Innovations in diabetic foot reconstruction using supermicrosurgery.

PubMed

Suh, Hyun Suk; Oh, Tae Suk; Hong, Joon Pio

2016-01-01

The treatment of diabetic foot ulceration is complex with multiple factors involved, and it may often lead to limb amputation. Hence, a multidisciplinary approach is warranted to cover the spectrum of treatment for diabetic foot, but in complex wounds, surgical treatment is inevitable. Surgery may involve the decision to preserve the limb by reconstruction or to amputate it. Reconstruction involves preserving the limb with secure coverage. Local flaps usually are able to provide sufficient coverage for small or moderate sized wound, but for larger wounds, soft tissue coverage involves flaps that are distantly located from the wound. Reconstruction of distant flap usually involves microsurgery, and now, further innovative methods such as supermicrosurgery have further given complex wounds a better chance to be reconstructed and limbs salvaged. This article reviews the microsurgery involved in reconstruction and introduces the new method of supermicrosurgery. Copyright © 2016 John Wiley & Sons, Ltd.

Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements

PubMed Central

Liu, Pengfei; Erez, Ayelet; Sreenath Nagamani, Sandesh C.; Dhar, Shweta U.; Kołodziejska, Katarzyna E.; Dharmadhikari, Avinash V.; Cooper, M. Lance; Wiszniewska, Joanna; Zhang, Feng; Withers, Marjorie A.; Bacino, Carlos A.; Campos-Acevedo, Luis Daniel; Delgado, Mauricio R.; Freedenberg, Debra; Garnica, Adolfo; Grebe, Theresa A.; Hernández-Almaguer, Dolores; Immken, LaDonna; Lalani, Seema R.; McLean, Scott D.; Northrup, Hope; Scaglia, Fernando; Strathearn, Lane; Trapane, Pamela; Kang, Sung-Hae L.; Patel, Ankita; Cheung, Sau Wai; Hastings, P. J.; Stankiewicz, Paweł; Lupski, James R.; Bi, Weimin

2011-01-01

SUMMARY Complex genomic rearrangements (CGR) consisting of two or more breakpoint junctions have been observed in genomic disorders. Recently, a chromosome catastrophe phenomenon termed chromothripsis, in which numerous genomic rearrangements are apparently acquired in one single catastrophic event, was described in multiple cancers. Here we show that constitutionally acquired CGRs share similarities with cancer chromothripsis. In the 17 CGR cases investigated we observed localization and multiple copy number changes including deletions, duplications and/or triplications, as well as extensive translocations and inversions. Genomic rearrangements involved varied in size and complexities; in one case, array comparative genomic hybridization revealed 18 copy number changes. Breakpoint sequencing identified characteristic features, including small templated insertions at breakpoints and microhomology at breakpoint junctions, which have been attributed to replicative processes. The resemblance between CGR and chromothripsis suggests similar mechanistic underpinnings. Such chromosome catastrophic events appear to reflect basic DNA metabolism operative throughout an organism’s life cycle. PMID:21925314

Total Teacher Effectiveness: Implication for Curriculum Change (TOC) in Hong Kong.

ERIC Educational Resources Information Center

Tsui, Kwok Tung; Cheng, Yin Cheong

This paper introduces the concept of total teacher effectiveness for facilitating educational reform and improvement, using target oriented curriculum (TOC) change in Hong Kong as an example. TOC change is a complex process that involves preparing, changing, and reinforcing teachers in multiple domains at multiple levels. Teacher effectiveness…

Fault diagnosis of sensor networked structures with multiple faults using a virtual beam based approach

NASA Astrophysics Data System (ADS)

Wang, H.; Jing, X. J.

2017-07-01

This paper presents a virtual beam based approach suitable for conducting diagnosis of multiple faults in complex structures with limited prior knowledge of the faults involved. The "virtual beam", a recently-proposed concept for fault detection in complex structures, is applied, which consists of a chain of sensors representing a vibration energy transmission path embedded in the complex structure. Statistical tests and adaptive threshold are particularly adopted for fault detection due to limited prior knowledge of normal operational conditions and fault conditions. To isolate the multiple faults within a specific structure or substructure of a more complex one, a 'biased running' strategy is developed and embedded within the bacterial-based optimization method to construct effective virtual beams and thus to improve the accuracy of localization. The proposed method is easy and efficient to implement for multiple fault localization with limited prior knowledge of normal conditions and faults. With extensive experimental results, it is validated that the proposed method can localize both single fault and multiple faults more effectively than the classical trust index subtract on negative add on positive (TI-SNAP) method.

Use of whole-exome sequencing to determine the genetic basis of multiple mitochondrial respiratory chain complex deficiencies.

PubMed

Taylor, Robert W; Pyle, Angela; Griffin, Helen; Blakely, Emma L; Duff, Jennifer; He, Langping; Smertenko, Tania; Alston, Charlotte L; Neeve, Vivienne C; Best, Andrew; Yarham, John W; Kirschner, Janbernd; Schara, Ulrike; Talim, Beril; Topaloglu, Haluk; Baric, Ivo; Holinski-Feder, Elke; Abicht, Angela; Czermin, Birgit; Kleinle, Stephanie; Morris, Andrew A M; Vassallo, Grace; Gorman, Grainne S; Ramesh, Venkateswaran; Turnbull, Douglass M; Santibanez-Koref, Mauro; McFarland, Robert; Horvath, Rita; Chinnery, Patrick F

2014-07-02

Mitochondrial disorders have emerged as a common cause of inherited disease, but their diagnosis remains challenging. Multiple respiratory chain complex defects are particularly difficult to diagnose at the molecular level because of the massive number of nuclear genes potentially involved in intramitochondrial protein synthesis, with many not yet linked to human disease. To determine the molecular basis of multiple respiratory chain complex deficiencies. We studied 53 patients referred to 2 national centers in the United Kingdom and Germany between 2005 and 2012. All had biochemical evidence of multiple respiratory chain complex defects but no primary pathogenic mitochondrial DNA mutation. Whole-exome sequencing was performed using 62-Mb exome enrichment, followed by variant prioritization using bioinformatic prediction tools, variant validation by Sanger sequencing, and segregation of the variant with the disease phenotype in the family. Presumptive causal variants were identified in 28 patients (53%; 95% CI, 39%-67%) and possible causal variants were identified in 4 (8%; 95% CI, 2%-18%). Together these accounted for 32 patients (60% 95% CI, 46%-74%) and involved 18 different genes. These included recurrent mutations in RMND1, AARS2, and MTO1, each on a haplotype background consistent with a shared founder allele, and potential novel mutations in 4 possible mitochondrial disease genes (VARS2, GARS, FLAD1, and PTCD1). Distinguishing clinical features included deafness and renal involvement associated with RMND1 and cardiomyopathy with AARS2 and MTO1. However, atypical clinical features were present in some patients, including normal liver function and Leigh syndrome (subacute necrotizing encephalomyelopathy) seen in association with TRMU mutations and no cardiomyopathy with founder SCO2 mutations. It was not possible to confidently identify the underlying genetic basis in 21 patients (40%; 95% CI, 26%-54%). Exome sequencing enhances the ability to identify potential nuclear gene mutations in patients with biochemically defined defects affecting multiple mitochondrial respiratory chain complexes. Additional study is required in independent patient populations to determine the utility of this approach in comparison with traditional diagnostic methods.

Attributional (Explanatory) Thinking about Failure in New Achievement Settings

ERIC Educational Resources Information Center

Perry, Raymond P.; Stupnisky, Robert H.; Daniels, Lia M.; Haynes, Tara L.

2008-01-01

Attributional (explanatory) thinking involves the appraisal of factors that contribute to performance and is instrumental to motivation and goal striving. Little is understood, however, concerning attributional thinking when multiple causes are involved in the transition to new achievement settings. Our study examined such complex attributional…

Novel Genome-Wide Screening Method Identifies Genes Important to Breast Cancer Metastasis | Center for Cancer Research

Cancer.gov

For patients with solid tumors, the primary cause of illness and death is metastasis, a complex process involving multiple steps and cooperation between cancerous and normal cells. Many genes must be involved, but few have been found and characterized.

HERMIES-3: A step toward autonomous mobility, manipulation, and perception

NASA Technical Reports Server (NTRS)

Weisbin, C. R.; Burks, B. L.; Einstein, J. R.; Feezell, R. R.; Manges, W. W.; Thompson, D. H.

1989-01-01

HERMIES-III is an autonomous robot comprised of a seven degree-of-freedom (DOF) manipulator designed for human scale tasks, a laser range finder, a sonar array, an omni-directional wheel-driven chassis, multiple cameras, and a dual computer system containing a 16-node hypercube expandable to 128 nodes. The current experimental program involves performance of human-scale tasks (e.g., valve manipulation, use of tools), integration of a dexterous manipulator and platform motion in geometrically complex environments, and effective use of multiple cooperating robots (HERMIES-IIB and HERMIES-III). The environment in which the robots operate has been designed to include multiple valves, pipes, meters, obstacles on the floor, valves occluded from view, and multiple paths of differing navigation complexity. The ongoing research program supports the development of autonomous capability for HERMIES-IIB and III to perform complex navigation and manipulation under time constraints, while dealing with imprecise sensory information.

[A complexity analysis of Chinese herbal property theory: the multiple expressions of herbal property].

PubMed

Jin, Rui; Zhang, Bing

2012-12-01

Chinese herbal property is the highly summarized concept of herbal nature and pharmaceutical effect, which reflect the characteristics of herbal actions on human body. These herbal actions, also interpreted as presenting the information about pharmaceutical effect contained in herbal property on the biological carrier, are defined as herbal property expressions. However, the biological expression of herbal property is believed to possess complex features for the involved complexity of Chinese medicine and organism. Firstly, there are multiple factors which could influence the expression results of herbal property such as the growth environment, harvest season and preparing methods of medicinal herbs, and physique and syndrome of body. Secondly, there are multiple biological approaches and biochemical indicators for the expression of the same property. This paper elaborated these complexities for further understanding of herbal property. The individuality of herbs and expression factors should be well analyzed in the related studies.

Identification of interacting proteins of the TaFVE protein involved in spike development in bread wheat.

PubMed

Zheng, Yong-Sheng; Lu, Yu-Qing; Meng, Ying-Ying; Zhang, Rong-Zhi; Zhang, Han; Sun, Jia-Mei; Wang, Mu-Mu; Li, Li-Hui; Li, Ru-Yu

2017-05-01

WD-40 repeat-containing protein MSI4 (FVE)/MSI4 plays important roles in determining flowering time in Arabidopsis. However, its function is unexplored in wheat. In the present study, coimmunoprecipitation and nanoscale liquid chromatography coupled to MS/MS were used to identify FVE in wheat (TaFVE)-interacting or associated proteins. Altogether 89 differentially expressed proteins showed the same downregulated expression trends as TaFVE in wheat line 5660M. Among them, 62 proteins were further predicted to be involved in the interaction network of TaFVE and 11 proteins have been shown to be potential TaFVE interactors based on curated databases and experimentally determined in other species by the STRING. Both yeast two-hybrid assay and bimolecular fluorescence complementation assay showed that histone deacetylase 6 and histone deacetylase 15 directly interacted with TaFVE. Multiple chromatin-remodelling proteins and polycomb group proteins were also identified and predicted to interact with TaFVE. These results showed that TaFVE directly interacted with multiple proteins to form multiple complexes to regulate spike developmental process, e.g. histone deacetylate, chromatin-remodelling and polycomb repressive complex 2 complexes. In addition, multiple flower development regulation factors (e.g. flowering locus K homology domain, flowering time control protein FPA, FY, flowering time control protein FCA, APETALA 1) involved in floral transition were also identified in the present study. Taken together, these results further elucidate the regulatory functions of TaFVE and help reveal the genetic mechanisms underlying wheat spike differentiation. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Icosahedral and decagonal quasicrystals of intermetallic compounds are multiple twins of cubic or orthorhombic crystals composed of very large atomic complexes with icosahedral point-group symmetry in cubic close packing or body-centered packing: Structure of decagonal Al6Pd

PubMed Central

Pauling, Linus

1989-01-01

A doubly icosahedral complex involves roughly spherical clusters of atoms with icosahedral point-group symmetry, which are themselves, in parallel orientation, icosahedrally packed. These complexes may form cubic crystallites; three structures of this sort have been identified. Analysis of electron diffraction photographs of the decagonal quasicrystal Al6Pd has led to its description as involving pentagonal twinning of an orthorhombic crystal with a = 51.6 Å, b = 37.6 Å, and c = 33.24 Å, with about 4202 atoms in the unit, comprising two 1980-atom doubly icosahedral complexes, each involving icosahedral packing of 45 44-atom icosahedral complexes (at 0 0 0 and 1/2 1/2 1/2) and 242 interstitial atoms. The complexes and clusters are oriented with one of their fivefold axes in the c-axis direction. Images PMID:16594092

Icosahedral and decagonal quasicrystals of intermetallic compounds are multiple twins of cubic or orthorhombic crystals composed of very large atomic complexes with icosahedral point-group symmetry in cubic close packing or body-centered packing: Structure of decagonal Al(6)Pd.

PubMed

Pauling, L

1989-12-01

A doubly icosahedral complex involves roughly spherical clusters of atoms with icosahedral point-group symmetry, which are themselves, in parallel orientation, icosahedrally packed. These complexes may form cubic crystallites; three structures of this sort have been identified. Analysis of electron diffraction photographs of the decagonal quasicrystal Al(6)Pd has led to its description as involving pentagonal twinning of an orthorhombic crystal with a = 51.6 A, b = 37.6 A, and c = 33.24 A, with about 4202 atoms in the unit, comprising two 1980-atom doubly icosahedral complexes, each involving icosahedral packing of 45 44-atom icosahedral complexes (at 0 0 0 and 1/2 1/2 1/2) and 242 interstitial atoms. The complexes and clusters are oriented with one of their fivefold axes in the c-axis direction.

Further Understanding of Complex Information Processing in Verbal Adolescents and Adults with Autism Spectrum Disorders

ERIC Educational Resources Information Center

Williams, Diane L.; Minshew, Nancy J.; Goldstein, Gerald

2015-01-01

More than 20?years ago, Minshew and colleagues proposed the Complex Information Processing model of autism in which the impairment is characterized as a generalized deficit involving multiple modalities and cognitive domains that depend on distributed cortical systems responsible for higher order abilities. Subsequent behavioral work revealed a…

Visualizing the Complex Process for Deep Learning with an Authentic Programming Project

ERIC Educational Resources Information Center

Peng, Jun; Wang, Minhong; Sampson, Demetrios

2017-01-01

Project-based learning (PjBL) has been increasingly used to connect abstract knowledge and authentic tasks in educational practice, including computer programming education. Despite its promising effects on improving learning in multiple aspects, PjBL remains a struggle due to its complexity. Completing an authentic programming project involves a…

Hierarchical Modeling of Sequential Behavioral Data: Examining Complex Association Patterns in Mediation Models

ERIC Educational Resources Information Center

Dagne, Getachew A.; Brown, C. Hendricks; Howe, George W.

2007-01-01

This article presents new methods for modeling the strength of association between multiple behaviors in a behavioral sequence, particularly those involving substantively important interaction patterns. Modeling and identifying such interaction patterns becomes more complex when behaviors are assigned to more than two categories, as is the case…

Students' Understanding of Acid, Base and Salt Reactions in Qualitative Analysis.

ERIC Educational Resources Information Center

Tan, Kim-Chwee Daniel; Goh, Ngoh-Khang; Chia, Lian-Sai; Treagust, David F.

2003-01-01

Uses a two-tier, multiple-choice diagnostic instrument to determine (n=915) grade 10 students' understanding of the acid, base, and salt reactions involved in basic qualitative analysis. Reports that many students did not understand the formation of precipitates and the complex salts, acid/salt-base reactions, and thermal decomposition involved in…

A Healthy Harvest: Adolescents Grow Food and Well-Being with Policy Implications for Education, Health and Community Planning

ERIC Educational Resources Information Center

Pevec, Illene Susan

2011-01-01

The severe youth health crisis involving overweight and obesity requires a complex policy response involving multiple domains: education, agriculture, health services, and community planning. This research examines gardening's affective benefits for adolescents and the potential school and youth gardens have to support healthy communities.…

Meaning Making through Multiple Modalities in a Biology Classroom: A Multimodal Semiotics Discourse Analysis

ERIC Educational Resources Information Center

Jaipal, Kamini

2010-01-01

The teaching of science is a complex process, involving the use of multiple modalities. This paper illustrates the potential of a multimodal semiotics discourse analysis framework to illuminate meaning-making possibilities during the teaching of a science concept. A multimodal semiotics analytical framework is developed and used to (1) analyze the…

Understanding large multiprotein complexes: applying a multiple allosteric networks model to explain the function of the Mediator transcription complex.

PubMed

Lewis, Brian A

2010-01-15

The regulation of transcription and of many other cellular processes involves large multi-subunit protein complexes. In the context of transcription, it is known that these complexes serve as regulatory platforms that connect activator DNA-binding proteins to a target promoter. However, there is still a lack of understanding regarding the function of these complexes. Why do multi-subunit complexes exist? What is the molecular basis of the function of their constituent subunits, and how are these subunits organized within a complex? What is the reason for physical connections between certain subunits and not others? In this article, I address these issues through a model of network allostery and its application to the eukaryotic RNA polymerase II Mediator transcription complex. The multiple allosteric networks model (MANM) suggests that protein complexes such as Mediator exist not only as physical but also as functional networks of interconnected proteins through which information is transferred from subunit to subunit by the propagation of an allosteric state known as conformational spread. Additionally, there are multiple distinct sub-networks within the Mediator complex that can be defined by their connections to different subunits; these sub-networks have discrete functions that are activated when specific subunits interact with other activator proteins.

Force-Manipulation Single-Molecule Spectroscopy Studies of Enzymatic Dynamics

NASA Astrophysics Data System (ADS)

Lu, H. Peter; He, Yufan; Lu, Maolin; Cao, Jin; Guo, Qing

2014-03-01

Subtle conformational changes play a crucial role in protein functions, especially in enzymatic reactions involving complex substrate-enzyme interactions and chemical reactions. We applied AFM-enhanced and magnetic tweezers-correlated single-molecule spectroscopy to study the mechanisms and dynamics of enzymatic reactions involved with kinase and lysozyme proteins. Enzymatic reaction turnovers and the associated structure changes of individual protein molecules were observed simultaneously in real-time by single-molecule FRET detections. Our single-molecule spectroscopy measurements of enzymatic conformational dynamics have revealed time bunching effect and intermittent coherence in conformational state change dynamics involving in enzymatic reaction cycles. The coherent conformational state dynamics suggests that the enzymatic catalysis involves a multi-step conformational motion along the coordinates of substrate-enzyme complex formation and product releasing. Our results support a multiple-conformational state model, being consistent with a complementary conformation selection and induced-fit enzymatic loop-gated conformational change mechanism in substrate-enzyme active complex formation.

Combination therapeutics in complex diseases.

PubMed

He, Bing; Lu, Cheng; Zheng, Guang; He, Xiaojuan; Wang, Maolin; Chen, Gao; Zhang, Ge; Lu, Aiping

2016-12-01

The biological redundancies in molecular networks of complex diseases limit the efficacy of many single drug therapies. Combination therapeutics, as a common therapeutic method, involve pharmacological intervention using several drugs that interact with multiple targets in the molecular networks of diseases and may achieve better efficacy and/or less toxicity than monotherapy in practice. The development of combination therapeutics is complicated by several critical issues, including identifying multiple targets, targeting strategies and the drug combination. This review summarizes the current achievements in combination therapeutics, with a particular emphasis on the efforts to develop combination therapeutics for complex diseases. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

What Gene-Environment Interactions Can Tell Us about Social Competence in Typical and Atypical Populations

ERIC Educational Resources Information Center

Iarocci, Grace; Yager, Jodi; Elfers, Theo

2007-01-01

Social competence is a complex human behaviour that is likely to involve a system of genes that interacts with a myriad of environmental risk and protective factors. The search for its genetic and environmental origins and influences is equally complex and will require a multidimensional conceptualization and multiple methods and levels of…

Network-based analysis of differentially expressed genes in cerebrospinal fluid (CSF) and blood reveals new candidate genes for multiple sclerosis

PubMed Central

Safari-Alighiarloo, Nahid; Taghizadeh, Mohammad; Tabatabaei, Seyyed Mohammad; Namaki, Saeed

2016-01-01

Background The involvement of multiple genes and missing heritability, which are dominant in complex diseases such as multiple sclerosis (MS), entail using network biology to better elucidate their molecular basis and genetic factors. We therefore aimed to integrate interactome (protein–protein interaction (PPI)) and transcriptomes data to construct and analyze PPI networks for MS disease. Methods Gene expression profiles in paired cerebrospinal fluid (CSF) and peripheral blood mononuclear cells (PBMCs) samples from MS patients, sampled in relapse or remission and controls, were analyzed. Differentially expressed genes which determined only in CSF (MS vs. control) and PBMCs (relapse vs. remission) separately integrated with PPI data to construct the Query-Query PPI (QQPPI) networks. The networks were further analyzed to investigate more central genes, functional modules and complexes involved in MS progression. Results The networks were analyzed and high centrality genes were identified. Exploration of functional modules and complexes showed that the majority of high centrality genes incorporated in biological pathways driving MS pathogenesis. Proteasome and spliceosome were also noticeable in enriched pathways in PBMCs (relapse vs. remission) which were identified by both modularity and clique analyses. Finally, STK4, RB1, CDKN1A, CDK1, RAC1, EZH2, SDCBP genes in CSF (MS vs. control) and CDC37, MAP3K3, MYC genes in PBMCs (relapse vs. remission) were identified as potential candidate genes for MS, which were the more central genes involved in biological pathways. Discussion This study showed that network-based analysis could explicate the complex interplay between biological processes underlying MS. Furthermore, an experimental validation of candidate genes can lead to identification of potential therapeutic targets. PMID:28028462

Advancing efforts to address youth violence involvement.

PubMed

Weist, M D; Cooley-Quille, M

2001-06-01

Discusses the increased public attention on violence-related problems among youth and the concomitant increased diversity in research. Youth violence involvement is a complex construct that includes violence experienced in multiple settings (home, school, neighborhood) and in multiple forms (as victims, witnesses, perpetrators, and through family members, friends, and the media). Potential impacts of such violence involvement are considerable, including increased internalizing and externalizing behaviors among youth and future problems in school adjustment and life-course development. This introductory article reviews key dimensions of youth-related violence, describes an American Psychological Association Task Force (Division 12) developed to advance relevant research, and presents examples of national resources and efforts that attempt to address this critical public health issue.

Mediator complex dependent regulation of cardiac development and disease.

PubMed

Grueter, Chad E

2013-06-01

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality. The risk factors for CVD include environmental and genetic components. Human mutations in genes involved in most aspects of cardiovascular function have been identified, many of which are involved in transcriptional regulation. The Mediator complex serves as a pivotal transcriptional regulator that functions to integrate diverse cellular signals by multiple mechanisms including recruiting RNA polymerase II, chromatin modifying proteins and non-coding RNAs to promoters in a context dependent manner. This review discusses components of the Mediator complex and the contribution of the Mediator complex to normal and pathological cardiac development and function. Enhanced understanding of the role of this core transcriptional regulatory complex in the heart will help us gain further insights into CVD. Copyright © 2013. Production and hosting by Elsevier Ltd.

A multiple translocation event in a patient with hexadactyly, facial dysmorphism, mental retardation and behaviour disorder characterised comprehensively by molecular cytogenetics. Case report and review of the literature.

PubMed

Seidel, Jörg; Heller, Anita; Senger, Gabriele; Starke, Heike; Chudoba, Ilse; Kelbova, Christina; Tönnies, Holger; Neitzel, Heidemarie; Haase, Claudia; Beensen, Volkmar; Zintl, Felix; Claussen, Uwe; Liehr, Thomas

2003-09-01

We report a 13-year-old female patient with multiple congenital abnormalities (microcephaly, facial dysmorphism, anteverted dysplastic ears and postaxial hexadactyly), mental retardation, and adipose-gigantism. Ultrasonography revealed no signs of a heart defect or renal abnormalities. She showed no speech development and suffered from a behavioural disorder. CNS abnormalities were excluded by cerebral MRI. Initial cytogenetic studies by Giemsa banding revealed an aberrant karyotype involving three chromosomes, t(2;4;11). By high resolution banding and multicolour fluoresence in-situ hybridisation (M-FISH, MCB), chromosome 1 was also found to be involved in the complex chromosomal aberrations, confirming the karyotype 46,XX,t(2;11;4).ish t(1;4;2;11)(q43;q21.1;p12-p13.1;p14.1). To the best of our knowledge no patient has been previously described with such a complex translocation involving 4 chromosomes. This case demonstrates that conventional chromosome banding techniques such as Giemsa banding are not always sufficient to characterise complex chromosomal abnormalities. Only by the additional utilisation of molecular cytogenetic techniques could the complexity of the present chromosomal rearrangements and the origin of the involved chromosomal material be detected. Further molecular genetic studies will be performed to clarify the chromosomal breakpoints potentially responsible for the observed clinical symptoms. This report demonstrates that multicolour-fluorescence in-situ hybridisation studies should be performed in patients with congenital abnormalities and suspected aberrant karyotypes in addition to conventional Giemsa banding.

Multiple Analogies for Complex Concepts: Antidotes for Analogy-Induced Misconception in Advanced Knowledge Acquisition. Technical Report No. 439.

ERIC Educational Resources Information Center

Spiro, Rand J.; And Others

This report argues that there exists a pervasive tendency for analogies to contribute to the development of entrenched misconceptions in the form of reducing complex new knowledge to the core of a source analogy. The report presents a taxonomy of ways that simple analogy induces conceptual error and an alternative approach involving integrated…

Implementation of a Manualized Communication Intervention for School-Aged Children with Pragmatic and Social Communication Needs in a Randomized Controlled Trial: The Social Communication Intervention Project

ERIC Educational Resources Information Center

Adams, Catherine; Lockton, Elaine; Gaile, Jacqueline; Earl, Gillian; Freed, Jenny

2012-01-01

Background: Speech-language interventions are often complex in nature, involving multiple observations, variable outcomes and individualization in treatment delivery. The accepted procedure associated with randomized controlled trials (RCT) of such complex interventions is to develop and implement a manual of intervention in order that reliable…

Neuropsychological and structural brain lesions in multiple sclerosis: a regional analysis.

PubMed

Swirsky-Sacchetti, T; Mitchell, D R; Seward, J; Gonzales, C; Lublin, F; Knobler, R; Field, H L

1992-07-01

Quantified lesion scores derived from MRI correlate significantly with neuropsychological testing in patients with multiple sclerosis (MS). Variables used to reflect disease severity include total lesion area (TLA), ventricular-brain ratio, and size of the corpus callosum. We used these general measures of cerebral lesion involvement as well as specific ratings of lesion involvement by frontal, temporal, and parieto-occipital regions to quantify the topographic distribution of lesions and consequent effects upon cognitive function. Lesions were heavily distributed in the parieto-occipital regions bilaterally. Neuropsychological tests were highly related to all generalized measures of cerebral involvement, with TLA being the best predictor of neuropsychological deficit. Mean TLA for the cognitively impaired group was 28.30 cm2 versus 7.41 cm2 for the cognitively intact group (p less than 0.0001). Multiple regression analyses revealed that left frontal lobe involvement best predicted impaired abstract problem solving, memory, and word fluency. Left parieto-occipital lesion involvement best predicted deficits in verbal learning and complex visual-integrative skills. Analysis of regional cerebral lesion load may assist in understanding the particular pattern and course of cognitive deficits in MS.

Equilibrium expert: an add-in to Microsoft Excel for multiple binding equilibrium simulations and parameter estimations.

PubMed

Raguin, Olivier; Gruaz-Guyon, Anne; Barbet, Jacques

2002-11-01

An add-in to Microsoft Excel was developed to simulate multiple binding equilibriums. A partition function, readily written even when the equilibrium is complex, describes the experimental system. It involves the concentrations of the different free molecular species and of the different complexes present in the experiment. As a result, the software is not restricted to a series of predefined experimental setups but can handle a large variety of problems involving up to nine independent molecular species. Binding parameters are estimated by nonlinear least-square fitting of experimental measurements as supplied by the user. The fitting process allows user-defined weighting of the experimental data. The flexibility of the software and the way it may be used to describe common experimental situations and to deal with usual problems such as tracer reactivity or nonspecific binding is demonstrated by a few examples. The software is available free of charge upon request.

Communication challenges in complex medical environments.

PubMed

Lee, Jessica D; Hohler, Anna

2014-06-01

The provision of health care is becoming increasingly complex and can involve multiple providers and care setting transitions, particularly as the population is living longer, and often with chronic disease. The Electronic Health Record (EHR) was intended to provide a comprehensive documentation of a patient's health-related information; however, health care systems often function in isolation with EHRs that are unique only to that system. The EHR may also limit face-to-face communication between treating physicians within the same system. It is only with diligent effort that changes in medical management plans are conveyed among providers. When multiple providers are involved in a patient's care, physician-to-patient communication may also suffer, which can impact patient satisfaction and outcome. This article describes a scenario in which several lapses in communication occurred, and it outlines other common pitfalls while providing possible solutions for improving communication across the health care spectrum.

The fuzzy cube and causal efficacy: representation of concomitant mechanisms in stroke.

PubMed

Jobe, Thomas H.; Helgason, Cathy M.

1998-04-01

Twentieth century medical science has embraced nineteenth century Boolean probability theory based upon two-valued Aristotelian logic. With the later addition of bit-based, von Neumann structured computational architectures, an epistemology based on randomness has led to a bivalent epidemiological methodology that dominates medical decision making. In contrast, fuzzy logic, based on twentieth century multi-valued logic, and computational structures that are content addressed and adaptively modified, has advanced a new scientific paradigm for the twenty-first century. Diseases such as stroke involve multiple concomitant causal factors that are difficult to represent using conventional statistical methods. We tested which paradigm best represented this complex multi-causal clinical phenomenon-stroke. We show that the fuzzy logic paradigm better represented clinical complexity in cerebrovascular disease than current probability theory based methodology. We believe this finding is generalizable to all of clinical science since multiple concomitant causal factors are involved in nearly all known pathological processes.

Clifford support vector machines for classification, regression, and recurrence.

PubMed

Bayro-Corrochano, Eduardo Jose; Arana-Daniel, Nancy

2010-11-01

This paper introduces the Clifford support vector machines (CSVM) as a generalization of the real and complex-valued support vector machines using the Clifford geometric algebra. In this framework, we handle the design of kernels involving the Clifford or geometric product. In this approach, one redefines the optimization variables as multivectors. This allows us to have a multivector as output. Therefore, we can represent multiple classes according to the dimension of the geometric algebra in which we work. We show that one can apply CSVM for classification and regression and also to build a recurrent CSVM. The CSVM is an attractive approach for the multiple input multiple output processing of high-dimensional geometric entities. We carried out comparisons between CSVM and the current approaches to solve multiclass classification and regression. We also study the performance of the recurrent CSVM with experiments involving time series. The authors believe that this paper can be of great use for researchers and practitioners interested in multiclass hypercomplex computing, particularly for applications in complex and quaternion signal and image processing, satellite control, neurocomputation, pattern recognition, computer vision, augmented virtual reality, robotics, and humanoids.

Coincidence and covariance data acquisition in photoelectron and -ion spectroscopy. I. Formal theory

NASA Astrophysics Data System (ADS)

Mikosch, Jochen; Patchkovskii, Serguei

2013-10-01

We derive a formal theory of noisy Poisson processes with multiple outcomes. We obtain simple, compact expressions for the probability distribution function of arbitrarily complex composite events and its moments. We illustrate the utility of the theory by analyzing properties of coincidence and covariance photoelectron-photoion detection involving single-ionization events. The results and techniques introduced in this work are directly applicable to more general coincidence and covariance experiments, including multiple ionization and multiple-ion fragmentation pathways.

A Quantitative Systems Pharmacology Approach to Infer Pathways Involved in Complex Disease Phenotypes.

PubMed

Schurdak, Mark E; Pei, Fen; Lezon, Timothy R; Carlisle, Diane; Friedlander, Robert; Taylor, D Lansing; Stern, Andrew M

2018-01-01

Designing effective therapeutic strategies for complex diseases such as cancer and neurodegeneration that involve tissue context-specific interactions among multiple gene products presents a major challenge for precision medicine. Safe and selective pharmacological modulation of individual molecular entities associated with a disease often fails to provide efficacy in the clinic. Thus, development of optimized therapeutic strategies for individual patients with complex diseases requires a more comprehensive, systems-level understanding of disease progression. Quantitative systems pharmacology (QSP) is an approach to drug discovery that integrates computational and experimental methods to understand the molecular pathogenesis of a disease at the systems level more completely. Described here is the chemogenomic component of QSP for the inference of biological pathways involved in the modulation of the disease phenotype. The approach involves testing sets of compounds of diverse mechanisms of action in a disease-relevant phenotypic assay, and using the mechanistic information known for the active compounds, to infer pathways and networks associated with the phenotype. The example used here is for monogenic Huntington's disease (HD), which due to the pleiotropic nature of the mutant phenotype has a complex pathogenesis. The overall approach, however, is applicable to any complex disease.

Inhibition during response preparation is sensitive to response complexity

PubMed Central

Saks, Dylan; Hoang, Timothy; Ivry, Richard B.

2015-01-01

Motor system excitability is transiently suppressed during the preparation of movement. This preparatory inhibition is hypothesized to facilitate response selection and initiation. Given that demands on selection and initiation processes increase with movement complexity, we hypothesized that complexity would influence preparatory inhibition. To test this hypothesis, we probed corticospinal excitability during a delayed-response task in which participants were cued to prepare right- or left-hand movements of varying complexity. Single-pulse transcranial magnetic stimulation was applied over right primary motor cortex to elicit motor evoked potentials (MEPs) from the first dorsal interosseous (FDI) of the left hand. MEP suppression was greater during the preparation of responses involving coordination of the FDI and adductor digiti minimi relative to easier responses involving only the FDI, independent of which hand was cued to respond. In contrast, this increased inhibition was absent when the complex responses required sequential movements of the two muscles. Moreover, complexity did not influence the level of inhibition when the response hand was fixed for the trial block, regardless of whether the complex responses were performed simultaneously or sequentially. These results suggest that preparatory inhibition contributes to response selection, possibly by suppressing extraneous movements when responses involve the simultaneous coordination of multiple effectors. PMID:25717168

Developing dimensions for a multicomponent multidisciplinary approach to obesity management: a qualitative study.

PubMed

Cochrane, Anita J; Dick, Bob; King, Neil A; Hills, Andrew P; Kavanagh, David J

2017-10-16

There have been consistent recommendations for multicomponent and multidisciplinary approaches for obesity management. However, there is no clear agreement on the components, disciplines or processes to be considered within such an approach. In this study, we explored multicomponent and multidisciplinary approaches through an examination of knowledge, skills, beliefs, and recommendations of stakeholders involved in obesity management. These stakeholders included researchers, practitioners, educators, and patients. We used qualitative action research methods, including convergent interviewing and observation, to assist the process of inquiry. The consensus was that a multicomponent and multidisciplinary approach should be based on four central meta-components (patient, practitioner, process, and environmental factors), and specific components of these factors were identified. Psychologists, dieticians, exercise physiologists and general practitioners were nominated as key practitioners to be included. A complex condition like obesity requires that multiple components be addressed, and that both patients and multiple disciplines are involved in developing solutions. Implementing cycles of continuous improvement to deal with complexity, instead of trying to control for it, offers an effective way to deal with complex, changing multisystem problems like obesity.

Characterization of a complex chromosomal rearrangement using chromosome, FISH, and microarray assays in a girl with multiple congenital abnormalities and developmental delay.

PubMed

Hemmat, Morteza; Yang, Xiaojing; Chan, Patricia; McGough, Robert A; Ross, Leslie; Mahon, Loretta W; Anguiano, Arturo L; Boris, Wang T; Elnaggar, Mohamed M; Wang, Jia-Chi J; Strom, Charles M; Boyar, Fatih Z

2014-01-01

Complex chromosomal rearrangements (CCRs) are balanced or unbalanced structural rearrangements involving three or more cytogenetic breakpoints on two or more chromosomal pairs. The phenotypic anomalies in such cases are attributed to gene disruption, superimposed cryptic imbalances in the genome, and/or position effects. We report a 14-year-old girl who presented with multiple congenital anomalies and developmental delay. Chromosome and FISH analysis indicated a highly complex chromosomal rearrangement involving three chromosomes (3, 7 and 12), seven breakpoints as a result of one inversion, two insertions, and two translocations forming three derivative chromosomes. Additionally, chromosomal microarray study (CMA) revealed two submicroscopic deletions at 3p12.3 (467 kb) and 12q13.12 (442 kb). We postulate that microdeletion within the ROBO1 gene at 3p12.3 may have played a role in the patient's developmental delay, since it has potential activity-dependent role in neurons. Additionally, factors other than genomic deletions such as loss of function or position effects may also contribute to the abnormal phenotype in our patient.

Specificity and multiplicity in the recognition of individuals: implications for the evolution of social behaviour.

PubMed

Wiley, R H

2013-02-01

Recognition of conspecifics occurs when individuals classify sets of conspecifics based on sensory input from them and associate these sets with different responses. Classification of conspecifics can vary in specificity (the number of individuals included in a set) and multiplicity (the number of sets differentiated). In other words, the information transmitted varies in complexity. Although recognition of conspecifics has been reported in a wide variety of organisms, few reports have addressed the specificity or multiplicity of this capability. This review discusses examples of these patterns, the mechanisms that can produce them, and the evolution of these mechanisms. Individual recognition is one end of a spectrum of specificity, and binary classification of conspecifics is one end of a spectrum of multiplicity. In some cases, recognition requires no more than simple forms of learning, such as habituation, yet results in individually specific recognition. In other cases, recognition of individuals involves complex associations of multiple cues with multiple previous experiences in particular contexts. Complex mechanisms for recognition are expected to evolve only when simpler mechanisms do not provide sufficient specificity and multiplicity to obtain the available advantages. In particular, the evolution of cooperation and deception is always promoted by specificity and multiplicity in recognition. Nevertheless, there is only one demonstration that recognition of specific individuals contributes to cooperation in animals other than primates. Human capacities for individual recognition probably have a central role in the evolution of complex forms of human cooperation and deception. Although relatively little studied, this capability probably rivals cognitive abilities for language. © 2012 The Author. Biological Reviews © 2012 Cambridge Philosophical Society.

Identifying Opportunities for Decision Support Systems in Support of Regional Resource Use Planning: An Approach Through Soft Systems Methodology.

PubMed

Zhu; Dale

2000-10-01

/ Regional resource use planning relies on key regional stakeholder groups using and having equitable access to appropriate social, economic, and environmental information and assessment tools. Decision support systems (DSS) can improve stakeholder access to such information and analysis tools. Regional resource use planning, however, is a complex process involving multiple issues, multiple assessment criteria, multiple stakeholders, and multiple values. There is a need for an approach to DSS development that can assist in understanding and modeling complex problem situations in regional resource use so that areas where DSSs could provide effective support can be identified, and the user requirements can be well established. This paper presents an approach based on the soft systems methodology for identifying DSS opportunities for regional resource use planning, taking the Central Highlands Region of Queensland, Australia, as a case study.

Multiple crack detection in 3D using a stable XFEM and global optimization

NASA Astrophysics Data System (ADS)

Agathos, Konstantinos; Chatzi, Eleni; Bordas, Stéphane P. A.

2018-02-01

A numerical scheme is proposed for the detection of multiple cracks in three dimensional (3D) structures. The scheme is based on a variant of the extended finite element method (XFEM) and a hybrid optimizer solution. The proposed XFEM variant is particularly well-suited for the simulation of 3D fracture problems, and as such serves as an efficient solution to the so-called forward problem. A set of heuristic optimization algorithms are recombined into a multiscale optimization scheme. The introduced approach proves effective in tackling the complex inverse problem involved, where identification of multiple flaws is sought on the basis of sparse measurements collected near the structural boundary. The potential of the scheme is demonstrated through a set of numerical case studies of varying complexity.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ragan, Eric

Several researchers have investigated phantom tactile sensation (i.e., the perception of a nonexistent actuator between two real actuators) and apparent tactile motion (i.e., the perception of a moving actuator due to time delays between onsets of multiple actuations). Prior work has focused primarily on determining appropriate Durations of Stimulation (DOS) and Stimulus Onset Asynchronies (SOA) for simple touch gestures, such as a single finger stroke. To expand upon this knowledge, we investigated complex touch gestures involving multiple, simultaneous points of contact, such as a whole hand touching the arm. To implement complex touch gestures, we modified the Tactile Brush algorithmmore » to support rectangular areas of tactile stimulation.« less

Theoretical Foundation of Copernicus: A Unified System for Trajectory Design and Optimization

NASA Technical Reports Server (NTRS)

Ocampo, Cesar; Senent, Juan S.; Williams, Jacob

2010-01-01

The fundamental methods are described for the general spacecraft trajectory design and optimization software system called Copernicus. The methods rely on a unified framework that is used to model, design, and optimize spacecraft trajectories that may operate in complex gravitational force fields, use multiple propulsion systems, and involve multiple spacecraft. The trajectory model, with its associated equations of motion and maneuver models, are discussed.

Measurements of gluconeogenesis and glycogenolysis: A methodological review

USDA-ARS?s Scientific Manuscript database

Gluconeogenesis is a complex metabolic process that involves multiple enzymatic steps regulated by myriad factors, including substrate concentrations, the redox state, activation and inhibition of specific enzyme steps, and hormonal modulation. At present, the most widely accepted technique to deter...

Integrating gene expression data with demographic, clinical, and environmental exposure information to reveal endotypes of childhood asthma

EPA Science Inventory

RATIONALE. Childhood asthma is a multifactorial disease whose pathogenesis involves complex interplay between genetic susceptibility and modulating external factors. Therefore, effectively characterizing these multiple etiological pathways, or “endotypes”, requires an integrative...

Multi-target drugs to address multiple checkpoints in complex inflammatory pathologies: evolutionary cues for novel "first-in-class" anti-inflammatory drug candidates: a reviewer's perspective.

PubMed

Mathew, Geetha; Unnikrishnan, M K

2015-10-01

Inflammation is a complex, metabolically expensive process involving multiple signaling pathways and regulatory mechanisms which have evolved over evolutionary timescale. Addressing multiple targets of inflammation holistically, in moderation, is probably a more evolutionarily viable strategy, as compared to current therapy which addresses drug targets in isolation. Polypharmacology, addressing multiple targets, is commonly used in complex ailments, suggesting the superior safety and efficacy profile of multi-target (MT) drugs. Phenotypic drug discovery, which generated successful MT and first-in-class drugs in the past, is now re-emerging. A multi-pronged approach, which modulates the evolutionarily conserved, robust and pervasive cellular mechanisms of tissue repair, with AMPK at the helm, regulating the complex metabolic/immune/redox pathways underlying inflammation, is perhaps a more viable strategy than addressing single targets in isolation. Molecules that modulate multiple molecular mechanisms of inflammation in moderation (modulating TH cells toward the anti-inflammatory phenotype, activating AMPK, stimulating Nrf2 and inhibiting NFκB) might serve as a model for a novel Darwinian "first-in-class" therapeutic category that holistically addresses immune, redox and metabolic processes associated with inflammatory repair. Such a multimodal biological activity is supported by the fact that several non-calorific pleiotropic natural products with anti-inflammatory action have been incorporated into diet (chiefly guided by the adaptive development of olfacto-gustatory preferences over evolutionary timescales) rendering such molecules, endowed with evolutionarily privileged molecular scaffolds, naturally oriented toward multiple targets.

Beyond the standard plate count: genomic views into microbial food ecology

USDA-ARS?s Scientific Manuscript database

Food spoilage is a complex process that involves multiple species with specific niches and metabolic processes; bacterial culturing techniques are the traditional methods for identifying the microbes responsible. These culture-dependent methods may be considered selective, targeting the isolation of...

Development of a Methodology for Incorporating FESWMS-2DH Results

DOT National Transportation Integrated Search

2000-05-01

This study presents the analysis of a complex flow system that contains two roadways with multiple openings: US Highway 75 and the Southeast Kansas Corridor. Typical analyses of floodplains at such sites involve the use of the one-dimensional backwat...

Peroxisome Biogenesis Disorders: Biological, Clinical and Pathophysiological Perspectives

ERIC Educational Resources Information Center

Braverman, Nancy E.; D'Agostino, Maria Daniela; MacLean, Gillian E.

2013-01-01

The peroxisome biogenesis disorders (PBD) are a heterogeneous group of autosomal recessive disorders in which peroxisome assembly is impaired, leading to multiple peroxisome enzyme deficiencies, complex developmental sequelae and progressive disabilities. Mammalian peroxisome assembly involves the protein products of 16 "PEX" genes;…

Setting Environmental Standards

ERIC Educational Resources Information Center

Fishbein, Gershon

1975-01-01

Recent court decisions have pointed out the complexities involved in setting environmental standards. Environmental health is composed of multiple causative agents, most of which work over long periods of time. This makes the cause-and-effect relationship between health statistics and environmental contaminant exposures difficult to prove in…

Applied statistics in agricultural, biological, and environmental sciences.

USDA-ARS?s Scientific Manuscript database

Agronomic research often involves measurement and collection of multiple response variables in an effort to understand the more complex nature of the system being studied. Multivariate statistical methods encompass the simultaneous analysis of all random variables measured on each experimental or s...

Overlapping Networks Engaged during Spoken Language Production and Its Cognitive Control

PubMed Central

Wise, Richard J.S.; Mehta, Amrish; Leech, Robert

2014-01-01

Spoken language production is a complex brain function that relies on large-scale networks. These include domain-specific networks that mediate language-specific processes, as well as domain-general networks mediating top-down and bottom-up attentional control. Language control is thought to involve a left-lateralized fronto-temporal-parietal (FTP) system. However, these regions do not always activate for language tasks and similar regions have been implicated in nonlinguistic cognitive processes. These inconsistent findings suggest that either the left FTP is involved in multidomain cognitive control or that there are multiple spatially overlapping FTP systems. We present evidence from an fMRI study using multivariate analysis to identify spatiotemporal networks involved in spoken language production in humans. We compared spoken language production (Speech) with multiple baselines, counting (Count), nonverbal decision (Decision), and “rest,” to pull apart the multiple partially overlapping networks that are involved in speech production. A left-lateralized FTP network was activated during Speech and deactivated during Count and nonverbal Decision trials, implicating it in cognitive control specific to sentential spoken language production. A mirror right-lateralized FTP network was activated in the Count and Decision trials, but not Speech. Importantly, a second overlapping left FTP network showed relative deactivation in Speech. These three networks, with distinct time courses, overlapped in the left parietal lobe. Contrary to the standard model of the left FTP as being dominant for speech, we revealed a more complex pattern within the left FTP, including at least two left FTP networks with competing functional roles, only one of which was activated in speech production. PMID:24966373

Overlapping networks engaged during spoken language production and its cognitive control.

PubMed

Geranmayeh, Fatemeh; Wise, Richard J S; Mehta, Amrish; Leech, Robert

2014-06-25

Spoken language production is a complex brain function that relies on large-scale networks. These include domain-specific networks that mediate language-specific processes, as well as domain-general networks mediating top-down and bottom-up attentional control. Language control is thought to involve a left-lateralized fronto-temporal-parietal (FTP) system. However, these regions do not always activate for language tasks and similar regions have been implicated in nonlinguistic cognitive processes. These inconsistent findings suggest that either the left FTP is involved in multidomain cognitive control or that there are multiple spatially overlapping FTP systems. We present evidence from an fMRI study using multivariate analysis to identify spatiotemporal networks involved in spoken language production in humans. We compared spoken language production (Speech) with multiple baselines, counting (Count), nonverbal decision (Decision), and "rest," to pull apart the multiple partially overlapping networks that are involved in speech production. A left-lateralized FTP network was activated during Speech and deactivated during Count and nonverbal Decision trials, implicating it in cognitive control specific to sentential spoken language production. A mirror right-lateralized FTP network was activated in the Count and Decision trials, but not Speech. Importantly, a second overlapping left FTP network showed relative deactivation in Speech. These three networks, with distinct time courses, overlapped in the left parietal lobe. Contrary to the standard model of the left FTP as being dominant for speech, we revealed a more complex pattern within the left FTP, including at least two left FTP networks with competing functional roles, only one of which was activated in speech production. Copyright © 2014 Geranmayeh et al.

Computational multiple steady states for enzymatic esterification of ethanol and oleic acid in an isothermal CSTR.

PubMed

Ho, Pang-Yen; Chuang, Guo-Syong; Chao, An-Chong; Li, Hsing-Ya

2005-05-01

The capacity of complex biochemical reaction networks (consisting of 11 coupled non-linear ordinary differential equations) to show multiple steady states, was investigated. The system involved esterification of ethanol and oleic acid by lipase in an isothermal continuous stirred tank reactor (CSTR). The Deficiency One Algorithm and the Subnetwork Analysis were applied to determine the steady state multiplicity. A set of rate constants and two corresponding steady states are computed. The phenomena of bistability, hysteresis and bifurcation are discussed. Moreover, the capacity of steady state multiplicity is extended to the family of the studied reaction networks.

Language, Culture, Gender, and Academic Socialization

ERIC Educational Resources Information Center

Morita, Naoko

2009-01-01

Recent research has explored the complex, situated process by which students from different cultural and linguistic backgrounds become socialized into academic discourses and practices. As part of a multiple case study involving seven international students, this study provides an in-depth analysis of the academic discourse socialization…

Proteomic analysis of lung tissue by DIGE

USDA-ARS?s Scientific Manuscript database

Lungs perform an essential physiological function, mediated by a complex series of events that involve the coordination of multiple cell types to support not only gaseous exchange, but homeostasis and protection from infection. Guinea pigs are an important animal disease model for a number of infect...

Characterization of a complex chromosomal rearrangement using chromosome, FISH, and microarray assays in a girl with multiple congenital abnormalities and developmental delay

PubMed Central

2014-01-01

Complex chromosomal rearrangements (CCRs) are balanced or unbalanced structural rearrangements involving three or more cytogenetic breakpoints on two or more chromosomal pairs. The phenotypic anomalies in such cases are attributed to gene disruption, superimposed cryptic imbalances in the genome, and/or position effects. We report a 14-year-old girl who presented with multiple congenital anomalies and developmental delay. Chromosome and FISH analysis indicated a highly complex chromosomal rearrangement involving three chromosomes (3, 7 and 12), seven breakpoints as a result of one inversion, two insertions, and two translocations forming three derivative chromosomes. Additionally, chromosomal microarray study (CMA) revealed two submicroscopic deletions at 3p12.3 (467 kb) and 12q13.12 (442 kb). We postulate that microdeletion within the ROBO1 gene at 3p12.3 may have played a role in the patient’s developmental delay, since it has potential activity-dependent role in neurons. Additionally, factors other than genomic deletions such as loss of function or position effects may also contribute to the abnormal phenotype in our patient. PMID:25478007

TbRGG1, an essential protein involved in kinetoplastid RNA metabolism that is associated with a novel multiprotein complex

PubMed Central

Hashimi, Hassan; Zíková, Alena; Panigrahi, Aswini K.; Stuart, Kenneth D.; Lukeš, Julius

2008-01-01

The uridine insertion/deletion RNA editing of kinetoplastid mitochondrial transcripts is performed by complex machinery involving a number of proteins and multiple protein complexes. Here we describe the effect of silencing of TbRGG1 gene by RNA interference on RNA editing in procyclic stage of Trypanosoma brucei. TbRGG1 is an essential protein for cell growth, the absence of which results in an overall decline of edited mRNAs, while the levels of never-edited RNAs remain unaltered. Repression of TbRGG1 expression has no effect on the 20S editosome and MRP1/2 complex. TAP-tag purification of TbRGG1 coisolated a novel multiprotein complex, and its association was further verified by TAP-tag analyses of two other components of the complex. TbRGG1 interaction with this complex appears to be mediated by RNA. Our results suggest that the TbRGG1 protein functions in stabilizing edited RNAs or editing efficiency and that the associated novel complex may have a role in mitochondrial RNA metabolism. We provisionally name it putative mitochondrial RNA-binding complex 1 (put-MRB complex 1). PMID:18369185

Gold nanoparticle-mediated laser stimulation causes a complex stress signal in neuronal cells

NASA Astrophysics Data System (ADS)

Johannsmeier, Sonja; Heeger, Patrick; Terakawa, Mitsuhiro; Kalies, Stefan; Heisterkamp, Alexander; Ripken, Tammo; Heinemann, Dag

2017-07-01

Gold nanoparticle mediated laser stimulation of neuronal cells allows for cell activation on a single-cell level. It could therefore be considered an alternative to classical electric neurostimulation. The physiological impact of this new approach has not been intensively studied so far. Here, we investigate the targeted cell's reaction to a laser stimulus based on its calcium response. A complex cellular reaction involving multiple sources has been revealed.

Both cis and trans Activities of Foot-and-Mouth Disease Virus 3D Polymerase Are Essential for Viral RNA Replication.

PubMed

Herod, Morgan R; Ferrer-Orta, Cristina; Loundras, Eleni-Anna; Ward, Joseph C; Verdaguer, Nuria; Rowlands, David J; Stonehouse, Nicola J

2016-08-01

The Picornaviridae is a large family of positive-sense RNA viruses that contains numerous human and animal pathogens, including foot-and-mouth disease virus (FMDV). The picornavirus replication complex comprises a coordinated network of protein-protein and protein-RNA interactions involving multiple viral and host-cellular factors. Many of the proteins within the complex possess multiple roles in viral RNA replication, some of which can be provided in trans (i.e., via expression from a separate RNA molecule), while others are required in cis (i.e., expressed from the template RNA molecule). In vitro studies have suggested that multiple copies of the RNA-dependent RNA polymerase (RdRp) 3D are involved in the viral replication complex. However, it is not clear whether all these molecules are catalytically active or what other function(s) they provide. In this study, we aimed to distinguish between catalytically active 3D molecules and those that build a replication complex. We report a novel nonenzymatic cis-acting function of 3D that is essential for viral-genome replication. Using an FMDV replicon in complementation experiments, our data demonstrate that this cis-acting role of 3D is distinct from the catalytic activity, which is predominantly trans acting. Immunofluorescence studies suggest that both cis- and trans-acting 3D molecules localize to the same cellular compartment. However, our genetic and structural data suggest that 3D interacts in cis with RNA stem-loops that are essential for viral RNA replication. This study identifies a previously undescribed aspect of picornavirus replication complex structure-function and an important methodology for probing such interactions further. Foot-and-mouth disease virus (FMDV) is an important animal pathogen responsible for foot-and-mouth disease. The disease is endemic in many parts of the world with outbreaks within livestock resulting in major economic losses. Propagation of the viral genome occurs within replication complexes, and understanding this process can facilitate the development of novel therapeutic strategies. Many of the nonstructural proteins involved in replication possess multiple functions in the viral life cycle, some of which can be supplied to the replication complex from a separate genome (i.e., in trans) while others must originate from the template (i.e., in cis). Here, we present an analysis of cis and trans activities of the RNA-dependent RNA polymerase 3D. We demonstrate a novel cis-acting role of 3D in replication. Our data suggest that this role is distinct from its enzymatic functions and requires interaction with the viral genome. Our data further the understanding of genome replication of this important pathogen. Copyright © 2016 Herod et al.

Both cis and trans Activities of Foot-and-Mouth Disease Virus 3D Polymerase Are Essential for Viral RNA Replication

PubMed Central

Herod, Morgan R.; Ferrer-Orta, Cristina; Loundras, Eleni-Anna; Ward, Joseph C.; Verdaguer, Nuria; Rowlands, David J.

2016-01-01

ABSTRACT The Picornaviridae is a large family of positive-sense RNA viruses that contains numerous human and animal pathogens, including foot-and-mouth disease virus (FMDV). The picornavirus replication complex comprises a coordinated network of protein-protein and protein-RNA interactions involving multiple viral and host-cellular factors. Many of the proteins within the complex possess multiple roles in viral RNA replication, some of which can be provided in trans (i.e., via expression from a separate RNA molecule), while others are required in cis (i.e., expressed from the template RNA molecule). In vitro studies have suggested that multiple copies of the RNA-dependent RNA polymerase (RdRp) 3D are involved in the viral replication complex. However, it is not clear whether all these molecules are catalytically active or what other function(s) they provide. In this study, we aimed to distinguish between catalytically active 3D molecules and those that build a replication complex. We report a novel nonenzymatic cis-acting function of 3D that is essential for viral-genome replication. Using an FMDV replicon in complementation experiments, our data demonstrate that this cis-acting role of 3D is distinct from the catalytic activity, which is predominantly trans acting. Immunofluorescence studies suggest that both cis- and trans-acting 3D molecules localize to the same cellular compartment. However, our genetic and structural data suggest that 3D interacts in cis with RNA stem-loops that are essential for viral RNA replication. This study identifies a previously undescribed aspect of picornavirus replication complex structure-function and an important methodology for probing such interactions further. IMPORTANCE Foot-and-mouth disease virus (FMDV) is an important animal pathogen responsible for foot-and-mouth disease. The disease is endemic in many parts of the world with outbreaks within livestock resulting in major economic losses. Propagation of the viral genome occurs within replication complexes, and understanding this process can facilitate the development of novel therapeutic strategies. Many of the nonstructural proteins involved in replication possess multiple functions in the viral life cycle, some of which can be supplied to the replication complex from a separate genome (i.e., in trans) while others must originate from the template (i.e., in cis). Here, we present an analysis of cis and trans activities of the RNA-dependent RNA polymerase 3D. We demonstrate a novel cis-acting role of 3D in replication. Our data suggest that this role is distinct from its enzymatic functions and requires interaction with the viral genome. Our data further the understanding of genome replication of this important pathogen. PMID:27194768

Analysis of a display and control system man-machine interface concept. Volume 1: Final technical report

NASA Technical Reports Server (NTRS)

Karl, D. R.

1972-01-01

An evaluation was made of the feasibility of utilizing a simplified man machine interface concept to manage and control a complex space system involving multiple redundant computers that control multiple redundant subsystems. The concept involves the use of a CRT for display and a simple keyboard for control, with a tree-type control logic for accessing and controlling mission, systems, and subsystem elements. The concept was evaluated in terms of the Phase B space shuttle orbiter, to utilize the wide scope of data management and subsystem control inherent in the central data management subsystem provided by the Phase B design philosophy. Results of these investigations are reported in four volumes.

Biofabricated constructs as tissue models: a short review.

PubMed

Costa, Pedro F

2015-04-01

Biofabrication is currently able to provide reliable models for studying the development of cells and tissues into multiple environments. As the complexity of biofabricated constructs is becoming increasingly higher their ability to closely mimic native tissues and organs is also increasing. Various biofabrication technologies currently allow to precisely build cell/tissue constructs at multiple dimension ranges with great accuracy. Such technologies are also able to assemble together multiple types of cells and/or materials and generate constructs closely mimicking various types of tissues. Furthermore, the high degree of automation involved in these technologies enables the study of large arrays of testing conditions within increasingly smaller and automated devices both in vitro and in vivo. Despite not yet being able to generate constructs similar to complex tissues and organs, biofabrication is rapidly evolving in that direction. One major hurdle to be overcome in order for such level of complex detail to be achieved is the ability to generate complex vascular structures within biofabricated constructs. This review describes several of the most relevant technologies and methodologies currently utilized within biofabrication and provides as well a brief overview of their current and future potential applications.

Efficient computation of the joint sample frequency spectra for multiple populations.

PubMed

Kamm, John A; Terhorst, Jonathan; Song, Yun S

2017-01-01

A wide range of studies in population genetics have employed the sample frequency spectrum (SFS), a summary statistic which describes the distribution of mutant alleles at a polymorphic site in a sample of DNA sequences and provides a highly efficient dimensional reduction of large-scale population genomic variation data. Recently, there has been much interest in analyzing the joint SFS data from multiple populations to infer parameters of complex demographic histories, including variable population sizes, population split times, migration rates, admixture proportions, and so on. SFS-based inference methods require accurate computation of the expected SFS under a given demographic model. Although much methodological progress has been made, existing methods suffer from numerical instability and high computational complexity when multiple populations are involved and the sample size is large. In this paper, we present new analytic formulas and algorithms that enable accurate, efficient computation of the expected joint SFS for thousands of individuals sampled from hundreds of populations related by a complex demographic model with arbitrary population size histories (including piecewise-exponential growth). Our results are implemented in a new software package called momi (MOran Models for Inference). Through an empirical study we demonstrate our improvements to numerical stability and computational complexity.

Efficient computation of the joint sample frequency spectra for multiple populations

PubMed Central

Kamm, John A.; Terhorst, Jonathan; Song, Yun S.

2016-01-01

A wide range of studies in population genetics have employed the sample frequency spectrum (SFS), a summary statistic which describes the distribution of mutant alleles at a polymorphic site in a sample of DNA sequences and provides a highly efficient dimensional reduction of large-scale population genomic variation data. Recently, there has been much interest in analyzing the joint SFS data from multiple populations to infer parameters of complex demographic histories, including variable population sizes, population split times, migration rates, admixture proportions, and so on. SFS-based inference methods require accurate computation of the expected SFS under a given demographic model. Although much methodological progress has been made, existing methods suffer from numerical instability and high computational complexity when multiple populations are involved and the sample size is large. In this paper, we present new analytic formulas and algorithms that enable accurate, efficient computation of the expected joint SFS for thousands of individuals sampled from hundreds of populations related by a complex demographic model with arbitrary population size histories (including piecewise-exponential growth). Our results are implemented in a new software package called momi (MOran Models for Inference). Through an empirical study we demonstrate our improvements to numerical stability and computational complexity. PMID:28239248

Data-collection strategy for challenging native SAD phasing.

PubMed

Olieric, Vincent; Weinert, Tobias; Finke, Aaron D; Anders, Carolin; Li, Dianfan; Olieric, Natacha; Borca, Camelia N; Steinmetz, Michel O; Caffrey, Martin; Jinek, Martin; Wang, Meitian

2016-03-01

Recent improvements in data-collection strategies have pushed the limits of native SAD (single-wavelength anomalous diffraction) phasing, a method that uses the weak anomalous signal of light elements naturally present in macromolecules. These involve the merging of multiple data sets from either multiple crystals or from a single crystal collected in multiple orientations at a low X-ray dose. Both approaches yield data of high multiplicity while minimizing radiation damage and systematic error, thus ensuring accurate measurements of the anomalous differences. Here, the combined use of these two strategies is described to solve cases of native SAD phasing that were particular challenges: the integral membrane diacylglycerol kinase (DgkA) with a low Bijvoet ratio of 1% and the large 200 kDa complex of the CRISPR-associated endonuclease (Cas9) bound to guide RNA and target DNA crystallized in the low-symmetry space group C2. The optimal native SAD data-collection strategy based on systematic measurements performed on the 266 kDa multiprotein/multiligand tubulin complex is discussed.

Global Education for the Secondary and College Student.

ERIC Educational Resources Information Center

Hughes, Steven; Otero, George

1989-01-01

Describes several activities which successfully involve students in learning about the complex nature of world affairs and issues which are globally interdependent. Activities fall under the four headings of awareness of planet, interdependence, multiple perspectives, and conflict management. Describes resources to use with the activities. (KO)

Effective Knowledge Integration in Emergency Response Organizations

ERIC Educational Resources Information Center

Gudi, Arvind

2009-01-01

Natural and man-made disasters have gained attention at all levels of policy-making in recent years. Emergency management tasks are inherently complex and unpredictable, and often require coordination among multiple organizations across different levels and locations. Effectively managing various knowledge areas and the organizations involved has…

Assessment of Students with Emotional and Behavioral Disorders

ERIC Educational Resources Information Center

Plotts, Cynthia A.

2012-01-01

Assessment and identification of children with emotional and behavioral disorders (EBD) is complex and involves multiple techniques, levels, and participants. While federal law sets the general parameters for identification in school settings, these criteria are vague and may lead to inconsistencies in selection and interpretation of assessment…

May Diet and Dietary Supplements Improve the Wellness of Multiple Sclerosis Patients? A Molecular Approach

PubMed Central

Riccio, Paolo; Rossano, Rocco; Liuzzi, Grazia Maria

2010-01-01

Multiple sclerosis is a complex and multifactorial neurological disease, and nutrition is one of the environmental factors possibly involved in its pathogenesis. At present, the role of nutrition is unclear, and MS therapy is not associated to a particular diet. MS clinical trials based on specific diets or dietary supplements are very few and in some cases controversial. To understand how diet can influence the course of MS and improve the wellness of MS patients, it is necessary to identify the dietary molecules, their targets and the molecular mechanisms involved in the control of the disease. The aim of this paper is to provide a molecular basis for the nutritional intervention in MS by evaluating at molecular level the effect of dietary molecules on the inflammatory and autoimmune processes involved in the disease. PMID:21461338

Emerging functions of multi-protein complex Mediator with special emphasis on plants.

PubMed

Malik, Naveen; Agarwal, Pinky; Tyagi, Akhilesh

2017-10-01

Mediator is a multi-subunit protein complex which is involved in transcriptional regulation in yeast and other eukaryotes. As a co-activator, it connects information from transcriptional activators/repressors to transcriptional machinery including RNA polymerase II and general transcription factors. It is not only involved in transcription initiation but also has important roles to play in transcription elongation and termination. Functional attributes of different Mediator subunits have been largely defined in yeast and mammalian systems earlier, while such studies in plants have gained momentum recently. Mediator regulates various processes related to plant development and is also involved in biotic and abiotic stress response. Thus, plant Mediator, like yeast and mammalian Mediator complex, is indispensable for plant growth and survival. Interaction of its multiple subunits with other regulatory proteins and their ectopic expression or knockdown in model plant like Arabidopsis and certain crop plants are paving the way to biochemical analysis and unravel molecular mechanisms of action of Mediator in plants.

Constitutional chromothripsis rearrangements involve clustered double-stranded DNA breaks and nonhomologous repair mechanisms.

PubMed

Kloosterman, Wigard P; Tavakoli-Yaraki, Masoumeh; van Roosmalen, Markus J; van Binsbergen, Ellen; Renkens, Ivo; Duran, Karen; Ballarati, Lucia; Vergult, Sarah; Giardino, Daniela; Hansson, Kerstin; Ruivenkamp, Claudia A L; Jager, Myrthe; van Haeringen, Arie; Ippel, Elly F; Haaf, Thomas; Passarge, Eberhard; Hochstenbach, Ron; Menten, Björn; Larizza, Lidia; Guryev, Victor; Poot, Martin; Cuppen, Edwin

2012-06-28

Chromothripsis represents a novel phenomenon in the structural variation landscape of cancer genomes. Here, we analyze the genomes of ten patients with congenital disease who were preselected to carry complex chromosomal rearrangements with more than two breakpoints. The rearrangements displayed unanticipated complexity resembling chromothripsis. We find that eight of them contain hallmarks of multiple clustered double-stranded DNA breaks (DSBs) on one or more chromosomes. In addition, nucleotide resolution analysis of 98 breakpoint junctions indicates that break repair involves nonhomologous or microhomology-mediated end joining. We observed that these eight rearrangements are balanced or contain sporadic deletions ranging in size between a few hundred base pairs and several megabases. The two remaining complex rearrangements did not display signs of DSBs and contain duplications, indicative of rearrangement processes involving template switching. Our work provides detailed insight into the characteristics of chromothripsis and supports a role for clustered DSBs driving some constitutional chromothripsis rearrangements. Copyright © 2012 The Authors. Published by Elsevier Inc. All rights reserved.

Blue rubber bleb nevus syndrome with simultaneous neurological and skeletal involvement.

PubMed

Tzoufi, Meropi S; Sixlimiri, Polyxeni; Nakou, Iliada; Argyropoulou, Maria I; Stefanidis, Constantinos J; Siamopoulou-Mavridou, Antigone

2008-08-01

Blue rubber bleb nevus syndrome (BRBNS) is a rare disorder characterized by venous malformations usually affecting the skin and the gastrointestinal tract. These skin haemangiomas are present at birth and deteriorate as the body grows, causing primarily cosmetic problems. The haemangiomas of the gastrointestinal tract may appear later in life and may bleed, causing chronic anaemia, or may present with severe complications such as rupture, intestinal torsion, and intussusception. Other organs may also be involved. This article describes a 13-year-old boy with multiple haemangiomas of the skin, the mucous membranes, and the gastrointestinal tract, which caused anaemia and ileoileic intussusception. In this patient, the nervous system was significantly affected with a haemangioma of the left occipital lobe, with complications of stroke. He also had multiple paravertebral heamangiomas, which caused pressure signs and symptoms. This boy suffered from complex partial and generalized seizures and cerebral palsy. Multiple skeletal anomalies were also present from birth. In the relevant literature, this is the first case of BRBNS with simultaneous neurological and skeletal involvement. Such cases should be recognized early, as they can lead to serious multiple health problems and handicaps.

Structural comparison of four different antibodies interacting with human papillomavirus 16 and mechanisms of neutralization

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guan, Jian; Bywaters, Stephanie M.; Brendle, Sarah A.

2015-09-15

Cryo-electron microscopy (cryo-EM) was used to solve the structures of human papillomavirus type 16 (HPV16) complexed with fragments of antibody (Fab) from three different neutralizing monoclonals (mAbs): H16.1A, H16.14J, and H263.A2. The structure-function analysis revealed predominantly monovalent binding of each Fab with capsid interactions that involved multiple loops from symmetry related copies of the major capsid protein. The residues identified in each Fab-virus interface map to a conformational groove on the surface of the capsomer. In addition to the known involvement of the FG and HI loops, the DE loop was also found to constitute the core of each epitope.more » Surprisingly, the epitope mapping also identified minor contributions by EF and BC loops. Complementary immunological assays included mAb and Fab neutralization. The specific binding characteristics of mAbs correlated with different neutralizing behaviors in pre- and post-attachment neutralization assays. - Highlights: • We present HPV16-Fab complexes from neutralizing mAbs: H16.1A, H16.14J, and H263.A2. • The structure-function analysis revealed predominantly monovalent binding of each mAb. • Capsid–Fab interactions involved multiple loops from symmetry related L1 proteins. • Besides the known FG and HI loops, epitope mapping also identified DE, EF, and BC loops. • Neutralizing assays complement the structures to show multiple neutralization mechanisms.« less

Sudden Death in a Patient with Carney's Complex

PubMed Central

Rothschild, James Adam; Kreso, Melissa; Slodzinski, Martin

2013-01-01

Carney’s complex is a rare autosomal dominantly inherited multiple endocrine neoplasia syndrome that involves spotty skin pigmentations, recurrent cardiac myxomas, endocrine hyperactivity, pituitary adenomas, peripheral nerve tumors, testicular tumors, and ovarian lesions. We present a case of sudden cardiac death in a 40 year old female with a history of Carney’s complex with recurrent cardiac myxomas presenting for exploratory laparotomy and enblock adnexal resection of a slowly enlarging right sided ovarian mass. This case highlights the risk for sudden death in these patients as well as the preoperative assessment that should be undertaken by the anesthesiologist as it relates to Carney’s complex. PMID:24223358

Microglial activation and the nitric oxide/cGMP/PKG pathway underlie enhanced neuronal vulnerability to mitochondrial dysfunction in experimental multiple sclerosis.

PubMed

Mancini, Andrea; Tantucci, Michela; Mazzocchetti, Petra; de Iure, Antonio; Durante, Valentina; Macchioni, Lara; Giampà, Carmela; Alvino, Alessandra; Gaetani, Lorenzo; Costa, Cinzia; Tozzi, Alessandro; Calabresi, Paolo; Di Filippo, Massimiliano

2018-05-01

During multiple sclerosis (MS), a close link has been demonstrated to occur between inflammation and neuro-axonal degeneration, leading to the hypothesis that immune mechanisms may promote neurodegeneration, leading to irreversible disease progression. Energy deficits and inflammation-driven mitochondrial dysfunction seem to be involved in this process. In this work we investigated, by the use of striatal electrophysiological field-potential recordings, if the inflammatory process associated with experimental autoimmune encephalomyelitis (EAE) is able to influence neuronal vulnerability to the blockade of mitochondrial complex IV, a crucial component for mitochondrial activity responsible of about 90% of total cellular oxygen consumption. We showed that during the acute relapsing phase of EAE, neuronal susceptibility to mitochondrial complex IV inhibition is markedly enhanced. This detrimental effect was counteracted by the pharmacological inhibition of microglia, of nitric oxide (NO) synthesis and its intracellular pathway (involving soluble guanylyl cyclase, sGC, and protein kinase G, PKG). The obtained results suggest that mitochondrial complex IV exerts an important role in maintaining neuronal energetic homeostasis during EAE. The pathological processes associated with experimental MS, and in particular the activation of microglia and of the NO pathway, lead to an increased neuronal vulnerability to mitochondrial complex IV inhibition, representing promising pharmacological targets. Copyright © 2018 Elsevier Inc. All rights reserved.

Molecular dynamics study of thermodynamic stability and dynamics of [Li(glyme)]+ complex in lithium-glyme solvate ionic liquids

NASA Astrophysics Data System (ADS)

Shinoda, Wataru; Hatanaka, Yuta; Hirakawa, Masashi; Okazaki, Susumu; Tsuzuki, Seiji; Ueno, Kazuhide; Watanabe, Masayoshi

2018-05-01

Equimolar mixtures of glymes and organic lithium salts are known to produce solvate ionic liquids, in which the stability of the [Li(glyme)]+ complex plays an important role in determining the ionic dynamics. Since these mixtures have attractive physicochemical properties for application as electrolytes, it is important to understand the dependence of the stability of the [Li(glyme)]+ complex on the ion dynamics. A series of microsecond molecular dynamics simulations has been conducted to investigate the dynamic properties of these solvate ionic liquids. Successful solvate ionic liquids with high stability of the [Li(glyme)]+ complex have been shown to have enhanced ion dynamics. Li-glyme pair exchange rarely occurs: its characteristic time is longer than that of ion diffusion by one or two orders of magnitude. Li-glyme pair exchange most likely occurs through cluster formation involving multiple [Li(glyme)]+ pairs. In this process, multiple exchanges likely take place in a concerted manner without the production of energetically unfavorable free glyme or free Li+ ions.

Nutritional Noise: Community Literacies and the Movement against Foods Labeled as "Natural"

ERIC Educational Resources Information Center

Trauth, Erin

2015-01-01

In the face of the $44 billion market--and rising--for foods labeled as "natural" (despite any formal regulatory oversight on the use of this term), this article examines multiple complex layers of community literacies and movements involving foods labeled as "natural," including an increasing availability of…

Mortality and Population Dynamics of Bemisia tabaci within a Multi-Crop System

USDA-ARS?s Scientific Manuscript database

The population dynamics of mobile polyphagous pests is governed by a complex set of interacting factors that involve multiple host-plants, seasonality, movement and demography. Bemisia tabaci is a multivoltine insect with no diapause that maintains population continuity by moving from one host to a...

Quasi 3D modeling of water flow in vadose zone and groundwater

USDA-ARS?s Scientific Manuscript database

The complexity of subsurface flow systems calls for a variety of concepts leading to the multiplicity of simplified flow models. One habitual simplification is based on the assumption that lateral flow and transport in unsaturated zone are not significant unless the capillary fringe is involved. In ...

Estimating US federal wildland fire managers' preferences toward competing strategic suppression objectives

Treesearch

David E. Calkin; Tyron Venn; Matthew Wibbenmeyer; Matthew P. Thompson

2012-01-01

Wildfire management involves significant complexity and uncertainty, requiring simultaneous consideration of multiple, non-commensurate objectives. This paper investigates the tradeoffs fire managers are willing to make among these objectives using a choice experiment methodology that provides three key advancements relative to previous stated-preference studies...

Sustainability: Why the Language and Ethics of Sustainability Matter in the Geoscience Classroom

ERIC Educational Resources Information Center

Metzger, Ellen P.; Curren, Randall R.

2017-01-01

Because challenges to sustainability arise at the intersection of human and biophysical systems they are inescapably embedded in social contexts and involve multiple stakeholders with diverse and often conflicting needs and value systems. Addressing complex and solution-resistant problems such as climate change, biodiversity loss, and…

The Role of Problem Solving in Complex Intraverbal Repertoires

ERIC Educational Resources Information Center

Sautter, Rachael A.; LeBlanc, Linda A.; Jay, Allison A.; Goldsmith, Tina R.; Carr, James E.

2011-01-01

We examined whether typically developing preschoolers could learn to use a problem-solving strategy that involved self-prompting with intraverbal chains to provide multiple responses to intraverbal categorization questions. Teaching the children to use the problem-solving strategy did not produce significant increases in target responses until…

Reconstruction of massive facial avulsive injury, secondary to animal bite.

PubMed

Motamed, Sadrollah; Niazi, Feizollah; Moosavizadeh, Seyed Mehdi; Gholizade Pasha, Abdolhamid; Motamed, Ali

2014-02-01

Management of facial soft tissue trauma requires complex reconstruction surgery. Animal bite on face is a common cause of facial tissue trauma with severe destruction. Evaluation of unit involvement is the first effort, followed by designation of reconstruction. In this case, we performed multiple reconstruction options.

US EPA'S LANDSCAPE ECOLOGY RESEARCH: ASSESSING TRENDS FOR WETLANDS AND SURFACE WATERS USING REMORE SENSING, GIS, AND FIELD-BASED TECHNIQUES

EPA Science Inventory

The US EPA, Environmental Sciences Division-Las Vegas is using a variety of geopspatical and statistical modeling approaches to locate and assess the complex functions of wetland ecosystems. These assessments involve measuring landscape characteristrics and change, at multiple s...

Person-Oriented Approaches to Profiling Learners in Technology-Rich Learning Environments for Ecological Learner Modeling

ERIC Educational Resources Information Center

Jang, Eunice Eunhee; Lajoie, Susanne P.; Wagner, Maryam; Xu, Zhenhua; Poitras, Eric; Naismith, Laura

2017-01-01

Technology-rich learning environments (TREs) provide opportunities for learners to engage in complex interactions involving a multitude of cognitive, metacognitive, and affective states. Understanding learners' distinct learning progressions in TREs demand inquiry approaches that employ well-conceived theoretical accounts of these multiple facets.…

Digital Games as Multirepresentational Environments for Science Learning: Implications for Theory, Research, and Design

ERIC Educational Resources Information Center

Virk, Satyugjit; Clark, Douglas; Sengupta, Pratim

2015-01-01

Environments in which learning involves coordinating multiple external representations (MERs) can productively support learners in making sense of complex models and relationships. Educational digital games provide an increasing popular medium for engaging students in manipulating and exploring such models and relationships. This article applies…

Lattice Boltzmann simulations of immiscible displacement process with large viscosity ratios

NASA Astrophysics Data System (ADS)

Rao, Parthib; Schaefer, Laura

2017-11-01

Immiscible displacement is a key physical mechanism involved in enhanced oil recovery and carbon sequestration processes. This multiphase flow phenomenon involves a complex interplay of viscous, capillary, inertial and wettability effects. The lattice Boltzmann (LB) method is an accurate and efficient technique for modeling and simulating multiphase/multicomponent flows especially in complex flow configurations and media. In this presentation we present numerical simulation results of displacement process in thin long channels. The results are based on a new psuedo-potential multicomponent LB model with multiple relaxation time collision (MRT) model and explicit forcing scheme. We demonstrate that the proposed model is capable of accurately simulating the displacement process involving fluids with a wider range of viscosity ratios (>100) and which also leads to viscosity-independent interfacial tension and reduction of some important numerical artifacts.

A comparative study of turbulence models for overset grids

NASA Technical Reports Server (NTRS)

Renze, Kevin J.; Buning, Pieter G.; Rajagopalan, R. G.

1992-01-01

The implementation of two different types of turbulence models for a flow solver using the Chimera overset grid method is examined. Various turbulence model characteristics, such as length scale determination and transition modeling, are found to have a significant impact on the computed pressure distribution for a multielement airfoil case. No inherent problem is found with using either algebraic or one-equation turbulence models with an overset grid scheme, but simulation of turbulence for multiple-body or complex geometry flows is very difficult regardless of the gridding method. For complex geometry flowfields, modification of the Baldwin-Lomax turbulence model is necessary to select the appropriate length scale in wall-bounded regions. The overset grid approach presents no obstacle to use of a one- or two-equation turbulence model. Both Baldwin-Lomax and Baldwin-Barth models have problems providing accurate eddy viscosity levels for complex multiple-body flowfields such as those involving the Space Shuttle.

Nucleation promoting factors regulate the expression and localization of Arp2/3 complex during meiosis of mouse oocytes.

PubMed

Liu, Jun; Wang, Qiao-Chu; Wang, Fei; Duan, Xing; Dai, Xiao-Xin; Wang, Teng; Liu, Hong-Lin; Cui, Xiang-Shun; Kim, Nam-Hyung; Sun, Shao-Chen

2012-01-01

The actin nucleation factor Arp2/3 complex is a main regulator of actin assembly and is involved in multiple processes like cell migration and adhesion, endocytosis, and the establishment of cell polarity in mitosis. Our previous work showed that the Arp2/3 complex was involved in the actin-mediated mammalian oocyte asymmetric division. However, the regulatory mechanisms and signaling pathway of Arp2/3 complex in meiosis is still unclear. In the present work, we identified that the nucleation promoting factors (NPFs) JMY and WAVE2 were necessary for the expression and localization of Arp2/3 complex in mouse oocytes. RNAi of both caused the degradation of actin cap intensity, indicating the roles of NPFs in the formation of actin cap. Moreover, JMY and WAVE2 RNAi decreased the expression of ARP2, a key component of Arp2/3 complex. However, knock down of Arp2/3 complex by Arpc2 and Arpc3 siRNA microinjection did not affect the expression and localization of JMY and WAVE2. Our results indicate that the NPFs, JMY and WAVE2, are upstream regulators of Arp2/3 complex in mammalian oocyte asymmetric division.

Ephus: Multipurpose Data Acquisition Software for Neuroscience Experiments

PubMed Central

Suter, Benjamin A.; O'Connor, Timothy; Iyer, Vijay; Petreanu, Leopoldo T.; Hooks, Bryan M.; Kiritani, Taro; Svoboda, Karel; Shepherd, Gordon M. G.

2010-01-01

Physiological measurements in neuroscience experiments often involve complex stimulus paradigms and multiple data channels. Ephus (http://www.ephus.org) is an open-source software package designed for general-purpose data acquisition and instrument control. Ephus operates as a collection of modular programs, including an ephys program for standard whole-cell recording with single or multiple electrodes in typical electrophysiological experiments, and a mapper program for synaptic circuit mapping experiments involving laser scanning photostimulation based on glutamate uncaging or channelrhodopsin-2 excitation. Custom user functions allow user-extensibility at multiple levels, including on-line analysis and closed-loop experiments, where experimental parameters can be changed based on recently acquired data, such as during in vivo behavioral experiments. Ephus is compatible with a variety of data acquisition and imaging hardware. This paper describes the main features and modules of Ephus and their use in representative experimental applications. PMID:21960959

Can multiple sclerosis as a cognitive disorder influence patients’ dreams?

PubMed Central

Owji, Mahsa

2013-01-01

Dream should be considered as a kind of cognitive ability that is formed parallel to other cognitive capabilities like language. On the other hand, multiple sclerosis (MS) is a complex disease that can involve different aspects of our cognition. Therefore, MS may influence patients’ dreams. In fact, we do not know what the importance of dream is in MS, but further studies may introduce dream and dreaming as a sign of improvement or progression in MS disease. PMID:24250908

Catalytic bismetallative multicomponent coupling reactions: scope, applications, and mechanisms

PubMed Central

Cho, Hee Yeon

2014-01-01

Catalytic reactions have played an indispensable role in organic chemistry for the last several decades. In particular, catalytic multicomponent reactions have attracted a lot of attention due to their efficiency and expediency towards complex molecule synthesis. The presence of bismetallic reagents (e.g. B–B, Si–Si, B–Si, Si–Sn, etc.) in this process renders the products enriched with various functional groups and multiple stereocenters. For this reason, catalytic bismetallative coupling is considered an effective method to generate the functional and stereochemical complexity of simple hydrocarbon substrates. This review highlights key developments of transition-metal catalyzed bismetallative reactions involving multiple π components. Specifically, it will highlight the scope, synthetic applications, and proposed mechanistic pathways of this process. PMID:24736839

Mass Spectrometry: A Technique of Many Faces

PubMed Central

Olshina, Maya A.; Sharon, Michal

2016-01-01

Protein complexes form the critical foundation for a wide range of biological process, however understanding the intricate details of their activities is often challenging. In this review we describe how mass spectrometry plays a key role in the analysis of protein assemblies and the cellular pathways which they are involved in. Specifically, we discuss how the versatility of mass spectrometric approaches provides unprecedented information on multiple levels. We demonstrate this on the ubiquitin-proteasome proteolytic pathway, a process that is responsible for protein turnover. We follow the various steps of this degradation route and illustrate the different mass spectrometry workflows that were applied for elucidating molecular information. Overall, this review aims to stimulate the integrated use of multiple mass spectrometry approaches for analyzing complex biological systems. PMID:28100928

Dystrophic Cardiomyopathy: Complex Pathobiological Processes to Generate Clinical Phenotype

PubMed Central

Tsuda, Takeshi; Fitzgerald, Kristi K.

2017-01-01

Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and X-linked dilated cardiomyopathy (XL-DCM) consist of a unique clinical entity, the dystrophinopathies, which are due to variable mutations in the dystrophin gene. Dilated cardiomyopathy (DCM) is a common complication of dystrophinopathies, but the onset, progression, and severity of heart disease differ among these subgroups. Extensive molecular genetic studies have been conducted to assess genotype-phenotype correlation in DMD, BMD, and XL-DCM to understand the underlying mechanisms of these diseases, but the results are not always conclusive, suggesting the involvement of complex multi-layers of pathological processes that generate the final clinical phenotype. Dystrophin protein is a part of dystrophin-glycoprotein complex (DGC) that is localized in skeletal muscles, myocardium, smooth muscles, and neuronal tissues. Diversity of cardiac phenotype in dystrophinopathies suggests multiple layers of pathogenetic mechanisms in forming dystrophic cardiomyopathy. In this review article, we review the complex molecular interactions involving the pathogenesis of dystrophic cardiomyopathy, including primary gene mutations and loss of structural integrity, secondary cellular responses, and certain epigenetic and other factors that modulate gene expressions. Involvement of epigenetic gene regulation appears to lead to specific cardiac phenotypes in dystrophic hearts. PMID:29367543

A Phosphorylated Cytoplasmic Autoantigen, GW182, Associates with a Unique Population of Human mRNAs within Novel Cytoplasmic Speckles

PubMed Central

Eystathioy, Theophany; Chan, Edward K. L.; Tenenbaum, Scott A.; Keene, Jack D.; Griffith, Kevin; Fritzler, Marvin J.

2002-01-01

A novel human cellular structure has been identified that contains a unique autoimmune antigen and multiple messenger RNAs. This complex was discovered using an autoimmune serum from a patient with motor and sensory neuropathy and contains a protein of 182 kDa. The gene and cDNA encoding the protein indicated an open reading frame with glycine-tryptophan (GW) repeats and a single RNA recognition motif. Both the patient's serum and a rabbit serum raised against the recombinant GW protein costained discrete cytoplasmic speckles designated as GW bodies (GWBs) that do not overlap with the Golgi complex, endosomes, lysosomes, or peroxisomes. The mRNAs associated with GW182 represent a clustered set of transcripts that are presumed to reside within the GW complexes. We propose that the GW ribonucleoprotein complex is involved in the posttranscriptional regulation of gene expression by sequestering a specific subset of gene transcripts involved in cell growth and homeostasis. PMID:11950943

Informed decision-making in elective major vascular surgery: analysis of 145 surgeon-patient consultations.

PubMed

Etchells, Edward; Ferrari, Michel; Kiss, Alex; Martyn, Nikki; Zinman, Deborah; Levinson, Wendy

2011-06-01

Prior studies show significant gaps in the informed decision-making process, a central goal of surgical care. These studies have been limited by their focus on low-risk decisions, single visits rather than entire consultations, or both. Our objectives were, first, to rate informed decision-making for major elective vascular surgery based on audiotapes of actual physician-patient conversations and, second, to compare ratings of informed decision-making for first visits to ratings for multiple visits by the same patient over time. We prospectively enrolled patients for whom vascular surgical treatment was a potential option at a tertiary care outpatient vascular surgery clinic. We audio-taped all surgeon-patient conversations, including multiple visits when necessary, until a decision was made. Using an existing method, we evaluated the transcripts for elements of decision-making, including basic elements (e.g., an explanation of the clinical condition), intermediate elements (e.g., risks and benefits) and complex elements (e.g., uncertainty around the decision). We analyzed 145 surgeon-patient consultations. Overall, 45% of consultations contained complex elements, whereas 23% did not contain the basic elements of decision-making. For the 67 consultations that involved multiple visits, ratings were significantly higher when evaluating all visits (50% complex elements) compared with evaluating only the first visit (33% complex elements, p < 0.001.) We found that 45% of consultations contained complex elements, which is higher than prior studies with similar methods. Analyzing decision-making over multiple visits yielded different results than analyzing decision-making for single visits.

A Multi-organisational Approach to Service Delivery

NASA Astrophysics Data System (ADS)

Purchase, Valerie; Mills, John; Parry, Glenn

Who is involved in delivering a service? There has been growing recognition in a wide variety of contexts that service is increasingly being delivered by multi-rather than single-organisational entities. Such recognition is evident not only in our experience but in a number of areas of literature including strategy development, core competence analysis, operations and supply chain management, and is reflected in and further facilitated by ICT developments. Customers have always been involved in some degree in the process of value delivery and such involvement is increasing to include complex co-creation of value. Such interactions are challenging when they involve individual customers, however, this becomes ever more challenging when the 'customer' is another organisation or when there are multiple 'customers'. Within this chapter we will consider some of the key drivers for a multi-organisational approach to service delivery; examine the ways in which the parties involved in service co-creation have expanded to include multiple service providers and customers; and finally, identify some of the challenges created by a multi-organisational approach to service delivery.

Immunotherapy for glioblastoma: playing chess, not checkers.

PubMed

Jackson, Christopher M; Lim, Michael

2018-04-24

Patients with glioblastoma (GBM) exhibit a complex state of immune dysfunction involving multiple mechanisms of local, regional, and systemic immune suppression and tolerance. These pathways are now being identified and their relative contributions explored. Delineating how these pathways are interrelated is paramount to effectively implementing immunotherapy for GBM. Copyright ©2018, American Association for Cancer Research.

Socio-Historical Factors Mediating Collaborative Teaching and Learning: A Design-Based Investigation and Intervention

ERIC Educational Resources Information Center

Hackett, Jacob

2016-01-01

Collaborative (Co-)teaching is a complex instructional delivery model used to improve teaching practice in inclusive settings. The model involves multiple certified teachers--representing both special and general education--sharing the same space and presenting material to classrooms with a wide variance in learning needs. Co-teaching has become…

The Neural Correlates of Driving Performance Identified Using Positron Emission Tomography

ERIC Educational Resources Information Center

Horikawa, E.; Okamura, N.; Tashiro, M.; Sakurada, Y.; Maruyama, M.; Arai, H.; Yamaguchi, K.; Sasaki, H.; Yanai, K.; Itoh, M.

2005-01-01

Driving is a complex behavior involving multiple cognitive domains. To identify neural correlates of driving performance, [^1^5O]H"2O positron emission tomography was performed using a simulated driving task. Compared with the resting condition, simulated driving increased regional cerebral blood flow (rCBF) in the cerebellum, occipital, and…

Dance band on the Titanic: biomechanical signaling in cardiac hypertrophy.

PubMed

Sussman, Mark A; McCulloch, Andrew; Borg, Thomas K

2002-11-15

Biomechanical signaling is a complex interaction of both intracellular and extracellular components. Both passive and active components are involved in the extracellular environment to signal through specific receptors to multiple signaling pathways. This review provides an overview of extracellular matrix, specific receptors, and signaling pathways for biomechanical stimulation in cardiac hypertrophy.

Looking out across Columbus: What We Mean by "Multiple Literacies"

ERIC Educational Resources Information Center

Bloome, David; Enciso, Patricia

2006-01-01

Literacy practices are intimately connected to the economic, social, cultural, educational, and intellectual dimensions of our lives; and similarly so, even the most ordinary events of our daily lives involve literacy practices. We argue that if schools are going to prepare young people to participate in and contribute to a diverse, complex, and…

Rigour and Complexity in Educational Research. Conducting Educational Research

ERIC Educational Resources Information Center

Berry, Kathleen; Kincheloe, Joe

2004-01-01

What does it mean to engage in rigorous research? What does a researcher need to know to produce such research? What is specifically involved in multiple method bricolage research? In an era where talk abounds about scientific rigour and evidence-based research in education, this groundbreaking book presents a new and compelling examination of…

Managing the University Campus: Exploring Models for the Future and Supporting Today's Decisions

ERIC Educational Resources Information Center

den Heijer, Alexandra

2012-01-01

Managing contemporary campuses and taking decisions that will impact on those of tomorrow is a complex task for universities worldwide. It involves strategic, financial, functional and physical aspects as well as multiple stakeholders. This article summarises the conclusions of a comprehensive PhD research project which was enriched with lessons…

Using Adult Learning Principles in Adult Basic and Literacy Education. Practice Application Brief.

ERIC Educational Resources Information Center

Imel, Susan

Adult basic and literacy education (ABLE) is a complex undertaking that serves diverse learners with a variety of needs. Although no definitive list of adult education principles exists in the literature, the following principles have been identified in multiple sources devoted to principles of effective adult education: involve learners in…

EVIDENCE THAT CA2+ SIGNALING AND TRANSCRIPTION FACTOR (CREB) ACTIVITIES STIMULATED BY POLYCHLORINATED BIPHENYLS ARE LOCALIZED TO DEVELOPING NEURONS.

EPA Science Inventory

Using a mixed culture of neonatal cortical cells, we have demonstrated that the polychlorinated biphenyl (PCB) mixture Aroclor 1254 (A1254) induces complex Ca2+i signals involving multiple receptors/channels (Inglefield and Shafer, J.Pharm.Exp.Ther. 295:105) and also activates/ p...

Effects of Normal Aging on Memory for Multiple Contextual Features

ERIC Educational Resources Information Center

Gagnon, Sylvain; Soulard, Kathleen; Brasgold, Melissa; Kreller, Joshua

2007-01-01

Twenty-four younger (18-35 years) and 24 older adult participants (65 or older) were exposed to three experimental conditions involving the memorization words and their associated contextual features, with contextual feature complexity increasing from Conditions 1 to 3. In Condition 1, words presented varied only on one binary feature (color,…

For Free: Continuity and Change by Team Teaching

ERIC Educational Resources Information Center

Liebel, Grischa; Burden, Håkan; Heldal, Rogardt

2017-01-01

Team teaching is advocated in education to offer students multiple explanations to complex concepts and to improve teacher development. However, team teaching is typically associated with high staff cost due to the increased amount of teachers involved. The authors argue that team teaching can be conducted in a cheap way by including novice…

The Anatomy Competence Score--A New Marker for Anatomical Ability

ERIC Educational Resources Information Center

Schoeman, Scarpa; Chandratilake, Madawa

2012-01-01

The assessment of students' ability in gross anatomy is a complex process as it involves the measurement of multiple facets. In this work, the authors developed and introduced the Anatomy Competence Score (ACS), which incorporates the three domains of anatomy teaching and assessment namely: theoretical knowledge, practical 3D application of the…

Finite burn maneuver modeling for a generalized spacecraft trajectory design and optimization system.

PubMed

Ocampo, Cesar

2004-05-01

The modeling, design, and optimization of finite burn maneuvers for a generalized trajectory design and optimization system is presented. A generalized trajectory design and optimization system is a system that uses a single unified framework that facilitates the modeling and optimization of complex spacecraft trajectories that may operate in complex gravitational force fields, use multiple propulsion systems, and involve multiple spacecraft. The modeling and optimization issues associated with the use of controlled engine burn maneuvers of finite thrust magnitude and duration are presented in the context of designing and optimizing a wide class of finite thrust trajectories. Optimal control theory is used examine the optimization of these maneuvers in arbitrary force fields that are generally position, velocity, mass, and are time dependent. The associated numerical methods used to obtain these solutions involve either, the solution to a system of nonlinear equations, an explicit parameter optimization method, or a hybrid parameter optimization that combines certain aspects of both. The theoretical and numerical methods presented here have been implemented in copernicus, a prototype trajectory design and optimization system under development at the University of Texas at Austin.

CT and MR imaging findings of lymphangioleiomyomatosis involving the uterus and pelvic cavity.

PubMed

Kim, You Sung; Rha, Sung Eun; Byun, Jae Young; Lee, Ahwon; Park, Jong Sup

2011-01-01

Lymphangioleiomyomatosis (LAM) is a rare idiopathic disease and this is characterized by a proliferation of abnormal smooth muscle cells in the lungs and in the lymphatic system of the thorax and retroperitoneum. The female genital tract is rarely affected by LAM. We report here on the CT and MR imaging findings of extensive LAM involving the uterus and pelvic cavity, and this was seen as multiple cystic uterine and parauterine masses with internal hemorrhage in a young female with tuberous sclerosis complex.

An Ontology for Modeling Complex Inter-relational Organizations

NASA Astrophysics Data System (ADS)

Wautelet, Yves; Neysen, Nicolas; Kolp, Manuel

This paper presents an ontology for organizational modeling through multiple complementary aspects. The primary goal of the ontology is to dispose of an adequate set of related concepts for studying complex organizations involved in a lot of relationships at the same time. In this paper, we define complex organizations as networked organizations involved in a market eco-system that are playing several roles simultaneously. In such a context, traditional approaches focus on the macro analytic level of transactions; this is supplemented here with a micro analytic study of the actors' rationale. At first, the paper overviews enterprise ontologies literature to position our proposal and exposes its contributions and limitations. The ontology is then brought to an advanced level of formalization: a meta-model in the form of a UML class diagram allows to overview the ontology concepts and their relationships which are formally defined. Finally, the paper presents the case study on which the ontology has been validated.

Structured plant metabolomics for the simultaneous exploration of multiple factors.

PubMed

Vasilev, Nikolay; Boccard, Julien; Lang, Gerhard; Grömping, Ulrike; Fischer, Rainer; Goepfert, Simon; Rudaz, Serge; Schillberg, Stefan

2016-11-17

Multiple factors act simultaneously on plants to establish complex interaction networks involving nutrients, elicitors and metabolites. Metabolomics offers a better understanding of complex biological systems, but evaluating the simultaneous impact of different parameters on metabolic pathways that have many components is a challenging task. We therefore developed a novel approach that combines experimental design, untargeted metabolic profiling based on multiple chromatography systems and ionization modes, and multiblock data analysis, facilitating the systematic analysis of metabolic changes in plants caused by different factors acting at the same time. Using this method, target geraniol compounds produced in transgenic tobacco cell cultures were grouped into clusters based on their response to different factors. We hypothesized that our novel approach may provide more robust data for process optimization in plant cell cultures producing any target secondary metabolite, based on the simultaneous exploration of multiple factors rather than varying one factor each time. The suitability of our approach was verified by confirming several previously reported examples of elicitor-metabolite crosstalk. However, unravelling all factor-metabolite networks remains challenging because it requires the identification of all biochemically significant metabolites in the metabolomics dataset.

Ternary liquid mixtures control the multiplicity, shape and internal structure of emulsion droplets

NASA Astrophysics Data System (ADS)

Haase, Martin F.; Brujic, Jasna

2014-03-01

It is important to control the shape, internal structure and stability of emulsion droplets for drug delivery, biochemical assays, and the design of materials with novel physical properties. Successful methods involve the mechanical manipulation of the flow of oil in water using complex microfluidic devices to make multiple emulsions with a sequential introduction of specific reactants. Instead, here we show how the thermodynamics of immiscible liquid mixtures tailor emulsions using a single dripping instability. For example, the initial composition and choice of surfactant govern the multiplicity of concentric alternating oil and water layers inside the droplets. Stabilizing ternary droplets using nanoparticles gives rise to a plethora of shapes whose geometry is defined by the deformability of the shell and the flow rate. Another option is to incorporate lipids to the multiple emulsion droplet, which form vesicles upon expulsion of the inner water droplets. Depending on the number of initial water droplets, these vesicles eventually form complex hollow topologies, which can be used as junctions or scaffolds for the self-assembly of colloidal particles in the future.

Meeting the complex needs of urban youth and their families through the 4Rs 2Ss Family Strengthening Program: The “real world” meets evidence-informed care

PubMed Central

Small, Latoya; Jackson, Jerrold; Gopalan, Geetha; McKay, Mary McKernan

2014-01-01

Youth living in poverty face compounding familial and environmental challenges in utilizing effective community mental health services. They have ongoing stressors that increase their dropout rate in mental health service use. Difficulties also exist in staying engaged in services when they are involved with the child welfare system. This study examines the 4Rs 2Ss Family Strengthening Program, developed across four broad conceptual categories related to parenting skills and family processes that form a multiple family group service delivery approach. A total of 321 families were enrolled in this randomized intervention study, assigned to either the 4Rs 2Ss Family Strengthening Program or standard care services. Caregivers and their children randomly assigned to the experimental condition received a 16 week multiple family group intervention through their respective outpatient community mental health clinic. Data was collected at baseline, midtest (8 weeks), posttest (16 weeks), and 6 month follow-up. Major findings include high engagement in the 4Rs 2Ss Family Strengthening Program, compared to standard services. Although child welfare status is not related to attendance, family stress and parental depression are also related to participant engagement in this multiple family group intervention. Involvement in the 4Rs 2Ss Family Strengthening Program resulted in improved effects for child behaviors. Lastly, no evidence of moderation effects on family stress, child welfare involvement, or parental needs were found. The 4Rs 2Ss Family Strengthening Program appeared able to engage families with more complex “real world” needs. PMID:26523115

Meeting the complex needs of urban youth and their families through the 4Rs 2Ss Family Strengthening Program: The "real world" meets evidence-informed care.

PubMed

Small, Latoya; Jackson, Jerrold; Gopalan, Geetha; McKay, Mary McKernan

2015-07-01

Youth living in poverty face compounding familial and environmental challenges in utilizing effective community mental health services. They have ongoing stressors that increase their dropout rate in mental health service use. Difficulties also exist in staying engaged in services when they are involved with the child welfare system. This study examines the 4Rs 2Ss Family Strengthening Program, developed across four broad conceptual categories related to parenting skills and family processes that form a multiple family group service delivery approach. A total of 321 families were enrolled in this randomized intervention study, assigned to either the 4Rs 2Ss Family Strengthening Program or standard care services. Caregivers and their children randomly assigned to the experimental condition received a 16 week multiple family group intervention through their respective outpatient community mental health clinic. Data was collected at baseline, midtest (8 weeks), posttest (16 weeks), and 6 month follow-up. Major findings include high engagement in the 4Rs 2Ss Family Strengthening Program, compared to standard services. Although child welfare status is not related to attendance, family stress and parental depression are also related to participant engagement in this multiple family group intervention. Involvement in the 4Rs 2Ss Family Strengthening Program resulted in improved effects for child behaviors. Lastly, no evidence of moderation effects on family stress, child welfare involvement, or parental needs were found. The 4Rs 2Ss Family Strengthening Program appeared able to engage families with more complex "real world" needs.

Lessons learned in multisite, nursing education research while studying a technology learning innovation.

PubMed

North, Sarah; Giddens, Jean

2013-10-01

Multiple challenges must be addressed when educational research is being conducted that involves a teaching innovation at multiple sites over time, including the consistent adoption and use of the intervention, attrition, response rates, and other aspects related to managing a complex study. After an 18-month nursing education study was conducted at multiple institutions across the United States, the authors' study team reflected on strategies that worked well, the challenges faced, and what could have been done differently. This article details the challenges and offers recommendations for other researchers conducting similar studies. Recommendations related to communication and engagement, innovation fidelity, survey fatigue, multiple institutional review board applications, and flexibility are provided. Copyright 2013, SLACK Incorporated.

Multiple Criteria Decision Analysis for Health Care Decision Making--An Introduction: Report 1 of the ISPOR MCDA Emerging Good Practices Task Force.

PubMed

Thokala, Praveen; Devlin, Nancy; Marsh, Kevin; Baltussen, Rob; Boysen, Meindert; Kalo, Zoltan; Longrenn, Thomas; Mussen, Filip; Peacock, Stuart; Watkins, John; Ijzerman, Maarten

2016-01-01

Health care decisions are complex and involve confronting trade-offs between multiple, often conflicting, objectives. Using structured, explicit approaches to decisions involving multiple criteria can improve the quality of decision making and a set of techniques, known under the collective heading multiple criteria decision analysis (MCDA), are useful for this purpose. MCDA methods are widely used in other sectors, and recently there has been an increase in health care applications. In 2014, ISPOR established an MCDA Emerging Good Practices Task Force. It was charged with establishing a common definition for MCDA in health care decision making and developing good practice guidelines for conducting MCDA to aid health care decision making. This initial ISPOR MCDA task force report provides an introduction to MCDA - it defines MCDA; provides examples of its use in different kinds of decision making in health care (including benefit risk analysis, health technology assessment, resource allocation, portfolio decision analysis, shared patient clinician decision making and prioritizing patients' access to services); provides an overview of the principal methods of MCDA; and describes the key steps involved. Upon reviewing this report, readers should have a solid overview of MCDA methods and their potential for supporting health care decision making. Copyright © 2016. Published by Elsevier Inc.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bae, Brian; Nayak, Dhananjaya; Ray, Ananya

RNA polymerase inhibitors like the CBR class that target the enzyme’s complex catalytic center are attractive leads for new antimicrobials. The catalysis by RNA polymerase involves multiple rearrangements of bridge helix, trigger loop, and active-center side chains that isomerize the triphosphate of bound NTP and two Mg 2+ ions from a preinsertion state to a reactive configuration. CBR inhibitors target a crevice between the N-terminal portion of the bridge helix and a surrounding cap region within which the bridge helix is thought to rearrange during the nucleotide addition cycle. Here, we report crystal structures of CBR inhibitor/Escherichia coli RNA polymerasemore » complexes as well as biochemical tests that establish two distinct effects of the inhibitors on the RNA polymerase catalytic site. One effect involves inhibition of trigger-loop folding via the F loop in the cap, which affects both nucleotide addition and hydrolysis of 3'-terminal dinucleotides in certain backtracked complexes. The second effect is trigger-loop independent, affects only nucleotide addition and pyrophosphorolysis, and may involve inhibition of bridge-helix movements that facilitate reactive triphosphate alignment.« less

Transcription Profiles Reveal Sugar and Hormone Signaling Pathways Mediating Flower Induction in Apple (Malus domestica Borkh.).

PubMed

Xing, Li-Bo; Zhang, Dong; Li, You-Mei; Shen, Ya-Wen; Zhao, Cai-Ping; Ma, Juan-Juan; An, Na; Han, Ming-Yu

2015-10-01

Flower induction in apple (Malus domestica Borkh.) is regulated by complex gene networks that involve multiple signal pathways to ensure flower bud formation in the next year, but the molecular determinants of apple flower induction are still unknown. In this research, transcriptomic profiles from differentiating buds allowed us to identify genes potentially involved in signaling pathways that mediate the regulatory mechanisms of flower induction. A hypothetical model for this regulatory mechanism was obtained by analysis of the available transcriptomic data, suggesting that sugar-, hormone- and flowering-related genes, as well as those involved in cell-cycle induction, participated in the apple flower induction process. Sugar levels and metabolism-related gene expression profiles revealed that sucrose is the initiation signal in flower induction. Complex hormone regulatory networks involved in cytokinin (CK), abscisic acid (ABA) and gibberellic acid pathways also induce apple flower formation. CK plays a key role in the regulation of cell formation and differentiation, and in affecting flowering-related gene expression levels during these processes. Meanwhile, ABA levels and ABA-related gene expression levels gradually increased, as did those of sugar metabolism-related genes, in developing buds, indicating that ABA signals regulate apple flower induction by participating in the sugar-mediated flowering pathway. Furthermore, changes in sugar and starch deposition levels in buds can be affected by ABA content and the expression of the genes involved in the ABA signaling pathway. Thus, multiple pathways, which are mainly mediated by crosstalk between sugar and hormone signals, regulate the molecular network involved in bud growth and flower induction in apple trees. © The Author 2015. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists.

Does linear separability really matter? Complex visual search is explained by simple search

PubMed Central

Vighneshvel, T.; Arun, S. P.

2013-01-01

Visual search in real life involves complex displays with a target among multiple types of distracters, but in the laboratory, it is often tested using simple displays with identical distracters. Can complex search be understood in terms of simple searches? This link may not be straightforward if complex search has emergent properties. One such property is linear separability, whereby search is hard when a target cannot be separated from its distracters using a single linear boundary. However, evidence in favor of linear separability is based on testing stimulus configurations in an external parametric space that need not be related to their true perceptual representation. We therefore set out to assess whether linear separability influences complex search at all. Our null hypothesis was that complex search performance depends only on classical factors such as target-distracter similarity and distracter homogeneity, which we measured using simple searches. Across three experiments involving a variety of artificial and natural objects, differences between linearly separable and nonseparable searches were explained using target-distracter similarity and distracter heterogeneity. Further, simple searches accurately predicted complex search regardless of linear separability (r = 0.91). Our results show that complex search is explained by simple search, refuting the widely held belief that linear separability influences visual search. PMID:24029822

Nucleation Promoting Factors Regulate the Expression and Localization of Arp2/3 Complex during Meiosis of Mouse Oocytes

PubMed Central

Liu, Jun; Wang, Qiao-Chu; Wang, Fei; Duan, Xing; Dai, Xiao-Xin; Wang, Teng; Liu, Hong-Lin; Cui, Xiang-Shun; Kim, Nam-Hyung; Sun, Shao-Chen

2012-01-01

The actin nucleation factor Arp2/3 complex is a main regulator of actin assembly and is involved in multiple processes like cell migration and adhesion, endocytosis, and the establishment of cell polarity in mitosis. Our previous work showed that the Arp2/3 complex was involved in the actin-mediated mammalian oocyte asymmetric division. However, the regulatory mechanisms and signaling pathway of Arp2/3 complex in meiosis is still unclear. In the present work, we identified that the nucleation promoting factors (NPFs) JMY and WAVE2 were necessary for the expression and localization of Arp2/3 complex in mouse oocytes. RNAi of both caused the degradation of actin cap intensity, indicating the roles of NPFs in the formation of actin cap. Moreover, JMY and WAVE2 RNAi decreased the expression of ARP2, a key component of Arp2/3 complex. However, knock down of Arp2/3 complex by Arpc2 and Arpc3 siRNA microinjection did not affect the expression and localization of JMY and WAVE2. Our results indicate that the NPFs, JMY and WAVE2, are upstream regulators of Arp2/3 complex in mammalian oocyte asymmetric division. PMID:23272233

Multiple quantum coherence spectroscopy.

PubMed

Mathew, Nathan A; Yurs, Lena A; Block, Stephen B; Pakoulev, Andrei V; Kornau, Kathryn M; Wright, John C

2009-08-20

Multiple quantum coherences provide a powerful approach for studies of complex systems because increasing the number of quantum states in a quantum mechanical superposition state increases the selectivity of a spectroscopic measurement. We show that frequency domain multiple quantum coherence multidimensional spectroscopy can create these superposition states using different frequency excitation pulses. The superposition state is created using two excitation frequencies to excite the symmetric and asymmetric stretch modes in a rhodium dicarbonyl chelate and the dynamic Stark effect to climb the vibrational ladders involving different overtone and combination band states. A monochromator resolves the free induction decay of different coherences comprising the superposition state. The three spectral dimensions provide the selectivity required to observe 19 different spectral features associated with fully coherent nonlinear processes involving up to 11 interactions with the excitation fields. The different features act as spectroscopic probes of the diagonal and off-diagonal parts of the molecular potential energy hypersurface. This approach can be considered as a coherent pump-probe spectroscopy where the pump is a series of excitation pulses that prepares a multiple quantum coherence and the probe is another series of pulses that creates the output coherence.

Moral motivation based on multiple developmental structures: an exploration of cognitive and emotional dynamics.

PubMed

Kaplan, Ulas; Tivnan, Terrence

2014-01-01

Intrapersonal variability and multiplicity in the complexity of moral motivation were examined from Dynamic Systems and Self-Determination Theory perspectives. L. Kohlberg's (1969) stages of moral development are reconceptualized as soft-assembled and dynamically transformable process structures of motivation that may operate simultaneously within person in different degrees. Moral motivation is conceptualized as the real-time process of self-organization of cognitive and emotional dynamics out of which moral judgment and action emerge. A detailed inquiry into intrapersonal variation in moral motivation is carried out based on the differential operation of multiple motivational structures. A total of 74 high school students and 97 college students participated in the study by completing a new questionnaire, involving 3 different hypothetical moral judgments. As hypothesized, findings revealed significant multiplicity in the within-person operation of developmental stage structures, and intrapersonal variability in the degrees to which stages were used. Developmental patterns were found in terms of different distributions of multiple stages between high school and college samples, as well as the association between age and overall motivation scores. Differential relations of specific emotions to moral motivation revealed and confirmed the value of differentiating multiple emotions. Implications of the present theoretical perspective and the findings for understanding the complexity of moral judgment and motivation are discussed.

Combined mining: discovering informative knowledge in complex data.

PubMed

Cao, Longbing; Zhang, Huaifeng; Zhao, Yanchang; Luo, Dan; Zhang, Chengqi

2011-06-01

Enterprise data mining applications often involve complex data such as multiple large heterogeneous data sources, user preferences, and business impact. In such situations, a single method or one-step mining is often limited in discovering informative knowledge. It would also be very time and space consuming, if not impossible, to join relevant large data sources for mining patterns consisting of multiple aspects of information. It is crucial to develop effective approaches for mining patterns combining necessary information from multiple relevant business lines, catering for real business settings and decision-making actions rather than just providing a single line of patterns. The recent years have seen increasing efforts on mining more informative patterns, e.g., integrating frequent pattern mining with classifications to generate frequent pattern-based classifiers. Rather than presenting a specific algorithm, this paper builds on our existing works and proposes combined mining as a general approach to mining for informative patterns combining components from either multiple data sets or multiple features or by multiple methods on demand. We summarize general frameworks, paradigms, and basic processes for multifeature combined mining, multisource combined mining, and multimethod combined mining. Novel types of combined patterns, such as incremental cluster patterns, can result from such frameworks, which cannot be directly produced by the existing methods. A set of real-world case studies has been conducted to test the frameworks, with some of them briefed in this paper. They identify combined patterns for informing government debt prevention and improving government service objectives, which show the flexibility and instantiation capability of combined mining in discovering informative knowledge in complex data.

Learning to Teach from Anticipating Lessons through Comics-Based Approximations of Practice

ERIC Educational Resources Information Center

Chen, Chia-Ling

2012-01-01

Teaching is complex and relational work that involves teacher's interactions with individual or multiple students around the subject matter. It has been argued that observation experiences (e.g. field placement or watching video clips) are not sufficient to help prospective teachers to develop knowledge of teaching. This study aims to…

Linking cellular zinc status to body weight and fat mass: mapping quantitative trait loci in Znt7 knockout mice

USDA-ARS?s Scientific Manuscript database

Zinc transporter 7 (Znt7, Slc30a7) knockout (KO) mice display abnormalities in body weight gain and body adiposity. Regulation of body weight and fatness is complex, involving multiple genetic and environmental factors. To understand how zinc homeostasis influences body weight gain and fat deposit a...

Providing Formative Assessment to Students Solving Multipath Engineering Problems with Complex Arrangements of Interacting Parts: An Intelligent Tutor Approach

ERIC Educational Resources Information Center

Steif, Paul S.; Fu, Luoting; Kara, Levent Burak

2016-01-01

Problems faced by engineering students involve multiple pathways to solution. Students rarely receive effective formative feedback on handwritten homework. This paper examines the potential for computer-based formative assessment of student solutions to multipath engineering problems. In particular, an intelligent tutor approach is adopted and…

Using Mouse Models to Explore Genotype-Phenotype Relationship in Down Syndrome

ERIC Educational Resources Information Center

Salehi, Ahmad; Faizi, Mehrdad; Belichenko, Pavel V.; Mobley, William C.

2007-01-01

Down Syndrome (DS) caused by trisomy 21 is characterized by a variety of phenotypes and involves multiple organs. Sequencing of human chromosome 21 (HSA21) and subsequently of its orthologues on mouse chromosome 16 have created an unprecedented opportunity to explore the complex relationship between various DS phenotypes and the extra copy of…

A Theoretically Grounded Exploration of the Social and Emotional Outcomes of Transition to Secondary School

ERIC Educational Resources Information Center

Waters, Stacey K.; Lester, Leanne; Wenden, Elizabeth; Cross, Donna

2012-01-01

Adolescent development involves a complex interplay between genetics, biology, and social and emotional relationships within multiple contexts of home, school and the broader community. The transition from primary to secondary school, coupled with the onset of puberty, can therefore be a difficult period for young people to negotiate at a critical…

Characterizing incentives: an investigation of wildfire response and environmental entry policy

Treesearch

Jude Bayham

2013-01-01

Policy makers face complex situations involving the analysis and weighting of multiple incentives that complicate the design of natural resource and environmental policy. The objective of this dissertation is to characterize policy makers’ incentives, and to investigate the consequences of those incentives on environmental and economic outcomes in the context of...

Killing Curiosity? An Analysis of Celebrated Identity Performances among Teachers and Students in Nine London Secondary Science Classrooms

ERIC Educational Resources Information Center

Archer, Louise; Dawson, Emily; DeWitt, Jennifer; Godec, Spela; King, Heather; Mau, Ada; Nomikou, Effrosyni; Seakins, Amy

2017-01-01

In this paper, we take the view that school classrooms are spaces that are constituted by complex power struggles (for voice, authenticity, and recognition), involving multiple layers of resistance and contestation between the "institution," teachers and students, which can have profound implications for students' science identity and…

Lesson Study and the Co-Construction of Pedagogical Knowledge among Secondary Specialty Teachers

ERIC Educational Resources Information Center

Mesa-Lema, Liliana

2014-01-01

Teacher learning in the workplace is situated within a complex context involving the individual and multiple aspects of an educational organization. The present action research study uses a socio-constructionist inquiry lens to further research the local and multifaceted nature of professional learning in schools. The goal is to re-conceptualize…

Mapping fuels at multiple scales: landscape application of the fuel characteristic classification system.

Treesearch

D. McKenzie; C.L. Raymond; L.-K.B. Kellogg; R.A. Norheim; A.G. Andreu; A.C. Bayard; K.E. Kopper; E. Elman

2007-01-01

Fuel mapping is a complex and often multidisciplinary process, involving remote sensing, ground-based validation, statistical modeling, and knowledge-based systems. The scale and resolution of fuel mapping depend both on objectives and availability of spatial data layers. We demonstrate use of the Fuel Characteristic Classification System (FCCS) for fuel mapping at two...

Managing wildfire events: risk-based decision making among a group of federal fire managers

Treesearch

Robyn S. Wilson; Patricia L. Winter; Lynn A. Maguire; Timothy Ascher

2011-01-01

Managing wildfire events to achieve multiple management objectives involves a high degree of decision complexity and uncertainty, increasing the likelihood that decisions will be informed by experience-based heuristics triggered by available cues at the time of the decision. The research reported here tests the prevalence of three risk-based biases among 206...

Infrared Multiple-Photon Dissociation spectroscopy of group II metal complexes with salicylate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ryan P. Dain; Gary Gresham; Gary S. Groenewold

2011-07-01

Ion-trap tandem mass spectrometry with collision-induced dissociation, and the combination of infrared multiple-photon dissociation (IRMPD) spectroscopy and density functional theory (DFT) calculations were used to characterize singly-charged, 1:1 complexes of Ca2+, Sr2+ and Ba2+ with salicylate. For each metal-salicylate complex, the CID pathways are: (a) elimination of CO2 and (b) formation of [MOH]+ where M=Ca2+, Sr2+ or Ba2+. DFT calculations predict three minima for the cation-salicylate complexes which differ in the mode of metal binding. In the first, the metal ion is coordinated by O atoms of the (neutral) phenol and carboxylate groups of salicylate. In the second, the cationmore » is coordinated by phenoxide and (neutral) carboxylic acid groups. The third mode involves coordination by the carboxylate group alone. The infrared spectrum for the metal-salicylate complexes contains a number of absorptions between 1000 – 1650 cm-1, and the best correlation between theoretical and experimental spectra for the structure that features coordination of the metal ion by phenoxide and the carbonyl group of the carboxylic acid group, consistent with calculated energies for the respective species.« less

Infrared multiple-photon dissociation spectroscopy of group II metal complexes with salicylate.

PubMed

Dain, Ryan P; Gresham, Gary; Groenewold, Gary S; Steill, Jeffrey D; Oomens, Jos; van Stipdonk, Michael J

2011-07-15

Ion trap tandem mass spectrometry with collision-induced dissociation, and the combination of infrared multiple-photon dissociation (IRMPD) spectroscopy and density functional theory (DFT) calculations, were used to characterize singly charged, 1:1 complexes of Ca(2+), Sr(2+) and Ba(2+) with salicylate. For each metal-salicylate complex, the CID pathways are: (a) elimination of CO(2) and (b) formation of [MOH](+) where M = Ca(2+), Sr(2+) or Ba(2+). DFT calculations predict three minima for the cation-salicylate complexes which differ in the mode of metal binding. In the first, the metal ion is coordinated by O atoms of the (neutral) phenol and carboxylate groups of salicylate. In the second, the cation is coordinated by phenoxide and (neutral) carboxylic acid groups. The third mode involves coordination by the carboxylate group alone. The infrared spectrum for the metal-salicylate complexes contains a number of absorptions between 1000 and 1650 cm(-1), and the best correlation between theoretical and experimental spectra is found for the structure that features coordination of the metal ion by phenoxide and the carbonyl O of the carboxylic acid group, consistent with the calculated energies for the respective species. Copyright © 2011 John Wiley & Sons, Ltd.

Hardware Implementation of a MIMO Decoder Using Matrix Factorization Based Channel Estimation

NASA Astrophysics Data System (ADS)

Islam, Mohammad Tariqul; Numan, Mostafa Wasiuddin; Misran, Norbahiah; Ali, Mohd Alauddin Mohd; Singh, Mandeep

2011-05-01

This paper presents an efficient hardware realization of multiple-input multiple-output (MIMO) wireless communication decoder that utilizes the available resources by adopting the technique of parallelism. The hardware is designed and implemented on Xilinx Virtex™-4 XC4VLX60 field programmable gate arrays (FPGA) device in a modular approach which simplifies and eases hardware update, and facilitates testing of the various modules independently. The decoder involves a proficient channel estimation module that employs matrix factorization on least squares (LS) estimation to reduce a full rank matrix into a simpler form in order to eliminate matrix inversion. This results in performance improvement and complexity reduction of the MIMO system. Performance evaluation of the proposed method is validated through MATLAB simulations which indicate 2 dB improvement in terms of SNR compared to LS estimation. Moreover complexity comparison is performed in terms of mathematical operations, which shows that the proposed approach appreciably outperforms LS estimation at a lower complexity and represents a good solution for channel estimation technique.

A Component Approach to Collaborative Scientific Software Development: Tools and Techniques Utilized by the Quantum Chemistry Science Application Partnership

DOE PAGES

Kenny, Joseph P.; Janssen, Curtis L.; Gordon, Mark S.; ...

2008-01-01

Cutting-edge scientific computing software is complex, increasingly involving the coupling of multiple packages to combine advanced algorithms or simulations at multiple physical scales. Component-based software engineering (CBSE) has been advanced as a technique for managing this complexity, and complex component applications have been created in the quantum chemistry domain, as well as several other simulation areas, using the component model advocated by the Common Component Architecture (CCA) Forum. While programming models do indeed enable sound software engineering practices, the selection of programming model is just one building block in a comprehensive approach to large-scale collaborative development which must also addressmore » interface and data standardization, and language and package interoperability. We provide an overview of the development approach utilized within the Quantum Chemistry Science Application Partnership, identifying design challenges, describing the techniques which we have adopted to address these challenges and highlighting the advantages which the CCA approach offers for collaborative development.« less

Porous polycarbene-bearing membrane actuator for ultrasensitive weak-acid detection and real-time chemical reaction monitoring.

PubMed

Sun, Jian-Ke; Zhang, Weiyi; Guterman, Ryan; Lin, Hui-Juan; Yuan, Jiayin

2018-04-30

Soft actuators with integration of ultrasensitivity and capability of simultaneous interaction with multiple stimuli through an entire event ask for a high level of structure complexity, adaptability, and/or multi-responsiveness, which is a great challenge. Here, we develop a porous polycarbene-bearing membrane actuator built up from ionic complexation between a poly(ionic liquid) and trimesic acid (TA). The actuator features two concurrent structure gradients, i.e., an electrostatic complexation (EC) degree and a density distribution of a carbene-NH 3 adduct (CNA) along the membrane cross-section. The membrane actuator performs the highest sensitivity among the state-of-the-art soft proton actuators toward acetic acid at 10 -6  mol L -1 (M) level in aqueous media. Through competing actuation of the two gradients, it is capable of monitoring an entire process of proton-involved chemical reactions that comprise multiple stimuli and operational steps. The present achievement constitutes a significant step toward real-life application of soft actuators in chemical sensing and reaction technology.

Brainlab: A Python Toolkit to Aid in the Design, Simulation, and Analysis of Spiking Neural Networks with the NeoCortical Simulator.

PubMed

Drewes, Rich; Zou, Quan; Goodman, Philip H

2009-01-01

Neuroscience modeling experiments often involve multiple complex neural network and cell model variants, complex input stimuli and input protocols, followed by complex data analysis. Coordinating all this complexity becomes a central difficulty for the experimenter. The Python programming language, along with its extensive library packages, has emerged as a leading "glue" tool for managing all sorts of complex programmatic tasks. This paper describes a toolkit called Brainlab, written in Python, that leverages Python's strengths for the task of managing the general complexity of neuroscience modeling experiments. Brainlab was also designed to overcome the major difficulties of working with the NCS (NeoCortical Simulator) environment in particular. Brainlab is an integrated model-building, experimentation, and data analysis environment for the powerful parallel spiking neural network simulator system NCS.

Brainlab: A Python Toolkit to Aid in the Design, Simulation, and Analysis of Spiking Neural Networks with the NeoCortical Simulator

PubMed Central

Drewes, Rich; Zou, Quan; Goodman, Philip H.

2008-01-01

Neuroscience modeling experiments often involve multiple complex neural network and cell model variants, complex input stimuli and input protocols, followed by complex data analysis. Coordinating all this complexity becomes a central difficulty for the experimenter. The Python programming language, along with its extensive library packages, has emerged as a leading “glue” tool for managing all sorts of complex programmatic tasks. This paper describes a toolkit called Brainlab, written in Python, that leverages Python's strengths for the task of managing the general complexity of neuroscience modeling experiments. Brainlab was also designed to overcome the major difficulties of working with the NCS (NeoCortical Simulator) environment in particular. Brainlab is an integrated model-building, experimentation, and data analysis environment for the powerful parallel spiking neural network simulator system NCS. PMID:19506707

Multiple Animal Studies for Medical Chemical Defense Program in Soldier/ Patient Decontamination and Drug Development on Task Order 84-6: Pyruvate Dehydrogenase System for Determining the Effectiveness of Arsenic Antidotes

DTIC Science & Technology

1988-03-11

adenine dinucleotide FAD = flavin-adenine dinucleotide iipS2 = lipoic acid lip(SH)2 = dihydrolipoic acid CoA = coenzyme A. SHepatic PDH complex activity...tissues has yet to be fully characterized, but it probably involves arsenic binding to the lipoic acid and dithiol moieties of the complex (Fluharty...covalently bound lipoic acid substrate of dihydrolipoyl transacetylase is greater per mole of L and CVAA than for sodium arsenite. This is possible

Coordinated Science Campaign Scheduling for Sensor Webs

NASA Technical Reports Server (NTRS)

Edgington, Will; Morris, Robert; Dungan, Jennifer; Williams, Jenny; Carlson, Jean; Fleming, Damian; Wood, Terri; Yorke-Smith, Neil

2005-01-01

Future Earth observing missions will study different aspects and interacting pieces of the Earth's eco-system. Scientists are designing increasingly complex, interdisciplinary campaigns to exploit the diverse capabilities of multiple Earth sensing assets. In addition, spacecraft platforms are being configured into clusters, trains, or other distributed organizations in order to improve either the quality or the coverage of observations. These simultaneous advances in the design of science campaigns and in the missions that will provide the sensing resources to support them offer new challenges in the coordination of data and operations that are not addressed by current practice. For example, the scheduling of scientific observations for satellites in low Earth orbit is currently conducted independently by each mission operations center. An absence of an information infrastructure to enable the scheduling of coordinated observations involving multiple sensors makes it difficult to execute campaigns involving multiple assets. This paper proposes a software architecture and describes a prototype system called DESOPS (Distributed Earth Science Observation Planning and Scheduling) that will address this deficiency.

Multiscale Modelling of Cancer Progression and Treatment Control: The Role of Intracellular Heterogeneities in Chemotherapy Treatment

NASA Astrophysics Data System (ADS)

Chaplain, Mark A. J.; Powathil, Gibin G.

Cancer is a complex, multiscale process involving interactions at intracellular, intercellular and tissue scales that are in turn susceptible to microenvironmental changes. Each individual cancer cell within a cancer cell mass is unique, with its own internal cellular pathways and biochemical interactions. These interactions contribute to the functional changes at the cellular and tissue scale, creating a heterogenous cancer cell population. Anticancer drugs are effective in controlling cancer growth by inflicting damage to various target molecules and thereby triggering multiple cellular and intracellular pathways, leading to cell death or cell-cycle arrest. One of the major impediments in the chemotherapy treatment of cancer is drug resistance driven by multiple mechanisms, including multi-drug and cell-cycle mediated resistance to chemotherapy drugs. In this article, we discuss two hybrid multiscale modelling approaches, incorporating multiple interactions involved in the sub-cellular, cellular and microenvironmental levels to study the effects of cell-cycle, phase-specific chemotherapy on the growth and progression of cancer cells.

Multiscale Modelling of Cancer Progression and Treatment Control: The Role of Intracellular Heterogeneities in Chemotherapy Treatment

NASA Astrophysics Data System (ADS)

Chaplain, Mark A. J.; Powathil, Gibin G.

2015-04-01

Cancer is a complex, multiscale process involving interactions at intracellular, intercellular and tissue scales that are in turn susceptible to microenvironmental changes. Each individual cancer cell within a cancer cell mass is unique, with its own internal cellular pathways and biochemical interactions. These interactions contribute to the functional changes at the cellular and tissue scale, creating a heterogenous cancer cell population. Anticancer drugs are effective in controlling cancer growth by inflicting damage to various target molecules and thereby triggering multiple cellular and intracellular pathways, leading to cell death or cell-cycle arrest. One of the major impediments in the chemotherapy treatment of cancer is drug resistance driven by multiple mechanisms, including multi-drug and cell-cycle mediated resistance to chemotherapy drugs. In this article, we discuss two hybrid multiscale modelling approaches, incorporating multiple interactions involved in the sub-cellular, cellular and microenvironmental levels to study the effects of cell-cycle, phase-specific chemotherapy on the growth and progression of cancer cells.

Structure Determination of Ornithine-Linked Cisplatin by Infrared Multiple Photon Dissociation Action Spectroscopy

NASA Astrophysics Data System (ADS)

He, Chenchen; Kimutai, Bett; Hamlow, Lucas; Roy, Harrison; Nei, Y.-W.; Bao, Xun; Gao, Juehan; Martens, Jonathan K.; Berden, Giel; Oomens, Jos; Maitre, Philippe; Steinmetz, Vincent; McNary, Christopher P.; Armentrout, Peter B.; Chow, C. S.; Rodgers, M. T.

2016-06-01

Cisplatin [(NH_3)_2PtCl_2], the first FDA-approved platinum-based anticancer drug, has been widely used in cancer chemotherapy. Its pharmacological mechanism has been identified as its ability to coordinate to genomic DNA with guanine as its major target. Amino acid-linked cisplatin derivatives are being investigated as alternatives for cisplatin that may exhibit altered binding selectivity such as that found for ornithine-linked cisplatin (Ornplatin, [(Orn)PtCl_2]), which exhibits a preference for adenine over guanine in RNA. Infrared multiple photon dissociation (IRMPD) action spectroscopy experiments and complementary electronic structure calculations are performed on a series of Ornplatin complexes to elucidate the nature of binding of the Orn amino acid to the Pt center and how that binding is influenced by the local environment. The complexes examined in the work include: [(Orn-H)PtCl_2]-, [(Orn)PtCl]+, [(Orn)Pt(H_2O)Cl]+, and [(Orn)PtCl_2+Na]+. In contrast to that found previously for the glycine-linked cisplatin complex (Glyplatin), which binds via the backbone amino and carboxylate groups, binding of Orn in these complexes is found to involve both the backbone and sidechain amino groups. Extensive broadening of the IRMPD spectrum for the [(Orn)Pt(H_2O)Cl]+ complex suggests that either multiple structures are contributing to the measured spectrum or strong intra-molecular hydrogen-binding interactions are present. The results for Ornplatin lead to an interesting discussion about the differences in selectivity and reactivity versus cisplatin.

Simulating maar-diatreme volcanic systems in bench-scale experiments

NASA Astrophysics Data System (ADS)

Andrews, R. G.; White, J. D. L.; Dürig, T.; Zimanowski, B.

2015-12-01

Maar-diatreme eruptions are incompletely understood, and explanations for the processes involved in them have been debated for decades. This study extends bench-scale analogue experiments previously conducted on maar-diatreme systems and attempts to scale the results up to both field-scale experimentation and natural volcanic systems in order to produce a reconstructive toolkit for maar volcanoes. These experimental runs produced via multiple mechanisms complex deposits that match many features seen in natural maar-diatreme deposits. The runs include deeper single blasts, series of descending discrete blasts, and series of ascending blasts. Debris-jet inception and diatreme formation are indicated by this study to involve multiple types of granular fountains within diatreme deposits produced under varying initial conditions. The individual energies of blasts in multiple-blast series are not possible to infer from the final deposits. The depositional record of blast sequences can be ascertained from the proportion of fallback sedimentation versus maar ejecta rim material, the final crater size and the degree of overturning or slumping of accessory strata. Quantitatively, deeper blasts involve a roughly equal partitioning of energy into crater excavation energy versus mass movement of juvenile material, whereas shallower blasts expend a much greater proportion of energy in crater excavation.

Biomechanism of chlorogenic acid complex mediated plasma free fatty acid metabolism in rat liver.

PubMed

H V, Sudeep; K, Venkatakrishna; Patel, Dipak; K, Shyamprasad

2016-08-05

Plasma free fatty acids (FFA) are involved in blood lipid metabolism as well as many health complications. The present study was conducted to evaluate the potential role of chlorogenic acid complex from green coffee bean (CGA7) on FFA metabolism in high fat diet fed rats. Hyperlipidemia was induced in Wistar rats using high-fat diet. The animals were given CGA7/orlistat concurrently for 42 days. The parameters analysed during the study include plasma and liver total cholesterol (TC), Triglycerides (TG) and FFA. AMPK activation in the liver was analysed through ELISA. The multiple factors involved in AMPK mediated FFA metabolism were analysed using western blotting. CGA7 (50, 100, 150 mg/kg BW) decreased triglycerides (TG) and FFA levels in plasma and liver. CGA7 administration led to the activation of AMP-activated protein kinase (AMPK) and a subsequent increase in the levels of carnitine palmitoyltransferase 1 (CPT-1). There was a decrease in acetyl-CoA carboxylase (ACC) activity as evident by the increase in its phosphorylation level. Chlorogenic acids improved the blood lipid metabolism in rats by alleviating the levels of FFA and TG, modulating the multiple factors in liver through AMPK pathway. The study concludes that CGA7 complex can be promoted as an active ingredient in nutrition for obesity management.

Decision making.

PubMed

Chambers, David W

2011-01-01

A decision is a commitment of resources under conditions of risk in expectation of the best future outcome. The smart decision is always the strategy with the best overall expected value-the best combination of facts and values. Some of the special circumstances involved in decision making are discussed, including decisions where there are multiple goals, those where more than one person is involved in making the decision, using trigger points, framing decisions correctly, commitments to lost causes, and expert decision makers. A complex example of deciding about removal of asymptomatic third molars, with and without an EBD search, is discussed.

Regulation of flower development in Arabidopsis by SCF complexes.

PubMed

Ni, Weimin; Xie, Daoxin; Hobbie, Lawrence; Feng, Baomin; Zhao, Dazhong; Akkara, Joseph; Ma, Hong

2004-04-01

SCF complexes are the largest and best studied family of E3 ubiquitin protein ligases that facilitate the ubiquitylation of proteins targeted for degradation. The SCF core components Skp1, Cul1, and Rbx1 serve in multiple SCF complexes involving different substrate-specific F-box proteins that are involved in diverse processes including cell cycle and development. In Arabidopsis, mutations in the F-box gene UNUSUAL FLORAL ORGANS (UFO) result in a number of defects in flower development. However, functions of the core components Cul1 and Rbx1 in flower development are poorly understood. In this study we analyzed floral phenotypes caused by altering function of Cul1 or Rbx1, as well as the effects of mutations in ASK1 and ASK2. Plants homozygous for a point mutation in the AtCUL1 gene showed reduced floral organ number and several defects in each of the four whorls. Similarly, plants with reduced AtRbx1 expression due to RNA interference also exhibited floral morphological defects. In addition, compared to the ask1 mutant, plants homozygous for ask1 and heterozygous for ask2 displayed enhanced reduction of B function, as well as other novel defects of flower development, including carpelloid sepals and an inhibition of petal development. Genetic analyses demonstrate that AGAMOUS (AG) is required for the novel phenotypes observed in the first and second whorls. Furthermore, the genetic interaction between UFO and AtCUL1 supports the idea that UFO regulates multiple aspects of flower development as a part of SCF complexes. These results suggest that SCF complexes regulate several aspects of floral development in Arabidopsis.

Assembly of micro/nanomaterials into complex, three-dimensional architectures by compressive buckling

NASA Astrophysics Data System (ADS)

Xu, Sheng; Yan, Zheng; Jang, Kyung-In; Huang, Wen; Fu, Haoran; Kim, Jeonghyun; Wei, Zijun; Flavin, Matthew; McCracken, Joselle; Wang, Renhan; Badea, Adina; Liu, Yuhao; Xiao, Dongqing; Zhou, Guoyan; Lee, Jungwoo; Chung, Ha Uk; Cheng, Huanyu; Ren, Wen; Banks, Anthony; Li, Xiuling; Paik, Ungyu; Nuzzo, Ralph G.; Huang, Yonggang; Zhang, Yihui; Rogers, John A.

2015-01-01

Complex three-dimensional (3D) structures in biology (e.g., cytoskeletal webs, neural circuits, and vasculature networks) form naturally to provide essential functions in even the most basic forms of life. Compelling opportunities exist for analogous 3D architectures in human-made devices, but design options are constrained by existing capabilities in materials growth and assembly. We report routes to previously inaccessible classes of 3D constructs in advanced materials, including device-grade silicon. The schemes involve geometric transformation of 2D micro/nanostructures into extended 3D layouts by compressive buckling. Demonstrations include experimental and theoretical studies of more than 40 representative geometries, from single and multiple helices, toroids, and conical spirals to structures that resemble spherical baskets, cuboid cages, starbursts, flowers, scaffolds, fences, and frameworks, each with single- and/or multiple-level configurations.

Multiple origins of interdependent endosymbiotic complexes in a genus of cicadas.

PubMed

Łukasik, Piotr; Nazario, Katherine; Van Leuven, James T; Campbell, Matthew A; Meyer, Mariah; Michalik, Anna; Pessacq, Pablo; Simon, Chris; Veloso, Claudio; McCutcheon, John P

2018-01-09

Bacterial endosymbionts that provide nutrients to hosts often have genomes that are extremely stable in structure and gene content. In contrast, the genome of the endosymbiont Hodgkinia cicadicola has fractured into multiple distinct lineages in some species of the cicada genus Tettigades To better understand the frequency, timing, and outcomes of Hodgkinia lineage splitting throughout this cicada genus, we sampled cicadas over three field seasons in Chile and performed genomics and microscopy on representative samples. We found that a single ancestral Hodgkinia lineage has split at least six independent times in Tettigades over the last 4 million years, resulting in complexes of between two and six distinct Hodgkinia lineages per host. Individual genomes in these symbiotic complexes differ dramatically in relative abundance, genome size, organization, and gene content. Each Hodgkinia lineage retains a small set of core genes involved in genetic information processing, but the high level of gene loss experienced by all genomes suggests that extensive sharing of gene products among symbiont cells must occur. In total, Hodgkinia complexes that consist of multiple lineages encode nearly complete sets of genes present on the ancestral single lineage and presumably perform the same functions as symbionts that have not undergone splitting. However, differences in the timing of the splits, along with dissimilar gene loss patterns on the resulting genomes, have led to very different outcomes of lineage splitting in extant cicadas.

The RTR Complex Partner RMI2 and the DNA Helicase RTEL1 Are Both Independently Involved in Preserving the Stability of 45S rDNA Repeats in Arabidopsis thaliana

PubMed Central

Knoll, Alexander; Puchta, Holger

2016-01-01

The stability of repetitive sequences in complex eukaryotic genomes is safeguarded by factors suppressing homologues recombination. Prominent in this is the role of the RTR complex. In plants, it consists of the RecQ helicase RECQ4A, the topoisomerase TOP3α and RMI1. Like mammals, but not yeast, plants harbor an additional complex partner, RMI2. Here, we demonstrate that, in Arabidopsis thaliana, RMI2 is involved in the repair of aberrant replication intermediates in root meristems as well as in intrastrand crosslink repair. In both instances, RMI2 is involved independently of the DNA helicase RTEL1. Surprisingly, simultaneous loss of RMI2 and RTEL1 leads to loss of male fertility. As both the RTR complex and RTEL1 are involved in suppression of homologous recombination (HR), we tested the efficiency of HR in the double mutant rmi2-2 rtel1-1 and found a synergistic enhancement (80-fold). Searching for natural target sequences we found that RTEL1 is required for stabilizing 45S rDNA repeats. In the double mutant with rmi2-2 the number of 45S rDNA repeats is further decreased sustaining independent roles of both factors in this process. Thus, loss of suppression of HR does not only lead to a destabilization of rDNA repeats but might be especially deleterious for tissues undergoing multiple cell divisions such as the male germline. PMID:27760121

The RTR Complex Partner RMI2 and the DNA Helicase RTEL1 Are Both Independently Involved in Preserving the Stability of 45S rDNA Repeats in Arabidopsis thaliana.

PubMed

Röhrig, Sarah; Schröpfer, Susan; Knoll, Alexander; Puchta, Holger

2016-10-01

The stability of repetitive sequences in complex eukaryotic genomes is safeguarded by factors suppressing homologues recombination. Prominent in this is the role of the RTR complex. In plants, it consists of the RecQ helicase RECQ4A, the topoisomerase TOP3α and RMI1. Like mammals, but not yeast, plants harbor an additional complex partner, RMI2. Here, we demonstrate that, in Arabidopsis thaliana, RMI2 is involved in the repair of aberrant replication intermediates in root meristems as well as in intrastrand crosslink repair. In both instances, RMI2 is involved independently of the DNA helicase RTEL1. Surprisingly, simultaneous loss of RMI2 and RTEL1 leads to loss of male fertility. As both the RTR complex and RTEL1 are involved in suppression of homologous recombination (HR), we tested the efficiency of HR in the double mutant rmi2-2 rtel1-1 and found a synergistic enhancement (80-fold). Searching for natural target sequences we found that RTEL1 is required for stabilizing 45S rDNA repeats. In the double mutant with rmi2-2 the number of 45S rDNA repeats is further decreased sustaining independent roles of both factors in this process. Thus, loss of suppression of HR does not only lead to a destabilization of rDNA repeats but might be especially deleterious for tissues undergoing multiple cell divisions such as the male germline.

Endocrine Responses to Resistance Exercise,

DTIC Science & Technology

1987-08-30

resistance training responses of selected hormones related to acute stress and growth promoting actions. Hormonal mechanisms appear to be involved with ...an important determinant of hormonal response. Still. little is known with regard to other single and multiple factor variables (e.g.. rest period...hormone through a direct interaction with a cytoplasmic receptor leading to the typical migration of the hormone-receptor complex to the nucleus

Bootstrap evaluation of a young Douglas-fir height growth model for the Pacific Northwest

Treesearch

Nicholas R. Vaughn; Eric C. Turnblom; Martin W. Ritchie

2010-01-01

We evaluated the stability of a complex regression model developed to predict the annual height growth of young Douglas-fir. This model is highly nonlinear and is fit in an iterative manner for annual growth coefficients from data with multiple periodic remeasurement intervals. The traditional methods for such a sensitivity analysis either involve laborious math or...

Beneath the Tip of the Iceberg: Exploring the Multiple Forms of University-Industry Linkages

ERIC Educational Resources Information Center

Ramos-Vielba, Irene; Fernandez-Esquinas, Manuel

2012-01-01

This article focuses on the wide variety of channels through which the process of knowledge transfer occurs. The overall objective is to show the complexity of relationships between researchers and firms in a university system, and to identify some specific factors that influence such interactions. Our case study involves a face-to-face survey of…

Molecular Identification of Human Fungal Pathogens

DTIC Science & Technology

2011-03-01

of the right lower tibia and fibula revealed nonenhancing edema of the skin and subcutaneous fat involving the medial distal right lower leg without...military hospital in Iraq and taken immediately to the operating room for complex pelvic fracture debridement and fixation, right lower extremity...patient’s comorbidities—which included acute kidney injury secondary to rhabdomyolysis, multiple fractures requiring surgical intervention, and pro

Therapeutic Guidance for Infants and Families: Using Multi-Family Groups as an Extension of Child-Parent Psychotherapy

ERIC Educational Resources Information Center

Frame, Laura; Ivins, Barbara; Wong, Lynette; Cantrell, Sally

2015-01-01

Treatment of very young children in foster care involves the complex dynamics of a child's trauma history, multiple relationships, and caregivers' and providers' feelings about working with the child welfare system. Through the story of a toddler removed from his parents and placed in foster care, the authors illustrate a model of combined group…

Systemic Ecological Illiteracy? Shedding Light on Meaning as an Act of Thought in Higher Learning

ERIC Educational Resources Information Center

Puk, Thomas G.; Stibbards, Adam

2012-01-01

Research on ecological literacy often takes for granted that participants understand, and can construct the meaning within, the complex concepts involved, simply because they are able to use the appropriate terminology in a "fluent" manner and/or can select the correct option on multiple choice tests. In this study, and in the larger…

Utilization of the Seniors Falls Investigation Methodology to Identify System-Wide Causes of Falls in Community-Dwelling Seniors

ERIC Educational Resources Information Center

Zecevic, Aleksandra A.; Salmoni, Alan W.; Lewko, John H.; Vandervoort, Anthoney A.; Speechley, Mark

2009-01-01

Purpose: As a highly heterogeneous group, seniors live in complex environments influenced by multiple physical and social structures that affect their safety. Until now, the major approach to falls research has been person centered. However, in industrial settings, the individuals involved in an accident are seen as the inheritors of system…

Practical applications of the bioinformatics toolbox for narrowing quantitative trait loci.

PubMed

Burgess-Herbert, Sarah L; Cox, Allison; Tsaih, Shirng-Wern; Paigen, Beverly

2008-12-01

Dissecting the genes involved in complex traits can be confounded by multiple factors, including extensive epistatic interactions among genes, the involvement of epigenetic regulators, and the variable expressivity of traits. Although quantitative trait locus (QTL) analysis has been a powerful tool for localizing the chromosomal regions underlying complex traits, systematically identifying the causal genes remains challenging. Here, through its application to plasma levels of high-density lipoprotein cholesterol (HDL) in mice, we demonstrate a strategy for narrowing QTL that utilizes comparative genomics and bioinformatics techniques. We show how QTL detected in multiple crosses are subjected to both combined cross analysis and haplotype block analysis; how QTL from one species are mapped to the concordant regions in another species; and how genomewide scans associating haplotype groups with their phenotypes can be used to prioritize the narrowed regions. Then we illustrate how these individual methods for narrowing QTL can be systematically integrated for mouse chromosomes 12 and 15, resulting in a significantly reduced number of candidate genes, often from hundreds to <10. Finally, we give an example of how additional bioinformatics resources can be combined with experiments to determine the most likely quantitative trait genes.

Immune Ecosystem of Virus-Infected Host Tissues.

PubMed

Maarouf, Mohamed; Rai, Kul Raj; Goraya, Mohsan Ullah; Chen, Ji-Long

2018-05-06

Virus infected host cells serve as a central immune ecological niche during viral infection and replication and stimulate the host immune response via molecular signaling. The viral infection and multiplication process involves complex intracellular molecular interactions between viral components and the host factors. Various types of host cells are also involved to modulate immune factors in delicate and dynamic equilibrium to maintain a balanced immune ecosystem in an infected host tissue. Antiviral host arsenals are equipped to combat or eliminate viral invasion. However, viruses have evolved with strategies to counter against antiviral immunity or hijack cellular machinery to survive inside host tissue for their multiplication. However, host immune systems have also evolved to neutralize the infection; which, in turn, either clears the virus from the infected host or causes immune-mediated host tissue injury. A complex relationship between viral pathogenesis and host antiviral defense could define the immune ecosystem of virus-infected host tissues. Understanding of the molecular mechanism underlying this ecosystem would uncover strategies to modulate host immune function for antiviral therapeutics. This review presents past and present updates of immune-ecological components of virus infected host tissue and explains how viruses subvert the host immune surveillances.

A functional TOC complex contributes to gravity signal transduction in Arabidopsis

PubMed Central

Strohm, Allison K.; Barrett-Wilt, Greg A.; Masson, Patrick H.

2014-01-01

Although plastid sedimentation has long been recognized as important for a plant's perception of gravity, it was recently shown that plastids play an additional function in gravitropism. The Translocon at the Outer envelope membrane of Chloroplasts (TOC) complex transports nuclear-encoded proteins into plastids, and a receptor of this complex, Toc132, was previously hypothesized to contribute to gravitropism either by directly functioning as a gravity signal transducer or by indirectly mediating the plastid localization of a gravity signal transducer. Here we show that mutations in multiple genes encoding TOC complex components affect gravitropism in a genetically sensitized background and that the cytoplasmic acidic domain of Toc132 is not required for its involvement in this process. Furthermore, mutations in TOC132 enhance the gravitropic defect of a mutant whose amyloplasts lack starch. Finally, we show that the levels of several nuclear-encoded root proteins are altered in toc132 mutants. These data suggest that the TOC complex indirectly mediates gravity signal transduction in Arabidopsis and support the idea that plastids are involved in gravitropism not only through their ability to sediment but also as part of the signal transduction mechanism. PMID:24795735

A functional TOC complex contributes to gravity signal transduction in Arabidopsis.

PubMed

Strohm, Allison K; Barrett-Wilt, Greg A; Masson, Patrick H

2014-01-01

Although plastid sedimentation has long been recognized as important for a plant's perception of gravity, it was recently shown that plastids play an additional function in gravitropism. The Translocon at the Outer envelope membrane of Chloroplasts (TOC) complex transports nuclear-encoded proteins into plastids, and a receptor of this complex, Toc132, was previously hypothesized to contribute to gravitropism either by directly functioning as a gravity signal transducer or by indirectly mediating the plastid localization of a gravity signal transducer. Here we show that mutations in multiple genes encoding TOC complex components affect gravitropism in a genetically sensitized background and that the cytoplasmic acidic domain of Toc132 is not required for its involvement in this process. Furthermore, mutations in TOC132 enhance the gravitropic defect of a mutant whose amyloplasts lack starch. Finally, we show that the levels of several nuclear-encoded root proteins are altered in toc132 mutants. These data suggest that the TOC complex indirectly mediates gravity signal transduction in Arabidopsis and support the idea that plastids are involved in gravitropism not only through their ability to sediment but also as part of the signal transduction mechanism.

Multiple forms of rhythmic movements in an adolescent boy with rhythmic movement disorder.

PubMed

Su, Changjun; Miao, Jianting; Liu, Yu; Liu, Rui; Lei, Gesheng; Zhang, Wei; Yang, Ting; Li, Zhuyi

2009-12-01

Rhythmic movement disorder (RMD) refers to a group of stereotyped, repetitive movements involving large muscles, usually occurring prior to the onset of sleep and persisting into sleep. RMD more commonly exhibits only one or two forms of rhythmic movements (RM) in most reported cases. However, multiple RM forms of RMD occurring in a patient in the same night have rarely been reported. In this report, we present the unique case of a 15-year-old boy with RMD affected by multiple forms of RM in the same night, including four known forms (i.e., body rocking, head banging, leg rolling, and rhythmic feet movements) and two new kinds of RM (bilateral rhythmic arm rocking and rhythmic hands movements). Two video-polysomnographic recordings were performed in this patient before starting pharmacologic treatment and after long-term oral clonazepam treatment (1.0mg nightly for 3 months). The characteristics of RMD with multiple RM forms and the effectiveness of clonazepam on the RM episodes and polysomnographic findings observed in our patient are discussed. This report raises the fact that a patient with RMD may present with multiple complex rhythmic movements disrupting sleep, which emphasizes that better understanding of the clinical features of complex rhythmic movements during sleep in primary care settings is essential for early clinical diagnosis and optimal management.

The multiple imputation method: a case study involving secondary data analysis.

PubMed

Walani, Salimah R; Cleland, Charles M

2015-05-01

To illustrate with the example of a secondary data analysis study the use of the multiple imputation method to replace missing data. Most large public datasets have missing data, which need to be handled by researchers conducting secondary data analysis studies. Multiple imputation is a technique widely used to replace missing values while preserving the sample size and sampling variability of the data. The 2004 National Sample Survey of Registered Nurses. The authors created a model to impute missing values using the chained equation method. They used imputation diagnostics procedures and conducted regression analysis of imputed data to determine the differences between the log hourly wages of internationally educated and US-educated registered nurses. The authors used multiple imputation procedures to replace missing values in a large dataset with 29,059 observations. Five multiple imputed datasets were created. Imputation diagnostics using time series and density plots showed that imputation was successful. The authors also present an example of the use of multiple imputed datasets to conduct regression analysis to answer a substantive research question. Multiple imputation is a powerful technique for imputing missing values in large datasets while preserving the sample size and variance of the data. Even though the chained equation method involves complex statistical computations, recent innovations in software and computation have made it possible for researchers to conduct this technique on large datasets. The authors recommend nurse researchers use multiple imputation methods for handling missing data to improve the statistical power and external validity of their studies.

Six to Ten Digits Multiplication Fun Learning Using Puppet Prototype

NASA Astrophysics Data System (ADS)

Islamiah Rosli, D.'oria; Ali, Azita; Peng, Lim Soo; Sujardi, Imam; Usodo, Budi; Adie Perdana, Fengky

2017-01-01

Logic and technical subjects require students to understand basic knowledge in mathematic. For instance, addition, minus, division and multiplication operations need to be mastered by students due to mathematic complexity as the learning mathematic grows higher. Weak foundation in mathematic also contribute to high failure rate in mathematic subjects in schools. In fact, students in primary schools are struggling to learn mathematic because they need to memorize formulas, multiplication or division operations. To date, this study will develop a puppet prototyping for learning mathematic for six to ten digits multiplication. Ten participants involved in the process of developing the prototype in this study. Students involved in the study were those from the intermediate class students whilst teachers were selected based on their vast knowledge and experiences and have more than five years of experience in teaching mathematic. Close participatory analysis will be used in the prototyping process as to fulfil the requirements of the students and teachers whom will use the puppet in learning six to ten digit multiplication in mathematic. Findings showed that, the students had a great time and fun learning experience in learning multiplication and they able to understand the concept of multiplication using puppet. Colour and materials of the puppet also help to attract student attention during learning. Additionally, students able to visualized and able to calculate accurate multiplication value and the puppet help them to recall in multiplying and adding the digits accordingly.

Using three dimensional silicone ``boots`` to solve complex remedial design problems in curtain walls

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Y.J.

1998-12-31

Stick system curtain wall leak problems are frequently caused by water entry at the splice joints of the curtain wall frame and failure of the internal metal joinery seals. Remedial solutions involving occupied buildings inevitably face the multiple constraints of existing construction and business operations not present during the original curtain wall construction. In most cases, even partial disassembly of the curtain wall for internal seal repairs is not feasible. Remedial solutions which must be executed from the exterior of the curtain wall often involve wet-applied or preformed sealant tape bridge joints. However, some of the more complex joints cannotmore » be repaired effectively or economically with the conventional bridge joint. Fortunately, custom fabricated three-dimensional preformed sealant boots are becoming available to address these situations. This paper discusses the design considerations and the selective use of three-dimensional preformed boots in sealing complex joint geometry that would not be effective with the conventional two-dimensional bridge joint.« less

Next generation communications satellites: multiple access and network studies

NASA Technical Reports Server (NTRS)

Meadows, H. E.; Schwartz, M.; Stern, T. E.; Ganguly, S.; Kraimeche, B.; Matsuo, K.; Gopal, I.

1982-01-01

Efficient resource allocation and network design for satellite systems serving heterogeneous user populations with large numbers of small direct-to-user Earth stations are discussed. Focus is on TDMA systems involving a high degree of frequency reuse by means of satellite-switched multiple beams (SSMB) with varying degrees of onboard processing. Algorithms for the efficient utilization of the satellite resources were developed. The effect of skewed traffic, overlapping beams and batched arrivals in packet-switched SSMB systems, integration of stream and bursty traffic, and optimal circuit scheduling in SSMB systems: performance bounds and computational complexity are discussed.

Characterizing complex structural variation in germline and somatic genomes

PubMed Central

Quinlan, Aaron R.; Hall, Ira M.

2011-01-01

Genome structural variation (SV) is a major source of genetic diversity in mammals and a hallmark of cancer. While SV is typically defined by its canonical forms – duplication, deletion, insertion, inversion and translocation – recent breakpoint mapping studies have revealed a surprising number of “complex” variants that evade simple classification. Complex SVs are defined by clustered breakpoints that arose through a single mutation but cannot be explained by one simple end-joining or recombination event. Some complex variants exhibit profoundly complicated rearrangements between distinct loci from multiple chromosomes, while others involve more subtle alterations at a single locus. These diverse and unpredictable features present a challenge for SV mapping experiments. Here, we review current knowledge of complex SV in mammals, and outline techniques for identifying and characterizing complex variants using next-generation DNA sequencing. PMID:22094265

Structural insights into the rhabdovirus transcription/replication complex.

PubMed

Ivanov, Ivan; Yabukarski, Filip; Ruigrok, Rob W H; Jamin, Marc

2011-12-01

The rhabdoviruses have a non-segmented single stranded negative-sense RNA genome. Their multiplication in a host cell requires three viral proteins in addition to the viral RNA genome. The nucleoprotein (N) tightly encapsidates the viral RNA, and the N-RNA complex serves as the template for both transcription and replication. The viral RNA-dependent RNA polymerase is a two subunit complex that consists of a large subunit, L, and a non-catalytic cofactor, the phosphoprotein, P. P also acts as a chaperone of nascent RNA-free N by forming a N(0)-P complex that prevents N from binding to cellular RNAs and from polymerizing in the absence of RNA. Here, we discuss the recent molecular and structural studies of individual components and multi-molecular complexes that are involved in the transcription/replication complex of these viruses with regard to their implication in viral transcription and replication. Copyright © 2011 Elsevier B.V. All rights reserved.

Electrophysiological correlates of cocktail-party listening.

PubMed

Lewald, Jörg; Getzmann, Stephan

2015-10-01

Detecting, localizing, and selectively attending to a particular sound source of interest in complex auditory scenes composed of multiple competing sources is a remarkable capacity of the human auditory system. The neural basis of this so-called "cocktail-party effect" has remained largely unknown. Here, we studied the cortical network engaged in solving the "cocktail-party" problem, using event-related potentials (ERPs) in combination with two tasks demanding horizontal localization of a naturalistic target sound presented either in silence or in the presence of multiple competing sound sources. Presentation of multiple sound sources, as compared to single sources, induced an increased P1 amplitude, a reduction in N1, and a strong N2 component, resulting in a pronounced negativity in the ERP difference waveform (N2d) around 260 ms after stimulus onset. About 100 ms later, the anterior contralateral N2 subcomponent (N2ac) occurred in the multiple-sources condition, as computed from the amplitude difference for targets in the left minus right hemispaces. Cortical source analyses of the ERP modulation, resulting from the contrast of multiple vs. single sources, generally revealed an initial enhancement of electrical activity in right temporo-parietal areas, including auditory cortex, by multiple sources (at P1) that is followed by a reduction, with the primary sources shifting from right inferior parietal lobule (at N1) to left dorso-frontal cortex (at N2d). Thus, cocktail-party listening, as compared to single-source localization, appears to be based on a complex chronology of successive electrical activities within a specific cortical network involved in spatial hearing in complex situations. Copyright © 2015 Elsevier B.V. All rights reserved.

Operational Issues: What Science in Available?

NASA Technical Reports Server (NTRS)

Rosekind, Mark R.; Neri, David F.

1997-01-01

Flight/duty/rest considerations involve two highly complex factors: the diverse demands of aviation operations and human physiology (especially sleep and circadian rhythms). Several core operational issues related to fatigue have been identified, such as minimum rest requirements, duty length, flight time considerations, crossing multiple time zones, and night flying. Operations also can involve on-call reserve status and callout, delays due to unforeseen circumstances (e.g., weather, mechanical), and on-demand flights. Over 40 years of scientific research is now available to apply to these complex issues of flight/duty/rest requirements. This research involves controlled 'laboratory studies, simulations, and data collected during regular flight operations. When flight/duty/rest requirements are determined they are typically based on a variety of considerations, such as operational demand, safety, economic, etc. Rarely has the available, state-of-the-art science been a consideration along with these other factors when determining flight/duty/rest requirements. While the complexity of the operational demand and human physiology precludes an absolute solution, there is an opportunity to take full advantage of the current scientific data. Incorporating these data in a rational operational manner into flight/duty/rest requirements can improve flight crew performance, alertness, and ultimately, aviation safety.

Multiple Criteria Decision Analysis for Health Care Decision Making--Emerging Good Practices: Report 2 of the ISPOR MCDA Emerging Good Practices Task Force.

PubMed

Marsh, Kevin; IJzerman, Maarten; Thokala, Praveen; Baltussen, Rob; Boysen, Meindert; Kaló, Zoltán; Lönngren, Thomas; Mussen, Filip; Peacock, Stuart; Watkins, John; Devlin, Nancy

2016-01-01

Health care decisions are complex and involve confronting trade-offs between multiple, often conflicting objectives. Using structured, explicit approaches to decisions involving multiple criteria can improve the quality of decision making. A set of techniques, known under the collective heading, multiple criteria decision analysis (MCDA), are useful for this purpose. In 2014, ISPOR established an Emerging Good Practices Task Force. The task force's first report defined MCDA, provided examples of its use in health care, described the key steps, and provided an overview of the principal methods of MCDA. This second task force report provides emerging good-practice guidance on the implementation of MCDA to support health care decisions. The report includes: a checklist to support the design, implementation and review of an MCDA; guidance to support the implementation of the checklist; the order in which the steps should be implemented; illustrates how to incorporate budget constraints into an MCDA; provides an overview of the skills and resources, including available software, required to implement MCDA; and future research directions. Copyright © 2016 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Design Requirements for Communication-Intensive Interactive Applications

NASA Astrophysics Data System (ADS)

Bolchini, Davide; Garzotto, Franca; Paolini, Paolo

Online interactive applications call for new requirements paradigms to capture the growing complexity of computer-mediated communication. Crafting successful interactive applications (such as websites and multimedia) involves modeling the requirements for the user experience, including those leading to content design, usable information architecture and interaction, in profound coordination with the communication goals of all stakeholders involved, ranging from persuasion to social engagement, to call for action. To face this grand challenge, we propose a methodology for modeling communication requirements and provide a set of operational conceptual tools to be used in complex projects with multiple stakeholders. Through examples from real-life projects and lessons-learned from direct experience, we draw on the concepts of brand, value, communication goals, information and persuasion requirements to systematically guide analysts to master the multifaceted connections of these elements as drivers to inform successful communication designs.

Service user involvement enhanced the research quality in a study using interpretative phenomenological analysis - the power of multiple perspectives.

PubMed

Mjøsund, Nina Helen; Eriksson, Monica; Espnes, Geir Arild; Haaland-Øverby, Mette; Jensen, Sven Liang; Norheim, Irene; Kjus, Solveig Helene Høymork; Portaasen, Inger-Lill; Vinje, Hege Forbech

2017-01-01

The aim of this study was to examine how service user involvement can contribute to the development of interpretative phenomenological analysis methodology and enhance research quality. Interpretative phenomenological analysis is a qualitative methodology used in nursing research internationally to understand human experiences that are essential to the participants. Service user involvement is requested in nursing research. We share experiences from 4 years of collaboration (2012-2015) on a mental health promotion project, which involved an advisory team. Five research advisors either with a diagnosis or related to a person with severe mental illness constituted the team. They collaborated with the research fellow throughout the entire research process and have co-authored this article. We examined the joint process of analysing the empirical data from interviews. Our analytical discussions were audiotaped, transcribed and subsequently interpreted following the guidelines for good qualitative analysis in interpretative phenomenological analysis studies. The advisory team became 'the researcher's helping hand'. Multiple perspectives influenced the qualitative analysis, which gave more insightful interpretations of nuances, complexity, richness or ambiguity in the interviewed participants' accounts. The outcome of the service user involvement was increased breadth and depth in findings. Service user involvement improved the research quality in a nursing research project on mental health promotion. The interpretative element of interpretative phenomenological analysis was enhanced by the emergence of multiple perspectives in the qualitative analysis of the empirical data. We argue that service user involvement and interpretative phenomenological analysis methodology can mutually reinforce each other and strengthen qualitative methodology. © 2016 The Authors. Journal of Advanced Nursing Published by John Wiley & Sons Ltd.

U-insertion/deletion RNA editing multiprotein complexes and mitochondrial ribosomes in Leishmania tarentolae are located in antipodal nodes adjacent to the kinetoplast DNA.

PubMed

Wong, Richard G; Kazane, Katelynn; Maslov, Dmitri A; Rogers, Kestrel; Aphasizhev, Ruslan; Simpson, Larry

2015-11-01

We studied the intramitochondrial localization of several multiprotein complexes involved in U-insertion/deletion RNA editing in trypanosome mitochondria. The editing complexes are located in one or two antipodal nodes adjacent to the kinetoplast DNA (kDNA) disk, which are distinct from but associated with the minicircle catenation nodes. In some cases the proteins are in a bilateral sheet configuration. We also found that mitoribosomes have a nodal configuration. This type of organization is consistent with evidence for protein and RNA interactions of multiple editing complexes to form an ~40S editosome and also an interaction of editosomes with mitochondrial ribosomes. Copyright © 2015 Elsevier B.V. and Mitochondria Research Society. All rights reserved.

Anti-inflammatory genes associated with multiple sclerosis: a gene expression study.

PubMed

Perga, S; Montarolo, F; Martire, S; Berchialla, P; Malucchi, S; Bertolotto, A

2015-02-15

Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system caused by a complex interaction between multiple genes and environmental factors. HLA region is the strongest susceptibility locus, but recent huge genome-wide association studies identified new susceptibility genes. Among these, BACH2, PTGER4, RGS1 and ZFP36L1 were highlighted. Here, a gene expression analysis revealed that three of them, namely BACH2, PTGER4 and ZFP36L1, are down-regulated in MS patients' blood cells compared to healthy subjects. Interestingly, all these genes are involved in the immune system regulation with predominant anti-inflammatory role and their reduction could predispose to MS development. Copyright © 2015 Elsevier B.V. All rights reserved.

Enhancing the Temporal Complexity of Distributed Brain Networks with Patterned Cerebellar Stimulation

PubMed Central

Farzan, Faranak; Pascual-Leone, Alvaro; Schmahmann, Jeremy D.; Halko, Mark

2016-01-01

Growing evidence suggests that sensory, motor, cognitive and affective processes map onto specific, distributed neural networks. Cerebellar subregions are part of these networks, but how the cerebellum is involved in this wide range of brain functions remains poorly understood. It is postulated that the cerebellum contributes a basic role in brain functions, helping to shape the complexity of brain temporal dynamics. We therefore hypothesized that stimulating cerebellar nodes integrated in different networks should have the same impact on the temporal complexity of cortical signals. In healthy humans, we applied intermittent theta burst stimulation (iTBS) to the vermis lobule VII or right lateral cerebellar Crus I/II, subregions that prominently couple to the dorsal-attention/fronto-parietal and default-mode networks, respectively. Cerebellar iTBS increased the complexity of brain signals across multiple time scales in a network-specific manner identified through electroencephalography (EEG). We also demonstrated a region-specific shift in power of cortical oscillations towards higher frequencies consistent with the natural frequencies of targeted cortical areas. Our findings provide a novel mechanism and evidence by which the cerebellum contributes to multiple brain functions: specific cerebellar subregions control the temporal dynamics of the networks they are engaged in. PMID:27009405

Genetic constraints on wing pattern variation in Lycaeides butterflies: A case study on mapping complex, multifaceted traits in structured populations.

PubMed

Lucas, Lauren K; Nice, Chris C; Gompert, Zachariah

2018-03-13

Patterns of phenotypic variation within and among species can be shaped and constrained by trait genetic architecture. This is particularly true for complex traits, such as butterfly wing patterns, that consist of multiple elements. Understanding the genetics of complex trait variation across species boundaries is difficult, as it necessitates mapping in structured populations and can involve many loci with small or variable phenotypic effects. Here, we investigate the genetic architecture of complex wing pattern variation in Lycaeides butterflies as a case study of mapping multivariate traits in wild populations that include multiple nominal species or groups. We identify conserved modules of integrated wing pattern elements within populations and species. We show that trait covariances within modules have a genetic basis and thus represent genetic constraints that can channel evolution. Consistent with this, we find evidence that evolutionary changes in wing patterns among populations and species occur in the directions of genetic covariances within these groups. Thus, we show that genetic constraints affect patterns of biological diversity (wing pattern) in Lycaeides, and we provide an analytical template for similar work in other systems. © 2018 John Wiley & Sons Ltd.

Cellular and synaptic network defects in autism

PubMed Central

Peça, João; Feng, Guoping

2012-01-01

Many candidate genes are now thought to confer susceptibility to autism spectrum disorder (ASD). Here we review four interrelated complexes, each composed of multiple families of genes that functionally coalesce on common cellular pathways. We illustrate a common thread in the organization of glutamatergic synapses and suggest a link between genes involved in Tuberous Sclerosis Complex, Fragile X syndrome, Angelman syndrome and several synaptic ASD candidate genes. When viewed in this context, progress in deciphering the molecular architecture of cellular protein-protein interactions together with the unraveling of synaptic dysfunction in neural networks may prove pivotal to advancing our understanding of ASDs. PMID:22440525

Current Concepts of Cardiac Amyloidosis: Diagnosis, Clinical Management, and the Need for Collaboration.

PubMed

Ritts, Alexandra J; Cornell, Robert F; Swiger, Kris; Singh, Jai; Goodman, Stacey; Lenihan, Daniel J

2017-04-01

Cardiac amyloidosis is a complex and vexing clinical condition that requires a high degree of suspicion for the diagnosis with a substantial amount of discipline to discern the extent of disease and the best available therapy. There is a complex interplay between multiple organ systems, and the clinical presentation may involve a myriad of confusing clinical symptoms. The diagnosis of cardiac amyloidosis can be confirmed with a combination of physical findings, cardiac biomarkers, noninvasive testing, and, if necessary, myocardial biopsy. Genetic testing is critical to establish the type of amyloidosis. Copyright © 2016 Elsevier Inc. All rights reserved.

Insights into aquatic toxicities of the antibiotics oxytetracycline and ciprofloxacin in the presence of metal: complexation versus mixture.

PubMed

Zhang, Yu; Cai, Xiyun; Lang, Xianming; Qiao, Xianliang; Li, Xuehua; Chen, Jingwen

2012-07-01

Co-contamination of ligand-like antibiotics (e.g., tetracyclines and quinolones) and heavy metals prevails in the environment, and thus the complexation between them is involved in environmental risks of antibiotics. To understand toxicological significance of the complex, effects of metal coordination on antibiotics' toxicity were investigated. The complexation of two antibiotics, oxytetracycline and ciprofloxacin, with three heavy metals, copper, zinc, and cadmium, was verified by spectroscopic techniques. The antibiotics bound metals via multiple coordination sites and rendered a mixture of various complexation speciations. Toxicity analysis indicated that metal coordination did modify the toxicity of the antibiotics and that antibiotic, metal, and their complex acted primarily as concentration addition. Comparison of EC(50) values revealed that the complex commonly was highest toxic and predominately correlated in toxicity to the mixture. Finally, environmental scenario analysis demonstrated that ignoring complexation would improperly classify environmental risks of the antibiotics. Copyright © 2012 Elsevier Ltd. All rights reserved.

[Occupational complexity and late-life memory and reasoning abilities].

PubMed

Ishioka, Yoshiko; Gondo, Yasuyuki; Masui, Yukie; Nakagawa, Takeshi; Tabuchi, Megumi; Ogawa, Madoka; Kamide, Kei; Ikebe, Kazunori; Arai, Yasumichi; Ishizaki, Tatsuro; Takahashi, Ryutaro

2015-08-01

This study examined the associations between the complexity of an individual's primary lifetime occupation and his or her late-life memory and reasoning performance, using data from 824 community-dwelling participants aged 69-72 years. The complexity of work with data, people, and things was evaluated based on the Japanese job complexity score. The associations between occupational complexity and participant's memory and reasoning abilities were examined in multiple regression analyses. An association was found between more comple work with people and higher memory performance, as well as between more complex work with data and higher reasoning performance, after having controlled for gender, school records, and education. Further, an interaction effect was observed between gender and complexity of work with data in relation to reasoning performance: work involving a high degree of complexity with data was associated with high reasoning performance in men. These findings suggest the need to consider late-life cognitive functioning within the context of adulthood experiences, specifically those related to occupation and gender.

Testing of Environmental Satellite Bus-Instrument Interfaces Using Engineering Models

NASA Technical Reports Server (NTRS)

Gagnier, Donald; Hayner, Rick; Nosek, Thomas; Roza, Michael; Hendershot, James E.; Razzaghi, Andrea I.

2004-01-01

This paper discusses the formulation and execution of a laboratory test of the electrical interfaces between multiple atmospheric scientific instruments and the spacecraft bus that carries them. The testing, performed in 2002, used engineering models of the instruments and the Aura spacecraft bus electronics. Aura is one of NASA s Earth Observatory System missions. The test was designed to evaluate the complex interfaces in the command and data handling subsystems prior to integration of the complete flight instruments on the spacecraft. A problem discovered during the flight integration phase of the observatory can cause significant cost and schedule impacts. The tests successfully revealed problems and led to their resolution before the full-up integration phase, saving significant cost and schedule. This approach could be beneficial for future environmental satellite programs involving the integration of multiple, complex scientific instruments onto a spacecraft bus.

Finding order in complexity: themes from the career of Dr. Robert F. Wagner

NASA Astrophysics Data System (ADS)

Myers, Kyle J.

2009-02-01

Over the course of his long and productive career, Dr. Robert F. Wagner built a framework for the evaluation of imaging systems based on a task-based, decision theoretic approach. His most recent contributions involved the consideration of the random effects associated with multiple readers of medical images and the logical extension of this work to the problem of the evaluation of multiple competing classifiers in statistical pattern recognition. This contemporary work expanded on familiar themes from Bob's many SPIE presentations in earlier years. It was driven by the need for practical solutions to current problems facing FDA'S Center for Devices and Radiological Health and the medical imaging community regarding the assessment of new computer-aided diagnosis tools and Bob's unique ability to unify concepts across a range of disciplines as he gave order to increasingly complex problems in our field.

Microcontroller-based real-time QRS detection.

PubMed

Sun, Y; Suppappola, S; Wrublewski, T A

1992-01-01

The authors describe the design of a system for real-time detection of QRS complexes in the electrocardiogram based on a single-chip microcontroller (Motorola 68HC811). A systematic analysis of the instrumentation requirements for QRS detection and of the various design techniques is also given. Detection algorithms using different nonlinear transforms for the enhancement of QRS complexes are evaluated by using the ECG database of the American Heart Association. The results show that the nonlinear transform involving multiplication of three adjacent, sign-consistent differences in the time domain gives a good performance and a quick response. When implemented with an appropriate sampling rate, this algorithm is also capable of rejecting pacemaker spikes. The eight-bit single-chip microcontroller provides sufficient throughput and shows a satisfactory performance. Implementation of multiple detection algorithms in the same system improves flexibility and reliability. The low chip count in the design also favors maintainability and cost-effectiveness.

A CFD study of complex missile and store configurations in relative motion

NASA Technical Reports Server (NTRS)

Baysal, Oktay

1995-01-01

An investigation was conducted from May 16, 1990 to August 31, 1994 on the development of computational fluid dynamics (CFD) methodologies for complex missiles and the store separation problem. These flowfields involved multiple-component configurations, where at least one of the objects was engaged in relative motion. The two most important issues that had to be addressed were: (1) the unsteadiness of the flowfields (time-accurate and efficient CFD algorithms for the unsteady equations), and (2) the generation of grid systems which would permit multiple and moving bodies in the computational domain (dynamic domain decomposition). The study produced two competing and promising methodologies, and their proof-of-concept cases, which have been reported in the open literature: (1) Unsteady solutions on dynamic, overlapped grids, which may also be perceived as moving, locally-structured grids, and (2) Unsteady solutions on dynamic, unstructured grids.

Matching multiple rigid domain decompositions of proteins

PubMed Central

Flynn, Emily; Streinu, Ileana

2017-01-01

We describe efficient methods for consistently coloring and visualizing collections of rigid cluster decompositions obtained from variations of a protein structure, and lay the foundation for more complex setups that may involve different computational and experimental methods. The focus here is on three biological applications: the conceptually simpler problems of visualizing results of dilution and mutation analyses, and the more complex task of matching decompositions of multiple NMR models of the same protein. Implemented into the KINARI web server application, the improved visualization techniques give useful information about protein folding cores, help examining the effect of mutations on protein flexibility and function, and provide insights into the structural motions of PDB proteins solved with solution NMR. These tools have been developed with the goal of improving and validating rigidity analysis as a credible coarse-grained model capturing essential information about a protein’s slow motions near the native state. PMID:28141528

Materials science. Assembly of micro/nanomaterials into complex, three-dimensional architectures by compressive buckling.

PubMed

Xu, Sheng; Yan, Zheng; Jang, Kyung-In; Huang, Wen; Fu, Haoran; Kim, Jeonghyun; Wei, Zijun; Flavin, Matthew; McCracken, Joselle; Wang, Renhan; Badea, Adina; Liu, Yuhao; Xiao, Dongqing; Zhou, Guoyan; Lee, Jungwoo; Chung, Ha Uk; Cheng, Huanyu; Ren, Wen; Banks, Anthony; Li, Xiuling; Paik, Ungyu; Nuzzo, Ralph G; Huang, Yonggang; Zhang, Yihui; Rogers, John A

2015-01-09

Complex three-dimensional (3D) structures in biology (e.g., cytoskeletal webs, neural circuits, and vasculature networks) form naturally to provide essential functions in even the most basic forms of life. Compelling opportunities exist for analogous 3D architectures in human-made devices, but design options are constrained by existing capabilities in materials growth and assembly. We report routes to previously inaccessible classes of 3D constructs in advanced materials, including device-grade silicon. The schemes involve geometric transformation of 2D micro/nanostructures into extended 3D layouts by compressive buckling. Demonstrations include experimental and theoretical studies of more than 40 representative geometries, from single and multiple helices, toroids, and conical spirals to structures that resemble spherical baskets, cuboid cages, starbursts, flowers, scaffolds, fences, and frameworks, each with single- and/or multiple-level configurations. Copyright © 2015, American Association for the Advancement of Science.

Heterogeneity of reward mechanisms.

PubMed

Lajtha, A; Sershen, H

2010-06-01

The finding that many drugs that have abuse potential and other natural stimuli such as food or sexual activity cause similar chemical changes in the brain, an increase in extracellular dopamine (DA) in the shell of the nucleus accumbens (NAccS), indicated some time ago that the reward mechanism is at least very similar for all stimuli and that the mechanism is relatively simple. The presently available information shows that the mechanisms involved are more complex and have multiple elements. Multiple brain regions, multiple receptors, multiple distinct neurons, multiple transmitters, multiple transporters, circuits, peptides, proteins, metabolism of transmitters, and phosphorylation, all participate in reward mechanisms. The system is variable, is changed during development, is sex-dependent, and is influenced by genetic differences. Not all of the elements participate in the reward of all stimuli. Different set of mechanisms are involved in the reward of different drugs of abuse, yet different mechanisms in the reward of natural stimuli such as food or sexual activity; thus there are different systems that distinguish different stimuli. Separate functions of the reward system such as anticipation, evaluation, consummation and identification; all contain function-specific elements. The level of the stimulus also influences the participation of the elements of the reward system, there are possible reactions to even below threshold stimuli, and excessive stimuli can change reward to aversion involving parts of the system. Learning and memory of past reward is an important integral element of reward and addictive behavior. Many of the reward elements are altered by repeated or chronic stimuli, and chronic exposure to one drug is likely to alter the response to another stimulus. To evaluate and identify the reward stimulus thus requires heterogeneity of the reward components in the brain.

A multiple-point geostatistical approach to quantifying uncertainty for flow and transport simulation in geologically complex environments

NASA Astrophysics Data System (ADS)

Cronkite-Ratcliff, C.; Phelps, G. A.; Boucher, A.

2011-12-01

In many geologic settings, the pathways of groundwater flow are controlled by geologic heterogeneities which have complex geometries. Models of these geologic heterogeneities, and consequently, their effects on the simulated pathways of groundwater flow, are characterized by uncertainty. Multiple-point geostatistics, which uses a training image to represent complex geometric descriptions of geologic heterogeneity, provides a stochastic approach to the analysis of geologic uncertainty. Incorporating multiple-point geostatistics into numerical models provides a way to extend this analysis to the effects of geologic uncertainty on the results of flow simulations. We present two case studies to demonstrate the application of multiple-point geostatistics to numerical flow simulation in complex geologic settings with both static and dynamic conditioning data. Both cases involve the development of a training image from a complex geometric description of the geologic environment. Geologic heterogeneity is modeled stochastically by generating multiple equally-probable realizations, all consistent with the training image. Numerical flow simulation for each stochastic realization provides the basis for analyzing the effects of geologic uncertainty on simulated hydraulic response. The first case study is a hypothetical geologic scenario developed using data from the alluvial deposits in Yucca Flat, Nevada. The SNESIM algorithm is used to stochastically model geologic heterogeneity conditioned to the mapped surface geology as well as vertical drill-hole data. Numerical simulation of groundwater flow and contaminant transport through geologic models produces a distribution of hydraulic responses and contaminant concentration results. From this distribution of results, the probability of exceeding a given contaminant concentration threshold can be used as an indicator of uncertainty about the location of the contaminant plume boundary. The second case study considers a characteristic lava-flow aquifer system in Pahute Mesa, Nevada. A 3D training image is developed by using object-based simulation of parametric shapes to represent the key morphologic features of rhyolite lava flows embedded within ash-flow tuffs. In addition to vertical drill-hole data, transient pressure head data from aquifer tests can be used to constrain the stochastic model outcomes. The use of both static and dynamic conditioning data allows the identification of potential geologic structures that control hydraulic response. These case studies demonstrate the flexibility of the multiple-point geostatistics approach for considering multiple types of data and for developing sophisticated models of geologic heterogeneities that can be incorporated into numerical flow simulations.

Using the Context, Input, Process, and Product Evaluation Model (CIPP) as a Comprehensive Framework to Guide the Planning, Implementation, and Assessment of Service-Learning Programs

ERIC Educational Resources Information Center

Zhang, Guili; Zeller, Nancy; Griffith, Robin; Metcalf, Debbie; Williams, Jennifer; Shea, Christine; Misulis, Katherine

2011-01-01

Planning, implementing, and assessing a service-learning project can be a complex task because service-learning projects often involve multiple constituencies and aim to meet both the needs of service providers and community partners. In this article, Stufflebeam's Context, Input, Process, and Product (CIPP) evaluation model is recommended as a…

Special Educators as Intervention Specialists: Dynamic Systems and the Complexity of Intensifying Intervention for Students With Emotional and Behavioral Disorders

ERIC Educational Resources Information Center

Farmer, Thomas W.; Sutherland, Kevin S.; Talbott, Elizabeth; Brooks, Debbie S.; Norwalk, Kate; Huneke, Michelle

2016-01-01

We present a dynamic systems perspective for the intensification of interventions for students with emotional and behavioral disorders (EBD). With this framework, we suggest behavior involves the contributions of multiple factors and reflects the interplay between the characteristics of the student and the ecologies in which he or she is embedded.…

Using Principal-Agent Theory as a Framework for Analysis in Evaluating the Multiple Stakeholders Involved in the Accreditation and Quality Assurance of International Medical Branch Campuses

ERIC Educational Resources Information Center

Borgos, Jill E.

2013-01-01

This article applies the theoretical framework of principal-agent theory in order to better understand the complex organisational relationships emerging between entities invested in the establishment and monitoring of cross-border international branch campus medical schools. Using the key constructs of principal-agent theory, information asymmetry…

Evaluation of a Technology for Teaching Complex Social Skills to Young Adults with Visual and Cognitive Impairments.

ERIC Educational Resources Information Center

Gumpel, Thomas P.; Nativ-Ari-Am, Hagit

2001-01-01

Two multiple baseline designs were used to evaluate a two-stage model for training four young adults with visual and cognitive impairments to grocery shop. A task-analytical flow chart of the behavioral skills involved in grocery shopping was used to increase completed skill steps and the number of correct items purchased. (Contains references.)…

Opportunities and challenges for carbon management on U.S. public lands. Chapter 18

Treesearch

Lisa Dilling; Richard Birdsey; Yude Pan

2013-01-01

Public lands are important constituents of the U.S. carbon (C) balance because they encompass large areas of forests and rangelands, although whether and how C might be actively managed on public lands is not yet clear. A decision to manage public lands for their C benefits would involve a complex set of interacting drivers and multiple jurisdictions, and would, as...

Genetic architecture of hybrid male sterility in Drosophila: analysis of intraspecies variation for interspecies isolation.

PubMed

Reed, Laura K; LaFlamme, Brooke A; Markow, Therese A

2008-08-27

The genetic basis of postzygotic isolation is a central puzzle in evolutionary biology. Evolutionary forces causing hybrid sterility or inviability act on the responsible genes while they still are polymorphic, thus we have to study these traits as they arise, before isolation is complete. Isofemale strains of D. mojavensis vary significantly in their production of sterile F(1) sons when females are crossed to D. arizonae males. We took advantage of the intraspecific polymorphism, in a novel design, to perform quantitative trait locus (QTL) mapping analyses directly on F(1) hybrid male sterility itself. We found that the genetic architecture of the polymorphism for hybrid male sterility (HMS) in the F(1) is complex, involving multiple QTL, epistasis, and cytoplasmic effects. The role of extensive intraspecific polymorphism, multiple QTL, and epistatic interactions in HMS in this young species pair shows that HMS is arising as a complex trait in this system. Directional selection alone would be unlikely to maintain polymorphism at multiple loci, thus we hypothesize that directional selection is unlikely to be the only evolutionary force influencing postzygotic isolation.

Long genes and genes with multiple splice variants are enriched in pathways linked to cancer and other multigenic diseases.

PubMed

Sahakyan, Aleksandr B; Balasubramanian, Shankar

2016-03-12

The role of random mutations and genetic errors in defining the etiology of cancer and other multigenic diseases has recently received much attention. With the view that complex genes should be particularly vulnerable to such events, here we explore the link between the simple properties of the human genes, such as transcript length, number of splice variants, exon/intron composition, and their involvement in the pathways linked to cancer and other multigenic diseases. We reveal a substantial enrichment of cancer pathways with long genes and genes that have multiple splice variants. Although the latter two factors are interdependent, we show that the overall gene length and splicing complexity increase in cancer pathways in a partially decoupled manner. Our systematic survey for the pathways enriched with top lengthy genes and with genes that have multiple splice variants reveal, along with cancer pathways, the pathways involved in various neuronal processes, cardiomyopathies and type II diabetes. We outline a correlation between the gene length and the number of somatic mutations. Our work is a step forward in the assessment of the role of simple gene characteristics in cancer and a wider range of multigenic diseases. We demonstrate a significant accumulation of long genes and genes with multiple splice variants in pathways of multigenic diseases that have already been associated with de novo mutations. Unlike the cancer pathways, we note that the pathways of neuronal processes, cardiomyopathies and type II diabetes contain genes long enough for topoisomerase-dependent gene expression to also be a potential contributing factor in the emergence of pathologies, should topoisomerases become impaired.

[Being cared for and caring: living with multiple chronic diseases (Leila)-a qualitative study about APN contributions to integrated care].

PubMed

Müller-Staub, Maria; Zigan, Nicole; Händler-Schuster, Daniela; Probst, Sebastian; Monego, Renate; Imhof, Lorenz

2015-04-01

Living with multiple chronic diseases is complex and leads to enhanced care needs. To foster integrated care a project called "Living with chronic disease" (Leila) was initiated. The aim was to develop an Advanced Practice Nursing (APN) service in collaboration with medical centers for persons who are living with multiple chronic diseases. The following research questions were addressed: 1. What are patients' experiences, referring physicians and APNs with the Leila-Service? 2. How are referral processes performed? 3. How do the involved groups experience collaboration and APN role development? A qualitative approach according grounded theory of Corbin and Strauss was used to explore the experiences with the Leila project and the interaction of the persons involved. 38 interviews were conducted with patients who are living with multiple chronic diseases, their APN's and the referring physicians. The findings revealed "Being cared for and caring" as main category. The data demonstrated how patients responded to their involvement into care and that they were taken as serious partners in the care process. The category "organizing everyday life" describes how patients learned to cope with the consequences of living with multiple chronic diseases. "Using all resources" as another category demonstrates how capabilities and strengths were adopted. The results of the cooperation- and allocation processes showed that the APN recognition and APN role performance have to be negotiated. Prospective APN-services for this patient population should be integrated along with physician networks and other service providers including community health nursing.

Advances in Tourette syndrome: diagnoses and treatment.

PubMed

Serajee, Fatema J; Mahbubul Huq, A H M

2015-06-01

Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder characterized by multiple motor tics and at least one vocal or phonic tic, and often one or more comorbid psychiatric disorders. Premonitory sensory urges before tic execution and desire for "just-right" perception are central features. The pathophysiology involves cortico-striato-thalamo-cortical circuits and possibly dopaminergic system. TS is considered a genetic disorder but the genetics is complex and likely involves rare mutations, common variants, and environmental and epigenetic factors. Treatment is multimodal and includes education and reassurance, behavioral interventions, pharmacologic, and rarely, surgical interventions. Copyright © 2015 Elsevier Inc. All rights reserved.

Murine natural killer immunoreceptors use distinct proximal signaling complexes to direct cell function

PubMed Central

May, Rebecca M.; Okumura, Mariko; Hsu, Chin-Jung; Bassiri, Hamid; Yang, Enjun; Rak, Gregory; Mace, Emily M.; Philip, Naomi H.; Zhang, Weiguo; Baumgart, Tobias; Orange, Jordan S.; Nichols, Kim E.

2013-01-01

Signaling pathways leading to natural killer (NK)–cell effector function are complex and incompletely understood. Here, we investigated the proximal signaling pathways downstream of the immunotyrosine-based activation motif (ITAM) bearing activating receptors. We found that the adaptor molecule SH2 domain-containing leukocyte protein of 76 kD (SLP-76) is recruited to microclusters at the plasma membrane in activated NK cells and that this is required for initiation of downstream signaling and multiple NK-cell effector functions in vitro and in vivo. Surprisingly, we found that 2 types of proximal signaling complexes involving SLP-76 were formed. In addition to the canonical membrane complex formed between SLP-76 and linker for activation of T cells (LAT) family members, a novel LAT family–independent SLP-76–dependent signaling pathway was identified. The LAT family–independent pathway involved the SH2 domain of SLP-76 and adhesion and degranulation-promoting adaptor protein (ADAP). Both the LAT family–dependent and ADAP-dependent pathway contributed to interferon-gamma production and cytotoxicity; however, they were not essential for other SLP-76–dependent events, including phosphorylation of AKT and extracellular signal–related kinase and cellular proliferation. These results demonstrate that NK cells possess an unexpected bifurcation of proximal ITAM-mediated signaling, each involving SLP-76 and contributing to optimal NK-cell function. PMID:23407547

Key aspects in managing safety when working with multiple contractors: A case study.

PubMed

Drupsteen, Linda; Rasmussen, Hanna B; Ustailieva, Erika; van Kampen, Jakko

2015-01-01

Working with multiple contractors in a shared workplace can introduce and increase safety risks due to complexity. The aim of this study was to explore how safety issues are recognized in a specific case and to identify whether clients and contractors perceive problems similarly. The safety issues are explored through a brief survey and a workshop in the maintenance department of a logistics company. The results indicate that culture and behavior are recognized differently by clients and by contractors. The contractors and client had different perceptions of involvement of contractors by the client. The contractors complained on lack of involvement, which was not fully recognized by the client. The case study used a practical approach to show differences in perception of safety within a project. The study illustrates the need for more applied studies and interventions on contractor safety.

Mpp10 represents a platform for the interaction of multiple factors within the 90S pre-ribosome

PubMed Central

Kharde, Satyavati; Ahmed, Yasar Luqman; Stier, Gunter; Kunze, Ruth; Sinning, Irmgard

2017-01-01

In eukaryotes, ribosome assembly is a highly complex process that involves more than 200 assembly factors that ensure the folding, modification and processing of the different rRNA species as well as the timely association of ribosomal proteins. One of these factors, Mpp10 associates with Imp3 and Imp4 to form a complex that is essential for the normal production of the 18S rRNA. Here we report the crystal structure of a complex between Imp4 and a short helical element of Mpp10 to a resolution of 1.88 Å. Furthermore, we extend the interaction network of Mpp10 and characterize two novel interactions. Mpp10 is able to bind the ribosome biogenesis factor Utp3/Sas10 through two conserved motifs in its N-terminal region. In addition, Mpp10 interacts with the ribosomal protein S5/uS7 using a short stretch within an acidic loop region. Thus, our findings reveal that Mpp10 provides a platform for the simultaneous interaction with multiple proteins in the 90S pre-ribosome. PMID:28813493

Characterize kinematic rupture history of large earthquakes with Multiple Haskell sources

NASA Astrophysics Data System (ADS)

Jia, Z.; Zhan, Z.

2017-12-01

Earthquakes are often regarded as continuous rupture along a single fault, but the occurrence of complex large events involving multiple faults and dynamic triggering challenges this view. Such rupture complexities cause difficulties in existing finite fault inversion algorithms, because they rely on specific parameterizations and regularizations to obtain physically meaningful solutions. Furthermore, it is difficult to assess reliability and uncertainty of obtained rupture models. Here we develop a Multi-Haskell Source (MHS) method to estimate rupture process of large earthquakes as a series of sub-events of varying location, timing and directivity. Each sub-event is characterized by a Haskell rupture model with uniform dislocation and constant unilateral rupture velocity. This flexible yet simple source parameterization allows us to constrain first-order rupture complexity of large earthquakes robustly. Additionally, relatively few parameters in the inverse problem yields improved uncertainty analysis based on Markov chain Monte Carlo sampling in a Bayesian framework. Synthetic tests and application of MHS method on real earthquakes show that our method can capture major features of large earthquake rupture process, and provide information for more detailed rupture history analysis.

Fluoxetine and norfluoxetine mediated complex drug-drug interactions: in vitro to in vivo correlation of effects on CYP2D6, CYP2C19 and CYP3A4

PubMed Central

Sager, Jennifer E; Lutz, Justin D; Foti, Robert S; Davis, Connie; Kunze, Kent L; Isoherranen, Nina

2014-01-01

Fluoxetine and its circulating metabolite norfluoxetine present a complex multiple inhibitor system that causes reversible or time-dependent inhibition of CYP2D6, CYP3A4, and CYP2C19 in vitro. While significant inhibition of all three enzymes in vivo is predicted, midazolam and lovastatin AUCs were unaffected by two week dosing of fluoxetine whereas dextromethorphan AUC was increased by 27-fold and omeprazole AUC by 7.1-fold. This observed discrepancy between in vitro risk assessment and in vivo DDI profile was rationalized by time-varying dynamic pharmacokinetic models that incorporated circulating concentrations of fluoxetine and norfluoxetine enantiomers, mutual inhibitor-inhibitor interactions and CYP3A4 induction. The dynamic models predicted all DDIs with less than 2-fold error. This study demonstrates that complex drug-drug interactions that involve multiple mechanisms, pathways and inhibitors with their metabolites can be predicted and rationalized via characterization of all the inhibitory species in vitro. PMID:24569517

Transcriptome analysis reveals the complexity of alternative splicing regulation in the fungus Verticillium dahliae.

PubMed

Jin, Lirong; Li, Guanglin; Yu, Dazhao; Huang, Wei; Cheng, Chao; Liao, Shengjie; Wu, Qijia; Zhang, Yi

2017-02-06

Alternative splicing (AS) regulation is extensive and shapes the functional complexity of higher organisms. However, the contribution of alternative splicing to fungal biology is not well studied. This study provides sequences of the transcriptomes of the plant wilt pathogen Verticillium dahliae, using two different strains and multiple methods for cDNA library preparations. We identified alternatively spliced mRNA isoforms in over a half of the multi-exonic fungal genes. Over one-thousand isoforms involve TopHat novel splice junction; multiple types of combinatory alternative splicing patterns were identified. We showed that one Verticillium gene could use four different 5' splice sites and two different 3' donor sites to produce up to five mature mRNAs, representing one of the most sophisticated alternative splicing model in eukaryotes other than animals. Hundreds of novel intron types involving a pair of new splice sites were identified in the V. dahliae genome. All the types of AS events were validated by using RT-PCR. Functional enrichment analysis showed that AS genes are involved in most known biological functions and enriched in ATP biosynthesis, sexual/asexual reproduction, morphogenesis, signal transduction etc., predicting that the AS regulation modulates mRNA isoform output and shapes the V. dahliae proteome plasticity of the pathogen in response to the environmental and developmental changes. These findings demonstrate the comprehensive alternative splicing mechanisms in a fungal plant pathogen, which argues the importance of this fungus in developing complicate genome regulation strategies in eukaryotes.

Structural determinants of APOBEC3B non-catalytic domain for molecular assembly and catalytic regulation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xiao, Xiao; Yang, Hanjing; Arutiunian, Vagan

The catalytic activity of human cytidine deaminase APOBEC3B (A3B) has been correlated with kataegic mutational patterns within multiple cancer types. The molecular basis of how the N-terminal non-catalytic CD1 regulates the catalytic activity and consequently, biological function of A3B remains relatively unknown. Here, we report the crystal structure of a soluble human A3B-CD1 variant and delineate several structural elements of CD1 involved in molecular assembly, nucleic acid interactions and catalytic regulation of A3B. We show that (i) A3B expressed in human cells exists in hypoactive high-molecular-weight (HMW) complexes, which can be activated without apparent dissociation into low-molecular-weight (LMW) species aftermore » RNase A treatment. (ii) Multiple surface hydrophobic residues of CD1 mediate the HMW complex assembly and affect the catalytic activity, including one tryptophan residue W127 that likely acts through regulating nucleic acid binding. (iii) One of the highly positively charged surfaces on CD1 is involved in RNA-dependent attenuation of A3B catalysis. (iv) Surface hydrophobic residues of CD1 are involved in heterogeneous nuclear ribonucleoproteins (hnRNPs) binding to A3B. The structural and biochemical insights described here suggest that unique structural features on CD1 regulate the molecular assembly and catalytic activity of A3B through distinct mechanisms.« less

STRIPAK complexes: structure, biological function, and involvement in human diseases.

PubMed

Hwang, Juyeon; Pallas, David C

2014-02-01

The mammalian striatin family consists of three proteins, striatin, S/G2 nuclear autoantigen, and zinedin. Striatin family members have no intrinsic catalytic activity, but rather function as scaffolding proteins. Remarkably, they organize multiple diverse, large signaling complexes that participate in a variety of cellular processes. Moreover, they appear to be regulatory/targeting subunits for the major eukaryotic serine/threonine protein phosphatase 2A. In addition, striatin family members associate with germinal center kinase III kinases as well as other novel components, earning these assemblies the name striatin-interacting phosphatase and kinase (STRIPAK) complexes. Recently, there has been a great increase in functional and mechanistic studies aimed at identifying and understanding the roles of STRIPAK and STRIPAK-like complexes in cellular processes of multiple organisms. These studies have identified novel STRIPAK and STRIPAK-like complexes and have explored their roles in specific signaling pathways. Together, the results of these studies have sparked increased interest in striatin family complexes because they have revealed roles in signaling, cell cycle control, apoptosis, vesicular trafficking, Golgi assembly, cell polarity, cell migration, neural and vascular development, and cardiac function. Moreover, STRIPAK complexes have been connected to clinical conditions, including cardiac disease, diabetes, autism, and cerebral cavernous malformation. In this review, we discuss the expression, localization, and protein domain structure of striatin family members. Then we consider the diverse complexes these proteins and their homologs form in various organisms, emphasizing what is known regarding function and regulation. Finally, we explore possible roles of striatin family complexes in disease, especially cerebral cavernous malformation. Copyright © 2013 Elsevier Ltd. All rights reserved.

Mitochondrial Ca2+ influx targets cardiolipin to disintegrate respiratory chain complex II for cell death induction

PubMed Central

Hwang, M-S; Schwall, C T; Pazarentzos, E; Datler, C; Alder, N N; Grimm, S

2014-01-01

Massive Ca2+ influx into mitochondria is critically involved in cell death induction but it is unknown how this activates the organelle for cell destruction. Using multiple approaches including subcellular fractionation, FRET in intact cells, and in vitro reconstitutions, we show that mitochondrial Ca2+ influx prompts complex II of the respiratory chain to disintegrate, thereby releasing an enzymatically competent sub-complex that generates excessive reactive oxygen species (ROS) for cell death induction. This Ca2+-dependent dissociation of complex II is also observed in model membrane systems, but not when cardiolipin is replaced with a lipid devoid of Ca2+ binding. Cardiolipin is known to associate with complex II and upon Ca2+ binding coalesces into separate homotypic clusters. When complex II is deprived of this lipid, it disintegrates for ROS formation and cell death. Our results reveal Ca2+ binding to cardiolipin for complex II disintegration as a pivotal step for oxidative stress and cell death induction. PMID:24948011

Facilitated Protein Association via Engineered Target Search Pathways Visualized by Paramagnetic NMR Spectroscopy.

PubMed

An, So Young; Kim, Eun-Hee; Suh, Jeong-Yong

2018-06-05

Proteins assemble to form functional complexes via the progressive evolution of nonspecific complexes formed by transient encounters. This target search process generally involves multiple routes that lead the initial encounters to the final complex. In this study, we have employed NMR paramagnetic relaxation enhancement to visualize the encounter complexes between histidine-containing phosphocarrier protein and the N-terminal domain of enzyme I and demonstrate that protein association can be significantly enhanced by engineering on-pathways. Specifically, mutations in surface charges away from the binding interface can elicit new on-pathway encounter complexes, increasing their binding affinity by an order of magnitude. The structure of these encounter complexes indicates that such on-pathways extend the built-in target search process of the native protein complex. Furthermore, blocking on-pathways by countering mutations reverts their binding affinity. Our study thus illustrates that protein interactions can be engineered by rewiring the target search process. Copyright © 2018 Elsevier Ltd. All rights reserved.

A simple and fast representation space for classifying complex time series

NASA Astrophysics Data System (ADS)

Zunino, Luciano; Olivares, Felipe; Bariviera, Aurelio F.; Rosso, Osvaldo A.

2017-03-01

In the context of time series analysis considerable effort has been directed towards the implementation of efficient discriminating statistical quantifiers. Very recently, a simple and fast representation space has been introduced, namely the number of turning points versus the Abbe value. It is able to separate time series from stationary and non-stationary processes with long-range dependences. In this work we show that this bidimensional approach is useful for distinguishing complex time series: different sets of financial and physiological data are efficiently discriminated. Additionally, a multiscale generalization that takes into account the multiple time scales often involved in complex systems has been also proposed. This multiscale analysis is essential to reach a higher discriminative power between physiological time series in health and disease.

Dissection of the complex genetic basis of craniofacial anomalies using haploid genetics and interspecies hybrids in Nasonia wasps

PubMed Central

Werren, John H.; Cohen, Lorna B.; Gadau, Juergen; Ponce, Rita; Baudry, Emmanuelle; Lynch, Jeremy A.

2016-01-01

The animal head is a complex structure where numerous sensory, structural and alimentary structures are concentrated and integrated, and its ontogeny requires precise and delicate interactions among genes, cells, and tissues. Thus, it is perhaps unsurprising that craniofacial abnormalities are among the most common birth defects in people, or that these defects have a complex genetic basis involving interactions among multiple loci. Developmental processes that depend on such epistatic interactions become exponentially more difficult to study in diploid organisms as the number of genes involved increases. Here, we present hybrid haploid males of the wasp species pair Nasonia vitripennis and Nasonia giraulti, which have distinct male head morphologies, as a genetic model of craniofacial development that possesses the genetic advantages of haploidy, along with many powerful genomic tools. Viable, fertile hybrids can be made between the species, and quantitative trail loci related to shape differences have been identified. In addition, a subset of hybrid males show head abnormalities, including clefting at the midline and asymmetries. Crucially, epistatic interactions among multiple loci underlie several developmental differences and defects observed in the F2 hybrid males. Furthermore, we demonstrate an introgression of a chromosomal region from N. giraulti into N. vitripennis that shows an abnormality in relative eye size, which maps to a region containing a major QTL for this trait. Therefore, the genetic sources of head morphology can, in principle, be identified by positional cloning. Thus, Nasonia is well positioned to be a uniquely powerful model invertebrate system with which to probe both development and complex genetics of craniofacial patterning and defects. PMID:26721604

Modular Organization of Residue-Level Contacts Shapes the Selection Pressure on Individual Amino Acid Sites of Ribosomal Proteins.

PubMed

Mallik, Saurav; Kundu, Sudip

2017-04-01

Understanding the molecular evolution of macromolecular complexes in the light of their structure, assembly, and stability is of central importance. Here, we address how the modular organization of native molecular contacts shapes the selection pressure on individual residue sites of ribosomal complexes. The bacterial ribosomal complex is represented as a residue contact network where nodes represent amino acid/nucleotide residues and edges represent their van der Waals interactions. We find statistically overrepresented native amino acid-nucleotide contacts (OaantC, one amino acid contacts one or multiple nucleotides, internucleotide contacts are disregarded). Contact number is defined as the number of nucleotides contacted. Involvement of individual amino acids in OaantCs with smaller contact numbers is more random, whereas only a few amino acids significantly contribute to OaantCs with higher contact numbers. An investigation of structure, stability, and assembly of bacterial ribosome depicts the involvement of these OaantCs in diverse biophysical interactions stabilizing the complex, including high-affinity protein-RNA contacts, interprotein cooperativity, intersubunit bridge, packing of multiple ribosomal RNA domains, etc. Amino acid-nucleotide constituents of OaantCs with higher contact numbers are generally associated with significantly slower substitution rates compared with that of OaantCs with smaller contact numbers. This evolutionary rate heterogeneity emerges from the strong purifying selection pressure that conserves the respective amino acid physicochemical properties relevant to the stabilizing interaction with OaantC nucleotides. An analysis of relative molecular orientations of OaantC residues and their interaction energetics provides the biophysical ground of purifying selection conserving OaantC amino acid physicochemical properties. © The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Differential Dynamic Engagement within 24 SH3 Domain: Peptide Complexes Revealed by Co-Linear Chemical Shift Perturbation Analysis

PubMed Central

Stollar, Elliott J.; Lin, Hong; Davidson, Alan R.; Forman-Kay, Julie D.

2012-01-01

There is increasing evidence for the functional importance of multiple dynamically populated states within single proteins. However, peptide binding by protein-protein interaction domains, such as the SH3 domain, has generally been considered to involve the full engagement of peptide to the binding surface with minimal dynamics and simple methods to determine dynamics at the binding surface for multiple related complexes have not been described. We have used NMR spectroscopy combined with isothermal titration calorimetry to comprehensively examine the extent of engagement to the yeast Abp1p SH3 domain for 24 different peptides. Over one quarter of the domain residues display co-linear chemical shift perturbation (CCSP) behavior, in which the position of a given chemical shift in a complex is co-linear with the same chemical shift in the other complexes, providing evidence that each complex exists as a unique dynamic rapidly inter-converting ensemble. The extent the specificity determining sub-surface of AbpSH3 is engaged as judged by CCSP analysis correlates with structural and thermodynamic measurements as well as with functional data, revealing the basis for significant structural and functional diversity amongst the related complexes. Thus, CCSP analysis can distinguish peptide complexes that may appear identical in terms of general structure and percent peptide occupancy but have significant local binding differences across the interface, affecting their ability to transmit conformational change across the domain and resulting in functional differences. PMID:23251481

A Network of Chromatin Factors Is Regulating the Transition to Postembryonic Development in Caenorhabditis elegans

PubMed Central

Erdelyi, Peter; Wang, Xing; Suleski, Marina; Wicky, Chantal

2016-01-01

Mi2 proteins are evolutionarily conserved, ATP-dependent chromatin remodelers of the CHD family that play key roles in stem cell differentiation and reprogramming. In Caenorhabditis elegans, the let-418 gene encodes one of the two Mi2 homologs, which is part of at least two chromatin complexes, namely the Nucleosome Remodeling and histone Deacetylase (NuRD) complex and the MEC complex, and functions in larval development, vulval morphogenesis, lifespan regulation, and cell fate determination. To explore the mechanisms involved in the action of LET-418/Mi2, we performed a genome-wide RNA interference (RNAi) screen for suppressors of early larval arrest associated with let-418 mutations. We identified 29 suppressor genes, of which 24 encode chromatin regulators, mostly orthologs of proteins present in transcriptional activator complexes. The remaining five genes vary broadly in their predicted functions. All suppressor genes could suppress multiple aspects of the let-418 phenotype, including developmental arrest and ectopic expression of germline genes in the soma. Analysis of available transcriptomic data and quantitative PCR revealed that LET-418 and the suppressors of early larval arrest are regulating common target genes. These suppressors might represent direct competitors of LET-418 complexes for chromatin regulation of crucial genes involved in the transition to postembryonic development. PMID:28007841

A Network of Chromatin Factors Is Regulating the Transition to Postembryonic Development in Caenorhabditis elegans.

PubMed

Erdelyi, Peter; Wang, Xing; Suleski, Marina; Wicky, Chantal

2017-02-09

Mi2 proteins are evolutionarily conserved, ATP-dependent chromatin remodelers of the CHD family that play key roles in stem cell differentiation and reprogramming. In Caenorhabditis elegans , the let-418 gene encodes one of the two Mi2 homologs, which is part of at least two chromatin complexes, namely the Nucleosome Remodeling and histone Deacetylase (NuRD) complex and the MEC complex, and functions in larval development, vulval morphogenesis, lifespan regulation, and cell fate determination. To explore the mechanisms involved in the action of LET-418/Mi2, we performed a genome-wide RNA interference (RNAi) screen for suppressors of early larval arrest associated with let-418 mutations. We identified 29 suppressor genes, of which 24 encode chromatin regulators, mostly orthologs of proteins present in transcriptional activator complexes. The remaining five genes vary broadly in their predicted functions. All suppressor genes could suppress multiple aspects of the let-418 phenotype, including developmental arrest and ectopic expression of germline genes in the soma. Analysis of available transcriptomic data and quantitative PCR revealed that LET-418 and the suppressors of early larval arrest are regulating common target genes. These suppressors might represent direct competitors of LET-418 complexes for chromatin regulation of crucial genes involved in the transition to postembryonic development. Copyright © 2017 Erdelyi et al.

Multiple sclerosis pathogenesis: missing pieces of an old puzzle.

PubMed

Rahmanzadeh, Reza; Brück, Wolfgang; Minagar, Alireza; Sahraian, Mohammad Ali

2018-06-08

Traditionally, multiple sclerosis (MS) was considered to be a CD4 T cell-mediated CNS autoimmunity, compatible with experimental autoimmune encephalitis model, which can be characterized by focal lesions in the white matter. However, studies of recent decades revealed several missing pieces of MS puzzle and showed that MS pathogenesis is more complex than the traditional view and may include the following: a primary degenerative process (e.g. oligodendroglial pathology), generalized abnormality of normal-appearing brain tissue, pronounced gray matter pathology, involvement of innate immunity, and CD8 T cells and B cells. Here, we review these findings and discuss their implications in MS pathogenesis.

Developing the human-computer interface for Space Station Freedom

NASA Technical Reports Server (NTRS)

Holden, Kritina L.

1991-01-01

For the past two years, the Human-Computer Interaction Laboratory (HCIL) at the Johnson Space Center has been involved in prototyping and prototype reviews of in support of the definition phase of the Space Station Freedom program. On the Space Station, crew members will be interacting with multi-monitor workstations where interaction with several displays at one time will be common. The HCIL has conducted several experiments to begin to address design issues for this complex system. Experiments have dealt with design of ON/OFF indicators, the movement of the cursor across multiple monitors, and the importance of various windowing capabilities for users performing multiple tasks simultaneously.

Rapamycin-induced oligomer formation system of FRB-FKBP fusion proteins.

PubMed

Inobe, Tomonao; Nukina, Nobuyuki

2016-07-01

Most proteins form larger protein complexes and perform multiple functions in the cell. Thus, artificial regulation of protein complex formation controls the cellular functions that involve protein complexes. Although several artificial dimerization systems have already been used for numerous applications in biomedical research, cellular protein complexes form not only simple dimers but also larger oligomers. In this study, we showed that fusion proteins comprising the induced heterodimer formation proteins FRB and FKBP formed various oligomers upon addition of rapamycin. By adjusting the configuration of fusion proteins, we succeeded in generating an inducible tetramer formation system. Proteins of interest also formed tetramers by fusing to the inducible tetramer formation system, which exhibits its utility in a broad range of biological applications. Copyright © 2015 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Additional considerations are required when preparing a protocol for a systematic review with multiple interventions.

PubMed

Chaimani, Anna; Caldwell, Deborah M; Li, Tianjing; Higgins, Julian P T; Salanti, Georgia

2017-03-01

The number of systematic reviews that aim to compare multiple interventions using network meta-analysis is increasing. In this study, we highlight aspects of a standard systematic review protocol that may need modification when multiple interventions are to be compared. We take the protocol format suggested by Cochrane for a standard systematic review as our reference and compare the considerations for a pairwise review with those required for a valid comparison of multiple interventions. We suggest new sections for protocols of systematic reviews including network meta-analyses with a focus on how to evaluate their assumptions. We provide example text from published protocols to exemplify the considerations. Standard systematic review protocols for pairwise meta-analyses need extensions to accommodate the increased complexity of network meta-analysis. Our suggested modifications are widely applicable to both Cochrane and non-Cochrane systematic reviews involving network meta-analyses. Copyright © 2017 Elsevier Inc. All rights reserved.

Multiple meanings of "gift" and its value for organ donation.

PubMed

Shaw, Rhonda M; Webb, Robert

2015-05-01

The "gift of life" metaphor is used to promote organ donation where commercialization is prohibited. In this article, we explore how multiple parties involved in organ transfer procedures think of gift terminology by drawing on interview data with transplantation specialists, organ transplant recipients, living directed donors and living nondirected donors. The interviews took place across New Zealand between October 2008 and May 2012, in participants' homes and hospital workplaces. The interviews were transcribed verbatim, coded manually, and thematically analyzed. Although gift language is often viewed as clear-cut, the gift trope has multiple meanings for different constituent and cultural groups, ranging from positive descriptors to obscuring and romanticizing the complexities of transplantation processes. To account for these multiple perspectives, we suggest new ethical models to capture the nuanced phenomenon of organ transfer in ways that recognize the full range of donation and reception experiences. © The Author(s) 2014.

Multi-criteria clinical decision support: A primer on the use of multiple criteria decision making methods to promote evidence-based, patient-centered healthcare.

PubMed

Dolan, James G

2010-01-01

Current models of healthcare quality recommend that patient management decisions be evidence-based and patient-centered. Evidence-based decisions require a thorough understanding of current information regarding the natural history of disease and the anticipated outcomes of different management options. Patient-centered decisions incorporate patient preferences, values, and unique personal circumstances into the decision making process and actively involve both patients along with health care providers as much as possible. Fundamentally, therefore, evidence-based, patient-centered decisions are multi-dimensional and typically involve multiple decision makers.Advances in the decision sciences have led to the development of a number of multiple criteria decision making methods. These multi-criteria methods are designed to help people make better choices when faced with complex decisions involving several dimensions. They are especially helpful when there is a need to combine "hard data" with subjective preferences, to make trade-offs between desired outcomes, and to involve multiple decision makers. Evidence-based, patient-centered clinical decision making has all of these characteristics. This close match suggests that clinical decision support systems based on multi-criteria decision making techniques have the potential to enable patients and providers to carry out the tasks required to implement evidence-based, patient-centered care effectively and efficiently in clinical settings.The goal of this paper is to give readers a general introduction to the range of multi-criteria methods available and show how they could be used to support clinical decision-making. Methods discussed include the balance sheet, the even swap method, ordinal ranking methods, direct weighting methods, multi-attribute decision analysis, and the analytic hierarchy process (AHP).

Multi-criteria clinical decision support: A primer on the use of multiple criteria decision making methods to promote evidence-based, patient-centered healthcare

PubMed Central

Dolan, James G.

2010-01-01

Current models of healthcare quality recommend that patient management decisions be evidence-based and patient-centered. Evidence-based decisions require a thorough understanding of current information regarding the natural history of disease and the anticipated outcomes of different management options. Patient-centered decisions incorporate patient preferences, values, and unique personal circumstances into the decision making process and actively involve both patients along with health care providers as much as possible. Fundamentally, therefore, evidence-based, patient-centered decisions are multi-dimensional and typically involve multiple decision makers. Advances in the decision sciences have led to the development of a number of multiple criteria decision making methods. These multi-criteria methods are designed to help people make better choices when faced with complex decisions involving several dimensions. They are especially helpful when there is a need to combine “hard data” with subjective preferences, to make trade-offs between desired outcomes, and to involve multiple decision makers. Evidence-based, patient-centered clinical decision making has all of these characteristics. This close match suggests that clinical decision support systems based on multi-criteria decision making techniques have the potential to enable patients and providers to carry out the tasks required to implement evidence-based, patient-centered care effectively and efficiently in clinical settings. The goal of this paper is to give readers a general introduction to the range of multi-criteria methods available and show how they could be used to support clinical decision-making. Methods discussed include the balance sheet, the even swap method, ordinal ranking methods, direct weighting methods, multi-attribute decision analysis, and the analytic hierarchy process (AHP) PMID:21394218

The Regulatory Interactions of p21 and PCNA in Human Breast Cancer

DTIC Science & Technology

2002-07-01

Proliferating cell nuclear antigen (PCNA) is a multifunctional enzyme involved in multiple cellular processes including DNA replication and repair...During DNA replication , PCNA function as an accessory factor- for the DNA polymerases E arid and are part of a multiprotein DNA replication complex...a cyclin-dependent kinase inhibitor, p21WAF1 ability to inhibit DNA replication in response to DNA damage has been wall characterized. Interestingly

An integrated modeling approach to support management decisions of coupled groundwater-agricultural systems under multiple uncertainties

NASA Astrophysics Data System (ADS)

Hagos Subagadis, Yohannes; Schütze, Niels; Grundmann, Jens

2015-04-01

The planning and implementation of effective water resources management strategies need an assessment of multiple (physical, environmental, and socio-economic) issues, and often requires new research in which knowledge of diverse disciplines are combined in a unified methodological and operational frameworks. Such integrative research to link different knowledge domains faces several practical challenges. Such complexities are further compounded by multiple actors frequently with conflicting interests and multiple uncertainties about the consequences of potential management decisions. A fuzzy-stochastic multiple criteria decision analysis tool was developed in this study to systematically quantify both probabilistic and fuzzy uncertainties associated with complex hydrosystems management. It integrated physical process-based models, fuzzy logic, expert involvement and stochastic simulation within a general framework. Subsequently, the proposed new approach is applied to a water-scarce coastal arid region water management problem in northern Oman, where saltwater intrusion into a coastal aquifer due to excessive groundwater extraction for irrigated agriculture has affected the aquifer sustainability, endangering associated socio-economic conditions as well as traditional social structure. Results from the developed method have provided key decision alternatives which can serve as a platform for negotiation and further exploration. In addition, this approach has enabled to systematically quantify both probabilistic and fuzzy uncertainties associated with the decision problem. Sensitivity analysis applied within the developed tool has shown that the decision makers' risk aversion and risk taking attitude may yield in different ranking of decision alternatives. The developed approach can be applied to address the complexities and uncertainties inherent in water resources systems to support management decisions, while serving as a platform for stakeholder participation.

Basic pharmacology of NMDA receptors.

PubMed

Gonda, Xenia

2012-01-01

NMDA receptors are ionotropic receptors mediating glutamatergic neurotransmission and play a role in several basic functions in the central nervous system, from regulating neurodevelopment and synaptic plasticity, learning and memory formation, cognitive processes, rhythm generation necessary for locomotor activity and breathing, and excitotoxicity. Due to their complex involvement in the above processes, NMDA receptors have been established to play a role in the etiopathology of several neuropsychiatric disorders such as ischaemia and traumatic brain injury, neurodegenerative disorders, pain syndromes, addiction, affective disorders and such neurodevelopmental disorders as autism or schizophrenia. NMDA receptors contain multiple types of subunits with distinct functional and pharmacological properties making the picture more complex. These receptors also offer multiple binding sites to be targeted with pharmacons, however, early broad-spectrum NMDA receptor antagonists had limited clinical use due to their intolerable adverse effect profile. The discovery of several types of subunit selective NMDA receptor antagonists may offer valuable therapeutic possibilities for several disorders, with improved clinical efficacy and decreased side effects. However, in spite of our increasing knowledge concerning the involvement of NMDA receptors in pathological processes, molecules with a selective action, tolerable side effect profile and good clinical efficacy are still only in clinical development in the majority of cases. Nevertheless, NMDA receptors offer a novel opportunity in the treatment of various neuropsychiatric conditions.

RPA homologs and ssDNA processing during meiotic recombination.

PubMed

Ribeiro, Jonathan; Abby, Emilie; Livera, Gabriel; Martini, Emmanuelle

2016-06-01

Meiotic homologous recombination is a specialized process that involves homologous chromosome pairing and strand exchange to guarantee proper chromosome segregation and genetic diversity. The formation and repair of DNA double-strand breaks (DSBs) during meiotic recombination differs from those during mitotic recombination in that the homologous chromosome rather than the sister chromatid is the preferred repair template. The processing of single-stranded DNA (ssDNA) formed on intermediate recombination structures is central to driving the specific outcomes of DSB repair during meiosis. Replication protein A (RPA) is the main ssDNA-binding protein complex involved in DNA metabolism. However, the existence of RPA orthologs in plants and the recent discovery of meiosis specific with OB domains (MEIOB), a widely conserved meiosis-specific RPA1 paralog, strongly suggest that multiple RPA complexes evolved and specialized to subdivide their roles during DNA metabolism. Here we review ssDNA formation and maturation during mitotic and meiotic recombination underlying the meiotic specific features. We describe and discuss the existence and properties of MEIOB and multiple RPA subunits in plants and highlight how they can provide meiosis-specific fates to ssDNA processing during homologous recombination. Understanding the functions of these RPA homologs and how they interact with the canonical RPA subunits is of major interest in the fields of meiosis and DNA repair.

Advances in combination therapy of lung cancer: Rationales, delivery technologies and dosage regimens.

PubMed

Wu, Lan; Leng, Donglei; Cun, Dongmei; Foged, Camilla; Yang, Mingshi

2017-08-28

Lung cancer is a complex disease caused by a multitude of genetic and environmental factors. The progression of lung cancer involves dynamic changes in the genome and a complex network of interactions between cancer cells with multiple, distinct cell types that form tumors. Combination therapy using different pharmaceuticals has been proven highly effective due to the ability to affect multiple cellular pathways involved in the disease progression. However, the currently used drug combination designs are primarily based on empirical clinical studies, and little attention has been given to dosage regimens, i.e. how administration routes, onsets, and durations of the combinations influence the therapeutic outcome. This is partly because combination therapy is challenged by distinct physicochemical properties and in vivo pharmacokinetics/pharmacodynamics of the individual pharmaceuticals, including small molecule drugs and biopharmaceuticals, which make the optimization of dosing and administration schedule challenging. This article reviews the recent advances in the design and development of combinations of pharmaceuticals for the treatment of lung cancer. Focus is primarily on rationales for the selection of specific combination therapies for lung cancer treatment, and state of the art of delivery technologies and dosage regimens for the combinations, tested in preclinical and clinical trials. Copyright © 2017 Elsevier B.V. All rights reserved.

Understanding the psychology of bullying: Moving toward a social-ecological diathesis-stress model.

PubMed

Swearer, Susan M; Hymel, Shelley

2015-01-01

With growing recognition that bullying is a complex phenomenon, influenced by multiple factors, research findings to date have been understood within a social-ecological framework. Consistent with this model, we review research on the known correlates and contributing factors in bullying/victimization within the individual, family, peer group, school and community. Recognizing the fluid and dynamic nature of involvement in bullying, we then expand on this model and consider research on the consequences of bullying involvement, as either victim or bully or both, and propose a social-ecological, diathesis-stress model for understanding the bullying dynamic and its impact. Specifically, we frame involvement in bullying as a stressful life event for both children who bully and those who are victimized, serving as a catalyst for a diathesis-stress connection between bullying, victimization, and psychosocial difficulties. Against this backdrop, we suggest that effective bullying prevention and intervention efforts must take into account the complexities of the human experience, addressing both individual characteristics and history of involvement in bullying, risk and protective factors, and the contexts in which bullying occurs, in order to promote healthier social relationships. (c) 2015 APA, all rights reserved).

Posttransplantation lymphoproliferative disease involving the pituitary gland.

PubMed

Meriden, Zina; Bullock, Grant C; Bagg, Adam; Bonatti, Hugo; Cousar, John B; Lopes, M Beatriz; Robbins, Mark K; Cathro, Helen P

2010-11-01

Posttransplantation lymphoproliferative disorders (PTLD) are heterogeneous lesions with variable morphology, immunophenotype, and molecular characteristics. Multiple distinct primary lesions can occur in PTLD, rarely with both B-cell and T-cell characteristics. Lesions can involve both grafted organs and other sites; however, PTLD involving the pituitary gland has not been previously reported. We describe a patient who developed Epstein-Barr virus-negative PTLD 13 years posttransplantation involving the terminal ileum and pituitary, which was simultaneously involved by a pituitary adenoma. Immunohistochemistry of the pituitary lesion showed expression of CD79a, CD3, and CD7 with clonal rearrangements of both T-cell receptor gamma chain (TRG@) and immunoglobulin heavy chain (IGH@) genes. The terminal ileal lesion was immunophenotypically and molecularly distinct. This is the first report of pituitary PTLD and illustrates the potentially complex nature of PTLD. Copyright © 2010 Elsevier Inc. All rights reserved.

Nonadiabatic excited-state molecular dynamics: modeling photophysics in organic conjugated materials.

PubMed

Nelson, Tammie; Fernandez-Alberti, Sebastian; Roitberg, Adrian E; Tretiak, Sergei

2014-04-15

To design functional photoactive materials for a variety of technological applications, researchers need to understand their electronic properties in detail and have ways to control their photoinduced pathways. When excited by photons of light, organic conjugated materials (OCMs) show dynamics that are often characterized by large nonadiabatic (NA) couplings between multiple excited states through a breakdown of the Born-Oppenheimer (BO) approximation. Following photoexcitation, various nonradiative intraband relaxation pathways can lead to a number of complex processes. Therefore, computational simulation of nonadiabatic molecular dynamics is an indispensable tool for understanding complex photoinduced processes such as internal conversion, energy transfer, charge separation, and spatial localization of excitons. Over the years, we have developed a nonadiabatic excited-state molecular dynamics (NA-ESMD) framework that efficiently and accurately describes photoinduced phenomena in extended conjugated molecular systems. We use the fewest-switches surface hopping (FSSH) algorithm to treat quantum transitions among multiple adiabatic excited state potential energy surfaces (PESs). Extended molecular systems often contain hundreds of atoms and involve large densities of excited states that participate in the photoinduced dynamics. We can achieve an accurate description of the multiple excited states using the configuration interaction single (CIS) formalism with a semiempirical model Hamiltonian. Analytical techniques allow the trajectory to be propagated "on the fly" using the complete set of NA coupling terms and remove computational bottlenecks in the evaluation of excited-state gradients and NA couplings. Furthermore, the use of state-specific gradients for propagation of nuclei on the native excited-state PES eliminates the need for simplifications such as the classical path approximation (CPA), which only uses ground-state gradients. Thus, the NA-ESMD methodology offers a computationally tractable route for simulating hundreds of atoms on ~10 ps time scales where multiple coupled excited states are involved. In this Account, we review recent developments in the NA-ESMD modeling of photoinduced dynamics in extended conjugated molecules involving multiple coupled electronic states. We have successfully applied the outlined NA-ESMD framework to study ultrafast conformational planarization in polyfluorenes where the rate of torsional relaxation can be controlled based on the initial excitation. With the addition of the state reassignment algorithm to identify instances of unavoided crossings between noninteracting PESs, NA-ESMD can now be used to study systems in which these so-called trivial unavoided crossings are expected to predominate. We employ this technique to analyze the energy transfer between poly(phenylene vinylene) (PPV) segments where conformational fluctuations give rise to numerous instances of unavoided crossings leading to multiple pathways and complex energy transfer dynamics that cannot be described using a simple Förster model. In addition, we have investigated the mechanism of ultrafast unidirectional energy transfer in dendrimers composed of poly(phenylene ethynylene) (PPE) chromophores and have demonstrated that differential nuclear motion favors downhill energy transfer in dendrimers. The use of native excited-state gradients allows us to observe this feature.

Ligand Binding: Molecular Mechanics Calculation of the Streptavidin-Biotin Rupture Force

NASA Astrophysics Data System (ADS)

Grubmuller, Helmut; Heymann, Berthold; Tavan, Paul

1996-02-01

The force required to rupture the streptavidin-biotin complex was calculated here by computer simulations. The computed force agrees well with that obtained by recent single molecule atomic force microscope experiments. These simulations suggest a detailed multiple-pathway rupture mechanism involving five major unbinding steps. Binding forces and specificity are attributed to a hydrogen bond network between the biotin ligand and residues within the binding pocket of streptavidin. During rupture, additional water bridges substantially enhance the stability of the complex and even dominate the binding inter-actions. In contrast, steric restraints do not appear to contribute to the binding forces, although conformational motions were observed.

Inflammatory arthritis mimicking Complex Regional Pain Syndrome (CRPS) in a child: A case report.

PubMed

Egilmez, Zeliha; Turgut, Selin Turan; Icagasioglu, Afitap; Bicakci, Irem

2016-01-01

Joint complaints in childhood are seen frequently and differential diagnosis can be difficult. Juvenile idiopathic arthritis (JIA) is the most common rheumatological disease of childhood. It involves peripheral joint arthritis, chronic synovitis, and extra-articular manifestations. Accurate diagnosis can take a long time and sometimes multiple diagnoses are used while following the patient until a final diagnosis can be reached. Arthritis may be triggered by trauma and confused with other diseases like complex regional pain syndrome (CRPS), in which trauma plays a role in the etiology. In the present case, ankle pain in an 8-year-old girl was misdiagnosed as CRPS.

Metabolic and nutritional aspects of cancer.

PubMed

Krawczyk, Joanna; Kraj, Leszek; Ziarkiewicz, Mateusz; Wiktor-Jędrzejczak, Wiesław

2014-08-22

Cancer, being in fact a generalized disease involving the whole organism, is most frequently associated with metabolic deregulation, a latent inflammatory state and anorexia of various degrees. The pathogenesis of this disorder is complex, with multiple dilemmas remaining unsolved. The clinical consequences of the above-mentioned disturbances include cancer-related cachexia and anorexia-cachexia syndrome. These complex clinical entities worsen the prognosis, and lead to deterioration of the quality of life and performance status, and thus require multimodal treatment. Optimal therapy should include nutritional support coupled with pharmacotherapy targeted at underlying pathomechanisms of cachexia. Nevertheless, many issues still need explanation, and efficacious and comprehensive therapy of cancer-related cachexia remains a future objective.

Unraveling secrets of telomeres: one molecule at a time

PubMed Central

Lin, Jiangguo; Kaur, Parminder; Countryman, Preston; Opresko, Patricia L.; Wang, Hong

2016-01-01

Telomeres play important roles in maintaining the stability of linear chromosomes. Telomere maintenance involves dynamic actions of multiple proteins interacting with long repetitive sequences and complex dynamic DNA structures, such as G-quadruplexes, T-loops and t-circles. Given the heterogeneity and complexity of telomeres, single-molecule approaches are essential to fully understand the structure-function relationships that govern telomere maintenance. In this review, we present a brief overview of the principles of single-molecule imaging and manipulation techniques. We then highlight results obtained from applying these single-molecule techniques for studying structure, dynamics and functions of G-quadruplexes, telomerase, and shelterin proteins. PMID:24569170

The expanding syndrome of amyotrophic lateral sclerosis: a clinical and molecular odyssey

PubMed Central

Turner, Martin R; Swash, Michael

2015-01-01

Recent advances in understanding amyotrophic lateral sclerosis (ALS) have delivered new questions. Disappointingly, the initial enthusiasm for transgenic mouse models of the disease has not been followed by rapid advances in therapy or prevention. Monogenic models may have inadvertently masked the true complexity of the human disease. ALS has evolved into a multisystem disorder, involving a final common pathway accessible via multiple upstream aetiological tributaries. Nonetheless, there is a common clinical core to ALS, as clear today as it was to Charcot and others. We stress the continuing relevance of clinical observations amid the increasing molecular complexity of ALS. PMID:25644224

Social media and social work education: understanding and dealing with the new digital world.

PubMed

Fang, Lin; Mishna, Faye; Zhang, Vivian F; Van Wert, Melissa; Bogo, Marion

2014-10-01

Accompanying the multiple benefits and innovations of social media are the complex ethical and pedagogical issues that challenge social work educators. Without a clear understanding of the blurred boundaries between public and private, the potentially limitless and unintended audiences, as well as the permanency of the information shared online, social work students who use social media can find themselves in difficult situations in their personal and professional lives. In this article, we present three scenarios that illustrate issues and complexities involving social media use by social work students, followed by a discussion and recommendations for social work educators.

An integrated modelling framework for neural circuits with multiple neuromodulators.

PubMed

Joshi, Alok; Youssofzadeh, Vahab; Vemana, Vinith; McGinnity, T M; Prasad, Girijesh; Wong-Lin, KongFatt

2017-01-01

Neuromodulators are endogenous neurochemicals that regulate biophysical and biochemical processes, which control brain function and behaviour, and are often the targets of neuropharmacological drugs. Neuromodulator effects are generally complex partly owing to the involvement of broad innervation, co-release of neuromodulators, complex intra- and extrasynaptic mechanism, existence of multiple receptor subtypes and high interconnectivity within the brain. In this work, we propose an efficient yet sufficiently realistic computational neural modelling framework to study some of these complex behaviours. Specifically, we propose a novel dynamical neural circuit model that integrates the effective neuromodulator-induced currents based on various experimental data (e.g. electrophysiology, neuropharmacology and voltammetry). The model can incorporate multiple interacting brain regions, including neuromodulator sources, simulate efficiently and easily extendable to large-scale brain models, e.g. for neuroimaging purposes. As an example, we model a network of mutually interacting neural populations in the lateral hypothalamus, dorsal raphe nucleus and locus coeruleus, which are major sources of neuromodulator orexin/hypocretin, serotonin and norepinephrine/noradrenaline, respectively, and which play significant roles in regulating many physiological functions. We demonstrate that such a model can provide predictions of systemic drug effects of the popular antidepressants (e.g. reuptake inhibitors), neuromodulator antagonists or their combinations. Finally, we developed user-friendly graphical user interface software for model simulation and visualization for both fundamental sciences and pharmacological studies. © 2017 The Authors.

An integrated modelling framework for neural circuits with multiple neuromodulators

PubMed Central

Vemana, Vinith

2017-01-01

Neuromodulators are endogenous neurochemicals that regulate biophysical and biochemical processes, which control brain function and behaviour, and are often the targets of neuropharmacological drugs. Neuromodulator effects are generally complex partly owing to the involvement of broad innervation, co-release of neuromodulators, complex intra- and extrasynaptic mechanism, existence of multiple receptor subtypes and high interconnectivity within the brain. In this work, we propose an efficient yet sufficiently realistic computational neural modelling framework to study some of these complex behaviours. Specifically, we propose a novel dynamical neural circuit model that integrates the effective neuromodulator-induced currents based on various experimental data (e.g. electrophysiology, neuropharmacology and voltammetry). The model can incorporate multiple interacting brain regions, including neuromodulator sources, simulate efficiently and easily extendable to large-scale brain models, e.g. for neuroimaging purposes. As an example, we model a network of mutually interacting neural populations in the lateral hypothalamus, dorsal raphe nucleus and locus coeruleus, which are major sources of neuromodulator orexin/hypocretin, serotonin and norepinephrine/noradrenaline, respectively, and which play significant roles in regulating many physiological functions. We demonstrate that such a model can provide predictions of systemic drug effects of the popular antidepressants (e.g. reuptake inhibitors), neuromodulator antagonists or their combinations. Finally, we developed user-friendly graphical user interface software for model simulation and visualization for both fundamental sciences and pharmacological studies. PMID:28100828

Defective ciliogenesis, embryonic lethality and severe impairment of the Sonic Hedgehog pathway caused by inactivation of the mouse complex A intraflagellar transport gene Ift122/Wdr10, partially overlapping with the DNA repair gene Med1/Mbd4

PubMed Central

Cortellino, Salvatore; Wang, Chengbing; Wang, Baolin; Bassi, Maria Rosaria; Caretti, Elena; Champeval, Delphine; Calmont, Amelie; Jarnik, Michal; Burch, John; Zaret, Kenneth; Larue, Lionel; Bellacosa, Alfonso

2009-01-01

Primary cilia are assembled and maintained by evolutionarily conserved intraflagellar transport (IFT) proteins that are involved in the coordinated movement of macromolecular cargo from the basal body to the cilium tip and back. The IFT machinery is organized in two structural complexes named complex A and complex B. Recently, inactivation in the mouse germline of Ift genes belonging to complex B revealed a requirement of ciliogenesis, or proteins involved in ciliogenesis, for Sonic Hedgehog (Shh) signaling in mammals. Here we report on a complex A mutant mouse, defective for the Ift122 gene. Ift122-null embryos show multiple developmental defects (exencephaly, situs viscerum inversus, delay in turning, hemorrhage and defects in limb development) that result in lethality. In the node, primary cilia were absent or malformed in homozygous mutant and heterozygous embryos, respectively. Impairment of the Shh pathway was apparent in both neural tube patterning (expansion of motoneurons and rostro-caudal level-dependent contraction or expansion of the dorso-lateral interneurons), and limb patterning (ectrosyndactyly). These phenotypes are distinct from both complex B IFT mutant embryos and embryos defective for the ciliary protein hennin/Arl13b, and suggest reduced levels of both Gli2/Gli3 activator and Gli3 repressor functions. We conclude that complex A and complex B factors play similar but distinct roles in ciliogenesis and Shh/Gli3 signaling. PMID:19000668

Intracortical Microstimulation Maps of Motor, Somatosensory, and Posterior Parietal Cortex in Tree Shrews (Tupaia belangeri) Reveal Complex Movement Representations.

PubMed

Baldwin, Mary K L; Cooke, Dylan F; Krubitzer, Leah

2017-02-01

Long-train intracortical microstimulation (LT-ICMS) is a popular method for studying the organization of motor and posterior parietal cortex (PPC) in mammals. In primates, LT-ICMS evokes both multijoint and multiple-body-part movements in primary motor, premotor, and PPC. In rodents, LT-ICMS evokes complex movements of a single limb in motor cortex. Unfortunately, very little is known about motor/PPC organization in other mammals. Tree shrews are closely related to both primates and rodents and could provide insights into the evolution of complex movement domains in primates. The present study investigated the extent of cortex in which movements could be evoked with ICMS and the characteristics of movements elicited using both short train (ST) and LT-ICMS in tree shrews. We demonstrate that LT-ICMS and ST-ICMS maps are similar, with the movements elicited with ST-ICMS being truncated versions of those elicited with LT-ICMS. In addition, LT-ICMS-evoked complex movements within motor cortex similar to those in rodents. More complex movements involving multiple body parts such as the hand and mouth were also elicited in motor cortex and PPC, as in primates. Our results suggest that complex movement networks present in PPC and motor cortex were present in mammals prior to the emergence of primates. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Calculations of reliability predictions for the Apollo spacecraft

NASA Technical Reports Server (NTRS)

Amstadter, B. L.

1966-01-01

A new method of reliability prediction for complex systems is defined. Calculation of both upper and lower bounds are involved, and a procedure for combining the two to yield an approximately true prediction value is presented. Both mission success and crew safety predictions can be calculated, and success probabilities can be obtained for individual mission phases or subsystems. Primary consideration is given to evaluating cases involving zero or one failure per subsystem, and the results of these evaluations are then used for analyzing multiple failure cases. Extensive development is provided for the overall mission success and crew safety equations for both the upper and lower bounds.

Multiple Replica Repulsion Technique for Efficient Conformational Sampling of Biological Systems

PubMed Central

Malevanets, Anatoly; Wodak, Shoshana J.

2011-01-01

Here, we propose a technique for sampling complex molecular systems with many degrees of freedom. The technique, termed “multiple replica repulsion” (MRR), does not suffer from poor scaling with the number of degrees of freedom associated with common replica exchange procedures and does not require sampling at high temperatures. The algorithm involves creation of multiple copies (replicas) of the system, which interact with one another through a repulsive potential that can be applied to the system as a whole or to portions of it. The proposed scheme prevents oversampling of the most populated states and provides accurate descriptions of conformational perturbations typically associated with sampling ground-state energy wells. The performance of MRR is illustrated for three systems of increasing complexity. A two-dimensional toy potential surface is used to probe the sampling efficiency as a function of key parameters of the procedure. MRR simulations of the Met-enkephalin pentapeptide, and the 76-residue protein ubiquitin, performed in presence of explicit water molecules and totaling 32 ns each, investigate the ability of MRR to characterize the conformational landscape of the peptide, and the protein native basin, respectively. Results obtained for the enkephalin peptide reflect more closely the extensive conformational flexibility of this peptide than previously reported simulations. Those obtained for ubiquitin show that conformational ensembles sampled by MRR largely encompass structural fluctuations relevant to biological recognition, which occur on the microsecond timescale, or are observed in crystal structures of ubiquitin complexes with other proteins. MRR thus emerges as a very promising simple and versatile technique for modeling the structural plasticity of complex biological systems. PMID:21843487

Multiple Mechanisms for the Thermal Decomposition of Metallaisoxazolin-5-ones from Computational Investigations.

PubMed

Zhou, Chen-Chen; Hawthorne, M Frederick; Houk, K N; Jiménez-Osés, Gonzalo

2017-08-18

The thermal decompositions of metallaisoxazolin-5-ones containing Ir, Rh, or Co are investigated using density functional theory. The experimentally observed decarboxylations of these molecules are found to proceed through retro-(3+2)-cycloaddition reactions, generating the experimentally reported η 2 side-bonded nitrile complexes. These intermediates can isomerize in situ to yield a η 1 nitrile complex. A competitive alternative pathway is also found where the decarboxylation happens concertedly with an aryl migration process, producing a η 1 isonitrile complex. Despite their comparable stability, these η 1 bonded species were not detected experimentally. The experimentally detected η 2 side bound species are likely involved in the subsequent C-H activation reactions with hydrocarbon solvents reported for some of these metallaisoxazolin-5-ones.

Framework for Smart Electronic Health Record- Linked Predictive Models to Optimize Care for Complex Digestive Diseases

DTIC Science & Technology

2015-03-01

data against previous published outcomes in AP and Chronic Pancreatitis (CP). This served as useful validation of our data set before entering the...These patients can develop multiple complications from their disease. In addition, the treatments for CD (both medical and surgical ) can impose...years of diagnosis. The treatment for CD can sometimes involve very expensive medications with potentially serious side effects, as well as surgical

Changing the Game: Human Security as Grand Strategy

DTIC Science & Technology

2014-06-01

convergence of multiple vulnerabilities in the en- vironment of the individual. LITERATURE REVIEW A growing body of literature exists that embraces...complexities of tomorrow. Decrements in the capacities of today to effectively deal with the com- plexities of tomorrow should then inform the targeted...Seek” against “The World As It Is.”14 Closing the decrement between “The World As It Is” and “The World We Seek” involves continued progress and

DNA-dependent protein kinase in nonhomologous end joining: a lock with multiple keys?

PubMed

Weterings, Eric; Chen, David J

2007-10-22

The DNA-dependent protein kinase (DNA-PK) is one of the central enzymes involved in DNA double-strand break (DSB) repair. It facilitates proper alignment of the two ends of the broken DNA molecule and coordinates access of other factors to the repair complex. We discuss the latest findings on DNA-PK phosphorylation and offer a working model for the regulation of DNA-PK during DSB repair.

Uncovering Neuronal Networks Defined by Consistent Between-Neuron Spike Timing from Neuronal Spike Recordings

PubMed Central

2018-01-01

Abstract It is widely assumed that distributed neuronal networks are fundamental to the functioning of the brain. Consistent spike timing between neurons is thought to be one of the key principles for the formation of these networks. This can involve synchronous spiking or spiking with time delays, forming spike sequences when the order of spiking is consistent. Finding networks defined by their sequence of time-shifted spikes, denoted here as spike timing networks, is a tremendous challenge. As neurons can participate in multiple spike sequences at multiple between-spike time delays, the possible complexity of networks is prohibitively large. We present a novel approach that is capable of (1) extracting spike timing networks regardless of their sequence complexity, and (2) that describes their spiking sequences with high temporal precision. We achieve this by decomposing frequency-transformed neuronal spiking into separate networks, characterizing each network’s spike sequence by a time delay per neuron, forming a spike sequence timeline. These networks provide a detailed template for an investigation of the experimental relevance of their spike sequences. Using simulated spike timing networks, we show network extraction is robust to spiking noise, spike timing jitter, and partial occurrences of the involved spike sequences. Using rat multineuron recordings, we demonstrate the approach is capable of revealing real spike timing networks with sub-millisecond temporal precision. By uncovering spike timing networks, the prevalence, structure, and function of complex spike sequences can be investigated in greater detail, allowing us to gain a better understanding of their role in neuronal functioning. PMID:29789811

The extraction of simple relationships in growth factor-specific multiple-input and multiple-output systems in cell-fate decisions by backward elimination PLS regression.

PubMed

Akimoto, Yuki; Yugi, Katsuyuki; Uda, Shinsuke; Kudo, Takamasa; Komori, Yasunori; Kubota, Hiroyuki; Kuroda, Shinya

2013-01-01

Cells use common signaling molecules for the selective control of downstream gene expression and cell-fate decisions. The relationship between signaling molecules and downstream gene expression and cellular phenotypes is a multiple-input and multiple-output (MIMO) system and is difficult to understand due to its complexity. For example, it has been reported that, in PC12 cells, different types of growth factors activate MAP kinases (MAPKs) including ERK, JNK, and p38, and CREB, for selective protein expression of immediate early genes (IEGs) such as c-FOS, c-JUN, EGR1, JUNB, and FOSB, leading to cell differentiation, proliferation and cell death; however, how multiple-inputs such as MAPKs and CREB regulate multiple-outputs such as expression of the IEGs and cellular phenotypes remains unclear. To address this issue, we employed a statistical method called partial least squares (PLS) regression, which involves a reduction of the dimensionality of the inputs and outputs into latent variables and a linear regression between these latent variables. We measured 1,200 data points for MAPKs and CREB as the inputs and 1,900 data points for IEGs and cellular phenotypes as the outputs, and we constructed the PLS model from these data. The PLS model highlighted the complexity of the MIMO system and growth factor-specific input-output relationships of cell-fate decisions in PC12 cells. Furthermore, to reduce the complexity, we applied a backward elimination method to the PLS regression, in which 60 input variables were reduced to 5 variables, including the phosphorylation of ERK at 10 min, CREB at 5 min and 60 min, AKT at 5 min and JNK at 30 min. The simple PLS model with only 5 input variables demonstrated a predictive ability comparable to that of the full PLS model. The 5 input variables effectively extracted the growth factor-specific simple relationships within the MIMO system in cell-fate decisions in PC12 cells.

The RSV F and G glycoproteins interact to form a complex on the surface of infected cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Low, Kit-Wei; Tan, Timothy; Ng, Ken

2008-02-08

In this study, the interaction between the respiratory syncytial virus (RSV) fusion (F) protein, attachment (G) protein, and small hydrophobic (SH) proteins was examined. Immunoprecipitation analysis suggested that the F and G proteins exist as a protein complex on the surface of RSV-infected cells, and this conclusion was supported by ultracentrifugation analysis that demonstrated co-migration of surface-expressed F and G proteins. Although our analysis provided evidence for an interaction between the G and SH proteins, no evidence was obtained for a single protein complex involving all three of the virus proteins. These data suggest the existence of multiple virus glycoproteinmore » complexes within the RSV envelope. Although the stimulus that drives RSV-mediated membrane fusion is unknown, the association between the G and F proteins suggest an indirect role for the G protein in this process.« less

Modeling Complex Equilibria in ITC Experiments: Thermodynamic Parameters Estimation for a Three Binding Site Model

PubMed Central

Le, Vu H.; Buscaglia, Robert; Chaires, Jonathan B.; Lewis, Edwin A.

2013-01-01

Isothermal Titration Calorimetry, ITC, is a powerful technique that can be used to estimate a complete set of thermodynamic parameters (e.g. Keq (or ΔG), ΔH, ΔS, and n) for a ligand binding interaction described by a thermodynamic model. Thermodynamic models are constructed by combination of equilibrium constant, mass balance, and charge balance equations for the system under study. Commercial ITC instruments are supplied with software that includes a number of simple interaction models, for example one binding site, two binding sites, sequential sites, and n-independent binding sites. More complex models for example, three or more binding sites, one site with multiple binding mechanisms, linked equilibria, or equilibria involving macromolecular conformational selection through ligand binding need to be developed on a case by case basis by the ITC user. In this paper we provide an algorithm (and a link to our MATLAB program) for the non-linear regression analysis of a multiple binding site model with up to four overlapping binding equilibria. Error analysis demonstrates that fitting ITC data for multiple parameters (e.g. up to nine parameters in the three binding site model) yields thermodynamic parameters with acceptable accuracy. PMID:23262283

Genetic Architecture of Hybrid Male Sterility in Drosophila: Analysis of Intraspecies Variation for Interspecies Isolation

PubMed Central

Reed, Laura K.; LaFlamme, Brooke A.; Markow, Therese A.

2008-01-01

Background The genetic basis of postzygotic isolation is a central puzzle in evolutionary biology. Evolutionary forces causing hybrid sterility or inviability act on the responsible genes while they still are polymorphic, thus we have to study these traits as they arise, before isolation is complete. Methodology/Principal Findings Isofemale strains of D. mojavensis vary significantly in their production of sterile F1 sons when females are crossed to D. arizonae males. We took advantage of the intraspecific polymorphism, in a novel design, to perform quantitative trait locus (QTL) mapping analyses directly on F1 hybrid male sterility itself. We found that the genetic architecture of the polymorphism for hybrid male sterility (HMS) in the F1 is complex, involving multiple QTL, epistasis, and cytoplasmic effects. Conclusions/Significance The role of extensive intraspecific polymorphism, multiple QTL, and epistatic interactions in HMS in this young species pair shows that HMS is arising as a complex trait in this system. Directional selection alone would be unlikely to maintain polymorphism at multiple loci, thus we hypothesize that directional selection is unlikely to be the only evolutionary force influencing postzygotic isolation. PMID:18728782

Dynamic hydro-climatic networks in pristine and regulated rivers

NASA Astrophysics Data System (ADS)

Botter, G.; Basso, S.; Lazzaro, G.; Doulatyari, B.; Biswal, B.; Schirmer, M.; Rinaldo, A.

2014-12-01

Flow patterns observed at-a-station are the dynamical byproduct of a cascade of processes involving different compartments of the hydro-climatic network (e.g., climate, rainfall, soil, vegetation) that regulates the transformation of rainfall into streamflows. In complex branching rivers, flow regimes result from the heterogeneous arrangement around the stream network of multiple hydrologic cascades that simultaneously occur within distinct contributing areas. As such, flow regimes are seen as the integrated output of a complex "network of networks", which can be properly characterized by its degree of temporal variability and spatial heterogeneity. Hydrologic networks that generate river flow regimes are dynamic in nature. In pristine rivers, the time-variance naturally emerges at multiple timescales from climate variability (namely, seasonality and inter-annual fluctuations), implying that the magnitude (and the features) of the water flow between two nodes may be highly variable across different seasons and years. Conversely, the spatial distribution of river flow regimes within pristine rivers involves scale-dependent transport features, as well as regional climatic and soil use gradients, which in small and meso-scale catchments (A < 103 km2) are usually mild enough to guarantee quite uniform flow regimes and high spatial correlations. Human-impacted rivers, instead, constitute hybrid networks where observed spatio-temporal patterns are dominated by anthropogenic shifts, such as landscape alterations and river regulation. In regulated rivers, the magnitude and the features of water flows from node to node may change significantly through time due to damming and withdrawals. However, regulation may impact river regimes in a spatially heterogeneous manner (e.g. in localized river reaches), with a significant decrease of spatial correlations and network connectivity. Provided that the spatial and temporal dynamics of flow regimes in complex rivers may strongly impact important biotic processes involved in the river food web (e.g. biofilm and riparian vegetation dynamics), the study of rivers as dynamic networks provides important clues to water management strategies and freshwater ecosystem studies.

Testing of Environmental Satellite Bus-Instrument Interfaces Using Engineering Models

NASA Technical Reports Server (NTRS)

Gagnier, Don; Hayner, Rick; Roza, Michael; Nosek, Thomas; Razzaghi, Andrea

2004-01-01

This paper discusses the formulation and execution of a laboratory test of the electrical interfaces between multiple atmospheric science instruments and the spacecraft bus that carries them. The testing, performed in 2002, used engineering models of the instruments that will be flown on the Aura s p a c m and of the Aura spacecraft bus electronics. Aura is one of NASA's Earth Observing System @OS) Program missions managed by the Goddard Space Flight Center. The test was designed to evaluate the complex interfaces in the spacecraft and instrument command and data handling (C&DH) subsystems prior to integration of the complete flight instruments on the spacecraft. A problem discovered during (and not before) the flight hardware integration phase can cause significant cost and schedule impacts. The testing successfully surfaced problems and led to their resolution before the full-up integration phase, saving significant cost and schedule time. This approach could be used on future environmental satellite programs involving multiple, complex scientific instruments being integrated onto a bus.

Quantitative measurement of binary liquid distributions using multiple-tracer x-ray fluorescence and radiography

DOE Office of Scientific and Technical Information (OSTI.GOV)

Halls, Benjamin R.; Meyer, Terrence R.; Kastengren, Alan L.

2015-01-01

The complex geometry and large index-of-refraction gradients that occur near the point of impingement of binary liquid jets present a challenging environment for optical interrogation. A simultaneous quadruple-tracer x-ray fluorescence and line-of-sight radiography technique is proposed as a means of distinguishing and quantifying individual liquid component distributions prior to, during, and after jet impact. Two different pairs of fluorescence tracers are seeded into each liquid stream to maximize their attenuation ratio for reabsorption correction and differentiation of the two fluids during mixing. This approach for instantaneous correction of x-ray fluorescence reabsorption is compared with a more time-intensive approach of usingmore » stereographic reconstruction of x-ray attenuation along multiple lines of sight. The proposed methodology addresses the need for a quantitative measurement technique capable of interrogating optically complex, near-field liquid distributions in many mixing systems of practical interest involving two or more liquid streams.« less

Lignocellulose Degradation Mechanisms Across the Tree of Life

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cragg, Simon M.; Beckham, Gregg T.; Bruce, Neil C.

Organisms use diverse mechanisms involving multiple complementary enzymes, particularly glycoside hydrolases (GHs), to deconstruct lignocellulose. Lytic polysaccharide monooxygenases (LPMOs) produced by bacteria and fungi facilitate deconstruction as does the Fenton chemistry of brown-rot fungi. Lignin depolymerisation is achieved by white-rot fungi and certain bacteria, using peroxidases and laccases. Meta-omics is now revealing the complexity of prokaryotic degradative activity in lignocellulose-rich environments. Protists from termite guts and some oomycetes produce multiple lignocellulolytic enzymes. We found that the Lignocellulose-consuming animals secrete some GHs, but most harbour a diverse enzyme-secreting gut microflora in a mutualism that is particularly complex in termites. Shipworms however,more » house GH-secreting and LPMO-secreting bacteria separate from the site of digestion and the isopod Limnoria relies on endogenous enzymes alone. Moreover, the omics revolution is identifying many novel enzymes and paradigms for biomass deconstruction, but more emphasis on function is required, particularly for enzyme cocktails, in which LPMOs may play an important role.« less

Lignocellulose Degradation Mechanisms Across the Tree of Life

DOE PAGES

Cragg, Simon M.; Beckham, Gregg T.; Bruce, Neil C.; ...

2015-11-14

Organisms use diverse mechanisms involving multiple complementary enzymes, particularly glycoside hydrolases (GHs), to deconstruct lignocellulose. Lytic polysaccharide monooxygenases (LPMOs) produced by bacteria and fungi facilitate deconstruction as does the Fenton chemistry of brown-rot fungi. Lignin depolymerisation is achieved by white-rot fungi and certain bacteria, using peroxidases and laccases. Meta-omics is now revealing the complexity of prokaryotic degradative activity in lignocellulose-rich environments. Protists from termite guts and some oomycetes produce multiple lignocellulolytic enzymes. We found that the Lignocellulose-consuming animals secrete some GHs, but most harbour a diverse enzyme-secreting gut microflora in a mutualism that is particularly complex in termites. Shipworms however,more » house GH-secreting and LPMO-secreting bacteria separate from the site of digestion and the isopod Limnoria relies on endogenous enzymes alone. Moreover, the omics revolution is identifying many novel enzymes and paradigms for biomass deconstruction, but more emphasis on function is required, particularly for enzyme cocktails, in which LPMOs may play an important role.« less

Multiple Choice Knapsack Problem: example of planning choice in transportation.

PubMed

Zhong, Tao; Young, Rhonda

2010-05-01

Transportation programming, a process of selecting projects for funding given budget and other constraints, is becoming more complex as a result of new federal laws, local planning regulations, and increased public involvement. This article describes the use of an integer programming tool, Multiple Choice Knapsack Problem (MCKP), to provide optimal solutions to transportation programming problems in cases where alternative versions of projects are under consideration. In this paper, optimization methods for use in the transportation programming process are compared and then the process of building and solving the optimization problems is discussed. The concepts about the use of MCKP are presented and a real-world transportation programming example at various budget levels is provided. This article illustrates how the use of MCKP addresses the modern complexities and provides timely solutions in transportation programming practice. While the article uses transportation programming as a case study, MCKP can be useful in other fields where a similar decision among a subset of the alternatives is required. Copyright 2009 Elsevier Ltd. All rights reserved.

Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory Chain Function.

PubMed

Floyd, Brendan J; Wilkerson, Emily M; Veling, Mike T; Minogue, Catie E; Xia, Chuanwu; Beebe, Emily T; Wrobel, Russell L; Cho, Holly; Kremer, Laura S; Alston, Charlotte L; Gromek, Katarzyna A; Dolan, Brendan K; Ulbrich, Arne; Stefely, Jonathan A; Bohl, Sarah L; Werner, Kelly M; Jochem, Adam; Westphall, Michael S; Rensvold, Jarred W; Taylor, Robert W; Prokisch, Holger; Kim, Jung-Ja P; Coon, Joshua J; Pagliarini, David J

2016-08-18

Mitochondria are essential for numerous cellular processes, yet hundreds of their proteins lack robust functional annotation. To reveal functions for these proteins (termed MXPs), we assessed condition-specific protein-protein interactions for 50 select MXPs using affinity enrichment mass spectrometry. Our data connect MXPs to diverse mitochondrial processes, including multiple aspects of respiratory chain function. Building upon these observations, we validated C17orf89 as a complex I (CI) assembly factor. Disruption of C17orf89 markedly reduced CI activity, and its depletion is found in an unresolved case of CI deficiency. We likewise discovered that LYRM5 interacts with and deflavinates the electron-transferring flavoprotein that shuttles electrons to coenzyme Q (CoQ). Finally, we identified a dynamic human CoQ biosynthetic complex involving multiple MXPs whose topology we map using purified components. Collectively, our data lend mechanistic insight into respiratory chain-related activities and prioritize hundreds of additional interactions for further exploration of mitochondrial protein function. Copyright © 2016 Elsevier Inc. All rights reserved.

Quantitative measurement of binary liquid distributions using multiple-tracer x-ray fluorescence and radiography

DOE PAGES

Halls, Benjamin R.; Meyer, Terrence R.; Kastengren, Alan L.

2015-01-23

The complex geometry and large index-of-refraction gradients that occur near the point of impingement of binary liquid jets present a challenging environment for optical interrogation. A simultaneous quadruple-tracer x-ray fluorescence and line-of-sight radiography technique is proposed as a means of distinguishing and quantifying individual liquid component distributions prior to, during, and after jet impact. Two different pairs of fluorescence tracers are seeded into each liquid stream to maximize their attenuation ratio for reabsorption correction and differentiation of the two fluids during mixing. This approach for instantaneous correction of x-ray fluorescence reabsorption is compared with a more time-intensive approach of usingmore » stereographic reconstruction of x-ray attenuation along multiple lines of sight. The proposed methodology addresses the need for a quantitative measurement technique capable of interrogating optically complex, near-field liquid distributions in many mixing systems of practical interest involving two or more liquid streams.« less

Ensuring Payload Safety in Missions with Special Partnerships

NASA Technical Reports Server (NTRS)

Staubus, Calvert A.; Willenbring, Rachel C.; Blankenship, Michael D.

2016-01-01

The National Aeronautics and Space Administration (NASA) Expendable Launch Vehicle (ELV) payload space flight missions involve cooperative work between NASA and partners including spacecraft (or payload) contractors, universities, nonprofit research centers, Agency payload organization, Range Safety organization, Agency launch service organizations, and launch vehicle contractors. The role of NASA's Safety and Mission Assurance (SMA) Directorate is typically fairly straightforward, but when a mission's partnerships become more complex, to realize cost and science benefits (e.g., multi-agency payload(s) or cooperative international missions), the task of ensuring payload safety becomes much more challenging. This paper discusses lessons learned from NASA safety professionals working multiple-agency missions and offers suggestions to help fellow safety professionals working multiple-agency missions.

Clinical and research searching on the wild side: exploring the veterinary literature

PubMed Central

Alpi, Kristine M.; Stringer, Elizabeth; DeVoe, Ryan S.; Stoskopf, Michael

2009-01-01

Zoological medicine furthers the health and well-being of captive and free-ranging wild animals. Effective information retrieval of the zoological medicine literature demands searching multiple databases, conference proceedings, and organization websites using a wide variety of keywords and controlled vocabulary. Veterinarians, residents, students, and the librarians who serve them must have patience for multiple search iterations to capture the majority of the available knowledge. The complexities of thorough literature searches are more difficult for nondomestic animal clinical cases and research reviews as demonstrated by three search requests involving poisonous snakes, a gorilla, and spiders. Expanding and better disseminating the knowledgebase of zoological medicine will make veterinary searching easier. PMID:19626142

Immunogenetic Management Software: a new tool for visualization and analysis of complex immunogenetic datasets

PubMed Central

Johnson, Z. P.; Eady, R. D.; Ahmad, S. F.; Agravat, S.; Morris, T; Else, J; Lank, S. M.; Wiseman, R. W.; O’Connor, D. H.; Penedo, M. C. T.; Larsen, C. P.

2012-01-01

Here we describe the Immunogenetic Management Software (IMS) system, a novel web-based application that permitsmultiplexed analysis of complex immunogenetic traits that are necessary for the accurate planning and execution of experiments involving large animal models, including nonhuman primates. IMS is capable of housing complex pedigree relationships, microsatellite-based MHC typing data, as well as MHC pyrosequencing expression analysis of class I alleles. It includes a novel, automated MHC haplotype naming algorithm and has accomplished an innovative visualization protocol that allows users to view multiple familial and MHC haplotype relationships through a single, interactive graphical interface. Detailed DNA and RNA-based data can also be queried and analyzed in a highly accessible fashion, and flexible search capabilities allow experimental choices to be made based on multiple, individualized and expandable immunogenetic factors. This web application is implemented in Java, MySQL, Tomcat, and Apache, with supported browsers including Internet Explorer and Firefox onWindows and Safari on Mac OS. The software is freely available for distribution to noncommercial users by contacting Leslie. kean@emory.edu. A demonstration site for the software is available at http://typing.emory.edu/typing_demo, user name: imsdemo7@gmail.com and password: imsdemo. PMID:22080300

The acidic transcription activator Gcn4 binds the mediator subunit Gal11/Med15 using a simple protein interface forming a fuzzy complex.

PubMed

Brzovic, Peter S; Heikaus, Clemens C; Kisselev, Leonid; Vernon, Robert; Herbig, Eric; Pacheco, Derek; Warfield, Linda; Littlefield, Peter; Baker, David; Klevit, Rachel E; Hahn, Steven

2011-12-23

The structural basis for binding of the acidic transcription activator Gcn4 and one activator-binding domain of the Mediator subunit Gal11/Med15 was examined by NMR. Gal11 activator-binding domain 1 has a four-helix fold with a small shallow hydrophobic cleft at its center. In the bound complex, eight residues of Gcn4 adopt a helical conformation, allowing three Gcn4 aromatic/aliphatic residues to insert into the Gal11 cleft. The protein-protein interface is dynamic and surprisingly simple, involving only hydrophobic interactions. This allows Gcn4 to bind Gal11 in multiple conformations and orientations, an example of a "fuzzy" complex, where the Gcn4-Gal11 interface cannot be described by a single conformation. Gcn4 uses a similar mechanism to bind two other unrelated activator-binding domains. Functional studies in yeast show the importance of residues at the protein interface, define the minimal requirements for a functional activator, and suggest a mechanism by which activators bind to multiple unrelated targets. Copyright © 2011 Elsevier Inc. All rights reserved.

An Integrated Crustal Dynamics Simulator

NASA Astrophysics Data System (ADS)

Xing, H. L.; Mora, P.

2007-12-01

Numerical modelling offers an outstanding opportunity to gain an understanding of the crustal dynamics and complex crustal system behaviour. This presentation provides our long-term and ongoing effort on finite element based computational model and software development to simulate the interacting fault system for earthquake forecasting. A R-minimum strategy based finite-element computational model and software tool, PANDAS, for modelling 3-dimensional nonlinear frictional contact behaviour between multiple deformable bodies with the arbitrarily-shaped contact element strategy has been developed by the authors, which builds up a virtual laboratory to simulate interacting fault systems including crustal boundary conditions and various nonlinearities (e.g. from frictional contact, materials, geometry and thermal coupling). It has been successfully applied to large scale computing of the complex nonlinear phenomena in the non-continuum media involving the nonlinear frictional instability, multiple material properties and complex geometries on supercomputers, such as the South Australia (SA) interacting fault system, South California fault model and Sumatra subduction model. It has been also extended and to simulate the hot fractured rock (HFR) geothermal reservoir system in collaboration of Geodynamics Ltd which is constructing the first geothermal reservoir system in Australia and to model the tsunami generation induced by earthquakes. Both are supported by Australian Research Council.

Immunogenetic Management Software: a new tool for visualization and analysis of complex immunogenetic datasets.

PubMed

Johnson, Z P; Eady, R D; Ahmad, S F; Agravat, S; Morris, T; Else, J; Lank, S M; Wiseman, R W; O'Connor, D H; Penedo, M C T; Larsen, C P; Kean, L S

2012-04-01

Here we describe the Immunogenetic Management Software (IMS) system, a novel web-based application that permits multiplexed analysis of complex immunogenetic traits that are necessary for the accurate planning and execution of experiments involving large animal models, including nonhuman primates. IMS is capable of housing complex pedigree relationships, microsatellite-based MHC typing data, as well as MHC pyrosequencing expression analysis of class I alleles. It includes a novel, automated MHC haplotype naming algorithm and has accomplished an innovative visualization protocol that allows users to view multiple familial and MHC haplotype relationships through a single, interactive graphical interface. Detailed DNA and RNA-based data can also be queried and analyzed in a highly accessible fashion, and flexible search capabilities allow experimental choices to be made based on multiple, individualized and expandable immunogenetic factors. This web application is implemented in Java, MySQL, Tomcat, and Apache, with supported browsers including Internet Explorer and Firefox on Windows and Safari on Mac OS. The software is freely available for distribution to noncommercial users by contacting Leslie.kean@emory.edu. A demonstration site for the software is available at http://typing.emory.edu/typing_demo , user name: imsdemo7@gmail.com and password: imsdemo.

Multiple primary malignancies of the liver and the colon: a complex diagnostic and decisional process with a final unanswered question.

PubMed

Portolani, Nazario; Baiocchi, Gianluca; Baronchelli, Carla; Gheza, Federico; Giulini, Stefano Maria

2014-03-29

We herein present the case of a 78-year-old man with an incidental finding of a solid hepatic mass without symptoms and only a laparotomic cholecystectomy for acute cholecystitis in the past surgical history. A colonoscopy, a magnetic resonance imaging scan, a positron emission tomography scan, and a computed tomography scan completed the preoperative workup: a neoplastic lesion 4.3×3 cm in size was diagnosed at segments IV and V, associated with a neoplastic involvement of the splenic flexure without signs of colonic occlusion. After colonic resection, a frozen section on a granulomatous-like tissue at gastric border suggested a diagnosis of an adenocarcinoma of bilio-pancreatic type, changing the surgical strategy to include gastric resection and hepatic pedicle node dissection. The discussion turns around the idea that a final diagnosis of colon cancer with regional nodal involvement (pT3N1) and metastatic gallbladder cancer with multiple peritoneal seedings cannot be excluded.

The effect of brain lesions on sound localization in complex acoustic environments.

PubMed

Zündorf, Ida C; Karnath, Hans-Otto; Lewald, Jörg

2014-05-01

Localizing sound sources of interest in cluttered acoustic environments--as in the 'cocktail-party' situation--is one of the most demanding challenges to the human auditory system in everyday life. In this study, stroke patients' ability to localize acoustic targets in a single-source and in a multi-source setup in the free sound field were directly compared. Subsequent voxel-based lesion-behaviour mapping analyses were computed to uncover the brain areas associated with a deficit in localization in the presence of multiple distracter sound sources rather than localization of individually presented sound sources. Analyses revealed a fundamental role of the right planum temporale in this task. The results from the left hemisphere were less straightforward, but suggested an involvement of inferior frontal and pre- and postcentral areas. These areas appear to be particularly involved in the spectrotemporal analyses crucial for effective segregation of multiple sound streams from various locations, beyond the currently known network for localization of isolated sound sources in otherwise silent surroundings.

COMPREHENSIVE ASSESSMENT OF COMPLEX TECHNOLOGIES: INTEGRATING VARIOUS ASPECTS IN HEALTH TECHNOLOGY ASSESSMENT.

PubMed

Lysdahl, Kristin Bakke; Mozygemba, Kati; Burns, Jacob; Brönneke, Jan Benedikt; Chilcott, James B; Ward, Sue; Hofmann, Bjørn

2017-01-01

Despite recent development of health technology assessment (HTA) methods, there are still methodological gaps for the assessment of complex health technologies. The INTEGRATE-HTA guidance for effectiveness, economic, ethical, socio-cultural, and legal aspects, deals with challenges when assessing complex technologies, such as heterogeneous study designs, multiple stakeholder perspectives, and unpredictable outcomes. The objective of this article is to outline this guidance and describe the added value of integrating these assessment aspects. Different methods were used to develop the various parts of the guidance, but all draw on existing, published knowledge and were supported by stakeholder involvement. The guidance was modified after application in a case study and in response to feedback from internal and external reviewers. The guidance consists of five parts, addressing five core aspects of HTA, all presenting stepwise approaches based on the assessment of complexity, context, and stakeholder involvement. The guidance on effectiveness, health economics and ethics aspects focus on helping users choose appropriate, or further develop, existing methods. The recommendations are based on existing methods' applicability for dealing with problems arising with complex interventions. The guidance offers new frameworks to identify socio-cultural and legal issues, along with overviews of relevant methods and sources. The INTEGRATE-HTA guidance outlines a wide range of methods and facilitates appropriate choices among them. The guidance enables understanding of how complexity matters for HTA and brings together assessments from disciplines, such as epidemiology, economics, ethics, law, and social theory. This indicates relevance for a broad range of technologies.

HIF-2α-ILK Is Involved in Mesenchymal Stromal Cell Angiogenesis in Multiple Myeloma Under Hypoxic Conditions

PubMed Central

Zhang, Xiaoying; Xu, Yinhui; Liu, Hongbo; Zhao, Pan; Chen, Yafang; Yue, Zhijie; Zhang, Zhiqing; Wang, Xiaofang

2018-01-01

Mesenchymal stromal cells are proven to be likely induce the angiogenic response in multiple myeloma and thus represent an enticing target for antiangiogenesis therapies for multiple myeloma. Substantial evidence indicates that angiogenesis in multiple myeloma is complex and involves direct production of angiogenic cytokines by abnormal plasma cells and these B-cell neoplasia generated pathophysiology change within the microenvironment. In this study, we demonstrated that mesenchymal stromal cells cultured with U266/Lp-1 under hypoxic conditions resulted in an increased α-smooth muscle actin expression and high productive levels of both hypoxia-inducible factor-2α and integrin-linked kinase proteins. Moreover, inhibition of hypoxia-inducible factor-2α by Small interfering RNA (siRNA) in mesenchymal stromal cells decreased the protein levels of both α-smooth muscle actin and integrin-linked kinase after mesenchymal stromal cells cultured with U266 under hypoxic conditions. We further demonstrated that transfection of integrin-linked kinase-siRNA reduced the protein level of α-smooth muscle actin and attenuated angiogenesis in vitro by decreasing the attachment of Q-dot labeled cells and secretion of angiogenic factors. In conclusion, our research showed that mesenchymal stromal cells cultured with myeloma cells under hypoxia participated in the angiogenesis of multiple myeloma, which is regulated by the hypoxia-inducible factor-2α-integrin-linked kinase pathway. Thus, targeting integrin-linked kinase may represent an effective strategy to block hypoxia-inducible factor-2α-induced angiogenesis in the treatment of multiple myeloma. PMID:29656700

Defense AT and L. Volume 44, Number 6, November-December 2015: Where Have All the Nunn-McCurdys Gone

DTIC Science & Technology

2015-11-01

must integrate with complex communications and information networks that involve specialized technical expertise in order to be effective. These...and control system programs that had to integrate into multiple networks and required interoperability with joint and coalition partners, some with...Selection Brian Schultz and David Dotson Competition is a key element in acquisition, but greater value is not always tied to lower prices or cost

Applying the Verona coding definitions of emotional sequences (VR-CoDES) in the dental context involving patients with complex communication needs: An exploratory study.

PubMed

Zhou, Yuefang; Black, Rolf; Freeman, Ruth; Herron, Daniel; Humphris, Gerry; Menzies, Rachel; Quinn, Sandra; Scott, Lesley; Waller, Annalu

2014-11-01

The VR-CoDES has been previously applied in the dental context. However, we know little about how dental patients with intellectual disabilities (ID) and complex communication needs express their emotional distress during dental visits. This is the first study explored the applicability of the VR-CoDES to a dental context involving patients with ID. Fourteen dental consultations were video recorded and coded using the VR-CoDES, assisted with the additional guidelines for the VR-CoDES in a dental context. Both inter- and intra-coder reliabilities were checked on the seven consultations where cues were observed. Sixteen cues (eight non-verbal) were identified within seven of the 14 consultations. Twenty responses were observed (12 reducing space) with four multiple responses. Cohen's Kappa were 0.76 (inter-coder) and 0.88 (intra-coder). With the additional guidelines, cues and responses were reliably identified. Cue expression was exhibited by non-verbal expression of emotion with people with ID in the literature. Further guidance is needed to improve the coding accuracy on multiple providers' responses and to investigate potential impacts of conflicting responses on patients. The findings provided a useful initial step towards an ongoing exploration of how healthcare providers identify and manage emotional distress of patients with ID. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

The effects of note-taking and trial transcript access on mock jury decisions in a complex civil trial.

PubMed

Horowitz, I A; ForsterLee, L

2001-08-01

Mock juries were either permitted to take notes or not and provided with access to the trial transcript during deliberations or were not given access. Juries viewed a videotape of a complex trial involving multiple plaintiffs. Note-taking juries were able to distinguish among differentially worthy plaintiffs when assigning awards while non note takers did not distinguish among the plaintiffs and allocated higher overall compensation. Note-taking was significantly more effective than access to trial transcripts in increasing jury competence. Note-taking juries appeared better able to recognize probative evidence and reject false lures than were non note-taking juries. Limits and implications of the present study were discussed.

The Role of Histone Deacetylases in Neurodegenerative Diseases and Small-Molecule Inhibitors as a Potential Therapeutic Approach

NASA Astrophysics Data System (ADS)

Bürli, Roland W.; Thomas, Elizabeth; Beaumont, Vahri

Neurodegenerative disorders are devastating for patients and their social environment. Their etiology is poorly understood and complex. As a result, there is clearly an urgent need for therapeutic agents that slow down disease progress and alleviate symptoms. In this respect, interference with expression and function of multiple gene products at the epigenetic level has offered much promise, and histone deacetylases play a crucial role in these processes. This review presents an overview of the biological pathways in which these enzymes are involved and illustrates the complex network of proteins that governs their activity. An overview of small molecules that interfere with histone deacetylase function is provided.

Dynamic Skin Patterns in Cephalopods

PubMed Central

How, Martin J.; Norman, Mark D.; Finn, Julian; Chung, Wen-Sung; Marshall, N. Justin

2017-01-01

Cephalopods are unrivaled in the natural world in their ability to alter their visual appearance. These mollusks have evolved a complex system of dermal units under neural, hormonal, and muscular control to produce an astonishing variety of body patterns. With parallels to the pixels on a television screen, cephalopod chromatophores can be coordinated to produce dramatic, dynamic, and rhythmic displays, defined collectively here as “dynamic patterns.” This study examines the nature, context, and potential functions of dynamic patterns across diverse cephalopod taxa. Examples are presented for 21 species, including 11 previously unreported in the scientific literature. These range from simple flashing or flickering patterns, to highly complex passing wave patterns involving multiple skin fields. PMID:28674500

The human gut microbiota and its interactive connections to diet.

PubMed

Milani, C; Ferrario, C; Turroni, F; Duranti, S; Mangifesta, M; van Sinderen, D; Ventura, M

2016-10-01

The microbiota of the gastrointestinal tract plays an important role in human health. In addition to their metabolic interactions with dietary constituents, gut bacteria may also be involved in more complex host interactions, such as modulation of the immune system. Furthermore, the composition of the gut microbiota may be important in reducing the risk of contracting particular gut infections. Changes in the microbiota during an individual's lifespan are accompanied by modifications in multiple health parameters, and such observations have prompted intense scientific efforts aiming to understand the complex interactions between the microbiota and its human host, as well as how this may be influenced by diet. © 2016 The British Dietetic Association Ltd.

Lessons learned from the dog genome.

PubMed

Wayne, Robert K; Ostrander, Elaine A

2007-11-01

Extensive genetic resources and a high-quality genome sequence position the dog as an important model species for understanding genome evolution, population genetics and genes underlying complex phenotypic traits. Newly developed genomic resources have expanded our understanding of canine evolutionary history and dog origins. Domestication involved genetic contributions from multiple populations of gray wolves probably through backcrossing. More recently, the advent of controlled breeding practices has segregated genetic variability into distinct dog breeds that possess specific phenotypic traits. Consequently, genome-wide association and selective sweep scans now allow the discovery of genes underlying breed-specific characteristics. The dog is finally emerging as a novel resource for studying the genetic basis of complex traits, including behavior.

Molecular Facts on the Structure and Dynamics of Electrolyte Species in Cu-Cl Cycle for Hydrogen Generation: An Insight from Molecular Dynamic Simulations.

PubMed

Sahu, Pooja; Ali, Sk Musharaf; Shenoy, K T; Mohan, S

2018-04-12

The Cu complex, which is the key chemical species in well-known Cu-Cl hybrid thermochemical cycles and also in numerous metal hydrometallurgical and sedimentary deposit processes, displays a wide variety of structural and dynamical characteristics that are further complicated by the presence of multiple oxidation states of Cu ions with different coordination chemistries, therefore they are difficult to explore from experiments alone. In this article, an attempt has been made to understand the coordination behavior of the Cu complex using MD simulations. The study provides compelling evidence of the experimentally observed multiple stoichiometries of Cu ions, i.e., 1:6:0, 1:5:1, and 1:4:2 for Cu + :H 2 O:Cl - and 1:6:0 for Cu 2+ :H 2 O:Cl - . The presence of the anionic Cu complex, [Cu + Cl 2 ] - ·2H 2 O, [Cu + Cl 2 ] - ·3H 2 O, [Cu 2+ Cl 3 ] - ·H 2 O, and [Cu 2+ Cl 3 ] - ·2H 2 O, was captured in the presence of excess chloride ions. Furthermore, the probability distribution profiles have been estimated to determine the most possible complex in the considered systems. The results establish structural and dynamical reformation of the Cu complex with change in the salt concentration or variation in the solvent medium in which they are dissolved. Moreover, the structure and kinetics of the Cu ions in the Cu-Cl electrolyzer have been explored over a large range of the electric field by extending the simulated systems for varied strengths of the electric fields. It has been observed that with an increase in the strength of the electric field, the water molecules lose their coordination strength with central Cu ions, which, on the other hand, results in a significant change in the structure of the captured complex. The diffusion dynamics of the ions is altered while applying the electric field, which is furthermore modified while increasing the strength of electric field beyond a critical limit. In fact, the diffusion mechanism of the ions was seen to be transformed from Brownian-like to linear motion and then to hopping diffusion with the increasing strength of the electric field. To the best of our knowledge, this is the first time when the multiple oxidation states of the Cu ion are explored using MD simulations, and the coexisting pictures of the multiple coordinations and the solvent effects have been clearly revealed. Also to date, the present article is the first one to report the insights of the structure and the dynamics of the ions in the Cu-Cl electrolyzer over a wide range of the electric field. The present studies will be very helpful in understanding the mechanism involved in numerous metal hydrometallurgical and sedimentary deposit processes and to comprehend the analogies involved in the electrode reactions of the Cu-Cl cycle for hydrogen generation.

Understanding the occupational and organizational boundaries to safe hospital discharge.

PubMed

Waring, Justin; Marshall, Fiona; Bishop, Simon

2015-01-01

Safe hospital discharge relies upon communication and coordination across multiple occupational and organizational boundaries. Our aim was to understand how these boundaries can exacerbate health system complexity and represent latent sociocultural threats to safe discharge. An ethnographic study was conducted in two local health and social care systems (health economies) in England, focusing on two clinical areas: stroke and hip fracture patients. Data collection involved 345 hours of observations and 220 semi-structured interviews with health and social care professionals, patients and their lay carers. Hospital discharge involves a dynamic network of interactions between heterogeneous health and social care actors, each characterized by divergent ways of organizing discharge activities; cultures of collaboration and interaction and understanding of what discharge involves and how it contributes to patient recovery. These interrelated dimensions elaborate the occupational and organisational boundaries that can influence communication and coordination in hospital discharge. Hospital discharge relies upon the coordination of multiple actors working across occupational and organizational boundaries. Attention to the sociocultural boundaries that influence communication and coordination can help inform interventions that might support enhanced discharge safety. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Constitutional chromothripsis involving the critical region of 9q21.13 microdeletion syndrome.

PubMed

Genesio, Rita; Fontana, Paolo; Mormile, Angela; Casertano, Alberto; Falco, Mariateresa; Conti, Anna; Franzese, Adriana; Mozzillo, Enza; Nitsch, Lucio; Melis, Daniela

2015-01-01

The chromothripsis is a biological phenomenon, first observed in tumors and then rapidly described in congenital disorders. The principle of the chromothripsis process is the occurrence of a local shattering to pieces and rebuilding of chromosomes in a random order. Congenital chromothripsis rearrangements often involve reciprocal rearrangements on multiple chromosomes and have been described as cause of contiguous gene syndromes. We hypothesize that chromothripsis could be responsible for known 9q21.13 microdeletion syndrome, causing a composite phenotype with additional features. The case reported is a 16- years-old female with a complex genomic rearrangement of chromosome 9 including the critical region of 9q21.13 microdeletion syndrome. The patient presents with platelet disorder and thyroid dysfunction in addition to the classical neurobehavioral phenotype of the syndrome. The presence of multiple rearrangements on the same chromosome 9 and the rebuilding of chromosome in a random order suggested that the rearrangement could origin from an event of chromthripsis. To our knowledge this is the first report of congenital chromothripsis involving chromosome 9. Furthermore this is the only case of 9q21.13 microdeletion syndrome due to chromothripsis.

Metal complexes of quinolone antibiotics and their applications: an update.

PubMed

Uivarosi, Valentina

2013-09-11

Quinolones are synthetic broad-spectrum antibiotics with good oral absorption and excellent bioavailability. Due to the chemical functions found on their nucleus (a carboxylic acid function at the 3-position, and in most cases a basic piperazinyl ring (or another N-heterocycle) at the 7-position, and a carbonyl oxygen atom at the 4-position) quinolones bind metal ions forming complexes in which they can act as bidentate, as unidentate and as bridging ligand, respectively. In the polymeric complexes in solid state, multiple modes of coordination are simultaneously possible. In strongly acidic conditions, quinolone molecules possessing a basic side nucleus are protonated and appear as cations in the ionic complexes. Interaction with metal ions has some important consequences for the solubility, pharmacokinetics and bioavailability of quinolones, and is also involved in the mechanism of action of these bactericidal agents. Many metal complexes with equal or enhanced antimicrobial activity compared to the parent quinolones were obtained. New strategies in the design of metal complexes of quinolones have led to compounds with anticancer activity. Analytical applications of complexation with metal ions were oriented toward two main directions: determination of quinolones based on complexation with metal ions or, reversely, determination of metal ions based on complexation with quinolones.

Multiple ligand simultaneous docking: orchestrated dancing of ligands in binding sites of protein.

PubMed

Li, Huameng; Li, Chenglong

2010-07-30

Present docking methodologies simulate only one single ligand at a time during docking process. In reality, the molecular recognition process always involves multiple molecular species. Typical protein-ligand interactions are, for example, substrate and cofactor in catalytic cycle; metal ion coordination together with ligand(s); and ligand binding with water molecules. To simulate the real molecular binding processes, we propose a novel multiple ligand simultaneous docking (MLSD) strategy, which can deal with all the above processes, vastly improving docking sampling and binding free energy scoring. The work also compares two search strategies: Lamarckian genetic algorithm and particle swarm optimization, which have respective advantages depending on the specific systems. The methodology proves robust through systematic testing against several diverse model systems: E. coli purine nucleoside phosphorylase (PNP) complex with two substrates, SHP2NSH2 complex with two peptides and Bcl-xL complex with ABT-737 fragments. In all cases, the final correct docking poses and relative binding free energies were obtained. In PNP case, the simulations also capture the binding intermediates and reveal the binding dynamics during the recognition processes, which are consistent with the proposed enzymatic mechanism. In the other two cases, conventional single-ligand docking fails due to energetic and dynamic coupling among ligands, whereas MLSD results in the correct binding modes. These three cases also represent potential applications in the areas of exploring enzymatic mechanism, interpreting noisy X-ray crystallographic maps, and aiding fragment-based drug design, respectively. 2010 Wiley Periodicals, Inc.

Complex pelvic ring injuries associated with floating knee in a poly-trauma patient: A case report.

PubMed

Zhou, Yuebin; Guo, Honggang; Cai, Zhiwei; Zhang, Yuan

2017-12-01

Complex pelvic ring fracture associated with floating knee is comparatively rare which usually results from high-energy trauma including vehicle-related accidence, falls from height, and earthquake-related injury. To our knowledge, few literatures have documented such injuries in the individual patient. Management of both injuries present challenges for surgical management and postoperative care. The purpose of this study is to prove the feasibility and benefits of damage control orthopedics (DCO). Our case involved a 45-year-old lady who was hit by a dilapidated building. The patient was anxious, pale and hemodynamically stable at the initial examination. The pelvis was unstable and there were obvious deformities in the left lower extremities. Significant degloved injuries in the left leg were noted. Her radiographs and physical examination verified the above signs. Unstable pelvic fractures, multiple fractures of bilateral lower limbs with floating knee injury, multiple pelvic and rib fractures and multiple degloving injuries and soft tissue contusion formed the characteristics of the multiple-injury. The algorithm of DCO was determined as the treatment. Early simplified procedures such as wound debridement, pelvis fixation, closed reduction and EF of the right shoulder joint, and chest wall fixation were conducted as soon as possible. After a period of time, internal fixations were applied to the fracture sites. The subsequent functional exercise was also conducted in accordance with this algorithm. This patient got recovery after the treatments which were guided by the criterion of DCO. The restoration of limb functional and the quality of life greatly improved. The DCO plays a decisive role in the first aid and follow-up treatment of this patient. The guidelines of management of complex pelvic ring injuries and floating knee should be established by authorities.

Surgeon preparedness for mass casualty events: Adapting essential military surgical lessons for the home front.

PubMed

Remick, Kyle N; Shackelford, Stacy; Oh, John S; Seery, Jason M; Grabo, Daniel; Chovanes, John; Gross, Kirby R; Nessen, Shawn C; Tai, Nigel Rm; Rickard, Rory F; Elster, Eric; Schwab, C W

2016-01-01

Military surgeons have gained familiarity and experience with mass casualty events (MCEs) as a matter of routine over the course of the last two conflicts in Afghanistan and Iraq. Over the same period of time, civilian surgeons have increasingly faced complex MCEs on the home front. Our objective is to summarize and adapt these combat surgery lessons to enhance civilian surgeon preparedness for complex MCEs on the home front. The authors describe the unique lessons learned from combat surgery over the course of the wars in Afghanistan and Iraq and adapt these lessons to enhance civilian surgical readiness for a MCE on the home front. Military Damage Control Surgery (mDCS) combines the established concept of clinical DCS (cDCS) with key combat situational awareness factors that enable surgeons to optimally care for multiple, complex patients, from multiple simultaneous events, with limited resources. These additional considerations involve the surgeon's role of care within the deployed trauma system and the battlefield effects. The proposed new concept of mass casualty DCS (mcDCS) similarly combines cDCS decisions with key factors of situational awareness for civilian surgeons faced with complex MCEs to optimize outcomes. The additional considerations for a civilian MCE include the surgeon's role of care within the regional trauma system and the incident effects. Adapting institutionalized lessons from combat surgery to civilian surgical colleagues will enhance national preparedness for complex MCEs on the home front.

Actin Out: Regulation of the Synaptic Cytoskeleton

PubMed Central

Spence, Erin F.; Soderling, Scott H.

2015-01-01

The small size of dendritic spines belies the elaborate role they play in excitatory synaptic transmission and ultimately complex behaviors. The cytoskeletal architecture of the spine is predominately composed of actin filaments. These filaments, which at first glance might appear simple, are also surprisingly complex. They dynamically assemble into different structures and serve as a platform for orchestrating the elaborate responses of the spine during spinogenesis and experience-dependent plasticity. Multiple mutations associated with human neurodevelopmental and psychiatric disorders involve genes that encode regulators of the synaptic cytoskeleton. A major, unresolved question is how the disruption of specific actin filament structures leads to the onset and progression of complex synaptic and behavioral phenotypes. This review will cover established and emerging mechanisms of actin cytoskeletal remodeling and how this influences specific aspects of spine biology that are implicated in disease. PMID:26453304

Spastic Paraplegia Type 7 Is Associated with Multiple Mitochondrial DNA Deletions

PubMed Central

Wedding, Iselin Marie; Koht, Jeanette; Tran, Gia Tuong; Misceo, Doriana; Selmer, Kaja Kristine; Holmgren, Asbjørn; Frengen, Eirik; Bindoff, Laurence; Tallaksen, Chantal M. E.; Tzoulis, Charalampos

2014-01-01

Spastic paraplegia 7 is an autosomal recessive disorder caused by mutations in the gene encoding paraplegin, a protein located at the inner mitochondrial membrane and involved in the processing of other mitochondrial proteins. The mechanism whereby paraplegin mutations cause disease is unknown. We studied two female and two male adult patients from two Norwegian families with a combination of progressive external ophthalmoplegia and spastic paraplegia. Sequencing of SPG7 revealed a novel missense mutation, c.2102A>C, p.H 701P, which was homozygous in one family and compound heterozygous in trans with a known pathogenic mutation c.1454_1462del in the other. Muscle was examined from an additional, unrelated adult female patient with a similar phenotype caused by a homozygous c.1047insC mutation in SPG7. Immunohistochemical studies in skeletal muscle showed mosaic deficiency predominantly affecting respiratory complex I, but also complexes III and IV. Molecular studies in single, microdissected fibres showed multiple mitochondrial DNA deletions segregating at high levels (38–97%) in respiratory deficient fibres. Our findings demonstrate for the first time that paraplegin mutations cause accumulation of mitochondrial DNA damage and multiple respiratory chain deficiencies. While paraplegin is not known to be directly associated with the mitochondrial nucleoid, it is known to process other mitochondrial proteins and it is possible therefore that paraplegin mutations lead to mitochondrial DNA deletions by impairing proteins involved in the homeostasis of the mitochondrial genome. These studies increase our understanding of the molecular pathogenesis of SPG7 mutations and suggest that SPG7 testing should be included in the diagnostic workup of autosomal recessive, progressive external ophthalmoplegia, especially if spasticity is present. PMID:24466038

[Autism in children. Speech, behavior and motor activity point to diagnosis].

PubMed

Neumärker, K J

2001-02-01

Austistic disorders characteristically involve specific impairments of social skills, of the language and of stereotyped body movements. L Kanner and H. Asperger were the first to describe these psychopathologic features, which still form the core of the diagnostic criteria of contemporary psychiatric classification systems, ICD-10 and DSM-IV, in the category pervasive developmental disorders. Useful diagnostic tools have been developed to establish the clinical diagnosis. The results of research point to a predominantly genetic pathogenesis involving a complex interaction of multiple genes. While no causal treatments are available for these heterogenic disorders, there are many therapeutic concepts. Although some treatments may achieve significant improvements, autistic disorders usually mean a lifelong individual impairment.

Assessment of wastewater treatment alternatives for small communities: An analytic network process approach.

PubMed

Molinos-Senante, María; Gómez, Trinidad; Caballero, Rafael; Hernández-Sancho, Francesc; Sala-Garrido, Ramón

2015-11-01

The selection of the most appropriate wastewater treatment (WWT) technology is a complex problem since many alternatives are available and many criteria are involved in the decision-making process. To deal with this challenge, the analytic network process (ANP) is applied for the first time to rank a set of seven WWT technology set-ups for secondary treatment in small communities. A major advantage of ANP is that it incorporates interdependent relationships between elements. Results illustrated that extensive technologies, constructed wetlands and pond systems are the most preferred alternatives by WWT experts. The sensitivity analysis performed verified that the ranking of WWT alternatives is very stable since constructed wetlands are almost always placed in the first position. This paper showed that ANP analysis is suitable to deal with complex decision-making problems, such as the selection of the most appropriate WWT system contributing to better understand the multiple interdependences among elements involved in the assessment. Copyright © 2015 Elsevier B.V. All rights reserved.

Cognition, dopamine and bioactive lipids in schizophrenia

PubMed Central

Condray, Ruth; Yao, Jeffrey K.

2011-01-01

Schizophrenia is a remarkably complex disorder with a multitude of behavioral and biological perturbations. Cognitive deficits are a core feature of this disorder, and involve abnormalities across multiple domains, including memory, attention, and perception. The complexity of this debilitating illness has led to a view that the key to unraveling its pathophysiology lies in deconstructing the clinically-defined syndrome into pathophysiologically distinct intermediate phenotypes. Accumulating evidence suggests that one of these intermediate phenotypes may involve phospholipid signaling abnormalities, particularly in relation to arachidonic acid (AA). Our data show relationships between levels of AA and performance on tests of cognition for schizophrenia patients, with defects in AA signaling associated with deficits in cognition. Moreover, dopamine may moderate these relationships between AA and cognition. Taken together, cognitive deficits, dopaminergic neurotransmission, and bioactive lipids have emerged as related features of schizophrenia. Existing treatment options for cognitive deficits in schizophrenia do not specifically target lipid-derived signaling pathways; understanding these processes could inform efforts to identify novel targets for treatment innovation. PMID:21196378

EEG based topography analysis in string recognition task

NASA Astrophysics Data System (ADS)

Ma, Xiaofei; Huang, Xiaolin; Shen, Yuxiaotong; Qin, Zike; Ge, Yun; Chen, Ying; Ning, Xinbao

2017-03-01

Vision perception and recognition is a complex process, during which different parts of brain are involved depending on the specific modality of the vision target, e.g. face, character, or word. In this study, brain activities in string recognition task compared with idle control state are analyzed through topographies based on multiple measurements, i.e. sample entropy, symbolic sample entropy and normalized rhythm power, extracted from simultaneously collected scalp EEG. Our analyses show that, for most subjects, both symbolic sample entropy and normalized gamma power in string recognition task are significantly higher than those in idle state, especially at locations of P4, O2, T6 and C4. It implies that these regions are highly involved in string recognition task. Since symbolic sample entropy measures complexity, from the perspective of new information generation, and normalized rhythm power reveals the power distributions in frequency domain, complementary information about the underlying dynamics can be provided through the two types of indices.

Risk and Representation in Research Ethics: The NunatuKavut Experience.

PubMed

Brunger, Fern; Russell, Todd

2015-10-01

This article examines Canadian policy governing the ethics of research involving Indigenous communities. Academics and community members collaborated in research to examine how best to apply the Tri-Council Policy Statement guidelines in a community with complex and multiple political and cultural jurisdictions. We examined issues of NunatuKavut (Southern Inuit) authority and representation in relation to governance of research in a context where community identity is complex and shifting, and new provincial legislation mandates centralized ethics review. We describe the politics of risk--the ways in which collective identity and research risks are co-constructed. Our case study illustrates that collective consent to research must emphasize shifting identity construction in relation to the particular risks and benefits invoked by the research question, to ascertain with which groups or individuals the negotiation of risk should take place in the first place. We conclude by describing a necessary re-imagining of policy governing research ethics involving Indigenous communities. © The Author(s) 2015.

Mena binds α5 integrin directly and modulates α5β1 function.

PubMed

Gupton, Stephanie L; Riquelme, Daisy; Hughes-Alford, Shannon K; Tadros, Jenny; Rudina, Shireen S; Hynes, Richard O; Lauffenburger, Douglas; Gertler, Frank B

2012-08-20

Mena is an Ena/VASP family actin regulator with roles in cell migration, chemotaxis, cell-cell adhesion, tumor cell invasion, and metastasis. Although enriched in focal adhesions, Mena has no established function within these structures. We find that Mena forms an adhesion-regulated complex with α5β1 integrin, a fibronectin receptor involved in cell adhesion, motility, fibronectin fibrillogenesis, signaling, and growth factor receptor trafficking. Mena bound directly to the carboxy-terminal portion of the α5 cytoplasmic tail via a 91-residue region containing 13 five-residue "LERER" repeats. In fibroblasts, the Mena-α5 complex was required for "outside-in" α5β1 functions, including normal phosphorylation of FAK and paxillin and formation of fibrillar adhesions. It also supported fibrillogenesis and cell spreading and controlled cell migration speed. Thus, fibroblasts require Mena for multiple α5β1-dependent processes involving bidirectional interactions between the extracellular matrix and cytoplasmic focal adhesion proteins.

Mena binds α5 integrin directly and modulates α5β1 function

PubMed Central

Riquelme, Daisy; Hughes-Alford, Shannon K.; Tadros, Jenny; Rudina, Shireen S.; O.Hynes, Richard; Lauffenburger, Douglas

2012-01-01

Mena is an Ena/VASP family actin regulator with roles in cell migration, chemotaxis, cell–cell adhesion, tumor cell invasion, and metastasis. Although enriched in focal adhesions, Mena has no established function within these structures. We find that Mena forms an adhesion-regulated complex with α5β1 integrin, a fibronectin receptor involved in cell adhesion, motility, fibronectin fibrillogenesis, signaling, and growth factor receptor trafficking. Mena bound directly to the carboxy-terminal portion of the α5 cytoplasmic tail via a 91-residue region containing 13 five-residue “LERER” repeats. In fibroblasts, the Mena–α5 complex was required for “outside-in” α5β1 functions, including normal phosphorylation of FAK and paxillin and formation of fibrillar adhesions. It also supported fibrillogenesis and cell spreading and controlled cell migration speed. Thus, fibroblasts require Mena for multiple α5β1-dependent processes involving bidirectional interactions between the extracellular matrix and cytoplasmic focal adhesion proteins. PMID:22908313

A heterobimetallic complex featuring a Ti–Co multiple bond and its application to the reductive coupling of ketones to alkenes† †Electronic supplementary information (ESI) available: Experimental procedures, additional spectroscopic data for 1–4, and computational details of 2 and 3. CCDC 1037714–1037716. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4sc03772c Click here for additional data file. Click here for additional data file.

PubMed Central

Wu, Bing; Bezpalko, Mark W.; Foxman, Bruce M.

2015-01-01

To explore metal–metal multiple bonds between first row transition metals, Ti/Co complexes supported by two phosphinoamide ligands have been synthesized and characterized. The Ti metalloligand Cl2Ti(XylNPiPr2)2 (1) was treated with CoI2 under reducing conditions, permitting isolation of the Ti/Co complex [(μ-Cl)Ti(XylNPiPr2)2CoI]2 (2). One electron reduction of complex 2 affords ClTi(XylNPiPr2)2CoPMe3 (3), which features a metal–metal triple bond and an unprecedentedly short Ti–Co distance of 2.0236(9) Å. This complex is shown to promote the McMurry coupling reaction of aryl ketones into alkenes, with concomitant formation of the tetranuclear complex [Ti(μ3-O)(NXylPiPr2)2CoI]2 (4). A cooperative mechanism involving bimetallic C 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 O bond activation and a cobalt carbene intermediate is proposed. PMID:29142672

A dominant mutation in mediator of paramutation2, one of three second-largest subunits of a plant-specific RNA polymerase, disrupts multiple siRNA silencing processes.

PubMed

Sidorenko, Lyudmila; Dorweiler, Jane E; Cigan, A Mark; Arteaga-Vazquez, Mario; Vyas, Meenal; Kermicle, Jerry; Jurcin, Diane; Brzeski, Jan; Cai, Yu; Chandler, Vicki L

2009-11-01

Paramutation involves homologous sequence communication that leads to meiotically heritable transcriptional silencing. We demonstrate that mop2 (mediator of paramutation2), which alters paramutation at multiple loci, encodes a gene similar to Arabidopsis NRPD2/E2, the second-largest subunit of plant-specific RNA polymerases IV and V. In Arabidopsis, Pol-IV and Pol-V play major roles in RNA-mediated silencing and a single second-largest subunit is shared between Pol-IV and Pol-V. Maize encodes three second-largest subunit genes: all three genes potentially encode full length proteins with highly conserved polymerase domains, and each are expressed in multiple overlapping tissues. The isolation of a recessive paramutation mutation in mop2 from a forward genetic screen suggests limited or no functional redundancy of these three genes. Potential alternative Pol-IV/Pol-V-like complexes could provide maize with a greater diversification of RNA-mediated transcriptional silencing machinery relative to Arabidopsis. Mop2-1 disrupts paramutation at multiple loci when heterozygous, whereas previously silenced alleles are only up-regulated when Mop2-1 is homozygous. The dramatic reduction in b1 tandem repeat siRNAs, but no disruption of silencing in Mop2-1 heterozygotes, suggests the major role for tandem repeat siRNAs is not to maintain silencing. Instead, we hypothesize the tandem repeat siRNAs mediate the establishment of the heritable silent state-a process fully disrupted in Mop2-1 heterozygotes. The dominant Mop2-1 mutation, which has a single nucleotide change in a domain highly conserved among all polymerases (E. coli to eukaryotes), disrupts both siRNA biogenesis (Pol-IV-like) and potentially processes downstream (Pol-V-like). These results suggest either the wild-type protein is a subunit in both complexes or the dominant mutant protein disrupts both complexes. Dominant mutations in the same domain in E. coli RNA polymerase suggest a model for Mop2-1 dominance: complexes containing Mop2-1 subunits are non-functional and compete with wild-type complexes.

Markers of sympathetic nervous system activity associate with complex plasma lipids in metabolic syndrome subjects.

PubMed

Nestel, Paul J; Khan, Anmar A; Straznicky, Nora E; Mellett, Natalie A; Jayawardana, Kaushala; Mundra, Piyushkumar A; Lambert, Gavin W; Meikle, Peter J

2017-01-01

Plasma sphingolipids including ceramides, and gangliosides are associated with insulin resistance (IR) through effects on insulin signalling and glucose metabolism. Our studies of subjects with metabolic syndrome (MetS) showed close relationships between IR and sympathetic nervous system (SNS) activity including arterial norepinephrine (NE). We have therefore investigated possible associations of IR and SNS activity with complex lipids that are involved in both insulin sensitivity and neurotransmission. We performed a cross-sectional assessment of 23 lipid classes/subclasses (total 339 lipid species) by tandem mass spectrometry in 94 overweight untreated subjects with IR (quantified by HOMA-IR, Matsuda index and plasma insulin). Independently of IR parameters, several circulating complex lipids associated significantly with arterial NE and NEFA (non-esterified fatty acids) and marginally with heart rate (HR). After accounting for BMI, HOMA-IR, systolic BP, age, gender, and correction for multiple comparisons, these associations were significant (p < 0.05): NE with ceramide, phosphatidylcholine, alkyl- and alkenylphosphatidylcholine and free cholesterol; NEFA with mono- di- and trihexosylceramide, G M3 ganglioside, sphingomyelin, phosphatidylcholine, alkyl- and alkenylphosphatidylcholine, phosphatidylinositol and free cholesterol; HR marginally (p = or <0.1>0.05) with ceramide, G M3 ganglioside, sphingomyelin, lysophosphatidylcholine, phosphatidylinositol, lysophosphatidylinositol and free cholesterol. Multiple subspecies of these lipids significantly associated with NE and NEFA. None of the IR biomarkers associated significantly with lipid classes/subclasses after correction for multiple comparisons. This is the first demonstration that arterial norepinephrine and NEFA, that reflect both SNS activity and IR, associate significantly with circulating complex lipids independently of IR, suggesting a role for such lipids in neural mechanisms operating in MetS. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Modeling of multiple equilibria in the self-aggregation of di-n-decyldimethylammonium chloride/octaethylene glycol monododecyl ether/cyclodextrin ternary systems.

PubMed

Leclercq, Loïc; Lubart, Quentin; Aubry, Jean-Marie; Nardello-Rataj, Véronique

2013-05-28

The surface tension equations of binary surfactant mixtures (di-n-decyldimethylammonium chloride and octaethylene glycol monododecyl ether) are established by combining the Szyszkowski equation of surfactant solutions, the ideal or nonideal mixing theory, and the phase separation model. For surfactant mixtures, the surface tension at the air-water interface is calculated using nonideal theory due to synergism between the two adsorbed surfactant types. The incorporation of cyclodextrin complexation model to the surface tension equations gives a robust model for the description of the surface tension isotherms of binary, ternary, and more complex systems involving numerous inclusion complexes. The surface tension data obtained experimentally shows excellent agreement with the theoretical model below and above the formation of micelles. The strong synergistic effect observed between the two surfactants is disrupted by the presence of CDs, leading to ideal behavior of ternary systems. Indeed, depending on the nature of the cyclodextrin (i.e., α, β, or γ), which allows a tuning of the cavity size, the binding constants with the surfactants are modified as well as the surface properties due to strong modification of equilibria involved in the ternary mixture.

Hunting down the chimera of multiple disciplinarity in conservation science.

PubMed

Pooley, Simon P; Mendelsohn, J Andrew; Milner-Gulland, E J

2014-02-01

The consensus is that both ecological and social factors are essential dimensions of conservation research and practice. However, much of the literature on multiple disciplinary collaboration focuses on the difficulties of undertaking it. This review of the challenges of conducting multiple disciplinary collaboration offers a framework for thinking about the diversity and complexity of this endeavor. We focused on conceptual challenges, of which 5 main categories emerged: methodological challenges, value judgments, theories of knowledge, disciplinary prejudices, and interdisciplinary communication. The major problems identified in these areas have proved remarkably persistent in the literature surveyed (c.1960-2012). Reasons for these failures to learn from past experience include the pressure to produce positive outcomes and gloss over disagreements, the ephemeral nature of many such projects and resulting lack of institutional memory, and the apparent complexity and incoherence of the endeavor. We suggest that multiple disciplinary collaboration requires conceptual integration among carefully selected multiple disciplinary team members united in investigating a shared problem or question. We outline a 9-point sequence of steps for setting up a successful multiple disciplinary project. This encompasses points on recruitment, involving stakeholders, developing research questions, negotiating power dynamics and hidden values and conceptual differences, explaining and choosing appropriate methods, developing a shared language, facilitating on-going communications, and discussing data integration and project outcomes. Although numerous solutions to the challenges of multiple disciplinary research have been proposed, lessons learned are often lost when projects end or experienced individuals move on. We urge multiple disciplinary teams to capture the challenges recognized, and solutions proposed, by their researchers while projects are in process. A database of well-documented case studies would showcase theories and methods from a variety of disciplines and their interactions, enable better comparative study and evaluation, and provide a useful resource for developing future projects and training multiple disciplinary researchers. © 2013 The Authors. Conservation Biology published by Wiley Periodicals, Inc. on behalf of Society for Conservation Biology.

Hunting Down the Chimera of Multiple Disciplinarity in Conservation Science

PubMed Central

POOLEY, SIMON P; MENDELSOHN, J ANDREW; MILNER-GULLAND, E J

2014-01-01

The consensus is that both ecological and social factors are essential dimensions of conservation research and practice. However, much of the literature on multiple disciplinary collaboration focuses on the difficulties of undertaking it. This review of the challenges of conducting multiple disciplinary collaboration offers a framework for thinking about the diversity and complexity of this endeavor. We focused on conceptual challenges, of which 5 main categories emerged: methodological challenges, value judgments, theories of knowledge, disciplinary prejudices, and interdisciplinary communication. The major problems identified in these areas have proved remarkably persistent in the literature surveyed (c.1960–2012). Reasons for these failures to learn from past experience include the pressure to produce positive outcomes and gloss over disagreements, the ephemeral nature of many such projects and resulting lack of institutional memory, and the apparent complexity and incoherence of the endeavor. We suggest that multiple disciplinary collaboration requires conceptual integration among carefully selected multiple disciplinary team members united in investigating a shared problem or question. We outline a 9-point sequence of steps for setting up a successful multiple disciplinary project. This encompasses points on recruitment, involving stakeholders, developing research questions, negotiating power dynamics and hidden values and conceptual differences, explaining and choosing appropriate methods, developing a shared language, facilitating on-going communications, and discussing data integration and project outcomes. Although numerous solutions to the challenges of multiple disciplinary research have been proposed, lessons learned are often lost when projects end or experienced individuals move on. We urge multiple disciplinary teams to capture the challenges recognized, and solutions proposed, by their researchers while projects are in process. A database of well-documented case studies would showcase theories and methods from a variety of disciplines and their interactions, enable better comparative study and evaluation, and provide a useful resource for developing future projects and training multiple disciplinary researchers. PMID:24299167

Complex inguinal hernia repairs.

PubMed

Beitler, J C; Gomes, S M; Coelho, A C J; Manso, J E F

2009-02-01

Complex inguinal hernia treatment is a challenge for general surgeons. The gold standard for the repair of inguinal hernias is the Lichtenstein repair (anterior approach). However, when multiple recurrent hernias or giant hernias are present, it is necessary to choose different approaches because the incidence of poor results increases. There are many preperitoneal approaches described in the literature. For example: (a) open procedure-Nyhus and Stoppa (b) laparoscopic technique-transabdominal pre-peritoneal (TAPP) and totally extraperitoneal (TEP). In this study, we show how we repair complicated cases using open access in huge unilateral or bilateral, recurrent, or multiple recurrent inguinal hernias. The present study includes the period from November 1993 through December 2007. One hundred and eighty-eight patients, divided into 121 with unilateral hernias and 67 with bilateral hernias, totaling 255 inguinal hernia repairs, were treated by the Nyhus or Stoppa preperitoneal approach, depending on whether they were unilateral or bilateral. We used progressive preoperative pneumoperitoneum for oversize inguinal hernias in all patients. Orchiectomy was necessary on only two occasions. Despite the repair complexity involved, we had only two known recurrences. The mortality was zero and the morbidity was acceptable. We conclude that an accurate open preperitoneal approach using mesh prosthesis for complex inguinal hernias is safe, with very low recurrent rates and low morbidity. Progressive preoperative pneumoperitoneum for giant hernias was shown to be an important factor in accomplishing good intraoperative and immediate postoperative results.

How are things adding up? Neural differences between arithmetic operations are due to general problem solving strategies.

PubMed

Tschentscher, Nadja; Hauk, Olaf

2014-05-15

A number of previous studies have interpreted differences in brain activation between arithmetic operation types (e.g. addition and multiplication) as evidence in favor of distinct cortical representations, processes or neural systems. It is still not clear how differences in general task complexity contribute to these neural differences. Here, we used a mental arithmetic paradigm to disentangle brain areas related to general problem solving from those involved in operation type specific processes (addition versus multiplication). We orthogonally varied operation type and complexity. Importantly, complexity was defined not only based on surface criteria (for example number size), but also on the basis of individual participants' strategy ratings, which were validated in a detailed behavioral analysis. We replicated previously reported operation type effects in our analyses based on surface criteria. However, these effects vanished when controlling for individual strategies. Instead, procedural strategies contrasted with memory retrieval reliably activated fronto-parietal and motor regions, while retrieval strategies activated parietal cortices. This challenges views that operation types rely on partially different neural systems, and suggests that previously reported differences between operation types may have emerged due to invalid measures of complexity. We conclude that mental arithmetic is a powerful paradigm to study brain networks of abstract problem solving, as long as individual participants' strategies are taken into account. Copyright © 2014 Elsevier Inc. All rights reserved.

Juvenile social experience and differential age-related changes in the dendritic morphologies of subareas of the prefrontal cortex in rats.

PubMed

Himmler, Brett T; Mychasiuk, Richelle; Nakahashi, Ayuno; Himmler, Stephanie M; Pellis, Sergio M; Kolb, Bryan

2018-04-01

Juvenile social interactions have been shown to influence the dendritic complexity of neurons in the prefrontal cortex (PFC). In particular, social play induces pruning of the cells in the medial prefrontal cortex (mPFC), whereas interacting with multiple partners, whether those interactions involve play or not, increases the complexity of cells in the orbital frontal cortex (OFC). Previous studies suggest that these changes differ in their stability during adulthood. In the present study, rats were reared in groups of either four (quads) or two (pairs) and the brains of the rats from each rearing condition were then harvested at 60 days (i.e., shortly after sexual maturity) and 100 days (i.e., fully adult). The rats housed with multiple partners had more complex neurons of the OFC at 60 days and this complexity declined to a comparable level to that of pair housed rats by 100 days. In contrast, the play-induced changes of the mPFC remained similar at both ages. These findings suggest that the changes in the PFC induced by different social experiences in the juvenile period differ in how long they are maintained in adulthood. Differences in the functions regulated by the OFC and the mPFC are considered with regard to these differences in the stability of juvenile-induced neural changes. © 2017 Wiley Periodicals, Inc.

Combining blue native polyacrylamide gel electrophoresis with liquid chromatography tandem mass spectrometry as an effective strategy for analyzing potential membrane protein complexes of Mycobacterium bovis bacillus Calmette-Guérin

PubMed Central

2011-01-01

Background Tuberculosis is an infectious bacterial disease in humans caused primarily by Mycobacterium tuberculosis, and infects one-third of the world's total population. Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccine has been widely used to prevent tuberculosis worldwide since 1921. Membrane proteins play important roles in various cellular processes, and the protein-protein interactions involved in these processes may provide further information about molecular organization and cellular pathways. However, membrane proteins are notoriously under-represented by traditional two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) and little is known about mycobacterial membrane and membrane-associated protein complexes. Here we investigated M. bovis BCG by an alternative proteomic strategy coupling blue native PAGE to liquid chromatography tandem mass spectrometry (LC-MS/MS) to characterize potential protein-protein interactions in membrane fractions. Results Using this approach, we analyzed native molecular composition of protein complexes in BCG membrane fractions. As a result, 40 proteins (including 12 integral membrane proteins), which were organized in 9 different gel bands, were unambiguous identified. The proteins identified have been experimentally confirmed using 2-D SDS PAGE. We identified MmpL8 and four neighboring proteins that were involved in lipid transport complexes, and all subunits of ATP synthase complex in their monomeric states. Two phenolpthiocerol synthases and three arabinosyltransferases belonging to individual operons were obtained in different gel bands. Furthermore, two giant multifunctional enzymes, Pks7 and Pks8, and four mycobacterial Hsp family members were determined. Additionally, seven ribosomal proteins involved in polyribosome complex and two subunits of the succinate dehydrogenase complex were also found. Notablely, some proteins with high hydrophobicity or multiple transmembrane helixes were identified well in our work. Conclusions In this study, we utilized LC-MS/MS in combination with blue native PAGE to characterize modular components of multiprotein complexes in BCG membrane fractions. The results demonstrated that the proteomic strategy was a reliable and reproducible tool for analysis of BCG multiprotein complexes. The identification in our study may provide some evidence for further study of BCG protein interaction. PMID:21241518

Nutraceuticals against Neurodegeneration: A Mechanistic Insight.

PubMed

Dadhania, Vivekkumar P; Trivedi, Priyanka P; Vikram, Ajit; Tripathi, Durga Nand

2016-01-01

The mechanisms underlying neurodegenerative disorders are complex and multifactorial; however, accumulating evidences suggest few common shared pathways. These common pathways include mitochondrial dysfunction, intracellular Ca2+ overload, oxidative stress and inflammation. Often multiple pathways co-exist, and therefore limit the benefits of therapeutic interventions. Nutraceuticals have recently gained importance owing to their multifaceted effects. These food-based approaches are believed to target multiple pathways in a slow but more physiological manner without causing severe adverse effects. Available information strongly supports the notion that apart from preventing the onset of neuronal damage, nutraceuticals can potentially attenuate the continued progression of neuronal destruction. In this article, we i) review the common pathways involved in the pathogenesis of the toxicants-induced neurotoxicity and neurodegenerative disorders with special emphasis on Alzheimer`s disease (AD), Parkinson`s disease (PD), Huntington`s disease (HD), Multiple sclerosis (MS) and Amyotrophic lateral sclerosis (ALS), and ii) summarize current research advancements on the effects of nutraceuticals against these detrimental pathways.

Nutraceuticals against Neurodegeneration: A Mechanistic Insight

PubMed Central

Dadhania, Vivekkumar P.; Trivedi, Priyanka P.; Vikram, Ajit; Tripathi, Durga Nand

2016-01-01

The mechanisms underlying neurodegenerative disorders are complex and multifactorial; however, accumulating evidences suggest few common shared pathways. These common pathways include mitochondrial dysfunction, intracellular Ca2+ overload, oxidative stress and inflammation. Often multiple pathways co-exist, and therefore limit the benefits of therapeutic interventions. Nutraceuticals have recently gained importance owing to their multifaceted effects. These food-based approaches are believed to target multiple pathways in a slow but more physiological manner without causing severe adverse effects. Available information strongly supports the notion that apart from preventing the onset of neuronal damage, nutraceuticals can potentially attenuate the continued progression of neuronal destruction. In this article, we i) review the common pathways involved in the pathogenesis of the toxicants-induced neurotoxicity and neurodegenerative disorders with special emphasis on Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Multiple sclerosis (MS) and Amyotrophic lateral sclerosis (ALS), and ii) summarize current research advancements on the effects of nutraceuticals against these detrimental pathways. PMID:26725888

Isolation with Migration Models for More Than Two Populations

PubMed Central

Hey, Jody

2010-01-01

A method for studying the divergence of multiple closely related populations is described and assessed. The approach of Hey and Nielsen (2007, Integration within the Felsenstein equation for improved Markov chain Monte Carlo methods in population genetics. Proc Natl Acad Sci USA. 104:2785–2790) for fitting an isolation-with-migration model was extended to the case of multiple populations with a known phylogeny. Analysis of simulated data sets reveals the kinds of history that are accessible with a multipopulation analysis. Necessarily, processes associated with older time periods in a phylogeny are more difficult to estimate; and histories with high levels of gene flow are particularly difficult with more than two populations. However, for histories with modest levels of gene flow, or for very large data sets, it is possible to study large complex divergence problems that involve multiple closely related populations or species. PMID:19955477

Isolation with migration models for more than two populations.

PubMed

Hey, Jody

2010-04-01

A method for studying the divergence of multiple closely related populations is described and assessed. The approach of Hey and Nielsen (2007, Integration within the Felsenstein equation for improved Markov chain Monte Carlo methods in population genetics. Proc Natl Acad Sci USA. 104:2785-2790) for fitting an isolation-with-migration model was extended to the case of multiple populations with a known phylogeny. Analysis of simulated data sets reveals the kinds of history that are accessible with a multipopulation analysis. Necessarily, processes associated with older time periods in a phylogeny are more difficult to estimate; and histories with high levels of gene flow are particularly difficult with more than two populations. However, for histories with modest levels of gene flow, or for very large data sets, it is possible to study large complex divergence problems that involve multiple closely related populations or species.

Crack Damage Detection Method via Multiple Visual Features and Efficient Multi-Task Learning Model.

PubMed

Wang, Baoxian; Zhao, Weigang; Gao, Po; Zhang, Yufeng; Wang, Zhe

2018-06-02

This paper proposes an effective and efficient model for concrete crack detection. The presented work consists of two modules: multi-view image feature extraction and multi-task crack region detection. Specifically, multiple visual features (such as texture, edge, etc.) of image regions are calculated, which can suppress various background noises (such as illumination, pockmark, stripe, blurring, etc.). With the computed multiple visual features, a novel crack region detector is advocated using a multi-task learning framework, which involves restraining the variability for different crack region features and emphasizing the separability between crack region features and complex background ones. Furthermore, the extreme learning machine is utilized to construct this multi-task learning model, thereby leading to high computing efficiency and good generalization. Experimental results of the practical concrete images demonstrate that the developed algorithm can achieve favorable crack detection performance compared with traditional crack detectors.

The intrinsically disordered C-terminal domain of the measles virus nucleoprotein interacts with the C-terminal domain of the phosphoprotein via two distinct sites and remains predominantly unfolded

PubMed Central

Bourhis, Jean-Marie; Receveur-Bréchot, Véronique; Oglesbee, Michael; Zhang, Xinsheng; Buccellato, Matthew; Darbon, Hervé; Canard, Bruno; Finet, Stéphanie; Longhi, Sonia

2005-01-01

Measles virus is a negative-sense, single-stranded RNA virus within theMononegavirales order,which includes several human pathogens, including rabies, Ebola, Nipah, and Hendra viruses. Themeasles virus nucleoprotein consists of a structured N-terminal domain, and of an intrinsically disordered C-terminal domain, NTAIL (aa 401–525), which undergoes induced folding in the presence of the C-terminal domain (XD, aa 459–507) of the viral phosphoprotein. With in NTAIL, an α-helical molecular recognition element (α-MoRE, aa 488–499) involved in binding to P and in induced folding was identified and then observed in the crystal structure of XD. Using small-angle X-ray scattering, we have derived a low-resolution structural model of the complex between XD and NTAIL, which shows that most of NTAIL remains disordered in the complex despite P-induced folding within the α-MoRE. The model consists of an extended shape accommodating the multiple conformations adopted by the disordered N-terminal region of NTAIL, and of a bulky globular region, corresponding to XD and to the C terminus of NTAIL (aa 486–525). Using surface plasmon resonance, circular dichroism, fluorescence spectroscopy, and heteronuclear magnetic resonance, we show that NTAIL has an additional site (aa 517–525) involved in binding to XD but not in the unstructured-to-structured transition. This work provides evidence that intrinsically disordered domains can establish complex interactions with their partners, and can contact them through multiple sites that do not all necessarily gain regular secondary structure. PMID:16046624

Living supramolecular polymerization achieved by collaborative assembly of platinum(II) complexes and block copolymers

PubMed Central

Zhang, Kaka; Yeung, Margaret Ching-Lam; Leung, Sammual Yu-Lut; Yam, Vivian Wing-Wah

2017-01-01

An important feature of biological systems to achieve complexity and precision is the involvement of multiple components where each component plays its own role and collaborates with other components. Mimicking this, we report living supramolecular polymerization achieved by collaborative assembly of two structurally dissimilar components, that is, platinum(II) complexes and poly(ethylene glycol)-b-poly(acrylic acid) (PEG-b-PAA). The PAA blocks neutralize the charges of the platinum(II) complexes, with the noncovalent metal–metal and π–π interactions directing the longitudinal growth of the platinum(II) complexes into 1D crystalline nanostructures, and the PEG blocks inhibiting the transverse growth of the platinum(II) complexes and providing the whole system with excellent solubility. The ends of the 1D crystalline nanostructures have been found to be active during the assembly and remain active after the assembly. One-dimensional segmented nanostructures with heterojunctions have been produced by sequential growth of two types of platinum(II) complexes. The PAA blocks act as adapters at the heterojunctions for lattice matching between chemically and crystallographically different platinum(II) complexes, achieving heterojunctions with a lattice mismatch as large as 21%. PMID:29078381

Upper extremity paraesthesia: clinical assessment and reasoning.

PubMed

Muscolino, Joseph E

2008-07-01

The art of clinical assessment involves an accurate determination of the cause(s) of a patient's symptoms. Given that a set of symptoms can be influenced by many contributing factors and features, assessment needs to differentially evaluate these. Accurate and appropriate treatment depends on differential assessment based on sound clinical reasoning. Many conditions derive from multiple causes demanding evaluation of as many etiological features as can be identified. The case review presented here involves a patient presenting with paraesthesia spreading into her right upper extremity. A complex history, involving her neck and contralateral upper extremity was assessed. The patient was found to have at least seven underlying, predisposing, and etiological, conditions capable of initiating, aggravating, or maintaining the presenting symptoms. Weighing the relative contributions of these often interacting features, and correlating this with the history, helped to identify a successful course of treatment.

Unmasking molecular profiles of bladder cancer.

PubMed

Piao, Xuan-Mei; Byun, Young Joon; Kim, Wun-Jae; Kim, Jayoung

2018-03-01

Precision medicine is designed to tailor treatments for individual patients by factoring in each person's specific biology and mechanism of disease. This paradigm shifted from a "one size fits all" approach to "personalized and precision care" requires multiple layers of molecular profiling of biomarkers for accurate diagnosis and prediction of treatment responses. Intensive studies are also being performed to understand the complex and dynamic molecular profiles of bladder cancer. These efforts involve looking bladder cancer mechanism at the multiple levels of the genome, epigenome, transcriptome, proteome, lipidome, metabolome etc. The aim of this short review is to outline the current technologies being used to investigate molecular profiles and discuss biomarker candidates that have been investigated as possible diagnostic and prognostic indicators of bladder cancer.

Energy Efficiency in Public Buildings through Context-Aware Social Computing.

PubMed

García, Óscar; Alonso, Ricardo S; Prieto, Javier; Corchado, Juan M

2017-04-11

The challenge of promoting behavioral changes in users that leads to energy savings in public buildings has become a complex task requiring the involvement of multiple technologies. Wireless sensor networks have a great potential for the development of tools, such as serious games, that encourage acquiring good energy and healthy habits among users in the workplace. This paper presents the development of a serious game using CAFCLA, a framework that allows for integrating multiple technologies, which provide both context-awareness and social computing. Game development has shown that the data provided by sensor networks encourage users to reduce energy consumption in their workplace and that social interactions and competitiveness allow for accelerating the achievement of good results and behavioral changes that favor energy savings.

A Standard Platform for Testing and Comparison of MDAO Architectures

NASA Technical Reports Server (NTRS)

Gray, Justin S.; Moore, Kenneth T.; Hearn, Tristan A.; Naylor, Bret A.

2012-01-01

The Multidisciplinary Design Analysis and Optimization (MDAO) community has developed a multitude of algorithms and techniques, called architectures, for performing optimizations on complex engineering systems which involve coupling between multiple discipline analyses. These architectures seek to efficiently handle optimizations with computationally expensive analyses including multiple disciplines. We propose a new testing procedure that can provide a quantitative and qualitative means of comparison among architectures. The proposed test procedure is implemented within the open source framework, OpenMDAO, and comparative results are presented for five well-known architectures: MDF, IDF, CO, BLISS, and BLISS-2000. We also demonstrate how using open source soft- ware development methods can allow the MDAO community to submit new problems and architectures to keep the test suite relevant.

A simple test of association for contingency tables with multiple column responses.

PubMed

Decady, Y J; Thomas, D R

2000-09-01

Loughin and Scherer (1998, Biometrics 54, 630-637) investigated tests of association in two-way tables when one of the categorical variables allows for multiple-category responses from individual respondents. Standard chi-squared tests are invalid in this case, and they developed a bootstrap test procedure that provides good control of test levels under the null hypothesis. This procedure and some others that have been proposed are computationally involved and are based on techniques that are relatively unfamiliar to many practitioners. In this paper, the methods introduced by Rao and Scott (1981, Journal of the American Statistical Association 76, 221-230) for analyzing complex survey data are used to develop a simple test based on a corrected chi-squared statistic.

Identifying mechanisms of change in a conversation therapy for aphasia using behaviour change theory and qualitative methods

PubMed Central

Best, Wendy; Beckley, Firle Christina; Maxim, Jane; Beeke, Suzanne

2016-01-01

Abstract Background Conversation therapy for aphasia is a complex intervention comprising multiple components and targeting multiple outcomes. UK Medical Research Council (MRC) guidelines published in 2008 recommend that in addition to measuring the outcomes of complex interventions, evaluation should seek to clarify how such outcomes are produced, including identifying the hypothesized mechanisms of change. Aims To identify mechanisms of change within a conversation therapy for people with aphasia and their partners. Using qualitative methods, the study draws on behaviour change theory to understand how and why participants make changes in conversation during and after therapy. Methods & Procedures Data were derived from 16 participants (eight people with aphasia; eight conversation partners) who were recruited to the Better Conversations with Aphasia research project and took part in an eight session conversation therapy programme. The dataset consists of in‐therapy discussions and post‐therapy interviews, which are analysed using Framework Analysis. Outcomes & Results Seven mechanisms of conversational behaviour change are identified and linked to theory. These show how therapy can activate changes to speakers’ skills and motivation for using specific behaviours, and to the conversational opportunities available for strategy use. Conclusions & Implications These clinically relevant findings offer guidance about the processes involved in producing behavioural change via conversation therapy. A distinction is made between the process involved in motivating change and that involved in embedding change. Differences are also noted between the process engaged in reducing unhelpful behaviour and that supporting new uses of compensatory strategies. Findings are expected to have benefits for those seeking to replicate therapy's core processes both in clinical practice and in future research. PMID:27882642

Identifying mechanisms of change in a conversation therapy for aphasia using behaviour change theory and qualitative methods.

PubMed

Johnson, Fiona M; Best, Wendy; Beckley, Firle Christina; Maxim, Jane; Beeke, Suzanne

2017-05-01

Conversation therapy for aphasia is a complex intervention comprising multiple components and targeting multiple outcomes. UK Medical Research Council (MRC) guidelines published in 2008 recommend that in addition to measuring the outcomes of complex interventions, evaluation should seek to clarify how such outcomes are produced, including identifying the hypothesized mechanisms of change. To identify mechanisms of change within a conversation therapy for people with aphasia and their partners. Using qualitative methods, the study draws on behaviour change theory to understand how and why participants make changes in conversation during and after therapy. Data were derived from 16 participants (eight people with aphasia; eight conversation partners) who were recruited to the Better Conversations with Aphasia research project and took part in an eight session conversation therapy programme. The dataset consists of in-therapy discussions and post-therapy interviews, which are analysed using Framework Analysis. Seven mechanisms of conversational behaviour change are identified and linked to theory. These show how therapy can activate changes to speakers' skills and motivation for using specific behaviours, and to the conversational opportunities available for strategy use. These clinically relevant findings offer guidance about the processes involved in producing behavioural change via conversation therapy. A distinction is made between the process involved in motivating change and that involved in embedding change. Differences are also noted between the process engaged in reducing unhelpful behaviour and that supporting new uses of compensatory strategies. Findings are expected to have benefits for those seeking to replicate therapy's core processes both in clinical practice and in future research. © 2016 Royal College of Speech and Language Therapists.

Identification of Single- and Multiple-Class Specific Signature Genes from Gene Expression Profiles by Group Marker Index

PubMed Central

Tsai, Yu-Shuen; Aguan, Kripamoy; Pal, Nikhil R.; Chung, I-Fang

2011-01-01

Informative genes from microarray data can be used to construct prediction model and investigate biological mechanisms. Differentially expressed genes, the main targets of most gene selection methods, can be classified as single- and multiple-class specific signature genes. Here, we present a novel gene selection algorithm based on a Group Marker Index (GMI), which is intuitive, of low-computational complexity, and efficient in identification of both types of genes. Most gene selection methods identify only single-class specific signature genes and cannot identify multiple-class specific signature genes easily. Our algorithm can detect de novo certain conditions of multiple-class specificity of a gene and makes use of a novel non-parametric indicator to assess the discrimination ability between classes. Our method is effective even when the sample size is small as well as when the class sizes are significantly different. To compare the effectiveness and robustness we formulate an intuitive template-based method and use four well-known datasets. We demonstrate that our algorithm outperforms the template-based method in difficult cases with unbalanced distribution. Moreover, the multiple-class specific genes are good biomarkers and play important roles in biological pathways. Our literature survey supports that the proposed method identifies unique multiple-class specific marker genes (not reported earlier to be related to cancer) in the Central Nervous System data. It also discovers unique biomarkers indicating the intrinsic difference between subtypes of lung cancer. We also associate the pathway information with the multiple-class specific signature genes and cross-reference to published studies. We find that the identified genes participate in the pathways directly involved in cancer development in leukemia data. Our method gives a promising way to find genes that can involve in pathways of multiple diseases and hence opens up the possibility of using an existing drug on other diseases as well as designing a single drug for multiple diseases. PMID:21909426

Cancer Systems Biology Consortium | Informatics Technology for Cancer Research (ITCR)

Cancer.gov

Cancer is a complex disease system involving multiple molecular, genetic, and cellular events. From its early initiation through progression and metastasis, cancer can adapt and evolve as a result of both internal and external signals. These properties make cancer difficult to predict, prevent, and treat. There has been significant progress in characterizing the genetics of cancer, as well as the downstream effects on the molecular and cellular pathways that are critical for the initiation and progression of cancer.

Coherence, Energy and Charge Transfers in De-Excitation Pathways of Electronic Excited State of Biomolecules in Photosynthesis

NASA Astrophysics Data System (ADS)

Bohr, Henrik G.; Malik, F. Bary

2013-11-01

The observed multiple de-excitation pathways of photo-absorbed electronic excited state in the peridinin-chlorophyll complex, involving both energy and charge transfers among its constituents, are analyzed using the bio-Auger (B-A) theory. It is also shown that the usually used Förster-Dexter theory, which does not allow for charge transfer, is a special case of B-A theory. The latter could, under appropriate circumstances, lead to excimers.

Supporting Space Systems Design via Systems Dependency Analysis Methodology

NASA Astrophysics Data System (ADS)

Guariniello, Cesare

The increasing size and complexity of space systems and space missions pose severe challenges to space systems engineers. When complex systems and Systems-of-Systems are involved, the behavior of the whole entity is not only due to that of the individual systems involved but also to the interactions and dependencies between the systems. Dependencies can be varied and complex, and designers usually do not perform analysis of the impact of dependencies at the level of complex systems, or this analysis involves excessive computational cost, or occurs at a later stage of the design process, after designers have already set detailed requirements, following a bottom-up approach. While classical systems engineering attempts to integrate the perspectives involved across the variety of engineering disciplines and the objectives of multiple stakeholders, there is still a need for more effective tools and methods capable to identify, analyze and quantify properties of the complex system as a whole and to model explicitly the effect of some of the features that characterize complex systems. This research describes the development and usage of Systems Operational Dependency Analysis and Systems Developmental Dependency Analysis, two methods based on parametric models of the behavior of complex systems, one in the operational domain and one in the developmental domain. The parameters of the developed models have intuitive meaning, are usable with subjective and quantitative data alike, and give direct insight into the causes of observed, and possibly emergent, behavior. The approach proposed in this dissertation combines models of one-to-one dependencies among systems and between systems and capabilities, to analyze and evaluate the impact of failures or delays on the outcome of the whole complex system. The analysis accounts for cascading effects, partial operational failures, multiple failures or delays, and partial developmental dependencies. The user of these methods can assess the behavior of each system based on its internal status and on the topology of its dependencies on systems connected to it. Designers and decision makers can therefore quickly analyze and explore the behavior of complex systems and evaluate different architectures under various working conditions. The methods support educated decision making both in the design and in the update process of systems architecture, reducing the need to execute extensive simulations. In particular, in the phase of concept generation and selection, the information given by the methods can be used to identify promising architectures to be further tested and improved, while discarding architectures that do not show the required level of global features. The methods, when used in conjunction with appropriate metrics, also allow for improved reliability and risk analysis, as well as for automatic scheduling and re-scheduling based on the features of the dependencies and on the accepted level of risk. This dissertation illustrates the use of the two methods in sample aerospace applications, both in the operational and in the developmental domain. The applications show how to use the developed methodology to evaluate the impact of failures, assess the criticality of systems, quantify metrics of interest, quantify the impact of delays, support informed decision making when scheduling the development of systems and evaluate the achievement of partial capabilities. A larger, well-framed case study illustrates how the Systems Operational Dependency Analysis method and the Systems Developmental Dependency Analysis method can support analysis and decision making, at the mid and high level, in the design process of architectures for the exploration of Mars. The case study also shows how the methods do not replace the classical systems engineering methodologies, but support and improve them.

Rapid heterogeneous assembly of multiple magma reservoirs prior to Yellowstone supereruptions.

PubMed

Wotzlaw, Jörn-Frederik; Bindeman, Ilya N; Stern, Richard A; D'Abzac, Francois-Xavier; Schaltegger, Urs

2015-09-10

Large-volume caldera-forming eruptions of silicic magmas are an important feature of continental volcanism. The timescales and mechanisms of assembly of the magma reservoirs that feed such eruptions as well as the durations and physical conditions of upper-crustal storage remain highly debated topics in volcanology. Here we explore a comprehensive data set of isotopic (O, Hf) and chemical proxies in precisely U-Pb dated zircon crystals from all caldera-forming eruptions of Yellowstone supervolcano. Analysed zircons record rapid assembly of multiple magma reservoirs by repeated injections of isotopically heterogeneous magma batches and short pre-eruption storage times of 10(3) to 10(4) years. Decoupled oxygen-hafnium isotope systematics suggest a complex source for these magmas involving variable amounts of differentiated mantle-derived melt, Archean crust and hydrothermally altered shallow-crustal rocks. These data demonstrate that complex magma reservoirs with multiple sub-chambers are a common feature of rift- and hotspot related supervolcanoes. The short duration of reservoir assembly documents rapid crustal remelting and two to three orders of magnitude higher magma production rates beneath Yellowstone compared to continental arc volcanoes. The short pre-eruption storage times further suggest that the detection of voluminous reservoirs of eruptible magma beneath active supervolcanoes may only be possible prior to an impending eruption.

Rapid heterogeneous assembly of multiple magma reservoirs prior to Yellowstone supereruptions

PubMed Central

Wotzlaw, Jörn-Frederik; Bindeman, Ilya N.; Stern, Richard A.; D’Abzac, Francois-Xavier; Schaltegger, Urs

2015-01-01

Large-volume caldera-forming eruptions of silicic magmas are an important feature of continental volcanism. The timescales and mechanisms of assembly of the magma reservoirs that feed such eruptions as well as the durations and physical conditions of upper-crustal storage remain highly debated topics in volcanology. Here we explore a comprehensive data set of isotopic (O, Hf) and chemical proxies in precisely U-Pb dated zircon crystals from all caldera-forming eruptions of Yellowstone supervolcano. Analysed zircons record rapid assembly of multiple magma reservoirs by repeated injections of isotopically heterogeneous magma batches and short pre-eruption storage times of 103 to 104 years. Decoupled oxygen-hafnium isotope systematics suggest a complex source for these magmas involving variable amounts of differentiated mantle-derived melt, Archean crust and hydrothermally altered shallow-crustal rocks. These data demonstrate that complex magma reservoirs with multiple sub-chambers are a common feature of rift- and hotspot related supervolcanoes. The short duration of reservoir assembly documents rapid crustal remelting and two to three orders of magnitude higher magma production rates beneath Yellowstone compared to continental arc volcanoes. The short pre-eruption storage times further suggest that the detection of voluminous reservoirs of eruptible magma beneath active supervolcanoes may only be possible prior to an impending eruption. PMID:26356304

Arabidopsis TOBAMOVIRUS MULTIPLICATION (TOM) 2 locus encodes a transmembrane protein that interacts with TOM1

PubMed Central

Tsujimoto, Yayoi; Numaga, Takuro; Ohshima, Kiyoshi; Yano, Masa-aki; Ohsawa, Ryuji; Goto, Derek B.; Naito, Satoshi; Ishikawa, Masayuki

2003-01-01

The tom2-1 mutation of Arabidopsis thaliana reduces the efficiency of intracellular multiplication of tobamoviruses. The tom2-1 mutant was derived from fast-neutron-irradiated seeds, and the original mutant line also carries ttm1, a dominant modifier that increases tobamovirus multiplication efficiency in a tobamovirus-strain-specific manner in the tom2-1 genetic background. Here, we show that the tom2-1 mutation involved a deletion of ∼20 kb in the nuclear genome. The deleted region included two genes named TOM2A and TOM2B that were both associated with the tom2-1 phenotype, whereas ttm1 corresponded to the translocation of part of the deleted region that included intact TOM2B but not TOM2A. TOM2A encodes a 280 amino acid putative four-pass transmembrane protein with a C-terminal farnesylation signal, while TOM2B encodes a 122 amino acid basic protein. The split-ubiquitin assay demonstrated an interaction of TOM2A both with itself and with TOM1, an integral membrane protein of A.thaliana presumed to be an essential constituent of tobamovirus replication complex. The data presented here suggest that TOM2A is also an integral part of the tobamovirus replication complex. PMID:12514139

Function of multiple Lis-Homology domain/WD-40 repeat-containing proteins in feed-forward transcriptional repression by silencing mediator for retinoic and thyroid receptor/nuclear receptor corepressor complexes.

PubMed

Choi, Hyo-Kyoung; Choi, Kyung-Chul; Kang, Hee-Bum; Kim, Han-Cheon; Lee, Yoo-Hyun; Haam, Seungjoo; Park, Hyoung-Gi; Yoon, Ho-Geun

2008-05-01

Lis-homology (LisH) motifs are involved in protein dimerization, and the discovery of the conserved N-terminal LisH domain in transducin beta-like protein 1 and its receptor (TBL1 and TBLR1) led us to examine the role of this domain in transcriptional repression. Here we show that multiple beta-transducin (WD-40) repeat-containing proteins interact to form oligomers in solution and that oligomerization depends on the presence of the LisH domain in each protein. Repression of transcription, as assayed using Gal4 fusion proteins, also depended on the presence of the LisH domain, suggesting that oligomerization is a prerequisite for efficient transcriptional repression. Furthermore, we show that the LisH domain is responsible for the binding to the hypoacetylated histone H4 tail and for stable chromatin targeting by the nuclear receptor corepressor complex. Mutations in conserved residues in the LisH motif of TBL1 and TBLR1 block histone binding, oligomerization, and transcriptional repression, supporting the functional importance of the LisH motif in transcriptional repression. Our results indicate that another WD-40 protein, TBL3, also preferentially binds to the N-terminal domain of TBL1 and TBLR1, and forms oligomers with other WD-40 proteins. Finally, we observed that the WD-40 proteins RbAp46 and RbAp48 of the sin3A corepressor complex failed to dimerize. We also found the specific interaction UbcH/E2 with TBL1, but not RbAp46/48. Altogether, our results thus indicate that the presence of multiple LisH/WD-40 repeat containing proteins is exclusive to nuclear receptor corepressor/ silencing mediator for retinoic and thyroid receptor complexes compared with other class 1 histone deacetylase-containing corepessor complexes.

Evaluation of metabolites extraction strategies for identifying different brain regions and their relationship with alcohol preference and gender difference using NMR metabolomics.

PubMed

Wang, Jie; Zeng, Hao-Long; Du, Hongying; Liu, Zeyuan; Cheng, Ji; Liu, Taotao; Hu, Ting; Kamal, Ghulam Mustafa; Li, Xihai; Liu, Huili; Xu, Fuqiang

2018-03-01

Metabolomics generate a profile of small molecules from cellular/tissue metabolism, which could directly reflect the mechanisms of complex networks of biochemical reactions. Traditional metabolomics methods, such as OPLS-DA, PLS-DA are mainly used for binary class discrimination. Multiple groups are always involved in the biological system, especially for brain research. Multiple brain regions are involved in the neuronal study of brain metabolic dysfunctions such as alcoholism, Alzheimer's disease, etc. In the current study, 10 different brain regions were utilized for comparative studies between alcohol preferring and non-preferring rats, male and female rats respectively. As many classes are involved (ten different regions and four types of animals), traditional metabolomics methods are no longer efficient for showing differentiation. Here, a novel strategy based on the decision tree algorithm was employed for successfully constructing different classification models to screen out the major characteristics of ten brain regions at the same time. Subsequently, this method was also utilized to select the major effective brain regions related to alcohol preference and gender difference. Compared with the traditional multivariate statistical methods, the decision tree could construct acceptable and understandable classification models for multi-class data analysis. Therefore, the current technology could also be applied to other general metabolomics studies involving multi class data. Copyright © 2017 Elsevier B.V. All rights reserved.

Complex matrix multiplication operations with data pre-conditioning in a high performance computing architecture

DOEpatents

Eichenberger, Alexandre E; Gschwind, Michael K; Gunnels, John A

2014-02-11

Mechanisms for performing a complex matrix multiplication operation are provided. A vector load operation is performed to load a first vector operand of the complex matrix multiplication operation to a first target vector register. The first vector operand comprises a real and imaginary part of a first complex vector value. A complex load and splat operation is performed to load a second complex vector value of a second vector operand and replicate the second complex vector value within a second target vector register. The second complex vector value has a real and imaginary part. A cross multiply add operation is performed on elements of the first target vector register and elements of the second target vector register to generate a partial product of the complex matrix multiplication operation. The partial product is accumulated with other partial products and a resulting accumulated partial product is stored in a result vector register.

Decoding the Heart through Next Generation Sequencing Approaches.

PubMed

Pawlak, Michal; Niescierowicz, Katarzyna; Winata, Cecilia Lanny

2018-06-07

: Vertebrate organs develop through a complex process which involves interaction between multiple signaling pathways at the molecular, cell, and tissue levels. Heart development is an example of such complex process which, when disrupted, results in congenital heart disease (CHD). This complexity necessitates a holistic approach which allows the visualization of genome-wide interaction networks, as opposed to assessment of limited subsets of factors. Genomics offers a powerful solution to address the problem of biological complexity by enabling the observation of molecular processes at a genome-wide scale. The emergence of next generation sequencing (NGS) technology has facilitated the expansion of genomics, increasing its output capacity and applicability in various biological disciplines. The application of NGS in various aspects of heart biology has resulted in new discoveries, generating novel insights into this field of study. Here we review the contributions of NGS technology into the understanding of heart development and its disruption reflected in CHD and discuss how emerging NGS based methodologies can contribute to the further understanding of heart repair.

Biomimicry Promotes the Efficiency of a 10-Step Sequential Enzymatic Reaction on Nanoparticles, Converting Glucose to Lactate.

PubMed

Mukai, Chinatsu; Gao, Lizeng; Nelson, Jacquelyn L; Lata, James P; Cohen, Roy; Wu, Lauren; Hinchman, Meleana M; Bergkvist, Magnus; Sherwood, Robert W; Zhang, Sheng; Travis, Alexander J

2017-01-02

For nanobiotechnology to achieve its potential, complex organic-inorganic systems must grow to utilize the sequential functions of multiple biological components. Critical challenges exist: immobilizing enzymes can block substrate-binding sites or prohibit conformational changes, substrate composition can interfere with activity, and multistep reactions risk diffusion of intermediates. As a result, the most complex tethered reaction reported involves only 3 enzymes. Inspired by the oriented immobilization of glycolytic enzymes on the fibrous sheath of mammalian sperm, here we show a complex reaction of 10 enzymes tethered to nanoparticles. Although individual enzyme efficiency was higher in solution, the efficacy of the 10-step pathway measured by conversion of glucose to lactate was significantly higher when tethered. To our knowledge, this is the most complex organic-inorganic system described, and it shows that tethered, multi-step biological pathways can be reconstituted in hybrid systems to carry out functions such as energy production or delivery of molecular cargo. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Biomimicry promotes the efficiency of a 10-step sequential enzymatic reaction on nanoparticles, converting glucose to lactate

PubMed Central

Mukai, Chinatsu; Gao, Lizeng; Nelson, Jacquelyn L.; Lata, James P.; Cohen, Roy; Wu, Lauren; Hinchman, Meleana M.; Bergkvist, Magnus; Sherwood, Robert W.; Zhang, Sheng; Travis, Alexander J.

2016-01-01

For nanobiotechnology to achieve its potential, complex organic-inorganic systems must grow to utilize the sequential functions of multiple biological components. Critical challenges exist: immobilizing enzymes can block substrate-binding sites or prohibit conformational changes, substrate composition can interfere with activity, and multistep reactions risk diffusion of intermediates. As a result, the most complex tethered reaction reported involves only 3 enzymes. Inspired by the oriented immobilization of glycolytic enzymes on the fibrous sheath of mammalian sperm, here we show a complex reaction of 10 enzymes tethered to nanoparticles. Although individual enzyme efficiency was higher in solution, the efficacy of the 10-step pathway measured by conversion of glucose to lactate was significantly higher when tethered. To our knowledge, this is the most complex organic-inorganic system described, and it shows that tethered, multi-step biological pathways can be reconstituted in hybrid systems to carry out functions such as energy production or delivery of molecular cargo. PMID:27901298

Constructing and Modifying Sequence Statistics for relevent Using informR in 𝖱

PubMed Central

Marcum, Christopher Steven; Butts, Carter T.

2015-01-01

The informR package greatly simplifies the analysis of complex event histories in 𝖱 by providing user friendly tools to build sufficient statistics for the relevent package. Historically, building sufficient statistics to model event sequences (of the form a→b) using the egocentric generalization of Butts’ (2008) relational event framework for modeling social action has been cumbersome. The informR package simplifies the construction of the complex list of arrays needed by the rem() model fitting for a variety of cases involving egocentric event data, multiple event types, and/or support constraints. This paper introduces these tools using examples from real data extracted from the American Time Use Survey. PMID:26185488

How much do we know about the coupling of G-proteins to serotonin receptors?

PubMed Central

2014-01-01

Serotonin receptors are G-protein-coupled receptors (GPCRs) involved in a variety of psychiatric disorders. G-proteins, heterotrimeric complexes that couple to multiple receptors, are activated when their receptor is bound by the appropriate ligand. Activation triggers a cascade of further signalling events that ultimately result in cell function changes. Each of the several known G-protein types can activate multiple pathways. Interestingly, since several G-proteins can couple to the same serotonin receptor type, receptor activation can result in induction of different pathways. To reach a better understanding of the role, interactions and expression of G-proteins a literature search was performed in order to list all the known heterotrimeric combinations and serotonin receptor complexes. Public databases were analysed to collect transcript and protein expression data relating to G-proteins in neural tissues. Only a very small number of heterotrimeric combinations and G-protein-receptor complexes out of the possible thousands suggested by expression data analysis have been examined experimentally. In addition this has mostly been obtained using insect, hamster, rat and, to a lesser extent, human cell lines. Besides highlighting which interactions have not been explored, our findings suggest additional possible interactions that should be examined based on our expression data analysis. PMID:25011628

How much do we know about the coupling of G-proteins to serotonin receptors?

PubMed

Giulietti, Matteo; Vivenzio, Viviana; Piva, Francesco; Principato, Giovanni; Bellantuono, Cesario; Nardi, Bernardo

2014-07-10

Serotonin receptors are G-protein-coupled receptors (GPCRs) involved in a variety of psychiatric disorders. G-proteins, heterotrimeric complexes that couple to multiple receptors, are activated when their receptor is bound by the appropriate ligand. Activation triggers a cascade of further signalling events that ultimately result in cell function changes. Each of the several known G-protein types can activate multiple pathways. Interestingly, since several G-proteins can couple to the same serotonin receptor type, receptor activation can result in induction of different pathways. To reach a better understanding of the role, interactions and expression of G-proteins a literature search was performed in order to list all the known heterotrimeric combinations and serotonin receptor complexes. Public databases were analysed to collect transcript and protein expression data relating to G-proteins in neural tissues. Only a very small number of heterotrimeric combinations and G-protein-receptor complexes out of the possible thousands suggested by expression data analysis have been examined experimentally. In addition this has mostly been obtained using insect, hamster, rat and, to a lesser extent, human cell lines. Besides highlighting which interactions have not been explored, our findings suggest additional possible interactions that should be examined based on our expression data analysis.

On the importance of considering heterogeneity in witnesses' competence levels when reconstructing crimes from multiple witness testimonies.

PubMed

Waubert de Puiseau, Berenike; Greving, Sven; Aßfalg, André; Musch, Jochen

2017-09-01

Aggregating information across multiple testimonies may improve crime reconstructions. However, different aggregation methods are available, and research on which method is best suited for aggregating multiple observations is lacking. Furthermore, little is known about how variance in the accuracy of individual testimonies impacts the performance of competing aggregation procedures. We investigated the superiority of aggregation-based crime reconstructions involving multiple individual testimonies and whether this superiority varied as a function of the number of witnesses and the degree of heterogeneity in witnesses' ability to accurately report their observations. Moreover, we examined whether heterogeneity in competence levels differentially affected the relative accuracy of two aggregation procedures: a simple majority rule, which ignores individual differences, and the more complex general Condorcet model (Romney et al., Am Anthropol 88(2):313-338, 1986; Batchelder and Romney, Psychometrika 53(1):71-92, 1988), which takes into account differences in competence between individuals. 121 participants viewed a simulated crime and subsequently answered 128 true/false questions about the crime. We experimentally generated groups of witnesses with homogeneous or heterogeneous competences. Both the majority rule and the general Condorcet model provided more accurate reconstructions of the observed crime than individual testimonies. The superiority of aggregated crime reconstructions involving multiple individual testimonies increased with an increasing number of witnesses. Crime reconstructions were most accurate when competences were heterogeneous and aggregation was based on the general Condorcet model. We argue that a formal aggregation should be considered more often when eyewitness testimonies have to be assessed and that the general Condorcet model provides a good framework for such aggregations.

An interdisciplinary approach to personalized medicine: case studies from a cardiogenetics clinic.

PubMed

Erskine, Kathleen E; Griffith, Eleanor; Degroat, Nicole; Stolerman, Marina; Silverstein, Louise B; Hidayatallah, Nadia; Wasserman, David; Paljevic, Esma; Cohen, Lilian; Walsh, Christine A; McDonald, Thomas; Marion, Robert W; Dolan, Siobhan M

2013-01-01

In the genomic age, the challenges presented by various inherited conditions present a compelling argument for an interdisciplinary model of care. Cardiac arrhythmias with a genetic basis, such as long QT syndrome, require clinicians with expertise in many specialties to address the complex genetic, psychological, ethical and medical issues involved in treatment. The Montefiore-Einstein Center for CardioGenetics has been established to provide personalized, interdisciplinary care for families with a history of sudden cardiac death or an acute cardiac event. Four vignettes of patient care are presented to illustrate the unique capacity of an interdisciplinary model to address genetic, psychological, ethical and medical issues. Because interdisciplinary clinics facilitate collaboration among multiple specialties, they allow for individualized, comprehensive care to be delivered to families who experience complex inherited medical conditions. As the genetic basis of many complex conditions is discovered, the advantages of an interdisciplinary approach for delivering personalized medicine will become more evident.

Genomic signatures of evolutionary transitions from solitary to group living

PubMed Central

Kapheim, Karen M.; Pan, Hailin; Li, Cai; Salzberg, Steven L.; Puiu, Daniela; Magoc, Tanja; Robertson, Hugh M.; Hudson, Matthew E.; Venkat, Aarti; Fischman, Brielle J.; Hernandez, Alvaro; Yandell, Mark; Ence, Daniel; Holt, Carson; Yocum, George D.; Kemp, William P.; Bosch, Jordi; Waterhouse, Robert M.; Zdobnov, Evgeny M.; Stolle, Eckart; Kraus, F. Bernhard; Helbing, Sophie; Moritz, Robin F. A.; Glastad, Karl M.; Hunt, Brendan G.; Goodisman, Michael A. D.; Hauser, Frank; Grimmelikhuijzen, Cornelis J. P.; Pinheiro, Daniel Guariz; Nunes, Francis Morais Franco; Soares, Michelle Prioli Miranda; Tanaka, Érica Donato; Simões, Zilá Luz Paulino; Hartfelder, Klaus; Evans, Jay D.; Barribeau, Seth M.; Johnson, Reed M.; Massey, Jonathan H.; Southey, Bruce R.; Hasselmann, Martin; Hamacher, Daniel; Biewer, Matthias; Kent, Clement F.; Zayed, Amro; Blatti, Charles; Sinha, Saurabh; Johnston, J. Spencer; Hanrahan, Shawn J.; Kocher, Sarah D.; Wang, Jun; Robinson, Gene E.; Zhang, Guojie

2017-01-01

The evolution of eusociality is one of the major transitions in evolution, but the underlying genomic changes are unknown. We compared the genomes of 10 bee species that vary in social complexity, representing multiple independent transitions in social evolution, and report three major findings. First, many important genes show evidence of neutral evolution as a consequence of relaxed selection with increasing social complexity. Second, there is no single road map to eusociality; independent evolutionary transitions in sociality have independent genetic underpinnings. Third, though clearly independent in detail, these transitions do have similar general features, including an increase in constrained protein evolution accompanied by increases in the potential for gene regulation and decreases in diversity and abundance of transposable elements. Eusociality may arise through different mechanisms each time, but would likely always involve an increase in the complexity of gene networks. PMID:25977371

Social evolution. Genomic signatures of evolutionary transitions from solitary to group living.

PubMed

Kapheim, Karen M; Pan, Hailin; Li, Cai; Salzberg, Steven L; Puiu, Daniela; Magoc, Tanja; Robertson, Hugh M; Hudson, Matthew E; Venkat, Aarti; Fischman, Brielle J; Hernandez, Alvaro; Yandell, Mark; Ence, Daniel; Holt, Carson; Yocum, George D; Kemp, William P; Bosch, Jordi; Waterhouse, Robert M; Zdobnov, Evgeny M; Stolle, Eckart; Kraus, F Bernhard; Helbing, Sophie; Moritz, Robin F A; Glastad, Karl M; Hunt, Brendan G; Goodisman, Michael A D; Hauser, Frank; Grimmelikhuijzen, Cornelis J P; Pinheiro, Daniel Guariz; Nunes, Francis Morais Franco; Soares, Michelle Prioli Miranda; Tanaka, Érica Donato; Simões, Zilá Luz Paulino; Hartfelder, Klaus; Evans, Jay D; Barribeau, Seth M; Johnson, Reed M; Massey, Jonathan H; Southey, Bruce R; Hasselmann, Martin; Hamacher, Daniel; Biewer, Matthias; Kent, Clement F; Zayed, Amro; Blatti, Charles; Sinha, Saurabh; Johnston, J Spencer; Hanrahan, Shawn J; Kocher, Sarah D; Wang, Jun; Robinson, Gene E; Zhang, Guojie

2015-06-05

The evolution of eusociality is one of the major transitions in evolution, but the underlying genomic changes are unknown. We compared the genomes of 10 bee species that vary in social complexity, representing multiple independent transitions in social evolution, and report three major findings. First, many important genes show evidence of neutral evolution as a consequence of relaxed selection with increasing social complexity. Second, there is no single road map to eusociality; independent evolutionary transitions in sociality have independent genetic underpinnings. Third, though clearly independent in detail, these transitions do have similar general features, including an increase in constrained protein evolution accompanied by increases in the potential for gene regulation and decreases in diversity and abundance of transposable elements. Eusociality may arise through different mechanisms each time, but would likely always involve an increase in the complexity of gene networks. Copyright © 2015, American Association for the Advancement of Science.

Systematic coarse-grained modeling of complexation between small interfering RNA and polycations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wei, Zonghui; Luijten, Erik, E-mail: luijten@northwestern.edu; Department of Materials Science and Engineering, Northwestern University, Evanston, Illinois 60208

All-atom molecular dynamics simulations can provide insight into the properties of polymeric gene-delivery carriers by elucidating their interactions and detailed binding patterns with nucleic acids. However, to explore nanoparticle formation through complexation of these polymers and nucleic acids and study their behavior at experimentally relevant time and length scales, a reliable coarse-grained model is needed. Here, we systematically develop such a model for the complexation of small interfering RNA (siRNA) and grafted polyethyleneimine copolymers, a promising candidate for siRNA delivery. We compare the predictions of this model with all-atom simulations and demonstrate that it is capable of reproducing detailed bindingmore » patterns, charge characteristics, and water release kinetics. Since the coarse-grained model accelerates the simulations by one to two orders of magnitude, it will make it possible to quantitatively investigate nanoparticle formation involving multiple siRNA molecules and cationic copolymers.« less

Associations among multiple markers and complex disease: models, algorithms, and applications.

PubMed

Assimes, Themistocles L; Olshen, Adam B; Narasimhan, Balasubramanian; Olshen, Richard A

2008-01-01

This chapter is a report on collaborations among its authors and others over many years. It devolves from our goal of understanding genes, their main and epistatic effects combined with interactions involving demographic and environmental features also, as together they predict genetically complex diseases. Thus, our goal is "association." Particular phenotypes of interest to us are hypertension, insulin resistance, angina, and myocardial infarction. Prediction of complex disease is notoriously difficult, though it would be made easier were we given strand-specific information on genotype. Unfortunately, with current technology, genotypic information comes to us "unphased." While obviously we have strand-specific information when genotype is homozygous, we do not have such information when genotype is heterozygous. To summarize, the ultimate goals of approaches we provide is to predict phenotype, typically untoward or not, within a specific window of time. Our approach is neither through linkage nor from finding haplotype frequencies per se.

From genotype to phenotype: genetics and medical practice in the new millennium.

PubMed Central

Weatherall, D

1999-01-01

The completion of the human genome project will provide a vast amount of information about human genetic diversity. One of the major challenges for the medical sciences will be to relate genotype to phenotype. Over recent years considerable progress has been made in relating the molecular pathology of monogenic diseases to the associated clinical phenotypes. Studies of the inherited disorders of haemoglobin, notably the thalassaemias, have shown how even in these, the simplest of monogenic diseases, there is remarkable complexity with respect to their phenotypic expression. Although studies of other monogenic diseases are less far advanced, it is clear that the same level of complexity will exist. This information provides some indication of the difficulties that will be met when trying to define the genes that are involved in common multigenic disorders and, in particular, in trying to relate disease phenotypes to the complex interactions between many genes and multiple environmental factors. PMID:10670020

Interactions of cisplatin with non-DNA targets and their influence on anticancer activity and drug toxicity: the complex world of the platinum complex.

PubMed

Mezencev, Roman

2015-01-01

Since the discovery of its anticancer activity in 1970s, cisplatin and its analogs have become widely used in clinical practice, being administered to 40-80% of patients undergoing chemotherapy for solid tumors. The fascinating story of this drug continues to evolve presently, which includes advances in our understanding of complexity of molecular mechanisms involved in its anticancer activity and drug toxicity. While genomic DNA has been generally recognized as the most critical pharmacological target of cisplatin, the results reported across multiple disciplines suggest that other targets and molecular interactions are likely involved in the anticancer mode of action, drug toxicity and resistance of cancer cells to this remarkable anticancer drug. This article reviews interactions of cisplatin with non-DNA targets, including RNAs, proteins, phospholipids and carbohydrates in the context of its pharmacological activity and drug toxicity. Some of these non-DNA targets and associated mechanisms likely act in a highly concerted manner towards the biological outcome in cisplatin-treated tumors; therefore, the understanding of complexity of cisplatin interactome may open new avenues for modulation of its clinical efficacy or for designing more efficient platinum-based anticancer drugs to reproduce the success of cisplatin in the treatment of highly curable testicular germ cell tumors in its therapeutic applications to other cancers.

Protein import and the origin of red complex plastids.

PubMed

Gould, Sven B; Maier, Uwe-G; Martin, William F

2015-06-15

The number and nature of endosymbioses involving red algal endosymbionts are debated. Gene phylogenies have become the most popular tool to untangle this issue, but they deliver conflicting results. As gene and lineage sampling has increased, so have both the number of conflicting trees and the number of suggestions in the literature for multiple tertiary, and even quaternary, symbioses that might reconcile the tree conflicts. Independent lines of evidence that can address the issue are needed. Here we summarize the mechanism and machinery of protein import into complex red plastids. The process involves protein translocation machinery, known as SELMA, that arose once in evolution, that facilitates protein import across the second outermost of the four plastid membranes, and that is always targeted specifically to that membrane, regardless of where it is encoded today. It is widely accepted that the unity of protein import across the two membranes of primary plastids is strong evidence for their single cyanobacterial origin. Similarly, the unity of SELMA-dependent protein import across the second outermost plastid membrane constitutes strong evidence for the existence of a single red secondary endosymbiotic event at the common origin of all red complex plastids. We furthermore propose that the two outer membranes of red complex plastids are derived from host endoplasmic reticulum in the initial red secondary endosymbiotic event. Copyright © 2015 Elsevier Ltd. All rights reserved.

Multilayer modeling and analysis of human brain networks

PubMed Central

2017-01-01

Abstract Understanding how the human brain is structured, and how its architecture is related to function, is of paramount importance for a variety of applications, including but not limited to new ways to prevent, deal with, and cure brain diseases, such as Alzheimer’s or Parkinson’s, and psychiatric disorders, such as schizophrenia. The recent advances in structural and functional neuroimaging, together with the increasing attitude toward interdisciplinary approaches involving computer science, mathematics, and physics, are fostering interesting results from computational neuroscience that are quite often based on the analysis of complex network representation of the human brain. In recent years, this representation experienced a theoretical and computational revolution that is breaching neuroscience, allowing us to cope with the increasing complexity of the human brain across multiple scales and in multiple dimensions and to model structural and functional connectivity from new perspectives, often combined with each other. In this work, we will review the main achievements obtained from interdisciplinary research based on magnetic resonance imaging and establish de facto, the birth of multilayer network analysis and modeling of the human brain. PMID:28327916

Superresolution radar imaging based on fast inverse-free sparse Bayesian learning for multiple measurement vectors

NASA Astrophysics Data System (ADS)

He, Xingyu; Tong, Ningning; Hu, Xiaowei

2018-01-01

Compressive sensing has been successfully applied to inverse synthetic aperture radar (ISAR) imaging of moving targets. By exploiting the block sparse structure of the target image, sparse solution for multiple measurement vectors (MMV) can be applied in ISAR imaging and a substantial performance improvement can be achieved. As an effective sparse recovery method, sparse Bayesian learning (SBL) for MMV involves a matrix inverse at each iteration. Its associated computational complexity grows significantly with the problem size. To address this problem, we develop a fast inverse-free (IF) SBL method for MMV. A relaxed evidence lower bound (ELBO), which is computationally more amiable than the traditional ELBO used by SBL, is obtained by invoking fundamental property for smooth functions. A variational expectation-maximization scheme is then employed to maximize the relaxed ELBO, and a computationally efficient IF-MSBL algorithm is proposed. Numerical results based on simulated and real data show that the proposed method can reconstruct row sparse signal accurately and obtain clear superresolution ISAR images. Moreover, the running time and computational complexity are reduced to a great extent compared with traditional SBL methods.

Tiered analytics for purity assessment of macrocyclic peptides in drug discovery: Analytical consideration and method development.

PubMed

Qian Cutrone, Jingfang Jenny; Huang, Xiaohua Stella; Kozlowski, Edward S; Bao, Ye; Wang, Yingzi; Poronsky, Christopher S; Drexler, Dieter M; Tymiak, Adrienne A

2017-05-10

Synthetic macrocyclic peptides with natural and unnatural amino acids have gained considerable attention from a number of pharmaceutical/biopharmaceutical companies in recent years as a promising approach to drug discovery, particularly for targets involving protein-protein or protein-peptide interactions. Analytical scientists charged with characterizing these leads face multiple challenges including dealing with a class of complex molecules with the potential for multiple isomers and variable charge states and no established standards for acceptable analytical characterization of materials used in drug discovery. In addition, due to the lack of intermediate purification during solid phase peptide synthesis, the final products usually contain a complex profile of impurities. In this paper, practical analytical strategies and methodologies were developed to address these challenges, including a tiered approach to assessing the purity of macrocyclic peptides at different stages of drug discovery. Our results also showed that successful progression and characterization of a new drug discovery modality benefited from active analytical engagement, focusing on fit-for-purpose analyses and leveraging a broad palette of analytical technologies and resources. Copyright © 2017. Published by Elsevier B.V.

SLIPPING MAGNETIC RECONNECTIONS WITH MULTIPLE FLARE RIBBONS DURING AN X-CLASS SOLAR FLARE

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zheng, Ruisheng; Chen, Yao; Wang, Bing, E-mail: ruishengzheng@sdu.edu.cn

2016-06-01

With the observations of the Solar Dynamics Observatory , we present the slipping magnetic reconnections with multiple flare ribbons (FRs) during an X1.2 eruptive flare on 2014 January 7. A center negative polarity was surrounded by several positive ones, and three FRs appeared. The three FRs showed apparent slipping motions, and hook structures formed at their ends. Due to the moving footpoints of the erupting structures, one tight semi-circular hook disappeared after the slippage along its inner and outer edges, and coronal dimmings formed within the hook. The east hook also faded as a result of the magnetic reconnection betweenmore » the arcades of a remote filament and a hot loop that was impulsively heated by the under flare loops. Our results are accordant with the slipping magnetic reconnection regime in three-dimensional standard model for eruptive flares. We suggest that the complex structures of the flare are likely a consequence of the more complex flux distribution in the photosphere, and the eruption involves at least two magnetic reconnections.« less

Lipid and protein composition as driving force for multiple sclerosis

NASA Astrophysics Data System (ADS)

Beck, Roy; Shaharabani, Rona

Physical models and experiments often reduce the number of components aiming to address the fundamental mechanisms. Nevertheless, the inherent heterogeneity is an essential ingredient in the biological context. We present our recent efforts to model and understand the development of multiple sclerosis (MS) from a biophysical perspective. Myelin sheath is a multilamellar complex of various lipids and proteins that surround axons and acts as an insulating layer for proper nerve conduction. In MS the myelin structure is disrupted impairing its function. Previous studies showed that MS is correlated with small lipid composition variation and reduction in the adhesive myelin basic protein. We found that such alterations result in pathological phase transition from a lamellar to inverted hexagonal that involve enhanced local curvature. Similar curvatures are also found in vivo in diseased myelin sheaths. Since the etiology and recovery pathways of MS are currently unclear, these findings delineate novel functional roles to dominant constituents in cytoplasmic myelin sheaths, shed new light on mechanisms disrupting lipid-protein complexes, and suggest new courses for diagnosis and treatment for MS.

Generics Substitution, Bioequivalence Standards, and International Oversight: Complex Issues Facing the FDA.

PubMed

Bate, Roger; Mathur, Aparna; Lever, Harry M; Thakur, Dinesh; Graedon, Joe; Cooperman, Tod; Mason, Preston; Fox, Erin R

2016-03-01

The regulations for assessing the quality of generic drugs and their bioequivalence to innovator products are outdated and need to be substantially modernized. There are multiple reasons why these changes are needed, including: (i) the regulations remain largely unchanged since the passage of the Hatch-Waxman Act in 1984; (ii) medication therapies have become substantially more complex over the three decades since the passage of the Act; (iii) a switch from an innovator drug to a generic drug, or switching from one generic to another, is not a benign process - there is substantial clinical professional judgment involved and in some instances these decisions should be better informed; and (iv) pharmaceutical ingredients for finished products, whether innovator or generic, are from multiple sources of supply, adding variability in their production, and which may not be accounted for in specification tolerances. When these elements are viewed together, they clearly suggest that more transparency of responsible manufacturers in product labels and updated standards for bioequivalence are required. Copyright © 2015 Elsevier Ltd. All rights reserved.

Managing Multiplicity: Conceptualizing Physician Cognition in Multipatient Environments.

PubMed

Chan, Teresa M; Mercuri, Mathew; Van Dewark, Kenneth; Sherbino, Jonathan; Schwartz, Alan; Norman, Geoff; Lineberry, Matthew

2018-05-01

Emergency physicians (EPs) regularly manage multiple patients simultaneously, often making time-sensitive decisions around priorities for multiple patients. Few studies have explored physician cognition in multipatient scenarios. The authors sought to develop a conceptual framework to describe how EPs think in busy, multipatient environments. From July 2014 to May 2015, a qualitative study was conducted at McMaster University, using a think-aloud protocol to examine how 10 attending EPs and 10 junior residents made decisions in multipatient environments. Participants engaged in the think-aloud exercise for five different simulated multipatient scenarios. Transcripts from recorded interviews were analyzed inductively, with an iterative process involving two independent coders, and compared between attendings and residents. The attending EPs and junior residents used similar processes to prioritize patients in these multipatient scenarios. The think-aloud processes demonstrated a similar process used by almost all participants. The cognitive task of patient prioritization consisted of three components: a brief overview of the entire cohort of patients to determine a general strategy; an individual chart review, whereby the participant created a functional patient story from information available in a file (i.e., vitals, brief clinical history); and creation of a relative priority list. Compared with residents, the attendings were better able to construct deeper and more complex patient stories. The authors propose a conceptual framework for how EPs prioritize care for multiple patients in complex environments. This study may be useful to teachers who train physicians to function more efficiently in busy clinical environments.

An investigation of multidisciplinary complex health care interventions - steps towards an integrative treatment model in the rehabilitation of People with Multiple Sclerosis

PubMed Central

2012-01-01

Background The Danish Multiple Sclerosis Society initiated a large-scale bridge building and integrative treatment project to take place from 2004–2010 at a specialized Multiple Sclerosis (MS) hospital. In this project, a team of five conventional health care practitioners and five alternative practitioners was set up to work together in developing and offering individualized treatments to 200 people with MS. The purpose of this paper is to present results from the six year treatment collaboration process regarding the development of an integrative treatment model. Discussion The collaborative work towards an integrative treatment model for people with MS, involved six steps: 1) Working with an initial model 2) Unfolding the different treatment philosophies 3) Discussing the elements of the Intervention-Mechanism-Context-Outcome-scheme (the IMCO-scheme) 4) Phrasing the common assumptions for an integrative MS program theory 5) Developing the integrative MS program theory 6) Building the integrative MS treatment model. The model includes important elements of the different treatment philosophies represented in the team and thereby describes a common understanding of the complexity of the courses of treatment. Summary An integrative team of practitioners has developed an integrative model for combined treatments of People with Multiple Sclerosis. The model unites different treatment philosophies and focuses on process-oriented factors and the strengthening of the patients’ resources and competences on a physical, an emotional and a cognitive level. PMID:22524586

Copper-catalyzed azide–alkyne cycloaddition (CuAAC) and beyond: new reactivity of copper(i) acetylides†

PubMed Central

Hein, Jason E.

2011-01-01

Copper-catalyzed azide–alkyne cycloaddition (CuAAC) is a widely utilized, reliable, and straightforward way for making covalent connections between building blocks containing various functional groups. It has been used in organic synthesis, medicinal chemistry, surface and polymer chemistry, and bioconjugation applications. Despite the apparent simplicity of the reaction, its mechanism involves multiple reversible steps involving coordination complexes of copper(i) acetylides of varying nuclearity. Understanding and controlling these equilibria is of paramount importance for channeling the reaction into the productive catalytic cycle. This tutorial review examines the history of the development of the CuAAC reaction, its key mechanistic aspects, and highlights the features that make it useful to practitioners in different fields of chemical science. PMID:20309487

The role of EMMPRIN in T cell biology and immunological diseases.

PubMed

Hahn, Jennifer Nancy; Kaushik, Deepak Kumar; Yong, V Wee

2015-07-01

EMMPRIN (CD147), originally described as an inducer of the expression of MMPs, has gained attention in its involvement in various immunologic diseases, such that anti-EMMPRIN antibodies are considered as potential therapeutic medications. Given that MMPs are involved in the pathogenesis of various disease states, it is relevant that targeting an upstream inducer would make for an effective therapeutic strategy. Additionally, EMMPRIN is now appreciated to have multiple roles apart from MMP induction, including in cellular functions, such as migration, adhesion, invasion, energy metabolism, as well as T cell activation and proliferation. Here, we review what is known about EMMPRIN in numerous immunologic/inflammatory disease conditions with a particular focus on its complex roles in T cell biology. © Society for Leukocyte Biology.

New Insights on Neurobiological Mechanisms underlying Alcohol Addiction

PubMed Central

Cui, Changhai; Noronha, Antonio; Morikawa, Hitoshi; Alvarez, Veronica A.; Stuber, Garret D.; Szumlinski, Karen K.; Kash, Thomas L.; Roberto, Marisa; Wilcox, Mark V.

2012-01-01

Alcohol dependence/addiction is mediated by complex neural mechanisms that involve multiple brain circuits and neuroadaptive changes in a variety of neurotransmitter and neuropeptide systems. Although recent studies have provided substantial information on the neurobiological mechanisms that drive alcohol drinking behavior, significant challenges remain in understanding how alcohol-induced neuroadaptations occur and how different neurocircuits and pathways cross-talk. This review article highlights recent progress in understanding neural mechanisms of alcohol addiction from the perspectives of the development and maintenance of alcohol dependence. It provides insights on cross talks of different mechanisms and reviews the latest studies on metaplasticity, structural plasticity, interface of reward and stress pathways, and cross-talk of different neural signaling systems involved in binge-like drinking and alcohol dependence. PMID:23159531

A View on Future Building System Modeling and Simulation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wetter, Michael

This chapter presents what a future environment for building system modeling and simulation may look like. As buildings continue to require increased performance and better comfort, their energy and control systems are becoming more integrated and complex. We therefore focus in this chapter on the modeling, simulation and analysis of building energy and control systems. Such systems can be classified as heterogeneous systems because they involve multiple domains, such as thermodynamics, fluid dynamics, heat and mass transfer, electrical systems, control systems and communication systems. Also, they typically involve multiple temporal and spatial scales, and their evolution can be described bymore » coupled differential equations, discrete equations and events. Modeling and simulating such systems requires a higher level of abstraction and modularisation to manage the increased complexity compared to what is used in today's building simulation programs. Therefore, the trend towards more integrated building systems is likely to be a driving force for changing the status quo of today's building simulation programs. Thischapter discusses evolving modeling requirements and outlines a path toward a future environment for modeling and simulation of heterogeneous building systems.A range of topics that would require many additional pages of discussion has been omitted. Examples include computational fluid dynamics for air and particle flow in and around buildings, people movement, daylight simulation, uncertainty propagation and optimisation methods for building design and controls. For different discussions and perspectives on the future of building modeling and simulation, we refer to Sahlin (2000), Augenbroe (2001) and Malkawi and Augenbroe (2004).« less

From problem solving to problem definition: scrutinizing the complex nature of clinical practice.

PubMed

Cristancho, Sayra; Lingard, Lorelei; Regehr, Glenn

2017-02-01

In medical education, we have tended to present problems as being singular, stable, and solvable. Problem solving has, therefore, drawn much of medical education researchers' attention. This focus has been important but it is limited in terms of preparing clinicians to deal with the complexity of the 21st century healthcare system in which they will provide team-based care for patients with complex medical illness. In this paper, we use the Soft Systems Engineering principles to introduce the idea that in complex, team-based situations, problems usually involve divergent views and evolve with multiple solution iterations. As such we need to shift the conversation from (1) problem solving to problem definition, and (2) from a problem definition derived exclusively at the level of the individual to a definition derived at the level of the situation in which the problem is manifested. Embracing such a focus on problem definition will enable us to advocate for novel educational practices that will equip trainees to effectively manage the problems they will encounter in complex, team-based healthcare.

Soils as relative-age dating tools

USGS Publications Warehouse

Markewich, Helaine Walsh; Pavich, Milan J.; Wysocki, Douglas A.

2017-01-01

Soils develop at the earth's surface via multiple processes that act through time. Precluding burial or disturbance, soil genetic horizons form progressively and reflect the balance among formation processes, surface age, and original substrate composition. Soil morphology provides a key link between process and time (soil age), enabling soils to serve as both relative and numerical dating tools for geomorphic studies and landscape evolution. Five major factors define the contemporary state of all soils: climate, organisms, topography, parent material, and time. Soils developed on similar landforms and parent materials within a given landscape comprise what we term a soil/landform/substrate complex. Soils on such complexes that differ in development as a function of time represent a soil chronosequence. In a soil chronosequence, time constitutes the only independent formation factor; the other factors act through time. Time dictates the variations in soil development or properties (field or laboratory measured) on a soil/landform/substrate complex. Using a dataset within the chronosequence model, we can also formulate various soil development indices based upon one or a combination of soil properties, either for individual soil horizons or for an entire profile. When we evaluate soil data or soil indices mathematically, the resulting equation creates a chronofunction. Chronofunctions help quantify processes and mechanisms involved in soil development, and relate them mathematically to time. These rigorous kinds of comparisons among and within soil/landform complexes constitute an important tool for relative-age dating. After determining one or more absolute ages for a soil/landform complex, we can calculate quantitative soil formation, and or landform-development rates. Multiple dates for several complexes allow rate calculations for soil/landform-chronosequence development and soil-chronofunction calibration.

Infrared multiple photon dissociation spectroscopy of group I and group II metal complexes with Boc-hydroxylamine.

PubMed

Dain, Ryan P; Gresham, Gary; Groenewold, Gary S; Steill, Jeffrey D; Oomens, Jos; Van Stipdonk, Michael J

2013-08-30

Hydroxamates are essential growth factors for some microbes, acting primarily as siderophores that solubilize iron for transport into a cell. Here we determined the intrinsic structure of 1:1 complexes between Boc-protected hydroxylamine and group I ([M(L)](+)) and group II ([M(L-H)](+)) cations, where M and L are the cation and ligand, respectively, which are convenient models for the functional unit of hydroxamate siderphores. The relevant complex ions were generated by electrospray ionization (ESI) and isolated and stored in a Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometer. Infrared spectra of the isolated complexes were collected by monitoring (infrared) photodissociation yield as a function of photon energy. Experimental spectra were then compared to those predicted by density functional theory (DFT) calculations. The infrared multiple photon dissociation (IRMPD) spectra collected are in good agreement with those predicted to be lowest-energy by DFT. The spectra for the group I complexes contain six resolved absorptions that can be attributed to amide I and II type and hydroxylamine N-OH vibrations. Similar absorptions are observed for the group II cation complexes, with shifts of the amide I and amide II vibrations due to the change in structure with deprotonation of the hydroxylamine group. IRMPD spectroscopy unequivocally shows that the intrinsic binding mode for the group I cations involves the O atoms of the amide carbonyl and hydroxylamine groups of Boc-hydroxylamine. A similar binding mode is preferred for the group II cations, except that in this case the metal ion is coordinated by the O atom of the deprotonated hydroxylamine group. Copyright © 2013 John Wiley & Sons, Ltd.

Distinct encoding of risk and value in economic choice between multiple risky options☆

PubMed Central

Wright, Nicholas D.; Symmonds, Mkael; Dolan, Raymond J.

2013-01-01

Neural encoding of value-based stimuli is suggested to involve representations of summary statistics, including risk and expected value (EV). A more complex, but ecologically more common, context is when multiple risky options are evaluated together. However, it is unknown whether encoding related to option evaluation in these situations involves similar principles. Here we employed fMRI during a task that parametrically manipulated EV and risk in two simultaneously presented lotteries, both of which contained either gains or losses. We found representations of EV in medial prefrontal cortex and anterior insula, an encoding that was dependent on which option was chosen (i.e. chosen and unchosen EV) and whether the choice was over gains or losses. Parietal activity reflected whether the riskier or surer option was selected, whilst activity in a network of regions that also included parietal cortex reflected both combined risk and difference in risk for the two options. Our findings provide support for the idea that summary statistics underpin a representation of value-based stimuli, and further that these summary statistics undergo distinct forms of encoding. PMID:23684860

Experiments in evaluation capacity building: Enhancing brain disorders research impact in Ontario.

PubMed

Nylen, Kirk; Sridharan, Sanjeev

2017-05-08

This paper is the introductory paper on a forum on evaluation capacity building for enhancing impacts of research on brain disorders. It describes challenges and opportunities of building evaluation capacity among community-based organizations in Ontario involved in enhancing brain health and supporting people living with a brain disorder. Using an example of a capacity building program called the "Evaluation Support Program", which is run by the Ontario Brain Institute, this forum discusses multiple themes including evaluation capacity building, evaluation culture and evaluation methodologies appropriate for evaluating complex community interventions. The goal of the Evaluation Support Program is to help community-based organizations build the capacity to demonstrate the value that they offer in order to improve, sustain, and spread their programs and activities. One of the features of this forum is that perspectives on the Evaluation Support Program are provided by multiple stakeholders, including the community-based organizations, evaluation team members involved in capacity building, thought leaders in the fields of evaluation capacity building and evaluation culture, and the funders. Copyright © 2017. Published by Elsevier Ltd.

Generation of Recombinant Polioviruses Harboring RNA Affinity Tags in the 5′ and 3′ Noncoding Regions of Genomic RNAs

PubMed Central

Flather, Dylan; Cathcart, Andrea L.; Cruz, Casey; Baggs, Eric; Ngo, Tuan; Gershon, Paul D.; Semler, Bert L.

2016-01-01

Despite being intensely studied for more than 50 years, a complete understanding of the enterovirus replication cycle remains elusive. Specifically, only a handful of cellular proteins have been shown to be involved in the RNA replication cycle of these viruses. In an effort to isolate and identify additional cellular proteins that function in enteroviral RNA replication, we have generated multiple recombinant polioviruses containing RNA affinity tags within the 3′ or 5′ noncoding region of the genome. These recombinant viruses retained RNA affinity sequences within the genome while remaining viable and infectious over multiple passages in cell culture. Further characterization of these viruses demonstrated that viral protein production and growth kinetics were unchanged or only slightly altered relative to wild type poliovirus. However, attempts to isolate these genetically-tagged viral genomes from infected cells have been hindered by high levels of co-purification of nonspecific proteins and the limited matrix-binding efficiency of RNA affinity sequences. Regardless, these recombinant viruses represent a step toward more thorough characterization of enterovirus ribonucleoprotein complexes involved in RNA replication. PMID:26861382

In silico Interrogation of Insect Central Complex Suggests Computational Roles for the Ellipsoid Body in Spatial Navigation.

PubMed

Fiore, Vincenzo G; Kottler, Benjamin; Gu, Xiaosi; Hirth, Frank

2017-01-01

The central complex in the insect brain is a composite of midline neuropils involved in processing sensory cues and mediating behavioral outputs to orchestrate spatial navigation. Despite recent advances, however, the neural mechanisms underlying sensory integration and motor action selections have remained largely elusive. In particular, it is not yet understood how the central complex exploits sensory inputs to realize motor functions associated with spatial navigation. Here we report an in silico interrogation of central complex-mediated spatial navigation with a special emphasis on the ellipsoid body. Based on known connectivity and function, we developed a computational model to test how the local connectome of the central complex can mediate sensorimotor integration to guide different forms of behavioral outputs. Our simulations show integration of multiple sensory sources can be effectively performed in the ellipsoid body. This processed information is used to trigger continuous sequences of action selections resulting in self-motion, obstacle avoidance and the navigation of simulated environments of varying complexity. The motor responses to perceived sensory stimuli can be stored in the neural structure of the central complex to simulate navigation relying on a collective of guidance cues, akin to sensory-driven innate or habitual behaviors. By comparing behaviors under different conditions of accessible sources of input information, we show the simulated insect computes visual inputs and body posture to estimate its position in space. Finally, we tested whether the local connectome of the central complex might also allow the flexibility required to recall an intentional behavioral sequence, among different courses of actions. Our simulations suggest that the central complex can encode combined representations of motor and spatial information to pursue a goal and thus successfully guide orientation behavior. Together, the observed computational features identify central complex circuitry, and especially the ellipsoid body, as a key neural correlate involved in spatial navigation.

In silico Interrogation of Insect Central Complex Suggests Computational Roles for the Ellipsoid Body in Spatial Navigation

PubMed Central

Fiore, Vincenzo G.; Kottler, Benjamin; Gu, Xiaosi; Hirth, Frank

2017-01-01

The central complex in the insect brain is a composite of midline neuropils involved in processing sensory cues and mediating behavioral outputs to orchestrate spatial navigation. Despite recent advances, however, the neural mechanisms underlying sensory integration and motor action selections have remained largely elusive. In particular, it is not yet understood how the central complex exploits sensory inputs to realize motor functions associated with spatial navigation. Here we report an in silico interrogation of central complex-mediated spatial navigation with a special emphasis on the ellipsoid body. Based on known connectivity and function, we developed a computational model to test how the local connectome of the central complex can mediate sensorimotor integration to guide different forms of behavioral outputs. Our simulations show integration of multiple sensory sources can be effectively performed in the ellipsoid body. This processed information is used to trigger continuous sequences of action selections resulting in self-motion, obstacle avoidance and the navigation of simulated environments of varying complexity. The motor responses to perceived sensory stimuli can be stored in the neural structure of the central complex to simulate navigation relying on a collective of guidance cues, akin to sensory-driven innate or habitual behaviors. By comparing behaviors under different conditions of accessible sources of input information, we show the simulated insect computes visual inputs and body posture to estimate its position in space. Finally, we tested whether the local connectome of the central complex might also allow the flexibility required to recall an intentional behavioral sequence, among different courses of actions. Our simulations suggest that the central complex can encode combined representations of motor and spatial information to pursue a goal and thus successfully guide orientation behavior. Together, the observed computational features identify central complex circuitry, and especially the ellipsoid body, as a key neural correlate involved in spatial navigation. PMID:28824390

Identification of evolutionarily conserved DNA damage response genes that alter sensitivity to cisplatin

PubMed Central

Gaponova, Anna V.; Deneka, Alexander Y.; Beck, Tim N.; Liu, Hanqing; Andrianov, Gregory; Nikonova, Anna S.; Nicolas, Emmanuelle; Einarson, Margret B.; Golemis, Erica A.; Serebriiskii, Ilya G.

2017-01-01

Ovarian, head and neck, and other cancers are commonly treated with cisplatin and other DNA damaging cytotoxic agents. Altered DNA damage response (DDR) contributes to resistance of these tumors to chemotherapies, some targeted therapies, and radiation. DDR involves multiple protein complexes and signaling pathways, some of which are evolutionarily ancient and involve protein orthologs conserved from yeast to humans. To identify new regulators of cisplatin-resistance in human tumors, we integrated high throughput and curated datasets describing yeast genes that regulate sensitivity to cisplatin and/or ionizing radiation. Next, we clustered highly validated genes based on chemogenomic profiling, and then mapped orthologs of these genes in expanded genomic networks for multiple metazoans, including humans. This approach identified an enriched candidate set of genes involved in the regulation of resistance to radiation and/or cisplatin in humans. Direct functional assessment of selected candidate genes using RNA interference confirmed their activity in influencing cisplatin resistance, degree of γH2AX focus formation and ATR phosphorylation, in ovarian and head and neck cancer cell lines, suggesting impaired DDR signaling as the driving mechanism. This work enlarges the set of genes that may contribute to chemotherapy resistance and provides a new contextual resource for interpreting next generation sequencing (NGS) genomic profiling of tumors. PMID:27863405

Structural changes at the metal ion binding site during the phosphoglucomutase reaction.

PubMed

Ray, W J; Post, C B; Liu, Y; Rhyu, G I

1993-01-12

An electron density map of the reactive, Cd2+ form of crystalline phosphoglucomutase from X-ray diffraction studies shows that the enzymic phosphate donates a nonbridging oxygen to the ligand sphere of the bound metal ion, which appears to be tetracoordinate. 31P and 113Cd NMR spectroscopy are used to assess changes in the properties of bound Cd2+ produced by substrate/product and by substrate/product analog inhibitors. The approximately 50 ppm downfield shift of the 113Cd resonance on formation of the complex of dephosphoenzyme and glucose 1,6-bisphosphate is associated with the initial sugar-phosphate binding step and likely involves a change in the geometry of the coordinating ligands. This interpretation is supported by spectral studies involving various complexes of the active Co2+ and Ni(2+)-enzyme. In addition, there is a loss of the 31P-113Cd J coupling that characterizes the monophosphate complexes of the Cd2+ enzyme either during or immediately after the PO3- transfer step that produces the bisphosphate complex, indicating a further change at the metal binding site. The implications of these observations with respect to the PO3- transfer process in the phosphoglucomutase reaction are considered. The apparent plasticity of the ligand sphere of the active site metal ion in this system may allow a single metal ion to act as a chaperone for a nonbridging oxygen during PO3- transfer or to allow a change in metal ion coordination during catalysis. A general NMR line shape/chemical-exchange analysis for evaluating binding in protein-ligand systems when exchange is intermediate to fast on the NMR time scale is described. Its application to the present system involves multiple exchange sites that depend on a single binding rate, thereby adding further constraints to the analysis.

The care network of the families involved in violence against children and adolescents: the Primary Health Care perspective.

PubMed

Carlos, Diene Monique; de Pádua, Elisabete Matallo Marchesini; da Silva, Lygia Maria Pereira; Silva, Marta Angélica Iossi; Marques, Walter Ernesto Ude; Leitão, Maria Neto da Cruz; Ferriani, Maria das Graças Carvalho

2017-08-01

To contribute the understanding of the network care provided to families involved in family violence against children and adolescents (FVACA), from the Primary Health Care (PHC) perspective. Children and adolescents figure among the main victims of violence around the world, which occurs predominantly in the family context. PHC-guided network care has emerged as a new process that contrasts with traditional approaches, which rely on fragmented, punctual and compensatory actions and produce simplified and segmented interventions in response to complex phenomena like violence. The Paradigm of Complexity interacts with the network care approach and, by articulating the multiple dimensions of the research phenomenon, contributes to its understanding. Qualitative research, based on the Paradigm of Complexity. Data were collected through minimal maps of the external institutional social network, focus groups and semi-structured interviews held with 41 PHC professionals in Brazil. The notions of comprehension and contextualisation as well as dialogical, recursive and holographic principles from complexity theory guided the data analysis. The two thematic categories that emerged revealed reduced institutional networks, with low-density and homogeneous bonds, which resulted in fragmented care in all stages of the care process. Although the network organisation of care for the families involved in FVACA is fundamental, the construction of these networks still represents a great challenge, as it requires the joint work of a multiprofessional team. For nursing to respond to the contemporary care demands in a contemplative and pertinent manner, a perspective and a reference framework need to be developed, leading to broader and more contextualised actions, with a multidimensional approach to the families and communities of which child and adolescent victims of violence are a part. © 2016 John Wiley & Sons Ltd.

A scheme to calculate higher-order homogenization as applied to micro-acoustic boundary value problems

NASA Astrophysics Data System (ADS)

Vagh, Hardik A.; Baghai-Wadji, Alireza

2008-12-01

Current technological challenges in materials science and high-tech device industry require the solution of boundary value problems (BVPs) involving regions of various scales, e.g. multiple thin layers, fibre-reinforced composites, and nano/micro pores. In most cases straightforward application of standard variational techniques to BVPs of practical relevance necessarily leads to unsatisfactorily ill-conditioned analytical and/or numerical results. To remedy the computational challenges associated with sub-sectional heterogeneities various sophisticated homogenization techniques need to be employed. Homogenization refers to the systematic process of smoothing out the sub-structural heterogeneities, leading to the determination of effective constitutive coefficients. Ordinarily, homogenization involves a sophisticated averaging and asymptotic order analysis to obtain solutions. In the majority of the cases only zero-order terms are constructed due to the complexity of the processes involved. In this paper we propose a constructive scheme for obtaining homogenized solutions involving higher order terms, and thus, guaranteeing higher accuracy and greater robustness of the numerical results. We present

Energy Efficiency in Public Buildings through Context-Aware Social Computing

PubMed Central

García, Óscar; Alonso, Ricardo S.; Prieto, Javier; Corchado, Juan M.

2017-01-01

The challenge of promoting behavioral changes in users that leads to energy savings in public buildings has become a complex task requiring the involvement of multiple technologies. Wireless sensor networks have a great potential for the development of tools, such as serious games, that encourage acquiring good energy and healthy habits among users in the workplace. This paper presents the development of a serious game using CAFCLA, a framework that allows for integrating multiple technologies, which provide both context-awareness and social computing. Game development has shown that the data provided by sensor networks encourage users to reduce energy consumption in their workplace and that social interactions and competitiveness allow for accelerating the achievement of good results and behavioral changes that favor energy savings. PMID:28398237

Food systems transition and disruptive low carbon innovation: implications for a food security research agenda.

PubMed

Tyfield, David

2011-07-01

There is a growing consensus that we are facing epochal challenges in global food security. Moreover, these challenges are multiple and complex. Meeting these challenges will involve nothing less than a wholesale socio-technical transition of the agri-food system. Optimizing the efficacy of the contribution of research to such a food security agenda will probably also need new institutional mechanisms and career structures to facilitate new kinds of collaborations and ongoing, longer-term projects. In short, the multiple challenges of food security demand a different political economy of research for effective intervention by science. In making this argument, the paper summarizes the major findings of a recent report regarding the potential impact of so-called 'disruptive' low-carbon innovations in China.

SoS Notebook: An Interactive Multi-Language Data Analysis Environment.

PubMed

Peng, Bo; Wang, Gao; Ma, Jun; Leong, Man Chong; Wakefield, Chris; Melott, James; Chiu, Yulun; Du, Di; Weinstein, John N

2018-05-22

Complex bioinformatic data analysis workflows involving multiple scripts in different languages can be difficult to consolidate, share, and reproduce. An environment that streamlines the entire processes of data collection, analysis, visualization and reporting of such multi-language analyses is currently lacking. We developed Script of Scripts (SoS) Notebook, a web-based notebook environment that allows the use of multiple scripting language in a single notebook, with data flowing freely within and across languages. SoS Notebook enables researchers to perform sophisticated bioinformatic analysis using the most suitable tools for different parts of the workflow, without the limitations of a particular language or complications of cross-language communications. SoS Notebook is hosted at http://vatlab.github.io/SoS/ and is distributed under a BSD license. bpeng@mdanderson.org.

A Bir1p–Sli15p Kinetochore Passenger Complex Regulates Septin Organization during Anaphase

PubMed Central

Thomas, Scott

2007-01-01

Kinetochore–passenger complexes in metazoans have been proposed to coordinate the segregation of chromosomes in anaphase with the induction of cytokinesis. Passenger protein homologues in the budding yeast Saccharomyces cerevisiae play a critical role early in mitosis, ensuring proper biorientation of kinetochore–microtubule attachments. Our recent work has implicated the passenger protein Bir1p (Survivin) and the inner kinetochore complex centromere binding factor 3 (CBF3) in the regulation of septin dynamics during anaphase. Here, we present data that is consistent with there being multiple passenger protein complexes. Our data show that Bir1p links together a large passenger complex containing Ndc10p, Sli15p (INCENP), and Ipl1p (Aurora B) and that the interaction between Bir1p and Sli15p is specifically involved in regulating septin dynamics during anaphase. Neither conditional alleles nor mutants of BIR1 that disrupt the interaction between Bir1p and Sli15p resulted in mono-attached kinetochores, suggesting that the Bir1p–Sli15p complex functions in anaphase and independently from Sli15p–Ipl1p complexes. We present a model for how discrete passenger complexes coordinate distinct aspects of mitosis. PMID:17652458

Linkage analyses of chromosome 6 loci, including HLA, in familial aggregations of Crohn disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hugot, J.P.; Laurent-Puig, P.; Gower-Rousseau, C.

1994-08-15

Segregation analyses of familial aggregations of Crohn disease have provided consistent results pointing to the involvement of a predisposing gene with a recessive mode of inheritance. Although extensively investigated, the role played by human leucocyte antigen (HLA) genes in this inflammatory bowel disease remains elusive and the major histocompatibility complex is a candidate region for the mapping of the Crohn disease susceptibility gene. A total of 25 families with multiple cases of Crohn disease was genotyped for HLA DRB1 and for 16 highly polymorphic loci evenly distributed on chromosome 6. The data were subjected to linkage analysis using the lodmore » score method. Neither individual nor combined lod scores for any family and for any locus tested reached values suggesting linkage or genetic heterogeneity. The Crohn disease predisposing locus was excluded from the whole chromosome 6 with lod scores less than -2. It was excluded from the major histocompatibility complex and from 91% of the chromosome 6 genetic map with lod scores less than -4. The major recessive gene involved in genetic predisposition to Crohn disease does not reside on the major histocompatibility complex nor on any locus mapping to chromosome 6. 37 refs., 2 figs., 2 tabs.« less

Disentangling polydispersity in the PCNA−p15PAF complex, a disordered, transient and multivalent macromolecular assembly

PubMed Central

Cordeiro, Tiago N.; Chen, Po-chia; De Biasio, Alfredo; Sibille, Nathalie; Blanco, Francisco J.; Hub, Jochen S.; Crehuet, Ramon

2017-01-01

Abstract The intrinsically disordered p15PAF regulates DNA replication and repair when interacting with the Proliferating Cell Nuclear Antigen (PCNA) sliding clamp. As many interactions between disordered proteins and globular partners involved in signaling and regulation, the complex between p15PAF and trimeric PCNA is of low affinity, forming a transient complex that is difficult to characterize at a structural level due to its inherent polydispersity. We have determined the structure, conformational fluctuations, and relative population of the five species that coexist in solution by combining small-angle X-ray scattering (SAXS) with molecular modelling. By using explicit ensemble descriptions for the individual species, built using integrative approaches and molecular dynamics (MD) simulations, we collectively interpreted multiple SAXS profiles as population-weighted thermodynamic mixtures. The analysis demonstrates that the N-terminus of p15PAF penetrates the PCNA ring and emerges on the back face. This observation substantiates the role of p15PAF as a drag regulating PCNA processivity during DNA repair. Our study reveals the power of ensemble-based approaches to decode structural, dynamic, and thermodynamic information from SAXS data. This strategy paves the way for deciphering the structural bases of flexible, transient and multivalent macromolecular assemblies involved in pivotal biological processes. PMID:28180305

The role of PACT in the RNA silencing pathway

PubMed Central

Lee, Yoontae; Hur, Inha; Park, Seong-Yeon; Kim, Young-Kook; Suh, Mi Ra; Kim, V Narry

2006-01-01

Small RNA-mediated gene silencing (RNA silencing) has emerged as a major regulatory pathway in eukaryotes. Identification of the key factors involved in this pathway has been a subject of rigorous investigation in recent years. In humans, small RNAs are generated by Dicer and assembled into the effector complex known as RNA-induced silencing complex (RISC) by multiple factors including hAgo2, the mRNA-targeting endonuclease, and TRBP (HIV-1 TAR RNA-binding protein), a dsRNA-binding protein that interacts with both Dicer and hAgo2. Here we describe an additional dsRNA-binding protein known as PACT, which is significant in RNA silencing. PACT is associated with an ∼500 kDa complex that contains Dicer, hAgo2, and TRBP. The interaction with Dicer involves the third dsRNA-binding domain (dsRBD) of PACT and the N-terminal region of Dicer containing the helicase motif. Like TRBP, PACT is not required for the pre-microRNA (miRNA) cleavage reaction step. However, the depletion of PACT strongly affects the accumulation of mature miRNA in vivo and moderately reduces the efficiency of small interfering RNA-induced RNA interference. Our study indicates that, unlike other RNase III type proteins, human Dicer may employ two different dsRBD-containing proteins that facilitate RISC assembly. PMID:16424907

Complex Frontal Pneumosinus Dilatans Associated with Meningioma: A Report of Two Cases and Associated Literature Review.

PubMed

Timms, Sara; Lakhani, Raj; Connor, Steve; Hopkins, Claire

2017-07-01

Introduction  Pneumosinus dilatans (PSD) is a rare phenomenon involving the expansion of the paranasal sinuses, without bony destruction or a mass. Previously documented cases have demonstrated simple expansion of a solitary air cell. We present two unique cases of PSD in the presence of meningioma, in which complex new cells developed within the frontal sinus. One of the two patients developed associated sinus disease. Case 1  A 28-year-old man presented with facial pain. A computed tomography scan showed an abnormally enlarged, septated right frontal sinus, not present on childhood scans. He underwent a modified endoscopic Lothrop approach to divide the septations, and his symptoms resolved. Case 2  A 72-year-old woman presented with a 3-month history of headaches. Scans revealed a left frontal meningioma and multiple enlarged, dilated left frontal air cells. She had no clinical sinusitis and therefore was managed conservatively. Conclusions  PSD has been widely documented in association with fibrous dysplasia and meningioma. The most prevalent theory of the mechanism of PSD is of obstruction of the sinus ostium causing sinus expansion through a "ball-valve" effect. Our cases, which demonstrate septated PSD, suggest a more complex process involving local mediators and highlight the need to consider underlying meningioma in pneumosinus dilatans.

Recognition of the Xenopus ribosomal core promoter by the transcription factor xUBF involves multiple HMG box domains and leads to an xUBF interdomain interaction.

PubMed

Leblanc, B; Read, C; Moss, T

1993-02-01

The interaction of the ribosomal transcription factor xUBF with the RNA polymerase I core promoter of Xenopus laevis has been studied both at the DNA and protein levels. It is shown that a single xUBF-DNA complex forms over the 40S initiation site (+1) and involves at least the DNA sequences between -20 and +60 bp. DNA sequences upstream of +10 and downstream of +18 are each sufficient to direct complex formation independently. HMG box 1 of xUBF independently recognizes the sequences -20 to -1 and +1 to +22 and the addition of the N-terminal dimerization domain to HMG box 1 stabilizes its interaction with these sequences approximately 10-fold. HMG boxes 2/3 interact with the DNA downstream of +22 and can independently position xUBF across the initiation site. The C-terminal segment of xUBF, HMG boxes 4, 5 or the acidic domain, directly or indirectly interact with HMG box 1, making the core promoter sequences between -11 and -15 hypersensitive to DNase. This interaction also requires the DNA sequences between +17 and +32, i.e. the HMG box 2/3 binding site. The data suggest extensive folding of the core promoter within the xUBF complex.

R2TP/Prefoldin-like component RUVBL1/RUVBL2 directly interacts with ZNHIT2 to regulate assembly of U5 small nuclear ribonucleoprotein

PubMed Central

Cloutier, Philippe; Poitras, Christian; Durand, Mathieu; Hekmat, Omid; Fiola-Masson, Émilie; Bouchard, Annie; Faubert, Denis; Chabot, Benoit; Coulombe, Benoit

2017-01-01

The R2TP/Prefoldin-like (R2TP/PFDL) complex has emerged as a cochaperone complex involved in the assembly of a number of critical protein complexes including snoRNPs, nuclear RNA polymerases and PIKK-containing complexes. Here we report on the use of multiple target affinity purification coupled to mass spectrometry to identify two additional complexes that interact with R2TP/PFDL: the TSC1–TSC2 complex and the U5 small nuclear ribonucleoprotein (snRNP). The interaction between R2TP/PFDL and the U5 snRNP is mostly mediated by the previously uncharacterized factor ZNHIT2. A more general function for the zinc-finger HIT domain in binding RUVBL2 is exposed. Disruption of ZNHIT2 and RUVBL2 expression impacts the protein composition of the U5 snRNP suggesting a function for these proteins in promoting the assembly of the ribonucleoprotein. A possible implication of R2TP/PFDL as a major effector of stress-, energy- and nutrient-sensing pathways that regulate anabolic processes through the regulation of its chaperoning activity is discussed. PMID:28561026

Biosimulation of Inflammation and Healing in Surgically Injured Vocal Folds

PubMed Central

Li, Nicole Y. K.; Vodovotz, Yoram; Hebda, Patricia A.; Abbott, Katherine Verdolini

2010-01-01

Objectives The pathogenesis of vocal fold scarring is complex and remains to be deciphered. The current study is part of research endeavors aimed at applying systems biology approaches to address the complex biological processes involved in the pathogenesis of vocal fold scarring and other lesions affecting the larynx. Methods We developed a computational agent-based model (ABM) to quantitatively characterize multiple cellular and molecular interactions involved in inflammation and healing in vocal fold mucosa after surgical trauma. The ABM was calibrated with empirical data on inflammatory mediators (eg, tumor necrosis factor) and extracellular matrix components (eg, hyaluronan) from published studies on surgical vocal fold injury in the rat population. Results The simulation results reproduced and predicted trajectories seen in the empirical data from the animals. Moreover, the ABM studies suggested that hyaluronan fragments might be the clinical surrogate of tissue damage, a key variable that in these simulations both is enhanced by and further induces inflammation. Conclusions A relatively simple ABM such as the one reported in this study can provide new understanding of laryngeal wound healing and generate working hypotheses for further wet-lab studies. PMID:20583741

Evolution of steroids during pregnancy: Maternal, placental and fetal synthesis.

PubMed

Morel, Yves; Roucher, Florence; Plotton, Ingrid; Goursaud, Claire; Tardy, Véronique; Mallet, Delphine

2016-06-01

Progesterone, estrogens, androgens and glucocorticoids are involved in pregnancy from implantation to parturition. Their biosynthesis and their metabolism result from complex pathways involving the fetus, the placenta and the mother. The absence of expression of some steroïdogenic enzymes as CYP17 in placenta and in adrenal fetal zone and the better determination of the onset and variation of others especially HSD3B2 during the pregnancy explain the production of the steroid hormones. Moreover the consequences of some disorders of steroidogenesis (especially aromatase, POR, CYP11A1 and 21-hydroxylase deficiencies) in fetus and mother during the pregnancy have permit to elucidate these complex pathways. This better knowledge of steroid hormones production associated with their dosages in maternal plasma/urine or amniotic fluid using new specific assays as LC-MS MS could facilitate the follow-up of normal and pathological pregnancies. Moreover, these advances should be a basis to evaluate the impact of multiple pathologies of the pregnancy and pharmacologic and xenobiotic consequences on their metabolism. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Biosimulation of inflammation and healing in surgically injured vocal folds.

PubMed

Li, Nicole Y K; Vodovotz, Yoram; Hebda, Patricia A; Abbott, Katherine Verdolini

2010-06-01

The pathogenesis of vocal fold scarring is complex and remains to be deciphered. The current study is part of research endeavors aimed at applying systems biology approaches to address the complex biological processes involved in the pathogenesis of vocal fold scarring and other lesions affecting the larynx. We developed a computational agent-based model (ABM) to quantitatively characterize multiple cellular and molecular interactions involved in inflammation and healing in vocal fold mucosa after surgical trauma. The ABM was calibrated with empirical data on inflammatory mediators (eg, tumor necrosis factor) and extracellular matrix components (eg, hyaluronan) from published studies on surgical vocal fold injury in the rat population. The simulation results reproduced and predicted trajectories seen in the empirical data from the animals. Moreover, the ABM studies suggested that hyaluronan fragments might be the clinical surrogate of tissue damage, a key variable that in these simulations both is enhanced by and further induces inflammation. A relatively simple ABM such as the one reported in this study can provide new understanding of laryngeal wound healing and generate working hypotheses for further wet-lab studies.

Crystal structure of Clostridium botulinum whole hemagglutinin reveals a huge triskelion-shaped molecular complex.

PubMed

Amatsu, Sho; Sugawara, Yo; Matsumura, Takuhiro; Kitadokoro, Kengo; Fujinaga, Yukako

2013-12-06

Clostridium botulinum HA is a component of the large botulinum neurotoxin complex and is critical for its oral toxicity. HA plays multiple roles in toxin penetration in the gastrointestinal tract, including protection from the digestive environment, binding to the intestinal mucosal surface, and disruption of the epithelial barrier. At least two properties of HA contribute to these roles: the sugar-binding activity and the barrier-disrupting activity that depends on E-cadherin binding of HA. HA consists of three different proteins, HA1, HA2, and HA3, whose structures have been partially solved and are made up mainly of β-strands. Here, we demonstrate structural and functional reconstitution of whole HA and present the complete structure of HA of serotype B determined by x-ray crystallography at 3.5 Å resolution. This structure reveals whole HA to be a huge triskelion-shaped molecule. Our results suggest that whole HA is functionally and structurally separable into two parts: HA1, involved in recognition of cell-surface carbohydrates, and HA2-HA3, involved in paracellular barrier disruption by E-cadherin binding.

Approach to the genetics of alcoholism: a review based on pathophysiology.

PubMed

Köhnke, Michael D

2008-01-01

Alcohol dependence is a common disorder with a heterogenous etiology. The results of family, twin and adoption studies on alcoholism are reviewed. These studies have revealed a heritability of alcoholism of over 50%. After evaluating the results, it was epidemiologically stated that alcoholism is heterogenous complex disorder with a multiple genetic background. Modern molecular genetic techniques allow examining specific genes involved in the pathophysiology of complex diseases such as alcoholism. Strategies for gene identification are introduced to the reader, including family-based and association studies. The susceptibility genes that are in the focus of this article have been chosen because they are known to encode for underlying mechanisms that are linked to the pathophysiology of alcoholism or that are important for the pharmacotherapeutic approaches in the treatment of alcohol dependence. Postulated candidate genes of the metabolism of alcohol and of the involved neurotransmitter systems are introduced. Genetic studies on alcoholism examining the metabolism of alcohol and the dopaminergic, GABAergic, glutamatergic, opioid, cholinergic and serotonergic neurotransmitter systems as well as the neuropeptide Y are presented. The results are critically discussed followed by a discussion of possible consequences.

Combining qualitative and quantitative operational research methods to inform quality improvement in pathways that span multiple settings

PubMed Central

Crowe, Sonya; Brown, Katherine; Tregay, Jenifer; Wray, Jo; Knowles, Rachel; Ridout, Deborah A; Bull, Catherine; Utley, Martin

2017-01-01

Background Improving integration and continuity of care across sectors within resource constraints is a priority in many health systems. Qualitative operational research methods of problem structuring have been used to address quality improvement in services involving multiple sectors but not in combination with quantitative operational research methods that enable targeting of interventions according to patient risk. We aimed to combine these methods to augment and inform an improvement initiative concerning infants with congenital heart disease (CHD) whose complex care pathway spans multiple sectors. Methods Soft systems methodology was used to consider systematically changes to services from the perspectives of community, primary, secondary and tertiary care professionals and a patient group, incorporating relevant evidence. Classification and regression tree (CART) analysis of national audit datasets was conducted along with data visualisation designed to inform service improvement within the context of limited resources. Results A ‘Rich Picture’ was developed capturing the main features of services for infants with CHD pertinent to service improvement. This was used, along with a graphical summary of the CART analysis, to guide discussions about targeting interventions at specific patient risk groups. Agreement was reached across representatives of relevant health professions and patients on a coherent set of targeted recommendations for quality improvement. These fed into national decisions about service provision and commissioning. Conclusions When tackling complex problems in service provision across multiple settings, it is important to acknowledge and work with multiple perspectives systematically and to consider targeting service improvements in response to confined resources. Our research demonstrates that applying a combination of qualitative and quantitative operational research methods is one approach to doing so that warrants further consideration. PMID:28062603

Integrative Perspectives of Academic Motivation

NASA Astrophysics Data System (ADS)

Chittum, Jessica Rebecca

My overall objective in this dissertation was to develop more integrative perspectives of several aspects of academic motivation. Rarely have researchers and theorists examined a more comprehensive model of academic motivation that pools multiple constructs that interact in a complex and dynamic fashion (Kaplan, Katz, & Flum, 2012; Turner, Christensen, Kackar-Cam, Trucano, & Fulmer, 2014). The more common trend in motivation research and theory has been to identify and explain only a few motivation constructs and their linear relationships rather than examine complex relationships involving "continuously emerging systems of dynamically interrelated components" (Kaplan et al., 2014, para. 4). In this dissertation, my co-author and I focused on a more integrative perspective of academic motivation by first reviewing varying characterizations of one motivation construct (Manuscript 1) and then empirically testing dynamic interactions among multiple motivation constructs using a person-centered methodological approach (Manuscript 2). Within the first manuscript (Chapter 2), a theoretical review paper, we summarized multiple perspectives of the need for autonomy and similar constructs in academic motivation, primarily autonomy in self-determination theory, autonomy supports, and choice. We provided an integrative review and extrapolated practical teaching implications. We concluded with recommendations for researchers and instructors, including a call for more integrated perspectives of academic motivation and autonomy that focus on complex and dynamic patterns in individuals' motivational beliefs. Within the second manuscript (Chapter 3), we empirically investigated students' motivation in science class as a complex, dynamic, and context-bound phenomenon that incorporates multiple motivation constructs. Following a person-centered approach, we completed cluster analyses of students' perceptions of 5 well-known motivation constructs (autonomy, utility value, expectancy, interest, and caring) in science class to determine whether or not the students grouped into meaningful "motivation profiles." 5 stable profiles emerged: (1) low motivation; (2) low value and high support; (3) somewhat high motivation; (4) somewhat high empowerment and values, and high support; and (5) high motivation. As this study serves as a proof of concept, we concluded by describing the 5 clusters. Together, these studies represent a focus on more integrative and person-centered approaches to studying and understanding academic motivation.

Autophagy in C. elegans development.

PubMed

Palmisano, Nicholas J; Meléndez, Alicia

2018-04-27

Autophagy involves the sequestration of cytoplasmic contents in a double-membrane structure referred to as the autophagosome and the degradation of its contents upon delivery to lysosomes. Autophagy activity has a role in multiple biological processes during the development of the nematode Caenorhabditis elegans. Basal levels of autophagy are required to remove aggregate prone proteins, paternal mitochondria, and spermatid-specific membranous organelles. During larval development, autophagy is required for the remodeling that occurs during dauer development, and autophagy can selectively degrade components of the miRNA-induced silencing complex, and modulate miRNA-mediated silencing. Basal levels of autophagy are important in synapse formation and in the germ line, to promote the proliferation of proliferating stem cells. Autophagy activity is also required for the efficient removal of apoptotic cell corpses by promoting phagosome maturation. Finally, autophagy is also involved in lipid homeostasis and in the aging process. In this review, we first describe the molecular complexes involved in the process of autophagy, its regulation, and mechanisms for cargo recognition. In the second section, we discuss the developmental contexts where autophagy has been shown to be important. Studies in C. elegans provide valuable insights into the physiological relevance of this process during metazoan development. Copyright © 2018 Elsevier Inc. All rights reserved.

Single-Molecule Spectroscopy and Imaging Studies of Protein Dynamics

NASA Astrophysics Data System (ADS)

Lu, H. Peter

2012-04-01

Enzymatic reactions and protein-protein interactions are traditionally studied at the ensemble level, despite significant static and dynamic inhomogeneities. Subtle conformational changes play a crucial role in protein functions, and these protein conformations are highly dynamic rather than being static. We applied AFM-enhanced single-molecule spectroscopy to study the mechanisms and dynamics of enzymatic reactions involved with kinase and lysozyme proteins. Enzymatic reaction turnovers and the associated structure changes of individual protein molecules were observed simultaneously in real-time by single-molecule FRET detections. Our single-molecule spectroscopy measurements of T4 lysozyme and HPPK enzymatic conformational dynamics have revealed time bunching effect and intermittent coherence in conformational state change dynamics involving in enzymatic reaction cycles. The coherent conformational state dynamics suggests that the enzymatic catalysis involves a multi-step conformational motion along the coordinates of substrate-enzyme complex formation and product releasing, presenting as an extreme dynamic behavior intrinsically related to the time bunching effect that we have reported previously. Our results of HPPK interaction with substrate support a multiple-conformational state model, being consistent with a complementary conformation selection and induced-fit enzymatic loop-gated conformational change mechanism in substrate-enzyme active complex formation. Our new approach is applicable to a wide range of single-molecule FRET measurements for protein conformational changes under enzymatic reactions.

Genetics of Vitiligo

PubMed Central

Spritz, Richard; Andersen, Genevieve

2016-01-01

Synopsis Vitiligo is “complex disorder” (also termed polygenic and multifactorial), reflecting simultaneous contributions of multiple genetic risk factors and environmental triggers. Large-scale genome-wide association studies, principally in European-derived whites and in Chinese, have discovered approximately 50 different genetic loci that contribute to vitiligo risk, some of which also contribute to other autoimmune diseases that are epidemiologically associated with vitiligo. At many of these vitiligo susceptibility loci the corresponding relevant genes have now been identified, and for some of these genes the specific DNA sequence variants that contribute to vitiligo risk are also now known. A large fraction of these genes encode proteins involved in immune regulation, a number of others play roles in cellular apoptosis, and still others are involved in regulating functions of melanocytes. For this last group, there appears to be an opposite relationship between susceptibility to vitiligo and susceptibility to melanoma, suggesting that vitiligo may engage a normal mechanism of immune surveillance for melanoma. While many of the specific biologic mechanisms through which these genetic factors operate to cause vitiligo remain to be elucidated, it is now clear that vitiligo is an autoimmune disease involving a complex relationship between programming and function of the immune system, aspects of the melanocyte autoimmune target, and dysregulation of the immune response. PMID:28317533

Auxin-BR Interaction Regulates Plant Growth and Development

PubMed Central

Tian, Huiyu; Lv, Bingsheng; Ding, Tingting; Bai, Mingyi; Ding, Zhaojun

2018-01-01

Plants develop a high flexibility to alter growth, development, and metabolism to adapt to the ever-changing environments. Multiple signaling pathways are involved in these processes and the molecular pathways to transduce various developmental signals are not linear but are interconnected by a complex network and even feedback mutually to achieve the final outcome. This review will focus on two important plant hormones, auxin and brassinosteroid (BR), based on the most recent progresses about these two hormone regulated plant growth and development in Arabidopsis, and highlight the cross-talks between these two phytohormones. PMID:29403511

Processing of energy materials in electromagnetic field

NASA Astrophysics Data System (ADS)

Rodzevich, A. P.; Kuzmina, L. V.; Gazenaur, E. G.; Krasheninin, V. I.

2015-09-01

This paper presents the research results of complex impact of mechanical stress and electromagnetic field on the defect structure of energy materials. As the object of research quite a typical energy material - silver azide was chosen, being a model in chemistry of solids. According to the experiments co-effect of magnetic field and mechanical stress in silver azide crystals furthers multiplication, stopper breakaway, shift of dislocations, and generation of superlattice dislocations - micro-cracks. A method of mechanical and electric strengthening has been developed and involves changing the density of dislocations in whiskers.

Error reduction, patient safety and institutional ethics committees.

PubMed

Meaney, Mark E

2004-01-01

Institutional ethics committees remain largely absent from the literature on error reduction and patient safety. In this paper, the author endeavors to fill the gap. As noted in the Hastings Center's recent report, "Promoting Patient Safety," the occurrence of medical error involves complex web of multiple factors. Human misstep is certainly one such factor, but not the only one. This paper builds on the Hastings Center's report in arguing that institutional ethics committees ought to play an integral role in the transformation of a "culture of blame" to a "culture of safety" in healthcare delivery.

Multiple Loci are associated with dilated cardiomyopathy in Irish wolfhounds.

PubMed

Philipp, Ute; Vollmar, Andrea; Häggström, Jens; Thomas, Anne; Distl, Ottmar

2012-01-01

Dilated cardiomyopathy (DCM) is a highly prevalent and often lethal disease in Irish wolfhounds. Complex segregation analysis indicated different loci involved in pathogenesis. Linear fixed and mixed models were used for the genome-wide association study. Using 106 DCM cases and 84 controls we identified one SNP significantly associated with DCM on CFA37 and five SNPs suggestively associated with DCM on CFA1, 10, 15, 21 and 17. On CFA37 MOGAT1 and ACSL3 two enzymes of the lipid metabolism were located near the identified SNP.

Multiple Loci Are Associated with Dilated Cardiomyopathy in Irish Wolfhounds

PubMed Central

Philipp, Ute; Vollmar, Andrea; Häggström, Jens; Thomas, Anne; Distl, Ottmar

2012-01-01

Dilated cardiomyopathy (DCM) is a highly prevalent and often lethal disease in Irish wolfhounds. Complex segregation analysis indicated different loci involved in pathogenesis. Linear fixed and mixed models were used for the genome-wide association study. Using 106 DCM cases and 84 controls we identified one SNP significantly associated with DCM on CFA37 and five SNPs suggestively associated with DCM on CFA1, 10, 15, 21 and 17. On CFA37 MOGAT1 and ACSL3 two enzymes of the lipid metabolism were located near the identified SNP. PMID:22761652

The bilinear complexity and practical algorithms for matrix multiplication

NASA Astrophysics Data System (ADS)

Smirnov, A. V.

2013-12-01

A method for deriving bilinear algorithms for matrix multiplication is proposed. New estimates for the bilinear complexity of a number of problems of the exact and approximate multiplication of rectangular matrices are obtained. In particular, the estimate for the boundary rank of multiplying 3 × 3 matrices is improved and a practical algorithm for the exact multiplication of square n × n matrices is proposed. The asymptotic arithmetic complexity of this algorithm is O( n 2.7743).

Trainee-associated outcomes in laparoscopic colectomy for cancer: propensity score analysis accounting for operative time, procedure complexity and patient comorbidity.

PubMed

Kasten, Kevin R; Celio, Adam C; Trakimas, Lauren; Manwaring, Mark L; Spaniolas, Konstantinos

2018-02-01

Surgical trainee association with operative outcomes is controversial. Studies are conflicting, possibly due to insufficient control of confounding variables such as operative time, case complexity, and heterogeneous patient populations. As operative complications worsen long-term outcomes in oncologic patients, understanding effect of trainee involvement during laparoscopic colectomy for cancer is of utmost importance. Here, we hypothesized that resident involvement was associated with worsened 30-day mortality and 30-day overall morbidity in this patient population. Patients undergoing laparoscopic colectomy for oncologic diagnosis from 2005 to 2012 were assessed using the American College of Surgeons National Surgical Quality Improvement Program dataset. Propensity score matching accounted for demographics, comorbidities, case complexity, and operative time. Attending only cases were compared to junior, middle, chief resident, and fellow level cohorts to assess primary outcomes of 30-day mortality and 30-day overall morbidity. A total of 13,211 patients met inclusion criteria, with 4075 (30.8%) cases lacking trainee involvement and 9136 (69.2%) involving a trainee. Following propensity matching, junior (PGY 1-2) and middle level (PGY 3-4) resident involvement was not associated with worsened outcomes. Chief (PGY 5) resident involvement was associated with worsened 30-day overall morbidity (15.5 vs. 18.6%, p = 0.01). Fellow (PGY > 5) involvement was associated with worsened 30-day overall morbidity (16.0 vs. 21.0%, p < 0.001), serious morbidity (9.3 vs. 13.5%, p < 0.001), minor morbidity (9.8 vs. 13.1%, p = 0.002), and surgical site infection (7.9 vs. 10.5%, p = 0.006). No differences were seen in 30-day mortality for any resident level. Following propensity-matched analysis of cancer patients undergoing laparoscopic colectomy, chief residents, and fellows were associated with worsened operative outcomes compared to attending along cases, while junior and mid-level resident outcomes were no different. Further study is necessary to determine what effect the PGY surgical trainee level has on post-operative morbidity in cancer patients undergoing laparoscopic colectomy in the context of multiple collinear factors.

Linking definitions, mechanisms, and modeling of drought-induced tree death.

PubMed

Anderegg, William R L; Berry, Joseph A; Field, Christopher B

2012-12-01

Tree death from drought and heat stress is a critical and uncertain component in forest ecosystem responses to a changing climate. Recent research has illuminated how tree mortality is a complex cascade of changes involving interconnected plant systems over multiple timescales. Explicit consideration of the definitions, dynamics, and temporal and biological scales of tree mortality research can guide experimental and modeling approaches. In this review, we draw on the medical literature concerning human death to propose a water resource-based approach to tree mortality that considers the tree as a complex organism with a distinct growth strategy. This approach provides insight into mortality mechanisms at the tree and landscape scales and presents promising avenues into modeling tree death from drought and temperature stress. Copyright © 2012 Elsevier Ltd. All rights reserved.

Dynamical analysis of uterine cell electrical activity model.

PubMed

Rihana, S; Santos, J; Mondie, S; Marque, C

2006-01-01

The uterus is a physiological system consisting of a large number of interacting smooth muscle cells. The uterine excitability changes remarkably with time, generally quiescent during pregnancy, the uterus exhibits forceful synchronized contractions at term leading to fetus expulsion. These changes characterize thus a dynamical system susceptible of being studied through formal mathematical tools. Multiple physiological factors are involved in the regulation process of this complex system. Our aim is to relate the physiological factors to the uterine cell dynamic behaviors. Taking into account a previous work presented, in which the electrical activity of a uterine cell is described by a set of ordinary differential equations, we analyze the impact of physiological parameters on the response of the model, and identify the main subsystems generating the complex uterine electrical activity, with respect to physiological data.

Protein Arms in the Kinetochore-Microtubule Interface of the Yeast DASH Complex

PubMed Central

Miranda, JJ L.; King, David S.

2007-01-01

The yeast DASH complex is a heterodecameric component of the kinetochore necessary for accurate chromosome segregation. DASH forms closed rings around microtubules with a large gap between the DASH ring and the microtubule cylinder. We characterized the microtubule-binding properties of limited proteolysis products and subcomplexes of DASH, thus identifying candidate polypeptide extensions involved in establishing the DASH-microtubule interface. The acidic C-terminal extensions of tubulin subunits are not essential for DASH binding. We also measured the molecular mass of DASH rings on microtubules with scanning transmission electron microscopy and found that approximately 25 DASH heterodecamers assemble to form each ring. Dynamic association and relocation of multiple flexible appendages of DASH may allow the kinetochore to translate along the microtubule surface. PMID:17460120

FPGA-based coprocessor for matrix algorithms implementation

NASA Astrophysics Data System (ADS)

Amira, Abbes; Bensaali, Faycal

2003-03-01

Matrix algorithms are important in many types of applications including image and signal processing. These areas require enormous computing power. A close examination of the algorithms used in these, and related, applications reveals that many of the fundamental actions involve matrix operations such as matrix multiplication which is of O (N3) on a sequential computer and O (N3/p) on a parallel system with p processors complexity. This paper presents an investigation into the design and implementation of different matrix algorithms such as matrix operations, matrix transforms and matrix decompositions using an FPGA based environment. Solutions for the problem of processing large matrices have been proposed. The proposed system architectures are scalable, modular and require less area and time complexity with reduced latency when compared with existing structures.

Complex Patterns of Local Adaptation in Teosinte

PubMed Central

Pyhäjärvi, Tanja; Hufford, Matthew B.; Mezmouk, Sofiane; Ross-Ibarra, Jeffrey

2013-01-01

Populations of widely distributed species encounter and must adapt to local environmental conditions. However, comprehensive characterization of the genetic basis of adaptation is demanding, requiring genome-wide genotype data, multiple sampled populations, and an understanding of population structure and potential selection pressures. Here, we used single-nucleotide polymorphism genotyping and data on numerous environmental variables to describe the genetic basis of local adaptation in 21 populations of teosinte, the wild ancestor of maize. We found complex hierarchical genetic structure created by altitude, dispersal events, and admixture among subspecies, which complicated identification of locally beneficial alleles. Patterns of linkage disequilibrium revealed four large putative inversion polymorphisms showing clinal patterns of frequency. Population differentiation and environmental correlations suggest that both inversions and intergenic polymorphisms are involved in local adaptation. PMID:23902747

Systems Biophysics of Gene Expression

PubMed Central

Vilar, Jose M.G.; Saiz, Leonor

2013-01-01

Gene expression is a process central to any form of life. It involves multiple temporal and functional scales that extend from specific protein-DNA interactions to the coordinated regulation of multiple genes in response to intracellular and extracellular changes. This diversity in scales poses fundamental challenges to the use of traditional approaches to fully understand even the simplest gene expression systems. Recent advances in computational systems biophysics have provided promising avenues to reliably integrate the molecular detail of biophysical process into the system behavior. Here, we review recent advances in the description of gene regulation as a system of biophysical processes that extend from specific protein-DNA interactions to the combinatorial assembly of nucleoprotein complexes. There is now basic mechanistic understanding on how promoters controlled by multiple, local and distal, DNA binding sites for transcription factors can actively control transcriptional noise, cell-to-cell variability, and other properties of gene regulation, including precision and flexibility of the transcriptional responses. PMID:23790365

Practical management of anticoagulation in patients with atrial fibrillation.

PubMed

Kovacs, Richard J; Flaker, Greg C; Saxonhouse, Sherry J; Doherty, John U; Birtcher, Kim K; Cuker, Adam; Davidson, Bruce L; Giugliano, Robert P; Granger, Christopher B; Jaffer, Amir K; Mehta, Bella H; Nutescu, Edith; Williams, Kim A

2015-04-07

Anticoagulation for atrial fibrillation has become more complex due to the introduction of new anticoagulant agents, the number and kinds of patients requiring therapy, and the interactions of those patients in the matrix of care. The management of anticoagulation has become a "team sport" involving multiple specialties in multiple sites of care. The American College of Cardiology, through the College's Anticoagulation Initiative, convened a roundtable of experts from multiple specialties to discuss topics important to the management of patients requiring anticoagulation and to make expert recommendations on issues such as the initiation and interruption of anticoagulation, quality of anticoagulation care, management of major and minor bleeding, and treatment of special populations. The attendees continued to work toward consensus on these topics, and present the key findings of this roundtable in a state-of- the-art review focusing on the practical aspects of anticoagulation care for the patient with atrial fibrillation. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Mass media in health promotion: an analysis using an extended information-processing model.

PubMed

Flay, B R; DiTecco, D; Schlegel, R P

1980-01-01

The information-processing model of the attitude and behavior change process was critically examined and extended from six to 12 levels for a better analysis of change due to mass media campaigns. Findings from social psychology and communications research, and from evaluations of mass media health promotion programs, were reviewed to determine how source, message, channel, receiver, and destination variables affect each of the levels of change of major interest (knowledge, beliefs, attitudes, intentions and behavior). Factors found to most likely induce permanent attitude and behavior change (most important in health promotion) were: presentation and repetition over long time periods, via multiple sources, at different times (including "prime" or high-exposure times), by multiple sources, in novel and involving ways, with appeals to multiple motives, development of social support, and provisions of appropriate behavioral skills, alternatives, and reinforcement (preferably in ways that get the active participation of the audience). Suggestions for evaluation of mass media programs that take account of this complexity were advanced.

A new derived and highly polymorphic chromosomal race of Liolaemus monticola (Iguanidae) from the 'Norte Chico' of Chile.

PubMed

Lamborot, M

1998-06-01

A multiple Robertsonian fission chromosomal race of the Liolaemus monticola complex in Chile is described and is shown to be the most derived and the most complex among the Liolaemus examined thus far. The 29 karyotyped lizards analysed from the locality of Mina Hierro Viejo, Petorca, Provincia de Valparaiso, Chile, exhibited a diploid chromosomal number ranging from 42 to 44, and several polymorphisms. The polymorphisms included: a pair 1 fission; a pair 2 fission plus a pericentric inversion in one of the fission products, which moved the NOR and satellite from the tip of the long arm of the metacentric 2 to the short arm of the fission product; a fission in pair 3; a polymorphism for an enlarged chromosome pair 6; and a polymorphism for a pericentric inversion in pair 7. This population is fixed for a fission of chromosome pair 4. A total of 76% of the lizards analysed were polymorphic for one or more pairs of chromosomes. We have compared these data with other Liolaemus monticola chromosomal races and calculated the Hardy-Weinberg ratios for the polymorphic chromosome pairs in this Multiple-Fission race. Karyotypic differences between the Northern (2n = 38-40) and the Multiple-Fission (2n = 42-44) races were attributed mainly to Robertsonian fissions, an enlarged chromosome and pericentric inversions involving the macrochromosomes and one microchromosome pair.

Validation and calibration of structural models that combine information from multiple sources.

PubMed

Dahabreh, Issa J; Wong, John B; Trikalinos, Thomas A

2017-02-01

Mathematical models that attempt to capture structural relationships between their components and combine information from multiple sources are increasingly used in medicine. Areas covered: We provide an overview of methods for model validation and calibration and survey studies comparing alternative approaches. Expert commentary: Model validation entails a confrontation of models with data, background knowledge, and other models, and can inform judgments about model credibility. Calibration involves selecting parameter values to improve the agreement of model outputs with data. When the goal of modeling is quantitative inference on the effects of interventions or forecasting, calibration can be viewed as estimation. This view clarifies issues related to parameter identifiability and facilitates formal model validation and the examination of consistency among different sources of information. In contrast, when the goal of modeling is the generation of qualitative insights about the modeled phenomenon, calibration is a rather informal process for selecting inputs that result in model behavior that roughly reproduces select aspects of the modeled phenomenon and cannot be equated to an estimation procedure. Current empirical research on validation and calibration methods consists primarily of methodological appraisals or case-studies of alternative techniques and cannot address the numerous complex and multifaceted methodological decisions that modelers must make. Further research is needed on different approaches for developing and validating complex models that combine evidence from multiple sources.

microRNA regulation of T lymphocyte immunity: modulation of molecular networks responsible for T cell activation, differentiation and development

PubMed Central

Podshivalova, Katie; Salomon, Daniel R.

2014-01-01

MicroRNAs (miRNA) are a class of small non-coding RNAs that constitute an essential and evolutionarily conserved mechanism for post-transcriptional gene regulation. Multiple miRNAs have been described to play key roles in T lymphocyte development, differentiation and function. In this review we highlight the current literature regarding the differential expression of miRNAs in various models of mouse and human T cell biology and emphasize mechanistic understandings of miRNA regulation of thymocyte development, T cell activation, and differentiation into effector and memory subsets. We describe the participation of miRNAs in complex regulatory circuits shaping T cell proteomes in a context-dependent manner. It is striking that some miRNAs regulate multiple processes, while others only appear in limited functional contexts. It is also evident that the expression and function of specific miRNAs can differ between mouse and human systems. Ultimately, it is not always correct to simplify the complex events of T cell biology into a model driven by only one or two master regulator miRNAs. In reality, T cell activation and differentiation involves the expression of multiple miRNAs with many mRNA targets and thus, the true extent of miRNA regulation of T cell biology is likely far more vast than currently appreciated. PMID:24099302

B cell biology: implications for treatment of systemic lupus erythematosus.

PubMed

Anolik, J H

2013-04-01

B cells are critical players in the orchestration of properly regulated immune responses, normally providing protective immunity without autoimmunity. Balance in the B cell compartment is achieved through the finely regulated participation of multiple B cell populations with different antibody-dependent and independent functions. Both types of functions allow B cells to modulate other components of the innate and adaptive immune system. Autoantibody-independent B cell functions include antigen presentation, T cell activation and polarization, and dendritic cell modulation. Several of these functions are mediated by the ability of B cells to produce immunoregulatory cytokines and chemokines and by their critical contribution to lymphoid tissue development and organization including the development of ectopic tertiary lymphoid tissue. Additionally, the functional versatility of B cells enables them to play either protective or pathogenic roles in autoimmunity. In turn, B cell dysfunction has been critically implicated in the pathophysiology of systemic lupus erythematosus (SLE), a complex disease characterized by the production of autoantibodies and heterogeneous clinical involvement. Thus, the breakdown of B cell tolerance is a defining and early event in the disease process and may occur by multiple pathways, including alterations in factors that affect B cell activation thresholds, B cell longevity, and apoptotic cell processing. Once tolerance is broken, autoantibodies contribute to autoimmunity by multiple mechanisms including immune-complex mediated Type III hypersensitivity reactions, type II antibody-dependent cytotoxicity, and by instructing innate immune cells to produce pathogenic cytokines including IFNα, TNF and IL-1. The complexity of B cell functions has been highlighted by the variable success of B cell-targeted therapies in multiple autoimmune diseases, including those conventionally viewed as T cell-mediated conditions. Given the widespread utilization of B cell depletion therapy in autoimmune diseases and the need for new therapeutic approaches in SLE, a better understanding of human B cell subsets and the balance of pathogenic and regulatory functions is of the essence.

Cellular and molecular mechanisms of age-related macular degeneration: from impaired autophagy to neovascularization.

PubMed

Klettner, Alexa; Kauppinen, Anu; Blasiak, Janusz; Roider, Johan; Salminen, Antero; Kaarniranta, Kai

2013-07-01

Age-related macular degeneration (AMD) is a complex, degenerative and progressive disease involving multiple genetic and environmental factors. It can result in severe visual loss e.g. AMD is the leading cause of blindness in the elderly in the western countries. Although age, genetics, diet, smoking, and many cardiovascular factors are known to be linked with this disease there is increasing evidence that long-term oxidative stress, impaired autophagy clearance and inflammasome mediated inflammation are involved in the pathogenesis. Under certain conditions these may trigger detrimental processes e.g. release of vascular endothelial growth factor (VEGF), causing choroidal neovascularization e.g. in wet AMD. This review ties together these crucial pathological threads in AMD. Copyright © 2013 Elsevier Ltd. All rights reserved.

Systems and precision medicine approaches to diabetes heterogeneity: a Big Data perspective.

PubMed

Capobianco, Enrico

2017-12-01

Big Data, and in particular Electronic Health Records, provide the medical community with a great opportunity to analyze multiple pathological conditions at an unprecedented depth for many complex diseases, including diabetes. How can we infer on diabetes from large heterogeneous datasets? A possible solution is provided by invoking next-generation computational methods and data analytics tools within systems medicine approaches. By deciphering the multi-faceted complexity of biological systems, the potential of emerging diagnostic tools and therapeutic functions can be ultimately revealed. In diabetes, a multidimensional approach to data analysis is needed to better understand the disease conditions, trajectories and the associated comorbidities. Elucidation of multidimensionality comes from the analysis of factors such as disease phenotypes, marker types, and biological motifs while seeking to make use of multiple levels of information including genetics, omics, clinical data, and environmental and lifestyle factors. Examining the synergy between multiple dimensions represents a challenge. In such regard, the role of Big Data fuels the rise of Precision Medicine by allowing an increasing number of descriptions to be captured from individuals. Thus, data curations and analyses should be designed to deliver highly accurate predicted risk profiles and treatment recommendations. It is important to establish linkages between systems and precision medicine in order to translate their principles into clinical practice. Equivalently, to realize their full potential, the involved multiple dimensions must be able to process information ensuring inter-exchange, reducing ambiguities and redundancies, and ultimately improving health care solutions by introducing clinical decision support systems focused on reclassified phenotypes (or digital biomarkers) and community-driven patient stratifications.

Perceptions of family-centred services in a paediatric rehabilitation programme: strengths and complexities from multiple stakeholders.

PubMed

Arcuri, G G; McMullan, A E; Murray, A E; Silver, L K; Bergthorson, M; Dahan-Oliel, N; Coutinho, F

2016-03-01

Family-centred services (FCS) are best practice in paediatric rehabilitation and describe philosophies and approaches to medical care that emphasize the partnership and involvement of parents. While evidence supports FCS, there are complexities to its successful implementation. This mixed-methods study aimed to measure the extent to which parents and the healthcare provider (HCP) perceive service provision as being family centred, and to describe barriers and facilitators to the delivery of FCS. Parents of children participating in a rehabilitation programme and HCPs providing services participated in this study. Parents completed the measure of processes of care-20 and participated in interviews, while HCPs completed the measure of processes of care-service providers and participated in a focus group. Quantitative analysis revealed that parents were mostly satisfied with features of FCS, which included communication and support between parents and HCPs, respect of diversity and parental collaboration and participation. Parents identified communication methods and psychosocial needs as areas that facilitated but sometimes detracted from FCS. Institutional barriers led to the identification of areas for improvement identified by multiple stakeholders. HCPs identified more areas for improvement than parents. When considering these barriers, it is evident that implementation is a complex process, impacted by institutional barriers. FCS needs to be investigated further, and systemic interventions should be used to facilitate its implementation. © 2015 John Wiley & Sons Ltd.

Climate Modeling with a Million CPUs

NASA Astrophysics Data System (ADS)

Tobis, M.; Jackson, C. S.

2010-12-01

Michael Tobis, Ph.D. Research Scientist Associate University of Texas Institute for Geophysics Charles S. Jackson Research Scientist University of Texas Institute for Geophysics Meteorological, oceanographic, and climatological applications have been at the forefront of scientific computing since its inception. The trend toward ever larger and more capable computing installations is unabated. However, much of the increase in capacity is accompanied by an increase in parallelism and a concomitant increase in complexity. An increase of at least four additional orders of magnitude in the computational power of scientific platforms is anticipated. It is unclear how individual climate simulations can continue to make effective use of the largest platforms. Conversion of existing community codes to higher resolution, or to more complex phenomenology, or both, presents daunting design and validation challenges. Our alternative approach is to use the expected resources to run very large ensembles of simulations of modest size, rather than to await the emergence of very large simulations. We are already doing this in exploring the parameter space of existing models using the Multiple Very Fast Simulated Annealing algorithm, which was developed for seismic imaging. Our experiments have the dual intentions of tuning the model and identifying ranges of parameter uncertainty. Our approach is less strongly constrained by the dimensionality of the parameter space than are competing methods. Nevertheless, scaling up remains costly. Much could be achieved by increasing the dimensionality of the search and adding complexity to the search algorithms. Such ensemble approaches scale naturally to very large platforms. Extensions of the approach are anticipated. For example, structurally different models can be tuned to comparable effectiveness. This can provide an objective test for which there is no realistic precedent with smaller computations. We find ourselves inventing new code to manage our ensembles. Component computations involve tens to hundreds of CPUs and tens to hundreds of hours. The results of these moderately large parallel jobs influence the scheduling of subsequent jobs, and complex algorithms may be easily contemplated for this. The operating system concept of a "thread" re-emerges at a very coarse level, where each thread manages atomic computations of thousands of CPU-hours. That is, rather than multiple threads operating on a processor, at this level, multiple processors operate within a single thread. In collaboration with the Texas Advanced Computing Center, we are developing a software library at the system level, which should facilitate the development of computations involving complex strategies which invoke large numbers of moderately large multi-processor jobs. While this may have applications in other sciences, our key intent is to better characterize the coupled behavior of a very large set of climate model configurations.

Large system change challenges: addressing complex critical issues in linked physical and social domains

NASA Astrophysics Data System (ADS)

Waddell, Steve; Cornell, Sarah; Hsueh, Joe; Ozer, Ceren; McLachlan, Milla; Birney, Anna

2015-04-01

Most action to address contemporary complex challenges, including the urgent issues of global sustainability, occurs piecemeal and without meaningful guidance from leading complex change knowledge and methods. The potential benefit of using such knowledge is greater efficacy of effort and investment. However, this knowledge and its associated tools and methods are under-utilized because understanding about them is low, fragmented between diverse knowledge traditions, and often requires shifts in mindsets and skills from expert-led to participant-based action. We have been engaged in diverse action-oriented research efforts in Large System Change for sustainability. For us, "large" systems can be characterized as large-scale systems - up to global - with many components, of many kinds (physical, biological, institutional, cultural/conceptual), operating at multiple levels, driven by multiple forces, and presenting major challenges for people involved. We see change of such systems as complex challenges, in contrast with simple or complicated problems, or chaotic situations. In other words, issues and sub-systems have unclear boundaries, interact with each other, and are often contradictory; dynamics are non-linear; issues are not "controllable", and "solutions" are "emergent" and often paradoxical. Since choices are opportunity-, power- and value-driven, these social, institutional and cultural factors need to be made explicit in any actionable theory of change. Our emerging network is sharing and building a knowledge base of experience, heuristics, and theories of change from multiple disciplines and practice domains. We will present our views on focal issues for the development of the field of large system change, which include processes of goal-setting and alignment; leverage of systemic transitions and transformation; and the role of choice in influencing critical change processes, when only some sub-systems or levels of the system behave in purposeful ways, while others are undeniably and unavoidably deterministic.

Constrained Multipoint Aerodynamic Shape Optimization Using an Adjoint Formulation and Parallel Computers

NASA Technical Reports Server (NTRS)

Reuther, James; Jameson, Antony; Alonso, Juan Jose; Rimlinger, Mark J.; Saunders, David

1997-01-01

An aerodynamic shape optimization method that treats the design of complex aircraft configurations subject to high fidelity computational fluid dynamics (CFD), geometric constraints and multiple design points is described. The design process will be greatly accelerated through the use of both control theory and distributed memory computer architectures. Control theory is employed to derive the adjoint differential equations whose solution allows for the evaluation of design gradient information at a fraction of the computational cost required by previous design methods. The resulting problem is implemented on parallel distributed memory architectures using a domain decomposition approach, an optimized communication schedule, and the MPI (Message Passing Interface) standard for portability and efficiency. The final result achieves very rapid aerodynamic design based on a higher order CFD method. In order to facilitate the integration of these high fidelity CFD approaches into future multi-disciplinary optimization (NW) applications, new methods must be developed which are capable of simultaneously addressing complex geometries, multiple objective functions, and geometric design constraints. In our earlier studies, we coupled the adjoint based design formulations with unconstrained optimization algorithms and showed that the approach was effective for the aerodynamic design of airfoils, wings, wing-bodies, and complex aircraft configurations. In many of the results presented in these earlier works, geometric constraints were satisfied either by a projection into feasible space or by posing the design space parameterization such that it automatically satisfied constraints. Furthermore, with the exception of reference 9 where the second author initially explored the use of multipoint design in conjunction with adjoint formulations, our earlier works have focused on single point design efforts. Here we demonstrate that the same methodology may be extended to treat complete configuration designs subject to multiple design points and geometric constraints. Examples are presented for both transonic and supersonic configurations ranging from wing alone designs to complex configuration designs involving wing, fuselage, nacelles and pylons.

Blind predictions of protein interfaces by docking calculations in CAPRI.

PubMed

Lensink, Marc F; Wodak, Shoshana J

2010-11-15

Reliable prediction of the amino acid residues involved in protein-protein interfaces can provide valuable insight into protein function, and inform mutagenesis studies, and drug design applications. A fast-growing number of methods are being proposed for predicting protein interfaces, using structural information, energetic criteria, or sequence conservation or by integrating multiple criteria and approaches. Overall however, their performance remains limited, especially when applied to nonobligate protein complexes, where the individual components are also stable on their own. Here, we evaluate interface predictions derived from protein-protein docking calculations. To this end we measure the overlap between the interfaces in models of protein complexes submitted by 76 participants in CAPRI (Critical Assessment of Predicted Interactions) and those of 46 observed interfaces in 20 CAPRI targets corresponding to nonobligate complexes. Our evaluation considers multiple models for each target interface, submitted by different participants, using a variety of docking methods. Although this results in a substantial variability in the prediction performance across participants and targets, clear trends emerge. Docking methods that perform best in our evaluation predict interfaces with average recall and precision levels of about 60%, for a small majority (60%) of the analyzed interfaces. These levels are significantly higher than those obtained for nonobligate complexes by most extant interface prediction methods. We find furthermore that a sizable fraction (24%) of the interfaces in models ranked as incorrect in the CAPRI assessment are actually correctly predicted (recall and precision ≥50%), and that these models contribute to 70% of the correct docking-based interface predictions overall. Our analysis proves that docking methods are much more successful in identifying interfaces than in predicting complexes, and suggests that these methods have an excellent potential of addressing the interface prediction challenge. © 2010 Wiley-Liss, Inc.

An Association Between Functional Polymorphisms of the Interleukin 1 Gene Complex and Schizophrenia Using Transmission Disequilibrium Test.

PubMed

Kapelski, Pawel; Skibinska, Maria; Maciukiewicz, Malgorzata; Pawlak, Joanna; Dmitrzak-Weglarz, Monika; Szczepankiewicz, Aleksandra; Zaremba, Dorota; Twarowska-Hauser, Joanna

2016-12-01

IL1 gene complex has been implicated in the etiology of schizophrenia. To assess whether IL1 gene complex is associated with susceptibility to schizophrenia in Polish population we conducted family-based study. Functional polymorphisms from IL1A (rs1800587, rs17561, rs11677416), IL1B (rs1143634, rs1143643, rs16944, rs4848306, rs1143623, rs1143633, rs1143627) and IL1RN (rs419598, rs315952, rs9005, rs4251961) genes were genotyped in 143 trio with schizophrenia. Statistical analysis was performed using transmission disequilibrium test. We have found a trend toward an association of rs1143627, rs16944, rs1143623 in IL1B gene with the risk of schizophrenia. Our results show a protective effect of allele T of rs4251961 in IL1RN against schizophrenia. We also performed haplotype analysis of IL1 gene complex and found a trend toward an association with schizophrenia of GAGG haplotype (rs1143627, rs16944, rs1143623, rs4848306) in IL1B gene, haplotypes: TG (rs315952, rs9005) and TT (rs4251961, rs419598) in IL1RN. Haplotype CT (rs4251961, rs419598) in IL1RN was found to be associated with schizophrenia. After correction for multiple testing associations did not reach significance level. Our results might support theory that polymorphisms of interleukin 1 complex genes (rs1143627, rs16944, rs1143623, rs4848306 in IL1B gene and rs4251961, rs419598, rs315952, rs9005 in IL1RN gene) are involved in the pathogenesis of schizophrenia, however, none of the results reach significance level after correction for multiple testing.

A Complex 6p25 Rearrangement in a Child With Multiple Epiphyseal Dysplasia

PubMed Central

Bedoyan, Jirair K.; Lesperance, Marci M.; Ackley, Todd; Iyer, Ramaswamy K.; Innis, Jeffrey W.; Misra, Vinod K.

2015-01-01

Genomic rearrangements are increasingly recognized as important contributors to human disease. Here we report on an 11½-year-old child with myopia, Duane retraction syndrome, bilateral mixed hearing loss, skeletal anomalies including multiple epiphyseal dysplasia, and global developmental delay, and a complex 6p25 genomic rearrangement. We have employed oligonucleotide-based comparative genomic hybridization arrays (aCGH) of different resolutions (44 and 244K) as well as a 1 M single nucleotide polymorphism (SNP) array to analyze this complex rearrangement. Our analyses reveal a complex rearrangement involving a ~2.21 Mb interstitial deletion, a ~240 kb terminal deletion, and a 70–80 kb region in between these two deletions that shows maintenance of genomic copy number. The interstitial deletion contains eight known genes, including three Forkhead box containing (FOX) transcription factors (FOXQ1, FOXF2, and FOXC1). The region maintaining genomic copy number partly overlaps the dual specificity protein phosphatase 22 (DUSP22) gene. Array analyses suggest a homozygous loss of genomic material at the 5′ end of DUSP22, which was corroborated using TaqMan® copy number analysis. It is possible that this homozygous genomic loss may render both copies of DUSP22 or its products non-functional. Our analysis suggests a rearrangement mechanism distinct from a previously reported replication-based error-prone mechanism without template switching for a specific 6p25 rearrangement with a 1.22 Mb interstitial deletion. Our study demonstrates the utility and limitations of using oligonucleotide-based aCGH and SNP array technologies of increasing resolutions in order to identify complex DNA rearrangements and gene disruptions. PMID:21204225

Morphodynamics of an eroding beach and foredune in the Mekong River delta: Implications for deltaic shoreline change

NASA Astrophysics Data System (ADS)

Anthony, E. J.; Dussouillez, P.; Dolique, F.; Besset, M.; Brunier, G.; Nguyen, V. L.; Goichot, M.

2017-09-01

River delta shorelines composed of sand may be characterized by complex spatial and temporal patterns of erosion and accretion even when sand supply is readily available. This is especially the case for deltas with multiple mouths subject to significant wave and tide influence. High-resolution topographical and wave and current measurements were conducted from 2010 to 2012 at Ba Dông beach, a popular resort located on the largest of the multiple inter-distributary plains of the Mekong River delta. Ba Dông beach is a mesotidal, multiple bar-trough system. The upper beach corresponds to the current active beach ridge in the sequence of ridges that have marked the progradation of the inter-distributary delta plains, and is capped by a low foredune that protects villages and agricultural land from marine flooding. During the low river-flow season, the beach is characterized by Northeast monsoon waves and strong longshore currents that transport sediment towards the southwest. Weaker longshore currents towards the northeast are generated by Southwest monsoon waves during the high river-flow season. Ba Dông beach underwent strong erosion between 2010 and 2012, following a phase of massive accretion. In 2012, this erosion resulted in breaching of the foredune, contributing to concerns that the Mekong delta had become vulnerable to retreat. The local erosion at Ba Dông needs to be considered, however, in the broader context of delta shoreline morphodynamics, which involves space- and time-varying patterns of beach accretion and erosion. These patterns are the present expressions of plan-view beach-ridge morphology in the delta, which is characterized by flaring and truncations that reflect changing beach morphodynamics in the course of deltaic progradation. We surmise that these patterns are related to complex interactions involving river water and sediment discharge, waves and wave-generated longshore currents, tidal currents, and shoreline orientation.

An efficient genome-wide association test for multivariate phenotypes based on the Fisher combination function.

PubMed

Yang, James J; Li, Jia; Williams, L Keoki; Buu, Anne

2016-01-05

In genome-wide association studies (GWAS) for complex diseases, the association between a SNP and each phenotype is usually weak. Combining multiple related phenotypic traits can increase the power of gene search and thus is a practically important area that requires methodology work. This study provides a comprehensive review of existing methods for conducting GWAS on complex diseases with multiple phenotypes including the multivariate analysis of variance (MANOVA), the principal component analysis (PCA), the generalizing estimating equations (GEE), the trait-based association test involving the extended Simes procedure (TATES), and the classical Fisher combination test. We propose a new method that relaxes the unrealistic independence assumption of the classical Fisher combination test and is computationally efficient. To demonstrate applications of the proposed method, we also present the results of statistical analysis on the Study of Addiction: Genetics and Environment (SAGE) data. Our simulation study shows that the proposed method has higher power than existing methods while controlling for the type I error rate. The GEE and the classical Fisher combination test, on the other hand, do not control the type I error rate and thus are not recommended. In general, the power of the competing methods decreases as the correlation between phenotypes increases. All the methods tend to have lower power when the multivariate phenotypes come from long tailed distributions. The real data analysis also demonstrates that the proposed method allows us to compare the marginal results with the multivariate results and specify which SNPs are specific to a particular phenotype or contribute to the common construct. The proposed method outperforms existing methods in most settings and also has great applications in GWAS on complex diseases with multiple phenotypes such as the substance abuse disorders.

Structural mechanisms of chaperone mediated protein disaggregation

PubMed Central

Sousa, Rui

2014-01-01

The ClpB/Hsp104 and Hsp70 classes of molecular chaperones use ATP hydrolysis to dissociate protein aggregates and complexes, and to move proteins through membranes. ClpB/Hsp104 are members of the AAA+ family of proteins which form ring-shaped hexamers. Loops lining the pore in the ring engage substrate proteins as extended polypeptides. Interdomain rotations and conformational changes in these loops coupled to ATP hydrolysis unfold and pull proteins through the pore. This provides a mechanism that progressively disrupts local secondary and tertiary structure in substrates, allowing these chaperones to dissociate stable aggregates such as β-sheet rich prions or coiled coil SNARE complexes. While the ClpB/Hsp104 mechanism appears to embody a true power-stroke in which an ATP powered conformational change in one protein is directly coupled to movement or structural change in another, the mechanism of force generation by Hsp70s is distinct and less well understood. Both active power-stroke and purely passive mechanisms in which Hsp70 captures spontaneous fluctuations in a substrate have been proposed, while a third proposed mechanism—entropic pulling—may be able to generate forces larger than seen in ATP-driven molecular motors without the conformational coupling required for a power-stroke. The disaggregase activity of these chaperones is required for thermotolerance, but unrestrained protein complex/aggregate dissociation is potentially detrimental. Disaggregating chaperones are strongly auto-repressed, and are regulated by co-chaperones which recruit them to protein substrates and activate the disaggregases via mechanisms involving either sequential transfer of substrate from one chaperone to another and/or simultaneous interaction of substrate with multiple chaperones. By effectively subjecting substrates to multiple levels of selection by multiple chaperones, this may insure that these potent disaggregases are only activated in the appropriate context. PMID:25988153

The meaning of spasticity to people with multiple sclerosis: what can health professionals learn?

PubMed

Morley, Alex; Tod, Angela; Cramp, Mary; Mawson, Sue

2013-07-01

Multiple sclerosis (MS) is the most common disabling neurological condition affecting young adults. One third of people on an American registry of people with MS (PWMS) reported having activities affected by spasticity. The psychosocial effects of spasticity in people with MS have been shown to be distressing and detrimental to emotional and social relationships when investigated from a psychology perspective. This paper investigates the impact of spasticity on the lives of people living with MS from a physiotherapeutic perspective. This study involved 12 semi-structured interviews with individuals experiencing MS-related spasticity. Ten sets of data were analyzed following framework analysis principles. Results suggest spasticity effects life experience of these PWMS in diverse and complex ways. Physical, psychological and social consequences of spasticity are closely linked and can be far reaching. Therapists need to be aware of links between specific physical symptoms and their psychosocial consequences if they want to improve peoples' quality of life. This paper provides in depth qualitative research evidence for the complexity of the spasticity experience for each individual, strengthening the argument for a patient-centred approach to treatment. These results also support the case for targeted interventions with effectiveness recorded in a patient-centred way. • Spasticity is suggested here to affect the lives of individuals with multiple sclerosis in diverse and far reaching ways. Therapists need to investigate this fully in subjective assessment to impact on people's quality of life. • Direct links were identified between treatable physical symptoms and far reaching consequences of spasticity. • Knowledge about the complexity of the spasticity experience for each individual will allow therapists to target interventions appropriately and accurately record effectiveness in a patient-centred way.

Beclin 1 Is Required for Neuron Viability and Regulates Endosome Pathways via the UVRAG-VPS34 Complex

PubMed Central

Wold, Mitchell S.; Gong, Shiaoching; Phillips, Greg R.; Dou, Zhixun; Zhao, Yanxiang; Heintz, Nathaniel; Zong, Wei-Xing; Yue, Zhenyu

2014-01-01

Deficiency of autophagy protein beclin 1 is implicated in tumorigenesis and neurodegenerative diseases, but the molecular mechanism remains elusive. Previous studies showed that Beclin 1 coordinates the assembly of multiple VPS34 complexes whose distinct phosphatidylinositol 3-kinase III (PI3K-III) lipid kinase activities regulate autophagy at different steps. Recent evidence suggests a function of beclin 1 in regulating multiple VPS34-mediated trafficking pathways beyond autophagy; however, the precise role of beclin 1 in autophagy-independent cellular functions remains poorly understood. Herein we report that beclin 1 regulates endocytosis, in addition to autophagy, and is required for neuron viability in vivo. We find that neuronal beclin 1 associates with endosomes and regulates EEA1/early endosome localization and late endosome formation. Beclin 1 maintains proper cellular phosphatidylinositol 3-phosphate (PI(3)P) distribution and total levels, and loss of beclin 1 causes a disruption of active Rab5 GTPase-associated endosome formation and impairment of endosome maturation, likely due to a failure of Rab5 to recruit VPS34. Furthermore, we find that Beclin 1 deficiency causes complete loss of the UVRAG-VPS34 complex and associated lipid kinase activity. Interestingly, beclin 1 deficiency impairs p40phox-linked endosome formation, which is rescued by overexpressed UVRAG or beclin 1, but not by a coiled-coil domain-truncated beclin 1 (a UVRAG-binding mutant), Atg14L or RUBICON. Thus, our study reveals the essential role for beclin 1 in neuron survival involving multiple membrane trafficking pathways including endocytosis and autophagy, and suggests that the UVRAG-beclin 1 interaction underlies beclin 1's function in endocytosis. PMID:25275521

A Type III Protein Arginine Methyltransferase from the Protozoan Parasite Trypanosoma brucei*

PubMed Central

Fisk, John C.; Sayegh, Joyce; Zurita-Lopez, Cecilia; Menon, Sarita; Presnyak, Vladimir; Clarke, Steven G.; Read, Laurie K.

2009-01-01

Arginine methylation is a widespread post-translational modification of proteins catalyzed by a family of protein arginine methyltransferases (PRMTs). The ancient protozoan parasite, Trypanosoma brucei, possesses five putative PRMTs, a relatively large number for a single-celled eukaryote. Trypanosomatids lack gene regulation at the level of transcription, instead relying on post-transcriptional control mechanisms that act at the levels of RNA turnover, translation, and editing, all processes that likely involve multiple RNA-binding proteins, which are common targets of arginine methylation. Here, we report the characterization of a trypanosome PRMT, TbPRMT7, which is homologous to human PRMT7. Interestingly, trypanosomatids are the only single-celled eukaryotes known to harbor a PRMT7 homologue. TbPRMT7 differs dramatically from all known metazoan PRMT7 homologues in lacking the second AdoMet binding-like domain that is required for activity of the human enzyme. Nevertheless, bacterially expressed TbPRMT7 exhibits robust methyltransferase activity toward multiple targets in vitro. High resolution ion exchange chromatography analysis of methylated substrates reveals that TbPRMT7 is a type III PRMT, catalyzing the formation of only monomethylarginine, thereby representing the only exclusively type III PRMT identified to date. TbPRMT7 is expressed in both mammalian and insect stage T. brucei and is apparently dispensable for growth in both life cycle stages. The enzyme is cytoplasmically localized and is a component of several higher order complexes in vivo. Together, our studies indicate that TbPRMT7 is a Type III PRMT, and its robust activity and presence in numerous complexes suggest it plays multiple roles during the complex T. brucei life cycle. PMID:19254949

A type III protein arginine methyltransferase from the protozoan parasite Trypanosoma brucei.

PubMed

Fisk, John C; Sayegh, Joyce; Zurita-Lopez, Cecilia; Menon, Sarita; Presnyak, Vladimir; Clarke, Steven G; Read, Laurie K

2009-04-24

Arginine methylation is a widespread post-translational modification of proteins catalyzed by a family of protein arginine methyltransferases (PRMTs). The ancient protozoan parasite, Trypanosoma brucei, possesses five putative PRMTs, a relatively large number for a single-celled eukaryote. Trypanosomatids lack gene regulation at the level of transcription, instead relying on post-transcriptional control mechanisms that act at the levels of RNA turnover, translation, and editing, all processes that likely involve multiple RNA-binding proteins, which are common targets of arginine methylation. Here, we report the characterization of a trypanosome PRMT, TbPRMT7, which is homologous to human PRMT7. Interestingly, trypanosomatids are the only single-celled eukaryotes known to harbor a PRMT7 homologue. TbPRMT7 differs dramatically from all known metazoan PRMT7 homologues in lacking the second AdoMet binding-like domain that is required for activity of the human enzyme. Nevertheless, bacterially expressed TbPRMT7 exhibits robust methyltransferase activity toward multiple targets in vitro. High resolution ion exchange chromatography analysis of methylated substrates reveals that TbPRMT7 is a type III PRMT, catalyzing the formation of only monomethylarginine, thereby representing the only exclusively type III PRMT identified to date. TbPRMT7 is expressed in both mammalian and insect stage T. brucei and is apparently dispensable for growth in both life cycle stages. The enzyme is cytoplasmically localized and is a component of several higher order complexes in vivo. Together, our studies indicate that TbPRMT7 is a Type III PRMT, and its robust activity and presence in numerous complexes suggest it plays multiple roles during the complex T. brucei life cycle.

Architecture of the Human Mitochondrial Iron-Sulfur Cluster Assembly Machinery.

PubMed

Gakh, Oleksandr; Ranatunga, Wasantha; Smith, Douglas Y; Ahlgren, Eva-Christina; Al-Karadaghi, Salam; Thompson, James R; Isaya, Grazia

2016-09-30

Fe-S clusters, essential cofactors needed for the activity of many different enzymes, are assembled by conserved protein machineries inside bacteria and mitochondria. As the architecture of the human machinery remains undefined, we co-expressed in Escherichia coli the following four proteins involved in the initial step of Fe-S cluster synthesis: FXN 42-210 (iron donor); [NFS1]·[ISD11] (sulfur donor); and ISCU (scaffold upon which new clusters are assembled). We purified a stable, active complex consisting of all four proteins with 1:1:1:1 stoichiometry. Using negative staining transmission EM and single particle analysis, we obtained a three-dimensional model of the complex with ∼14 Å resolution. Molecular dynamics flexible fitting of protein structures docked into the EM map of the model revealed a [FXN 42-210 ] 24 ·[NFS1] 24 ·[ISD11] 24 ·[ISCU] 24 complex, consistent with the measured 1:1:1:1 stoichiometry of its four components. The complex structure fulfills distance constraints obtained from chemical cross-linking of the complex at multiple recurring interfaces, involving hydrogen bonds, salt bridges, or hydrophobic interactions between conserved residues. The complex consists of a central roughly cubic [FXN 42-210 ] 24 ·[ISCU] 24 sub-complex with one symmetric ISCU trimer bound on top of one symmetric FXN 42-210 trimer at each of its eight vertices. Binding of 12 [NFS1] 2 ·[ISD11] 2 sub-complexes to the surface results in a globular macromolecule with a diameter of ∼15 nm and creates 24 Fe-S cluster assembly centers. The organization of each center recapitulates a previously proposed conserved mechanism for sulfur donation from NFS1 to ISCU and reveals, for the first time, a path for iron donation from FXN 42-210 to ISCU. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Architecture of the Human Mitochondrial Iron-Sulfur Cluster Assembly Machinery*

PubMed Central

Gakh, Oleksandr; Ranatunga, Wasantha; Smith, Douglas Y.; Ahlgren, Eva-Christina; Al-Karadaghi, Salam; Thompson, James R.; Isaya, Grazia

2016-01-01

Fe-S clusters, essential cofactors needed for the activity of many different enzymes, are assembled by conserved protein machineries inside bacteria and mitochondria. As the architecture of the human machinery remains undefined, we co-expressed in Escherichia coli the following four proteins involved in the initial step of Fe-S cluster synthesis: FXN42–210 (iron donor); [NFS1]·[ISD11] (sulfur donor); and ISCU (scaffold upon which new clusters are assembled). We purified a stable, active complex consisting of all four proteins with 1:1:1:1 stoichiometry. Using negative staining transmission EM and single particle analysis, we obtained a three-dimensional model of the complex with ∼14 Å resolution. Molecular dynamics flexible fitting of protein structures docked into the EM map of the model revealed a [FXN42–210]24·[NFS1]24·[ISD11]24·[ISCU]24 complex, consistent with the measured 1:1:1:1 stoichiometry of its four components. The complex structure fulfills distance constraints obtained from chemical cross-linking of the complex at multiple recurring interfaces, involving hydrogen bonds, salt bridges, or hydrophobic interactions between conserved residues. The complex consists of a central roughly cubic [FXN42–210]24·[ISCU]24 sub-complex with one symmetric ISCU trimer bound on top of one symmetric FXN42–210 trimer at each of its eight vertices. Binding of 12 [NFS1]2·[ISD11]2 sub-complexes to the surface results in a globular macromolecule with a diameter of ∼15 nm and creates 24 Fe-S cluster assembly centers. The organization of each center recapitulates a previously proposed conserved mechanism for sulfur donation from NFS1 to ISCU and reveals, for the first time, a path for iron donation from FXN42–210 to ISCU. PMID:27519411

Detection of susceptibility genes as modifiers due to subgroup differences in complex disease.

PubMed

Bergen, Sarah E; Maher, Brion S; Fanous, Ayman H; Kendler, Kenneth S

2010-08-01

Complex diseases invariably involve multiple genes and often exhibit variable symptom profiles. The extent to which disease symptoms, course, and severity differ between affected individuals may result from underlying genetic heterogeneity. Genes with modifier effects may or may not also influence disease susceptibility. In this study, we have simulated data in which a subset of cases differ by some effect size (ES) on a quantitative trait and are also enriched for a risk allele. Power to detect this 'pseudo-modifier' gene in case-only and case-control designs was explored blind to case substructure. Simulations involved 1000 iterations and calculations for 80% power at P<0.01 while varying the risk allele frequency (RAF), sample size (SS), ES, odds ratio (OR), and proportions of the case subgroups. With realistic values for the RAF (0.20), SS (3000) and ES (1), an OR of 1.7 is necessary to detect a pseudo-modifier gene. Unequal numbers of subjects in the case groups result in little decrement in power until the group enriched for the risk allele is <30% or >70% of the total case population. In practice, greater numbers of subjects and selection of a quantitative trait with a large range will provide researchers with greater power to detect a pseudo-modifier gene. However, even under ideal conditions, studies involving alleles with low frequencies or low ORs are usually underpowered for detection of a modifier or susceptibility gene. This may explain some of the inconsistent association results for many candidate gene studies of complex diseases.

Thermodynamic aspects of dicarboxylate recognition by simple artificial receptors.

PubMed

Linton, B R; Goodman, M S; Fan, E; van Arman, S A; Hamilton, A D

2001-11-02

Recognition of dicarboxylates by bis-functional hydrogen-bonding receptors displays divergent thermodynamics in different solvent systems. NMR titration and isothermal titration calorimetry indicated that neutral bis-urea and bis-thiourea receptors form exothermic complexes with dicarboxylates in DMSO, with a near zero entropic contribution to binding. The increased binding strength of bis-guanidinium receptors precluded quantitative measurement of binding constants in DMSO, but titration calorimetry offered a qualitative picture of the association. Formation of these 1:1 complexes was also exothermic, but additional endothermic events occurred at both lower and higher host-guest ratios. These events indicated multiple binding equilibria but did not always occur at a discrete 2:1 or 1:2 host-guest molar ratio, suggesting higher aggregates. With increasing amounts of methanol as solvent, bis-guanidinium receptors form more endothermic complexes with dicarboxylates, with a favorable entropy of association. This switch from association driven by enthalpy to one driven by entropy may reflect a change from complexation involving the formation of hydrogen bonds to that promoted by solvent liberation from binding sites.

HTLV-1 Tax protein recruitment into IKKε and TBK1 kinase complexes enhances IFN-I expression.

PubMed

Diani, Erica; Avesani, Francesca; Bergamo, Elisa; Cremonese, Giorgia; Bertazzoni, Umberto; Romanelli, Maria Grazia

2015-02-01

The Tax protein expressed by human T-cell leukemia virus type 1 (HTLV-1) plays a pivotal role in the deregulation of cellular pathways involved in the immune response, inflammation, cell survival, and cancer. Many of these effects derive from Tax multiple interactions with host factors, including the subunits of the IKK-complex that are required for NF-κB activation. IKKɛ and TBK1 are two IKK-related kinases that allow the phosphorylation of interferon regulatory factors that trigger IFN type I gene expression. We observed that IKKɛ and TBK1 recruit Tax into cellular immunocomplexes. We also found that TRAF3, which regulates cell receptor signaling effectors, forms complexes with Tax. Transactivation analyses revealed that expression of Tax, in presence of IKKɛ and TBK1, enhances IFN-β promoter activity, whereas the activation of NF-κB promoter is not modified. We propose that Tax may be recruited into the TBK1/IKKɛ complexes as a scaffolding-adaptor protein that enhances IFN-I gene expression. Copyright © 2014 Elsevier Inc. All rights reserved.

"Structure and dynamics in complex chemical systems: Gaining new insights through recent advances in time-resolved spectroscopies.” ACS Division of Physical Chemistry Symposium presented at the Fall National ACS Meeting in Boston, MA, August 2015

DOE Office of Scientific and Technical Information (OSTI.GOV)

Crawford, Daniel

8-Session Symposium on STRUCTURE AND DYNAMICS IN COMPLEX CHEMICAL SYSTEMS: GAINING NEW INSIGHTS THROUGH RECENT ADVANCES IN TIME-RESOLVED SPECTROSCOPIES. The intricacy of most chemical, biochemical, and material processes and their applications are underscored by the complex nature of the environments in which they occur. Substantial challenges for building a global understanding of a heterogeneous system include (1) identifying unique signatures associated with specific structural motifs within the heterogeneous distribution, and (2) resolving the significance of each of multiple time scales involved in both small- and large-scale nuclear reorganization. This symposium focuses on the progress in our understanding of dynamics inmore » complex systems driven by recent innovations in time-resolved spectroscopies and theoretical developments. Such advancement is critical for driving discovery at the molecular level facilitating new applications. Broad areas of interest include: Structural relaxation and the impact of structure on dynamics in liquids, interfaces, biochemical systems, materials, and other heterogeneous environments.« less

Illuminating the Reaction Pathways of Viromimetic Assembly.

PubMed

Cingil, Hande E; Boz, Emre B; Biondaro, Giovanni; de Vries, Renko; Cohen Stuart, Martien A; Kraft, Daniela J; van der Schoot, Paul; Sprakel, Joris

2017-04-05

The coassembly of well-defined biological nanostructures relies on a delicate balance between attractive and repulsive interactions between biomolecular building blocks. Viral capsids are a prototypical example, where coat proteins exhibit not only self-interactions but also interact with the cargo they encapsulate. In nature, the balance between antagonistic and synergistic interactions has evolved to avoid kinetic trapping and polymorphism. To date, it has remained a major challenge to experimentally disentangle the complex kinetic reaction pathways that underlie successful coassembly of biomolecular building blocks in a noninvasive approach with high temporal resolution. Here we show how macromolecular force sensors, acting as a genome proxy, allow us to probe the pathways through which a viromimetic protein forms capsids. We uncover the complex multistage process of capsid assembly, which involves recruitment and complexation, followed by allosteric growth of the proteinaceous coat. Under certain conditions, the single-genome particles condense into capsids containing multiple copies of the template. Finally, we derive a theoretical model that quantitatively describes the kinetics of recruitment and growth. These results shed new light on the origins of the pathway complexity in biomolecular coassembly.

Semantic Structures of One-Step Word Problems Involving Multiplication or Division.

ERIC Educational Resources Information Center

Schmidt, Siegbert; Weiser, Werner

1995-01-01

Proposes a four-category classification of semantic structures of one-step word problems involving multiplication and division: forming the n-th multiple of measures, combinatorial multiplication, composition of operators, and multiplication by formula. This classification is compatible with semantic structures of addition and subtraction word…

Roles of mTOR Signaling in Brain Development.

PubMed

Lee, Da Yong

2015-09-01

mTOR is a serine/threonine kinase composed of multiple protein components. Intracellular signaling of mTOR complexes is involved in many of physiological functions including cell survival, proliferation and differentiation through the regulation of protein synthesis in multiple cell types. During brain development, mTOR-mediated signaling pathway plays a crucial role in the process of neuronal and glial differentiation and the maintenance of the stemness of neural stem cells. The abnormalities in the activity of mTOR and its downstream signaling molecules in neural stem cells result in severe defects of brain developmental processes causing a significant number of brain disorders, such as pediatric brain tumors, autism, seizure, learning disability and mental retardation. Understanding the implication of mTOR activity in neural stem cells would be able to provide an important clue in the development of future brain developmental disorder therapies.

Sustaining self-management in diabetes mellitus.

PubMed

Mitchell-Brown, Fay

2014-01-01

Successful management of diabetes depends on the individual's ability to manage and control symptoms. Self-management of diabetes is believed to play a significant role in achieving positive outcomes for patients. Adherence to self-management behaviors supports high-quality care, which reduces and delays disease complications, resulting in improved quality of life. Because self-management is so important to diabetes management and involves a lifelong commitment for all patients, health care providers should actively promote ways to maintain and sustain behavior change that support adherence to self-management. A social ecological model of behavior change (McLeroy, Bibeau, Steckler, & Glanz, 1988) helps practitioners provide evidence-based care and optimizes patients' clinical outcomes. This model supports self-management behaviors through multiple interacting interventions that can help sustain behavior change. Diabetes is a complex chronic disease; successful management must use multiple-level interventions.

Immune complex-mediated autoimmunity in a patient With Smith-Magenis syndrome (del 17p11.2).

PubMed

Yang, Jianying; Chandrasekharappa, Settara C; Vilboux, Thierry; Smith, Ann C M; Peterson, Erik J

2014-08-01

Smith-Magenis syndrome (SMS) is a sporadic congenital disorder involving multiple organ systems caused by chromosome 17p11.2 deletions. Smith-Magenis syndrome features craniofacial and skeletal anomalies, cognitive impairment, and neurobehavioral abnormalities. In addition, some SMS patients may exhibit hypogammaglobulinemia. We report the first case of SMS-associated autoimmunity in a woman who presented with adult onset of multiple autoimmune disorders, including systemic lupus erythematosus, antiphospholipid antibody syndrome, and autoimmune hepatitis. Molecular analysis using single-nucleotide polymorphism array confirmed a de novo 3.8-Mb deletion (breakpoints, chr17: 16,660,721-20,417,975), resulting in haploinsufficiency for TACI (transmembrane activator and CAML interactor). Our data are consistent with potential loss of function for the BAFF (B cell-activating factor) receptor TACI as a contributing factor to human autoimmune phenomena.

Multiple cenozoic invasions of Africa by penguins (Aves, Sphenisciformes)

PubMed Central

Ksepka, Daniel T.; Thomas, Daniel B.

2012-01-01

Africa hosts a single breeding species of penguin today, yet the fossil record indicates that a diverse array of now-extinct taxa once inhabited southern African coastlines. Here, we show that the African penguin fauna had a complex history involving multiple dispersals and extinctions. Phylogenetic analyses and biogeographic reconstructions incorporating new fossil material indicate that, contrary to previous hypotheses, the four Early Pliocene African penguin species do not represent an endemic radiation or direct ancestors of the living Spheniscus demersus (blackfooted penguin). A minimum of three dispersals to Africa, probably assisted by the eastward-flowing Antarctic Circumpolar and South Atlantic currents, occurred during the Late Cenozoic. As regional sea-level fall eliminated islands and reduced offshore breeding areas during the Pliocene, all but one penguin lineage ended in extinction, resulting in today's depleted fauna. PMID:21900330

Design of oligonucleotides for microarrays and perspectives for design of multi-transcriptome arrays.

PubMed

Nielsen, Henrik Bjørn; Wernersson, Rasmus; Knudsen, Steen

2003-07-01

Optimal design of oligonucleotides for microarrays involves tedious and laborious work evaluating potential oligonucleotides relative to a series of parameters. The currently available tools for this purpose are limited in their flexibility and do not present the oligonucleotide designer with an overview of these parameters. We present here a flexible tool named OligoWiz for designing oligonucleotides for multiple purposes. OligoWiz presents a set of parameter scores in a graphical interface to facilitate an overview for the user. Additional custom parameter scores can easily be added to the program to extend the default parameters: homology, DeltaTm, low-complexity, position and GATC-only. Furthermore we present an analysis of the limitations in designing oligonucleotide sets that can detect transcripts from multiple organisms. OligoWiz is available at www.cbs.dtu.dk/services/OligoWiz/.

Bent dark soliton dynamics in two spatial dimensions beyond the mean field approximation

NASA Astrophysics Data System (ADS)

Mistakidis, Simeon; Katsimiga, Garyfallia; Koutentakis, Georgios; Kevrekidis, Panagiotis; Schmelcher, Peter; Theory Group of Fundamental Processes in Quantum Physics Team

2017-04-01

The dynamics of a bented dark soliton embedded in two spatial dimensions beyond the mean-field approximation is explored. We examine the case of a single bented dark soliton comparing the mean-field approximation to a correlated approach that involves multiple orbitals. Fragmentation is generally present and significantly affects the dynamics, especially in the case of stronger interparticle interactions and in that of lower atom numbers. It is shown that the presence of fragmentation allows for the appearance of solitonic and vortex structures in the higher-orbital dynamics. In particular, a variety of excitations including dark solitons in multiple orbitals and vortex-antidark complexes is observed to arise spontaneously within the beyond mean-field dynamics. Deutsche Forschungsgemeinschaft (DFG) in the framework of the SFB 925 ``Light induced dynamics and control of correlated quantum systems''.

A hybrid approach to parameter identification of linear delay differential equations involving multiple delays

NASA Astrophysics Data System (ADS)

Marzban, Hamid Reza

2018-05-01

In this paper, we are concerned with the parameter identification of linear time-invariant systems containing multiple delays. The approach is based upon a hybrid of block-pulse functions and Legendre's polynomials. The convergence of the proposed procedure is established and an upper error bound with respect to the L2-norm associated with the hybrid functions is derived. The problem under consideration is first transformed into a system of algebraic equations. The least squares technique is then employed for identification of the desired parameters. Several multi-delay systems of varying complexity are investigated to evaluate the performance and capability of the proposed approximation method. It is shown that the proposed approach is also applicable to a class of nonlinear multi-delay systems. It is demonstrated that the suggested procedure provides accurate results for the desired parameters.

Inflammatory pathways in cervical cancer - the UCT contribution.

PubMed

Sales, Kurt Jason; Katz, Arieh Anthony

2012-03-23

Cervical cancer is the leading gynaecological malignancy in Southern Africa. The main causal factor for development of the disease is infection of the cervix with human papillomavirus. It is a multi-step disease with several contributing co-factors including multiple sexual partners, a compromised immune system and cervical inflammation caused by infections with Chlamydia trachomatis or Neisseria gonorrhoeae. Inflammation involves extensive tissue remodelling events which are orchestrated by complex networks of cytokines, chemokines and bio-active lipids working across multiple cellular compartments to maintain tissue homeostasis. Many pathological disorders or diseases, including cervical cancer, are characterised by the exacerbated activation and maintenance of inflammatory pathways. In this review we highlight our findings pertaining to activation of inflammatory pathways in cervical cancers, addressing their potential role in pathological changes of the cervix and the significance of these findings for intervention strategies.

Experience Modulates the Reproductive Response to Heat Stress in C. elegans via Multiple Physiological Processes

PubMed Central

Gouvêa, Devin Y.; Aprison, Erin Z.; Ruvinsky, Ilya

2015-01-01

Natural environments are considerably more variable than laboratory settings and often involve transient exposure to stressful conditions. To fully understand how organisms have evolved to respond to any given stress, prior experience must therefore be considered. We investigated the effects of individual and ancestral experience on C. elegans reproduction. We documented ways in which cultivation at 15°C or 25°C affects developmental time, lifetime fecundity, and reproductive performance after severe heat stress that exceeds the fertile range of the organism but is compatible with survival and future fecundity. We found that experience modulates multiple aspects of reproductive physiology, including the male and female germ lines and the interaction between them. These responses vary in their environmental sensitivity, suggesting the existence of complex mechanisms for coping with unpredictable and stressful environments. PMID:26713620

Neural mechanisms of sequence generation in songbirds

NASA Astrophysics Data System (ADS)

Langford, Bruce

Animal models in research are useful for studying more complex behavior. For example, motor sequence generation of actions requiring good muscle coordination such as writing with a pen, playing an instrument, or speaking, may involve the interaction of many areas in the brain, each a complex system in itself; thus it can be difficult to determine causal relationships between neural behavior and the behavior being studied. Birdsong, however, provides an excellent model behavior for motor sequence learning, memory, and generation. The song consists of learned sequences of notes that are spectrographically stereotyped over multiple renditions of the song, similar to syllables in human speech. The main areas of the songbird brain involve in singing are known, however, the mechanisms by which these systems store and produce song are not well understood. We used a custom built, head-mounted, miniature motorized microdrive to chronically record the neural firing patterns of identified neurons in HVC, a pre-motor cortical nucleus which has been shown to be important in song timing. These were done in Bengalese finch which generate a song made up of stereotyped notes but variable note sequences. We observed song related bursting in neurons projecting to Area X, a homologue to basal ganglia, and tonic firing in HVC interneurons. Interneuron had firing rate patterns that were consistent over multiple renditions of the same note sequence. We also designed and built a light-weight, low-powered wireless programmable neural stimulator using Bluetooth Low Energy Protocol. It was able to generate perturbations in the song when current pulses were administered to RA, which projects to the brainstem nucleus responsible for syringeal muscle control.

Decreased cerebellar-cerebral connectivity contributes to complex task performance

PubMed Central

Knops, André

2016-01-01

The cerebellum's role in nonmotor processes is now well accepted, but cerebellar interaction with cerebral targets is not well understood. Complex cognitive tasks activate cerebellar, parietal, and frontal regions, but the effective connectivity between these regions has never been tested. To this end, we used psycho-physiological interactions (PPI) analysis to test connectivity changes of cerebellar and parietal seed regions in complex (2-digit by 1-digit multiplication, e.g., 12 × 3) vs. simple (1-digit by 1-digit multiplication, e.g., 4 × 3) task conditions (“complex − simple”). For cerebellar seed regions (lobule VI, hemisphere and vermis), we found significantly decreased cerebellar-parietal, cerebellar-cingulate, and cerebellar-frontal connectivity in complex multiplication. For parietal seed regions (PFcm, PFop, PFm) we found significantly increased parietal-parietal and parietal-frontal connectivity in complex multiplication. These results suggest that decreased cerebellar-cerebral connectivity contributes to complex task performance. Interestingly, BOLD activity contrasts revealed partially overlapping parietal areas of increased BOLD activity but decreased cerebellar-parietal PPI connectivity. PMID:27334957

Conditional Creation and Rescue of Nipbl-Deficiency in Mice Reveals Multiple Determinants of Risk for Congenital Heart Defects

PubMed Central

Jacobs, Russell E.; Lopez-Burks, Martha E.; Choi, Hojae; Wikenheiser, Jamie; Hallgrimsson, Benedikt; Jamniczky, Heather A.; Fraser, Scott E.; Lander, Arthur D.; Calof, Anne L.

2016-01-01

Elucidating the causes of congenital heart defects is made difficult by the complex morphogenesis of the mammalian heart, which takes place early in development, involves contributions from multiple germ layers, and is controlled by many genes. Here, we use a conditional/invertible genetic strategy to identify the cell lineage(s) responsible for the development of heart defects in a Nipbl-deficient mouse model of Cornelia de Lange Syndrome, in which global yet subtle transcriptional dysregulation leads to development of atrial septal defects (ASDs) at high frequency. Using an approach that allows for recombinase-mediated creation or rescue of Nipbl deficiency in different lineages, we uncover complex interactions between the cardiac mesoderm, endoderm, and the rest of the embryo, whereby the risk conferred by genetic abnormality in any one lineage is modified, in a surprisingly non-additive way, by the status of others. We argue that these results are best understood in the context of a model in which the risk of heart defects is associated with the adequacy of early progenitor cell populations relative to the sizes of the structures they must eventually form. PMID:27606604

Development and initial outcomes of an upper gastrointestinal multidisciplinary clinic.

PubMed

Brown, Anna; Wylie, Neil; Rodgers, Michael; Casement, Jonathan; McIlree, Neil; Gray, Lindsay; Mulholland, Glen; Volkova, Vicki; van der Watt, Erna; Booth, Michael; Koea, Jonathan

2016-07-01

Patients with upper gastrointestinal cancer are often comorbid and require complex surgical treatments for their cancers, meaning that their preoperative assessment can be based around numerous outpatient assessments with multiple services. A multidisciplinary clinic (MDC) was developed for the assessment of patients with confirmed or suspected upper gastrointestinal cancers. Face-to-face meetings were held between stakeholder services at Waitemata District Health Board, and clinic resource allocated. Significant IT modification of existing clinic booking software was required. Between September 2014, and September 2015, there were a total of 165 new patient, and 710 follow-up appointments. All new patients were seen by a surgeon and then other specialties. Of the 165 new patient appointments, 146 (88%) patients had a definitive treatment plan in place and were cleared by anaesthesia and intensive care at the end of the clinic. Staff and patients report high levels of satisfaction for the clinic. A dedicated MDC has provided a single forum where complex patients can be reviewed, and a definitive treatment plan formulated in nearly 90% of patients, even when this involves multiple medical and paramedical specialties with high levels of patient and clinician satisfaction.

Management of heart failure in the new era: the role of scores.

PubMed

Mantegazza, Valentina; Badagliacca, Roberto; Nodari, Savina; Parati, Gianfranco; Lombardi, Carolina; Di Somma, Salvatore; Carluccio, Erberto; Dini, Frank Lloyd; Correale, Michele; Magrì, Damiano; Agostoni, Piergiuseppe

2016-08-01

Heart failure is a widespread syndrome involving several organs, still characterized by high mortality and morbidity, and whose clinical course is heterogeneous and hardly predictable.In this scenario, the assessment of heart failure prognosis represents a fundamental step in clinical practice. A single parameter is always unable to provide a very precise prognosis. Therefore, risk scores based on multiple parameters have been introduced, but their clinical utility is still modest. In this review, we evaluated several prognostic models for acute, right, chronic, and end-stage heart failure based on multiple parameters. In particular, for chronic heart failure we considered risk scores essentially based on clinical evaluation, comorbidities analysis, baroreflex sensitivity, heart rate variability, sleep disorders, laboratory tests, echocardiographic imaging, and cardiopulmonary exercise test parameters. What is at present established is that a single parameter is not sufficient for an accurate prediction of prognosis in heart failure because of the complex nature of the disease. However, none of the scoring systems available is widely used, being in some cases complex, not user-friendly, or based on expensive or not easily available parameters. We believe that multiparametric scores for risk assessment in heart failure are promising but their widespread use needs to be experienced.

Environmental Interactions and Epistasis Are Revealed in the Proteomic Responses to Complex Stimuli

PubMed Central

Samir, Parimal; Rahul; Slaughter, James C.; Link, Andrew J.

2015-01-01

Ultimately, the genotype of a cell and its interaction with the environment determine the cell’s biochemical state. While the cell’s response to a single stimulus has been studied extensively, a conceptual framework to model the effect of multiple environmental stimuli applied concurrently is not as well developed. In this study, we developed the concepts of environmental interactions and epistasis to explain the responses of the S. cerevisiae proteome to simultaneous environmental stimuli. We hypothesize that, as an abstraction, environmental stimuli can be treated as analogous to genetic elements. This would allow modeling of the effects of multiple stimuli using the concepts and tools developed for studying gene interactions. Mirroring gene interactions, our results show that environmental interactions play a critical role in determining the state of the proteome. We show that individual and complex environmental stimuli behave similarly to genetic elements in regulating the cellular responses to stimuli, including the phenomena of dominance and suppression. Interestingly, we observed that the effect of a stimulus on a protein is dominant over other stimuli if the response to the stimulus involves the protein. Using publicly available transcriptomic data, we find that environmental interactions and epistasis regulate transcriptomic responses as well. PMID:26247773

Redox cofactors insertion in prokaryotic molybdoenzymes occurs via a conserved folding mechanism

PubMed Central

Arias-Cartin, Rodrigo; Ceccaldi, Pierre; Schoepp-Cothenet, Barbara; Frick, Klaudia; Blanc, Jean-Michel; Guigliarelli, Bruno; Walburger, Anne; Grimaldi, Stéphane; Friedrich, Thorsten; Receveur-Brechot, Véronique; Magalon, Axel

2016-01-01

A major gap of knowledge in metalloproteins is the identity of the prefolded state of the protein before cofactor insertion. This holds for molybdoenzymes serving multiple purposes for life, especially in energy harvesting. This large group of prokaryotic enzymes allows for coordination of molybdenum or tungsten cofactors (Mo/W-bisPGD) and Fe/S clusters. Here we report the structural data on a cofactor-less enzyme, the nitrate reductase respiratory complex and characterize the conformational changes accompanying Mo/W-bisPGD and Fe/S cofactors insertion. Identified conformational changes are shown to be essential for recognition of the dedicated chaperone involved in cofactors insertion. A solvent-exposed salt bridge is shown to play a key role in enzyme folding after cofactors insertion. Furthermore, this salt bridge is shown to be strictly conserved within this prokaryotic molybdoenzyme family as deduced from a phylogenetic analysis issued from 3D structure-guided multiple sequence alignment. A biochemical analysis with a distantly-related member of the family, respiratory complex I, confirmed the critical importance of the salt bridge for folding. Overall, our results point to a conserved cofactors insertion mechanism within the Mo/W-bisPGD family. PMID:27886223

Critical and speculative review of the roles of multi-protein complexes in starch biosynthesis in cereals.

PubMed

Crofts, Naoko; Nakamura, Yasunori; Fujita, Naoko

2017-09-01

Starch accounts for the majority of edible carbohydrate resources generated through photosynthesis. Amylopectin is the major component of starch and is one of highest-molecular-weight biopolymers. Rapid and systematic synthesis of frequently branched hydro-insoluble amylopectin and efficient accumulation into amyloplasts of cereal endosperm is crucial. The functions of multiple starch biosynthetic enzymes, including elongation, branching, and debranching enzymes, must be temporally and spatially coordinated. Accordingly, direct evidence of protein-protein interactions of starch biosynthetic enzymes were first discovered in developing wheat endosperm in 2004, and they have since been shown in the developing seeds of other cereals. This review article describes structural characteristics of starches as well as similarities and differences in protein complex formation among different plant species and among mutant plants that are deficient in specific starch biosynthetic enzymes. In addition, evidence for protein complexes that are involved in the initiation stages of starch biosynthesis is summarized. Finally, we discuss the significance of protein complexes and describe new methods that may elucidate the mechanisms and roles of starch biosynthetic enzyme complexes. Copyright © 2017 Elsevier B.V. All rights reserved.

Neurophysiological basis of creativity in healthy elderly people: a multiscale entropy approach.

PubMed

Ueno, Kanji; Takahashi, Tetsuya; Takahashi, Koichi; Mizukami, Kimiko; Tanaka, Yuji; Wada, Yuji

2015-03-01

Creativity, which presumably involves various connections within and across different neural networks, reportedly underpins the mental well-being of older adults. Multiscale entropy (MSE) can characterize the complexity inherent in EEG dynamics with multiple temporal scales. It can therefore provide useful insight into neural networks. Given that background, we sought to clarify the neurophysiological bases of creativity in healthy elderly subjects by assessing EEG complexity with MSE, with emphasis on assessment of neural networks. We recorded resting state EEG of 20 healthy elderly subjects. MSE was calculated for each subject for continuous 20-s epochs. Their relevance to individual creativity was examined concurrently with intellectual function. Higher individual creativity was linked closely to increased EEG complexity across higher temporal scales, but no significant relation was found with intellectual function (IQ score). Considering the general "loss of complexity" theory of aging, our finding of increased EEG complexity in elderly people with heightened creativity supports the idea that creativity is associated with activated neural networks. Results reported here underscore the potential usefulness of MSE analysis for characterizing the neurophysiological bases of elderly people with heightened creativity. Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

The effect of orthostatic stress on multiscale entropy of heart rate and blood pressure.

PubMed

Turianikova, Zuzana; Javorka, Kamil; Baumert, Mathias; Calkovska, Andrea; Javorka, Michal

2011-09-01

Cardiovascular control acts over multiple time scales, which introduces a significant amount of complexity to heart rate and blood pressure time series. Multiscale entropy (MSE) analysis has been developed to quantify the complexity of a time series over multiple time scales. In previous studies, MSE analyses identified impaired cardiovascular control and increased cardiovascular risk in various pathological conditions. Despite the increasing acceptance of the MSE technique in clinical research, information underpinning the involvement of the autonomic nervous system in the MSE of heart rate and blood pressure is lacking. The objective of this study is to investigate the effect of orthostatic challenge on the MSE of heart rate and blood pressure variability (HRV, BPV) and the correlation between MSE (complexity measures) and traditional linear (time and frequency domain) measures. MSE analysis of HRV and BPV was performed in 28 healthy young subjects on 1000 consecutive heart beats in the supine and standing positions. Sample entropy values were assessed on scales of 1-10. We found that MSE of heart rate and blood pressure signals is sensitive to changes in autonomic balance caused by postural change from the supine to the standing position. The effect of orthostatic challenge on heart rate and blood pressure complexity depended on the time scale under investigation. Entropy values did not correlate with the mean values of heart rate and blood pressure and showed only weak correlations with linear HRV and BPV measures. In conclusion, the MSE analysis of heart rate and blood pressure provides a sensitive tool to detect changes in autonomic balance as induced by postural change.

Planning and executing complex large-scale exercises.

PubMed

McCormick, Lisa C; Hites, Lisle; Wakelee, Jessica F; Rucks, Andrew C; Ginter, Peter M

2014-01-01

Increasingly, public health departments are designing and engaging in complex operations-based full-scale exercises to test multiple public health preparedness response functions. The Department of Homeland Security's Homeland Security Exercise and Evaluation Program (HSEEP) supplies benchmark guidelines that provide a framework for both the design and the evaluation of drills and exercises; however, the HSEEP framework does not seem to have been designed to manage the development and evaluation of multiple, operations-based, parallel exercises combined into 1 complex large-scale event. Lessons learned from the planning of the Mississippi State Department of Health Emergency Support Function--8 involvement in National Level Exercise 2011 were used to develop an expanded exercise planning model that is HSEEP compliant but accounts for increased exercise complexity and is more functional for public health. The Expanded HSEEP (E-HSEEP) model was developed through changes in the HSEEP exercise planning process in areas of Exercise Plan, Controller/Evaluator Handbook, Evaluation Plan, and After Action Report and Improvement Plan development. The E-HSEEP model was tested and refined during the planning and evaluation of Mississippi's State-level Emergency Support Function-8 exercises in 2012 and 2013. As a result of using the E-HSEEP model, Mississippi State Department of Health was able to capture strengths, lessons learned, and areas for improvement, and identify microlevel issues that may have been missed using the traditional HSEEP framework. The South Central Preparedness and Emergency Response Learning Center is working to create an Excel-based E-HSEEP tool that will allow practice partners to build a database to track corrective actions and conduct many different types of analyses and comparisons.

Biospecimen Complexity-the Next Challenge for Cancer Research Biobanks?

PubMed

Watson, Peter H

2017-02-15

Purpose: Biospecimens (e.g., tissues, bloods, fluids) are critical for translational cancer research to generate the necessary knowledge to guide implementation of precision medicine. Rising demand and the need for higher quality biospecimens are already evident. Experimental Design: The recent increase in requirement for biospecimen complexity in terms of linked biospecimen types, multiple preservation formats, and longitudinal data was explored by assessing trends in cancer research publications from 2000 to 2014. Results: A PubMed search shows that there has been an increase in both raw numbers and the relative proportion (adjusted for total numbers of articles in each period) of the subgroups of articles typically associated with the use of biospecimens and both dense treatment and/or outcomes data and multiple biospecimen formats. Conclusions: Increasing biospecimen complexity is a largely unrecognized and new pressure on cancer research biobanks. New approaches to cancer biospecimen resources are needed such as the implementation of more efficient and dynamic consent mechanisms, stronger participant involvement in biobank governance, development of requirements for registration of collections, and models to establish stock targets for biobanks. In particular, the latter two approaches would enable funders to establish a better balance between biospecimen supply and research demand, reduce expenditure on duplicate collections, and encourage increased efficiency of biobanks to respond to the research need for more complex cases. This in turn would also enable biobanks to focus more on quality and standardization that are surely factors in the even more important arena of research reproducibility. Clin Cancer Res; 23(4); 894-8. ©2016 AACR . ©2016 American Association for Cancer Research.

Does the Aristotle Score predict outcome in congenital heart surgery?

PubMed

Kang, Nicholas; Tsang, Victor T; Elliott, Martin J; de Leval, Marc R; Cole, Timothy J

2006-06-01

The Aristotle Score has been proposed as a measure of 'complexity' in congenital heart surgery, and a tool for comparing performance amongst different centres. To date, however, it remains unvalidated. We examined whether the Basic Aristotle Score was a useful predictor of mortality following open-heart surgery, and compared it to the Risk Adjustment in Congenital Heart Surgery (RACHS-1) system. We also examined the ability of the Aristotle Score to measure performance. The Basic Aristotle Score and RACHS-1 risk categories were assigned retrospectively to 1085 operations involving cardiopulmonary bypass in children less than 18 years of age. Multiple logistic regression analysis was used to determine the significance of the Aristotle Score and RACHS-1 category as independent predictors of in-hospital mortality. Operative performance was calculated using the Aristotle equation: performance = complexity x survival. Multiple logistic regression identified RACHS-1 category to be a powerful predictor of mortality (Wald 17.7, p < 0.0001), whereas Aristotle Score was only weakly associated with mortality (Wald 4.8, p = 0.03). Age at operation and bypass time were also highly significant predictors of postoperative death (Wald 13.7 and 33.8, respectively, p < 0.0001 for both). Operative performance was measured at 7.52 units. The Basic Aristotle Score was only weakly associated with postoperative mortality in this series. Operative performance appeared to be inflated by the fact that the overall complexity of cases was relatively high in this series. An alternative equation (performance = complexity/mortality) is proposed as a fairer and more logical method of risk-adjustment.

Genome-wide meta-analysis identifies multiple novel associations and ethnic heterogeneity of psoriasis susceptibility.

PubMed

Yin, Xianyong; Low, Hui Qi; Wang, Ling; Li, Yonghong; Ellinghaus, Eva; Han, Jiali; Estivill, Xavier; Sun, Liangdan; Zuo, Xianbo; Shen, Changbing; Zhu, Caihong; Zhang, Anping; Sanchez, Fabio; Padyukov, Leonid; Catanese, Joseph J; Krueger, Gerald G; Duffin, Kristina Callis; Mucha, Sören; Weichenthal, Michael; Weidinger, Stephan; Lieb, Wolfgang; Foo, Jia Nee; Li, Yi; Sim, Karseng; Liany, Herty; Irwan, Ishak; Teo, Yikying; Theng, Colin T S; Gupta, Rashmi; Bowcock, Anne; De Jager, Philip L; Qureshi, Abrar A; de Bakker, Paul I W; Seielstad, Mark; Liao, Wilson; Ståhle, Mona; Franke, Andre; Zhang, Xuejun; Liu, Jianjun

2015-04-23

Psoriasis is a common inflammatory skin disease with complex genetics and different degrees of prevalence across ethnic populations. Here we present the largest trans-ethnic genome-wide meta-analysis (GWMA) of psoriasis in 15,369 cases and 19,517 controls of Caucasian and Chinese ancestries. We identify four novel associations at LOC144817, COG6, RUNX1 and TP63, as well as three novel secondary associations within IFIH1 and IL12B. Fine-mapping analysis of MHC region demonstrates an important role for all three HLA class I genes and a complex and heterogeneous pattern of HLA associations between Caucasian and Chinese populations. Further, trans-ethnic comparison suggests population-specific effect or allelic heterogeneity for 11 loci. These population-specific effects contribute significantly to the ethnic diversity of psoriasis prevalence. This study not only provides novel biological insights into the involvement of immune and keratinocyte development mechanism, but also demonstrates a complex and heterogeneous genetic architecture of psoriasis susceptibility across ethnic populations.

[New approaches in pharmacology: numerical modelling and simulation].

PubMed

Boissel, Jean-Pierre; Cucherat, Michel; Nony, Patrice; Dronne, Marie-Aimée; Kassaï, Behrouz; Chabaud, Sylvie

2005-01-01

The complexity of pathophysiological mechanisms is beyond the capabilities of traditional approaches. Many of the decision-making problems in public health, such as initiating mass screening, are complex. Progress in genomics and proteomics, and the resulting extraordinary increase in knowledge with regard to interactions between gene expression, the environment and behaviour, the customisation of risk factors and the need to combine therapies that individually have minimal though well documented efficacy, has led doctors to raise new questions: how to optimise choice and the application of therapeutic strategies at the individual rather than the group level, while taking into account all the available evidence? This is essentially a problem of complexity with dimensions similar to the previous ones: multiple parameters with nonlinear relationships between them, varying time scales that cannot be ignored etc. Numerical modelling and simulation (in silico investigations) have the potential to meet these challenges. Such approaches are considered in drug innovation and development. They require a multidisciplinary approach, and this will involve modification of the way research in pharmacology is conducted.

Zc3h13/Flacc is required for adenosine methylation by bridging the mRNA-binding factor Rbm15/Spenito to the m6A machinery component Wtap/Fl(2)d

PubMed Central

Knuckles, Philip; Lence, Tina; Haussmann, Irmgard U.; Jacob, Dominik; Kreim, Nastasja; Carl, Sarah H.; Masiello, Irene; Hares, Tina; Villaseñor, Rodrigo; Hess, Daniel; Andrade-Navarro, Miguel A.; Biggiogera, Marco; Helm, Mark; Soller, Matthias; Bühler, Marc; Roignant, Jean-Yves

2018-01-01

N6-methyladenosine (m6A) is the most abundant mRNA modification in eukaryotes, playing crucial roles in multiple biological processes. m6A is catalyzed by the activity of methyltransferase-like 3 (Mettl3), which depends on additional proteins whose precise functions remain poorly understood. Here we identified Zc3h13 (zinc finger CCCH domain-containing protein 13)/Flacc [Fl(2)d-associated complex component] as a novel interactor of m6A methyltransferase complex components in Drosophila and mice. Like other components of this complex, Flacc controls m6A levels and is involved in sex determination in Drosophila. We demonstrate that Flacc promotes m6A deposition by bridging Fl(2)d to the mRNA-binding factor Nito. Altogether, our work advances the molecular understanding of conservation and regulation of the m6A machinery. PMID:29535189

Genome-wide meta-analysis identifies multiple novel associations and ethnic heterogeneity of psoriasis susceptibility

PubMed Central

Yin, Xianyong; Low, Hui Qi; Wang, Ling; Li, Yonghong; Ellinghaus, Eva; Han, Jiali; Estivill, Xavier; Sun, Liangdan; Zuo, Xianbo; Shen, Changbing; Zhu, Caihong; Zhang, Anping; Sanchez, Fabio; Padyukov, Leonid; Catanese, Joseph J.; Krueger, Gerald G.; Duffin, Kristina Callis; Mucha, Sören; Weichenthal, Michael; Weidinger, Stephan; Lieb, Wolfgang; Foo, Jia Nee; Li, Yi; Sim, Karseng; Liany, Herty; Irwan, Ishak; Teo, Yikying; Theng, Colin T. S.; Gupta, Rashmi; Bowcock, Anne; De Jager, Philip L.; Qureshi, Abrar A.; de Bakker, Paul I. W.; Seielstad, Mark; Liao, Wilson; Ståhle, Mona; Franke, Andre; Zhang, Xuejun; Liu, Jianjun

2015-01-01

Psoriasis is a common inflammatory skin disease with complex genetics and different degrees of prevalence across ethnic populations. Here we present the largest trans-ethnic genome-wide meta-analysis (GWMA) of psoriasis in 15,369 cases and 19,517 controls of Caucasian and Chinese ancestries. We identify four novel associations at LOC144817, COG6, RUNX1 and TP63, as well as three novel secondary associations within IFIH1 and IL12B. Fine-mapping analysis of MHC region demonstrates an important role for all three HLA class I genes and a complex and heterogeneous pattern of HLA associations between Caucasian and Chinese populations. Further, trans-ethnic comparison suggests population-specific effect or allelic heterogeneity for 11 loci. These population-specific effects contribute significantly to the ethnic diversity of psoriasis prevalence. This study not only provides novel biological insights into the involvement of immune and keratinocyte development mechanism, but also demonstrates a complex and heterogeneous genetic architecture of psoriasis susceptibility across ethnic populations. PMID:25903422

36 CFR 800.14 - Federal agency program alternatives.

Code of Federal Regulations, 2010 CFR

2010-07-01

... program or the resolution of adverse effects from certain complex project situations or multiple... by the agreement. (3) Developing programmatic agreements for complex or multiple undertakings. Consultation to develop a programmatic agreement for dealing with the potential adverse effects of complex...

Immunoglobulin A multiple myeloma with cutaneous involvement in a dog.

PubMed

Mayer, Monique N; Kerr, Moira E; Grier, Candace K; Macdonald, Valerie S

2008-07-01

An 8-year-old rottweiler, diagnosed with multiple myeloma and multiple sites of cutaneous involvement, was treated with chemotherapy and radiation therapy. The diagnostic criteria for canine multiple myeloma, limitations of diagnostic testing for light chain proteinuria in dogs, and the role of radiation therapy in multiple myeloma patients is discussed.

Immunoglobulin A multiple myeloma with cutaneous involvement in a dog

PubMed Central

Mayer, Monique N.; Kerr, Moira E.; Grier, Candace K.; MacDonald, Valerie S.

2008-01-01

An 8-year-old rottweiler, diagnosed with multiple myeloma and multiple sites of cutaneous involvement, was treated with chemotherapy and radiation therapy. The diagnostic criteria for canine multiple myeloma, limitations of diagnostic testing for light chain proteinuria in dogs, and the role of radiation therapy in multiple myeloma patients is discussed. PMID:18827847

A new VLSI complex integer multiplier which uses a quadratic-polynomial residue system with Fermat numbers

NASA Technical Reports Server (NTRS)

Truong, T. K.; Hsu, I. S.; Chang, J. J.; Shyu, H. C.; Reed, I. S.

1986-01-01

A quadratic-polynomial Fermat residue number system (QFNS) has been used to compute complex integer multiplications. The advantage of such a QFNS is that a complex integer multiplication requires only two integer multiplications. In this article, a new type Fermat number multiplier is developed which eliminates the initialization condition of the previous method. It is shown that the new complex multiplier can be implemented on a single VLSI chip. Such a chip is designed and fabricated in CMOS-pw technology.

A new VLSI complex integer multiplier which uses a quadratic-polynomial residue system with Fermat numbers

NASA Technical Reports Server (NTRS)

Shyu, H. C.; Reed, I. S.; Truong, T. K.; Hsu, I. S.; Chang, J. J.

1987-01-01

A quadratic-polynomial Fermat residue number system (QFNS) has been used to compute complex integer multiplications. The advantage of such a QFNS is that a complex integer multiplication requires only two integer multiplications. In this article, a new type Fermat number multiplier is developed which eliminates the initialization condition of the previous method. It is shown that the new complex multiplier can be implemented on a single VLSI chip. Such a chip is designed and fabricated in CMOS-Pw technology.

A Simple Approach to Evaluate the Kinetic Rate Constant for ATP Synthesis in Resting Human Skeletal Muscle at 7 T

PubMed Central

Ren, Jimin; Sherry, A. Dean; Malloy, Craig R.

2015-01-01

Inversion transfer (IT) is a well-established technique with multiple attractive features for analysis of kinetics. However, its application in measurement of ATP synthesis rate in vivo has lagged behind the more common ST techniques. One well-recognized issue with IT is the complexity of data analysis in comparison to much simpler analysis by ST. This complexity arises, in part, because the γ-ATP spin is involved in multiple chemical reactions and magnetization exchanges, whereas Pi is involved in a single reaction, Pi → γ-ATP. By considering the reactions involving γ-ATP only as a lumped constant, the rate constant for the reaction of physiological interest, kPi→γATP, can be determined. Here, we present a new IT data analysis method to evaluate kPi→γATP using data collected from resting human skeletal muscle at 7T. The method is based on the basic Bloch-McConnell equation, which relates kPi→γATP with ṁPi, the rate of Pi magnetization change. The kPi→γATP value is accessed from ṁPi data by more familiar linear correlation approaches. For a group of human subjects (n = 15), the kPi→γATP value derived for resting calf muscle was 0.066 ± 0.017 s−1, in agreement with literature reported values. In this study we also explored possible time-saving strategies to speed up data acquisition for kPi→γATP evaluation using simulations. The analysis indicates that it is feasible to carry out a 31P inversion transfer experiment in ~10 minutes or shorter at 7T with reasonable outcome in kPi→γATP variance for measurement of ATP synthesis in resting human skeletal muscle. We believe that this new IT data analysis approach will facilitate the wide acceptance of IT to evaluate ATP synthesis rate in vivo. PMID:25943328

Father Involvement and Young, Rural African American Men's Engagement in Substance Misuse and Multiple Sexual Partnerships.

PubMed

Barton, Allen W; Kogan, Steven M; Cho, Junhan; Brown, Geoffrey L

2015-12-01

This study was designed to examine the associations of biological father and social father involvement during childhood with African American young men's development and engagement in risk behaviors. With a sample of 505 young men living in the rural South of the United States, a dual mediation model was tested in which retrospective reports of involvement from biological fathers and social fathers were linked to young men's substance misuse and multiple sexual partnerships through men's relational schemas and future expectations. Results from structural equation modeling indicated that levels of involvement from biological fathers and social fathers predicted young men's relational schemas; only biological fathers' involvement predicted future expectations. In turn, future expectations predicted levels of substance misuse, and negative relational schemas predicted multiple sexual partnerships. Biological fathers' involvement evinced significant indirect associations with young men's substance misuse and multiple sexual partnerships through both schemas and expectations; social fathers' involvement exhibited an indirect association with multiple sexual partnerships through relational schemas. Findings highlight the unique influences of biological fathers and social fathers on multiple domains of African American young men's psychosocial development that subsequently render young men more or less likely to engage in risk behaviors.

Aspects of porosity prediction using multivariate linear regression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Byrnes, A.P.; Wilson, M.D.

1991-03-01

Highly accurate multiple linear regression models have been developed for sandstones of diverse compositions. Porosity reduction or enhancement processes are controlled by the fundamental variables, Pressure (P), Temperature (T), Time (t), and Composition (X), where composition includes mineralogy, size, sorting, fluid composition, etc. The multiple linear regression equation, of which all linear porosity prediction models are subsets, takes the generalized form: Porosity = C{sub 0} + C{sub 1}(P) + C{sub 2}(T) + C{sub 3}(X) + C{sub 4}(t) + C{sub 5}(PT) + C{sub 6}(PX) + C{sub 7}(Pt) + C{sub 8}(TX) + C{sub 9}(Tt) + C{sub 10}(Xt) + C{sub 11}(PTX) + C{submore » 12}(PXt) + C{sub 13}(PTt) + C{sub 14}(TXt) + C{sub 15}(PTXt). The first four primary variables are often interactive, thus requiring terms involving two or more primary variables (the form shown implies interaction and not necessarily multiplication). The final terms used may also involve simple mathematic transforms such as log X, e{sup T}, X{sup 2}, or more complex transformations such as the Time-Temperature Index (TTI). The X term in the equation above represents a suite of compositional variable and, therefore, a fully expanded equation may include a series of terms incorporating these variables. Numerous published bivariate porosity prediction models involving P (or depth) or Tt (TTI) are effective to a degree, largely because of the high degree of colinearity between p and TTI. However, all such bivariate models ignore the unique contributions of P and Tt, as well as various X terms. These simpler models become poor predictors in regions where colinear relations change, were important variables have been ignored, or where the database does not include a sufficient range or weight distribution for the critical variables.« less

Differences in Thoracic Injury Causation Patterns Between Seat Belt Restrained Children and Adults

PubMed Central

Arbogast, Kristy B.; Locey, Caitlin M.; Zonfrillo, Mark R.

2012-01-01

The objective of this research was to delineate age-based differences in specific thoracic injury diagnoses for seat belt restrained rear seat occupants and describe the associated injury causation in order to provide insight into how the load of the seat belt is transferred to occupants of various sizes. Using data from the Crash Investigation Research and Engineering Network (CIREN), 20 cases of rear seated, lap and shoulder belt restrained occupants with AIS2+ thoracic injuries in frontal crashes were reviewed. Seven were children and adolescents age 8–15 years, 5 were 16–24 years, 3 were 25–54 years, and 5 were 55+ years. Six of the seven 8–15 year olds sustained injuries to the lung in the form of pulmonary contusion or pneumothorax. Only three of the seven sustained a skeletal (sternum or rib) fracture; only one of these three involved multiple ribs bilaterally. In contrast, four of the five 16–24 year olds sustained at least one rib fracture - often multiple and bilateral. The adult cohort (25+ years) was involved in predominantly more minor crashes; however they all sustained complex rib fractures – seven of the eight involved multiple ribs, four of the eight were also bilateral. Belt compression – either from the shoulder belt or the lap belt – was identified as the primary cause of the thoracic injuries. Often, there was clear evidence of the location of belt loading from AIS 1 chest contusions or abrasions. These findings have implications for age-based thoracic injury criteria suggesting that that different metrics may be needed for different age groups. PMID:23169131

3-D decoupled inversion of complex conductivity data in the real number domain

NASA Astrophysics Data System (ADS)

Johnson, Timothy C.; Thomle, Jonathan

2018-01-01

Complex conductivity imaging (also called induced polarization imaging or spectral induced polarization imaging when conducted at multiple frequencies) involves estimating the frequency-dependent complex electrical conductivity distribution of the subsurface. The superior diagnostic capabilities provided by complex conductivity spectra have driven advancements in mechanistic understanding of complex conductivity as well as modelling and inversion approaches over the past several decades. In this work, we demonstrate the theory and application for an approach to 3-D modelling and inversion of complex conductivity data in the real number domain. Beginning from first principles, we demonstrate how the equations for the real and imaginary components of the complex potential may be decoupled. This leads to a description of the real and imaginary source current terms, and a corresponding assessment of error arising from an assumption necessary to complete the decoupled modelling. We show that for most earth materials, which exhibit relatively small phases (e.g. less than 0.2 radians) in complex conductivity, these errors become insignificant. For higher phase materials, the errors may be quantified and corrected through an iterative procedure. We demonstrate the accuracy of numerical forward solutions by direct comparison to corresponding analytic solutions. We demonstrate the inversion using both synthetic and field examples with data collected over a waste infiltration trench, at frequencies ranging from 0.5 to 7.5 Hz.

Semiparametric bivariate zero-inflated Poisson models with application to studies of abundance for multiple species

USGS Publications Warehouse

Arab, Ali; Holan, Scott H.; Wikle, Christopher K.; Wildhaber, Mark L.

2012-01-01

Ecological studies involving counts of abundance, presence–absence or occupancy rates often produce data having a substantial proportion of zeros. Furthermore, these types of processes are typically multivariate and only adequately described by complex nonlinear relationships involving externally measured covariates. Ignoring these aspects of the data and implementing standard approaches can lead to models that fail to provide adequate scientific understanding of the underlying ecological processes, possibly resulting in a loss of inferential power. One method of dealing with data having excess zeros is to consider the class of univariate zero-inflated generalized linear models. However, this class of models fails to address the multivariate and nonlinear aspects associated with the data usually encountered in practice. Therefore, we propose a semiparametric bivariate zero-inflated Poisson model that takes into account both of these data attributes. The general modeling framework is hierarchical Bayes and is suitable for a broad range of applications. We demonstrate the effectiveness of our model through a motivating example on modeling catch per unit area for multiple species using data from the Missouri River Benthic Fishes Study, implemented by the United States Geological Survey.

Mouse and Guinea Pig Models of Tuberculosis.

PubMed

Orme, Ian M; Ordway, Diane J

2016-08-01

This article describes the nature of the host response to Mycobacterium tuberculosis in the mouse and guinea pig models of infection. It describes the great wealth of information obtained from the mouse model, reflecting the general availability of immunological reagents, as well as genetic manipulations of the mouse strains themselves. This has led to a good understanding of the nature of the T-cell response to the infection, as well as an appreciation of the complexity of the response involving multiple cytokine- and chemokine-mediated systems. As described here and elsewhere, we have a growing understanding of how multiple CD4-positive T-cell subsets are involved, including regulatory T cells, TH17 cells, as well as the subsequent emergence of effector and central memory T-cell subsets. While, in contrast, our understanding of the host response in the guinea pig model is less advanced, considerable strides have been made in the past decade in terms of defining the basis of the immune response, as well as a better understanding of the immunopathologic process. This model has long been the gold standard for vaccine testing, and more recently is being revisited as a model for testing new drug regimens (bedaquiline being the latest example).

Reptin/Ruvbl2 is a Lrrc6/Seahorse interactor essential for cilia motility

PubMed Central

Zhao, Lu; Yuan, Shiaulou; Cao, Ying; Kallakuri, Sowjanya; Li, Yuanyuan; Kishimoto, Norihito; DiBella, Linda; Sun, Zhaoxia

2013-01-01

Primary ciliary dyskinesia (PCD) is an autosomal recessive disease caused by defective cilia motility. The identified PCD genes account for about half of PCD incidences and the underlying mechanisms remain poorly understood. We demonstrate that Reptin/Ruvbl2, a protein known to be involved in epigenetic and transcriptional regulation, is essential for cilia motility in zebrafish. We further show that Reptin directly interacts with the PCD protein Lrrc6/Seahorse and this interaction is critical for the in vivo function of Lrrc6/Seahorse in zebrafish. Moreover, whereas the expression levels of multiple dynein arm components remain unchanged or become elevated, the density of axonemal dynein arms is reduced in reptinhi2394 mutants. Furthermore, Reptin is highly enriched in the cytosol and colocalizes with Lrrc6/Seahorse. Combined, these results suggest that the Reptin-Lrrc6/Seahorse complex is involved in dynein arm formation. We also show that although the DNA damage response is induced in reptinhi2394 mutants, it remains unchanged in cilia biogenesis mutants and lrrc6/seahorse mutants, suggesting that increased DNA damage response is not intrinsic to ciliary defects and that in vertebrate development, Reptin functions in multiple processes, both cilia specific and cilia independent. PMID:23858445

Reptin/Ruvbl2 is a Lrrc6/Seahorse interactor essential for cilia motility.

PubMed

Zhao, Lu; Yuan, Shiaulou; Cao, Ying; Kallakuri, Sowjanya; Li, Yuanyuan; Kishimoto, Norihito; DiBella, Linda; Sun, Zhaoxia

2013-07-30

Primary ciliary dyskinesia (PCD) is an autosomal recessive disease caused by defective cilia motility. The identified PCD genes account for about half of PCD incidences and the underlying mechanisms remain poorly understood. We demonstrate that Reptin/Ruvbl2, a protein known to be involved in epigenetic and transcriptional regulation, is essential for cilia motility in zebrafish. We further show that Reptin directly interacts with the PCD protein Lrrc6/Seahorse and this interaction is critical for the in vivo function of Lrrc6/Seahorse in zebrafish. Moreover, whereas the expression levels of multiple dynein arm components remain unchanged or become elevated, the density of axonemal dynein arms is reduced in reptin(hi2394) mutants. Furthermore, Reptin is highly enriched in the cytosol and colocalizes with Lrrc6/Seahorse. Combined, these results suggest that the Reptin-Lrrc6/Seahorse complex is involved in dynein arm formation. We also show that although the DNA damage response is induced in reptin(hi2394) mutants, it remains unchanged in cilia biogenesis mutants and lrrc6/seahorse mutants, suggesting that increased DNA damage response is not intrinsic to ciliary defects and that in vertebrate development, Reptin functions in multiple processes, both cilia specific and cilia independent.

Overview and diagnosis of multiple sclerosis.

PubMed

Hunter, Samuel F

2016-06-01

Multiple sclerosis (MS), a chronic inflammatory disease of unknown etiology, involves an immunemediated attack of the central nervous system (CNS) that produces demyelination and axonal/neuronal damage, resulting in characteristic multifocal lesions apparent on magnetic resonance imaging and a variety of neurologic manifestations. The disease pathology is characterized by multifocal lesions within the CNS, in both the white matter and gray matter, with perivenular inflammatory cell infiltrates, demyelination, axonal transection, neuronal degeneration, and gliosis. MS pathogenesis is complex, as it involves both T- and B-cell mechanisms and is heterogeneous in presentation. Relatively recently, the historical 4 core clinical categories of MS were revised in an effort to improve characterization of the clinical course, better identify where a given patient is positioned in the disease spectrum, and to guide clinical studies. In young and middle-aged adults, MS is one of the most common contributors to neurologic disability, and it exerts detrimental effects on a patient's productivity and health-related quality of life. Typically, patients with MS have a long life span, although healthcare utilization increases over time. As a consequence, the disease places a substantial burden on patients and their caregivers/families, as well as employers, the healthcare system, and society.

A learning controller for nonrepetitive robotic operation

NASA Technical Reports Server (NTRS)

Miller, W. T., III

1987-01-01

A practical learning control system is described which is applicable to complex robotic and telerobotic systems involving multiple feedback sensors and multiple command variables. In the controller, the learning algorithm is used to learn to reproduce the nonlinear relationship between the sensor outputs and the system command variables over particular regions of the system state space, rather than learning the actuator commands required to perform a specific task. The learned information is used to predict the command signals required to produce desired changes in the sensor outputs. The desired sensor output changes may result from automatic trajectory planning or may be derived from interactive input from a human operator. The learning controller requires no a priori knowledge of the relationships between the sensor outputs and the command variables. The algorithm is well suited for real time implementation, requiring only fixed point addition and logical operations. The results of learning experiments using a General Electric P-5 manipulator interfaced to a VAX-11/730 computer are presented. These experiments involved interactive operator control, via joysticks, of the position and orientation of an object in the field of view of a video camera mounted on the end of the robot arm.

Modeling complex systems in the geosciences

NASA Astrophysics Data System (ADS)

Balcerak, Ernie

2013-03-01

Many geophysical phenomena can be described as complex systems, involving phenomena such as extreme or "wild" events that often do not follow the Gaussian distribution that would be expected if the events were simply random and uncorrelated. For instance, some geophysical phenomena like earthquakes show a much higher occurrence of relatively large values than would a Gaussian distribution and so are examples of the "Noah effect" (named by Benoit Mandelbrot for the exceptionally heavy rain in the biblical flood). Other geophysical phenomena are examples of the "Joseph effect," in which a state is especially persistent, such as a spell of multiple consecutive hot days (heat waves) or several dry summers in a row. The Joseph effect was named after the biblical story in which Joseph's dream of seven fat cows and seven thin ones predicted 7 years of plenty followed by 7 years of drought.

Entry inhibitors in the treatment of HIV-1 infection.

PubMed

Tilton, John C; Doms, Robert W

2010-01-01

Infection of target cells by HIV is a complex, multi-stage process involving attachment to host cells and CD4 binding, coreceptor binding, and membrane fusion. Drugs that block HIV entry are collectively known as entry inhibitors, but comprise a complex group of drugs with multiple mechanisms of action depending on the stage of the entry process at which they act. Two entry inhibitors, maraviroc and enfuvirtide, have been approved for the treatment of HIV-1 infection, and a number of agents are in development. This review covers the entry inhibitors and their use in the management of HIV-1 infection. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, Vol 85, issue 1, 2010. Copyright 2009 Elsevier B.V. All rights reserved.

Spatial aliasing for efficient direction-of-arrival estimation based on steering vector reconstruction

NASA Astrophysics Data System (ADS)

Yan, Feng-Gang; Cao, Bin; Rong, Jia-Jia; Shen, Yi; Jin, Ming

2016-12-01

A new technique is proposed to reduce the computational complexity of the multiple signal classification (MUSIC) algorithm for direction-of-arrival (DOA) estimate using a uniform linear array (ULA). The steering vector of the ULA is reconstructed as the Kronecker product of two other steering vectors, and a new cost function with spatial aliasing at hand is derived. Thanks to the estimation ambiguity of this spatial aliasing, mirror angles mathematically relating to the true DOAs are generated, based on which the full spectral search involved in the MUSIC algorithm is highly compressed into a limited angular sector accordingly. Further complexity analysis and performance studies are conducted by computer simulations, which demonstrate that the proposed estimator requires an extremely reduced computational burden while it shows a similar accuracy to the standard MUSIC.

A multiple-shape memory polymer-metal composite actuator capable of programmable control, creating complex 3D motion of bending, twisting, and oscillation

NASA Astrophysics Data System (ADS)

Shen, Qi; Trabia, Sarah; Stalbaum, Tyler; Palmre, Viljar; Kim, Kwang; Oh, Il-Kwon

2016-04-01

Development of biomimetic actuators has been an essential motivation in the study of smart materials. However, few materials are capable of controlling complex twisting and bending deformations simultaneously or separately using a dynamic control system. Here, we report an ionic polymer-metal composite actuator having multiple-shape memory effect, and is able to perform complex motion by two external inputs, electrical and thermal. Prior to the development of this type of actuator, this capability only could be realized with existing actuator technologies by using multiple actuators or another robotic system. This paper introduces a soft multiple-shape-memory polymer-metal composite (MSMPMC) actuator having multiple degrees-of-freedom that demonstrates high maneuverability when controlled by two external inputs, electrical and thermal. These multiple inputs allow for complex motions that are routine in nature, but that would be otherwise difficult to obtain with a single actuator. To the best of the authors’ knowledge, this MSMPMC actuator is the first solitary actuator capable of multiple-input control and the resulting deformability and maneuverability.

A multiple-shape memory polymer-metal composite actuator capable of programmable control, creating complex 3D motion of bending, twisting, and oscillation

PubMed Central

Shen, Qi; Trabia, Sarah; Stalbaum, Tyler; Palmre, Viljar; Kim, Kwang; Oh, Il-Kwon

2016-01-01

Development of biomimetic actuators has been an essential motivation in the study of smart materials. However, few materials are capable of controlling complex twisting and bending deformations simultaneously or separately using a dynamic control system. Here, we report an ionic polymer-metal composite actuator having multiple-shape memory effect, and is able to perform complex motion by two external inputs, electrical and thermal. Prior to the development of this type of actuator, this capability only could be realized with existing actuator technologies by using multiple actuators or another robotic system. This paper introduces a soft multiple-shape-memory polymer-metal composite (MSMPMC) actuator having multiple degrees-of-freedom that demonstrates high maneuverability when controlled by two external inputs, electrical and thermal. These multiple inputs allow for complex motions that are routine in nature, but that would be otherwise difficult to obtain with a single actuator. To the best of the authors’ knowledge, this MSMPMC actuator is the first solitary actuator capable of multiple-input control and the resulting deformability and maneuverability. PMID:27080134