported. The period 1950-2010 is emphasized, although rainfall and SST data from 1901-2010 are used to place the recent long rains decline in a multidecadal context. For the latter case, climate model simulations and isolated basin SST experiments are also utilized. Climatologically, rainfall exhibits a unimodal June-August (JJA) maximum in west-central Ethiopia with a generally bimodal [MAM and October-December (OND) maxima] distribution in locations to the south and east. Emphasis will be on these three seasons. SST anomalies in the tropical Pacific and Indian Oceans show the strongest association with drought during OND in locations having a bimodal annual cycle, with weaker associations during MAM. The influence of the El Niño-Southern Oscillation (ENSO) phenomenon critically depends on its ability to affect SSTs outside the Pacific. Salient features of the anomalous atmospheric circulation during drought events in different locations and seasons are discussed. The post-1998 decline in the long rains is found to be driven strongly (although not necessarily exclusively) by natural multidecadal variability in the tropical Pacific rather than anthropogenic climate change. This conclusion is supported by observational analyses and climate model experiments, which are presented. © 2014 American Meteorological Society. Source


Talati A.,Columbia University
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2013

The familial nature of major depressive disorder (MDD) is now well recognized. We followed children and grandchildren of probands with and without MDD to examine transmission of depression over generations, and to identify early vulnerability markers prior to the onset of disease. The study now includes three generations and five completed assessment waves spanning 25 years, with a sixth wave underway. Beginning with the fourth wave, we collected measures of brain structure (magnetic resonance imaging, MRI) and physiology (electroencephalography, EEG) and DNA in order to examine at a biological level why the offspring of depressed parents were at higher risk. In this paper, we provide an overview of the study design, the main findings, including new data, and the role of the high-risk design in translational research. We demonstrate that offspring of depressed parents ('high-risk'), when compared with those of non-depressed parents ('low-risk'), were at increased risk for depressive and anxiety disorders, with anxiety appearing earlier and being a predisposing factor for MDD. Offspring with two generations previously affected were at greatest risk. Thinning of the cortical mantle (MRI) and reduced resting-state activity (EEG) within the right parieto-temporal hemisphere differentiated high- from low-risk offspring, regardless of whether the offspring had MDD, suggesting that these measures might serve as familial trait markers for depression and related syndromes. The high- and low-risk offspring also differed by serotonin transporter promoter length polymorphism genotypes, even though the same genotypes were not associated with the presence of MDD. The high-risk epidemiological design appears to be a particularly valuable asset in translational research as it allows targeting of biological processes that emerge prior to the onset of disease, and identifies individuals at high risk for the disorder who may carry the trait or marker but not yet be affected. Source


Identifying the multiple dysregulated oncoproteins that contribute to tumorigenesis in a given patient is crucial for developing personalized treatment plans. However, accurate inference of aberrant protein activity in biological samples is still challenging as genetic alterations are only partially predictive and direct measurements of protein activity are generally not feasible. To address this problem we introduce and experimentally validate a new algorithm, virtual inference of protein activity by enriched regulon analysis (VIPER), for accurate assessment of protein activity from gene expression data. We used VIPER to evaluate the functional relevance of genetic alterations in regulatory proteins across all samples in The Cancer Genome Atlas (TCGA). In addition to accurately infer aberrant protein activity induced by established mutations, we also identified a fraction of tumors with aberrant activity of druggable oncoproteins despite a lack of mutations, and vice versa. In vitro assays confirmed that VIPER-inferred protein activity outperformed mutational analysis in predicting sensitivity to targeted inhibitors. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. Source


Vanitallie T.B.,Columbia University
Metabolism: Clinical and Experimental | Year: 2013

The most opportune time for preventive intervention in sporadic Alzheimer's disease (spAD) is early in its preclinical stage (pcAD), when the odds of preventing or minimizing later disabling neurodegeneration are most favorable. The efficacy of promising preventive interventions should be assessed in patients in the earliest discernible phase of pcAD. This will require application of personalized medicine techniques, with use of suitable biomarkers to detect pcAD in individuals believed to be spAD-prone. This review focuses on the genetic biomarker, apolipoprotein E (apoE) ε4, and on certain neuroimaging biomarkers, such as structural MRI (sMRI), fluorodeoxyglucose- positron emission tomography (FDG-PET), and PET-amyloid tracers capable of delineating the extent and distribution of amyloid-beta (Aβ) deposits in the brain, that can be useful in identifying cognitively normal people who are at enhanced risk of developing spAD. Many years before AD symptoms appear, such neuroimaging procedures can disclose signature abnormalities of brain structure, function, and amyloid levels in cognitively normal apoE ε4 allele carriers and/or individuals with a family history of spAD. Although no effective treatment for spAD is yet available, there is evidence that, by taking a proactive personalized-medicine approach, the practicing physician may be able to reduce risk in AD-prone patients by attending to such modifiable AD risk factors as hypertension, obesity, type 2 diabetes, insulin resistance, hypercholesterolemia, sedentary lifestyle, and current cigarette smoking. Young patients who are ε4 positive should be advised to avoid participation in contact sports or other activities that expose them to risk of traumatic brain injury. © 2013 Elsevier Inc. Source


Miller E.A.,Columbia University | Schekman R.,University of California at Berkeley
Current Opinion in Cell Biology | Year: 2013

Long known as a coat system that generates small transport vesicles from the endoplasmic reticulum (ER), the COPII coat also drives ER export of cargo proteins that are too large to be contained within these canonical carriers. With crystal and cryo-EM structures giving an atomic level view of coat architecture, current advances in the field have focused on understanding how the coat adapts to the different geometries of the underlying cargo. Combined with a growing appreciation for the specific roles of individual COPII paralogs in diverse aspects of mammalian physiology, the field is poised to understand how coat assembly and post-translational modification permits structural rigidity but geometric flexibility to handle the diverse cargoes that exit the ER. © 2013 Elsevier Ltd. Source


Menou K.,Columbia University
Astrophysical Journal | Year: 2012

We present scaling laws for advection, radiation, magnetic drag, and ohmic dissipation in the atmospheres of hot giant exoplanets. In the limit of weak thermal ionization, ohmic dissipation increases with the planetary equilibrium temperature (T eq ≳ 1000K) faster than the insolation power does, eventually reaching values ≳ 1% of the insolation power, which may be sufficient to inflate the radii of hot Jupiters. At higher T eq values still magnetic drag rapidly brakes the atmospheric winds, which reduces the associated ohmic dissipation power. For example, for a planetary field strength B = 10G, the fiducial scaling laws indicate that ohmic dissipation exceeds 1% of the insolation power over the equilibrium temperature range T eq ∼ 1300-2000K, with a peak contribution at T ∼eq 1600K. Evidence for magnetically dragged winds at the planetary thermal photosphere could emerge in the form of reduced longitudinal offsets for the dayside infrared hotspot. This suggests the possibility of an anticorrelation between the amount of hotspot offset and the degree of radius inflation, linking the atmospheric and interior properties of hot giant exoplanets in an observationally testable way. While providing a useful framework to explore the magnetic scenario, the scaling laws also reveal strong parameter dependencies, in particular with respect to the unknown planetary magnetic field strength. © 2012. The American Astronomical Society. All rights reserved. Source


Garcia-Saenz S.,Columbia University
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2013

We consider multi-Galileon theory, the most general Galilean invariant theory with N scalar fields linearly coupled to the trace of the stress-energy tensor. We study the behavior of perturbations on a static spherically symmetric background with a massive point source, and show that, under the assumptions of stability and successful Vainshtein screening, solutions cannot be found that are free of both superluminal propagation and slowly moving, strongly coupled fluctuations. The latter imply that the theoretical and phenomenological issues related to a very low strong-interaction scale cannot be avoided in this model. © 2013 American Physical Society. Source


Shear M.K.,Columbia University
Depression and Anxiety | Year: 2012

Acute grief is emotionally intense, cognitively preoccupying, and disruptive, but grief is not an illness; major depression and anxiety disorders are. Grief and mourning have a purpose. They provide an intense, focused opportunity to reregulate emotion and to engage in a learning process that is aimed at reconfiguring life without the deceased-both the internal life of the mind, and ongoing life in the world. A bereaved person needs to figure out how to find meaning, purpose, joy, and satisfaction in life without someone who has previously been central to these feelings. This reconfiguration is a very natural process that tends to occur in fits and starts as bereaved people move forward and deal with everyday life. Nevertheless, a knowledgeable, empathic and supportive clinician can foster good adjustment. Successful mourning is, however, not a given. For some people, the mourning process is derailed and acute grief is inordinately painful and prolonged. For others, the stress of bereavement triggers the onset or worsening of symptoms of MDD, an anxiety disorder or another psychiatric or medical condition, suicidality or negative health behaviors. Clinicians need to be alert to all of these problematic responses to loss. In the wake of bereavement, we need to both facilitate effective mourning and diagnose and treat co-occurring conditions. © 2012 Wiley Periodicals, Inc. Source


Landa A.,Columbia University
Psychosomatic medicine | Year: 2012

Somatoform pain is a highly prevalent, debilitating condition and a tremendous public health problem. Effective treatments for somatoform pain are urgently needed. The etiology of this condition is, however, still unknown. On the basis of a review of recent basic and clinical research, we propose one potential mechanism of symptom formation in somatoform pain and a developmental theory of its pathogenesis. Emerging evidence from animal and human studies in developmental neurobiology, cognitive-affective neuroscience, psychoneuroimmunology, genetics, and epigenetics, as well as that from clinical and treatment studies on somatoform pain, points to the existence of a shared neural system that underlies physical and social pain. Research findings also show that nonoptimal early experiences interact with genetic predispositions to influence the development of this shared system and the ability to regulate it effectively. Interpersonal affect regulation between infant and caregiver is crucial for the optimal development of these brain circuits. The aberrant development of this shared neural system during infancy, childhood, and adolescence may therefore ultimately lead to an increased sensitivity to physical and social pain and to problems with their regulation in adulthood. The authors critically review translational research findings that support this theory and discuss its clinical and research implications. Specifically, the proposed theory and research review suggest that psychotherapeutic and/or pharmacological interventions that foster the development of affect regulation capacities in an interpersonal context will also serve to more effectively modulate aberrantly activated neural pain circuits and thus be of particular benefit for the treatment of somatoform pain. Source


Fernandes R.M.,University of Minnesota | Millis A.J.,Columbia University
Physical Review Letters | Year: 2013

In several families of iron-based superconducting materials, a d-wave pairing instability may compete with the leading s-wave instability. Here, we show that when both states have comparable free energies, superconducting and nematic degrees of freedom are strongly coupled. Whereas nematic order causes a sharp nonanalytic increase in Tc, nematic fluctuations can change the character of the s-wave to d-wave transition, favoring an intermediate state that does not break time-reversal symmetry but does break tetragonal symmetry. The coupling between superconductivity and nematicity is also manifested in the strong softening of the shear modulus across the superconducting transition. Our results show that nematicity can be used as a diagnostic tool to search for unconventional pairing states in iron pnictides and chalcogenides. © 2013 American Physical Society. Source


Stachowiak J.C.,University of Texas at Austin | Brodsky F.M.,University of California at San Francisco | Miller E.A.,Columbia University
Nature Cell Biology | Year: 2013

Many cellular membrane-bound structures exhibit distinct curvature that is driven by the physical properties of their lipid and protein constituents. Here we review how cells manipulate and control this curvature in the context of dynamic events such as vesicle-mediated membrane traffic. Lipids and cargo proteins each contribute energy barriers that must be overcome during vesicle formation. In contrast, protein coats and their associated accessory proteins drive membrane bending using a variety of interdependent physical mechanisms. We survey the energy costs and drivers involved in membrane curvature, and draw a contrast between the stochastic contributions of molecular crowding and the deterministic assembly of protein coats. These basic principles also apply to other cellular examples of membrane bending events, including important disease-related problems such as viral egress. © 2013 Macmillan Publishers Limited. All rights reserved. Source


Ferrante A.W.,Columbia University
Diabetes, Obesity and Metabolism | Year: 2013

Although the pathological role of the immune system in several metabolic disorders, including type 1 diabetes mellitus (T1DM) and Addison's disease, has long been recognized and studied, only in the last decade has it become apparent that the immune system plays a broad and more subtle role in local and systemic metabolism. It is now apparent that the immune system monitors and responds to specific metabolic cues in both pathologic and non-pathologic settings through a set of processes dubbed immunometabolism. Expansion of adipose tissue mass, activation of lipolysis, eating a high fat diet and even non-shivering thermogenesis all lead to the recruitment and activation of immune cells in key metabolic tissues. The responses are complex and not completely defined, and indeed, as is typical of rapidly evolving research areas, there are some conflicting reports, especially related to the metabolic consequences of manipulation of immune function. However, what is clear is the consensus that metabolic processes, especially obesity and obesity-related complications, activate both the innate and adaptive arms of the immune system. Canonical immune processes consist of discrete steps: surveillance, recognition, effector action and resolution. Over the last decade evidence for each part of the immune response has been found at the intersection of the immune system with metabolism. Although evidence for immune surveillance and modulation of metabolism has been found in the liver, muscle, hypothalamus and pancreas, immune cell function has been most intensively studied and best understood in adipose tissue where studies continue to provide insights into the intersection of the metabolic and immune systems. Here we review the modulation of immune cell populations in adipose tissue and discuss regulatory processes implicated in controlling the interface between metabolism and immunologic function. © 2013 John Wiley & Sons Ltd. Source


Haythe J.,Columbia University
Progress in Cardiovascular Diseases | Year: 2012

Pulmonary artery hypertension is a complex and multi-faceted disease process with numerous etiologies. Chronic thromboembolic pulmonary hypertension (CTEPH) is an underdiagnosed and highly treatable form of pulmonary hypertension. In this disease, certain patients with a history of pulmonary thromboembolic disease go on to develop elevated pulmonary artery pressures, shortness of breath, and progressive right heart failure. This article will review the epidemiology, pathophysiology, diagnosis and treatment of CTEPH with a review of pulmonary thromboendarterectomy surgery. © 2012 Elsevier Inc. Source


Lin H.V.,Merck And Co. | Accili D.,Columbia University
Cell Metabolism | Year: 2011

We review mechanisms that regulate production of glucose by the liver, focusing on areas of budding consensus, and endeavoring to provide a candid assessment of lingering controversies. We also attempt to reconcile data from tracer studies in humans and large animals with the growing compilation of mouse knockouts that display changes in glucose production. A clinical hallmark of diabetes, excessive glucose production remains key to its treatment. Hence, we attempt to integrate emerging pathways into the broader goal to rejuvenate the staid antidiabetic pharmacopeia. © 2011 Elsevier Inc. Source


Reizis B.,Columbia University
Current Opinion in Immunology | Year: 2010

Plasmacytoid dendritic cells (PDC) represent a distinct immune cell type specialized in direct virus recognition and rapid secretion of type I interferon. The origin and lineage affiliation of PDC have been controversial, partly because PDC show features of both lymphocytes and dendritic cells (DC). Recent studies helped elucidate the cellular and molecular basis of PDC development. In particular, the common developmental origin and genetic similarity of PDC and classical antigen-presenting DC have been established. In addition, E protein transcription factor E2-2 was shown to control lineage commitment and gene expression program of PDC. Because E proteins are essential regulators of lymphocyte development, E2-2 activity may underlie the distinct 'lymphoid' features of PDC. © 2010 Elsevier Ltd. Source


Janke C.,Center University | Bulinski J.C.,Columbia University
Nature Reviews Molecular Cell Biology | Year: 2011

Half a century of biochemical and biophysical experiments has provided attractive models that may explain the diverse functions of microtubules within cells and organisms. However, the notion of functionally distinct microtubule types has not been explored with similar intensity, mostly because mechanisms for generating divergent microtubule species were not yet known. Cells generate distinct microtubule subtypes through expression of different tubulin isotypes and through post-translational modifications, such as detyrosination and further cleavage to Î "2-tubulin, acetylation, polyglutamylation and polyglycylation. The recent discovery of enzymes responsible for many tubulin post-translational modifications has enabled functional studies demonstrating that these post-translational modifications may regulate microtubule functions through an amazing range of mechanisms. © 2011 Macmillan Publishers Limited. All rights reserved. Source


Hillman E.M.C.,Columbia University
Annual Review of Neuroscience | Year: 2014

Functional magnetic resonance imaging (fMRI) provides a unique view of the working human mind. The blood-oxygen-level-dependent (BOLD) signal, detected in fMRI, reflects changes in deoxyhemoglobin driven by localized changes in brain blood flow and blood oxygenation, which are coupled to underlying neuronal activity by a process termed neurovascular coupling. Over the past 10 years, a range of cellular mechanisms, including astrocytes, pericytes, and interneurons, have been proposed to play a role in functional neurovascular coupling. However, the field remains conflicted over the relative importance of each process, while key spatiotemporal features of BOLD response remain unexplained. Here, we review current candidate neurovascular coupling mechanisms and propose that previously overlooked involvement of the vascular endothelium may provide a more complete picture of how blood flow is controlled in the brain. We also explore the possibility and consequences of conditions in which neurovascular coupling may be altered, including during postnatal development, pathological states, and aging, noting relevance to both stimulus-evoked and resting-state fMRI studies. © Copyright ©2014 by Annual Reviews. All rights reserved. Source


Dela Cruz F.S.,Columbia University
Frontiers in Oncology | Year: 2013

Sarcomas represent a clinically and biologically diverse group of malignant connective tissue tumors. Despite aggressive conventional therapy, a large proportion of sarcoma patients experience disease recurrence which will ultimately result in mortality. The presence of a unique population of cells, referred to as cancer stem cells (CSCs), have been proposed to be responsible for refractory responses to current chemotherapies as well underlying the basis for metastasis and relapse of disease - clinical corollaries to what has been termed the CSC hypothesis. The presence of CSCs have been suggested in a variety of hematologic and solid malignancies, and only more recently in sarcomas. Based on our current understanding of normal stem cell biology and evidence obtained from the study of malignant hematopoietic and solid tumors, researchers have identified candidate cell surface markers (CD133, CD117, Stro-1), biochemical markers (aldehyde dehydrogenase activity), and cytological characteristics (side population and spherical colony formation) that may identify putative sarcoma CSCs. In this review, we explore the current state of evidence that may suggest the existence of sarcoma CSCs. We present research in osteosarcoma, the Ewing's sarcoma family of tumors, rhabdomyosarcoma, as well as other sarcoma subtypes to describe commonly used molecular and biochemical markers, as well as techniques, used in the identification, isolation, and characterization of candidate sarcoma CSCs. We will also discuss the current controversies and challenges that face research in sarcoma CSC.© 2013 Dela Cruz. Source


Despite recent changes to expand the ART eligibility criteria in sub-Saharan Africa, many patients still initiate ART in the advanced stages of HIV infection, which contributes to increased early mortality rates, poor patient outcomes, and onward transmission. To evaluate individual and clinic-level factors associated with late ART initiation in Mozambique, we conducted a retrospective sex-specific analysis of data from 36,411 adult patients who started ART between January 2005 and June 2009 at 25 HIV clinics in Mozambique. Late ART initiation was defined as CD4 count<100 cells/μL or WHO stage IV. Mixed effects models were used to identify patient- and clinic-level factors associated with late ART initiation. The proportion of patients initiating ART late decreased from 46% to 37% during 2005-2007, but remained constant (between 37-33%) from 2007-2009. Of those who initiated ART late (median CD4 = 57 cells/μL), 5% were known to have died and 54% were lost to clinic within 6 months of ART initiation (compared with 2% and 47% among other patients starting ART [median CD4 = 192 cells/μL]). In multivariate analysis, female sex and pregnancy at ART initiation (AOR(female_not_pregnant_vs._male) = 0.66, 95%CI [0.62-0.69]; AOR(pregnant_vs._non_pregnant) = 0.60, 95%CI [0.49-0.73]), younger and older age (AOR(15-25_vs.26-30) = 0.86, 95%CI [0.79-0.94], AOR(>45_vs.26-30) = 0.72, 95%CI [0.67-0.77]), entry into care via PMTCT (AOR(entry_through_PMTCT_vs.VCT) = 0.42, 95%CI [0.35-0.50]), marital status (AOR(married/in union_vs.single) = 0.87, 95%CI [0.83-0.92]), education (AOR(secondary_or_higher_vs.primary) = 0.87, 95%CI [0.83-0.93]) and year of ART initiation were associated with a lower likelihood of late ART initiation. Clinic-level factors independently associated with a lower likelihood of late ART initiation included CD4 machine on-site (AOR(CD4_machine_onsite_vs.offsite) = 0.83, 95%CI [0.74-0.94]) and presence of PMTCT services onsite (AOR = 0.85, 95%CI [0.77-0.93]). The risk of starting ART late remained persistently high. Efforts are needed to ensure identification and enrollment of patients at earlier stages of HIV disease. Individual and clinic level factors identified may provide clues for upstream structural interventions. Source


Peek J.E.G.,Columbia University
Astrophysical Journal Letters | Year: 2013

Both the Galactic 21 cm line flux from neutral hydrogen (H I) in interstellar medium and the far-infrared (FIR) emission from Galactic dust grains have been used to estimate the strength of Galactic reddening of distant sources. In this work we use a collection of uniform color distant galaxies as color standards to determine whether the H I method or the FIR method is superior. We find that the two methods both produce reasonably accurate maps, but that both show significant errors as compared to the typical color of the background galaxies. We find that a mixture of the FIR and H I maps in roughly a 2-to-1 ratio is clearly superior to either map alone. We recommend that future reddening maps should use both sets of data, and that well-constructed FIR and H I maps should both be vigorously pursued. © 2013 The American Astronomical Society. All rights reserved. Source


Conflicts of interest (COIs) in research have received increasing attention, but many questions arise about how Institutional Review Boards (IRBs) view and approach these. Methods: I conducted in-depth interviews of 2 hours each with 46 US IRB chairs, administrators, and members, exploring COI and other issues related to research integrity. I contacted leaders of 60 IRBs (every fourth one among the top 240 institutions by NIH funding), and interviewed IRB leaders from 34 of these institutions (response rate = 55%). Data were analyzed using standard qualitative methods, informed by Grounded Theory. Results: IRBs confront financial and non-financial COIs of PIs, institutions, and IRBs themselves. IRB members may seek to help, or compete with, principal investigators (PIs). Non-financial COI also often appear to be "indirect financial" conflicts based on gain (or loss) not to oneself, but to one's colleagues or larger institution. IRBs faced challenges identifying and managing these COI, and often felt that they could be more effective. IRBs' management of their own potential COI vary, and conflicted members may observe, participate, and/or vote in discussions. Individual IRB members frequently judge for themselves whether to recuse themselves. Challenges arise in addressing these issues, since institutions and PIs need funding, financial information is considered confidential, and COI can be unconscious. Conclusions: This study, the first to explore qualitatively how IRBs confront COIs and probe how IRBs confront non-financial COIs, suggests that IRBs face several types of financial and non-financial COIs, involving themselves, PIs, and institutions, and respond varyingly. These data have critical implications for practice and policy. Disclosure of indirect and non-financial COIs to subjects may not be feasible, partly since IRBs, not PIs, are conflicted. Needs exist to consider guidelines and clarifications concerning when and how, in protocol reviews, IRB members should recuse themselves from participating, observing, and/or voting. © 2011 Robert Klitzman. Source


Bornfeldt K.E.,University of Washington | Tabas I.,Columbia University
Cell Metabolism | Year: 2011

Progress in preventing atherosclerotic coronary artery disease (CAD) has been stalled by the epidemic of type 2 diabetes. Further advances in this area demand a thorough understanding of how two major features of type 2 diabetes, insulin resistance and hyperglycemia, impact atherosclerosis. Insulin resistance is associated with systemic CAD risk factors, but increasing evidence suggests that defective insulin signaling in atherosclerotic lesional cells also plays an important role. The role of hyperglycemia in CAD associated with type 2 diabetes is less clear. Understanding the mechanisms whereby type 2 diabetes exacerbates CAD offers hope for new therapeutic strategies to prevent and treat atherosclerotic vascular disease. © 2011 Elsevier Inc. Source


Marks A.R.,Columbia University
Journal of Clinical Investigation | Year: 2013

Ca2+-dependent signaling is highly regulated in cardiomyocytes and determines the force of cardiac muscle contraction. Ca2+ cycling refers to the release and reuptake of intracellular Ca2+ that drives muscle contraction and relaxation. In failing hearts, Ca2+ cycling is profoundly altered, resulting in impaired contractility and fatal cardiac arrhythmias. The key defects in Ca2+ cycling occur at the level of the sarcoplasmic reticulum (SR), a Ca2+ storage organelle in muscle. Defects in the regulation of Ca2+ cycling proteins including the ryanodine receptor 2, cardiac (RyR2)/ Ca2+ release channel macromolecular complexes and the sarcoplasmic/endoplasmic reticulum Ca 2+ ATPase 2a (SERCA2a)/phospholamban complex contribute to heart failure. RyR2s are oxidized, nitrosylated, and PKA hyperphosphorylated, resulting in "leaky" channels in failing hearts. These leaky RyR2s contribute to depletion of Ca2+ from the SR, and the leaking Ca 2+ depolarizes cardiomyocytes and triggers fatal arrhythmias. SERCA2a is downregulated and phospholamban is hypophosphorylated in failing hearts, resulting in impaired SR Ca2+ reuptake that conspires with leaky RyR2 to deplete SR Ca2+. Two new therapeutic strategies for heart failure (HF) are now being tested in clinical trials: (a) fixing the leak in RyR2 channels with a novel class of Ca2+-release channel stabilizers called Rycals and (b) increasing expression of SERCA2a to improve SR Ca 2+ reuptake with viral-mediated gene therapy. There are many potential opportunities for additional mechanism-based therapeutics involving the machinery that regulates Ca2+ cycling in the heart. Source


Masters R.K.,Columbia University
American Journal of Epidemiology | Year: 2013

In this study, we analyzed age variation in the association between obesity status and US adult mortality risk. Previous studies have found that the association between obesity and mortality risk weakens with age. We argue that existing results were derived from biased estimates of the obesity-mortality relationship because models failed to account for confounding influences from respondents' ages at survey and/or cohort membership. We employed a series of Cox regression models in data from 19 cross-sectional, nationally representative waves of the US National Health Interview Survey (1986-2004), linked to the National Death Index through 2006, to examine age patterns in the obesity-mortality association between ages 25 and 100 years. Findings suggest that survey-based estimates of age patterns in the obesity-mortality relationship are significantly confounded by disparate cohort mortality and age-related survey selection bias. When these factors are accounted for in Cox survival models, the obesity-mortality relationship is estimated to grow stronger with age. © 2013 © The Author 2013. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. Source


Wasserman G.A.,Columbia University
Environmental health : a global access science source | Year: 2014

In recent studies in Bangladesh and elsewhere, exposure to arsenic (As) via drinking water is negatively associated with performance-related aspects of child intelligence (e.g., Perceptual Reasoning, Working Memory) after adjustment for social factors. Because findings are not easily generalizable to the US, we examine this relation in a US population. In 272 children in grades 3-5 from three Maine school districts, we examine associations between drinking water As (WAs) and intelligence (WISC-IV). On average, children had resided in their current home for 7.3 years (approximately 75% of their lives). In unadjusted analyses, household well WAs is associated with decreased scores on most WISC-IV Indices. With adjustment for maternal IQ and education, HOME environment, school district and number of siblings, WAs remains significantly negatively associated with Full Scale IQ and Perceptual Reasoning, Working Memory and Verbal Comprehension scores. Compared to those with WAs < 5 μg/L, exposure to WAs ≥ 5 μg/L was associated with reductions of approximately 5-6 points in both Full Scale IQ (p < 0.01) and most Index scores (Perceptual Reasoning, Working Memory, Verbal Comprehension, all p's < 0.05). Both maternal IQ and education were associated with lower levels of WAs, possibly reflecting behaviors (e.g., water filters, residential choice) limiting exposure. Both WAs and maternal measures were associated with school district. The magnitude of the association between WAs and child IQ raises the possibility that levels of WAs ≥ 5 μg/L, levels that are not uncommon in the United States, pose a threat to child development. Source


Hatzenbuehler M.L.,Columbia University
Pediatrics | Year: 2011

OBJECTIVE: To determine whether the social environment surrounding lesbian, gay, and bisexual youth may contribute to their higher rates of suicide attempts, controlling for individual-level risk factors. METHODS: A total of 31 852 11th grade students (1413 [4.4%] lesbian, gay, and bisexual individuals) in Oregon completed the Oregon Healthy Teens survey in 2006 -2008. We created a composite index of the social environment in 34 counties, including (1) the proportion of same-sex couples, (2) the proportion of registered Democrats, (3) the presence of gay-straight alliances in schools, and (4) school policies (nondiscrimination and antibullying) that specifically protected lesbian, gay, and bisexual students. RESULTS: Lesbian, gay, and bisexual youth were significantly more likely to attempt suicide in the previous 12 months, compared with heterosexuals (21.5% vs 4.2%). Among lesbian, gay, and bisexual youth, the risk of attempting suicide was 20% greater in unsupportive environments compared to supportive environments. A more supportive social environment was significantly associated with fewer suicide attempts, controlling for sociodemographic variables and multiple risk factors for suicide attempts, including depressive symptoms, binge drinking, peer victimization, and physical abuse by an adult (odds ratio: 0.97 [95% confidence interval: 0.96-0.99]). CONCLUSIONS: This study documents an association between an objective measure of the social environment and suicide attempts among lesbian, gay, and bisexual youth. The social environment appears to confer risk for suicide attempts over and above individual-level risk factors. These results have important implications for the development of policies and interventions to reduce sexual orientation-related disparities in suicide attempts. Copyright © 2011 by the American Academy of Pediatrics. Source


Seung H.S.,Princeton University | Sumbul U.,Columbia University
Neuron | Year: 2014

We describe recent progress toward defining neuronal cell types in the mouse retina and attempt to extract lessons that may be generally useful in the mammalian brain. Achieving a comprehensive catalog of retinal cell types now appears within reach, because researchers have achieved consensus concerning two fundamental challenges. The first is accuracy-defining pure cell types rather than settling for neuronal classes that are mixtures of types. The second is completeness-developing methods guaranteed to eventually identify all cell types, as well as criteria for determining when all types have been found. Case studies illustrate how these two challenges are handled by combining state-of-the-art molecular, anatomical, and physiological techniques. Progress is also being made in observing and modeling connectivity between cell types. Scaling up to larger brain regions, such as the cortex, will require not only technical advances but also careful consideration of the challenges of accuracy and completeness. © 2014 Elsevier Inc. Source


Tall A.R.,Columbia University | Yvan-Charvet L.,Institut Universitaire de France
Nature Reviews Immunology | Year: 2015

Hypercholesterolaemia leads to cholesterol accumulation in macrophages and other immune cells, which promotes inflammatory responses, including augmentation of Toll-like receptor (TLR) signalling, inflammasome activation, and the production of monocytes and neutrophils in the bone marrow and spleen. On a cellular level, activation of TLR signalling leads to decreased cholesterol efflux, which results in further cholesterol accumulation and the amplification of inflammatory responses. Although cholesterol accumulation through the promotion of inflammatory responses probably has beneficial effects in the response to infections, it worsens diseases that are associated with chronic metabolic inflammation, including atherosclerosis and obesity. Therapeutic interventions such as increased production or infusion of high-density lipoproteins may sever the links between cholesterol accumulation and inflammation, and have beneficial effects in patients with metabolic diseases. © 2015 Macmillan Publishers Limited. All rights reserved. Source


Yuste R.,Columbia University
Nature Reviews Neuroscience | Year: 2015

For over a century, the neuron doctrine - which states that the neuron is the structural and functional unit of the nervous system - has provided a conceptual foundation for neuroscience. This viewpoint reflects its origins in a time when the use of single-neuron anatomical and physiological techniques was prominent. However, newer multineuronal recording methods have revealed that ensembles of neurons, rather than individual cells, can form physiological units and generate emergent functional properties and states. As a new paradigm for neuroscience, neural network models have the potential to incorporate knowledge acquired with single-neuron approaches to help us understand how emergent functional states generate behaviour, cognition and mental disease. © 2015 Macmillan Publishers Limited. All rights reserved. Source


Yamamoto A.,Columbia University | Yue Z.,Mount Sinai School of Medicine
Annual Review of Neuroscience | Year: 2014

Autophagy is a conserved catabolic process that delivers the cytosol and cytosolic constituents to the lysosome. Its fundamental role is to maintain cellular homeostasis and to protect cells from varying insults, including misfolded proteins and damaged organelles. Beyond these roles, the highly specialized cells of the brain have further adapted autophagic pathways to suit their distinct needs. In this review, we briefly summarize our current understanding of the different forms of autophagy and then offer a closer look at how these pathways impact neuronal and glial functions. The emerging evidence indicates that not only are autophagy pathways essential for neural health, but they have a direct impact on developmental and neurodegenerative processes. Taken together, as we unravel the complex roles autophagy pathways play, we will gain the necessary insight to modify these pathways to protect the human brain and treat neurodegenerative diseases. © Copyright ©2014 by Annual Reviews. All rights reserved. Source


Some of the most common and devastating disorders of the brain target the hippocampal formation. The hippocampal formation is a complex circuit of interconnected regions, and it is assumed that clues into the causes of these disorders are embedded within the circuit. Neuroimaging tools have been optimized to interrogate the malfunctioning hippocampal circuit, and by applying these tools to patients in the earliest stages of disease and to animal models, patterns of regional vulnerability have been established for Alzheimer's disease, schizophrenia, and cognitive aging. More recently, studies have begun deciphering the cellular and molecular reasons underlying regional dysfunction. Collectively, this information clarifies the pathophysiology of these disorders and informs on therapeutic strategies. © 2014 Elsevier Inc. Source


Palmer A.G.,Columbia University
Accounts of Chemical Research | Year: 2015

ConspectusBiological activities of enzymes, including regulation or coordination of mechanistic stages preceding or following the chemical step, may depend upon kinetic or equilibrium changes in protein conformations. Exchange of more open or flexible conformational states with more closed or constrained states can influence inhibition, allosteric regulation, substrate recognition, formation of the Michaelis complex, side reactions, and product release. NMR spectroscopy has long been applied to the study of conformational dynamic processes in enzymes because these phenomena can be characterized over multiple time scales with atomic site resolution. Laboratory-frame spin-relaxation measurements, sensitive to reorientational motions on picosecond-nanosecond time scales, and rotating-frame relaxation-dispersion measurements, sensitive to chemical exchange processes on microsecond-millisecond time scales, provide information on both conformational distributions and kinetics. This Account reviews NMR spin relaxation studies of the enzymes ribonuclease HI from mesophilic (Escherichia coli) and thermophilic (Thermus thermophilus) bacteria, E. coli AlkB, and Saccharomyces cerevisiae triosephosphate isomerase to illustrate the contributions of conformational flexibility and dynamics to diverse steps in enzyme mechanism.Spin relaxation measurements and molecular dynamics (MD) simulations of the bacterial ribonuclease H enzymes show that the handle region, one of three loop regions that interact with substrates, interconverts between two conformations. Comparison of these conformations with the structure of the complex between Homo sapiens ribonuclease H and a DNA:RNA substrate suggests that the more closed state is inhibitory to binding. The large population of the closed conformation in T. Thermophilus ribonuclease H contributes to the increased Michaelis constant compared with the E. coli enzyme. NMR spin relaxation and fluorescence spectroscopy have characterized a conformational transition in AlkB between an open state, in which the side chains of methionine residues in the active site are disordered, and a closed state, in which these residues are ordered. The open state is highly populated in the AlkB/Zn(II) complex, and the closed state is highly populated in the AlkB/Zn(II)/2OG/substrate complex, in which 2OG is the 2-oxoglutarate cosubstrate and the substrate is a methylated DNA oligonucleotide. The equilibrium is shifted to approximately equal populations of the two conformations in the AlkB/Zn(II)/2OG complex. The conformational shift induced by 2OG ensures that 2OG binds to AlkB/Zn(II) prior to the substrate. In addition, the opening rate of the closed conformation limits premature release of substrate, preventing generation of toxic side products by reaction with water. Closure of active site loop 6 in triosephosphate isomerase is critical for forming the Michaelis complex, but reopening of the loop after the reaction is (partially) rate limiting. NMR spin relaxation and MD simulations of triosephosphate isomerase in complex with glycerol 3-phosphate demonstrate that closure of loop 6 is a highly correlated rigid-body motion. The MD simulations also indicate that motions of Gly173 in the most flexible region of loop 6 contribute to opening of the active site loop for product release. Considered together, these three enzyme systems illustrate the power of NMR spin relaxation investigations in providing global insights into the role of conformational dynamic processes in the mechanisms of enzymes from initial activation to final product release. © 2015 American Chemical Society. Source


Grishok A.,Columbia University
Advances in Genetics | Year: 2013

The significance of noncoding RNAs in animal biology is being increasingly recognized. The nematode Caenorhabditis elegans has an extensive system of short RNAs that includes microRNAs, piRNAs, and endogenous siRNAs, which regulate development, control life span, provide resistance to viruses and transposons, and monitor gene duplications. Progress in our understanding of short RNAs was stimulated by the discovery of RNA interference, a phenomenon of sequence-specific gene silencing induced by exogenous double-stranded RNA, at the turn of the twenty-first century. This chapter provides a broad overview of the exogenous and endogenous RNAi processes in C. elegans and describes recent advances in genetic, genomic, and molecular analyses of nematode's short RNAs and proteins involved in the RNAi-related pathways. © 2013 Elsevier Inc. Source


Beloborodov A.M.,Columbia University
Astrophysical Journal | Year: 2013

The twisted magnetospheres of magnetars must sustain a persistent flow of electron-positron plasma. The flow dynamics is controlled by the radiation field around the hot neutron star. The problem of plasma motion in the self-consistent radiation field is solved using the method of virtual beams. The plasma and radiation exchange momentum via resonant scattering and self-organize into the "radiatively locked" outflow with a well-defined, decreasing Lorentz factor. There is an extended zone around the magnetar where the plasma flow is ultra-relativistic; its Lorentz factor is self-regulated so that it can marginally scatter thermal photons. The flow becomes slow and opaque in an outer equatorial zone, where the decelerated plasma accumulates and annihilates; this region serves as a reflector for the thermal photons emitted by the neutron star. The e ± flow carries electric current, which is sustained by a moderate induced electric field. The electric field maintains a separation between the electron and positron velocities, against the will of the radiation field. The two-stream instability is then inevitable, and the induced turbulence can generate low-frequency emission. In particular, radio emission may escape around the magnetic dipole axis of the star. Most of the flow energy is converted to hard X-ray emission, which is examined in an accompanying paper. © 2013. The American Astronomical Society. All rights reserved. Source


Hershman D.L.,Columbia University
Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2013

Chemotherapy-induced peripheral neuropathy (CIPN) is common and leads to suboptimal treatment. Acetyl-L-carnitine (ALC) is a natural compound involved in neuronal protection. Studies have suggested ALC may be effective for the prevention and treatment of CIPN. A 24-week randomized double-blind trial comparing ALC (3,000 mg per day) with placebo in women undergoing adjuvant taxane-based chemotherapy was conducted. The primary objective was to determine if ALC prevents CIPN as measured by the 11-item neurotoxicity (NTX) component of the Functional Assessment of Cancer Therapy (FACT) -Taxane scale at 12 weeks. Secondary objectives included changes in 24-week end points, functional status (FACT-Trial Outcome Index [TOI]), fatigue (Functional Assessment of Chronic Illness Therapy [FACIT] -Fatigue), and NTX grade. A total of 409 patients were evaluable (208 received ALC; 201, placebo). In a multivariate linear regression, week-12 scores were 0.9 points lower (more CIPN) with ALC than placebo (95% CI, -2.2 to 0.4; P = .17), whereas week-24 scores were 1.8 points lower with ALC (95% CI, -3.2 to -0.4; P = .01). Patients receiving ALC were more likely to have a > 5-point decrease in FACT-NTX scores (38% v 28%; P = .05), and FACT-TOI scores were 3.5 points lower with ALC (P = .03). Grade 3 to 4 neurotoxicity was more frequent in the ALC arm (eight v one). No differences between arms were observed for FACIT-Fatigue or other toxicities. Serum carnitine level increased with ALC but remained stable with placebo. There was no evidence that ALC affected CIPN at 12 weeks; however, ALC significantly increased CIPN by 24 weeks. This is the first study to our knowledge showing that a nutritional supplement increased CIPN. Patients should be discouraged from using supplements without proven efficacy. Source


PURPOSE: The roles of nonaffiliated and nonscientific institutional review board (IRB) members at academic medical centers have received some attention, but questions remain-Who are they, what do they do, and whom, if anyone, do they represent? METHOD: The author interviewed 46 IRB chairs, directors, administrators, and members in 2007-2009. He contacted the leadership of 60 IRBs (every fourth one in the list of the top 240 institutions by National Institutes of Health funding), interviewed IRB leaders from 34 of these institutions, then recruited 7 additional members from these IRBs to interview. RESULTS: Regular IRB members often called these individuals community members and were confused as to who these members were, or should be, and whether they did, or should, represent anyone and, if so, whom. IRBs encountered challenges in finding, training, and retaining these community members. Tensions emerged because nonscientific members, by definition, have no scientific training, so they have difficulty understanding key aspects of protocols, making them feel unempowered to contribute to reviews. IRBs varied in how much they encouraged these members to participate, in what ways, and with what success. CONCLUSIONS: At academic medical centers, IRBs struggled with how to view, choose, employ, and retain nonaffiliated and nonscientific members, and they varied widely in these regards. Some IRBs had these members review entire protocols, others only limited parts (particularly reading consent forms for comprehension), pro forma. Yet, at times, these members' input proved very important. These findings have critical implications for policy, practice, and research. Source


Siddiqi S.,Columbia University
PloS one | Year: 2012

Expression of Piwi proteins is confined to early development and stem cells during which they suppress transposon migration via DNA methylation to ensure genomic stability. Piwi's genomic protective function conflicts with reports that its human ortholog, Hiwi, is expressed in numerous cancers and prognosticates shorter survival. However, the role of Hiwi in tumorigenesis has not been examined. Here we demonstrate that (1) over-expressing Hiwi in sarcoma precursors inhibits their differentiation in vitro and generates sarcomas in vivo; (2) transgenic mice expressing Hiwi (mesodermally restricted) develop sarcomas; and (3) inducible down-regulation of Hiwi in human sarcomas inhibits growth and re-establishes differentiation. Our data indicates that Hiwi is directly tumorigenic and Hiwi-expressing cancers may be addicted to Hiwi expression. We further show that Hiwi associated DNA methylation and cyclin-dependent kinase inhibitor (CDKI) silencing is reversible along with Hiwi-induced tumorigenesis, via DNA-methyltransferase inhibitors. Our studies reveal for the first time not only a novel oncogenic role for Hiwi as a driver of tumorigenesis, but also suggest that the use of epigenetic agents may be clinically beneficial for treatment of tumors that express Hiwi. Additionally, our data showing that Hiwi-associated DNA hyper-methylation with subsequent genetic and epigenetic changes favoring a tumorigenic state reconciles the conundrum of how Hiwi may act appropriately to promote genomic integrity during early development (via transposon silencing) and inappropriately in adult tissues with subsequent tumorigenesis. Source


Miller E.A.,Columbia University
Genetics | Year: 2013

The secretory pathway is responsible for the synthesis, folding, and delivery of a diverse array of cellular proteins. Secretory protein synthesis begins in the endoplasmic reticulum (ER), which is charged with the tasks of correctly integrating nascent proteins and ensuring correct post-translational modification and folding. Once ready for forward traffic, proteins are captured into ER-derived transport vesicles that form through the action of the COPII coat. COPII-coated vesicles are delivered to the early Golgi via distinct tethering and fusion machineries. Escaped ER residents and other cycling transport machinery components are returned to the ER via COPI-coated vesicles, which undergo similar tethering and fusion reactions. Ultimately, organelle structure, function, and cell homeostasis are maintained by modulating protein and lipid flux through the early secretory pathway. In the last decade, structural and mechanistic studies have added greatly to the strong foundation of yeast genetics on which this field was built. Here we discuss the key players that mediate secretory protein biogenesis and trafficking, highlighting recent advances that have deepened our understanding of the complexity of this conserved and essential process. © 2013 by the Genetics Society of America. Source


Lu Q.,University of Delaware | Chen J.G.,Columbia University | Xiao J.Q.,University of Delaware
Angewandte Chemie - International Edition | Year: 2013

The depletion of traditional energy resources as well as the desire to reduce high CO2 emissions associated with energy production means that energy storage is now becoming more important than ever. New functional electrode materials are urgently needed for next-generation energy storage systems, such as supercapacitors or batteries, tomeet the ever increasing demand for higher energy and power densities. Advances in nanotechnology are essential to meet those future challenges. It is critical to develop ways of synthesizing new nanomaterials with enhanced properties or combinations of properties to meet future challenges. In this Minireview we discuss several important recent studies in developing nanostructured pseudocapacitor electrodes, and summarize three major parameters that are the most important in determining the performance of electrode materials. A technique to optimize these parameters simultaneously and to achieve both high energy and power densities is also introduced. © 2013 Wiley-VCH Verlag GmbH and Co. KGaA, Weinheim. Source


Grueber W.B.,Columbia University
Cold Spring Harbor perspectives in biology | Year: 2010

The spatial pattern of branches within axonal or dendritic arbors and the relative arrangement of neighboring arbors with respect to one another impact a neuron's potential connectivity. Although arbors can adopt diverse branching patterns to suit their functions, evenly spread branches that avoid clumping or overlap are a common feature of many axonal and dendritic arbors. The degree of overlap between neighboring arbors innervating a surface is also characteristic within particular neuron types. The arbors of some populations of neurons innervate a target with a comprehensive and nonoverlapping "tiled" arrangement, whereas those of others show substantial territory overlap. This review focuses on cellular and molecular studies that have provided insight into the regulation of spatial arrangements of neurite branches within and between arbors. These studies have revealed principles that govern arbor arrangements in dendrites and axons in both vertebrates and invertebrates. Diverse molecular mechanisms controlling the spatial patterning of sister branches and neighboring arbors have begun to be elucidated. Source


Vunjak-Novakovic G.,Columbia University
Tissue engineering. Part B, Reviews | Year: 2010

Cardiac tissue engineering aims to create functional tissue constructs that can reestablish the structure and function of injured myocardium. Engineered constructs can also serve as high-fidelity models for studies of cardiac development and disease. In a general case, the biological potential of the cell-the actual "tissue engineer"-is mobilized by providing highly controllable three-dimensional environments that can mediate cell differentiation and functional assembly. For cardiac regeneration, some of the key requirements that need to be met are the selection of a human cell source, establishment of cardiac tissue matrix, electromechanical cell coupling, robust and stable contractile function, and functional vascularization. We review here the potential and challenges of cardiac tissue engineering for developing therapies that could prevent or reverse heart failure. Source


Mao J.J.,Columbia University
Tissue engineering. Part B, Reviews | Year: 2010

The face distinguishes one human being from another. When the face is disfigured because of trauma, tumor removal, congenital anomalies, or chronic diseases, the patient has a strong desire for functional and esthetic restoration. Current practice of facial reconstruction using autologous grafts, synthetic fillers, and prostheses is frequently below the surgeon's and patient's expectations. Facial reconstruction is yet to take advantage of recent advances in seemingly unrelated fields of stem cell biology, chemical engineering, biomaterials, and tissue engineering. "Biosurgery," a new concept that we propose, will incorporate novel principles and strategies of bioactive cues, biopolymers, and/or cells to restore facial defects. Small facial defects can likely be reconstructed by cell homing and without cell transplantation. A critical advantage of cell homing is that agilely recruited endogenous cells have the potential to harness the host's innate capacity for regeneration, thus accelerating the rate of regulatory and commercialization processes for product development. Large facial defects, however, may not be restorable without cell delivery per our understanding at this time. New breakthrough in biosurgery will likely originate from integrated strategies of cell biology, cytokine biology, chemical engineering, biomaterials, and tissue engineering. Regardless of cell homing or cell delivery approaches, biosurgery not only will minimize surgical trauma and repetitive procedures, but also produce long-lasting results. At the same time, caution must be exercised against the development of products that lack scientific basis or dogmatic combination of cells, biomaterials, and biomolecules. Together, scientifically derived biosurgery will undoubtedly develop into new technologies that offer increasingly natural reconstruction and/or augmentation of the face. Source


Hess H.,Columbia University
Annual Review of Biomedical Engineering | Year: 2011

Biomolecular motors, in particular motor proteins from the kinesin and myosin families, can be used to explore engineering applications of molecular motors in general. Their outstanding performance enables the experimental study of hybrid systems, where bio-inspired functions such as sensing, actuation, and transport rely on the nanoscale generation of mechanical force. Scaling laws and theoretical studies demonstrate the optimality of biomolecular motor designs and inform the development of synthetic molecular motors. Copyright © 2011 by Annual Reviews. All rights reserved. Source


Worman H.J.,Columbia University
Cold Spring Harbor perspectives in biology | Year: 2010

In the past decade, a wide range of fascinating monogenic diseases have been linked to mutations in the LMNA gene, which encodes the A-type nuclear lamins, intermediate filament proteins of the nuclear envelope. These diseases include dilated cardiomyopathy with variable muscular dystrophy, Dunnigan-type familial partial lipodystrophy, a Charcot-Marie-Tooth type 2 disease, mandibuloacral dysplasia, and Hutchinson-Gilford progeria syndrome. Several diseases are also caused by mutations in genes encoding B-type lamins and proteins that associate with the nuclear lamina. Studies of these so-called laminopathies or nuclear envelopathies, some of which phenocopy common human disorders, are providing clues about functions of the nuclear envelope and insights into disease pathogenesis and human aging. Source


Sun L.,Columbia University
British journal of anaesthesia | Year: 2010

A great deal of concern has recently arisen regarding the safety of anaesthesia in infants and children. There is mounting and convincing preclinical evidence in rodents and non-human primates that anaesthetics in common clinical use are neurotoxic to the developing brain in vitro and cause long-term neurobehavioural abnormalities in vivo. An estimated 6 million children (including 1.5 million infants) undergo surgery and anaesthesia each year in the USA alone, so the clinical relevance of anaesthetic neurotoxicity is an urgent matter of public health. Clinical studies that have been conducted on the long-term neurodevelopmental effects of anaesthetic agents in infants and children are retrospective analyses of existing data. Two large-scale clinical studies are currently underway to further address this issue. The PANDA study is a large-scale, multisite, ambi-directional sibling-matched cohort study in the USA. The aim of this study is to examine the neurodevelopmental effects of exposure to general anaesthesia during inguinal hernia surgery before 36 months of age. Another large-scale study is the GAS study, which will compare the neurodevelopmental outcome between two anaesthetic techniques, general sevoflurane anaesthesia and regional anaesthesia, in infants undergoing inguinal hernia repair. These study results should contribute significant information related to anaesthetic neurotoxicity in children. Source


DeFries R.,Columbia University | Rosenzweig C.,NASA
Proceedings of the National Academy of Sciences of the United States of America | Year: 2010

Increasing food production and mitigating climate change are two primary but seemingly contradictory objectives for tropical landscapes. This special feature examines synergies and trade-offs among these objectives. Four themes emerge from the papers: the important roles of both forest and agriculture sectors for climate mitigation in tropical countries; the minor contribution from deforestation-related agricultural expansion to overall food production at global and continental scales; the opportunities for synergies between improved food production and reductions in greenhouse gas emissions through diversion of agricultural expansion to already-cleared lands, improved soil, crop, and livestock management, and agroforestry; and the need for targeted policy and management interventions to make these synergistic opportunities a reality. We conclude that agricultural intensification is a key factor to meet dual objectives of food production and climate mitigation, but there is no single panacea for balancing these objectives in all tropical landscapes. Place-specific strategies for sustainable land use emerge from assessments of current land use, demographics, and other biophysical and socioeconomic characteristics, using a whole-landscape, multisector perspective. Source


Dall'Armi C.,Columbia University
Nature communications | Year: 2010

Although macroautophagy is known to be an essential degradative process whereby autophagosomes mediate the engulfment and delivery of cytoplasmic components into lysosomes, the lipid changes underlying autophagosomal membrane dynamics are undetermined. Here, we show that phospholipase D1 (PLD1), which is primarily associated with the endosomal system, partially relocalizes to the outer membrane of autophagosome-like structures upon nutrient starvation. The localization of PLD1, as well as the starvation-induced increase in PLD activity, are altered by wortmannin, a phosphatidylinositol 3-kinase inhibitor, suggesting PLD1 may act downstream of Vps34. Pharmacological inhibition of PLD and genetic ablation of PLD1 in mouse cells decreased the starvation-induced expansion of LC3-positive compartments, consistent with a role of PLD1 in the regulation of autophagy. Furthermore, inhibition of PLD results in higher levels of Tau and p62 aggregates in organotypic brain slices. Our in vitro and in vivo findings establish a role for PLD1 in autophagy. Source


Aparicio S.,University of British Columbia | Hidalgo M.,Gastrointestinal Cancer Clinical Research Unit | Kung A.L.,Columbia University
Nature Reviews Cancer | Year: 2015

Patient-derived xenograft (PDX) models are now being widely used in cancer research and have the potential to greatly inform our understanding of cancer biology. However, many questions remain, especially regarding the ability of PDX models to affect clinical decision making. With these points in mind, we asked three scientists to give their opinions on the generation and uses of PDX models and the future of this field. © 2015 Macmillan Publishers Limited. All rights reserved. Source


Beloborodov A.M.,Columbia University
Astrophysical Journal | Year: 2013

Observations indicate that the peak of a gamma-ray burst spectrum forms in the opaque region of an ultrarelativistic jet. Recent radiative transfer calculations support this picture and show that the spectral peak is inherited from initially thermal radiation, which is changed by heating into a broad photon distribution with a high-energy tail. We discuss the processes that regulate the observed position of the spectral peak Epk. The opaque jet has three radial zones: (1) the Planck zone r < RP where a blackbody spectrum is enforced; this zone ends where the Thomson optical depth decreases to τ ≈ 105, (2) the Wien zone RP < r < RW with a Kompaneets parameter y ≫ 1 where radiation has a Bose-Einstein spectrum, and (3) the Comptonization zone r > RW where the radiation spectrum develops a high-energy tail. Besides the initial jet temperature, an important factor regulating Epk is internal dissipation (of bulk motions and magnetic energy) at large distances from the central engine. Dissipation in the Planck zone reduces Epk, and dissipation in the Wien zone can increase Epk. In jets with subdominant magnetic fields, the predicted Epk varies around 1 MeV up to a maximum value of about 10 MeV. If the jet carries an energetically important magnetic field, Epk can be additionally increased by dissipation of magnetic energy. This increase is suggested by observations, which show Epk up to about 20 MeV. We also consider magnetically dominated jets; then a simple model of magnetic dissipation gives Epk ≈ 30 ΓW keV where ΓW is the jet Lorentz factor at the Wien radius RW. © 2013. The American Astronomical Society. All rights reserved. Source


Naeem S.,Columbia University | Duffy J.E.,Virginia Institute of Marine Science | Zavaleta E.,University of California at Santa Cruz
Science | Year: 2012

Ecosystems worldwide are rapidly losing taxonomic, phylogenetic, genetic, and functional diversity as a result of human appropriation of natural resources, modification of habitats and climate, and the spread of pathogenic, exotic, and domestic plants and animals. Twenty years of intense theoretical and empirical research have shown that such biotic impoverishment can markedly alter the biogeochemical and dynamic properties of ecosystems, but frontiers remain in linking this research to the complexity of wild nature, and in applying it to pressing environmental issues such as food, water, energy, and biosecurity. The question before us is whether these advances can take us beyond merely invoking the precautionary principle of conserving biodiversity to a predictive science that informs practical and specific solutions to mitigate and adapt to its loss. Source


We use a diagrammatic approach to study color-neutral heavy particle production in nucleus-nucleus collisions in a quasi-classical approximation without small-x evolution. In order to treat the two nuclei symmetrically, we use the Coulomb gauge which gives the appropriate light cone gauge for each nucleus. The resulting cross section is factorized into a product of two Weizsäcker-Williams gluon distributions of the two nuclei when the transverse momentum of the produced scalar particle is around the saturation momentum. We confirm our results in covariant gauge where the transverse momentum broadening of hard gluons can be described as a diffusion process. The transverse momentum factorization manifests itself in light cone gauge but not so clearly in covariant gauge. © 2012 Elsevier B.V. Source


Marshall B.D.L.,Brown University | Galea S.,Columbia University
American Journal of Epidemiology | Year: 2015

Calls for the adoption of complex systems approaches, including agent-based modeling, in the field of epidemiology have largely centered on the potential for such methods to examine complex disease etiologies, which are characterized by feedback behavior, interference, threshold dynamics, and multiple interacting causal effects. However, considerable theoretical and practical issues impede the capacity of agent-based methods to examine and evaluate causal effects and thus illuminate new areas for intervention. We build on this work by describing how agent-based models can be used to simulate counterfactual outcomes in the presence of complexity. We show that these models are of particular utility when the hypothesized causal mechanisms exhibit a high degree of interdependence between multiple causal effects and when interference (i.e., one person's exposure affects the outcome of others) is present and of intrinsic scientific interest. Although not without challenges, agent-based modeling (and complex systems methods broadly) represent a promising novel approach to identify and evaluate complex causal effects, and they are thus well suited to complement other modern epidemiologic methods of etiologic inquiry. © 2014 The Author. Source


Costantini F.,Columbia University
Wiley Interdisciplinary Reviews: Developmental Biology | Year: 2012

The mammalian kidney, which at maturity contains thousands of nephrons joined to a highly branched collecting duct (CD) system, is an important model system for studying the development of a complex organ. Furthermore, congenital anomalies of the kidney and urinary tract, often resulting from defects in ureteric bud branching morphogenesis, are relatively common human birth defects. Kidney development is initiated by interactions between the nephric duct and the metanephric mesenchyme, leading to the outgrowth and repeated branching of the ureteric bud epithelium, which gives rise to the entire renal CD system. Meanwhile, signals from the ureteric bud induce the mesenchyme cells to form the nephron epithelia. This review focuses on development of the CD system, with emphasis on the mouse as an experimental system. The major topics covered include the origin and development of the nephric duct, formation of the ureteric bud, branching morphogenesis of the ureteric bud, and elongation of the CDs. The signals, receptors, transcription factors, and other regulatory molecules implicated in these processes are discussed. In addition, our current knowledge of cellular behaviors that are controlled by these genes and underlie development of the collecting system is reviewed. © 2012 Wiley Periodicals, Inc. Source


Urpelainen J.,Columbia University
Energy for Sustainable Development | Year: 2014

In many developing countries, the national electricity grid fails to provide rural communities with a reliable supply of electricity. Given the high socio-economic cost of this policy failure, both scholars and policymakers have recently become interested in off-grid electrification programs. However, the relationship between national grid expansion and off-grid electrification remains unclear. Are these two approaches independent of each other, or perhaps even competitors? This article develops a taxonomy that allows grid expansion and off-grid electrification to complement each other. Explicit policy integration is necessary to encourage investment in off-grid electrification and avoid duplication of effort. Otherwise, there is a danger that the poorest and geographically most remote segments of the rural population could be left outside electrification efforts. As an illustration, the article offers a case study of India. © 2013 International Energy Initiative. Source


Wright J.D.,Columbia University
Obstetrics and Gynecology | Year: 2011

Objective: To estimate the effects of surgeon and hospital volume on perioperative morbidity and mortality in women who underwent hysterectomy for endometrial cancer. Methods:Patients who underwent abdominal hysterectomy for endometrial cancer between 2003 and 2007 and who recorded in an inpatient, acute-care database were examined. Procedure-associated intraoperative, perioperative, and postoperative medical complications, as well as hospital readmission, length of stay, intensive care unit (ICU) use, and mortality were examined. Surgeons and hospitals were stratified into volume-based tertiles and outcomes analyzed using multivariable, generalized estimating equations. Rssults: A total of 6,015 women were identified. After adjustment for case-mix variables and hospital volume, perioperative surgical complications (15.2% compared with 11.7%) (odds ratio [OR] 0.57; 95 confidence interval [CI] 0.38-0.85), medical complications (31.4% compared with 22.0%) (OR 0.57; 95% CI 0.37-0.88), and ICU utilization (8.9% compared with 3.5%) (OR 0.47; 95% CI 0.28-0.80) were lower in patients treated by high-volume surgeons. Surgeon volume had no independent effect on the rates of operative injury (OR 0.82; 95% CI 0.32-2.08), transfusion (OR 2.33; 95% CI 0.93-5.36), length of stay (OR 0.60; 95% CI 0.25-1.41), or readmission (OR 1.05; 95% CI 0.51-2.14). Whereas patients treated at high-volume hospitals were less likely to require ICU care (9.3% compared with 4.3%) (OR 0.44; 95% CI 025-0.77), hospital volume had no independent effect on any of the other primary outcomes of interest (P>.05 for all). CONCLUSION:: Perioperative surgical complications, medical complications, and ICU requirements are lower in patients treated by high-volume surgeons. Hospital volume had little independent effect on outcomes. © 2011 The American College of Obstetricians and Gynecologists. Source


Lobell D.B.,Stanford University | Schlenker W.,Columbia University | Schlenker W.,National Bureau of Economic Research | Costa-Roberts J.,Stanford University
Science | Year: 2011

Efforts to anticipate how climate change will affect future food availability can benefit from understanding the impacts of changes to date. We found that in the cropping regions and growing seasons of most countries, with the important exception of the United States, temperature trends from 1980 to 2008 exceeded one standard deviation of historic year-to-year variability. Models that link yields of the four largest commodity crops to weather indicate that global maize and wheat production declined by 3.8 and 5.5%, respectively, relative to a counterfactual without climate trends. For soybeans and rice, winners and losers largely balanced out. Climate trends were large enough in some countries to offset a significant portion of the increases in average yields that arose from technology, carbon dioxide fertilization, and other factors. Source


Steinberg S.F.,Columbia University
Physiology | Year: 2012

Protein kinase C (PKC) isoforms have emerged as important regulators of cardiac contraction, hypertrophy, and signaling pathways that influence ischemic/reperfusion injury. This review focuses on newer concepts regarding PKC isoform-specific activation mechanisms and actions that have implications for the development of PKC-targeted therapeutics. © 2012 Int. Union Physiol. Sci./Am. Physiol. Soc. Source


Lobo R.A.,Columbia University
Journal of Clinical Endocrinology and Metabolism | Year: 2013

The media attention surrounding the publication of the initial results of WHI in 2002 led to fear and confusion regarding the use of hormonal therapy (HT) after menopause. This led to a dramatic reduction in prescriptions for HT in the United States and around the world. Although in 2002 it was stated that the results pertained to all women receiving HT, subsequent studies from the Women's Health Initiative (WHI) and others clearly showed that younger women and those close to menopause had a very beneficial risk-to-benefit ratio. Indeed, the results showed similar protective effects for coronary disease and a reduction in mortality that had been shown in earlier observational studies, which had also focused on younger symptomatic women. In younger women, the increased number of cases of venous thrombosis and ischemic stroke was low, rendering them "rare" events using World Health Organization nomenclature. Breast cancer rates were also low and were found to be decreased with estrogen alone. In women receiving estrogen and progestogen for the first time in the WHI, breast cancer rates did not increase significantly for 7 years. Other data suggest that other regimens and the use of other progestogens may also be safer. It has been argued that in the 10 years since WHI, many women have been denied HT, including those with severe symptoms, and that this has significantly disadvantaged a generation of women. Some reports have also suggested an increased rate of osteoporotic fractures since the WHI. Therefore, the question is posed as to whether we have now come full circle in our understanding of the use of HT in younger women. Although it is appropriate to treat women with symptoms at the onset of menopause, because there is no proven therapy for primary prevention, in some women the use of HT for this role may at least be entertained. Copyright © 2013 by The Endocrine Society. Source


Javitt D.C.,Columbia University
Handbook of Experimental Pharmacology | Year: 2012

Schizophrenia is a severe neuropsychiatric disorder without adequate current treatment. Recent theories of schizophrenia focus on disturbances of glutamatergic neurotransmission particularly at N-methyl-d-aspartate (NMDA)-type glutamate receptors. NMDA receptors are regulated in vivo by the amino acids glycine and d-serine. Glycine levels, in turn, are regulated by glycine type I (GlyT1) transporters, which serve to maintain low subsaturating glycine levels in the vicinity of the NMDA receptor. A proposed approach to treatment of schizophrenia, therefore, is inhibition of GlyT1-mediated transport. Over the past decade, several well tolerated, high affinity GlyT1 inhibitors have been developed and shown to potentiate NMDA receptor-mediated neurotransmission in animal models relevant to schizophrenia. In addition, clinical trials have been conducted with sarcosine (N-methylglycine), a naturally occurring GlyT1 inhibitor, and with the high affinity compound RG1678. Although definitive trials remain ongoing, encouraging results to date have been reported. © 2012 Springer-Verlag Berlin Heidelberg. Source


Mann J.J.,Columbia University
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2013

A stress-diathesis explanatory model of suicidal behaviour has proved to be of heuristic value, and both clinical and neurobiological components can be integrated into such a model. A trait deficiency in serotonin input to the anterior cingulate and ventromedial prefrontal cortex is found in association with suicide, and more recently non-fatal suicidal behaviour, and is linked to decision-making and suicide intent by imaging and related studies in vivo. The same neural circuitry and serotonin deficiency may contribute to impulsive aggressive traits that are part of the diathesis for suicidal behaviour and are associated with early onset mood disorders and greater risk for suicidal behaviour. Other brain areas manifest deficient serotonin input, that is, a trait related to recurrent major depressive disorder and bipolar disorder. Thus the serotonin system is involved in both the diathesis for suicidal behaviour in terms of decision-making, and to a major stressor, namely episodes of major depression. Source


Walsh K.,Columbia University
Journal of general internal medicine | Year: 2014

Reserve and National Guard (NG) soldiers report disproportionate mental health problems relative to active duty military upon returning from the Iraq and Afghanistan conflicts. However, few studies have examined whether exposure to particular types of traumatic events (e.g., lifetime sexual violence) is associated with this increased burden of psychopathology. The current study examined the prevalence of lifetime sexual violence exposure as well as the adjusted odds and population attributable fraction of psychopathology associated with sexual violence in a large sample of male and female Reserve and NG soldiers. Baseline structured telephone interviews were conducted in 2009. 1,030 Reserve (23 % female) and 973 NG (15 % female) soldiers. Four items assessed lifetime and deployment-related sexual violence. Probable lifetime and past-year posttraumatic stress disorder (PTSD) and depression were assessed with the PTSD Checklist and the Patient Health Questionnaire, respectively. Lifetime sexual violence prevalence was 37.4 % and 27.6 % among Reserve and NG women, and 4.3 % and 3.7 % among Reserve and NG men, respectively. Recent deployment-related sexual violence ranged from 1.4 to 2.6 % for women and 0 % for men. Regression analyses indicated that the adjusted odds of probable past-year and lifetime PTSD and depression were 1.2 to 3.5 times greater among those reporting sexual violence relative to non-victims. The proportion of probable lifetime PTSD and depression attributable to sexual violence was 45.2 % and 16.6 %, respectively, in the Reserves, and 10.3 % and 6.2 %, respectively, in the NG. Lifetime sexual violence prevalence was high among female soldiers, with approximately one-third of Reserve and National Guard women reporting a history. The majority of sexual violence was not related to the most recent deployment; however, sexual violence contributed to a high burden of psychopathology. Findings emphasize a need to screen for lifetime sexual violence and associated mental disorders in military samples. Source


Steinberg S.F.,Columbia University
Circulation Research | Year: 2013

Oxidative stress accompanies a wide spectrum of clinically important cardiac disorders, including ischemia/reperfusion, diabetes mellitus, and hypertensive heart disease. Although reactive oxygen species (ROS) can activate signaling pathways that contribute to ischemic preconditioning and cardioprotection, high levels of ROS induce structural modifications of the sarcomere that impact on pump function and the pathogenesis of heart failure. However, the precise nature of the redox-dependent change in contractility is determined by the source/identity of the oxidant species, the level of oxidative stress, and the chemistry/position of oxidant-induced posttranslational modifications on individual proteins within the sarcomere. This review focuses on various ROS-induced posttranslational modifications of myofilament proteins (including direct oxidative modifications of myofilament proteins, myofilament protein phosphorylation by ROS-activated signaling enzymes, and myofilament protein cleavage by ROS-activated proteases) that have been implicated in the control of cardiac contractility. © 2012 American Heart Association, Inc. Source


Yang I.-S.,Columbia University
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2012

Slowroll after tunneling is a crucial step in one popular framework of the multiverse-false vacuum eternal inflation. In a landscape with a large number of fields, we provide a heuristic estimation for its probability. We find that the chance to slowroll is exponentially suppressed, where the exponent comes from the number of fields. However, the relative probability to have more e-foldings is only mildly suppressed as Ne-α with α∼3. Based on these two properties, we show that the false vacuum eternal inflation picture is still self-consistent and may have a strong preference between different slowroll models. © 2012 American Physical Society. Source


No prospective studies exist on the relationship between change in periodontal clinical and microbiological status and progression of carotid atherosclerosis. The Oral Infections and Vascular Disease Epidemiology Study examined 420 participants at baseline (68 ± 8 years old) and follow-up. Over a 3-year median follow-up time, clinical probing depth (PD) measurements were made at 75 766 periodontal sites, and 5008 subgingival samples were collected from dentate participants (average of 7 samples/subject per visit over 2 visits) and quantitatively assessed for 11 known periodontal bacterial species by DNA-DNA checkerboard hybridization. Common carotid artery intima-medial thickness (CCA-IMT) was measured using high-resolution ultrasound. In 2 separate analyses, change in periodontal status (follow-up to baseline), defined as (1) longitudinal change in the extent of sites with a ≥ 3-mm probing depth (Δ%PD ≥ 3) and (2) longitudinal change in the relative predominance of bacteria causative of periodontal disease over other bacteria in the subgingival plaque (Δetiologic dominance), was regressed on longitudinal CCA-IMT progression adjusting for age, sex, race/ethnicity, diabetes, smoking status, education, body mass index, systolic blood pressure, and low-density lipoprotein cholesterol and high-density lipoprotein cholesterol. Mean (SE) CCA-IMT increased during follow-up by 0.139 ± 0.008 mm. Longitudinal IMT progression attenuated with improvement in clinical or microbial periodontal status. Mean CCA-IMT progression varied inversely across quartiles of longitudinal improvement in clinical periodontal status (Δ%PD ≥ 3) by 0.18 (0.02), 0.16 (0.01), 0.14 (0.01), and 0.07 (0.01) mm (P for trend<0.0001). Likewise, mean CCA-IMT increased by 0.20 (0.02), 0.18 (0.02), 0.15 (0.02), and 0.12 (0.02) mm (P<0.0001) across quartiles of longitudinal improvement in periodontal microbial status (Δetiologic dominance). Longitudinal improvement in clinical and microbial periodontal status is related to a decreased rate of carotid artery IMT progression at 3-year average follow-up. Source


Purpose To review data for ophthalmologists published online from the Physician Payments Sunshine Act. Design Retrospective data review using data acquired from a publicly available electronic database. Methods A database was downloaded from the Centers for Medicare and Medicaid Services website under Identified General Payments to Physicians and a primary specialty of ophthalmology. Basic statistical analysis was performed including mean, median, and range of payments for both single payments and per provider. Main Outcome Measures Data summary by category of payment and geographic region and comparison with other surgical subspecialties. Results From August 1, 2013, through December 31, 2013, a total of 55 996 individual payments were reported to 9855 ophthalmologists for a total of $10 926 447. The mean amount received in a single payment was $195.13 (range, $0.04-$193 073). The mean amount received per physician identifier (ID) was $1108 (range, $1-$397 849), and the median amount was $112.01. Consulting fees made up the largest percentage of fees. There was not a large difference in payments received by region. The mean payments for the subspecialties of dermatology, neurosurgery, orthopedic surgery, and urology ranged from $954 to $6980, and median payments in each field by physician ID ranged from $88 to $173. Conclusions A large amount of data were released by the Centers for Medicare and Medicaid Services for the Physician Payment Sunshine Act. In ophthalmology, mean and median payments per physician did not vary greatly from other surgical subspecialties. Most single payments were less than $100, and most physicians received less than $500 in total payments. Payments for consulting made up the largest category of spending. How this affects patient perception, patient care, and medical costs warrants further study. © 2015 American Academy of Ophthalmology. Source


Ludwig D.S.,Childrens Hospital Boston | Currie J.,Columbia University
The Lancet | Year: 2010

Background Excessive weight gain during pregnancy seems to increase birthweight and the offspring's risk of obesity later in life. However, this association might be confounded by genetic and other shared effects. We aimed to examine the association between maternal weight gain and birthweight using state-based birth registry data that allowed us to compare several pregnancies in the same mother. Methods In this population-based cohort study, we used vital statistics natality records to examine all known births in Michigan and New Jersey, USA, between Jan 1, 1989, and Dec 31, 2003. From an initial sample of women with more than one singleton birth in the database, we made the following exclusions: gestation less than 37 weeks or 41 weeks or more; maternal diabetes; birthweight less than 500 g or more than 7000 g; and missing data for pregnancy weight gain. We examined how differences in weight gain that occurred during two or more pregnancies for each woman predicted the birthweight of her offspring, using a within-subject design to reduce confounding to a minimum. Findings Our analysis included 513 501 women and their 1 164 750 offspring. We noted a consistent association between pregnancy weight gain and birthweight (β 7·35, 95 CI 7·10-7·59, p<0·0001). Infants of women who gained more than 24 kg during pregnancy were 148·9 g (141·7-156·0) heavier at birth than were infants of women who gained 8-10 kg. The odds ratio of giving birth to an infant weighing more than 4000 g was 2·26 (2·09-2·44) for women who gained more than 24 kg during pregnancy compared with women who gained 8-10 kg. Interpretation Maternal weight gain during pregnancy increases birthweight independently of genetic factors. In view of the apparent association between birthweight and adult weight, obesity prevention efforts targeted at women during pregnancy might be beneficial for offspring. Funding US National Institutes of Health. © 2010 Elsevier Ltd. Source


Defects in Membrane Frizzled-related Protein (MFRP) cause autosomal recessive retinitis pigmentosa (RP). MFRP codes for a retinal pigment epithelium (RPE)-specific membrane receptor of unknown function. In patient-specific induced pluripotent stem (iPS)-derived RPE cells, precise levels of MFRP, and its dicistronic partner CTRP5, are critical to the regulation of actin organization. Overexpression of CTRP5 in naïve human RPE cells phenocopied behavior of MFRP-deficient patient RPE (iPS-RPE) cells. AAV8 (Y733F) vector expressing human MFRP rescued the actin disorganization phenotype and restored apical microvilli in patient-specific iPS-RPE cell lines. As a result, AAV-treated MFRP mutant iPS-RPE recovered pigmentation and transepithelial resistance. The efficacy of AAV-mediated gene therapy was also evaluated in Mfrprd6/Mfrprd6 mice-an established preclinical model of RP-and long-term improvement in visual function was observed in AAV-Mfrp-treated mice. This report is the first to indicate the successful use of human iPS-RPE cells as a recipient for gene therapy. The observed favorable response to gene therapy in both patient-specific cell lines, and the Mfrprd6/Mfrprd6 preclinical model suggests that this form of degeneration caused by MFRP mutations is a potential target for interventional trials.Molecular Therapy (2014); doi:10.1038/mt.2014.100. Source


Anastasian Z.H.,Columbia University
British Journal of Anaesthesia | Year: 2014

Anaesthetic management of the acute stroke patient demands consideration of the penumbra as the central focus. Recent studies have shown that patients who receive general anaesthesia for endovascular therapy for acute ischaemic stroke have worse outcomes than those who receive local anaesthesia. Although baseline condition of the patients in these studies differed, we should heed the warnings evident in the results. 'Time is brain': therapy should be quickly provided. Arterial pressure should be monitored carefully upon induction, avoiding a drastic reduction, and allowing for a reduction in arterial pressure upon recanalization. Keeping these factors in mind, anaesthetic technique (general, monitored anaesthesia care, or local) must be selected considering the individual patient's risks and benefits. Unfortunately, there are no proven neuroprotective strategies to date for use in acute ischaemic stroke. © The Author 2014. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. Source


Tinoco Jr. I.,University of California at Berkeley | Gonzalez Jr. R.L.,Columbia University
Genes and Development | Year: 2011

The last 15 years have witnessed the development of tools that allow the observation and manipulation of single molecules. The rapidly expanding application of these technologies for investigating biological systems of ever-increasing complexity is revolutionizing our ability to probe the mechanisms of biological reactions. Here, we compare the mechanistic information available from single-molecule experiments with the information typically obtained from ensemble studies and show how these two experimental approaches interface with each other. We next present a basic overview of the toolkit for observing and manipulating biology one molecule at a time. We close by presenting a case study demonstrating the impact that single-molecule approaches have had on our understanding of one of life's most fundamental biochemical reactions: the translation of a messenger RNA into its encoded protein by the ribosome. © 2011 by Cold Spring Harbor Laboratory Press. Source


Attia E.,Columbia University
Annual Review of Medicine | Year: 2010

Anorexia nervosa (AN) is a serious mental illness categorized by a failure to maintain a minimally normal weight, a fear of gaining weight or becoming fat, and preoccupations about body shape or weight. AN is associated with significant morbidity and a mortality rate as high as that seen in any psychiatric illness. Biological factors, including genetic predisposition, appear to play a role in the development of AN. Treatment is challenging both because interventions with clear empirical support have not been identified and because individuals affected by AN are typically reluctant to undergo weight restoration. Preliminary studies suggest that family-based treatment may be useful for younger patients with AN. Treatment development for adults with AN and pursuit of neurobiological correlates of AN remain high-priority research areas. © 2010 by Annual Reviews All rights reserved. Source


Schwabe R.F.,Columbia University | Jobin C.,University of Florida
Nature Reviews Cancer | Year: 2013

Microbiota and host form a complex 'super-organism' in which symbiotic relationships confer benefits to the host in many key aspects of life. However, defects in the regulatory circuits of the host that control bacterial sensing and homeostasis, or alterations of the microbiome, through environmental changes (infection, diet or lifestyle), may disturb this symbiotic relationship and promote disease. Increasing evidence indicates a key role for the bacterial microbiota in carcinogenesis. In this Opinion article, we discuss links between the bacterial microbiota and cancer, with a particular focus on immune responses, dysbiosis, genotoxicity, metabolism and strategies to target the microbiome for cancer prevention. © 2013 Macmillan Publishers Limited. All rights reserved. Source


Canzio D.,Columbia University | Larson A.,University of California at San Francisco | Narlikar G.J.,University of California at San Francisco
Trends in Cell Biology | Year: 2014

Heterochromatin protein 1 (HP1) proteins were originally identified as critical components in heterochromatin-mediated gene silencing and are now recognized to play essential roles in several other processes including gene activation. Several eukaryotes possess more than one HP1 paralog. Despite high sequence conservation, the HP1 paralogs achieve diverse functions. Further, in many cases, the same HP1 paralog is implicated in multiple functions. Recent biochemical studies have revealed interesting paralog-specific biophysical differences and unanticipated conformational versatility in HP1 proteins that may account for this functional promiscuity. Here we review these findings and describe a molecular framework that aims to link the conformational flexibility of HP1 proteins observed in vitro with their functional promiscuity observed in vivo. © 2014 Elsevier Ltd. Source


Van Heeringen K.,Ghent University | Mann J.J.,Columbia University
The Lancet Psychiatry | Year: 2014

The stress-diathesis model posits that suicide is the result of an interaction between state-dependent (environmental) stressors and a trait-like diathesis or susceptibility to suicidal behaviour, independent of psychiatric disorders. Findings from post-mortem studies of the brain and from genomic and in-vivo neuroimaging studies indicate a biological basis for this diathesis, indicating the importance of neurobiological screening and interventions, in addition to cognitive and mood interventions, in the prevention of suicide. Early-life adversity and epigenetic mechanisms might explain some of the link between suicide risk and brain circuitry and neurochemistry abnormalities. Results from a range of studies using diverse designs and post-mortem and in-vivo techniques show impairments of the serotonin neurotransmitter system and the hypothalamic-pituitary-adrenal axis stress-response system in the diathesis for suicidal behaviour. These impairments manifest as impaired cognitive control of mood, pessimism, reactive aggressive traits, impaired problem solving, over-reactivity to negative social signs, excessive emotional pain, and suicidal ideation, leading to suicidal behaviour. Biomarkers related to the diathesis might help to inform risk-assessment procedures and treatment choice in the prevention of suicide. © 2014 Elsevier Ltd. Source


Liver resection in patients with underlying liver disease remains a formidable challenge. It requires adequate patient selection, a precise surgical plan, and avoidance of additional ischemic insults during surgery. Precise estimation of the residual liver volume using computed tomography or magnetic resonance imaging and computer-assisted volumetry allows the calculation of residual to total liver volume (RLV/TLV) ratios. Although RLV/TLV ratios over 20 to 25% are considered sufficient in healthy livers, patients with cirrhosis may only tolerate resections that result in RLV/TLV ratios over 40% and higher. Conventional laboratory tests may not be able to sufficiently predict liver reserve after resection. Dynamic tests such as indocyanine green clearance have been used to assess residual liver function and assist in deciding about operability of patients with underlying liver disease undergoing extensive resections. Intraoperative management should focus on avoiding blood loss and ischemic injury to the liver. Low central venous pressure may reduce blood loss and is recommended if tolerated without impeding renal perfusion. Portal vein and hepatic artery occlusion during resection can reduce blood loss, but will cause ischemic insult to the liver that may jeopardize residual liver function and induce postoperative hepatic failure. When feasible, vascular occlusion should be avoided in patients with underlying liver disease. The postoperative recovery is usually fast if sufficient liver remains. However, vigilance is required to detect liver dysfunction and treat its complications. © 2013 by Thieme Medical Publishers, Inc. Source


Ivanov I.I.,Columbia University | Littman D.R.,Howard Hughes Medical Institute
Current Opinion in Microbiology | Year: 2011

Intestinal bacteria form a resident community that has co-evolved with the mammalian host. In addition to playing important roles in digestion and harvesting energy, commensal bacteria are crucial for the proper functioning of mucosal immune defenses. Most of these functions have been attributed to the presence of large numbers of 'innocuous' resident bacteria that dilute or occupy niches for intestinal pathogens or induce innate immune responses that sequester bacteria in the lumen, thus quenching excessive activation of the mucosal immune system. However it has recently become obvious that commensal bacteria are not simply beneficial bystanders, but are important modulators of intestinal immune homeostasis and that the composition of the microbiota is a major factor in pre-determining the type and robustness of mucosal immune responses. Here we review specific examples of individual members of the microbiota that modify innate and adaptive immune responses, and we focus on potential mechanisms by which such species-specific signals are generated and transmitted to the host immune system. © 2010 Elsevier Ltd. Source


Recent research has found that children who attended pre-kindergarten programs in childhood were more likely to be healthy as adults. One intuitive way of improving population health and longevity may therefore be to invest in pre-kindergarten programs. However, much of the research linking pre-kindergarten programs to health is very recent and has not been synthesized. In this paper, I review the mechanisms linking pre-kindergarten programs in childhood to adult longevity, and the experimental evidence backing up these linkages. I conclude with a critical exploration of whether investments in pre-kindergarten programs could also serve as investments in public health. © 2014 Elsevier Ltd. Source


Califano A.,Columbia University
Molecular Systems Biology | Year: 2011

This is an open-access article distributed under the terms of the Creative Commons Attribution Noncommercial No Derivative Works 3.0 Unported License, which permits distribution and reproduction in any medium,provided the original author and source are credited.This license does not permit commercial exploitation or the creation of derivativeworks without specific permission. © 2011 EMBO and Macmillan Publishers Limited. All rights reserved. Source


Laugesen M.J.,Columbia University
Chest | Year: 2014

Most physicians are unfamiliar with the details of the Resource-Based Relative Value Scale (RBRVS) and how changes in the RBRVS influence Medicare and private reimbursement rates. Physicians in a wide variety of settings may benefit from understanding the RBRVS, including physicians who are employees, because many organizations use relative value units as productivity measures. Despite the complexity of the RBRVS, its logic and ideal are simple: In theory, the resource usage (comprising physician work, practice expense, and liability insurance premium costs) for one service is relative to the resource usage of all others. Ensuring relativity when new services are introduced or existing services are changed is, therefore, critical. Since the inception of the RBRVS, the American Medical Association's Relative Value Scale Update Committee (RUC) has made recommendations to the Centers for Medicare & Medicaid Services on changes to relative value units. The RUC's core focus is to develop estimates of physician work, but work estimates also partly determine practice expense payments. Critics have attributed various health-care system problems, including declining and growing gaps between primary care and specialist incomes, to the RUC's role in the RBRVS update process. There are persistent concerns regarding the quality of data used in the process and the potential for services to be overvalued. The Affordable Care Act addresses some of these concerns by increasing payments to primary care physicians, requiring reevaluation of the data underlying work relative value units, and reviewing misvalued codes. © 2014 American College of Chest Physicians. Source


Huey E.D.,Columbia University
Neurobiology of aging | Year: 2012

This study aimed to evaluate genetic variability in the FUS and TDP-43 genes, known to be mainly associated with amyotrophic lateral sclerosis (ALS), in patients with the diagnoses of frontotemporal lobar degeneration (FTLD) and corticobasal syndrome (CBS). We screened the DNA of 228 patients for all the exons and flanking introns of FUS and TDP-43 genes. We identified 2 novel heterozygous missense mutations in FUS: P106L (g.22508384C>T) in a patient with behavioral variant frontotemporal dementia (bvFTD) and Q179H in several members of a family with behavioral variant FTD. We also identified the N267S mutation in TDP-43 in a CBS patient, previously only reported in 1 ALS family and 1 FTD patient. Additionally, we identified 2 previously reported heterozygous insertion and deletion mutations in Exon 5 of FUS; Gly174-Gly175 del GG (g. 4180-4185 delGAGGTG) in an FTD patient and Gly175-Gly176 ins GG (g. 4185-4186 insGAGGTG) in a patient with diagnosis of CBS. Not least, we have found a series of variants in FUS also in neurologically normal controls. In summary, we report that genetic variability in FUS and TDP-43 encompasses a wide range of phenotypes (including ALS, FTD, and CBS) and that there is substantial genetic variability in FUS gene in neurologically normal controls. Copyright © 2012 Elsevier Inc. All rights reserved. Source


Al-Bassam J.,University of California at Davis | Chang F.,Columbia University
Trends in Cell Biology | Year: 2011

The molecular mechanisms by which microtubule-associated proteins (MAPs) regulate the dynamic properties of microtubules (MTs) are still poorly understood. We review recent advances in our understanding of two conserved families of MAPs, the XMAP215/Dis1 and CLASP family of proteins. In vivo and in vitro studies show that XMAP215 proteins act as microtubule polymerases at MT plus ends to accelerate MT assembly, and CLASP proteins promote MT rescue and suppress MT catastrophe events. These are structurally related proteins that use conserved TOG domains to recruit tubulin dimers to MTs. We discuss models for how these proteins might use these individual tubulin dimers to regulate dynamic behavior of MT plus ends. © 2011 Elsevier Ltd. Source


LaCour M.J.,University of California at Los Angeles | Green D.P.,Columbia University
Science | Year: 2014

Can a single conversation change minds on divisive social issues, such as same-sex marriage? A randomized placebo-controlled trial assessed whether gay (n = 22) or straight (n = 19) messengers were effective at encouraging voters (n = 972) to support same-sex marriage and whether attitude change persisted and spread to others in voters' social networks. The results, measured by an unrelated panel survey, show that both gay and straight canvassers produced large effects initially, but only gay canvassers' effects persisted in 3-week, 6-week, and 9-month follow-ups.We also find strong evidence of within-household transmission of opinion change, but only in the wake of conversations with gay canvassers. Contact with gay canvassers further caused substantial change in the ratings of gay men and lesbians more generally. These large, persistent, and contagious effects were confirmed by a follow-up experiment. Contact with minorities coupled with discussion of issues pertinent to them is capable of producing a cascade of opinion change. Source


Keromytis A.D.,Columbia University
IEEE Communications Surveys and Tutorials | Year: 2012

We present a comprehensive survey of Voice over IP security academic research, using a set of talpubs publications forming a closed cross-citation set. We classify these papers according to an extended version of the VoIP Security Alliance (VoIPSA) Threat Taxonomy. Our goal is to provide a roadmap for researchers seeking to understand existing capabilities and to identify gaps in addressing the numerous threats and vulnerabilities present in VoIP systems. We discuss the implications of our findings with respect to vulnerabilities reported in a variety of VoIP products. We identify two specific problem areas (denial of service, and service abuse) as requiring significant more attention from the research community. We also find that the overwhelming majority of the surveyed work takes a black box view of VoIP systems that avoids examining their internal structure and implementation. Such an approach may miss the mark in terms of addressing the main sources of vulnerabilities, i.e., implementation bugs and misconfigurations. Finally, we argue for further work on understanding cross-protocol and cross-mechanism vulnerabilities (emergent properties), which are the byproduct of a highly complex system-of-systems and an indication of the issues in future large-scale systems. © 1998-2012 IEEE. Source


Understanding the molecular pathogenesis of lymphoma has led to paradigm-changing treatment opportunities. One example involves tailoring specific agents based on the cell of origin in aggressive lymphomas. Germinal center (GC)-derived diffuse large B-cell lymphoma (DLBCL) is known to be driven by an addiction to Bcl6, whereas the activated B-cell (ABC) subtype is driven by nuclear factor κB. In the GC subtype, there is a critical inverse relationship between Bcl6 and p53, the functional status of which is linked to each transcription factor's degree of acetylation. Deacetylation of Bcl6 is required for its transcriptional repressor effects allowing for the oncogene to drive lymphomagenesis. Conversely, acetylation of p53 is activating when class III deacetylases (DACs), or sirtuins, are inhibited by niacinamide. Treatment of DLBCL cell lines with pan-DAC inhibitors in combination with niacinamide produces synergistic cytotoxicity in GC over ABC subtypes. This correlated with acetylation of both Bcl6 and p53. This combination also produced remissions in a spontaneous aggressive B-cell lymphoma mouse model expressing Bcl6. In a phase 1 proof-of-principle clinical trial, 24% of patients with relapsed or refractory lymphoma attained a response to vorinostat and niacinamide, and 57% experienced disease stabilization. We report herein on the preclinical and clinical activity of this targeted strategy in aggressive lymphomas. This trial was registered at www.clinicaltrials.gov as #NCT00691210. Source


Kuperman G.J.,Columbia University
Journal of the American Medical Informatics Association | Year: 2011

Health-information exchange, that is, enabling the interoperability of automated health data, can facilitate important improvements in healthcare quality and efficiency. A vision of interoperability and its benefits was articulated more than a decade ago. Since then, important advances toward the goal have been made. The advent of the Health Information Technology for Economic and Clinical Health Act and the meaningful use program is already having a significant impact on the direction that health-information exchange will take. This paper describes how interoperability activities have unfolded over the last decade and explores how recent initiatives are likely to affect the directions and benefits of health-information exchange. Source


Rubin M.R.,Columbia University
Current Osteoporosis Reports | Year: 2015

Substantial evidence exists that in addition to the well-known complications of diabetes, increased fracture risk is an important morbidity. This risk is probably due, at least in part, to altered bone remodeling and bone cell function in diabetes. Circulating biochemical markers of bone formation, including P1NP, osteocalcin and bone-specific alkaline phosphatase have been found to be decreased in type 2 diabetes (T2D) and may be predictive of fractures independently of bone mineral density (BMD). These findings have been corroborated by preliminary histomorphometric data. Reductions in the bone resorption marker serum CTx in T2D have also been reported. Serum sclerostin levels have been found to be increased in T2D and appear to be predictive of fracture risk independent of BMD. Other factors such as bone marrow fat saturation, advanced glycation endproduct (AGE) accumulation, and microarchitectural changes might also relate to bone cell function and fracture risk in diabetes. © 2015, Springer Science+Business Media New York. Source


Fahn S.,Columbia University
Movement Disorders | Year: 2015

It took exactly 150 years since James Parkinson's description in 1817 of the illness bearing his name until the development of effective therapy for this disorder, namely, the introduction of high-dosage levodopa by George Cotzias in 1967. During the first 50 years, no effective therapy was available, but neurologists reported using different agents, including metals. Then, around 1867, Charcot found solanaceous alkaloids to be somewhat helpful, and these became the accepted and popular therapy for the next 75 years. When basic scientists discovered that these alkaloids had central antimuscarinic activity, pharmaceutical chemists developed synthetic chemical agents that were equally effective, with possibly less adverse effects, and around 1950 these synthetic drugs became the standard medical therapy for Parkinson's disease (PD). The link between dopamine and PD did not take place until 1957, 140 years after Parkinson's Essay. The clue came from research on reserpine, a drug derived from the Rauwolfia plant that caused a sedative effect, now recognized as a drug-induced parkinsonian state. Initial investigations revealed that reserpine caused the release and depletion of serotonin stores in the brain. With that knowledge, Arvid Carlsson, a young pharmacologist in Sweden, decided to explore the possibility that reserpine might also affect brain catecholamines. In his now famous, elegant, and simple experiment, he showed that injecting l-dopa, the precursor of catecholamines, alleviated the reserpine-induced parkinsonian state in animals, whereas the precursor of serotonin failed to do so. Carlsson then developed a highly sensitive assay to measure dopamine, and his lab found that dopamine is selectively present in high concentrations in the striatum and that administered l-dopa could restore the dopamine depleted by reserpine. Carlsson postulated that all these findings implicate dopamine in motor disorders. Oleh Hornykiewicz, a young pharmacologist in Vienna, on being aware of the regional localization of brain dopamine, decided to measure it in the brains of people who had PD and postencephalitic parkinsonism. In 1960, he reported finding markedly depleted dopamine in the striatum in these conditions. Immediately after, Hornykiewicz teamed up with the geriatrician, Walther Birkmayer, to inject small doses of l-dopa intravenously (IV) into PD patients. They found benefit and pursued this treatment, but the gastrointestinal side effects limited the dosage, and many neurologists were doubtful that the effects from l-dopa were any better than those with antimuscarinic agents. A number of neurologists tested such low doses of IV l-dopa and even higher oral dosages, but without showing any dramatic benefit, not better than the antimuscarinics. Some of these studies were small, controlled trials. This general lack of efficacy with l-dopa prevailed, and neurologists were discouraged about l-dopa until 1967, when George C. Cotzias, a neuropharmacologist in New York, reported his results. He thought that PD may be result from the loss of neuromelanin in the substantia nigra, and he decided to try to replenish the depleted neuromelanin. Among the agents he tried was dl-dopa. He wisely began with low oral doses and increased the dosage slowly and steadily, thereby limiting the gastrointestinal complication. He also treated his patients for a long duration, months in a government-supported hospital. In the accompanying videotape of an interview Cotzias gave in 1970, he describes much of his success to be able to observe his patients over months while building up the dosage very slowly and observe for signs of toxicity. When higher doses, usually over 12 g/day, were reached, dramatic antiparkinsonian effects were observed, and a revolutionary new treatment for PD was established. © 2014 International Parkinson and Movement Disorder Society. Source


Kotas M.E.,Yale University | Kotas M.E.,Columbia University | Medzhitov R.,Yale University | Medzhitov R.,Howard Hughes Medical Institute
Cell | Year: 2015

While modernization has dramatically increased lifespan, it has also witnessed the increasing prevalence of diseases such as obesity, hypertension, and type 2 diabetes. Such chronic, acquired diseases result when normal physiologic control goes awry and may thus be viewed as failures of homeostasis. However, while nearly every process in human physiology relies on homeostatic mechanisms for stability, only some have demonstrated vulnerability to dysregulation. Additionally, chronic inflammation is a common accomplice of the diseases of homeostasis, yet the basis for this connection is not fully understood. Here we review the design of homeostatic systems and discuss universal features of control circuits that operate at the cellular, tissue, and organismal levels. We suggest a framework for classification of homeostatic signals that is based on different classes of homeostatic variables they report on. Finally, we discuss how adaptability of homeostatic systems with adjustable set points creates vulnerability to dysregulation and disease. This framework highlights the fundamental parallels between homeostatic and inflammatory control mechanisms and provides a new perspective on the physiological origin of inflammation. © 2015 Elsevier Inc. Source


Hirschberg J.,Columbia University | Manning C.D.,Stanford University
Science | Year: 2015

Natural language processing employs computational techniques for the purpose of learning, understanding, and producing human language content. Early computational approaches to language research focused on automating the analysis of the linguistic structure of language and developing basic technologies such asmachine translation, speech recognition, and speech synthesis.Today's researchers refine and make use of such tools in real-world applications, creating spoken dialogue systems and speech-to-speech translation engines, mining social media for information about health or finance, and identifying sentiment and emotion toward products and services.We describe successes and challenges in this rapidly advancing area. Source


Kousteni S.,Columbia University
Bone | Year: 2012

FoxO1, one of the four FoxO isoforms of Forkhead transcription factors, is highly expressed in insulin-responsive tissues, including pancreas, liver, skeletal muscle and adipose tissue, as well as in the skeleton. In all these tissues FoxO1 orchestrates the transcriptional cascades regulating glucose metabolism. Indeed, FoxO1 is a major target of insulin which inhibits its transcriptional activity via nuclear exclusion. In the pancreas, FoxO1 regulates β-cell formation and function by a balanced dual mode of action that suppresses β-cell proliferation but promotes survival. Hepatic glucose production is promoted and lipid metabolism is regulated by FoxO1 such that under insulin resistance they lead to hyperglycemia and dyslipidemia, two features of type 2 diabetes. In skeletal muscle FoxO1 maintains energy homeostasis during fasting and provides energy supply through breakdown of carbohydrates, a process that leads to atrophy and underlies glycemic control in insulin resistance. In a dual function, FoxO1 regulates energy and nutrient homeostasis through energy storage in white adipose tissue, but promotes energy expenditure in brown adipose tissue. In its most recently discovered novel role, FoxO1 acts as a transcriptional link between the skeleton and pancreas as well as other insulin target tissues to regulate energy homeostasis. Through its expression in osteoblasts it controls glucose metabolism, insulin sensitivity and energy expenditure. In a feedback mode of regulation, FoxO1 is also a target of insulin signaling in osteoblasts. Insulin suppresses activity of osteoblastic FoxO1 thus promoting beneficial effects of osteoblasts on glucose metabolism. The multiple actions of FoxO1 in all glucose-regulating organs, along with clinical studies suggesting that its glycemic properties are conserved in humans, establish this transcription factor as a master regulator of energy metabolism across species. This article is part of a Special Issue entitled: Interactions Between Bone, Adipose Tissue and Metabolism. © 2011 Elsevier Inc. Source


Warren M.P.,Columbia University
Journal of Clinical Endocrinology and Metabolism | Year: 2011

Context: The endocrinopathies associated with eating disorders involve multiple systems and mechanisms designed to preserve energy and protect essential organs. Those systems that are most affected are in need of significant energy, such as the reproductive and skeletal systems. The changes in neuropeptides and in the hypothalamic axis that mediate these changes also receive input from neuroendocrine signals sensitive to satiety and food intake and in turn may be poised to provide significant energy conservation. These adaptive changes are described, including the thyroid, GH, and cortisol axes, as well as the gastrointestinal tract. Evidence Acquisition: Articles were found via PubMed search for both original articles and reviews summarizing current understanding of the endocrine changes of eating disorders based on peer review publications on the topic between 1974 and 2009. Conclusion: The signals that control weight and food intake are complex and probably involve multiple pathways that appear to have as a central control the hypothalamus, in particular the medial central area. The hypothalamic dysfunction of eating disorders provides a reversible experiment of nature that gives insight into understanding the role of various neuropeptides signaling nutritional status, feeding behavior, skeletal repair, and reproductive function. Copyright © 2011 by The Endocrine Society. Source


Mao Y.,Columbia University
Trends in Cell Biology | Year: 2011

The mammalian diaphanous-related (mDia) formin proteins are well known for their actin-nucleation and filament-elongation activities in mediating actin dynamics. They also directly bind to microtubules and regulate microtubule stabilization at the leading edge of the cell during cell migration. Recently, the formin mDia3 was shown to associate with the kinetochore and to contribute to metaphase chromosome alignment, a process in which kinetochores form stable attachments with growing and shrinking microtubules. We suggest that the formin mDia3 could contribute to the regulation of kinetochore-bound microtubule dynamics, in coordination with attachment via its own microtubule-binding activity, as well as via its interaction with the tip-tracker EB1 (end-binding protein 1). © 2011 Elsevier Ltd. Source


Choi S.H.,Seoul National University | Ginsberg H.N.,Columbia University
Trends in Endocrinology and Metabolism | Year: 2011

Insulin resistance (IR) affects not only the regulation of carbohydrate metabolism but all aspects of lipid and lipoprotein metabolism. IR is associated with increased secretion of VLDL and increased plasma triglycerides, as well as with hepatic steatosis, despite the increased VLDL secretion. Here we link IR with increased VLDL secretion and hepatic steatosis at both the physiologic and molecular levels. Increased VLDL secretion, together with the downstream effects on high density lipoprotein (HDL) cholesterol and low density lipoprotein (LDL) size, is proatherogenic. Hepatic steatosis is a risk factor for steatohepatitis and cirrhosis. Understanding the complex inter-relationships between IR and these abnormalities of liver lipid homeostasis will provide insights relevant to new therapies for these increasing clinical problems. © 2011 Elsevier Ltd. Source


Sassen S.,Columbia University
Globalizations | Year: 2013

This essay focuses on the larger assemblage of elements that promoted and facilitated the sharp increase in foreign land acquisitions by governments and firms since 2006. The concern is not to document the empirics of foreign land acquisition. Conceptually the essay negotiates between the specifics of the current phase of land acquisitions, on the one hand, and, on the other, the assemblage of practices, norms, and shifting jurisdictions within which those acquisitions take place. This assemblage of diverse elements does not present itself explicitly as governance. But I argue it is a type of governance embedded in larger structural processes shaping our global modernity; in fact, it may have had deeper effects on the current phase of land acquisitions than some of the explicit governance instruments for regulating land acquisitions. This mode of analysis is based on the conceptual and methodological work I developed in my book, Territory, Authority, Rights (Sassen, 2008); put succinctly it proposes that to explain the x (in this case, foreign land acquisitions) requires a focus on the non-x (in this case, that larger assemblage of elements that amounts to a structural enablement and embedded governance). This deeper structural level is also what makes the current phase of land acquisitions potentially deeply consequential, to the point of signaling the further disassembling of national territory. Such disassembling can enable the rise of a new type of global geopolitics, one where national sovereign territory increasingly is subject to nonnational systems of authority-from familiar IMF and WTO conditionality to elementary controls by diverse foreign actors over growing stretches of a country's land. © 2013 Copyright Taylor and Francis Group, LLC. Source


Xiao X.,Columbia University
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2014

Assuming the existence of the dS/CFT correspondence, we construct local scalar fields with m2>(d2)2 in de Sitter space by smearing over conformal field theory operators on the future or past boundary. To maintain bulk microcausality and recover the bulk Wightman function in the Euclidean vacuum, the smearing prescription must involve two sets of single-trace operators with dimensions Δ and d-Δ. Thus the local operator prescription in de Sitter space differs from the analytic continuation from the prescription in anti-de Sitter space. Pushing a local operator in the global patch to future or past infinity is shown to lead to an operator relation between single-trace operators in conformal field theories at I±, which can be interpreted as a basis transformation, also identified as the relation between an operator in CFT and its shadow operator. Construction of spin-s gauge field operators is discussed, and it is shown that the construction of higher spin gauge fields in de Sitter space is equivalent to constructing scalar fields with specific values of mass parameter m2<(d2)2. An acausal higher spin bulk operator that matches onto boundary higher spin current is constructed. Implementation of the scalar operator constructions in AdS and dS with embedding formalism is briefly described. © 2014 American Physical Society. Source


Noronha J.,Columbia University
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2010

We show that in four-dimensional gauge theories dual to five-dimensional Einstein gravity coupled to a single scalar field in the bulk, the derivative of the single heavy quark free energy in the deconfined phase is dFQ(T)/dT∼-1/cs2(T), where cs(T) is the speed of sound. This general result provides a direct link between the softest point in the equation of state of strongly-coupled plasmas and the deconfinement phase transition described by the expectation value of the Polyakov loop. We give an explicit example of a gravity dual with black hole solutions that can reproduce the lattice results for the expectation value of the Polyakov loop and the thermodynamics of SU(3) Yang-Mills theory in the (nonperturbative) temperature range between Tc and 3Tc. © 2010 The American Physical Society. Source


Kim P.,Columbia University
Nature Materials | Year: 2010

The topological nature of a certain type of grain boundary in polycrystalline graphene may be used to customize the electrical transport properties. The zone folding method involves folding the 2D band structure along the 1D band that follows the grain boundary. The folded 2D graphene band is then projected on the 1D mini-band, reflecting the periodic structure imposed by the periodicity of the grain boundary. A similar zone-folding approach is applied to nanotubes to understand the chirality dependence of metallic and semi-conducting nanotubes. The zone-folding approach in graphene result in two types of folded 1D band structure, depending on the chiral nature of the vector d, which is determined by the atomic lattice vectors in each domain. Matching the relative chiral nature of each graphene domain across the boundary leads to two different categories of the grain boundary that includes type I, where both sides of the grain boundary has similar chirality, and type II, where the relative chirality is different. Source


Curley J.P.,Columbia University
BioEssays | Year: 2011

Imprinted genes (IGs) are expressed or silenced according to their parent-of-origin. These genes are known to play a role in regulating offspring growth, development and infant behaviors such as suckling and ultrasonic calls. In adults, neurally expressed IGs coordinate several behaviors including maternal care, sex, feeding, emotionality, and cognition. However, despite evidence from human psychiatric disorders and evolutionary theory that maternally and paternally expressed genes should also regulate social behavior, little empirical data from mouse research exists. This paper discusses data from a recent study (Garfield et al., 2011) that the IG Grb10 governs unique aspects of mouse social behavior and interprets the relevance of these findings for the future of this field. © 2011 WILEY Periodicals, Inc. Source


Brus L.,Columbia University
Nano Letters | Year: 2010

To celebrate the tenth anniversary of Nano Letters, this short commentary discusses a scientific issue of current interest, increased electron-electron interactions in nanostructures. The two major factors of reduced dimensionality and low screening are analyzed. Carbon nanotubes and graphene are molecular in many of their properties and show strong electron-electron interactions. In specific circumstances, excited-state decay by exciton generation rather than phonon generation can be efficient in carbon nanotubes. © 2010 American Chemical Society. Source


Brittenham G.M.,Columbia University
New England Journal of Medicine | Year: 2011

A 16-year-old boy with sickle cell anemia undergoes routine screening with transcranial Doppler ultrasonography to assess the risk of stroke. This examination shows an abnormally elevated blood-flow velocity in the middle cerebral artery. The hemoglobin level is 7.2 g per deciliter, the reticulocyte count is 12.5%, and the fetal hemoglobin level is 8.0%. Long-term treatment with red-cell transfusion is initiated to prevent stroke. A hematologist recommends prophylactic iron-chelating therapy. Copyright © 2011 Massachusetts Medical Society. Source


Costantini F.,Columbia University
Developmental Cell | Year: 2010

The two major components of the kidney, the collecting system and the nephron, have different developmental histories. The collecting system arises by the reiterated branching of a simple epithelial tube, while the nephron forms from a cloud of mesenchymal cells that coalesce into epithelial vesicles. Each develops into a morphologically complex and highly differentiated structure, and together they provide essential filtration and resorption functions. In this review, we will consider their embryological origin and the genes controlling their morphogenesis, patterning, and differentiation, with a focus on recent advances in several areas. © 2010 Elsevier Inc. Source


Rothman S.M.,Columbia University
American journal of public health | Year: 2011

Health advocacy organizations (HAOs) are influential stakeholders in health policy. Although their advocacy tends to closely correspond with the pharmaceutical industry's marketing aims, the financial relationships between HAOs and the pharmaceutical industry have rarely been analyzed. We used Eli Lilly and Company's grant registry to examine its grant-giving policies. We also examined HAO Web sites to determine their grant-disclosure patterns. Only 25% of HAOs that received Lilly grants acknowledged Lilly's contributions on their Web sites, and only 10% acknowledged Lilly as a grant event sponsor. No HAO disclosed the exact amount of a Lilly grant. As highly trusted organizations, HAOs should disclose all corporate grants, including the purpose and the amount. Absent this disclosure, legislators, regulators, and the public cannot evaluate possible conflicts of interest or biases in HAO advocacy. Source


Objective: To perform a population-based analysis comparing the performance of the 1988 and 2009 International Federation of Gynecology and Obstetrics (FIGO) staging systems. Methods: Women with endometrioid adenocarcinoma of the uterus treated between 1988 and 2006 and recorded in the Surveillance, Epidemiology, and End Results database were analyzed. Women were classified based on 1988 and 2009 FIGO staging systems. Major changes in the 2009 system include: 1) classification of patients with stage IA and IB tumors as stage IA; 2) elimination of stage IIA; and 3) stratification of stage IIIC into pelvic nodes only (IIIC1) or paraaortic nodal (IIIC2) involvement. Survival and use of adjuvant therapy were analyzed. Results: A total of 81,902 women were identified. Based on the 1988 staging system, survival for stage IA was 90.7% (95% confidence interval [CI], 90-91%) compared with 88.9% (95% CI 88-89%) for IB tumors. In the 2009 system, survival was 89.6% (95% CI 89-90%) for stage IA and 77.6% (95% CI 76-79%) for stage IB. The survival for FIGO 1988 stage IIA was superior to stage IC, whereas in the 2009 system, survival for stage II was inferior to all stage I patients. The newly defined stage IIIC substages are prognostically different. Survival for stage IIIC1 was 57.0% (95% CI 54-60%) compared with 49.4% (95% CI 46-53%) for stage IIIC2. Conclusion: The 2009 FIGO staging system for uterine corpus cancer is highly prognostic. The reduction in stage I substages and the separation of stage III will further clarify important prognostic features. © 2010 by The American College of Obstetricians and Gynecologists. Source


Tabas I.,Columbia University
Circulation Research | Year: 2010

Prolonged activation of the endoplasmic reticulum (ER) stress pathway known as the unfolded protein response (UPR) can lead to cell pathology and subsequent tissue dysfunction. There is now ample evidence that the UPR is chronically activated in atherosclerotic lesional cells, particularly advanced lesional macrophages and endothelial cells. The stressors in advanced lesions that can lead to prolonged activation of the UPR include oxidative stress, oxysterols, and high levels of intracellular cholesterol and saturated fatty acids. Importantly, these arterial wall stressors may be especially prominent in the settings of obesity, insulin resistance, and diabetes, all of which promote the clinical progression of atherosclerosis. In the case of macrophages, prolonged ER stress triggers apoptosis, which in turn leads to plaque necrosis if the apoptotic cells are not rapidly cleared. ER stress-induced endothelial cell apoptosis may also contribute to plaque progression. Another potentially important proatherogenic effect of prolonged ER stress is activation of inflammatory pathways in macrophages and, perhaps in response to atheroprone shear stress, endothelial cells. Although exciting work over the last decade has begun to shed light on the mechanisms and in vivo relevance of ER stress-driven atherosclerosis, much more work is needed to fully understand this area and to enable an informed approach to therapeutic translation. © 2010 American Heart Association, Inc. Source


Fahn S.,Columbia University
Movement Disorders | Year: 2011

The classification of movement disorders has evolved. Even the terminology has shifted, from an anatomical one of extrapyramidal disorders to a phenomenological one of movement disorders. The history of how this shift came about is described. The history of both the definitions and the classifications of the various neurologic conditions is then reviewed. First is a review of movement disorders as a group; then, the evolving classifications for 3 of them-parkinsonism, dystonia, and tremor-are covered in detail. © 2011 Movement Disorder Society. Source


Prins S.J.,Columbia University
Psychiatric Services | Year: 2014

Objective: People with mental illnesses are understood to be overrepresented in the U.S. criminal justice system, and accurate prevalence estimates in corrections settings are crucial for planning and implementing preventive and diversionary policies and programs. Despite consistent scholarly attention to mental illness in corrections facilities, only two federal self-report surveys are typically cited, and they may not represent the extent of relevant data. This systematic review was conducted to develop a broader picture of mental illness prevalence in U.S. state prisons and to identify methodological challenges to obtaining accurate and consistent estimates. Methods: MEDLINE, PsycINFO, the National Criminal Justice Reference Service, Social Services Abstracts, Social Work Abstracts, and Sociological Abstracts were searched. Studies were included if they were published between 1989 and 2013, focused on U.S. state prisons, reported prevalence of diagnoses and symptoms of DSM axis I disorders, and identified screening and assessment strategies. Results: Twenty-eight articles met inclusion criteria. Estimates of current and lifetime prevalence of mental illnesses varied widely; however, the range of prevalence estimates for particular disorders was much greater - and tended to be higher - in prisons than in community samples. Conclusions: Definitions of mental illnesses, sampling strategies, and case ascertainment strategies likely contributed to inconsistency in findings. Other reasons for study heterogeneity are discussed, and implications for public health are explored. Source


de Jong A.,Columbia University
Immunological Reviews | Year: 2015

Summary: Over two decades ago, it was discovered that the human T-cell repertoire contains T cells that do not recognize peptide antigens in the context of MHC molecules but instead respond to lipid antigens presented by CD1 antigen-presenting molecules. The ability of T cells to 'see' lipid antigens bound to CD1 enables these lymphocytes to sense changes in the lipid composition of cells and tissues as a result of infections, inflammation, or malignancies. Although foreign lipid antigens have been shown to function as antigens for CD1-restricted T cells, many CD1-restricted T cells do not require foreign antigens for activation but instead can be activated by self-lipids presented by CD1. This review highlights recent developments in the field, including the identification of common mammalian lipids that function as autoantigens for αβ and γδ T cells, a novel mode of T-cell activation whereby CD1a itself rather than lipids serves as the autoantigen, and various mechanisms by which the activation of CD1-autoreactive T cells is regulated. As CD1 can induce T-cell effector functions in the absence of foreign antigens, multiple mechanisms are in place to regulate this self-reactivity, and stimulatory CD1-lipid complexes appear to be tightly controlled in space and time. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Source


Small S.A.,Columbia University | Petsko G.A.,New York Medical College
Nature Reviews Neuroscience | Year: 2015

Retromer is a protein assembly that has a central role in endosomal trafficking, and retromer dysfunction has been linked to a growing number of neurological disorders. First linked to Alzheimer disease, retromer dysfunction causes a range of pathophysiological consequences that have been shown to contribute to the core pathological features of the disease. Genetic studies have established that retromer dysfunction is also pathogenically linked to Parkinson disease, although the biological mechanisms that mediate this link are only now being elucidated. Most recently, studies have shown that retromer is a tractable target in drug discovery for these and other disorders of the nervous system. © 2015 Macmillan Publishers Limited. All rights reserved. Source


Brenner D.J.,Columbia University
The British journal of radiology | Year: 2014

Quantifying radiation-induced cancer risks associated with radiological examinations is not easy, which has resulted in much controversy. We can clarify the situation by distinguishing between higher dose examinations, such as CT, positron emission tomography-CT or fluoroscopically guided interventions, and lower dose "conventional" X-ray examinations. For higher dose examinations, the epidemiological data, from atomic bomb survivors exposed to low doses and from direct epidemiological studies of paediatric CT, are reasonably consistent, suggesting that we do have a reasonable quantitative understanding of the individual risks: in summary, very small but unlikely to be zero. For lower dose examinations, we have very little data, and the situation is much less certain, however, the collective dose from these lower dose examinations is comparatively unimportant from a public health perspective. Source


Sackeim H.A.,Columbia University
Journal of ECT | Year: 2014

Retrograde amnesia for autobiographical information is the most critical adverse effect of electroconvulsive therapy (ECT). Much, if not most, modern research demonstrating long-term autobiographical amnesia after ECT has used either the Columbia University Autobiographical Memory Interview (CUAMI) or the short form of this scale (CUAMI-SF). Semkovska and McLoughlin claimed that studies using these instruments should be dismissed and the findings ignored owing to a lack of normative data, as well as concerns about the reliability and validity of these instruments. In this commentary, the development and use of these scales is reviewed. It is shown that Semkovska and McLoughlin's critique is factually incorrect, as normative data were simultaneously collected in virtually all studies using these instruments. Furthermore, there is substantial evidence supporting the reliability and validity of these scales. Indeed, these instruments are the only neuropsychological tests repeatedly shown to covary with patient self-evaluations of ECT's effects on memory and have repeatedly demonstrated long-term differences in the magnitude of amnesia as a function of ECT technique. Findings with the CUAMI and CUAMI-SF provide key evidence regarding ECT's adverse cognitive effect profile. It is inaccurate and inadvisable to continue to deny that ECT can exert long-term adverse effects in this domain. Copyright © 2014 by Lippincott Williams &Wilkins. Source


Tanaka T.,Columbia University
Monthly Notices of the Royal Astronomical Society | Year: 2011

We discuss Green's function solutions of the equation for a geometrically thin, axisymmetric Keplerian accretion disc with a viscosity prescription ν Rn. The mathematical problem was solved by Lynden-Bell & Pringle for the special cases with boundary conditions of zero-viscous torque and zero mass flow at the disc centre. While it has been widely established that the observational appearance of astrophysical discs depends on the physical size of the central object(s), exact time-dependent solutions with boundary conditions imposed at finite radius have not been published for a general value of the power-law index n. We derive exact Green's function solutions that satisfy either a zero-torque or a zero-flux condition at a non-zero inner boundary Rin > 0, for an arbitrary initial surface density profile. Whereas the viscously dissipated power diverges at the disc centre for the previously known solutions with Rin= 0, the new solutions with Rin > 0 have finite expressions for the disc luminosity that agree, in the limit t→∞, with standard expressions for steady-state disc luminosities. The new solutions are applicable to the evolution of the innermost regions of thin accretion discs. © 2010 The Author. Journal compilation © 2010 RAS. Source


Gordon A.M.,Columbia University
Developmental Medicine and Child Neurology | Year: 2011

Impaired hand function is among the most functionally disabling symptoms of unilateral cerebral palsy. Evidence-based treatment approaches are generally lacking. However, recent approaches providing intensive upper extremity training appear promising. In this review, we first describe two such approaches, constraint-induced movement therapy (CIMT) and bimanual training (hand-arm bimanual intensive therapy). We then summarize findings across more than 100 participants in our CIMT/bimanual training studies since 1997. We show that (1) at high intensities, CIMT and bimanual training improve dexterity and bimanual upper extremity use; (2) bimanual training may allow direct practice of functionally meaningful goals, and such practice may transfer to unpracticed goals and improve bimanual coordination; (3) 90hours of CIMT and bimanual training leads to greater improvements than 60hours of the same treatments; (4) higher doses may be required for bimanual training; (5) increased dosing frequency and shaping may be needed for older children; and (6) combined CIMT/bimanual approaches may be useful, but require sufficient intensity. Together these findings suggest that dosage (treatment amount and frequency), more so than ingredients, may well be the key to successful training protocols, especially for older children. Such rehabilitation efforts should be 'child-friendly', and as least invasive as possible, especially because these approaches may be provided throughout development. © 2011 Mac Keith Press. Source


DeFries R.,Columbia University
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2013

The Brazilian state of Mato Grosso was a global deforestation hotspot in the early 2000s. Deforested land is used predominantly to produce meat for distal consumption either through cattle ranching or soya bean for livestock feed. Deforestation declined dramatically in the latter part of the decade through a combination of market forces, policies, enforcement and improved monitoring. This study assesses how representative the national-level drivers underlying Mato Grosso's export-oriented deforestation are in other tropical forest countries based on agricultural exports, commercial agriculture and urbanization. We also assess how pervasive the governance and technical monitoring capacity that enabled Mato Grosso's decline in deforestation is in other countries. We find that between 41 and 54 per cent of 2000-2005 deforestation in tropical forest countries (other than Brazil) occurred in countries with drivers similar to Brazil. Very few countries had national-level governance and capacity similar to Brazil. Results suggest that the ecological, hydrological and social consequences of land-use change for export-oriented agriculture as discussed in this Theme Issue were applicable in about one-third of all tropical forest countries in 2000-2005. However, the feasibility of replicating Mato Grosso's success with controlling deforestation is more limited. Production landscapes to support distal consumption similar to Mato Grosso are likely to become more prevalent and are unlikely to follow a land-use transition model with increasing forest cover. Source


Snoeck H.-W.,Columbia University
Current Opinion in Hematology | Year: 2013

Purpose of Review: Aging of the hematopoietic system is associated with myeloid malignancies, anemia and immune dysfunction. As hematopoietic stem cells (HSCs) generate all cells of the hematopoietic system, age-associated changes in HSCs may underlie many features of the aged hematopoietic system. Recent findings on age-associated changes in HSCs are reviewed here. RECENT FINDINGS: Aged HSCs are myeloid biased, have acquired DNA damage and are functionally compromised. However, overall function of the HSC compartment is well maintained through age-associated expansion of HSCs. Many age-related changes in the hematopoietic system, in particular the clonal myeloid bias of HSCs and the decrease in B and T-cell development, in fact begin during development. Furthermore, HSCs possess specific protective mechanisms aimed at maintaining their number, even at the expense of accumulating damaged cells. SUMMARY: We argue that age-related changes in HSCs and in the hematopoietic system may not entirely be due to a degenerative aging process, but are the result of developmental and stem cell-protective mechanisms aimed at maximizing fitness during reproductive life. These mechanisms may be disadvantageous later in life as damaged HSCs accumulate and establishment of responses to neoantigens becomes compromised because of the reduced generation of naive T and B cells. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source


Duncan R.G.,Rutgers University | Rivet A.E.,Columbia University
Science | Year: 2013

New science education standards build upon research-based cognitive models of how learning unfolds over time. Source


Gelman A.,Columbia University
Epidemiology | Year: 2013

Like many Bayesians, I have often represented classical confidence intervals as posterior probability intervals and interpreted one-sided P values as the posterior probability of a positive effect. These are valid conditional on the assumed noninformative prior but typically do not make sense as unconditional probability statements. As Sander Greenland has discussed in much of his work over the years, epidemiologists and applied scientists in general have knowledge of the sizes of plausible effects and biases. I believe that a direct interpretation of P values as posterior probabilities can be a useful start-if we recognize that such summaries systematically overestimate the strength of claims from any particular dataset. In this way, I am in agreement with Greenland and Poole's interpretation of the one-sided P value as a lower bound of a posterior probability, although I am less convinced of the practical utility of this bound, given that the closeness of the bound depends on a combination of sample size and prior distribution.The default conclusion from a noninformative prior analysis will almost invariably put too much probability on extreme values. A vague prior distribution assigns much of its probability on values that are never going to be plausible, and this disturbs the posterior probabilities more than we tend to expect-something that we probably do not think about enough in our routine applications of standard statistical methods. Greenland and Poole1 perform a valuable service by opening up these calculations and placing them in an applied context. © 2012 by Lippincott William & Wilkins. Source


Winchester R.,Columbia University
Arthritis and rheumatism | Year: 2012

Rigorously ascertained cases of psoriatic arthritis in subjects presenting to a rheumatology unit were compared with cases of psoriasis in subjects presenting to a dermatology unit, where subjects with musculoskeletal features were excluded, to address 1) the extent to which the contribution of the major histocompatibility complex (MHC) to psoriatic arthritis susceptibility resembles that in psoriasis, and 2) whether MHC genes determine quantitative traits within the psoriatic arthritis phenotype. Separate discovery and validation subcohorts of patients recruited from a relatively homogeneous population were studied by sequence-based HLA typing, in which frequencies of the HLA-B and HLA-C alleles and haplotypes were compared. In patients with psoriatic arthritis, the frequency of C*06:02 was lower than that in patients with psoriasis (28.7% versus 57.5%; P = 9.9 × 10(-12) ). Three haplotypes containing B*27:05 or B*39:01 were significantly increased in frequency in patients with psoriatic arthritis, but not in those with psoriasis. The structurally related B*39:06 allele was not increased in frequency. B*27 was associated with an interval of 0.98 years between skin and musculoskeletal disease (P = 2.05 × 10(-6) ), compared with an interval of 10.14 years for C*06. Preliminary evidence suggested that B*38:01 and B*08 may be associated with psoriatic arthritis susceptibility, and that allotypes encoding P2 pockets that bind side chains opposite in charge from those encoded by the B*27 and B*39 molecules may exert a protective role. These findings suggest that the psoriasis phenotype results from two patterns of MHC effect. The first involves the classic psoriasis susceptibility gene C*06, which confers more penetrant skin disease with less prevalent and more time-dependent musculoskeletal phenotype development. The second pattern appears to be mediated by HLA-B alleles, notably B*27, and includes temporally more coincident musculoskeletal involvement that is nearly equivalent in penetrance to that of the skin disease. Copyright © 2012 by the American College of Rheumatology. Source


Lazar A.A.,Columbia University
IEEE Transactions on Information Theory | Year: 2010

The recovery of (weak) stimuli encoded with a population of HodgkinHuxley neurons is investigated. In the absence of a stimulus, the HodgkinHuxley neurons are assumed to be tonically spiking. The methodology employed calls for 1) finding an inputoutput (I/O) equivalent description of the HodgkinHuxley neuron and 2) devising a recovery algorithm for stimuli encoded with the I/O equivalent neuron(s). A HodgkinHuxley neuron with multiplicative coupling is I/O equivalent with an Integrate-and-Fire neuron with a variable threshold sequence. For bandlimited stimuli a perfect recovery of the stimulus can be achieved provided that a Nyquist-type rate condition is satisfied. A HodgkinHuxley neuron with additive coupling and deterministic conductances is first-order I/O equivalent with a Project-Integrate-and-Fire neuron that integrates a projection of the stimulus on the phase response curve. The stimulus recovery is formulated as a spline interpolation problem in the space of finite length bounded energy signals. A HodgkinHuxley neuron with additive coupling and stochastic conductances is shown to be first-order I/O equivalent with a Project-Integrate-and-Fire neuron with random thresholds. For stimuli modeled as elements of Sobolev spaces the reconstruction algorithm minimizes a regularized quadratic optimality criterion. Finally, all previous recovery results of stimuli encoded with HodgkinHuxley neurons with multiplicative and additive coupling, and deterministic and stochastic conductances are extended to stimuli encoded with a population of HodgkinHuxley neurons. © 2006 IEEE. Source


Pickrell J.K.,New York Genome Center | Pickrell J.K.,Columbia University
American Journal of Human Genetics | Year: 2014

Annotations of gene structures and regulatory elements can inform genome-wide association studies (GWASs). However, choosing the relevant annotations for interpreting an association study of a given trait remains challenging. I describe a statistical model that uses association statistics computed across the genome to identify classes of genomic elements that are enriched with or depleted of loci influencing a trait. The model naturally incorporates multiple types of annotations. I applied the model to GWASs of 18 human traits, including red blood cell traits, platelet traits, glucose levels, lipid levels, height, body mass index, and Crohn disease. For each trait, I used the model to evaluate the relevance of 450 different genomic annotations, including protein-coding genes, enhancers, and DNase-I hypersensitive sites in over 100 tissues and cell lines. The fraction of phenotype-associated SNPs influencing protein sequence ranged from around 2% (for platelet volume) up to around 20% (for low-density lipoprotein cholesterol), repressed chromatin was significantly depleted for SNPs associated with several traits, and cell-type-specific DNase-I hypersensitive sites were enriched with SNPs associated with several traits (for example, the spleen in platelet volume). Finally, reweighting each GWAS by using information from functional genomics increased the number of loci with high-confidence associations by around 5%. © 2014 The American Society of Human Genetics. Source


John Mann J.,Columbia University
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2013

A stress-diathesis explanatory model of suicidal behaviour has proved to be of heuristic value, and both clinical and neurobiological components can be integrated into such a model. A trait deficiency in serotonin input to the anterior cingulate and ventromedial prefrontal cortex is found in association with suicide, and more recently non-fatal suicidal behaviour, and is linked to decision-making and suicide intent by imaging and related studies in vivo. The same neural circuitry and serotonin deficiency may contribute to impulsive aggressive traits that are part of the diathesis for suicidal behaviour and are associated with early onset mood disorders and greater risk for suicidal behaviour. Other brain areas manifest deficient serotonin input, that is, a trait related to recurrent major depressive disorder and bipolar disorder. Thus the serotonin system is involved in both the diathesis for suicidal behaviour in terms of decision-making, and to a major stressor, namely episodes of major depression. © 2013 The Author(s) Published by the Royal Society. All rights reserved. Source


Rossin-Slater M.,Columbia University
Journal of Public Economics | Year: 2013

A large body of evidence indicates that conditions in-utero and health at birth matter for individuals' long-run outcomes, suggesting potential value in programs aimed at pregnant women and young children. This paper uses a novel identification strategy and data from birth and administrative records over 2005-2009 to provide causal estimates of the effects of geographic access to the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC). My empirical approach uses within-ZIP-code variation in WIC clinic presence together with maternal fixed effects, and accounts for the potential endogeneity of mobility, gestational-age bias, and measurement error in gestation. I find that access to WIC increases food benefit take-up, pregnancy weight gain, birth weight, and the probability of breastfeeding initiation at the time of hospital discharge. The estimated effects are strongest for mothers with a high school education or less, who are most likely eligible for WIC services. © 2013 Elsevier B.V. Source


Rubenstein D.R.,Columbia University
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2012

Darwin was initially puzzled by the processes that led to ornamentation in males-what he termed sexual selection-and those that led to extreme cooperation and altruism in complex animal societies-what was later termed kin selection. Here, I explore the relationships between sexual and kin selection theory by examining how social competition for reproductive opportunities-particularly in females-and sexual conflict over mating partners are inherent and critical parts of complex altruistic societies. I argue that (i) patterns of reproductive sharing within complex societies can drive levels of social competition and reproductive conflict not only in males but also in females living in social groups, and ultimately the evolution of female traits such as ornaments and armaments; (ii) mating conflict over female choice of sexual partners can influence kin structure within groups and drive the evolution of complex societies; and (iii) patterns of reproductive sharing and conflict among females may also drive the evolution of complex societies by influencing kin structure within groups. Ultimately, complex societies exhibiting altruistic behaviour appear to have only arisen in taxa where social competition over reproductive opportunities and sexual conflict over mating partners were low. Once such societies evolved, there were important selective feedbacks on traits used to regulate and mediate intra-sexual competition over reproductive opportunities, particularly in females. © 2012 The Royal Society. Source


Cont R.,Columbia University
IEEE Signal Processing Magazine | Year: 2011

The availability of high-frequency data on transactions, quotes, and order flow in electronic order-driven markets has revolutionized data processing and statistical modeling techniques in finance and brought up new theoretical and computational challenges. Market dynamics at the transaction level cannot be characterized solely in terms the dynamics of a single price, and one must also take into account the interaction between buy and sell orders of different types by modeling the order flow at the bid price, ask price, and possibly other levels of the limit order book. © 2011 IEEE. Source


Crotts A.P.S.,Columbia University
Astrophysical Journal Letters | Year: 2015

Type Ia SN 2014J exploded in the nearby starburst galaxy M82 = NGC 3032 and was discovered at Earth about seven days later on 2014 January 21, reaching maximum light in V around 2014 February 5. SN 2014J is the closest SN Ia in at least four decades and probably many more. Recent Hubble Space Telescope/WFC3 imaging (2014 September 5 and 2015 February 2) of M82 in the vicinity of SN 2014J reveals a light echo at radii of about 0.6 arcsec from the supernova (SN; corresponding to about 12 pc at the distance of M82). Likely additional light echoes reside at a smaller radii of about 0.4 arcsec The major echo signal corresponds to echoing material about 330 pc in the foreground of SN 2014J and tends to be bright where pre-existing nebular structure in M82 is also bright. The second, likely echo corresponds to foreground distances of 80 pc in front of the SN. Even one year after maximum light, there are indications of further echo structures appearing at smaller radii, and future observations may show how extinction in these affect detected echo farther from the SN, which will affect interpretation of details of the three-dimensional structure of this gas and dust. Given enough data, we might even use these considerations to constrain the near-SN material's shadowing on distant echoing clouds, even without directly observing the foreground structure. This is in addition to echoes in the near future that might also reveal circumstellar structure around SN 2014J's progenitor star from direct imaging observations and other techniques. © 2015. The American Astronomical Society. All rights reserved. Source


Hendrickson W.A.,Columbia University | Hendrickson W.A.,New York Structural Biology Center
Quarterly Reviews of Biophysics | Year: 2014

X-ray diffraction patterns from crystals of biological macromolecules contain sufficient information to define atomic structures, but atomic positions are inextricable without having electron-density images. Diffraction measurements provide amplitudes, but the computation of electron density also requires phases for the diffracted waves. The resonance phenomenon known as anomalous scattering offers a powerful solution to this phase problem. Exploiting scattering resonances from diverse elements, the methods of MAD (multiwavelength anomalous diffraction) and SAD (single-wavelength anomalous diffraction) now predominate for de novo determinations of atomic-level biological structures. This review describes the physical underpinnings of anomalous diffraction methods, the evolution of these methods to their current maturity, the elements, procedures and instrumentation used for effective implementation, and the realm of applications. © 2014 Cambridge University Press. Source


Cerda M.,Columbia University
American Journal of Epidemiology | Year: 2012

Neighborhood-level interventions provide an opportunity to better understand the impact that neighborhoods have on health. In 2004, municipal authorities in Medellín, Colombia, built a public transit system to connect isolated low-income neighborhoods to the city's urban center. Transit-oriented development was accompanied by municipal investment in neighborhood infrastructure. In this study, the authors examined the effects of this exogenous change in the built environment on violence. Neighborhood conditions and violence were assessed in intervention neighborhoods (n = 25) and comparable control neighborhoods (n = 23) before (2003) and after (2008) completion of the transit project, using a longitudinal sample of 466 residents and homicide records from the Office of the Public Prosecutor. Baseline differences between these groups were of the same magnitude as random assignment of neighborhoods would have generated, and differences that remained after propensity score matching closely resembled imbalances produced by paired randomization. Permutation tests were used to estimate differential change in the outcomes of interest in intervention neighborhoods versus control neighborhoods. The decline in the homicide rate was 66% greater in intervention neighborhoods than in control neighborhoods (rate ratio = 0.33, 95% confidence interval: 0.18, 0.61), and resident reports of violence decreased 75% more in intervention neighborhoods (odds ratio = 0.25, 95% confidence interval 0.11, 0.67). These results show that interventions in neighborhood physical infrastructure can reduce violence. American Journal of Epidemiology © The Author 2012. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. Source


Holcman D.,Ecole Normale Superieure de Paris | Yuste R.,Columbia University
Nature reviews. Neuroscience | Year: 2015

Cable theory and the Goldman-Hodgkin-Huxley-Katz models for the propagation of ions and voltage within a neuron have provided a theoretical foundation for electrophysiology and been responsible for many cornerstone advances in neuroscience. However, these theories break down when they are applied to small neuronal compartments, such as dendritic spines, synaptic terminals or small neuronal processes, because they assume spatial and ionic homogeneity. Here we discuss a broader theory that uses the Poisson-Nernst-Planck (PNP) approximation and electrodiffusion to more accurately model the constraints that neuronal nanostructures place on electrical current flow. This extension of traditional cable theory could advance our understanding of the physiology of neuronal nanocompartments. Source


Boundary work refers to the strategies deployed by professionals in the arenas of the public, the law and the workplace to define and defend jurisdictional authority. Little attention has been directed to the role of documents in negotiating professional claims. While boundary work over induced abortion has been extensively documented, few studies have examined jurisdictional disputes over the treatment of abortion complications, or post-abortion care (PAC). This study explores how medical providers deploy medical records in boundary work over the treatment of complications of spontaneous and induced abortion in Senegal, where induced abortion is prohibited under any circumstance. Findings are based on an institutional ethnography of Senegal's national PAC program over a period of 13 months between 2010 and 2011. Data collection methods included in-depth interviews with 36 health care professionals, observation of PAC services at three hospitals, a review of abortion records at each hospital, and a case review of illegal abortions prosecuted by the state. Findings show that health providers produce a particular account of the type of abortion treated through a series of practices such as the patient interview and the clinical exam. Providers obscure induced abortion in medical documents in three ways: the use of terminology that does not differentiate between induced and spontaneous abortion in PAC registers, the omission of data on the type of abortion altogether in PAC registers, and reporting the total number but not the type of abortions treated in hospital data transmitted to state health authorities. The obscuration of suspected induced abortion in the record permits providers to circumvent police inquiry at the hospital. PAC has been implemented in approximately 50 countries worldwide. This study demonstrates the need for additional research on how medical professionals negotiate conflicting medical and legal obligations in the daily practice of treating abortion complications. © 2014 Elsevier Ltd. Source


Rossin M.,Columbia University
Journal of Health Economics | Year: 2011

This paper evaluates the impacts of unpaid maternity leave provisions of the 1993 Family and Medical Leave Act (FMLA) on children's birth and infant health outcomes in the United States. My identification strategy uses variation in pre-FMLA maternity leave policies across states and variation in which firms are covered by FMLA provisions. Using Vital Statistics data and difference-in-difference-in-difference methodology, I find that maternity leave led to small increases in birth weight, decreases in the likelihood of a premature birth, and substantial decreases in infant mortality for children of college-educated and married mothers, who were most able to take advantage of unpaid leave. My results are robust to the inclusion of numerous controls for maternal, child, and county characteristics, state, year, and month fixed effects, and state-year interactions, as well as across several different specifications. © 2011 Elsevier B.V. Source


Wallace R.,Columbia University
Physics of Life Reviews | Year: 2012

The cross-sectional decontextualization afflicting contemporary neuroscience - attributing to 'the brain' what is the province of the whole organism - is mirrored by an evolutionary decontextualization exceptionalizing consciousness. The living state is characterized by cognitive processes at all scales and levels of organization. Many can be associated with dual information sources that 'speak' a 'language' of behavior-in-context. Shifting global broadcasts analogous to consciousness, albeit far slower - wound healing, tumor control, immune function, gene expression, etc. - have emerged through repeated evolutionary exaptation of the crosstalk and noise inherent to all information transmission. These recruit 'unconscious' cognitive modules into tunable arrays as needed to meet threats and opportunities across multiple frames of reference. The development is straightforward, based on the powerful necessary conditions imposed by the asymptotic limit theorems of communication theory, in the same sense that the Central Limit Theorem constrains sums of stochastic variates. Recognition of information as a form of free energy instantiated by physical processes that consume free energy permits analogs to phase transition and nonequilibrium thermodynamic arguments, leading to 'dynamic regression models' useful for data analysis. © 2012 Elsevier B.V. Source


Johnston L.A.,Columbia University
Cold Spring Harbor Perspectives in Medicine | Year: 2014

Studies in Drosophila and mammals have made it clear that genetic mutations that arise in somatic tissues are rapidly recognized and eliminated, suggesting that cellular fitness is tightly monitored. During development, damaged, mutant, or otherwise unfit cells are prevented from contributing to the tissue and are instructed to die,whereas healthy cells benefit and populate the animal. This cell selection process, known as cell competition, eliminates somatic genetic heterogeneity and promotes tissue fitness during development. Yet cell competition also has a dark side. Super competition can be exploited by incipient cancers to subvert cellular cooperation and promote selfish behavior. Evidence is accumulating that MYCplays a key role in regulation of social behavior within tissues. Given the high number of tumors with deregulated MYC, studies of cell competition promise to yield insight into how the local environment yields to and participates in the early stages of tumor formation. © 2014 Cold Spring Harbor Laboratory Press; all rights reserved. Source


Liu X.S.,Columbia University
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research | Year: 2012

Despite the dramatic bone loss that occurs during lactation, bone mineral density rapidly recovers after offspring are weaned and milk production stops. The goal of this study is to quantify site-specific changes in bone quantity and quality during and after lactation in a mouse model. We used micro computed tomography (μCT), individual trabecula segmentation (ITS), digital topological analysis (DTA)-based tissue mineral density (TMD) analysis, and micro finite element analysis (μFEA) to quantify the effects of lactation and weaning on bone microarchitecture, mineralization, and stiffness at the spine, tibia, and femur. We found a significant decrease in trabecular plate microarchitecture, tissue mineralization of the trabecular surface, trabecular central skeleton, and intervening envelopes, and whole bone stiffness in lactating versus nulliparous mice at all three sites. In recovered mice, all these different aspects of bone quality were comparable to nulliparous mice at the spine. In contrast, trabecular plate microarchitecture and whole bone stiffness at the tibia and femur in recovered mice were lower than nulliparous mice, as were central trabecular tissue mineralization and cortical structure at the femur. These findings are consistent with clinical observations of partial recovery of femoral bone mineral density BMD after lactation in humans. The observed differences in trabecular surface tissue mineralization in nulliparous, lactating, and recovered mice are consistent with prior observations that maternal bone turnover shifts from resorption to formation at the time of pup weaning. The significant differences in trabecular central tissue mineralization during these three states suggest that osteocytes may contribute to the reversible loss of mineral during and after lactation. Future studies are necessary to determine whether differing functions of various bone cells at individual skeletal sites cause site-specific skeletal changes during and after lactation. Copyright © 2012 American Society for Bone and Mineral Research. Source


Smok D.A.,Columbia University
Seminars in Perinatology | Year: 2014

Up to half of all aortic dissections and ruptures in women younger than 40 years are associated with pregnancy. In pregnancy, women with aortic disease such as arteritis and aortitis are at significant risk of aneurysmal formation and dissection with potential for catastrophic outcomes. Pregnancy places predisposed women at an increased risk of dissection due to physiological and hormonal changes that occur, particularly those with connective tissue disorders, genetic syndromes, congenital heart disease, and other heritable and acquired conditions involving the aorta. Thus, preconception counseling and preparation are advised to determine which patients may cautiously pursue pregnancy, to optimize medical management prior to conception (antihypertensive medications and anticoagulants in the setting of mechanical valves), to identify women in whom aortic root repair should occur prior to pregnancy, and lastly, those in whom pregnancy is contraindicated. Additionally, discussion of the heritable nature of many aortic conditions and associated syndromes is indicated. Preconception and genetic counseling, management by a multidisciplinary team, along with close echocardiographic surveillance and medical management, are recommended if precursors of dissection are identified. © 2014 . Source


Hsiang S.M.,Columbia University
Proceedings of the National Academy of Sciences of the United States of America | Year: 2010

Understanding the economic impact of surface temperatures is an important question for both economic development and climate change policy. This study shows that in 28 Caribbean-basin countries, the response of economic output to increased temperatures is structurally similar to the response of labor productivity to high temperatures, a mechanism omitted from economic models of future climate change. This similarity is demonstrated by isolating the direct influence of temperature fromthat of tropical cyclones, an important correlate. Notably, output losses occurring in nonagricultural production (-2.4%/+1 °C) substantially exceed losses occurring in agricultural production (-0.1%/+1 °C). Thus, these results suggest that current models of future climate change that focus on agricultural impacts but omit the response of workers to thermal stress may underestimate the global economic costs of climate change. Source


Hyperglycemia, hypoglycemia, and increased glucose variability have each been shown to be independently associated with increased risk of mortality in the critically ill. Sechterberger and colleagues have completed a large observational cohort study that demonstrates that diabetic status modulates these relationships in clinically meaningful ways. These findings corroborate, in a strikingly consistent manner, those of another very recently published large observational study. © 2013 BioMed Central Ltd. Source


Roberts M.J.,North Carolina State University | Schlenker W.,Columbia University
American Economic Review | Year: 2013

We present a new framework to identify supply elasticities of storable commodities where past shocks are used as exogenous price shifters. In the agricultural context, past yield shocks change inventory levels and futures prices of agricultural commodities. We use our estimated elasticities to evaluate the impact of the 2009 Renewable Fuel Standard on commodity prices, quantities, and food consumers' surplus for the four basic staples: corn, rice, soybeans, and wheat. Prices increase 20 percent if one-third of commodities used to produce ethanol are recycled as feedstock, with a positively skewed 95 percent confidence interval that ranges from 14 to 35 percent. Source


A method, apparatus, and medium are provided for tracing the origin of network transmissions. Connection records are maintained at computer system for storing source and destination addresses. The connection records also maintain a statistical distribution of data corresponding to the data payload being transmitted. The statistical distribution can be compared to that of the connection records in order to identify the sender. The location of the sender can subsequently be determined from the source address stored in the connection record. The process can be repeated multiple times until the location of the original sender has been traced.


Patent
Columbia University | Date: 2014-05-07

The present disclosure is directed to methods and systems for processing a thin film samples. In an exemplary method, semiconductor thin films are loaded onto two different loading fixtures, laser beam pulses generated by a laser source system are split into first laser beam pulses and second laser beam pulses, the thin film loaded on one loading fixture is irradiated with the first laser beam pulses to induce crystallization while the thin film loaded on the other loading fixture is irradiated with the second laser beam pulses. In a preferred embodiment, at least a portion of the thin film that is loaded on the first loading fixture is irradiated while at least a portion of the thin film that is loaded on the second loading fixture is also being irradiated. In an exemplary embodiment, the laser source system includes first and second laser sources and an integrator that combines the laser beam pulses generated by the first and second laser sources to form combined laser beam pulses. In certain exemplary embodiments, the methods and system further utilize additional loading fixtures for processing additional thin film samples. In such methods and systems, the irradiation of thin film samples loaded on some of the loading fixtures can be performed while thin film samples are being loaded onto the remaining loading fixtures. In certain exemplary methods and systems, the crystallization processing of the semiconductor thin film samples can consist of a sequential lateral solidification (SLS) process.


Patent
Columbia University | Date: 2011-12-16

The invention discloses biomarkers for human autism. The invention provides methods for treating, preventing, and diagnosing human autism and autism-related disorders.


An Advanced Laser Fluorometer (ALF) can combine spectrally and temporally resolved measurements of laser-stimulated emission (LSE) for characterization of dissolved and particulate matter, including fluorescence constituents, in liquids. Spectral deconvolution (SDC) analysis of LSE spectral measurements can accurately retrieve information about individual fluorescent bands, such as can be attributed to chlorophyll-a (Chl-a), phycobiliprotein (PBP) pigments, or chromophoric dissolved organic matter (CDOM), among others. Improved physiological assessments of photosynthesizing organisms can use SDC analysis and temporal LSE measurements to assess variable fluorescence corrected for SDC-retrieved background fluorescence. Fluorescence assessments of Chl-a concentration based on LSE spectral measurements can be improved using photo-physiological information from temporal measurements. Quantitative assessments of PBP pigments, CDOM, and other fluorescent constituents, as well as basic structural characterizations of photosynthesizing populations, can be performed using SDC analysis of LSE spectral measurements.


Patent
Columbia University | Date: 2010-08-27

A microfluidic separation device suitable for high throughput applications such as medical treatments, and associated methods and systems, are described. Embodiments are suitable for treatment of end stage renal disease.


In one aspect, the present invention is directed to methods for fabricating multilayer polymacromer compositions. In some embodiments, the multilayer polymacromer compositions described herein can comprise heterobifunctional macromolecules and heterotrifunctional molecules.


Patent
Columbia University | Date: 2010-06-25

Provided is dental stem cell comprising an Oct3/4 transgene. Also provided is a method of making a pluripotent stem cell. Additionally, a method of preparing an insulin-secreting cell is provided. Further provided is an insulin-secreting cell prepared by that method. A method of preparing a chondrocyte-like cell is also provided, as is a chondrocyte-like cell prepared by that method. Additionally provided is a method of preparing a myocyte-like cell. Also, a myocyte-like cell prepared by that method is provided. A method of preparing a hair follicle-like cell is additionally provided, as is a hair follicle-like cell prepared by that method. A method of preparing a neuron-like cell is additionally provided, as is a neuron-like cell prepared by that method.


Patent
Columbia University | Date: 2011-05-31

A fabricated electromechanical device is disclosed herein. An exemplary device includes, a substrate, at least one layer of a high-transconductance material separated from the substrate by a dielectric medium, a first electrode in electrical contact with the at least one layer of a high-transconductance material and separated from the substrate by at least one first supporting member, a second electrode in electrical contact with the layer of a high-transconductance material and separated from the substrate by at least one second supporting member, where the first electrode is electrically separate from the second electrode, and a third electrode separated from the at least one layer of high-transconductance material by a dielectric medium and separated from each of the first electrode and the second electrode by a dielectric medium.


Patent
Columbia University | Date: 2011-12-20

Apparatus and methods can include an optical waveguide coupled to a photonic crystal comprising a dielectric material, the photonic crystal located on an exterior surface of the optical waveguide and comprising a first surface including a first array of periodic features on or within the dielectric material, the array extending in at least two dimensions and including an effective dielectric permittivity different from the surrounding dielectric material. In an example, the periodic features include a specified lattice constant, the periodic features configured to extract a portion of propagating optical energy from the waveguide through the photonic crystal, the portion determined at least in part by the specified lattice constant.


Encoding information in a material using a material tracing system includes storing information to be encoded in the material, generating a number based on the information, determining an amount of at least one tracer to be incorporated into the material corresponding to the number, and incorporating the determined amount of the at least one tracer into the material. Decoding information encoded in the material includes measuring an amount of the at least one tracer, in some embodiments after tracer activation, determining a number corresponding to the measured at least one tracer, and decoding the number to obtain information associated with the material. A material tracing system is also provided.


Patent
Columbia University | Date: 2013-03-13

Systems and methods for heating a material wherein the system includes an electrical contact adapted to receive current and a glassy carbon heater in electrical communication with the electrical contact. In one embodiment, the sample is thermally evaporated. In one embodiment, a holding element adapted to hold the material, located in such proximity to the glassy carbon heater so as to receive heat generated by the glassy carbon heater, is included.


Methods, systems, and media for identifying similar songs using jumpcodes are provided. In some embodiments, methods for a cover song from a query song are provided, the methods comprising: identifying a query song jumpcode for the query song, wherein the query song jumpcode is indicative of changes in prominent pitch over a portion of the query song; identifying a plurality of reference song jumpcodes for a reference song, wherein each of the reference song jumpcodes is indicative of changes in prominent pitch over a portion of the reference song; determining if the query song jumpcode matches any of the plurality of reference song jumpcodes; and upon determining that the query song jumpcode matches at least one of the plurality of reference song jumpcodes, generating an indication that the reference song is a cover song of the query song.


Patent
Columbia University | Date: 2011-09-26

The present invention relates to aptamer/drug conjugate complexes and the use of such complexes, together with a trigger compound, to inducibly release a drug. Through these complexes, the present invention provides a means for establishing a drug reservoir in a subject, whereby drug may be released as needed. One specific embodiment of the invention provides an aptamer/insulin conjugate complex from which insulin may be released by an innocuous, orally administrable trigger, such as quinine.


Patent
Columbia University | Date: 2015-07-27

A fabricated electromechanical device is disclosed herein. An exemplary device includes, a substrate, at least one layer of a high-transconductance material separated from the substrate by a dielectric medium, a first electrode in electrical contact with the at least one layer of a high-transconductance material and separated from the substrate by at least one first supporting member, a second electrode in electrical contact with the layer of a high-transconductance material and separated from the substrate by at least one second supporting member, where the first electrode is electrically separate from the second electrode, and a third electrode separated from the at least one layer of high-transconductance material by a dielectric medium and separated from each of the first electrode and the second electrode by a dielectric medium.


Patent
Columbia University | Date: 2015-09-01

Techniques for fabricating diamond nanostructures including application of a self-assembled hard mask to a surface of a diamond substrate to define a pattern of masked regions having a predetermined diameter surrounded by an exposed portion. The exposed portion can be vertically etched to a predetermined depth using inductively coupled plasma to form a plurality of nanoposts corresponding to the masked regions. The nanoposts can be harvested to obtain a nanostructure with a diameter correspond