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The University of Chicago is a private research university in Chicago, Illinois.Founded by the American Baptist Education Society with a donation from oil magnate and philanthropist John D. Rockefeller, the University of Chicago was incorporated in 1890; William Rainey Harper became the university's first president in 1891, and the first classes were held in 1892. Both Harper and future president Robert Maynard Hutchins advocated for Chicago's curriculum to be based upon theoretical and perennial issues rather than applied science and commercial utility.The university consists of the College of the University of Chicago, various graduate programs and interdisciplinary committees organized into four divisions, six professional schools, and a school of continuing education. Chicago is particularly well known for its professional schools, which include the Pritzker School of Medicine, the Booth School of Business, the Law School, and the Divinity School. The university enrolls approximately 5,000 students in the College and about 15,000 students overall.University of Chicago scholars have played a major role in the development of various academic disciplines, including: the Chicago school of economics, the Chicago school of sociology, the law and economics movement in legal analysis, the Chicago school of literary criticism, the Chicago school of religion, the school of political science known as behavioralism, and in the physics leading to the world's first man-made, self-sustaining nuclear reaction. The university is also home to the University of Chicago Press, the largest university press in the United States.The University of Chicago is home to many prominent alumni. 89 Nobel laureates have been affiliated with the university as visiting professors, students, faculty, or staff, the fourth most of any institution in the world. When its affiliate, the Marine Biological Laboratory, is included, Chicago has produced more Nobel prize winners than any other university in the world. In addition, Chicago's alumni include 49 Rhodes Scholars, 9 Fields Medalists, 20 National Humanities Medalists and 13 billionaire graduates. Wikipedia.

Naoz S.,Harvard - Smithsonian Center for Astrophysics | Fabrycky D.C.,University of Chicago
Astrophysical Journal | Year: 2014

Many close stellar binaries are accompanied by a faraway star. The "eccentric Kozai-Lidov" (EKL) mechanism can cause dramatic inclination and eccentricity fluctuations, resulting in tidal tightening of inner binaries of triple stars. We run a large set of Monte Carlo simulations, including the secular evolution of the orbits, general relativistic precession, and tides, and we determine the semimajor axis, eccentricity, inclination, and spin-orbit angle distributions of the final configurations. We find that the efficiency of forming tight binaries (≲ 16 days) when taking the EKL mechanism into account is 21%, and about 4% of all simulated systems ended up in a merger event. These merger events can lead to the formation of blue stragglers. Furthermore, we find that the spin-orbit angle distribution of the inner binaries carries a signature of the initial setup of the system; thus, observations can be used to disentangle close binaries' birth configuration. The resulting inner and outer final orbits' period distributions and their estimated fraction suggest that secular dynamics may be a significant channel for the formation of close binaries in triples and even blue stragglers. © 2014. The American Astronomical Society. All rights reserved..

Pritchard J.K.,University of Chicago
Nature Genetics | Year: 2011

Two new studies take distinct population genetic approaches to analyzing whole-genome sequencing data sets in order to estimate human demographic parameters. These papers refine our understanding of the relationships among human populations while illustrating both the possibilities and the statistical challenges of fitting demographic models to whole-genome data sets. © 2011 Nature America, Inc. All rights reserved.

Familial hypercholesterolemia (FH) is a common autosomal co-dominant genetic disorder that results in severely increased levels of LDL-C. Patients with FH are at an increased risk for premature coronary artery disease. Expert panels therefore recommend initiation of lipid-lowering therapy in childhood to reduce the very high lifetime risk of coronary artery disease. The bile acid sequestrant colesevelam is indicated to reduce elevated LDL-C levels in adults with primary hyperlipidemia and in boys and postmenarchal girls (aged 10-17 years) with heterozygous FH. Objective: The purpose of this article was to review currently available data on the use of colesevelam in the treatment of heterozygous FH. Methods: PubMed and Google Scholar were searched to identify clinical trials evaluating colesevelam in patients with heterozygous FH. Results: The search returned 2 results (both multicenter, multinational studies): 1 study conducted in adults and the other in pediatric patients. In the study in adults with refractory FH, the addition of colesevelam to a maximally tolerated regimen of a statin plus ezetimibe provided a significantly greater reduction from baseline in LDL-C levels compared with placebo. Significantly greater reductions from baseline in LDL-C were also seen in pediatric patients with heterozygous FH receiving colesevelam (alone or in combination with statins) compared with placebo. Colesevelam was generally well tolerated in studies in patients with FH; consistent with other colesevelam studies, gastrointestinal disorders were the most common drug-related adverse events, but these events rarely led to study withdrawal. Conclusions: Currently available data demonstrate that colesevelam, alone or in combination therapy, is efficacious and well tolerated in the treatment of heterozygous FH in adults and pediatric patients, supporting its use as a treatment option in both of these patient populations. © 2013 Elsevier HS Journals, Inc.

Chervonsky A.V.,University of Chicago
Cold Spring Harbor Perspectives in Biology | Year: 2013

The commensal microbiota affects many aspects of mammalian health including control of the immune system to such a extent that a "commensalocentric" view of the maintenance of overall health could be suggested. Autoimmunity is a case of mistaken identity: The immune system reacts to self-tissues and cells as if they were pathogens. Autoimmune reactions can be both advanced or blocked by the commensal microbiota, which can affect innate and adaptive arms of immune responses as well as the mechanisms of "innate-adaptive connection." Whether specific microbial lineages affect immunity and autoimmunity (the "specific lineage hypothesis") or multiple lineages can tip the homeostatic balance that regulates host/microbiota homeostasis toward reduced or enhanced host reactivity (the "balanced signal hypothesis") is yet unknown. The complexity of host/microbiota interactions needs to be fully appreciated in order to find the means for prophylaxis and treatment of autoimmune disorders. © 2013 Cold Spring Harbor Laboratory Press; all rights reserved.

Lu J.-X.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | Qiang W.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | Yau W.-M.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | Schwieters C.D.,U.S. National Institutes of Health | And 2 more authors.
Cell | Year: 2013

In vitro, β-amyloid (Aβ) peptides form polymorphic fibrils, with molecular structures that depend on growth conditions, plus various oligomeric and protofibrillar aggregates. Here, we investigate structures of human brain-derived Aβ fibrils, using seeded fibril growth from brain extract and data from solid-state nuclear magnetic resonance and electron microscopy. Experiments on tissue from two Alzheimer's disease (AD) patients with distinct clinical histories showed a single predominant 40 residue Aβ (Aβ40) fibril structure in each patient; however, the structures were different from one another. A molecular structural model developed for Aβ40 fibrils from one patient reveals features that distinguish in-vivo- from in-vitro-produced fibrils. The data suggest that fibrils in the brain may spread from a single nucleation site, that structural variations may correlate with variations in AD, and that structure-specific amyloid imaging agents may be an important future goal. PaperFlick © 2013 Elsevier Inc.

Pinto J.M.,University of Chicago
Proceedings of the American Thoracic Society | Year: 2011

Olfaction represents an ancient, evolutionarily critical physiologic system. In humans, chemosensation mediates safety, nutrition, sensation of pleasure, and general well-being. Factors that affect human olfaction included structural aspects of the nasal cavity that can modulate airflow and therefore odorant access to the olfactory cleft, and inflammatory disease, which can affect both airflow as well as olfactory nerve function. After signals are generated, olfactory information is processed and coded in the olfactory bulb and disseminated to several areas in the brain. The discovery of olfactory receptors by Axel and Buck sparked greater understanding of the molecular basis of olfaction. However, the precise mechanisms used by this system are still under great scrutiny due to the complexity of understanding how an enormous number of chemically diverse odorant molecules are coded into signals understood by the brain. Additionally, it has been challenging to dissect olfactory sensation due to the multiple areas of areas of the brain that receive and modulate this information. Consequently, our knowledge of olfactory dysfunction in humans remains primitive. Aging represents the major cause of loss of smell, although a number of clinical and environmental factors are thought to affect chemosensory function. Treatment options focus on reducing sinonasal inflammation when present, ruling out other treatable causes, and counseling patients on safety measures.

Frisch P.C.,University of Chicago | Redfield S.,Wesleyan University | Slavin J.D.,Harvard - Smithsonian Center for Astrophysics
Annual Review of Astronomy and Astrophysics | Year: 2011

The Solar System is embedded in a flow of low-density, warm, and partially ionized interstellar material that has been sampled directly by in situ measurements of interstellar neutral gas and dust in the heliosphere. Absorption line data reveal that this interstellar gas is part of a larger cluster of local interstellar clouds, which is spatially and kinematically divided into additional small-scale structures indicating ongoing interactions. An origin for the clouds that is related to star formation in the Scorpius-Centaurus OB association is suggested by the dynamic characteristics of the flow. Variable depletions observed within the local interstellar medium (ISM) suggest an inhomogeneous Galactic environment, with shocks that destroy grains in some regions. Although photoionization models of the circumheliospheric ISM do an excellent job of reproducing the observed properties of the surrounding ISM, the unknown characteristics of the very low-density hot plasma filling the Local Bubble introduces uncertainty about the source of ionization and nature of cloud boundaries. Recent observations of small cold clouds provide new insight into the processes affecting the local ISM. A fuller understanding of the local ISM can provide insights into the past and future Galactic environment of the Sun, and deeper knowledge of the astrospheres of nearby stars. © 2011 by Annual Reviews. All rights reserved.

Koo M.,Sungkyunkwan University | Fishbach A.,University of Chicago
Journal of Personality and Social Psychology | Year: 2010

Pursuing a series of progressive (e.g., professional) goals that form a goal ladder often leads to a trade-off between moving up to a more advanced level and repeating the same goal level. This article investigates how monitoring one's current goal in terms of remaining actions versus completed actions influences the desire to move up the goal ladder. The authors propose that a focus on remaining (vs. completed) actions increases the motivation to move up to a more advanced level, whereas the focus on completed (vs. remaining) actions increases the satisfaction derived from the present level. They find support for these predictions across several goal ladders, ranging from academic and professional ladders to simple, experimental tasks. They further find that individuals strategically attend to information about remaining (vs. completed) actions to prepare to move up the goal ladder. © 2010 American Psychological Association.

Graziani C.,University of Chicago
New Astronomy | Year: 2011

Beginning with the 2002 discovery of the "Amati Relation" of GRB spectra, there has been much interest in the possibility that this and other correlations of GRB phenomenology might be used to make GRBs into standard candles. One recurring apparent difficulty with this program has been that some of the primary observational quantities to be fit as "data" - to wit, the isotropic-equivalent prompt energy Eiso and the collimation-corrected "total" prompt energy Eγ - depend for their construction on the very cosmological models that they are supposed to help constrain. This is the so-called "circularity problem" of standard candle GRBs. This paper is intended to point out that the circularity problem is not in fact a problem at all, except to the extent that it amounts to a self-inflicted wound. It arises essentially because of an unfortunate choice of data variables - "source-frame" variables such as Eiso, which are unnecessarily encumbered by cosmological considerations. If, instead, the empirical correlations of GRB phenomenology which are formulated in source-variables are mapped to the primitive observational variables (such as fluence) and compared to the observations in that space, then all taint of circularity disappears. I also indicate here a set of procedures for encoding high-dimensional empirical correlations (such as between Eiso, Epk(src),tjet(src), and T45(src)) in a "Gaussian Tube" smeared model that includes both the correlation and its intrinsic scatter, and how that source-variable model may easily be mapped to the space of primitive observables, to be convolved with the measurement errors and fashioned into a likelihood. I discuss the projections of such Gaussian tubes into sub-spaces, which may be used to incorporate data from GRB events that may lack some element of the data (for example, GRBs without ascertained jet-break times). In this way, a large set of inhomogeneously observed GRBs may be assimilated into a single analysis, so long as each possesses at least two correlated data attributes. © 2010 Elsevier B.V. All rights reserved.

De Cara J.M.,University of Chicago
Current Cardiology Reports | Year: 2012

Modern advances in cancer treatment have resulted in improved survival. As a result, effects of cancer therapy on other organ systems such as the heart are more likely to become clinically relevant. One such possibility is chemotherapy-related left ventricular dysfunction. Although in clinical practice cardiotoxicity is evaluated by symptoms and left ventricular ejection fraction, these occur relatively late in the disease process after the heart's compensatory mechanisms have been expended. Ideally, left ventricular dysfunction would be identified early so that cancer patients and their physicians can make informed decisions about their therapeutic options and institute careful surveillance and early initiation of cardioprotective medication where appropriate. This review discusses the role of echocardiography to detect subclinical left ventricular dysfunction in cancer patients exposed to chemotherapy with potential cardiotoxicity, particularly anthracyclines and trastuzumab. © Springer Science+Business Media, LLC 2012.

Wagner L.D.,Rti International | Rein D.B.,University of Chicago
Ophthalmology | Year: 2013

Objective: To model the factors that are associated with the use of eye care services among the US population with and without diabetes, stratifying by age group. Design: Meta-analysis. Participants: We analyzed data from 3 datasets: the Behavioral Risk Factors Surveillance System combined years 2006-2009, the National Health and Nutrition Examination Survey combined years 2005-2008, and the National Health Interview Survey year 2008. For all 3 datasets, we analyzed data from all survey participants aged 40 years or older who participated in vision-related survey modules. Methods: We performed multivariate logistic regression analyses to assess associations between any eye care use within the previous year and 14 indicators of patient demographics and health. We estimated separate regressions for persons with and without diabetes stratified by age group. We combined estimates across datasets using a random effects model estimated using Markov Chain Monte Carlo algorithms. Main Outcome Measures: Use of eye care in the previous year and personal factors associated with eye care use. Results: Annual eye care use rates ranged from 46% to 51% in participants without diabetes and 64% to 72% in participants with diabetes. For people with and without diabetes, health insurance, an eye disease diagnosis, and higher income were associated with higher odds of eye care use. Being male was associated with lower odds of eye care use in some diabetes status and age group categories. Other variables, such as more education, being married, black race, Hispanic/Latino ethnicity, health status, heavy drinking, and limited ability to read small print, were associated with eye care use in only some diabetes status and age group categories. Conclusions: Our findings indicate that economic and ocular health factors are associated with the greatest odds of annual eye care use. Access to health insurance and income levels greater than $35 000 US dollars (value at the time of interview) are associated with eye care use independently of other demographic factors. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. © 2013 American Academy of Ophthalmology.

Walter J.K.,Childrens Hospital of Philadelphia | Ross L.F.,University of Chicago
Pediatrics | Year: 2014

Although clinicians may value respecting a patient's or surrogate's autonomy in decision-making, it is not always clear how to proceed in clinical practice. The confusion results, in part, from which conception of autonomy is used to guide ethical practice. Reliance on an individualistic conception such as the "in-control agent" model prioritizes self-sufficiency in decision-making and highlights a decisionmaker's capacity to have reason transcend one's emotional experience. An alternative model of autonomy, relational autonomy, highlights the social context within which all individuals exist and acknowledges the emotional and embodied aspects of decision-makers. These 2 conceptions of autonomy lead to different interpretations of several aspects of ethical decision-making. The in-control agent model believes patients or surrogates should avoid both the influence of others and emotional persuasion in decision-making. As a result, providers have a limited role to play and are expected to provide medical expertise but not interfere with the individual's decisionmaking process. In contrast, a relational autonomy approach acknowledges the central role of others in decision-making, including clinicians, who have a responsibility to engage patients' and surrogates' emotional experiences and offer clear guidance when patients are confronting serious illness. In the pediatric setting, in which decision-making is complicated by having a surrogate decisionmaker in addition to a patient, these conceptions of autonomy also may influence expectations about the role that adolescents can play in decision-making. Copyright © 2014 by the American Academy of Pediatrics.

Mateo J.M.,University of Chicago
Biology Letters | Year: 2010

Glucocorticoids regulate glucose concentrations and responses to unpredictable events, while also modulating cognition. Juvenile Belding's ground squirrels (Urocitellus Beldingi) learn to respond to whistle and trill alarm calls, warning of aerial and terrestrial predators, respectively, shortly after emerging from natal burrows at one month of age. Alarm calls can cause physiological reactions and arousal, and this arousal, coupled with watching adult responses, might help juveniles learn associations between calls and behavioural responses. I studied whether young show differential cortisol responses to alarm and non-alarm calls, using playbacks of U. Beldingi whistles, trills, squeals (a conspecific control vocalization) and silent controls. Trills elicited very high cortisol responses, and, using an individual's response to the silent control as baseline, only their response to a trill was significantly higher than baseline. This cortisol increase would provide glucose for extended vigilance and escape efforts, which is appropriate for evading terrestrial predators which hunt for long periods. Although whistles do not elicit a cortisol response, previous research has shown that they do result in bradycardia, which enhances attention and information processing. This is a novel demonstration of two physiological responses to two alarm calls, each appropriate to the threats represented by the calls. © 2010 The Royal Society.

Murray Sherman S.,University of Chicago
Neuroscientist | Year: 2014

Metabotropic glutamate receptors (mGluRs) are found throughout thalamus and cortex and are clearly important to circuit behavior in both structures, and so considering only participation of ionotropic glutamate receptors (e.g., [R,S]-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA] and N-methyl-d-aspartate receptors [NMDA] receptors) in glutamatergic processing would be an unfortunate oversimplification. These mGluRs are found both postsynaptically, on target cells of glutamatergic afferents, and presynaptically, on various synaptic terminals themselves, and when activated, they produce prolonged effects lasting at least hundreds of msec to several sec and perhaps longer. Two main types exist: activation of group I mGluRs causes postsynaptic depolarization, and group II, hyperpolarization. Both types are implicated in synaptic plasticity, both short term and long term. Their evident importance in functioning of thalamus and cortex makes it critical to develop a better understanding of how these receptors are normally activated, especially because they also seem implicated in a wide range of neurological and cognitive pathologies. © 2013 The Author(s).

Lengyel E.,University of Chicago
American Journal of Pathology | Year: 2010

The biology of ovarian carcinoma differs from that of hematogenously metastasizing tumors because ovarian cancer cells primarily disseminate within the peritoneal cavity and are only superficially invasive. However, since the rapidly proliferating tumors compress visceral organs and are only temporarily chemosensitive, ovarian carcinoma is a deadly disease, with a cure rate of only 30%. There are a number of genetic and epigenetic changes that lead to ovarian carcinoma cell transformation. Ovarian carcinoma could originate from any of three potential sites: the surfaces of the ovary, the fallopian tube, or the mesothelium-lined peritoneal cavity. Ovarian cacinoma tumorigenesis then either progresses along a stepwise mutation process from a slow growing borderline tumor to a well-differentiated carcinoma (type I) or involves a genetically unstable high-grade serous carcinoma that metastasizes rapidly (type II). During initial tumorigenesis, ovarian carcinoma cells undergo an epithelial-to- mesenchymal transition, which involves a change in cadherin and integrin expression and upregulation of proteolytic pathways. Carried by the peritoneal fluid, cancer cell spheroids overcome anoikis and attach preferentially on the abdominal peritoneum or omentum, where the cancer cells revert to their epithelial phenotype. The initial steps of metastasis are regulated by a controlled interaction of adhesion receptors and proteases, and late metastasis is characterized by the oncogene-driven fast growth of tumor nodules on mesothelium covered surfaces, causing ascites, bowel obstruction, and tumor cachexia. Copyright © American Society for Investigative Pathology.

Te H.S.,Center for Liver Diseases | Jensen D.M.,University of Chicago
Clinics in Liver Disease | Year: 2010

This article reviews the prevalence, disease burden, genotype distribution, and transmission patterns of hepatitis B virus (HBV) and hepatitis C virus in the 6 World Health Organization regions. The global epidemiology of hepatitis B and C demonstrates a predominantly declining prevalence of the diseases. Improvement in the control of hepatitis B has been largely achieved with implementation of a more universal HBV vaccine program, although a large gap still remains in the effort toward global prevention of hepatitis B. The transmission of hepatitis C has been greatly impacted by mandatory screening of blood donors in most countries in the world, although intravenous drug use continues to be a major source of infection. Public education regarding the risks of exposure to infected paraphernalia as well as household items such as razors is necessary in the continuing effort to curb this disease. © 2010 Elsevier Inc. All rights reserved.

Raju A.,National University of Singapore | Chang D.W.,University of Chicago
Annals of Surgery | Year: 2015

Objective: A comprehensive literature review of VLNT with updates and comparisons on current application, techniques, results, studies and possible future implications. Background: Lymphedema is a debilitating condition that often results secondary to treatment of cancer. Unfortunately there is no cure. However, microsurgical procedures such as VLNT has gained popularity as there have been increasing reports that VLNT may help alleviate the severity of lymphedema. Methods: A review of literature was conducted over major medical indices (PubMed-MEDLINE, Factiva, Scopus, Sciencedirect, EMBASE). Search terms were focused on vascularized, lymph node transfer (also autologous, lymph node transplant) to cover both human and animal studies. Each study was verified for the nature of the procedure; a free microsurgical flap containing lymph nodes for the purpose of relieving lymphedema. Results: There are human and animal studies that individually report clear benefits, but because of methodological shortcomings comparative studies with uniform patient selection and monitoring are lacking. Conclusions: Although the results with the use of VLNT for treatment of lymphedema have been largely positive, further exploration into standardized protocols for diagnosis, treatment optimization, and patient outcomes assessment is needed. © 2014 Wolters Kluwer Health, Inc. All rights reserved.

Collier J.H.,University of Chicago | Segura T.,University of California at Los Angeles
Biomaterials | Year: 2011

This manuscript is part of a debate on the statement that " the use of short synthetic adhesion peptides, like RGD, is the best approach in the design of biomaterials that guide cell behavior for regenerative medicine and tissue engineering" We take the position that although there are some acknowledged disadvantages of using short peptide ligands within biomaterials, it is not necessary to discard the notion of using peptides within biomaterials entirely, but rather to reinvent and evolve their use. Peptides possess advantageous chemical definition, access to non-native chemistries, amenability to de novo design, and applicability within parallel approaches. Biomaterials development programs that require such aspects may benefit from a peptide-based strategy. © 2011 Elsevier Ltd.

Krogh-Jespersen S.,University of Chicago | Echols C.H.,University of Texas at Austin
Child Development | Year: 2012

Children's confidence in their own knowledge may influence their willingness to learn novel information from others. Twenty-four-month-old children's (N=160) willingness to learn novel labels for either familiar or novel objects from an adult speaker was tested in 1 of 5 conditions: accurate, inaccurate, knowledgeable, ignorant, or uninformative. Children were willing to learn a second label for an object from a reliable informant in the accurate, knowledgeable, and uninformative conditions; children were less willing to apply a novel label to a familiar object if the speaker previously was inaccurate or had expressed ignorance. However, when the objects were novel, children were willing to learn the label regardless of the speaker's knowledge level. © 2012 The Authors. Child Development © 2012 Society for Research in Child Development, Inc.

Leslie A.B.,University of Chicago
New Phytologist | Year: 2010

•Among many species of living conifers the presence of pollen with air bladders (saccate pollen) is strongly associated with downward-facing ovules and the production of pollination drops. This combination of features enables saccate pollen grains captured in the pollination drop to float upwards into the ovule. Despite the importance of this mechanism in understanding reproduction in living conifers and in extinct seed plants with similar morphologies, experiments designed to test its effectiveness have yielded equivocal results.•In vitro and in vivo pollination experiments using saccate and nonsaccate pollen were performed using modeled ovules and two Pinus species during their natural pollination period.•Buoyant saccate pollen readily floated through aqueous droplets, separating these grains from nonbuoyant pollen and spores. Ovules that received saccate pollen, nonsaccate pollen or a mixture of both all showed larger amounts and higher proportions of saccate pollen inside ovules after drop secretion.•These results demonstrate that flotation is an effective mechanism of pollen capture and transport in gymnosperms, and suggest that the prevalence of saccate grains and downward-facing ovules in the evolutionary history of seed plants is a result of the widespread use of this mechanism. © The Author (2010). Journal compilation © New Phytologist Trust (2010).

Goldin-Meadow S.,University of Chicago
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2014

The goal of this paper is to widen the lens on language to include the manual modality. We look first at hearing children who are acquiring language from a spoken language model and find that even before they use speech to communicate, they use gesture. Moreover, those gestures precede, and predict, the acquisition of structures in speech. We look next at deaf children whose hearing losses prevent them from using the oral modality, and whose hearing parents have not presented them with a language model in the manual modality. These children fall back on the manual modality to communicate and use gestures, which take on many of the forms and functions of natural language. Thesehomemadegesturesystemsconstitutethefirststepintheemergenceof manual sign systems that are shared within deaf communities and are fullfledged languages. We end by widening the lens on signlanguage to include gesture and find that signers not only gesture, but they also use gesture in learning contexts just as speakers do. These findings suggest that what is key in gesture's ability to predict learning is its ability to add a second representational format to communication, rather than a second modality. Gesture can thus be language, assuming linguistic forms and functions, when other vehicles are not available; but when speech or sign is possible,gesture works along with language, providing an additional representational format that can promote learning. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

Couch S.M.,University of Chicago | O'Connor E.P.,University of Toronto
Astrophysical Journal | Year: 2014

Three-dimensional (3D) simulations of core-collapse supernovae (CCSNe) are granting new insight into the as-yet-uncertain mechanism that drives successful explosions. While there is still debate about whether explosions are obtained more easily in 3D than in 2D, it is undeniable that there exist qualitative and quantitative differences between the results of 3D and 2D simulations. We present an extensive set of high-resolution 1D, 2D, and 3D CCSN simulations with multispecies neutrino leakage carried out in two different progenitors. Our simulations confirm the results of Couch indicating that 2D explodes more readily than 3D. We argue that this is due to the inadequacies of 2D to accurately capture important aspects of the 3D dynamics. We find that without artificially enhancing the neutrino heating rate, we do not obtain explosions in 3D. We examine the development of neutrino-driven convection and the standing accretion shock instability (SASI) and find that, in separate regimes, either instability can dominate. We find evidence for growth of the SASI for both 15 M ⊙ and 27 M⊙ progenitors; however, it is weaker in 3D exploding models. The growth rate of both instabilities is artificially enhanced along the symmetry axis in 2D as compared with our axis-free 3D Cartesian simulations. Our work highlights the growing consensus that CCSNe must be studied in 3D if we hope to solve the mystery of how the explosions are powered. © 2014. The American Astronomical Society. All rights reserved.

Teitler S.,National Academic Quiz Tournaments LLC | Konigl A.,University of Chicago
Astrophysical Journal | Year: 2014

We propose that the reported dearth of Kepler objects of interest (KOIs) with orbital periods Porb ∈ 2-3 days around stars with rotation periods Prot ∈ 5-10 days can be attributed to tidal ingestion of close-in planets by their host stars. We show that the planet distribution in this region of the log Porb-log Prot plane is qualitatively reproduced with a model that incorporates tidal interaction and magnetic braking as well as the dependence on the stellar core-envelope coupling timescale. We demonstrate the consistency of this scenario with the inferred break in the Porb distribution of close-in KOIs and point out a potentially testable prediction of this interpretation. © 2014. The American Astronomical Society. All rights reserved.

Malyshkin L.M.,University of Chicago | Boldyrev S.,University of Wisconsin - Madison
Physical Review Letters | Year: 2010

Amplification of magnetic field due to kinematic turbulent dynamo action is studied in the regime of small magnetic Prandtl numbers. Such a regime is relevant for planets and stars interiors, as well as for liquid-metal laboratory experiments. A comprehensive analysis based on the Kazantsev-Kraichnan model is reported, which establishes the dynamo threshold and the dynamo growth rates for varying kinetic helicity of turbulent fluctuations. It is proposed that in contrast with the case of large magnetic Prandtl numbers, the kinematic dynamo action at small magnetic Prandtl numbers is significantly affected by kinetic helicity, and it can be made quite efficient with an appropriate choice of the helicity spectrum. © 2010 The American Physical Society.

Prabhakar N.R.,University of Chicago | Peers C.,University of Leeds
Physiology | Year: 2014

Carotid bodies detect hypoxia in arterial blood, translating this stimulus into physiological responses via the CNS. It is long established that ion channels are critical to this process. More recent evidence indicates that gasotransmitters exert powerful influences on O2 sensing by the carotid body. Here, we review current understanding of hypoxia-dependent production of gasotransmitters, how they regulate ion channels in the carotid body, and how this impacts carotid body function. ©2014 Int. Union Physiol. Sci./Am. Physiol. Soc.

Patti M.G.,University of Chicago
JAMA Surgery | Year: 2016

IMPORTANCE Gastroesophageal reflux disease (GERD) is prevalent worldwide, particularly in developed countries. It is estimated that the prevalence of GERD in the United States is approximately 20%and that it is increasing because of the epidemic of obesity. OBJECTIVE To review the pathophysiology, clinical presentation, diagnostic evaluation, and treatment of GERD. EVIDENCE REVIEW A search of PubMed was conducted for the years spanning 1985 to 2015 and included the following terms: heartburn, regurgitation, dysphagia, gastroesophageal reflux disease, cough, aspiration, laryngitis, GERD, GORD, endoscopy, manometry, pH monitoring, proton pump inhibitors, open fundoplication, and laparoscopic fundoplication. Only articles in English were included. FINDINGS Lifestyle modifications, proton pump inhibitors, and laparoscopic fundoplication are proven treatment modalities for GERD. Endoscopic procedures have not been proven as effective. A Roux-en-Y gastric bypass is the procedure of choice when GERD and morbid obesity coexist. CONCLUSIONS AND RELEVANCE Gastroesophageal reflux disease is a highly prevalent disease. Once the diagnosis has been established, the best results are obtained by a multidisciplinary team with the goal of individualizing treatment for patients. Copyright 2016 American Medical Association. All rights reserved.

Mulmuley K.D.,University of Chicago
Proceedings - Annual IEEE Symposium on Foundations of Computer Science, FOCS | Year: 2012

It is shown that black-box derandomization of polynomial identity testing (PIT) is essentially equivalent to derandomization of Noether's Normalization Lemma for explicit algebraic varieties, the problem that lies at the heart of the foundational classification problem of algebraic geometry. Specifically: (1) It is shown that in characteristic zero black-box derandomization of PIT for diagonal depth three circuits brings the problem of derandomizing Noether's Normalization Lemma, for the ring of invariants of any explicit linear action of a classical algebraic group of constant dimension, from EXPSPACE (where it is currently) to P. Next it is shown that assuming the Generalized Riemann Hypothesis (GRH), instead of the black-box derandomization hypothesis, brings the problem from EXPSPACE to quasi-PH, instead of P. Thus black-box derandomization of diagonal depth three circuits takes us farther than GRH here on the basis of the current knowledge. Variants of the main implication are also shown assuming, instead of the black-box derandomization hypothesis in characteristic zero, Boolean lower bounds for constant-depth threshold circuits or uniform Boolean conjectures, in conjunction with GRH. These results may explain in a unified way why proving lower bounds or derandomization results for constant-depth arithmetic circuits in characteristic zero or constant-depth Boolean threshold circuits, or proving uniform Boolean conjectures without relativizable proofs has turned out to be so hard, and also why GRH has turned out to be so hard from the complexity-theoretic perspective. Thus this investigation reveals that the foundational problems of Geometry (classification and GRH) and Complexity Theory (lower bounds and derandomization) share a common root difficulty that lies at the junction of these two fields. We refer to it as the GCT chasm. (2) It is shown that black-box derandomization of PIT in a strengthened form implies derandomization of Noether's Normalization Lemma in a strict form for any explicit algebraic variety. (3) Conversely, it is shown that derandomization of Noether's Normalization Lemma in a strict form for specific explicit varieties implies this strengthened form of black box derandomization of PIT and its various variants. (4) A unified geometric complexity theory (GCT) approach to derandomization and classification is formulated on the basis of this equivalence. (5) It is illustrated by showing that Noether's Normalization Lemma for the ring of invariants of any explicit linear action of a classical algebraic group can be quasi-derandomized unconditionally) if the dimension of the group is constant. © 2012 IEEE.

Hawkley L.C.,University of Chicago | Capitanio J.P.,University of California at Davis
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2015

Sociality permeates each of the fundamental motives of human existence and plays a critical role in evolutionary fitness across the lifespan. Evidence for this thesis draws from research linking deficits in social relationship—as indexed by perceived social isolation (i.e. loneliness)—with adverse health and fitness consequences at each developmental stage of life. Outcomes include depression, poor sleep quality, impaired executive function, accelerated cognitive decline, unfavourable cardiovascular function, impaired immunity, altered hypothalamic pituitary–adrenocortical activity, a pro-inflammatory gene expression profile and earlier mortality. Gaps in this research are summarized with suggestions for future research. In addition, we argue that a better understanding of naturally occurring variation in loneliness, and its physiological and psychological underpinnings, in non-human species may be a valuable direction to better understand the persistence of a ‘lonely’ phenotype in social species, and its consequences for health and fitness. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

Davidson M.H.,University of Chicago
Journal of Clinical Lipidology | Year: 2010

Cholesteryl ester transfer protein (CETP) plays an important role in reverse cholesterol transport and the maintenance of cholesterol homeostasis. The consequences of CETP activity are influenced by triglyceride (TG) levels. When TG levels are increased, CETP promotes transfer of cholesteryl esters to VLDL and the generation of atherogenic dyslipidemia. Combined activities of CETP and hepatic lipase in the presence of TG-rich lipoproteins generate small, dense HDL and LDL particles. Inhibition of CETP may reduce the risk of atherosclerosis in patients with dyslipidemia. Decreasing CETP activity has consistently inhibited atherosclerosis in animal models. Three small-molecule CETP inhibitors, dalcetrapib, torcetrapib, and anacetrapib, have been or are being tested in phase 3 clinical studies. All three demonstrated potentially beneficial effects on the lipid profile in patients with dyslipidemia. Imaging studies with torcetrapib failed to show an effect on atherosclerosis in humans, probably because of the off-target effect on the RAAS. Preclinical evidence suggests that dalcetrapib seems to lack the off-target adverse effects on the RAAS that potentially caused the clinical development of torcetrapib to be halted. The lack of adverse effects on the RAAS remains to be confirmed in phase 3 studies with dalcetrapib. CETP inhibition as a therapeutic strategy remains a valid option to be tested with a CETP inhibitor that does not share torcetrapib's off-target effects. © 2010 National Lipid Association. All rights reserved.

Niewold T.B.,University of Chicago
Journal of Interferon and Cytokine Research | Year: 2011

Interferon alpha (IFN-α) is a critical mediator of human systemic lupus erythematosus (SLE). This review will summarize evidence supporting the role for IFN-α in the initiation of human SLE. IFN-α functions in viral immunity at the interface of innate and adaptive immunity, a position well suited to setting thresholds for autoimmunity. Some individuals treated with IFN-α for chronic viral infections develop de novo SLE, which frequently resolves when IFN-α is withdrawn, supporting the idea that IFN-α was causal. Abnormally high IFN-α levels are clustered within SLE families, suggesting that high serum IFN-α is a heritable risk factor for SLE. Additionally, SLE-risk genetic variants in the IFN-α pathway are gain of function in nature, resulting in either higher circulating IFN-α levels or greater sensitivity to IFN-α signaling in SLE patients. A recent genome-wide association study has identified additional novel genetic loci associated with high serum IFN-α in SLE patients. These data support the idea that genetically determined endogenous elevations in IFN-α predispose to human SLE. It is possible that some of these gain-of-function polymorphisms in the IFN-α pathway are useful in viral defense, and that risk of SLE is a burden we have taken on in the fight to defend ourselves against viral infection. © 2011, Mary Ann Liebert, Inc.

Davidson M.H.,University of Chicago
Current Treatment Options in Cardiovascular Medicine | Year: 2012

The premature stopping of the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health) study due to futility has called into question the clinical value of high-density lipoprotein cholesterol (HDL-C) increases. The failure of estrogen therapy in the HERS (Heart and Estrogen/ progestin Replacement Study) trial and the cholesteryl ester transfer protein (CETP) inhibitors torcetrapib (in the ILLUMINATE [Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events] trial) and, most recently, dalcetrapib in the dal-OUTCOMES trial has cast doubt on the "HDL-raising hypothesis" for providing additional benefits on top of statin therapy. The AIM-HIGH trial was designed to equalize low-density lipoprotein cholesterol (LDL-C) levels between the two treatment groups while the niacin arm would have a higher HDL-C. The study population included patients with low HDL-C and cardiovascular disease (CVD); because this population has a high residual risk for CVD on statin therapy, these patients were most likely to benefit from the niacin HDL-C-raising effect. These findings are disappointing because clinicians have used extended-release niacin to treat patients with low HDL-C because niacin has demonstrated benefit in earlier reported studies in conjunction with statins and other drugs, as observed in the Cholesterol Lowering Atherosclerosis Study (CLAS) and the HDL-Atherosclerosis Treatment Study (HATS). In the Coronary Drug Project, niacin alone was shown to reduce myocardial infarction, stroke, and the need for coronary bypass surgery. Niacin does not increase the number of HDL particles to the same extent it raises HDL-C. Niacin alters the composition of HDL, making the particle larger, which is similar to the effects of CETP inhibition on HDL. Both niacin and CETP inhibitors decrease the catabolism of HDL, thereby increasing the size of the HDL particle and raising HDL-C. Dalcetrapib, which does not decrease LDL-C while raising HDL-C, was recently discontinued from clinical development due to a interim analysis that determined that the study was futile. Anacetrapib, which markedly increases HDLC while also significantly lowering LDL-C, remains in clinical development, with a large cardiovascular end point trial currently enrolling 30,000 high-risk patients. For now, the goal remains the achievement of LDL-C and non-HDL targets, and low HDL-c remains a significant independent risk factor, but there is insufficient evidence that raising HDL-C will provide a clinical benefit. © Springer Science+Business Media, LLC 2012.

Lee D.,University of Chicago
Journal of Computational Physics | Year: 2013

In this paper, we extend the unsplit staggered mesh scheme (USM) for 2D magnetohydrodynamics (MHD) [D. Lee, A.E. Deane, An unsplit staggered mesh scheme for multidimensional magnetohydrodynamics, J. Comput. Phys. 228 (2009) 952-975] to a full 3D MHD scheme. The scheme is a finite-volume Godunov method consisting of a constrained transport (CT) method and an efficient and accurate single-step, directionally unsplit multidimensional data reconstruction-evolution algorithm, which extends Colella's original 2D corner transport upwind (CTU) method [P. Colella, Multidimensional upwind methods for hyperbolic conservation laws, J. Comput. Phys. 87 (1990) 446-466]. We present two types of data reconstruction-evolution algorithms for 3D: (1) a reduced CTU scheme and (2) a full CTU scheme. The reduced 3D CTU scheme is a variant of a simple 3D extension of Collela's 2D CTU method and is considered as a direct extension from the 2D USM scheme. The full 3D CTU scheme is our primary 3D solver which includes all multidimensional cross-derivative terms for stability. The latter method is logically analogous to the 3D unsplit CTU method by Saltzman [J. Saltzman, An unsplit 3D upwind method for hyperbolic conservation laws, J. Comput. Phys. 115 (1994) 153-168]. The major novelties in our algorithms are twofold. First, we extend the reduced CTU scheme to the full CTU scheme which is able to run with CFL numbers close to unity. Both methods utilize the transverse update technique developed in the 2D USM algorithm to account for transverse fluxes without solving intermediate Riemann problems, which in turn gives cost-effective 3D methods by reducing the total number of Riemann solves. The proposed algorithms are simple and efficient especially when including multidimensional MHD terms that maintain in-plane magnetic field dynamics. Second, we introduce a new CT scheme that makes use of proper upwind information in taking averages of electric fields. Our 3D USM schemes can be easily combined with various reconstruction methods (e.g., first-order Godunov, second-order MUSCL-Hancock, third-order PPM and fifth-order WENO), and a wide choice of 1D based Riemann solvers (e.g., local Lax-Friedrichs, HLLE, HLLC, HLLD, and Roe). The 3D USM-MHD solver is available in the University of Chicago Flash Center's official FLASH release. © 2013 Elsevier Inc.

Weber C.R.,University of Chicago
Annals of the New York Academy of Sciences | Year: 2012

A principal role of tight junctions is to seal the apical intercellular space and limit paracellular flux of ions and molecules. Despite the fact that tight junctions form heavily cross-linked structures, functional studies have fostered the hypothesis that the tight junction barrier is dynamic and defined by opening and closing events. However, it has been impossible to directly measure tight junction barrier function with sufficient resolution to detect such events. Nevertheless, recent electrophysiological and sieving studies have provided tremendous insight into the presence of at least two pathways of trans-tight junction flux: a high-capacity ion-selective "pore" pathway and a low-capacity "leak" pathway that allows the passage of macromolecules. Furthermore, it is now known that the tight junction molecular structure is highly dynamic and that dynamics are correlated with barrier function. Taken together, these data support a dynamic model of tight junction conductance and suggest that regulation of tight junction openings and closings may provide sensitive means of barrier regulation. © 2012 New York Academy of Sciences.

Ciesla F.J.,University of Chicago
Astrophysical Journal Letters | Year: 2014

Understanding the phases of water ice that were present in the solar nebula has implications for understanding cometary and planetary compositions as well as the internal evolution of these bodies. Here we show that amorphous ice formed more readily than previously recognized, with formation at temperatures <70 K being possible under protoplanetary disk conditions. We further argue that photodesorption and freeze-out of water molecules near the surface layers of the solar nebula would have provided the conditions needed for amorphous ice to form. This processing would be a natural consequence of ice dynamics and would allow for the trapping of noble gases and other volatiles in water ice in the outer solar nebula. © 2014. The American Astronomical Society. All rights reserved.

Parker C.V.,James Franck Institute | Ha L.-C.,James Franck Institute | Chin C.,James Franck Institute | Chin C.,University of Chicago
Nature Physics | Year: 2013

One of the intriguing properties of quantum many-body systems is the emergence of long-range order from particles with short-range interactions. For example, magnetism involves the long-range ordering of electron spins. Systems of ultracold atoms are rapidly emerging as precise and controllable simulators of magnetism and other phenomena. Spinor condensates are a powerful tool in this regard; however, the spin interaction is typically weak and accessible only when multiple atomic internal states are collisionally stable. Here we demonstrate a lattice-shaking technique for hybridizing Bloch bands in optical lattices to introduce a strong effective spin interaction and the formation of large ferromagnetic domains. Our band hybridization method is independent of the atomic internal state, and can be widely applied to quantum simulators to explore new magnetic phases in optical lattices with tunable band structure. © 2013 Macmillan Publishers Limited.

Rosenfield R.L.,University of Chicago
Pediatrics | Year: 2015

Consensus has recently been reached by international pediatric subspecialty societies that otherwise unexplained persistent hyperandrogenic anovulation using age-and stage-appropriate standards are appropriate diagnostic criteria for polycystic ovary syndrome (PCOS) in adolescents. The purpose of this review is to summarize these recommendations and discuss their basis and implications. Anovulation is indicated by abnormal uterine bleeding, which exists when menstrual cycle length is outside the normal range or bleeding is excessive: cycles outside 19 to 90 days are always abnormal, and most are 21 to 45 days even during the first postmenarcheal year. Continued menstrual abnormality in a hyperandrogenic adolescent for 1 year prognosticates at least 50% risk of persistence. Hyperandrogenism is best indicated by persistent elevation of serum testosterone above adult norms as determined in a reliable reference laboratory. Because hyperandrogenemia documentation can be problematic, moderate-severe hirsutism constitutes clinical evidence of hyperandrogenism. Moderate-severe inflammatory acne vulgaris unresponsive to topical treatment is an indication to test for hyperandrogenemia. Treatment of PCOS is symptom-directed. Cyclic estrogenprogestin oral contraceptives are ordinarily the preferred first-line medical treatment because they reliably improve both the menstrual abnormality and hyperandrogenism. First-line treatment of the comorbidities of obesity and insulin resistance is lifestyle modification with calorie restriction and increased exercise. Metformin in conjunction with behavior modification is indicated for glucose intolerance. Although persistence of hyperandrogenic anovulation for ≥2 years ensures the distinction of PCOS from physiologic anovulation, early workup is advisable to make a provisional diagnosis so that combined oral contraceptive treatment, which will mask diagnosis by suppressing hyperandrogenemia, is not unnecessarily delayed. © 2015 by the American Academy of Pediatrics.

Odenike O.,University of Chicago
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2013

Myelofibrosis (MF), including primary MF, postpolycythemia vera MF, and postessential thrombocythemia MF, is a clonal stem cell disorder characterized by BM fibrosis, extramedullary hematopoiesis, and a variable propensity to transform into acute leukemia. Allogeneic stem cell transplantation is the only known cure for MF, but its applicability is limited by the advanced age of most patients and by comorbid conditions. In the past decade, there has been an explosion of information on the molecular-genetic features associated with these diseases, fueled recently by the discovery of the JAK2V617F mutation. The development of JAK inhibitors has represented a significant therapeutic advance for these diseases; however, their use in MF has not yet been associated with eradication or a significant suppression of the malignant clone. In this era, much remains to be understood about MF, but it is likely that the identification of key pathogenetic drivers of the disease, coupled with the availability of novel molecularly targeted agents, will result in the discovery of new agents that significantly alter the natural history of the disease. This review focuses on recent and ongoing efforts in the development of novel agents in MF that go beyond the field of JAK inhibitors.

Upham N.S.,University of Chicago | Patterson B.D.,Field Museum of Natural History
Molecular Phylogenetics and Evolution | Year: 2012

The rodent superfamily Octodontoidea comprises 6 families, 38 genera, and 193 living species of spiny rats, tuco-tucos, degus, hutias, and their relatives. All are endemic to the Neotropical Region where they represent roughly three-quarters of extant caviomorphs. Although caviomorph monophyly is well established and phylogenetic hypotheses exist for several families, understanding of octodontoid relationships is clouded by sparse taxon sampling and single-gene analyses. We examined sequence variation in one mitochondrial (12S rRNA) and three nuclear genes (vWF, GHR, and RAG1) across all caviomorph families (including 47 octodontoid species), all phiomorph families, and the sole remaining hystricognath family, using the gundi (Ctenodactylus) and springhaas (Pedetes) as outgroups. Our analyses support the monophyly of Phiomorpha, Caviomorpha, and the caviomorph superfamilies Cavioidea (Dasyproctidae, Cuniculidae, and Caviidae, the latter including Hydrochoerus), Erethizontoidea, Chinchilloidea (including Dinomyidae), and Octodontoidea. Cavioids and erethizontoids are strongly supported as sisters, whereas chinchilloids appear to be sister to octodontoids. Among octodontoids, Abrocomidae is consistently recovered as the basal element, sister to a pair of strongly supported clades; one includes Octodontidae and Ctenomyidae as reciprocally monophyletic lineages, whereas the other includes taxa currently allocated to Echimyidae, Capromyidae and Myocastoridae. Capromys appears near the base of this clade, in keeping with current classification, but Myocastor is nested securely inside a clade of Echimyidae that also contains eumysopines, echimyines and dactylomyines. Another, more weakly supported clade of Echimyidae contains fossorial and scansorial taxa from the Chaco-Cerrado-Caatinga and the Atlantic Forest. Biogeographic analyses robustly recover the Patagonia-Southern Andes complex as ancestral for the Octodontoidea, with three component lineages emerging by the Oligocene-Miocene boundary (∼23. Ma): (1) stem abrocomids in the Central and Southern Andes; (2) a lineage leading to octodontids plus ctenomyids in Patagonia, later dispersing into the Chaco-Cerrado-Caatinga; and (3) a lineage leading to echimyids, capromyids, and myocastorids that subsequently radiated in more mesic biomes, including Amazonia, Atlantic Forest, and the Antilles. This reconstruction refutes earlier ideas that the diverse, generalized, mainly lowland family Echimyidae, which appears early in the fossil record, gave rise to the Andean lineages of octodontoids-instead, the reverse derivation appears to be true. We recommend formal synonymy of Myocastoridae with Echimyidae but defer a similar treatment of Capromyidae until additional hutia taxa and sequences can be analyzed. © 2012 Elsevier Inc.

Jakubowiak A.,University of Chicago
Seminars in Hematology | Year: 2012

In the last decade, the introduction of novel agents including the immunomodulatory drugs thalidomide and lenalidomide, and the first-in-class proteasome inhibitor bortezomib, has dramatically improved clinical outcome in patients with relapsed/refractory multiple myeloma (MM) compared to conventional chemotherapy alone. Although combination treatment approaches with traditional cytotoxic agents and novel agents have led to response rates as high as 85% in patients with relapsed/refractory disease, not all patients will respond to established novel agents, and even those who do respond will ultimately relapse or become refractory to currently available regimens. There is no generally accepted standard treatment for patients with relapsed/refractory disease; however, both disease-related (eg, quality and duration of response to previous therapies and the aggressiveness of the relapse) and patient-related (eg, preexisting toxicities, comorbid conditions, quality of life, age, and performance status) factors should be considered when selecting the best treatment option. This article will review up-to-date approaches for managing patients with relapsed/refractory MM, including the efficacy and safety of established novel agents, the use of adjunctive/supportive care, and strategies for tailored treatment. © 2012 Elsevier Inc.

Lecuit T.,Institut Universitaire de France | Lenne P.-F.,Institut Universitaire de France | Munro E.,University of Chicago
Annual Review of Cell and Developmental Biology | Year: 2011

Cell shape changes underlie a large set of biological processes ranging from cell division to cell motility. Stereotyped patterns of cell shape changes also determine tissue remodeling events such as extension or invagination. In vitro and cell culture systems have been essential to understanding the fundamental physical principles of subcellular mechanics. These are now complemented by studies in developing organisms that emphasize how cell and tissue morphogenesis emerge from the interplay between force-generating machines, such as actomyosin networks, and adhesive clusters that transmit tensile forces at the cell cortex and stabilize cell-cell and cell-substrate interfaces. Both force production and transmission are self-organizing phenomena whose adaptive features are essential during tissue morphogenesis. A new era is opening that emphasizes the similarities of and allows comparisons between distant dynamic biological phenomena because they rely on core machineries that control universal features of cytomechanics. © 2011 by Annual Reviews. All rights reserved.

Van Dillen L.F.,Leiden University | Papies E.K.,University Utrecht | Hofmann W.,University of Chicago
Journal of Personality and Social Psychology | Year: 2013

The present research shows in 4 studies that cognitive load can reduce the impact of temptations on cognition and behavior and, thus, challenges the proposition that distraction always hampers selfregulation. Participants performed different speeded categorization tasks with pictures of attractive and neutral food items (Studies 1-3) and attractive and unattractive female faces (Study 4), while we assessed their reaction times as an indicator of selective attention (Studies 1, 3, and 4) or as an indicator of hedonic thoughts about food (Study 2). Cognitive load was manipulated by a concurrent digit span task. Results show that participants displayed greater attention to tempting stimuli (Studies 1, 3, and 4) and activated hedonic thoughts in response to palatable food (Study 2), but high cognitive load completely eliminated these effects. Moreover, cognitive load during the exposure to attractive food reduced food cravings (Study 1) and increased healthy food choices (Study 3). Finally, individual differences in sensitivity to food temptations (Study 3) and interest in alternative relationship partners (Study 4) predicted selective attention to attractive stimuli, but again, only when cognitive load was low. Our findings suggest that recognizing the tempting value of attractive stimuli in our living environment requires cognitive resources. This has the important implication that, contrary to traditional views, performing a concurrent demanding task may actually diminish the captivating power of temptation and thus facilitate self-regulation. © 2012 American Psychological Association.

Knutson K.L.,University of Chicago
Social Science and Medicine | Year: 2013

Sleep is a biological imperative associated with cardiometabolic disease risk. As such, a thorough discussion of the sociocultural and demographic determinants of sleep is warranted, if not overdue. This paper begins with a brief review of the laboratory and epidemiologic evidence linking sleep deficiency, which includes insufficient sleep and poor sleep quality, with increased risk of chronic cardiometabolic diseases such as obesity, diabetes and hypertension. Identification of the determinants of sleep deficiency is the critical next step to understanding the role sleep plays in human variation in health and disease. Therefore, the majority of this paper describes the different biopsychosocial determinants of sleep, including age, gender, psychosocial factors (depression, stress and loneliness), socioeconomic position and race/ethnicity. In addition, because sleep duration is partly determined by behavior, it will be shaped by cultural values, beliefs and practices. Therefore, possible cultural differences that may impact sleep are discussed. If certain cultural, ethnic or social groups are more likely to experience sleep deficiency, then these differences in sleep could increase their risk of cardiometabolic diseases. Furthermore, if the mechanisms underlying the increased risk of sleep deficiency in certain populations can be identified, interventions could be developed to target these mechanisms, reduce sleep differences and potentially reduce cardiometabolic disease risk. © 2012 Elsevier Ltd.

Tew W.P.,Sloan Kettering Cancer Center | Fleming G.F.,University of Chicago
Gynecologic Oncology | Year: 2015

Half of ovarian cancer patients are over the age of 65, and as the population ages, the number of older women with ovarian cancer is increasing. Older women with ovarian cancer receive less surgery and chemotherapy than younger women, suffer worse toxicity from surgery and chemotherapy than younger women, and have worse survival. Performance status has been shown to be an inadequate tool to predict toxicity of older patients from therapy. Use of formal geriatric assessment tools is a promising direction for stratifying older patients on trials. We review current data on outcomes with surgery and chemotherapy in the older population, and discuss geriatric assessment tools being studied to aid decisions regarding which older patients will tolerate standard therapy and which will not. Modified treatment regimens and interventions to decrease morbidities in the vulnerable older population should be useful. © 2014 Elsevier Inc. All rights reserved.

Babic N.,University of Chicago
Journal of Medical Biochemistry | Year: 2012

The term"personalized medicine" (PM) was coined in the late 1990s, but was not introduced to general US public until about a decade later, through Genomics and Personalized Medicine Act. According to this act, PM is defined as any clinical practice model that utilizes genomic and family history information to customize diagnostic and therapeutic interventions and improve health outcomes. One of the emerging disciplines essential for implementation of PM is clinical pharmacogenomics (PGx), where patient's genetic information is utilized to personalize drug therapy. PGx testing includes mostly detection of small DNA variations, such single nucleotide polymorphisms (SNPs), insertions, and deletions in the genes encoding the drug transporters, receptors and metabolizing enzymes. By providing the right drug at the optimal dose to each patient, PGx promises to significantly improve drug efficacy and prevent adverse drug reactions. In the early 2000s, the US Food and Drug Administration joined scientists and laboratorians in their efforts to translate recent genetic advances into clinical practice by requiring the drug manufacturers to include genetic information on their product labels. To date several drugs including irinotecan, warfarin, abacavir and clopidogrel are labeled with the information relating different enzymatic polymorphisms with the adverse drug effects or the impaired drug efficacy. The majority of PGx testing involves SNP detection within the family of Cytochrome (CYP) P450 enzymes responsible for metabolism of most drugs, such as anti-depressants (e.g. CYP2D6) and anticoagulants (e.g. CYP2C9, 2C19) to name a few. PGx tests are still very low volume tests and it is not clear how and to what extent genotyping information is being utilized in the clinical practice, mostly due to the lack of outcome studies demonstrating the clinical utility of PGx testing. For instance, it is well known that approximately 30% of Caucasian population carries a polymorphic CYP2C9 allele that predisposes them to higher warfarin sensitivity and thus to increased bleeding risk. How - ever, there are no large, randomized outcome studies that conclusively demonstrate reduction of bleeding events or decrease in hospitalization rates in population dosed based on genotype information. The clinicians are thus reluctant to incorporate warfarin genotyping into their practice. Despite the attention PGx has received in recent years, the adoption of PGx into routine clinical testing is still far from being commonplace. The barriers to wider adoption and implementation of PGx include lack of education and understanding by prescribing physicians regarding the available tests, lack of consensus guidelines on interpretation and use of genotype results and scarcity of randomized controlled trials demonstrating the clinical utility of PGx testing. However, as ge netic testing is becoming increasingly patient driven thought di - rect-to-consumer testing, clinicians and laboratorians must continue to work toward full implementation of PGx testing into routine clinical practice.

Ross L.F.,University of Chicago
Journal of Inherited Metabolic Disease | Year: 2012

The traditional focus of newborn screening (NBS) is testing infants for medical conditions like phenylketonuria (PKU) that may cause significant morbidity or mortality unless treatment is initiated early. Although the Wilson and Jungner criteria were not designed specifically for NBS, the public health screening criteria have been used, with some modifications, to justify what conditions are included in a universal NBS panel. These criteria are being challenged by platform technologies like tandem mass spectrometry (MS/MS) that allow for the identification of numerous conditions on a single sample because they identify many conditions and variants simultaneously, some of which meet and others which fail to meet the criteria. In this manuscript, I evaluate three lysosomal storage diseases included in this multiplex screening test-Pompe disease, Fabry disease, and Krabbe disease. I show that they fail to meet some of the critical Wilson and Jungner criteria and thus are not ready for inclusion in universal NBS panels. Rather, screening for these conditions should only be performed in the research context with institutional review board approval and parental permission. © SSIEM and Springer 2011.

Schoggins J.W.,University of Texas Southwestern Medical Center | Randall G.,University of Chicago
Cell Host and Microbe | Year: 2013

It is becoming apparent that infections by a major class of viruses, those with envelopes, can be inhibited during their entry at the step of fusion with cellular membranes. In this review, we discuss multiple innate immune mechanisms that have evolved to modify the lipid composition of cellular and viral membranes to inhibit virion fusion of enveloped viruses. © 2013 Elsevier Inc.

Lahey B.B.,University of Chicago
Psychological Bulletin | Year: 2014

Frick, Ray, Thornton, and Kahn (2014) presented a comprehensive and well-articulated review of studies relevant to the validity and utility of using callous-unemotional traits to subtype the diagnosis of conduct disorder (CD). Like definitions of subtypes of CD in previous versions of the Diagnostic and Statistical Manual of Mental Disorders, the available evidence on the validity of the new subtypes of CD in the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5; American Psychiatric Association, 2013) based on callous-unemotional traits is thin. Nonetheless, the target article makes a compelling argument for further study of callous-unemotional and related traits to better understand the heterogeneity of CD. In particular, the possibilities that callous-unemotional traits may facilitate understanding of etiology and psychobiological mechanisms and may help predict the prognosis and treatment outcomes of children with CD deserve greater study. Future research must be stronger than previous research, however, in using more appropriate samples of children with CD along with more informative designs, and in conducting analyses to directly test the incremental validity of callous-unemotional traits as a subtyping variable beyond the severity or aggressiveness of CD. © 2014 American Psychological Association.

Adams E.J.,University of Chicago
Molecular Immunology | Year: 2013

CD1 molecules are Major Histocompatibility Complex (MHC) class I-like proteins that present diverse lipid antigens to T cells. Most of our understanding of CD1 lipid presentation and T cell recognition has come from study of the invariant Natural Killer T cell recognition of CD1d. However, in addition to CD1d, humans possess three additional CD1 molecules: CD1a, CD1b and CD1c, referred to as the Group 1 CD1s. The lack of an appropriate murine molecule to probe the function and disease relevance of these molecules has hindered understanding their precise immunological role, despite their pivotal role in human immunity. In this perspective, we discuss the progress of functional and molecular studies of CD1c. CD1c has been shown to specifically present lipids from Mycobacterium tuberculosis and other related pathogenic mycobacteria. αβ T cells reactive to these lipids presented in the context of CD1c have been characterized and upon stimulation secrete IFN-γ, an important cytokine in tuberculosis disease clearance. Other ligands characterized for CD1c include PI and PC, a lipopeptide with a dodecameric peptide moiety and sulfatides. These structurally and chemically diverse ligands suggest that CD1c has the capacity to present a wide repertoire of antigens to reactive T cells. Indeed, a substantial percentage (∼2%) of the circulating αβ T cell population is reactive to CD1c presenting endogenous antigens, suggesting that this particular Group 1 molecule may play an important role in the human immune response. © 2012 Elsevier Ltd.

Murray Sherman S.,University of Chicago | Guillery R.W.,Medical Research Council Anatomical Neuropharmacology Unit
Journal of Neurophysiology | Year: 2011

Essentially all cortical areas receive thalamic inputs and send outputs to lower motor centers. Cortical areas communicate with each other by means of direct corticocortical and corticothalamocortical pathways, often organized in parallel. We distinguish these functionally, stressing that the transthalamic pathways are class 1 (formerly known as "driver") pathways capable of transmitting information, whereas the direct pathways vary, being either class 2 (formerly known as "modulator") or class 1. The transthalamic pathways provide a thalamic gate that can be open or closed (and otherwise more subtly modulated), and these inputs to the thalamus are generally branches of axons with motor functions. Thus the transthalamic corticocortical pathways that can be gated carry information about the cortical processing in one cortical area and also about the motor instructions currently being issued from that area and copied to other cortical areas. © 2011 the American Physiological Society.

Gajewski T.F.,University of Chicago
Molecular Oncology | Year: 2012

The remarkable specificity of the immune system through antigen recognition has long attracted investigators to the possibility of immune-based therapy for cancer. Previous cancer immunotherapeutics had been restricted to non-specific immunomodulatory agents, such as the cytokines IL-2 or IFN-α. However, the molecular definition of cancer-associated antigens introduced the possibility of specific vaccines and adoptive T cell approaches aiming to target the tumor cells more specifically. The recent introduction of total exome sequencing has enabled the identification of patient tumor-specific epitopes generated through somatic point mutations, raising the possibility of targeting tumor antigens in individual patients which are even more tumor-specific. Transcriptional profiling and immunohistochemistry analyses have revealed a subset of patients with a pre-existing T cell-inflamed tumor microenvironment. This phenotype may be predictive of clinical outcome to immunotherapies and offers the possibility of a predictive biomarker. Further analysis of these tumors has identified a set of defined immune suppressive factors which themselves are being targeted with new immunotherapeutics, already with interesting early phase clinical trial results. Understanding not only the expression of tumor antigens but also the dynamic between a growing tumor and the host immune response is thus generating a rich set of opportunities for the specific immunotherapy of cancer. © 2012 Federation of European Biochemical Societies.

De Bettencourt-Dias A.,University of Nevada, Reno | Barber P.S.,University of Alabama | Viswanathan S.,University of Chicago
Coordination Chemistry Reviews | Year: 2014

Recent advances in the coordination of lanthanide ions and sensitization of their luminescence with aromatic N-donor ligands are presented. © 2014 Elsevier B.V.

Hillar C.J.,Mathematical science Research Institute | Lim L.-H.,University of Chicago
Journal of the ACM | Year: 2013

We prove that multilinear (tensor) analogues of many efficiently computable problems in numerical linear algebra are NP-hard. Our list includes: determining the feasibility of a system of bilinear equations, deciding whether a 3-tensor possesses a given eigenvalue, singular value, or spectral norm; approximating an eigenvalue, eigenvector, singular vector, or the spectral norm; and determining the rank or best rank-1 approximation of a 3-tensor. Furthermore, we show that restricting these problems to symmetric tensors does not alleviate their NP-hardness. We also explain how deciding nonnegative definiteness of a symmetric 4-tensor is NP-hard and how computing the combinatorial hyperdeterminant is NP-, #P-, and VNP-hard. Categories and Subject Descriptors: G.1.3 [Numerical Analysis]: Numerical Linear Algebra General Terms: Algorithms, Theory Additional Key Words and Phrases: Numerical multilinear algebra, tensor rank, tensor eigenvalue, tensor singular value, tensor spectral norm, system of multilinear equations, hyperdeterminants, symmetric tensors, nonnegative definite tensors, bivariate matrix polynomials, NP-hardness, #P-hardness, VNP-hardness, undecidability, polynomial time approximation schemes. © 2013 ACM.

Brunel N.,University of Chicago | Hakim V.,University Pierre and Marie Curie | Richardson M.J.E.,University of Warwick
Current Opinion in Neurobiology | Year: 2014

At the single neuron level, information processing involves the transformation of input spike trains into an appropriate output spike train. Building upon the classical view of a neuron as a threshold device, models have been developed in recent years that take into account the diverse electrophysiological make-up of neurons and accurately describe their input-output relations. Here, we review these recent advances and survey the computational roles that they have uncovered for various electrophysiological properties, for dendritic arbor anatomy as well as for short-term synaptic plasticity. © 2014 Elsevier Ltd.

Brown M.T.,Rush University Medical Center | Bussell J.K.,University of Chicago
Mayo Clinic Proceedings | Year: 2011

The treatment of chronic illnesses commonly includes the longterm use of pharmacotherapy. Although these medications are effective in combating disease, their full benefits are often not realized because approximately 50% of patients do not take their medications as prescribed. Factors contributing to poor medication adherence are myriad and include those that are related to patients (eg, suboptimal health literacy and lack of involvement in the treatment decision-making process), those that are related to physicians (eg, prescription of complex drug regimens, communication barriers, ineffective communication of information about adverse effects, and provision of care by multiple physicians), and those that are related to health care systems (eg, office visit time limitations, limited access to care, and lack of health information technology). Because barriers to medication adherence are complex and varied, solutions to improve adherence must be multifactorial. To assess general aspects of medication adherence using cardiovascular disease as an example, a MEDLINE-based literature search (January 1, 1990, through March 31, 2010) was conducted using the following search terms: cardiovascular disease, health literacy, medication adherence, and pharmacotherapy. Manual sorting of the 405 retrieved articles to exclude those that did not address cardiovascular disease, medication adherence, or health literacy in the abstract yielded 127 articles for review. Additional references were obtained from citations within the retrieved articles. This review surveys the findings of the identified articles and presents various strategies and resources for improving medication adherence. © 2011 Mayo Foundation for Medical Education and Research.

Nephropathy is a common microvascular complication among patients with type 2 diabetes mellitus and a major cause of kidney failure. It is characterized by albuminuria (≥300 mg/d) and a reduced glomerular filtration rate and is often present at the time of diabetes diagnosis after the kidney has been exposed to chronic hyperglycemia during the prediabetic phase. A low glomerular filtration rate (<60 mL/min/1.73 m2) is also an independent risk factor for cardiovascular events and death. Detection of diabetic nephropathy during its initial stages provides the opportunity for early therapeutic interventions to prevent or delay the onset of complications and improve outcomes. An intensive and multifactorial management approach is needed that targets all risk determinants simultaneously. The strategy should comprise lifestyle modifications (smoking cessation, weight loss, increased physical activity, and dietary changes) coupled with therapeutic achievement of blood glucose, blood pressure, and lipid goals that are evidence-based. Prescribing decisions should take into account demographic factors, level of kidney impairment, adverse effects, risk of hypoglycemia, tolerability, and effects on other risk factors and comorbidities. Regular and comprehensive follow-up assessments with appropriate adjustment of the therapeutic regimen to maintain risk factor control is a vital component of care, including referral to specialists, when required. © 2011 Mayo Foundation for Medical Education and Research.

Steiner D.F.,University of Chicago
Methods in Molecular Biology | Year: 2011

Studies of the biosynthesis of insulin in a human insulinoma beginning in 1965 provided the first evidence for a precursor of insulin, the first such prohormone to be identified. Further studies with isolated rat islets then confirmed that the precursor became labeled more rapidly than insulin and later was converted to insulin by a proteolytic processing system located mainly within the secretory granules of the beta cell and was then stored or secreted. The precursor was designated "proinsulin" in 1967 and was isolated and sequenced from beef and pork sources. These structural studies confirmed that the precursor was a single polypeptide chain which began with the B chain of insulin, continued through a connecting segment of 30-35 amino acids and terminated with the A chain. Paired basic residues were identified at the sites of excision of the C-peptide. Human proinsulin and C-peptide were then similarly obtained and sequenced. The human C-peptide assay was developed and provided a useful tool for measuring insulinlevels indirectly in diabetics treated with insulin. The discovery of other precursor proteins for a variety of peptide hormones, neuropeptides, or plasma proteins then followed, with all having mainly dibasic cleavage sites for processing. The subsequent discovery of a similar biosynthetic pathway in yeast led to the identification of eukaryotic families of specialized processing subtilisin-like endopeptidases coupled with carboxypeptidase B-like exopeptidases. Most neuroendocrine peptides are processed by two specialized members of this family - PC2 and/or PC1/3 - followed by carboxypeptidase E (CPE). This brief report concentrates mainly on the role of insulin biosynthesis in providing a useful early paradigm of precursor processing in the secretory pathway. © 2011 Springer Science+Business Media, LLC.

Wang Y.-C.,Howard Hughes Medical Institute | Khan Z.,University of Chicago | Wieschaus E.,Howard Hughes Medical Institute
Developmental Cell | Year: 2013

Localized cell shape change initiates epithelial folding, while neighboring cell invagination determines the final depth of an epithelial fold. The mechanism that controls the extent of invagination remains unknown. During Drosophila gastrulation, a higher number of cells undergo invagination to form the deep posterior dorsal fold, whereas far fewer cells become incorporated into the initially very similar anterior dorsal fold. We find that a decrease in α-catenin activity causes the anterior fold to invaginate as extensively as the posterior fold. In contrast, constitutive activation of the small GTPase Rap1 restricts invagination of both dorsal folds in an α-catenin-dependent manner. Rap1 activity appears spatially modulated by Rapgap1, whose expression levels are high in the cells that flank the posterior fold but low in the anterior fold. We propose a modelwhereby distinct activity states of Rap1 modulate α-catenin-dependent coupling between junctions and actin to control the extent of epithelial invagination. © 2013 Elsevier Inc.

Alegre M.-L.,University of Chicago
Science Translational Medicine | Year: 2015

High-throughput sequencing of the T cell receptor Vβ CDR3 region allowed longitudinal tracking of alloreactive T cells in kidney transplant patients, revealing clonal deletion as a mechanism of transplantation tolerance (Morris et al., this issue). © 2015, American Association for the Advancement of Science. All rights reserved.

Knutson K.L.,University of Chicago
American journal of human biology : the official journal of the Human Biology Council | Year: 2014

Sleep comprises one-third of one's life, yet little is known about sleep in developing countries. Furthermore, many studies in industrialized countries have reported that sleep duration and quality decline with aging, but whether this association persists globally is unknown. This study's objectives were to characterize sleep in a community without electricity in Haiti and to examine associations between measures of sleep and age. Fifty-eight Haiti residents (50% women) in four age groups, 18-30, 31-50, 51-64, and ≥ 65 years participated. Three days of wrist actigraphy were used to estimate sleep patterns. Mean (standard deviation) values of sleep measures were: 20:57 (0:40) for sleep onset, 4:54 (0:43) for sleep end, 9.3 (1.2) h for time in bed, 7.0 (1.0) h for sleep duration, 54 (24) min awake after sleep onset, and 88.7 (5.4)% for sleep maintenance (percentage of sleep period actually spent sleeping). There were no significant differences in the sleep measures between men and women. Regression analyses adjusting for sex, household size, and number of people sleeping in the same room indicated that only sleep fragmentation differed by age group. Specifically, mean fragmentation was higher in the youngest age group than all other age groups, which did not differ from one another. Average time in bed in this Haitian sample was greater than previously reported for industrialized countries like the United States (9.3 versus. 7-8 h);, however, actual sleep duration averaged only 7 h. No age-related decline in sleep duration or quality was observed in Haiti. Copyright © 2013 Wiley Periodicals, Inc.

Bezanilla F.,University of Chicago | Villalba-Galea C.A.,Virginia Commonwealth University
Journal of General Physiology | Year: 2013

The voltage dependence of charges in voltage-sensitive proteins, typically displayed as charge versus voltage (Q-V) curves, is often quantified by fitting it to a simple two-state Boltzmann function. This procedure overlooks the fact that the fitted parameters, including the total charge, may be incorrect if the charge is moving in multiple steps. We present here the derivation of a general formulation for Q-V curves from multistate sequential models, including the case of infinite number of states. We demonstrate that the commonly used method to estimate the charge per molecule using a simple Boltzmann fit is not only inadequate, but in most cases, it underestimates the moving charge times the fraction of the field. © 2013 Bezanilla and Villalba-Galea.

Abney M.,University of Chicago
Genetic Epidemiology | Year: 2015

This article discusses problems with and solutions to performing valid permutation tests for quantitative trait loci in the presence of polygenic effects. Although permutation testing is a popular approach for determining statistical significance of a test statistic with an unknown distribution-for instance, the maximum of multiple correlated statistics or some omnibus test statistic for a gene, gene-set, or pathway-naive application of permutations may result in an invalid test. The risk of performing an invalid permutation test is particularly acute in complex trait mapping where polygenicity may combine with a structured population resulting from the presence of families, cryptic relatedness, admixture, or population stratification. I give both analytical derivations and a conceptual understanding of why typical permutation procedures fail and suggest an alternative permutation-based algorithm, MVNpermute, that succeeds. In particular, I examine the case where a linear mixed model is used to analyze a quantitative trait and show that both phenotype and genotype permutations may result in an invalid permutation test. I provide a formula that predicts the amount of inflation of the type 1 error rate depending on the degree of misspecification of the covariance structure of the polygenic effect and the heritability of the trait. I validate this formula by doing simulations, showing that the permutation distribution matches the theoretical expectation, and that my suggested permutation-based test obtains the correct null distribution. Finally, I discuss situations where naive permutations of the phenotype or genotype are valid and the applicability of the results to other test statistics. © 2015 WILEY PERIODICALS, INC.

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

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

Golomb H.M.,University of Chicago
Leukemia and Lymphoma | Year: 2011

Treatment of hairy cell leukemia (HCL), a disease first described in 1958, has evolved from splenectomy, which resulted in a normalization of blood counts in about 41% of patients and an improvement in the remaining 59% of patients but with a time to failure of only approximately 19 months, through treatment in the early 1980s with interferon, which resulted in the same high overall response rate but with a time to failure of approximately 31 months. Subsequently, therapy with either pentostatin or cladribine showed an increase in the complete remission (CR) rate to approximately 80â€"90%, with only a small percentage of patients relapsing at approximately 30 months. More recently, patients who have failed either or both of these drugs have been shown to respond to rituximab or the experimental drug, BL22 (HA22). With these documented successes, the outlook for patients diagnosed with HCL, 50 years after the disease was first described, is so positive that patients with HCL have survival curves similar to those for the appropriate age-related cohorts. © 2011 Informa UK, Ltd.

Heterodontosaurids comprise an important early radiation of small-bodied herbivores that persisted for approximately 100 My from Late Triassic to Early Cretaceous time. Review of available fossils unequivocally establishes Echinodon as a very small-bodied, late-surviving northern heterodontosaurid similar to the other northern genera Fruitadens and Tianyulong. Tianyulong from northern China has unusual skeletal proportions, including a relatively large skull, short forelimb, and long manual digit II. The southern African heterodontosaurid genus Lycorhinus is established as valid, and a new taxon from the same formation is named Pegomastax africanus gen. n., sp. n. Tooth replacement and tooth-to-tooth wear is more common than previously thought among heterodontosaurids, and in Heterodontosaurus the angle of tooth-to-tooth shear is shown to increase markedly during maturation. Long-axis rotation of the lower jaw during occlusion is identified here as the most likely functional mechanism underlying marked tooth wear in mature specimens of Heterodontosaurus. Extensive tooth wear and other evidence suggests that all heterodontosaurids were predominantly or exclusively herbivores. Basal genera such as Echinodon, Fruitadens and Tianyulong with primitive, subtriangular crowns currently are known only from northern landmasses. All other genera except the enigmatic Pisanosaurus have deeper crown proportions and currently are known only from southern landmasses. © Paul C. Sereno.

Goldin-Meadow S.,University of Chicago
Developmental Review | Year: 2015

Piaget was a master at observing the routine behaviors children produce as they go from knowing less to knowing more about at a task, and making inferences not only about how the children understood the task at each point, but also about how they progressed from one point to the next. In this paper, I examine a routine behavior that Piaget overlooked - the spontaneous gestures speakers produce as they explain their solutions to a problem. These gestures are not mere hand waving. They reflect ideas that the speaker has about the problem, often ideas that are not found in that speaker's talk. But gesture can do more than reflect ideas - it can also change them. In this sense, gesture behaves like any other action; both gesture and action on objects facilitate learning problems on which training was given. However, only gesture promotes transferring the knowledge gained to problems that require generalization. Gesture is, in fact, a special kind of action in that it represents the world rather than directly manipulating the world (gesture does not move objects around). The mechanisms by which gesture and action promote learning may therefore differ - gesture is able to highlight components of an action that promote abstract learning while leaving out details that could tie learning to a specific context. Because it is both an action and a representation, gesture can serve as a bridge between the two and thus be a powerful tool for learning abstract ideas. © 2015 Elsevier Inc.

Roux B.,University of Chicago
Biophysical Journal | Year: 2010

The ability to discriminate between different cations efficiently is essential for the proper physiological functioning of many membrane transport proteins. One obvious mechanism of ion selectivity is when a binding site is structurally constrained by the protein architecture and its geometry is precisely adapted to fit an ion of a given size. This mechanism is not effective in the case of flexible protein binding sites that are able to deform structurally or to adapt to a bound ion. In this study, the concept of nontrivial ion selectivity arising in a highly flexible protein binding site conceptually represented as a microdroplet of ligands confined to a small volume is explored. The environment imposed by the spatial confinement is a critical feature of the reduced models. A large number of reduced binding site models (1077) comprising typical ion-coordinating ligands (carbonyl, hydroxyl, carboxylate, water) are constructed and characterized for Na+/K - and Ca2-/Ba2- size selectivity using free energy perturbation molecular dynamics simulations. Free energies are highly correlated with the sum of ion-ligand and ligand-ligand mean interactions, but the relative balance of those two contributions is different for K +-selective and Na+-selective binding sites. The analysis indicates that both the number and the type of ligands are important factors in ion selectivity. © 2010 by the Biophysical Society.

Klevtsov S.,University of Cologne | Wiegmann P.,University of Chicago
Physical Review Letters | Year: 2015

We argue that in addition to the Hall conductance and the nondissipative component of the viscous tensor, there exists a third independent transport coefficient, which is precisely quantized. It takes constant values along quantum Hall plateaus. We show that the new coefficient is the Chern number of a vector bundle over moduli space of surfaces of genus 2 or higher and therefore cannot change continuously along the plateau. As such, it does not transpire on a sphere or a torus. In the linear response theory, this coefficient determines intensive forces exerted on electronic fluid by adiabatic deformations of geometry and represents the effect of the gravitational anomaly. We also present the method of computing the transport coefficients for quantum Hall states. © 2015 American Physical Society. © 2015 American Physical Society.

Marinescu I.,University of Chicago
Journal of Health Economics | Year: 2014

The HIV epidemic has dramatically decreased labor supply among prime-age adults in Sub-Saharan Africa. Using within-country variation in regional HIV prevalence and a synthetic panel, I find that HIV significantly increases the capital-labor ratio in urban manufacturing firms. The impact of HIV on average wages is positive but imprecisely estimated. In contrast, HIV has a large positive impact on the skill premium. The impact of HIV on the wages of low skilled workers is insignificantly different from 0, and is strongly dampened by competition from rural migrants. The HIV epidemic disproportionately increases the incomes of high-skilled survivors, thus increasing inequality. © 2014 Elsevier B.V.

Sallan L.C.,University of Chicago | Friedman M.,University of Oxford
Proceedings of the Royal Society B: Biological Sciences | Year: 2012

Adaptive radiations, bouts of morphological divergence coupled with taxonomic proliferation, underpin biodiversity. The most widespread model of radiations assumes a single round, or 'early burst', of elevated phenotypic divergence followed by a decline in rates of change or even stasis. A vertebrate-specific model proposes separate stages: initial divergence in postcranial traits related to habitat use, followed by diversification in cranial morphology linked to trophic demands. However, there is little empirical evidence for either hypothesis. Here, we show that, contrary to both models, separate large-scale radiations of actinopterygian fishes proceeded through distinct cranial and later postcranial stages of morphological diversification. Early actinopterygians and acanthomorph teleosts dispersed in cranial morphospace immediately following the end-Devonian extinction and the Cretaceous origin of the acanthomorph clade, respectively. Significant increases in postcranial morphological variation do not occur until one interval after cranial diversification commenced. Therefore, our results question the universality of the 'general vertebrate model'. Based on the results of model-fitting exercises and application of the divergence order test, we find little evidence that the early onset of cranial diversification in these two radiations is due to elevated rates of cranial change relative to postcranial change early in their evolutionary histories. Instead, postcranial and cranial patterns are best fit by an Ornstein-Uhlenbeck model, which is characterized by constant evolutionary rates coupled with a strong central tendency. Other groups have been reported to show early saturation of cranial morphospace or tropic roles early in their histories, but it is unclear whether these patterns are attributable to dynamics similar to those inferred for our two model radiations. © 2011 The Royal Society.

Upadhye A.,Argonne National Laboratory | Hu W.,University of Chicago | Khoury J.,University of Pennsylvania
Physical Review Letters | Year: 2012

Chameleon scalar fields are dark-energy candidates which suppress fifth forces in high density regions of the Universe by becoming massive. We consider chameleon models as effective field theories and estimate quantum corrections to their potentials. Requiring that quantum corrections be small, so as to allow reliable predictions of fifth forces, leads to an upper bound m<0.0073(ρ/10gcm -3)1 /3eV for gravitational-strength coupling whereas fifth force experiments place a lower bound of m>0.0042eV. An improvement of less than a factor of two in the range of fifth force experiments could test all classical chameleon field theories whose quantum corrections are well controlled and couple to matter with nearly gravitational strength regardless of the specific form of the chameleon potential. © 2012 American Physical Society.

Luke J.J.,University of Chicago | Ott P.A.,Dana-Farber Cancer Institute
Oncotarget | Year: 2015

Checkpoint inhibitors are revolutionizing treatment options and expectations for patients with melanoma. Ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), was the first approved checkpoint inhibitor. Emerging long-term data indicate that approximately 20% of ipilimumabtreated patients achieve long-term survival. The first programmed death 1 (PD-1) inhibitor, pembrolizumab, was recently approved by the United States Food and Drug Administration for the treatment of melanoma; nivolumab was previously approved in Japan. PD-1 inhibitors are also poised to become standard of care treatment for other cancers, including non-small cell lung cancer, renal cell carcinoma and Hodgkin's lymphoma. Immunotherapy using checkpoint inhibition is a different treatment approach to chemotherapy and targeted agents: instead of directly acting on the tumor to induce tumor cell death, checkpoint inhibitors enhance or de novostimulate antitumor immune responses to eliminate cancer cells. Initial data suggest that objective anti-tumor response rates may be higher with anti-PD-1 agents compared with ipilimumab and the safety profile may be more tolerable. This review explores the development and next steps for PD-1 pathway inhibitors, including discussion of their novel mechanism of action and clinical data to-date, with a focus on melanoma.

Peter M.E.,University of Chicago
Oncogene | Year: 2010

Micro(mi)RNAs are small noncoding RNAs that regulate expression of the majority of the genes in the genome at either the messenger RNA (mRNA) level (by degrading mRNA) or the protein level (by blocking translation). miRNAs are thought to be components of vast regulatory networks. Currently, the field is focused primarily on identifying novel targets of individual miRNAs. This focus is about to undergo a dramatic change. In a new paper by Wu et al. (2010) it is experimentally confirmed that multiple miRNAs target the same gene, suggesting that it is the combination of all these activities that determines the expression of miRNA target genes. This study ushers in a new era of miRNA research that focuses on networks more than on individual connections between miRNA and strongly predicted targets. © 2010 Macmillan Publishers Limited. All rights reserved.

Steck T.L.,University of Chicago | Lange Y.,Rush University Medical Center
Trends in Cell Biology | Year: 2010

Recent evidence suggests that the major pathways mediating cell cholesterol homeostasis respond to a common signal: active membrane cholesterol. Active cholesterol is the fraction that exceeds the complexing capacity of the polar bilayer lipids. Increments in plasma membrane cholesterol exceeding this threshold have an elevated chemical activity (escape tendency) and redistribute via diverse transport proteins to both circulating plasma lipoproteins and intracellular organelles. Active cholesterol thereby prompts several feedback responses. It is the substrate for its own esterification and for the synthesis of regulatory side-chain oxysterols. It also stimulates manifold pathways that down-regulate the biosynthesis, curtail the ingestion and increase the export of cholesterol. Thus, the abundance of cell cholesterol is tightly coupled to that of its polar lipid partners through active cholesterol. © 2010 Elsevier Ltd.

Lyons I.M.,University of Western Ontario | Ansari D.,University of Western Ontario | Beilock S.L.,University of Chicago
Human Brain Mapping | Year: 2015

Are symbolic and nonsymbolic numbers coded differently in the brain? Neuronal data indicate that overlap in numerical tuning curves is a hallmark of the approximate, analogue nature of nonsymbolic number representation. Consequently, patterns of fMRI activity should be more correlated when the representational overlap between two numbers is relatively high. In bilateral intraparietal sulci (IPS), for nonsymbolic numbers, the pattern of voxelwise correlations between pairs of numbers mirrored the amount of overlap in their tuning curves under the assumption of approximate, analogue coding. In contrast, symbolic numbers showed a flat field of modest correlations more consistent with discrete, categorical representation (no systematic overlap between numbers). Directly correlating activity patterns for a given number across formats (e.g., the numeral "6" with six dots) showed no evidence of shared symbolic and nonsymbolic number-specific representations. Overall (univariate) activity in bilateral IPS was well fit by the log of the number being processed for both nonsymbolic and symbolic numbers. IPS activity is thus sensitive to numerosity regardless of format; however, the nature in which symbolic and nonsymbolic numbers are encoded is fundamentally different. © 2014 Wiley Periodicals, Inc.

Childs E.,University of Chicago
Nutrition Reviews | Year: 2014

Sales of energy products have grown enormously in recent years. Manufacturers claim that the products, in the form of drinks, shots, supplements, and gels, enhance physical and cognitive performance, while users believe the products promote concentration, alertness, and fun. Most of these products contain caffeine, a mild psychostimulant, as their foremost active ingredient. However, they also contain additional ingredients, e.g., carbohydrates, amino acids, herbal extracts, vitamins, and minerals, often in unspecified amounts and labeled as an "energy blend." It is not clear whether these additional ingredients provide any physical or cognitive enhancement beyond that provided by caffeine alone. This article reviews the available empirical data on the interactive effects of these ingredients and caffeine on sleep and cognitive performance and suggests objectives for future study. © 2014 International Life Sciences Institute.

Tung J.,Duke University | Gilad Y.,University of Chicago
Cellular and Molecular Life Sciences | Year: 2013

Social environmental conditions, particularly the experience of social adversity, have long been connected with health and mortality in humans and other social mammals. Efforts to identify the physiological basis for these effects have historically focused on their neurological, endocrinological, and immunological consequences. Recently, this search has been extended to understanding the role of gene regulation in sensing, mediating, and determining susceptibility to social environmental variation. Studies in laboratory rodents, captive primates, and human populations have revealed correlations between social conditions and the regulation of a large number of genes, some of which are likely causal. Gene expression responses to the social environment are, in turn, mediated by a set of underlying regulatory mechanisms, of which epigenetic marks are the best studied to date. Importantly, a number of genes involved in the response to the social environment are also associated with susceptibility to other external stressors, as well as certain diseases. Hence, gene regulatory studies are a promising avenue for understanding, and potentially developing strategies to address, the effects of social adversity on health. © 2013 The Author(s).

Pack C.C.,Montreal Neurological Institute | Bensmaia S.J.,University of Chicago
PLoS Biology | Year: 2015

While the different sensory modalities are sensitive to different stimulus energies, they are often charged with extracting analogous information about the environment. Neural systems may thus have evolved to implement similar algorithms across modalities to extract behaviorally relevant stimulus information, leading to the notion of a canonical computation. In both vision and touch, information about motion is extracted from a spatiotemporal pattern of activation across a sensory sheet (in the retina and in the skin, respectively), a process that has been extensively studied in both modalities. In this essay, we examine the processing of motion information as it ascends the primate visual and somatosensory neuraxes and conclude that similar computations are implemented in the two sensory systems. © 2015 Pack, Bensmaia.

Favus M.J.,University of Chicago
New England Journal of Medicine | Year: 2010

A 67-year-old woman was referred by her primary care physician for treatment of osteoporosis and progressive bone loss. One year before the visit, the patient had discontinued hormone-replacement therapy. She had subsequently begun to experience midback pain and lost 3.8 cm (1.5 in.) in height. A dual-energy x-ray absorptiometry (DXA) scan showed bone mineral density T scores of -3.1 at the lumbar spine and -2.8 at the femoral neck, which are consistent with a diagnosis of osteoporosis. One year later, a second scan showed a further decrease of 5.4% in bone mineral density at the lumbar spine (Fig. 1), as well as a compression fracture of the 11th thoracic vertebra (Fig. 2). Results of blood and urine tests ruled out the common secondary causes of osteoporosis. To prevent additional vertebral fractures, oral bisphosphonate therapy was recommended. Copyright © 2010 Massachusetts Medical Society.

Knutson K.L.,University of Chicago
Best Practice and Research: Clinical Endocrinology and Metabolism | Year: 2010

Laboratory studies have found that short-term sleep restriction is associated with impairments in glucose metabolism, appetite regulation and blood pressure regulation. This chapter reviews the epidemiologic evidence for an association between habitual sleep duration and quality and risk of cardiometabolic diseases including obesity, diabetes and hypertension. Multiple studies observed a cross-sectional association between short sleep duration (generally <6 h per night) and increased body mass index or obesity, prevalent diabetes and prevalent hypertension. Many studies also reported an association between self-reported long sleep duration (generally >8 h per night) and cardiometabolic disease. There have been a few prospective studies and several, but not all, have found an association between short sleep and incident diabetes, hypertension and markers of cardiovascular disease. Future prospective epidemiologic studies need to include objective measures of sleep, and intervention studies are needed in order to establish a causal link between impaired or insufficient sleep and cardiometabolic disease risk. © 2010 Published by Elsevier Ltd.

The Newport Member of the Astoria Formation, exposed on the central Oregon coast, was deposited at shallow marine depths during the Early Miocene global warming that led to the Middle Miocene Climate Optimum. This record thus provides the opportunity to examine a coastal environment over past warming and ask if the low oxygen conditions observed in recent years on the modern Oregon shelf is a recent phenomenon or a repeated symptom of global warming.Although δ18O variation can be influenced by freshwater flux, if due to temperature δ18O values suggest 2.4-4.5°C of local warming during deposition of the Newport Member. Species of Buliminacea, Fursenkoina, and Nonionella, abundant in organic-rich, low-oxygen sediments in modern seas, increased in proportional abundance after warming began. In addition, the offset in δ13C values between epifaunal to shallow infaunal taxa and a deeper infaunal species is greater in sediments with higher abundances of these taxa, further supporting increased organic carbon flux. An increase in laminated sediments coincident with these faunal and geochemical changes suggests dysoxic conditions accompanied the increase in organic carbon. Taken together, this multiproxy record suggests that high-organic, low-oxygen, environments developed in shallow waters during Early Miocene warming, perhaps driven by similar upwelling mechanisms thought to drive hypoxia on the modern Oregon coast. © 2011 Elsevier B.V.

The structure of cranidial shape variation in the early ptychoparioid trilobites Crassifimbra walcotti, Crassifimbra? metalaspis (new combination), and Eokochaspis nodosa is explored using landmark-based geometric morphometric techniques, and is found to be generally similar among the species. Allometry is the strongest single source of cranidial shape variation within each species. The species share several trends in their respective patterns of ontogenetic shape change, but differ in the relative magnitude of these shared trends. Species-specific trends are also present. Each species follows a unique trajectory of ontogenetic shape change. The species exhibit subtle but significant differences in mean cranidial shape even at small size (sagittal length 1.75 mm); the magnitude of interspecific differences becomes larger at larger size (sagittal length 4.2 mm). For conspecific cranidia of a given size, the major pattern of covariance among anatomical parts is essentially identical to the pattern of covariance among those parts during ontogeny. Developmentally determined covariance patterns among cranidial regions might be responsible for ontogenetic shape change and a portion of non-allometric shape intraspecific variation. Interspecific differences in cranidial shape resulted from complex local modifications to growth pattern and cannot be attributed to simple ontogenetic scaling. The new collections permit the first description of non-cranidial sclerites of C. walcotti. A cephalic median organ is documented on C. walcotti, representing the oldest known occurrence of this structure in trilobites. © 2011 The Paleontological Society.

Goldman D.P.,University of Southern California | Philipson T.,University of Chicago
Health Affairs | Year: 2014

In this commentary we debunk a number of the most common misconceptions about cancer treatment, such as claims that the war on cancer has been a failure and that treatment costs are unsustainable. In addition, there is good evidence that patients value these treatments more highly than traditional cost-effectiveness analysis would indicate. We argue that coverage policies placing undue burden on patients are socially wasteful and will likely discourage further innovation. © 2014 Project HOPE-The People-to-People Health Foundation, Inc.

Godley L.A.,University of Chicago
Seminars in Hematology | Year: 2014

Germline testing for familial predisposition to myeloid malignancies is becoming more common with the recognition of multiple familial syndromes. Currently, Clinical Laboratory Improvement Amendments-approved testing exists for the following: familial platelet disorder with propensity to acute myeloid leukemia, caused by mutations in RUNX1; familial myelodysplastic syndrome/acute myeloid leukemia with mutated GATA2; familial acute myeloid leukemia with mutated CEBPA; and the inherited bone marrow failure syndromes, including dyskeratosis congenita, a disease of abnormal telomere maintenance. With the recognition of additional families with a genetic component to their myeloid diseases, new predisposition alleles are likely to be identified. Awareness of the existence of these syndromes will facilitate proper genetic counseling, appropriate testing, and clinical management of these cases. © 2014 Elsevier Inc.

Vokes E.E.,University of Chicago
The oncologist | Year: 2010

The addition of chemotherapy to radiotherapy in the treatment of locally advanced squamous cell carcinoma of the head and neck (SCCHN) patients improves survival. Meta-analyses of randomized trials have indicated that the benefit of this approach is associated with the timing of chemotherapy administration. It has been demonstrated that the greatest survival benefit over locoregional treatment alone is seen with the concurrent administration of chemotherapy and radiotherapy. However, sequential chemotherapy administration, in the form of induction chemotherapy followed by radiotherapy or concurrent chemoradiotherapy, has been successful as a strategy for organ function preservation in patients with potentially resectable SCCHN. In addition, a meta-analysis of trials using platinum and 5-fluorouracil (PF)-containing induction regimens demonstrated a significant survival benefit for this approach over locoregional treatment alone in locally advanced disease. In recent years, the introduction of the taxanes into induction chemotherapy has provided physicians with more active regimens. The triplet combination induction regimen of docetaxel, cisplatin, and 5-fluorouracil has been shown to be more effective in prolonging survival than the doublet PF. Current trials are testing whether the addition of induction chemotherapy to standard concomitant chemoradiotherapy is superior to concomitant chemoradiotherapy alone.

Neuromonitoring of the recurrent laryngeal nerve is increasingly utilized in thyroid and parathyroid surgery. Many studies have examined this practice with respect to rates of nerve injury. We have reviewed this literature with specific focus on ethical and medicolegal issues. The preponderance of data fail to show that neuromonitoring significantly reduces the rates of nerve injury in thyroid and parathyroid surgery. However, potential benefits can nevertheless be identified for patients in predicting nerve injuries and reducing risks of bilateral recurrent laryngeal nerve injury. The primary ethical and medicolegal issues raised by neuromonitoring relate to setting high expectations of unproven benefit and not utilizing the technology to gain the most information for patient care decision making. Neuromonitoring can provide valuable information to surgeons about the functioning of the recurrent laryngeal nerve and external branch of the superior laryngeal nerve. Surgeons should follow guidelines for optimal use of neuromonitoring but should not overestimate the benefits of neuromonitoring when discussing the technology with patients.

Chervonsky A.V.,University of Chicago
Current Opinion in Immunology | Year: 2012

The interactions of commensal microorganisms with the host's immune system are in the spotlight. The intestinal microbiota provides both stimulatory and inhibitory signals to the host ensuring its own survival and contributing to resistance to pathogens. Some microbial lineages do this better than others and are attracting a lot of attention. The microbial influences go beyond the gut and have profound effects on infections and autoimmunity in distant locations. Commensals are also involved in regulation of 'tolerance to pathogens', a fundamental type of response to infections that does not reduce pathogen burden but keeps the host healthy. © 2012 Elsevier Ltd.

Kohn E.C.,U.S. National Cancer Institute | Hurteau J.,University of Chicago
Cancer | Year: 2013

The field of ovarian cancer research has made marked progress in better understanding ovarian cancer and redefining its types. New information is putting into doubt that mutations in KRAS and/or BRAF always portend poor outcome, at least not in low-grade serous ovarian cancers. © 2012 American Cancer Society.

Cornwell E.Y.,Cornell University | Waite L.J.,University of Chicago
Journal of Health and Social Behavior | Year: 2012

Hypertension is one of the most prevalent chronic diseases among older adults, but rates of blood pressure control are low. In this article, we explore the role of social network ties and network-based resources (e.g., information and support) in hypertension diagnosis and management. We use data from the National Social Life, Health, and Aging Project to identify older adults with undiagnosed or uncontrolled hypertension. We find that network characteristics and emotional support are associated with hypertension diagnosis and control. Importantly, the risks of undiagnosed and uncontrolled hypertension are lower among those with larger social networks-if they discuss health issues with their network members. When these lines of communication are closed, network size is associated with greater risk for undiagnosed and uncontrolled hypertension. Health care utilization partially mediates associations with diagnosis, but the benefits of network resources for hypertension control do not seem to stem from health-related behaviors. © American Sociological Association 2012.

Grossman L.,University of Chicago
Meteoritics and Planetary Science | Year: 2010

Equilibrium thermodynamic calculations of the sequence of condensation of phases from a cooling gas of solar composition at total pressures thought to have prevailed in the inner part of the solar nebula successfully predict the primary mineral assemblages of refractory inclusions in CM2 and CV3 chondrites. Many refractory inclusions in CM2 chondrites contain a relatively SiO 2-poor assemblage (spinel, hibonite, grossite, perovskite, corundum) that represents a high-temperature stage of condensation, and some may be pristine condensates that escaped later melting. Compact Type A and Type B refractory inclusions, consisting of spinel, melilite, perovskite, Ca-rich clinopyroxene ± anorthite, in CV3 chondrites are more SiO 2-rich and equilibrated with the solar nebular gas at a slightly lower temperature. Textures of many of these objects indicate that they underwent melting after condensation, crystallizing into the same phase assemblage as their precursors. The Ti 3+/Ti 4+ ratio of their pyroxene indicates that this process occurred in a gas whose oxygen fugacity was approximately 8.5 log units below that of the iron-wüstite buffer, making them the only objects in chondrites known to have formed in a system whose composition was close to that of the sun. Relative to CI chondrites, these inclusions are uniformly enriched in a group of elements (e.g., Ca, REE, Zr, Ta, Ir) that are chemically diverse except for their high condensation temperatures in a system of solar composition. The enrichment factor, 17.5, can be interpreted to mean that these objects represent either the first 5.7 wt% of the condensable matter to condense during nebular cooling or the residue after vaporization of 94.3% of a CI chondrite precursor. The Mg and Si isotopic compositions of Types A and B inclusions are mass-fractionated by up to 10 and 4 ‰/amu, respectively. When interpreted in terms of Rayleigh fractionation during evaporation of Mg and Si from the inclusions while they were molten, the isotopic compositions imply that up to 60% of the Mg and up to 25% of the Si were evaporated, and that approximately 80% of the enrichment in refractory (CaO+Al 2O 3) relative to more volatile (MgO+SiO 2) in the average inclusion is due to initial condensation and approximately 20% due to subsequent evaporation. The mineralogical composition, including the Ti 3+/Ti 4+ ratio of the pyroxene, in Inti, a particle sampled from Comet Wild 2 by the Stardust spacecraft, is nearly identical to that of a Type B inclusion, indicating that comets contain not only the lowest-temperature condensates in the form of ices but the highest-temperature condensates as well. The FeO/(FeO+MgO) ratios of olivine and pyroxene in the matrix and chondrules of carbonaceous and ordinary chondrites are too high to be made in a system of solar composition, requiring s only 1 or 2 log units below iron-wüstite, more than 10 5 times higher than that of a solar gas. Various ways have been devised to generate cosmic gases sufficiently oxidizing to stabilize significant FeO in olivine at temperatures above those where Fe-Mg interdiffusion in olivine ceases. One is by vertical settling of dust toward the nebular midplane, enriching a region in dust relative to gas. Because dust is enriched in oxygen compared to carbon and hydrogen relative to solar composition, a higher results from total vaporization of the region, but the factor by which theoretical models have so far enriched the dust is 10 times too low. Another is by transporting icy bodies from the outer part of the nebula into the hot, inner part where vaporization of water ice occurs. Not only does this method fail to make the needed by a factor of 30-1000 but it also ignores simultaneous evaporation of carbon-bearing ices that would make the even lower. © The Meteoritical Society, 2010.

Raikhel E.,University of Chicago
Culture, Medicine and Psychiatry | Year: 2010

The dominant modalities of treatment for alcoholism in Russia are suggestion-based methods developed by narcology-the subspecialty of Russian psychiatry which deals with addiction. A particularly popular method is the use of disulfiram-an alcohol antagonist-for which narcologists commonly substitute neutral substances. Drawing on 14 months of fieldwork at narcological clinics in St. Petersburg, this article examines the epistemological and institutional conditions which facilitate this practice of "placebo therapy." I argue that narcologists' embrace of such treatments has been shaped by a clinical style of reasoning specific to a Soviet and post-Soviet psychiatry, itself the product of contested Soviet politics over the knowledge of the mind and brain. This style of reasoning has facilitated narcologists' understanding of disulfiram as a behavioral, rather than a pharmacological, treatment and has disposed them to amplify patients' responses through attention to the performative aspects of the clinical encounter and through management of the treatment's broader reputation as an effective therapy. Moreover, such therapies have generally depended upon, and helped to reinforce, clinical encounters premised on a steeply hierarchical physician-patient relationship. © Springer Science+Business Media, LLC 2009.

Tung A.,University of Chicago
British journal of anaesthesia | Year: 2010

The rising incidence of obesity has led to increased prevalence of a distinct, obesity-related metabolic syndrome. This syndrome is characterized by truncal obesity, insulin resistance, altered lipid levels, and hypertension. Definition of the metabolic syndrome rests on a set of clinical criteria instead of a single diagnostic test. It carries a different risk profile than obesity alone, and poses special challenges for the anaesthesiologist. These include preoperative risk stratification for common comorbidities, identifying reasonable thresholds for implementing preoperative risk reduction, overcoming obesity-related issues in intraoperative management, and delivering safe postoperative care. The metabolic syndrome predisposes to coronary artery disease, congestive heart failure, obstructive sleep apnoea, pulmonary dysfunction, and deep venous thrombosis. Because its different presentations can have different risk profiles, anaesthesiologists should assess the cumulative risk of each component of the metabolic syndrome separately, which significantly complicates preoperative management. Since obesity itself is difficult to treat, preoperative risk reduction can be difficult. Few data exist to inform best practice as to the anaesthetic care of patients with metabolic syndrome. This review evaluates and synthesizes current evidence regarding perioperative care for patients with the metabolic syndrome, including indications for preoperative testing; use of aspirin, β-blockers, statins, heparin, and angiotensin-converting enzyme inhibitors; anaesthetic strategies including regional anaesthesia; and postoperative management including continuous positive pressure ventilation by mask, prevention of pulmonary embolism, and indications for advanced respiratory monitoring.

Harms M.J.,University of Oregon | Thornton J.W.,University of Oregon | Thornton J.W.,University of Chicago
Nature Reviews Genetics | Year: 2013

The repertoire of proteins and nucleic acids in the living world is determined by evolution; their properties are determined by the laws of physics and chemistry. Explanations of these two kinds of causality-the purviews of evolutionary biology and biochemistry, respectively-are typically pursued in isolation, but many fundamental questions fall squarely at the interface of fields. Here we articulate the paradigm of evolutionary biochemistry, which aims to dissect the physical mechanisms and evolutionary processes by which biological molecules diversified and to reveal how their physical architecture facilitates and constrains their evolution. We show how an integration of evolution with biochemistry moves us towards a more complete understanding of why biological molecules have the properties that they do. © 2013 Macmillan Publishers Limited. All rights reserved.

Wu C.,University of Chicago
Journal of High Energy Physics | Year: 2014

We study parity-violating effects, particularly the generation of angular momentum density and its relation to the parity-odd and dissipationless transport coefficient Hall viscosity, in strongly-coupled quantum fluid systems in 2+1 dimensions using holographic method. We employ a class of 3+1-dimensional holographic models of Einstein-Maxwell system with gauge and gravitational Chern-Simons terms coupled to a dynamical scalar field. The scalar can condensate and break the parity spontaneously. We find that when the scalar condensates, a non-vanishing angular momentum density and an associated edge current are generated, and they receive contributions from both gauge and gravitational Chern-Simons terms. The angular momentum density does not satisfy a membrane paradigm form because the vector mode fluctuations from which it is calculated are effectively massive. On the other hand, the emergence of Hall viscosity is a consequence of the gravitational Chern-Simons term alone and it has membrane paradigm form. We present both general analytic results and numeric results which take back-reactions into account. The ratio between Hall viscosity and angular momentum density resulting from the gravitational Chern-Simons term has in general a deviation from the universal 1/2 value obtained from field theory and condensed matter physics. © 2014, The Author(s).

Pan T.,University of Chicago
Annual Review of Genetics | Year: 2013

The composition of the cellular proteome is commonly thought to strictly adhere to the genetic code. However, accumulating evidence indicates that cells also regulate the synthesis of mutant protein molecules that deviate from the genetic code. Production of mutant proteins generally occurs when cells are stressed or when they undergo environmental adaptation, but production varies in amounts and specificity. The deliberate synthesis of mutant proteins suggests that some of these proteins can be useful in cellular stress response and adaptation. This review describes the occurrence of, the translation mechanisms for, and the functional hypotheses on regulated synthesis of mutant proteins. © 2013 by Annual Reviews. All rights reserved.

Pennacchio L.A.,Lawrence Berkeley National Laboratory | Bickmore W.,University of Edinburgh | Dean A.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | Nobrega M.A.,University of Chicago | Bejerano G.,Stanford University
Nature Reviews Genetics | Year: 2013

It is estimated that the human genome contains hundreds of thousands of enhancers, so understanding these gene-regulatory elements is a crucial goal. Several fundamental questions need to be addressed about enhancers, such as how do we identify them all, how do they work, and how do they contribute to disease and evolution? Five prominent researchers in this field look at how much we know already and what needs to be done to answer these questions. © 2013 Macmillan Publishers Limited. All rights reserved.

List J.A.,University of Chicago | Samek A.S.,University of Wisconsin - Madison
Journal of Health Economics | Year: 2015

We leverage behavioral economics to explore new approaches to tackling child food choice and consumption. Using a field experiment with >1500 children, we report several key insights. We find that incentives have large influences: in the control, 17% of children prefer the healthy snack, whereas introduction of small incentives increases take-up of the healthy snack to ~75%. There is some evidence that the effects continue post-treatment, consistent with a model of habit formation. We find little evidence that the framing of incentives (loss vs. gain) matters. Educational messaging alone has little effect, but we observe a combined effect of messaging and incentives: together they provide an important influence on food choice. © 2014 Elsevier B.V.

Lahey B.B.,University of Chicago | Waldman I.D.,Emory University
Journal of Child Psychology and Psychiatry and Allied Disciplines | Year: 2012

Background: A better understanding of the nature and etiology of conduct disorder (CD) can inform nosology and vice versa. We posit that any prevalent form of psychopathology, including CD, can be best understood if it is studied in the context of other correlated forms of child and adolescent psychopathology using formal models to guide inquiry. Methods: Review of both cross-sectional and longitudinal studies of the place of CD in the phenotypic and causal structure of prevalent psychopathology, with an emphasis on similarities and differences between CD and oppositional defiant disorder (ODD). Papers were located using Web of Science by topic searches with no restriction on year of publication. Results: Although some important nosologic questions remain unanswered, the dimensional phenotype of CD is well defined. CD differs from other disorders in its correlates, associated impairment, and course. Nonetheless, it is robustly correlated with many other prevalent dimensions of psychopathology both concurrently and predictively, including both other 'externalizing' disorders and some 'internalizing' disorders. Based on emerging evidence, we hypothesize that these concurrent and predictive correlations result primarily from widespread genetic pleiotropy, with some genetic factors nonspecifically influencing risk for multiple correlated dimensions of psychopathology. In contrast, environmental influences mostly act to differentiate dimensions of psychopathology from one another both concurrently and over time. CD and ODD share half of their genetic influences, but their genetic etiologies are distinct in other ways. Unlike most other dimensions of psychopathology, half of the genetic influences on CD appear to be unique to CD. In contrast, ODD broadly shares nearly all of its genetic influences with other disorders and has little unique genetic variance. Conclusions: Conduct disorder is a relatively distinct syndrome at both phenotypic and etiologic levels, but much is revealed by studying CD in the context of its causal and phenotypic associations with other disorders over time. Advancing and refining formal causal models that specify the common and unique causes and biological mechanisms underlying each correlated dimension of psychopathology should facilitate research on the fundamental nature and nosology of CD. © 2011 The Authors. Journal of Child Psychology and Psychiatry © 2011 Association for Child and Adolescent Mental Health.

Sherman R.A.,University of Chicago
Astrophysical Journal | Year: 2012

We present CARMA observations in 3.3mm continuum and several molecular lines of the surroundings of N14, N22, and N74, three infrared bubbles from the GLIMPSE catalog. We have discovered 28 compact continuum sources and confirmed their associations with the bubbles using velocity information from HCO + and HCN. We have also mapped small-scale structures of N 2H + emission in the vicinity of the bubbles. By combining our data with survey data from GLIMPSE, MIPSGAL, BGPS, and MAGPIS, we establish about half of our continuum sources as star-forming cores. We also use survey data with the velocity information from our molecular line observations to describe the morphology of the bubbles and the nature of the fragmentation. We conclude from the properties of the continuum sources that N74 likely is at the near kinematic distance, which was previously unconfirmed. We also present tentative evidence of molecular clouds being more fragmented on bubble rims compared to dark clouds, suggesting that triggered star formation may occur, though our findings do not conform to a classic collect-and-collapse model. © 2012. The American Astronomical Society. All rights reserved.

Wyman M.,University of Chicago
Physical Review Letters | Year: 2011

The mystery of dark energy suggests that there is new gravitational physics on long length scales. Yet light degrees of freedom in gravity are strictly limited by Solar System observations. We can resolve this apparent contradiction by adding a Galilean-invariant scalar field to gravity. Called Galileons, these scalars have strong self-interactions near overdensities, like the Solar System, that suppress their dynamical effect. These nonlinearities are weak on cosmological scales, permitting new physics to operate. In this Letter, we point out that a massive-gravity-inspired coupling of Galileons to stress energy can enhance gravitational lensing. Because the enhancement appears at a fixed scaled location for dark matter halos of a wide range of masses, stacked cluster analysis of weak lensing data should be able to detect or constrain this effect. © 2011 American Physical Society.

Rubin D.T.,University of Chicago
American Journal of Gastroenterology | Year: 2013

Given the known dysbiosis of gut microflora in inflammatory bowel disease, there has been great enthusiasm about the potential for fecal microbiota transplantation (FMT) as a treatment. This editorial accompanies a prospective series of five patients with ulcerative colitis who underwent FMT, but did not achieve remission. I discuss the important observations from this study and point out that the lack of clinical efficacy and observed side effects warrant caution in the ongoing pursuit of this treatment option. © 2013 by the American College of Gastroenterology.

Price K.A.R.,Mayo Medical School | Cohen E.E.,University of Chicago
Current Treatment Options in Oncology | Year: 2012

Opinion statement: Head and neck squamous cell carcinoma is now the 8th most common cancer affecting men in the United States largely due to a rising epidemic of oropharynx cancer (tonsil and tongue base) associated with the human papillomavirus (HPV). The median overall survival for recurrent or metastatic head and neck cancer (R/M HNSCC) remains less than 1 year despite modern chemotherapy and targeted agents. Palliative chemotherapy and the epidermal growth factor receptor inhibitor, cetuximab, constitute the backbone of treatment for patients with R/M HNSCC. Platinum doublets studied in phase III trials include cisplatin/5-FU, cisplatin/paclitaxel, and cisplatin/pemetrexed. Platinum chemotherapy in combination with 5-fluorouracil and cetuximab has resulted in the longest median overall survival. Combination platinum regimens increase response rates and toxicity but not survival and should be reserved for patients who are symptomatic from their disease for whom the benefit of a partial response may be worth the cost of increased treatment-related side effects. For many patients who are asymptomatic with a low disease burden, single agent regimens are appropriate to balance treatment with side effects. Drugs commonly used as single agents in the treatment of R/M HNSCC include docetaxel, paclitaxel, cetuximab, capecitabine, pemetrexed, and methotrexate. Best supportive care alone is often appropriate for poor performance status patients. Palliative radiation therapy is beneficial for treating symptomatic metastatic sites. Aggressive symptom management is imperative for all patients and often should include referral to experts in palliative care and pain management. New therapies currently under investigation include mTOR inhibitors, anti-angiogenic agents, and IGF1R inhibitors. Given the poor prognosis for most patients with R/M HNSCC, enrollment in clinical trials investigating novel approaches to therapy should be encouraged. © 2012 Springer Science+Business Media, LLC.

Pan T.,University of Chicago
Trends in Biochemical Sciences | Year: 2013

N6-methyl-adenosine (m6A) is the most abundant modification in mammalian mRNA and long non-coding RNA. First discovered in the 1970s, m6A modification has been proposed to function in mRNA splicing, export, stability, and immune tolerance. Interest and excitement in m6A modification has recently been revived based on the discovery of a mammalian enzyme that removes m6A and the application of deep sequencing to localize modification sites. The m6A demethylase fat mass and obesity associated protein (FTO) controls cellular energy homeostasis and is the first enzyme discovered that reverses an RNA modification. m6A Sequencing demonstrates cell-type- and cell-state-dependent m6A patterns, indicating that m6A modifications are highly regulated. This review describes the current knowledge of mammalian m6A modifications and future perspectives on how to push the field forward. © 2012 Elsevier Ltd.

Nagylaki T.,University of Chicago
Theoretical Population Biology | Year: 2011

Partial panmixia can be regarded as the limiting case of long-distance migration. The effect of incorporating partial panmixia into neutral models of geographical variation is investigated. The monoecious, diploid population is subdivided into randomly mating colonies that exchange gametes independently of genotype. The gametes fuse wholly at random, including self-fertilization. Generations are discrete and nonoverlapping; the analysis is restricted to a single locus; every allele mutates to new alleles at the same rate. Introducing some panmixia intensifies sufficiently weak migration. A general formula is derived for the migration effective population number, Ne, and Ne is evaluated explicitly in a number of models with nonconservative migration. Usually, Ne increases as the panmictic rate, b, increases; in particular, this result holds for two demes, and generically if the underlying migration is either sufficiently weak or panmixia is sufficiently strong. However, in an analytic model, there exists an open set of parameters for which Ne decreases as b increases. Migration is conservative in the island and circular-habitat models, which are studied in detail. In the former, including some panmixia simply alters the underlying migration rate, increasing (decreasing) it if it is less (greater) than the panmictic value. For the circular habitat, the probability of identity in allelic state at equilibrium is calculated in a nonlocal, continuous-space, continuous-time approximation. In both models, by an efficient, general method, the expected homozygosity, effective number of alleles, and differentiation of gene frequencies are evaluated and discussed; their monotonicity properties with respect to all the parameters are determined; and in the model of infinitely many sites, the mean coalescence times and nucleotide diversities are studied similarly. For the probability of identity at equilibrium in the unbounded stepping-stone model in arbitrarily many dimensions, introducing some panmixia merely replaces the mutation rate by a larger parameter. If the average probability of identity is initially zero, as for identity by descent, then the same conclusion holds for all time. © 2010 Elsevier Inc.

Stephens M.,University of Chicago
PLoS ONE | Year: 2013

We consider the problem of assessing associations between multiple related outcome variables, and a single explanatory variable of interest. This problem arises in many settings, including genetic association studies, where the explanatory variable is genotype at a genetic variant. We outline a framework for conducting this type of analysis, based on Bayesian model comparison and model averaging for multivariate regressions. This framework unifies several common approaches to this problem, and includes both standard univariate and standard multivariate association tests as special cases. The framework also unifies the problems of testing for associations and explaining associations - that is, identifying which outcome variables are associated with genotype. This provides an alternative to the usual, but conceptually unsatisfying, approach of resorting to univariate tests when explaining and interpreting significant multivariate findings. The method is computationally tractable genome-wide for modest numbers of phenotypes (e.g. 5-10), and can be applied to summary data, without access to raw genotype and phenotype data. We illustrate the methods on both simulated examples, and to a genome-wide association study of blood lipid traits where we identify 18 potential novel genetic associations that were not identified by univariate analyses of the same data. © 2013 Matthew Stephens.

Gallicchio J.,University of Chicago | Friedman A.S.,Massachusetts Institute of Technology | Kaiser D.I.,Massachusetts Institute of Technology
Physical Review Letters | Year: 2014

We propose a practical scheme to use photons from causally disconnected cosmic sources to set the detectors in an experimental test of Bell's inequality. In current experiments, with settings determined by quantum random number generators, only a small amount of correlation between detector settings and local hidden variables, established less than a millisecond before each experiment, would suffice to mimic the predictions of quantum mechanics. By setting the detectors using pairs of quasars or patches of the cosmic microwave background, observed violations of Bell's inequality would require any such coordination to have existed for billions of years - an improvement of 20 orders of magnitude. © 2014 American Physical Society.

Batell B.,University of Chicago | Essig R.,State University of New York at Stony Brook | Surujon Z.,State University of New York at Stony Brook
Physical Review Letters | Year: 2014

We present new constraints on sub-GeV dark matter and dark photons from the electron beam-dump experiment E137 conducted at SLAC in 1980-1982. Dark matter interacting with electrons (e.g., via a dark photon) could have been produced in the electron-target collisions and scattered off electrons in the E137 detector, producing the striking, zero-background signature of a high-energy electromagnetic shower that points back to the beam dump. E137 probes new and significant ranges of parameter space and constrains the well-motivated possibility that dark photons that decay to light dark-sector particles can explain the ∼3.6σ discrepancy between the measured and standard model value of the muon anomalous magnetic moment. It also restricts the parameter space in which the relic density of dark matter in these models is obtained from thermal freeze-out. E137 also convincingly demonstrates that (cosmic) backgrounds can be controlled and thus serves as a powerful proof of principle for future beam-dump searches for sub-GeV dark-sector particles scattering off electrons in the detector. © 2014 American Physical Society.

Bramante J.,University of Notre Dame | Linden T.,University of Chicago
Physical Review Letters | Year: 2014

The paucity of old millisecond pulsars observed at the galactic center of the Milky Way could be the result of dark matter accumulating in and destroying neutron stars. In regions of high dark matter density, dark matter clumped in a pulsar can exceed the Schwarzschild limit and collapse into a natal black hole which destroys the pulsar. We examine what dark matter models are consistent with this hypothesis and find regions of parameter space where dark matter accumulation can significantly degrade the neutron star population within the galactic center while remaining consistent with observations of old millisecond pulsars in globular clusters and near the solar position. We identify what dark matter couplings and masses might cause a young pulsar at the galactic center to unexpectedly extinguish. Finally, we find that pulsar collapse age scales inversely with the dark matter density and linearly with the dark matter velocity dispersion. This implies that maximum pulsar age is spatially dependent on position within the dark matter halo of the Milky Way. In turn, this pulsar age spatial dependence will be dark matter model dependent. © 2014 American Physical Society.

Rowley D.B.,University of Chicago
Journal of Geology | Year: 2013

High-resolution digital elevation models of Earth's solid-fluid interface reveal that Earth's bimodal elevation distribution is characterized by a dominant mode at or very close to present-day sea level. It is hypothesized that sea level is Earth's dominant modal elevation because it is the only elevation where two opposing first-order surface processes- erosion and deposition-act to increase the area of a single elevation. The observation that sea level is the dominant elevation implies that (1) the time needed for the modal elevation to adjust is very short and/or (2) long-term (~106- 107 yr) mean sea level has not varied significantly from its present height. The mass of material that defines the sea level modal elevation is quite small, whether integrated over 1 or 100 m of thickness, and could be transported in!104 yr. This would suggest that the shoreline, at no matter what height relative to the present 0-m elevation, was probably always Earth's dominant elevation. However, Eurasia, North America, and Australia have dominant elevations near sea level, and their entire above-sea-level hypsometries appear to be graded to present-day sea level. In contrast, Africa and South America have dominant elevations significantly higher than sea level and appear to be graded to elevations significantly higher than sea level. The erosional adjustment time scale of continental hypsom-etries is 1107 yr. This would suggest that Eurasia, North America, and Australia have been graded to a height of sea level close to present-day 0 m on a time scale of at least one to a few times 107 yr. Reconstruction of a new global sea level curve for the past 150 m.yr. using areas of continental flooding as a function of time suggest that long-term sea level has been at or close to present-day sea level on a time scale of 40 m.yr. and was not more than ~150 m higher at any time in the past 150 m.yr. Given 106-107-yr time scales and modest amplitudes of sea level variability, it is perhaps not surprising that most continents are characterized by modern sea level as their dominant modal elevation. © 2013 by The University of Chicago.

Mathematical aspects of coverage and gaps in genome assembly have received substantial attention by bioinformaticians. Typical problems under consideration suppose that reads can be experimentally obtained from a single genome and that the number of reads will be set to cover a large percentage of that genome at a desired depth. In metagenomics experiments genomes from multiple species are simultaneously analyzed and obtaining large numbers of reads per genome is unlikely. We propose the probability of obtaining at least one contig of a desired minimum size from each novel genome in the pool without restriction based on depth of coverage as a metric for metagenomic experimental design. We derive an approximation to the distribution of maximum contig size for single genome assemblies using relatively few reads. This approximation is verified in simulation studies and applied to a number of different metagenomic experimental design problems, ranging in difficulty from detecting a single novel genome in a pool of known species to detecting each of a random number of novel genomes collectively sized and with abundances corresponding to given distributions in a single pool. © 2010 Stephen A. Stanhope.

Ross L.F.,University of Chicago
Perspectives in Biology and Medicine | Year: 2016

This article examines two typical bioethics frameworks: the “Four Principles” by Beauchamp and Childress, and the “Four Boxes” by Jonsen, Siegler, and Winslade. I show how they are inadequate to address the ethical issues raised by pediatrics, in part because they do not pay adequate attention to families. I then consider an alternate framework proposed by Buchanan and Brock that focuses on four questions that must be addressed for the patient who lacks decisional capacity. This model also does not give adequate respect for the family, particularly the intimate family. I then describe my own framework, which provides answers to Buchanan and Brock’s four questions in a way that is consistent with the intimate family and its need for protection from state intervention. © 2016 by Johns Hopkins University Press.

Eaton D.A.R.,University of Chicago
Bioinformatics | Year: 2014

Motivation: Restriction-site-associated genomic markers are a powerful tool for investigating evolutionary questions at the population level, but are limited in their utility at deeper phylogenetic scales where fewer orthologous loci are typically recovered across disparate taxa. While this limitation stems in part from mutations to restriction recognition sites that disrupt data generation, an additional source of data loss comes from the failure to identify homology during bioinformatic analyses. Clustering methods that allow for lower similarity thresholds and the inclusion of indel variation will perform better at assembling RADseq loci at the phylogenetic scale. Results: PyRAD is a pipeline to assemble de novo RADseq loci with the aim of optimizing coverage across phylogenetic datasets. It uses a wrapper around an alignment-clustering algorithm, which allows for indel variation within and between samples, as well as for incomplete overlap among reads (e.g. paired-end). Here I compare PyRAD with the program Stacks in their performance analyzing a simulated RADseq dataset that includes indel variation. Indels disrupt clustering of homologous loci in Stacks but not in PyRAD, such that the latter recovers more shared loci across disparate taxa. I show through reanalysis of an empirical RADseq dataset that indels are a common feature of such data, even at shallow phylogenetic scales. PyRAD uses parallel processing as well as an optional hierarchical clustering method, which allows it to rapidly assemble phylogenetic datasets with hundreds of sampled individuals. © The Author 2014.

Kessner D.,University of California at Los Angeles | Novembre J.,University of Chicago
Bioinformatics | Year: 2014

Summary: forqs is a forward-in-time simulation of recombination, quantitative traits and selection. It was designed to investigate haplotype patterns resulting from scenarios where substantial evolutionary change has taken place in a small number of generations due to recombination and/or selection on polygenic quantitative traits.Availability and implementation: forqs is implemented as a command-line C++ program. Source code and binary executables for Linux, OSX and Windows are freely available under a permissive BSD license: https://bitbucket.org/dkessner/forqs.Contact: Supplementary information: Supplementary data are available at Bioinformatics online. © 2013 The Author.

McPeek M.S.,University of Chicago
Journal of Computational Biology | Year: 2012

We consider the problem of case-control association testing in samples that contain related individuals, where we assume the pedigree structure is known. Typically, for each marker tested, some individuals will have missing genotype data. The MQLS method has been proposed for association testing in this situation. We show that the MQLS method is equivalent to an approach in which missing genotypes are imputed using the best linear unbiased predictor (BLUP) based on relatives' genotype data. Viewed this way, the MQLS exactly corrects for the imputation error and for the extra correlation due to imputation. We also investigate the amount of additional power for detecting association that is provided by this BLUP imputation approach. © 2012, Mary Ann Liebert, Inc.

Zacny J.P.,University of Chicago
Pharmacology Biochemistry and Behavior | Year: 2010

Sensation-seeking is a personality trait that is linked to use and abuse of drugs. Laboratory studies have established that high sensation seekers, as measured by different instruments, are more likely to report abuse liability-related subjective effects from drugs such as nicotine, alcohol, and d-amphetamine than low sensation seekers. One class of drugs that has not been studied to date in this fashion is opioids. Accordingly, a retrospective analysis encompassing five studies that examined oxycodone effects, including its abuse liability-related effects, was conducted in subjects categorized as high or low sensation seekers. In addition, because there appear to be sex differences in how males and females respond to opioids, this factor was taken into account in the analysis. Seventy one subjects who scored on the lower end (15 and 19 low sensation-seeking males and females, respectively) or the higher end (23 and 14 high sensation-seeking males and females) of the Disinhibition subscale of the Sensation-Seeking Scale-Form V were studied for their responses to 0, 10, and 20 mg of oral oxycodone. Ratings of "pleasant bodily sensations" were significantly higher after oxycodone administration than placebo only in male and female high sensation seekers. Ratings of "take again," "drug liking," "carefree," and "elated (very happy)" also tended to differentiate high from low sensation seekers although Group. × Dose interactions were only marginally significant with the latter three ratings. Male and female low sensation seekers and female high sensation seekers reported dysphoric effects (e.g., ratings of nauseated) particularly after administration of the 20 mg oxycodone dose. The results of this analysis provide suggestive evidence that high sensation seekers are more likely to experience greater positive subjective effects from oxycodone than low sensation seekers, but likelihood of experiencing negative effects is more complex (involving both sensation-seeking status and sex). © 2010 Elsevier Inc.

Prabhakar N.R.,University of Chicago
Respiratory Physiology and Neurobiology | Year: 2012

Carotid bodies are sensory organs for monitoring arterial blood oxygen (O2) levels, and the ensuing reflexes maintain cardio-respiratory homeostasis during hypoxia. This article provides a brief update of the role of carbon monoxide (CO) and hydrogen sulfide (H2S) in hypoxic sensing by the carotid body. Glomus cells, the primary site of O2 sensing in the carotid body express heme oxygenase-2 (HO-2), a CO catalyzing enzyme. HO-2 is a heme containing enzyme and has high affinity for O2. Hypoxia inhibits HO-2 activity and reduces CO generation. Pharmacological and genetic approaches suggest that CO inhibits carotid body sensory activity. Stimulation of carotid body activity by hypoxia may reflect reduced formation of CO. Glomus cells also express cystathionine γ-lyase (CSE), an H2S generating enzyme. Exogenous application of H2S donors, like hypoxia, stimulate the carotid body activity and CSE knockout mice exhibit severely impaired sensory excitation by hypoxia, suggesting that CSE catalyzed H2S is an excitatory gas messenger. Hypoxia increases H2S generation in the carotid body, and this response was attenuated or absent in CSE knockout mice. HO inhibitor increased and CO donor inhibited H2S generation. It is proposed that carotid body response to hypoxia requires interactions between HO-2-CO and CSE-H2S systems. © 2012 Elsevier B.V.

Marsano J.,University of Chicago
Physical Review Letters | Year: 2011

We sharpen constraints related to hypercharge flux in F-theory grand unified theories that possess U(1) symmetries and argue that they arise as a consequence of four-dimensional anomaly cancellation. This gives a physical explanation for all restrictions that were observed in spectral cover models while demonstrating that the phenomenological implications for a well-motivated set of models are not tied to any particular formalism. © 2011 American Physical Society.

Shapiro J.A.,University of Chicago
Progress in Biophysics and Molecular Biology | Year: 2013

This paper will discuss the philosophical background to evolutionary theory and present multiple counterfactuals to each of the following seven empirically unsustainable but nonetheless widespread assumptions about genomic (DNA-based) evolution:. 1. " All heredity transmission occurs from parent to progeny" . 2. " Mutations are the result of inevitable replication errors" . 3. " Mutations occur at constant low probabilities over time" (= there are " mutation rates"). 4. " Virus infection cannot induce genetic changes giving heritable resistance" . 5. " Mutations cannot be targeted within the genome" . 6. " Spontaneous hereditary changes are localized and limited to those of small effect" . 7. " Cells cannot integrate DNA change with biologically useful adaptive needs" .The summary take-home lesson is that we have to change from thinking of the genome as a read-only memory (ROM) that dictates the fate of the cell or organism to conceptualizing the genome as a read-write (RW) organelle modified transiently or permanently by the cell at different time scales. © 2012 Elsevier Ltd.

Mulmuley K.D.,University of Chicago
Communications of the ACM | Year: 2012

Geometric complexity theory (GCT) is an approach via algebraic geometry and representation theory toward the P vs. NP and related problems. It was proposed in a series of papers and was developed further in Bürgisser and Ikenmeyer, Bürgisser et al. and Landsberg et al. This article gives an informal overview of GCT. It is meant to be an update on the status of the P vs. NP problem reported in Fortnow.11 See Mulmuley for a more detailed, formal overview of GCT. Let us begin by recalling an algebraic variant of the P vs. NP problem introduced in a seminal paper. It can be formulated in a very concrete form as the permanent vs. determinant problem. Here the permanent of an n × n variable matrix X is defined just like the determinant but without signs. © 2012 ACM.

McCann A.,University of Chicago
Astrophysical Journal | Year: 2015

Due to the low gamma-ray fluxes from pulsars above 50 GeV and the small collecting area of space-based telescopes, the gamma-ray emission discovered by the Fermi Large Area Telescope (LAT) in ∼150 pulsars is largely unexplored at these energies. In this regime, the uncertainties on the spectral data points and/or the constraints from upper limits are not sufficient to provide robust tests of competing emission models in individual pulsars. The discovery of power-law-type emission from the Crab pulsar at energies exceeding 100 GeV provides a compelling justification for exploration of other pulsars at these energies. We applied the method of aperture photometry to measure pulsar emission spectra from Fermi-LAT data and present a stacked analysis of 115 pulsars selected from the Second Fermi-LAT catalog of gamma-ray pulsars. This analysis, which uses an average of ∼4.2 yr of data per pulsar, aggregates low-level emission which cannot be resolved in individual objects but can be detected in an ensemble. We find no significant stacked excess at energies above 50 GeV. An upper limit of 30% of the Crab pulsar level is found for the average flux from 115 pulsars in the 100-177 GeV energy range at the 95% confidence level. Stacked searches exclusive to the young pulsar sample, the millisecond pulsar sample, and several other promising sub-samples also return no significant excesses above 50 GeV. © 2015. The American Astronomical Society. All rights reserved..

Among sexually reproducing species, differences between the sexes within species are ubiquitous. Despite the clear effect of sex differences on sex ratios and population growth rates, demographic models rarely consider both sexes explicitly. Here I explore the causes of extreme female-biased sex ratios in two marine angiosperms (Phyllospadix spp.). Using demographic data, I develop twosex matrix projection models to assess the magnitude of demographic differences necessary to generate observed sex ratios and the consequences of sex differences for population growth rates. I demonstrate that small sex differences in survival can generate biased sex ratios, but the importance of sexual reproduction differs markedly between species. Even in the absence of a direct trade-off between sexual and asexual reproduction, the presence of two reproductive modes affects both the importance of sex and the sex-ratio bias. Using sensitivity analyses, I quantify the contribution of shared and sex-specific vital rates and show that until males become rare, the sensitivity of sex-specific vital rates is small relative to that of shared vital rates. I demonstrate that placing sex differences in the context of a demographic model that includes biologically motivated lifehistory trade-offs can explain the maintenance of sex-specific life histories and the persistence of skewed sex ratios. © 2010 by The University of Chicago.

Fang H.,University of Southern California | Fang H.,University of Chicago | DeClerck Y.A.,University of Southern California | DeClerck Y.A.,Saban Research Institute
Cancer Research | Year: 2013

It is clear that tumor cells do not act alone but in close interaction with the extracellular matrix and with stromal cells in the tumor microenvironment (TME). As our understanding of tumor cell-stroma interactions increased over the last two decades, significant efforts have been made to develop agents that interfere with these interactions. Here, we discuss four different therapeutic strategies that target the TME, focusing on agents that are at the most advanced stage of preclinical or clinical development. We end this review by outlining some of the lessons we have learned so far from the development of TME-targeting agents. © 2013 American Association for Cancer Research.

Jeevanandam V.,University of Chicago
Seminars in Thoracic and Cardiovascular Surgery | Year: 2012

Left ventricular assist devices improve survival for New York Heart Association class IV patients as both destination therapy and bridge-to-transplant therapy. This clinical benefit has been demonstrated in multiple clinical trials whose medical comparator arm consists of patients with very poor survival. This article discusses the potential use of left ventricular assist devices in a less sick group of patients with end-stage congestive heart failure. © 2012 Elsevier Inc.

Rappazzo A.F.,University of Delaware | Parker E.N.,University of Chicago
Astrophysical Journal Letters | Year: 2013

We investigate the dynamical evolution of magnetic fields in closed regions of solar and stellar coronae. To understand under which conditions current sheets form, we examine dissipative and ideal reduced magnetohydrodynamic models in Cartesian geometry, where two magnetic field components are present: the strong guide field B 0, extended along the axial direction, and the dynamical orthogonal field b. Magnetic field lines thread the system along the axial direction that spans the length L and are line-tied at the top and bottom plates. The magnetic field b initially has only large scales, with its gradient (current) length scale of the order of ℓb . We identify the magnetic intensity threshold b/B 0 ∼ ℓb /L. For values of b below this threshold, field-line tension inhibits the formation of current sheets, while above the threshold they form quickly on fast ideal timescales. In the ideal case, above the magnetic threshold, we show that current sheets thickness decreases in time until it becomes smaller than the grid resolution, with the analyticity strip width δ decreasing at least exponentially, after which the simulations become underresolved. © 2013. The American Astronomical Society. All rights reserved.

Moffat K.,University of Chicago
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2014

Time-resolved X-ray crystallography and solution scattering have been successfully conducted on proteins on time-scales down to around 100 ps, set by the duration of the hard X-ray pulses emitted by synchrotron sources. The advent of hard X-ray free-electron lasers (FELs), which emit extremely intense, very brief, coherent X-ray pulses, opens the exciting possibility of time-resolved experiments with femtosecond time resolution on macromolecular structure, in both single crystals and solution. The X-ray pulses emitted by an FEL differ greatly in many properties from those emitted by a synchrotron, in ways that at first glance make time-resolved measurements of X-ray scattering with the required accuracy extremely challenging. This opens up several questions which I consider in this brief overview. Are there likely to be chemically and biologically interesting structural changes to be revealed on the femtosecond time-scale? How shall time-resolved experiments best be designed and conducted to exploit the properties of FELs and overcome challenges that they pose? To date, fast time-resolved reactions have been initiated by a brief laser pulse, which obviously requires that the system under study be light-sensitive. Although this is true for proteins of the visual system and for signalling photoreceptors, it is not naturally the case for most interesting biological systems. To generate more biological targets for time-resolved study, can this limitation be overcome by optogenetic, chemical or other means? © 2014 The Author(s) Published by the Royal Society. All rights reserved.

Sosnick T.R.,University of Chicago | Barrick D.,Johns Hopkins University
Current Opinion in Structural Biology | Year: 2011

Rather than stressing the most recent advances in the field, this review highlights the fundamental topics where disagreement remains and where adequate experimental data are lacking. These topics include properties of the denatured state and the role of residual structure, the nature of the fundamental steps and barriers, the extent of pathway heterogeneity and non-native interactions, recent comparisons between theory and experiment, and finally, dynamical properties of the folding reaction. © 2010 Elsevier Ltd.

Grant J.E.,University of Chicago
New England Journal of Medicine | Year: 2014

A 19-year-old man is brought to his primary physician by his father, who explains that his son washes his hands a hundred times a day, will not touch anything that has been touched by someone else without scrubbing it first, and has a fear of germs that has left him isolated in his bedroom, unable to eat, and wishing he were dead. Although the father reports that his son has always been finicky, this problem started approximately 2 years ago and has gradually become completely disabling. How should this patient be evaluated and treated? Copyright © 2014 Massachusetts Medical Society.

Lewis J.C.,University of Chicago | Coelho P.S.,California Institute of Technology | Arnold F.H.,California Institute of Technology
Chemical Society Reviews | Year: 2011

The development of new catalytic methods to functionalize carbon-hydrogen (C-H) bonds continues to progress at a rapid pace due to the significant economic and environmental benefits of these transformations over traditional synthetic methods. In nature, enzymes catalyze regio- and stereoselective C-H bond functionalization using transformations ranging from hydroxylation to hydroalkylation under ambient reaction conditions. The efficiency of these enzymes relative to analogous chemical processes has led to their increased use as biocatalysts in preparative and industrial applications. Furthermore, unlike small molecule catalysts, enzymes can be systematically optimized via directed evolution for a particular application and can be expressed in vivo to augment the biosynthetic capability of living organisms. While a variety of technical challenges must still be overcome for practical application of many enzymes for C-H bond functionalization, continued research on natural enzymes and on novel artificial metalloenzymes will lead to improved synthetic processes for efficient synthesis of complex molecules. In this critical review, we discuss the most prevalent mechanistic strategies used by enzymes to functionalize non-acidic C-H bonds, the application and evolution of these enzymes for chemical synthesis, and a number of potential biosynthetic capabilities uniquely enabled by these powerful catalysts (110 references). © 2011 The Royal Society of Chemistry.

Sanders K.,University of Chicago
Classical and Quantum Gravity | Year: 2013

When studying the causal propagation of a field φ in a globally hyperbolic spacetime M, one often wants to express the physical intuition that φ has compact support in spacelike directions, or that its support is a spacelike compact set. We compare a number of logically distinct formulations of this idea, and of the complementary idea of timelike compactness, and we clarify their interrelations. E.g., a closed set A⊂M has a compact intersection with all Cauchy surfaces if and only if A⊂J(K) for some compact set K. (However, it does not suffice to consider only those Cauchy surfaces that partake in a given foliation of M.) Similarly, a closed set A⊂M is contained in a region of the form J+(Σ-)∩J -(Σ+) for two Cauchy surfaces Σ ± if and only if the intersection of A with J(K) is compact for all compact K. We also treat advanced, retarded and future and past compact sets in a similar way. © 2013 IOP Publishing Ltd.

Fang K.,University of Chicago
Journal of Cosmology and Astroparticle Physics | Year: 2015

Charged particles can be accelerated to higher than PeV energies in the electro-magnetic wind of a fast-spinning newborn pulsar to produce high-energy neutrinos, through hadronuclear interactions in the supernova remnant. Here we explore the detectability and observational signatures of these high-energy neutrinos. We show that their spectral index varies approximately from 1.5 to 2, depending on the relevant pulsar properties and observation time. We also apply the scenario to existing young pulsars in the local universe and find the corresponding neutrino flux well below current detection limits. Finally, we estimate the birth rate of fast-spinning pulsars in the local Universe that can be observed by the IceCube observatory to be 0.07 per year, with an upper limit of 0.29 per year. © 2015 IOP Publishing Ltd and Sissa Medialab srl .

Ciesla F.J.,University of Chicago
Astrophysical Journal | Year: 2010

The chemical and physical evolution of primitive materials in protoplanetary disks are determined by the types of environments they are exposed to and their residence times within each environment. Here, a method for calculating representative paths of materials in diffusive protoplanetary disks is developed and applied to understanding how the vertical trajectories that particles take impact their overall evolution. The methods are general enough to be applied to disks with uniform diffusivity, the so-called constant-α cases, and disks with a spatially varying diffusivity, such as expected in "layered-disks." The average long-term dynamical evolution of small particles and gaseous molecules is independent of the specific form of the diffusivity in that they spend comparable fractions of their lifetimes at different heights in the disk. However, the paths that individual particles and molecules take depend strongly on the form of the diffusivity leading to a different range of behavior of particles in terms of deviations from the mean. As temperatures, gas densities, chemical abundances, and photon fluxes will vary with height in protoplanetary disks, the different paths taken by primitive materials will lead to differences in their chemical and physical evolution. Examples of differences in gas phase chemistry and photochemistry are explored here. The methods outlined here provide a powerful tool that can be integrated with chemical models to understand the formation and evolution of primitive materials in protoplanetary disks on timescales of 105-106 years. © 2010. The American Astronomical Society.

Couch S.M.,University of Chicago
Astrophysical Journal | Year: 2013

We present one-dimensional (1D), two-dimensional (2D), and three-dimensional (3D) hydrodynamical simulations of core-collapse supernovae including a parameterized neutrino heating and cooling scheme in order to investigate the critical core neutrino luminosity (L crit) required for explosion. In contrast to some previous works, we find that 3D simulations explode later than 2D simulations, and that L crit at fixed mass accretion rate is somewhat higher in three dimensions than in two dimensions. We find, however, that in two dimensions L crit increases as the numerical resolution of the simulation increases. In contrast to some previous works, we argue that the average entropy of the gain region is in fact not a good indicator of explosion but is rather a reflection of the greater mass in the gain region in two dimensions. We compare our simulations to semi-analytic explosion criteria and examine the nature of the convective motions in two dimensions and three dimensions. We discuss the balance between neutrino-driven buoyancy and drag forces. In particular, we show that the drag force will be proportional to a buoyant plume's surface area while the buoyant force is proportional to a plume's volume and, therefore, plumes with greater volume-to-surface-area ratios will rise more quickly. We show that buoyant plumes in two dimensions are inherently larger, with greater volume-to-surface-area ratios, than plumes in three dimensions. In the scenario that the supernova shock expansion is dominated by neutrino-driven buoyancy, this balance between buoyancy and drag forces may explain why 3D simulations explode later than 2D simulations and why L crit increases with resolution. Finally, we provide a comparison of our results with other calculations in the literature. © 2013. The American Astronomical Society. All rights reserved.

Devkota S.,Harvard University | Chang E.B.,University of Chicago
Current Opinion in Gastroenterology | Year: 2013

Purpose of Review: To present and evaluate the recent findings that contribute to our understanding of the functional impact of diet on the enteric microbiome and outcomes of disease. Recent Findings: Nutrients in excess and in deficiency have significant impact on gut microbial communities in both rodents and humans, acting directly on the microbiota or indirectly via altering host physiology. Furthermore, the effects of diet on the microbiome in determining health or disease can differ substantially depending on the age and environment of the individual. Summary: Dietary compounds can have profound short-term and long-term effects on the assemblage of the gut microbiome, which in turn affects the host-microbe interactions critically important for intestinal, metabolic, and immune homeostasis. Until recently, the mechanisms underlying these effects were poorly understood. However, new insights have now been gained, made possible through the application of advanced technologies and bioinformatics, novel experimental models, and human research. As a result, our conceptual framework for understanding the impact of diet on the gut microbiome, health, and disease has advanced considerably, bringing the promise of better tools of risk assessment, diagnostics, and therapeutic intervention in an age of personalized medicine. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Couch S.M.,University of Chicago | Ott C.D.,California Institute of Technology | Ott C.D.,University of Tokyo
Astrophysical Journal Letters | Year: 2013

Multi-dimensional simulations of advanced nuclear burning stages of massive stars suggest that the Si/O layers of presupernova stars harbor large deviations from the spherical symmetry typically assumed for presupernova stellar structure. We carry out three-dimensional core-collapse supernova simulations with and without aspherical velocity perturbations to assess their potential impact on the supernova hydrodynamics in the stalled-shock phase. Our results show that realistic perturbations can qualitatively alter the postbounce evolution, triggering an explosion in a model that fails to explode without them. This finding underlines the need for a multi-dimensional treatment of the presupernova stage of stellar evolution. © 2013. The American Astronomical Society. All rights reserved..

Hooper D.,Fermi National Accelerator Laboratory | Hooper D.,University of Chicago | Slatyer T.R.,Institute for Advanced Study
Physics of the Dark Universe | Year: 2013

We study the variation of the spectrum of the Fermi Bubbles with Galactic latitude. Far from the Galactic plane (|b| ≳ 30°), the observed gamma-ray emission is nearly invariant with latitude, and is consistent with arising from inverse Compton scattering of the interstellar radiation field by cosmic-ray electrons with an approximately power-law spectrum. The same electrons in the presence of microgauss-scale magnetic fields can also generate the the observed microwave "haze". At lower latitudes (|b| ≲ 20°), in contrast, the spectrum of the emission correlated with the Bubbles possesses a pronounced spectral feature peaking at ~1-4GeV (in E2dN/dE) which cannot be generated by any realistic spectrum of electrons. Instead, we conclude that a second (non-inverse-Compton) emission mechanism must be responsible for the bulk of the low-energy, low-latitude emission. This second component is spectrally similar to the excess GeV emission previously reported from the Galactic Center (GC), and also appears spatially consistent with a luminosity per volume falling approximately as r-2.4, where r is the distance from the GC. Consequently, we argue that the spectral feature visible in the low-latitude Bubbles is most likely the extended counterpart of the GC excess, now detected out to at least ~2-3 kpc from the GC. The spectrum and angular distribution of the signal is broadly consistent with that predicted from ~10GeV dark matter particles annihilating to leptons, or from ~50GeV dark matter particles annihilating to quarks, following a distribution similar to, but slightly steeper than, the canonical Navarro-Frenk-White (NFW) profile. We also consider millisecond pulsars as a possible astrophysical explanation for the signal, as observed millisecond pulsars possess a spectral cutoff at approximately the required energy. Any such scenario would require a large population of unresolved millisecond pulsars extending at least 2-3 kpc from the GC. © 2013 The Authors.

Kay L.M.,University of Chicago
Current Opinion in Neurobiology | Year: 2015

Neural oscillations are ubiquitous in olfactory systems of mammals, insects and molluscs. Neurophysiological and computational investigations point to common mechanisms for gamma or odor associated oscillations across phyla (40-100. Hz in mammals, 20-30. Hz in insects, 0.5-1.5. Hz in molluscs), engaging the reciprocal dendrodendritic synapse between excitatory principle neurons and inhibitory interneurons in the olfactory bulb (OB), antennal lobe (AL), or procerebrum (PrC). Recent studies suggest important mechanisms that may modulate gamma oscillations, including neuromodulators and centrifugal input to the OB and AL. Beta (20. Hz) and theta (2-12. Hz) oscillations coordinate activity within and across brain regions. Olfactory beta oscillations are associated with odor learning and depend on centrifugal OB input, while theta oscillations are strongly associated with respiration. © 2014.

Baroody F.M.,University of Chicago
Proceedings of the American Thoracic Society | Year: 2011

The nose is an integral part of the upper airway and the first contact of the body with inspired air. It is located in close proximity to several related airway structures that include the ears, paranasal sinuses,andeyes. It is also closely linked to the lower airway. Multiple lines of evidence support a close interaction and influence of the nose on these contiguous and distant organs via neural reflexes and systemic inflammatory processes. These interactions are reviewed in light of existing evidence.

Prabhakar N.R.,University of Chicago
Respiratory Physiology and Neurobiology | Year: 2011

Recent studies have shown that acute intermittent hypoxia (IH) induces sensory plasticity of the carotid body manifested as sensory long-term facilitation (LTF), which requires prior conditioning with chronic IH and is mediated by reactive oxygen species (ROS). The purpose of this article is to provide a brief review of chronic IH-induced sensory LTF of the carotid body, sources of ROS, mechanisms underlying sensory LTF and its functional significance. Development of sensory LTF requires conditioning with several days of chronic IH. It is completely reversible following re-oxygenation, does not depend on the severity of hypoxia used for IH conditioning, not species specific and is selectively evoked by acute repetitive hypoxia but not by repetitive hypercapnia. Sensory LTF is not associated morphological changes in the carotid body and is expressed in chronic IH treated adult but not in neonatal rat carotid bodies. Chronic IH increases ROS levels in the carotid body involving 5-HT mediated activation of NADPH oxidase-2 (NOX2) and subsequent inhibition of the mitochondrial complex I. Sensory LTF can be prevented by inhibitors of 5-HT receptors, NOX inhibitors as well as by anti-oxidants. The signaling pathways mediating the sensory LTF are summarized in the second figure. It is suggested that sensory LTF contributes to the persistent sympathetic excitation under chronic IH. © 2011 Elsevier B.V.

Zakrzewski J.L.,Sloan Kettering Cancer Center | Van Den Brink M.R.M.,Sloan Kettering Cancer Center | Hubbell J.A.,Institute of Bioengineering | Hubbell J.A.,University of Chicago
Nature Biotechnology | Year: 2014

Regenerative therapies that use allogeneic cells are likely to encounter immunological barriers similar to those that occur with transplantation of solid organs and allogeneic hematopoietic stem cells (HSCs). Decades of experience in clinical transplantation hold valuable lessons for regenerative medicine, offering approaches for developing tolerance-induction treatments relevant to cell therapies. Outside the field of solid-organ and allogeneic HSC transplantation, new strategies are emerging for controlling the immune response, such as methods based on biomaterials or mimicry of antigen-specific peripheral tolerance. Novel biomaterials can alter the behavior of cells in tissue-engineered constructs and can blunt host immune responses to cells and biomaterial scaffolds. Approaches to suppress autoreactive immune cells may also be useful in regenerative medicine. The most innovative solutions will be developed through closer collaboration among stem cell biologists, transplantation immunologists and materials scientists. © 2014 Nature America, Inc.

Collar J.I.,University of Chicago
Physical Review C - Nuclear Physics | Year: 2013

A new experimental evaluation of the quenching factor for nuclear recoils in NaI[Tl] is described. Systematics affecting previous measurements are addressed by careful characterization of the emission spectrum of the neutron source, use of a small scintillator coupled to an ultra-bialkali high-quantum-efficiency photomultiplier, and evaluation of nonlinearities in the electron recoil response via Compton scattering. A trend towards a rapidly diminishing quenching factor with decreasing sodium recoil energy is revealed. Additionally, no evidence for crystal lattice channeling of low-energy recoiling ions is found in a scintillator of known crystallographic orientation. A discussion on how these findings affect dark matter searches employing NaI[Tl] (e.g., DAMA/LIBRA) is offered. © 2013 American Physical Society.

Minsky B.D.,University of Chicago
Seminars in Oncology | Year: 2011

In the past two decades, substantial progress has been made in the adjuvant management of colorectal cancer. Chemotherapy has improved overall survival in patients with node-positive (N+) disease. In contrast with colon cancer, which has a low incidence of local recurrence, patients with rectal cancer have a higher incidence requiring the addition of pelvic radiation therapy (chemoradiation). Patients with rectal cancer have a number of unique management considerations: for example, the role of short-course radiation, whether postoperative adjuvant chemotherapy is necessary for all patients, and if the type of surgery following chemoradiation should be based on the response rate. More accurate imaging techniques and/or molecular markers may help identify patients with positive pelvic nodes to reduce the chance of overtreatment with preoperative therapy. Will more effective systemic agents both improve the results of radiation as well as modify the need for pelvic radiation? This review will address these and other controversies specific to patients with rectal cancer. © 2011 Elsevier Inc. All rights reserved.

Bapst D.W.,University of Chicago
PLoS ONE | Year: 2013

Morphology-based phylogenetic analyses are the only option for reconstructing relationships among extinct lineages, but often find support for conflicting hypotheses of relationships. The resulting lack of phylogenetic resolution is generally explained in terms of data quality and methodological issues, such as character selection. A previous suggestion is that sampling ancestral morphotaxa or sampling multiple taxa descended from a long-lived, unchanging lineage can also yield clades which have no opportunity to share synapomorphies. This lack of character information leads to a lack of 'intrinsic' resolution, an issue that cannot be solved with additional morphological data. It is unclear how often we should expect clades to be intrinsically resolvable in realistic circumstances, as intrinsic resolution must increase as taxonomic sampling decreases. Using branching simulations, I quantify intrinsic resolution across several models of morphological differentiation and taxonomic sampling. Intrinsically unresolvable clades are found to be relatively frequent in simulations of both extinct and living taxa under realistic sampling scenarios, implying that intrinsic resolution is an issue for morphology-based analyses of phylogeny. Simulations which vary the rates of sampling and differentiation were tested for their agreement to observed distributions of durations from well-sampled fossil records and also having high intrinsic resolution. This combination only occurs in those datasets when differentiation and sampling rates are both unrealistically high relative to branching and extinction rates. Thus, the poor phylogenetic resolution occasionally observed in morphological phylogenetics may result from a lack of intrinsic resolvability within groups. © 2013 David Bapst.

Matlin K.S.,University of Chicago
Nature Reviews Molecular Cell Biology | Year: 2011

The signal hypothesis, formulated by Günter Blobel and David Sabatini in 1971, and elaborated by Blobel and his colleagues between 1975 and 1980, fundamentally expanded our view of cells by introducing the concept of topogenic signals. Cells were no longer just morphological entities with compartmentalized biochemical functions; they were now active participants in the creation and perpetuation of their own form and identity, the decoders of linear genetic information into three dimensions. © 2011 Macmillan Publishers Limited. All rights reserved.

Benartzi S.,University of California at Los Angeles | Benartzi S.,Global Finance | Thaler R.H.,University of Chicago
Science | Year: 2013

Behavioral economics can be scaled up to have a major, positive impact on certain behaviors, such as retirement savings.

Decety J.,University of Chicago
Annals of the New York Academy of Sciences | Year: 2011

There is strong evidence that empathy has deep evolutionary, biochemical, and neurological underpinnings. Even the most advanced forms of empathy in humans are built on more basic forms and remain connected to core mechanisms associated with affective communication, social attachment, and parental care. Social neuroscience has begun to examine the neurobiological mechanisms that instantiate empathy, especially in response to signals of distress and pain, and how certain dispositional and contextual moderators modulate its experience. Functional neuroimaging studies document a circuit that responds to the perception of others' distress. Activation of this circuit reflects an aversive response in the observer, and this information may act as a trigger to inhibit aggression or prompt motivation to help. Moreover, empathy in humans is assisted by other domain-general high-level cognitive abilities, such as executive functions, mentalizing, and language, which expand the range of behaviors that can be driven by empathy. © 2011 New York Academy of Sciences.

Allesina S.,University of Chicago
PLoS ONE | Year: 2011

Nepotistic practices are detrimental for academia. Here I show how disciplines with a high likelihood of nepotism can be detected using standard statistical techniques based on shared last names among professors. As an example, I analyze the set of all 61,340 Italian academics. I find that nepotism is prominent in Italy, with particular disciplinary sectors being detected as especially problematic. Out of 28 disciplines, 9 - accounting for more than half of Italian professors - display a significant paucity of last names. Moreover, in most disciplines a clear north-south trend emerges, with likelihood of nepotism increasing with latitude. Even accounting for the geographic clustering of last names, I find that for many disciplines the probability of name-sharing is boosted when professors work in the same institution or sub-discipline. Using these techniques policy makers can target cuts and funding in order to promote fair practices. © 2011 Stefano Allesina.

Kent S.B.H.,University of Chicago
Angewandte Chemie - International Edition | Year: 2013

Erythropoietin, commonly known as EPO, is a glycoprotein hormone that stimulates the production of red blood cells. Recombinant EPO has been described as "arguably the most successful drug spawned by the revolution in recombinant DNA technology". Recently, the EPO glycoprotein molecule has re-emerged as a major target of synthetic organic chemistry. In this article I will give an account of an important body of earlier work on the chemical synthesis of a designed EPO analogue that had full biological activity and improved pharmacokinetic properties. The design and synthesis of this "synthetic erythropoiesis protein" was ahead of its time, but has gained new relevance in recent months. Here I will document the story of one of the major accomplishments of synthetic chemistry in a more complete way than is possible in the primary literature, and put the work in its contemporaneous context. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Angelos P.,University of Chicago
American Journal of Surgery | Year: 2014

Surgical ethics as a specific discipline is relatively new to many. Surgical ethics focuses on the ethical issues that are particularly important to the care of surgical patients. Informed consent for surgical procedures, the level of responsibility that surgeons feel for their patients' outcomes, and the management of surgical innovation are specific issues that are important in surgical ethics and are different from other areas of medicine. The future of surgical progress is dependent on surgical innovation, yet the nature of surgical innovation raises specific concerns that challenge the professionalism of surgeons. These concerns will be considered in the following pages. © 2014 Elsevier Inc.All rights reserved.

Storb U.,University of Chicago
Advances in Immunology | Year: 2014

In this review, I discuss the currently available experimental evidence concerning the molecular interactions of the activation-induced cytidine deaminase (AID) with transcription of its target genes. The basic question that underlies the transcription relationship is how the process of somatic hypermutation of Ig genes can be restricted to their variable (V) regions. This hallmark of SHM assures that high affinity antibodies can be created while the biological functions of their constant (C) region are undisturbed. I present a revised model of AID function in somatic hypermutation (SHM): In a B cell that produces AID protein and undergoes mutation of the V regions of the expressed Ig heavy and light chain genes, only some of the transcription complexes initiating at the active V-region promoters are associated with AID. When AID travels with the elongating RNA polymerase (pol), it attracts proteins that cause the pausing/stalling of pol and termination of transcription, followed by termination of SHM. This differential AID loading model would allow the mutating B cell to continue producing full-length Ig proteins that are required to avoid apoptosis by permitting the cell to assemble functional B cell receptors. © 2014 Elsevier Inc.

Nagylaki T.,University of Chicago
Theoretical Population Biology | Year: 2012

In spatially distributed populations, global panmixia can be regarded as the limiting case of long-distance migration. The effect of incorporating partial panmixia into single-locus clines maintained by migration and selection is investigated. In a diallelic, two-deme model without dominance, partial panmixia can increase or decrease both the polymorphic area in the plane of the migration rates and the equilibrium gene-frequency difference between the two demes. For multiple alleles, under the assumptions that the number of demes is large and both migration and selection are arbitrary but weak, a system of integro-partial differential equations is derived. For two alleles with conservative migration, (i) a Lyapunov functional is found, suggesting generic global convergence of the gene frequency; (ii) conditions for the stability or instability of the fixation states, and hence for a protected polymorphism, are obtained; and (iii) a variational representation of the minimal selection-migration ratio λ0 (the principal eigenvalue of the linearized system) for protection from loss is used to prove that λ0 is an increasing function of the panmictic rate and to deduce the effect on λ0 of changes in selection and migration. The unidimensional step-environment with uniform population density, homogeneous, isotropic migration, and no dominance is examined in detail: An explicit characteristic equation is derived for λ0; bounds on λ0 are established; and λ0 is approximated in four limiting cases. An explicit formula is also deduced for the globally asymptotically stable cline in an unbounded habitat with a symmetric environment; partial panmixia maintains some polymorphism even as the distance from the center of the cline tends to infinity. © 2011 Elsevier Inc.

Glick B.S.,University of Chicago
BioEssays | Year: 2014

COPII coated vesicles bud from an ER domain termed the transitional ER (tER), but the mechanism that clusters COPII vesicles at tER sites is unknown. tER sites are closely associated with early Golgi or pre-Golgi structures, suggesting that the clustering of nascent COPII vesicles could be achieved by tethering to adjacent membranes. This model challenges the prevailing view that COPII vesicles are clustered by a scaffolding protein at the ER surface. Although Sec16 was proposed to serve as such a scaffolding protein, recent data suggest that rather than organizing COPII into higher-order structures, Sec16 acts at the level of individual COPII vesicles to regulate COPII turnover. A plausible synthesis is that tER sites are created by tethering to Golgi membranes and are regulated by Sec16. Meanwhile, the COPII vesicles that bud from tER sites are thought to nucleate new Golgi cisternae. Thus, an integrated self-organization process may generate tER-Golgi units. © 2014 WILEY Periodicals, Inc.

Ismayilova L.,University of Chicago
American Journal of Public Health | Year: 2015

Objectives. I examined the individual- and community-level factors associated with spousal violence in post-Soviet countries. Methods. I used population-based data from the Demographic and Health Survey conducted between 2005 and 2012. My sample included currently married women of reproductive age (n = 3932 in Azerbaijan, n = 4053 in Moldova, n = 1932 in Ukraine, n = 4361 in Kyrgyzstan, and n = 4093 in Tajikistan). I selected respondents using stratified multistage cluster sampling. Because of the nested structure of the data, multilevel logistic regressions for survey data were fitted to examine factors associated with spousal violence in the last 12 months. Results. Partner's problem drinking was the strongest risk factor associated with spousal violence in all 5 countries. In Moldova, Ukraine, and Kyrgyzstan, women with greater financial power than their spouses were more likely to experience violence. Effects of community economic deprivation and of empowerment status of women in the community on spousal violence differed across countries. Women living in communities with a high tolerance of violence faced a higher risk of spousal violence in Moldova and Ukraine. In more traditional countries (Azerbaijan, Kyrgyzstan, and Tajikistan), spousal violence was lower in conservative communities with patriarchal gender beliefs or higher financial dependency on husbands. Conclusions. My findings underscore the importance of examining individual risk factors in the context of community-level factors and developing individualand community-level interventions.

Josephson M.A.,University of Chicago
Clinical Journal of the American Society of Nephrology | Year: 2014

Late kidney transplant dysfunction may be a harbinger of graft failure. For many years, calcineurin inhibitor toxicity was felt to be the main cause for graft dysfunction with fibrosis and transplant loss. Recently this idea has come into question. With the observation that peritubular capillary C4d staining in kidney allografts may indicate antibodymediated injury in conjunctionwith biopsy study findings, an appreciation for antibody-mediated rejection as amajor cause of late graft dysfunction and loss has emerged. Twenty percent to 30% of patients develop de novo donorspecific antibodies after kidney transplantation. There are noUS Food andDrugAdministration-approved treatments for antibody-mediated rejection, nor have any randomized controlled trials assessed efficacy. Off-label treatment strategies include some combination of plasma exchange, intravenous immunoglobulin, and rituximab. Other approaches, including splenectomy, bortezomib, and eculizumab, have also been tried. © 2014 by the American Society of Nephrology.

Rosner J.L.,University of Chicago
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2012

The experimental uncertainty on the branching fraction B(Λ c→pK -π +)=(5.0±1.3)% has not decreased since 1998, despite a much larger data sample. Uncertainty in this quantity dominates that in many other quantities, including branching fractions of Λ c to other modes, branching fractions of b-flavored baryons, and fragmentation fractions of charmed and bottom quarks. Here we advocate a lattice QCD calculation of the form factors in Λ c→Λ l +ν l (the case l=e + is simpler as the mass of the lepton can be neglected). Such a calculation would yield an absolute prediction for the rate for Λ c→Λ l +ν l. When combined with the Λ c lifetime, it could provide a calibration for an improved set of Λ c branching fractions as long as the accuracy exceeds about 25%. © 2012 American Physical Society.

Rosner J.L.,University of Chicago
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2012

The production of top-antitop pairs at the Fermilab Tevatron shows a forward-backward asymmetry in which the top quark tends to follow the proton direction, while the antitop tends to follow the antiproton direction. The effect grows with increasing effective mass m tt̄ of the top-antitop pair, and with increasing rapidity difference between the top and antitop. The observed effect is about 3 times as large as predicted by next-to-leading-order QCD, but with the same sign. An estimate of nonfactorizable effects based on a QCD string picture finds they are negligible, but that small distortions of the m t spectrum are possible. Tests for such effects, both at and above the level of this estimate, are suggested. © 2012 American Physical Society.

Hogan C.J.,University of Chicago
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2012

A theory of position of massive bodies is proposed that results in an observable quantum behavior of geometry at the Planck scale, t P. Departures from classical world lines in flat spacetime are described by Planckian noncommuting operators for position in different directions, as defined by interactions with null waves. The resulting evolution of position wave functions in two dimensions displays a new kind of directionally coherent quantum noise of transverse position. The amplitude of the effect in physical units is predicted with no parameters, by equating the number of degrees of freedom of position wave functions on a 2D space-like surface with the entropy density of a black hole event horizon of the same area. In a region of size L, the effect resembles spatially and directionally coherent random transverse shear deformations on time scale L/c with typical amplitude √ct PL. This quantum-geometrical "holographic noise" in position is not describable as fluctuations of a quantized metric, or as any kind of fluctuation, dispersion or propagation effect in quantum fields. In a Michelson interferometer the effect appears as noise that resembles a random Planckian walk of the beam splitter for durations up to the light-crossing time. Signal spectra and correlation functions in interferometers are derived, and predicted to be comparable with the sensitivities of current and planned experiments. It is proposed that nearly colocated Michelson interferometers of laboratory scale, cross-correlated at high frequency, can test the Planckian noise prediction with current technology. © 2012 American Physical Society.

Shapiro J.A.,University of Chicago
RNA Biology | Year: 2014

The development of rigorous molecular taxonomy pioneered by Carl Woese has freed evolution science to explore numerous cellular activities that lead to genome change in evolution. These activities include symbiogenesis, inter- and intracellular horizontal DNA transfer, incorporation of DNA from infectious agents, and natural genetic engineering, especially the activity of mobile elements. This article reviews documented examples of all these processes and proposes experiments to extend our understanding of cell-mediated genome change.© 2014 Landes Bioscience.

Hinterbichler K.,Perimeter Institute for Theoretical Physics | Joyce A.,University of Chicago
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2015

We show that there is a special choice of parameters for which the Galileon theory is invariant under an enhanced shift symmetry whose nonlinear part is quadratic in the coordinates. This symmetry fixes the theory to be equivalent to one with only even powers of the field, with no free coefficients, and accounts for the improved soft-limit behavior observed in the quartic Galileon S-matrix. © 2015 American Physical Society.

Hooper D.,Fermi National Accelerator Laboratory | Hooper D.,University of Chicago
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2015

With the goal of generating the Galactic Center gamma-ray excess, we revisit models in which the dark matter interacts with the Standard Model through the exchange of a new neutral gauge boson, Z′. We find several scenarios that can account for this signal, while respecting all existing constraints from colliders and direct-detection experiments. In such models, the Z′ either 1) couples axially to light quarks and is leptophobic, 2) couples dominantly to the third generation, or 3) is near resonance, mZ′≈2mDM. We identify an example of an anomaly-free U(1)′ that leads to an axial and leptophobic Z′. Many of the models presented here are within the reach of near-future direct-detection experiments, such as LUX and XENON1T. © 2015 American Physical Society.

Motohashi H.,University of Chicago
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2015

We consider Rp inflation with p≈2, allowing small deviation from R2 inflation. Using the inflaton potential in the Einstein frame, we construct a consistency relation between the scalar spectral index, the tensor-to-scalar ratio, as well as the running of the scalar spectral index, which will be useful to constrain a deviation from R2 inflation in future observations. © 2015 American Physical Society.

Frisch P.C.,University of Chicago
Astrophysical Journal | Year: 2010

Many studies of the Loop I magnetic superbubble place the Sun at the edges of the bubble. One recent study models the polarized radio continuum of Loop I as two magnetic shells with the Sun embedded in the rim of the "S1" shell. If the Sun is in such a shell, it should be apparent in both the local interstellar magnetic field and the distribution of nearby interstellar material. The properties of these subshells are compared to the interstellar magnetic field and the distribution of interstellar Fe+ and Ca + within ∼ 55pc of the Sun. Although the results are not conclusive, the interstellar magnetic field direction obtained from polarized stars within 30pc is consistent with the interstellar magnetic field direction of the S1 shell. The distribution of nearby interstellar Fe+ with log N(Fe+) < 12.5cm-2 is described equally well by a uniform distribution or an origin in spherical shell-like features. Higher column densities of Fe+ (log N(Fe+)>12.5cm -2) tend to be better described by the path length of the sightline through the S1 and S2 subshells. Column densities of the recombinant ion Ca + are found to increase with the strength of the interstellar radiation field, rather than with star distance or total pathlength through the two magnetic subshells. The ion Ca+ cannot be used to trace the distribution of local interstellar gas unless the spatial variations in the radiation field are included in the calculation of the ionization balance, in addition to possible abundance variations. The result is that a model of Loop I as composed of two spherical magnetic subshells remains a viable description of the distribution of nearby low density interstellar medium, but is not yet proven. © 2010 The American Astronomical Society. All rights reserved.

Sulmasy D.P.,University of Chicago
Genetics in Medicine | Year: 2015

Genetic exceptionalism, the view that genomic information is different from other types of sensitive information and deserves exceptional types of protections, has been roundly criticized. However, the public still expresses special fears about the access others might have to their genomic information. In this article, it is argued that there may be a basis for the public perception that genomic information is special, even if it cannot be said that policies could or should be enacted to protect the privacy and confidentiality of genomic information that would be exceptional relative to the protections one would enact to protect other types of sensitive information. The special nature of genomic information lies in understanding that it is neither personal property nor mere information. A genome is, at one and the same time, a physical aspect of a person and information about that person. Genomic data are embodied information that partially constitutes as well as describes individuals and that connects them in physical ways to their ancestors and their relatives. All forms of privacy need to be protected, but some intimate aspects of our lives command special respect. To see a genome is more analogous to seeing a naked body than to seeing a social security number. This metaphor suggests that clinicians and investigators ought to respect the special concerns of patients regarding genomic information while not claiming that there are any exceptional measures one could take to protect genomic privacy. Suggestions are given for how this view might affect patient interactions, consent discussions, public policy, and public trust in genomic research and clinical genetics. © American College of Medical Genetics and Genomics.

Bakris G.L.,University of Chicago | Molitch M.,Northwestern University
Diabetes Care | Year: 2014

OBJECTIVE The rationale for this study was to review the data on microalbuminuria (MA), an amount of albumin in the urine of 30-299mg/day, in patients with diabetes in the context of cardiovascular risk and development of kidney disease. The objective was to reviewthe pathophysiology ofMA in patientswith diabetes and reviewthe data from trials regarding MA in the context of risk for cardiovascular events or kidney disease progression. RESEARCH DESIGN AND METHODS Data sources were all PubMed-referenced articles in English-language peerreviewed journals since 1964. Studies selected had to have a minimum 1-year follow-up and be either a randomized trial linking MA to cardiovascular or kidney disease outcome, a meta-analysis/systematic review, or a large observational cohort study. RESULTS The data suggest that MA is a risk marker for cardiovascular events and possibly for kidney disease development. Its presence alone, however, does not indicate established kidney disease, especially if the estimated glomerular filtration rate is >60 mL/min/1.73 m2. An increase in MA, when blood pressure and other risk factors are controlled, portends a poor prognosis for kidney outcomes over time. Early in the course of diabetes, aggressive risk factor management focused on glycemic and blood pressure goals is important to delay kidney disease development and reduce cardiovascular risk. CONCLUSIONS MA is a marker of cardiovascular disease risk and should be monitored per guidelines once or twice a year for progression to macroalbuminuria and kidney disease development, especially if plasma glucose, lipids, and blood pressure are at guideline goals.© 2014 by the American Diabetes Association.

Adams E.J.,University of Chicago
Current Opinion in Immunology | Year: 2014

CD1 molecules bind and present lipid-based antigens to T cells. Humans express both Group 1 (CD1a, CD1b and CD1c) and Group 2 (CD1d) CD1 molecules with nonredundant functions in the human immune response. Studies of Group 1 CD1 molecules and the T cells that respond to them have lagged behind Group 2 due to the lack of a suitable model system. However, recent work has thrust the Group 1 CD1s into the limelight, revealing their importance in tissue surveillance and microbial defense. Here I review recent advances in Group 1 CD1 lipid presentation, the T cell populations that respond to them and the role of CD1 molecules in engagement of human γδ T cells. © 2013 Elsevier Ltd.

Ehrmann D.A.,University of Chicago
Steroids | Year: 2012

Polycystic ovary syndrome (PCOS) affects between 5% and 8% of women, making it one of the most common endocrinopathies in women. The disorder typically has its onset at puberty with evidence of excessive androgen production, obesity, and insulin resistance. Women with PCOS are more insulin resistant than weight-matched controls and have an exceptionally high prevalence of early-onset impaired glucose tolerance (30-40%), and type 2 diabetes (up to 10%). Over the past several years, chronic decreases in sleep duration and/or quality have been identified as a risk for the development of a number of metabolic derangements that are strikingly similar to those seen in PCOS. Specifically, decreased sleep quality due to obstructive sleep apnea (OSA) has been causally linked to insulin resistance, glucose intolerance, dyslipidemia and hypertension independent of body mass index (BMI). Until recently, however, it had not been recognized that OSA is present in a disproportionate number of women with PCOS: the risk for OSA is at least 5- to 10-fold higher compared to the risk in similarly obese women without PCOS. The causes and consequences of OSA in women with PCOS are addressed in this manuscript. © 2011 Elsevier Inc. All rights reserved.

Nash P.D.,University of Chicago
FEBS Letters | Year: 2012

The serendipitous discovery of the SH2 domain unleashed a sea-change in our conceptual molecular understanding of protein function. The reductionist approaches that followed from the recognition of modular protein interaction domains transformed our understanding of cellular signal transduction systems, how they evolve and how they may be manipulated. We now recognize thousands of conserved protein modules - many of which have been described in structure and function, implicated in disease, or underlie targeted therapeutics. The reductionist study of isolated protein modules has enabled the reconstruction of the protein interaction networks that underlie cellular signalling. Protein modules themselves are becoming tools to probe cellular activation states and identify key interactions hubs in both normal and diseased cells and the concept of protein modularity is central to the field of synthetic biology. This brief word of introduction serves to highlight the historical impact of the very powerful idea of protein modules and sets the stage for the exciting on-going discoveries discussed in this issue. © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Venters T.M.,University of Chicago | Venters T.M.,NASA
Astrophysical Journal | Year: 2010

As very high energy (VHE) photons propagate through the extragalactic background light (EBL), they interact with the soft photons and initiate electromagnetic cascades of lower energy photons and electrons. The collective intensity of a cosmological population emitting at VHEs will be attenuated at the highest energies through interactions with the EBL and enhanced at lower energies by the resulting cascade. We calculate the cascade radiation created by VHE photons produced by blazars and investigate the effects of cascades on the collective intensity of blazars and the resulting effects on the extragalactic gamma-ray background. We find that cascade radiation greatly enhances the collective intensity from blazars at high energies before turning over due to attenuation. The prominence of the resulting features depends on the blazar gamma-ray luminosity function, spectral index distribution, and the model of the EBL. We additionally calculate the cascade radiation from the distinct spectral sub-populations of blazars, BL Lacertae (BL Lacs) objects, and flat-spectrum radio quasars (FSRQs), finding that the collective intensity of BL Lacs is considerably more enhanced by cascade radiation than that of the FSRQs. Finally, we discuss the implications that this analysis and upcoming Fermi observations could have for the nature of the EBL, the evolution of blazars, blazar spectra, and other sources of gamma-ray radiation. © 2010. The American Astronomical Society. All rights reserved..

Gerson S.A.,Radboud University Nijmegen | Woodward A.L.,University of Chicago
Child Development | Year: 2014

Prior research suggests that infants' action production affects their action understanding, but little is known about the aspects of motor experience that render these effects. In Study 1, the relative contributions of self-produced (n = 30) and observational (n = 30) action experience on 3-month-old infants' action understanding was assessed using a visual habituation paradigm. In Study 2, generalization of training to a new context was examined (n = 30). Results revealed a unique effect of active over observational experience. Furthermore, findings suggest that benefits of trained actions do not generalize broadly, at least following brief training. © 2013 Society for Research in Child Development, Inc.

Dutton R.P.,University of Chicago
British Journal of Surgery | Year: 2012

Background: Successful outcome from damage control surgery (DCS) depends as much on elements of resuscitation and non-operative management as on details of the procedure itself. The early management of patients in haemorrhagic shock has undergone substantial revision in the past decade and is now known as 'haemostatic resuscitation'. Methods: An updated literature review describing the anaesthetic and resuscitative management of patients with active, ongoing traumatic haemorrhage was distilled to present the current knowledge of the pathophysiology, recommended treatments and areas of active controversy. Results: Current practice in military and civilian trauma centres is described, along with the degree of evidence in support of clinical decisions. Resuscitation of patients with ongoing traumatic haemorrhage has changed substantially in the past two decades. Optimal management now includes deliberate hypotension to minimize blood loss, early use of blood products (especially plasma) and administration of antifibrinolytic therapy. Areas of debate include the role of clotting factor concentrates and depth of anaesthesia. Conclusion: Resuscitation strategies during DCS may be as important as the anatomical repair itself. Recommendations include avoidance of hypothermia, maintenance of a lower than normal blood pressure, and early support of the coagulation system in patients likely to require massive transfusion. Controversies include the optimal ratio of plasma to red blood cells for empirical resuscitation, the ideal role of clotting factor concentrates, and the potential benefit of early, deep anaesthesia. Future research will centre on the complex interaction between the humoral elements of coagulation and the vascular endothelium that regulates perfusion, clotting and integrity of the circulation. Copyright © 2011 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

Couch S.M.,University of Chicago
Astrophysical Journal | Year: 2013

We study the dependence of the delayed neutrino-heating mechanism for core-collapse supernovae on the equation of state (EOS). Using a simplified treatment of the neutrino physics with a parameterized neutrino luminosity, we explore the relationship between explosion time, mass accretion rate, and neutrino luminosity for a 15 M ⊙ progenitor in 1D and 2D. We test the EOS most commonly used in core-collapse simulations: the models of Lattimer & Swesty and the model of Shen et al. We find that for a given neutrino luminosity, "stiffer" EOS, where stiffness is determined by a combination of nuclear matter properties not just incompressibility, K, explode later than "softer" EOS. The EOS of Shen et al., being the stiffest EOS, by virtue of larger incompressibility and symmetry energy slope, L, explodes later than any of the Lattimer & Swesty EOS models. Amongst the Lattimer & Swesty EOS that all share the same value of L, the explosion time increases with increasing nuclear incompressibility, K. We find that this holds in both 1D and 2D, while for all of the models, explosions are obtained more easily in 2D than in 1D. We argue that this EOS dependence is due in part to a greater amount of acoustic flux from denser proto-neutron star atmospheres that result from a softer EOS. We also discuss the relevance of approximate instability criteria to realistic simulations. © 2013. The American Astronomical Society. All rights reserved.

Wiegmann P.B.,University of Chicago
Physical Review B - Condensed Matter and Materials Physics | Year: 2013

We show that the fractional quantum Hall effect can be phenomenologically described as a special flow of a quantum incompressible Euler liquid. This flow consists of a large number of vortices of the same chirality. In this approach each vortex is identified with an electron while the fluid is neutral. We show that the Laughlin wave function naturally emerges as a stationary flow of the system of vortices in quantum fluid dynamics. Here we develop the hydrodynamics of the vortex liquid and are able to consistently quantize it. As a demonstration of the efficiency of the hydrodynamics we show how subtle features of the fractional quantum Hall effect such as effects of Lorentz shear stress, the structure function, the Hall current in a nonuniform magnetic field, and Hall conductance in a curved spatial landscape naturally follow from the hydrodynamics approach. © 2013 American Physical Society.

Coccaro E.F.,University of Chicago
American Journal of Psychiatry | Year: 2012

A disorder of impulsive aggression has been included in DSM since the first edition. In DSM-III, this disorder was codified as intermittent explosive disorder, and it was thought to be rare. However, the diagnostic criteria for the disorder were poorly operationalized, and empirical research was limited until research criteria were developed a decade ago. Subsequently, renewed interest in disorders of impulsive aggression led to a recent series of community-based studies that have documented intermittent explosive disorder to be as common as many other psychiatric disorders. Other recent research indicates that compared with DSM-IV criteria for intermittent explosive disorder, research criteria for the disorder better identify individuals with elevated levels of aggression, impulsivity, familial risk of aggression, and abnormalities in neurobiological markers of aggression. In addition, other data strongly suggest important delimitation from other disorders previously thought to obscure the diagnostic uniqueness of intermittent explosive disorder. Overall, these data suggest that the diagnostic validity for the integrated research criteria is substantial and is now sufficient for recognition and inclusion in DSM-5.

Rich J.D.,University of Chicago
Cardiology Clinics | Year: 2012

Right ventricular (RV) failure that develops following LVAD placement is an important and challenging complication that occurs in approximately 15-25% of LVAD patients. Thus, a thorough evaluation that identifies pre-operative clinical predictors of RV failure is crucial to aid in the appropriate treatment and prognostication. Following LVAD implant, three major physiologic changes invariably occur that will influence RV function: an increase in RV preload, a decrease in RV afterload, and an alteration in RV contractility. Management strategies exist to minimize the likelihood and severity of RV failure post-LVAD. Further studies are needed that also focus on intermediate and late post-LVAD RV failure. © 2012 Elsevier Inc.

Rich S.,University of Chicago
Cardiology Clinics | Year: 2012

The right ventricle (RV) is not well suited to chronic pressure overload and often fails to adequately compensate. Mechanisms that allow the RV to respond to acute pressure overload often become maladaptive and contribute to its failure, including the effects of pulmonary hypertension on RV myocardial perfusion, the influence of interventricular dependence on RV function, and metabolic shifts in the RV myocardium from fatty acid to glycolysis. Medications to treat pulmonary hypertension have focused on pulmonary vasodilatation. Their effects on RV function may determine their effectiveness. How new medications affect right ventricular performance must be addressed. © 2012 Elsevier Inc.

Stigler S.M.,University of Chicago
Biometrika | Year: 2012

Karl Pearson's role in the transformation that took the 19th century statistics of Laplace and Gauss into the modern era of 20th century multivariate analysis is examined from a new point of view. By viewing Pearson's work in the context of a motto he adopted from Charles Darwin, a philosophical theme is identified in Pearson's statistical work, and his three major achievements are briefly described. © 2011 Biometrika Trust.

Decety J.,University of Chicago
Current Opinion in Behavioral Sciences | Year: 2015

Empathy reflects an innate ability to perceive and be sensitive to the emotional states of others coupled with a motivation to care for their wellbeing. It has evolved in the context of parental care for offspring as well as within kinship. Current work demonstrates that empathy is underpinned by circuits connecting the brainstem, amygdala, basal ganglia, anterior cingulate cortex, insula and orbitofrontal cortex, which are conserved across many species. Empirical studies document that empathetic reactions emerge early in life, and that they are not automatic. Rather they are heavily influenced and modulated by interpersonal and contextual factors, which impact behavior and cognitions. However, the mechanisms supporting empathy are also flexible and amenable to behavioral interventions that can promote caring beyond kin and kith. © 2014 Elsevier Ltd.

Arina A.,University of Chicago | Bronte V.,University of Verona
Current Opinion in Immunology | Year: 2015

Novel models of autochthonous tumorigenesis and adoptive T cell therapy (ATT) are providing new clues regarding the pro-tumorigenic and immunosuppressive effects of myeloid-derived suppressor cells (MDSC), and their interaction with T cells. New findings are shifting the perception of the main level at which MDSC act, from direct cell-to-cell suppression to others, such as limiting T cell infiltration. Adoptively transferred, high-avidity T cells recognizing peptides with high-affinity for MHC-I eliminated large tumors. However, low-avidity T cells or low-affinity peptides resulted in failure to eradicate tumors. Manipulation of intratumoral myeloid cells improved the outcome of otherwise unsuccessful ATT. Therefore, therapeutic intervention directed at the tumor stroma might be required when using suboptimal T cells for ATT. © 2015 Published by Elsevier Ltd.

Kay L.M.,University of Chicago
Progress in Brain Research | Year: 2014

Olfactory system neural oscillations as seen in the local field potential have been studied for many decades. Recent research has shown that there is a functional role for the most studied gamma oscillations (40-100. Hz in rats and mice, and 20. Hz in insects), without which fine odor discrimination is poor. When these oscillations are increased artificially, fine discrimination is increased, and when rats learn difficult and highly overlapping odor discriminations, gamma is increased in power. Because of the depth of study on this oscillation, it is possible to point to specific changes in neural firing patterns as represented by the increase in gamma oscillation amplitude. However, we know far less about the mechanisms governing beta oscillations (15-30. Hz in rats and mice), which are best associated with associative learning of responses to odor stimuli. These oscillations engage every part of the olfactory system that has so far been tested, plus the hippocampus, and the beta oscillation frequency band is the one that is most reliably coherent with other regions during odor processing. Respiratory oscillations overlapping with the theta frequency band (2-12. Hz) are associated with odor sniffing and normal breathing in rats. They also show coupling in some circumstances between olfactory areas and rare coupling between the hippocampus and olfactory bulb. The latter occur in specific learning conditions in which coherence strength is negatively or positively correlated with performance, depending on the task. There is still much to learn about the role of neural oscillations in learning and memory, but techniques that have been brought to bear on gamma oscillations (current source density, computational modeling, slice physiology, behavioral studies) should deliver much needed knowledge of these events. © 2014 Elsevier B.V.

Singleton P.A.,Section of Pulmonary and Critical Care | Singleton P.A.,University of Chicago
Advances in Cancer Research | Year: 2014

Vascular integrity or the maintenance of blood vessel continuity is a fundamental process regulated by endothelial cell-cell junctions. Defects in endothelial barrier function are an initiating factor in several disease processes including tumor angiogenesis and metastasis. The glycosaminoglycan, hyaluronan (HA), maintains vascular integrity through specific mechanisms including HA-binding protein signaling in caveolin-enriched microdomains, a subset of lipid rafts. Certain disease states, including cancer, increase enzymatic hyaluronidase activity and reactive oxygen species generation, which break down high molecular weight HA (HMW-HA) to low molecular weight fragments (LMW-HA). LMW-HA can activate specific HA-binding proteins during tumor progression to promote disruption of endothelial cell-cell contacts. In contrast, exogenous administration of HMW-HA promotes enhancement of vascular integrity. This review focuses on the roles of HA in regulating angiogenic and metastatic processes based on its size and the HA-binding proteins present. Further, potential therapeutic applications of HMW-HA in treating cancer are discussed. © 2014 Elsevier Inc.

Goykhman M.,University of Chicago
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2015

We use the replica trick approach to calculate, in the large-N limit, the entanglement c-function in two-dimensional quantum chromodynamics with the gauge group U(N) and quark in the fundamental representation ('t Hooft model). We show explicitly that the result is equal to a sum (with certain numerical coefficients) of entanglement c-functions of free massive scalars, which represent mesons in the spectrum of the 't Hooft model. Interestingly, each meson contributes as a pointlike particle. We provide an explanation for why this is the case. © 2015 American Physical Society.

Rosner J.L.,University of Chicago
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2015

The search for νμ→νe oscillations by the MiniBooNE Collaboration at Fermilab has revealed a low-energy signal which could be due either to electrons produced by νe or photons produced by the interaction of the weak neutral current on the target nucleus. One contribution to the latter is a Wess-Zumino-Witten anomaly leading to a term in the Lagrangian proportional to εμνκλZμωνFκλ. This term is normalized with the help of the known rates for the processes f1→ργ and τ→ντa1. A rate of about 1/4 of that employed in several previous estimates is obtained. As the anomaly term had already been found to play a subdominant role in photon production (e.g., in comparison with Δ excitation and decay), the present estimate reduces its strength even further. © 2015 American Physical Society.

Tian B.,University of Chicago | Lieber C.M.,Harvard University
Annual Review of Analytical Chemistry | Year: 2013

Research at the interface between nanoscience and biology could yield breakthroughs in fundamental science and lead to revolutionary technologies. In this review, we focus on the interfaces between nanoelectronics and biology. First, we discuss nanoscale field effect transistors (nanoFETs) as probes to study cellular systems; specifically, we describe the development of nanoFETs that are comparable in size to biological nanostructures involved in communication through synthesized nanowires. Second, we review current progress in multiplexed extracellular sensing using planar nanoFET arrays. Third, we describe the designs and implementation of three distinct nanoFETs used to perform the first intracellular electrical recording from single cells. Fourth, we present recent progress in merging electronic and biological systems at the three-dimensional tissue level by use of macro-porous nanoelectronic scaffolds. Finally, we discuss future developments in this research area, unique challenges and opportunities, and the tremendous impact these nanoFET-based technologies might have on biological and medical sciences. Copyright © 2013 by Annual Reviews.

Niyogi P.,University of Chicago
Journal of Machine Learning Research | Year: 2013

Manifold regularization (Belkin et al., 2006) is a geometrically motivated framework for machine learning within which several semi-supervised algorithms have been constructed. Here we try to provide some theoretical understanding of this approach. Our main result is to expose the natural structure of a class of problems on which manifold regularization methods are helpful. We show that for such problems, no supervised learner can learn effectively. On the other hand, a manifold based learner (that knows the manifold or learns it from unlabeled examples) can learn with relatively few labeled examples. Our analysis follows a minimax style with an emphasis on finite sample results (in terms of n: the number of labeled examples). These results allow us to properly interpret manifold regularization and related spectral and geometric algorithms in terms of their potential use in semi-supervised learning. © 2013 Partha Niyogi.

Cardiovascular (CV) disease remains the major cause of mortality and morbidity in patients with type 2 diabetes mellitus (T2DM). The pathogenesis of CV disease in T2DM is complex and multifactorial, and includes abnormalities in endothelial cells, vascular smooth muscle cells, myocardium, platelets, and the coagulation cascade. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a newer class of agents that act by potentiating the action of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide. This review summarizes CV disease pathophysiology in T2DM and the potential effect of DPP-4 inhibitors on CV risk in patients with T2DM. Preclinical and small observational studies and post hoc analyses of clinical trial data suggest that DPP-4 inhibitors may have beneficial CV effects. Some effects of DPP-4 inhibitors are GLP-1 dependent, whereas others may be due to GLP-1–independent actions of DPP-4 inhibitors. Analyses of major adverse CV events occurring during clinical development of DPP-4 inhibitors found no increased risk of CV events or mortality and even a potential reduction in CV events. Two large CV outcome trials have been completed and report that saxagliptin and alogliptin did not increase or decrease adverse CV outcomes in patients with T2DM and CV disease or at high risk for adverse CV events. More patients in the saxagliptin group than in the placebo group were hospitalized for heart failure, and there was a similar numerically increased risk of hospitalization for heart failure with alogliptin; however, the risk was not significantly greater compared with placebo. Dipeptidyl peptidase-4 inhibitors may affect some of the pathologic processes involved in the increased CV risk inherent in T2DM. © Postgraduate Medicine.

Issa N.P.,University of Chicago
Pediatric Neurology | Year: 2014

Background Several pediatric seizure disorders have common electrophysiological features during slow-wave sleep that produce different syndromes based on which part of the developing brain is involved. These disorders, of which continuous spike-wave in slow-wave sleep and Landau-Kleffner are the most common, are characterized by continuous spike-wave activity during slow-wave sleep, developmentally regulated onset and termination of abnormal electrical activity, and loss of previously acquired skills. Over the last 20 years, a variety of basic science findings suggest how spike-wave activity during sleep can cause the observed clinical outcomes. Methods Literature review and analysis. Results The role of slow-wave sleep in normal cortical plasticity during developmental critical periods, how disruption of slow-wave sleep by electrographic seizures could affect cortical maps and development, and the organization and functional connectivity of the thalamic structures that when damaged are thought to produce these seizure disorders are reviewed. Conclusions Potential therapeutic directions are proposed based on the mechanisms of plasticity and anatomical structures involved in cortical plasticity during slow-wave sleep. © 2014 Elsevier Inc. All rights reserved.

Son D.T.,University of Chicago | Spivak B.Z.,University of Washington
Physical Review B - Condensed Matter and Materials Physics | Year: 2013

We consider the classical magnetoresistance of a Weyl metal in which the electron Fermi surface possesses nonzero fluxes of the Berry curvature. Such a system may exhibit large negative magnetoresistance with unusual anisotropy as a function of the angle between the electric and magnetic fields. In this case the system can support an additional type of plasma wave. These phenomena are consequences of the chiral anomaly in electron transport theory. © 2013 American Physical Society.

Mulmuley K.D.,University of Chicago
Journal of the ACM | Year: 2011

This article gives an overview of the geometric complexity theory (GCT) approach towards the P vs. NP and related problems focusing on its main complexity theoretic results. These are: (1) two concrete lower bounds, which are currently the best known lower bounds in the context of the P vs. NC and permanent vs. determinant problems, (2) the Flip Theorem, which formalizes the self-referential paradox in the P vs. NP problem, and (3) the Decomposition Theorem, which decomposes the arithmetic P vs. NP and permanent vs. determinant problems into subproblems without self-referential difficulty, consisting of positivity hypotheses in algebraic geometry and representation theory and easier hardness hypotheses. © 2011 ACM.

Newville M.,University of Chicago
Reviews in Mineralogy and Geochemistry | Year: 2014

The basic physical principles of X-ray Absorption Fine-Structure (XAFS) are presented. XAFS is an element-specific spectroscopy in which measurements are made by tuning the X-ray energy at and above a selected core-level binding energy of a specified element. Although XAFS is a well-established technique providing reliable and useful information about the chemical and physical environment of the probe atom, its requirement of an energy-tunable X-ray source means it is primarily done with synchrotron radiation sources and so is somewhat less common than other spectroscopic analytical methods. XAFS spectra are especially sensitive to the oxidation state and coordination chemistry of the selected element. In addition, the extended oscillations of the XAFS spectra are sensitive to the distances, coordination number and species of the atoms immediately surrounding the selected element. This Extended X-ray Absorption Fine-Structure (EXAFS) is the main focus of this chapter. As it is element-specific, XAFS places few restrictions on the form of the sample, and can be used in a variety of systems and bulk physical environments, including crystals, glasses, liquids, and heterogeneous mixtures. Additionally, XAFS can often be done on low-concentration elements (typically down to a few ppm), and so has applications in a wide range of scientific fields, including chemistry, biology, catalysis research, material science, environmental science, and geology. Special attention in this chapter is given to the basic concepts used in analysis and modeling of EXAFS spectra. Copyright © Mineralogical Society of America.

Patterson K.C.,University of Pennsylvania | Strek M.E.,University of Chicago
Chest | Year: 2014

Both inherited and acquired immunodeficiency and chronic pulmonary disease predispose to the development of a variety of pulmonary syndromes in response to Aspergillus, a fungus that is ubiquitous in the environment. These syndromes include invasive aspergillosis, which is now recognized to occur in patients with critical illness without neutropenia and in those with mild degrees of immunosuppression, including from corticosteroid use in the setting of COPD. Chronic pulmonary aspergillosis includes simple aspergilloma, which is occasionally complicated by life-threatening hemoptysis, and progressive destructive cavitary disease requiring antifungal therapy. Allergic bronchopulmonary aspergillosis occurs almost exclusively in patients with asthma or cystic fi brosis. Recent advances in each of these syndromes include a greater understanding of the underlying pathophysiology and hosts at risk; improved diagnostic algorithms; and the availability of more eff ective and well-tolerated therapies. Improvement in outcomes for Aspergillus pulmonary syndromes requires that physicians recognize the varied and sometimes subtle presentations, be aware of populations at risk of illness, and institute potentially life-saving therapies early in the disease course. © 2014 American College of Chest Physicians.

Heller S.B.,University of Pennsylvania | Heller S.B.,University of Chicago
Science | Year: 2014

Every day, acts of violence injure more than 6000 people in the United States. Despite decades of social science arguing that joblessness among disadvantaged youth is a key cause of violent offending, programs to remedy youth unemployment do not consistently reduce delinquency. This study tests whether summer jobs, which shift focus from remediation to prevention, can reduce crime. In a randomized controlled trial among 1634 disadvantaged high school youth in Chicago, assignment to a summer jobs program decreases violence by 43% over 16 months (3.95 fewer violent-crime arrests per 100 youth). The decline occurs largely after the 8-week intervention ends. The results suggest the promise of using low-cost, well-targeted programs to generate meaningful behavioral change, even with a problem as complex as youth violence.

Abbot D.S.,University of Chicago
Journal of Climate | Year: 2014

Recent general circulation model (GCM) simulations have challenged the idea that a snowball Earth would be nearly entirely cloudless. This is important because clouds would provide a strong warming to a highalbedo snowball Earth. GCM results suggest that clouds could lower the threshold CO2 needed to deglaciate a snowball by a factor of 10-100, enough to allow consistency with geochemical data. Here a cloud-resolving model is used to investigate cloud and convection behavior in a snowball Earth climate. The model produces convection that extends vertically to a similar temperature as modern tropical convection. This convection produces clouds that resemble stratocumulus clouds under an inversion on modern Earth, which slowly dissipate by sedimentation of cloud ice. There is enough cloud ice for the clouds to be optically thick in the longwave, and the resulting cloud radiative forcing is similar to that produced in GCMs run in snowball conditions. This result is robust to large changes in the cloud microphysics scheme because the cloud longwave forcing, which dominates the total forcing, is relatively insensitive to cloud amount and particle size. The cloud-resolving model results are therefore consistent with the idea that clouds would provide a large warming to a snowball Earth, helping to allow snowball deglaciation. © 2014 American Meteorological Society.

Heckman J.J.,University of Chicago
Pediatrics | Year: 2013

Pediatricians should consider the costs and benefits of preventing rather than treating childhood diseases. We present an integrated developmental approach to child and adult health that considers the costs and benefits of interventions over the life cycle. We suggest policies to promote child health that are currently outside the boundaries of conventional pediatrics. We discuss current challenges to the field and suggest avenues for future research. Copyright © 2013 by the American Academy of Pediatrics.

Background: Debate regarding the monophyly and relationships of the avian order Pelecaniformes represents a classic example of discord between morphological and molecular estimates of phylogeny. This lack of consensus hampers interpretation of the group's fossil record, which has major implications for understanding patterns of character evolution (e.g., the evolution of wing-propelled diving) and temporal diversification (e.g., the origins of modern families). Relationships of the Pelecaniformes were inferred through parsimony analyses of an osteological dataset encompassing 59 taxa and 464 characters. The relationships of the Plotopteridae, an extinct family of wing-propelled divers, and several other fossil pelecaniforms (Limnofregata, Prophaethon, Lithoptila,? Borvocarbo stoeffelensis) were also assessed. The antiquity of these taxa and their purported status as stem members of extant families makes them valuable for studies of higher-level avian diversification. Methodology/Principal Findings: Pelecaniform monophyly is not recovered, with Phaethontidae recovered as distantly related to all other pelecaniforms, which are supported as a monophyletic Steganopodes. Some anatomical partitions of the dataset possess different phylogenetic signals, and partitioned analyses reveal that these discrepancies are localized outside of Steganopodes, and primarily due to a few labile taxa. The Plotopteridae are recovered as the sister taxon to Phalacrocoracoidea, and the relationships of other fossil pelecaniforms representing key calibration points are well supported, including Limnofregata (sister taxon to Fregatidae), Prophaethon and Lithoptila (successive sister taxa to Phaethontidae), and Borvocarbo stoeffelensis (sister taxon to Phalacrocoracidae). These relationships are invariant when 'backbone' constraints based on recent avian phylogenies are imposed. Conclusions/Significance: Relationships of extant pelecaniforms inferred from morphology are more congruent with molecular phylogenies than previously assumed, though notable conflicts remain. The phylogenetic position of the Plotopteridae implies that wing-propelled diving evolved independently in plotopterids and penguins, representing a remarkable case of convergent evolution. Despite robust support for the placement of fossil taxa representing key calibration points, the successive outgroup relationships of several "stem fossil + crown family" clades are variable and poorly supported across recent studies of avian phylogeny. Thus, the impact these fossils have on inferred patterns of temporal diversification depends heavily on the resolution of deep nodes in avian phylogeny. © 2010 Nathan D. Smith.

Dutton R.P.,University of Chicago
British Journal of Anaesthesia | Year: 2012

SummaryRecommendations for resuscitation of patients in early haemorrhagic shock, with active ongoing bleeding, have evolved in recent years. This review covers current theories of the pathophysiology of shock and recommended treatments, including damage control surgery, deliberate hypotensive management, administration of antifibrinolytics, early support of the coagulation system, and the possible role of deep anaesthesia. Future directions for resuscitation research are discussed. © 2012 The Author [2012].

Environmental day length drives nocturnal pineal melatonin secretion, which in turn generates or entrains seasonal cycles of physiology, reproduction, and behavior. In mammals, melatonin (MEL) binds to a number of receptor subtypes including high-affinity (MT1 and MT2) and low-affinity (MT3, nuclear orphan receptors) binding sites, which are distributed throughout the central nervous system and periphery. The MEL receptors that mediate photoperiodic reproductive and behavioral responses to MEL have not been identified in a reproductively photoperiodic species. Here I tested the hypothesis that MT1 receptors are necessary and sufficient to engage photoperiodic responses by challenging male Siberian hamsters (Phodopus sungorus), a species that does not express functional MT2 receptors, with ramelteon (RAM), a specific MT1/MT2 receptor agonist. In hamsters housed in a long-day photoperiod, late-afternoon RAM treatment inhibited gonadotropin secretion, induced gonadal regression, and suppressed food intake and body mass, mimicking effects of MEL. In addition, chronic (24 h/d) RAM infusions were sufficient to obscure endogenous MEL signaling, and these treatments attenuated gonadal regression in short days. Together, the outcomes indicate that signaling at the MT1 receptor is sufficient and necessary to mediate the effects of photoperiod-driven changes in MEL on behavior and reproductive function in a reproductively photoperiodic mammal. Copyright © 2010 by The Endocrine Society.

Lingen M.W.,University of Chicago
Cancer Prevention Research | Year: 2010

This perspective on the report by Pattani et al. in this issue of the journal (beginning on page 1093) examines the utility of detecting hypermethylation of the candidate tumor suppressor genes endothelin receptor type B (EDNRB) and kinesin family member 1A (KIF1A) as a means of oral cancer or premalignancy screening. The data discussed here raise the possibility that saliva-based hypermethylation studies may hold promise as a cancer screening platform. This perspective also discusses some of the challenges and current limitations of developing biomarkers to screen not only for oral premalignancy and early cancer but for human papillomavirus-related oropharyngeal neoplasia as well. ©2010 AACR.

Novak M.,University of Chicago
Proceedings. Biological sciences / The Royal Society | Year: 2013

Intraguild predation theory centres on two predictions: (i) for an omnivore and an intermediate predator (IG-prey) to coexist on shared resources, the IG-prey must be the superior resource competitor, and (ii) increasing resource productivity causes the IG-prey's equilibrium abundance to decline. I tested these predictions with a series of species-rich food webs along New Zealand's rocky shores, focusing on two predatory whelks, Haustrum haustorium, a trophic omnivore, and Haustrum scobina, the IG-prey. In contrast to theory, the IG-prey's abundance increased with productivity. Furthermore, feeding rates and allometric considerations indicate a competitive advantage for the omnivore when non-shared prey are considered, despite the IG-prey's superiority for shared prey. Nevertheless, clear and regular cross-gradient changes in network structure and interaction strengths were observed that challenge the assumptions of current theory. These insights suggest that the consideration of consumer-dependent functional responses, non-equilibrium dynamics, the dynamic nature of prey choice and non-trophic interactions among basal prey will be fruitful avenues for theoretical development.

Bergelson J.,University of Chicago | Roux F.,Lille University of Science and Technology
Nature Reviews Genetics | Year: 2010

A major challenge in evolutionary biology and plant breeding is to identify the genetic basis of complex quantitative traits, including those that contribute to adaptive variation. Here we review the development of new methods and resources to fine-map intraspecific genetic variation that underlies natural phenotypic variation in plants. In particular, the analysis of 107 quantitative traits reported in the first genome-wide association mapping study in Arabidopsis thaliana sets the stage for an exciting time in our understanding of plant adaptation. We also argue for the need to place phenotypeĝ€ "genotype association studies in an ecological context if one is to predict the evolutionary trajectories of plant species. © 2010 Macmillan Publishers Limited. All rights reserved.

Ross L.F.,University of Chicago
American Journal of Medical Genetics, Part A | Year: 2012

In April 2011, the American Congress of Obstetricians and Gynecologists (formerly the American College of Obstetrics and Gynecology [ACOG]), updated its policy on carrier screening for cystic fibrosis and proposed that because of the increasing difficulty in assigning a single ethnicity to individuals, "It is reasonable, therefore to offer CF carrier screening to all patients." However, ACOG continues to use ethnicity in its guidelines about carrier testing for autosomal recessive disorders like sickle cell disease (SCD) and Tay-Sachs disease (TSD). This practice is in marked contrast with newborn screening (NBS) which is universally provided for all conditions. In this manuscript, I evaluate the discrepant role of ethnicity in NBS and carrier screening. I argue that ACOG needs to adopt the position it now takes for CF regarding prenatal carrier testing for all conditions. To promote equity in prenatal testing decision making, health care policies must acknowledge the diversity of the populations that we serve and empower all women and couples to make more fully informed reproductive decisions by offering prenatal carrier testing to all. © 2011 Wiley Periodicals, Inc.

Oka T.,University of Chicago
Chemical Reviews | Year: 2013

The history of H3 + is a succession of inspiring discoveries, grueling hard work, big surprises, and many puzzles and mistakes with their unexpected resolutions. Interstellar chemistry is the exciting playing ground of kinematics where individual characteristics of molecules appear in rare form rather than being washed out by the boring entropy maximum principle. A well-known means of breakdown of 3-fold symmetry is by the Jahn-Teller effect, which results from the interaction between degenerated electronic and vibrational states. The SSB of rotational levels of H3 + occurs similarly through interaction between the vibrational and the rotational motion.

Kidwell S.M.,University of Chicago
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

With overwhelming evidence of change in habitats, biologists today must assume that few, if any, study areas are natural and that biological variability is superimposed on trends rather than stationary means. Paleobiological data from the youngest sedimentary record, including death assemblages actively accumulating on modern land surfaces and seabeds, provide unique information on the status of present-day species, communities, and biomes over the last few decades to millennia and on their responses to natural and anthropogenic environmental change. Key advances have established the accuracy and resolving power of paleobiological information derived from naturally preserved remains and of proxy evidence for environmental conditions and sample age so that fossil data can both implicate and exonerate human stressors as the drivers of biotic change and permit the effects of multiple stressors to be disentangled. Legacy effects from Industrial and even pre-Industrial anthropogenic extirpations, introductions, (de)nutrification, and habitat conversion commonly emerge as the primary factors underlying the present-day status of populations and communities; within the last 2 million years, climate change has rarely been sufficient to drive major extinction pulses absent other human pressures, which are now manifold. Young fossil records also provide rigorous access to the baseline composition and dynamics of modern-day biota under pre-Industrial conditions, where insights include the millennial-scale persistence of community structures, the dominant role of physical environmental conditions rather than biotic interactions in determining community composition and disassembly, and the existence of naturally alternating states.

Rottman B.M.,University of Chicago | Keil F.C.,Yale University
Cognitive Psychology | Year: 2012

Seven studies examined how people learn causal relationships in scenarios when the variables are temporally dependent - the states of variables are stable over time. When people intervene on X, and Y subsequently changes state compared to before the intervention, people infer that X influences Y. This strategy allows people to learn causal structures quickly and reliably when variables are temporally stable (Experiments 1 and 2). People use this strategy even when the cover story suggests that the trials are independent (Experiment 3). When observing variables over time, people believe that when a cause changes state, its effects likely change state, but an effect may change state due to an exogenous influence in which case its observed cause may not change state at the same time. People used this strategy to learn the direction of causal relations and a wide variety of causal structures (Experiments 4-6). Finally, considering exogenous influences responsible for the observed changes facilitates learning causal directionality (Experiment 7). Temporal reasoning may be the norm rather than the exception for causal learning and may reflect the way most events are experienced naturalistically. © 2011 Elsevier Inc..

Schilsky R.L.,University of Chicago
Oncologist | Year: 2013

Publicly sponsored trials, conducted primarily by cooperative groups sponsored by the National Cancer Institute, and commercially sponsored trials are necessary to create new knowledge, improve the care of oncology patients, and develop new drugs and devices. Commercial sponsors launch clinical trials that will result in drug approval, label extension, expansion of market share, and an increase in shareholder value. Conversely, publicly sponsored trials seek to optimize therapy for a particular disease, create new knowledge, and improve public health; these trials can also result in label extension of a drug and even in initial drug approval. Publicly sponsored trials may combine and/or compare drugs developed by different commercial sponsors, develop multimodality therapies (e.g., the combination of chemotherapy and radiation), or develop novel treatment schedules or routes of drug administration (e.g., intraperitoneal chemotherapy). Publicly sponsored trials are more likely to focus on therapies for rare diseases and to study survivorship and quality of life; these areas may not be a priority for commercial entities. Screening and prevention strategies have been developed almost exclusively by the public sector given the large sample size and long follow-up period needed to complete the trial and, therefore, the lack of short-term commercial gain. Finally, given the public nature of the funding, clinical investigators are expected to publish their results even if the outcomes are unfavorable for the investigational therapy. With the ongoing reorganization of the cooperative groups to form a national clinical trials network, opportunities exist to create a robust platform for biomarker discovery and validation through the expanded collection of well-annotated biospecimens obtained from clinical trial participants. Thus, publicly funded trials are vital to developing and refining new cancer treatments and disseminating results to the medical community and the general public. © AlphaMed Press 2013.

Penev P.D.,University of Chicago
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Driven by the demands and opportunities of modern life, many people habitually sleep less than 6 h a night. In the sleep clinic, chronic sleep restriction is recognized by the diagnosis of insufficient sleep syndrome (ICSD-9, 307.49-4), which is receiving increased scrutiny as a potential risk to metabolic health. Its relevance for the practicing endocrinologist is highlighted by a stream of epidemiological data that show an association of insufficient sleep with increased incidence of obesity and related morbidities. A central theme of this update is the notion that sleep loss incurs additional metabolic cost, which triggers a set of neuroendocrine, metabolic, and behavioral adaptations aimed at increasing food intake and conserving energy. Although this coordinated response may have evolved to offset the metabolic demands of extended wakefulness in natural habitats with limited food availability, it can be maladaptive in the context of a modern environment that allows many to overeat while maintaining a sedentary lifestyle without sufficient sleep. Importantly, such sleep loss-related metabolic adaptation may undermine the success of behavioral interventions based on reduced caloric intake and increased physical activity to lower metabolic risk in obesity-prone individuals. This emerging perspective is based on data from recently published human interventional studies and requires further experimental support. Nevertheless, it now seems prudent to recommend that overweight and obese individuals attempting to reduce their caloric intake and maintain increased physical activity should obtain adequate sleep and, if needed, seek effective treatment for any coexisting sleep disorders. Copyright © 2012 by The Endocrine Society.

Liu H.,Michigan State University | Waite L.,University of Chicago
Journal of Health and Social Behavior | Year: 2014

Working from a life course perspective, we develop hypotheses about age and gender differences in the link between marital quality and cardiovascular risk and test them using data from the first two waves of the National Social Life, Health, and Aging Project. The analytic sample includes 459 married women and 739 married men (aged 57–85 in the first wave) who were interviewed in both waves. We apply Heckmantype corrections for selection bias due to mortality and marriage. Cardiovascular risk is measured as hypertension, rapid heart rate, C-reactive protein, and general cardiovascular events. Results suggest that changes in marital quality and cardiovascular risk are more closely related for older married people than for their younger counterparts and that the link between marital quality and cardiovascular risk is more pronounced among women than among men at older ages. These findings fit with the gendered life course perspective and cumulative disadvantage framework. © American Sociological Association 2014.

Stroke prevention is of vital importance in the management of atrial fibrillation (AF), though the proven strategy of systemic anticoagulation for thromboembolic prophylaxis is underutilized for a variety of reasons. The left atrial appendage (LAA) has long been suspected as the principal source of arterial emboli, particularly in nonvalvular AF, and a variety of techniques for its exclusion from the circulation have been developed. This review highlights the history of the LAA as a target of intervention, and the parallel advances in three minimally invasive strategies for its exclusion: percutaneous occlusion of the LAA orifice from within the left atrium, closed-chest ligation via a percutaneous pericardial approach, and minimally invasive thoracoscopic surgery. While further study is necessary, available evidence suggests that effective LAA exclusion is becoming a viable alternative to anticoagulation for stroke prevention in nonvalvular AF. © 2013 Springer Science+Business Media.

Neutze R.,Gothenburg University | Moffat K.,University of Chicago
Current Opinion in Structural Biology | Year: 2012

X-ray free electron lasers (XFELs) are potentially revolutionary X-ray sources because of their very short pulse duration, extreme peak brilliance and high spatial coherence, features that distinguish them from today's synchrotron sources. We review recent time-resolved Laue diffraction and time-resolved wide angle X-ray scattering (WAXS) studies at synchrotron sources, and initial static studies at XFELs. XFELs have the potential to transform the field of time-resolved structural biology, yet many challenges arise in devising and adapting hardware, experimental design and data analysis strategies to exploit their unusual properties. Despite these challenges, we are confident that XFEL sources are poised to shed new light on ultrafast protein reaction dynamics. © 2012 Elsevier Ltd.

Maestripieri D.,University of Chicago
Evolutionary psychology : an international journal of evolutionary approaches to psychology and behavior | Year: 2014

Individual differences in morningness/eveningness are relatively stable over time and, in part, genetically based. The night-owl pattern is more prevalent in men than in women, particularly after puberty and before women reach menopause. It has been suggested that eveningness evolved relatively recently in human evolutionary history and that this trait may be advantageous to individuals pursuing short-term mating strategies. Consistent with this hypothesis, eveningness is associated with extraversion, novelty-seeking, and in males, with a higher number of sexual partners. In this study, I investigated whether eveningness is associated with short-term relationship orientation, higher risk-taking, and higher testosterone or cortisol. Both female and male night-owls were more likely to be single than in long-term relationships than early morning individuals. Eveningness was associated with higher risk-taking in women but not in men; this association was not testosterone-dependent but mediated by cortisol. Female night-owls had average cortisol profiles and risk-taking tendencies more similar to those of males than to those of early-morning females. Taken together, these findings provide some support to the hypothesis that eveningness is associated with psychological and behavioral traits that are instrumental in short-term mating strategies, with the evidence being stronger for women than for men.

Murgu S.D.,University of Chicago
Chest | Year: 2015

The purpose of this article is to provide an update on evidence-based methods for mediastinal staging in patients with lung cancer. This is a review of the recently published studies and a summary of relevant guidelines addressing the role of CT scan, PET scan, endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA), and mediastinoscopy as pertinent to lung cancer staging and restaging. The focus is on how these diagnostic methods fi t into the best algorithm for patients with chest imaging abnormalities suspected of malignant disease. Several studies, meta-analyses, and systematic reviews specifi cally targeted the role of PET scan, EBUS-TBNA, and mediastinoscopy for detecting mediastinal lymph node involvement in patients suff ering from lung cancer. Based on the recommendations from the currently published guidelines, algorithms of care are proposed for staging and restaging of the mediastinum. © 2015 American College Of Chest Physicians.

Maimaran M.,Northwestern University | Fishbach A.,University of Chicago
Journal of Consumer Research | Year: 2014

Marketers, educators, and caregivers often refer to instrumental benefits to convince preschoolers to eat (e.g., “This food will make you strong”). We propose that preschoolers infer that if food is instrumental to achieve a goal, it is less tasty, and therefore they consume less of it. Accordingly, we find that preschoolers (3–5.5 years old) rated crackers as less tasty and consumed fewer of them when the crackers were presented as instrumental to achieving a health goal (studies 1–2). In addition, preschoolers consumed fewer carrots and crackers when these were presented as instrumental to knowing how to read (study 3) and to count (studies 4–5). This research supports an inference account for the negative impact of certain persuasive messages on consumption: preschoolers who are exposed to one association (e.g., between eating carrots and intellectual performance) infer another association (e.g., between carrots and taste) must be weaker. © 2014 by JOURNAL OF CONSUMER RESEARCH, Inc.

Allaix M.E.,University of Chicago | Fichera A.,University of Washington
Annals of Surgical Oncology | Year: 2013

Introduction: Treatment of rectal cancer has evolved during the last few decades due to more in-depth knowledge of rectal cancer biology and major advances in the field of preoperative staging, medical management and surgical techniques. Consequently, treatment strategies are shifting moving towards a more personalized approach based on the response to treatment. Currently topics of controversy are centered around the indication for neoadjuvant radiation therapy in locally advanced rectal cancer and the role of surgery in patients with complete clinical response after neoadjuvant combined modality therapy. This manuscript aims to critically evaluate the evolution of treatment of rectal cancer during the last three decades and future directions. Methods: A review of the literature has been performed in PubMed/Medline electronic databases. Results: Treatment modalities are moving towards a tailored approach to rectal cancer patients based on the response to chemoradiation. A "wait-and- see" approach and local excision by Transanal Endoscopic Microsurgery (TEM) are strategies recently proposed in case of complete clinical response. Conclusions: The standard of care still requires that locally advanced rectal cancer should be treated by neoadjuvant chemoradiation therapy followed by total mesorectal excision, including patients with a clinical complete response. Further evidence is needed to endorse a "wait-and-see" strategy and to define the role of TEM. © 2013 Society of Surgical Oncology.

Jakubowiak A.J.,University of Chicago
Cancer Treatment Reviews | Year: 2014

Carfilzomib is a proteasome inhibitor that binds selectively and irreversibly to its target. In July 2012, carfilzomib received accelerated approval in the United States for the treatment of relapsed and refractory multiple myeloma. Based on emerging preclinical data and clinical results, the total dose, infusion time, and administration schedule of carfilzomib have evolved during phase I and phase II clinical studies, with the aim of optimizing the risk-benefit profile of the agent. Based on in vitro and in vivo findings and encouraging phase I tolerability data, a consecutive-day, twice-weekly dosing schedule was implemented early in the development program. Other phase II studies have led to further refinements in the dosing schedule of carfilzomib, resulting in the current approved schedule for carfilzomib to be administered intravenously over 2-10. min on 2 consecutive days each week for 3. weeks of a 28-day cycle. Prolonged infusion over 30. min has also been assessed in clinical studies to enable the use of higher carfilzomib doses with the aim of improving drug tolerability and efficacy. These data collectively informed the dosing and scheduling schemas for carfilzomib in ongoing trials, including phase I and II studies of combination regimens, and the randomized phase III trials ASPIRE, FOCUS, ENDEAVOR, and CLARION. Additional studies are underway to examine alternative dosing schedules (e.g., once-weekly dosing [CHAMPION-1]). © 2014 The Author.

Basu A.,University of Chicago
Medical Decision Making | Year: 2010

Background. Much of the literature on obesity has consistently documented the unprecedented rise in body weight over the past 2 decades. Less attention is paid to future projections of the population distribution of body mass index (BMI). Objective. To forecast the distribution of BMI in children (6-17 years) and adults (>17 years) in the United States (US) by age group, sex, and race over the period 2004-2014. Methods. Analysis of Medical Expenditure Panel Survey data (2001-2002 and 2004- 2005) to estimate and compare the 1-year transitions across BMI categories for children and adults. Forecasting distributions of obesity over 2004-2014 using a probabilistic population-level simulation model and validating it with prevalence data from 2005-2006 National Health and Nutrition Examination Survey. Results. During 2004- 2005, a majority of adults in each BMI category remained in the same category after 1 year, these estimates being not significantly different than the corresponding estimates in 2001-2002. Among children, stabilities within BMI categories are low during 2004-2005, and compared with 2001-2002, transition probabilities into overweight class 2 from other BMI categories increase substantially. Forecasts reveal significant increases in the risk of overweight category among children 6 to 9 years old (5% to 14% in 5 years), with a greater increase anticipated in males, and increases in the overweight category for many years to come for adults, although the adult obesity prevalence remains at the current levels. Conclusions. Although the absolute levels of obesity remain high among US adults, the growth in obesity appears to have stagnated. On the contrary, continued growth in the prevalence of the highest BMI category for children is anticipated.

Mullane K.,University of Chicago
Therapeutic Advances in Chronic Disease | Year: 2014

The incidence of Clostridium difficile infection (CDI) has risen 400% in the last decade. It currently ranks as the third most common nosocomial infection. CDI has now crossed over as a community-acquired infection. The major failing of current therapeutic options for the management of CDI is recurrence of disease after the completion of treatment. Fidaxomicin has been proven to be superior to vancomycin in successful sustained clinical response to therapy. Improved outcomes may be due to reduced collateral damage to the gut microflora by fidaxomicin, bactericidal activity, inhibition of Clostridial toxin formation and inhibition of new sporulation. This superiority is maintained in groups previously reported as being at high risk for CDI recurrence including those: with relapsed infection after a single treatment course; on concomitant antibiotic therapy; aged >65 years; with cancer; and with chronic renal insufficiency. Because the acquisition cost of fidaxomicin far exceeds that of metronidazole or vancomycin, in order to rationally utilize this agent, it should be targeted to those populations who are at high risk for relapse and in whom the drug has demonstrated superiority. In this manuscript is reviewed the changing epidemiology of CDI, current treatment options for this infection, proposed benefits of fidaxomicin over currently available antimicrobial options, available analysis of cost effectiveness of the drug, and is given recommendations for judicious use of the drug based upon the available published literature. © The Author(s), 2013.

Purpose:This article examines the extent to which positive and negative support from children prior to and after spousal loss and changes in support from pre- to post-loss affect widowed older adults' depressive symptoms, anxiety, and anger 18 months following widowhood.Design and Methods:Analyses are based on the Changing Lives of Older Couples, a prospective study of 1,532 married individuals aged 65 years and older. The analytic sample includes 148 widowed persons who have at least one living child and participated in the baseline and two follow-up interviews conducted 6 and 18 months following widowhood.Results:The analyses revealed that higher levels of positive support from children 6 months following widowhood were associated with fewer depressive symptoms at the 18-month follow-up, whereas higher levels of negative support 18 months after loss and a decrease in positive support following loss were associated with more depressive symptoms. Greater negative support both prior to and after loss was associated with greater anxiety, whereas greater negative support 6 months after loss and an increase in negative support following loss were related to greater anger.Implications:Given their differential impact on widowed persons' psychological adjustment, both positive and negative aspects of social support as well as its changing nature should be considered in working with bereaved older adults. © 2009 The Author. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved.

Lauderdale D.S.,University of Chicago
Behavioral Sleep Medicine | Year: 2014

There is no standard way to ask about sleep duration in surveys, and little is known about the comparability of different questions. This article reports on a randomized survey experiment designed to test 1 type of variation: 1 question about usual sleep hours versus 2 questions separately asking about weekday and weekend sleep. Mean sleep duration was significantly shorter (7.03 hr vs. 7.28 hr) for the single question than a weighted average from 2 questions, and race and ethnicity contrasts differed by question format. Correlations between sleep duration and reported sleep need were significantly higher for the 2-question format. These results demonstrate that question wording can affect reported sleep duration in complicated ways, making it difficult to compare studies that use different questions. © 2014 Copyright Taylor and Francis Group, LLC.

Kay L.M.,University of Chicago
Current Biology | Year: 2011

Stimulating arbitrary collections of as few as 300 neurons in the primary olfactory cortex of mice suffices for associative learning independent of any odor stimulation. Thus, programmed spatial relationships may not exist in piriform cortex, making flexible random associations the rule. © 2011 Elsevier Ltd.

Foote M.,University of Chicago
Biology Letters | Year: 2012

The distribution of species among genera and higher taxa has largely untapped potential to reveal among-clade variation in rates of origination and extinction. The probability distribution of the number of species within a genus is modelled with a stochastic, time-homogeneous birth-death model having two parameters: the rate of species extinction, m, and the rate of genus origination, g, each scaled as a multiple of the rate of withingenus speciation, l. The distribution is more sensitive to g than to m, although m affects the size of the largest genera. The species : genus ratio depends strongly on both g and m, and so is not a good diagnostic of evolutionary dynamics. The proportion of monotypic genera, however, depends mainly on g, and so may provide an index of the genus origination rate. Application to living marinemolluscs ofNewZealandshowsthatbivalves have a higher relative rate of genus origination than gastropods. This is supported by the analysis of palaeontological data. This concordance suggests that analysis of living taxonomic distributions may allow inference of macroevolutionary dynamics even without a fossil record. © 2011 The Royal Society.

Variation is a ubiquitous feature of speech. Listeners must take into account context-induced variation to recover the interlocutor's intended message. When listeners fail to normalize for context-induced variation properly, deviant percepts become seeds for new perceptual and production norms. In question is how deviant percepts accumulate in a systematic fashion to give rise to sound change (i.e., new pronunciation norms) within a given speech community. The present study investigated subjects' classification of /s/ and /∫/ before /a/ or /u/ spoken by a male or a female voice. Building on modern cognitive theories of autism-spectrum condition, which see variation in autism-spectrum condition in terms of individual differences in cognitive processing style, we established a significant correlation between individuals' normalization for phonetic context (i.e., whether the following vowel is /a/ or /u/) and talker voice variation (i.e., whether the talker is male or female) in speech and their "autistic" traits, as measured by the Autism Spectrum Quotient (AQ). In particular, our mixed-effect logistic regression models show that women with low AQ (i.e., the least "autistic") do not normalize for phonetic coarticulation as much as men and high AQ women. This study provides first direct evidence that variability in human's ability to compensate for context-induced variations in speech perceptually is governed by the individual's sex and cognitive processing style. These findings lend support to the hypothesis that the systematic infusion of new linguistic variants (i.e., the deviant percepts) originate from a sub-segment of the speech community that consistently under-compensates for contextual variation in speech. © 2010 Alan C. L. Yu.

Muller M.,University of Gottingen | De Pablo J.J.,University of Chicago | De Pablo J.J.,Argonne National Laboratory
Annual Review of Materials Research | Year: 2013

Polymeric materials can assemble into a multitude of intricate nanoscale morphologies whose free energy differs by only a fraction of the thermal energy per molecule. Such small free-energy differences pose a challenge for modeling and simulation but also offer exciting opportunities to direct the assembly of such materials into morphologies that do not correspond to those of equilibrium bulk structures. Over the past decade, significant progress has been achieved in our ability to guide their self-assembly through the use of confinement, topographical or chemical patterns, and electric fields. In contrast, approaches to guide self-assembly by tailoring the dynamics of structure formation have received less attention. This review discusses opportunities and challenges of recently developed computational strategies to predict the dynamics of self-assembly of polymeric materials on the basis of the underlying free-energy landscape. © Copyright © 2013 by Annual Reviews. All rights reserved.

Immunogenic tumors grow progressively even when heavily infiltrated by CD8(+) T cells. We investigated how to rescue CD8(+) T cell function in long-established immunogenic melanomas that contained a high percentage of endogenous PD-1(+) tumor-specific CD8(+) T cells that were dysfunctional. Treatment with αPD-L1 and αCTLA-4 blocking antibodies did not prevent tumors from progressing rapidly. We then tested exogenous tumor-specific antigen delivery into tumors using Salmonella Typhimurium A1-R to increase antigen levels and generate a proinflammatory tumor microenvironment. Antigen-producing A1-R rescued the endogenous tumor-specific CD8(+) T cell response: proliferation was induced in the lymphoid organs and effector function was recovered in the tumor. Treatment with antigen-producing A1-R led to improved mouse survival and resulted in 32% rejection of long-established immunogenic melanomas. Following treatment with antigen-producing A1-R, the majority of tumor-specific CD8(+) T cells still expressed a high level of PD-1 in the tumor. Combining antigen-producing A1-R with αPD-L1 blocking antibody enhanced the expansion of tumor-specific CD8(+) T cells and resulted in 80% tumor rejection. Collectively, these data demonstrate a powerful new therapeutic approach to rescue dysfunctional endogenous tumor-specific CD8(+) T cells and eradicate advanced immunogenic tumors.

Polson N.G.,University of Chicago | Scott J.G.,University of Texas at Austin
Biometrika | Year: 2013

We use the theory of normal variance-mean mixtures to derive a data-augmentation scheme for a class of common regularization problems. This generalizes existing theory on normal variance mixtures for priors in regression and classification. It also allows variants of the expectation-maximization algorithm to be brought to bear on a wider range of models than previously appreciated. We demonstrate the method on several examples, focusing on the case of binary logistic regression. We also show that quasi-Newton acceleration can substantially improve the speed of the algorithm without compromising its robustness. © 2013 Biometrika Trust.

Dworsky A.,University of Chicago
Child Abuse and Neglect | Year: 2015

Despite the high rate of early parenthood among youth in foster care as well as the increased risk of child maltreatment among children whose adolescent parents have been neglected or abused, very little is known about child welfare services involvement among children whose parents were in foster care when they were born. This study uses administrative data from the Illinois Department of Children and Family Services (DCFS) to examine the occurrence of child abuse and neglect investigations, indicated reports and out of home care placements among the children of youth in foster. Thirty-nine percent of the children were the subject of at least one CPS investigation, 17 percent had at least one indicated report and 11 percent were placed in out of home care at least once before their 5th birthday. Cox proportional hazard models are also estimated to identify characteristics of parenting foster youth and their placement histories associated with the risk of child welfare services involvement. Implications of the findings for policy and practice are discussed. © 2015 Elsevier Ltd.

Gaba R.C.,University of Chicago
American Journal of Roentgenology | Year: 2012

OBJECTIVE. The objective of our study was to assess patterns of chemoembolization use; identify variations in application, technique, and follow-up; and recognize areas of practice conformity and divergence. MATERIALS AND METHODS. During August and September 2010, Society of Interventional Radiology (SIR) members with "chemoembolization expertise" were invited to participate in an anonymous online questionnaire. RESULTS. Two hundred sixty-eight of 1157 invited SIR members (23%) answered the 34-item survey. Respondents were predominantly male (93%) fellowship-trained full-time interventional radiologists (IRs) (87%) in practice for less than 15 years (69%) at community hospitals (61%) in the United States (91%). IRs (53%) most commonly drove therapeutic decision making. Most respondents (61%) performed 1-5 chemoembolizations per month and preferred drug-eluting beads to iodized oil for unifocal (46% vs 39%, respectively) and multifocal (40% vs 30%) hepatocellular carcinoma (HCC), although 90Y radioembolization was favored when portal vein thrombosis was present (48% vs 28%). IRs showed variability in recognized procedure contraindications. Most respondents agreed on chemotherapeutic regimen but showed variable particle embolization use (17-45%) during oily chemoembolization. The 100- to 300-μm (49%) LC Beads (AngioDynamics) (65%) were the favored drug-eluting beads. Lobar chemoembolization was preferred. Treatment endpoints lacked consensus, but substasis was most desirable (56%). Up to 19% of respondents performed outpatient chemoembolization. Concurrent percutaneous ablation was infrequently used (applied in 0-25% of cases by 61-91% of respondents). Most (up to 74%) IRs preferred CT follow-up with the decision for retreatment based on CT evidence of viable disease (93%). CONCLUSION. Variability in chemoembolization practice exists among IRs. Continued investigation of treatment strategies and devices is necessary to better optimize and standardize transcatheter therapies for liver tumors. © American Roentgen Ray Society.

Berlin A.,University of Chicago
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2016

We explore the possibility that the recently reported diphoton excess at ATLAS and CMS can be accommodated within a minimal extension of a left-right symmetric model. Our setup is able to simultaneously explain the Run 2 diphoton and Run 1 diboson excesses, while providing a standard thermal freeze-out of weak-scale dark matter. In this scenario, the 750 GeV neutral right-handed Higgs triplet is responsible for the diphoton excess. Interactions of this state with the neutral and charged components of dark matter multiplets provide the dominant mechanisms for production and decay. A striking signature of this model is the additional presence of missing energy in the diphoton channel. © 2016 American Physical Society..

Son D.T.,University of Chicago
Physical Review X | Year: 2015

We propose a particle-hole symmetric theory of the Fermi-liquid ground state of a half-filled Landau level. This theory should be applicable for a Dirac fermion in the magnetic field at charge neutrality, as well as for the ν=1/2 quantum Hall ground state of nonrelativistic fermions in the limit of negligible inter- Landau-level mixing. We argue that when particle-hole symmetry is exact, the composite fermion is a massless Dirac fermion, characterized by a Berry phase of p around the Fermi circle. We write down a tentative effective field theory of such a fermion and discuss the discrete symmetries, in particular, CP. The Dirac composite fermions interact through a gauge, but non-Chern-Simons, interaction. The particle-hole conjugate pair of Jain-sequence states at filling factors n/(2n + 1) and (n + 1)/(2n + 1), which in the conventional composite fermion picture corresponds to integer quantum Hall states with different filling factors, n and n + 1, is now mapped to the same half-integer filling factor n + 1/2 of the Dirac composite fermion. The Pfaffian and anti-Pfaffian states are interpreted as d-wave Bardeen-Cooper-Schrieffer paired states of the Dirac fermion with orbital angular momentum of opposite signs, while s-wave pairing would give rise to a particle-hole symmetric non-Abelian gapped phase. When particle-hole symmetry is not exact, the Dirac fermion has a CP-breaking mass. The conventional fermionic Chern-Simons theory is shown to emerge in the nonrelativistic limit of the massive theory.

Tiedt A.D.,University of Chicago
Journals of Gerontology - Series B Psychological Sciences and Social Sciences | Year: 2013

Objectives. This study compared changes in self-reported depressive symptoms in the United States and Japan across 2 points in time. The investigation focused on the gendered processes of intergenerational coresidence and support as the primary distinctions between nations.Methods. Fixed-effects models were fit to examine the covariates of depressive symptoms in the Health and Retirement Study (HRS) and the Nihon University Japanese Longitudinal Study of Aging.Results. Gender differences in depressive symptoms persisted across survey waves in both nations, with Japanese men reporting sharper increases by Time 2 than Japanese women. Getting older was associated with more depressive symptoms among Japanese men, whereas income provided a slight buffering effect. Coresiding with daughters also appeared to protect Japanese men and women with functional limitations from depressive symptoms. HRS data demonstrated that changes in marital status and physical health were correlated with increased depressive symptoms for men and women in the United States.Discussion. The analyses revealed more variety in Center for Epidemiologic Studies Depression scale reports by gender in Japan than in the United States. Future research should consider the diversity of contemporary Japanese households, reflecting new interpretations of traditional family support relationships. © 2013 The Author.

Rosenfield R.L.,University of Chicago
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Context: Adolescents are at high risk for menstrual dysfunction. The diagnosis of anovulatory disorders that may have long-term health consequences is too often delayed. Evidence Acquisition: A review of the literature in English was conducted, and data were summarized and integrated from the author's perspective. MainFindings: Normal adolescent anovulation causes only minor menstrual cycle irregularity: most cycles range from 21-45 days, even in the first postmenarcheal year, 90% by the fourth year. Approximately half of symptomatic menstrual irregularity is due to neuroendocrine immaturity, and half is associated with increased androgen levels. The former is manifest as aluteal or short/deficient luteal phase cycles and usually resolves spontaneously. The latter seems related to polycystic ovary syndrome because adolescent androgen levels are associated with adult androgens and ovulatory dysfunction, but data are sparse. Obesity causes hyperandrogenemia and, via unclear mechanisms, seems to suppress LH; itmaymimicpolycystic ovary syndrome.Therole of pubertal insulin resistance in physiological adolescent anovulation is unclear. High-sensitivity gonadotropin and steroid assays, the latter by specialty laboratories, are necessary for accurate diagnosis of pubertal disorders. Polycystic ovaries are a normal ultrasonographic finding in young women and are associated with nearly 2-fold increased anti-Müllerian hormone levels. Oral contraceptives are generally the first-line treatment for ongoing menstrual dysfunction, and the effects of treatment are similar among preparations. Conclusions: Menstrual cycle duration persistently outside 21-45 days in adolescents is unusual, and persistence 1 year suggests that disordered hypothalamic-pituitary-gonadal function be considered. Research is neededonthe mechanisms and prognosis of adolescent anovulation. Copyright © 2013 by The Endocrine Society.

Prabhakar N.R.,University of Chicago
Journal of Physiology | Year: 2013

The carotid body is a sensory organ for detecting arterial blood O2 levels and reflexly mediates systemic cardiac, vascular and respiratory responses to hypoxia. This article presents a brief review of the roles of gaseous messengers in the sensory transduction at the carotid body, genetic and epigenetic influences on hypoxic sensing and the role of the carotid body chemoreflex in cardiorespiratory diseases. Type I (also called glomus) cells, the site of O2 sensing in the carotid body, express haem oxygenase-2 and cystathionine-γ-lyase, the enzymes which catalyse the generation of CO and H2S, respectively. Physiological studies have shown that CO is an inhibitory gas messenger, which contributes to the low sensory activity during normoxia, whereas H2S is excitatory and mediates sensory stimulation by hypoxia. Hypoxia-evoked H2S generation in the carotid body requires the interaction of cystathionine-γ-lyase with haem oxygenase-2, which generates CO. Hypoxia-inducible factors 1 and 2 constitute important components of the genetic make-up in the carotid body, which influence hypoxic sensing by regulating the intracellular redox state via transcriptional regulation of pro- and antioxidant enzymes. Recent studies suggest that developmental programming of the carotid body response to hypoxia involves epigenetic changes, e.g. DNA methylation of genes encoding redox-regulating enzymes. Emerging evidence implicates heightened carotid body chemoreflex in the progression of autonomic morbidities associated with cardiorespiratory diseases, such as sleep-disordered breathing with apnoea, congestive heart failure and essential hypertension. © 2013 The Author. The Journal of Physiology © 2013 The Physiological Society.

Knipe R.S.,Harvard University | Tager A.M.,Harvard University | Liao J.K.,University of Chicago
Pharmacological Reviews | Year: 2015

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive lung scarring, short median survival, and limited therapeutic options, creating great need for new pharmacologic therapies. IPF is thought to result from repetitive environmental injury to the lung epithelium, in the context of aberrant host wound healing responses. Tissue responses to injury fundamentally involve reorganization of the actin cytoskeleton of participating cells, including epithelial cells, fibroblasts, endothelial cells, and macrophages. Actin filament assembly and actomyosin contraction are directed by the Rho-associated coiledcoil forming protein kinase (ROCK) family of serine/ threonine kinases (ROCK1 and ROCK2). As would therefore be expected, lung ROCK activation has been demonstrated in humans with IPF and in animal models of this disease. ROCK inhibitors can prevent fibrosis in these models, and more importantly, induce the regression of already established fibrosis. Here we review ROCK structure and function, upstream activators and downstream targets of ROCKs in pulmonary fibrosis, contributions of ROCKs to profibrotic cellular responses to lung injury, ROCK inhibitors and their efficacy in animal models of pulmonary fibrosis, and potential toxicities of ROCK inhibitors in humans, as well as involvement of ROCKs in fibrosis in other organs. As we discuss, ROCK activation is required for multiple profibrotic responses, in the lung and multiple other organs, suggesting ROCK participation in fundamental pathways that contribute to the pathogenesis of a broad array of fibrotic diseases. Multiple lines of evidence therefore indicate that ROCK inhibition has great potential to be a powerful therapeutic tool in the treatment of fibrosis, both in the lung and beyond. © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

A phylogenetic hypothesis is presented for all 95 species of the family Vibrionaceae (Bacteria: Gammaproteobacteria) based on a combined analysis of eight molecular loci (16S rRNA, gyrB, recA, rpoA, gapA, mreB, topA, atpA) for up to 9337 nucleotide characters. Members of this taxon exhibit diverse life histories, including bioluminescence, pathogenicity to human and marine organisms, symbiosis, quorum sensing and extremophilic environment living, making a hypothesis of phylogenetic history important to studies addressing these traits from an evolutionary perspective. It is proposed that this phylogenetic set of relationships replaces previous phenetic hypotheses and be used to construct a phylogenetic taxonomy. Recent taxonomic proposals, including the validity of four, instead of one, families representing the 95 species and historical notions of genera within the group are compared with the presented phylogenetic hypothesis. Character support is traced through the tree and is used to address these taxonomic proposals. Photobacterium is not a monophyletic group as it is currently delimited. Aliivibrio is found within Photobacterium, suggesting a new definition for Photobacterium that includes all species of Aliivibrio. Enterovibrio, Salinivibrio and Grimontia, previously thought to be distinct from and basal to Photobacterium and Vibrio, are found nested deeply within a large Vibrio clade. © The Willi Hennig Society 2010.

Mokhlesi B.,University of Chicago
Respiratory Care | Year: 2010

Obesity hyoventilation syndrome (OHS) is defined as the triad of obesity, daytime hypoventilation, and sleep-disordered breathing in the absence of an alternative neuromuscular, mechanical or metabolic explanation for hypoventilation. During the last 3 decades the prevalence of extreme obesity has markedly increased in the United States and other countries. With such a global epidemic of obesity, the prevalence of OHS is bound to increase. Patients with OHS have a lower quality of life, with increased healthcare expenses, and are at higher risk of developing pulmonary hypertension and early mortality, compared to eucapnic patients with sleep-disordered breathing. OHS often remains undiagnosed until late in the course of the disease. Early recognition is important, as these patients have significant morbidity and mortality. Effective treatment can lead to significant improvement in patient outcomes, underscoring the importance of early diagnosis. This review will include disease definition and epidemiology, clinical characteristics of the syndrome, pathophysiology, and morbidity and mortality associated with it. Lastly, treatment modalities will be discussed in detail. © 2010 Daedalus Enterprises.

Larsen P.E.,Argonne National Laboratory | Field D.,Natural Environment Research Council | Gilbert J.A.,Argonne National Laboratory | Gilbert J.A.,University of Chicago
Nature Methods | Year: 2012

Understanding the interactions between the Earth's microbiome and the physical, chemical and biological environment is a fundamental goal of microbial ecology. We describe a bioclimatic modeling approach that leverages artificial neural networks to predict microbial community structure as a function of environmental parameters and microbial interactions. This method was better at predicting observed community structure than were any of several single-species models that do not incorporate biotic interactions. The model was used to interpolate and extrapolate community structure over time with an average Bray-Curtis similarity of 89.7. Additionally, community structure was extrapolated geographically to create the first microbial map derived from single-point observations. This method can be generalized to the many microbial ecosystems for which detailed taxonomic data are currently being generated, providing an observation-based modeling technique for predicting microbial taxonomic structure in ecological studies. © 2012 Nature America, Inc. All rights reserved.

Vardiman J.,University of Chicago
Leukemia Research | Year: 2012

The purpose of any classification of hematologic neoplasms is to provide reliable criteria for their diagnosis and their classification into clinically relevant disease entities. In 1982, the French - American - British (FAB) group introduced such a classification for the myelodysplastic syndromes (MDS), a heterogenous group of diseases that prior to the FAB scheme was often referred to only as "preleukemia." Over the ensuing two decades, the FAB classification facilitated hundreds of morphologic, clinical, and genetic studies that helped to clarify the disease process and its management. The World Health Organization (WHO) classification of MDS is a consensus classification first introduced in 2001 and revised in 2008. It maintains much of the structure and philosophy of the FAB classification, but draws upon more recently acquired biologic and clinical information to refine the diagnostic criteria and improve its prognostic value. This paper outlines the evolution from the FAB to the WHO classification of MDS and gives a glimpse of what might lie beyond. © 2012 Elsevier Ltd.

Grove E.A.,University of Chicago
Genes and Development | Year: 2011

In canonicalWnt signaling, β-catenin translocates to the cell nucleus, interacting with Tcf/Lef factors to activate transcription of Wnt target genes. In this issue of Genes & Development, Vacik and colleagues (pp. 1783-1795) report that a highly conserved sequence in intron 5 of Tcf7l2 conceals an internal promoter region that, when activated by Vax2, drives transcription of truncated Tcf7l2 mRNAs. The encoded Tcf7l2 protein binds to DNA, but not β-catenin, and therefore acts as a dominant-negative Wnt antagonist. © 2011 by Cold Spring Harbor Laboratory Press.

Sprague S.M.,University of Chicago
Current Opinion in Endocrinology, Diabetes and Obesity | Year: 2010

Purpose Of Review: Renal osteodystrophy is a complex disorder of bone associated with chronic kidney disease (CKD). Disturbances in mineral metabolism, which include, phosphate retention, hypocalcemia, vitamin D deficiency, and hyperparathyroidism develop early in the progression of CKD. The Kidney Disease: Improving Global Outcomes (KDIGO) has proposed a new classification system to understand the complex pathophysiology in mineral metabolism and bone disease. Understanding this pathophysiology has become especially important, as recent evidence has suggested that disordered mineral metabolism is associated with increased cardiovascular mortality and morbidity in patients with CKD. Recent Findings: This review discusses the effect of these disturbances on the skeleton and how they result in altered bone structure and turnover. The degree of hyperparathyroidism appears to affect bone turnover; however, bone biopsies appear to be the only definitive method to specifically diagnose the bone lesion. Summary: This review will assist the clinician in the early identification of patients at risk of renal osteodystrophy. Therapeutic strategies could then be employed to prevent and correct these disturbances in mineral metabolism and, thus, avoid patient morbidity. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Brown R.L.,University of Chicago
Targeted Oncology | Year: 2011

In recent years, tyrosine kinase inhibitors (TKIs) have emerged as a new class of anti-cancer therapy with proven efficacy in several types of carcinoma. Although generally considered less toxic than cytotoxic chemotherapy, TKIs do have significant side effects including fatigue and hypertension. In addition, TKI-induced thyroid dysfunction is now recognized as a common toxicity that is associated with some TKI inhibitors. Detection of TKI-induced thyroid dysfunction requires routine monitoring of thyroid function and, in some cases, may require treatment. This review provides a comprehensive assessment of literature evaluating TKI-induced thyroid dysfunction, focusing on the potential mechanisms that result in this toxicity, whether the development of thyroid dysfunction is clinically meaningful, and controversies regarding treatment with thyroid hormone therapy. © Springer-Verlag 2011.

Bhattacharya B.,University of Montreal | Gronau M.,Technion - Israel Institute of Technology | Rosner J.L.,University of Chicago
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2013

CP asymmetries have been measured recently by the LHCb collaboration in three-body B+ decays to final states involving charged pions and kaons. Large asymmetries with opposite signs at a level of about 60% have been observed in B±→π±(or K±)π+π- and B±→π±K+K- for restricted regions in the Dalitz plots involving π+π- and K+K- with low invariant mass. U-spin is shown to predict corresponding δS=0 and δS=1 asymmetries with opposite signs and inversely proportional to their branching ratios, in analogy with a successful relation predicted thirteen years ago between asymmetries in Bs→K-π+ and B0→K+π-. We compare these predictions with the measured integrated asymmetries. Effects of specific resonant or non-resonant partial waves on enhanced asymmetries for low-pair-mass regions of the Dalitz plot are studied in B±→π±π+π-. The closure of low-mass π+π- and K+K- channels involving only ππ↔KK- rescattering may explain by CPT approximately equal magnitudes and opposite signs measured in B±→π±π+π- and B±→π±K+K-. © 2013 Elsevier B.V.

Sollid L.M.,University of Oslo | Jabri B.,University of Chicago
Current Opinion in Immunology | Year: 2011

Posttranslational modification (PTM) of antigen is a way to break T-cell tolerance to self-antigens and promote autoimmunity. However, the precise mechanisms by which modifications would facilitate autoimmune T-cell responses and how they relate to particular autoimmune-associated MHC molecules remain elusive. Celiac disease is a T-cell mediated enteropathy with a strong HLA association where the immune response is directed mainly against deamidated cereal gluten peptides that have been modified by the enzyme transglutaminase 2. The disease is further characterized by autoantibodies to transglutaminase 2 that have extraordinary high disease specificity and sensitivity. There have been important advances in the knowledge of celiac disease pathogenesis, and these insights may be applicable to other autoimmune disorders where PTM plays a role. This insight gives clues for understanding the involvement of PTMs in other autoimmune diseases. © 2011 Elsevier Ltd.

Guillery R.W.,Marmara University | Sherman S.M.,University of Chicago
Brain Research Reviews | Year: 2011

Many of the axons that carry messages to the thalamus for relay to the cerebral cortex are branched in a pattern long known from Golgi preparations. They send one branch to the thalamus and the other to motor centers of the brainstem or spinal cord. Because the thalamic branches necessarily carry copies of the motor instructions their messages have the properties of efference copies. That is, they can be regarded as providing reliable information about impending instructions contributing to movements that will produce changes in inputs to receptors, thus allowing neural centers to compensate for these changes of input. We consider how a sensory pathway like the medial lemniscus, the spinothalamic tract or the optic tract can also be seen to act as a pathway for an efference copy. The direct connections that ascending and cortical inputs to the thalamus also establish to motor outputs create sensorimotor relationships that provide cortex with a model of activity in lower circuits and link the sensory and the motor sides of behavior more tightly than can be expected from motor outputs with a single, central origin. These transthalamic connectional patterns differ from classical models of separate neural pathways for carrying efference copies of actions generated at higher levels, and introduce some different functional possibilities. © 2010 Elsevier B.V.

A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delayGirirajan et al. (2010)Nature Genetics 42(3):203-209 © 2010 John Wiley & Sons A/S.

The goal of this report is to review the relationships between Landau-Kleffner syndrome (LKS), electrical status epilepticus during sleep (ESES), and continuous spike-waves during sleep (CSWS). LKS is a clinical syndrome involving mainly acquired aphasia and sometimes seizures. Other clinical findings include cognitive impairments and global regression of behavior. The EEG may evolve from more benign conditions into ESES (or CSWS), seen in 50% of patients with LKS, or may also show focal findings. Seizures include atypical absence, generalized tonic-clonic, atonic, and partial motor attacks. Effective medications are discussed. The EEG patterns CSWS and ESES are likely equivalent terms. CSWS is used by some authors, and ESES by others. Patients with these patterns usually show mental retardation, seizures, and global regression. More benign EEG patterns, like focal discharges, may develop into these more severe generalized patterns, which are associated with atypical absences, negative myoclonus, and cognitive disturbances. Memory disorders are common, because the nearly continuous generalized discharges in sleep do not allow for the memory consolidation that also occurs during sleep. Medications and possible etiologies are discussed. © 2010 Elsevier Inc.

Beeler J.A.,University of Chicago
Brain Research | Year: 2011

Dopamine denervation gives rise to abnormal corticostriatal plasticity; however, its role in the symptoms and progression of Parkinson's disease (PD) has not been articulated or incorporated into current clinical models. The 'integrative selective gain' framework proposed here integrates dopaminergic mechanisms known to modulate basal ganglia throughput into a single conceptual framework: (1) synaptic weights, the neural instantiation of accumulated experience and skill modulated by dopamine-dependent plasticity and (2) system gain, the operating parameters of the basal ganglia, modulated by dopamine's on-line effects on cell excitability, glutamatergic transmission and the balance between facilitatory and inhibitory pathways. Within this framework and based on recent work, a hypothesis is presented that prior synaptic weights and established skills can facilitate motor performance and preserve function despite diminished dopamine; however, dopamine denervation induces aberrant corticostriatal plasticity that degrades established synaptic weights and replaces them with inappropriate, inhibitory learning that inverts the function of the basal ganglia resulting in 'anti-optimization' of motor performance. Consequently, mitigating aberrant corticostriatal plasticity represents an important therapeutic objective, as reflected in the long-duration response to levodopa, reinterpreted here as the correction of aberrant learning. It is proposed that viewing aberrant corticostriatal plasticity and learning as a provisional endophenotype of PD would facilitate investigation of this hypothesis. © 2011 Elsevier B.V.

Ober C.,University of Chicago | Vercelli D.,University of Arizona
Trends in Genetics | Year: 2011

Many environmental risk factors for common, complex human diseases have been revealed by epidemiologic studies, but how genotypes at specific loci modulate individual responses to environmental risk factors is largely unknown. Gene-environment interactions will be missed in genome-wide association studies and could account for some of the 'missing heritability' for these diseases. In this review, we focus on asthma as a model disease for studying gene-environment interactions because of relatively large numbers of candidate gene-environment interactions with asthma risk in the literature. Identifying these interactions using genome-wide approaches poses formidable methodological problems, and elucidating molecular mechanisms for these interactions has been challenging. We suggest that studying gene-environment interactions in animal models, although more tractable, might not be sufficient to shed light on the genetic architecture of human diseases. Lastly, we propose avenues for future studies to find gene-environment interactions. © 2010 Elsevier Ltd.