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Washington University in St. Louis is a private research university located in St. Louis, Missouri, United States. Founded in 1853, and named after George Washington, the university has students and faculty from all 50 U.S. states and more than 120 countries. Twenty-two Nobel laureates have been affiliated with Washington University, nine having done the major part of their pioneering research at the university. Washington University's undergraduate program is ranked 14th in the nation and 7th in admissions selectivity by U.S. News and World Report. The university is ranked 30th in the world by the Academic Ranking of World Universities. In 2006, the university received $434 million in federal research funds, ranking seventh among private universities receiving federal research and development support, and in the top four in funding from the National Institutes of Health.Washington University is made up of seven graduate and undergraduate schools that encompass a broad range of academic fields. Officially incorporated as "The Washington University," the university is occasionally referred to as "WUSTL," an acronym derived from its initials. More commonly, however, students refer to the university as "Wash. U." To prevent confusion over its location, the Board of Trustees added the phrase "in St. Louis" in 1976. Wikipedia.

Golumbek P.,Washington University in St. Louis
Seminars in Pediatric Neurology | Year: 2010

Autoimmune diseases make up a significant portion of the acute and chronic caseload of all pediatric neurologists. By comparing these diseases and their treatments side by side, common themes become evident. Therapeutic decisions follow patterns dependent on the clinical situation. Physicians must adapt therapy based on individual clinical responses. This article provides an overview of the current therapeutic options as they relate to the more common pediatric neuroimmune disorders. © 2010 Elsevier Inc.

Pickard W.F.,Washington University in St. Louis
Energy Policy | Year: 2013

Renewable energy is abundant, but not necessarily near the urban centers where it will be used. Therefore, it must be transported; and this transport entails a systemic energy penalty. In this paper simple qualitative calculations are introduced to show (i) that high-voltage direct-current (HVDC) power lines for megameter and greater distances are unlikely to achieve power capacities much beyond 2. GW, although they can be paralleled; (ii) that most sources and sinks of electric power are rather less than 10,000. km apart; (iii) that such long lines can be constructed to have transmission losses. <~2%; and (iv) that lines of such low loss in fact meet minimal standards of intergenerational equity. © 2013 Elsevier Ltd.

Wall L.L.,University of Washington | Wall L.L.,Washington University in St. Louis
Obstetrical and Gynecological Survey | Year: 2012

An obstetric fistula is classically regarded as an "accident of childbirth" in which prolonged obstructed labor leads to destruction of the vesicovaginal/rectovaginal septum with consequent loss of urinary and/or fecal control. Obstetric fistula is highly stigmatizing and afflicted women often become social outcasts. Although obstetric fistula has been eliminated from advanced industrialized nations, it remains a major public health problem in the world's poorest countries. Several million cases of obstetric fistula are currently thought to exist in sub-Saharan Africa and south Asia. Although techniques for the surgical repair of such injuries are well known, it is less clear which strategies effectively prevent fistulas, largely because of the complex interactions among medical, social, economic, and environmental factors present in those countries where fistulas are prevalent. This article uses the Haddon matrix, a standard tool for injury analysis, to examine the factors influencing obstetric fistula formation in low-resource countries. Construction of a Haddon matrix provides a "wide angle" overview of this tragic clinical problem. The resulting analysis suggests that the most effective short-term strategies for obstetric fistula prevention will involve enhanced surveillance of labor, improved access to emergency obstetric services (particularly cesarean delivery), competent medical care for women both during and after obstructed labor, and the development of specialist fistula centers to treat injured women where fistula prevalence is high. The long-term strategies to eradicate obstetric fistula must include universal access to emergency obstetric care, improved access to family planning services, increased education for girls and women, community economic development, and enhanced gender equity. Successful eradication of the obstetric fistula will require the mobilization of sufficient political will at both the international and individual country levels to ensure that adequate resources are devoted to this problem and that maternal health becomes a high priority on national political agendas. TARGET AUDIENCE: Obstetricians & Gynecologists and Family Physicians LEARNING OBJECTIVES: After participating in this CME activity, physicians should be better able to apply the Haddon matrix, a tool commonly used for injury analysis, to the field of obstetrics and gynecology; analyze the problem of obstructed labor and obstetric fistula formation in low-resource countries using the Haddon matrix, and implement possible strategies for the prevention of obstetric fistulas and the mitigation of harm in cases of obstructed labor that arise from the use of the Haddon matrix. Copyright © 2012 by Lippincott Williams & Wilkins.

Lynch M.,Indiana University | Abegg A.,Washington University in St. Louis
Molecular Biology and Evolution | Year: 2010

A central problem in evolutionary theory concerns the mechanisms by which adaptations requiring multiple mutations emerge in natural populations. We develop a series of expressions that clarify the scaling of the time to establishment of complex adaptations with population size, mutation rate, magnitude of the selective disadvantage of intermediate-state alleles, and the complexity of the adaptation. In general, even in the face of deleterious intermediate steps, the time to establishment is minimized in populations with very large size. Under a broad range of conditions, the time to establishment also scales by no more than the square of the mutation rate, regardless of the number of sites contributing to the adaptive change, demonstrating that the emergence of complex adaptations is only weakly constrained by the independent acquisition of mutations at the underlying sites. Mutator alleles with deleterious side effects have only moderate effects on the rate of adaptation in large populations but can cause a quantum decrease in the time to establishment of some adaptive alleles in small populations, although probably not at a high enough rate to offset the increased deleterious mutation load. Transient hypermutability, whereby a subset of gamete-producing cells mutate at an elevated rate in a nonheritable manner, may also elevate the rate of adaptation, although the effect is modest and appears to result from a simple increase in the rate of transitions between intermediate states rather than from the saltational production of doublet mutations. Taken together, these results illustrate the plausibility of the relatively rapid emergence of specific complex adaptations by conventional population genetic mechanisms and provide insight into the relative incidences of various paths of allelic adaptation in organisms with different population genetic features. © The Author 2010. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved.

Moeller K.D.,Washington University in St. Louis
Organometallics | Year: 2014

Organometallic reagents and catalysts are powerful tools for site-selectively modifying the surface of a microelectrode array. In this context, the reagents or catalysts are generated at the electrodes in the array and then destroyed again in the solution above the array. In this way, they can be used to conduct reactions that are confined to the regions of the array immediately surrounding the electrodes used. In the review presented, this general strategy is applied to a series of organometallic reactions that serve to illustrate the scope of synthetic chemistry possible. (Figure Presented) © 2014 American Chemical Society.

Liang W.-W.,Academia Sinica, Taiwan | Liang W.-W.,National Yang Ming University | Liang W.-W.,Washington University in St. Louis | Cheng S.-C.,Academia Sinica, Taiwan
Genes and Development | Year: 2015

The DEAD-box RNA helicase Prp5 is required for the formation of the prespliceosome through an ATP-dependent function to remodel U2 small nuclear ribonucleoprotein particles (snRNPs) and an ATP-independent function of unknown mechanism. Prp5 has also been implicated in proofreading the branch site sequence, but the molecular mechanism has not been well characterized. Using actin precursor mRNA (pre-mRNA) carrying branch sitemutations, we identified a Prp5-containing prespliceosome with Prp5 directly bound to U2 small nuclear RNA (snRNA). Prp5 is in contact with U2 in regions on and near the branchpoint-interacting stem–loop (BSL), suggesting that Prp5 may function in stabilizing the BSL. Regardless of its ATPase activity, Prp5 mutants that suppress branch site mutations associate with the spliceosome less tightly and allow more tri-snRNP binding for the reaction to proceed. Our results suggest a novel mechanism for how Prp5 functions in prespliceosome formation and proofreading of the branch site sequence. Prp5 binds to the spliceosome in association with U2 by interacting with the BSL and is released upon the base-pairing of U2 with the branch site to allow the recruitment of the tri-snRNP. Mutations impairing U2–branch site base-pairing retard Prp5 release and impede tri-snRNP association. Prp5 mutations that destabilize the Prp5–U2 interaction suppress branch site mutations by allowing progression of the pathway. © 2015 Liang and Cheng.

Levy P.T.,Washington University in St. Louis
Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography | Year: 2014

BACKGROUND: Establishment of the range of normal values and associated variations of two-dimensional (2D) speckle-tracking echocardiography (STE)-derived right ventricular (RV) strain is a prerequisite for its routine clinical application in children. The objectives of this study were to perform a meta-analysis of normal ranges of RV longitudinal strain measurements derived by 2D STE in children and to identify confounders that may contribute to differences in reported measures.METHODS: A systematic review was conducted in PubMed, Embase, Scopus, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov. Search hedges were created to cover the concepts of pediatrics, STE, and the right heart ventricle. Two investigators independently identified and included studies if they reported the 2D STE-derived RV strain measure RV peak global longitudinal strain, peak global longitudinal systolic strain rate, peak global longitudinal early diastolic strain rate, peak global longitudinal late diastolic strain rate, or segmental longitudinal strain at the apical, middle, and basal ventricular levels in healthy children. Quality and reporting of the studies were assessed. The weighted mean was estimated using random effects with 95% confidence intervals (CIs), heterogeneity was assessed using Cochran's Q statistic and the inconsistency index (I(2)), and publication bias was evaluated using funnel plots and Egger's test. Effects of demographic, clinical, equipment, and software variables were assessed in a metaregression.RESULTS: The search identified 226 children from 10 studies. The reported normal mean values of peak global longitudinal strain among the studies varied from -20.80% to -34.10% (mean, -29.03%; 95% CI, -31.52% to -26.54%), peak global longitudinal systolic strain rate varied from -1.30 to -2.40 sec(-1) (mean, -1.88 sec(-1); 95% CI, -2.10 to -1.59 sec(-1)), peak global longitudinal early diastolic strain rate ranged from 1.7 to 2.69 sec(-1) (mean, 2.34 sec(-1); 95% CI, 2.00 to 2.67 sec(-1)), and peak global longitudinal late diastolic strain rate ranged from 1.00 to 1.30 sec(-1) (mean, 1.18 sec(-1); 95% CI, 1.04 to 1.33 sec(-1)). A significant base-to-apex segmental strain gradient (P < .05) was observed in the RV free wall. There was significant between-study heterogeneity and inconsistency (I(2) > 88% and P < .01 for each strain measure), which was not explained by age, gender, body surface area, heart rate, frame rate, tissue-tracking methodology, equipment, or software. The metaregression showed that these effects were not significant determinants of variations among normal ranges of strain values. There was no evidence of publication bias (P = .59).CONCLUSIONS: This study is the first to define normal values of 2D STE-derived RV strain in children on the basis of a meta-analysis. The normal mean value in children for RV global strain is -29.03% (95% CI, -31.52% to -26.54%). The normal mean value for RV global systolic strain rate is -1.88 sec(-1) (95% CI, -2.10 to -1.59 sec(-1)). RV segmental strain has a stable base-to-apex gradient that highlights the dominance of deep longitudinal layers of the right ventricle that are aligned base to apex. Variations among different normal ranges did not appear to be dependent on differences in demographic, clinical, or equipment parameters in this meta-analysis. All of the eligible studies used equipment and software from one manufacturer (GE Healthcare). Copyright © 2014 American Society of Echocardiography. Published by Mosby, Inc. All rights reserved.

Woo A.,Washington University in St. Louis
Seminars in Plastic Surgery | Year: 2012

Velopharyngeal dysfunction (VPD) is a generic term which describes a set of disorders resulting in the leakage of air into the nasal passages during speech production. As a result, speech samples can demonstrate hypernasality, nasal emissions, and poor intelligibility. The finding of VPD can be secondary to several causes: anatomic, musculoneuronal, or behavioral/mislearning. To identify the etiology of VPD, patients must undergo a thorough velopharyngeal assessment comprised of perceptual speech evaluation and functional imaging, including video nasendoscopy and speech videofluoroscopy. These studies are then evaluated by a multidisciplinary team of specialists, who can decide on an optimal course for patient management. A treatment plan is developed and may include speech therapy, use of a prosthetic device, and/or surgical intervention. Different surgical options are discussed, including posterior pharyngeal flap, sphincter pharyngoplasty, Furlow palatoplasty, palatal re-repair, and posterior pharyngeal wall augmentation. Copyright © 2012 by Thieme Medical Publishers, Inc.

Sanz C.M.,Washington University in St. Louis
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2013

The emergence of technology has been suggested to coincide with scarcity of staple resources that led to innovations in the form of tool-assisted strategies to diversify or augment typical diets. We examined seasonal patterns of several types of tool use exhibited by a chimpanzee (Pan troglodytes) population residing in central Africa, to determine whether their technical skills provided access to fallback resources when preferred food items were scarce. Chimpanzees in the Goualougo Triangle exhibit a diverse repertoire of tool behaviours, many of which are exhibited throughout the year. Further, they have developed specific tool sets to overcome the issues of accessibility to particular food items. Our conclusion is that these chimpanzees use a sophisticated tool technology to cope with seasonal changes in relative food abundance and gain access to high-quality foods. Subgroup sizes were smaller in tool using contexts than other foraging contexts, suggesting that the size of the social group may not be as important in promoting complex tool traditions as the frequency and type of social interactions. Further, reports from other populations and species showed that tool use may occur more often in response to ecological opportunities and relative profitability of foraging techniques than scarcity of resources.

Ozcan A.,Washington University in St. Louis
IEEE Transactions on Medical Imaging | Year: 2011

A new, sample independent optimization criterion for minimizing the effect of the imaging gradients, including the directional awareness they create, is defined for diffusion tensor imaging (DTI) experiments. The DTI linear algebraic framework is expanded to a normed space to design optimal diffusion gradient schemes (DGS) in an integral fashion without separating the magnitude and direction of the DGS vectors. The feasible space of DGS vectors, for which the estimation equations are determinate, thus a hard constraint for the optimization, is parametrized. Newly generated optimal DGSs demonstrate on an isotropic sample and an ex-vivo baboon brain that the optimization goals are reached as well as a significant increase in estimation performance. © 2006 IEEE.

Li J.-S.,Washington University in St. Louis
IEEE Transactions on Automatic Control | Year: 2011

In this article, we investigate the problem of simultaneously steering an uncountable family of finite-dimensional time-varying linear systems with the same control signal. This class of control problems motivates further research in the new subject of control theory called Ensemble Control, a notion coming from the study of complex spin dynamics in nuclear magnetic resonance spectroscopy and imaging. We derive the necessary and sufficient controllability conditions and an accompanying analytical optimal control law for an ensemble of finite-dimensional time-varying linear systems. We show that ensemble controllability is in connection with singular values of the operator characterizing the system dynamics. In addition, the problem of optimal ensemble control of harmonic oscillators is studied to demonstrate the controllability results. We show that the optimal solutions are pertinent to the study of time-frequency limited signals and prolate spheroidal wave functions. A systematic study of ensemble control systems has immediate applications to dynamical systems with parameter uncertainty as well as to wide-ranging areas such as neuroscience and quantum control. The work in ensemble control will foster further developments in mathematical control and systems theory. © 2006 IEEE.

Domenech Rodriguez M.M.,Utah State University | Baumann A.A.,Washington University in St. Louis | Schwartz A.L.,Utah State University
American Journal of Community Psychology | Year: 2011

The cultural tailoring of interventions to reach underserved groups has moved from descriptive and proscriptive models to their application with existing evidence based treatments. To date few published examples illustrate the process of cultural adaptation. The current paper documents the adaptation of an evidence based parent training intervention, Parent Management Training-Oregon Model (PMTO™), for Spanish-speaking Latino parents using both process (Domenech Rodríguez and Wieling in Voices of color: first-person accounts of ethnic minority therapists, Sage, Thousand Oaks, 2004) and content (Bernal et al. in J Abnorm Child Psychol 23:67-82, 1995) models. The adaptation took place in stages: a pilot study to ensure feasibility, focus groups to establish appropriate format and goals, and a test of the intervention. Throughout the process the treatment manual was treated as a living document. Changes were applied and documented as the team developed improvements for the adaptation. The present discussion details both process adaptations, (e.g., engaging the treatment developer, community leaders, and parents, and decentering the manual), and content adaptations, (e.g., shaping the appropriateness of language, persons, metaphors, concepts, contexts, methods, and goals). The current research provides support for the idea that cultural adaptations can improve service delivery to diverse groups and can be conducted systematically with documentation for replication purposes. Suggestions for improving the empirical measurement and documentation of the adaptation process are included. © 2010 Society for Community Research and Action.

Leonard J.C.,Washington University in St. Louis
Pediatric Clinics of North America | Year: 2013

Once a child is determined to be at risk of having a cervical spine injury, clinicians must take appropriate precautions to avoid potential worsening of neurologic deficits. Occasionally these decisions are made in the absence of adequate cervical spine imaging when dealing with a child's unstable airway or other life-threatening injuries. Furthermore, clinicians have to make decisions regarding appropriate diagnostic testing to evaluate for potential injury. Decisions regarding testing should take into consideration the clinical presentation of the patient, aiming to order appropriate testing for those at risk and avoid unnecessary testing for those without signs of cervical spine injury. © 2013 Elsevier Inc.

Stein P.K.,Washington University in St. Louis | Pu Y.,CardioNet
Sleep Medicine Reviews | Year: 2012

Heart rate (HR) is modulated by the combined effects of the sympathetic and parasympathetic nervous systems. Therefore, measurement of changes in HR over time (heart rate variability or HRV) provides information about autonomic functioning. HRV has been used to identify high risk people, understand the autonomic components of different disorders and to evaluate the effect of different interventions, etc. Since the signal required to measure HRV is already being collected on the electrocardiogram (ECG) channel of the polysomnogram (PSG), collecting data for research on HRV and sleep is straightforward, but applications have been limited. As reviewed here, HRV has been applied to understand autonomic changes during different sleep stages. It has also been applied to understand the effect of sleep-disordered breathing, periodic limb movements and insomnia both during sleep and during the daytime. HRV has been successfully used to screen people for possible referral to a Sleep Lab. It has also been used to monitor the effects of continuous positive airway pressure (CPAP). A novel HRV measure, cardiopulmonary coupling (CPC) has been proposed for sleep quality. Evidence also suggests that HRV collected during a PSG can be used in risk stratification models, at least for older adults. Caveats for accurate interpretation of HRV are also presented. © 2011 Elsevier Ltd.

Bhattacharjee P.,Washington University in St. Louis | Bhattacharjee P.,Saha Institute of Nuclear Physics | Chaudhury S.,Saha Institute of Nuclear Physics | Kundu S.,Saha Institute of Nuclear Physics
Astrophysical Journal | Year: 2014

The rotation curve (RC) of our Galaxy, the Milky Way, is constructed starting from its very inner regions (few hundred parsecs) out to a large galactocentric distance of 200 kpc using kinematical data on a variety of tracer objects moving in the gravitational potential of the Galaxy, without assuming any theoretical models of the visible and dark matter (DM) components of the Galaxy. We study the effect on the RC due to the uncertainties in the values of the Galactic constants (GCs) R 0 and V 0 (these being the Sun's distance from and circular rotation speed around the Galactic center, respectively) and the velocity anisotropy parameter β of the halo tracer objects used for deriving the RC at large galactocentric distances. The resulting RC in the disk region is found to depend significantly on the choice of the GCs, while the dominant uncertainty in the RC at large distances beyond the stellar disk comes from the uncertainty in the value of β. In general we find that the mean RC steadily declines at distances beyond 60 kpc, independently of the value of β. Also, at a given radius, the circular speed is lower for larger values of β (i.e., for more radially biased velocity anisotropy). Considering that the largest possible value of β is unity, which corresponds to stellar orbits being purely radial, our results for the case of β = 1 give a lower limit to the total mass of the Galaxy within 200 kpc, M(200 kpc) ≳ (6.8 ± 4.1) × 1011 M ⊙, independently of any model of the DM halo of the Galaxy. © 2014. The American Astronomical Society. All rights reserved.

Yeung L.L.,University of Florida | Brandes S.B.,Washington University in St. Louis
Urology | Year: 2013

Objective: To survey urologic reconstruction experts to determine practice and surveillance patterns used after urethroplasty. Methods: We conducted an international survey of the members of the Society of Genitourinary Reconstructive Surgeons between July 23 and October 13, 2010 through email. Participants were surveyed regarding the nomenclature used to define strictures, urethroplasty practice patterns, follow-up practice patterns, and methods used to screen for stricture recurrence. Results: The response rate was 48.9% (n = 90). Urethroplasty failure was commonly defined as the need for a secondary urethral procedure (60.0%), significant narrowing on imaging (14.4%), urethral narrowing preventing passage of 16F cystoscope (12.2%) or poor uroflow, or American Urological Association Symptom Score (7.8%). Only one-third of responders followed up their patients >3 years after surgery. To screen for stricture recurrence, 85% used uroflowmetry, 56% used postvoid residual, 19% used flexible cystoscopy, and 17% used retrograde urethrography. Nearly half (48%) of the surgeons did not use validated instruments to evaluate the quality of life after urethroplasty. For those who used validated questionnaires, the ones most often used were the American Urological Association Symptom Score (41%) and Sexual Health Inventory for Men (19%). Conclusion: There is no consensus regarding follow-up practices after urethroplasty. Most experts define urethroplasty failure as "need for a secondary procedure," do not follow-up patients for a long-term, and do not use validated questionnaires. A standardized definition for stricture recurrence and a standardized follow-up protocol are desperately needed to allow for effective comparison of results between studies. © 2013 Elsevier Inc. All Rights Reserved.

Woodroofe R.,Washington University in St. Louis
Journal of Combinatorial Theory. Series A | Year: 2011

A recent framework for generalizing the Erdo{double acute}s-Ko-Rado theorem, due to Holroyd, Spencer, and Talbot, defines the Erdo{double acute}s-Ko-Rado property for a graph in terms of the graph's independent sets. Since the family of all independent sets of a graph forms a simplicial complex, it is natural to further generalize the Erdo{double acute}s-Ko-Rado property to an arbitrary simplicial complex. An advantage of working in simplicial complexes is the availability of algebraic shifting, a powerful shifting (compression) technique, which we use to verify a conjecture of Holroyd and Talbot in the case of sequentially Cohen-Macaulay near-cones. © 2010 Elsevier Inc.

Kwate N.O.A.,Rutgers University | Goodman M.S.,Washington University in St. Louis
Social Science and Medicine | Year: 2014

Accumulated evidence has demonstrated that social position matters for health. Those with greater socioeconomic resources and greater perceived standing in the social hierarchy have better health than those with fewer resources and lower perceived standing. Race is another salient axis by which health is stratified in the U.S., but few studies have examined the benefit of White privilege. In this paper, we investigated how perceptions of inequality and subjective and objective social status affected the health and well-being of N=630 White residents in three Boston neighborhoods lying on a social gradient differentiated by race, ethnicity, income and prestige. Outcomes were self-rated health, dental health, and happiness. Results suggested that: neighborhood residence was not associated with health after controlling for individual level factors (e.g., positive ratings of the neighborhood, education level); objective measures of socioeconomic status were associated with better self-reported and dental health, but subjective assessments of social position were more strongly associated; and White residents living in the two wealthiest neighborhoods, and who perceived Black families as welcome in their neighborhoods enjoyed better health than those who believed them to be less welcome. However, those who lived in the least wealthy and most diverse neighborhood fared worse when reporting Black families to be welcome. These results suggest that White privilege and relative social position interact to shape health outcomes. © 2014 Elsevier Ltd.

Baumard N.,University of Pennsylvania | Boyer P.,Washington University in St. Louis
Trends in Cognitive Sciences | Year: 2013

Moralizing religions, unlike religions with morally indifferent gods or spirits, appeared only recently in some (but not all) large-scale human societies. A crucial feature of these new religions is their emphasis on proportionality (between deeds and supernatural rewards, between sins and penance, and in the formulation of the Golden Rule, according to which one should treat others as one would like others to treat oneself). Cognitive science models that account for many properties of religion can be extended to these religions. Recent models of evolved dispositions for fairness in cooperation suggest that proportionality-based morality is highly intuitive to human beings. The cultural success of moralizing movements, secular or religious, could be explained based on proportionality. © 2013 Elsevier Ltd.

Carpenter C.R.,Washington University in St. Louis | Platts-Mills T.F.,University of North Carolina at Chapel Hill
Clinics in Geriatric Medicine | Year: 2013

Alternative management methods are essential to ensure high-quality and efficient emergency care for the growing number of geriatric adults worldwide. Protocols to support early condition-specific treatment of older adults with acute severe illness and injury are needed. Improved emergency department care for older adults will require providers to address the influence of other factors on the patient's health. This article describes recent and ongoing efforts to enhance the quality of emergency care for older adults using alternative management approaches spanning the spectrum from prehospital care, through the emergency department, and into evolving inpatient or outpatient processes of care. © 2013 Elsevier Inc.

Chang Y.V.,University of Washington | Chang Y.V.,Washington University in St. Louis
Magnetic Resonance in Medicine | Year: 2012

We present a new phase-based method for mapping the amplitude of the radio-frequency field (B 1) of a transmitter coil in three-dimension. This method exploits the noncommutation relation between rotations about orthogonal axes. Our implementation of this principle in the current work results in a simple relation between the phase of the final magnetization and the flip angle (FA). In this study, we focus on FAs less than 90°. Our method is rapid and easy to implement compared with the existing B 1 mapping schemes. The mapping sequence can be simply obtained by adding to a regular three-dimensional gradient-echo sequence a magnetization preparation radio-frequency pulse of the same FA but orthogonal in phase to the excitation radio-frequency pulse. This method is demonstrated capable of generating reliable maps of the B 1 field within 1 min using FAs no larger than 60°. We show that it is robust against T 1, small chemical shift, and mild background inhomogeneity. This method may especially be suitable for B 1 mapping in situations (e.g., long-T 1 and hyperpolarized-gas imaging) where magnitude-based methods are not readily applicable. A noise calculation of the FA map using this method is also presented. Copyright © 2011 Wiley Periodicals, Inc.

Bartlett N.L.,Washington University in St. Louis
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2010

Despite the use of less toxic chemotherapy and more limited doses and fields of radiation, the prognosis for patients with all stages of classical Hodgkin lymphoma (HL) has continued to improve over the last 20 years. The challenge today is better identification of prognostic markers that will allow even further reduction of therapy in the most favorable subsets and new approaches for those who have a high risk of failure with current approaches. Most ongoing clinical trials for newly diagnosed HL base therapy decisions on the result of an interim restaging PET/CT, de-escalating for early responders and escalating for patients with a suboptimal response. While awaiting the results of these important trials, the debates rage on regarding the use of consolidative radiotherapy in early stage HL and the use of escalated BEACOPP in advanced stage disease. Unfortunately, we still face the very difficult decision with nearly every patient with HL of "too much," risking long-term consequences, or "too little," risking relapse and the need for additional toxic therapy. At present, we need to make these very difficult initial treatment decisions with inadequate data, but reassured by the excellent outcomes for most patients and encouraged by the new agents available for those who fail first-line therapy.

Gru A.A.,Washington University in St. Louis | Santa Cruz D.J.,WCP Laboratories
Seminars in Diagnostic Pathology | Year: 2013

The head and neck area has disproportionate number of cutaneous tumors given the surface area, as compared with the rest of the body. Many of the tumors are related to chronic actinic damage and the most common by far are squamous and basal cell carcinomas. Atypical fibroxanthoma refers to a group of usually indolent cutaneous tumors that occur in older adults and are characterized histologically by a population of fusiform, epithelioid, and pleomorphic cells, numerous cells in mitosis, and intracytoplasmic lipidization in some cells. Numerous histologic variants have been described, including a clear-cell, desmoplastic or keloidal, granular, angiomatoid, hemosiderotic, and myxoid, among others. These tumors have a mesenchymal immunophenotype. Some authors believe that atypical fibroxanthoma is a dedifferentiated variant of squamous cell carcinoma. We present a review of this particular neoplasm with special emphasis on the histomorphology, subtypes, immunophenotypic profile, and discussion of differential diagnosis. © 2013 Elsevier Inc.

Dixit R.,Washington University in St. Louis
Current Biology | Year: 2013

A new study reveals that DELLA proteins directly interact with the prefoldin complex, thus regulating tubulin subunit availability in a gibberellin-dependent manner. This finding provides a mechanistic link between the growth-promoting plant hormone gibberellin and cortical microtubule organization. © 2013 Elsevier Ltd.

Rebmann T.,Washington University in St. Louis | Greene L.R.,Rochester General Health System
American Journal of Infection Control | Year: 2010

The Association for Professionals in Infection Control and Epidemiology (APIC) began publishing their series of Elimination Guides in 2007. Since then, 9 Elimination Guides have been developed that cover a range of important infection prevention issues, including the prevention of catheter-related bloodstream infections, ventilator-associated pneumonia, and catheter-associated urinary tract infections (CAUTIs), as well as mediastinitis surgical site surveillance. Multidrug-resistant organisms, including methicillin-resistant Staphylococcus aureus, Clostridium difficile, and multidrug-resistant Acinetobacter baumannii, also have been the focus of APIC Elimination Guides. The content of each of these Elimination Guides will be summarized in a series of upcoming Brief Reports published in The Journal. This article provides an executive summary of the APIC Elimination Guide for CAUTIs. Infection preventionists are encouraged to obtain the original, full-length APIC Elimination Guide for more thorough coverage of CAUTI prevention. Copyright © 2010 by the Association for Professionals in Infection Control and Epidemiology, Inc.

Cooper M.A.,Howard Hughes Medical Institute | Yokoyama W.M.,Washington University in St. Louis | Yokoyama W.M.,Howard Hughes Medical Institute
Immunological Reviews | Year: 2010

Natural killer (NK) cells are lymphocytes with the capacity to produce cytokines and kill target cells upon activation. NK cells have long been categorized as members of the innate immune system and as such have been thought to follow the 'rules' of innate immunity, including the principle that they have no immunologic memory, a property thought to be strictly limited to adaptive immunity. However, recent studies have suggested that NK cells have the capacity to alter their behavior based on prior activation. This property is analogous to adaptive immune memory; however, some NK cell memory-like functions are not strictly antigen dependent and can be demonstrated following cytokine stimulation. Here, we discuss the recent evidence that NK cells can exhibit properties of immunologic memory, focusing on the ability of cytokines to non-specifically induce memory-like NK cells with enhanced responses to restimulation. © 2010 John Wiley & Sons A/S.

BACKGROUND:: Isoflurane is a potent volatile anesthetic; however, it evokes airway irritation and neurogenic constriction through transient receptor potential (TRP) A1 channels and sensitizes TRPV1 channels, which colocalizes with TRPA1 in most of the vagal C-fibers innervating the airway. However, little is known about the precise effects of these two channels on the respiratory function during isoflurane anesthesia.METHODS:: By using a rodent behavioral model and whole-body plethysmograph, the authors examined the response of Trpa1 and Trpv1 mice to isoflurane anesthesia and monitored their respiratory functions during anesthesia.RESULTS:: This study showed that Trpa1 mice (n = 9), but not Trpv1 mice (n = 11), displayed a shortened induction latency compared with wild-type mice (n = 10) during isoflurane anesthesia (33 ± 2.0 s in wild-type and 33 ± 3.8 s in Trpv1 vs. 17 ± 1.8 in Trpa1 at 2.2 minimum alveolar concentrations). By contrast, their response to the nonpungent volatile anesthetic sevoflurane is indistinguishable from wild-type mice (24 ± 3.6 s in wild-type vs. 26 ± 1.0 s in Trpa1 at 2.4 minimum alveolar concentrations). The authors discovered that Trpa1 mice inhaled more anesthetic but maintained better respiratory function. Further respiration pattern analysis revealed that isoflurane triggered nociceptive reflexes and led to prolonged resting time between breaths during isoflurane induction as well as decreased dynamic pulmonary compliance, an indicator of airway constriction, throughout isoflurane anesthesia in wild-type and Trpv1 mice, but not in Trpa1 mice.CONCLUSION:: Activation of TRPA1 by isoflurane negatively affects anesthetic induction latency by altering respiratory patterns and impairing pulmonary compliance. Copyright © by 2015, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. All Rights Reserved.

Li Z.-Y.,CAS Institute of Physics | Xia Y.,Washington University in St. Louis
Nano Letters | Year: 2010

Single-molecule detection via surface-enhanced Raman scattering (SERS) has raised great interest over the past decade. The usual approach toward this goal is to harness the strong surface plasmon resonance of light with complex metallic nanostructures, such as particle aggregates, two-particle gaps, sharp tips, or particles with sharp apexes. Here we propose another route toward the goal by introducing gain medium into single metal nanoparticles with simple geometry. Our calculations show that cubic gold nanobox particles that contain a gain material within the core can create an extremely high enhancement factor of local field intensity larger than 10 8 and a SERS enhancement factor on the order of 10 16 - 10 17. © 2010 American Chemical Society.

Larson D.E.,Washington University in St. Louis
PLoS computational biology | Year: 2010

We present a computer simulation and associated experimental validation of assembly of glial-like support cells into the interweaving hexagonal lattice that spans the Drosophila pupal eye. This process of cell movements organizes the ommatidial array into a functional pattern. Unlike earlier simulations that focused on the arrangements of cells within individual ommatidia, here we examine the local movements that lead to large-scale organization of the emerging eye field. Simulations based on our experimental observations of cell adhesion, cell death, and cell movement successfully patterned a tracing of an emerging wild-type pupal eye. Surprisingly, altering cell adhesion had only a mild effect on patterning, contradicting our previous hypothesis that the patterning was primarily the result of preferential adhesion between IRM-class surface proteins. Instead, our simulations highlighted the importance of programmed cell death (PCD) as well as a previously unappreciated variable: the expansion of cells' apical surface areas, which promoted rearrangement of neighboring cells. We tested this prediction experimentally by preventing expansion in the apical area of individual cells: patterning was disrupted in a manner predicted by our simulations. Our work demonstrates the value of combining computer simulation with in vivo experiments to uncover novel mechanisms that are perpetuated throughout the eye field. It also demonstrates the utility of the Glazier-Graner-Hogeweg model (GGH) for modeling the links between local cellular interactions and emergent properties of developing epithelia as well as predicting unanticipated results in vivo.

Adams-Leander S.,Washington University in St. Louis
Nephrology nursing journal : journal of the American Nephrology Nurses' Association | Year: 2011

In many cases, optimal treatment for end stage renal disease (ESRD) is living kidney donation. African Americans are of interest because of high incidence of ESRD, documented disparities regarding kidney transplantation, and under-representation in living kidney donor research. An interpretive qualitative study was conducted among African Americans to improve understanding of living donation to genetically or emotionally related recipients. Two major themes emerged - context of living kidney donation and work of living kidney donors. Specially noted are the influence of spiritual and religious practices, and experiences of participants with history of substance abuse. Research recommendations and clinical implications are presented.

Cobanera E.,Indiana University Bloomington | Ortiz G.,Indiana University Bloomington | Nussinov Z.,Washington University in St. Louis
Physical Review Letters | Year: 2010

We show how classical and quantum dualities, as well as duality relations that appear only in a sector of certain theories (emergent dualities), can be unveiled, and systematically established. Our method relies on the use of morphisms of the bond algebra of a quantum Hamiltonian. Dualities are characterized as unitary mappings implementing such morphisms, whose even powers become symmetries of the quantum problem. Dual variables, which have been guessed in the past, can be derived in our formalism. We obtain new self-dualities for four-dimensional Abelian gauge field theories. © 2010 The American Physical Society.

Engle E.K.,Washington University in St. Louis | Fay J.C.,University of Washington
PLoS Genetics | Year: 2012

Changes in gene expression are commonly observed during evolution. However, the phenotypic consequences of expression divergence are frequently unknown and difficult to measure. Transcriptional regulators provide a mechanism by which phenotypic divergence can occur through multiple, coordinated changes in gene expression during development or in response to environmental changes. Yet, some changes in transcriptional regulators may be constrained by their pleiotropic effects on gene expression. Here, we use a genome-wide screen for promoters that are likely to have diverged in function and identify a yeast transcription factor, FZF1, that has evolved substantial differences in its ability to confer resistance to sulfites. Chimeric alleles from four Saccharomyces species show that divergence in FZF1 activity is due to changes in both its coding and upstream noncoding sequence. Between the two closest species, noncoding changes affect the expression of FZF1, whereas coding changes affect the expression of SSU1, a sulfite efflux pump activated by FZF1. Both coding and noncoding changes also affect the expression of many other genes. Our results show how divergence in the coding and promoter region of a transcription factor alters the response to an environmental stress. © 2012 Engle, Fay.

McKinnon W.B.,Washington University in St. Louis
Geophysical Research Letters | Year: 2015

Enceladus's degree 2 gravity, determined by Cassini, is nominally nonhydrostatic to 3σ (J2/C22 = 3.38-3.63, as opposed to 10/3). Iess et al. (2014) interpret this in terms of a hydrostatic interior (core) and isostatic (not hydrostatic) floating ice shell. Enceladus's rapid (1.37 d) synchronous spin and tide distorts its shape substantially, though, enough that the predicted hydrostatic J2/C22 is not 10/3 but closer to 3.25. This leads to the following revision to the internal picture of Enceladus, compared with Iess et al.: (1) the satellite's core is somewhat smaller and slightly denser (190 km radius and 2450 kg/m3); (2) the compensation depth (shell thickness) of the global (degree 2) ice shell is ≈ 50 km, rather close to the base of the modeled ice + water layer; and (3) the compensation depth (shell thickness) beneath the South Polar Terrain (from J3) remains shallower (thinner) at ≈ 30 km, independent of but influenced by the degree 2 solution. ©2015. American Geophysical Union. All Rights Reserved.

Kinch M.S.,Washington University in St. Louis | Flath R.,Institute for Life science Collaboration
Drug Discovery Today | Year: 2015

The way in which new medicines are discovered has irreversibly changed and the future sustainability of the enterprise is characterized by an unprecedented period of uncertainty. Herein, we convey that these changes provide unprecedented opportunities for many different players within the private and public sectors to work together and develop new models that ensure the sustainability of activities that have had an extraordinary impact; in terms of promoting public health and driving economic value. Specific examples of experiments are provided to demonstrate some of the new thinking that will be needed to ensure continuation of new drug discovery.

Vaughn A.E.,University of North Carolina at Chapel Hill | Tabak R.G.,Washington University in St. Louis | Bryant M.J.,University of Leeds | Ward D.S.,University of North Carolina at Chapel Hill
International Journal of Behavioral Nutrition and Physical Activity | Year: 2013

During the last decade, there has been a rapid increase in development of instruments to measure parent food practices. Because these instruments often measure different constructs, or define common constructs differently, an evaluation of these instruments is needed. A systematic review of the literature was conducted to identify existing measures of parent food practices and to assess the quality of their development. The initial search used terms capturing home environment, parenting behaviors, feeding practices and eating behaviors, and was performed in October of 2009 using PubMed/Medline, PsychInfo, Web of knowledge (ISI), and ERIC, and updated in July of 2012. A review of titles and abstracts was used to narrow results, after which full articles were retrieved and reviewed. Only articles describing development of measures of parenting food practices designed for families with children 2-12 years old were retained for the current review. For each article, two reviewers extracted data and appraised the quality of processes used for instrument development and evaluation. The initial search yielded 28,378 unique titles; review of titles and abstracts narrowed the pool to 1,352 articles; from which 57 unique instruments were identified. The review update yielded 1,772 new titles from which14 additional instruments were identified. The extraction and appraisal process found that 49% of instruments clearly identified and defined concepts to be measured, and 46% used theory to guide instrument development. Most instruments (80%) had some reliability testing, with internal consistency being the most common (79%). Test-retest or inter-rater reliability was reported for less than half the instruments. Some form of validity evidence was reported for 84% of instruments. Construct validity was most commonly presented (86%), usually with analysis of associations with child diet or weight/BMI. While many measures of food parenting practices have emerged, particularly in recent years, few have demonstrated solid development methods. Substantial variation in items across different scales/constructs makes comparison between instruments extremely difficult. Future efforts should be directed toward consensus development of food parenting practices constructs and measures. © 2013 Vaughn et al.; licensee BioMed Central Ltd.

Hofmeister A.M.,Washington University in St. Louis
Physics of the Earth and Planetary Interiors | Year: 2010

Examining length and time scales reveals ruinous problems in diverse determinations of thermal conductivity (k) involving the diamond anvil cell (DAC). (1) Conditions in laboratory experiments are optically thick (diffusive) for low-frequency phonons, but optically thin (ballistic) for high-frequency photons. Because speeds of photons are about ×105 those of phonons, ballistic photons transport heat over the short length and time scales of pulse-heating measurements in the DAC intended to measure phonons. Ballistic transport was confirmed by conducting pulse-heating experiments under various conditions. Not accounting for this time-dependent effect produces fallacious values for the lattice contribution to k. (2) In DAC optical spectroscopy, strong refraction was misinterpreted as sample absorption and its affect on path length went unnoticed, resulting in invalid calculations of the radiative diffusive component of k. Better estimates of lower mantle k are summarized. Scaling aspects point to the controls exerted by radiative transfer early in Earth's history and the importance of mantle layers to Earth's present thermal state. Diffusion of radiation is fast, making retention of primordial heat improbable: thus today's Earth is in quasi-steady-state, wherein its emitted heat is derived solely from current radiogenic contents. © 2010 Elsevier B.V.

Calvert A.L.,Washington University in St. Louis
Journal of the experimental analysis of behavior | Year: 2010

Humans discount larger delayed rewards less steeply than smaller rewards, whereas no such magnitude effect has been observed in rats (and pigeons). It remains possible that rats' discounting is sensitive to differences in the quality of the delayed reinforcer even though it is not sensitive to amount. To evaluate this possibility, Experiment 1 examined discounting of qualitatively different food reinforcers: highly preferred versus nonpreferred food pellets. Similarly, Experiment 2 examined discounting of highly preferred versus nonpreferred liquid reinforcers. In both experiments, an adjusting-amount procedure was used to determine the amount of immediate reinforcer that was judged to be of equal subjective value to the delayed reinforcer. The amount and quality of the delayed reinforcer were varied across conditions. Discounting was well described by a hyperbolic function, but no systematic effects of the quantity or the quality of the delayed reinforcer were observed.

Dresser R.,Washington University in St. Louis
Journal of Law, Medicine and Ethics | Year: 2012

Novel nanomedical interventions require human testing to evaluate their safety and effectiveness. To establish a proper evidentiary basis for human trials, nanomedical innovations must first be subjected to animal and other laboratory testing. But it is uncertain whether the traditional laboratory approaches to safety evaluation will supply adequate information on nanotechnology risks to humans. This uncertainty, together with other features of nanomedical innovation, heightens the ethical challenges in conducting FIH nanotrials. © 2012 American Society of Law, Medicine & Ethics, Inc.

Pickard W.F.,Washington University in St. Louis | Abbott D.,University of Adelaide
Proceedings of the IEEE | Year: 2012

The storage of power line frequency electrical energy as electrical energy is limited to capacitors and inductors, and neither has proven particularly practical where massive amounts of energy are involved. When electric power is needed, the stored energy is back-converted to electricity and returned to the grid. These conversions, however, are not ideally efficient, and each process is characterized by a figure of merit called the cycle efficiency, defined as the ratio of the total joules delivered to the grid over a suitable study period divided by the total joules received from the grid during the same period. As the number of grid-connected CSP farms increases, the resulting spatial diversity provides opportunity for averaging out the intermittency. Also, if CSP farms are connected across several time zones, and even across seasonal boundaries, the need for storage is lessened. It makes little sense to convert electricity to heat to store it because of the low efficiency of back conversion.

Taylor J.-S.,Washington University in St. Louis
DNA Repair | Year: 2015

How DNA damaged is formed, recognized, and repaired in chromatin is an area of intense study. To better understand the structure activity relationships of damaged chromatin, mono and dinucleosomes containing site-specific damage have been prepared and studied. This review will focus on the design, synthesis, and characterization of model systems of damaged chromatin for structural, physical, and enzymatic studies. © 2015 Elsevier B.V.

Paris P.C.,Washington University in St. Louis
Meccanica | Year: 2014

The primary objective of this work is to discuss the origins, background and development of the elastic crack tip stress intensity factor, K, as they occurred. The further development of the three modes and the compilations of related formulas in the literature are discussed. The origins of applications to static crack growth stability, and sub-critical growth due to fatigue and environmental effects are included. Significant events such as the formation of the ASTM committee on Fracture Mechanics, the adoption of Damage Tolerance Analysis by the aircraft industry using Fracture Mechanics as a basis, and the further extension of the methods to large-scale plasticity conditions are presented. Finally a discussion of early predictions of crack paths is discussed. © 2014 Springer Science+Business Media Dordrecht.

Kostakioti M.,Washington University in St. Louis
Cold Spring Harbor perspectives in medicine | Year: 2013

Biofilm formation constitutes an alternative lifestyle in which microorganisms adopt a multicellular behavior that facilitates and/or prolongs survival in diverse environmental niches. Biofilms form on biotic and abiotic surfaces both in the environment and in the healthcare setting. In hospital wards, the formation of biofilms on vents and medical equipment enables pathogens to persist as reservoirs that can readily spread to patients. Inside the host, biofilms allow pathogens to subvert innate immune defenses and are thus associated with long-term persistence. Here we provide a general review of the steps leading to biofilm formation on surfaces and within eukaryotic cells, highlighting several medically important pathogens, and discuss recent advances on novel strategies aimed at biofilm prevention and/or dissolution.

Kollef M.H.,Washington University in St. Louis
BMC infectious diseases | Year: 2014

Gram-positive bacteria to include methicillin-resistant Staphylococcus aureus (MRSA), methicillin-susceptible Staphylococcus aureus (MSSA), and enterococci, to include vancomycin-resistant enterococci (VRE), display a remarkable array of resistance and virulence factors, which have contributed to their prominent role in infections of the critically ill. Over the last three decades infections with these pathogens has increased as has their overall resistance to available antimicrobial agents. This has led to the development of a number of new antibiotics for the treatment of Gram-positive bacteria. At present, it is important that clinicians recognize the changing resistance patterns and epidemiology of Gram-positive bacteria as these factors may impact patient outcomes. The increasing range of these pathogens, such as the emergence of community-associated MRSA clones, emphasizes that all specialties of physicians treating infections should have a good understanding of the infections caused by Gram-positive bacteria in their area of practice. When initiating empiric antibiotics, it is of vital importance that this therapy be timely and appropriate, as delays in treatment are associated with adverse outcomes. Although vancomycin has traditionally been considered a first-line therapy for serious MRSA infections, multiple concerns with this agent have opened the door for alternative agents demonstrating efficacy in this role. Similarly, the expansion of VRE as a pathogen in the ICU setting has required the development of agents targeting this important pathogen.

Dorn G.W.,Washington University in St. Louis | Dorn G.W.,University of Washington | Kitsis R.N.,Yeshiva University
Circulation Research | Year: 2015

Mitochondrial research is experiencing a renaissance, in part, because of the recognition that these endosymbiotic descendants of primordial protobacteria seem to be pursuing their own biological agendas. Not only is mitochondrial metabolism required to produce most of the biochemical energy that supports their eukaryotic hosts (us) but mitochondria can actively (through apoptosis and programmed necrosis) or passively (through reactive oxygen species toxicity) drive cellular dysfunction or demise. The cellular mitochondrial collective autoregulates its population through biogenic renewal and mitophagic culling; mitochondrial fission and fusion, 2 components of mitochondrial dynamism, are increasingly recognized as playing central roles as orchestrators of these processes. Mitochondrial dynamism is rare in striated muscle cells, so cardiac-specific genetic manipulation of mitochondrial fission and fusion factors has proven useful for revealing noncanonical functions of mitochondrial dynamics proteins. Here, we review newly described functions of mitochondrial fusion/fission proteins in cardiac mitochondrial quality control, cell death, calcium signaling, and cardiac development. A mechanistic conceptual paradigm is proposed in which cell death and selective organelle culling are not distinct processes, but are components of a unified and integrated quality control mechanism that exerts different effects when invoked to different degrees, depending on pathophysiological context. This offers a plausible explanation for seemingly paradoxical expression of mitochondrial dynamics and death factors in cardiomyocytes wherein mitochondrial morphometric remodeling does not normally occur and the ability to recover from cell suicide is severely limited. © 2014 American Heart Association, Inc.

Carter C.S.,University of California at Davis | Barch D.M.,Washington University in St. Louis
Schizophrenia Bulletin | Year: 2012

The Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia initiative, funded by an R13 conference grant from the National Institute of Mental Health, has sought to facilitate the translation of measures from the basic science of cognition into practical brain-based tools to measure treatment effects on cognition in schizophrenia. In this overview article, we summarize the process and products of the sixth meeting in this series, which focused on the identification of promising imaging paradigms, based on the measurement of cognitive evoked potentials (event-related potential) of cognition-related time-frequency analyses of the electroencephalography as well as functional magnetic resonance imaging. A total of 23 well-specified paradigms from cognitive neuroscience that measure cognitive functions previously identified as targets for treatment development were identified at the meeting as being recommended for the further developmental work needed in order to validate and optimize them as biomarker measures. Individual paradigms are discussed in detail in 6 domain-based articles in this volume. Ongoing issues related to the development of these and other measures as valid, sensitive and reliable measurement, and assessment tools, as well as the steps necessary for the development of specific measures for use as biomarkers for treatment development and personalized medicine, are discussed. © 2011 The Author.

Schaefer S.Y.,University of Washington | Patterson C.B.,Washington University in St. Louis | Lang C.E.,University of Washington
Neurorehabilitation and Neural Repair | Year: 2013

Background. Although task-specific training is emerging as a viable approach for recovering motor function after stroke, there is little evidence for whether the effects of such training transfer to other functional motor tasks not directly practiced in therapy. Objective. The purpose of the current study was to test whether training on one motor task in individuals with chronic hemiparesis poststroke would transfer to untrained tasks that were either spatiotemporally similar or different. Methods. In all, 11 participants with chronic mild to moderate hemiparesis following stroke completed 5 days of supervised massed practice of a feeding task with their affected side. Performance on the feeding task, along with 2 other untrained functional upper-extremity motor tasks (sorting, dressing) was assessed before and after training. Results. Performance of all 3 tasks improved significantly after training exclusively on 1 motor task. The amount of improvement in the untrained tasks was comparable and was not dependent on the degree of similarity to the trained task. Conclusions. Because the number and type of tasks that can be practiced are often limited within standard stroke rehabilitation, results from this study will be useful for designing task-specific training plans to maximize therapy benefits. © The Author(s) 2013.

Kotipatruni R.P.,Washington University in St. Louis
Integrative biology : quantitative biosciences from nano to macro | Year: 2012

Meningiomas are the second most common brain tumor, and 20-30% of these tumors are aggressive. The aggressive subtypes are characterized by a capacity for invasion of normal brain with frequent and destructive recurrence patterns. Effective local therapies include surgery and radiation, but there is a need for novel molecular targets to improve survival and reduce morbidity for this group or cancer patients. We have recently identified the N-Myc downstream regulated gene 4, NDRG4, protein as being overexpressed in aggressive meningioma, and in this report, demonstrate its role in cell survival, invasion/migration and angiogenesis. Downregulation of NDRG4 mRNA and protein expression in two high-grade meningioma cancer cell lines, IOMM-Lee and CH-157 MN resulted in reduction in cell survival, DNA fragmentation and G2-M cell cycle arrest. NDRG4 downregulation also decreased cellular invasion and migration, as determined by spheroid migration, linear and radial wound healing, Boyden chamber matrigel invasion, and 3D invasion assays. To determine the effect of NDRG4 depletion on angiogenesis, we studied the immortalized brain endothelial cell line, bEnd.3. We treated bEnd.3 cells with conditioned media from NDRG4-depleted IOMM-Lee and CH-157 MN cells and abrogated their ability to elicit bEnd.3 capillary-like tubes, to proliferate, and to invade. NDRG4 is not overexpressed in bEnd.3 cells and direct NDRG4 depletion had no effect on the cells. This study is significant as it is the first to demonstrate the functional role of NDRG4 in various aspects of meningioma tumor biology. NDRG4 is involved in modulating cell proliferation, invasion, migration and angiogenesis in meningioma, and may play a valuable role as a molecular target in its treatment.

Olsen K.M.,Washington University in St. Louis
Nature Genetics | Year: 2012

A new study shows that three independent mutations in the Sh1 gene, which encodes a YABBY transcription factor, gave rise to the non-shattering seed phenotype in domesticated sorghum. This same gene may have also had a role in the domestication of other cereals, including maize and rice. © 2012 Nature America, Inc. All rights reserved.

Morley S.C.,Washington University in St. Louis
International Journal of Cell Biology | Year: 2012

L-plastin is a leukocyte-specific protein that cross-links actin filaments into tight bundles, increasing the stability of actin-based structures such as podosomes and lamellipodia. While first identified as an abundant cytoplasmic protein in hematopoietically derived cells over 25 years ago, the requirement for L-plastin in multiple functions critical for immunity, such as antigen receptor signaling, adhesion, and motility, has only recently become clear. L-plastin has been identified as an important component in cellular processes critical for neutrophil, macrophage, osteoclast, eosinophil, and T- and B-lymphocyte biology. Following a brief description of the structure and function of L-plastin, the regulation of immune cell functions by L-plastin will be reviewed in detail. Copyright © 2012 Sharon Celeste Morley.

Dearing J.W.,Kaiser Permanente | Kreuter M.W.,Washington University in St. Louis
Patient Education and Counseling | Year: 2010

Objective: The best innovations in cancer communication do not necessarily achieve uptake by researchers, public health and clinical practitioners, and policy makers. This paper describes design activities that can be applied and combined for the purpose of spreading effective cancer communication innovations. Methods: A previously developed Push-Pull-Infrastructure Model is used to organize and highlight the types of activities that can be deployed during the design phase of innovations. Scientific literature about the diffusion of innovations, knowledge utilization, marketing, public health, and our experiences in working to spread effective practices, programs, and policies are used for this purpose. Results: Attempts to broaden the reach, quicken the uptake, and facilitate the use of cancer communication innovations can apply design activities to increase the likelihood of diffusion. Some simple design activities hold considerable promise for improving dissemination and subsequent diffusion. Conclusion: Augmenting current dissemination practices with evidence-based concepts from diffusion science, marketing science, and knowledge utilization hold promise for improving results by eliciting greater market pull. Practice implications: Inventors and change agencies seeking to spread cancer communication innovations can experience more success by explicit consideration of design activities that reflect an expanded version of the Push-Pull-Infrastructure Model. © 2010 Elsevier Ireland Ltd.

Chun S.,Washington University in St. Louis
PloS one | Year: 2013

Preterm birth is a complex disorder defined by gestations of less than 37 weeks. While preterm birth is estimated to have a significant genetic component, relative few genes have been associated with preterm birth. Polymorphism in one such gene, follicle-stimulating hormone receptor (FSHR), has been associated with preterm birth in Finnish and African American mothers but not other populations. To refine the genetic association of FSHR with preterm birth we conducted a fine-mapping study at the FSHR locus in a Finnish cohort. We sequenced a total of 44 kb, including protein-coding and conserved non-coding regions, in 127 preterm and 135 term mothers. Overall, we identified 288 single nucleotide variants and 65 insertion/deletions of 1-2 bp across all subjects. While no common SNPs in protein-coding regions were associated with preterm birth, including one previously associated with timing of fertilization, multiple SNPs spanning the first and second intron showed the strongest associations. Analysis of the associated SNPs revealed that they form both a protective (OR = 0.50, 95% CI = 0.25-0.93) as well as a risk (OR = 1.89, 95% CI = 1.08-3.39) haplotype with independent effects. In these haplotypes, two SNPs, rs12052281 and rs72822025, were predicted to disrupt ZEB1 and ELF3 transcription factor binding sites, respectively. Our results show that multiple haplotypes at FSHR are associated with preterm birth and we discuss the frequency and structure of these haplotypes outside of the Finnish population as a potential explanation for the absence of FSHR associations in some populations.

Gao L.,University of Illinois at Urbana - Champaign | Wang L.V.,Washington University in St. Louis
Physics Reports | Year: 2016

Multidimensional optical imaging has seen remarkable growth in the past decade. Rather than measuring only the two-dimensional spatial distribution of light, as in conventional photography, multidimensional optical imaging captures light in up to nine dimensions, providing unprecedented information about incident photons' spatial coordinates, emittance angles, wavelength, time, and polarization. Multidimensional optical imaging can be accomplished either by scanning or parallel acquisition. Compared with scanning-based imagers, parallel acquisition-also dubbed snapshot imaging-has a prominent advantage in maximizing optical throughput, particularly when measuring a datacube of high dimensions. Here, we first categorize snapshot multidimensional imagers based on their acquisition and image reconstruction strategies, then highlight the snapshot advantage in the context of optical throughput, and finally we discuss their state-of-the-art implementations and applications. © 2015 Elsevier B.V.

Inglis R.F.,Washington University in St. Louis
ISME Journal | Year: 2016

The evolution of bacterial resistance to conventional antimicrobials is a widely documented phenomenon with gravely important consequences for public health. However, bacteria also produce a vast repertoire of natural antimicrobials, presumably in order to kill competing species. Bacteriocins are a common class of protein-based antimicrobials that have been shown to have an important role in the ecology and evolution of bacterial communities. Relative to the evolution of antibiotic resistance, little is known about how novel resistance to these toxic compounds evolves. In this study, we present results illustrating that, although resistance is able to evolve, it remains critically dependent on the environmental context. Resistance to bacteriocins, in particular the pyocin S2, evolves readily when iron is present but less so when iron is limiting, because the receptor for this pyocin is also required for iron uptake during iron limitation. This suggests that although resistance to bacteriocins can easily evolve, environmental conditions will determine how and when resistance occurs.The ISME Journal advance online publication, 23 February 2016; doi:10.1038/ismej.2016.15. © 2016 International Society for Microbial Ecology

Trinkaus E.,Washington University in St. Louis
American Journal of Physical Anthropology | Year: 2012

The distal half of a right human humerus (E.898), recovered ex situ in 1925 by Hrdlička at the Broken Hill Mine, Kabwe, Zambia, has figured prominently in assessments of Middle Pleistocene Homo postcranial variation and of the phylogenetic polarity and functional anatomy of Pleistocene Homo upper limb morphology. Reassessment of distal humeral features that distinguish modern human and some archaic Homo humeri, especially relative olecranon breadth and medial and lateral pillar thicknesses, confirm previous studies placing it morphologically close to recent humans, as well as possibly to Early Pleistocene Homo. However, it completely lacks stratigraphic context, and there is faunal and archeological evidence for human activity at Broken Hill from the Middle Pleistocene to the Holocene. Given its uncertain geological age and modern human morphology, the Broken Hill E.898 humerus should not be used in analyses of Pleistocene humans until it is securely dated. Copyright © 2012 Wiley Periodicals, Inc.

Mesfin A.,Washington University in St. Louis
Orthopedics | Year: 2012

To the authors' knowledge, few reports have been published in the English literature of using total knee arthroplasty and total hip arthroplasty for the treatment of hereditary multiple exostoses. This article describes 2 patients with hereditary multiple exostoses, 1 treated with total hip arthroplasty and 1 treated with total knee arthroplasty. Bony deformities make arthroplasty uniquely challenging in patients undergoing total hip or knee arthroplasty. An expanded metaphysis of the proximal femur, coxa valga deformity, and the presence of hardware from previous reconstructive surgeries can make total hip arthroplasty technically difficult. Substantial bony deformity of the distal femur, valgus deformity of the knee, and sizing issues that necessitate custom implants can make total knee arthroplasty difficult. The most common bony deformities in hereditary multiple exostoses are short stature, limb-length discrepancy, valgus deformity at the knee and ankle, and asymmetry of the pectoral and pelvic girdles. Most reported surgical treatments for patients with hereditary multiple exostoses focus on the pediatric population or the management of malignant transformation of exostoses. Studies that specifically address the conditions associated with knee deformities focus on extra-articular deformity correction rather than arthroplasty.When arthroplasty is necessary in this patient population, an understanding of the commonly occurring deformities can help with preoperative planning and surgical management. All painful lesions must be evaluated for malignant transformation. Bone scans can be useful during workup. All specimens should be sent for pathologic evaluation. Such patients are challenging because of the distorted hip anatomy and valgus knee deformity. The current 2 cases illustrate specific challenges that can be anticipated and underscore key principles for arthroplasty in the management of hereditary multiple exostoses. Copyright 2012, SLACK Incorporated.

Gruev V.,Washington University in St. Louis
Optics Express | Year: 2011

In this paper we present a procedure for fabricating an array of micropolarization filter array via an optimized interference lithography and microfabrication procedure. The filter array is composed of two linear polarization filters offset by 45 degrees with pixel pitch of 18 microns. The individual polarization filters are composed of aluminum nanowires with 140 nm pitch, 140 nm height and 70 nm width. The maximum extinction ratio of the pixelated filters is measured to be 95 at 700nm wavelength. © 2011 Optical Society of America.

Murayama K.,University of Reading | Miyatsu T.,Washington University in St. Louis | Buchli D.,University of California at Los Angeles | Storm B.C.,University of California at Santa Cruz
Psychological Bulletin | Year: 2014

Retrieving a subset of items can cause the forgetting of other items, a phenomenon referred to as retrieval-induced forgetting. According to some theorists, retrieval-induced forgetting is the consequence of an inhibitory mechanism that acts to reduce the accessibility of nontarget items that interfere with the retrieval of target items. Other theorists argue that inhibition is unnecessary to account for retrievalinduced forgetting, contending instead that the phenomenon can be best explained by noninhibitory mechanisms, such as strength-based competition or blocking. The current article provides the first major meta-analysis of retrieval-induced forgetting, conducted with the primary purpose of quantitatively evaluating the multitude of findings that have been used to contrast these 2 theoretical viewpoints. The results largely supported inhibition accounts but also provided some challenging evidence, with the nature of the results often varying as a function of how retrieval-induced forgetting was assessed. Implications for further research and theory development are discussed. © 2014 American Psychological Association.

Chelaru F.,Washington University in St. Louis
Nature methods | Year: 2014

Visualization is an integral aspect of genomics data analysis. Algorithmic-statistical analysis and interactive visualization are most effective when used iteratively. Epiviz (http://epiviz.cbcb.umd.edu/), a web-based genome browser, and the Epivizr Bioconductor package allow interactive, extensible and reproducible visualization within a state-of-the-art data-analysis platform.

Rypel A.L.,Washington University in St. Louis
Oikos | Year: 2014

A frequent assumption in invasion ecology is that invasive species have enhanced growth rates in their invasive ranges. However, invasions frequently occur in sub-tropical and tropical environments where growth could be higher simply due to climatic conditions rather than novel habitat. In this study, a meta-analysis of growth rates (length-at-age data) was completed for six invasive freshwater fish species: common carp Cyprinus carpio, largemouth bass Micropterus salmoides, brown trout Salmo trutta, brown bullhead Ictalurus nebulosus, flathead catfish Pylodictis olivaris and northern snakehead Channa argus. Significant effects of climate on growth were observed for all species except common carp, and following normalization of growth for climate effects, a range of growth responses between native and invasive populations were revealed. Two species (brown trout, flathead catfish) showed significantly increased growth rates in invasive compared to native ranges, but two species (common carp, largemouth bass) showed significantly faster growth in native ranges, and two other species (northern snakehead, brown bullhead) showed no difference in growth rates. No species showed both significantly enhanced growth rates and initial sizes in invasive compared to native ranges. Using the comparative method, countergradient growth variations were apparent for all species within their native ranges and for all but one species in invasive ranges. Invasive populations of freshwater fish do not always grow faster when invasive and future studies need to consider growth covariates (e.g. climate and countergradient growth) prior to comparing life-history differences between invasive and native populations. © 2013 The Authors.

Rios A.,University of Surrey | Polls A.,University of Barcelona | Dickhoff W.H.,Washington University in St. Louis
Physical Review C - Nuclear Physics | Year: 2014

We study the one-body momentum distribution at different densities in nuclear matter, with special emphasis on its components at high momentum. Explicit calculations for finite neutron-proton asymmetry, based on the ladder self-consistent Green's function approach, allow us to access the isospin dependence of momentum distributions and elucidate their role in neutron-rich systems. Comparisons with the deuteron momentum distribution indicate that a substantial proportion of high-momentum components are dominated by tensor correlations. We identify the density dependence of these tensor correlations in the momentum distributions. Further, we find that high-momentum components are determined by the density of each subspecies and we provide a new isospin-asymmetry scaling of these components. We use different realistic nucleon-nucleon interactions to quantify the model dependence of our results. © 2014 Published by the American Physical Society.

Balzer D.T.,Washington University in St. Louis
Current Opinion in Pediatrics | Year: 2012

PURPOSE OF REVIEW: A recent development within pediatric cardiology is percutaneous pulmonary valve implantation (PPVI). This has extended the life of surgical conduits and decreased the number of surgical procedures required. Early reports focused on feasibility and safety of the technique; recent literature has focused on avoidance of complications such as stent fractures and on expanding the procedure to nonconduit implantation. The purpose of this review is to summarize the recent data regarding stent fractures and alternative uses of the valve. RECENT FINDINGS: Stent fractures following PPVI are reported in 20-28% of patients. Prestenting has recently been shown to be protective and to extend the freedom from stent fractures. The use of PPVI has also been reported in nonconduit positions such as in bioprosthetic tricuspid valves, branch pulmonary arteries, aortic and mitral positions. In addition, the valve has been implanted in higher pressure environments. The short-term success in these applications appears to be quite good. SUMMARY: PPVI has allowed extension of the life of surgical conduits and failure of the valve is mainly related to stent fractures. Recent developments have minimized this complication. In addition, use of the valve has been extended to nontraditional locations and short-term results are favorable. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Berk D.R.,Washington University in St. Louis
Pediatric Dermatology | Year: 2012

Terra firma-forme dermatosis is an idiopathic condition characterized by acquired, dirtlike plaques despite normal hygiene. A diagnosis can be reached by removing lesions with gentle alcohol swabbing. Although Terra firma-forme dermatosis was first described more than 20 years ago and is thought to be not uncommon in clinical practice, it has never been systematically studied. There are few publications about this condition, including no case series of more than six patients. In particular, little is known about the incidence, peak age groups, and most common locations of Terra firma-forme dermatosis. A retrospective review was conducted to identify cases of Terra firma-forme dermatosis in a single-provider practice consisting of 55% pediatric and 45% adult patients. Thirty-one patients with Terra firma-forme dermatosis were identified, including 10 who presented with Terra firma-forme dermatosis as their primary concern. Only two patients were older than 17 years. The median duration of lesions was 4 months. The most common lesion locations were the neck, ankles, and face. Before presenting to the dermatology clinic, three patients had undergone endocrine evaluations, and four had been prescribed topical corticosteroids. Terra firma-forme dermatosis is relatively common and most often occurs in children on the neck or posterior malleolus. This series exemplifies the importance of recognizing Terra firma-forme dermatosis so as to provide rapid relief for patients and avoid unnecessary tests and treatments. © 2011 Wiley Periodicals, Inc.

Macroporous hydrogels may have direct applications in regenerative medicine as scaffolds to support tissue formation. Hydrogel microspheres may be used as drug-delivery vehicles or as building blocks to assemble modular scaffolds. A variety of techniques exist to produce macroporous hydrogels and hydrogel microspheres. A subset of these relies on liquid-liquid two-phase systems. Within this subset, vastly different types of polymerization processes are found. In this review, the history, terminology and classification of liquid-liquid two-phase polymerization and crosslinking are described. Instructive examples of hydrogel microsphere and macroporous scaffold formation by precipitation/dispersion, emulsion and suspension polymerizations are used to illustrate the nature of these processes. The role of the kinetics of phase separation in determining the morphology of scaffolds and microspheres is also delineated. Brief descriptions of miniemulsion, microemulsion polymerization and ionotropic gelation are also included. © 2010 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Katz J.I.,Washington University in St. Louis
Modern Physics Letters A | Year: 2016

Fast radio bursts (FRBs) are millisecond bursts of radio radiation at frequencies of about 1 GHz, recently discovered in pulsar surveys. They have not yet been definitively identified with any other astronomical object or phenomenon. The bursts are strongly dispersed, indicating passage through a high column density of low density plasma. The most economical interpretation is that this is the intergalactic medium, indicating that FRB are at "cosmological" distances with redshifts in the range 0.3-1.3. Their inferred brightness temperatures are as high as 1037 K, implying coherent emission by "bunched" charges, as in radio pulsars. I review the astronomical sites, objects and emission processes that have been proposed as the origin of FRB, with particular attention to soft gamma repeaters (SGRs) and giant pulsar pulses. © 2016 World Scientific Publishing Company.

Morrow-Howell N.,Washington University in St. Louis
The journals of gerontology. Series B, Psychological sciences and social sciences | Year: 2010

OBJECTIVES: This review summarizes the current knowledge about volunteering in later life and suggests 5 research questions at the forefront of knowledge development. RESULTS: Rates of volunteering do not decline significantly until the middle of the 7th decade, and older volunteers commit more hours than younger volunteers. Older adults with more human and social capital tend to volunteer, and there is good evidence of a reciprocal relationship between volunteering and well-being. Program and policy developments in the field are outstripping production of knowledge to support evidence-based practices. DISCUSSION: Research on the dynamics of volunteering over the life course as well as the patterns of activities that co-occur with volunteering is needed to guide program development. Research methods and findings from transdisciplinary work on the mechanisms through which psychosocial conditions affect health must be extended to the study of the effects of volunteering on older adults. Finally, we need to engage in more applied social science aimed at improving volunteer management, especially recruitment and retention of older volunteers.

Boden M.T.,Center for Innovation to Implementation | Thompson R.J.,Washington University in St. Louis
Emotion | Year: 2015

Emotion theories posit that effective emotion regulation depends upon the nuanced information provided by emotional awareness; attending to and understanding one's own emotions. Additionally, the strong associations between facets of emotional awareness and various forms of psychopathology may be partially attributable to associations with emotion regulation. These logically compelling hypotheses are largely uninvestigated, including which facets compose emotional awareness and how they relate to emotion regulation strategies and psychopathology. We used exploratory structural equation modeling of individual difference measures among a large adult sample (n = 919) recruited online. Results distinguished 4 facets of emotional awareness (type clarity, source clarity, involuntary attention to emotion, and voluntary attention to emotion) that were differentially associated with expressive suppression, acceptance of emotions, and cognitive reappraisal. Facets were associated with depression both directly and indirectly via associations with emotion regulation strategies. We discuss implications for theory and research on emotional awareness, emotion regulation, and psychopathology. © 2014 American Psychological Association.

Repovs G.,University of Ljubljana | Barch D.M.,Washington University in St. Louis
Frontiers in Human Neuroscience | Year: 2012

A growing number of studies have reported altered functional connectivity in schizophrenia during putatively "task-free" states and during the performance of cognitive tasks. However, there have been few systematic examinations of functional connectivity in schizophrenia across rest and different task states to assess the degree to which altered functional connectivity reflects a stable characteristic or whether connectivity changes vary as a function of task demands. We assessed functional connectivity during rest and during three working memory loads of an N-back task (0-back, 1-back, 2-back) among: (1) individuals with schizophrenia (N = 19); (2) the siblings of individuals with schizophrenia (N = 28); (3) healthy controls (N = 10); and (4) the siblings of healthy controls (N = 17). We examined connectivity within and between four brain networks: (1) frontal-parietal (FP); (2) cingulo-opercular (CO); (3) cerebellar (CER); and (4) default mode (DMN). In terms of within-network connectivity, we found that connectivity within the DMN and FP increased significantly between resting state and 0-back, while connectivity within the CO and CER decreased significantly between resting state and 0-back. Additionally, we found that connectivity within both the DMN and FP was further modulated by memory load. In terms of between network connectivity, we found that the DMN became significantly more "anti-correlated" with the FP, CO, and CER networks during 0-back as compared to rest, and that connectivity between the FP and both CO and CER networks increased with memory load. Individuals with schizophrenia and their siblings showed consistent reductions in connectivity between both the FP and CO networks with the CER network, a finding that was similar in magnitude across rest and all levels of working memory load. These findings are consistent with the hypothesis that altered functional connectivity in schizophrenia reflects a stable characteristic that is present across cognitive states. © 2012 Repovš and Barch.

Thompson B.,Arizona State University | Moon T.S.,Washington University in St. Louis | Nielsen D.R.,Arizona State University
Current Opinion in Biotechnology | Year: 2014

The versatile functionality of microbial biocatalysts offers a promising solution to the growing need to replace conventional, petroleum-derived fuels, chemicals, and materials with sustainable alternatives from renewable biomass. Whereas metabolic pathway engineering and strain optimization have greatly expanded the range of attainable bioproducts, it is by coupling microbial biosynthesis with traditional chemical conversions that the diversity of products that can ultimately be derived from biomass is truly beginning to reach its full potential. As will be the focus of this short review, such 'hybrid' strategies are now facilitating the generation of new and useful value-added bioproducts from renewable sources, the likes of which have previously been unattainable via biological routes alone. © 2014 Elsevier Ltd.

Solomatov V.S.,Washington University in St. Louis
Physics of the Earth and Planetary Interiors | Year: 2012

Numerical simulations of infinite Prandtl number convection in the stagnant lid regime of temperature-dependent viscosity convection demonstrate the existence of spatially localized, stable convective cells below the critical Rayleigh number (subcritical convection). These solutions are in stark contrast to the usual, supercritical, convective planforms, where convective cells form in the entire layer. The isolated cell has a shape of an axisymmetric dome with an upwelling at the center and thus appears as a very weak plume. Formation of these structures requires subcritical conditions and a localized initial temperature perturbation but does not require any spatial heterogeneity in the material properties or the heat flux. When several localized plumes form, they tend to attract to each other and form stable clusters. This type of subcritical convection may play a role in the formation and longevity of localized features on planetary bodies, including the crustal dichotomy and Tharsis region on Mars and the asymmetric pattern of volcanism on Mercury. © 2012 Elsevier B.V.

Akcakaya M.,ARCON Corporation | Nehorai A.,Washington University in St. Louis
IEEE Transactions on Signal Processing | Year: 2011

We consider the effect of imperfect separability in the received signals on the detection performance of multi-input multi-output (MIMO) radar with widely separated antennas. The mutual orthogonality among the received signals is often assumed but cannot be achieved in practice for all Doppler and delay pairs. We introduce a data model considering the correlation among the data from different transmitter-receiver pairs as unknown parameters. Based on the expectation maximization algorithm, we propose a method to estimate the target, correlation, and noise parameters. We then use the estimates of these parameters to develop a statistical decision test. Employing the asymptotic statistical characteristics and the numerical performance of the test, we analyze the sensitivity of the MIMO radar with respect to changes in the cross-correlation levels of the measurements. We demonstrate the effect of the increase in the correlation among the received signals from different transmitters on the detection performance. © 2011 IEEE.

Brandt K.E.,Washington University in St. Louis
Plastic and Reconstructive Surgery | Year: 2010

The Maintenance of Certification module series is designed to help the clinician structure his or her study in specific areas appropriate to his or her clinical practice. This article is prepared to accompany practice-based assessment of preoperative assessment, anesthesia, surgical treatment plan, perioperative management, and outcomes. In this format, the clinician is invited to compare his or her methods of patient assessment and treatment, outcomes, and complications, with authoritative, information-based references. This information base is then used for self-assessment and benchmarking in parts II and IV of the Maintenance of Certification process of the American Board of Plastic Surgery. This article is not intended to be an exhaustive treatise on the subject. Rather, it is designed to serve as a reference point for further in-depth study by review of the reference articles presented. © 2010 by the American Society of Plastic Surgeons.

Graubert T.,Washington University in St. Louis
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2011

Myelodysplastic syndromes (MDS) are a heterogenous group of hematologic malignancies characterized by clonal expansion of BM myeloid cells with impaired differentiation. The identification of recurrent mutations in MDS samples has led to new insights into the pathophysiology of these disorders. Of particular interest is the recent recognition that genes involved in the regulation of histone function (EZH2, ASXL1, and UTX) and DNA methylation (DNMT3A, IDH1/IDH2, and TET2) are recurrently mutated in MDS, providing an important link between genetic and epigenetic alterations in this disease. The mechanism by which these mutated genes contribute to disease pathogenesis is an active area of research, with a current focus on which downstream target genes may be affected. Recent advances from sequencing studies suggest that multiple mutations are required for MDS initiation and progression to acute myeloid leukemia (AML). The past several years have yielded many new insights, but the complete genetic landscape of MDS is not yet known. Moreover, few (if any) of the findings are sufficiently robust to be incorporated into routine clinical practice at this time. Additional studies will be required to understand the prognostic implications of these mutations for treatment response, progression to AML, and survival.

Botero C.A.,North Carolina State University | Botero C.A.,Washington University in St. Louis | Weissing F.J.,University of Groningen | Wright J.,Norwegian University of Science and Technology | Rubenstein D.R.,Columbia University
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

In an era of rapid climate change, there is a pressing need to understand how organisms will cope with faster and less predictable variation in environmental conditions. Here we develop a unifying model that predicts evolutionary responses to environmentally driven fluctuating selection and use this theoretical framework to explore the potential consequences of altered environmental cycles. We first show that the parameter space determined by different combinations of predictability and timescale of environmental variation is partitioned into distinct regions where a single mode of response (reversible phenotypic plasticity, irreversible phenotypic plasticity, bet-hedging, or adaptive tracking) has a clear selective advantage over all others. We then demonstrate that, although significant environmental changes within these regions can be accommodated by evolution, most changes that involve transitions between regions result in rapid population collapse and often extinction. Thus, the boundaries between response mode regions in our model correspond to evolutionary tipping points, where even minor changes in environmental parameters can have dramatic and disproportionate consequences on population viability. Finally, we discuss how different life histories and genetic architectures may influence the location of tipping points in parameter space and the likelihood of extinction during such transitions. These insights can help identify and address some of the cryptic threats to natural populations that are likely to result from any natural or human-induced change in environmental conditions. They also demonstrate the potential value of evolutionary thinking in the study of global climate change. © 2015, National Academy of Sciences. All rights reserved.

Bathias C.,Paris West University Nanterre La Defense | Paris P.C.,Washington University in St. Louis
International Journal of Fatigue | Year: 2010

According to the Paris-Hertzberg crack growth law, an analytical model shows that cracks grow from a flaw very quickly from the short to the long cracks regime, during gigacycle fatigue. The location of the initiation, at the surface or inside, has a small effect. This means that the key problem is the nucleation of the crack around the flaws as it is shown by Lukas et al. and Mughrabi and Stanzl [Lukas P, Kunz L, Svoboda M, Bokuvka O. Fatigue behaviour of ultra fine-grain copper in VHCF regime. In: VHCF4, Ann Arbor; 2007. p. 265-70, [1]; Mughrabi H, Stanzl S. Fatigue damage evolution in ductile single phase FCC metals in the UHCF regime. In: VHCF4, Ann Arbor; 2007. p. 75-82, [2]]. This approach is applied to a PM Ni alloy which is used for aircraft turbine. It is concluded that the damage tolerance concept is to be applied with cautiousness for VHCF prediction, in PM alloys. © 2009.

Quinn E.A.,Washington University in St. Louis
American Journal of Physical Anthropology | Year: 2013

Maternal reproductive investment includes both the energetic costs of gestation and lactation. For most humans, the metabolic costs of lactation will exceed those of gestation. Mothers must balance reproductive investment in any single offspring against future reproductive potential. Among mammals broadly, mothers may differentially invest in offspring based on sex and maternal condition provided such differences investment influence future offspring reproductive success. For humans, there has been considerable debate if there are physiological differences in maternal investment by offspring sex. Two recent studies have suggested that milk composition differs by infant sex, with male infants receiving milk containing higher fat and energy; prior human studies have not reported sex-based differences in milk composition. This study investigates offspring sex-based differences in milk macronutrients, milk energy, and nursing frequency (per 24 h) in a sample of 103 Filipino mothers nursing infants less than 18 months of age. We found no differences in milk composition by infant sex. There were no significant differences in milk composition of mothers nursing first-born versus later-born sons or daughters or between high- and low-income mothers nursing daughters or sons. Nursing frequency also showed no significant differences by offspring sex, sex by birth order, or sex by maternal economic status. In the Cebu sample, there is no support for sex-based differences in reproductive investment during lactation as indexed by milk composition or nursing frequency. Further investigation in other populations is necessary to evaluate the potential for sex-based differences in milk composition among humans. Am J Phys Anthropol 152:209-216, 2013. © 2013 Wiley Periodicals, Inc. Copyright © 2013 Wiley Periodicals, Inc.

Kamilar J.M.,Yale University | Guidi L.M.,Washington University in St. Louis
Journal of Biogeography | Year: 2010

Aim: Our goals are: to examine the relative degree of phylogenetic overdispersion or clustering of species in communities relative to the entire species pool, to test for across-continent differences in community phylogenetic structure, and to examine the relationship between species richness and community phylogenetic structure. Location: Africa, Madagascar, Asia, and the Neotropics. Methods: We collected species composition and phylogenetic data for over 100 primate communities. For each community, we calculated two measures of phylogenetic structure: (1) the net relatedness index (NRI), which provides a measure of the mean pairwise phylogenetic distance among all species in the community; and (2) the nearest taxon index (NTI), which measures the relative phylogenetic distance among the closest related species in a community. Both measures are relative to the phylogeny of the species in the entire species pool. The phylocom package uses a randomization procedure to test whether the NRI and NTI values are higher or lower than expected by chance alone. In addition, we used a Kruskal-Wallis test to examine differences in NRI and NTI across continents, and linear regressions to examine the relationship between species richness and NRI/NTI. Results: We found that the majority of individual primate communities in Africa, Asia and the Neotropics consist of member species that are neither more nor less closely related than expected by chance alone. Yet 37% of Malagasy communities contain species that are more distantly related to each other compared with random species assemblages. Also, we found that the average degree of relatedness among species in communities differed significantly across continents, with African and Malagasy communities consisting of more distantly related taxa compared with communities in Asia and the Neotropics. Finally, we found a significant negative relationship between species richness and phylogenetic distance among species in African, Asian and Malagasy communities. The average relatedness among species in communities decreased as community size increased. Main conclusions: The majority of individual primate communities exhibit a phylogenetic structure no different from random. Yet there are across-continent differences in the phylogenetic structure of primate communities that probably result from the unique ecological and evolutionary characteristics exhibited by the endemic species found on each continent. In particular, the recent extinctions of numerous primates on Madagascar are likely responsible for the low levels of evolutionary relatedness among species in Malagasy communities. © 2010 Blackwell Publishing Ltd.

Cryer P.E.,Washington University in St. Louis
Handbook of Clinical Neurology | Year: 2013

The concept of hypoglycemia-associated autonomic failure (HAAF) in diabetes posits that recent antecedent hypoglycemia, as well as sleep or prior exercise, causes both defective glucose counterregulation (by attenuating the adrenomedullary epinephrine response, in the setting of absent insulin and glucagon responses) and hypoglycemia unawareness (by attenuating the sympathoadrenal, largely the sympathetic neural, response) and thus a vicious cycle of recurrent hypoglycemia. Albeit with different time courses, the pathophysiology of defense against hypoglycemia - no decrease in therapeutic insulin, no increase in glucagon and an attenuated increase in sympathoadrenal activity - is the same in type 1 diabetes and advanced type 2 diabetes. Hypoglycemia unawareness is reversible by 2-3 weeks of scrupulous avoidance of hypoglycemia in most affected patients. The pathophysiology of HAAF in diabetes explains why the incidence of hypoglycemia increases as patients approach the absolute endogenous insulin deficient end of the disease, provides a comprehensive set of risk factors including those indicative of HAAF, and leads logically to the practice of hypoglycemia risk factor reduction. Because of the risk of hypoglycemic mortality, presumably from cardiac arrhythmias, glycemic goals in diabetes should be individualized, based in part on the risk of hypoglycemia. By practicing hypoglycemia risk reduction - addressing the issue, applying the principles of aggressive glycemic therapy and considering both the conventional risk factors and those indicative of HAAF - it is possible to both improve glycemic control and reduce the risk of hypoglycemia in many patients with diabetes. © 2013 Elsevier B.V.

Bugg J.M.,Washington University in St. Louis
Attention, Perception, and Psychophysics | Year: 2015

The item-specific proportion congruence (ISPC) effect refers to the attenuation of interference for mostly incongruent relative to mostly congruent items. In the present study, qualitatively different ISPC effects were observed in letter- and arrow-based flanker tasks despite their common use of the original two-item set design. Consistent with the predictions of the dual item-specific mechanisms account, contingency-driven ISPC effects were observed when stimuli were used that attracted attention to the irrelevant dimension (Experiments 1, 3, and 6), whereas control-driven ISPC effects were observed when attention was attracted to the relevant dimension (Experiments 2, 4, and 5). The evidence for control-driven ISPC effects in the two-item set design (1) challenges the contingency account, which claims that ISPC effects are solely contingency-driven, and (2) supports an expanded definition of cognitive control that includes fast and flexible adjustments that minimize attention to distractors upon encountering stimuli that have previously been associated with a history of conflict. © 2014, The Psychonomic Society, Inc.

Wall L.L.,Washington University in St. Louis | Brown D.,Barnes Jewish Hospital Ethics Program
American Journal of Obstetrics and Gynecology | Year: 2010

The practice of gynecological surgery is being reshaped by commercial interests that are promoting the use of trochar-and-mesh surgical kits for the treatment of stress incontinence and pelvic organ prolapse. In this article, we review the recent history of these surgical innovations and discuss the implications of changes in surgical practice that are driven by commercial interests of this kind. We situate this phenomenon within the general "life cycle" of surgical innovation and point out the dangers inherent in the adoption of new procedures without adequate evidence to support their safety and efficacy. We highlight the ethical responsibilities surgeons and their professional organizations have in making sure such innovations are safe and effective before they come into widespread use. Finally, we offer some policy suggestions to ensure that this process has proper oversight. © 2010.

Singamaneni S.,Washington University in St. Louis | Tsukruk V.V.,Georgia Institute of Technology
Soft Matter | Year: 2010

Although buckling instabilities in elastic solids have been known for a long time, high interest in this phenomenon is relatively recent. The current and prospective applications in flexible electronics, materials with tunable surface properties (adhesion and wettability), responsive photonic and phononic structures, and reinforced nanocomposites led to a surge in the interest in buckling instabilities. In fact, some of the applications, such as flexible electronics and metrology, have advanced at a tremendous pace only within the past few years. In this review, we discuss some of the most recent progress in the fundamental understanding of buckling instabilities in periodic multi-component polymer materials and porous polymer structures. We also discuss how the buckling can be localized to predetermined regions and hence form periodic instability patterns. Finally, we present several recent examples where buckling instabilities have been employed as a patterning tool to realize complex surface arrays of various materials. © 2010 The Royal Society of Chemistry.

Holtzman D.M.,Washington University in St. Louis
Neurobiology of Aging | Year: 2011

Over the past 15 years, cerebrospinal fluid (CSF) biomarkers have been shown to be useful for both the diagnosis as well as the prognosis in Alzheimer's disease. It has been shown the CSF levels of amyloid-β (Aβ)42 are a very good marker for the presence of amyloid deposition in the brain regardless of clinical status and that total tau and phosphorylated forms of tau are useful in detection of neurodegeneration. When combined together, these CSF markers are useful not only in differential diagnosis but also in predicting conversion and rate of progression from mild cognitive impairment/very mild dementia to more severe impairment. The markers are also useful in predicting conversion from cognitive normalcy to very mild dementia. This field is briefly reviewed and recommendations for future studies in this area are provided. © 2011 Elsevier Inc.

Xiao J.,Princeton University | Furukawa Y.,Washington University in St. Louis
International Journal of Computer Vision | Year: 2014

Virtual exploration tools for large indoor environments (e.g. museums) have so far been limited to either blueprint-style 2D maps that lack photo-realistic views of scenes, or ground-level image-to-image transitions, which are immersive but ill-suited for navigation. On the other hand, photorealistic aerial maps would be a useful navigational guide for large indoor environments, but it is impossible to directly acquire photographs covering a large indoor environment from aerial viewpoints. This paper presents a 3D reconstruction and visualization system for automatically producing clean and well-regularized texture-mapped 3D models for large indoor scenes, from ground-level photographs and 3D laser points. The key component is a new algorithm called “inverse constructive solid geometry (CSG)” for reconstructing a scene with a CSG representation consisting of volumetric primitives, which imposes powerful regularization constraints. We also propose several novel techniques to adjust the 3D model to make it suitable for rendering the 3D maps from aerial viewpoints. The visualization system enables users to easily browse a large-scale indoor environment from a bird’s-eye view, locate specific room interiors, fly into a place of interest, view immersive ground-level panorama views, and zoom out again, all with seamless 3D transitions. We demonstrate our system on various museums, including the Metropolitan Museum of Art in New York City—one of the largest art galleries in the world. © 2014, Springer Science+Business Media New York.

Ben-Shahar Y.,Washington University in St. Louis
Advances in Genetics | Year: 2011

All animals use a sophisticated array of receptor proteins to sense their external and internal environments. Major advances have been made in recent years in understanding the molecular and genetic bases for sensory transduction in diverse modalities, indicating that both metabotropic and ionotropic pathways are important in sensory functions. Here, I review the historical background and recent advances in understanding the roles of a relatively newly discovered family of receptors, the degenerin/epithelial sodium channels (DEG/ENaC). These animal-specific cation channels show a remarkable sequence and functional diversity in different species and seem to exert their functions in diverse sensory modalities. Functions for DEG/ENaC channels have been implicated in mechanosensation as well as chemosensory transduction pathways. In spite of overall sequence diversity, all family members share a unique protein topology that includes just two transmembrane domains and an unusually large and highly structured extracellular domain, that seem to be essential for both their mechanical and chemical sensory functions. This review will discuss many of the recent discoveries and controversies associated with sensory function of DEG/ENaC channels in both vertebrate and invertebrate model systems, covering the role of family members in taste, mechanosensation, and pain. © 2011 Elsevier Inc.

Axoplasmically transported proteins synthesized in neuronal somata labeled by radioactively labeled amino acids (tritium), following local targeted injections for tracing of pathways in the central nervous system using autoradiography. Results from a number of neuronal systems, including: the rat olfactory bulb; cortico-thalamic projections in the mouse; commissural connections of the rat hippocampus; and retinal projections in the monkey and chick are documented. Pathway origins are clear, as the number and distribution of the labeled cells and the normal structure of the injection site is preserved.Light and electron microscopic autoradiography shows that proteins are transported, at two rates: rapid transport (>100. mm/day) of fewer proteins accumulating in axon terminals; and, slow transport (1-5. mm/day) of the bulk of labeled proteins distributed along the length of axons. Different survival times can be selected to evaluate terminal projection field(s) or pathways from origin to termination. The clarity of autoradiographic labeling of pathways and their terminations is comparable to other techniques (such as the Nauta-Gygax and the Fink-Heimer methods and the electron microscopy of terminal degeneration). Labeled amino acids do not label molecules in fibers of passage and there is no retrograde transport of labeled material from the axon terminals. The functional polarity of fiber pathways can be easily established. We summarize the merits of this technique is based upon an established physiological properties of neurons that are summarized in contrast to currently used techniques dependent upon pathological changes in neurons, axons, or axonal terminals. The cytoarchitecture of layer IV in mouse SmI cerebral cortex was examined in.formalin-fixed, Nissl-stained and Cox-fixed, Golgi-Nissl-stained sections cut coronally and tangentially to the pia, A multicellular cytoarchitectonic unit is described in layer IV, roughly cylindrical, 100-400. um in diameter, and perpendicular to the pia. Because of their characteristic shape we call these structures barrels. Each barrel is a ring of neurons, the side, which surrounds a less cellular hollow. The nearly acellular reigion surrounding each barrel and separating adjacent barrels is the septum. Barrels are discussed in relation to observations reported in several earlier papers on the mouse cortex. The barrel field (all barrels) has remarkable constancy by all measures: from one hemisphere to the next and from one specimen to the next. A consistent part of the barrel field is the postero-medial barrel subield (PMBSF). Barrels in the PMBSF are larger, elliptical in shape, organized into five distinct rows and their numbers are constant. It is postulated that each barrel in the PMBSF is the cortical correlate of a contralateral mystacial vibrissa (whisker). On the basis of counts of barrels and of all facial sinus hairs a 'one barrel-one vibrissa' hypothesis is proposed. The general hypothesis is that barrels are the morphological manifestation in layer IV of the functional cortical columns discovered by physiologists. The barrels offer excellent opportunities for integrated studies of sensory cerebral cortex at a degree of resolution previously not possible. This article is part of a Special Issue entitled SI:50th Anniversary Issue. © 2016.

Bakhsh W.R.,Washington University in St. Louis
Journal of surgical orthopaedic advances | Year: 2014

Mycobacterium kansasii is an acid-fast bacillus most commonly associated with pulmonary pathology. Infection of the spine is exceedingly rare, with just three reported cases, two of which were in human immunodeficiency virus and acquired immunodeficiency syndrome patients. This case report presents a case of vertebral osteomyelitis secondary to M. kansasii infection and reviews existing literature on this pathogen. The patient, a 37-year-old male with sarcoidosis, sustained a M. kansasii infection of the spine, resulting in vertebral osteomyelitis of L1 and L2 and discitis of the L1-L2 disc. This finding was confirmed by bone and intervertebral disc biopsy. Initially, the patient was thought to have a compression fracture of L2. However, the decision to perform a biopsy was made because of the patient's persistent febrile episodes and magnetic resonance imaging findings. The patient did not have any neurological deficits. He was successfully treated with antimicrobials, with no recurrent symptoms at 2-year follow-up. This case is the first reported case of a M. kansasii infection of the spine in a patient with sarcoidosis.

Song P.,Washington University in St. Louis
New Genetics and Society | Year: 2011

Thousands of foreign patients have sought experimental stem cell therapies in China since 2001. Despite critical scrutiny from scientific experts and tightening guidelines on the conduct of translational medicine, stem cell clinics have continued to proliferate in contemporary China. This article delves beyond regulatory exteriors to provide an ethnographic account of why unauthorized stem cell clinics targeting foreign clients have flourished under "socialism with Chinese characteristics." As the former emphasis on preventive care during Mao's era of collectivism has given way to a market-driven pursuit of high-tech interventions, changes in the political economy of healthcare have transformed China's urban medical system into a laboratory for entrepreneurial tactics. This article traces how medical entrepreneurs operate within and beyond the socialist market economy by co-opting public hospital facilities for private gain and capitalizing on the hope and hype over stem cell research to promote dubious procedures. Rather than producing biopolitical modes of governance, formal regulation in China often invites enterprising tactics and hybrid practices that ultimately remake the boundaries between public and private, as well as ethical and unethical. © 2011 Taylor & Francis.

Capriles J.M.,Washington University in St. Louis
Quaternary International | Year: 2013

This paper reviews archaeological research of Late Pleistocene and Early Holocene sites in Bolivia. Given that few projects have explicitly dealt with issues related to early human peopling of the country, an attempt is made to provide a comprehensive overview of known available data, focusing on radiocarbon dated sites. Recent research in different regions of the country is not only improving understanding of the variability of early human settlements, but also providing new perspectives in relation to human adaptation and climate change. Furthermore, ongoing research in Iroco and Cueva Bautista, in the highland region of the country, shows that human colonization of high-altitude ecosystems (>3800 m asl) occurred, at least, by 13,000 cal BP. © 2012 Elsevier Ltd and INQUA.

McGill J.B.,Washington University in St. Louis
Therapeutic Advances in Endocrinology and Metabolism | Year: 2012

Patients with type 2 diabetes mellitus (T2DM) frequently require multiple therapies to effectively control hyperglycemia, and many new agents for glucose control have been developed over the past few decades. Linagliptin is a recently approved oral antidiabetic drug that acts by inhibiting the enzyme dipeptidyl peptidase-4 (DPP-4). Unlike other DPP-4 inhibitors, linagliptin is excreted chiefly via the enterohepatic system, and can be used without dose adjustment in patients with renal or hepatic impairment. Linagliptin was approved by the US Food and Drug Administration based on a large development program, including four pivotal trials in patients with T2DM, assessing the efficacy and safety of linagliptin when used as monotherapy or in combination with other oral antidiabetes drugs. Linagliptin was associated with significant improvements in glycosylated hemoglobin, fasting plasma glucose and postprandial glucose, and more patients receiving linagliptin showed meaningful improvements and achieved targets for glycosylated hemoglobin. Linagliptin was well tolerated, with an adverse event profile similar to that of placebo, and low rates of hypoglycemic events. Taken together, the pivotal trials confirm linagliptin is effective and safe in patients with T2DM: the convenience of oral dosing with no requirement for dose adjustment in patients with renal or hepatic impairment make linagliptin a valuable option when considering therapies for patients with T2DM. © The Author(s), 2012.

Gruev V.,Washington University in St. Louis | Van Der Spiege J.,University of Pennsylvania | Engheta N.,University of Pennsylvania
Optics Express | Year: 2010

Traditional imaging systems capture and replicate the imaged environment in terms of color and intensity. One important property of light, which the human eye is blind to and is ignored by traditional imaging systems, is polarization. In this paper we present a novel, low power imaging sensor capable of recording the optical properties of partially linearly polarized light in real-time. The imaging sensor combines polymer polarization filters with a CMOS image sensor in order to compute the first three Stokes parameters at the focal plane. The imaging array contains 100 × 100 pixels and consumes 48mW at 30 fps. © 2010 Optical Society of America.

Krawczynski H.,Washington University in St. Louis
Astrophysical Journal | Year: 2012

NASA's Small Explorer Mission GEMS (Gravity and Extreme Magnetism SMEX), scheduled for launch in 2014, will have the sensitivity to detect and measure the linear polarization properties of the 0.5keV and 2-10keV X-ray emission of a considerable number of galactic and extragalactic sources. The prospect of sensitive X-ray polarimetry justifies a closer look at the polarization properties of the basic emission mechanisms. In this paper, we present analytical and numerical calculations of the linear polarization properties of inverse Compton scattered radiation. We describe a generally applicable formalism that can be used to numerically compute the polarization properties in the Thomson and Klein-Nishina regimes. We use the code to perform for the first time a detailed comparison of numerical results and the earlier analytical results derived by Bonometto et al. for scatterings in the Thomson regime. Furthermore, we use the numerical formalism to scrutinize the polarization properties of synchrotron self-Compton (SSC) emission, and of inverse Compton radiation emitted in the Klein-Nishina regime. We conclude with a discussion of the scientific potential of future GEMS observations of blazars. The GEMS mission will be able to confirm the synchrotron origin of the low-energy emission component from high-frequency-peaked BL Lac objects. Furthermore, the observations have the potential to decide between an SSC and external-Compton origin of the high-energy emission component from flat spectrum radio quasars and low-frequency-peaked BL Lac objects.

Fay J.C.,Washington University in St. Louis
Molecular Ecology | Year: 2012

Domesticated organisms demonstrate our capacity to influence wild species but also provide us with the opportunity to understand rapid evolution in the context of substantially altered environments and novel selective pressures. Recent advances in genetics and genomics have brought unprecedented insights into the domestication of many organisms and have opened new avenues for further improvements to be made. Yet, our ability to engineer biological systems is not without limits; genetic manipulation is often quite difficult. The budding yeast, Saccharomyces cerevisiae, is not only one of the most powerful model organisms, but is also the premier producer of fermented foods and beverages around the globe. As a model system, it entertains a hefty workforce dedicated to deciphering its genome and the function it encodes at a rich mechanistic level. As a producer, it is used to make leavened bread, and dozens of different alcoholic beverages, such as beer and wine. Yet, applying the awesome power of yeast genetics to understanding its origins and evolution requires some knowledge of its wild ancestors and the environments from which they were derived. A number of surprisingly diverse lineages of S. cerevisiae from both primeval and secondary forests in China have been discovered by Wang and his colleagues. These lineages substantially expand our knowledge of wild yeast diversity and will be a boon to elucidating the ecology, evolution and domestication of this academic and industrial workhorse. © 2012 Blackwell Publishing Ltd.

Sprague S.M.,University of Chicago | Coyne D.,Washington University in St. Louis
Clinical Journal of the American Society of Nephrology | Year: 2010

Effective treatment options for managing secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD) have advanced steadily since the early 1980s, from surgical removal of the parathyroid gland to pharmacologic intervention focused on reestablishing hormonal and mineral balances. In addition, earlier recognition of CKD via estimated GFR and educational efforts have led to advancements in diagnosis and treatment of elevated parathyroid hormone (PTH) and vitamin D deficiency. Clinical studies support the efficacy and safety of vitamin D receptor (VDR) agonists as effective treatments for SHPT. A number of considerations to ensure optimal SHPT control in CKD patients are apparent. VDR agonists effectively treat SHPT and vitamin D deficiency, but dosing needs to be optimized for each patient because the patient responds in an individualized manner to treatment to suppress and stabilize PTH levels. VDR agonist therapy should be continuous to ensure continued PTH suppression, coupled with strict monitoring of calcium and phosphorus to ensure compliance within target ranges. Awareness of the complex and beneficial effects of VDR agonists contributes to improved benefits in bone mineral disease and lower mortality risks. Copyright © 2010 by the American Society of Nephrology.

Pham C.T.N.,Washington University in St. Louis
Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology | Year: 2011

Rheumatoid arthritis (RA) is a common inflammatory disease characterized by progressive bone and cartilage destruction, resulting in severe functional limitations, shortened lifespan, and increased mortality rates. Recent advances and new treatment approaches have significantly delayed disease progression and improved the quality of life for many patients. Yet few patients attain or can be maintained in disease remission without continuous immunosuppressive therapy. In addition, a sizable portion of patients also fails to respond or eventually develops tolerance to current therapies. Thus there is a continued need for the development of new therapeutic strategies for the treatment of RA. Unlike conventional drugs, nanosystems are designed to deliver therapeutic agents specifically to the site of inflammation, therefore avoiding potential systemic and off-target unwanted effects. They allow investigators to consider or reconsider therapeutic agents that were previously deemed too toxic to deliver through a systemic route. This article reviews recent nanotechnology-based strategies that are being developed for the treatment of inflammatory arthritis. © 2011 John Wiley & Sons, Inc..

Quinn E.A.,Washington University in St. Louis
American journal of human biology : the official journal of the Human Biology Council | Year: 2014

Recently, there has been considerable debate regarding the appropriate amount of iron fortification for commercial infant formula. Globally, there is considerable variation in formula iron content, from 4 to 12 mg iron/L. However, how much fortification is necessary is unclear. Human milk is low in iron (0.2-0.5 mg/L), with the majority of infant iron stores accumulated during gestation. Over the first few months of life, these stores are depleted in breastfeeding infants. This decline has been previously largely perceived as pathological; it may be instead an adaptive mechanism to minimize iron availability to pathogens coinciding with complementary feeding. Many of the pathogens involved in infantile illnesses require iron for growth and replication. By reducing infant iron stores at the onset of complementary feeding, infant physiology may limit its availability to these pathogens, decreasing frequency and severity of infection. This adaptive strategy for iron regulation during development is undermined by the excess dietary iron commonly found in infant formula, both the iron that can be incorporated into the body and the excess iron that will be excreted in feces. Some of this excess iron may promote the growth of pathogenic, iron requiring bacteria disrupting synergistic microflora commonly found in breastfed infants. Evolutionarily, mothers who produced milk with less iron and infants who had decreased iron stores at the time of weaning may have been more likely to survive the transition to solid foods by having limited iron available for pathogens. Contemporary fortification practices may undermine these adaptive mechanisms and increase infant illness risk. Copyright © 2013 Wiley Periodicals, Inc.

Arur S.,University of Texas M. D. Anderson Cancer Center | Schedl T.,Washington University in St. Louis
Nature Protocols | Year: 2014

Post-translational modifications alter protein structure, affecting activity, stability, localization and/or binding partners. Antibodies that specifically recognize post-translationally modified proteins have a number of uses including immunocytochemistry and immunoprecipitation of the modified protein to purify protein-protein and protein-nucleic acid complexes. However, antibodies directed at modified sites on individual proteins are often nonspecific. Here we describe a protocol to purify polyclonal antibodies that specifically detect the modified protein of interest. The approach uses iterative rounds of subtraction and affinity purification, using stringent washes to remove antibodies that recognize the unmodified protein and low sequence complexity epitopes containing the modified amino acid. Dot blot and western blot assays are used to assess antibody preparation specificity. The approach is designed to overcome the common occurrence that a single round of subtraction and affinity purification is not sufficient to obtain a modified protein-specific antibody preparation. One full round of antibody purification and specificity testing takes 6 d of discontinuous time. © 2014 Nature America, Inc. All rights reserved.

Catalano J.G.,Washington University in St. Louis
Geochimica et Cosmochimica Acta | Year: 2011

Ordering of interfacial water at the hematite and corundum (0. 0. 1)-water interfaces has been characterized using in situ high resolution specular X-ray reflectivity measurements. The hematite (0. 0. 1) surface was prepared through an annealing process to produce a surface isostructural with corundum (0. 0. 1), facilitating direct comparison. Interfacial water was found to display a similar structure on this pair of isostructural surfaces. A single layer of adsorbed water having a large vibrational amplitude was present on each surface and additional ordering of water extended at least 1. nm into the bulk fluid, with the degree of ordering decreasing with increasing distance from the surfaces. Consistent with prior studies of the (0. 1. 2) and (1. 1. 0) surfaces of hematite and corundum, the configuration of water above the (0. 0. 1) surfaces is primarily controlled by the surface structure, specifically the arrangement of surface functional groups. However, interfacial water at the (0. 0. 1) surfaces displayed significantly larger vibrational amplitudes throughout the interfacial region than at other isostructural sets of hematite and corundum surfaces, indicating weaker ordering. Comparison of the vibrational amplitudes of adsorbed water on a series of oxide, silicate, and phosphate mineral surfaces suggests that the presence or absence of a substantial interfacial electrostatic field is the primary control on water ordering and not the surface structure itself. On surfaces for which charge originates dominantly through protonation-deprotonation reactions the controlling factor appears to be whether conditions exist where most functional groups are uncharged as opposed to the net surface charge. The doubly coordinated functional groups on hematite and corundum (0. 0. 1) surfaces are largely uncharged under slightly acidic to circumneutral pH conditions, leading to weak ordering, whereas singly coordinated groups on (0. 1. 2) and (1. 1. 0) surfaces of these phases are always charged, even when the net surface charge is zero, and induce strong water ordering. Surfaces lacking structural charge can thus be divided into two distinct classes that induce either strong or weak ordering of interfacial water. Surface functional group coordination is the ultimate control on this division as it determines the charge state of such groups under different protonation configurations. Ion adsorption and electron transfer processes may differ between these classes of surfaces because of the effect of water ordering strength on interfacial capacitances and hydrogen bonding. © 2011 Elsevier Ltd.

Ciorba M.A.,Washington University in St. Louis
Clinical Gastroenterology and Hepatology | Year: 2012

The enteric microbiota contribute to gastrointestinal health, and their disruption has been associated with many disease states. Some patients consume probiotic products in attempts to manipulate the intestinal microbiota for health benefit. It is important for gastroenterologists to improve their understanding of the mechanisms of probiotics and the evidence that support their use in practice. Clinical trials have assessed the therapeutic effects of probiotic agents for several disorders, including antibiotic- or Clostridium difficile-associated diarrhea, irritable bowel syndrome, and the inflammatory bowel diseases. Although probiotic research is a rapidly evolving field, there are sufficient data to justify a trial of probiotics for treatment or prevention of some of these conditions. However, the capacity of probiotics to modify disease symptoms is likely to be modest and varies among probiotic strains-not all probiotics are right for all diseases. The current review provides condition-specific rationale for using probiotic therapy and literature-based recommendations. © 2012 AGA Institute.

Colditz G.A.,University of Washington | Wolin K.Y.,University of Washington | Gehlert S.,Washington University in St. Louis
Science Translational Medicine | Year: 2012

More than half of the cancer occurring today is preventable by applying knowledge that we already have. Tobacco, obesity, and physical inactivity are the modifiable causes of cancer that generate the most disease. Cancer burden can be reduced by alterations in individual and population behaviors and by public health efforts as long as these changes are driven by sound scientific knowledge and social commitment to change. The obstacles to these efforts are societal and arise from the organization of institutions, including academia, and in the habits of daily life. To achieve maximal possible cancer prevention, we will need better ways to implement what we know and improved infrastructure that will better incentivize and support transdisciplinary, multilevel research and successful intervention.

Wolk D.M.,University of Arizona | Dunne Jr. W.M.,Washington University in St. Louis
Journal of Clinical Microbiology | Year: 2011

Rapid identification of microorganisms in the clinical microbiology laboratory can be of great value for selection of optimal patient management strategies for infections caused by bacteria, viruses, fungi, mycobacteria, and parasites. Rapid identification of microorganisms in clinical samples enables expedient de-escalation from broad-spectrum agents to targeted antimicrobial therapy. The switch to tailored therapy minimizes risks of antibiotics, namely, disruption of normal flora, toxic side effects, and selective pressure. There is a critical need for new technologies in clinical microbiology, particularly for bloodstream infections, in which associated mortality is among the highest of all infections. Just as importantly, there is a need for the clinical laboratory community to embrace the practices of evidence-based interventional laboratory medicine and collaborate in translational research projects to establish the clinical utility, cost benefit, and impact of new technologies. Copyright © 2011, American Society for Microbiology. All Rights Reserved.

Goodenough U.,Washington University in St. Louis | Heitman J.,Duke University
Cold Spring Harbor Perspectives in Biology | Year: 2014

Sexual reproduction is a nearly universal feature of eukaryotic organisms. Given its ubiquity and shared core features, sex is thought to have arisen once in the last common ancestor to all eukaryotes. Using the perspectives of molecular genetics and cell biology, we consider documented and hypothetical scenarios for the instantiation and evolution of meiosis, fertilization, sex determination, uniparental inheritance of organelle genomes, and speciation. © 2014 Cold Spring Harbor Laboratory Press; all rights reserved.

Kendler K.S.,Virginia Commonwealth University | Zachar P.,Auburn University at Montgomery | Craver C.,Washington University in St. Louis
Psychological Medicine | Year: 2011

This essay explores four answers to the question What kinds of things are psychiatric disorders? Essentialist kinds are classes whose members share an essence from which their defining features arise. Although elegant and appropriate for some physical (e.g. atomic elements) and medical (e.g. Mendelian disorders) phenomena, this model is inappropriate for psychiatric disorders, which are multi-factorial and fuzzy. Socially constructed kinds are classes whose members are defined by the cultural context in which they arise. This model excludes the importance of shared physiological mechanisms by which the same disorder could be identified across different cultures. Advocates of practical kinds put off metaphysical questions about reality and focus on defining classes that are useful. Practical kinds models for psychiatric disorders, implicit in the DSM nosologies, do not require that diagnoses be grounded in shared causal processes. If psychiatry seeks to tie disorders to etiology and underlying mechanisms, a model first proposed for biological species, mechanistic property cluster (MPC) kinds, can provide a useful framework. MPC kinds are defined not in terms of essences but in terms of complex, mutually reinforcing networks of causal mechanisms. We argue that psychiatric disorders are objectively grounded features of the causal structure of the mind/brain. MPC kinds are fuzzy sets defined by mechanisms at multiple levels that act and interact to produce the key features of the kind. Like species, psychiatric disorders are populations with central paradigmatic and more marginal members. The MPC view is the best current answer to What kinds of things are psychiatric disorders? © Cambridge University Press 2010.

The pressure-driven mass-flow hypothesis of phloem translocation associated with Ernst Mnch has become hegemonic and has been mathematically modelled in many, many different fashions but not, apparently, in one chosen so that it gives simple algebraic predictions of (i) the speed of translocation; (ii) the saccharide concentration at the source; and (iii) the pressure offset due to translocation. To overcome this deficit, the problem was drastically simplified by assuming that: (i) radial variations could be neglected; (ii) osmotic water uptake was restricted to sink and source regions of negligible thickness; (iii) there was a constant rate of saccharide loading at the source; and (iv) the sink strength was sufficient to lower the photosynthate concentration at the extreme distal end of the sieve tube to levels at which it becomes unimportant. The resulting system of quadratic algebraic equations was then solved for the translocation speed, which was shown to vary as the square-root of the loading rate. Also found were the offset of the intra-tube hydrostatic pressure and the sap saccharide concentration at the source, which, likewise, vary as the square-root of the loading rate. © CSIRO 2012.

Fike D.,Washington University in St. Louis
Nature Geoscience | Year: 2010

The timing and nature of changes in the chemistry of the early oceans are intensely debated. Geochemical analyses show that a prominent transition to sulphidic marine conditions 1.8 billion years ago may have been restricted to near-shore environments. © 2010 Macmillan Publishers Limited. All rights reserved.

Kornfeld S.,Washington University in St. Louis
Molecular biology of the cell | Year: 2010

We now recognize that a large number of membrane and soluble proteins contain covalently linked oligosaccharides that exhibit a vast array of structures and participate in a wide variety of biological processes. Nowhere is this better illustrated than the mannose 6-phosphate (Man-6-P) recognition system that mediates the trafficking of newly synthesized acid hydrolases to lysosomes in higher eukaryotes. The Asn-linked high-mannose oligosaccharides of these hydrolases facilitate folding of the nascent proteins in the endoplasmic reticulum via interaction with lectin-type chaperones and after phosphorylation in the Golgi, function as ligands for binding to Man-6-P receptors, a critical step in their transport to lysosomes. Failure to synthesize the Man-6-P recognition marker results in a serious lysosomal storage disease, one of a growing number of genetic conditions, termed congenital disorders of glycosylation, that result from faulty glycan biosynthesis.

Jain R.,Washington University in St. Louis | Templin F.,Boeing Company
IEEE Journal on Selected Areas in Communications | Year: 2012

Two key challenges in the design of datalinks for unmanned aircraft (UAS) systems compared to other wireless links are the long range of distances and speeds that need to be covered. The 960 - 1164 MHz part of the IEEE L band has been identified as a candidate spectrum for future manned and unmanned aircraft datalinks. The amount of spectrum available in the L-Band is not sufficient to support video applications common in UASs and so dual-band designs using both L-Band and C-Band are being considered. For L-Band, two projects funded by EUROCONTROL L-Band Digital Aeronautical Communications Systems 1 and 2 (L-DACS1 and L-DACS2) are often mentioned for use in UAS also. We briefly discuss issues with their use for UAS. We compare the two proposals in terms of their scalability, spectral efficiency, and interference resistance. Then we discuss several issues in UAS datalink design including availability, networking, preemption, and chaining. We also propose ways to mitigate interference with other systems in the L-Band. © 2012 IEEE.

Butler J.P.,Harvard University | Loring S.H.,Beth Israel Deaconess Medical Center | Patz S.,Harvard University | Tsuda A.,Harvard University | And 2 more authors.
New England Journal of Medicine | Year: 2012

A 33-year-old woman underwent a right-sided pneumonectomy in 1995 for treatment of a lung adenocarcinoma. As expected, there was an abrupt decrease in her vital capacity, but unexpectedly, it increased during the subsequent 15 years. Serial computed tomographic (CT) scans showed progressive enlargement of the remaining left lung and an increase in tissue density. Magnetic resonance imaging (MRI) with the use of hyperpolarized helium-3 gas showed overall acinar-airway dimensions that were consistent with an increase in the alveolar number rather than the enlargement of existing alveoli, but the alveoli in the growing lung were shallower than in normal lungs. This study provides evidence that new lung growth can occur in an adult human. Copyright © 2012 Massachusetts Medical Society.

Stah D.,Washington University in St. Louis
Christian Bioethics | Year: 2014

With H. Tristram Engelhardt, Jr., I believe a Christian bioethics that can be collapsed into a rationalistic ethic fails to be authentically Christian. In apparent opposition to Engelhardt, however, I believe that the theologian Paul Tillich would echo the necessary distinctiveness of a Christian metaphysics and morality. In what follows, I will argue that Tillich offers liberal Protestants an entry point into conversing with bioethics through his method of merging metaphysical claims with the Christian message. In defense of Tillich's theological method in bioethics, I will first explain why he should not be considered "post-Christian" in the sense Engelhardt implies. Next, I will explicate Tillich's correlational method and compare it with the methods of more conservative theologians whom Engelhardt appears to favor. Finally, I will describe how Tillich's insights might be helpful in constructing a distinct liberal Protestant bioethics. To remain distinct in the field of bioethics, liberal theologians need to reconnect with the vision of the world that made them unique in the first place, and in so doing, we will see the difference that liberal theologies can make to the field of bioethics. © The Author 2014.All rights reserved.

Satoh A.,University of Washington | Brace C.S.,University of Washington | Rensing N.,University of Washington | Cliften P.,University of Washington | And 5 more authors.
Cell Metabolism | Year: 2013

Summary The mammalian Sir2 ortholog Sirt1 plays an important role in metabolic regulation. However, the role of Sirt1 in the regulation of aging and longevity is still controversial. Here we demonstrate that brain-specific Sirt1-overexpressing (BRASTO) transgenic mice show significant life span extension in both males and females, and aged BRASTO mice exhibit phenotypes consistent with a delay in aging. These phenotypes are mediated by enhanced neural activity specifically in the dorsomedial and lateral hypothalamic nuclei (DMH and LH, respectively), through increased orexin type 2 receptor (Ox2r) expression. We identified Nk2 homeobox 1 (Nkx2-1) as a partner of Sirt1 that upregulates Ox2r transcription and colocalizes with Sirt1 in the DMH and LH. DMH/LH-specific knockdown of Sirt1, Nkx2-1, or Ox2r and DMH-specific Sirt1 overexpression further support the role of Sirt1/Nkx2-1/Ox2r-mediated signaling for longevity-associated phenotypes. Our findings indicate the importance of DMH/LH-predominant Sirt1 activity in the regulation of aging and longevity in mammals. © 2013 Elsevier Inc.

Dresser R.,Washington University in St. Louis
Science | Year: 2012

New U.S. rules should ensure assessment of subjects' understanding, compensation for injury, and standards of study quality.

McGill J.B.,Washington University in St. Louis
International Journal of Clinical Practice | Year: 2010

Aims: To review the non-glycaemic effects of liraglutide, including potential improvements in body weight, systolic blood pressure (SBP) and pancreatic beta-cell function. Key findings: Liraglutide induced weight loss of around 2-3 kg compared with weight increases of 1-2 kg with active comparators such as insulin glargine, rosiglitazone and glimepiride. Exenatide demonstrated similar weight benefits to liraglutide, but the dipeptidyl peptidase-4 (DPP-4) inhibitors, sitagliptin, saxagliptin and vildagliptin, were weight neutral. Liraglutide was associated with decreases in SBP of 2-7 mmHg, whereas exenatide, vildagliptin and sitagliptin demonstrated SBP reductions of around 2-3 mmHg. Measures of pancreatic beta-cell function were improved with liraglutide vs. placebo, rosiglitazone and exenatide. However, DPP-4 inhibitors appear to have less effect on beta-cell function than glucagon-like peptide-1 (GLP-1) receptor agonists. Conclusions: In addition to glycaemic control, liraglutide and the other incretin-based therapies offer additional non-glycaemic benefits to varying degrees. The ability of GLP-1 receptor agonists to provide modest, but clinically relevant improvements in body weight and SBP, and to potentially benefit beta-cell function make them an exciting therapeutic option for individuals with diabetes. In contrast, DPP-4 inhibitors are weight neutral and may have lesser benefits on beta-cell function. © 2010 Blackwell Publishing Ltd.

Luke D.A.,George Washington University | Stamatakis K.A.,Washington University in St. Louis
Annual Review of Public Health | Year: 2012

Complex systems abound in public health. Complex systems are made up of heterogeneous elements that interact with one another, have emergent properties that are not explained by understanding the individual elements of the system, persist over time, and adapt to changing circumstances. Public health is starting to use results from systems science studies to shape practice and policy, for example in preparing for global pandemics. However, systems science study designs and analytic methods remain underutilized and are not widely featured in public health curricula or training. In this review we present an argument for the utility of systems science methods in public health, introduce three important systems science methods (system dynamics, network analysis, and agent-based modeling), and provide three case studies in which these methods have been used to answer important public health science questions in the areas of infectious disease, tobacco control, and obesity. © 2012 by Annual Reviews. All rights reserved.

Sept D.,University of Michigan | Carlsson A.E.,Washington University in St. Louis
Quarterly Reviews of Biophysics | Year: 2014

The past decade has witnessed significant developments in molecular biology techniques, fluorescent labeling, and super-resolution microscopy, and together these advances have vastly increased our quantitative understanding of the cell. This detailed knowledge has concomitantly opened the door for biophysical modeling on a cellular scale. There have been comprehensive models produced describing many processes such as motility, transport, gene regulation, and chemotaxis. However, in this review we focus on a specific set of phenomena, namely cell polarization, F-actin waves, and cytokinesis. In each case, we compare and contrast various published models, highlight the relevant aspects of the biology, and provide a sense of the direction in which the field is moving. Copyright © Cambridge University Press 2014.

Visscher C.,Southwest Research Institute | Fegley Jr. B.,Washington University in St. Louis
Astrophysical Journal Letters | Year: 2013

In the giant impact theory for lunar origin, the Moon forms from material ejected by the impact into an Earth-orbiting disk. Here we report the initial results from a silicate melt-vapor equilibrium chemistry model for such impact-generated planetary debris disks. In order to simulate the chemical behavior of a two-phase (melt+vapor) disk, we calculate the temperature- dependent pressure and chemical composition of vapor in equilibrium with molten silicate from 2000 to 4000 K. We consider the elements O, Na, K, Fe, Si, Mg, Ca, Al, Ti, and Zn for a range of bulk silicate compositions (Earth, Moon, Mars, eucrite parent body, angrites, and ureilites). In general, the disk atmosphere is dominated by Na, Zn, and O2 at lower temperatures (<3000 K) and SiO, O2, and O at higher temperatures. The high-temperature chemistry is consistent for any silicate melt composition, and we thus expect abundant SiO, O2, and O to be a common feature of hot, impact-generated debris disks. In addition, the saturated silicate vapor is highly oxidizing, with oxygen fugacity () values (and hence H 2O/H2 and CO2/CO ratios) several orders of magnitude higher than those in a solar-composition gas. High values in the disk atmosphere are found for any silicate composition because oxygen is the most abundant element in rock. We thus expect high oxygen fugacity to be a ubiquitous feature of any silicate melt-vapor disk produced via collisions between rocky planets. © 2013. The American Astronomical Society. All rights reserved.

Shyr D.,Washington University in St. Louis | Liu Q.,Vanderbilt University
Biological Procedures Online | Year: 2013

The wide application of next-generation sequencing (NGS), mainly through whole genome, exome and transcriptome sequencing, provides a high-resolution and global view of the cancer genome. Coupled with powerful bioinformatics tools, NGS promises to revolutionize cancer research, diagnosis and therapy. In this paper, we review the recent advances in NGS-based cancer genomic research as well as clinical application, summarize the current integrative oncogenomic projects, resources and computational algorithms, and discuss the challenge and future directions in the research and clinical application of cancer genomic sequencing. © 2013 Shyr and Liu; licensee BioMed Central Ltd.

Griffin I.J.,University of California at Davis | Cooke R.J.,Washington University in St. Louis
Early Human Development | Year: 2012

The long-term effects of prematurity, early diet and catch-up growth on metabolic risk and body adiposity are of increasing interest to Neonatologists. Poor growth is known to be associated with poorer neuro-developmental outcome but concern exists that increased rates of "catch-up" (or "recovery") growth may be associated with increased adiposity and the later development of metabolic syndrome.In this manuscript we review the published data on body composition in preterm infants, and present new analyses of body adiposity in preterm infants during the 12-15. months of life, and the effect of growth rate (weight gain) on body adiposity.We conclude that although preterm infants have increased adiposity at term corrected age, they generally have lower body fat than their term peers during the rest of the 12-15. months of life. Although more rapid "catch-up" growth in preterm infants during the first year of life is associated with greater body fatness than slower rates of growth, these higher rates of growth lead to body composition more similar to that of the term-born infant, than do slower rates of growth.Although more studies are needed to determine whether these short-term increases or the longer-term decreases in adiposity modify the risk on chronic diseases such as diabetes mellitus, hypertension or other components of the metabolic syndrome, the widely held concern that preterm babies have greater adiposity than their term peers, and that this is worsened by greater amounts of catch-up growth, are not supported by the available evidence. © 2012 Elsevier Ireland Ltd.

Shenoy S.,Washington University in St. Louis | Darcy M.,Mallinckrodt Institute of Radiology
American Journal of Roentgenology | Year: 2013

OBJECTIVE. The rising prevalence of end-stage renal disease has resulted in increasing focus on delivery of vascular access care for hemodialysis. Duplex Doppler ultrasound, with its unique ability to reliably evaluate both structural and functional aspects of the peripheral vessels, is the preferred imaging modality for access planning and follow-up. CONCLUSION. This article will review how ultrasound is currently used to evaluate patients pre-, intra-, and postoperatively for vascular access. © American Roentgen Ray Society.

Fay J.C.,Washington University in St. Louis
Current Opinion in Genetics and Development | Year: 2013

The power of yeast genetics has now been extensively applied to phenotypic variation among strains of Saccharomyces cerevisiae. As a result, over 100 genes and numerous sequence variants have been identified, providing us with a general characterization of mutations underlying quantitative trait variation. Most quantitative trait alleles exert considerable phenotypic effects and alter conserved amino acid positions within protein coding sequences. When examined, quantitative trait alleles influence the expression of numerous genes, most of which are unrelated to an allele's phenotypic effect. The profile of quantitative trait alleles has proven useful to reverse quantitative genetics approaches and supports the use of systems genetics approaches to synthesize the molecular basis of trait variation across multiple strains. © 2013 Elsevier Ltd.

Carlson B.A.,Washington University in St. Louis
Current Biology | Year: 2015

The high voltage discharge generated by electric eels is a powerful predatory weapon. A new study shows that eels exploit basic physics to increase the voltage delivered to prey, inducing muscle fatigue that turns challenging prey items into easy targets. © 2015 Elsevier Ltd. All rights reserved.

Kubanek J.,Washington University in St. Louis | Schalk G.,New York State Department of Health
Neuroinformatics | Year: 2015

Electrocorticography (ECoG) records neural signals directly from the surface of the cortex. Due to its high temporal and favorable spatial resolution, ECoG has emerged as a valuable new tool in acquiring cortical activity in cognitive and systems neuroscience. Many studies using ECoG visualized topographies of cortical activity or statistical tests on a three-dimensional model of the cortex, but a dedicated tool for this function has not yet been described. In this paper, we describe the NeuralAct package that serves this purpose. This package takes as input the 3D coordinates of the recording sensors, a cortical model in the same coordinate system (e.g., Talairach), and the activation data to be visualized at each sensor. It then aligns the sensor coordinates with the cortical model, convolves the activation data with a spatial kernel, and renders the resulting activations in color on the cortical model. The NeuralAct package can plot cortical activations of an individual subject as well as activations averaged over subjects. It is capable to render single images as well as sequences of images. The software runs under Matlab and is stable and robust. We here provide the tool and describe its visualization capabilities and procedures. The provided package contains thoroughly documented code and includes a simple demo that guides the researcher through the functionality of the tool. © 2014, Springer Science+Business Media New York.

Osbaldiston R.,Eastern Kentucky University | Schott J.P.,Washington University in St. Louis
Environment and Behavior | Year: 2012

To provide practitioners with useful information about how to promote pro-environmental behavior (PEB), a meta-analysis was performed on 87 published reports containing 253 experimental treatments that measured an observed, not self-reported, behavioral outcome. Most studies combined multiple treatments, and this confounding precluded definitive conclusions about which individual treatments are most effective. Treatments that included cognitive dissonance, goal setting, social modeling, and prompts provided the overall largest effect sizes (Hedge's g > 0.60). Further analyses indicated that different treatments have been more effective for certain behaviors. Although average effect sizes are based on small numbers of studies, effective combinations of treatments and behaviors are making it easy to recycle, setting goals for conserving gasoline, and modeling home energy conservation. The results also reveal several gaps in the literature that should guide further research, including both treatments and PEB that have not been tested. © The Author(s) 2012.

Chen M.,University of Sydney | Blankenship R.E.,Washington University in St. Louis
Trends in Plant Science | Year: 2011

A limiting factor for photosynthetic organisms is their light-harvesting efficiency, that is the efficiency of their conversion of light energy to chemical energy. Small modifications or variations of chlorophylls allow photosynthetic organisms to harvest sunlight at different wavelengths. Oxygenic photosynthetic organisms usually utilize only the visible portion of the solar spectrum. The cyanobacterium Acaryochloris marina carries out oxygenic photosynthesis but contains mostly chlorophyll d and only traces of chlorophyll a. Chlorophyll d provides a potential selective advantage because it enables Acaryochloris to use infrared light (700-750. nm) that is not absorbed by chlorophyll a. Recently, an even more red-shifted chlorophyll termed chlorophyll f has been reported. Here, we discuss using modified chlorophylls to extend the spectral region of light that drives photosynthetic organisms. © 2011 Elsevier Ltd.

With aging, the skeleton may lose its ability to respond to positive mechanical stimuli. We hypothesized that aged mice are less responsive to loading than young-adult mice. We subjected aged (22 months) and young-adult (7 months) BALB/c male mice to daily bouts of axial tibial compression for 1 week and evaluated cortical and trabecular responses using micro-computed tomography (μCT) and dynamic histomorphometry. The right legs of 95 mice were loaded for 60 rest-inserted cycles per day to 8, 10, or 12 N peak force (generating mid-diaphyseal strains of 900 to 1900 με endocortically and 1400 to 3100 με periosteally). At the mid-diaphysis, mice from both age groups showed a strong anabolic response on the endocortex (Ec) and periosteum (Ps) [Ec.MS/BS and Ps.MS/BS: loaded (right) versus control (left), p < .05]. Generally, bone formation increased with increasing peak force. At the endocortical surface, contrary to our hypothesis, aged mice had a significantly greater response to loading than young-adult mice (Ec.MS/BS and Ec.BFR/BS: 22 months versus 7 months, p < .001). Responses at the periosteal surface did not differ between age groups (p > .05). The loading-induced increase in bone formation resulted in increased cortical area in both age groups (loaded versus control, p < .05). In contrast to the strong cortical response, loading only weakly stimulated trabecular bone formation. Serial (in vivo) μCT examinations at the proximal metaphysis revealed that loading caused a loss of trabecular bone in 7-month-old mice, whereas it appeared to prevent bone loss in 22-month-old mice. In summary, 1 week of daily tibial compression stimulated a robust endocortical and periosteal bone-formation response at the mid-diaphysis in both young-adult and aged male BALB/c mice. We conclude that aging does not limit the short-term anabolic response of cortical bone to mechanical stimulation in our animal model. © 2010 American Society for Bone and Mineral Research.

Jeong K.C.,University of Florida | Sutherland M.C.,Washington University in St. Louis | Vogel J.P.,University of Washington
Molecular Microbiology | Year: 2015

Summary: The Legionella pneumophilaDot/Icm T4SS injects ~300 protein effector proteins into host cells. Dot/Icm substrates have been proposed to contain a carboxy-terminal signal sequence that is necessary and sufficient for export, although both traits have been demonstrated for only a small fraction of these proteins. In this study, we discovered that export of the substrate SidJ is mediated by dual signal sequences that include a conventional C-terminal domain and a novel internal motif. The C-terminal signal sequence facilitates secretion of SidJ into host cells at early points of infection, whereas the internal signal sequence mediates secretion at later time points. Interestingly, only the internal signal sequence is necessary for complementation of the intracellular growth defect of a ΔsidJ mutant. Although this is the first report of a Dot/Icm substrate being secreted by an internal signal sequence, many other substrates may be exported in a similar manner. In addition, efficient translocation of SidJ is dependent on the chaperone-like type IV adaptors IcmS/IcmW. Five IcmS/IcmW binding domains that are distinct from both signal sequences were elucidated and, interestingly, only secretion mediated by the internal signal sequence requires IcmS/IcmW. Thus, Legionella employs multiple sophisticated molecular mechanisms to regulate the export of SidJ. Export of the protein SidJ, a Legionella Dot/Icm type IV secretion substrate, is mediated by a c-terminal and internal signal sequence that share homology. In addition, optimal secretion of SidJ requires multiple binding sites for the chaperone IcmS/IcmW. © 2015 John Wiley & Sons Ltd.

Lachin J.M.,George Washington University | White N.H.,Washington University in St. Louis | Hainsworth D.P.,University of Missouri | Sun W.,George Washington University | And 2 more authors.
Diabetes | Year: 2015

The Diabetes Control and Complications Trial (DCCT) demonstrated that a mean of 6.5 years of intensive therapy aimed at near-normal glucose levels reduced the risk of development and progression of retinopathy by as much as 76% compared with conventional therapy. The Epidemiology of Diabetes Interventions and Complications study (EDIC) observational follow-up showed that the risk of further progression of retinopathy 4 years after the DCCT ended was also greatly reduced in the former intensive group, despite nearly equivalent levels of HbA1c, a phenomenon termed metabolic memory. Metabolic memory was shown to persist through 10 years of follow-up. We now describe the risk of further progression of retinopathy, progression to proliferative diabetic retinopathy, clinically significant macular edema, and the need for intervention (photocoagulation or anti-VEGF) over 18 years of follow-up in EDIC. The cumulative incidence of each retinal outcome continues to be lower in the former intensive group. However, the year-to-year incidence of these outcomes is now similar, owing in large part to a reduction in risk in the former conventional treatment group. © 2015 by the American Diabetes Association.

Li X.-Y.,Tsinghua University | Ju T.,Washington University in St. Louis | Hu S.-M.,Tsinghua University
ACM Transactions on Graphics | Year: 2013

We present a new method for interpolating both boundary values and gradients over a 2D polygonal domain. Despite various previous efforts, it remains challenging to define a closed-form interpolant that produces natural-looking functions while allowing flexible control of boundary constraints. Our method builds on an existing transfinite interpolant over a continuous domain, which in turn extends the classical mean value interpolant. We re-derive the interpolant from the mean value property of biharmonic functions, and prove that the interpolant indeed matches the gradient constraints when the boundary is piece-wise linear. We then give closed-form formula (as generalized barycentric coordinates) for boundary constraints represented as polynomials up to degree 3 (for values) and 1 (for normal derivatives) over each polygon edge. We demonstrate the flexibility and efficiency of our coordinates in two novel applications, smooth image deformation using curved cage networks and adaptive simplification of gradient meshes. Copyright © ACM. Copyright © ACM 2013.

Kovacs S.J.,Washington University in St. Louis
Clinical Medicine Insights: Cardiology | Year: 2015

Heart failure has reached epidemic proportions, and diastolic heart failure or heart failure with preserved ejection fraction (HFpEF) constitutes about 50% of all heart failure admissions. Long-term prognosis of both reduced ejection fraction heart failure and HFpEF are similarly dismal. No pharmacologic agent has been developed that actually treats or repairs the physiologic deficit(s) responsible for HFpEF. Because the physiology of dias-tole is both subtle and counterintuitive, its role in heart failure has received insufficient attention. In this review, the focus is on the physiology of diastole in heart failure, the dominant physiologic laws that govern the process in all hearts, how all hearts work as a suction pump, and, therefore, the elucidation and characterization of what actually is meant by “diastolic function”. The intent is for the reader to understand what diastolic function actually is, what it is not, and how to measure it. Proper measurement of diastolic function requires one to go beyond the usual E/A, E/E′, etc. phenomenological metrics and employ more rigorous causality (mathematical modeling) based parameters of diastolic function. The method simultaneously provides new physiologic insight into the meaning of in vivo “equilibrium volume” of the left ventricle (LV), longitudinal versus transverse volume accommodation of the chamber, diastatic “ringing” of the mitral annulus, and the mechanism of L-wave generation, as well as availability of a load-independent index of diastolic function (LIIDF). One important consequence of understanding what diastolic function is, is the recognition that all that current therapies can do is basically alter the load, rather than actually “repair” the functional components (chamber stiffness, chamber relaxation). If beneficial (biological/structural/metabolic) remodeling due to therapy does manifest ultimately as improved diastolic function, it is due to resumption of normal physiology (as in alleviation of isch-emia) or activation of compensatory pathways already devised by evolution. In summary, meaningful quantitative characterization of diastolic function in any clinical setting, including heart failure, requires metrics based on physiologic mechanisms that quantify the suction pump attribute of the heart. This requires advancing beyond phenomenological global indexes such as E/A, E/E′, Vp, etc. and employing causality (mathematical modeling) based parameters of diastolic function easily obtained via the parametrized diastolic function (PDF) formalism. © the authors, publisher and licensee Libertas Academica Limited.

Musiek E.S.,Washington University in St. Louis
Frontiers in Pharmacology | Year: 2015

Disturbance of the circadian system, manifested as disrupted daily rhythms of physiologic parameters such as sleep, activity, and hormone secretion, has long been observed as a symptom of several neurodegenerative diseases, including Alzheimer disease. Circadian abnormalities have generally been considered consequences of the neurodegeneration. Recent evidence suggests, however, that circadian disruption might actually contribute to the neurodegenerative process, and thus might be a modifiable cause of neural injury. Herein we will review the evidence implicating circadian rhythms disturbances and clock gene dysfunction in neurodegeneration, with an emphasis on future research directions and potential therapeutic implications for neurodegenerative diseases. © 2015 Musiek.

Egawa T.,Washington University in St. Louis
Advances in Immunology | Year: 2015

During blood cell development, hematopoietic stem cells generate diverse mature populations via several rounds of binary fate decisions. At each bifurcation, precursors adopt one fate and inactivate the alternative fate either stochastically or in response to extrinsic stimuli and stably maintain the selected fates. Studying of these processes would contribute to better understanding of etiology of immunodeficiency and leukemia, which are caused by abnormal gene regulation during the development of hematopoietic cells. The CD4+ helper versus CD8+ cytotoxic T-cell fate decision serves as an excellent model to study binary fate decision processes. These two cell types are derived from common precursors in the thymus. Positive selection of their TCRs by self-peptide presented on either MHC class I or class II triggers their fate decisions along with mutually exclusive retention and silencing of two coreceptors, CD4 and CD8. In the past few decades, extensive effort has been made to understand the T-cell fate decision processes by studying regulation of genes encoding the coreceptors and selection processes. These studies have identified several key transcription factors and gene regulatory networks. In this chapter, I will discuss recent advances in our understanding of the binary cell fate decision processes of T cells.

Wang R.E.,Washington University in St. Louis
Current Medicinal Chemistry | Year: 2011

Recent progresses in cancer therapy suggest the importance of targeting more than one protein targets or signaling pathways. In events of stresses including the therapeutic treatments, damaged proteins are either repaired by heat shock proteins or ubiquitin-tagged for proteasome-dependent protein degradation. Heat shock proteins mediated protein protection and cell signaling, as well as the ubiquitin- proteasomal degradation are thus central to cellular homeostasis, and are reported to play substantial roles in tumor cells' rapidmetabolism and stimuli-resistance. The up-regulated heat shock protein 90 (HSP90), heat shock protein 70 (HSP70) and 26S proteasome in cancer cells have been thereby recognized as important drug targets and are under intensive studies in recent years. While most research focuses on each target in a separate manner, simultaneous inhibition of more than one target results in an enhanced efficacy, especially in single-drug-resistant cancer cell line. In this review, current development of chemical inhibitors for these three core targets is summarized respectively and the progress on related simultaneous inhibitions has been discussed. In a perspective view, combined inhibitions of HSP 90/70 and the 26S proteasome could be a promising approach in cancer therapy and may suggest a future direction for drug-screening. © 2011 Bentham Science Publishers.

OBJECTIVES:: Treatment algorithms for cardiac arrest are rescuer centric and vary little from patient to patient. The objective of this study was to determine if cardiopulmonary resuscitation–targeted to arterial blood pressure and coronary perfusion pressure rather than optimal guideline care would improve 24-hour survival in a porcine model of ventricular fibrillation cardiac arrest. DATA SOURCES:: Preclinical animal laboratory using female 3-month-old swine. STUDY SELECTION:: A randomized interventional study. DATA EXTRACTION:: After induction of anesthesia and 7 minutes of untreated ventricular fibrillation, 16 female 3-month-old swine were randomized to 1) blood pressure care: titration of chest compression depth to a systolic blood pressure of 100 mm Hg and vasopressor dosing to maintain coronary perfusion pressure of greater than 20 mm Hg or 2) guideline care: chest compression depth targeted to 51 mm and standard guideline vasopressor dosing. Animals received manual cardiopulmonary resuscitation for 10 minutes before the first defibrillation attempt and standardized postresuscitation care for 24 hours. DATA SYNTHESIS:: Twenty-four–hour survival was more likely with blood pressure care versus guideline care (0/8 vs 5/8; p < 0.03), and all survivors had normal neurologic examinations. Mean coronary perfusion pressure prior to defibrillation was significantly higher with blood pressure care (28 ± 3 vs 10 ± 6 mm Hg; p < 0.01). Chest compression depth was lower with blood pressure care (48 ± 0.4 vs 44 ± 0.5 mm Hg; p < 0.05), and the number of vasopressor doses was higher with blood pressure care (median, 3 [range, 1–7] vs 2 [range, 2–2]; p < 0.01). CONCLUSIONS:: Individualized goal-directed hemodynamic resuscitation targeting systolic blood pressure of 100 mm Hg and coronary perfusion pressure of greater than 20 mm Hg improved 24-hour survival compared with guideline care in this model of ventricular fibrillation cardiac arrest. Copyright © by 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Federgruen A.,Columbia University | Yang N.,Washington University in St. Louis
Operations Research | Year: 2011

We propose and analyze a general periodic-review model in which the firm has access to a set of potential suppliers, each with specific yield and price characteristics. Assuming that unsatisfied demand is backlogged, the firm incurs three types of costs: (i) procurement costs, (ii) inventory-carrying costs for units carried over from one period to the next, and (iii) backlogging costs. A procurement strategy requires the specification, in each period, of (i) the set of suppliers to be retained, (ii) their respective shares in this period's replenishments, as well as (iii) the traditional aggregate order placed (among the various suppliers). We show how the optimal procurement strategy can be obtained with an efficient algorithm. A base-stock policy is no longer optimal, but in each period there exists a maximum inventory level, such that orders are placed if and only if the starting inventory is below this threshold. In each period it is optimal to retain a given number of suppliers that are cheapest in terms of that period's effective cost rates, i.e., the expected cost per usable unit. The optimal number of suppliers to be retained in a given period depends on all current and future parameters and distributions, but this dependence can be aggregated into a single so-called benchmark cost measure. Under Normal yield and demand distributions, the suppliers' market shares are determined by a single aggregate score, itself the product of a simple reliability score and a cost score. © 2011 INFORMS.

Rose P.S.,Mayo Medical School | Buchowski J.M.,Washington University in St. Louis
Journal of the American Academy of Orthopaedic Surgeons | Year: 2011

Spinal metastases are found in most patients who die of cancer. The number of patients with symptomatic spinal metastases likely will increase as therapy for the primary disease improves and as cardiovascular mortality decreases. Understanding the epidemiology of metastatic spine disease and its presentation is essential to developing a diagnostic strategy. Treatment may involve chemotherapy, corticosteroids, radiotherapy, surgery, and/or percutaneous procedures (eg, vertebroplasty, kyphoplasty). A rational treatment plan can help improve quality of life, preserve neurologic function, and prolong survival. © 2011 by the American Academy of Orthopaedic Surgeons.

Bonaccorso A.,National Institute of Nuclear Physics, Italy | Charity R.J.,Washington University in St. Louis
Physical Review C - Nuclear Physics | Year: 2014

The optical-model potential for the n + 9Be reaction is obtained by two methods. The first method is from a modification and generalization of previous work [Bonaccorso and Bertsch, Phys. Rev. C 63, 044604 (2001)PRVCAN0556-281310.1103/PhysRevC.63.044604] and the second is from a dispersive-optical-model fit. The two potentials and also quantities derived from the S matrices used to calculate neutron knockout cross sections are compared. © 2014 American Physical Society.

Collins B.T.,Washington University in St. Louis
Acta Cytologica | Year: 2013

Objective: Telepathology in cytopathology is becoming more commonly utilized, and newer technologic infrastructures afford the laboratory a variety of options. The options and design of a telepathology system are driven by the clinical needs. This is primarily focused on providing rapid on-site evaluation service for fine needle aspiration. Study Design: The clinical requirements and needs of a system are described. Available tools to design and implement a telepathology system are covered, including methods of image capture, network connectivity and remote viewing options. Results: The primary telepathology method currently used and described involves the delivery via a network connection of a live video image to a remote site which is passively viewed by an internet web-based browser. By utilizing live video information and a voice connection to the on-site location, the remote viewer can collect clinical information and direct their view of the slides. Conclusions: Telepathology systems for use in cytopathology can be designed and implemented with commercially available infrastructure. It is necessary for the laboratory to validate the designed system and adhere to the required regulatory requirements. Telepathology for cytopathology can be reliably utilized by adapting existing technology, and newer advances hold great promise for further applications in the cytopathology laboratory. © 2013 S. Karger AG, Basel.

Bieschke J.,Washington University in St. Louis
Neurotherapeutics | Year: 2013

Protein misfolding disorders, such as Alzheimer's disease and Parkinson's disease, have in common that a protein accumulates in an insoluble form in the affected tissue. The process of aggregation follows a mechanism of seeded polymerization. Although the toxic species is still not well defined, the process, rather than the end product, of fibril formation is likely the main culprit in amyloid toxicity. These findings suggest that therapeutic strategies directed against the protein misfolding cascade should focus on depleting aggregation intermediates rather than on large fibrillar aggregates. Recent studies involving natural compounds have suggested new intervention strategies. The polyphenol epi-gallocatechine-3-gallate (EGCG), the main polyphenol in Camilla sinensis, binds directly to a large number of proteins that are involved in protein misfolding diseases and inhibits their fibrillization. Instead, it promotes the formation of stable, spherical aggregates. These spherical aggregates are not cytotoxic, have a lower β-sheet content than fibrils, and do not catalyze fibril formation. Correspondingly, epi-gallocatechine-3-gallate remodels amyloid fibrils into aggregates with the same properties. Derivatives of Orcein, which is a phenoxazine dye that can be isolated from the lichen Roccella tinctoria, form a second promising class of natural compounds. They accelerate fibril formation of the Alzheimer's disease-related amyloid-beta peptide. At the same time these compounds deplete oligomeric and protofibrillar forms of the peptide. These compounds may serve as proof-of-principle for the strategies of promoting and redirecting fibril formation. Both may emerge as two promising new therapeutic approaches to intervening into protein misfolding processes. © 2013 The American Society for Experimental NeuroTherapeutics, Inc.

Raman B.,Washington University in St. Louis | Stopfer M.,U.S. National Institutes of Health | Semancik S.,U.S. National Institute of Standards and Technology
ACS Chemical Neuroscience | Year: 2014

Biology has inspired solutions to many engineering problems, including those encountered in chemical sensing. Modern approaches to chemical sensing have been based on the biological principle of combining cross-selective chemical sensors with a pattern recognition engine to identify odors. Here, we review some recent advances made in mimicking biological design and computing principles to develop an electronic nose. The resulting technology will have important applications in fundamental biological research, as well as in industrial, security, and medical domains. © 2011 American Chemical Society.

Hogenesch J.B.,University of Pennsylvania | Herzog E.D.,Washington University in St. Louis
FEBS Letters | Year: 2011

Circadian clocks are present in most organisms and provide an adaptive mechanism to coordinate physiology and behavior with predictable changes in the environment. Genetic, biochemical, and cellular experiments have identified more than a dozen component genes and a signal transduction pathway that support cell-autonomous, circadian clock function. One of the hallmarks of biological clocks is their ability to reset to relevant stimuli while ignoring most others. We review recent results showing intracellular and intercellular mechanisms that convey this robust timekeeping to a variety of circadian cell types. © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Kurby C.A.,Grand Valley State University | Zacks J.M.,Washington University in St. Louis
Memory and Cognition | Year: 2012

During narrative comprehension, readers construct representations of the situation described by a text, called situation models. Theories of situation model construction and event comprehension posit two distinct types of situation model updating: incremental updating of individual situational dimensions, and global updates in which an old model is abandoned and a new one created. No research to date has directly tested whether readers update their situation models incrementally, globally, or both. We investigated whether both incremental and global updating occur during narrative comprehension. Participants typed what they were thinking while reading an extended narrative, and then segmented the narrative into meaningful events. Each typed think-aloud response was coded for whether it mentioned characters, objects, space, time, goals, or causes. There was evidence for both incremental and global updating: Readers mentioned situation dimensions more when those dimensions changed, controlling for the onset of a new event. Readers also mentioned situation dimensions more at points when a new event began than during event middles, controlling for the presence of situational change. These results support theories that claim that readers engage in both incremental and global updating during extended narrative comprehension. © 2012 Psychonomic Society, Inc.

Mangunuru H.P.R.,Old Dominion University | Yang H.,Washington University in St. Louis | Wang G.,Old Dominion University
Chemical Communications | Year: 2013

We report the synthesis and self-assembling properties of a new class of tripeptoids synthesized by a one-pot Ugi reaction from simple starting materials. Among the focused library of tripeptoids synthesized, several efficient low molecular weight gelators were obtained for aqueous DMSO and ethanol mixtures. © 2013 The Royal Society of Chemistry.

Ogilvie M.C.,Washington University in St. Louis
Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences | Year: 2011

Recent approaches to quark confinement are reviewed, with an emphasis on their connection to renormalization group (RG) methods. Basic concepts related to confinement are introduced: the string tension, Wilson loops and Polyakov lines, string breaking, string tension scaling laws, centre symmetry breaking and the deconfinement transition at non-zero temperature. Current topics discussed include confinement on R3 × S1, the real-space RG, the functional RG and the Schwinger-Dyson equation approach to confinement. © 2011 The Royal Society.

Clifford D.B.,Washington University in St. Louis | DeLuca A.,Instituto Of Clinica Delle Malattie Infettive | Simpson D.M.,The New School | Arendt G.,Heinrich Heine University Dusseldorf
The Lancet Neurology | Year: 2010

Background: Treatment of multiple sclerosis with natalizumab is complicated by rare occurrence of progressive multifocal leukoencephalopathy (PML). Between July, 2006, and November, 2009, there were 28 cases of confirmed PML in patients with multiple sclerosis treated with natalizumab. Assessment of these clinical cases will help to inform future therapeutic judgments and improve the outcomes for patients. Recent developments: The risk of PML increases with duration of exposure to natalizumab over the first 3 years of treatment. No new cases occurred during the first two years of natalizumab marketing but, by the end of November, 2009, 28 cases had been confirmed, of which eight were fatal. The median treatment duration to onset of symptoms was 25 months (range 6-80 months). The presenting symptoms most commonly included changes in cognition, personality, and motor performance, but several cases had seizures as the first clinical event. Although PML has developed in patients without any previous use of disease-modifying therapies for multiple sclerosis, previous therapy with immunosuppressants might increase risk. Clinical diagnosis by use of MRI and detection of JC virus in the CSF was established in all but one case. Management of PML has routinely used plasma exchange (PLEX) or immunoabsorption to hasten clearance of natalizumab and shorten the period in which natalizumab remains active (usually several months). Exacerbation of symptoms and enlargement of lesions on MRI have occurred within a few days to a few weeks after PLEX, indicative of immune reconstitution inflammatory syndrome (IRIS). This syndrome seems to be more common and more severe in patients with natalizumab-associated PML than it is in patients with HIV-associated PML. Where next?: Diagnosis of natalizumab-associated PML requires optimised clinical vigilance, reliable and sensitive PCR testing of the JC virus, and broadened criteria for recognition of PML lesions by use of MRI, including contrast enhancement. Optimising the management of IRIS reactions will be needed to improve outcomes. Predictive markers for patients at risk for PML must be sought. It is crucial to monitor the risk incurred during use of natalizumab beyond 3 years. © 2010 Elsevier Ltd. All rights reserved.

Gehlert S.,Washington University in St. Louis
Journal of Adolescent Health | Year: 2013

Turning disciplinary knowledge about preadolescents' and adolescents' exposure to risk factors for cancer as adults into solutions for preventing such an outcome requires that investigators from a variety of backgrounds and disciplines come together to share knowledge. Optimally, these collaborations would occur across two dimensions: (1) transdisciplinary, from the molecular or cellular level (e.g., animal studies of endocrine disruption) to the societal level (e.g., economic studies related to state tobacco policies); and (2) translational, using basic research findings in clinical and other sciences to implement prevention programs and public policy. Only when collaboration is commonplace can the disparate groups of investigators working on cancer prevention during preadolescence and adolescence gain a holistic picture of the risk factors, inform one another's work, and learn what we need to know to devise successful interventions for preventing cancer. Working transdisciplinarily also helps to ensure that messages to health professionals, policymakers, the news media, and the public are consistent and coordinated. At present, those investigating preadolescent and adolescent risk for adult cancer disseminate their knowledge individually, thus missing the opportunity to synthesize knowledge, coordinate dissemination, and implement prevention programs. In this article, we distinguish multidisciplinary, interdisciplinary, and transdisciplinary approaches; argue for the benefits of a transdisciplinary approach to devising successful solutions; and explore how to achieve transdisciplinary functioning. © 2013 Society for Adolescent Health and Medicine. All rights reserved.

Sabounchi N.S.,Washington University in St. Louis | Rahmandad H.,Virginia Polytechnic Institute and State University | Ammerman A.,University of North Carolina at Chapel Hill
International Journal of Obesity | Year: 2013

Basal metabolic rate (BMR) represents the largest component of total energy expenditure and is a major contributor to energy balance. Therefore, accurately estimating BMR is critical for developing rigorous obesity prevention and control strategies. Over the past several decades, numerous BMR formulas have been developed targeted to different population groups. A comprehensive literature search revealed 248 BMR estimation equations developed using diverse ranges of age, gender, race, fat-free mass, fat mass, height, waist-to-hip ratio, body mass index and weight. A subset of 47 studies included enough detail to allow for development of meta-regression equations. Utilizing these studies, meta-equations were developed targeted to 20 specific population groups. This review provides a comprehensive summary of available BMR equations and an estimate of their accuracy. An accompanying online BMR prediction tool (available at http://www.sdl.ise.vt.edu/tutorials.html) was developed to automatically estimate BMR based on the most appropriate equation after user-entry of individual age, race, gender and weight. © 2013 Macmillan Publishers Limited.

Xiao Y.,Washington University in St. Louis
Nature Chemical Biology | Year: 2016

Biosynthesis enables renewable production of manifold compounds, yet often biosynthetic performance must be improved for it to be economically feasible. Nongenetic, cell-to-cell variations in protein and metabolite concentrations are naturally inherent, suggesting the existence of both high- and low-performance variants in all cultures. Although having an intrinsic source of low performers might cause suboptimal ensemble biosynthesis, the existence of high performers suggests an avenue for performance enhancement. Here we develop in vivo population quality control (PopQC) to continuously select for high-performing, nongenetic variants. We apply PopQC to two biosynthetic pathways using two alternative design principles and demonstrate threefold enhanced production of both free fatty acid (FFA) and tyrosine. We confirm that PopQC improves ensemble biosynthesis by selecting for nongenetic high performers. Additionally, we use PopQC in fed-batch FFA production and achieve 21.5 g l-1 titer and 0.5 g l-1 h-1 productivity. Given the ubiquity of nongenetic variation, PopQC should be applicable to a variety of metabolic pathways for enhanced biosynthesis. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

Solomatov V.S.,Washington University in St. Louis
Gondwana Research | Year: 2015

A number of arguments lead to the magma ocean hypothesis, that during Earth's very early history our planet experienced such a high degree of melting that the silicate molten reservoir that was formed during that time can be properly termed a magma ocean. These arguments are based on both geophysical and geochemical grounds. Theories of planetary accretion point out the inevitability of planet-size impactors at the end of accretion. They lead to energy-based arguments for the early molten Earth and the existence of magma ocean and they also lead to the giant impact hypothesis of Moon formation. The giant impact hypothesis is now broadly supported by observations. The strongest arguments for the existence of the magma ocean come from studies of various isotopic systems indicating extensive mantle differentiation in the early history of the planet. However, how this differentiation happened is unclear. Fluid dynamical models suggest that either equilibrium crystallization or fractional crystallization or, more likely, a combination of them could have controlled the evolution of the magma ocean. At the early stages of magma ocean crystallization, convection was extremely vigorous and any substantial crystal-melt segregation can be initially avoided. Crystallization largely proceeded from bottom up but can be complicated by the onset of crystallization somewhere in the middle. Crystal-melt segregation and chemical differentiation are inevitable at some stage of magma ocean crystallization and can proceed in different directions at different depths, depending on the sign of crystal-melt density difference. This can result in the formation of molten layers near the core-mantle boundary and near the surface. Complete solidification of these remaining partially molten layers may have taken billions of years. It is possible that plate tectonics was born at that time and was a complex transition from a turbulent convection in the magma ocean to some early form of plate tectonics, that is mantle convection with surface recycling, and eventually to the present-day plate tectonics. The fluid dynamics of this transition is yet to be understood. © 2015.

Bernard C.,Washington University in St. Louis | Golterman M.,Autonomous University of Barcelona
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2013

It has been widely assumed that partially quenched chiral perturbation theory is the correct low-energy effective theory for partially quenched QCD. Here we present arguments supporting this assumption. First, we show that, for partially quenched QCD with staggered quarks, a transfer matrix can be constructed. This transfer matrix is not Hermitian, but it is bounded, and it can be used to construct correlation functions in the usual way. Combining these observations with an extension of the Vafa-Witten theorem to the partially quenched theory allows us to argue that the partially quenched theory satisfies the cluster property. By extending Leutwyler's analysis of the unquenched case to the partially quenched theory, we then conclude that the existence and properties of the transfer matrix as well as clustering are sufficient for partially quenched chiral perturbation theory to be the correct low-energy theory for partially quenched QCD. © 2013 American Physical Society.

Although general relativity (GR) has been tested extensively in the weak-gravity regime, similar tests in the strong-gravity regime are still missing. In this paper, we explore the possibility to use X-ray spectropolarimetric observations of black holes in X-ray binaries to distinguish between the Kerr metric and the phenomenological metrics introduced by Johannsen & Psaltis (which are not vacuum solutions of Einstein's equation) and thus to test the no-hair theorem of GR. To this end, we have developed a numerical code that calculates the radial brightness profiles of accretion disks and parallel transports the wave vector and polarization vector of photons through the Kerr and non-GR spacetimes. We used the code to predict the observational appearance of GR and non-GR accreting black hole systems. We find that the predicted energy spectra and energy-dependent polarization degree and polarization direction do depend strongly on the underlying spacetime. However, for large regions of the parameter space, the GR and non-GR metrics lead to very similar observational signatures, making it difficult to observationally distinguish between the two types of models. © 2012. The American Astronomical Society. All rights reserved..

Tang S.Y.,University of Miami | Kouvelis P.,Washington University in St. Louis
Production and Operations Management | Year: 2014

We consider coordination issues in supply chains where supplier's production process is subject to random yield losses. For a simple supply chain with a single supplier and retailer facing deterministic demand, a pay back contract which has the retailer paying a discount price for the supplier's excess units can provide the right incentive for the supplier to increase his production size and achieve coordination. Building upon this result, we consider coordination issues for two other supply chains: one with competing retailers, the other with stochastic demand. When retailers compete for both demand and supply, they tend to over-order. We show that a combination of a pay back and revenue sharing mechanism can coordinate the supply chain, with the pay back mechanism correcting the supplier's under-producing problem and the revenue sharing mechanism correcting the retailers' over-ordering problem. When demand is stochastic, we consider a modified pay-back-revenue-sharing contract under which the retailer agrees to not only purchase the supplier's excess output (beyond the retailer's order), but also share with the supplier a portion of the revenue made from the sales of the excess output. We show that this contract, by giving the supplier additional incentives in the form of revenue share, can achieve coordination. © 2014 Production and Operations Management Society.

Han X.,Sanford Burnham Institute for Medical Research | Yang K.,University of Washington | Gross R.W.,University of Washington | Gross R.W.,Washington University in St. Louis
Mass Spectrometry Reviews | Year: 2012

Since our last comprehensive review on multi-dimensional mass spectrometry-based shotgun lipidomics (Mass Spectrom. Rev. 24 (2005), 367), many new developments in the field of lipidomics have occurred. These developments include new strategies and refinements for shotgun lipidomic approaches that use direct infusion, including novel fragmentation strategies, identification of multiple new informative dimensions for mass spectrometric interrogation, and the development of new bioinformatic approaches for enhanced identification and quantitation of the individual molecular constituents that comprise each cell's lipidome. Concurrently, advances in liquid chromatography-based platforms and novel strategies for quantitative matrix-assisted laser desorption/ionization mass spectrometry for lipidomic analyses have been developed. Through the synergistic use of this repertoire of new mass spectrometric approaches, the power and scope of lipidomics has been greatly expanded to accelerate progress toward the comprehensive understanding of the pleiotropic roles of lipids in biological systems. Copyright © 2011 Wiley Periodicals, Inc.

Smith M.V.,Washington University in St. Louis
The American journal of sports medicine | Year: 2011

Acetabular labrum tears are now commonly diagnosed in young and active patients. Because the role of the acetabular labrum is incompletely understood, it is critical to determine how these tears affect native hip biomechanics. Radial and circumferential labral tears significantly decrease hip stability and significantly alter strain patterns in the anterior and anterior-superior acetabular labrum. Controlled laboratory study. Twenty-two human cadaveric hips without evidence of degeneration or dysplasia were assigned to a circumferential tear (n = 11) and a radial tear (n = 11) group. The hips were tested in a neutral position with an average compressive force of 25 N. In the circumferential tear group, the labral states were intact; 1-, 2-, and 3-cm circumferential tears; a 3-cm partial labrectomy; and a full labrectomy. In the radial tear group, the labral states were intact; a radial tear; a 1-, 2-, and 3-cm partial labrectomy; and a full labrectomy. The effect of labral injury on the stability ratio (peak dislocation force/compressive loads) and labral strain in the anterior and anterior-superior labrum was analyzed using repeated-measures analysis of variance. There was no significant difference in stability ratio after circumferential tears 3 cm or less in size compared with the intact labral state. Strain in the anterior and anterior-superior labrum was either unchanged or increased after circumferential labral tear. There was no significant difference in stability ratio after a radial tear or a 1-cm partial labrectomy compared with the intact labral state. A 2-cm partial labrectomy significantly decreased the stability ratio. Anterior and anterior-superior labral strain significantly decreased after a radial tear. Under the influence of joint compression in a neutral hip position, the acetabular labrum continues to resist femoral head dislocation despite detachment from the acetabular rim. A radial tear in the acetabular labrum decreases adjacent labral strain, but removal of 2 cm or more of the acetabular labrum is needed before hip stability decreases. The findings suggest that the acetabular labrum continues to function to resist femoral head translation despite chondral-labral separation and that labral preservation, particularly with larger tears, may be important for maintaining hip stability. Further studies are needed to determine the effect of partial labral excision on the stability ratio with the hip in provocative positions such as extension, external rotation, and abduction.

Chase J.M.,Washington University in St. Louis
Science | Year: 2010

Net primary productivity is a principal driver of biodiversity; large-scale regions with higher productivity generally have more species. This pattern emerges because β-diversity (compositional variation across local sites) increases with productivity, but the mechanisms underlying this phenomenon are unknown. Using data from a long-term experiment in replicate ponds, I show that higher βdiversity at higher productivity resulted from a stronger role for stochastic relative to deterministic assembly processes with increasing productivity. This shift in the relative importance of stochasticity was most consistent with the hypothesis of more intense priority effects leading to multiple stable equilibria at higher productivity. Thus, shifts in community assembly mechanisms across a productivity gradient may underlie one of the most prominent biodiversity gradients on the planet.

Fabbre V.D.,Washington University in St. Louis
Gerontologist | Year: 2015

Purpose of the Study: Most understandings of successful aging are developed within a heteronormative cultural framework, leading to a dearth of theoretical and empirical scholarship relevant to lesbian, gay, bisexual, transgender, and queer (LGBTQ) older adults. This study explores the experiences of transgender persons who contemplate or pursue a gender transition in later life in order to develop culturally diverse conceptualizations of health and wellness in older age. Design and Methods: Using the extended case method, in-depth interviews were conducted with male-to-female-identified persons (N = 22) who have seriously contemplated or pursued a gender transition past the age of 50. In addition, 170hr of participant observation was carried out at 3 national transgender conferences generating ethnographic field notes on the topics of aging and gender transitions in later life. Results: Interpretive analyses suggest that many transgender older adults experience challenges to their gender identities that put their emotional and physical well-being at risk. Contemporary queer theory is used to understand these experiences and argue that greater attention to experiences of queer "failure" and negotiating "success on new terms" may be integral aspects of growth and development for transgender older adults. Implications: The Baby Boom generation is aging in a post-Stonewall, LGBTQ civil rights era, yet gerontology's approach to gender and sexual identity has largely been formulated from a heteronormative perspective. A framework for understanding older transgender persons' experiences informed by queer theory offers a new orientation for conceptualizing successful aging in the lives of marginalized gender and sexual minorities. © 2014 The Author.

Subrahmanyan R.,Raman Research Institute | Subrahmanyan R.,U.S. National Radio Astronomy Observatory | Cowsik R.,Washington University in St. Louis
Astrophysical Journal | Year: 2013

Analyses of the distribution of absolute brightness temperature over the radio sky have recently led to suggestions that there exists a substantial unexplained extragalactic radio background. Consequently, there have been numerous attempts to place constraints on plausible origins of this "excess." We suggest here that this expectation of a large extragalactic background, over and above that contributed by the sources observed in the surveys, is based on an extremely simple geometry adopted to model the Galactic emission and the procedure adopted in the estimation of the extragalactic contribution. In this paper, we derive the extragalactic radio background from wide-field radio images using a more realistic modeling of the Galactic emission and decompose the sky maps at 150, 408, and 1420 MHz into anisotropic Galactic and isotropic extragalactic components. The anisotropic Galactic component is assumed to arise from a highly flattened spheroid representing the thick disk, embedded in a spherical halo, both centered at the Galactic center, along with Galactic sources, filamentary structures, and Galactic loops and spurs. All components are constrained to be positive and the optimization scheme minimizes the sky area occupied by the complex filaments. We show that in contrast with simple modeling of Galactic emission as a plane parallel slab, the more realistic modeling yields estimates for the uniform extragalactic brightness that are consistent with expectations from known extragalactic radio source populations. © 2013. The American Astronomical Society. All rights reserved.

Katz J.I.,Washington University in St. Louis
Astrophysical Journal | Year: 2016

The widths, dispersion measures (DMs), dispersion indices, and fluences of Fast Radio Bursts (FRBs) impose coupled constraints that all models must satisfy. The non-monotonic dependence of burst widths (after deconvolution of instrumental effects) on DMs excludes the intergalactic medium as the location of scattering that broadens the FRBs in time. Temporal broadening far greater than that of pulsars at similar high Galactic latitudes implies that scattering occurs close to the sources where high densities and strong turbulence or heterogeneity are plausible. FRB energetics are consistent with supergiant pulses from young, fast, high-field pulsars at cosmological distances. The distribution of FRB DMs is: (1) inconsistent with that of expanding clouds (such as SNRs); (2) inconsistent with space-limited source populations (such as the local Supercluster); and (3) consistent with intergalactic dispersion of a homogeneous source population at cosmological distances. Finally, the FRB log N-log S relation also indicates a cosmological distribution aside from the anomalously bright Lorimer burst. © 2016. The American Astronomical Society. All rights reserved.

Chambers J.R.,Washington University in St. Louis | Swan L.K.,University of Florida | Heesacker M.,University of Florida
Psychological Science | Year: 2014

Three studies examined Americans' perceptions of incomes and income inequality using a variety of criterion measures. Contrary to recent findings indicating that Americans underestimate wealth inequality, we found that Americans not only overestimated the rise of income inequality over time, but also underestimated average incomes. Thus, economic conditions in America are more favorable than people seem to realize. Furthermore, ideological differences emerged in two of these studies, such that political liberals overestimated the rise of inequality more than political conservatives. Implications of these findings for public policy debates and ideological disagreements are discussed. © The Author(s) 2013.

Chung Y.S.,Washington University in St. Louis | Barch D.M.,Conte Center for the Neuroscience of Mental Illness
Schizophrenia Research | Year: 2011

Individuals with schizophrenia show deficits both in facial emotion recognition and context processing (Kohler, C.G., Walker, J.B., Martin, E.A., Healey, K.M., Moberg, P.J., 2010. Facial emotion perception in schizophrenia: a meta-analytic review. Schizophr. Bull. 36, 1009-1019). Recent evidence suggests context information can affect facial emotion recognition (Aviezer, H., Bentin, S., Hassin, R.R., Meschino, W.S., Kennedy, J., Grewal, S., Esmail, S., Cohen, S., Moscovitch, M., 2009. Not on the face alone: perception of contextualized face expressions in Huntington's disease. Brain 132, 1633-1644). Thus, individuals with schizophrenia may have deficits in facial emotion processing, at least in part, due to impairments in processing context information (Green, M.J., Waldron, J.H., Coltheart, M., 2007. Emotional context processing is impaired in schizophrenia. Cogn. Neuropsychiatry 12, 259-280.). We used a novel experimental task, the Emotion Context Processing Task (ECPT) to examine the influences of emotional context (IAPS pictures) on the processing of subtle surprised faces in schizophrenia. One of the task conditions included a manipulation designed to determine whether enhancing attention to the context (by requiring a categorization judgment on the context pictures) would facilitate the influence of context on facial emotion processing in schizophrenia. In addition, we tested whether deficits on a non-social context processing would predict deficits in the influence of context on facial emotion processing in schizophrenia. We administered the Dot Probe Expectancy Task (a non-social context processing task) and the ECPT to individuals with schizophrenia (n = 35) and healthy controls (n = 32). Individuals with schizophrenia showed an intact influence of context information on facial emotion recognition. The manipulation designed to enhance attention to emotional context reduced the effect of context for both groups. In schizophrenia, better processing of non-social context was associated with a stronger influence of context on valence ratings of facial expressions in the negative context condition. These results suggest in schizophrenia, similar mechanisms may influence the processing of context for both social and non-social information. © 2011 Elsevier B.V.

Fay J.C.,Washington University in St. Louis
Trends in Genetics | Year: 2011

The abundance of genome polymorphism and divergence data has provided unprecedented insight into how mutation, drift and natural selection shape genome evolution. Application of the McDonald-Kreitman (MK) test to such data indicates a pervasive influence of positive selection, particularly in Drosophila species. However, evidence for positive selection in other species ranging from yeast to humans is often weak or absent. Although evidence for positive selection could be obscured in some species, there is also reason to believe that the frequency of adaptive substitutions could be overestimated as a result of epistatic fitness effects or hitchhiking of deleterious mutations. Based on these considerations it is argued that the common assumption of independence among sites must be relaxed before abandoning the neutral theory of molecular evolution. © 2011 Elsevier Ltd. All rights reserved.

Hohmann-Marriott M.F.,University of Otago | Blankenship R.E.,Washington University in St. Louis
Annual Review of Plant Biology | Year: 2011

Energy conversion of sunlight by photosynthetic organisms has changed Earth and life on it. Photosynthesis arose early in Earth's history, and the earliest forms of photosynthetic life were almost certainly anoxygenic (non-oxygen evolving). The invention of oxygenic photosynthesis and the subsequent rise of atmospheric oxygen approximately 2.4 billion years ago revolutionized the energetic and enzymatic fundamentals of life. The repercussions of this revolution are manifested in novel biosynthetic pathways of photosynthetic cofactors and the modification of electron carriers, pigments, and existing and alternative modes of photosynthetic carbon fixation. The evolutionary history of photosynthetic organisms is further complicated by lateral gene transfer that involved photosynthetic components as well as by endosymbiotic events. An expanding wealth of genetic information, together with biochemical, biophysical, and physiological data, reveals a mosaic of photosynthetic features. In combination, these data provide an increasingly robust framework to formulate and evaluate hypotheses concerning the origin and evolution of photosynthesis. Copyright © 2011 by Annual Reviews. All rights reserved.

Matthieu M.M.,Washington University in St. Louis
Suicide & life-threatening behavior | Year: 2010

Given recent policy initiatives to address suicide risk among older persons and veterans, community-based elder serving agencies may serve an important role in identifying and referring individuals at risk for suicide. A review of state-level long-term assessment instruments was conducted to determine whether veteran status and suicide are assessed. Data from forty-three state's Units on Aging instruments were content analyzed. Results indicate that over two thirds of the states in this review included questions about suicide and veterans in their assessments, 69.8% and 67.4% respectively. Suicide risk among elders and veterans must be addressed at local, state, and federal levels so that concerted attention and oversight can be provided for matching elders to the services they need.

El-Achkar T.M.,Washington University in St. Louis | Wu X.-R.,New York University
American Journal of Kidney Diseases | Year: 2012

Uromodulin, also known as Tamm-Horsfall protein, is a glycoprotein expressed exclusively by renal tubular cells lining the thick ascending limb of the loop of Henle. Although the physiologic functions of this protein remain elusive, significant progress has been made during the last decade that highlights the importance of uromodulin in the pathophysiology of various diseases, such as medullary cystic kidney disease, urinary tract infections, and nephrolithiasis. Meanwhile, there is renewed interest in the role of uromodulin in kidney injury, both acute and chronic. In this article, we review the existing evidence that supports a role for uromodulin in acute kidney injury, chronic kidney disease, and renal inflammation. Contrary to the conventional view of uromodulin as an instigator in kidney injury, new data from uromodulin knockout mice show a protective role for this protein in acute kidney injury, possibly through downregulating interstitial inflammation. In chronic kidney disease, uromodulin excretion, when adjusted for kidney function, is increased; the significance of this is unclear. Although it has been suggested that uromodulin exacerbates progressive kidney injury, we propose that the elevation in uromodulin secretion is instead reactive to injury and reflects an increase of uromodulin in the renal parenchyma, where it slows the injury process.

Odibo A.,Washington University in St. Louis
Obstetrical and Gynecological Survey | Year: 2010

The definitive diagnosis of fetal chromosomal abnormalities is only accomplished through tests that sample fetal tissue. These procedures- amniocentesis, chorionic villus sampling and cordocentesis-are invasive and carry with them the risks of bleeding, rupture of membranes, and even pregnancy loss. Current recommendations from the American College of Obstetricians and Gynecologists state that all women should be offered screening, regardless of maternal age. However, the exact screening test to apply to pregnant women is still a matter of debate.The goal of any screening method should be high detection (sensitivity) at low screen positive rates. Recent attention has focused on additional ultrasound markers to potentially improve the detection rate. Given that mid-face hypoplasia and a flattened nose are characteristic features of Down syndrome, investigators have tried to utilize its prenatal appearance-or more specifically, its absence-to enhance the detection of trisomy 21 (T21).The purpose of this document is to review the data on the utility of the nasal bone as a marker for T21. Particular attention will focus on its use in the first trimester versus second trimester as well as future directions for its potential incorporation into screening strategies. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians LEARNING OBJECTIVES: After completion of this article, the reader will be able to relate the prenatal and postnatal nasal phenotypes for Down syndrome, identify the potential role and pitfalls of nasal bone characteristics in screening for Down syndrome, and describe 3 different methods to define fetal nasal bone hypoplasia. © 2009 by Lippincott Williams & Wilkins.

Alhamad T.,Washington University in St. Louis
Transplantation | Year: 2016

BACKGROUND: Donor obesity, defined as donor body mass index (D-BMI) of 30 kg/m or greater, has been associated with increased risk of technical failure and poor pancreas allograft outcomes. Many transplant centers establish a threshold of D-BMI of 30 kg/m to decline donor offers for pancreas transplantation. However, no previous studies differentiate the impact of mild (D-BMI, 30-35 kg/m) versus severe obesity (D-BMI, ≥35 kg/m) on pancreas allograft outcomes. METHODS: We examined Organ Procurement Transplant Network database records for 9916 simultaneous pancreas-kidney transplants (SPKT) performed between 2000 and 2013. We categorized donor body mass index (D-BMI) into 4 groups: 20 to 25 (n = 5724), 25 to 30 (n = 3303), 30 to 35 (n = 751), and 35 to 50 kg/m (n= 138). Associations of D-BMI with pancreas and kidney allograft failure were assessed by multivariate Cox regression adjusted for recipient, donor, and transplant factors. RESULTS: Compared with D-BMI 20 to 25 kg/m, only D-BMI 35 to 50 kg/m was associated with significantly higher pancreas allograft [adjusted hazard ratio [aHR], 1.37; 95% confidence interval (CI], 1.04-1.79] and kidney allograft (aHR, 1.36; CI, 1.02-1.82) failure over the study period (13 years). Donor BMI 30 to 35 kg/m did not impact pancreas allograft (aHR, 0.99; CI, 0.86-1.37) or kidney allograft (aHR, 0.98; CI, 0.84-1.15) failure. Similar patterns were noted at 3 months, and 1, 5, and 10 years posttransplant. CONCLUSIONS: These data support that pancreata from mildly obese donors (BMI, 30-35 kg/m) can be safely used for transplantation, with comparable short-term and long-term outcomes as organs from lean donors. Consideration of pancreata from obese donors may decrease the pancreas discard rate. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Wan S.-H.,Foundation Medicine | Vogel M.W.,Washington University in St. Louis | Chen H.H.,Mayo Medical School
Journal of the American College of Cardiology | Year: 2014

Pre-clinical diastolic dysfunction (PDD) has been broadly defined as left ventricular diastolic dysfunction without the diagnosis of congestive heart failure (HF) and with normal systolic function. PDD is an entity that remains poorly understood, yet has definite clinical significance. Although few original studies have focused on PDD, it has been shown that PDD is prevalent, and that there is a clear progression from PDD to symptomatic HF including dyspnea, edema, and fatigue. In diabetic patients and in patients with coronary artery disease or hypertension, it has been shown that patients with PDD have a significantly higher risk of progression to heart failure and death compared with patients without PDD. Because of these findings and the increasing prevalence of the heart failure epidemic, it is clear that an understanding of PDD is essential to decreasing patients' morbidity and mortality. This review will focus on what is known concerning pre-clinical diastolic dysfunction, including definitions, staging, epidemiology, pathophysiology, and the natural history of the disease. In addition, given the paucity of trials focused on PDD treatment, studies targeting risk factors associated with the development of PDD and therapeutic trials for heart failure with preserved ejection fraction will be reviewed. © 2014 by the American College of Cardiology Foundation.

Kring A.M.,University of California at Berkeley | Barch D.M.,Washington University in St. Louis
European Neuropsychopharmacology | Year: 2014

A range of emotional and motivation impairments have long been clinically documented in people with schizophrenia, and there has been a resurgence of interest in understanding the psychological and neural mechanisms of the so-called "negative symptoms" in schizophrenia, given their lack of treatment responsiveness and their role in constraining function and life satisfaction in this illness. Negative symptoms comprise two domains, with the first covering diminished motivation and pleasure across a range of life domains and the second covering diminished verbal and non-verbal expression and communicative output. In this review, we focus on four aspects of the motivation/pleasure domain, providing a brief review of the behavioral and neural underpinnings of this domain. First, we cover liking or in-the-moment pleasure: immediate responses to pleasurable stimuli. Second, we cover anticipatory pleasure or wanting, which involves prediction of a forthcoming enjoyable outcome (reward) and feeling pleasure in anticipation of that outcome. Third, we address motivation, which comprises effort computation, which involves figuring out how much effort is needed to achieve a desired outcome, planning, and behavioral response. Finally, we cover the maintenance emotional states and behavioral responses. Throughout, we consider the behavioral manifestations and brain representations of these four aspects of motivation/pleasure deficits in schizophrenia. We conclude with directions for future research as well as implications for treatment. © 2013 Elsevier B.V. and ECNP.

Cooke R.,Washington University in St. Louis
Annals of Nutrition and Metabolism | Year: 2011

The fundamental principle underlying nutritional support is that intake meets needs thereby ensuring the best outcome, which, in the case of the preterm infant, is optimal growth and development. Achieving this goal is problematic. Most, if not all, very-low-birth-weight infants (VLBWI) are undernourished and under-grown when they are first discharged from the hospital. This has important implications for the nutritional care of preterm, particularly the breast-fed, VLBWI after hospital discharge. Copyright © 2011 S. Karger AG, Basel.

Peipert J.F.,Washington University in St. Louis
Obstetrics and Gynecology | Year: 2011

Objective: To estimate 12-month satisfaction and continuation rates of intrauterine device (IUD) and implant users enrolled in the Contraceptive CHOICE Project and compare these measures with women using the oral contraceptive pills (OCPs). Methods:We analyzed 12-month data from the first 5,087 participants enrolled in a prospective cohort study of women in the St. Louis region offered contraception at no cost for 3 years. The primary purpose of CHOICE is to promote the use of long-acting reversible contraception (IUDs and implants) and to reduce unintended pregnancies in our region. This analysis includes those participants who received their baseline contraceptive method within 3 months of enrollment and who reached the 12-month follow-up telephone survey time point (n=4,167). Rssults: Sixty-eight percent of our participants chose a long-acting reversible contraception method (45% levonorgestrel intrauterine system, 10% copper IUD, and 13% subdermal implant), 23% chose combined hormonal methods (11% OCPs, 10% vaginal ring, and 2% transdermal patch), and 8% chose depot medroxyprogesterone acetate. Long-acting reversible contraception users had higher 12-month continuation rates (86%) than OCP users (55%). The two IUDs had the highest 12-month continuation rates: levonorgestrel intrauterine system (88%) and copper IUD (84%). Women using the implant also had very high rates of continuation at 1 year (83%). Satisfaction mirrored continuation: more than 80% of users were satisfied with the IUD compared with 54% satisfied with OCPs. CONCLUSION:: IUDs and the subdermal implant have the highest rates of satisfaction and 12-month continuation. Given that long-acting reversible contraception methods have the highest contraceptive efficacy, these methods should be the first-line contraceptive methods offered to patients. © 2011 The American College of Obstetricians and Gynecologists.

Bernabe K.Q.,Washington University in St. Louis
Current Opinion in Pediatrics | Year: 2012

Purpose of Review: In contrast to adult literature, data for pressure ulcers in children is limited. Incidence and prevalence of this skin integrity issue in pediatric hospitals is still widely unknown, perhaps because increased awareness and prevention of the phenomenon have been slow to develop. Moreover, identification of at-risk patients is lacking, and current guidelines and interventions to prevent skin breakdown are those that have been adapted from adult care and are not supported by evidence-based data in children. Recent Findings: Awareness and prevention of pressure ulcers in the pediatric acute care setting are becoming a priority. In 2008, the Centers for Medicare and Medicaid Services listed certain hospital acquired conditions for which facilities would no longer be additionally reimbursed. A pressure ulcer, stage III or higher, is included in that list and referred to as a 'never event' as it is a condition that could be reasonably prevented by use of evidence-based guidelines. Summary: Pediatric pressure ulcers are a serious and largely preventable condition. Increased awareness, and accurate and timely assessment to recognize at-risk children, can lead to pressure ulcer prevention. More studies are needed to better define risk factors and effective prevention of pediatric pressure ulcers. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Prat A.,University of North Carolina at Chapel Hill | Ellis M.J.,Washington University in St. Louis | Perou C.M.,University of North Carolina at Chapel Hill
Nature Reviews Clinical Oncology | Year: 2012

Gene-expression profiling has had a considerable impact on our understanding of breast cancer biology, and more recently on clinical care. Two statistical approaches underlie these advancements. Supervised analyses have led to the development of gene-expression signatures designed to predict survival and/or treatment response, which has resulted in the development of new clinical assays. Unsupervised analyses have identified numerous biological signatures including signatures of cell type of origin, signaling pathways, and of cellular proliferation. Included within these biological signatures are the molecular subtypes known as the 'intrinsic' subtypes of breast cancer. This classification has expanded our appreciation of the heterogeneity of breast cancer and has provided a way to sub-classify the disease in a manner that might have clinical utility. In this Review, we discuss the clinical utility of gene-expression- based assays and their technical potential as clinical tools vis-a-vis the performance of breast cancer biomarkers that are the current standard of care. © 2011 Macmillan Publishers Limited. All rights reserved.

Zamboni N.,ETH Zurich | Saghatelian A.,Salk Institute for Biological Studies | Patti G.J.,Washington University in St. Louis
Molecular Cell | Year: 2015

Renewed interest in metabolic research over the last two decades has inspired an explosion of technological developments for studying metabolism. At the forefront of methodological innovation is an approach referred to as "untargeted" or "discovery" metabolomics. The experimental objective of this technique is to comprehensively measure the entire metabolome, which constitutes a largely undefined set of molecules. Given its potential comprehensive coverage, untargeted metabolomics is often the first choice of experiments for investigators pursuing a metabolic research question. It is important to recognize, however, that untargeted metabolomics may not always be the optimal experimental approach. Conventionally, untargeted metabolomics only provides information about relative differences in metabolite pool sizes. Therefore, depending on the specific scientific question at hand, a complementary approach involving stable isotopes (such as metabolic flux analysis) may be better suited to provide biological insights. Unlike untargeted metabolomics, stable-isotope methods can provide information about differences in reaction rates. © 2015 Elsevier Inc.

Katz J.I.,Washington University in St. Louis
Energy and Environmental Science | Year: 2010

The possibility of offsetting greenhouse gas warming by introducing artificial aerosols into the stratosphere to increase the Earth's albedo has been widely discussed, but little attention has been given to the details of its implementation. It is usually assumed that the aerosols would be sulfuric acid droplets (hydrated sulfur trioxide), like natural volcanic aerosols. Other materials may be more advantageous, but sophisticated "engineered" particles probably cannot be produced in sufficient quantity. I consider a variety of possible injection vehicles. Aircraft are unlikely to have sufficient lift capability to the necessary altitudes, guns are inefficient, and exotic methods like balloons and chimneys face daunting difficulties. Simple rockets are proven and economical, and can deliver material to any desired altitude. Artificial injection begins at a much higher aerosol (or precursor) density than a volcanic plume, raising novel issues of chemical kinetics and particle agglomeration. Detailed experimental and theoretical investigation are required to establish the feasibility of stratospheric aerosol geoengineering. An appendix argues that natural, as well as anthropogenic, climate change may pose challenges that could be met by these methods. © 2010 The Royal Society of Chemistry.

Dudukovic M.P.,Washington University in St. Louis
Chemical Engineering Science | Year: 2010

This manuscript summarizes the plenary lecture delivered at the ISCRE 20 meeting in Kyoto on Tuesday, September 9, 2008. The scope, history and status of our chemical reaction engineering (CRE) discipline are briefly outlined complementing the broad review presented by Professor J. Schouten in a plenary lecture a day earlier (Schouten, 2008). It is argued here that the key challenge for CRE is the development of new more efficient and profitable technologies. This is to be accomplished via an improved science-based scale-up methodology for transfer of molecular discoveries to sustainable non-polluting processes that can meet the future energy, environmental, food and materials needs of the world. Available foundations for such scale-up are introduced and the role of science in developing the improved methodology for multiphase systems is described. It is also argued that progress in implementing the desired environmentally benign processes depends, in addition to overcoming technical challenges, on achieving changes in the socio-economic and political arena. Global regulations and peer pressures are needed to provide the economic incentives for cleaner and sustainable processes. © 2009 Elsevier Ltd. All rights reserved.

Rudy Y.,Washington University in St. Louis
Annals of the New York Academy of Sciences | Year: 2010

Cardiac arrhythmias are a major cause of death and disability. Despite the clinical need and the importance of studying arrhythmia mechanisms in humans, a noninvasive imaging modality for cardiac electrophysiology is not yet available for routine application. Here we describe such a noninvasive imaging modality, electrocardiographic imaging (ECGI), and provide examples of its application in various (normal and abnormal) cardiac rhythms. © 2010 New York Academy of Sciences.

Galanek J.D.,Washington University in St. Louis
Culture, Medicine and Psychiatry | Year: 2013

Large numbers of individuals in U. S. prisons meet DSM criteria for severe psychiatric disorder. These individuals also have co-occurring personality and substance abuse disorders, medical conditions, and histories of exposure to social pathologies. Based on nine months of ethnographic fieldwork in a U. S. prison, focusing on staff narratives, I utilize interpretivist and constructivist perspectives to analyze how mental health clinicians construct psychiatric disorder among inmates. Discrete categorization of disorders may be confounded by the clinical co-morbidities of inmates and the prison context. Incarcerated individuals' responses to the institutional context substantially inform mental health staffs' illness construction and the prison itself is identified as an etiological agent for disordered behaviors. In addition, diagnostic processes are found to be indeterminate, contested, and shaped by interactions with staff. Analysis of illness construction reveals that what is at stake for clinicians is not only provision of appropriate treatment, but also mandates for the safety and security of the institution. Enmeshed in these mandates, prison mental health becomes a particular local form of psychiatric knowledge. This paper contributes to anthropological approaches to mental disorder by demonstrating how local contexts mediate psychiatric knowledge and contribute to the limited ethnographic record of prisons. © 2012 Springer Science+Business Media New York.

Queller D.C.,Washington University in St. Louis
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2014

Multiple organisms can sometimes affect a common phenotype. For example, the portion of a leaf eaten by an insect is a joint phenotype of the plant and insect and the amount of food obtained by an offspring can be a joint trait with its mother. Here, I describe the evolution of joint phenotypes in quantitative genetic terms. A joint phenotype for multiple species evolves as the sum of additive genetic variances in each species, weighted by the selection on each species. Selective conflict between the interactants occurs when selection takes opposite signs on the joint phenotype. The mean fitness of a population changes not just through its own genetic variance but also through the genetic variance for its fitness that resides in other species, an update of Fisher's fundamental theorem of natural selection. Some similar results, using inclusive fitness, apply to within-species interactions. The models provide a framework for understanding evolutionary conflicts at all levels. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

Austin P.F.,Washington University in St. Louis
Current Opinion in Urology | Year: 2010

PURPOSE OF REVIEW: Recent randomized control trials have demonstrated the efficacy of male circumcision in reducing the incidence of HIV infection in geographic areas epidemic with AIDS. Ancillary studies from these trials and others have emerged with more data on further public health benefits. We review the findings of these new trials as well as new studies pertaining to male circumcision. RECENT FINDINGS: Male circumcision appears to reduce the infection of several sexually transmitted diseases in randomized control trials and there is evidence suggesting this public health benefit is passed on to their female partners. Additionally, male circumcision appears to reduce penile cancer and cervical cancer and is likely due to elimination of foreskin harboring human papilloma virus. The benefit of circumcision in newborns seems most applicable in the first 3 months of life. SUMMARY: Increasing data support the value of male circumcision in geographic areas with high prevalence of HIV, sexually transmitted diseases and genital cancers. The application of these public health benefits to other countries worldwide remains to be seen. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Dresser R.,Washington University in St. Louis
Journal of Law, Medicine and Ethics | Year: 2010

Research using human embryonic stem cells raises an array of complex ethical issues, including, but by no means limited to, the moral status of developing human life. Unfortunately much of the public discussion fails to take into account this complexity. Advocacy for liberal and conservative positions on human embryonic stem cell research can be simplistic and misleading. Ethical concepts such as truth-telling, scientific integrity, and social justice should be part of the debate over federal support for human embryonic stem cell research. Moreover, the debate should be conducted in accord with principles of deliberative democracy, including respect for people holding competing views. © 2010 American Society of Law, Medicine & Ethics, Inc.

Xu H.,Washington University in St. Louis
Obstetrics and gynecology | Year: 2012

To estimate the contraceptive failure rates of the etonogestrel subdermal contraceptive implant in overweight and obese women and compare failure rates with women of normal weight and women using intrauterine devices (IUDs). The Contraceptive CHOICE Project is a large prospective cohort study designed to promote the use of long-acting reversible contraceptive methods to reduce unintended pregnancies in the St Louis region. Participants are provided reversible contraception of their choice at no cost. We collected baseline height and weight of each participant. During each survey, participants were asked about missed menses and possible pregnancies. Any participant who suspected a pregnancy was asked to come in for urine pregnancy testing. Analysis includes the first 8,445 participants enrolled in CHOICE of which 1,168 chose the implant and 4,200 chose the IUD. Student's t test, χ test, and Kaplan-Meier survival curves were used to perform statistical analyses to estimate failure rates in overweight and obese women using the implant and IUDs. Of the women choosing the implant, 28% were overweight and 35% were obese. Of the women who chose an IUD, 27% were overweight and 35% were obese. The 3-year cumulative failure rates for implant and IUD users were less than one per 100 women-years and did not vary by body mass index. We found no decrease in the effectiveness of the implant in overweight or obese women. The implant may be offered as a first-line contraceptive method to any woman seeking a reversible and reliable birth control method.

Andreescu C.,University of Pittsburgh | Lenze E.,Washington University in St. Louis
British Journal of Psychiatry | Year: 2012

The common territory shared by anxiety and depression has always been a contentious subject. Research in favour of anxious depression as a potentially treatment-relevant subtype has been limited by diagnostic dilemmas and crude measurement. The most recent evidence from genetics, neuropeptide systems and functional neuroimaging suggests a valid diagnostic construct.

Faccio R.,Washington University in St. Louis
Annals of the New York Academy of Sciences | Year: 2011

The bone destruction attending skeletal metastasis is mediated by tumor-recruited osteoclasts (OCs). Hence, OCs are principal therapeutic targets in afflicted individuals. On the other hand, one-third of patients develop further skeletal-related events within two years of initiating antiresorptive therapies, suggesting that additional cells modulate bone tumor growth. Previous studies showing amelioration of bone metastases by targeting the OCs were performed in immune-compromised animals injected with human breast cancer cells. Consequently, the contribution of the immune system to bone tumor growth was unclear. Using genetic models of immune and OC modulation (PLCγ2 andLyn), as well as pharmacological inhibition of OCs and T cells, we now demonstrate that a condition of immune deficiency can interfere with the antitumor effects of OC blockade. Thus, our findings expand the current tumor/bone vicious cycle model to include T cells as additional regulators of bone tumor growth, regardless of the OC status. © 2011 New York Academy of Sciences.

Will C.M.,Washington University in St. Louis
American Journal of Physics | Year: 2010

This Resource Letter provides an introduction to some of the main current topics in experimental tests of general relativity as well as to some of the historical literature. It is intended to serve as a guide to the field for upper-division undergraduate and graduate students, both theoretical and experimental, and for workers in other fields of physics who wish learn about experimental gravity. The topics covered include alternative theories of gravity, tests of the principle of equivalence, solar-system and binary-pulsar tests, searches for new physics in gravitational arenas, and tests of gravity in new regimes, involving astrophysics and gravitational radiation. © 2010 American Association of Physics Teachers.

Samarajeewa S.,Texas A&M University | Shrestha R.,Texas A&M University | Li Y.,Washington University in St. Louis | Li Y.,Harvard University | Wooley K.L.,Texas A&M University
Journal of the American Chemical Society | Year: 2012

Comparative studies of bulk samples of hydrolytically degradable poly(lactic acid) (PLA) vs core-shell block copolymer micelles having PLA cores revealed remarkable acceleration in the proteinase K enzymatic hydrolysis of the nanoparticulate forms and demonstrated that even with amidation-based shell cross-linking the core domain remained accessible. Kinetic analyses by 1H NMR spectroscopy showed less than 20% lactic acid released from enzymatically catalyzed hydrolysis of poly(l-lactic acid) in bulk, whereas ca. 70% of the core degraded within 48 h for block copolymer micelles of poly(N-(acryloyloxy)succinimide-copolymer-N-acryloylmorpholine) -block-poly(L-lactic acid) (P(NAS-co-NAM)-b-PLLA), with only a slight reduction to ca. 50% for the shell cross-linked derivatives. Rigorous characterization measurements by NMR spectroscopy, fluorescence spectroscopy, dynamic light scattering, atomic force microscopy, and transmission electron microscopy were employed to confirm core excavation. These studies provide important fundamental understanding of the effects of nanoscopic dimensions on protein-polymer interactions and polymer degradability, which will guide the development of these degradable nanoconstructs to reach their potential for controlled release of therapeutics and biological clearance. © 2011 American Chemical Society.

Gibson M.K.,University of Washington | Forsberg K.J.,University of Washington | Dantas G.,University of Washington | Dantas G.,Washington University in St. Louis
ISME Journal | Year: 2015

Antibiotic resistance is a dire clinical problem with important ecological dimensions. While antibiotic resistance in human pathogens continues to rise at alarming rates, the impact of environmental resistance on human health is still unclear. To investigate the relationship between human-associated and environmental resistomes, we analyzed functional metagenomic selections for resistance against 18 clinically relevant antibiotics from soil and human gut microbiota as well as a set of multidrug-resistant cultured soil isolates. These analyses were enabled by Resfams, a new curated database of protein families and associated highly precise and accurate profile hidden Markov models, confirmed for antibiotic resistance function and organized by ontology. We demonstrate that the antibiotic resistance functions that give rise to the resistance profiles observed in environmental and human-associated microbial communities significantly differ between ecologies. Antibiotic resistance functions that most discriminate between ecologies provide resistance to β-lactams and tetracyclines, two of the most widely used classes of antibiotics in the clinic and agriculture. We also analyzed the antibiotic resistance gene composition of over 6000 sequenced microbial genomes, revealing significant enrichment of resistance functions by both ecology and phylogeny. Together, our results indicate that environmental and human-associated microbial communities harbor distinct resistance genes, suggesting that antibiotic resistance functions are largely constrained by ecology. © 2015 International Society for Microbial Ecology All rights reserved.

Kotagiri N.,University of Washington | Niedzwiedzki D.M.,Washington University in St. Louis | Ohara K.,University of Washington | Achilefu S.,University of Washington
Angewandte Chemie - International Edition | Year: 2013

Let me get my nanoruler: Activatable probes based on radionuclide and quantum dots (QDs) were constructed using DNA as a linker. Cerenkov radiation from 64Cu was used to excite the QDs in a distance-dependent manner. The luminescence was lowest nearest to the QD and increased with distance. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Fitch W.T.,University of Vienna | Braccini S.N.,Washington University in St. Louis
Annals of the New York Academy of Sciences | Year: 2013

We review evidence for and against lateralization of manual control, communication, visual processing, and auditory processing in nonhuman primates. Compared to humans and some other vertebrate species, manual specialization in nonhuman primates is relatively weak. A right-bias in chimpanzees may exist, but is so weak that many studies using simple tasks fail to reveal it. Slightly stronger biases may exist in baboons and chimpanzees for communicative signals in the manual and facial domains. Several studies have found robust visual side biases that depend on the object being viewed, in primates including chimpanzees. Evidence for lateralization of auditory processing remains inconclusive. We conclude that the robust, species-wide lateralization that exists in humans is unusual, and perhaps unique among primates, and discuss several possible evolutionary explanations for this strong asymmetry. In particular, we consider the hypothesis that preexisting hemispheric asymmetry for perception and language processing drove the evolution of human handedness. © 2013 New York Academy of Sciences.

Mattingly G.,Washington University in St. Louis
CNS Spectrums | Year: 2010

Attention-deficit/hyperactivity disorder (ADHD) is a highly genetic neuropsychiatric disorder that can cause impairment at school, work, home, and in social relationships. Once considered a childhood disorder, as many as 65% of children with ADHD continue to exhibit symptoms into adulthood. While a mainstay of ADHD patient care, immediate-release stimulant use has been constrained by concerns about safety, tolerability, and issues related to nonmedical use and abuse. These concerns have prompted interest in developing modified versions or new delivery systems for stimulants. Prodrugs have been used in pharmaceutical development to optimize delivery of an active drug or to minimize toxicity. Prodrugs are pharmacologically inactive compounds that require in vivo conversion to release therapeutically active medications. Lisdexamfetamine dimesylate (LDX) is an inactive, water-soluble prodrug in which d-amphetamine is bonded to l-lysine, a naturally occurring amino acid. After oral ingestion, LDX is metabolized into l-lysine and active d-amphetamine. This review of LDX presents the efficacy, safety, and pharmacokinetic profile of this novel stimulant medication, and is intended to help clinicians understand its role in treating children and adults with ADHD. © MBL Communications Inc.

Arango C.M.,Washington University in St. Louis
Journal of physical activity & health | Year: 2011

Active school transport (AST) is a recommended strategy to promote physical activity (PA) and prevent overweight (OW) in school-aged children. In many developing countries, such as Colombia, this association has not been well characterized. To determine the association between AST and weight status in a representative sample of adolescents from Montería, Colombia. Participants were 546 adolescents (278 boys) aged 11 to 18 years old from 14 randomly selected schools in Montería, Colombia in 2008. The PA module of the Global School Health Survey (GSHS-2007) was used to determine the prevalence of AST. To identify OW, participants were classified according to CDC 2000 criteria (BMI ≥ 85th percentile). Association between AST and OW was determined by binomial logistic regression. Odds ratios adjusted for age, sex, location of school, compliance with PA, and screen time recommendations showed that adolescents who reported AST had a significantly lower likelihood to be OW compared with adolescents who reported nonactive transportation (OR = 0.5, 95% CI 0.3-0.8, P < .05). These results support the importance of AST as a useful PA domain with potential implications for overweight prevention, in rapidly developing settings. Further epidemiologic and intervention studies addressing AST are needed in the region.

Hogan T.M.,University of Chicago | Olade T.O.,University of Chicago | Carpenter C.R.,Washington University in St. Louis
Academic Emergency Medicine | Year: 2014

Background The aging of America poses a challenge to emergency departments (EDs). Studies show that elderly patients have poor outcomes despite increased testing, prolonged periods of observation, and higher admission rates. In response, emergency medicine (EM) leaders have implemented strategies for improved ED elder care, enhancing expertise, equipment, policies, and protocols. One example is the development of geriatric EDs gaining in popularity nationwide. To the authors' knowledge, this is the first research to systematically identify and qualitatively characterize the existence, locations, and features of geriatric EDs across the United States. Objectives The primary objective was to determine the number, distribution, and characteristics of geriatric EDs in the United States in 2013. Methods This was a survey with potential respondents identified via a snowball sampling of known geriatric EDs, EM professional organizations' geriatric interest groups, and a structured search of the Internet using multiple search engines. Sites were contacted by telephone, and those confirming geriatric EDs presence received the survey via e-mail. Category questions included date of opening, location, volumes, staffing, physical plant changes, screening tools, policies, and protocols. Categories were reported based on general interest to those seeking to understand components of a geriatric ED. Results Thirty-six hospitals confirmed geriatric ED existence and received surveys. Thirty (83%) responded to the survey and confirmed presence or plans for geriatric EDs: 24 (80%) had existing geriatric EDs, and six (20%) were planning to open geriatric EDs by 2014. The majority of geriatric EDs are located in the Midwest (46%) and Northeast (30%) regions of the United States. Eighty percent serve from 5,000 to 20,000 elder patients annually. Seventy percent of geriatric EDs are attached to the main ED, and 66% have from one to 10 geriatric beds. Physical plant changes include modifications to beds (96%), lighting (90%), flooring (83%), visual aids (73%), and sound level (70%). Seventy-seven percent have staff overlapping with the nongeriatric portion of their ED, and 80% require geriatric staff didactics. Sixty-seven percent of geriatric EDs report discharge planning for geriatric ED patients, and 90% of geriatric EDs had direct follow-up through patient callbacks. Conclusions The snowball sample identification of U.S. geriatric EDs resulted in 30 confirmed respondents. There is significant variation in the components constituting a geriatric ED. The United States should consider external validation of self-identified geriatric EDs to standardize the quality and type of care patients can expect from an institution with an identified geriatric ED. © 2014 by the Society for Academic Emergency Medicine.

Pickard W.F.,Washington University in St. Louis
Energy Policy | Year: 2010

It is argued: (i) that the harvesting of terrestrial solar radiation to perform useful work is at least an order of magnitude more efficient when carried out by solar-thermal or solar-photovoltaic processes than when carried out by way of biomass conversion and (ii) that, therefore, biomass energy is unlikely to compete successfully with inanimately harvested solar energy-except of course in restricted niche applications. © 2009 Elsevier Ltd. All rights reserved.

Colatat P.,Washington University in St. Louis
Research Policy | Year: 2015

Research funding is known to affect the rate and direction of scientific and inventive activity. Most commonly, this is understood as occurring through the allocation of funds toward certain types of research and by altering the disclosure regime. This paper calls attention to another set of factors that likely also influence scientific and technological outcomes, but has gone largely unexamined: organizational practices at research funding organizations. I explore these factors in a mixed-methods study of the Defense Advanced Research Projects Agency (DARPA). Leveraging 39 interviews of DARPA-funded scientists and program managers, I describe DARPA's agency-driven approach to research program development and intense interpersonal management style. Next, I investigate the impact of these organizational practices on the behaviors of sponsored researchers, in particular the tendency of scientists to form novel collaborations. Using patent disclosure data from the Massachusetts Institute of Technology (MIT) Technology Licensing Office and employing coarsened exact matching to identify a control set of collaborations, I find that DARPA-funded research is at least 6.0 percentage points more likely to involve novel collaborations. A detailed exploration of the novel collaborations presents a picture that is consistent with the paper's description of collaboration-promoting practices at DARPA. By identifying important organizational practices and examining their impact on scientist behavior, this paper aims to highlight the potential influence of organization practices on scientific and inventive activity. © 2015 Elsevier B.V.

Stone G.D.,Washington University in St. Louis
Science Technology and Human Values | Year: 2011

Despite its use to exemplify how the world is "flat," India is in many ways "spiky." Hyderabad is a prosperous hub of information-communication technology (ICT) while its impoverished agricultural hinterland is best known for dysfunctional agriculture and farmer suicide. Based on the belief that a lack of knowledge and skill lay at the root of agrarian distress, the "e-Sagu" project aimed to leverage the city's scientific expertise and ICT capability to aid cotton farmers. The project fit with a national surge of "last mile" projects bringing ICT to the village, but it was unique in using ICT to connect farmers directly with agricultural scientists acting as advisors. Such projects fit the interests of many actors, which has led to an unrealistic national enthusiasm about their impacts. This article uses the first five years of the project as a lens to view the cultural nature of both indigenous agricultural knowledge and "scientific" agricultural advising. Unlike lay publics whose uptake of science is better known, with farmers the invention and adoption of agro-scientific knowledge is deeply embedded in daily productive activities and sociocultural interactions. E-Sagu eventually had to abandon its construction of agricultural science as objective and acultural, resorting to rural methods of persuasion. It also found that it could only survive by joining forces with companies promoting commodification of agricultural inputs, which was a cause of the agrarian distress it sought to alleviate. © The Author(s) 2011.

Synovial sarcomas are aggressive soft-tissue malignancies that express chromosomal translocation-generated fusion genes, SS18-SSX1 or SS18-SSX2 in most cases. Here, we report a mouse sarcoma model expressing SS18-SSX1, complementing our prior model expressing SS18-SSX2. Exome sequencing identified no recurrent secondary mutations in tumors of either genotype. Most of the few mutations identified in single tumors were present in genes that were minimally or not expressed in any of the tumors. Chromosome 6, either entirely or around the fusion gene expression locus, demonstrated a copy number gain in a majority of tumors of both genotypes. Thus, by fusion oncogene coding sequence alone, SS18-SSX1 and SS18-SSX2 can each drive comparable synovial sarcomagenesis, independent from other genetic drivers. SS18-SSX1 and SS18-SSX2 tumor transcriptomes demonstrated very few consistent differences overall. In direct tumorigenesis comparisons, SS18-SSX2 was slightly more sarcomagenic than SS18-SSX1, but equivalent in its generation of biphasic histologic features. Meta-analysis of human synovial sarcoma patient series identified two tumor–gentoype–phenotype correlations that were not modeled by the mice, namely a scarcity of male hosts and biphasic histologic features among SS18-SSX2 tumors. Re-analysis of human SS18-SSX1 and SS18-SSX2 tumor transcriptomes demonstrated very few consistent differences, but highlighted increased native SSX2 expression in SS18-SSX1 tumors. This suggests that the translocated locus may drive genotype–phenotype differences more than the coding sequence of the fusion gene created. Two possible roles for native SSX2 in synovial sarcomagenesis are explored. Thus, even specific partial failures of mouse genetic modeling can be instructive to human tumor biology.Oncogene advance online publication, 7 March 2016; doi:10.1038/onc.2016.38. © 2016 Macmillan Publishers Limited

Pickard W.F.,Washington University in St. Louis
Energy Policy | Year: 2010

It is pointed out that the apparent decision of the United States to end development of the Yucca Flat, Nevada repository for permanent disposal of radioactive waste may inadvertently place it at variance with the disposal principles of the International Atomic Energy Agency (IAEA) which caution nuclear nations that "The burden on future generations shall be minimized by safely disposing of high level radioactive wastes at an appropriate time, technical, social and economic factors being taken into account." It is then shown that the IAEA's ten technical criteria for underground disposal can seemingly be met by storing vitrified waste a kilometer underground in the crystalline basement rock of a mid-continent shield, where: (a) it should be invulnerable to redistribution by incompetence, natural disaster, or terrorism and (b) there is no obvious pathway for leakage into the biosphere. Finally, a method is proposed by which the storage impasse may be broken. © 2009 Elsevier Ltd. All rights reserved.

Fontana L.,Washington University in St. Louis | Fontana L.,University of Brescia | Hu F.B.,Harvard University
Aging Cell | Year: 2014

Excess body weight and adiposity cause insulin resistance, inflammation, and numerous other alterations in metabolic and hormonal factors that promote atherosclerosis, tumorigenesis, neurodegeneration, and aging. Studies in both animals and humans have demonstrated a beneficial role of dietary restriction and leanness in promoting health and longevity. Epidemiological studies have found strong direct associations between increasing body mass index (BMI) and risks of developing type 2 diabetes, cardiovascular disease, and several types of cancer, beginning from BMI of 20-21 kg m-2. Although a recent meta-analysis suggests that overweight individuals have significantly lower overall mortality than normal-weight individuals, these data are likely to be an artifact produced by serious methodological problems, especially confounding by smoking, reverse causation due to existing chronic disease, and nonspecific loss of lean mass and function in the frail elderly. From a clinical and public health point of view, maintaining a healthy weight through diet and physical activity should remain the cornerstone in the prevention of chronic diseases and the promotion of healthy aging. © 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Haswell E.S.,Washington University in St. Louis | Phillips R.,California Institute of Technology | Rees D.C.,Howard Hughes Medical Institute
Structure | Year: 2011

While mechanobiological processes employ diverse mechanisms, at their heart are force-induced perturbations in the structure and dynamics of molecules capable of triggering subsequent events. Among the best characterized force-sensing systems are bacterial mechanosensitive channels. These channels reflect an intimate coupling of protein conformation with the mechanics of the surrounding membrane; the membrane serves as an adaptable sensor that responds to an input of applied force and converts it into an output signal, interpreted for the cell by mechanosensitive channels. The cell can exploit this information in a number of ways: ensuring cellular viability in the presence of osmotic stress and perhaps also serving as a signal transducer for membrane tension or other functions. This review focuses on the bacterial mechanosensitive channels of large (MscL) and small (MscS) conductance and their eukaryotic homologs, with an emphasis on the outstanding issues surrounding the function and mechanism of this fascinating class of molecules. © 2011 Elsevier Ltd.

Trinkaus E.,Washington University in St. Louis
American Journal of Physical Anthropology | Year: 2011

The La Chapelle-aux-Saints 1 Neandertal has figured prominently in considerations of Neandertal body size and proportions. In this context, a reassessment of its major long bones and a reassembly of its principal pelvic elements (sacrum and right ilium) was undertaken. There are secure measurements for its humeral and radial lengths and its femoral head diameter, but the femoral and tibial lengths were almost certainly greater than previous values. The resultant humeral, femoral and tibial lengths are similar to those of other male Neandertals, its femoral head diameter is among the largest known for Middle and Late Pleistocene humans, but its radial length is relatively short. The pelvic assembly provides modest bi-iliac and inlet transverse diameters compared with the few sufficiently complete and undistorted Middle and Late Pleistocene archaic human pelves, but its dimensions are similar to those of large male early modern humans. Copyright © 2011 Wiley-Liss, Inc.

Rakovan J.F.,Miami University Ohio | Pasteris J.D.,Washington University in St. Louis
Elements | Year: 2015

Apatite has numerous applications that benefit society. The atomic arrangement of the apatite crystal structure and its rich and variable chemistry impart unique properties, which permit a wide range of technological and scientific applications in an array of disciplines outside of the traditional Earth sciences, including ecology, agronomy, biology, medicine, archeology, environmental remediation, and materials science. In our daily lives, apatite is essential for sustaining and enhancing human life through agricultural amendments, through bone replacements, through fluorescent lights, and through environmental remediation of contaminated soils. Apatite is truly a technological gem.

Faccio R.,Washington University in St. Louis
Ageing Research Reviews | Year: 2011

As the skeleton ages, the balanced formation and resorption of normal bone remodeling is lost, and bone loss predominates. The osteoclast is the specialized cell that is responsible for bone resorption. It is a highly polarized cell that must adhere to the bone surface and migrate along it while resorbing, and cytoskeletal reorganization is critical. Podosomes, highly dynamic actin structures, mediate osteoclast motility. Resorbing osteoclasts form a related actin complex, the sealing zone, which provides the boundary for the resorptive microenvironment. Similar to podosomes, the sealing zone rearranges itself to allow continuous resorption while the cell is moving. The major adhesive protein controlling the cytoskeleton is αvβ3 integrin, which collaborates with the growth factor M-CSF and the ITAM receptor DAP12. In this review, we discuss the signaling complexes assembled by these molecules at the membrane, and their downstream mediators that control OC motility and function via the cytoskeleton. © 2009 Elsevier Ireland Ltd.

Carpenter C.R.,Washington University in St. Louis
Academic emergency medicine : official journal of the Society for Academic Emergency Medicine | Year: 2011

Acutely swollen or painful joints are common complaints in the emergency department (ED). Septic arthritis in adults is a challenging diagnosis, but prompt differentiation of a bacterial etiology is crucial to minimize morbidity and mortality. The objective was to perform a systematic review describing the diagnostic characteristics of history, physical examination, and bedside laboratory tests for nongonococcal septic arthritis. A secondary objective was to quantify test and treatment thresholds using derived estimates of sensitivity and specificity, as well as best-evidence diagnostic and treatment risks and anticipated benefits from appropriate therapy. Two electronic search engines (PUBMED and EMBASE) were used in conjunction with a selected bibliography and scientific abstract hand search. Inclusion criteria included adult trials of patients presenting with monoarticular complaints if they reported sufficient detail to reconstruct partial or complete 2 × 2 contingency tables for experimental diagnostic test characteristics using an acceptable criterion standard. Evidence was rated by two investigators using the Quality Assessment Tool for Diagnostic Accuracy Studies (QUADAS). When more than one similarly designed trial existed for a diagnostic test, meta-analysis was conducted using a random effects model. Interval likelihood ratios (LRs) were computed when possible. To illustrate one method to quantify theoretical points in the probability of disease whereby clinicians might cease testing altogether and either withhold treatment (test threshold) or initiate definitive therapy in lieu of further diagnostics (treatment threshold), an interactive spreadsheet was designed and sample calculations were provided based on research estimates of diagnostic accuracy, diagnostic risk, and therapeutic risk/benefits. The prevalence of nongonococcal septic arthritis in ED patients with a single acutely painful joint is approximately 27% (95% confidence interval [CI] = 17% to 38%). With the exception of joint surgery (positive likelihood ratio [+LR] = 6.9) or skin infection overlying a prosthetic joint (+LR = 15.0), history, physical examination, and serum tests do not significantly alter posttest probability. Serum inflammatory markers such as white blood cell (WBC) counts, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) are not useful acutely. The interval LR for synovial white blood cell (sWBC) counts of 0 × 10(9)-25 × 10(9)/L was 0.33; for 25 × 10(9)-50 × 10(9)/L, 1.06; for 50 × 10(9)-100 × 10(9)/L, 3.59; and exceeding 100 × 10(9)/L, infinity. Synovial lactate may be useful to rule in or rule out the diagnosis of septic arthritis with a +LR ranging from 2.4 to infinity, and negative likelihood ratio (-LR) ranging from 0 to 0.46. Rapid polymerase chain reaction (PCR) of synovial fluid may identify the causative organism within 3 hours. Based on 56% sensitivity and 90% specificity for sWBC counts of >50 × 10(9)/L in conjunction with best-evidence estimates for diagnosis-related risk and treatment-related risk/benefit, the arthrocentesis test threshold is 5%, with a treatment threshold of 39%. Recent joint surgery or cellulitis overlying a prosthetic hip or knee were the only findings on history or physical examination that significantly alter the probability of nongonococcal septic arthritis. Extreme values of sWBC (>50 × 10(9)/L) can increase, but not decrease, the probability of septic arthritis. Future ED-based diagnostic trials are needed to evaluate the role of clinical gestalt and the efficacy of nontraditional synovial markers such as lactate. © 2011 by the Society for Academic Emergency Medicine.

Riek A.E.,Washington University in St. Louis
Missouri medicine | Year: 2011

Pharmacotherapy is effective in decreasing the incidence of osteoporotic fracture, morbidity, and mortality. This benefit is pronounced in patients at highest risk for fracture: those with prior osteoporotic fracture, very low bone mineral density, or receiving chronic corticosteroid treatment. We review the best pharmacotherapeutic options currently available for treating osteoporosis.

Brangwynne C.P.,Princeton University | Tompa P.,Vrije Universiteit Brussel | Tompa P.,Hungarian Academy of Sciences | Pappu R.V.,Washington University in St. Louis
Nature Physics | Year: 2015

Intracellular organelles are either membrane-bound vesicles or membrane-less compartments that are made up of proteins and RNA. These organelles play key biological roles, by compartmentalizing the cell to enable spatiotemporal control of biological reactions. Recent studies suggest that membrane-less intracellular compartments are multicomponent viscous liquid droplets that form via phase separation. Proteins that have an intrinsic tendency for being conformationally heterogeneous seem to be the main drivers of liquid-liquid phase separation in the cell. These findings highlight the relevance of classical concepts from the physics of polymeric phase transitions for understanding the assembly of intracellular membrane-less compartments. However, applying these concepts is challenging, given the heteropolymeric nature of protein sequences, the complex intracellular environment, and non-equilibrium features intrinsic to cells. This provides new opportunities for adapting established theories and for the emergence of new physics. © 2015 Macmillan Publishers Limited. All rights reserved.

Normand B.,Renmin University of China | Nussinov Z.,Washington University in St. Louis
Physical Review Letters | Year: 2014

We demonstrate that the insulating one-band Hubbard model on the pyrochlore lattice contains, for realistic parameters, an extended quantum spin-liquid phase. This is a three-dimensional spin liquid formed from a highly degenerate manifold of dimer-based states, which is a subset of the classical dimer coverings obeying the ice rules. It possesses spinon excitations, which are both massive and deconfined, and on doping it exhibits spin-charge separation. We discuss the realization of this state in effective S=1/2 pyrochlore materials. © 2014 American Physical Society.

Colditz G.A.,Washington University in St. Louis
Cancer Causes and Control | Year: 2010

The case for continued follow-up of existing cohorts arises from the key attributes of cohorts that are already meeting the goals proposed by Potter for the creation of a new cohort. These attributes include the basic nature of ongoing cohorts in that they are, by design, hypothesis-driven and must adapt to emerging technologies over time. Importantly, cohort investigators must identify and address gaps in knowledge that will inform public health strategies and clinical practices. Above all, cohorts must capitalize on their unique features to address public health priorities and inform our prevention strategies. Continued follow-up adds substantial return on investment to guide cancer prevention. © The Author(s) 2010.

Marshall G.R.,Washington University in St. Louis
Journal of Computer-Aided Molecular Design | Year: 2013

Molecular mechanics attempts to represent intermolecular interactions in terms of classical physics. Initial efforts assumed a point charge located at the atom center and coulombic interactions. It is been recognized over multiple decades that simply representing electrostatics with a charge on each atom failed to reproduce the electrostatic potential surrounding a molecule as estimated by quantum mechanics. Molecular orbitals are not spherically symmetrical, an implicit assumption of monopole electrostatics. This perspective reviews recent evidence that requires use of multipole electrostatics and polarizability in molecular modeling. © 2013 Springer Science+Business Media Dordrecht.

Lee H.J.,Seoul National University | Lee H.J.,Washington University in St. Louis | Kweon J.,Seoul National University | Kim E.,Seoul National University | And 3 more authors.
Genome Research | Year: 2012

Despite the recent discoveries of and interest in numerous structural variations (SVs) - which include duplications and inversions - in the human and other higher eukaryotic genomes, little is known about the etiology and biology of these SVs, partly due to the lack of molecular tools with which to create individual SVs in cultured cells and model organisms. Here, we present a novelmethod of inducing duplications and inversions in a targeted manner without pre-manipulation of the genome. We found that zinc finger nucleases (ZFNs) designed to target two different sites in a human chromosome could introduce two concurrent double-strand breaks, whose repair via non-homologous end-joining (NHEJ) gives rise to targeted duplications and inversions of the genomic segments of up to a mega base pair (bp) in length between the two sites. Furthermore, we demonstrated that a ZFN pair could induce the inversion of a 140-kbp chromosomal segment that contains a portion of the blood coagulation factor VIII gene to mimic the inversion genotype that is associated with some cases of severe hemophilia A. This same ZFN pair could be used, in theory, to revert the inverted region to restore genomic integrity in these hemophilia A patients.We propose that ZFNs can be employed asmolecular tools to study mechanisms of chromosomal rearrangements and to create SVs in a predetermined manner so as to study their biological roles. In addition, our method raises the possibility of correcting genetic defects caused by chromosomal rearrangements and holds new promise in gene and cell therapy. © 2012 by Cold Spring Harbor Laboratory Press.

McBride C.M.,National Human Genome Research Institute | Wade C.H.,National Human Genome Research Institute | Kaphingst K.A.,Washington University in St. Louis
Annual Review of Genomics and Human Genetics | Year: 2010

In this report, we describe the evolution and types of genetic information provided directly to consumers, discuss potential advantages and disadvantages of these products, and review research evaluating consumer responses to direct-to-consumer (DTC) genetic testing. The available evidence to date has focused on predictive tests and does not suggest that individuals, health care providers, or health care systems have been harmed by a DTC provision of genetic information. An understanding of consumer responses to susceptibility tests has lagged behind. The Multiplex Initiative is presented as a case study of research to understand consumers' responses to DTC susceptibility tests. Three priority areas are recommended for accelerated research activities to inform public policy regarding DTC genetic information: (a) exploring consumer's long-term responses to DTC genetic testing on a comprehensive set of outcomes, (b) evaluating optimal services to support decision making about genetic testing, and (c) evaluating best practices in promoting genetic competencies among health providers. © 2010 by Annual Reviews. All rights reserved.

Chen Z.,Washington University in St. Louis
Nanoscale | Year: 2014

Fabrication and synthesis of helical nanoribbons have received increasing attention because of the broad applications of helical nanostructures in nano-elecromechanical/micro-electromechanical systems (NEMS/MEMS), sensors, active materials, drug delivery, etc. In this paper, I study the mechanical principles used in designing strained helical nanoribbons, and propose the use of a full three-dimensional finite element method to simulate the coexistence of both left- and right-handed segments in the same strained nanoribbon. This work can both help understand the large deformation behaviours of such nanostructures and assist in the design of helical nanostructures for engineering applications. © 2014 the Partner Organisations.

Cui J.,Washington University in St. Louis
Journal of Physiology | Year: 2010

Ion channels and lipid phosphatases adopt a transmembrane voltage sensor domain (VSD) that moves in response to physiological variations of the membrane potential to control their activities. However, the VSD movements and coupling to the channel or phosphatase activities may differ depending on various interactions between the VSD and its host molecules. BK-type voltage, Ca2+ and Mg2+ activated K+ channels contain the VSD and a large cytosolic domain (CTD) that binds Ca2+and Mg2+. VSD movements are coupled to BK channel opening with a unique allosteric mechanism and are modulated by Ca2+ and Mg2+ binding via the interactions among the channel pore, VSD and CTD. These properties are energetically advantageous for the pore to be controlled by multiple stimuli, revealing the adaptability of the VSD to its host molecules and showing the potential for intracellular signals to affect the VSD in order to modulate the function of its host molecules. © 2010 The Author. Journal compilation © 2010 The Physiological Society.

Carlson B.A.,Washington University in St. Louis
Journal of Experimental Biology | Year: 2016

Sensory systems play a key role in social behavior by mediating the detection and analysis of communication signals. In mormyrid fishes, electric signals are processed within a dedicated sensory pathway, providing a unique opportunity to relate sensory biology to social behavior. Evolutionary changes within this pathway led to new perceptual abilities that have been linked to increased rates of signal evolution and species diversification in a lineage called 'clade A'. Previous field observations suggest that clade-A species tend to be solitary and territorial, whereas non-clade-A species tend to be clustered in high densities suggestive of schooling or shoaling. To explore behavioral differences between species in these lineages in greater detail, I studied population densities, social interactions, and electric signaling in two mormyrid species, Gnathonemus victoriae (clade A) and Petrocephalus degeni (non-clade A), from Lwamunda Swamp, Uganda. Petrocephalus degeni was found at higher population densities, but intraspecific diversity in electric signal waveform was greater in G. victoriae. In the laboratory, G. victoriae exhibited strong shelter-seeking behavior and competition for shelter, whereas P. degeni were more likely to abandon shelter in the presence of conspecifics as well as electric mimics of signaling conspecifics. In other words, P. degeni exhibited social affiliation whereas G. victoriae exhibited social competition. Further, P. degeni showed correlated electric signaling behavior whereas G. victoriae showed anti-correlated signaling behavior. These findings extend previous reports of social spacing, territoriality, and habitat preference among mormyrid species, suggesting that evolutionary divergence in electrosensory processing relates to differences in social behavior. © 2016. Published by The Company of Biologists Ltd.

Strasberg S.M.,Washington University in St. Louis | Fields R.,Barnes Jewish Hospital
Cancer Journal (United States) | Year: 2012

Adenocarcinoma of the body and tail of the pancreas is an aggressive malignancy, and classically there have been few survivors after surgery. Radical antegrade modular pancreatosplenectomy and distal pancreatectomy with celiac axis resection are new procedures for these tumors. Radical antegrade modular pancreatosplenectomy is designed to establish an operation with oncologic rationales both for the dissection planes used to achieve negative margins and the extent of node dissection. The extent of lymph node dissection is based on the descriptions of N1 lymph node drainage, and dissection planes are based on fascial planes of the retroperitoneum. Radical antegrade modular pancreatosplenectomy is modular, adjusting the posterior plane of dissection based on the position of the tumor on preoperative computed tomograms. It is also performed right to left to increase visibility and control blood supply early. Radical antegrade modular pancreatosplenectomy is not an extended pancreatectomy but brings the rationales of the modern Whipple procedure to left-sided tumors. In long-term results from our center in 47 patients, there was a high negative tangential margin rate of 89% and an actuarial overall 5-year survival rate of 35.5%. The actual 5-year survival in 23 patients was 30.4%. Distal pancreatectomy with celiac axis resection is a procedure for cancers that have involved the celiac axis. It is based on the fact that resection of the celiac axis may be performed without devascularizing the liver, which then receives its blood supply by the pancreaticoduodenal arcade. It is an extended pancreatectomy. Mature long term results are just becoming available. Results with distal pancreatectomy with celiac axis resection are mixed with some series reporting few or no long-term survivors, whereas others report long-term survival at approximately 20%. Copyright © 2012 by Lippincott Williams &Wilkins.

Allen G.E.,Washington University in St. Louis
Journal of the History of Biology | Year: 2013

While from a late twentieth- and early twenty-first century perspective, the ideologies of eugenics (controlled reproduction to eliminate the genetically unfit and promote the reproduction of the genetically fit) and environmental conservation and preservation, may seem incompatible, they were promoted simultaneously by a number of figures in the progressive era in the decades between 1900 and 1950. Common to the two movements were the desire to preserve the "best" in both the germ plasm of the human population and natural environments (including not only natural resources, but also undisturbed nature preserves such as state and national parks and forests). In both cases advocates sought to use the latest advances in science to bolster and promote their plans, which in good progressive style, involved governmental planning and social control. This article explores the interaction of eugenic and conservationist ideologies in the careers of Sacramento banker and developer Charles M. Goethe and his friend and mentor, wealthy New York lawyer Madison Grant. In particular, the article suggests how metaphors of nature supported active work in both arenas. © 2012 Springer Science+Business Media B.V.

Hindi R.A.,Washington University in St. Louis
ACI Structural Journal | Year: 2011

Circular concrete members were reinforced with a conventional single spiral and a new confinement technique consisting of two opposing spirals (cross spirals). Eighteen members were studied under pure reverse cyclic torsional loading to investigate advantages of the new confinement technique. Cross spirals allow improved strength and ductility or increased spiral spacing to aid concrete aggregate passage during construction. Members with conventional single-spiral and new cross-spiral reinforcement schemes were constructed using identical methods and materials. All members had diameters of 200 mm (8 in.); lengths of 1000, 800, 600, and 400 mm (39, 32, 24, and 16 in.); and spiral spacings varying from 25 to 90 mm (1 to 3.5 in.). Results from cross-spiral members are compared with those of single-spiral members to evaluate the performance of the new cross-spiral confinement technique. Copyright © 2011, American Concrete Institute. All rights reserved.

Mills J.C.,Washington University in St. Louis | Shivdasani R.A.,Dana-Farber Cancer Institute | Shivdasani R.A.,Harvard University
Gastroenterology | Year: 2011

Advances in our understanding of stem cells in the gastrointestinal tract include the identification of molecular markers of stem and early progenitor cells in the small intestine. Although gastric epithelial stem cells have been localized, little is known about their molecular biology. Recent reports describe the use of inducible Cre recombinase activity to indelibly label candidate stem cells and their progeny in the distal stomach, (ie, the antrum and pylorus). No such lineage labeling of epithelial stem cells has been reported in the gastric body (corpus). Among stem cells in the alimentary canal, those of the adult corpus are unique in that they lie close to the lumen and increase proliferation following loss of a single mature progeny lineage, the acid-secreting parietal cell. They are also unique in that they neither depend on Wnt signaling nor express the surface marker Lgr5. Because pathogenesis of gastric adenocarcinoma has been associated with abnormal patterns of gastric differentiation and with chronic tissue injury, there has been much research on the response of stomach epithelial stem cells to inflammation. Chronic inflammation, as induced by infection with Helicobacter pylori, affects differentiation and promotes metaplasias. Several studies have identified cellular and molecular mechanisms in spasmolytic polypeptideexpressing (pseudopyloric) metaplasia. Researchers have also begun to identify signaling pathways and events that take place during embryonic development that eventually establish the adult stem cells to maintain the specific features and functions of the stomach mucosa. We review the cytologic, molecular, functional, and developmental properties of gastric epithelial stem cells. © 2011 AGA Institute.

Liu T.,Washington University in St. Louis | Daniels C.K.,Idaho State University | Cao S.,Roswell Park Cancer Institute
Pharmacology and Therapeutics | Year: 2012

Heat shock cognate protein 70 (HSC70) is a constitutively expressed molecular chaperone which belongs to the heat shock protein 70 (HSP70) family. HSC70 shares some of the structural and functional similarity with HSP70. HSC70 also has different properties compared with HSP70 and other heat shock family members. HSC70 performs its full functions by the cooperation of co-chaperones. It interacts with many other molecules as well and regulates various cellular functions. It is also involved in various diseases and may become a biomarker for diagnosis and potential therapeutic targets for design, discovery, and development of novel drugs to treat various diseases. In this article, we provide a comprehensive review on HSC70 from the literatures including the basic general information such as classification, structure and cellular location, genetics and function, as well as its protein association and interaction with other proteins. In addition, we also discussed the relationship of HSC70 and related clinical diseases such as cancer, cardiovascular, neurological, hepatic and many other diseases and possible therapeutic potential and highlight the progress and prospects of research in this field. Understanding the functions of HSC70 and its interaction with other molecules will help us to reveal other novel properties of this protein. Scientists may be able to utilize this protein as a biomarker and therapeutic target to make significant advancement in scientific research and clinical setting in the future. © 2012 Elsevier Inc. All rights reserved.

Elgin S.C.R.,Washington University in St. Louis | Reuter G.,Martin Luther University of Halle Wittenberg
Cold Spring Harbor Perspectives in Biology | Year: 2013

Position-effect variegation (PEV) results when a gene normally in euchromatin is juxtaposed with hetero-chromatin by rearrangement or transposition. When heterochromatin packaging spreads across the het-erochromatin/euchromatin border, it causes transcriptional silencing in a stochastic pattern. PEV is intensely studied in Drosophila using the white gene. Screens for dominant mutations that suppress or enhance white variegation have identified many conserved epigenetic factors, including the histone H3 lysine 9 methyltransferase SU(VAR)3-9. Heterochromatin protein HP1a binds H3K9me2/3 and interacts with SU(VAR)3-9, creating a core memory system. Genetic, molecular, and biochemical analysis of PEV in Drosophila has contributed many key findings concerning establishment and maintenance of hetero-chromatin with concomitant gene silencing. © 2013 Cold Spring Harbor Laboratory Press; all rights reserved.

Tripodi S.J.,Florida State University | Pettus-Davis C.,Washington University in St. Louis
International Journal of Law and Psychiatry | Year: 2013

Women are entering US prisons at nearly double the rate of men and are the fastest growing prison population. Current extant literature focuses on the prevalence of the incarceration of women, but few studies exist that emphasize the different trajectories to prison. For example, women prisoners have greater experiences of prior victimization, more reports of mental illness, and higher rates of illicit substance use. The purpose of this study was to understand the prevalence of childhood victimization and its association with adult mental health problems, substance abuse disorders, and further sexual victimization. The research team interviewed a random sample of 125 women prisoners soon to be released from prison to gather information on their childhood physical and sexual victimization, mental health and substance abuse problems as an adult, and sexual victimization in the year preceding incarceration. Results indicate that women prisoners in this sample, who were both physically and sexually victimized as children, were more likely to be hospitalized as an adult for a psychological or emotional problem. Women who were sexually victimized or both physically and sexually victimized were more likely to attempt suicide. Women who experienced physical victimization as children and women who were both physically and sexually victimized were more likely to have a substance use disorder and women who were sexually abused as children or both physically and sexually victimized were more likely to be sexually abused in the year preceding prison. This article ends with a discussion about prisons' role in providing treatment for women prisoners and basing this treatment on women's trajectories to prison, which disproportionately include childhood victimization and subsequent mental health and substance use problems. © 2012 Elsevier Ltd.

Zheng Y.,Fudan University | Li Y.-F.,Oklahoma State University | Sunkar R.,Oklahoma State University | Zhang W.,Fudan University | Zhang W.,Washington University in St. Louis
Nucleic Acids Research | Year: 2012

In plants, microRNAs (miRNAs) regulate their mRNA targets by precisely guiding cleavages between the 10th and 11th nucleotides in the complementary regions. High-throughput sequencing-based methods, such as PARE or degradome profiling coupled with a computational analysis of the sequencing data, have recently been developed for identifying miRNA targets on a genome-wide scale. The existing algorithms limit the number of mismatches between a miRNA and its targets and strictly do not allow a mismatch or G:U Wobble pair at the position 10 or 11. However, evidences from recent studies suggest that cleavable targets with more mismatches exist indicating that a relaxed criterion can find additional miRNA targets. In order to identify targets including the ones with weak complementarities from degradome data, we developed a computational method called SeqTar that allows more mismatches and critically mismatch or G:U pair at the position 10 or 11. Precisely, two statistics were introduced in SeqTar, one to measure the alignment between miRNA and its target and the other to quantify the abundance of reads at the center of the miRNA complementary site. By applying SeqTar to publicly available degradome data sets from Arabidopsis and rice, we identified a substantial number of novel targets for conserved and non-conserved miRNAs in addition to the reported ones. Furthermore, using RLM 5′-RACE assay, we experimentally verified 12 of the novel miRNA targets (6 each in Arabidopsis and rice), of which some have more than 4 mismatches and have mismatches or G:U pairs at the position 10 or 11 in the miRNA complementary sites. Thus, SeqTar is an effective method for identifying miRNA targets in plants using degradome data sets. © 2012 The Author(s).

Bostrom K.I.,University of California at Los Angeles | Rajamannan N.M.,Northwestern University | Towler D.A.,Washington University in St. Louis
Circulation Research | Year: 2011

Vascular calcification increasingly afflicts our aging, dysmetabolic population. Once considered only a passive process of dead and dying cells, vascular calcification has now emerged as a highly regulated form of biomineralization organized by collagenous and elastin extracellular matrices. During skeletal bone formation, paracrine epithelial-mesenchymal and endothelial-mesenchymal interactions control osteochondrocytic differentiation of multipotent mesenchymal progenitor cells. These paracrine osteogenic signals, mediated by potent morphogens of the bone morphogenetic protein and wingless-type MMTV integration site family member (Wnt) superfamilies, are also active in the programming of arterial osteoprogenitor cells during vascular and valve calcification. Inflammatory cytokines, reactive oxygen species, and oxylipids-increased in the clinical settings of atherosclerosis, diabetes, and uremia that promote arteriosclerotic calcification-elicit the ectopic vascular activation of osteogenic morphogens. Specific extracellular and intracellular inhibitors of bone morphogenetic protein-Wnt signaling have been identified as contributing to the regulation of osteogenic mineralization during development and disease. These inhibitory pathways and their regulators afford the development of novel therapeutic strategies to prevent and treat valve and vascular sclerosis. © 2011 American Heart Association, Inc.

Xie J.,Washington University in St. Louis
Nanoscale | Year: 2010

Biodegradable nanofibers produced by electrospinning represent a new class of promising scaffolds to support nerve regeneration. We begin with a brief discussion on the electrospinning of nanofibers and methods for controlling the structure, porosity, and alignment of the electrospun nanofibers. The methods include control of the nanoscale morphology and microscale alignment of the nanofibers, as well as the fabrication of macroscale, three-dimensional tubular structures. We then highlight recent studies that utilize electrospun nanofibers to manipulate biological processes relevant to nervous tissue regeneration, including stem cell differentiation, guidance of neurite extension, and peripheral nerve injury treatments. The main objective of this feature article is to provide valuable insights into methods for investigating the mechanisms of neurite growth on novel nanofibrous scaffolds and optimization of the nanofiber scaffolds and conduits for repairing peripheral nerve injuries.

De Valpine P.,University of California at Berkeley | Harmon-Threatt A.N.,Washington University in St. Louis
Ecology | Year: 2013

Many ecological studies investigate how organisms use resources, such as habitats or foods, in relation to availability or other variables. Related statistical problems include analysis of proportions of species or genotypes in a community or population. These require statistical modeling of compositional count data: data on relative proportions of each category collected as counts. Common methods for analyzing compositional count data lack one or more important considerations. Some methods lack explicit accommodation of count data, dealing instead with proportions. Others do not handle between-sample heterogeneity for overdispersed data. Yet others do not allow general types of relationships between explanatory variables and resource use. All three components have been combined in a Bayesian framework, but for frequentist hypothesis tests and AIC model selection, maximumlikelihood estimation is needed. Here we propose the Dirichlet-multinomial distribution to accommodate overdispersed compositional count data. This approach can be used flexibly in combination with explanatory models, but the only correlations among compositional proportions that it can accommodate are the negative correlations due to the fact that proportions must sum to 1. Many existing models can be generalized to use the Dirichletmultinomial distribution for residual variation, and the flexibility of the approach allows new hypotheses that have often not been considered in resource preference analysis, including that availability has no relation to use. We also highlight a new design for resource use studies, with multiple individual-use data sets from each of multiple sites, with different explanatory data for each site. We illustrate the approach with three examples. For two previously published habitat use data sets, we support the original conclusions and show that use is not unrelated to availability. For a data set of pollen collected by multiple bees from each of two sites, pollen use differs between the sites. Using bootstrap goodness-of-fit tests, we illustrate that the Dirichlet-multinomial is acceptable for two of the examples but unsuitable for one of the habitat use examples. © 2013 by the Ecological Society of America.

Transplantation therapy for diabetes is limited by unavailability of donor organs and outcomes complicated by immunosuppressive drug toxicity. Xenotransplantation is a strategy to overcome supply problems. Implantation of tissue obtained early during embryogenesis is a way to reduce transplant immunogenicity. Insulin-producing cells originating from embryonic pig pancreas obtained very early following pancreatic primordium formation [embryonic day 28 (E28)] engraft long-term in inbred diabetic Lewis or Zucker Diabetic Fatty (ZDF) rats or rhesus macaques. Endocrine cells originating from embryonic pig pancreas transplanted in host mesentery migrate to mesenteric lymph nodes, engraft, normalize glucose tolerance in rats and improve glucose tolerance in rhesus macaques without the need for immune suppression. Engraftment of primordia is permissive for engraftment of an insulin-expressing cell component from porcine islets implanted subsequently without immune suppression. Similarities between findings in inbred rat and non-human primate hosts bode well for successful translation to humans of what could be a novel xenotransplantation strategy for the treatment of diabetes. © 2012 Landes Bioscience.

Morrow L.E.,Creighton University | Kollef M.H.,Washington University in St. Louis | Casale T.B.,Creighton University
American Journal of Respiratory and Critical Care Medicine | Year: 2010

Rationale: Enteral administration of probiotics may modify the gastrointestinal environment in a manner that preferentially favors the growth of minimally virulent species. It is unknown whether probiotic modification of the upper aerodigestive flora can reduce nosocomial infections. Objectives: To determine whether oropharyngeal and gastric administration of Lactobacillus rhamnosus GG can reduce the incidence of ventilator-associated pneumonia (VAP). Methods: We performed a prospective, randomized, double-blind, placebo-controlled trial of 146 mechanically ventilated patients at high risk of developing VAP. Patients were randomly assigned to receive enteral probiotics (n = 68) or an inert inulin-based placebo (n = 70) twice a day in addition to routine care. Measurements and Main Results: Patients treated with Lactobacillus were significantly less likely to develop microbiologically confirmed VAP compared with patients treated with placebo (40.0 vs. 19.1%; P = 0.007). Although patients treated with probiotics had significantly less Clostridium difficile-associated diarrhea than patients treated with placebo (18.6 vs. 5.8%; P = 0.02), the duration of diarrhea per episode was not different between groups (13.2 ± 7.4 vs. 9.8 ± 4.9 d; P = 0.39). Patients treated with probiotics had fewer days of antibiotics prescribed for VAP (8.6 ± 10.3 vs. 5.6 ± 7.8 d; P = 0.05) and for C. difficile-associated diarrhea (2.1 ± 4.8 SD d vs. 0.5 ± 2.3 d; P = 0.02). No adverse events related to probiotic administration were identified. Conclusions: These pilot data suggest that L. rhamnosus GG is safe and efficacious in preventing VAP in a select, high-risk ICU population. Clinical trial registered with www.clinicaltrials.gov (NCT00613795).

Wu X.-J.,CAS Institute of Vertebrate Paleontology and Paleoanthropology | Trinkaus E.,Washington University in St. Louis
Comptes Rendus - Palevol | Year: 2014

The earlier Late Pleistocene mandibular ramus from Xujiayao (northern China) preserves traits that vary distributionally among western Old World Pleistocene Homo samples and between Early/Middle Pleistocene archaic humans and Late Pleistocene modern humans in eastern Eurasia. Xujiayao 14 presents a lateral mandibular notch crest, an open mandibular foramen, a wide ramus, an asymmetrical mandibular notch, an enlarged superior medial pterygoid tubercle, (probably) a retromolar space, and gonial eversion, as well as an unusual depression in the planum triangulare. The first two traits appear ancestral for Later Pleistocene and recent Homo and are dominant among modern humans. The second two traits largely separate Xujiayao 14 and archaic Homo from modern humans. The next two traits are found in the highest frequency among the Neandertals, although gonial eversion contrasts with Late Pleistocene Neandertals. Xujiayao 14, in the context of Pleistocene and recent Homo samples and the other Xujiayao human remains, therefore provides a morphological mosaic, highlighting regional variation through the Pleistocene. © 2013 Académie des sciences.

Kouvelis P.,Washington University in St. Louis | Zhao W.,Shanghai JiaoTong University
Operations Research | Year: 2012

We consider a supply chain with a retailer and a supplier: A newsvendor-like retailer has a single opportunity to order a product from a supplier to satisfy future uncertain demand. Both the retailer and supplier are capital constrained and in need of short-term financing. In the presence of bankruptcy risks for both the retailer and supplier, we model their strategic interaction as a Stackelberg game with the supplier as the leader. We use the supplier early payment discount scheme as a decision framework to analyze all decisions involved in optimally structuring the trade credit contract (discounted wholesale price if paying early, financing rate if delaying payment) from the supplier's perspective. Under mild assumptions we conclude that a risk-neutral supplier should always finance the retailer at rates less than or equal to the risk-free rate. The retailer, if offered an optimally structured trade credit contract, will always prefer supplier financing to bank financing. Furthermore, under optimal trade credit contracts, both the supplier's profit and supply chain efficiency improve, and the retailer might improve his profits relative to under bank financing (or equivalently, a rich retailer under wholesale price contracts), depending on his current "wealth" (working capital and collateral). © 2012 INFORMS.

Goodenough U.,Washington University in St. Louis
Plant Journal | Year: 2015

Summary During the period 1950-1970, groundbreaking research on the genetic mapping of Chlamydomonas reinhardtii and the use of mutant strains to analyze photosynthesis was conducted in the laboratory of R. Paul Levine at Harvard University. An account of this era, based in part on interviews with Levine, is presented. Significance Statement Research on Chlamydomonas reinhardtii was launched during the 1950-1970 period, and many key future investigators were trained in the Levine lab. Important insights into the sequence of the photosynthetic electron transport chain were also obtained. © 2015 The Author.

Kim H.J.,Washington University in St. Louis
Instructional course lectures | Year: 2013

The treatment of metastatic disease to the spine involves a comprehensive evaluation of the patient and an individualized treatment plan based on the tumor type and location, the extent of the disease, and the general medical condition of the patient. Careful consideration of these factors dictates the treatment options, which include surgery, radiation, chemotherapy, and/or palliative options. Patients with a good overall prognosis may be considered candidates for more aggressive surgical resections, such as en bloc resections, whereas those with a poor prognosis may benefit from less invasive piecemeal resections to decompress the spine and restore neurologic function while minimizing the morbidity associated with more invasive procedures. The goals of surgery are tailored to the overall prognosis and should be aimed at optimizing the quality of the patient's life.

Cole M.W.,Rutgers University | Cole M.W.,Washington University in St. Louis | Repovs G.,University of Ljubljana | Anticevic A.,Yale University
Neuroscientist | Year: 2014

Recent findings suggest the existence of a frontoparietal control system consisting of flexible hubs that regulate distributed systems (e.g., visual, limbic, motor) according to current task goals. A growing number of studies are reporting alterations of this control system across a striking range of mental diseases. We suggest this may reflect a critical role for the control system in promoting and maintaining mental health. Specifically, we propose that this system implements feedback control to regulate symptoms as they arise (e.g., excessive anxiety reduced via regulation of amygdala), such that an intact control system is protective against a variety of mental illnesses. Consistent with this possibility, recent results indicate that several major mental illnesses involve altered brain-wide connectivity of the control system, likely altering its ability to regulate symptoms. These results suggest that this "immune system of the mind" may be an especially important target for future basic and clinical research. © The Author(s) 2014.

Kay K.N.,Washington University in St. Louis | Weiner K.S.,Stanford University | Grill-Spector K.,Stanford University
Current Biology | Year: 2015

Ventral temporal cortex (VTC) is the latest stage of the ventral "what" visual pathway, which is thought to code the identity of a stimulus regardless of its position or size [1, 2]. Surprisingly, recent studies show that position information can be decoded from VTC [3-5]. However, the computational mechanisms by which spatial information is encoded in VTC are unknown. Furthermore, how attention influences spatial representations in human VTC is also unknown because the effect of attention on spatial representations has only been examined in the dorsal "where" visual pathway [6-10]. Here, we fill these significant gaps in knowledge using an approach that combines functional magnetic resonance imaging and sophisticated computational methods. We first develop a population receptive field (pRF) model [11, 12] of spatial responses in human VTC. Consisting of spatial summation followed by a compressive nonlinearity, this model accurately predicts responses of individual voxels to stimuli at any position and size, explains how spatial information is encoded, and reveals a functional hierarchy in VTC. We then manipulate attention and use our model to decipher the effects of attention. We find that attention to the stimulus systematically and selectively modulates responses in VTC, but not early visual areas. Locally, attention increases eccentricity, size, and gain of individual pRFs, thereby increasing position tolerance. However, globally, these effects reduce uncertainty regarding stimulus location and actually increase position sensitivity of distributed responses across VTC. These results demonstrate that attention actively shapes and enhances spatial representations in the ventral visual pathway. © 2015 Elsevier Ltd All rights reserved.

Ferguson T.A.,Washington University in St. Louis | Green D.R.,St Jude Childrens Research Hospital
Autophagy | Year: 2014

The retinal pigment epithelium (RPE) is a single layer of nonregenerating cells essential to homeostasis in the retina and the preservation of vision. While the RPE perform a number of important functions, 2 essential processes are phagocytosis, which removes the most distal tips of the photoreceptors to support disk renewal, and the visual cycle, which maintains the supply of chromophore for regeneration of photobleached visual pigments. We recently reported that these processes are linked by a noncanonical form of autophagy termed LC3-associated phagocytosis (LAP) in which components of the autophagy pathway are co-opted by phagocytosis to recover vitamin A in support of optimal vision. Here we summarize these findings.© 2014 Landes Bioscience.

Karpicke J.D.,Purdue University | Roediger III H.L.,Washington University in St. Louis
Memory and Cognition | Year: 2010

Expanding retrieval practice refers to the idea that gradually increasing the spacing interval between repeated tests ought to promote optimal long-term retention. Belief in the superiority of this technique is widespread, but empirical support is scarce. In addition, virtually all research on expanding retrieval has examined the learning of word pairs in paired-associate tasks. We report two experiments in which we examined the learning of text materials with expanding and equally spaced retrieval practice schedules. Subjects studied brief texts and recalled them in an initial learning phase. We manipulated the spacing of the repeated recall tests and examined final recall 1 week later. Overall we found that (1) repeated testing enhanced retention more than did taking a single test, (2) testing with feedback (restudying the passages) produced better retention than testing without feedback, but most importantly (3) there were no differences between expanding and equally spaced schedules of retrieval practice. Repeated retrieval enhanced long-term retention, but how the repeated tests were spaced did not matter. © 2010 The Psychonomic Society, Inc.

Benson P.,Washington University in St. Louis
Medical Anthropology Quarterly | Year: 2010

This article examines how North Carolina tobacco farmers think about the moral ambiguities of tobacco business. Drawing on ethnographic research with tobacco farmers and archival research on the tobacco industry, I specify the core psychological defense mechanisms that tobacco companies have crafted for people associated with the industry. I also document local social, cultural, and economic factors in rural North Carolina that underpin ongoing rural dependence on tobacco despite the negativity that surrounds tobacco and structural adjustments. This article contributes to our knowledge about tobacco farmers and tobacco farming communities, which is important for tobacco-control strategies. I reflect on ethical and economic paradoxes related to the rise of corporate social responsibility in the tobacco industry, where an official legal framing of consumption, focused on informed adult consumer autonomy and health education, is promoted to undermine more robust public health prevention efforts. © 2010 by the American Anthropological Association.

Hou J.,Washington University in St. Louis | Rajagopal M.,University of Kansas Medical Center | Yu A.S.L.,University of Kansas Medical Center
Annual Review of Physiology | Year: 2013

Claudins are tight junction membrane proteins that regulate paracellular permeability of renal epithelia to small ions, solutes, and water. Claudins interact within the cell membrane and between neighboring cells to form tight junction strands and constitute both the paracellular barrier and the pore. The first extracellular domain of cla