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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.

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.

Conrad J.M.,Massachusetts Institute of Technology | Shaevitz M.H.,Columbia University
Physical Review Letters | Year: 2010

New low-cost, high-power proton cyclotrons open the opportunity for a novel precision search for CP violation in the light neutrino sector. The accelerators can produce decay-at-rest neutrino beams located at multiple distances from a Gd-doped ultralarge water Cherenkov detector in order to search for CP violation in ν̄μ→ν̄e oscillations at short baselines. This new type of search complements presently proposed experiments, providing measurements that could lead to a substantially better exploration of CP violation in the neutrino sector. © 2010 The American Physical Society.

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.

Objective: To discuss implications for educational policy and practice relevant to closing the achievement gap based on the literature review and synthesis presented in 7 articles of the October 2011 special issue of the Journal of School Health. Methods: Implications for closing the achievement gap are drawn from analyses of current literature. Results: During the past several decades, school reform efforts to close the achievement gap have focused on various strategies, yielding very limited progress. Educationally relevant health disparities influence students' motivation and ability to learn, but reducing these disparities has been largely overlooked as an element of an overall strategy for closing the achievement gap. If these health problems are not addressed, the educational benefits of other school reform efforts will be jeopardized. Conclusions: Healthier students are better learners. School health programs and services that are evidence based, strategically planned to influence academic achievement, and effectively coordinated warrant validation as a cohesive school improvement initiative for closing the achievement gap. National, state, and local responsibilities for supporting school health are outlined, including shared strategies; leadership from the U.S. Department of Education; policy development; guidance, technical assistance, and professional development; accountability and data and software systems; and a research agenda. To date, the U.S. Department of Education has not provided leadership for integrating evidence-based, strategically planned, and effectively coordinated school health programs and services into the fundamental mission of schools. Now is an opportune time for change. © 2011, American School Health Association.

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.

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

Objectives: To outline the prevalence and disparities of physical activity among school-aged urban minority youth, causal pathways through which low levels of physical activity and fitness adversely affects academic achievement, and proven or promising approaches for schools to increase physical activity and physical fitness among youth. Methods: Literature review. Results: A large proportion of youth is insufficiently physically active. Estimates of population-wide levels of physical activity indicate that Black and Hispanic youth are less physically active than White youth, with disparities particularly evident for females. The population segments of youth with lowest levels of physical activity and fitness also have least access to school-based physical activity opportunities and resources. Physical activity affects metabolism and all major body systems, exerting powerful positive influences on the brain and spinal cord and, consequently, on emotional stability, physical health, and motivation and ability to learn. The cornerstone of school-based physical activity programs should be a high-quality physical education program based on national standards. Such programs are strongly recommended by the Task Force on Community Preventive Services as a way to increase physical activity and physical fitness among youth. Conclusions: Physical inactivity is highly and disproportionately prevalent among school-aged urban minority youth, has a negative impact on academic achievement through its effects on cognition, and effective practices are available for schools to address this problem. Increasing students' physical activity and physical fitness can best be achieved through a comprehensive approach that includes physical education, wise use of recess and after-school times, co-curricular physical activity opportunities, and bicycling or walking to and from school. © 2011, American School Health Association.

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.

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.

Halpern J.P.,Columbia University
Astrophysical Journal Letters | Year: 2011

Originally selected as a neutron star (NS) candidate in the ROSAT All-Sky Survey, 1RXS J141256.0+792204 ("Calvera") was discovered to be a 59ms X-ray pulsar in a pair of XMM-Newton observations by Zane etal. Surprisingly, their claimed detection of this pulsar in Fermi γ-ray data requires no period derivative, severely restricting its dipole magnetic field strength, spin-down luminosity, and distance to small values. This implies that the cooling age of Calvera is much younger than its characteristic spin-down age. If so, it could be a mildly recycled pulsar, or the first "orphaned" central compact object (CCO). Here we show that the published Fermi ephemeris fails to align the pulse phases of the two X-ray observations with each other, which indicates that the Fermi detection is almost certainly spurious. Analysis of additional Fermi data also does not confirm the γ-ray detection. This leaves the spin-down rate of Calvera less constrained, and its place among the families of NSs uncertain. It could still be either an ordinary pulsar, a mildly recycled pulsar, or an orphaned CCO. © 2011. The American Astronomical Society. All rights reserved.

Cherukupalli R.,Columbia University
American Journal of Public Health | Year: 2010

Economic studies of taxation typically estimate external costs of tobacco use to be low and refrain from recommending large tobacco taxes. Behavioral economics suggests that a rational decision-making process by individuals fully aware of tobacco's hazards might still lead to overconsumption through the psychological tendency to favor immediate gratification over future harm. Taxes can serve as a self-control device to help reduce tobacco use and enable successful quit attempts. Whether taxes are appropriately high depends on how excessively people underrate the harm from tobacco use and varies with a country's circumstances. Such taxes are likely to be more equitable for poorer subgroups than traditional economic analysis suggests, which would strengthen the case for increased tobacco taxation globally.

Pineda A.M.,Columbia University
The Journal of heart valve disease | Year: 2013

The study aim was to determine the safety and efficacy of a minimally invasive right mini-thoracotomy for aortic valve replacement (AVR) in patients who had undergone previous median sternotomy. Between January 2005 and December 2011, a total of 3,603 consecutive cases was retrospectively reviewed to identify patients with previous median sternotomy who subsequently underwent AVR. The outcomes of patients having minimally invasive surgery were compared with those in whom a median sternotomy approach had been employed. Among 77 patients identified, 36 (47%) underwent a minimally invasive approach, and 41 (53%) had a median sternotomy. The mean age of the minimally invasive group (33 males, three females) was 75.3 +/- 9.0 years, and that of the median sternotomy group (33 males, eight females) was 68.2 +/- 13.6 years (p = 0.009). The minimally invasive group had more prior sternotomy for coronary artery bypass graft surgery (86% versus 59%, p = 0.007), and fewer for prior valve surgery (33% versus 59%, p = 0.02). In-hospital mortality was zero for the minimally invasive cohort versus four (10%) in the median sternotomy group (p = 0.08); composite postoperative complications occurred in six (17%) versus 19 (46%) (p = 0.005) of these two groups, respectively. The median intensive care unit and total hospital length of stay were 48 h [interquartile range (IQR) 41-97] versus 69 h [IQR 45-174] (p = 0.03), and seven days [IQR 5-10] versus 9 days [IQR 7-15] (p = 0.03) for the minimally invasive and median sternotomy group, respectively. Minimally invasive AVR via a right mini-thoracotomy in patients with previous cardiac surgery can be performed safely, and is associated with shorter intensive care unit and total hospital stays, a lower morbidity, and a trend towards lower mortality.

Harper K.N.,Columbia University
American journal of physical anthropology | Year: 2013

Though agriculture is often viewed as one of humanity's crowning achievements, skeletal evidence indicates that dependence on domesticated plants and animals was accompanied by an increase in infectious disease. Scientists have proposed that many important infections emerged in the period following the advent of agriculture, as a result of newly dense populations and novel proximity to domestic animals that served as reservoirs for novel pathogens. Here, we review genomic evidence regarding pathogen origins, analyzing these data using the epidemiological transition framework. Genetic information has forced us to reconsider how and when many important pathogens emerged; it appears that a number of infections thought to result from contact with domesticated animals arose much earlier than agriculture was adopted. We also consider the broader effect of agriculture upon the microbiome, exploring potential consequences for human health. We end by discussing the changes in the human microbe-scape we are likely to see in the future. Copyright © 2013 Wiley Periodicals, Inc.

Cha W.,Columbia University
Nature Materials | Year: 2016

Exploiting 2D materials for spintronic applications can potentially realize next-generation devices featuring low power consumption and quantum operation capability. The magnetic exchange field (MEF) induced by an adjacent magnetic insulator enables efficient control of local spin generation and spin modulation in 2D devices without compromising the delicate material structures. Using graphene as a prototypical 2D system, we demonstrate that its coupling to the model magnetic insulator (EuS) produces a substantial MEF (>14 T) with the potential to reach hundreds of tesla, which leads to orders-of-magnitude enhancement of the spin signal originating from the Zeeman spin Hall effect. Furthermore, the new ferromagnetic ground state of Dirac electrons resulting from the strong MEF may give rise to quantized spin-polarized edge transport. The MEF effect shown in our graphene/EuS devices therefore provides a key functionality for future spin logic and memory devices based on emerging 2D materials in classical and quantum information processing. © 2016 Nature Publishing Group

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.

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.

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.

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.

Wichterle H.,Columbia University | Gifford D.,Massachusetts Institute of Technology | Mazzoni E.,New York University
Science | Year: 2013

A universal method for classifying neuronal subtypes will increase our understanding of the human brain.

Jurcic J.G.,Columbia University
Immunotherapy | Year: 2013

Radioimmunotherapy (RIT) represents an attractive strategy to deliver radiation selectively to tumor and other target organs while minimizing toxicity to normal tissues. RIT with β-particle-emitting isotopes targeting CD33, CD45 and CD66 can potentially allow intensification of conditioning before hematopoietic cell transplantation (HCT) in leukemia. Similarly, RIT directed against CD20 has shown promise in the setting of autologous and allogeneic HCT for B-cell lymphomas. α-particle immunotherapy with isotopes such as bismuth-213, actinium-225 and astatinine-211 offers the possibility of more selective and efficient killing of target cells while sparing the surrounding normal cells. Pretargeting strategies may further improve target:normal organ dose ratios. While RIT has demonstrated significant antitumor activity, ultimately, randomized studies will be required to determine if conditioning regimens that include this therapeutic modality can improve patient outcomes after HCT. © 2013 Future Medicine Ltd.

Wang L.,Columbia University
Nature Photonics | Year: 2016

The success of metal-based plasmonics for manipulating light at the nanoscale has been empowered by imaginative designs and advanced nano-fabrication. However, the fundamental optical and electronic properties of elemental metals, the prevailing plasmonic media, are difficult to alter using external stimuli. This limitation is particularly restrictive in applications that require modification of the plasmonic response at sub-picosecond timescales. This handicap has prompted the search for alternative plasmonic media, with graphene emerging as one of the most capable candidates for infrared wavelengths. Here we visualize and elucidate the properties of non-equilibrium photo-induced plasmons in a high-mobility graphene monolayer. We activate plasmons with femtosecond optical pulses in a specimen of graphene that otherwise lacks infrared plasmonic response at equilibrium. In combination with static nano-imaging results on plasmon propagation, our infrared pump–probe nano-spectroscopy investigation reveals new aspects of carrier relaxation in heterostructures based on high-purity graphene. © 2016 Nature Publishing Group

Pon L.A.,Columbia University
Current Biology | Year: 2013

Mitochondria form a dynamic network in which organelles fuse or divide in response to metabolic changes or cellular stress. New work shows that mitochondria do not divide in isolation from other cellular structures. Rather, they carry out this process in partnership with the endoplasmic reticulum and actin filaments. © 2013 Elsevier Ltd.

Guarrera J.V.,Columbia University
Liver Transplantation | Year: 2012

Key Points 1. Hypothermic machine perfusion (HMP) is in its infancy in clinical liver transplantation. Potential benefits include diminished preservation injury (PI) and improved graft function. 2. We have employed HMP in 21 extended criteria donor (ECD livers) at our center with excellent clinical outcomes. 3. Our experience with liver HMP is the only reported clinical experience worldwide representing a total of 41 successful liver transplant cases showing improved outcomes and diminished markers of ischemia/reperfusion injury. 4. Further multicenter and large scale trials are now warranted to further explore the benefits and applicability of liver HMP into the clinical mainstream. © 2012 AASLD.

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.

Tanaka T.L.,Max Planck Institute for Astrophysics | Li M.,Columbia University
Monthly Notices of the Royal Astronomical Society | Year: 2014

The origins of the ∼109 M⊙ quasar supermassive black holes (BHs) at redshifts z > 6 remain a theoretical puzzle. One possibility is that they grew from ∼105 M⊙ BHs formed in the 'direct collapse' of pristine, atomic-cooling (temperatures ≳ 8000 K; PAC) gas that did not fragment to form ordinary stars due to a lack of molecular hydrogen and metals. We propose that baryonic streaming - the relic relative motion of gas with respect to dark matter from cosmological recombination - provides a natural mechanism for establishing the conditions necessary for direct collapse. This effect delays the formation of the first stars by inhibiting the infall of gas into dark matter haloes; streaming velocities more than twice the root-mean-square value could forestall star formation until halo virial temperatures ≳ 8000 K. The resulting PAC gas can proceed to form massive BHs by any of the mechanisms proposed in the literature to induce direct collapse in the absence of an ultraviolet background. This scenario produces haloes containing PAC gas at a characteristic redshift z ∼ 30. It can explain the abundance of the most luminous quasars at z ≈ 6, regardless of whether direct collapse occurs in nearly all or less than 1 per cent of PAC haloes. © 2014 The Authors Published by Oxford University Press on behalf of the Royal Astronomical Society.

Sparrow J.R.,Columbia University
Advances in Experimental Medicine and Biology | Year: 2010

Mice harboring a null mutation in Abca4/Abcr serve as a model of autosomal recessive Stargardt disease. Consistent with the human retinal disorder, deficiency in Abcr is associated with substantial accumulations of lipofuscin pigments in retinal pigment epithelial (RPE) cells. To observe for photoreceptor cell degeneration in these mutant mice, outer nuclear layer (ONL) thickness was measured at 200 μm intervals superior and inferior to the optic nerve head. ONL width in Abcr -/- mouse was reduced at 8-9 month and 11 and 13 months relative to Abcr +/+ mice; thinning was more pronounced centrally and in superior retina. The numbers of photoreceptor nuclei spanning the width of the outer nuclear layer were also reduced. No evidence of age-related ONL thinning was observed in Abcr +/+ mice at these ages. We conclude that albino Abcr -/- mice exhibit progressive photoreceptor cell loss that is detectable at 8 months of age and that has worsened by 11 and 13 months of age. The measurement of ONL thickness is an established approach to assessing photoreceptor cell integrity and can be used in preclinical studies using Abcr -/- mice. © Springer Science+Business Media, LLC 2010.

Metzger B.D.,Columbia University | Piro A.L.,California Institute of Technology
Monthly Notices of the Royal Astronomical Society | Year: 2014

The coalescence of binary neutron stars (NSs) may in some cases produce a stable massive NS remnant rather than a black hole. Due to the substantial angular momentum from the binary, such a remnant is born rapidly rotating and likely acquires a strong magnetic field (a 'millisecond magnetar'). Magnetic spin-down deposits a large fraction of the rotational energy from the magnetar behind the small quantity of mass ejected during the merger. If the magnetar outflow is indeed trapped behind the ejecta (instead of placing most of its energy into a collimated jet), this has the potential for creating a bright transient that could be useful for determining whether an NS or black holewas formed in the merger.We investigate the expected signature of such an event, including for the first time the important impact of e± pairs injected by the millisecond magnetar into the surrounding nebula. These pairs cool via synchrotron and inverse Compton emission, producing a pair cascade and hard X-ray spectrum. A fraction of these X-rays are absorbed by the ejecta walls and re-emitted as thermal radiation, leading to an optical/UV transient peaking at a luminosity of ~1043-1044 erg s-1 on a time-scale of several hours to days. This is dimmer than predicted by simpler analytic models because the large optical depth of e± pairs across the nebula suppresses the efficiency with which the magnetar spin-down luminosity is thermalized. Nevertheless, the optical/UV emission is more than two orders of magnitude brighter than a radioactively powered 'kilonova'. In some cases, nebular X-rays are sufficiently luminous to re-ionize the ejecta, in which case nonthermal X-rays escape the ejecta unattenuated with a similar peak luminosity and time-scale as the optical radiation.We discuss the implications of our results for the temporally extended X-ray emission that is observed to follow some short gamma-ray bursts (GRBs), including the kilonova candidates GRB 080503 and GRB 130603B. © 2014 The Authors Published by Oxford University Press on behalf of the Royal Astronomical Society.

Kharbanda A.B.,Columbia University
Archives of pediatrics & adolescent medicine | Year: 2012

To validate and refine a clinical prediction rule to identify which children with acute abdominal pain are at low risk for appendicitis (Low-Risk Appendicitis Rule). Prospective, multicenter, cross-sectional study. Ten pediatric emergency departments. Children and adolescents aged 3 to 18 years who presented with suspected appendicitis from March 1, 2009, through April 30, 2010. The test performance of the Low-Risk Appendicitis Rule. Among 2625 patients enrolled, 1018 (38.8% [95% CI, 36.9%-40.7%]) had appendicitis. Validation of the rule resulted in a sensitivity of 95.5% (95% CI, 93.9%-96.7%), specificity of 36.3% (33.9%-38.9%), and negative predictive value of 92.7% (90.1%-94.6%). Theoretical application would have identified 573 (24.0%) as being at low risk, misclassifying 42 patients (4.5% [95% CI, 3.4%-6.1%]) with appendicitis. We refined the prediction rule, resulting in a model that identified patients at low risk with (1) an absolute neutrophil count of 6.75 × 103/μL or less and no maximal tenderness in the right lower quadrant or (2) an absolute neutrophil count of 6.75 × 103/μL or less with maximal tenderness in the right lower quadrant but no abdominal pain with walking/jumping or coughing. This refined rule had a sensitivity of 98.1% (95% CI, 97.0%-98.9%), specificity of 23.7% (21.7%-25.9%), and negative predictive value of 95.3% (92.3%-97.0%). We have validated and refined a simple clinical prediction rule for pediatric appendicitis. For patients identified as being at low risk, clinicians should consider alternative strategies, such as observation or ultrasonographic examination, rather than proceeding to immediate computed tomographic imaging.

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.

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.

Chernikov A.,Columbia University
Nature Photonics | Year: 2015

Control of the optical properties of matter on ultrashort timescales is of both fundamental interest and central importance for applications in photonics. It is desirable to achieve pronounced changes over a broad spectral range using the least possible amount of material. Here, we demonstrate a dramatic change over a spectral range of hundreds of meV on the femtosecond timescale in the optical response of atomically thin two-dimensional crystals of the transition-metal dichalcogenide WS2 following excitation by intense optical pump pulses. Our findings reveal the role of extremely strong Coulomb interactions. At the direct gap, we observe a Mott transition from excitonic states to free carriers, accompanied by a giant bandgap renormalization of approximately 500 meV and the development of population inversion. © 2015 Nature Publishing Group

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.

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.

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.

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.

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.

Kousteni S.,Columbia University
Current Osteoporosis Reports | Year: 2011

Several mechanisms contribute to the decline of all physiologic functions during aging. As a consequence, disease incidence increases with age. Central to this multifactorial process is the increase in oxidative stress levels, which correlates with age-related disease pathogenesis in animal models and in humans. Accordingly, skeletal aging and aging-related bone diseases are also associated with accumulation of reactive oxygen species. In a variety of organs, including the skeleton, mutations in components of antioxidant defense pathways have been found to lead to progressive degenerative diseases. The molecules involved are highly conserved, can sense and respond to increases in oxidative stress levels, alterations in energy status, DNA and protein damage, and they all have a common transcriptional target, the FoxO family of Forkhead transcription factors. Oxidative stress promotes both the transcriptional activity and protein stability of FoxOs. In turn, activated FoxOs promote antioxidant defense by controlling the expression of genes involved in the oxidative stress response, DNA repair, cell cycle, and apoptosis. Among the FoxO isoforms, FoxO1 in osteoblasts uses a previously unrecognized mechanism to preserve redox balance by promoting protein synthesis and subsequently inhibiting cell cycle arrest. This evidence indicates that FoxO1 integrates and orchestrates responses to different stress signals to maintain bone cell function and preserve skeletal homeostasis. © 2011 Springer Science+Business Media, LLC.

Beloborodov A.M.,Columbia University | Beloborodov A.M.,RAS Lebedev Physical Institute
Monthly Notices of the Royal Astronomical Society | Year: 2010

Nuclear and Coulomb collisions in gamma-ray burst (GRB) jets create a hot e± plasma. This collisional heating starts when the jet is still opaque, and extends to the transparent region. The e± plasma radiates its energy. As a result, a large fraction of the jet energy is converted to escaping radiation with a well-defined spectrum. The process is simulated in detail using the known rates of collisions and accurate calculations of radiative transfer in the expanding jet. The result reproduces the spectra of observed GRBs that typically peak near 1 MeV and extend to much higher energies with a photon index β ∼ -2.5. This suggests that collisional heating may be the main mechanism for GRB emission. © 2010 The Author. Journal compilation © 2010 RAS.

Clemens T.L.,Johns Hopkins University | Karsenty G.,Columbia University
Journal of Bone and Mineral Research | Year: 2011

The past five years have witnessed the emergence and discovery of unexpected functions played by the skeleton in whole-organism physiology. Among these newly described tasks is the role of bone in the control of energy metabolism, which is achieved through the secretion of osteocalcin, an osteoblasts-derived hormone regulating insulin secretion, insulin sensitivity, and energy expenditure. These initial findings raised several fundamental questions on the nature of insulin action in bone. Discoveries made independently by our two groups have provided answers recently to some of these questions. Through the analysis of mice lacking insulin receptor (InsR) only in osteoblasts, we found that insulin signaling in these cells favors whole-body glucose homeostasis. Importantly, this function of insulin signaling in osteoblasts was achieved through the negative regulation of osteocalcin carboxylation and bioavailability. Our studies also established that insulin signaling in osteoblasts was a positive regulator not only of postnatal bone acquisition but also of bone resorption. Interestingly, it appears that insulin signaling in osteoblasts induced osteocalcin activation by stimulating osteoclast activity. Indeed, the low pH generated during bone resorption is a sufficient means to decarboxylate osteocalcin. Our findings establish that the osteoblast is an important target used by insulin to control whole-body glucose homeostasis and identify bone resorption as the mechanism regulating osteocalcin activation. Copyright © 2011 American Society for Bone and Mineral Research.

Wapner R.J.,Columbia University
Seminars in Perinatology | Year: 2013

Antenatal corticosteroids have been proven to accelerate fetal lung development and reduce neonatal morbidity and mortality when given between 28 and 34 weeks of gestation. However, there is only limited research to guide their use in the periviable period (22-26 weeks). Laboratory studies suggest that it is biologically plausible for antenatal steroids to be effective in this gestational period. In addition, cohort studies have demonstrated the efficacy of antenatal corticosteroids in reducing neonatal mortality and IVH. Follow-up studies performed between 18 and 22 months of age also suggest a long-term benefit to antenatal use in this period. Based on this information, antenatal corticosteroids should be used in appropriate patients at high risk for preterm birth at 23-26 weeks of gestation. An advantageous outcome to treatment at 22 weeks is less certain. © 2013 Elsevier Inc.

Cheung Y.K.,Columbia University
Clinical Trials | Year: 2013

Background In the planning of a dose finding study, a primary design objective is to maintain high accuracy in terms of the probability of selecting the maximum tolerated dose. While numerous dose finding methods have been proposed in the literature, concrete guidance on sample size determination is lacking. Purpose With a motivation to provide quick and easy calculations during trial planning, we present closed form formulae for sample size determination associated with the use of the Bayesian continual reassessment method (CRM). Methods We examine the sampling distribution of a nonparametric optimal design and exploit it as a proxy to empirically derive an accuracy index of the CRM using linear regression. Results We apply the formulae to determine the sample size of a phase I trial of PTEN-long in pancreatic cancer patients and demonstrate that the formulae give results very similar to simulation. The formulae are implemented by an R function getn in the package dfcrm. Limitations The results are developed for the Bayesian CRM and should be validated by simulation when used for other dose finding methods. Conclusions The analytical formulae we propose give quick and accurate approximation of the required sample size for the CRM. The approach used to derive the formulae can be applied to obtain sample size formulae for other dose finding methods. © 2012 The Author(s).

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.

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.

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.

Bienstock D.,Columbia University
SIAM Journal on Optimization | Year: 2016

Recent research has focused on the complexity of extensions of the classical trust-region subproblem, which addresses the minimization of a quadratic function over a unit ball in Rn, a problem of importance in many applications. Even though the trust-region subproblem can be considered well-solved (from the perspective of both theory and implementation), even minor extensions are NP-hard. The Celis-Dennis-Tapia (CDT) problem is an extension of the trust-region subproblem, involving the minimization of a quadratic function over the intersection of two ellipsoids in Rn. In this paper we show how to adapt a construction of Barvinok so as to obtain a polynomialtime algorithm for quadratic programming with a fixed number of quadratic constraints (one of which is ellipsoidal) under the bit model of computing. © 2016 Society for Industrial and Applied Mathematics.

BACKGROUND:: Cesarean delivery (CD) is associated with significantly increased risks of anesthesia-related adverse events (ARAEs) and nonanesthetic perioperative morbidity compared with vaginal delivery. Temporal trends in these adverse outcomes remain unknown despite efforts to improve maternal safety. This study examines temporal trends in ARAEs and nonanesthetic perioperative complications in CDs in New York hospitals. METHODS:: Data are from the State Inpatient Database for New York, 2003–2012. ARAEs, including minor and major ARAEs, and nonanesthetic perioperative complications were identified through International Classification of Diseases, Ninth Revision, Clinical Modification codes. Statistical significance in time trends was assessed using the Cochran–Armitage test and multivariable logistic regression. RESULTS:: Of the 785,854 CDs studied, 5,715 (730 per 100,000; 95% CI, 710 to 750) had at least one ARAE and 7,040 had at least one perioperative complication (890 per 100,000; 95% CI, 870 to 920). The overall annual rate of ARAEs decreased from 890 per 100,000 in 2003 to 660 in 2012 (25% decrease; 95% CI, 16 to 34; P < 0.0001). The rate of minor ARAEs decreased 23% (95% CI, 13 to 32) and of major ARAEs decreased 43% (95% CI, 23 to 63). No decrease was observed in the rate of ARAEs for CDs performed under general anesthesia. The rate of nonanesthetic complications increased 47% (95% CI, 31 to 63; P < 0.0001). CONCLUSIONS:: Anesthesia-related outcomes in cesarean deliveries appear to have improved significantly across hospitals in New York in the past decade. Perioperative nonanesthetic complications remain a serious healthcare issue. © by 2015, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. All Rights Reserved.

Gorin S.S.,Columbia University
Annals of Behavioral Medicine | Year: 2010

The aims of this commentary are two-fold: First, to amplify some of the points that Aspinwall, Tedeschi, Coyne, Tennen, and Ranchor have raised, noting the importance of a return to basics. Second, to posit next steps in theory development and methods at the intersection of health psychology, positive psychology, and cancer. Additional theory development, more applications of large prospective studies, and instrument refinements are warranted to understand the effects of positive constructs on health outcomes and adaptation to cancer. This area of research would be strengthened by studies that incorporate survival, health-related quality of life, and well-being outcome measures, using cancer registries and/or multiple raters. More observational studies are necessary. Attention to social justice questions is suggested in future studies at the intersection of these fields. © The Society of Behavioral Medicine 2010.

Lu J.T.,Columbia University
Current Opinion in Cardiology | Year: 2010

Purpose of review: As genetic testing for long QT syndrome (LQTS) has become readily available, important advances are being made in understanding the exact link between ion channel mutation and observed phenotype. This paper reviews recent findings in the literature. Recent findings: Congenital LQTS is an important cause of sudden cardiac death. To date, 12 genes have been identified as the cause of congenital LQTS. With increasing availability of genetic testing, subtype-specific management of LQTS has become the standard of care. Detailed correlative studies between LQTS mutations and clinical phenotypes are leading the field towards 'mutation-specific' management within LQTS subtypes. A clear link between the distinct functional/biophysical defect in each LQT mutation and disease phenotype is complicated by the variable penetrance and pleiotropic expression of clinical phenotype. This is especially evident with the overlap syndrome now documented for several sodium channel (SCN5A) mutations. Summary: The management of LQTS has become subtype-specific due to the availability of genotype information. Review of recent literature suggests that 'mutation-specific' management is possible based upon distinct functional/biophysical characteristics of mutations within each LQT gene. Further research is required to clearly delineate the molecular and cellular mechanisms underlying variable penetrance, and pleiotropic expression of LQTS mutations. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

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.

The Time to Change campaign in England has attempted to change attitudes to mental illness at population level. The concept of cultural context is introduced to look at how mental illness functions in society and whether any change in the current context is feasible. Declaration of interest None. © 2013 Society for Endocrinology.

Fahn S.,Columbia University
Movement Disorders | Year: 2010

Many people with Parkinson's disease (PD) and their family members ask their physicians "What is happening in research on Parkinson's disease? Is there anything new?" As the initial speaker at the symposium organized by the Parkinson's Disease Foundation in celebration of its 50th anniversary, I sought to address these questions, focusing on research published between the years 1997 and 2007. I cataloged the advances I considered most important in the field, recognizing my viewpoint is a subjective one and most likely differs from similar listings that others would put together. Space limitation allows me to discuss only a tiny fraction of the remarkable new findings that have been discovered during this 10-year span. Nevertheless, I expect the readers of this summation of advances in the field to be as impressed as I am on the wealth, breadth, and excitement stirring in the field of PD research. Included in this overview are highlights in both laboratory science and clinical science of PD research. In the former category are advances in knowledge on the genetics of PD; potential etiologic and pathogenic causes, especially the better understanding of endogenous factors within dopaminergic neurons; pathologic changes including deposition of alpha-synuclein aggregates; and the consequences of altered alpha-synuclein on the degradation of proteins by both the ubiquitin-proteasomal pathway and the lysosome. Clinical science has also been very active and impressively productive with important clinical advances. In this category are new information on the epidemiology of PD, including awareness of additional factors (besides smoking) that might slow the onset and worsening of PD, such as caffeine and urate; neuroimaging with positron emission tomography and single photon emission tomography; keener awareness of nonmotor features of PD and their impact on quality of life for the persons with PD and their family; recognition of behavioral complications of medications utilized to treat PD, such as impulse control problems; appreciation of the natural history of PD with the increasing impairments as the disease relentlessly worsens over time; the many controlled clinical trials attempting to slow the progression of the disease and to provide new symptomatic therapies; and surgical approaches to alleviate symptoms and progression, including cellular and gene therapy as well as deep brain stimulation. © 2010 Movement Disorder Society.

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.

Blitzer A.,Columbia University
European Journal of Neurology | Year: 2010

Spasmodic dysphonia is a focal laryngeal dystonia, with adductor, abductor, mixed, respiratory and singer's types. Our series over 24 years includes 1300 patients. 82% are of the adductor type; 63% were female; 12% had a positive family history and 82.4% had a focal distribution. All of the patients were managed with varying degrees of success with individualised dosing of botulinum neurotoxin A injected into the laryngeal musculature under EMG guidance. © 2010 The Author(s).

Esvelt K.M.,Wyss Institute for Biologically Inspired Engineering | Wang H.H.,Wyss Institute for Biologically Inspired Engineering | Wang H.H.,Harvard University | Wang H.H.,Columbia University
Molecular Systems Biology | Year: 2013

Genome-modification technologies enable the rational engineering and perturbation of biological systems. Historically, these methods have been limited to gene insertions or mutations at random or at a few pre-defined locations across the genome. The handful of methods capable of targeted gene editing suffered from low efficiencies, significant labor costs, or both. Recent advances have dramatically expanded our ability to engineer cells in a directed and combinatorial manner. Here, we review current technologies and methodologies for genome-scale engineering, discuss the prospects for extending efficient genome modification to new hosts, and explore the implications of continued advances toward the development of flexibly programmable chasses, novel biochemistries, and safer organismal and ecological engineering. © 2013 EMBO and Macmillan Publishers Limited.

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.

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.

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.

Beghi E.,Mario Negri Institute for Pharmacological Research | Hesdorffer D.,Columbia University
Epilepsia | Year: 2014

The incidence, prevalence, and mortality of epilepsy vary across countries with different economies. Differences can be explained by methodological problems, premature mortality, seizure remission, socioeconomic factors, and stigma. Diagnostic misclassification - one possible explanation - may result from inclusion of patients with acute symptomatic or isolated unprovoked seizures. Other sources of bias include age and ethnic origin of the target population, definitions of epilepsy, retrospective versus prospective ascertainment, sources of cases, and experienced and perceived stigma. Premature mortality is an issue in low-income countries (LICs), where treatment gap, brain infections, and traumatic brain injuries are more common than in high-income countries (HICs). Death rates may reflect untreated continued seizures or inclusion of acute symptomatic seizures. Lack of compliance with antiepileptic drugs has been associated with increased risk for death, increased hospital admissions, motor vehicle accidents, and fractures in poor communities. Epilepsy is a self-remitting clinical condition in up to 50% of cases. Studies in untreated individuals from LICs have shown that the proportion of remissions overlaps that of countries where patients receive treatment. When the identification of patients is based on spontaneous reports (e.g., door-to-door surveys), patients in remission may be less likely to disclose the disease for fear of stigmatization with no concurrent benefits. This might lead to underascertainment of cases when assessing the lifetime prevalence of epilepsy. In LICs, the proportion of people living in poverty is greater than in HICs. Poverty is associated with risk factors for epilepsy, risk for developing epilepsy, and increased mortality. The high incidence and prevalence of epilepsy found in LICs is also observed in low income individuals from HICs. Epileptogenic conditions are associated with an increased mortality. This may partly explain the difference between incidence and lifetime prevalence of epilepsy in LICs. Poverty within LICs and HICs could be a preventable cause of mortality in epilepsy. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here. © Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.

Talchai S.C.,King Mongkuts University of Technology Thonburi | Accili D.,Columbia University
Diabetes | Year: 2015

β-Cell dysfunction in diabetes results from abnormalities of insulin production, secretion, and cell number. These abnormalities may partly arise from altered developmental programming of β-cells. Foxo1 is important to maintain adult β-cells, but little is known about its role in pancreatic progenitor cells as determinants of future β-cell function. We addressed this question by generating an allelic series of somatic Foxo1 knockouts at different stages of pancreatic development in mice. Surprisingly, ablation of Foxo1 in pancreatic progenitors resulted in delayed appearance of Neurogenin3(+) progenitors and their persistence into adulthood as a self-replicating pool, causing a fourfold increase of β-cell mass. Similarly, Foxo1 ablation in endocrine progenitors increased their numbers, extended their survival, and expanded β-cell mass. In contrast, ablation of Foxo1 in terminally differentiated β-cells did not increase β-cell mass nor did it affect Neurogenin3 expression. Despite the increased β-cell mass, islets from mice lacking Foxo1 in pancreatic or endocrine progenitors responded poorly to glucose, resulting in glucose intolerance. We conclude that Foxo1 integrates cues that determine developmental timing, pool size, and functional features of endocrine progenitor cells, resulting in a legacy effect on adult β-cell mass and function. Our results illustrate how developmental programming predisposes to β-cell dysfunction in adults and raise questions on the desirability of increasing β-cell mass for therapeutic purposes in type 2 diabetes. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Nagaike T.,Columbia University
RNA biology | Year: 2011

3' processing of mRNA precursors is frequently coupled to transcription by RNA polymerase II (RNAP II). This coupling is well known to involve the C-terminal domain of the RNAP II largest subunit, but a variety of other transcription-associated factors have also been suggested to mediate coupling. Our recent studies have provided direct evidence that transcriptional activators can enhance the efficiency of transcription-coupled 3' processing. In this point-of-view, we discuss the mechanisms that underlie coupling, and their implications for control of alternative polyadenylation, which is emerging as a significant regulator of cell growth control.

Gerasimidis S.,Columbia University
Journal of Constructional Steel Research | Year: 2014

Most of the approaches to the progressive collapse analysis of steel frames have focused so far on computational methods which try to capture the solution of the system responding to localized damage. For the case of progressive collapse, damage is included in the model through the removal of a key element of the structure. The computational difficulty of these approaches, however, makes it very hard for practicing engineers to perform these analyses. For that reason, it is very important for the engineering community to develop simple and reliable analytical tools which could provide useful information on the response of a structure to a column loss. This paper applies a threat-independent analytical method regarding the corner column loss case, which has been presented by the author in previous papers to a wide range of symmetric and non-symmetric steel moment-resisting (sway) frames. The analytical and simple method can indicate the collapse mechanism of a steel frame for the case of a corner column loss through the development of critical ductility curves. The impact of the number of floors, the column removal location, the vertical irregularity and the design of the frames is also studied. © 2013 Elsevier Ltd. All rights reserved.

Kang K.,Columbia University
Tunnelling and Underground Space Technology | Year: 2010

This paper investigates the characteristic length scale in an analytical correlation of critical ventilation velocity. The critical ventilation velocity is defined as the minimum airflow velocity to prevent smoke backlayering and is often used for smoke control in tunnels. Using a one-dimensional assumption of uniform mixing, the correlation of critical ventilation velocity was derived from the Froude number, which considered tunnel height as the characteristic length scale. Using numerical modelling, this study examines the effects of enclosure blockage ratio and tunnel width or aspect ratio on critical ventilation velocity. In particular, the results suggest that the correlation with tunnel hydraulic diameter may provide a better characterization of critical ventilation velocity. This is supported from the experimental data reported by others on the effect of tunnel width. The practical implications of using hydraulic diameter in determining critical ventilation velocity are discussed. © 2009 Elsevier Ltd.

Background: During gene conversion, genetic information is transferred unidirectionally between highly homologous but non-allelic regions of DNA. While germ-line gene conversion has been implicated in the pathogenesis of some diseases, somatic gene conversion has remained technically difficult to investigate on a large scale.Methods: A novel analysis technique is proposed for detecting the signature of somatic gene conversion from SNP microarray data. The Wellcome Trust Case Control Consortium has gathered SNP microarray data for two control populations and cohorts for bipolar disorder (BD), cardiovascular disease (CAD), Crohn's disease (CD), hypertension (HT), rheumatoid arthritis (RA), type-1 diabetes (T1D) and type-2 diabetes (T2D). Using the new analysis technique, the seven disease cohorts are analyzed to identify cohort-specific SNPs at which conversion is predicted. The quality of the predictions is assessed by identifying known disease associations for genes in the homologous duplicons, and comparing the frequency of such associations with background rates.Results: Of 28 disease/locus pairs meeting stringent conditions, 22 show various degrees of disease association, compared with only 8 of 70 in a mock study designed to measure the background association rate (P < 10-9). Additional candidate genes are identified using less stringent filtering conditions. In some cases, somatic deletions appear likely. RA has a distinctive pattern of events relative to other diseases. Similarities in patterns are apparent between BD and HT.Conclusions: The associations derived represent the first evidence that somatic gene conversion could be a significant causative factor in each of the seven diseases. The specific genes provide potential insights about disease mechanisms, and are strong candidates for further study. Please see Commentary: http://www.biomedcentral.com/1741-7015/9/13/abstract. © 2011 Ross; licensee BioMed Central Ltd.

I present modeling of the X-ray pulsations from the central compact object (CCO) PSR J1852+0040 in the Galactic supernova remnant Kesteven 79. In the context of thermal surface radiation from a rotating neutron star (NS), a conventional polar cap model can reproduce the broad, large-amplitude X-ray pulse only with a "pencil plus fan" beam emission pattern, which is characteristic of ≳ 1012 G NS atmospheres, much greater than the ∼1010 G external dipole field inferred from the pulsar spin-down rate. This discrepancy can be explained by an axially displaced dipole. For other beaming patterns, it is necessary to invoke high-aspect-ratio emitting regions that are greatly longitudinally elongated, possibly due to an extremely offset dipole. For all assumed emission models, the existence of strong internal magnetic fields (≳ 1014 G) that preferentially channel internal heat to only a portion of the exterior is required to account for the implied high-temperature contrast across the stellar surface. This lends further observational evidence in support of the "hidden" strong magnetic field scenario, in which CCOs possess submerged magnetic fields that are substantially stronger than the external dipole field, presumably due to burial by fallback of supernova ejecta. I also conduct phase-resolved X-ray spectroscopy and find no evidence for prominent spin-phase-dependent absorption features that could be produced by cyclotron absorption/scattering. © 2014. The American Astronomical Society. All rights reserved.

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.

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

This commentary reflects on the first decade of the Teaching and Learning Moments (TLM) feature of Academic Medicine. The author places the feature within the context of a growing movement within health care to improve reflective practice through the practice of reflective writing and reading. As an example of the opportunity these reflective activities afford, the author depicts a seminar in which students and faculty from four health sciences schools learn together about culture, illness, and health care. The participants find that their own capacity to examine and write about aspects of their own lived experience contributes to their understanding of patients. The seminar has been a meaningful adventure for these students and clinicians, as the TLM feature has been for its authors and readers. Meeting on the grounds of stories of patients and of themselves, readers and writers demonstrate for themselves how their source of commitment to health is to be found very deep within the self. As a dividend, these moments of teaching and learning provide what is needed to become members of effective health care teams.

Goldman J.S.,Columbia University
Current Neurology and Neuroscience Reports | Year: 2012

The discovery of new autosomal dominant and susceptibility genes for Alzheimer's disease (AD) and frontotemporal degeneration (FTD) is revealing important new information about the neurodegenerative process and the risk for acquiring these diseases. It is becoming increasingly clear that both the mechanisms that drive these diseases and their phenotypes overlap. New technologies will assist access to genetic testing but may increase difficulty with genetic test interpretation. Thus, the process of genetic counseling and testing for these diseases is becoming more complex. This article will review current knowledge on the genetics of AD and FTD and suggest clinical guidelines for helping families to navigate through these complexities. The implications of future discoveries will be offered. © Springer Science+Business Media, LLC 2012.

Goodwin R.D.,Columbia University
Current Psychiatry Reports | Year: 2012

The prevalence of asthma has risen dramatically, especially among youth, in recent years, and asthma is now among the most common chronic conditions. Recent studies suggest a relationship between asthma and suicidal ideation, suicide attempt, and death by suicide. This paper reviews the literature, summarizes the weight of evidence, and discusses the clinical implications and future directions for research. © Springer Science+Business Media, LLC 2011.

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.

Woo S.-H.,Howard Hughes Medical Institute | Lumpkin E.A.,Columbia University | Patapoutian A.,Howard Hughes Medical Institute
Trends in Cell Biology | Year: 2015

The Merkel cell-neurite complex is a unique vertebrate touch receptor comprising two distinct cell types in the skin. Its presence in touch-sensitive skin areas was recognized more than a century ago, but the functions of each cell type in sensory transduction have been unclear. Three recent studies demonstrate that Merkel cells are mechanosensitive cells that function in touch transduction via Piezo2. One study concludes that Merkel cells, rather than sensory neurons, are principal sites of mechanotransduction, whereas two other studies report that both Merkel cells and neurons encode mechanical inputs. Together, these studies settle a long-standing debate on whether or not Merkel cells are mechanosensory cells, and enable future investigations of how these skin cells communicate with neurons. © 2014 Elsevier Ltd.

Danziger S.,Ben - Gurion University of the Negev | Levav J.,Columbia University | Avnaim-Pesso L.,Ben - Gurion University of the Negev
Proceedings of the National Academy of Sciences of the United States of America | Year: 2011

Are judicial rulings based solely on laws and facts? Legal formalism holds that judges apply legal reasons to the facts of a case in a rational, mechanical, and deliberative manner. In contrast, legal realists argue that the rational application of legal reasons does not sufficiently explain the decisions of judges and that psychological, political, and social factors influence judicial rulings. We test the common caricature of realism that justice is "what the judge ate for breakfast" in sequential parole decisions made by experienced judges.We record the judges' two daily food breaks, which result in segmenting the deliberations of the day into three distinct "decision sessions." We find that the percentage of favorable rulings drops gradually from ≈65% to nearly zero within each decision session and returns abruptly to ≈65% after a break. Our findings suggest that judicial rulings can be swayed by extraneous variables that should have no bearing on legal decisions.

Deckelbaum R.J.,Columbia University | Torrejon C.,University of Chile
Journal of Nutrition | Year: 2012

Dietary fatty acids (FA) are increasingly recognized as major biologic regulators and have properties that relate to health outcomes and disease. The longer chain, more bioactive (n-6) (or omega-6) FA and (n-3) (or omega-3) FA share similar elongation and desaturation enzymes in their conversion from the essential (n-6) FA, linoleic acid, and (n-3) FA, a-linolenic acid (ALA). Conversion from these essential FA is very inefficient. However, now for the (n-3) FA series, soy oil can be enriched with (n-3) stearidonic acid (SDA) to allow for much more efficient conversion to longer chain EPA. EPA and the longer chain DHA possess distinct physical and biological properties that generally impart properties to cells and tissue, which underlie their ability to promote health and prevent disease. Although active in a number of areas of human biology, mechanisms of action of EPA and DHA are perhaps best defined in cardiovascular disease. There is concern that to reach the intake recommendations of EPA and DHA, their supply from cold water fish will be insufficient. Gaps in understanding mechanisms of action of (n-3) FA in a number of health and disease areas as well as optimal sources and intake levels for each need to be defined by further research. Because of the inefficient conversion of ALA, the appearance of SDA in enriched soy oil offers a biologically effective and cost effective approach to providing a sustainable plant source for (n-3) FA in the future. © 2012 American Society for Nutrition.

Kang S.M.,Columbia University | Polvani L.M.,University of Applied and Environmental Sciences
Journal of Climate | Year: 2011

Astrong correlation between the latitudes of the eddy-driven jet and of the Hadley cell edge, on interannual time scales, is found to exist during austral summer, in both the NCEP-NCAR reanalysis and the models participating in the Coupled Model Intercomparison Project, phase 3 (CMIP3). In addition, a universal ratio close to 1:2 characterizes the robust connection between these two latitudes on a year-to-year basis: for a 2° shift of the eddy-driven jet, the edge of the Hadley cell shifts by 1°. This 1:2 interannual ratio remains the same in response to climate change, even though the values of the two latitudes increase. The corresponding trends are also highly correlated; in the CMIP3 scenario integrations, however, no universal ratio appears to exist connecting these long-term trends. In austral winter and in the Northern Hemisphere, no strong interannual correlations are found. © 2011 American Meteorological Society.

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.

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.

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.

Fernandez R.,Institute for Advanced Study | Metzger B.D.,Columbia University
Monthly Notices of the Royal Astronomical Society | Year: 2013

Expulsion of neutron-rich matter following the merger of neutron star binaries is crucial to the radioactively powered electromagnetic counterparts of these events and to their relevance as sources of r-process nucleosynthesis. Here we explore the long-term (viscous) evolution of remnant black hole accretion discs formed in such mergers by means of two-dimensional, time-dependent hydrodynamical simulations. The evolution of the electron fraction due to charged-current weak interactions is included, and neutrino self-irradiation is modelled as a lightbulb that accounts for the disc geometry and moderate optical depth effects. Over several viscous times (~1 s), a fraction of ~10 per cent of the initial disc mass is ejected as a moderately neutron-rich wind (Ye ~ 0.2) powered by viscous heating and nuclear recombination, with neutrino self-irradiation playing a sub-dominant role. Although the properties of the outflow vary in time and direction, their mean values in the heavy-element production region are relatively robust to variations in the initial conditions of the disc and the magnitude of its viscosity. The outflow is sufficiently neutron-rich that most of the ejecta forms heavy r-process elements with mass number A {greater-than or approximate} 130, thus representing a new astrophysical source of r-process nucleosynthesis, distinct from that produced in the dynamical ejecta. Due to its moderately high entropy, disc outflows contain a small residual fraction ~1 per cent of helium, which could produce a unique spectroscopic signature. © 2013 The Authors Published by Oxford University Press on behalf of the Royal Astronomical Society.

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.

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.

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.

It has become increasingly common to view and discuss autism as a form of difference, rather than a disorder. Moreover, the autism spectrum has generated new possibilities for personhood and social inclusion. These developments have typically been ascribed to the recent work of autistic autobiographers and autistic self-advocates associated with the neurodiversity movement, who are providing a sort of linguistic infrastructure to support autistic personhood. Drawing on historical and ethnographic research, this article makes the complementary and analogous claim that parents of autistic children have used autism therapies to create a technical infrastructure to support autistic personhood. The article follows an earlier genealogical thread to argue that parents have used the techniques and technologies of behavioral therapies (sometimes said to be incommensurable with neurodiversity's philosophy) in ways that have actually helped establish this autism-as-difference view. They have done so by translating their child's behaviors and utterances and engaging in forms of 'joint embodiment' with her to create enabling 'prosthetic environments' where her unique personhood can be recognized. Through an ethnographic focus on 'prosaic technologies' and the politics of everyday practice, the article also provides a thicker and more grounded account of what Ian Hacking calls the "looping effect of human kinds". © 2014 Macmillan Publishers Ltd.

Kelly K.M.,Columbia University
British Journal of Haematology | Year: 2012

Most children and adolescents with newly diagnosed high-risk Hodgkin lymphoma (HL) will achieve remission and cure with conventional chemotherapy with or without radiation therapy. However, these therapies can lead to long-term side effects. Therapy is titrated on the basis of risk group stratification using clinical prognostic factors and, in most cases, then refined through assessment of interim or end of chemotherapy response, primarily using functional imaging with fluorodeoxyglucose positron emission tomography. No study has clearly demonstrated the factors that are sufficient in identifying the patients at highest risk for relapse that may benefit from therapy intensification. This review summarizes recent clinical trials in paediatric high-risk HL, along with key findings from studies in adults with high-risk HL that are applicable to the paediatric population. New directions in prognostic classification and targeted therapies are reviewed. Considerations for clinical practice at the current time outside the clinical trial setting are provided. © 2011 Blackwell Publishing Ltd.

Gutierrez C.,Columbia University
Nature Physics | Year: 2016

Relativistic fermions that are incident on a high potential barrier can pass through unimpeded, a striking phenomenon termed the ‘Klein paradox’ in quantum electrodynamics. Electrostatic potential barriers in graphene provide a solid-state analogue to realize this phenomenon. Here, we use scanning tunnelling microscopy to directly probe the transmission of electrons through sharp circular potential wells in graphene created by substrate engineering. We find that electrons in this geometry display quasi-bound states where the electron is trapped for a finite time before escaping via Klein tunnelling. We show that the continuum Dirac equation can be successfully used to model the energies and wavefunctions of these quasi-bound states down to atomic dimensions. We demonstrate that by tuning the geometry of the barrier it is possible to trap particular energies and angular momentum states with increased efficiency, showing that atomic-scale electrostatic potentials can be used to engineer quantum transport through graphene. © 2016 Nature Publishing Group

Dela Cruz F.,Columbia University
Discovery medicine | Year: 2011

Sarcomas are malignant solid tumors of mesenchymal origin which consist of 10-15% of all pediatric malignancies and associated with significantly high mortality rates despite current therapies. Oncogenic fusion genes, resulting from non-random chromosomal translocations, characterize a subset of sarcomas including rhabdomyosarcoma, the Ewing's sarcoma family of tumors, and synovial sarcoma. As investigators gain further insight into the role that fusion genes play in the development and progression of sarcomas, we are slowly uncovering novel molecules and pathways that are proving to be essential for the growth and maintenance of sarcomas and other malignancies. MicroRNAs (miRs) have been implicated in a diversity of human diseases including cancer. Only recently, has miR deregulation been shown to be an important component of sarcomagenesis. This review summarizes the recent discoveries tying miR deregulation to sarcoma biology and will discuss the potential and feasibility of miRs as novel therapeutic adjuncts to current therapies. The methodological approaches utilized in the study of miR biology and development of miR-based treatment regimens can serve as a paradigm for future investigations in other translocation-associated solid tumors.

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

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

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.

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.

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.

McAllister W.,Columbia University
American journal of public health | Year: 2011

In homelessness research and policymaking, it seems to be axiomatic that single adults experience 3 temporally based types of homelessness: chronic, episodic, and transitional. We discuss problems with the theorization of this typology and with the research design, data analysis, and time-aggregated conceptualization and measurement of temporality in the empirical work supporting the typology. To address the latter, we suggest a time-patterned approach to temporality and report a 10-group typology that differs significantly from the more familiar 3-group typology. We argue that which approach is used-and how typologies are developed more generally-should be based on theory and the uses to which typologies are put rather than on claims to being more true.

Sun W.,Columbia University
International Journal for Numerical Methods in Engineering | Year: 2015

An adaptively stabilized monolithic finite element model is proposed to simulate the fully coupled thermo-hydro-mechanical behavior of porous media undergoing large deformation. We first formulate a finite-deformation thermo-hydro-mechanics field theory for non-isothermal porous media. Projection-based stabilization procedure is derived to eliminate spurious pore pressure and temperature modes due to the lack of the two-fold inf-sup condition of the equal-order finite element. To avoid volumetric locking due to the incompressibility of solid skeleton, we introduce a modified assumed deformation gradient in the formulation for non-isothermal porous solids. Finally, numerical examples are given to demonstrate the versatility and efficiency of this thermo-hydro-mechanical model. © 2015John Wiley & Sons, Ltd.

Single-molecule fluorescence resonance energy transfer (smFRET) has emerged as a powerful tool for mechanistic investigations of increasingly complex biochemical systems. Recently, we and others have successfully used smFRET to directly investigate the role of structural dynamics in the function and regulation of the cellular protein synthesis machinery. A significant challenge to these experiments, and to analogous experiments in similarly complex cellular machineries, is the need for specific and efficient fluorescent labeling of the biochemical system at locations that are both mechanistically informative and minimally perturbative to the biological activity. Here, we describe the development of a highly purified, fluorescently labeled in vitro translation system that we have successfully designed for smFRET studies of protein synthesis. The general approaches we outline should be amenable to single-molecule fluorescence studies of other complex biochemical systems. Copyright 2010 Elsevier Inc. All rights reserved.

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.

Stoffel E.M.,University of Michigan | Kastrinos F.,Columbia University
Clinical Gastroenterology and Hepatology | Year: 2014

Although 30% of individuals diagnosed with colorectal cancer (CRC) report a family history of the disease, only 5% to 6% carry germline mutations in genes associated with known hereditary cancer syndromes. The evaluation and management of families affected with CRC can be complicated by variability in disease phenotypes and limited sensitivity of genetic tests. In this review, we examine what is currently known about familial CRC and what we have yet to learn, and explore how novel genomic approaches might be used to identify additional genetic and epigenetic factors implicated in heritable risk for cancer. © 2014 AGA Institute.

Schmidt G.A.,Columbia University
Journal of Quaternary Science | Year: 2010

I discuss the role of model/data comparisons for past climate changes and use of such comparisons for enhancing credibility in future projections. I outline a framework in which data synthesis combined with suitable modelling targets should be able to reduce uncertainty in both. By focusing on areas that the latest Intergovernmental Panel on Climate Change assessment report (IPCC AR4) highlighted as being particularly uncertain in future projections, or where current models produce a very wide range of responses, the relevance of palaeoclimate data could be greatly enhanced. Specific targets include: the long-term behaviour of El Nin ̃o events and the potential response to volcanic and solar forcing; the variability of subtropical rainfall and the extent of the Hadley Circulation and their response to orbital and high-latitude forcing; ice sheet responses on sub- millennial timescales; multidecadal changes in the North Atlantic ocean circulation and, certainly, overall climate sensitivity. In each case, I highlight data synthesis steps and modelling approaches necessary for reducing the uncertainty. In particular, I stress the need for coordinated model simulation archives that are conformal to those used in simulations of the 20th century and beyond and the consistency of models used for past and future climate simulations. Published in 2009 by John Wiley & Sons, Ltd.

Mohan S.,Columbia University
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons | Year: 2012

The number of kidneys obtained from deceased diabetic donors available for transplantation has increased >eightfold increase in the past 15 years. We assessed allograft outcomes associated with deceased diabetic donors and compared them with that of standard and extended criteria donors (ECD) in the UNOS data registry. We identified 1982 recipients of diabetic standard criteria donors over a 10-year period from 1995 through 2004. Both overall and death-censored survival of organs from diabetic standard criteria donors was significantly better than that of organs obtained from nondiabetic ECD while inferior to that from nondiabetic standard criteria donors. Compared with ECD donors, diabetic donors had lower serum creatinine, less cold ischemia and these kidneys were less likely to be pump-perfused. Recipients of diabetic kidneys were younger and less likely to experience delayed graft function compared with recipient of ECD kidneys. More recently, many diabetic donor kidneys have been given to diabetic recipients with early graft survival being similar to that among nondiabetic recipients. These findings demonstrate the potential to expand and to improve utilization of this resource without compromising outcomes for recipients. Improved, evidence-based evaluation and allocation of deceased diabetic donor kidneys is needed to optimize their use. © Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.

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.

Katzberg R.W.,University of California at Davis | Newhouse J.H.,Columbia University
Radiology | Year: 2010

From the multiple perspectives described, it is our belief that the risk of CIN with CE CT has been exaggerated. Clinical rates and adverse outcomes from cardiac catheterization and intervention cannot be extrapolated to the clinical experience with CE CT. It appears that all currently used nonionic CM have similar safety profiles. We believe that modern CM pose only a small risk to renal function and that thresholds of creatinine above which CM are withheld for CT should be increased to improve the accuracy of CT examinations. The population of patients with mild to moderate renal dysfunction who would then receive CM should be analyzed carefully to determine whether the thresholds subsequently can be increased further. International radiologic professional organizations, such as the American College of Radiology, should revisit the basis of their practice guidelines to reduce their implications about the danger of CIN with CE CT. © RSNA, 2010.

Mojtabai R.,Johns Hopkins University | Olfson M.,Columbia University
Archives of General Psychiatry | Year: 2010

Context: Psychotropic medication polypharmacy is common in psychiatric outpatient settings and, in some patient groups, may have increased in recent years. Objective: To examine patterns and recent trends in psychotropic polypharmacy among visits to office-based psychiatrists. Design: Annual data from the 1996-2006 cross-sectional National Ambulatory Medical Care Surveys were analyzed to examine patterns and trends in psychotropic polypharmacy within nationally representative samples of 13 079 visits to office-based psychiatrists. Setting: Office-based psychiatry practices in the United States. Participants: Outpatients with mental disorder diagnoses visiting office-based psychiatrists. Main Outcome Measure: Number of medications prescribed in each visit and specific medication combinations. Results: There was an increase in the number of psychotropic medications prescribed across years; visits with 2 or more medications increased from 42.6% in 1996-1997 to 59.8% in 2005-2006; visits with 3 or more medications increased from 16.9% to 33.2% (both P<.001). The median number of medications prescribed in each visit increased from 1 in 1996-1997 to 2 in 2005-2006 (mean increase: 40.1%). The increasing trend of psychotropic polypharmacy was mostly similar across visits by different patient groups and persisted after controlling for background characteristics. Prescription for 2 or more antidepressants, antipsychotics, sedative-hypnotics, and antidepressant-antipsychotic combinations, but not other combinations, significantly increased across survey years. There was no increase in prescription of mood stabilizer combinations. In multivariate analyses, the odds of receiving 2 or more antidepressants were significantly associated with a diagnosis of major depression (odds ratio [OR], 3.44; 99% confidence interval [CI], 2.58-4.58); 2 or more antipsychotics, with schizophrenia (OR, 6.75; 99% CI, 3.52-12.92); 2 or more mood stabilizers, with bipolar disorder (OR, 15.46; 99% CI, 6.77-35.31); and 2 or more sedative-hypnotics, with anxiety disorders (OR, 2.13; 99% CI, 1.41-3.22). Conclusions: There has been a recent significant increase in polypharmacy involving antidepressant and antipsychotic medications. While some of these combinations are supported by clinical trials, many are of unproven efficacy. These trends put patients at increased risk of drug-drug interactions with uncertain gains for quality of care and clinical outcomes. ©2010 American Medical Association. All rights reserved.

Haughn G.,Columbia University
Briefings in Functional Genomics and Proteomics | Year: 2010

Genetic analysis represents a powerful tool that establishes a direct link between the biochemical function of a gene product and its role in vivo. Genome sequencing projects have identified large numbers of plant genes for which no role has yet been defined. To address this problem a number of techniques have been developed, over the last 15 years, to enable researchers to identify plants with mutations in genes of known sequence.These reverse genetic approaches include RNAi and related technologies and screening of populations mutagenised by insertion (PCR), deletion (PCR) and pointmutation (TILLING), each with its own strengths and weaknesses.The development of next-generation sequencing techniques now allows such screening to be done by sequencing. In the future, it is likely that the genomes of thousands of plants from mutagenised populations will be sequenced allowing for the identification of plants with mutations in specific genes to be done in silico. © The Author 2010. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org.

Wang J.,IBM | Kumar S.,Google | Chang S.-F.,Columbia University
IEEE Transactions on Pattern Analysis and Machine Intelligence | Year: 2012

Hashing-based approximate nearest neighbor (ANN) search in huge databases has become popular due to its computational and memory efficiency. The popular hashing methods, e.g., Locality Sensitive Hashing and Spectral Hashing, construct hash functions based on random or principal projections. The resulting hashes are either not very accurate or are inefficient. Moreover, these methods are designed for a given metric similarity. On the contrary, semantic similarity is usually given in terms of pairwise labels of samples. There exist supervised hashing methods that can handle such semantic similarity, but they are prone to overfitting when labeled data are small or noisy. In this work, we propose a semi-supervised hashing (SSH) framework that minimizes empirical error over the labeled set and an information theoretic regularizer over both labeled and unlabeled sets. Based on this framework, we present three different semi-supervised hashing methods, including orthogonal hashing, nonorthogonal hashing, and sequential hashing. Particularly, the sequential hashing method generates robust codes in which each hash function is designed to correct the errors made by the previous ones. We further show that the sequential learning paradigm can be extended to unsupervised domains where no labeled pairs are available. Extensive experiments on four large datasets (up to 80 million samples) demonstrate the superior performance of the proposed SSH methods over state-of-the-art supervised and unsupervised hashing techniques. © 2012 IEEE.

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.

Elkind M.S.V.,Columbia University
Infectious Disorders - Drug Targets | Year: 2010

Atherosclerosis is a chronic inflammatory process, and several common bacterial and viral infections have been hypothesized to contribute to the inflammation of the vascular wall that leads to atherosclerosis. More recently, investigators have found preliminary evidence that the aggregate burden of these chronic infections, rather than any single organism, may contribute to atherosclerosis and risk of clinical vascular events, including ischemic stroke. This aggregate burden of infections, which has been variably labeled "infectious burden" or "pathogen burden," may be associated with stroke through mechanisms independent of atherosclerosis, as well, including platelet aggregation and endothelial dysfunction. Host factors, moreover, may interact with infectious burden to modify the risk of disease associated with these infections. Currently there is no commonly accepted group of organisms or method of assessing infectious burden, and not all studies confirm an association of infection and stroke risk. Nonetheless, if infectious burden does play a role in atherosclerosis or stroke, it is plausible that preventive anti-infective treatment, such as vaccination, or antibiotics, would reduce the risk of incident or recurrent stroke. While influenza vaccination has been recommended to prevent recurrence among those with coronary disease, similar recommendations for stroke patients have not yet been made. Large scale randomized clinical trials of macrolide antibiotics for coronary patients, moreover, have been negative. Further studies are needed, however, to determine whether an association between infectious burden and stroke exists, and whether infectious burden may be a target for intervention. © 2010 Bentham Science Publishers Ltd.

The spatial and temporal regulation of gene expression during development requires the concerted actions of sequence-specific transcriptional regulators and epigenetic chromatin modifiers, which are thought to function within precise nuclear compartments. However, coordination of these activities within the dynamic context of the nuclear environment is still largely unresolved. Here we discuss the implications of our recent work showing that transcriptional repression by the Msx1 homeoprotein is associated with global redistribution of the H3K27me3 repressive mark to the nuclear periphery during development.

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.

Nicolis A.,Columbia University | Piazza F.,Paris West University Nanterre La Defense
Physical Review Letters | Year: 2013

We adapt the Goldstone theorem to study spontaneous symmetry breaking in relativistic theories at finite charge density. It is customary to treat systems at finite density via nonrelativistic Hamiltonians. Here, we highlight the importance of the underlying relativistic dynamics. This leads to seemingly new results whenever the charge in question is spontaneously broken and does not commute with other broken charges. We find that that the latter interpolate gapped excitations. In contrast, all existing versions of the Goldstone theorem predict the existence of gapless modes. We derive exact nonperturbative expressions for their gaps, in terms of the chemical potential and of the symmetry algebra. © 2013 American Physical Society.

Klose A.D.,Columbia University
Journal of Quantitative Spectroscopy and Radiative Transfer | Year: 2010

This note serves as an introduction to two papers by Klose et al. [2,3] and provides a brief review of the latest developments in optical tomography of scattering tissue. We discuss advancements made in solving the forward model for light propagation based on the radiative transfer equation, in reconstructing scattering and absorption cross sections of tissue, and in molecular imaging of luminescent sources. © 2010 Elsevier Ltd.

Previous research suggests that religiousness correlates with less criminal behavior and that this relationship is partially mediated by higher self-control. Because most studies are cross-sectional, causality remains uncertain as stable between-subject factors may influence self-control, religiousness, and offending, confounding their relationships. Moreover, directionality may be reversed with higher self-control leading to both higher religiousness and less offending. The current research aimed to directly exclude these possibilities using longitudinal data from 1,354 adolescents participating in the Pathways to Desistance Study. Results indicated that short-term, within-subject increased religiousness predicted decreased future criminal behavior and that this effect was partially mediated by increased self-control. A reversed model in which past self-control predicted future religiousness was not significant. These findings suggest that religiousness may be causally related to offending, and self-control is likely one of multiple mediating processes. Additional research in this area appears warranted and may yield effective strategies for reducing criminal behavior and improving self-control. © 2014 International Association for Correctional and Forensic Psychology.

Marsano A.,Columbia University
Biotechnology progress | Year: 2010

We investigated the effects of the initial stiffness of a three-dimensional elastomer scaffold--highly porous poly(glycerol sebacate)--on functional assembly of cardiomyocytes cultured with perfusion for 8 days. The polymer elasticity varied with the extent of polymer cross-links, resulting in three different stiffness groups, with compressive modulus of 2.35 ± 0.03 (low), 5.28 ± 0.36 (medium), and 5.99 ± 0.40 (high) kPa. Laminin coating improved the efficiency of cell seeding (from 59 ± 15 to 90 ± 21%), resulting in markedly increased final cell density, construct contractility, and matrix deposition, likely because of enhanced cell interaction and spreading on scaffold surfaces. Compact tissue was formed in the low and medium stiffness groups, but not in the high stiffness group. In particular, the low stiffness group exhibited the greatest contraction amplitude in response to electric field pacing, and had the highest compressive modulus at the end of culture. A mathematical model was developed to establish a correlation between the contractile amplitude and the cell distribution within the scaffold. Taken together, our findings suggest that the contractile function of engineered cardiac constructs positively correlates with low compressive stiffness of the scaffold. © 2010 American Institute of Chemical Engineers

Motor impairment and functional limitations are known sequelae of Parkinson's disease. Occupational therapy (OT) is recognized as an important adjunct to pharmacological management. This critical review provides an update on the effectiveness of OT. Eight studies were included in the review, three on occupational therapy task-related training, two on functional training with external cues and three on OT as part of interdisciplinary treatment. Due to lack of level I studies, it is difficult to determine conclusively the effect of OT. However, there is evidence to suggest that treatment produces improvements in motor and quality of life for the duration of therapy. Implications for future studies and practice are discussed. © 2010 Movement Disorder Society.

This article reviews the design and operation of both flat-panel detector (FPD) and image intensifier fluoroscopy systems. The different components of each imaging chain and their functions are explained and compared. FPD systems have multiple advantages such as a smaller size, extended dynamic range, no spatial distortion, and greater stability. However, FPD systems typically have the same spatial resolution for all fields of view (FOVs) and are prone to ghosting. Image intensifier systems have better spatial resolution with the use of smaller FOVs (magnification modes) and tend to be less expensive. However, the spatial resolution of image intensifier systems is limited by the television system to which they are coupled. Moreover, image intensifier systems are degraded by glare, vignetting, spatial distortions, and defocusing effects. FPD systems do not have these problems. Some recent innovations to fluoroscopy systems include automated filtration, pulsed fluoroscopy, automatic positioning, dose-area product meters, and improved automatic dose rate control programs. Operator-selectable features may affect both the patient radiation dose and image quality; these selectable features include dose level setting, the FOV employed, fluoroscopic pulse rates, geometric factors, display software settings, and methods to reduce the imaging time. ©RSNA, 2011.

Dobrowolska H.,Columbia University
Cytometry. Part B, Clinical cytometry | Year: 2013

The diagnosis of AML with monocytic differentiation is limited by the lack of highly sensitive and specific monocytic markers. Immunoglobulin-like transcript 3 (ILT3) is an immune inhibitory receptor expressed by myelomonocytic cells and at high levels by tolerogenic dendritic cells. Using flow cytometry, we analyzed the expression of ILT3 in 37 patients with AML and 20 patients with no detectable disease. We showed that ILT3 was expressed in all cases of AML displaying monocytic differentiation (FAB M4/M5; N = 18), but not in AML M1/M2 and M3 (N = 19; P < 0.0001). Co-expression of ILT3 and immature cell markers, such as CD34 and CD117, was observed in monoblastic leukemia. ILT3 expression was preserved after treatment in M4/M5 patients with refractory or relapsed disease. ILT3 expression was associated with the presence of cytogenetic abnormalities linked to an intermediate prognosis (P = 0.001). Rare CD45dimCD34+CD117+ILT3+ cells were identified in noninvolved bone marrow, suggesting that ILT3 expression is acquired at an early stage by normal myelomonocytic precursors. ILT3 is a highly sensitive and specific marker which distinguishes AML with monocytic differentiation from other types of AML. Testing of ILT3 expression should be incorporated into the initial diagnostic work-up and monitoring of patients with AML. Copyright © 2012 International Clinical Cytometry Society.

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

The atmospheres of hot Jupiters and other strongly forced exoplanets are susceptible to a thermal instability in the presence of ohmic dissipation, weak magnetic drag, and strong winds. The instability occurs in radiatively dominated atmospheric regions when the ohmic dissipation rate increases with temperature faster than the radiative (cooling) rate. The instability domain covers a specific range of atmospheric pressures and temperatures, typically P 3-300 mbar and T 1500-2500 K for hot Jupiters, which makes it a candidate mechanism to explain the dayside thermal "inversions" inferred for a number of such exoplanets. The instability is suppressed by high levels of non-thermal photoionization, in possible agreement with a recently established observational trend. We highlight several shortcomings of the instability treatment presented here. Understanding the emergence and outcome of the instability, which should result in locally hotter atmospheres with stronger levels of drag, will require global nonlinear atmospheric models with adequate MHD prescriptions. © 2012. The American Astronomical Society. All rights reserved.

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.

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.

Klitzman R.,Columbia University
BMC Medical Ethics | Year: 2011

Background: Centralization of IRB reviews have been increasing in the US and elsewhere, but many questions about it remain. In the US, a few centralized IRBs (CIRBs) have been established, but how they do and could operate remain unclear. Methods. I contacted 60 IRBs (every fourth one in the list of the top 240 institutions by NIH funding), and interviewed leaders from 34 (response rate = 55%) and an additional 12 members and administrators. Results: These interviewees had often interacted with CIRBs, but supported local reviews, and offered advantages and disadvantages of each. Interviewees argued that local IRBs can provide "local knowledge" of subjects and PIs, and "curbside consults" with PIs, facilitating mutual trust. PIs may interact more fully and informally, and hence effectively with local IRBs. IRBs also felt additional responsibility to protect "their own" subjects. Respondents mentioned a few advantages of CIRBs (e.g., CIRBs may streamline reviews), though far more rarely and cursorily. Overall, interviewees were wary of CIRBs, which they saw as varying widely in quality, depending on who happened to be members. Both local and centralized IRBs appear to have unintended consequences. For instance, discrepancies arose between IRBs that appeared to reflect differences in institutional culture and history, and personalities of chairs and/or vocal members, more than in local community values per se, and thus do not seem to be the intent of the regulations. While some critics see CIRBs as solutions to many IRB problems, critical tradeoffs and uncertainties emerge. Conclusions: These data have critical implications for future policy and research. Debates need to evolve beyond simply a binary discussion of whether CIRBs should replace local IRBs, to examine how and to what degree different models might operate, and what the relative advantages and disadvantages of each are. While some critics see CIRBs as panaceas, certain problems appear likely to continue. Careful consideration needs to be given to whether the advantages of local IRBs outweigh the problems that result, and whether a system can be developed that provides these benefits, while avoiding the disadvantages of local IRBs. © 2011 Klitzman; licensee BioMed Central Ltd.

Lassman A.B.,Columbia University
Current Oncology Reports | Year: 2013

Anaplastic oligodendrogliomas are rare primary brain tumors. However, they respond more effectively to treatment and have a better prognosis than commoner varieties. About 25 year ago, reports emerged that oligodendrogliomas can respond robustly and durably to chemotherapy with procarbazine, lomustine (CCNU), and vincristine (PCV). It was also discovered that co-deletion of chromosome arms 1p and 19q is more commonly observed in oligodendrogliomas (rather than astrocytomas). Early results of phase III trials confirmed that 1p/19q co-deletion was a favorable prognostic marker. Mature results now conclusively demonstrate that co-deletion also predicts longer survival from the addition of PCV chemotherapy to radiotherapy for newly diagnosed disease. However, changes in the treatment landscape, including a preference for deferred radiotherapy, the emergence of temozolomide as a better tolerated chemotherapy regimen, and the discovery of other biomarkers (e.g. IDH mutation and MGMT promoter methylation) that occurred in the interim emphasize the need for earlier, validated, and acceptable trial end points. © 2012 Springer Science+Business Media New York.

Lewis T.T.,Emory University | Cogburn C.D.,Columbia University | Williams D.R.,Health Science University | Williams D.R.,Harvard University
Annual Review of Clinical Psychology | Year: 2015

Over the past two decades, research examining the impact of self-reported experiences of discrimination on mental and physical health has increased dramatically. Studies have found consistent associations between exposure to discrimination and a wide range of Diagnostic and Statistical Manual of Mental Disorders (DSM)-diagnosed mental disorders as well as objective physical health outcomes. Associations are seen in cross-sectional as well as longitudinal studies and persist even after adjustment for confounding variables, including personality characteristics and other threats to validity. However, controversies remain, particularly around the best approach to measuring experiences of discrimination, the significance of racial ethnic discrimination versus overall mistreatment, the need to account for "intersectionalities," and the importance of comprehensive assessments. These issues are discussed in detail, along with emerging areas of emphasis including cyber discrimination, anticipatory stress or vigilance around discrimination, and interventions with potential to reduce the negative effects of discrimination on health. We also discuss priorities for future research and implications for interventions and policy. © 2015 by Annual Reviews. All rights reserved.

Klein H.L.,New York University | Symington L.S.,Columbia University
Cell | Year: 2012

The Sgs1 DNA helicase and its mammalian homolog BLM control crossover formation in mitotic cells. Zakharyevich et al. and De Muyt et al. now uncover a key role for Sgs1 in meiotic crossover regulation, which in turn reveals a joint molecule resolution pathway that produces the majority of crossovers in budding yeast. © 2012 Elsevier Inc.

Duncan D.T.,Harvard Youth Violence Prevention Center | Hatzenbuehler M.L.,Columbia University
American Journal of Public Health | Year: 2014

Objectives. We examined whether past-year suicidality among sexualminority adolescents was more common in neighborhoods with a higher prevalence of hate crimes targeting lesbian, gay, bisexual, and transgender (LGBT) individuals. Methods. Participants' data came from a racially/ethnically diverse population-based sample of 9th- through 12th-grade public school students in Boston, Massachusetts (n = 1292). Of these, 108 (8.36%) reported a minority sexual orientation. We obtained data on LGBT hate crimes involving assaults or assaults with battery between 2005 and 2008 from the Boston Police Department and linked the data to the adolescent's residential address. Results. Sexual-minority youths residing in neighborhoods with higher rates of LGBT assault hate crimes were significantly more likely to report suicidal ideation (P = .013) and suicide attempts (P = .006), than were those residing in neighborhoods with lower LGBT assault hate crime rates. We observed no relationships between overall neighborhood-level violent and property crimes and suicidality among sexual-minority adolescents (P > .05), providing evidence for specificity of the results to LGBT assault hate crimes. Conclusions. Neighborhood context (i.e., LGBT hate crimes) may contribute to sexual-orientation disparities in adolescent suicidality, highlighting potential targets for community-level suicide-prevention programs.

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.

Kitcher P.,Columbia University
Behaviour | Year: 2014

I offer an account of the evolution of ethical life, using it to elaborate a meta-ethical perspective and a normative stance. In light of these discussions, I attempt to answer my title question. © 2014 Koninklijke Brill NV, Leiden, The Netherlands.

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.

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

Sykes M.,Columbia University
Bone Marrow Transplantation | Year: 2015

The success of allogeneic hematopoietic cell transplantation (HCT) has been limited by transplant-associated toxicities related to the conditioning regimens used and to graft-vs-host disease (GVHD). The frequency and severity of GVHD observed when extensive HLA barriers are transgressed has greatly impeded the routine use of extensively HLA-mismatched HCT. Allogeneic HCT also has potential as an approach to organ allograft tolerance induction, but this potential has not been previously realized because of the toxicity associated with traditional conditioning. This paper reviews an approach to HCT involving reduced intensity conditioning that demonstrated sufficient safety in patients with hematologic malignancies, even in the HLA-mismatched transplant setting, to be applied for the induction of kidney allograft tolerance in humans with no other indication for HCT. These studies provided the first successful example of intentional organ allograft tolerance induction across HLA barriers in humans. Current data and hypotheses on the mechanisms of tolerance in these patients are reviewed.

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.

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

Objectives: To outline the prevalence and disparities of teen pregnancy among school-aged urban minority youth, causal pathways through which nonmarital teen births adversely affects academic achievement, and proven or promising approaches for schools to address this problem. Methods: Literature review. Results: In 2006, the birth rate among 15- to 17-year-old non-Hispanic Blacks (36.1 per 1000) was more than three times as high, and the birth rate among Hispanics (47.9 per 1000) was more than four times as high as the birth rate among non-Hispanic Whites (11.8 per 1000). Compared with women who delay childbearing until age 30, teen mothers' education is estimated to be approximately 2 years shorter. Teen mothers are 10-12% less likely to complete high school and have 14-29% lower odds of attending college. School-based programs have the potential to help teens acquire the knowledge and skills needed to postpone sex, practice safer sex, avoid unintended pregnancy, and if pregnant, to complete high school and pursue postsecondary education. Most students in US middle and high schools receive some kind of sex education. Federal policies and legislation have increased use of the abstinence-only-until-marriage approach, which is disappointing considering the lack of evidence that this approach is effective. Conclusions: Nonmarital teen births are highly and disproportionately prevalent among school-aged urban minority youth, have a negative impact on educational attainment, and effective practices are available for schools to address this problem. Teen pregnancy exerts an important influence on educational attainment among urban minority youth. Decisions about what will be taught should be informed by empirical data documenting the effectiveness of alternative approaches. © 2011, American School Health Association.

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.

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.

Fellouris G.,Columbia University | Moustakides G.V.,University of Patras
IEEE Transactions on Information Theory | Year: 2011

An asymptotically optimum test for the problem of decentralized sequential hypothesis testing is presented. The induced communication between sensors and fusion center is asynchronous and limited to 1-bit data. When the sensors observe continuously stochastic processes with continuous paths, the proposed test is order-2 asymptotically optimal, in the sense that its inflicted performance loss is bounded. When the sensors take discrete time observations, the proposed test achieves order-1 asymptotic optimality, i.e., the ratio of its performance over the optimal performance tends to 1. Moreover, we show theoretically and corroborate with simulations that the performance of the suggested test in discrete time can be significantly improved when the sensors sample their underlying continuous time processes more frequently, a property which is not enjoyed by other centralized or decentralized tests in the literature. © 2006 IEEE.

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.

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.

Radhakrishnan J.,Columbia University | Cattran D.C.,Toronto General Research Institute
Kidney International | Year: 2012

The KDIGO guideline for glomerulonephritis is designed to assist health-care providers in treating patients with glomerular diseases. A guideline is not a set of rules but is intended to allow the practitioner to make an informed decision based on the available evidence. Due to its general nature and the variability of strength of the available studies, it is often difficult to directly apply a guideline to the care of an individual patient. This commonly relates to the limited generalizability of the evidence, i.e., does not cover every clinical scenario. To underscore this point, we have introduced within the context of the glomerulonephritis guideline cases with specific features to illustrate the constant need for clinical judgment. These vignettes are intended to demonstrate how the best treatment plans should be individualized and take into account patient preference and clinical acumen, as well as the best available evidence. © 2012 International Society of Nephrology.

Sever P.S.,Imperial College London | Messerli F.H.,Columbia University
European Heart Journal | Year: 2011

Raised levels of blood pressure result from the complex interplay of environmental and genetic factors. The complexity of blood pressure control mechanisms has major implications for individual responsiveness to antihypertensive drugs. The underlying haemodynamic disorder in the majority of cases is a rise in peripheral vascular resistance. This observation led to the discovery and development of increasingly sophisticated and targeted vasodilators, although many of the earlier antihypertensive drugs, by virtue of their actions blocking the sympathetic nervous system, had a vasodilator component to their mode of action. A recent meta-analysis of placebo controlled trials of monotherapy in unselected hypertensives, reports average (placebo-corrected) blood pressure responses to single agents of 9.1 mmHg systolic and 5.5 mmHg diastolic pressure. These average values disguise the extremely wide ranging responses in individuals across a fall of 2030 mmHg systolic at one extreme, to no effect at all, or even a small rise in blood pressure at the other. The second factor determining individual responses to monotherapy is the extent to which initial falls in pressure are opposed by reflex responses in counter regulatory mechanisms that are activated following the blood pressure reduction. Thus, a satisfactory blood pressure response is rarely reached with monotherapy alone. What then is the next step if blood pressure is not a goal after the patient has been treated with monotherapy for a few weeks? Should you uptitrate, substitute or combine? © 2011 The Author.

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.

Nenkova A.,University of Pennsylvania | McKeown K.,Columbia University
Foundations and Trends in Information Retrieval | Year: 2011

It has now been 50 years since the publication of Luhn's seminal paperon automatic summarization. During these years the practical need forautomatic summarization has become increasingly urgent and numer-ous papers have been published on the topic. As a result, it has become harder to find a single reference that gives an overview of past efforts or a complete view of summarization tasks and necessary system com-ponents. This article attempts to fill this void by providing a com-prehensive overview of research in summarization, including the more traditional efforts in sentence extraction as well as the most novel recent approaches for determining important content, for domain and genre specific summarization and for evaluation of summarization. We also discuss the challenges that remain open, in particular the need for lan-guage generation and deeper semantic understanding of language that would be necessary for future advances in the field. © 2011 A. Nenkova and K. McKeown.

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

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.

Chen J.J.,Columbia University
Journal of neurovirology | Year: 2011

Case reports have linked varicella-zoster virus (VZV) to gastrointestinal disorders, including severe abdominal pain preceding fatal varicella and acute colonic pseudoobstruction (Ogilvie's syndrome). Because we had previously detected DNA and transcripts encoding latency-associated VZV gene products in the human gut, we sought to determine whether latent VZV is present in the human enteric nervous system (ENS) and, if so, to identify the cells in which it is located and its route to the bowel. Neither DNA, nor transcripts encoding VZV gene products, could be detected in resected gut from any of seven control children (<1 year old) who had not received the varicella vaccine or experienced varicella; however, VZV DNA and transcripts were each found to be present in resected bowel from 6/6 of children with a past history of varicella and in that of 6/7 of children who received the varicella vaccine. Both wild-type (WT) and vaccine-type (vOka) VZV thus establish latent infection in human gut. To determine routes by which VZV might gain access to the bowel, we injected guinea pigs with human or guinea pig lymphocytes expressing green fluorescent protein (GFP) under the control of the VZV ORF66 gene (VZV(OKA66.GFP)). GFP-expressing enteric neurons were found throughout the bowel within 2 days and continued to be present for greater than 6 weeks. DNA encoding VZV gene products also appeared in enteric and dorsal root ganglion (DRG) neurons following intradermal administration of WT-VZV and in enteric neurons after intradermal injection of VZV(OKA66.GFP); moreover, a small number of guinea pig DRG neurons were found to project both to the skin and the intraperitoneal viscera. Viremia, in which lymphocytes carry VZV, or axonal transport from DRG neurons infected through their epidermal projections are thus each potential routes that enable VZV to gain access to the ENS.

Stojanovic M.N.,Columbia University
Israel Journal of Chemistry | Year: 2011

In this review I present a chemist's perspective on molecular computing and molecular robotics. I start with nucleic acid catalysts and then show how the application of some concepts from computer sciences and macroscopic robotics enable engineering of interesting behaviors in molecular systems. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Fisher D.R.,Columbia University
Global Environmental Politics | Year: 2010

What happened to non-governmental organizations' participation at the COP-15 round of climate negotiations in Copenhagen? Although the climate regime has been seen as relatively open to civil society, everything changed in Copenhagen and civil society became increasingly disenfranchised. This article discusses the three main forces that led to civil society's disenfranchisement at this round of the climate negotiations: increased registration, poor planning by the Danish organizers and the United Nations Framework Convention on Climate Change Secretariat, and the merging of movements. I conclude by discussing implications of the increase in civil society disenfranchisement to the climate regime and to the study of global environmental politics more broadly. © 2010 by the Massachusetts Institute of Technology.

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.

Gallego G.,Columbia University | Wang R.,Johns Hopkins Carey Business School
Operations Research | Year: 2014

We study firms that sell multiple substitutable products and customers whose purchase behavior follows a nested logit model, of which the multinomial logit model is a special case. Customers make purchasing decisions sequentially under the nested logit model: they first select a nest of products and subsequently purchase one within the selected nest. We consider the multiproduct pricing problem under the general nested logit model with product- differentiated price sensitivities and arbitrary nest coefficients. We show that the adjusted markup, defined as price minus cost minus the reciprocal of price sensitivity, is constant for all the products within a nest at optimality. This reduces the problem's dimension to a single variable per nest. We also show that the adjusted nest-level markup is nest invariant for all the nests, which further reduces the problem to maximizing a single-variable unimodal function under mild conditions. We also use this result to simplify the oligopolistic multiproduct price competition and characterize the Nash equilibrium. We also consider more general attraction functions that include the linear utility and the multiplicative competitive interaction models as special cases, and we show that similar techniques can be used to significantly simplify the corresponding pricing problems. © 2014 INFORMS.

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.

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.

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.

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.

Breslow R.,Columbia University
Tetrahedron Letters | Year: 2011

For life to start on earth and elsewhere, it is critical that the building blocks - amino acids and sugars - be in predominant homochiral form. Over the past century, the origin of terrestrial prebiotic homochirality has been the subject of many speculations. In this Letter I summarize the experimental evidence for ways in which some meteoritic components could have led to the dominance of l amino acids and d sugars on earth, and the most likely way in which the original chiral excesses in the meteorites were formed. © 2010 Elsevier Ltd. All rights reserved.

Breslow R.,Columbia University
Tetrahedron Letters | Year: 2011

For life to start on earth and elsewhere, it is critical that the building blocks - amino acids and sugars - be in predominant homochiral form. Over the past century the origin of terrestrial prebiotic homochirality has been the subject of many speculations. In this Letter I summarize the experimental evidence for ways in which some meteoritic components could have led to the dominance of l amino acids and d sugars on earth, and the most likely way in which the original chiral excesses in the meteorites were formed. © 2011 Elsevier Ltd. All rights reserved.

Spruill T.M.,Columbia University
Current Hypertension Reports | Year: 2010

Genetic and behavioral factors do not fully explain the development of hypertension, and there is increasing evidence suggesting that psychosocial factors may also play an important role. Exposure to chronic stress has been hypothesized as a risk factor for hypertension, and occupational stress, stressful aspects of the social environment, and low socioeconomic status have each been studied extensively. The study of discrimination is a more recent and rapidly growing area of investigation and may also help to explain the well-known racial disparities in hypertension. Research regarding mechanisms underlying stress effects on hypertension has largely focused on cardiovascular reactivity, but delayed recovery to the pre-stress level is increasingly being evaluated as another possible pathway. Recent findings in each of these areas are reviewed, and directions for future research are discussed. © 2010 Springer Science+Business Media, LLC.

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.

Arterial smooth muscle (SM) cells respond autonomously to changes in intravascular pressure, adjusting tension to maintain vessel diameter. The values of membrane potential (Vm) and sarcoplasmic Ca2+ concentration (Cain) within minutes of a change in pressure are the results of two opposing pathways, both of which use Ca2+ as a signal. This works because the two Ca2+-signaling pathways are confined to distinct microdomains in which the Ca2+ concentrations needed to activate key channels are transiently higher than Cain. A mathematical model of an isolated arterial SM cell is presented that incorporates the two types of microdomains. The first type consists of junctions between cisternae of the peripheral sarcoplasmic reticulum (SR), containing ryanodine receptors (RyRs), and the sarcolemma, containing voltage- and Ca2+-activated K+ (BK) channels. These junctional microdomains promote hyperpolarization, reduced Cain, and relaxation. The second type is postulated to form around stretch-activated nonspecific cation channels and neighboring Ca2+-activated Cl- channels, and promotes the opposite (depolarization, increased Cain, and contraction). The model includes three additional compartments: the sarcoplasm, the central SR lumen, and the peripheral SR lumen. It incorporates 37 protein components. In addition to pressure, the model accommodates inputs of α- and β-adrenergic agonists, ATP, 11,12-epoxyeicosatrienoic acid, and nitric oxide (NO). The parameters of the equations were adjusted to obtain a close fit to reported Vm and Cain as functions of pressure, which have been determined in cerebral arteries. The simulations were insensitive to ±10% changes in most of the parameters. The model also simulated the effects of inhibiting RyR, BK, or voltage-activated Ca2+ channels on Vm and Cain. Deletion of BKβ1 subunits is known to increase arterial-SM tension. In the model, deletion of β1 raised Cain at all pressures, and these increases were reversed by NO. © 2015 Karlin.

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.

Shaw R.M.,University of California at San Francisco | Colecraft H.M.,Columbia University
Cardiovascular Research | Year: 2013

In the heart, Ca2+ influx via CaV1.2 L-type calcium channels (LTCCs) is a multi-functional signal that triggers muscle contraction, controls action potential duration, and regulates gene expression. The use of LTCC Ca2+ as a multi-dimensional signalling molecule in the heart is complicated by several aspects of cardiac physiology. Cytosolic Ca2+ continuously cycles between ∼100 nM and ∼1 μM with each heartbeat due to Ca2+ linked signalling from LTCCs to ryanodine receptors. This rapid cycling raises the question as to how cardiac myocytes distinguish the Ca2+ fluxes originating through L-type channels that are dedicated to contraction from Ca2+ fluxes originating from other L-type channels that are used for non-contraction-related signalling. In general, disparate Ca2+ sources in cardiac myocytes such as current through differently localized LTCCs as well as from IP3 receptors can signal selectively to Ca2+-dependent effectors in local microdomains that can be impervious to the cytoplasmic Ca2+ transients that drive contraction. A particular challenge for diversified signalling via cardiac LTCCs is that they are voltage-gated and, therefore, open and presumably flood their microdomains with Ca2+ with each action potential. Thus spatial localization of Cav1.2 channels to different types of microdomains of the ventricular cardiomyocyte membrane as well as the existence of particular macromolecular complexes in each Cav1.2 microdomain are important to effect different types of Cav1.2 signalling. In this review we examine aspects of Cav1.2 structure, targeting and signalling in two specialized membrane microdomains-transverse tubules and caveolae. © 2012 The Author.

Zairis S.,Columbia University
Nature Methods | Year: 2016

Protein synthesis in eukaryotes is regulated by diverse reprogramming mechanisms that expand the coding capacity of individual genes. Here, we exploit one such mechanism, termed −1 programmed ribosomal frameshifting (−1 PRF), to engineer ligand-responsive RNA switches that regulate protein expression. First, efficient −1 PRF stimulatory RNA elements were discovered by in vitro selection; then, ligand-responsive switches were constructed by coupling −1 PRF stimulatory elements to RNA aptamers using rational design and directed evolution in Saccharomyces cerevisiae. We demonstrate that −1 PRF switches tightly control the relative stoichiometry of two distinct protein outputs from a single mRNA, exhibiting consistent ligand response across whole populations of cells. Furthermore, −1 PRF switches were applied to build single-mRNA logic gates and an apoptosis module in yeast. Together, these results showcase the potential for harnessing translation-reprogramming mechanisms for synthetic biology, and they establish −1 PRF switches as powerful RNA tools for controlling protein synthesis in eukaryotes. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

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.

David C.J.,Columbia University
Transcription | Year: 2011

Work over the last two decades has provided a wealth of data indicating that the RNA polymerase II transcriptional machinery can play an important role in facilitating the splicing of its transcripts. In particular, the C-terminal domain of the RNA polymerase II large subunit (CTD) is central in the coupling of transcription and splicing. While this has long been assumed to involve physical interactions between splicing factors and the CTD, few functional connections between the CTD and such factors have been established. We recently used a biochemical approach to identify a splicing factor that interacts directly with the CTD to activate splicing and, in doing so, may play a role in the process of spliceosome assembly.

Pilkauskas N.V.,Columbia University
Maternal and Child Health Journal | Year: 2014

In the US, the prevalence of three-generation households, where a grandparent, parent and child coreside, has increased in the last decade. Three-generation coresidence during infancy is particularly common and as many as 15 % of infants live in a three-generation household shortly after birth. Although prior research has linked family structure with breastfeeding behavior, no research has studied whether breastfeeding behavior varies by grandparent coresidence. This study is the first to investigate the association between three-generation coresidence and breastfeeding behaviors. This paper uses two data sets, the Early Childhood Longitudinal Study - Birth Cohort (n ~ 8,250), a nationally representative study of US children, and the Fragile Families and Child Wellbeing Study (n = 4,053), an urban sample of mostly low-income unmarried US mothers, to study the association between three-generation coresidence and breastfeeding initiation and duration using multivariate logistic regressions with extensive socio-demographic controls. Three-generation coresidence was associated with lower odds of breastfeeding initiation among the less advantaged mothers but not in the nationally representative sample of mothers. In comparison, three-generation coresidence was associated with lower odds of breastfeeding for 6 months or greater in both study samples. Three-generation coresidence may serve as a marker for differences in the likelihood of breastfeeding that can help inform public health strategies aimed at increasing breastfeeding rates. Research studying interventions with grandparents and the effects on breastfeeding behaviors may be a useful next step in public health promotion of breastfeeding. © 2014 Springer Science+Business Media New York.

De Vaan M.,Columbia University
Research Policy | Year: 2014

This paper examines how network relations between firms influence firm survival by explicitly addressing the moderating role of changing technological regimes. Using longitudinal data on 1385 developers and 190 publishers of video games in the global video game industry between 1972 and 2007, the analyses show that the effect of network ties between developers and publishers on the survival probability of developers is moderated by the level of technological turbulence in the industry. The results show that the effect of network partner failure on firm survival is dependent on the strength of ties. The failure of strongly tied network partners harms developers in stable periods and benefits them in turbulent eras, while no such relation is found for weakly tied network partners. Network partner diversity positively affects firm performance in epochs of technological turbulence, while the effect plays no significant role for firm survival in stable settings. The results indicate that the relation between interfirm network relations and firm survival are moderated by sequences of technological renewal in the video game industry which causes the industry to go through an evolution that deviates from the typical S-shaped trajectory found in industries that are characterized by strong path-dependent processes. © 2014 Elsevier B.V. All rights reserved.

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.

Block P.,Columbia University
Hydrology and Earth System Sciences | Year: 2011

Integration of seasonal precipitation forecasts into water resources operations and planning is practically nonexistent, even in regions of scarcity. This is often attributable to water manager's tendency to act in a risk averse manner, preferring to avoid consequences of poor forecasts, at the expense of unrealized benefits. Convincing demonstrations of forecast value are therefore desirable to support assimilation into practice. A dynamically linked system, including forecast, rainfall-runoff, and hydropower models, is applied to the upper Blue Nile basin in Ethiopia to compare benefits and reliability generated by actual forecasts against a climatology-based approach, commonly practiced in most water resources systems. Processing one hundred decadal sequences demonstrates superior forecast-based benefits in 68 cases, a respectable advancement, however benefits in a few forecast-based sequences are noticeably low, likely to dissuade manager's adoption. A hydropower sensitivity test reveals a propensity toward poor-decision making when forecasts over-predict wet conditions. Tailoring the precipitation forecast to highlight critical dry forecasts minimizes this inclination, resulting in 97% of the sequences favoring the forecast-based approach. Considering managerial risk preferences for the system, even risk-averse actions, if coupled with forecasts, exhibit superior benefits and reliability compared with risk-taking tendencies conditioned on climatology. © 2011 Author(s) CC Attribution 3.0 License.

Rauscher E.,University of Arizona | Menou K.,Columbia University
Astrophysical Journal | Year: 2012

We present a new version of our code for modeling the atmospheric circulation on gaseous exoplanets, now employing a "double-gray" radiative transfer scheme, which self-consistently solves for fluxes and heating throughout the atmosphere, including the emerging (observable) infrared flux. We separate the radiation into infrared and optical components, each with its own absorption coefficient, and solve standard two-stream radiative transfer equations. We use a constant optical absorption coefficient, while the infrared coefficient can scale as a power law with pressure; however, for simplicity, the results shown in this paper use a constant infrared coefficient. Here we describe our new code in detail and demonstrate its utility by presenting a generic hot Jupiter model. We discuss issues related to modeling the deepest pressures of the atmosphere and describe our use of the diffusion approximation for radiative fluxes at high optical depths. In addition, we present new models using a simple form for magnetic drag on the atmosphere. We calculate emitted thermal phase curves and find that our drag-free model has the brightest region of the atmosphere offset by ∼12° from the substellar point and a minimum flux that is 17% of the maximum, while the model with the strongest magnetic drag has an offset of only ∼2° and a ratio of 13%. Finally, we calculate rates of numerical loss of kinetic energy at ∼15% for every model except for our strong-drag model, where there is no measurable loss; we speculate that this is due to the much decreased wind speeds in that model. © © 2012. The American Astronomical Society. All rights reserved.

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.

Harel S.,Columbia University
The Journal of investigative dermatology | Year: 2012

The identification of causative genes carries the promise of new and innovative therapeutic strategies for both inherited and acquired hair disorders. Moreover, the delineation of the relationships between similar phenotypes, resulting from mutations affecting seemingly distinct regulatory pathways, paves the way to improved diagnosis and treatment. Finally, understanding the biological processes governing HF development and maintenance may have implications for more general disease processes in the skin, such as inflammation and cancer.

Mellins C.A.,Columbia University | Malee K.M.,Northwestern University
Journal of the International AIDS Society | Year: 2013

Introduction: Across the globe, children born with perinatal HIV infection (PHIV) are reaching adolescence and young adulthood in large numbers. The majority of research has focused on biomedical outcomes yet there is increasing awareness that long-term survivors with PHIV are at high risk for mental health problems, given genetic, biomedical, familial and environmental risk. This article presents a review of the literature on the mental health functioning of perinatally HIV-infected (PHIV+) adolescents, corresponding risk and protective factors, treatment modalities and critical needs for future interventions and research. Methods: An extensive review of online databases was conducted. Articles including: (1) PHIV+ youth; (2) age 10 and older; (3) mental health outcomes; and (4) mental health treatment were reviewed. Of 93 articles identified, 38 met inclusion criteria, the vast majority from the United States and Europe. Results: These studies suggest that PHIV+ youth experience emotional and behavioural problems, including psychiatric disorders, at higher than expected rates, often exceeding those of the general population and other high-risk groups. Yet, the specific role of HIV per se remains unclear, as uninfected youth with HIV exposure or those living in HIV-affected households displayed similar prevalence rates in some studies, higher rates in others and lower rates in still others. Although studies are limited with mixed findings, this review indicates that child-health status, cognitive function, parental health and mental health, stressful life events and neighbourhood disorder have been associated with worse mental health outcomes, while parent-child involvement and communication, and peer, parent and teacher social support have been associated with better function. Few evidence-based interventions exist; CHAMP+, a mental health programme for PHIV+ youth, shows promise across cultures. Conclusions: This review highlights research limitations that preclude both conclusions and full understanding of aetiology. Conversely, these limitations present opportunities for future research. Many PHIV+ youth experience adequate mental health despite vulnerabilities. However, the focus of research to date highlights the identification of risks rather than positive attributes, which could inform preventive interventions. Development and evaluation of mental health interventions and preventions are urgently needed to optimize mental health, particularly for PHIV+ youth growing up in low-and-middle income countries. © 2013 Mellins CA and Malee KM; licensee International AIDS Society.

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.

Dimauro S.,Columbia University
Journal of Inherited Metabolic Disease | Year: 2011

This articles reviews the development of mitochondrial medicine from the premolecular era (1962-1988), when mitochondrial diseases were defined on the basis of clinical examination, muscle biopsy, and biochemical criteria, through the molecular era, when the full complexity of these disorders became evident. In a chronological order, I have followed the introduction of new pathogenic concepts that have shaped a rational genetic classification of these clinically heterogeneous disorders. Thus, mitochondrial DNA (mtDNA)-related diseases can be divided into two main groups: those that impair mitochondrial protein synthesis in toto, and those that affect specific respiratory chain proteins. Mutations in nuclear DNA can affect components of respiratory chain complexes (direct hits) or assembly proteins (indirect hits), but they can also impair mtDNA integrity (multiple mtDNA mutations), replication (mtDNA depletion), or mtDNA translation. Besides these disorders that affect the respiratory chain directly, defects in other mitochondrial functions may also affect oxidative phosphorylation, including problems in mitochondrial protein import, alterations of the inner mitochondrial membrane lipid composition, and defects of mitochondrial dynamics. The enormous and still ongoing progress in our understanding of mitochondrial medicine was made possible by the intense collaboration of an international cadre of "mitochondriacs." Having published my first paper on a patient with mitochondrial myopathy 37 years ago (DiMauro et al., 1973), I feel qualified to write a history of the mitochondrial diseases, a fascinating, still evolving, and continuously puzzling area of medicine. In each section, I follow a chronological order of the salient discoveries and I show only the portraits of distinguished deceased mitochondriacs and those whose names became eponyms of mitochondrial diseases. © 2010 SSIEM and Springer.

Chakhalian J.,University of Arkansas | Freeland J.W.,Argonne National Laboratory | Millis A.J.,Columbia University | Panagopoulos C.,Nanyang Technological University | And 2 more authors.
Reviews of Modern Physics | Year: 2014

Finding new collective electronic states in materials is one of the fundamental goals of condensed matter physics. Atomic-scale superlattices formed from transition metal oxides are a particularly appealing hunting ground for new physics. In bulk form, transition metal oxides exhibit a remarkable range of magnetic, superconducting, and multiferroic phases that are of great scientific interest and are potentially capable of providing innovative energy, security, electronics, and medical technology platforms. In superlattices new states may emerge at the interfaces where dissimilar materials meet. This Colloquium illustrates the essential features that make transition metal oxide-based heterostructures an appealing discovery platform for emergent properties with a few selected examples, showing how charge redistributes, magnetism and orbital polarization arises, and ferroelectric order emerges from heterostructures comprised of oxide components with nominally contradictory behavior with the aim providing insight into the creation and control of novel behavior at oxide interfaces by suitable mechanical, electrical, or optical boundary conditions and excitations. © 2014 American Physical Society.

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.

Olfson M.,Columbia University | Marcus S.C.,University of Pennsylvania | Bridge J.A.,Ohio State University
Archives of General Psychiatry | Year: 2012

Context: Although concern exists over the quality of emergency mental health services, little is known about the mental health care of adults who are admitted to emergency departments for deliberately harming themselves and then discharged to the community. Objective: To describe the predictors of emergency department discharge, the emergency mental health assessments, and the follow-up outpatient mental health care of adult Medicaid beneficiaries treated for deliberate selfharm. Design: A retrospective longitudinal cohort analysis. Setting: National Medicaid claims data supplemented with county-level sociodemographic variables and Medicaid state policy survey data. Participants: Adults aged 21 to 64 years who were treated in emergency departments for 7355 episodes of deliberate self-harm, focusing on those who were discharged to the community (4595 episodes). Main Outcome Measures: Rates and adjusted risk ratios (ARRs) of discharge to the community, mental health assessments in the emergency department, and outpatient mental health visits during the 30 days following the emergency department visit. Results: Most patients (62.5%) were discharged to the community. Emergency department discharge was directly related to younger patient age (21-31 years vs 45-64 years) (ARR, 1.18 [99% confidence interval {CI}, 1.10- 1.25]) and self-harm by cutting (ARR, 1.18 [99% CI, 1.12- 1.24]) and inversely related to poisoning (ARR, 0.84 [99% CI, 0.80-0.89]) and recent psychiatric hospitalization (ARR, 0.74 [99% CI, 0.67-0.81]). Approximately one-half of discharged patients (47.5%) received a mental health assessment in the emergency department, and a similar percentage of discharged patients (52.4%) received a follow-up outpatient mental health visit within 30 days. Follow-up mental health care was directly related to recent outpatient mental health care (ARR, 2.30 [99% CI, 2.11-2.50]) and treatment in a state with Medicaid coverage of mental health clinic services (ARR, 1.13 [99% CI, 1.05-1.22]) and inversely related to African American (ARR, 0.86 [99% CI, 0.75-0.96]) and Hispanic (ARR, 0.86 [99% CI, 0.75-0.99]) race/ethnicity. Conclusion: Most adult Medicaid beneficiaries who present for emergency care for deliberate self-harm are discharged to the community, and many do not receive emergency mental health assessments or follow-up outpatient mental health care. ©2012 American Medical Association. All rights reserved.

Parsey R.V.,Columbia University
Journal of Nuclear Medicine | Year: 2010

Serotonin is a modulatory neurotransmitter in the human brain that regulates mood, anger, reward, aggression, and appetite and plays a central role in brain development. These effects are mediated through the interaction of serotonin with at least 15 different receptor molecules. Through the development and careful characterization of novel radiotracers, we have been able to visualize and quantify in vivo many of the key molecular sites-including serotonin receptors, reuptake transporters, and enzymes-responsible for serotonin metabolism. The clinical goals of serotonin imaging are to aid in determining the pathophysiology of brain disorders, to determine novel therapeutic strategies, to predict treatment, to estimate risk, and to determine individualized dosing strategies. Despite the contradictory results of early studies, the field as a whole has made significant progress on nearly all of these fronts, and advances in methodology suggest paths toward coherence. Through concerted, directed, and cooperative efforts, the routine use of serotonin imaging in the clinic will most likely be achieved in the next decade. Copyright © 2010 by the Society of Nuclear Medicine, Inc.

Reitz C.,Columbia University
Molecular Genetics and Genomics | Year: 2015

The retromer coat complex is a vital component of the intracellular trafficking mechanism sorting cargo from the endosomes to the trans-Golgi network or to the cell surface. In recent years, genes encoding components of the retromer coat complex and members of the vacuolar protein sorting 10 (Vps10) family of receptors, which play pleiotropic functions in protein trafficking and intracellular/intercellular signaling in neuronal and non-neuronal cells and are primary cargos of the retromer complex, have been implicated as genetic risk factors for sporadic and autosomal dominant forms of several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease and frontotemporal lobar degeneration. In addition to their functions in protein trafficking, the members of the Vps10 receptor family (sortilin, SorL1, SorCS1, SorCS2, and SorCS3) modulate neurotrophic signaling pathways. Both sortilin and SorCS2 act as cell surface receptors to mediate acute responses to proneurotrophins. In addition, sortilin can modulate the intracellular response to brain-derived neurotrophic factor (BDNF) by direct control of BDNF levels and regulating anterograde trafficking of Trk receptors to the synapse. This review article summarizes the emerging data from this rapidly growing field of intracellular trafficking signaling in the pathogenesis of neurodegeneration. © 2014, Springer-Verlag Berlin Heidelberg.

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.

Iordanou K.,Columbia University
Journal of Cognition and Development | Year: 2010

Instant-messaging software was used as a method to promote development of argumentation skills in middle schoolers. Transfer of skills across content domains was the major question investigated. Forty sixth graders engaged in electronic dialogues with peers on a controversial topic-for half a science topic (dinosaur extinction) and for half a social topic (home schooling). During 13 sessions, participants worked with a partner in arguing with a suc- cession of pairs of classmates who held an opposing view on the topic; in addition, they engaged in some reflective activities based on transcriptions of the dialogues. Another 18 sixth graders served in a control (noninterven- tion) condition. Although transfer occurred in both directions, science con- dition participants exhibited transfer of skills to the social topic to a greater extent than did social condition participants to the science topic. Results show the transfer, and hence generality, of developing argument skills but also sug- gest the importance as well as feasibility of fostering argument skills within science and social domains. © 2010 Taylor & Francis Group, LLC.

Kotchetkov I.S.,Columbia University
Neurosurgical focus | Year: 2010

Brain-computer interfaces (BCIs) are devices that acquire and transform neural signals into actions intended by the user. These devices have been a rapidly developing area of research over the past 2 decades, and the military has made significant contributions to these efforts. Presently, BCIs can provide humans with rudimentary control over computer systems and robotic devices. Continued advances in BCI technology are especially pertinent in the military setting, given the potential for therapeutic applications to restore function after combat injury, and for the evolving use of BCI devices in military operations and performance enhancement. Neurosurgeons will play a central role in the further development and implementation of BCIs, but they will also have to navigate important ethical questions in the translation of this highly promising technology. In the following commentary the authors discuss realistic expectations for BCI use in the military and underscore the intersection of the neurosurgeon's civic and clinical duty to care for those who serve their country.

Yin H.M.,Columbia University
International Journal of Solids and Structures | Year: 2010

Opening-mode fractures in layered materials are commonly found in a layer with uniform spacing that is nearly proportional to the thickness of the fractured layer. However, when fracture spacing reduces to a certain value, fracture density is saturated and no new fracture forms. If a loading condition is fixed, there exists a critical thickness of the layer, below which no fracture forms. This paper presents a three-layer model, containing a weak layer between two stronger layers, to interpret the fracture saturation and critical thickness of layered materials. Using elastic governing equations and a weak form stress boundary condition, a closed-form solution of elastic fields in the weak layer is derived and the energy release rate for opening-mode fracture is obtained. Interestingly, the normal stress between such fractures undergoes a transition from tensile to compressive with increasing applied tensile loading, which causes fracture saturation. Explicit expressions of critical fracture-spacing-to-layer-thickness ratio and critical thickness are derived for fracture saturation and fracture free conditions, respectively. Comparison with the existing numerical simulation results demonstrates the capability of this model. This explicit, analytical solution is useful to structural design and geosciences. © 2009 Elsevier Ltd. All rights reserved.

Weimer L.H.,Columbia University
Neurologist | Year: 2010

Laboratories able to test autonomic function are increasingly available and rely on batteries of well-accepted, noninvasive tests. Tests of parasympathetic cardiovagal, sympathetic vasoconstriction, and sudomotor (sweating) function are most commonly employed. Common examples include heart rate variability to various challenges, Valsalva maneuver, standing and tilt-table studies, and various sudomotor methods. New techniques and technical refinements continue to be described. Most studies rely on perturbations of complex systems and not direct assessment. Testing has helped to improve disease recognition and prompted advances in classification, pathophysiology, and treatment. Major areas impacted include hereditary and immune-mediated autonomic neuropathy, diabetic autonomic neuropathy, distal symmetric polyneuropathy, Parkinson disease and other autonomic failure syndromes, orthostatic intolerance, and unexplained syncope. © 2010 by Lippincott Williams & Wilkins.

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.

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.

Fried L.P.,Columbia University
Gerontologist | Year: 2016

The world is aging as a result of unprecedented successes worldwide adding 30 years of life expectancy and presenting great opportunities for all of society, but only if we invest effectively. This article, written as a requested background article for the World Health Organization 2015 World Report on Aging, proposes that creating health into the oldest ages could lay the basis for a third demographic dividend resulting from the societal benefits from the generative social capital of older adults, on top of the second demographic dividend's savings associated with longer lives. The combination would contribute to stronger and wealthier societies, greater success of the young, and increased societal ability to provide the humane supports needed at the end of life, plus a dividend that would endure. We now know that prevention works at every age and into the oldest ages. A life-course approach to prevention and health promotion is the key investment. The creation of geriatrically knowledgeable and integrated public health, medical and social care systems has the potential to amplify capabilities and well-being to the end of life. Healthy older populations bring both desire for engagement and unique talents. Institutions designed to create impactful roles for older adults to contribute to the success of the young can activate the societal benefits and further enhance health at older ages. Creating a new vision for the opportunities of an older age is the first critical step toward experiencing the benefits of our longer lives and creating a sustained third demographic dividend. © 2016 The Author 2016.

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.

Veenstra-VanderWeele J.,Columbia University | Warren Z.,Vanderbilt University
Neuropsychopharmacology | Year: 2015

Neuropsychiatric disorders vary substantially in age of onset but are best understood within the context of neurodevelopment. Here, we review opportunities for intervention at critical points in developmental trajectories. We begin by discussing potential opportunities to prevent neuropsychiatric disorders. Once symptoms begin to emerge, a number of interventions have been studied either before a diagnosis can be made or shortly after diagnosis. Although some of these interventions are helpful, few are based upon an understanding of pathophysiology, and most ameliorate rather than resolve symptoms. As such, in the next portion of the review, we turn our discussion to genetic syndromes that are rare phenocopies of common diagnoses such as autism spectrum disorder or schizophrenia. Cellular or animal models of these syndromes point to specific regulatory or signaling pathways. As examples, findings from the mouse models of Fragile X and Rett syndromes point to potential treatments now being tested in randomized clinical trials. Paralleling oncology, we can hope that our treatments will move from nonspecific, like chemotherapies thrown at a wide range of tumor types, to specific, like the protein kinase inhibitors that target molecularly defined tumors. Some of these targeted treatments later show benefit for a broader, yet specific, array of cancers. We can hope that medications developed within rare neurodevelopmental syndromes will similarly help subgroups of patients with disruptions in overlapping signaling pathways. The insights gleaned from treatment development in rare phenocopy syndromes may also teach us how to test treatments based upon emerging common genetic or environmental risk factors. © 2015 American College of Neuropsychopharmacology. All rights reserved.

Bezard E.,University of Bordeaux Segalen | Przedborski S.,Columbia University
Movement Disorders | Year: 2011

Parkinson's disease is a neurodegenerative disorder whose cardinal manifestations are due primarily to a profound deficit in brain dopamine. Since the 1980s, several therapeutic strategies have been discovered to treat the symptoms of this neurological disorder, but as of yet, none halts or retards the neurodegenerative process. In an attempt to shed light on the neurobiology of Parkinson's disease, a number of experimental models have been developed, especially during the last 25 years. They come essentially in 3 flavors: pharmacological (eg, reserpine), toxic (eg, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), and genetic (eg, transgenic synuclein mice). These models can also be recast as etiologic, pathogenic, and symptomatic/pathophysiologic, as each may contribute to our understanding of the cause, the mechanisms, and the treatment of Parkinson's disease. In this review, we will discuss the question of Parkinson's disease models, starting from the period when this journal was born to today. During this journey of 25 years, we will discuss both the significant contributions of the Parkinson's disease models and hurdles that remain to be overcome to one day cure this neurological disease. © 2011 Movement Disorder Society.

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.

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.

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.

Sauer M.V.,Columbia University
Fertility and Sterility | Year: 2015

Advanced age is a risk factor for female infertility, pregnancy loss, fetal anomalies, stillbirth, and obstetric complications. These concerns are based on centuries-old observations, yet women are delaying childbearing to pursue educational and career goals in greater numbers than ever before. As a result, reproductive medicine specialists are treating more patients with age-related infertility and recurrent pregnancy loss, while obstetricians are faced with managing pregnancies often complicated by both age and comorbidities. The media portrayal of a youthful but older woman, able to schedule her reproductive needs and balance family and job, has fueled the myth that "you can have it all," rarely characterizing the perils inherent to advanced-age reproduction. Reproductive medicine specialists and obstetrician/gynecologists should promote more realistic views of the evidence-based realities of advanced maternal age pregnancy, including its high-risk nature and often compromised outcomes. Doctors should also actively educate both patients and the public that there is a real danger of childlessness if individuals choose to delay reproduction. © 2015 American Society for Reproductive Medicine.

Sparrow J.R.,Columbia University
Advances in Experimental Medicine and Biology | Year: 2010

Genetic association studies and investigations of the constituents of subretinal deposits (drusen) have implicated complement dysregulation as one factor predisposing individuals to increased risk of age-related macular degeneration (AMD). Here we review evidence that molecular fragments released by photooxidation of the bisretinoids of retinal pigment epithelial lipofuscin, can activate complement. Complement activation by this mechanism is dependent on the alternative pathway. The diretinal conjugates comprising RPE lipofuscin accumulate in the cells throughout the lifetime of an individual. As such, these photooxidative processes, in a setting of complement dysregulation could contribute to chronic inflammation underlying AMD pathogenesis. © Springer Science+Business Media, LLC 2010.

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.

Marshall R.S.,Columbia University
Journal of Alzheimer's Disease | Year: 2012

Cerebral hemodynamic impairment has come under examination over the years as an independent cause for cognitive dysfunction, but only recently has the advance of imaging and ultrasound technology permitted a fuller investigation of physiopathology. Beyond the impact of fixed structural lesions such as infarction and white matter hyperintensities, hemodynamic dysfunction, which includes hypoperfusion and altered cerebral autoregulation, may be independently associated with cognitive decline. More importantly, whereas vascular-related structural pathology may produce so-called vascular dementia, disorders of blood flow and blood flow regulation may also present clinically as mild cognitive impairment or even frank dementia, but may in fact be reversible. Hemodynamic effects may occur at the level of the cerebral hemisphere due to restricted flow through a large vessel of the neck or head, at a global level in the setting of cardiac failure, or intrinsically due to dysfunction of the endothelium in the microvasculature. This review surveys clinical, imaging, and physiological evidence for the association between hemodynamic abnormalities at these different levels and cognitive impairment. © 2012 - IOS Press and the authors. All rights reserved.

Karsenty G.,Columbia University | K. Yadav V.,Wellcome Trust Sanger Institute
Annual Review of Medicine | Year: 2011

The molecular elucidation of two human skeletal dysplasias revealed that they are caused by an increase or a decrease in the synthesis of serotonin by enterochromaffin cells of the gut. This observation revealed a novel and powerful endocrine means to regulate bone mass. Exploiting these findings in the pharmacological arena led to the demonstration that inhibiting synthesis of gut-derived serotonin could be an effective means to treat low-bone-mass diseases such as osteoporosis. © 2011 by Annual Reviews. All rights reserved.

The actin depolymerizing factors (ADFs) play important roles in several cellular processes that require cytoskeletal rearrangements, such as cell migration, but little is known about the in vivo functions of ADFs in developmental events like branching morphogenesis. While the molecular control of ureteric bud (UB) branching during kidney development has been extensively studied, the detailed cellular events underlying this process remain poorly understood. To gain insight into the role of actin cytoskeletal dynamics during renal branching morphogenesis, we studied the functional requirements for the closely related ADFs cofilin1 (Cfl1) and destrin (Dstn) during mouse development. Either deletion of Cfl1 in UB epithelium or an inactivating mutation in Dstn has no effect on renal morphogenesis, but simultaneous lack of both genes arrests branching morphogenesis at an early stage, revealing considerable functional overlap between cofilin1 and destrin. Lack of Cfl1 and Dstn in the UB causes accumulation of filamentous actin, disruption of normal epithelial organization, and defects in cell migration. Animals with less severe combinations of mutant Cfl1 and Dstn alleles, which retain one wild-type Cfl1 or Dstn allele, display abnormalities including ureter duplication, renal hypoplasia, and abnormal kidney shape. The results indicate that ADF activity, provided by either cofilin1 or destrin, is essential in UB epithelial cells for normal growth and branching.

Hoffman M.D.,Adobe Research | Gelman A.,Columbia University
Journal of Machine Learning Research | Year: 2014

Hamiltonian Monte Carlo (HMC) is a Markov chain Monte Carlo (MCMC) algorithm that avoids the random walk behavior and sensitivity to correlated parameters that plague many MCMC methods by taking a series of steps informed by first-order gradient information. These features allow it to converge to high-dimensional target distributions much more quickly than simpler methods such as random walk Metropolis or Gibbs sampling. However, HMC's performance is highly sensitive to two user-specified parameters: a step size e and a desired number of steps L. In particular, if L is too small then the algorithm exhibits undesirable random walk behavior, while if L is too large the algorithm wastes computation. We introduce the No-U-Turn Sampler (NUTS), an extension to HMC that eliminates the need to set a number of steps L. NUTS uses a recursive algorithm to build a set of likely candidate points that spans a wide swath of the target distribution, stopping automatically when it starts to double back and retrace its steps. Empirically, NUTS performs at least as efficiently as (and sometimes more efficiently than) a well tuned standard HMC method, without requiring user intervention or costly tuning runs. We also derive a method for adapting the step size parameter e on the fly based on primal-dual averaging. NUTS can thus be used with no hand-tuning at all, making it suitable for applications such as BUGS-style automatic inference engines that require efficient "turnkey" samplers. © 2014 Matthew D. Hoffman and Andrew Gelman.

Hassan S.F.,The Oskar Klein Center | Rosen R.A.,Columbia University
Journal of High Energy Physics | Year: 2012

In massive gravity and in bimetric theories of gravity, two constraints are needed to eliminate the two phase-space degrees of freedom of the Boulware-Deser ghost. For recently proposed non-linear theories, a Hamiltonian constraint has been shown to exist and an associated secondary constraint was argued to arise as well. In this paper we explicitly demonstrate the existence of the secondary constraint. Thus the Boulware-Deser ghost is completely absent from these non-linear massive gravity theories and from the corresponding bimetric theories. Equivalently, this proves the existence of classically ghostfree theories of massive spin-2 fields, in both fixed and dynamical gravitational backgrounds. © SISSA 2012.

Hassan S.F.,The Oskar Klein Center | Rosen R.A.,Columbia University
Journal of High Energy Physics | Year: 2012

Generically, non-linear bimetric theories of gravity suffer from the same Boulware-Deser ghost instability as non-linear theories of massive gravity. However, recently proposed theories of massive gravity have been shown to be ghost-free. These theories are formulated with respect to a flat, non-dynamical reference metric. In this work we show that it is possible to give dynamics to the reference metric in such a way that the consistency of the theory is maintained. The result is a non-linear bimetric theory of a massless spin-2 field interacting with a massive spin-2 field that is free of the Boulware-Deser ghost. To our knowledge, this is the first construction of such a ghost-free bimetric theory. © 2012 SISSA.

Cai N.,Hong Kong University of Science and Technology | Kou S.,Columbia University
Operations Research | Year: 2012

We obtain a closed-form solution for the double-Laplace transform of Asian options under the hyper-exponential jump diffusion model. Similar results were available previously only in the special case of the Black-Scholes model (BSM). Even in the case of the BSM, our approach is simpler as we essentially use only Itô's formula and do not need more advanced results such as those of Bessel processes and Lamperti's representation. As a by-product we also show that a well-known recursion relating to Asian options has a unique solution in a probabilistic sense. The double-Laplace transform can be inverted numerically via a two-sided Euler inversion algorithm. Numerical results indicate that our pricing method is fast, stable, and accurate; and it performs well even in the case of low volatilities. © 2012 INFORMS.

Gershengorn H.B.,Yeshiva University | Wunsch H.,Columbia University
Critical Care Medicine | Year: 2013

OBJECTIVE:: Multiple studies suggest that routine use of pulmonary artery catheters is not beneficial in critically ill patients. Little is known about the patterns of "uptake" of practice change that involves removal of a device previously considered standard of care, rather than adoption of a new technique or technology. Our objective was to assess recent pulmonary artery catheter use across ICUs and identify factors associated with high use. DESIGN:: Cohort study. SETTING:: U.S. ICUs in Project IMPACT. PATIENTS:: Adult ICU admissions from 2001 to 2008. INTERVENTIONS:: None. MEASUREMENTS AND MAIN RESULTS:: Trends in pulmonary artery catheter use from 2001 to 2008 were assessed. For 2006-2008, we compared pulmonary artery catheter use across ICUs. We assessed characteristics of ICUs and hospitals in the top quartile for in-ICU pulmonary artery catheter placement (vs the bottom quartile) using chi-square and t tests and factors associated with in-ICU pulmonary artery catheter insertion using multilevel mixed effects logistic regression. Total pulmonary artery catheter use decreased from 10.8% of patients (2001-2003) to 6.2% (2006-2008; p < 0.001); insertion of pulmonary artery catheters in ICU decreased from 4.2% to 2.2% (p < 0.001). In 2006-2008, ICUs in the top quartile for in-ICU pulmonary artery catheter insertion (3.4-25.0% of patients) were more often surgical (54.2% vs 21.7% in the lowest quartile, p = 0.070), teaching hospitals (54.2% vs 4.3%, p = 0.001), and had surgeon leadership (40.9% vs 13.0%, p = 0.067). After multivariable regression, surgical patients (p < 0.001) and all patients in surgical ICUs (p = 0.057) were more likely to have pulmonary artery catheters placed in ICU. CONCLUSIONS:: Use of pulmonary artery catheters in ICU patients has declined but with significant variation across units. Removal of this technology has occurred most in nonsurgical ICUs and patients. Copyright © 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.

Hinterbichler K.,University of Pennsylvania | Rosen R.A.,Columbia University
Journal of High Energy Physics | Year: 2012

We construct consistent theories of multiple interacting spin-2 fields in arbitrary spacetime dimensions using a vielbein formulation. We show that these theories have the additional primary constraints needed to eliminate potential ghosts, to all orders in the fields, and to all orders beyond any decoupling limit. We postulate that the number of spin-2 fields interacting at a single vertex is limited by the number of spacetime dimensions. We then show that, for the case of two spin-2 fields, the vielbein theory is equivalent to the recently proposed theories of ghost-free massive gravity and bi-metric gravity. The vielbein formulation greatly simplifies the proof that these theories have an extra primary constraint which eliminates the Boulware-Deser ghost. © SISSA 2012.

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.

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.

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.

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.

Brooks C.L.,Stemline Therapeutics | Gu W.,Columbia University
FEBS Letters | Year: 2011

The ubiquitination pathway is a highly dynamic and coordinated process that regulates degradation as well as numerous processes of proteins within a cell. The p53 tumor suppressor and several factors in the pathway are regulated by ubiquitin as well as ubiquitin-like proteins. These modifications are critical for the function of p53 and control both the degradation of the protein as well as localization and activity. Importantly, more recent studies have identified deubiquitination enzymes that can specifically remove ubiquitin moieties from p53 or other factors in the pathway, and the reversible nature of this process adds yet another layer of regulatory control of p53. This review highlights the recent advances in our knowledge of ubiquitin and the p53 pathway. © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

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

Single-molecule biology has matured in recent years, driven to greater sophistication by the development of increasingly advanced experimental techniques. A progressive appreciation for its unique strengths is attracting research that spans an exceptionally broad swath of physiological phenomena--from the function of nucleosomes to protein diffusion in the cell membrane. Newfound enthusiasm notwithstanding, the single-molecule approach is limited to an intrinsically defined set of biological questions; such limitation applies to all experimental approaches, and an explicit statement of the boundaries delineating each set offers a guide to most fruitfully orienting in vitro single-molecule research in the future. Here, we briefly describe a simple conceptual framework to categorize how submolecular, molecular and intracellular processes are studied. We highlight the domain of single-molecule biology in this scheme, with an emphasis on its ability to probe various forms of heterogeneity inherent to populations of discrete biological macromolecules. We then give a general overview of our high-throughput DNA curtain methodology for studying protein-nucleic acid interactions, and by contextualizing it within this framework, we explore what might be the most enticing avenues of future research. We anticipate that a focus on single-molecule biology's unique strengths will suggest a new generation of experiments with greater complexity and more immediately translatable physiological relevance.

Mancia F.,Columbia University | Love J.,New York Structural Biology Center
Current Opinion in Structural Biology | Year: 2011

Structural genomics approaches on integral membrane proteins have been postulated for over a decade, yet specific efforts are lagging years behind their soluble counterparts. Indeed, high throughput methodologies for production and characterization of prokaryotic integral membrane proteins are only now emerging, while large-scale efforts for eukaryotic ones are still in their infancy. Presented here is a review of recent literature on actively ongoing structural genomics of membrane protein initiatives, with a focus on those aimed at implementing interesting techniques aimed at increasing our rate of success for this class of macromolecules. © 2011 Elsevier Ltd.

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

Objectives: To outline the prevalence and disparities of aggression and violence among school-aged urban minority youth, causal pathways through which aggression and violence adversely affects academic achievement, and proven or promising approaches for schools to address these problems. Methods: Literature review. Results: Recent national data indicate that among students aged 12-18, approximately 628,200 violent crimes and 868,100 thefts occurred. Physical fighting was more commonly reported by Blacks and Hispanics (44.7% and 40.4%, respectively) than Whites (31.7%). In-school threats and injuries were nearly twice as prevalent in cities as in suburbs and towns or rural areas (10% vs 6% and 5%, respectively). Associations between exposure to and exhibition of aggression and violence and unfavorable educational outcomes are well documented. Causal pathways through which aggression and violence impede learning include cognition, school connectedness, and absenteeism. Disruptive classroom behavior is a well-recognized and significant impediment to teaching and learning. Compelling research has shown that various school-based programs can significantly reduce the nature and extent of aggressive and violent behaviors. Conclusions: Violence and aggressive behavior are highly and disproportionately prevalent among school-aged urban minority youth, have a negative impact on academic achievement by adversely affecting cognition, school connectedness, and absenteeism, and effective practices are available for schools to address this problem. Once the domain of criminal justice, aggression and violence are now recognized as an appropriate and important focus of the education and public health systems. Implementing evidence-based school policies and programs to reduce aggression and violence must be a high priority to help close the achievement gap. © 2011, American School Health Association.

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.

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.

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.

Background: Salvage cryosurgery (SC) is a recognised option for patients who fail either primary radiation or cryosurgery. Objective: To report outcomes of patients undergoing SC. Design, setting, and participants: A consecutive series of 396 patients who had failed either primary radiotherapy or cryosurgery underwent SC between October 1994 and August 2011. Outcome measurements and statistical analysis: Demographic and clinical parameters before primary and salvage treatment were evaluated; disease-free-survival (DFS), overall-survival (OS), disease-specific-survival (DSS), and complications were assessed. Results and limitations: Sufficient follow-up data were available for 328 patients. Median age was 65.8 yr (range: 45-81 yr), median serum prostate-specific antigen (PSA) level was 8.0 ng/ml (range: 0.6-290.0 ng/ml). After primary treatment, median time to recurrence was 55 mo (range: 0.0-183.6 mo). SC was performed at a median of 67.5 mo (range: 7.0-212.7 mo) later; median pre-SC PSA level was 4.0 ng/ml (range: 0.1-112.4 ng/ml). Median PSA nadir was 0.2 ng/ml (range: 0.01-70.70 ng/ml), reached after a median of 2.6 mo (range: 2.0-67.3 mo) after SC. Median follow-up was 47.8 mo (range: 1.6-203.5 mo). Respective 5- and 10-yr DFS was 63% and 35%; OS: 74% and 45%; and DSS: 91% and 79%. In univariate analyses, time from primary treatment to SC or recurrence, PSA level before SC, and PSA nadir after SC were all significant predictors of recurrence (p ≤ 0.01). PSA before SC and time to recurrence were also predictive of DSS (p = 0.003 and p = 0.01, respectively). In multivariate analyses, only PSA nadir after SC was predictive of recurrence and DSS (p < 0.001 and p = 0.012, respectively). Complications were rare (range: 0.6-4.6%). Fifty-five patients (16.7%) underwent focal SC. Median PSA nadir after focal SC was 0.44 ng/ml (range: 0.04-20.1 ng/ml). Twenty-seven patients (49%) experienced recurrence. Respective 5- and 10-yr DFS was 47% and 42%; OS: 87% and 81%; and DSS: 100% and 83%. Conclusions: Our analysis confirms SC as an effective treatment option for patients failing primary therapy. Patients experienced excellent survival outcome and minimal associated morbidity after SC. Focal SC is an efficacious treatment for properly selected patients. © 2012 European Association of Urology.

Zeltser L.M.,Columbia University | Seeley R.J.,University of Cincinnati | Tschop M.H.,TU Munich
Nature Neuroscience | Year: 2012

Maintaining energy balance is of paramount importance for metabolic health and survival. It is achieved through the coordinated regulation of neuronal circuits that control a wide range of physiological processes affecting energy intake and expenditure, such as feeding, metabolic rate, locomotor activity, arousal, growth and reproduction. Neuronal populations distributed throughout the CNS but highly enriched in the mediobasal hypothalamus, sense hormonal, nutrient and neuronal signals of systemic energy status and relay this information to secondary neurons that integrate the information and regulate distinct physiological parameters in a manner that promotes energy homeostasis. To achieve this, it is critical that neuronal circuits provide information about short-term changes in nutrient availability in the larger context of long-term energy status. For example, the same signals lead to different cellular and physiological responses if delivered under fasted versus fed conditions. Thus, there is a clear need to have mechanisms that rapidly and reversibly adjust responsiveness of hypothalamic circuits to acute changes in nutrient availability. © 2012 Nature America, Inc. All rights reserved.

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.

Ross K.A.,Columbia University
PLoS ONE | Year: 2014

Background: Many aspects of autoimmune disease are not well understood, including the specificities of autoimmune targets, and patterns of co-morbidity and cross-heritability across diseases. Prior work has provided evidence that somatic mutation caused by gene conversion and deletion at segmentally duplicated loci is relevant to several diseases. Simple tandem repeat (STR) sequence is highly mutable, both somatically and in the germ-line, and somatic STR mutations are observed under inflammation. Results: Protein-coding genes spanning STRs having markers of mutability, including germ-line variability, high total length, repeat count and/or repeat similarity, are evaluated in the context of autoimmunity. For the initiation of autoimmune disease, antigens whose autoantibodies are the first observed in a disease, termed primary autoantigens, are informative. Three primary autoantigens, thyroid peroxidase (TPO), phogrin (PTPRN2) and filaggrin (FLG), include STRs that are among the eleven longest STRs spanned by protein-coding genes. This association of primary autoantigens with long STR sequence is highly significant (p<3:0×10-7) . Long STRs occur within twenty genes that are associated with sixteen common autoimmune diseases and atherosclerosis. The repeat within the TTC34 gene is an outlier in terms of length and a link with systemic lupus erythematosus is proposed. Conclusions: The results support the hypothesis that many autoimmune diseases are triggered by immune responses to proteins whose DNA sequence mutates somatically in a coherent, consistent fashion. Other autoimmune diseases may be caused by coherent somatic mutations in immune cells. The coherent somatic mutation hypothesis has the potential to be a comprehensive explanation for the initiation of many autoimmune diseases. © 2014 Kenneth Andrew Ross.

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.

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.

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.

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.

Waters C.,Columbia University
Neurologic Clinics | Year: 2013

The rotigotine transdermal system is a dopamine receptor agonist delivered over a 24-hour period. It is approved for the treatment of idiopathic Parkinson's disease (PD). This article reviews the development of the rotigotine transdermal system, including rotigotine's receptor profile, steady-state pharmacokinetics, and metabolism. Preclinical studies of rotigotine in animal models of PD and proof-of-concept studies in patients with PD are reviewed. These preclinical and clinical studies established this system as an effective method for providing continuous rotigotine delivery across the skin providing the basis for continued clinical development of rotigotine for the treatment of early and advanced PD. © 2013 Elsevier Inc.

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.

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.

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.

Tabas I.,Columbia University
Circulation Research | Year: 2013

Prevention of atherosclerotic vascular disease through systemic risk factor management has had great success, but cardiovascular disease is still the leading cause of death. One approach to this treatment gap is complementary arterial wall-based therapy that inhibits either the trigger of atherosclerosis, lipoprotein retention, or its pathobiological consequences, nonresolving inflammation. A recent article by Kastrup et al describes a technical advance that brings this approach closer to reality. The investigators have developed and validated a drug-eluting adhesive biogel that has the durability and stability to provide chronic therapy directly to plaques in the setting of pulsatile arterial blood flow. This advance expands the opportunity to develop drugs that retard atherosclerotic plaque progression and promote plaque resolution and regression. Copyright © 2013 American Heart Association, Inc.

Barcellos-Hoff M.H.,New York University | Lyden D.,New York Medical College | Lyden D.,Champalimaud Metastasis Center | Wang T.C.,Columbia University
Nature Reviews Cancer | Year: 2013

The concept of the tumour microenvironment recognizes that the interplay between cancer cells and stromal cells is a crucial determinant of cancer growth. In this Perspectives article, we propose the novel concept that the tumour microenvironment is built through rate-limiting steps during multistage carcinogenesis. Construction of a 'precancer niche' is a necessary and early step that is required for initiated cells to survive and evolve; subsequent niche expansion and maturation accompany tumour promotion and progression, respectively. As such, cancer niches represent an emergent property of a tumour that could be a robust target for cancer prevention and therapy. © 2013 Macmillan Publishers Limited.

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.

Wolfenson H.,Weizmann Institute of Science | Wolfenson H.,Columbia University | Lavelin I.,Weizmann Institute of Science | Geiger B.,Weizmann Institute of Science
Developmental Cell | Year: 2013

Integrin-mediated cell adhesions to the extracellular matrix (ECM) contribute to tissue morphogenesis and coherence and provide cells with vital environmental cues. These apparently static structures display remarkable plasticity and dynamic properties: they exist in multiple, interconvertible forms that are constantly remodeled in response to changes in ECM properties, cytoskeletal organization, cell migration, and signaling processes. Thus, integrin-mediated environmental sensing enables cells to adapt to chemical and physical properties of the surrounding matrix by modulating their proliferation, differentiation, and survival. This intriguing interplay between the apparently robust structure of matrix adhesions and their highly dynamic properties is the focus of this article. © 2013 Elsevier Inc.

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.

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.

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.

This study examined the dyadic association of terror attack survivors' and spouses' internal resources, tendency to forgive (self, others, and situational forgiveness), self-esteem, and the external resource of social support, as associated with victims' and spouses' posttraumatic stress disorder (PTSD) symptoms, using the actor-partner interdependence model. Based on lists by the One Family organization in Israel, 108 couples participated in the study. The study results demonstrate that in the dyad relationship, survivors' tendency to forgive others and social support relate both to survivors' decreased levels of PTSD symptom severity (β = .20, p = 021; β = .55 p < 001) and spouses' decreased levels of PTSD symptom severity (β = .21, p = 015; β = .27, p = 004), whereas spouses' self-esteem relates to both spouses' and survivors' decreased levels of PTSD symptom severity (β = .57, p < 001; β = .14, p = 041). The findings underscore the role of the survivor-spouse unit by highlighting the dyad relationship of internal and external resources as associated with both survivors' and spouses' PTSD symptoms. Theoretical and clinical implications of the findings are discussed. © 2013 International Society for Traumatic Stress Studies.

Brenner D.J.,Columbia University
Reviews on Environmental Health | Year: 2010

There has been a rapid increase in the population dose from medical radiation within the last 20 years, particularly due to the increase in CT usage. Currently, about 65 million adult and 5 million pediatric CT exams are being performed in the US each year. CT-related x-ray doses are small, but very much larger than for most conventional radiological examinations. CT-related x-ray doses are large enough that there is statistically-significant epidemiological evidence of a small increase in cancer risk. Risks are larger for children. Estimated individual risks from CT are small, but the increasing population dose from increased CT usage leads to concerns about future public health problems. The various CT-based health screening applications are not yet quite ready for mass use, but will be soon, resulting in an expected further jump in CT usage. There is considerable potential, using ongoing technological developments, to reduce radiation doses per CT scan, and therefore the risks. There are significant numbers of CT scans (perhaps 1/3) which, based on medical considerations alone, either need not be done, or could reasonably be replaced with other imaging modalities. Developing and following clinical decision rules can reduce unnecessary CT usage. Communication between physician and patient about the benefits and also about the potential small risks of CT is a positive development, unlikely to reduce patient compliance.

Arcia A.,Columbia University
Health Education and Behavior | Year: 2014

Facebook advertisements were used to recruit nulliparous women in the first 20 weeks of pregnancy for an online survey about their childbirth preferences. A campaign of ads was targeted to women, aged 18 to 44 years, residing in the United States. The ads were viewed 10,577,381 times by 7,248,985 unique Facebook users over 18 weeks in 2011. The ad campaign yielded 6,094 clicks by 5,963 unique users at a mean cost of $0.63 per click and a unique click-through rate of 0.08%. Of those who clicked through to the study site, 18% (n = 1,075) consented to participate. The participant pool was reduced to 344 women after application of strict eligibility criteria. Participants represented 43 states and the District of Columbia, their mean age was 20.9 years (Mdn = 19.0, SD = 4.0), and their mean weeks' gestation was 11.5 (SD = 5.8). The campaign cost was $3,821.81 or $11.11 per eligible participant. © 2013 Society for Public Health Education.

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.

Perera F.,Columbia University
American Journal of Public Health | Year: 2014

Scientific evidence is an increasingly important driver of social and environmental policy concerning child health. This trend began earlier than generally recognized. The child labor reform movement of the Gilded Age and early Progressive Era reflected not only moral and economic forces but also the dramatic advances during the later decades of the 19th century in scientific knowledge concerning children's biological and psychological vulnerability to environmental and psychosocial stressors. The growing importance of scientific information in shaping policy concerning children's health between 1870 and 1900 is illustrated by the events leading up to and following the New York State Child Labor Law of 1886. Child labor reform during this period was a critical step in the development of a science-based as well as a valuedriven movement to protect children's environmental health and well-being that continues today.

Kumar S.K.,Columbia University | Krishnamoorti R.,University of Houston
Annual Review of Chemical and Biomolecular Engineering | Year: 2010

It is well recognized that nanocomposites formed by adding nanoparticles to polymers can have significantly enhanced properties relative to the native polymer. This review focuses on three aspects that are central to the outstanding problem of realizing these promised property improvements. First, we ask if there exist general strategies to control nanoparticle spatial distribution. This is an important question because it is commonly accepted that the nanoparticle dispersion state crucially affects property improvements. Because ideas on macroscale composites suggest that optimizing different properties requires different dispersion states, we next ask if we can predict a priori the particle dispersion and organization state that can optimize one (or more) properties of the resulting nanocomposite. Finally, we examine the role that particle shape plays in affecting dispersion and hence property control. This review focuses on recent advances concerning these underpinning points and how they affect measurable properties relevant to engineering applications. Copyright © 2010 by Annual Reviews. All rights reserved.

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.

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.

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.

Wright N.E.,Columbia University | Snyder S.A.,Scripps Research Institute
Angewandte Chemie - International Edition | Year: 2014

Explorations into a series of different approaches for 9-membered carbocycle formation have afforded the first reported example of a 9-exo-dig ring closure via a AuIII-promoted reaction between an alkyne and an aryl ring as well as several additional, unique Friedel-Crafts-type cyclizations. Analyses of the factors leading to the success of these transformations are provided, with the application of one of the developed 9-membered ring closures affording an efficient and scalable synthesis of the bioactive resveratrol trimer caraphenol A. That synthesis proceeded with an average yield of 89 % per step (7.8 % overall yield) and has provided access to more than 600 mg of the target molecule. Fun with Friedel-Crafts: Explorations into 9-membered carbocycle formation have afforded the first 9-exo-dig ring closure via a AuIII-promoted reaction between an alkyne and an aryl ring along with several additional, unique Friedel-Crafts-type cyclizations. Application of one of the 9-membered ring closures enabled an efficient and scalable (600 mg) synthesis of the resveratrol trimer caraphenol A in an average yield of 89 % per step. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Rubin D.B.,York College | VanHooser S.D.,Brandeis University | Miller K.D.,York College | Miller K.D.,Columbia University
Neuron | Year: 2015

Neurons in sensory cortex integrate multiple influences to parse objects and support perception. Across multiple cortical areas, integration is characterized by two neuronal response properties: (1) surround suppression-modulatory contextual stimuli suppress responses to driving stimuli; and (2) "normalization"-responses to multiple driving stimuli add sublinearly. These depend on input strength: for weak driving stimuli, contextual influences facilitate or more weakly suppress and summation becomes linear or supralinear. Understanding the circuit operations underlying integration is critical to understanding cortical function and disease. We present a simple, general theory. A wealth of integrative properties, including the above, emerge robustly from four cortical circuit properties: (1) supralinear neuronal input/output functions; (2) sufficiently strong recurrent excitation; (3) feedback inhibition; and (4) simple spatial properties of intracortical connections. Integrative properties emerge dynamically as circuit properties, with excitatory and inhibitory neurons showing similar behaviors. In new recordings in visual cortex, we confirm key model predictions. © 2015 Elsevier Inc.

Casey S.E.,Columbia University
Conflict and Health | Year: 2015

Provision of reproductive health (RH) services is a minimum standard of health care in humanitarian settings; however access to these services is often limited. This systematic review, one component of a global evaluation of RH in humanitarian settings, sought to explore the evidence regarding RH services provided in humanitarian settings and to determine if programs are being evaluated. In addition, the review explored which RH services receive more attention based on program evaluations and descriptive data. Peer-reviewed papers published between 2004 and 2013 were identified via the Ovid MEDLINE database, followed by a PubMed search. Papers on quantitative evaluations of RH programs, including experimental and non-experimental designs that reported outcome data, implemented in conflict and natural disaster settings, were included. Of 5,669 papers identified in the initial search, 36 papers describing 30 programs met inclusion criteria. Twenty-five papers described programs in sub-Saharan Africa, six in Asia, two in Haiti and three reported data from multiple countries. Some RH technical areas were better represented than others: seven papers reported on maternal and newborn health (including two that also covered family planning), six on family planning, three on sexual violence, 20 on HIV and other sexually transmitted infections and two on general RH topics. In comparison to the program evaluation papers identified, three times as many papers were found that reported RH descriptive or prevalence data in humanitarian settings. While data demonstrating the magnitude of the problem are crucial and were previously lacking, the need for RH services and for evaluations to measure their effectiveness is clear. Program evaluation and implementation science should be incorporated into more programs to determine the best ways to serve the RH needs of people affected by conflict or natural disaster. Standard program design should include rigorous program evaluation, and the results must be shared. The papers demonstrated both that RH programs can be implemented in these challenging settings, and that women and men will use RH services when they are of reasonable quality. © 2015 Casey; licensee BioMed Central Ltd.

Bomback A.S.,Columbia University
Discovery medicine | Year: 2011

Over the last two decades, adrenocorticotropic hormone (ACTH) has re-emerged as a potentially effective therapy for nephrotic syndrome, particularly for patients who have failed more conventional immunosuppressive therapies. The initial experience in Europe using synthetic ACTH in membranous nephropathy led to a randomized trial in which ACTH performed comparably to a combined regimen of steroids and alkylating agents. Observational data from American patients treated with natural ACTH gel for resistant nephrotic syndrome have also been promising. While we await larger clinical trials of ACTH in the nephrotic patient population, we still also await a more precise understanding of how the therapy achieves remission of proteinuria. We discuss a number of possible mechanisms for ACTH's beneficial effects on the inflammation and injury that occurs in nephrotic syndrome.

Brenner D.J.,Columbia University
Radiation Research | Year: 2010

The annual number of CT scans in the U.S. is now over 70 million. The concern is that organ doses from CT are typically far larger than those from conventional X-ray examinations, and there is epidemiological evidence of a small but significant increased cancer risk at typical CT doses. Because CT is a superb diagnostic tool and because individual CT risks are small, when a CT scan is clinically indicated, the CT benefit/risk balance is by far in the patient's favor. Nevertheless, CT should operate under the ALARA (As Low As Reasonably Achievable) principle, and opportunities exist to reduce the significant population dose associated with CT without compromising patient care. The first opportunity is to reduce the dose per scan, and improved technology has much potential here. The second opportunity is selective replacement of CT with other modalities, such as for many head and spinal examinations (with MRI), and for diagnosing appendicitis (selective use of ultrasound + CT). Finally, a fraction of CT scans could be avoided entirely, as indicated by CT decision rules: Clinical decision rules for CT use represent a powerful approach for slowing down the increase in CT use, because they have the potential to overcome some of the major factors that result in some CT scans being undertaken when they are potentially not clinically helpful. In the U.S. and potentially elsewhere, legislative approaches are a possible option, to improve quality control and reduce clinically unneeded CT use, and it is also possible that upcoming changes in heath care economics will tend to slow the increase in such CT use. © by Radiation Research Society.

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.

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.

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.

Intraoperative cardiac arrest (ICA) is a rare but potentially catastrophic event. There is a paucity of recent epidemiological data on the incidence and risk factors for ICA. The objective of this study was to assess the incidence, risk factors, and survival outcome of ICAs in adults undergoing noncardiac surgery. The authors analyzed prospectively collected data for all noncardiac cases in the American College of Surgeons National Surgical Quality Improvement Program database from the years 2005 to 2007 (n = 362,767). The incidence of ICA was 7.22 per 10,000 surgeries. After adjustment for American Society of Anesthesiologists physical status and other covariates, the odds of ICA increased progressively with the amount of transfusion (adjusted odds ratios = 2.51, 7.59, 11.40, and 29.68 for those receiving 1-3, 4-6, 7-9, and ≥ 10 units of erythrocytes, respectively). Other significant risk factors for ICA were emergency surgery (adjusted odds ratio = 2.04, 95% CI = 1.45-2.86) and being functionally dependent presurgery (adjusted odds ratio = 2.33, 95% CI = 1.69-3.22). Of the 262 patients with ICA, 116 (44.3%) died within 24 h, and 164 (62.6%) died within 30 days. Intraoperative blood loss as indicated by the amount of transfusion was the most important predictor of ICA. The urgency of surgery and the preoperative composite indicators of health such as American Society of Anesthesiologists status and functional status were other important risk factors. The high case fatality suggests that primary prevention might be the key to reducing mortality from ICA.

Walsh B.T.,Columbia University
American Journal of Psychiatry | Year: 2013

Objective: In this review, based on recent advances in cognitive neuroscience, the author presents a formulation in which the marked persistence of anorexia nervosa can be usefully understood as a wellingrained maladaptive habit. Method: The author reviewed the relevant literature on the development and course of anorexia nervosa and interpreted critical features in light of developments in cognitive neuroscience. Results: Anorexia nervosa is a well characterized disorder with remarkable persistence both across history and among affected individuals. Food restriction, the salient behavioral feature of the disorder, often begins innocently but gradually takes on a life of its own. Over time, it becomes highly entrenched and resistant to change through either psychological or pharmacological treatment. Cognitive neuroscience has described two related but distinct processes that underlie the acquisition of new patterns of behavior, namely, action-outcome and stimulusresponse learning. It is likely that both processes are engaged in the development of anorexia nervosa and that stimulusresponse learning (that is, habit formation) is critical to the persistence of the dieting behavior. Conclusions: The formulation of the dieting behavior characteristic of anorexia nervosa as a well-entrenched habit provides a basis for understanding the striking persistence of this disorder. This model helps explain the resistance of anorexia nervosa to interventions that have established efficacy in related disorders and implies that addressing the dieting behavior is critical, especially early in the course of the illness, before it has become ingrained.

This article reviews the development of international research on the relationship between discrimination and health. It provides an overview of theoretical and empirical work on stigma and prejudice and their impact on discrimination and health. It argues that the literature on these issues has drawn primarily from social psychology and has focused on the impact of attitudes associated with stigma and prejudice on discriminatory practices and consequently health outcomes. It also identifies a growing trend in recent research towards a reconceptualization of stigma, prejudice and discrimination from the perspective of social inequality and structural violence, highlighting relations of power and exclusion that reinforce vulnerability within a complex social and political process. It concludes by briefly examining the ways in which this reconceptualization of discriminatory practices has generated a growing interest in the linkages between health and human rights and renewed interest in health and social justice; two major trends in the field of global public health.