Interesting Images: Multiple Coronary Artery Aneurysms

PubMed Central

Howard, Jonathon M; Viswanath, Omar; Armas, Alfredo; Santana, Orlando; Rosen, Gerald P

2017-01-01

We present the case of a 65-year-old male who presented with stable angina and dyspnea on exertion. His initial workup yielded a positive treadmill stress test for reversible apical ischemia, and transthoracic echocardiogram demonstrated impaired systolic function. Cardiac catheterization was then performed, revealing severe atherosclerotic disease including multiple coronary artery aneurysms. As a result, the patient was advised to and subsequently underwent a coronary artery bypass graft. This case highlights the presence of multiple coronary artery aneurysms and the ability to appreciate these pathologic findings on multiple imaging modalities, including coronary angiogram, transesophageal echocardiography, and direct visualization through the surgical field. PMID:28701599

Teaching Core Content Embedded in a Functional Activity to Students with Moderate Intellectual Disability Using a Simultaneous Prompting Procedure

ERIC Educational Resources Information Center

Karl, Jennifer; Collins, Belva C.; Hager, Karen D.; Ault, Melinda Jones

2013-01-01

The purpose of this study was to investigate the effects of a simultaneous prompting procedure in teaching four secondary students with moderate intellectual disability to acquire and generalize core content embedded in a functional activity. Data gathered within the context of a multiple probe design revealed that all participants learned the…

Cell- and virus-mediated regulation of the barrier-to-autointegration factor's phosphorylation state controls its DNA binding, dimerization, subcellular localization, and antipoxviral activity.

PubMed

Jamin, Augusta; Wicklund, April; Wiebe, Matthew S

2014-05-01

Barrier-to-autointegration factor (BAF) is a DNA binding protein with multiple cellular functions, including the ability to act as a potent defense against vaccinia virus infection. This antiviral function involves BAF's ability to condense double-stranded DNA and subsequently prevent viral DNA replication. In recent years, it has become increasingly evident that dynamic phosphorylation involving the vaccinia virus B1 kinase and cellular enzymes is likely a key regulator of multiple BAF functions; however, the precise mechanisms are poorly understood. Here we analyzed how phosphorylation impacts BAF's DNA binding, subcellular localization, dimerization, and antipoxviral activity through the characterization of BAF phosphomimetic and unphosphorylatable mutants. Our studies demonstrate that increased phosphorylation enhances BAF's mobilization from the nucleus to the cytosol, while dephosphorylation restricts BAF to the nucleus. Phosphorylation also impairs both BAF's dimerization and its DNA binding activity. Furthermore, our studies of BAF's antiviral activity revealed that hyperphosphorylated BAF is unable to suppress viral DNA replication or virus production. Interestingly, the unphosphorylatable BAF mutant, which is capable of binding DNA but localizes predominantly to the nucleus, was also incapable of suppressing viral replication. Thus, both DNA binding and localization are important determinants of BAF's antiviral function. Finally, our examination of how phosphatases are involved in regulating BAF revealed that PP2A dephosphorylates BAF during vaccinia infection, thus counterbalancing the activity of the B1 kinase. Altogether, these data demonstrate that phosphoregulation of BAF by viral and cellular enzymes modulates this protein at multiple molecular levels, thus determining its effectiveness as an antiviral factor and likely other functions as well. The barrier-to-autointegration factor (BAF) contributes to cellular genomic integrity in multiple ways, the best characterized of which are as a host defense against cytoplasmic DNA and as a regulator of mitotic nuclear reassembly. Although dynamic phosphorylation involving both viral and cellular enzymes is likely a key regulator of multiple BAF functions, the precise mechanisms involved are poorly understood. Here we demonstrate that phosphorylation coordinately regulates BAF's DNA binding, subcellular localization, dimerization, and antipoxviral activity. Overall, our findings provide new insights into how phosphoregulation of BAF modulates this protein at multiple levels and governs its effectiveness as an antiviral factor against foreign DNA.

Role of executive functions in prospective memory in multiple sclerosis: Impact of the strength of cue-action association.

PubMed

Dagenais, Emmanuelle; Rouleau, Isabelle; Tremblay, Alexandra; Demers, Mélanie; Roger, Élaine; Jobin, Céline; Duquette, Pierre

2016-01-01

Patients diagnosed with multiple sclerosis (MS) often report prospective memory (PM) deficits. Although PM is important for daily functioning, it is not formally assessed in clinical practice. The aim of this study was to examine the role of executive functions in MS patients' PM revealed by the effect of strength of cue-action association on PM performance. Thirty-nine MS patients were compared to 18 healthy controls matched for age, gender, and education on a PM task modulating the strength of association between the cue and the intended action. Deficits in MS patients affecting both prospective and retrospective components of PM were confirmed using 2 × 2 × 2 mixed analyses of variance (ANOVAs). Among patients, multiple regression analyses revealed that the impairment was modulated by the efficiency of executive functions, whereas retrospective memory seemed to have little impact on PM performance, contrary to expectation. More specifically, results of 2 × 2 × 2 mixed-model analyses of covariance (ANCOVAs) showed that low-executive patients had more difficulty detecting and, especially, retrieving the appropriate action when the cue and the action were unrelated, whereas high-executive patients' performance seemed to be virtually unaffected by the cue-action association. Using an objective measure, these findings confirm the presence of PM deficits in MS. They also suggest that such deficits depend on executive functioning and can be reduced when automatic PM processes are engaged through semantic cue-action association. They underscore the importance of assessing PM in clinical settings through a cognitive evaluation and offer an interesting avenue for rehabilitation.

Segregated Systems of Human Brain Networks.

PubMed

Wig, Gagan S

2017-12-01

The organization of the brain network enables its function. Evaluation of this organization has revealed that large-scale brain networks consist of multiple segregated subnetworks of interacting brain areas. Descriptions of resting-state network architecture have provided clues for understanding the functional significance of these segregated subnetworks, many of which correspond to distinct brain systems. The present report synthesizes accumulating evidence to reveal how maintaining segregated brain systems renders the human brain network functionally specialized, adaptable to task demands, and largely resilient following focal brain damage. The organizational properties that support system segregation are harmonious with the properties that promote integration across the network, but confer unique and important features to the brain network that are central to its function and behavior. Copyright © 2017 Elsevier Ltd. All rights reserved.

High-Throughput Analysis of Promoter Occupancy Reveals New Targets for Arx, a Gene Mutated in Mental Retardation and Interneuronopathies

PubMed Central

Quillé, Marie-Lise; Hirchaud, Edouard; Baron, Daniel; Benech, Caroline; Guihot, Jeanne; Placet, Morgane; Mignen, Olivier; Férec, Claude; Houlgatte, Rémi; Friocourt, Gaëlle

2011-01-01

Genetic investigations of X-linked intellectual disabilities have implicated the ARX (Aristaless-related homeobox) gene in a wide spectrum of disorders extending from phenotypes characterised by severe neuronal migration defects such as lissencephaly, to mild or moderate forms of mental retardation without apparent brain abnormalities but with associated features of dystonia and epilepsy. Analysis of Arx spatio-temporal localisation profile in mouse revealed expression in telencephalic structures, mainly restricted to populations of GABAergic neurons at all stages of development. Furthermore, studies of the effects of ARX loss of function in humans and animal models revealed varying defects, suggesting multiple roles of this gene during brain development. However, to date, little is known about how ARX functions as a transcription factor and the nature of its targets. To better understand its role, we combined chromatin immunoprecipitation and mRNA expression with microarray analysis and identified a total of 1006 gene promoters bound by Arx in transfected neuroblastoma (N2a) cells and in mouse embryonic brain. Approximately 24% of Arx-bound genes were found to show expression changes following Arx overexpression or knock-down. Several of the Arx target genes we identified are known to be important for a variety of functions in brain development and some of them suggest new functions for Arx. Overall, these results identified multiple new candidate targets for Arx and should help to better understand the pathophysiological mechanisms of intellectual disability and epilepsy associated with ARX mutations. PMID:21966449

Rotor noise due to blade-turbulence interaction

NASA Astrophysics Data System (ADS)

Ishimaru, K.

1983-01-01

The time-averaged intensity density function of the acoustic radiation from rotating blades is derived by replacing blades with rotating dipoles. This derivation is done under the following turbulent inflow conditions: turbulent ingestion with no inlet strut wakes, inflow turbulence elongation and contraction with no inlet strut wakes, and inlet strut wakes. Dimensional analysis reveals two non-dimensional parameters which play important roles in generating the blade-passing frequency tone and its multiples. The elongation and contraction of inflow turbulence has a strong effect on the generation of the blade-passing frequency tone and its multiples. Increasing the number of rotor blades widens the peak at the blade-passing frequency and its multiples. Increasing the rotational speed widens the peak under the condition that the non-dimensional parameter involving the rotational speed is fixed. The number of struts and blades should be chosen so that (the least common multiple of them)-(rotational speed) is in the cutoff range of Sears' function, in order to minimize the effect of the mean flow deficit on the time averaged intensity density function.

Using Spatial Multiple Regression to Identify Intrinsic Connectivity Networks Involved in Working Memory Performance

PubMed Central

Gordon, Evan M.; Stollstorff, Melanie; Vaidya, Chandan J.

2012-01-01

Many researchers have noted that the functional architecture of the human brain is relatively invariant during task performance and the resting state. Indeed, intrinsic connectivity networks (ICNs) revealed by resting-state functional connectivity analyses are spatially similar to regions activated during cognitive tasks. This suggests that patterns of task-related activation in individual subjects may result from the engagement of one or more of these ICNs; however, this has not been tested. We used a novel analysis, spatial multiple regression, to test whether the patterns of activation during an N-back working memory task could be well described by a linear combination of ICNs delineated using Independent Components Analysis at rest. We found that across subjects, the cingulo-opercular Set Maintenance ICN, as well as right and left Frontoparietal Control ICNs, were reliably activated during working memory, while Default Mode and Visual ICNs were reliably deactivated. Further, involvement of Set Maintenance, Frontoparietal Control, and Dorsal Attention ICNs was sensitive to varying working memory load. Finally, the degree of left Frontoparietal Control network activation predicted response speed, while activation in both left Frontoparietal Control and Dorsal Attention networks predicted task accuracy. These results suggest that a close relationship between resting-state networks and task-evoked activation is functionally relevant for behavior, and that spatial multiple regression analysis is a suitable method for revealing that relationship. PMID:21761505

Conservation of tubulin-binding sequences in TRPV1 throughout evolution.

PubMed

Sardar, Puspendu; Kumar, Abhishek; Bhandari, Anita; Goswami, Chandan

2012-01-01

Transient Receptor Potential Vanilloid sub type 1 (TRPV1), commonly known as capsaicin receptor can detect multiple stimuli ranging from noxious compounds, low pH, temperature as well as electromagnetic wave at different ranges. In addition, this receptor is involved in multiple physiological and sensory processes. Therefore, functions of TRPV1 have direct influences on adaptation and further evolution also. Availability of various eukaryotic genomic sequences in public domain facilitates us in studying the molecular evolution of TRPV1 protein and the respective conservation of certain domains, motifs and interacting regions that are functionally important. Using statistical and bioinformatics tools, our analysis reveals that TRPV1 has evolved about ∼420 million years ago (MYA). Our analysis reveals that specific regions, domains and motifs of TRPV1 has gone through different selection pressure and thus have different levels of conservation. We found that among all, TRP box is the most conserved and thus have functional significance. Our results also indicate that the tubulin binding sequences (TBS) have evolutionary significance as these stretch sequences are more conserved than many other essential regions of TRPV1. The overall distribution of positively charged residues within the TBS motifs is conserved throughout evolution. In silico analysis reveals that the TBS-1 and TBS-2 of TRPV1 can form helical structures and may play important role in TRPV1 function. Our analysis identifies the regions of TRPV1, which are important for structure-function relationship. This analysis indicates that tubulin binding sequence-1 (TBS-1) near the TRP-box forms a potential helix and the tubulin interactions with TRPV1 via TBS-1 have evolutionary significance. This interaction may be required for the proper channel function and regulation and may also have significance in the context of Taxol®-induced neuropathy.

Exploration of Multi-State Conformational Dynamics and Underlying Global Functional Landscape of Maltose Binding Protein

PubMed Central

Wang, Yong; Tang, Chun; Wang, Erkang; Wang, Jin

2012-01-01

An increasing number of biological machines have been revealed to have more than two macroscopic states. Quantifying the underlying multiple-basin functional landscape is essential for understanding their functions. However, the present models seem to be insufficient to describe such multiple-state systems. To meet this challenge, we have developed a coarse grained triple-basin structure-based model with implicit ligand. Based on our model, the constructed functional landscape is sufficiently sampled by the brute-force molecular dynamics simulation. We explored maltose-binding protein (MBP) which undergoes large-scale domain motion between open, apo-closed (partially closed) and holo-closed (fully closed) states responding to ligand binding. We revealed an underlying mechanism whereby major induced fit and minor population shift pathways co-exist by quantitative flux analysis. We found that the hinge regions play an important role in the functional dynamics as well as that increases in its flexibility promote population shifts. This finding provides a theoretical explanation of the mechanistic discrepancies in PBP protein family. We also found a functional “backtracking” behavior that favors conformational change. We further explored the underlying folding landscape in response to ligand binding. Consistent with earlier experimental findings, the presence of ligand increases the cooperativity and stability of MBP. This work provides the first study to explore the folding dynamics and functional dynamics under the same theoretical framework using our triple-basin functional model. PMID:22532792

A convergent functional architecture of the insula emerges across imaging modalities.

PubMed

Kelly, Clare; Toro, Roberto; Di Martino, Adriana; Cox, Christine L; Bellec, Pierre; Castellanos, F Xavier; Milham, Michael P

2012-07-16

Empirical evidence increasingly supports the hypothesis that patterns of intrinsic functional connectivity (iFC) are sculpted by a history of evoked coactivation within distinct neuronal networks. This, together with evidence of strong correspondence among the networks defined by iFC and those delineated using a variety of other neuroimaging techniques, suggests a fundamental brain architecture detectable across multiple functional and structural imaging modalities. Here, we leverage this insight to examine the functional organization of the human insula. We parcellated the insula on the basis of three distinct neuroimaging modalities - task-evoked coactivation, intrinsic (i.e., task-independent) functional connectivity, and gray matter structural covariance. Clustering of these three different covariance-based measures revealed a convergent elemental organization of the insula that likely reflects a fundamental brain architecture governing both brain structure and function at multiple spatial scales. While not constrained to be hierarchical, our parcellation revealed a pseudo-hierarchical, multiscale organization that was consistent with previous clustering and meta-analytic studies of the insula. Finally, meta-analytic examination of the cognitive and behavioral domains associated with each of the insular clusters obtained elucidated the broad functional dissociations likely underlying the topography observed. To facilitate future investigations of insula function across healthy and pathological states, the insular parcels have been made freely available for download via http://fcon_1000.projects.nitrc.org, along with the analytic scripts used to perform the parcellations. Copyright © 2012 Elsevier Inc. All rights reserved.

Multiple Fractures in Patient with Graves' Disease Accompanied by Isolated Hypogonadotropic Hypogonadism.

PubMed

Yi, Hyon-Seung; Kim, Ji Min; Ju, Sang Hyeon; Lee, Younghak; Kim, Hyun Jin; Kim, Koon Soon

2016-02-01

Isolated hypogonadotropic hypogonadism (IHH) is known to decrease bone mineral density due to deficiency of sex steroid hormone. Graves' disease is also an important cause of secondary osteoporosis. However, IHH does not preclude the development of primary hyperthyroidism caused by Graves' disease, leading to more severe osteoporosis rapidly. Here, we describe the first case of 35-year-old Asian female patient with IHH accompanied by Graves' disease and osteoporosis-induced multiple fractures. Endocrine laboratory findings revealed preserved anterior pituitary functions except for secretion of gonadotropins and showed primary hyperthyroidism with positive autoantibodies. Sella magnetic resonance imaging showed slightly small sized pituitary gland without mass lesion. Dual energy X-ray absorptiometry revealed severe osteoporosis in lumbar spine and femur neck of the patient. Plain film radiography of the pelvis and shoulder revealed a displaced and nondisplaced fracture, respectively. After surgical fixation with screws for the femoral fracture, the patient was treated with antithyroid medication, calcium, and vitamin D until now and has been recovering fairly well. We report a patient of IHH with Graves' disease and multiple fractures that is a first case in Korea.

Death Anxiety as a Function of Aging Anxiety

ERIC Educational Resources Information Center

Benton, Jeremy P.; Christopher, Andrew N.; Walter, Mark I.

2007-01-01

To assess how different facets of aging anxiety contributed to the prediction of tangible and existential death anxiety, 167 Americans of various Christian denominations completed a battery of questionnaires. Multiple regression analyses, controlling for demographic variables and previously demonstrated predictors of death anxiety, revealed that…

Optimal function explains forest responses to global change

Treesearch

Roderick Dewar; Oskar Franklin; Annikki Makela; Ross E. McMurtrie; Harry T. Valentine

2009-01-01

Plant responses to global changes in carbon dioxide (CO2), nitrogen, and water availability are critical to future atmospheric CO2 concentrations, hydrology, and hence climate. Our understanding of those responses is incomplete, however. Multiple-resource manipulation experiments and empirical observations have revealed a...

Circuit-wide Transcriptional Profiling Reveals Brain Region-Specific Gene Networks Regulating Depression Susceptibility.

PubMed

Bagot, Rosemary C; Cates, Hannah M; Purushothaman, Immanuel; Lorsch, Zachary S; Walker, Deena M; Wang, Junshi; Huang, Xiaojie; Schlüter, Oliver M; Maze, Ian; Peña, Catherine J; Heller, Elizabeth A; Issler, Orna; Wang, Minghui; Song, Won-Min; Stein, Jason L; Liu, Xiaochuan; Doyle, Marie A; Scobie, Kimberly N; Sun, Hao Sheng; Neve, Rachael L; Geschwind, Daniel; Dong, Yan; Shen, Li; Zhang, Bin; Nestler, Eric J

2016-06-01

Depression is a complex, heterogeneous disorder and a leading contributor to the global burden of disease. Most previous research has focused on individual brain regions and genes contributing to depression. However, emerging evidence in humans and animal models suggests that dysregulated circuit function and gene expression across multiple brain regions drive depressive phenotypes. Here, we performed RNA sequencing on four brain regions from control animals and those susceptible or resilient to chronic social defeat stress at multiple time points. We employed an integrative network biology approach to identify transcriptional networks and key driver genes that regulate susceptibility to depressive-like symptoms. Further, we validated in vivo several key drivers and their associated transcriptional networks that regulate depression susceptibility and confirmed their functional significance at the levels of gene transcription, synaptic regulation, and behavior. Our study reveals novel transcriptional networks that control stress susceptibility and offers fundamentally new leads for antidepressant drug discovery. Copyright © 2016 Elsevier Inc. All rights reserved.

Soda pans of the Pannonian steppe harbor unique bacterial communities adapted to multiple extreme conditions.

PubMed

Szabó, Attila; Korponai, Kristóf; Kerepesi, Csaba; Somogyi, Boglárka; Vörös, Lajos; Bartha, Dániel; Márialigeti, Károly; Felföldi, Tamás

2017-05-01

Soda pans of the Pannonian steppe are unique environments regarding their physical and chemical characteristics: shallowness, high turbidity, intermittent character, alkaline pH, polyhumic organic carbon concentration, hypertrophic condition, moderately high salinity, sodium and carbonate ion dominance. The pans are highly productive environments with picophytoplankton predominance. Little is known about the planktonic bacterial communities inhabiting these aquatic habitats; therefore, amplicon sequencing and shotgun metagenomics were applied to reveal their composition and functional properties. Results showed a taxonomically complex bacterial community which was distinct from other soda lakes regarding its composition, e.g. the dominance of class Alphaproteobacteria was observed within phylum Proteobacteria. The shotgun metagenomic analysis revealed several functional gene components related to the harsh and at the same time hypertrophic environmental conditions, e.g. proteins involved in stress response, transport and hydrolase systems targeting phytoplankton-derived organic matter. This is the first detailed report on the indigenous planktonic bacterial communities coping with the multiple extreme conditions present in the unique soda pans of the Pannonian steppe.

Cluster analysis differentiates high and low community functioning in schizophrenia: Subgroups differ on working memory but not other neurocognitive domains.

PubMed

Alden, Eva C; Cobia, Derin J; Reilly, James L; Smith, Matthew J

2015-10-01

Schizophrenia is characterized by impairment in multiple aspects of community functioning. Available literature suggests that community functioning may be enhanced through cognitive remediation, however, evidence is limited regarding whether specific neurocognitive domains may be treatment targets. We characterized schizophrenia subjects based on their level of community functioning through cluster analysis in an effort to identify whether specific neurocognitive domains were associated with variation in functioning. Schizophrenia (SCZ, n=60) and control (CON, n=45) subjects completed a functional capacity task, social competence role-play, functional attainment interview, and a neuropsychological battery. Multiple cluster analytic techniques were used on the measures of functioning in the schizophrenia subjects to generate functionally-defined subgroups. MANOVA evaluated between-group differences in neurocognition. The cluster analysis revealed two distinct groups, consisting of 36 SCZ characterized by high levels of community functioning (HF-SCZ) and 24 SCZ with low levels of community functioning (LF-SCZ). There was a main group effect for neurocognitive performance (p<0.001) with CON outperforming both SCZ groups in all neurocognitive domains. Post-hoc tests revealed that HF-SCZ had higher verbal working memory compared to LF-SCZ (p≤0.05, Cohen's d=0.78) but the two groups did not differ in remaining domains. The cluster analysis classified schizophrenia subjects in HF-SCZ and LF-SCZ using a multidimensional assessment of community functioning. Moreover, HF-SCZ demonstrated rather preserved verbal working memory relative to LF-SCZ. The results suggest that verbal working memory may play a critical role in community functioning, and is a potential cognitive treatment target for schizophrenia subjects. Copyright © 2015 Elsevier B.V. All rights reserved.

Tagging methyl-CpG-binding domain proteins reveals different spatiotemporal expression and supports distinct functions.

PubMed

Wood, Kathleen H; Johnson, Brian S; Welsh, Sarah A; Lee, Jun Y; Cui, Yue; Krizman, Elizabeth; Brodkin, Edward S; Blendy, Julie A; Robinson, Michael B; Bartolomei, Marisa S; Zhou, Zhaolan

2016-04-01

DNA methylation is recognized by methyl-CpG-binding domain (MBD) proteins. Multiple MBDs are linked to neurodevelopmental disorders in humans and mice. However, the functions of MBD2 are poorly understood. We characterized Mbd2 knockout mice and determined spatiotemporal expression of MBDs and MBD2-NuRD (nucleosome remodeling deacetylase) interactions. We analyzed behavioral phenotypes, generated biotin-tagged MBD1 and MBD2 knockin mice, and performed biochemical studies of MBD2-NuRD. Most behavioral measures are minimally affected in Mbd2 knockout mice. In contrast to other MBDs, MBD2 shows distinct expression patterns. Unlike most MBDs, MBD2 is ubiquitously expressed in all tissues examined and appears dispensable for brain functions measured in this study. We provide novel genetic tools and reveal new directions to investigate MBD2 functions in vivo.

Characterization and functional analyses of a novel chicken CD8a variant X1 (CD8a1)

USDA-ARS?s Scientific Manuscript database

We provide the first description of cloning, as well as structural and functional analysis of a novel variant in the chicken CD8alpha family, termed the CD8-alpha X1 (CD8alpha1) gene. Multiple alignment of CD8alpha1 with known CD8alpha and beta sequences of other species revealed relatively low con...

Muscle mania: the quest for the perfect body.

PubMed

Hameed, Maira; Sahu, Ajay; Johnson, Maria B

2016-12-01

We describe the case of a young man with repeated hospital presentations for a variety of symptoms related to excessive bodybuilding and associated behaviours. He presented to our department (radiology) with right arm pain and loss of function. Ultrasound showed complete triceps rupture, rare in young patients and multiple cystic areas within the muscles of the arm. MRI revealed these to be multiple proteinaceous lesions within the muscle bellies and the possibility of self-innoculation was raised by the reporting radiologist. The patient subsequently admitted to injecting coconut oil to improve muscle contour lost secondary to injury. A review of his hospital presentations was then made and revealed further concerning practices performed by the patient to enhance his muscular appearance. 2016 BMJ Publishing Group Ltd.

Dynamic equilibrium of heterogeneous and interconvertible multipotent hematopoietic cell subsets

PubMed Central

Weston, Wendy; Zayas, Jennifer; Perez, Ruben; George, John; Jurecic, Roland

2014-01-01

Populations of hematopoietic stem cells and progenitors are quite heterogeneous and consist of multiple cell subsets with distinct phenotypic and functional characteristics. Some of these subsets also appear to be interconvertible and oscillate between functionally distinct states. The multipotent hematopoietic cell line EML has emerged as a unique model to study the heterogeneity and interconvertibility of multipotent hematopoietic cells. Here we describe extensive phenotypic and functional heterogeneity of EML cells which stems from the coexistence of multiple cell subsets. Each of these subsets is phenotypically and functionally heterogeneous, and displays distinct multilineage differentiation potential, cell cycle profile, proliferation kinetics, and expression pattern of HSC markers and some of the key lineage-associated transcription factors. Analysis of their maintenance revealed that on a population level all EML cell subsets exhibit cell-autonomous interconvertible properties, with the capacity to generate all other subsets and re-establish complete parental EML cell population. Moreover, all EML cell subsets generated during multiple cell generations maintain their distinct phenotypic and functional signatures and interconvertible properties. The model of EML cell line suggests that interconvertible multipotent hematopoietic cell subsets coexist in a homeostatically maintained dynamic equilibrium which is regulated by currently unknown cell-intrinsic mechanisms. PMID:24903657

Dynamic equilibrium of heterogeneous and interconvertible multipotent hematopoietic cell subsets.

PubMed

Weston, Wendy; Zayas, Jennifer; Perez, Ruben; George, John; Jurecic, Roland

2014-06-06

Populations of hematopoietic stem cells and progenitors are quite heterogeneous and consist of multiple cell subsets with distinct phenotypic and functional characteristics. Some of these subsets also appear to be interconvertible and oscillate between functionally distinct states. The multipotent hematopoietic cell line EML has emerged as a unique model to study the heterogeneity and interconvertibility of multipotent hematopoietic cells. Here we describe extensive phenotypic and functional heterogeneity of EML cells which stems from the coexistence of multiple cell subsets. Each of these subsets is phenotypically and functionally heterogeneous, and displays distinct multilineage differentiation potential, cell cycle profile, proliferation kinetics, and expression pattern of HSC markers and some of the key lineage-associated transcription factors. Analysis of their maintenance revealed that on a population level all EML cell subsets exhibit cell-autonomous interconvertible properties, with the capacity to generate all other subsets and re-establish complete parental EML cell population. Moreover, all EML cell subsets generated during multiple cell generations maintain their distinct phenotypic and functional signatures and interconvertible properties. The model of EML cell line suggests that interconvertible multipotent hematopoietic cell subsets coexist in a homeostatically maintained dynamic equilibrium which is regulated by currently unknown cell-intrinsic mechanisms.

A Simple Secure Hash Function Scheme Using Multiple Chaotic Maps

NASA Astrophysics Data System (ADS)

Ahmad, Musheer; Khurana, Shruti; Singh, Sushmita; AlSharari, Hamed D.

2017-06-01

The chaotic maps posses high parameter sensitivity, random-like behavior and one-way computations, which favor the construction of cryptographic hash functions. In this paper, we propose to present a novel hash function scheme which uses multiple chaotic maps to generate efficient variable-sized hash functions. The message is divided into four parts, each part is processed by a different 1D chaotic map unit yielding intermediate hash code. The four codes are concatenated to two blocks, then each block is processed through 2D chaotic map unit separately. The final hash value is generated by combining the two partial hash codes. The simulation analyses such as distribution of hashes, statistical properties of confusion and diffusion, message and key sensitivity, collision resistance and flexibility are performed. The results reveal that the proposed anticipated hash scheme is simple, efficient and holds comparable capabilities when compared with some recent chaos-based hash algorithms.

An Investigation of Dental Luting Cement Solubility as a Function of the Marginal Gap.

DTIC Science & Technology

1988-05-01

way ANOVA for the Phase 1 Diffusion Study revealed that there were statistically significant differences between the test groups. A Duncan’s Multiple...cement. The 25, 50, and 75 micron groups demonstrated no statistically significant differences in the amount of remaining luting cement. ( p< 0.05) A...one-way ANOVA was also performed on Phase 2 Dynamic Study. This test revealed that there were statistically significant differences among the test

Multiple myeloma-related deregulation of bone marrow-derived CD34(+) hematopoietic stem and progenitor cells.

PubMed

Bruns, Ingmar; Cadeddu, Ron-Patrick; Brueckmann, Ines; Fröbel, Julia; Geyh, Stefanie; Büst, Sebastian; Fischer, Johannes C; Roels, Frederik; Wilk, Christian Matthias; Schildberg, Frank A; Hünerlitürkoglu, Ali-Nuri; Zilkens, Christoph; Jäger, Marcus; Steidl, Ulrich; Zohren, Fabian; Fenk, Roland; Kobbe, Guido; Brors, Benedict; Czibere, Akos; Schroeder, Thomas; Trumpp, Andreas; Haas, Rainer

2012-09-27

Multiple myeloma (MM) is a clonal plasma cell disorder frequently accompanied by hematopoietic impairment. We show that hematopoietic stem and progenitor cells (HSPCs), in particular megakaryocyte-erythrocyte progenitors, are diminished in the BM of MM patients. Genomic profiling of HSPC subsets revealed deregulations of signaling cascades, most notably TGFβ signaling, and pathways involved in cytoskeletal organization, migration, adhesion, and cell-cycle regulation in the patients. Functionally, proliferation, colony formation, and long-term self-renewal were impaired as a consequence of activated TGFβ signaling. In accordance, TGFβ levels in the BM extracellular fluid were elevated and mesenchymal stromal cells (MSCs) had a reduced capacity to support long-term hematopoiesis of HSPCs that completely recovered on blockade of TGFβ signaling. Furthermore, we found defective actin assembly and down-regulation of the adhesion receptor CD44 in MM HSPCs functionally reflected by impaired migration and adhesion. Still, transplantation into myeloma-free NOG mice revealed even enhanced engraftment and normal differentiation capacities of MM HSPCs, which underlines that functional impairment of HSPCs depends on MM-related microenvironmental cues and is reversible. Taken together, these data implicate that hematopoietic suppression in MM emerges from the HSPCs as a result of MM-related microenvironmental alterations.

Cloning and characterization of the murine homolog of the sno proto-oncogene reveals a novel splice variant

NASA Technical Reports Server (NTRS)

Pelzer, T.; Lyons, G. E.; Kim, S.; Moreadith, R. W.; Blomqvist, C. G. (Principal Investigator)

1996-01-01

The cellular function(s) of the SNO protein remain undefined. To gain a better understanding of possible developmental roles of this cellular proto-oncogene, we have cloned two murine sno cDNAs and have investigated their expression patterns in embryonic and postnatal tissues. A single major transcript of 7.5 kb is detected in multiple tissues by Northern blot. However, reverse transcriptase polymerase chain reaction (RT-PCR) and RNAse protection assays revealed a novel splice variant in every tissue examined. Two isoforms, termed sno N and sno-dE3 (dE3, deletion within exon 3), were identified. The sno-dE3 isoform employs a novel 5' splice site located within the coding region of the third exon and deletes potential kinase recognition motifs. Transcripts of both sno isoforms accumulate ubiquitously but are most abundant in the developing central nervous system. The in situ hybridization patterns of sno expression during murine development suggest potential roles in tissues with a high degree of cellular proliferation. Expression in terminally differentiated tissues such as muscle and neurons indicates that SNO may have multiple functional activities.

Functional profiles reveal unique ecological roles of various biological soil crust organisms

USGS Publications Warehouse

Bowker, M.A.; Mau, R.L.; Maestre, F.T.; Escolar, C.; Castillo-Monroy, A. P.

2011-01-01

1. At the heart of the body of research on biodiversity effects on ecosystem function is the debate over whether different species tend to be functionally singular or redundant. When we consider ecosystem multi-function, the provision of multiple ecosystem functions simultaneously, we may find that seemingly redundant species may in fact play unique roles in ecosystems. 2. Over the last few decades, the significance of biological soil crusts (BSCs) as ecological boundaries and ecosystem engineers, and their multi-functional nature, has become increasingly well documented. We compiled 'functional profiles' of the organisms in this understudied community, to determine whether functional singularity emerges when multiple ecosystem functions are considered. 3. In two data sets, one representing multiple sites around the semi-arid regions of Spain (regional scale), and another from a single site in central Spain (local scale), we examined correlations between the abundance or frequency of BSC species in a community, and multiple surrogates of ecosystem functioning. There was a wide array of apparent effects of species on specific functions. 4. Notably, in gypsiferous soils and at regional scale, we found that indicators of carbon (C) and phosphorus cycling were apparently suppressed and promoted by the lichens Diploschistes diacapsis and Squamarina lentigera, respectively. The moss Pleurochaete squarrosa appears to promote C cycling in calcareous soils at this spatial scale. At the local scale in gypsiferous soils, D. diacapsis positively correlated with carbon cycling, but negatively with nitrogen cycling, whereas numerous lichens exhibited the opposite profile. 5. We found a high degree of functional singularity, i.e. that species were highly individualistic in their effects on multiple functions. Many functional attributes were not easily predictable from existing functional grouping systems based primarily on morphology. 6. Our results suggest that maintaining species-rich BSC communities is crucial to maintain the overall functionality of ecosystems dominated by these organisms, and that dominance and the outcome of competition could be highly influential in the determination of such functionality. ?? 2011 The Authors. Functional Ecology ?? 2011 British Ecological Society.

Efficiency and Productivity Analysis of Multidivisional Firms

NASA Astrophysics Data System (ADS)

Gong, Binlei

Multidivisional firms are those who have footprints in multiple segments and hence using multiple technologies to convert inputs to outputs, which makes it difficult to estimate the resource allocations, aggregated production functions, and technical efficiencies of this type of companies. This dissertation aims to explore and reveal such unobserved information by several parametric and semiparametric stochastic frontier analyses and some other structural models. In the empirical study, this dissertation analyzes the productivity and efficiency for firms in the global oilfield market.

Large‐scale analysis reveals populational contributions of cortical spike rate and synchrony to behavioural functions

PubMed Central

Saiki, Akiko; Fujiwara‐Tsukamoto, Yoko; Sakai, Yutaka; Isomura, Yoshikazu

2016-01-01

Key points There have been few systematic population‐wide analyses of relationships between spike synchrony within a period of several milliseconds and behavioural functions.In this study, we obtained a large amount of spike data from > 23,000 neuron pairs by multiple single‐unit recording from deep layer neurons in motor cortical areas in rats performing a forelimb movement task.The temporal changes of spike synchrony in the whole neuron pairs were statistically independent of behavioural changes during the task performance, although some neuron pairs exhibited correlated changes in spike synchrony.Mutual information analyses revealed that spike synchrony made a smaller contribution than spike rate to behavioural functions.The strength of spike synchrony between two neurons was statistically independent of the spike rate‐based preferences of the pair for behavioural functions. Abstract Spike synchrony within a period of several milliseconds in presynaptic neurons enables effective integration of functional information in the postsynaptic neuron. However, few studies have systematically analysed the population‐wide relationships between spike synchrony and behavioural functions. Here we obtained a sufficiently large amount of spike data among regular‐spiking (putatively excitatory) and fast‐spiking (putatively inhibitory) neuron subtypes (> 23,000 pairs) by multiple single‐unit recording from deep layers in motor cortical areas (caudal forelimb area, rostral forelimb area) in rats performing a forelimb movement task. After holding a lever, rats pulled the lever either in response to a cue tone (external‐trigger trials) or spontaneously without any cue (internal‐trigger trials). Many neurons exhibited functional spike activity in association with forelimb movements, and the preference of regular‐spiking neurons in the rostral forelimb area was more biased toward externally triggered movement than that in the caudal forelimb area. We found that a population of neuron pairs with spike synchrony does exist, and that some neuron pairs exhibit a dependence on movement phase during task performance. However, the population‐wide analysis revealed that spike synchrony was statistically independent of the movement phase and the spike rate‐based preferences of the pair for behavioural functions, whereas spike rates were clearly dependent on the movement phase. In fact, mutual information analyses revealed that the contribution of spike synchrony to the behavioural functions was small relative to the contribution of spike rate. Our large‐scale analysis revealed that cortical spike rate, rather than spike synchrony, contributes to population coding for movement. PMID:27488936

Large-scale analysis reveals populational contributions of cortical spike rate and synchrony to behavioural functions.

PubMed

Kimura, Rie; Saiki, Akiko; Fujiwara-Tsukamoto, Yoko; Sakai, Yutaka; Isomura, Yoshikazu

2017-01-01

There have been few systematic population-wide analyses of relationships between spike synchrony within a period of several milliseconds and behavioural functions. In this study, we obtained a large amount of spike data from > 23,000 neuron pairs by multiple single-unit recording from deep layer neurons in motor cortical areas in rats performing a forelimb movement task. The temporal changes of spike synchrony in the whole neuron pairs were statistically independent of behavioural changes during the task performance, although some neuron pairs exhibited correlated changes in spike synchrony. Mutual information analyses revealed that spike synchrony made a smaller contribution than spike rate to behavioural functions. The strength of spike synchrony between two neurons was statistically independent of the spike rate-based preferences of the pair for behavioural functions. Spike synchrony within a period of several milliseconds in presynaptic neurons enables effective integration of functional information in the postsynaptic neuron. However, few studies have systematically analysed the population-wide relationships between spike synchrony and behavioural functions. Here we obtained a sufficiently large amount of spike data among regular-spiking (putatively excitatory) and fast-spiking (putatively inhibitory) neuron subtypes (> 23,000 pairs) by multiple single-unit recording from deep layers in motor cortical areas (caudal forelimb area, rostral forelimb area) in rats performing a forelimb movement task. After holding a lever, rats pulled the lever either in response to a cue tone (external-trigger trials) or spontaneously without any cue (internal-trigger trials). Many neurons exhibited functional spike activity in association with forelimb movements, and the preference of regular-spiking neurons in the rostral forelimb area was more biased toward externally triggered movement than that in the caudal forelimb area. We found that a population of neuron pairs with spike synchrony does exist, and that some neuron pairs exhibit a dependence on movement phase during task performance. However, the population-wide analysis revealed that spike synchrony was statistically independent of the movement phase and the spike rate-based preferences of the pair for behavioural functions, whereas spike rates were clearly dependent on the movement phase. In fact, mutual information analyses revealed that the contribution of spike synchrony to the behavioural functions was small relative to the contribution of spike rate. Our large-scale analysis revealed that cortical spike rate, rather than spike synchrony, contributes to population coding for movement. © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.

Analysis of Globodera rostochiensis effectors reveals conserved functions of SPRYSEC proteins in suppressing and eliciting plant immune responses

USDA-ARS?s Scientific Manuscript database

Potato cyst nematodes (PCNs), including Globodera rostochiensis (Woll.), are important pests of potato. Plant parasitic nematodes produce multiple effector proteins, secreted from their stylets, to successfully infect their hosts. These include proteins that are delivered to the apoplast, as well as...

Teachers and Students' Conceptions of Computer-Based Models in the Context of High School Chemistry: Elicitations at the Pre-intervention Stage

NASA Astrophysics Data System (ADS)

Waight, Noemi; Gillmeister, Kristina

2014-04-01

This study examined teachers' and students' initial conceptions of computer-based models—Flash and NetLogo models—and documented how teachers and students reconciled notions of multiple representations featuring macroscopic, submicroscopic and symbolic representations prior to actual intervention in eight high school chemistry classrooms. Individual in-depth interviews were conducted with 32 students and 6 teachers. Findings revealed an interplay of complex factors that functioned as opportunities and obstacles in the implementation of technologies in science classrooms. Students revealed preferences for the Flash models as opposed to the open-ended NetLogo models. Altogether, due to lack of content and modeling background knowledge, students experienced difficulties articulating coherent and blended understandings of multiple representations. Concurrently, while the aesthetic and interactive features of the models were of great value, they did not sustain students' initial curiosity and opportunities to improve understandings about chemistry phenomena. Most teachers recognized direct alignment of the Flash model with their existing curriculum; however, the benefits were relegated to existing procedural and passive classroom practices. The findings have implications for pedagogical approaches that address the implementation of computer-based models, function of models, models as multiple representations and the role of background knowledge and cognitive load, and the role of teacher vision and classroom practices.

Epithelial Integrity Is Maintained by a Matriptase-Dependent Proteolytic Pathway

PubMed Central

List, Karin; Kosa, Peter; Szabo, Roman; Bey, Alexandra L.; Wang, Chao Becky; Molinolo, Alfredo; Bugge, Thomas H.

2009-01-01

A pericellular proteolytic pathway initiated by the transmembrane serine protease matriptase plays a critical role in the terminal differentiation of epidermal tissues. Matriptase is constitutively expressed in multiple other epithelia, suggesting a putative role of this membrane serine protease in general epithelial homeostasis. Here we generated mice with conditional deletion of the St14 gene, encoding matriptase, and show that matriptase indeed is essential for the maintenance of multiple types of epithelia in the mouse. Thus, embryonic or postnatal ablation of St14 in epithelial tissues of diverse origin and function caused severe organ dysfunction, which was often associated with increased permeability, loss of tight junction function, mislocation of tight junction-associated proteins, and generalized epithelial demise. The study reveals that the homeostasis of multiple simple and stratified epithelia is matriptase-dependent, and provides an important animal model for the exploration of this membrane serine protease in a range of physiological and pathological processes. PMID:19717635

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.

Functional dissociations between four basic arithmetic operations in the human posterior parietal cortex: A cytoarchitectonic mapping study

PubMed Central

Rosenberg-Lee, Miriam; Chang, Ting Ting; Young, Christina B; Wu, Sarah; Menon, Vinod

2011-01-01

Although lesion studies over the past several decades have focused on functional dissociations in posterior parietal cortex (PPC) during arithmetic, no consistent view has emerged of its differential involvement in addition, subtraction, multiplication, and division. To circumvent problems with poor anatomical localization, we examined functional overlap and dissociations in cytoarchitectonically-defined subdivisions of the intraparietal sulcus (IPS), superior parietal lobule (SPL) and angular gyrus (AG), across these four operations. Compared to a number identification control task, all operations except addition, showed a consistent profile of left posterior IPS activation and deactivation in the right posterior AG. Multiplication and subtraction differed significantly in right, but not left, IPS and AG activity, challenging the view that the left AG differentially subserves retrieval during multiplication. Although addition and multiplication both rely on retrieval, multiplication evoked significantly greater activation in right posterior IPS, as well as the prefrontal cortex, lingual and fusiform gyri, demonstrating that addition and multiplication engage different brain processes. Comparison of PPC responses to the two pairs of inverse operations: division vs. multiplication and subtraction vs. addition revealed greater activation of left lateral SPL during division, suggesting that processing inverse relations is operation specific. Our findings demonstrate that individual IPS, SPL and AG subdivisions are differentially modulated by the four arithmetic operations and they point to significant functional heterogeneity and individual differences in activation and deactivation within the PPC. Critically, these effects are related to retrieval, calculation and inversion, the three key cognitive processes that are differentially engaged by arithmetic operations. Our findings point to distributed representation of these processes in the human PPC and also help explain why lesion and previous imaging studies have yielded inconsistent findings. PMID:21616086

Functional dissociations between four basic arithmetic operations in the human posterior parietal cortex: a cytoarchitectonic mapping study.

PubMed

Rosenberg-Lee, Miriam; Chang, Ting Ting; Young, Christina B; Wu, Sarah; Menon, Vinod

2011-07-01

Although lesion studies over the past several decades have focused on functional dissociations in posterior parietal cortex (PPC) during arithmetic, no consistent view has emerged of its differential involvement in addition, subtraction, multiplication, and division. To circumvent problems with poor anatomical localization, we examined functional overlap and dissociations in cytoarchitectonically defined subdivisions of the intraparietal sulcus (IPS), superior parietal lobule (SPL) and angular gyrus (AG), across these four operations. Compared to a number identification control task, all operations except addition, showed a consistent profile of left posterior IPS activation and deactivation in the right posterior AG. Multiplication and subtraction differed significantly in right, but not left, IPS and AG activity, challenging the view that the left AG differentially subserves retrieval during multiplication. Although addition and multiplication both rely on retrieval, multiplication evoked significantly greater activation in right posterior IPS, as well as the prefrontal cortex, lingual and fusiform gyri, demonstrating that addition and multiplication engage different brain processes. Comparison of PPC responses to the two pairs of inverse operations: division versus multiplication and subtraction versus addition revealed greater activation of left lateral SPL during division, suggesting that processing inverse relations is operation specific. Our findings demonstrate that individual IPS, SPL and AG subdivisions are differentially modulated by the four arithmetic operations and they point to significant functional heterogeneity and individual differences in activation and deactivation within the PPC. Critically, these effects are related to retrieval, calculation and inversion, the three key cognitive processes that are differentially engaged by arithmetic operations. Our findings point to distribute representation of these processes in the human PPC and also help explain why lesion and previous imaging studies have yielded inconsistent findings. Copyright © 2011 Elsevier Ltd. All rights reserved.

Olfactory function in chemical workers exposed to acrylate and methacrylate vapors.

PubMed Central

Schwartz, B S; Doty, R L; Monroe, C; Frye, R; Barker, S

1989-01-01

An investigation of the olfactory function of 731 workers at a chemical facility which manufacturers acrylates and methacrylates was undertaken using a standardized quantitative test. In a cross-sectional analysis of the data, no associations of chemical exposure with olfactory test scores were observed. A nested case-control study designed to evaluate the cumulative effects of exposure on olfactory function, however, revealed elevated crude exposure odds ratios (95% confidence interval) of 2.0 (1.1, 3.8) for all workers and 6.0 (1.7, 21.5) for workers who never smoked cigarettes. Logistic regression analysis, adjusting for multiple confounders, revealed exposure odds ratios of 2.8 (1.1, 7.0) and 13.5 (2.1, 87.6) in these same groups, respectively, and a dose-response relationship between olfactory dysfunction and cumulative exposure scores--semi-quantitative indices of lifetime exposure to the acrylates. The data also revealed decreasing exposure odds ratios with increasing duration since last exposure to these chemicals, suggesting that the effects may be reversible. PMID:2784947

LncRNA-HIT Functions as an Epigenetic Regulator of Chondrogenesis through Its Recruitment of p100/CBP Complexes.

PubMed

Carlson, Hanqian L; Quinn, Jeffrey J; Yang, Yul W; Thornburg, Chelsea K; Chang, Howard Y; Stadler, H Scott

2015-12-01

Gene expression profiling in E 11 mouse embryos identified high expression of the long noncoding RNA (lncRNA), LNCRNA-HIT in the undifferentiated limb mesenchyme, gut, and developing genital tubercle. In the limb mesenchyme, LncRNA-HIT was found to be retained in the nucleus, forming a complex with p100 and CBP. Analysis of the genome-wide distribution of LncRNA-HIT-p100/CBP complexes by ChIRP-seq revealed LncRNA-HIT associated peaks at multiple loci in the murine genome. Ontological analysis of the genes contacted by LncRNA-HIT-p100/CBP complexes indicate a primary role for these loci in chondrogenic differentiation. Functional analysis using siRNA-mediated reductions in LncRNA-HIT or p100 transcripts revealed a significant decrease in expression of many of the LncRNA-HIT-associated loci. LncRNA-HIT siRNA treatments also impacted the ability of the limb mesenchyme to form cartilage, reducing mesenchymal cell condensation and the formation of cartilage nodules. Mechanistically the LncRNA-HIT siRNA treatments impacted pro-chondrogenic gene expression by reducing H3K27ac or p100 activity, confirming that LncRNA-HIT is essential for chondrogenic differentiation in the limb mesenchyme. Taken together, these findings reveal a fundamental epigenetic mechanism functioning during early limb development, using LncRNA-HIT and its associated proteins to promote the expression of multiple genes whose products are necessary for the formation of cartilage.

LncRNA-HIT Functions as an Epigenetic Regulator of Chondrogenesis through Its Recruitment of p100/CBP Complexes

PubMed Central

Carlson, Hanqian L.; Quinn, Jeffrey J.; Yang, Yul W.; Thornburg, Chelsea K.; Chang, Howard Y.; Stadler, H. Scott

2015-01-01

Gene expression profiling in E 11 mouse embryos identified high expression of the long noncoding RNA (lncRNA), LNCRNA-HIT in the undifferentiated limb mesenchyme, gut, and developing genital tubercle. In the limb mesenchyme, LncRNA-HIT was found to be retained in the nucleus, forming a complex with p100 and CBP. Analysis of the genome-wide distribution of LncRNA-HIT-p100/CBP complexes by ChIRP-seq revealed LncRNA-HIT associated peaks at multiple loci in the murine genome. Ontological analysis of the genes contacted by LncRNA-HIT-p100/CBP complexes indicate a primary role for these loci in chondrogenic differentiation. Functional analysis using siRNA-mediated reductions in LncRNA-HIT or p100 transcripts revealed a significant decrease in expression of many of the LncRNA-HIT-associated loci. LncRNA-HIT siRNA treatments also impacted the ability of the limb mesenchyme to form cartilage, reducing mesenchymal cell condensation and the formation of cartilage nodules. Mechanistically the LncRNA-HIT siRNA treatments impacted pro-chondrogenic gene expression by reducing H3K27ac or p100 activity, confirming that LncRNA-HIT is essential for chondrogenic differentiation in the limb mesenchyme. Taken together, these findings reveal a fundamental epigenetic mechanism functioning during early limb development, using LncRNA-HIT and its associated proteins to promote the expression of multiple genes whose products are necessary for the formation of cartilage. PMID:26633036

A Prototype System for Retrieval of Gene Functional Information

PubMed Central

Folk, Lillian C.; Patrick, Timothy B.; Pattison, James S.; Wolfinger, Russell D.; Mitchell, Joyce A.

2003-01-01

Microarrays allow researchers to gather data about the expression patterns of thousands of genes simultaneously. Statistical analysis can reveal which genes show statistically significant results. Making biological sense of those results requires the retrieval of functional information about the genes thus identified, typically a manual gene-by-gene retrieval of information from various on-line databases. For experiments generating thousands of genes of interest, retrieval of functional information can become a significant bottleneck. To address this issue, we are currently developing a prototype system to automate the process of retrieval of functional information from multiple on-line sources. PMID:14728346

Diamond surface functionalization with biomimicry - Amine surface tether and thiol moiety for electrochemical sensors

NASA Astrophysics Data System (ADS)

Sund, James B.; Causey, Corey P.; Wolter, Scott D.; Parker, Charles B.; Stoner, Brian R.; Toone, Eric J.; Glass, Jeffrey T.

2014-05-01

The surface of conducting diamond was functionalized with a terminal thiol group that is capable of binding and detecting nitrogen-oxygen species. The functionalization process employed multiple steps starting with doped diamond films grown by plasma enhanced chemical vapor deposition followed by hydrogen termination and photochemical attachment of a chemically protected amine alkene. The surface tether was deprotected to reveal the amine functionality, which enabled the tether to be extended with surface chemistry to add a terminal thiol moiety for electrochemical sensing applications. Each step of the process was validated using X-ray photoelectron spectroscopy analysis.

Use of a Drosophila Genome-Wide Conserved Sequence Database to Identify Functionally Related cis-Regulatory Enhancers

PubMed Central

Brody, Thomas; Yavatkar, Amarendra S; Kuzin, Alexander; Kundu, Mukta; Tyson, Leonard J; Ross, Jermaine; Lin, Tzu-Yang; Lee, Chi-Hon; Awasaki, Takeshi; Lee, Tzumin; Odenwald, Ward F

2012-01-01

Background: Phylogenetic footprinting has revealed that cis-regulatory enhancers consist of conserved DNA sequence clusters (CSCs). Currently, there is no systematic approach for enhancer discovery and analysis that takes full-advantage of the sequence information within enhancer CSCs. Results: We have generated a Drosophila genome-wide database of conserved DNA consisting of >100,000 CSCs derived from EvoPrints spanning over 90% of the genome. cis-Decoder database search and alignment algorithms enable the discovery of functionally related enhancers. The program first identifies conserved repeat elements within an input enhancer and then searches the database for CSCs that score highly against the input CSC. Scoring is based on shared repeats as well as uniquely shared matches, and includes measures of the balance of shared elements, a diagnostic that has proven to be useful in predicting cis-regulatory function. To demonstrate the utility of these tools, a temporally-restricted CNS neuroblast enhancer was used to identify other functionally related enhancers and analyze their structural organization. Conclusions: cis-Decoder reveals that co-regulating enhancers consist of combinations of overlapping shared sequence elements, providing insights into the mode of integration of multiple regulating transcription factors. The database and accompanying algorithms should prove useful in the discovery and analysis of enhancers involved in any developmental process. Developmental Dynamics 241:169–189, 2012. © 2011 Wiley Periodicals, Inc. Key findings A genome-wide catalog of Drosophila conserved DNA sequence clusters. cis-Decoder discovers functionally related enhancers. Functionally related enhancers share balanced sequence element copy numbers. Many enhancers function during multiple phases of development. PMID:22174086

What have we learned about GPER function in physiology and disease from knockout mice?

PubMed Central

Prossnitz, Eric R.; Hathaway, Helen J.

2015-01-01

Estrogens, predominantly 17β-estradiol, exert diverse effects throughout the body in both normal and patho-physiology, during development and in reproductive, metabolic, endocrine, cardiovascular, nervous, musculoskeletal and immune systems. Estrogen and its receptors also play important roles in carcinogenesis and therapy, particularly for breast cancer. In addition to the classical nuclear estrogen receptors (ERα and ERβ) that traditionally mediate predominantly genomic signaling, the G protein-coupled estrogen receptor GPER has become recognized as a critical mediator of rapid signaling in response to estrogen. Mouse models, and in particular knockout (KO) mice, represent an important approach to understand the functions of receptors in normal physiology and disease. Whereas ERα KO mice display multiple significant defects in reproduction and mammary gland development, ERβ KO phenotypes are more limited, and GPER KO exhibit no reproductive deficits. However, the study of GPER KO mice over the last six years has revealed that GPER deficiency results in multiple physiological alterations including obesity, cardiovascular dysfunction, insulin resistance and glucose intolerance. In addition, the lack of estrogen-mediated effects in numerous tissues of GPER KO mice, studied in vivo or ex vivo, including those of the cardiovascular, endocrine, nervous and immune systems, reveals GPER as a genuine mediator of estrogen action. Importantly, GPER KO mice have also revealed roles for GPER in breast carcinogenesis and metastasis. In combination with the supporting effects of GPER-selective ligands and GPER knockdown approaches, GPER KO mice demonstrate the therapeutic potential of targeting GPER activity in diseases as diverse as obesity, diabetes, multiple sclerosis, hypertension, atherosclerosis, myocardial infarction, stroke and cancer. PMID:26189910

Structured association analysis leads to insight into Saccharomyces cerevisiae gene regulation by finding multiple contributing eQTL hotspots associated with functional gene modules.

PubMed

Curtis, Ross E; Kim, Seyoung; Woolford, John L; Xu, Wenjie; Xing, Eric P

2013-03-21

Association analysis using genome-wide expression quantitative trait locus (eQTL) data investigates the effect that genetic variation has on cellular pathways and leads to the discovery of candidate regulators. Traditional analysis of eQTL data via pairwise statistical significance tests or linear regression does not leverage the availability of the structural information of the transcriptome, such as presence of gene networks that reveal correlation and potentially regulatory relationships among the study genes. We employ a new eQTL mapping algorithm, GFlasso, which we have previously developed for sparse structured regression, to reanalyze a genome-wide yeast dataset. GFlasso fully takes into account the dependencies among expression traits to suppress false positives and to enhance the signal/noise ratio. Thus, GFlasso leverages the gene-interaction network to discover the pleiotropic effects of genetic loci that perturb the expression level of multiple (rather than individual) genes, which enables us to gain more power in detecting previously neglected signals that are marginally weak but pleiotropically significant. While eQTL hotspots in yeast have been reported previously as genomic regions controlling multiple genes, our analysis reveals additional novel eQTL hotspots and, more interestingly, uncovers groups of multiple contributing eQTL hotspots that affect the expression level of functional gene modules. To our knowledge, our study is the first to report this type of gene regulation stemming from multiple eQTL hotspots. Additionally, we report the results from in-depth bioinformatics analysis for three groups of these eQTL hotspots: ribosome biogenesis, telomere silencing, and retrotransposon biology. We suggest candidate regulators for the functional gene modules that map to each group of hotspots. Not only do we find that many of these candidate regulators contain mutations in the promoter and coding regions of the genes, in the case of the Ribi group, we provide experimental evidence suggesting that the identified candidates do regulate the target genes predicted by GFlasso. Thus, this structured association analysis of a yeast eQTL dataset via GFlasso, coupled with extensive bioinformatics analysis, discovers a novel regulation pattern between multiple eQTL hotspots and functional gene modules. Furthermore, this analysis demonstrates the potential of GFlasso as a powerful computational tool for eQTL studies that exploit the rich structural information among expression traits due to correlation, regulation, or other forms of biological dependencies.

Comprehensive molecular profiling of 718 Multiple Myelomas reveals significant differences in mutation frequencies between African and European descent cases

PubMed Central

Christofferson, Austin; Aldrich, Jessica; Jewell, Scott; Kittles, Rick A.; Derome, Mary; Craig, David Wesley; Carpten, John D.

2017-01-01

Multiple Myeloma (MM) is a plasma cell malignancy with significantly greater incidence and mortality rates among African Americans (AA) compared to Caucasians (CA). The overall goal of this study is to elucidate differences in molecular alterations in MM as a function of self-reported race and genetic ancestry. Our study utilized somatic whole exome, RNA-sequencing, and correlated clinical data from 718 MM patients from the Multiple Myeloma Research Foundation CoMMpass study Interim Analysis 9. Somatic mutational analyses based upon self-reported race corrected for ancestry revealed significant differences in mutation frequency between groups. Of interest, BCL7A, BRWD3, and AUTS2 demonstrate significantly higher mutation frequencies among AA cases. These genes are all involved in translocations in B-cell malignancies. Moreover, we detected a significant difference in mutation frequency of TP53 and IRF4 with frequencies higher among CA cases. Our study provides rationale for interrogating diverse tumor cohorts to best understand tumor genomics across populations. PMID:29166413

Methamphetamine Exposure, Iron Deficiency, and Implications for Cognitive-Communicative Function: A Case Study

ERIC Educational Resources Information Center

Goldberg, Lynette R.; Heiss, Cynthia J.; White, Letitia; Kaf, Wafaa A.; Becker, Alan; Schindler, Jessica B.; Dion, Nancy; Oswalt, Jill

2010-01-01

Methamphetamine (meth) exposure during fetal development has the potential to adversely affect the development of multiple organ systems. An interdisciplinary case study of a 4-year 11-month-old child born to a mother addicted to meth revealed significant cognitive and communicative delays. Possible meth-related consequences for these delays…

Multiple loss-of-function 5-O-Glucosyltransferase alleles revealed in Vitis vinifera, but not in other Vitis species

USDA-ARS?s Scientific Manuscript database

Anthocyanins in red grapes (Vitis genus) are important components of wine and beneficial to human health. These antioxidant compounds are present in two glycosylation states: monoglucoside (3-O-glucoside) and diglucoside (3, 5-di-O-glucoside). While monoglucoside anthocyanins are present in all pigm...

Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: Implications for therapy

PubMed Central

Tovar, Christian; Rosinski, James; Filipovic, Zoran; Higgins, Brian; Kolinsky, Kenneth; Hilton, Holly; Zhao, Xiaolan; Vu, Binh T.; Qing, Weiguo; Packman, Kathryn; Myklebost, Ola; Heimbrook, David C.; Vassilev, Lyubomir T.

2006-01-01

The p53 tumor suppressor retains its wild-type conformation and transcriptional activity in half of all human tumors, and its activation may offer a therapeutic benefit. However, p53 function could be compromised by defective signaling in the p53 pathway. Using a small-molecule MDM2 antagonist, nutlin-3, to probe downstream p53 signaling we find that the cell-cycle arrest function of the p53 pathway is preserved in multiple tumor-derived cell lines expressing wild-type p53, but many have a reduced ability to undergo p53-dependent apoptosis. Gene array analysis revealed attenuated expression of multiple apoptosis-related genes. Cancer cells with mdm2 gene amplification were most sensitive to nutlin-3 in vitro and in vivo, suggesting that MDM2 overexpression may be the only abnormality in the p53 pathway of these cells. Nutlin-3 also showed good efficacy against tumors with normal MDM2 expression, suggesting that many of the patients with wild-type p53 tumors may benefit from antagonists of the p53–MDM2 interaction. PMID:16443686

The Neuropeptide Tac2 Controls a Distributed Brain State Induced by Chronic Social Isolation Stress.

PubMed

Zelikowsky, Moriel; Hui, May; Karigo, Tomomi; Choe, Andrea; Yang, Bin; Blanco, Mario R; Beadle, Keith; Gradinaru, Viviana; Deverman, Benjamin E; Anderson, David J

2018-05-17

Chronic social isolation causes severe psychological effects in humans, but their neural bases remain poorly understood. 2 weeks (but not 24 hr) of social isolation stress (SIS) caused multiple behavioral changes in mice and induced brain-wide upregulation of the neuropeptide tachykinin 2 (Tac2)/neurokinin B (NkB). Systemic administration of an Nk3R antagonist prevented virtually all of the behavioral effects of chronic SIS. Conversely, enhancing NkB expression and release phenocopied SIS in group-housed mice, promoting aggression and converting stimulus-locked defensive behaviors to persistent responses. Multiplexed analysis of Tac2/NkB function in multiple brain areas revealed dissociable, region-specific requirements for both the peptide and its receptor in different SIS-induced behavioral changes. Thus, Tac2 coordinates a pleiotropic brain state caused by SIS via a distributed mode of action. These data reveal the profound effects of prolonged social isolation on brain chemistry and function and suggest potential new therapeutic applications for Nk3R antagonists. Copyright © 2018 Elsevier Inc. All rights reserved.

Motor imagery learning modulates functional connectivity of multiple brain systems in resting state.

PubMed

Zhang, Hang; Long, Zhiying; Ge, Ruiyang; Xu, Lele; Jin, Zhen; Yao, Li; Liu, Yijun

2014-01-01

Learning motor skills involves subsequent modulation of resting-state functional connectivity in the sensory-motor system. This idea was mostly derived from the investigations on motor execution learning which mainly recruits the processing of sensory-motor information. Behavioral evidences demonstrated that motor skills in our daily lives could be learned through imagery procedures. However, it remains unclear whether the modulation of resting-state functional connectivity also exists in the sensory-motor system after motor imagery learning. We performed a fMRI investigation on motor imagery learning from resting state. Based on previous studies, we identified eight sensory and cognitive resting-state networks (RSNs) corresponding to the brain systems and further explored the functional connectivity of these RSNs through the assessments, connectivity and network strengths before and after the two-week consecutive learning. Two intriguing results were revealed: (1) The sensory RSNs, specifically sensory-motor and lateral visual networks exhibited greater connectivity strengths in precuneus and fusiform gyrus after learning; (2) Decreased network strength induced by learning was proved in the default mode network, a cognitive RSN. These results indicated that resting-state functional connectivity could be modulated by motor imagery learning in multiple brain systems, and such modulation displayed in the sensory-motor, visual and default brain systems may be associated with the establishment of motor schema and the regulation of introspective thought. These findings further revealed the neural substrates underlying motor skill learning and potentially provided new insights into the therapeutic benefits of motor imagery learning.

Comprehensive Analysis of Interaction Networks of Telomerase Reverse Transcriptase with Multiple Bioinformatic Approaches: Deep Mining the Potential Functions of Telomere and Telomerase.

PubMed

Hou, Chunyu; Wang, Fei; Liu, Xuewen; Chang, Guangming; Wang, Feng; Geng, Xin

2017-08-01

Telomerase reverse transcriptase (TERT) is the protein component of telomerase complex. Evidence has accumulated showing that the nontelomeric functions of TERT are independent of telomere elongation. However, the mechanisms governing the interaction between TERT and its target genes are not clearly revealed. The biological functions of TERT are not fully elucidated and have thus far been underestimated. To further explore these functions, we investigated TERT interaction networks using multiple bioinformatic databases, including BioGRID, STRING, DAVID, GeneCards, GeneMANIA, PANTHER, miRWalk, mirTarBase, miRNet, miRDB, and TargetScan. In addition, network diagrams were built using Cytoscape software. As competing endogenous RNAs (ceRNAs) are endogenous transcripts that compete for the binding of microRNAs (miRNAs) by using shared miRNA recognition elements, they are involved in creating widespread regulatory networks. Therefore, the ceRNA regulatory networks of TERT were also investigated in this study. Interestingly, we found that the three genes PABPC1, SLC7A11, and TP53 were present in both TERT interaction networks and ceRNAs target genes. It was predicted that TERT might play nontelomeric roles in the generation or development of some rare diseases, such as Rift Valley fever and dyscalculia. Thus, our data will help to decipher the interaction networks of TERT and reveal the unknown functions of telomerase in cancer and aging-related diseases.

Rotor Noise due to Blade-Turbulence Interaction.

NASA Astrophysics Data System (ADS)

Ishimaru, Kiyoto

The time-averaged intensity density function of the acoustic radiation from rotating blades is derived by replacing blades with rotating dipoles. This derivation is done under the following turbulent inflow conditions: turbulent ingestion with no inlet strut wakes, inflow turbulence elongation and contraction with no inlet strut wakes, and inlet strut wakes. Dimensional analysis reveals two non-dimensional parameters which play important roles in generating the blade-passing frequency tone and its multiples. The elongation and contraction of inflow turbulence has a strong effect on the generation of the blade-passing frequency tone and its multiples. Increasing the number of rotor blades widens the peak at the blade-passing frequency and its multiples. Increasing the rotational speed widens the peak under the condition that the non-dimensional parameter involving the rotational speed is fixed. The number of struts and blades should be chosen so that (the least common multiple of them)(.)(rotational speed) is in the cutoff range of Sears' function, in order to minimize the effect of the mean flow deficit on the time averaged intensity density function. The acoustic intensity density function is not necessarily stationary even if the inflow turbulence is homogeneous and isotropic. The time variation of the propagation path due to the rotation should be considered in the computation of the intensity density function; for instance, in the present rotor specification, the rotor radius is about 0.3 m and the rotational speed Mach number is about 0.2.

Comparative limb proportions reveal differential locomotor morphofunctions of alligatoroids and crocodyloids

NASA Astrophysics Data System (ADS)

Iijima, Masaya; Kubo, Tai; Kobayashi, Yoshitsugu

2018-03-01

Although two major clades of crocodylians (Alligatoroidea and Crocodyloidea) were split during the Cretaceous period, relatively few morphological and functional differences between them have been known. In addition, interaction of multiple morphofunctional systems that differentiated their ecology has barely been assessed. In this study, we examined the limb proportions of crocodylians to infer the differences of locomotor functions between alligatoroids and crocodyloids, and tested the correlation of locomotor and feeding morphofunctions. Our analyses revealed crocodyloids including Gavialis have longer stylopodia (humerus and femur) than alligatoroids, indicating that two groups may differ in locomotor functions. Fossil evidence suggested that alligatoroids have retained short stylopodia since the early stage of their evolution. Furthermore, rostral shape, an indicator of trophic function, is correlated with limb proportions, where slender-snouted piscivorous taxa have relatively long stylopodia and short overall limbs. In combination, trophic and locomotor functions might differently delimit the ecological opportunity of alligatoroids and crocodyloids in the evolution of crocodylians.

Metal-Free Multiple Carbon-Carbon and Carbon-Hydrogen Bond Activations via Charge-Switching Mechanism in Unstrained Diindolylmethanes.

PubMed

Challa, Chandrasekhar; Varughese, Sunil; Suresh, Cherumuttathu H; Lankalapalli, Ravi S

2017-08-18

A transformation of the unstrained phenol substituted 3,3'-diindolylmethanes (DIPMs) to 2,3'-diindolylketones (DIKs) by double C-C single bond cleavage with associated rearrangements, triggered by phenyliodine(III) diacetate (PIDA), is reported. Density functional theory studies reveal a mechanism involving multiple "charge-switching" steps by synergistic involvement of the two indole units with overall low activation energy. The indole 'charge-switching' mechanism in DIPMs was further extended toward synthesis of a natural product motif cyclohepta[b]indole from biaryl appended DIBM.

The use of dwell time cross-correlation functions to study single-ion channel gating kinetics.

PubMed Central

Ball, F G; Kerry, C J; Ramsey, R L; Sansom, M S; Usherwood, P N

1988-01-01

The derivation of cross-correlation functions from single-channel dwell (open and closed) times is described. Simulation of single-channel data for simple gating models, alongside theoretical treatment, is used to demonstrate the relationship of cross-correlation functions to underlying gating mechanisms. It is shown that time irreversibility of gating kinetics may be revealed in cross-correlation functions. Application of cross-correlation function analysis to data derived from the locust muscle glutamate receptor-channel provides evidence for multiple gateway states and time reversibility of gating. A model for the gating of this channel is used to show the effect of omission of brief channel events on cross-correlation functions. PMID:2462924

Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity

PubMed Central

Anastassiadis, Theonie; Deacon, Sean W.; Devarajan, Karthik; Ma, Haiching; Peterson, Jeffrey R.

2011-01-01

Small-molecule protein kinase inhibitors are central tools for elucidating cellular signaling pathways and are promising therapeutic agents. Due to evolutionary conservation of the ATP-binding site, most kinase inhibitors that target this site promiscuously inhibit multiple kinases. Interpretation of experiments utilizing these compounds is confounded by a lack of data on the comprehensive kinase selectivity of most inhibitors. Here we profiled the activity of 178 commercially available kinase inhibitors against a panel of 300 recombinant protein kinases using a functional assay. Quantitative analysis revealed complex and often unexpected kinase-inhibitor interactions, with a wide spectrum of promiscuity. Many off-target interactions occur with seemingly unrelated kinases, revealing how large-scale profiling can be used to identify multi-targeted inhibitors of specific, diverse kinases. The results have significant implications for drug development and provide a resource for selecting compounds to elucidate kinase function and for interpreting the results of experiments that use them. PMID:22037377

Inference of Low and High-Grade Glioma Gene Regulatory Networks Delineates the Role of Rnd3 in Establishing Multiple Hallmarks of Cancer

PubMed Central

Turan, Nil; Soulet, Fabienne; Mohd Zahari, Maihafizah; Ryan, Katie R.; Durant, Sarah; He, Shan; Herbert, John; Ankers, John; Heath, John K.; Bjerkvig, Rolf; Bicknell, Roy; Hotchin, Neil A.; Bikfalvi, Andreas; Falciani, Francesco

2015-01-01

Gliomas are a highly heterogeneous group of brain tumours that are refractory to treatment, highly invasive and pro-angiogenic. Glioblastoma patients have an average survival time of less than 15 months. Understanding the molecular basis of different grades of glioma, from well differentiated, low-grade tumours to high-grade tumours, is a key step in defining new therapeutic targets. Here we use a data-driven approach to learn the structure of gene regulatory networks from observational data and use the resulting models to formulate hypothesis on the molecular determinants of glioma stage. Remarkably, integration of available knowledge with functional genomics datasets representing clinical and pre-clinical studies reveals important properties within the regulatory circuits controlling low and high-grade glioma. Our analyses first show that low and high-grade gliomas are characterised by a switch in activity of two subsets of Rho GTPases. The first one is involved in maintaining normal glial cell function, while the second is linked to the establishment of multiple hallmarks of cancer. Next, the development and application of a novel data integration methodology reveals novel functions of RND3 in controlling glioma cell migration, invasion, proliferation, angiogenesis and clinical outcome. PMID:26132659

Integrative analysis of signaling pathways and diseases associated with the miR-106b/25 cluster and their function study in berberine-induced multiple myeloma cells.

PubMed

Gu, Chunming; Li, Tianfu; Yin, Zhao; Chen, Shengting; Fei, Jia; Shen, Jianping; Zhang, Yuan

2017-05-01

Berberine (BBR), a traditional Chinese herbal medicine compound, has emerged as a novel class of anti-tumor agent. Our previous microRNA (miRNA) microarray demonstrated that miR-106b/25 was significantly down-regulated in BBR-treated multiple myeloma (MM) cells. Here, systematic integration showed that miR-106b/25 cluster is involved in multiple cancer-related signaling pathways and tumorigenesis. MiREnvironment database revealed that multiple environmental factors (drug, ionizing radiation, hypoxia) affected the miR-106b/25 cluster expression. By targeting the seed region in the miRNA, tiny anti-mir106b/25 cluster (t-anti-mir106b/25 cluster) significantly induced suppression in cell viability and colony formation. Western blot validated that t-anti-miR-106b/25 cluster effectively inhibited the expression of P38 MAPK and phospho-P38 MAPK in MM cells. These findings indicated the miR-106b/25 cluster functioned as oncogene and might provide a novel molecular insight into MM.

Amino acid positions subject to multiple coevolutionary constraints can be robustly identified by their eigenvector network centrality scores.

PubMed

Parente, Daniel J; Ray, J Christian J; Swint-Kruse, Liskin

2015-12-01

As proteins evolve, amino acid positions key to protein structure or function are subject to mutational constraints. These positions can be detected by analyzing sequence families for amino acid conservation or for coevolution between pairs of positions. Coevolutionary scores are usually rank-ordered and thresholded to reveal the top pairwise scores, but they also can be treated as weighted networks. Here, we used network analyses to bypass a major complication of coevolution studies: For a given sequence alignment, alternative algorithms usually identify different, top pairwise scores. We reconciled results from five commonly-used, mathematically divergent algorithms (ELSC, McBASC, OMES, SCA, and ZNMI), using the LacI/GalR and 1,6-bisphosphate aldolase protein families as models. Calculations used unthresholded coevolution scores from which column-specific properties such as sequence entropy and random noise were subtracted; "central" positions were identified by calculating various network centrality scores. When compared among algorithms, network centrality methods, particularly eigenvector centrality, showed markedly better agreement than comparisons of the top pairwise scores. Positions with large centrality scores occurred at key structural locations and/or were functionally sensitive to mutations. Further, the top central positions often differed from those with top pairwise coevolution scores: instead of a few strong scores, central positions often had multiple, moderate scores. We conclude that eigenvector centrality calculations reveal a robust evolutionary pattern of constraints-detectable by divergent algorithms--that occur at key protein locations. Finally, we discuss the fact that multiple patterns coexist in evolutionary data that, together, give rise to emergent protein functions. © 2015 Wiley Periodicals, Inc.

Mathematics of gravitational lensing: multiple imaging and magnification

NASA Astrophysics Data System (ADS)

Petters, A. O.; Werner, M. C.

2010-09-01

The mathematical theory of gravitational lensing has revealed many generic and global properties. Beginning with multiple imaging, we review Morse-theoretic image counting formulas and lower bound results, and complex-algebraic upper bounds in the case of single and multiple lens planes. We discuss recent advances in the mathematics of stochastic lensing, discussing a general formula for the global expected number of minimum lensed images as well as asymptotic formulas for the probability densities of the microlensing random time delay functions, random lensing maps, and random shear, and an asymptotic expression for the global expected number of micro-minima. Multiple imaging in optical geometry and a spacetime setting are treated. We review global magnification relation results for model-dependent scenarios and cover recent developments on universal local magnification relations for higher order caustics.

Integrated optics to improve resolution on multiple configuration

NASA Astrophysics Data System (ADS)

Liu, Hua; Ding, Quanxin; Guo, Chunjie; Zhou, Liwei

2015-04-01

Inspired to in order to reveal the structure to improve imaging resolution, further technical requirement is proposed in some areas of the function and influence on the development of multiple configuration. To breakthrough diffraction limit, smart structures are recommended as the most efficient and economical method, while by used to improve the system performance, especially on signal to noise ratio and resolution. Integrated optics were considered in the selection, with which typical multiple configuration, by use the method of simulation experiment. Methodology can change traditional design concept and to develop the application space. Our calculations using multiple matrix transfer method, also the correlative algorithm and full calculations, show the expected beam shaping through system and, in particular, the experimental results will support our argument, which will be reported in the presentation.

Phosphorylation-dependent cleavage regulates von Hippel Lindau proteostasis and function

PubMed Central

German, Peter; Bai, Shanshan; Liu, Xian-De; Sun, Mianen; Zhou, Lijun; Kalra, Sarathi; Zhang, Xuesong; Minelli, Rosalba; Scott, Kenneth L.; Mills, Gordon B.; Jonasch, Eric; Ding, Zhiyong

2016-01-01

Loss of von Hippel Lindau (VHL) protein function is a key driver of VHL diseases, including sporadic and inherited clear cell renal cell carcinoma. Modulation of the proteostasis of VHL, especially missense point-mutated VHL, is a promising approach to augmenting VHL levels and function. VHL proteostasis is regulated by multiple mechanisms including folding, chaperone binding, complex formation, and phosphorylation. Nevertheless, many details underlying the regulations of VHL proteostasis are unknown. VHL is expressed as two variants, VHL30 and VHL19. Furthermore, the long form variant of VHL was often detected as multiple bands by Western blotting. However, how these multiple species of VHL are generated and whether the process regulates VHL proteostasis and function are unknown. We hypothesized that the two major species are generated by VHL protein cleavage, and the cleavage regulates VHL proteostasis and subsequent function. We characterized VHL species using genetic and pharmacologic approaches and showed that VHL was first cleaved at the N-terminus by chymotrypsin C before being directed for proteasomal degradation. Casein kinase 2-mediated phosphorylation at VHL N-terminus was required for the cleavage. Furthermore, inhibition of cleavage stabilized VHL protein, thereby promoting HIF downregulation. Our study reveals a novel mechanism regulating VHL proteostasis and function, which is significant for identifying new drug targets and developing new therapeutic approaches targeting VHL deficiency in VHL diseases. PMID:26973240

Influence of Disruptive Behavior Disorders on Academic Performance and School Functions of Youths with Attention-Deficit/Hyperactivity Disorder.

PubMed

Liu, Chao-Yu; Huang, Wei-Lieh; Kao, Wei-Chih; Gau, Susan Shur-Fen

2017-12-01

Childhood attention-deficit/hyperactivity disorder (ADHD) and comorbid oppositional defiant disorder/conduct disorder (ODD/CD) are associated with negative school outcomes. The study aimed to examine the impact of ADHD and ODD/CD on various school functions. 395 youths with ADHD (244 with ADHD + ODD/CD and 151 with ADHD only) and 156 controls received semi-structured psychiatric interviews. School functions were assessed and compared between each group with a multiple-level model. The results showed that youths with ADHD had poorer performance across different domains of school functioning. Youths with ADHD + ODD/CD had more behavioral problems but similar academic performance than those with ADHD only. The multiple linear regression models revealed that ADHD impaired academic performance while ODD/CD aggravated behavioral problems. Our findings imply that comorbid ODD/CD may specifically contribute to social difficulties in youths with ADHD. Measures of early detection and intervention for ODD/CD should be conducted to prevent adverse outcomes.

Selection of multiple umbrella species for functional and taxonomic diversity to represent urban biodiversity.

PubMed

Sattler, T; Pezzatti, G B; Nobis, M P; Obrist, M K; Roth, T; Moretti, M

2014-04-01

Surrogates, such as umbrella species, are commonly used to reduce the complexity of quantifying biodiversity for conservation purposes. The presence of umbrella species is often indicative of high taxonomic diversity; however, functional diversity is now recognized as an important metric for biodiversity and thus should be considered when choosing umbrella species. We identified umbrella species associated with high taxonomic and functional biodiversity in urban areas in Switzerland. We analyzed 39,752 individuals of 574 animal species from 96 study plots and 1397 presences of 262 plant species from 58 plots. Thirty-one biodiversity measures of 7 taxonomic groups (plants, spiders, bees, ground beetles, lady bugs, weevils and birds) were included in within- and across-taxa analyses. Sixteen measures were taxonomical (species richness and species diversity), whereas 15 were functional (species traits including mobility, resource use, and reproduction). We used indicator value analysis to identify umbrella species associated with single or multiple biodiversity measures. Many umbrella species were indicators of high biodiversity within their own taxonomic group (from 33.3% in weevils to 93.8% in birds), to a lesser extent they were indicators across taxa. Principal component analysis revealed that umbrella species for multiple measures of biodiversity represented different aspects of biodiversity, especially with respect to measures of taxonomic and functional diversity. Thus, even umbrella species for multiple measures of biodiversity were complementary in the biodiversity aspects they represented. Thus, the choice of umbrella species based solely on taxonomic diversity is questionable and may not represent biodiversity comprehensively. Our results suggest that, depending on conservation priorities, managers should choose multiple and complementary umbrella species to assess the state of biodiversity. © 2013 Society for Conservation Biology.

Juxtaposed scripts, traits, and the dynamics of personality.

PubMed

Thorne, A

1995-09-01

Although personality is theoretically composed of multiple facets that function in lively interrelatedness, the interplay among these multiplicities has mostly been missed by research that focuses on traits as the primary unit of personality. The juxtaposition of contrary interpersonal scripts is a promising way to capture dynamic processes of personality. A case study is used to illustrate the dynamic interplay between sociotropic (extraverted) and avoidant scripts. Whereas standard trait measures do not reveal how extraversion and avoidance co-relate in everyday experience, the dynamics are revealed by study of interpersonal scripts in narratives of memorable encounters. Similarities between the present approach and recent dialectical approaches to the self-concept are discussed (Hermans & Kempen, 1993). Such approaches, particularly when articulated so as to interface with more generalized units of personality, can be highly useful for advancing understanding of personality dynamics.

Nitrogen: Unraveling the Secret to Stable Carbon-Supported Pt-Alloy Electrocatalysts

DTIC Science & Technology

2013-10-01

materials reveal broad N1s spectra, indicative of formation of multiple functionalities including but not limited to pyridinic, graphitic and pyrrolic ...network along with nitrogen substitutional defects, while high-dosage increases vacancy agglomerations and pyridinic and pyrrolic nitrogen defects...Article Online highly oriented pyrolytic graphite (HOPG) surface. Simulated defects included pyridinic (Npyridinic), pyrrolic (Npyrrolic), graphitic

Understanding Communities of Neglectful Parents: Child Caregiving Networks and Child Neglect

ERIC Educational Resources Information Center

Roditti, Martha G.

2005-01-01

This article focuses on family social networks and the community of caregivers of neglected children. If neglect is part of family functioning, who watches over the children? Using a case study approach, this study researched 12 children and their parents. Several concepts, such as multiple caregiving and kin keepers, revealed that study children…

Cyber Victimization and Perceived Stress: Linkages to Late Adolescents' Cyber Aggression and Psychological Functioning

ERIC Educational Resources Information Center

Wright, Michelle F.

2015-01-01

The present study examined multiple sources of strain, particular cyber victimization, and perceived stress from parents, peers, and academics, in relation to late adolescents' (ages 16-18; N = 423) cyber aggression, anxiety, and depression, each assessed 1 year later (Time 2). Three-way interactions revealed that the relationship between Time 1…

Evolution of the stellar mass function in multiple-population globular clusters

NASA Astrophysics Data System (ADS)

Vesperini, Enrico; Hong, Jongsuk; Webb, Jeremy J.; D'Antona, Franca; D'Ercole, Annibale

2018-05-01

We present the results of a survey of N-body simulations aimed at studying the effects of the long-term dynamical evolution on the stellar mass function (MF) of multiple stellar populations in globular clusters. Our simulations show that if first-(1G) and second-generation (2G) stars have the same initial MF (IMF), the global MFs of the two populations are affected similarly by dynamical evolution and no significant differences between the 1G and 2G MFs arise during the cluster's evolution. If the two populations have different IMFs, dynamical effects do not completely erase memory of the initial differences. Should observations find differences between the global 1G and 2G MFs, these would reveal the fingerprints of differences in their IMFs. Irrespective of whether the 1G and 2G populations have the same global IMF or not, dynamical effects can produce differences between the local (measured at various distances from the cluster centre) 1G and 2G MFs; these differences are a manifestation of the process of mass segregation in populations with different initial structural properties. In dynamically old and spatially mixed clusters, however, differences between the local 1G and 2G MFs can reveal differences between the 1G and 2G global MFs. In general, for clusters with any dynamical age, large differences between the local 1G and 2G MFs are more likely to be associated with differences in the global MF. Our study also reveals a dependence of the spatial mixing rate on the stellar mass, another dynamical consequence of the multiscale nature of multiple-population clusters.

Gene silencing reveals multiple functions of Na+/K+-ATPase in the salmon louse (Lepeophtheirus salmonis).

PubMed

Komisarczuk, Anna Z; Kongshaug, Heidi; Nilsen, Frank

2018-02-01

Na + /K + -ATPase has a key function in a variety of physiological processes including membrane excitability, osmoregulation, regulation of cell volume, and transport of nutrients. While knowledge about Na + /K + -ATPase function in osmoregulation in crustaceans is extensive, the role of this enzyme in other physiological and developmental processes is scarce. Here, we report characterization, transcriptional distribution and likely functions of the newly identified L. salmonis Na + /K + -ATPase (LsalNa + /K + -ATPase) α subunit in various developmental stages. The complete mRNA sequence was identified, with 3003 bp open reading frame encoding a putative protein of 1001 amino acids. Putative protein sequence of LsalNa + /K + -ATPase revealed all typical features of Na + /K + -ATPase and demonstrated high sequence identity to other invertebrate and vertebrate species. Quantitative RT-PCR analysis revealed higher LsalNa + /K + -ATPase transcript level in free-living stages in comparison to parasitic stages. In situ hybridization analysis of copepodids and adult lice revealed LsalNa + /K + -ATPase transcript localization in a wide variety of tissues such as nervous system, intestine, reproductive system, and subcuticular and glandular tissue. RNAi mediated knock-down of LsalNa + /K + -ATPase caused locomotion impairment, and affected reproduction and feeding. Morphological analysis of dsRNA treated animals revealed muscle degeneration in larval stages, severe changes in the oocyte formation and maturation in females and abnormalities in tegmental glands. Thus, the study represents an important foundation for further functional investigation and identification of physiological pathways in which Na + /K + -ATPase is directly or indirectly involved. Copyright © 2018 Elsevier Inc. All rights reserved.

Imposture, inauthenticity, and feeling fraudulent.

PubMed

Gediman, H K

1985-01-01

This paper deals with imposturous tendencies as ubiquitous and heterogeneous. They may enter into neurotic conflict and compromise, and also reflect an ego function disturbance involving multiple, shifting identities and subsequent problems in the subjective sense of reality of the self and objects. Imposture in a person undergoing analysis is, however, not only a function of individual character and psychopathology; it is also a function of certain inevitable requirements of the analytic situation which constitute a "pull" for its emergence. Vulnerable individuals will respond to this pull in revealing ways. Three case summaries illustrate the spectrum of imposturous tendencies.

Dual role of wingless signaling in stem-like hematopoietic precursor maintenance in Drosophila.

PubMed

Sinenko, Sergey A; Mandal, Lolitika; Martinez-Agosto, Julian A; Banerjee, Utpal

2009-05-01

In Drosophila, blood development occurs in a specialized larval hematopoietic organ, the lymph gland (LG), within which stem-like hemocyte precursors or prohemocytes differentiate to multiple blood cell types. Here we show that components of the Wingless (Wg) signaling pathway are expressed in prohemocytes. Loss- and gain-of-function analysis indicates that canonical Wg signaling is required for maintenance of prohemocytes and negatively regulates their differentiation. Wg signals locally in a short-range fashion within different compartments of the LG. In addition, Wg signaling positively regulates the proliferation and maintenance of cells that function as a hematopoietic niche in Drosophila, the posterior signaling center (PSC), and in the proliferation of crystal cells. Our studies reveal a conserved function of Wg signaling in the maintenance of stem-like blood progenitors and reveal an involvement of this pathway in the regulation of hemocyte differentiation through its action in the hematopoietic niche.

Whole-brain activity maps reveal stereotyped, distributed networks for visuomotor behavior.

PubMed

Portugues, Ruben; Feierstein, Claudia E; Engert, Florian; Orger, Michael B

2014-03-19

Most behaviors, even simple innate reflexes, are mediated by circuits of neurons spanning areas throughout the brain. However, in most cases, the distribution and dynamics of firing patterns of these neurons during behavior are not known. We imaged activity, with cellular resolution, throughout the whole brains of zebrafish performing the optokinetic response. We found a sparse, broadly distributed network that has an elaborate but ordered pattern, with a bilaterally symmetrical organization. Activity patterns fell into distinct clusters reflecting sensory and motor processing. By correlating neuronal responses with an array of sensory and motor variables, we find that the network can be clearly divided into distinct functional modules. Comparing aligned data from multiple fish, we find that the spatiotemporal activity dynamics and functional organization are highly stereotyped across individuals. These experiments systematically reveal the functional architecture of neural circuits underlying a sensorimotor behavior in a vertebrate brain. Copyright © 2014 Elsevier Inc. All rights reserved.

Whole-brain activity maps reveal stereotyped, distributed networks for visuomotor behavior

PubMed Central

Portugues, Ruben; Feierstein, Claudia E.; Engert, Florian; Orger, Michael B.

2014-01-01

Summary Most behaviors, even simple innate reflexes, are mediated by circuits of neurons spanning areas throughout the brain. However, in most cases, the distribution and dynamics of firing patterns of these neurons during behavior are not known. We imaged activity, with cellular resolution, throughout the whole brains of zebrafish performing the optokinetic response. We found a sparse, broadly distributed network that has an elaborate, but ordered, pattern, with a bilaterally symmetrical organization. Activity patterns fell into distinct clusters reflecting sensory and motor processing. By correlating neuronal responses with an array of sensory and motor variables, we find that the network can be clearly divided into distinct functional modules. Comparing aligned data from multiple fish, we find that the spatiotemporal activity dynamics and functional organization are highly stereotyped across individuals. These experiments reveal, for the first time in a vertebrate, the comprehensive functional architecture of the neural circuits underlying a sensorimotor behavior. PMID:24656252

Functional dynamics of cell surface membrane proteins

NASA Astrophysics Data System (ADS)

Nishida, Noritaka; Osawa, Masanori; Takeuchi, Koh; Imai, Shunsuke; Stampoulis, Pavlos; Kofuku, Yutaka; Ueda, Takumi; Shimada, Ichio

2014-04-01

Cell surface receptors are integral membrane proteins that receive external stimuli, and transmit signals across plasma membranes. In the conventional view of receptor activation, ligand binding to the extracellular side of the receptor induces conformational changes, which convert the structure of the receptor into an active conformation. However, recent NMR studies of cell surface membrane proteins have revealed that their structures are more dynamic than previously envisioned, and they fluctuate between multiple conformations in an equilibrium on various timescales. In addition, NMR analyses, along with biochemical and cell biological experiments indicated that such dynamical properties are critical for the proper functions of the receptors. In this review, we will describe several NMR studies that revealed direct linkage between the structural dynamics and the functions of the cell surface membrane proteins, such as G-protein coupled receptors (GPCRs), ion channels, membrane transporters, and cell adhesion molecules.

Social Function in Multiple X and Y Chromosome Disorders: XXY, XYY, XXYY, XXXY

PubMed Central

Visootsak, Jeannie; Graham, John M.

2014-01-01

Klinefelter syndrome (47,XXY) was initially described in the context of its endocrinologic and physical features; however, subsequent studies have revealed specific impairments in verbal skills and social functioning. Males with sex chromosomal aneuploidies are known to have variability in their developmental profile with the majority presenting with expressive language deficits. As a consequence of language delays, they have an increased likelihood of language-based learning disabilities and social-emotional problems that may persist through adulthood. Studies on males with 47,XXY have revealed unique behavioral and social profiles with possible vulnerability to autistic traits. The prevalence of males with more than one extra sex chromosome (e.g., 48,XXYY and 48,XXXY) and an additional Y (e.g., 47,XYY) is less common, but it is important to understand their social functioning as it provides insight into treatment implications. PMID:20014367

Functional dynamics of cell surface membrane proteins.

PubMed

Nishida, Noritaka; Osawa, Masanori; Takeuchi, Koh; Imai, Shunsuke; Stampoulis, Pavlos; Kofuku, Yutaka; Ueda, Takumi; Shimada, Ichio

2014-04-01

Cell surface receptors are integral membrane proteins that receive external stimuli, and transmit signals across plasma membranes. In the conventional view of receptor activation, ligand binding to the extracellular side of the receptor induces conformational changes, which convert the structure of the receptor into an active conformation. However, recent NMR studies of cell surface membrane proteins have revealed that their structures are more dynamic than previously envisioned, and they fluctuate between multiple conformations in an equilibrium on various timescales. In addition, NMR analyses, along with biochemical and cell biological experiments indicated that such dynamical properties are critical for the proper functions of the receptors. In this review, we will describe several NMR studies that revealed direct linkage between the structural dynamics and the functions of the cell surface membrane proteins, such as G-protein coupled receptors (GPCRs), ion channels, membrane transporters, and cell adhesion molecules. Copyright © 2013 Elsevier Inc. All rights reserved.

Computational gene expression profiling under salt stress reveals patterns of co-expression

PubMed Central

Sanchita; Sharma, Ashok

2016-01-01

Plants respond differently to environmental conditions. Among various abiotic stresses, salt stress is a condition where excess salt in soil causes inhibition of plant growth. To understand the response of plants to the stress conditions, identification of the responsible genes is required. Clustering is a data mining technique used to group the genes with similar expression. The genes of a cluster show similar expression and function. We applied clustering algorithms on gene expression data of Solanum tuberosum showing differential expression in Capsicum annuum under salt stress. The clusters, which were common in multiple algorithms were taken further for analysis. Principal component analysis (PCA) further validated the findings of other cluster algorithms by visualizing their clusters in three-dimensional space. Functional annotation results revealed that most of the genes were involved in stress related responses. Our findings suggest that these algorithms may be helpful in the prediction of the function of co-expressed genes. PMID:26981411

Joint cross-correlation analysis reveals complex, time-dependent functional relationship between cortical neurons and arm electromyograms

PubMed Central

Zhuang, Katie Z.; Lebedev, Mikhail A.

2014-01-01

Correlation between cortical activity and electromyographic (EMG) activity of limb muscles has long been a subject of neurophysiological studies, especially in terms of corticospinal connectivity. Interest in this issue has recently increased due to the development of brain-machine interfaces with output signals that mimic muscle force. For this study, three monkeys were implanted with multielectrode arrays in multiple cortical areas. One monkey performed self-timed touch pad presses, whereas the other two executed arm reaching movements. We analyzed the dynamic relationship between cortical neuronal activity and arm EMGs using a joint cross-correlation (JCC) analysis that evaluated trial-by-trial correlation as a function of time intervals within a trial. JCCs revealed transient correlations between the EMGs of multiple muscles and neural activity in motor, premotor and somatosensory cortical areas. Matching results were obtained using spike-triggered averages corrected by subtracting trial-shuffled data. Compared with spike-triggered averages, JCCs more readily revealed dynamic changes in cortico-EMG correlations. JCCs showed that correlation peaks often sharpened around movement times and broadened during delay intervals. Furthermore, JCC patterns were directionally selective for the arm-reaching task. We propose that such highly dynamic, task-dependent and distributed relationships between cortical activity and EMGs should be taken into consideration for future brain-machine interfaces that generate EMG-like signals. PMID:25210153

From Whole-Brain Data to Functional Circuit Models: The Zebrafish Optomotor Response.

PubMed

Naumann, Eva A; Fitzgerald, James E; Dunn, Timothy W; Rihel, Jason; Sompolinsky, Haim; Engert, Florian

2016-11-03

Detailed descriptions of brain-scale sensorimotor circuits underlying vertebrate behavior remain elusive. Recent advances in zebrafish neuroscience offer new opportunities to dissect such circuits via whole-brain imaging, behavioral analysis, functional perturbations, and network modeling. Here, we harness these tools to generate a brain-scale circuit model of the optomotor response, an orienting behavior evoked by visual motion. We show that such motion is processed by diverse neural response types distributed across multiple brain regions. To transform sensory input into action, these regions sequentially integrate eye- and direction-specific sensory streams, refine representations via interhemispheric inhibition, and demix locomotor instructions to independently drive turning and forward swimming. While experiments revealed many neural response types throughout the brain, modeling identified the dimensions of functional connectivity most critical for the behavior. We thus reveal how distributed neurons collaborate to generate behavior and illustrate a paradigm for distilling functional circuit models from whole-brain data. Copyright © 2016 Elsevier Inc. All rights reserved.

Multiple Multi-Copper Oxidase Gene Families in Basidiomycetes – What for?

PubMed Central

Kües, Ursula; Rühl, Martin

2011-01-01

Genome analyses revealed in various basidiomycetes the existence of multiple genes for blue multi-copper oxidases (MCOs). Whole genomes are now available from saprotrophs, white rot and brown rot species, plant and animal pathogens and ectomycorrhizal species. Total numbers (from 1 to 17) and types of mco genes differ between analyzed species with no easy to recognize connection of gene distribution to fungal life styles. Types of mco genes might be present in one and absent in another fungus. Distinct types of genes have been multiplied at speciation in different organisms. Phylogenetic analysis defined different subfamilies of laccases sensu stricto (specific to Agaricomycetes), classical Fe2+-oxidizing Fet3-like ferroxidases, potential ferroxidases/laccases exhibiting either one or both of these enzymatic functions, enzymes clustering with pigment MCOs and putative ascorbate oxidases. Biochemically best described are laccases sensu stricto due to their proposed roles in degradation of wood, straw and plant litter and due to the large interest in these enzymes in biotechnology. However, biological functions of laccases and other MCOs are generally little addressed. Functions in substrate degradation, symbiontic and pathogenic intercations, development, pigmentation and copper homeostasis have been put forward. Evidences for biological functions are in most instances rather circumstantial by correlations of expression. Multiple factors impede research on biological functions such as difficulties of defining suitable biological systems for molecular research, the broad and overlapping substrate spectrum multi-copper oxidases usually possess, the low existent knowledge on their natural substrates, difficulties imposed by low expression or expression of multiple enzymes, and difficulties in expressing enzymes heterologously. PMID:21966246

Interindividual differences in cognitive flexibility: influence of gray matter volume, functional connectivity and trait impulsivity

PubMed Central

Langner, Robert; Cieslik, Edna C.; Rottschy, Claudia; Eickhoff, Simon B.

2016-01-01

Cognitive flexibility, a core aspect of executive functioning, is required for the speeded shifting between different tasks and sets. Using an interindividual differences approach, we examined whether cognitive flexibility, as assessed by the Delis–Kaplan card-sorting test, is associated with gray matter volume (GMV) and functional connectivity (FC) of regions of a core network of multiple cognitive demands as well as with different facets of trait impulsivity. The core multiple-demand network was derived from three large-scale neuroimaging meta-analyses and only included regions that showed consistent associations with sustained attention, working memory as well as inhibitory control. We tested to what extent self-reported impulsivity as well as GMV and resting-state FC in this core network predicted cognitive flexibility independently and incrementally. Our analyses revealed that card-sorting performance correlated positively with GMV of the right anterior insula, FC between bilateral anterior insula and midcingulate cortex/supplementary motor area as well as the impulsivity dimension “Premeditation.” Importantly, GMV, FC and impulsivity together accounted for more variance of card-sorting performance than every parameter alone. Our results therefore indicate that various factors contribute individually to cognitive flexibility, underlining the need to search across multiple modalities when aiming to unveil the mechanisms behind executive functioning. PMID:24878823

Multiple functional attributes of glucose-monitoring neurons in the medial orbitofrontal (ventrolateral prefrontal) cortex.

PubMed

Szabó, István; Hormay, Edina; Csetényi, Bettina; Nagy, Bernadett; Lénárd, László; Karádi, Zoltán

2018-02-01

Multiple functional attributes of glucose-monitoring neurons in the medial orbitofrontal (ventrolateral prefrontal) cortex. NEUROSCI BIOBEHAV REV 73(1) XXX-XXX, 2017.- Special chemosensory cells, the glucose-monitoring (GM) neurons, reportedly involved in the central feeding control, exist in the medial orbitofrontal (ventrolateral prefrontal) cortex (mVLPFC). Electrophysiological, metabolic and behavioral studies reveal complex functional attributes of these cells and raise their homeostatic significance. Single neuron recordings, by means of the multibarreled microelectrophoretic technique, elucidate differential sensitivities of limbic forebrain neurons in the rat and the rhesus monkey to glucose and other chemicals, whereas gustatory stimulations demonstrate their distinct taste responsiveness. Metabolic examinations provide evidence for alteration of blood glucose level in glucose tolerance test and elevation of plasma triglyceride concentration after destruction of the local GM cells by streptozotocin (STZ). In behavioral studies, STZ microinjection into the mVLPFC fails to interfere with the acquisition of saccharin conditioned taste avoidance, does cause, however, taste perception deficit in taste reactivity tests. Multiple functional attributes of GM neurons in the mVLPFC, within the frame of the hierarchically organized central GM neuronal network, appear to play important role in the maintenance of the homeostatic balance. Copyright © 2017 Elsevier Ltd. All rights reserved.

Motor Imagery Learning Modulates Functional Connectivity of Multiple Brain Systems in Resting State

PubMed Central

Zhang, Hang; Long, Zhiying; Ge, Ruiyang; Xu, Lele; Jin, Zhen; Yao, Li; Liu, Yijun

2014-01-01

Background Learning motor skills involves subsequent modulation of resting-state functional connectivity in the sensory-motor system. This idea was mostly derived from the investigations on motor execution learning which mainly recruits the processing of sensory-motor information. Behavioral evidences demonstrated that motor skills in our daily lives could be learned through imagery procedures. However, it remains unclear whether the modulation of resting-state functional connectivity also exists in the sensory-motor system after motor imagery learning. Methodology/Principal Findings We performed a fMRI investigation on motor imagery learning from resting state. Based on previous studies, we identified eight sensory and cognitive resting-state networks (RSNs) corresponding to the brain systems and further explored the functional connectivity of these RSNs through the assessments, connectivity and network strengths before and after the two-week consecutive learning. Two intriguing results were revealed: (1) The sensory RSNs, specifically sensory-motor and lateral visual networks exhibited greater connectivity strengths in precuneus and fusiform gyrus after learning; (2) Decreased network strength induced by learning was proved in the default mode network, a cognitive RSN. Conclusions/Significance These results indicated that resting-state functional connectivity could be modulated by motor imagery learning in multiple brain systems, and such modulation displayed in the sensory-motor, visual and default brain systems may be associated with the establishment of motor schema and the regulation of introspective thought. These findings further revealed the neural substrates underlying motor skill learning and potentially provided new insights into the therapeutic benefits of motor imagery learning. PMID:24465577

The effects of rehearsal on the functional neuroanatomy of episodic autobiographical and semantic remembering: a functional magnetic resonance imaging study.

PubMed

Svoboda, Eva; Levine, Brian

2009-03-11

This study examined the effects of rehearsal on the neural substrates supporting episodic autobiographical and semantic memory. Stimuli were collected prospectively using audio recordings, thereby bringing under experimental control ecologically valid, naturalistic autobiographical stimuli. Participants documented both autobiographical and semantic stimuli over a period of 6-8 months, followed by a rehearsal manipulation during the 3 d preceding scanning. During functional magnetic resonance imaging scanning, participants were exposed to recordings that they were hearing for the first, second, or eighth time. Rehearsal increased the rated vividness with which information was remembered, particularly for autobiographical events. Neuroimaging findings revealed rehearsal-related suppression of activation in regions supporting episodic autobiographical and semantic memory. Episodic autobiographical and semantic memory produced distinctly different patterns of regional activation that held even after eight repetitions. Region of interest analyses further indicated a functional anatomical dissociation in response to rehearsal and memory conditions. These findings revealed that the hippocampus was specifically engaged by episodic autobiographical memory, whereas both memory conditions engaged the parahippocampal cortex. Our data suggest that, when retrieval cues are potent enough to engage a vivid episodic recollection, the episodic/semantic dissociation within medial temporal lobe structures endure even with multiple stimulus repetitions. These findings support the multiple trace theory, which predicts that the hippocampus is engaged in the retrieval of rich episodic recollection regardless of repeated reactivation such as that occurring with the passage of time.

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

Dispersion of response times reveals cognitive dynamics.

PubMed

Holden, John G; Van Orden, Guy C; Turvey, Michael T

2009-04-01

Trial-to-trial variation in word-pronunciation times exhibits 1/f scaling. One explanation is that human performances are consequent on multiplicative interactions among interdependent processes-interaction dominant dynamics. This article describes simulated distributions of pronunciation times in a further test for multiplicative interactions and interdependence. Individual participant distributions of approximately 1,100 word-pronunciation times were successfully mimicked for each participant in combinations of lognormal and power-law behavior. Successful hazard function simulations generalized these results to establish interaction dominant dynamics, in contrast with component dominant dynamics, as a likely mechanism for cognitive activity. (c) 2009 APA, all rights reserved

Dispersion of Response Times Reveals Cognitive Dynamics

PubMed Central

Holden, John G.; Van Orden, Guy C.; Turvey, Michael T.

2013-01-01

Trial to trial variation in word pronunciation times exhibits 1/f scaling. One explanation is that human performances are consequent on multiplicative interactions among interdependent processes – interaction dominant dynamics. This article describes simulated distributions of pronunciation times in a further test for multiplicative interactions and interdependence. Individual participant distributions of ≈1100 word pronunciation times are successfully mimicked for each participant in combinations of lognormal and power law behavior. Successful hazard function simulations generalize these results to establish interaction dominant dynamics, in contrast with component dominant dynamics, as a likely mechanism for cognitive activity. PMID:19348544

Predicting Human Protein Subcellular Locations by the Ensemble of Multiple Predictors via Protein-Protein Interaction Network with Edge Clustering Coefficients

PubMed Central

Du, Pufeng; Wang, Lusheng

2014-01-01

One of the fundamental tasks in biology is to identify the functions of all proteins to reveal the primary machinery of a cell. Knowledge of the subcellular locations of proteins will provide key hints to reveal their functions and to understand the intricate pathways that regulate biological processes at the cellular level. Protein subcellular location prediction has been extensively studied in the past two decades. A lot of methods have been developed based on protein primary sequences as well as protein-protein interaction network. In this paper, we propose to use the protein-protein interaction network as an infrastructure to integrate existing sequence based predictors. When predicting the subcellular locations of a given protein, not only the protein itself, but also all its interacting partners were considered. Unlike existing methods, our method requires neither the comprehensive knowledge of the protein-protein interaction network nor the experimentally annotated subcellular locations of most proteins in the protein-protein interaction network. Besides, our method can be used as a framework to integrate multiple predictors. Our method achieved 56% on human proteome in absolute-true rate, which is higher than the state-of-the-art methods. PMID:24466278

Community assembly of the ferns of Florida.

PubMed

Sessa, Emily B; Chambers, Sally M; Li, Daijiang; Trotta, Lauren; Endara, Lorena; Burleigh, J Gordon; Baiser, Benjamin

2018-03-01

Many ecological and evolutionary processes shape the assembly of organisms into local communities from a regional pool of species. We analyzed phylogenetic and functional diversity to understand community assembly of the ferns of Florida at two spatial scales. We built a phylogeny for 125 of the 141 species of ferns in Florida using five chloroplast markers. We calculated mean pairwise dissimilarity (MPD) and mean nearest taxon distance (MNTD) from phylogenetic distances and functional trait data for both spatial scales and compared the results to null models to assess significance. Our results for over vs. underdispersion in functional and phylogenetic diversity differed depending on spatial scale and metric considered. At the county scale, MPD revealed evidence for phylogenetic overdispersion, while MNTD revealed phylogenetic and functional underdispersion, and at the conservation area scale, MPD revealed phylogenetic and functional underdispersion while MNTD revealed evidence only of functional underdispersion. Our results are consistent with environmental filtering playing a larger role at the smaller, conservation area scale. The smaller spatial units are likely composed of fewer local habitat types that are selecting for closely related species, with the larger-scale units more likely to be composed of multiple habitat types that bring together a larger pool of species from across the phylogeny. Several aspects of fern biology, including their unique physiology and water relations and the importance of the independent gametophyte stage of the life cycle, make ferns highly sensitive to local, microhabitat conditions. © 2018 The Authors. American Journal of Botany is published by Wiley Periodicals, Inc. on behalf of the Botanical Society of America.

ONC201 kills breast cancer cells in vitro by targeting mitochondria.

PubMed

Greer, Yoshimi Endo; Porat-Shliom, Natalie; Nagashima, Kunio; Stuelten, Christina; Crooks, Dan; Koparde, Vishal N; Gilbert, Samuel F; Islam, Celia; Ubaldini, Ashley; Ji, Yun; Gattinoni, Luca; Soheilian, Ferri; Wang, Xiantao; Hafner, Markus; Shetty, Jyoti; Tran, Bao; Jailwala, Parthav; Cam, Maggie; Lang, Martin; Voeller, Donna; Reinhold, William C; Rajapakse, Vinodh; Pommier, Yves; Weigert, Roberto; Linehan, W Marston; Lipkowitz, Stanley

2018-04-06

We report a novel mechanism of action of ONC201 as a mitochondria-targeting drug in cancer cells. ONC201 was originally identified as a small molecule that induces transcription of TNF-related apoptosis-inducing ligand (TRAIL) and subsequently kills cancer cells by activating TRAIL death receptors. In this study, we examined ONC201 toxicity on multiple human breast and endometrial cancer cell lines. ONC201 attenuated cell viability in all cancer cell lines tested. Unexpectedly, ONC201 toxicity was not dependent on either TRAIL receptors nor caspases. Time-lapse live cell imaging revealed that ONC201 induces cell membrane ballooning followed by rupture, distinct from the morphology of cells undergoing apoptosis. Further investigation found that ONC201 induces phosphorylation of AMP-dependent kinase and ATP loss. Cytotoxicity and ATP depletion were significantly enhanced in the absence of glucose, suggesting that ONC201 targets mitochondrial respiration. Further analysis indicated that ONC201 indirectly inhibits mitochondrial respiration. Confocal and electron microscopic analysis demonstrated that ONC201 triggers mitochondrial structural damage and functional impairment. Moreover, ONC201 decreased mitochondrial DNA (mtDNA). RNAseq analysis revealed that ONC201 suppresses expression of multiple mtDNA-encoded genes and nuclear-encoded mitochondrial genes involved in oxidative phosphorylation and other mitochondrial functions. Importantly, fumarate hydratase deficient cancer cells and multiple cancer cell lines with reduced amounts of mtDNA were resistant to ONC201. These results indicate that cells not dependent on mitochondrial respiration are ONC201-resistant. Our data demonstrate that ONC201 kills cancer cells by disrupting mitochondrial function and further suggests that cancer cells that are dependent on glycolysis will be resistant to ONC201.

ONC201 kills breast cancer cells in vitro by targeting mitochondria

PubMed Central

Greer, Yoshimi Endo; Porat-Shliom, Natalie; Nagashima, Kunio; Stuelten, Christina; Crooks, Dan; Koparde, Vishal N.; Gilbert, Samuel F.; Islam, Celia; Ubaldini, Ashley; Ji, Yun; Gattinoni, Luca; Soheilian, Ferri; Wang, Xiantao; Hafner, Markus; Shetty, Jyoti; Tran, Bao; Jailwala, Parthav; Cam, Maggie; Lang, Martin; Voeller, Donna; Reinhold, William C.; Rajapakse, Vinodh; Pommier, Yves; Weigert, Roberto; Linehan, W. Marston; Lipkowitz, Stanley

2018-01-01

We report a novel mechanism of action of ONC201 as a mitochondria-targeting drug in cancer cells. ONC201 was originally identified as a small molecule that induces transcription of TNF-related apoptosis-inducing ligand (TRAIL) and subsequently kills cancer cells by activating TRAIL death receptors. In this study, we examined ONC201 toxicity on multiple human breast and endometrial cancer cell lines. ONC201 attenuated cell viability in all cancer cell lines tested. Unexpectedly, ONC201 toxicity was not dependent on either TRAIL receptors nor caspases. Time-lapse live cell imaging revealed that ONC201 induces cell membrane ballooning followed by rupture, distinct from the morphology of cells undergoing apoptosis. Further investigation found that ONC201 induces phosphorylation of AMP-dependent kinase and ATP loss. Cytotoxicity and ATP depletion were significantly enhanced in the absence of glucose, suggesting that ONC201 targets mitochondrial respiration. Further analysis indicated that ONC201 indirectly inhibits mitochondrial respiration. Confocal and electron microscopic analysis demonstrated that ONC201 triggers mitochondrial structural damage and functional impairment. Moreover, ONC201 decreased mitochondrial DNA (mtDNA). RNAseq analysis revealed that ONC201 suppresses expression of multiple mtDNA-encoded genes and nuclear-encoded mitochondrial genes involved in oxidative phosphorylation and other mitochondrial functions. Importantly, fumarate hydratase deficient cancer cells and multiple cancer cell lines with reduced amounts of mtDNA were resistant to ONC201. These results indicate that cells not dependent on mitochondrial respiration are ONC201-resistant. Our data demonstrate that ONC201 kills cancer cells by disrupting mitochondrial function and further suggests that cancer cells that are dependent on glycolysis will be resistant to ONC201. PMID:29719618

Lysophosphatidic Acid Signals through Multiple Receptors in Osteoclasts to Elevate Cytosolic Calcium Concentration, Evoke Retraction, and Promote Cell Survival*

PubMed Central

Lapierre, Danielle M.; Tanabe, Natsuko; Pereverzev, Alexey; Spencer, Martha; Shugg, Ryan P. P.; Dixon, S. Jeffrey; Sims, Stephen M.

2010-01-01

Lysophosphatidic acid (LPA) is a bioactive phospholipid whose functions are mediated by multiple G protein-coupled receptors. We have shown that osteoblasts produce LPA, raising the possibility that it mediates intercellular signaling among osteoblasts and osteoclasts. Here we investigated the expression, signaling and function of LPA receptors in osteoclasts. Focal application of LPA elicited transient increases in cytosolic calcium concentration ([Ca2+]i), with 50% of osteoclasts responding at ∼400 nm LPA. LPA-induced elevation of [Ca2+]i was blocked by pertussis toxin or the LPA1/3 receptor antagonist VPC-32183. LPA caused sustained retraction of osteoclast lamellipodia and disrupted peripheral actin belts. Retraction was insensitive to VPC-32183 or pertussis toxin, indicating involvement of a distinct signaling pathway. In this regard, inhibition of Rho-associated kinase stimulated respreading after LPA-induced retraction. Real-time reverse transcription-PCR revealed transcripts encoding LPA1 and to a lesser extent LPA2, LPA4, and LPA5 receptor subtypes. LPA induced nuclear translocation of NFATc1 and enhanced osteoclast survival, effects that were blocked by VPC-32183 or by a specific peptide inhibitor of NFAT activation. LPA slightly reduced the resorptive activity of osteoclasts in vitro. Thus, LPA binds to at least two receptor subtypes on osteoclasts: LPA1, which couples through Gi/o to elevate [Ca2+]i, activate NFATc1, and promote survival, and a second receptor that likely couples through G12/13 and Rho to evoke and maintain retraction through reorganization of the actin cytoskeleton. These findings reveal a signaling axis in bone through which LPA, produced by osteoblasts, acts on multiple receptor subtypes to induce pleiotropic effects on osteoclast activity and function. PMID:20551326

Forging our understanding of lncRNAs in the brain.

PubMed

Andersen, Rebecca E; Lim, Daniel A

2018-01-01

During both development and adulthood, the human brain expresses many thousands of long noncoding RNAs (lncRNAs), and aberrant lncRNA expression has been associated with a wide range of neurological diseases. Although the biological significance of most lncRNAs remains to be discovered, it is now clear that certain lncRNAs carry out important functions in neurodevelopment, neural cell function, and perhaps even diseases of the human brain. Given the relatively inclusive definition of lncRNAs-transcripts longer than 200 nucleotides with essentially no protein coding potential-this class of noncoding transcript is both large and very diverse. Furthermore, emerging data indicate that lncRNA genes can act via multiple, non-mutually exclusive molecular mechanisms, and specific functions are difficult to predict from lncRNA expression or sequence alone. Thus, the different experimental approaches used to explore the role of a lncRNA might each shed light upon distinct facets of its overall molecular mechanism, and combining multiple approaches may be necessary to fully illuminate the function of any particular lncRNA. To understand how lncRNAs affect brain development and neurological disease, in vivo studies of lncRNA function are required. Thus, in this review, we focus our discussion upon a small set of neural lncRNAs that have been experimentally manipulated in mice. Together, these examples illustrate how studies of individual lncRNAs using multiple experimental approaches can help reveal the richness and complexity of lncRNA function in both neurodevelopment and diseases of the brain.

Phospho-selective mechanisms of arrestin conformations and functions revealed by unnatural amino acid incorporation and 19F-NMR

PubMed Central

Yang, Fan; Yu, Xiao; Liu, Chuan; Qu, Chang-Xiu; Gong, Zheng; Liu, Hong-Da; Li, Fa-Hui; Wang, Hong-Mei; He, Dong-Fang; Yi, Fan; Song, Chen; Tian, Chang-Lin; Xiao, Kun-Hong; Wang, Jiang-Yun; Sun, Jin-Peng

2015-01-01

Specific arrestin conformations are coupled to distinct downstream effectors, which underlie the functions of many G-protein-coupled receptors (GPCRs). Here, using unnatural amino acid incorporation and fluorine-19 nuclear magnetic resonance (19F-NMR) spectroscopy, we demonstrate that distinct receptor phospho-barcodes are translated to specific β-arrestin-1 conformations and direct selective signalling. With its phosphate-binding concave surface, β-arrestin-1 ‘reads' the message in the receptor phospho-C-tails and distinct phospho-interaction patterns are revealed by 19F-NMR. Whereas all functional phosphopeptides interact with a common phosphate binding site and induce the movements of finger and middle loops, different phospho-interaction patterns induce distinct structural states of β-arrestin-1 that are coupled to distinct arrestin functions. Only clathrin recognizes and stabilizes GRK2-specific β-arrestin-1 conformations. The identified receptor-phospho-selective mechanism for arrestin conformation and the spacing of the multiple phosphate-binding sites in the arrestin enable arrestin to recognize plethora phosphorylation states of numerous GPCRs, contributing to the functional diversity of receptors. PMID:26347956

Representation of the Physiological Factors Contributing to Postflight Changes in Functional Performance Using Motion Analysis Software

NASA Technical Reports Server (NTRS)

Parks, Kelsey

2010-01-01

Astronauts experience changes in multiple physiological systems due to exposure to the microgravity conditions of space flight. To understand how changes in physiological function influence functional performance, a testing procedure has been developed that evaluates both astronaut postflight functional performance and related physiological changes. Astronauts complete seven functional and physiological tests. The objective of this project is to use motion tracking and digitizing software to visually display the postflight decrement in the functional performance of the astronauts. The motion analysis software will be used to digitize astronaut data videos into stick figure videos to represent the astronauts as they perform the Functional Tasks Tests. This project will benefit NASA by allowing NASA scientists to present data of their neurological studies without revealing the identities of the astronauts.

Multiple conformations are a conserved and regulatory feature of the RB1 5′ UTR

PubMed Central

Kutchko, Katrina M.; Sanders, Wes; Ziehr, Ben; Phillips, Gabriela; Solem, Amanda; Halvorsen, Matthew; Weeks, Kevin M.; Moorman, Nathaniel

2015-01-01

Folding to a well-defined conformation is essential for the function of structured ribonucleic acids (RNAs) like the ribosome and tRNA. Structured elements in the untranslated regions (UTRs) of specific messenger RNAs (mRNAs) are known to control expression. The importance of unstructured regions adopting multiple conformations, however, is still poorly understood. High-resolution SHAPE-directed Boltzmann suboptimal sampling of the Homo sapiens Retinoblastoma 1 (RB1) 5′ UTR yields three distinct conformations compatible with the experimental data. Private single nucleotide variants (SNVs) identified in two patients with retinoblastoma each collapse the structural ensemble to a single but distinct well-defined conformation. The RB1 5′ UTRs from Bos taurus (cow) and Trichechus manatus latirostris (manatee) are divergent in sequence from H. sapiens (human) yet maintain structural compatibility with high-probability base pairs. SHAPE chemical probing of the cow and manatee RB1 5′ UTRs reveals that they also adopt multiple conformations. Luciferase reporter assays reveal that 5′ UTR mutations alter RB1 expression. In a traditional model of disease, causative SNVs disrupt a key structural element in the RNA. For the subset of patients with heritable retinoblastoma-associated SNVs in the RB1 5′ UTR, the absence of multiple structures is likely causative of the cancer. Our data therefore suggest that selective pressure will favor multiple conformations in eukaryotic UTRs to regulate expression. PMID:25999316

The neuropeptide PDF acts directly on evening pacemaker neurons to regulate multiple features of circadian behavior.

PubMed

Lear, Bridget C; Zhang, Luoying; Allada, Ravi

2009-07-01

Discrete clusters of circadian clock neurons temporally organize daily behaviors such as sleep and wake. In Drosophila, a network of just 150 neurons drives two peaks of timed activity in the morning and evening. A subset of these neurons expresses the neuropeptide pigment dispersing factor (PDF), which is important for promoting morning behavior as well as maintaining robust free-running rhythmicity in constant conditions. Yet, how PDF acts on downstream circuits to mediate rhythmic behavior is unknown. Using circuit-directed rescue of PDF receptor mutants, we show that PDF targeting of just approximately 30 non-PDF evening circadian neurons is sufficient to drive morning behavior. This function is not accompanied by large changes in core molecular oscillators in light-dark, indicating that PDF RECEPTOR likely regulates the output of these cells under these conditions. We find that PDF also acts on this focused set of non-PDF neurons to regulate both evening activity phase and period length, consistent with modest resetting effects on core oscillators. PDF likely acts on more distributed pacemaker neuron targets, including the PDF neurons themselves, to regulate rhythmic strength. Here we reveal defining features of the circuit-diagram for PDF peptide function in circadian behavior, revealing the direct neuronal targets of PDF as well as its behavioral functions at those sites. These studies define a key direct output circuit sufficient for multiple PDF dependent behaviors.

Correlates of Social Functioning in Autism Spectrum Disorder: The Role of Social Cognition.

PubMed

Bishop-Fitzpatrick, Lauren; Mazefsky, Carla A; Eack, Shaun M; Minshew, Nancy J

2017-03-01

Individuals with autism spectrum disorder (ASD) experience marked challenges with social function by definition, but few modifiable predictors of social functioning in ASD have been identified in extant research. This study hypothesized that deficits in social cognition and motor function may help to explain poor social functioning in individuals with ASD. Cross-sectional data from 108 individuals with ASD and without intellectual disability ages 9 through 27.5 were used to assess the relationship between social cognition and motor function, and social functioning. Results of hierarchical multiple regression analyses revealed that greater social cognition, but not motor function, was significantly associated with better social functioning when controlling for sex, age, and intelligence quotient. Post-hoc analyses revealed that, better performance on second-order false belief tasks was associated with higher levels of socially adaptive behavior and lower levels of social problems. Our findings support the development and testing of interventions that target social cognition in order to improve social functioning in individuals with ASD. Interventions that teach generalizable skills to help people with ASD better understand social situations and develop competency in advanced perspective taking have the potential to create more durable change because their effects can be applied to a wide and varied set of situations and not simply a prescribed set of rehearsed situations.

The R-spondin family of proteins: emerging regulators of WNT signaling

PubMed Central

Jin, Yong-Ri; Yoon, Jeong Kyo

2012-01-01

Recently, the R-spondin (RSPO) family of proteins has emerged as important regulators of WNT signaling. Considering the wide spectrum of WNT signaling functions in normal biological processes and disease conditions, there has been a significantly growing interest in understanding the functional roles of RSPOs in multiple biological processes and determining the molecular mechanisms by which RSPOs regulate the WNT signaling pathway. Recent advances in the RSPO research field revealed some of the in vivo functions of RSPOs and provided new information regarding the mechanistic roles of RSPO activity in regulation of WNT signaling. Herein, we review recent progress in RSPO research with an emphasis on signaling mechanisms and biological functions. PMID:22982762

Hyperpolarized functional magnetic resonance of murine skeletal muscle enabled by multiple tracer-paradigm synchronizations.

PubMed

Leftin, Avigdor; Roussel, Tangi; Frydman, Lucio

2014-01-01

Measuring metabolism's time- and space-dependent responses upon stimulation lies at the core of functional magnetic resonance imaging. While focusing on water's sole resonance, further insight could arise from monitoring the temporal responses arising from the metabolites themselves, in what is known as functional magnetic resonance spectroscopy. Performing these measurements in real time, however, is severely challenged by the short functional timescales and low concentrations of natural metabolites. Dissolution dynamic nuclear polarization is an emerging technique that can potentially alleviate this, as it provides a massive sensitivity enhancement allowing one to probe low-concentration tracers and products in a single-scan. Still, conventional implementations of this hyperpolarization approach are not immediately amenable to the repeated acquisitions needed in real-time functional settings. This work proposes a strategy for functional magnetic resonance of hyperpolarized metabolites that bypasses this limitation, and enables the observation of real-time metabolic changes through the synchronization of stimuli-triggered, multiple-bolus injections of the metabolic tracer 13C1-pyruvate. This new approach is demonstrated with paradigms tailored to reveal in vivo thresholds of murine hind-limb skeletal muscle activation, involving the conversion of 13C1-pyruvate to 13C1-lactate and 13C1-alanine. These functional hind-limb studies revealed that graded skeletal muscle stimulation causes commensurate increases in glycolytic metabolism in a frequency- and amplitude-dependent fashion, that can be monitored on the seconds/minutes timescale using dissolution dynamic nuclear polarization. Spectroscopic imaging further allowed the in vivo visualization of uptake, transformation and distribution of the tracer and products, in fast-twitch glycolytic and in slow-twitch oxidative muscle fiber groups. While these studies open vistas in time and sensitivity for metabolic functional magnetic resonance studies in muscle, the simplicity of our approach makes this technique amenable to a wide range of functional metabolic tracer studies.

Differential Effects of the Catechol-O-Methyltransferase Val158Met Genotype on the Cognitive Function of Schizophrenia Patients and Healthy Japanese Individuals

PubMed Central

Tsuchimine, Shoko; Yasui-Furukori, Norio; Kaneda, Ayako; Kaneko, Sunao

2013-01-01

Background The functional polymorphism Val158Met in the catechol-O-methyltransferase (COMT) gene has been associated with differences in prefrontal cognitive functions in patients with schizophrenia and healthy individuals. Several studies have indicated that the Met allele is associated with better performance on measures of cognitive function. We investigated whether the COMT Val158Met genotype was associated with cognitive function in 149 healthy controls and 118 patients with schizophrenia. Methods Cognitive function, including verbal memory, working memory, motor speed, attention, executive function and verbal fluency, was assessed by the Brief Assessment of Cognition in Schizophrenia (BACS-J). We employed a one-way analysis of variance (ANOVA) and a multiple regression analysis to determine the associations between the COMT Val158Met genotype and the BACS-J measurements. Results The one-way ANOVA revealed a significant difference in the scores on the Tower of London, a measure of executive function, between the different Val158Met genotypes in the healthy controls (p = 0.023), and a post-hoc analysis showed significant differences between the scores on the Tower of London in the val/val genotype group (18.6 ± 2.4) compared to the other two groups (17.6 ± 2.7 for val/met and 17.1 ± 3.2 for met/met; p = 0.027 and p = 0.024, respectively). Multiple regression analyses revealed that executive function was significantly correlated with the Val158Met genotype (p = 0.003). However, no evidence was found for an effect of the COMT on any cognitive domains of the BACS-J in the patients with schizophrenia. Conclusion These data support the hypothesis that the COMT Val158Met genotype maintains an optimal level of dopamine activity. Further studies should be performed that include a larger sample size and include patients on and off medication, as these patients would help to confirm our findings. PMID:24282499

Perceptual suppression revealed by adaptive multi-scale entropy analysis of local field potential in monkey visual cortex.

PubMed

Hu, Meng; Liang, Hualou

2013-04-01

Generalized flash suppression (GFS), in which a salient visual stimulus can be rendered invisible despite continuous retinal input, provides a rare opportunity to directly study the neural mechanism of visual perception. Previous work based on linear methods, such as spectral analysis, on local field potential (LFP) during GFS has shown that the LFP power at distinctive frequency bands are differentially modulated by perceptual suppression. Yet, the linear method alone may be insufficient for the full assessment of neural dynamic due to the fundamentally nonlinear nature of neural signals. In this study, we set forth to analyze the LFP data collected from multiple visual areas in V1, V2 and V4 of macaque monkeys while performing the GFS task using a nonlinear method - adaptive multi-scale entropy (AME) - to reveal the neural dynamic of perceptual suppression. In addition, we propose a new cross-entropy measure at multiple scales, namely adaptive multi-scale cross-entropy (AMCE), to assess the nonlinear functional connectivity between two cortical areas. We show that: (1) multi-scale entropy exhibits percept-related changes in all three areas, with higher entropy observed during perceptual suppression; (2) the magnitude of the perception-related entropy changes increases systematically over successive hierarchical stages (i.e. from lower areas V1 to V2, up to higher area V4); and (3) cross-entropy between any two cortical areas reveals higher degree of asynchrony or dissimilarity during perceptual suppression, indicating a decreased functional connectivity between cortical areas. These results, taken together, suggest that perceptual suppression is related to a reduced functional connectivity and increased uncertainty of neural responses, and the modulation of perceptual suppression is more effective at higher visual cortical areas. AME is demonstrated to be a useful technique in revealing the underlying dynamic of nonlinear/nonstationary neural signal.

Minimal invasive epicardial lead implantation: optimizing cardiac resynchronization with a new mapping device for epicardial lead placement.

PubMed

Maessen, J G; Phelps, B; Dekker, A L A J; Dijkman, B

2004-05-01

To optimize resynchronization in biventricular pacing with epicardial leads, mapping to determine the best pacing site, is a prerequisite. A port access surgical mapping technique was developed that allowed multiple pace site selection and reproducible lead evaluation and implantation. Pressure-volume loops analysis was used for real time guidance in targeting epicardial lead placement. Even the smallest changes in lead position revealed significantly different functional results. Optimizing the pacing site with this technique allowed functional improvement up to 40% versus random pace site selection.

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

Genome multiplication as adaptation to tissue survival: evidence from gene expression in mammalian heart and liver.

PubMed

Anatskaya, Olga V; Vinogradov, Alexander E

2007-01-01

To elucidate the functional significance of genome multiplication in somatic tissues, we performed a large-scale analysis of ploidy-associated changes in expression of non-tissue-specific (i.e., broadly expressed) genes in the heart and liver of human and mouse (6585 homologous genes were analyzed). These species have inverse patterns of polyploidization in cardiomyocytes and hepatocytes. The between-species comparison of two pairs of homologous tissues with crisscross contrast in ploidy levels allows the removal of the effects of species and tissue specificity on the profile of gene activity. The different tests performed from the standpoint of modular biology revealed a consistent picture of ploidy-associated alteration in a wide range of functional gene groups. The major effects consisted of hypoxia-inducible factor-triggered changes in main cellular processes and signaling pathways, activation of defense against DNA lesions, acceleration of protein turnover and transcription, and the impairment of apoptosis, the immune response, and cytoskeleton maintenance. We also found a severe decline in aerobic respiration and stimulation of sugar and fatty acid metabolism. These metabolic rearrangements create a special type of metabolism that can be considered intermediate between aerobic and anaerobic. The metabolic and physiological changes revealed (reflected in the alteration of gene expression) help explain the unique ability of polyploid tissues to combine proliferation and differentiation, which are separated in diploid tissues. We argue that genome multiplication promotes cell survival and tissue regeneration under stressful conditions.

Coordinately Co-opted Multiple Transposable Elements Constitute an Enhancer for wnt5a Expression in the Mammalian Secondary Palate

PubMed Central

Kimura-Yoshida, Chiharu; Yan, Kuo; Bormuth, Olga; Ding, Qiong; Nakanishi, Akiko; Sasaki, Takeshi; Hirakawa, Mika; Sumiyama, Kenta; Furuta, Yasuhide; Tarabykin, Victor; Matsuo, Isao; Okada, Norihiro

2016-01-01

Acquisition of cis-regulatory elements is a major driving force of evolution, and there are several examples of developmental enhancers derived from transposable elements (TEs). However, it remains unclear whether one enhancer element could have been produced via cooperation among multiple, yet distinct, TEs during evolution. Here we show that an evolutionarily conserved genomic region named AS3_9 comprises three TEs (AmnSINE1, X6b_DNA and MER117), inserted side-by-side, and functions as a distal enhancer for wnt5a expression during morphogenesis of the mammalian secondary palate. Functional analysis of each TE revealed step-by-step retroposition/transposition and co-option together with acquisition of a binding site for Msx1 for its full enhancer function during mammalian evolution. The present study provides a new perspective suggesting that a huge variety of TEs, in combination, could have accelerated the diversity of cis-regulatory elements involved in morphological evolution. PMID:27741242

YY1 Regulates Melanocyte Development and Function by Cooperating with MITF

PubMed Central

Bell, Robert J. A.; Tran, Thanh-Nga T.; Haq, Rizwan; Liu, Huifei; Love, Kevin T.; Langer, Robert; Anderson, Daniel G.; Larue, Lionel; Fisher, David E.

2012-01-01

Studies of coat color mutants have greatly contributed to the discovery of genes that regulate melanocyte development and function. Here, we generated Yy1 conditional knockout mice in the melanocyte-lineage and observed profound melanocyte deficiency and premature gray hair, similar to the loss of melanocytes in human piebaldism and Waardenburg syndrome. Although YY1 is a ubiquitous transcription factor, YY1 interacts with M-MITF, the Waardenburg Syndrome IIA gene and a master transcriptional regulator of melanocytes. YY1 cooperates with M-MITF in regulating the expression of piebaldism gene KIT and multiple additional pigmentation genes. Moreover, ChIP–seq identified genome-wide YY1 targets in the melanocyte lineage. These studies mechanistically link genes implicated in human conditions of melanocyte deficiency and reveal how a ubiquitous factor (YY1) gains lineage-specific functions by co-regulating gene expression with a lineage-restricted factor (M-MITF)—a general mechanism which may confer tissue-specific gene expression in multiple lineages. PMID:22570637

Mediator-regulated transcription through the +1 nucleosome.

PubMed

Nock, Adam; Ascano, Janice M; Barrero, Maria J; Malik, Sohail

2012-12-28

Many genes are regulated at the level of a Pol II that is recruited to a nucleosome-free region upstream of the +1 nucleosome. How the Mediator coactivator complex, which functions at multiple steps, affects transcription through the promoter proximal region, including this nucleosome, remains largely unaddressed. We have established a fully defined in vitro assay system to delineate mechanisms for Pol II transit across the +1 nucleosome. Our results reveal cooperative functions of multiple cofactors, particularly of Mediator and elongation factor SII, in transcribing into this nucleosome. This is achieved, in part, through an unusual activity of SII that alters the intrinsic catalytic properties of promoter-proximal Pol II and, in concert with the Mediator, leads to enhancement in transcription of nucleosomal DNA. Our data provide additional mechanistic bases for Mediator function after recruitment of Pol II and, potentially, for regulation of genes controlled via nucleosome-mediated promoter-proximal pausing. Copyright © 2012 Elsevier Inc. All rights reserved.

[Application progress of proteomic in pharmacological study of Chinese medicinal formulae].

PubMed

Liu, Yu-Qian; Zhan, Shu-Yu; Ruan, Yu-Er; Zuo, Zhi-Yan; Ji, Xiao-Ming; Wang, Shuai-Jie; Ding, Bao-Yue

2017-10-01

Chinese medicinal formulae are the important means of clinical treatment in traditional Chinese medicine. It is urgent to use modern advanced scientific and technological means to reveal the complicated mechanism of Chinese medicinal formulae because they have the function characteristics of multiple components, multiple targets and integrated regulation. The systematic and comprehensive research model of proteomic is in line with the function characteristics of Chinese medicinal formulae, and proteomic has been widely used in the study of pharmacological mechanism of Chinese medicinal formulae. The recent applications of proteomic in pharmacological study of Chinese medicinal formulae in anti-cardiovascular and cerebrovascular diseases, anti-liver disease, antidiabetic, anticancer, anti-rheumatoid arthritis and other diseases were reviewed in this paper, and then the future development direction of proteomic in pharmacological study of Chinese medicinal formulae was put forward. This review is to provide the ideas and method for proteomic research on function mechanism of Chinese medicinal formulae. Copyright© by the Chinese Pharmaceutical Association.

Multi-gene phylogenetic analysis reveals the multiple origin and evolution of mangrove physiological traits through exaptation

NASA Astrophysics Data System (ADS)

Sahu, Sunil Kumar; Singh, Reena; Kathiresan, Kandasamy

2016-12-01

Mangroves are taxonomically diverse group of salt-tolerant, mainly arboreal, flowering plants that grow in tropical and sub-tropical regions and have adapted themselves to thrive in such obdurate surroundings. While evolution is often understood exclusively in terms of adaptation, innovation often begins when a feature adapted for one function is co-opted for a different purpose and the co-opted features are called exaptations. Thus, one of the fundamental issues is what features of mangroves have evolved through exaptation. We attempt to address these questions through molecular phylogenetic approach using chloroplast and nuclear markers. First, we determined if these mangroves specific traits have evolved multiple times in the phylogeny. Once the multiple origins were established, we then looked at related non-mangrove species for characters that could have been co-opted by mangrove species. We also assessed the efficacy of these molecular sequences in distinguishing mangroves at the species level. This study revealed the multiple origin of mangroves and shed light on the ancestral characters that might have led certain lineages of plants to adapt to estuarine conditions and also traces the evolutionary history of mangroves and hitherto unexplained theory that mangroves traits (aerial roots and viviparous propagules) evolved as a result of exaptation rather than adaptation to saline habitats.

3D receiver function Kirchhoff depth migration image of Cascadia subduction slab weak zone

NASA Astrophysics Data System (ADS)

Cheng, C.; Allen, R. M.; Bodin, T.; Tauzin, B.

2016-12-01

We have developed a highly computational efficient algorithm of applying 3D Kirchhoff depth migration to telesismic receiver function data. Combine primary PS arrival with later multiple arrivals we are able to reveal a better knowledge about the earth discontinuity structure (transmission and reflection). This method is highly useful compare with traditional CCP method when dipping structure is met during the imaging process, such as subduction slab. We apply our method to the reginal Cascadia subduction zone receiver function data and get a high resolution 3D migration image, for both primary and multiples. The image showed us a clear slab weak zone (slab hole) in the upper plate boundary under Northern California and the whole Oregon. Compare with previous 2D receiver function image from 2D array(CAFE and CASC93), the position of the weak zone shows interesting conherency. This weak zone is also conherent with local seismicity missing and heat rising, which lead us to think about and compare with the ocean plate stucture and the hydralic fluid process during the formation and migration of the subduction slab.

Cognitive Performance in Older Adults with Stable Heart Failure: Longitudinal Evidence for Stability and Improvement

PubMed Central

Alosco, Michael L.; Garcia, Sarah; Spitznagel, Mary Beth; van Dulmen, Manfred; Cohen, Ronald; Sweet, Lawrence H.; Josephson, Richard; Hughes, Joel; Rosneck, Jim; Gunstad, John

2013-01-01

Cognitive impairment is prevalent in heart failure (HF), though substantial variability in the pattern of cognitive impairment is found across studies. To clarify the nature of cognitive impairment in HF, we examined longitudinal trajectories across multiple domains of cognition in HF patients using latent growth class modeling. 115 HF patients completed a neuropsychological battery at baseline, 3-months and 12-months. Participants also completed the Beck Depression Inventory-II (BDI-II). Latent class growth analyses revealed a three-class model for attention/executive function, four-class model for memory, and a three-class model for language. The slope for attention/executive function and language remained stable, while improvements were noted in memory performance. Education and BDI-II significantly predicted the intercept for attention/executive function and language abilities. The BDI-II also predicted baseline memory. The current findings suggest that multiple performance-based classes of neuropsychological test performance exist within cognitive domains, though case-controlled prospective studies with extended follow-ups are needed to fully elucidate changes and predictors of cognitive function in HF. PMID:23906182

A malignant cause of hypoglycaemia: a metastatic insulin-secreting pancreatic neuroendocrine carcinoma.

PubMed

Sandoval, Mark Anthony; Pagsisihan, Daveric; Berberabe, A'Ericson; Palugod-Lopez, Elaine Gayle

2016-03-18

Most cases of insulinomas are benign. We report a case of a malignant form of insulinoma. A 46-year-old man presented with behavioural changes associated with hypoglycaemia. Diagnostic work up revealed high serum insulin, high C-peptide and low glucose levels, compatible with endogenous hyperinsulinaemic hypoglycaemia. CT imaging of the abdomen revealed a pancreatic head mass and multiple liver masses. Biopsy of the pancreatic mass revealed a grade three pancreatic neuroendocrine carcinoma. Histological analysis of a liver mass showed that it was identical to the pancreatic mass, confirming its metastatic nature. The patient underwent distal pancreatectomy with en bloc splenectomy. There was persistence of hypoglycaemic symptoms after removal of the pancreatic mass, suggesting that the liver metastases were also functioning. Symptoms were controlled by diazoxide and octreotide long-acting release. The patient is already 1 year postsurgery with no recurrence of severe hypoglycaemia, and he has good functional capacity and has returned to his office job. 2016 BMJ Publishing Group Ltd.

A malignant cause of hypoglycaemia: a metastatic insulin-secreting pancreatic neuroendocrine carcinoma

PubMed Central

Sandoval, Mark Anthony; Pagsisihan, Daveric; Berberabe, A'Ericson; Palugod-Lopez, Elaine Gayle

2016-01-01

Most cases of insulinomas are benign. We report a case of a malignant form of insulinoma. A 46-year-old man presented with behavioural changes associated with hypoglycaemia. Diagnostic work up revealed high serum insulin, high C-peptide and low glucose levels, compatible with endogenous hyperinsulinaemic hypoglycaemia. CT imaging of the abdomen revealed a pancreatic head mass and multiple liver masses. Biopsy of the pancreatic mass revealed a grade three pancreatic neuroendocrine carcinoma. Histological analysis of a liver mass showed that it was identical to the pancreatic mass, confirming its metastatic nature. The patient underwent distal pancreatectomy with en bloc splenectomy. There was persistence of hypoglycaemic symptoms after removal of the pancreatic mass, suggesting that the liver metastases were also functioning. Symptoms were controlled by diazoxide and octreotide long-acting release. The patient is already 1 year postsurgery with no recurrence of severe hypoglycaemia, and he has good functional capacity and has returned to his office job. PMID:26994053

An expanded allosteric network in PTP1B by multitemperature crystallography, fragment screening, and covalent tethering.

PubMed

Keedy, Daniel A; Hill, Zachary B; Biel, Justin T; Kang, Emily; Rettenmaier, T Justin; Brandao-Neto, Jose; Pearce, Nicholas M; von Delft, Frank; Wells, James A; Fraser, James S

2018-06-07

Allostery is an inherent feature of proteins, but it remains challenging to reveal the mechanisms by which allosteric signals propagate. A clearer understanding of this intrinsic circuitry would afford new opportunities to modulate protein function. Here we have identified allosteric sites in protein tyrosine phosphatase 1B (PTP1B) by combining multiple-temperature X-ray crystallography experiments and structure determination from hundreds of individual small-molecule fragment soaks. New modeling approaches reveal 'hidden' low-occupancy conformational states for protein and ligands. Our results converge on allosteric sites that are conformationally coupled to the active-site WPD loop and are hotspots for fragment binding. Targeting one of these sites with covalently tethered molecules or mutations allosterically inhibits enzyme activity. Overall, this work demonstrates how the ensemble nature of macromolecular structure, revealed here by multitemperature crystallography, can elucidate allosteric mechanisms and open new doors for long-range control of protein function. © 2018, Keedy et al.

Enhancement of antibody functions through Fc multiplications

PubMed Central

Wang, Qun; Cvitkovic, Romana; Bonnell, Jessica; Chang, Chien-Ying; Koksal, Adem C.; O'Connor, Ellen; Gao, Xizhe; Yu, Xiang-Qing; Wu, Herren; Stover, C. Kendall; Dall'Acqua, William F.; Xiao, Xiaodong

2017-01-01

ABSTRACT Antibodies carry out a plethora of functions through their crystallizable fragment (Fc) regions, which can be naturally tuned by the adoption of several isotypes and post-translational modifications. Protein engineering enables further Fc function modulations through modifications of the interactions between the Fc and its functional partners, including FcγR, FcRn, complement complex, and additions of auxiliary functional units. Due to the many functions embedded within the confinement of an Fc, a suitable balance must be maintained for a therapeutic antibody to be effective and safe. The outcome of any Fc engineering depends on the interplay among all the effector molecules involved. In this report, we assessed the effects of Fc multiplication (or tandem Fc) on antibody functions. Using IgG1 as a test case, we found that, depending on the specifically designed linker, Fc multiplication led to differentially folded, stable molecules with unique pharmacokinetic profiles. Interestingly, the variants with 3 copies of Fc improved in vitro opsonophagocytic killing activity and displayed significantly improved protective efficacies in a Klebsiella pneumoniae mouse therapeutic model despite faster clearance compared with its IgG1 counterpart. There was no adverse effect observed or pro-inflammatory cytokine release when the Fc variants were administered to animals. We further elucidated that enhanced binding to various effector molecules by IgG-3Fc created a “sink” leading to the rapid clearance of the 3Fc variants, and identified the increased FcRn binding as one strategy to facilitate “sink” escape. These findings reveal new opportunities for novel Fc engineering to further expand our abilities to manipulate and improve antibody therapeutics. PMID:28102754

Long-term psychosocial consequences of surgical congenital malformations.

PubMed

Diseth, Trond H; Emblem, Ragnhild

2017-10-01

Surgical congenital malformations often represent years of treatment, large number of hospital stays, treatment procedures, and long-term functional sequels affecting patients' psychosocial functioning. Both functional defects and psychosocial difficulties that occur commonly in childhood may pass through adolescence on to adulthood. This overview presents reports published over the past 3 decades to elucidate the long-term psychosocial consequences of surgical congenital malformations. Literature searches conducted on PubMed database revealed that less than 1% of all the records of surgical congenital malformations described long-term psychosocial consequences, but with diverse findings. This inconsistency may be due to methodological differences or deficiencies; especially in study design, patient sampling, and methods. Most of the studies revealed that the functional deficits may have great impact on patients' mental health, psychosocial functioning, and QoL; both short- and long-term negative consequences. Factors other than functional problems, e.g., repeated anesthesia, multiple hospitalization, traumatic treatment procedures, and parental dysfunctioning, may also predict long-term mental health and psychosocial functioning. Through multidisciplinary approach, pediatric surgeons should also be aware of deficits in emotional and psychosocial functioning. To achieve overall optimal psychosocial functioning, the challenge is to find a compromise between physically optimal treatment procedures and procedures that are not psychologically detrimental. Copyright © 2017. Published by Elsevier Inc.

Allelic imbalance of multiple sclerosis susceptibility genes IKZF3 and IQGAP1 in human peripheral blood.

PubMed

Keshari, Pankaj K; Harbo, Hanne F; Myhr, Kjell-Morten; Aarseth, Jan H; Bos, Steffan D; Berge, Tone

2016-04-14

Multiple sclerosis is a chronic inflammatory, demyelinating disease of the central nervous system. Recent genome-wide studies have revealed more than 110 single nucleotide polymorphisms as associated with susceptibility to multiple sclerosis, but their functional contribution to disease development is mostly unknown. Consistent allelic imbalance was observed for rs907091 in IKZF3 and rs11609 in IQGAP1, which are in strong linkage disequilibrium with the multiple sclerosis associated single nucleotide polymorphisms rs12946510 and rs8042861, respectively. Using multiple sclerosis patients and healthy controls heterozygous for rs907091 and rs11609, we showed that the multiple sclerosis risk alleles at IKZF3 and IQGAP1 are expressed at higher levels as compared to the protective allele. Furthermore, individuals homozygous for the multiple sclerosis risk allele at IQGAP1 had a significantly higher total expression of IQGAP1 compared to individuals homozygous for the protective allele. Our data indicate a possible regulatory role for the multiple sclerosis-associated IKZF3 and IQGAP1 variants. We suggest that such cis-acting mechanisms may contribute to the multiple sclerosis association of single nucleotide polymorphisms at IKZF3 and IQGAP1.

Engineering of a conditional allele reveals multiple roles of XRN2 in Caenorhabditis elegans development and substrate specificity in microRNA turnover.

PubMed

Miki, Takashi S; Rüegger, Stefan; Gaidatzis, Dimos; Stadler, Michael B; Großhans, Helge

2014-04-01

Although XRN2 proteins are highly conserved eukaryotic 5'→3' exonucleases, little is known about their function in animals. Here, we characterize Caenorhabditis elegans XRN2, which we find to be a broadly and constitutively expressed nuclear protein. An xrn-2 null mutation or loss of XRN2 catalytic activity causes a molting defect and early larval arrest. However, by generating a conditionally mutant xrn-2ts strain de novo through an approach that may be also applicable to other genes of interest, we reveal further functions in fertility, during embryogenesis and during additional larval stages. Consistent with the known role of XRN2 in controlling microRNA (miRNA) levels, we can demonstrate that loss of XRN2 activity stabilizes some rapidly decaying miRNAs. Surprisingly, however, other miRNAs continue to decay rapidly in xrn-2ts animals. Thus, XRN2 has unanticipated miRNA specificity in vivo, and its diverse developmental functions may relate to distinct substrates. Finally, our global analysis of miRNA stability during larval stage 1 reveals that miRNA passenger strands (miR*s) are substantially less stable than guide strands (miRs), supporting the notion that the former are mostly byproducts of biogenesis rather than a less abundant functional species.

A high throughput mutagenic analysis of yeast sumo structure and function

PubMed Central

Newman, Heather A.; Lu, Jian; Carson, Caryn; Boeke, Jef D.

2017-01-01

Sumoylation regulates a wide range of essential cellular functions through diverse mechanisms that remain to be fully understood. Using S. cerevisiae, a model organism with a single essential SUMO gene (SMT3), we developed a library of >250 mutant strains with single or multiple amino acid substitutions of surface or core residues in the Smt3 protein. By screening this library using plate-based assays, we have generated a comprehensive structure-function based map of Smt3, revealing essential amino acid residues and residues critical for function under a variety of genotoxic and proteotoxic stress conditions. Functionally important residues mapped to surfaces affecting Smt3 precursor processing and deconjugation from protein substrates, covalent conjugation to protein substrates, and non-covalent interactions with E3 ligases and downstream effector proteins containing SUMO-interacting motifs. Lysine residues potentially involved in formation of polymeric chains were also investigated, revealing critical roles for polymeric chains, but redundancy in specific chain linkages. Collectively, our findings provide important insights into the molecular basis of signaling through sumoylation. Moreover, the library of Smt3 mutants represents a valuable resource for further exploring the functions of sumoylation in cellular stress response and other SUMO-dependent pathways. PMID:28166236

"I think I use them, but I'm not sure what each one is called": Integration of multiple literacies in secondary social studies and science classes

NASA Astrophysics Data System (ADS)

Lickteig, Amanda D.

In the past, literacy was viewed solely as the basic, functional skills of reading and writing. However, with the New London Group's (1996) proposal of multiliteracies and the more recent push for a plurality of literacies (NCTE, 2011), teachers have been urged to expand their definitions of literacy. This qualitative study explores how secondary-level social studies and science teachers perceive literacies and identifies their instructional literacies practices. Data were collected through a pre- and post-questionnaire, three focus group sessions, classroom observations, field notes, and artifacts. This study solicited nearly one hundred secondary social studies and science teachers from three Midwestern school districts. Eight educators (four social studies and four science) participated in the study that took place in the spring of 2015. Furthermore, a generous grant from a local chapter of Phi Delta Kappa partially funded this research. After applying initial and holistic codes to the data, nine themes emerged: conventional, progressive, hesitant/emerging, collaborate, calibrate, perform, practice, interdisciplinary, and intradisciplinary. The nine themes were further classified by how they appeared in the data: dispositional themes, behavioral themes, and bridge themes. Throughout the data analysis, contemporary genre theory guided the study (Devitt, 2004). Descriptive codes, derived from contemporary genre theory, further revealed that the situational, social, historical, and individual aspects of genre influence teachers' pedagogical practices related to multiple literacies across disciplines. Therefore, the ways in which teachers perceived multiple literacies and implemented them into classroom instruction are multifaceted and vary depending on grade level, content area, and teaching location. However, teachers' dispositions regarding literacy move beyond a traditional mindset of functional reading and writing as they engage in professional learning opportunities and collaborate within and across disciplines and grade levels. This study provides secondary educators insight into the prominence of multiple literacies present across content areas while also revealing the teaching methods and instructional strategies that foster multiple literacies.

Genetic Diversity of Coastal Bottlenose Dolphins Revealed by Structurally and Functionally Diverse Hemoglobins

PubMed Central

Remington, Nicole; Stevens, Robert D.; Wells, Randall S.; Hohn, Aleta; Dhungana, Suraj; Taboy, Celine H.; Crumbliss, Alvin L.; Henkens, Robert; Bonaventura, Celia

2007-01-01

Studies of structure-function relationships in the respiratory proteins of marine mammals revealed unexpected variations in the number and types of hemoglobins (Hbs) present in coastal bottlenose dolphins, Tursiops truncatus. We obtained blood samples from free-ranging coastal bottlenose dolphins as a component of capture-release studies. We found that the oxygen-binding functions of bottlenose dolphin blood are poised between effector-saturated and unsaturated levels, enabling exercise-dependent shifts in oxygen transfer functions. Isolated bottlenose dolphin Hbs showed elevated pH sensitivities (Bohr effects) and appreciably lower oxygen affinities than adult human Hb in the absence of allosteric effectors. These properties may be an adaptive modification that enhance oxygen delivery during diving episodes when oxygen tensions and effector levels are low. The Hbs of individual dolphins showed similar oxygen affinities, responses to effectors, and expression of heme-heme interaction in oxygen binding, but differed in their redox potentials and rates of autoxidation. The heterogeneity suggested by these functional variations in Hbs of individual dolphins was born out by variations in the molecular weights and numbers of their α and β globin chains. Although coastal bottlenose dolphins were expected to have a single type of Hb, the mass differences observed revealed considerable genetic diversity. There were multiple Hb forms in some individuals and differences in Hb patterns among individuals within the same community. PMID:17604574

Genetic diversity of coastal bottlenose dolphins revealed by structurally and functionally diverse hemoglobins.

PubMed

Remington, Nicole; Stevens, Robert D; Wells, Randall S; Holn, Aleta; Dhungana, Suraj; Taboy, Celine H; Crumbliss, Alvin L; Henkens, Robert; Bonaventura, Celia

2007-08-15

Studies of structure-function relationships in the respiratory proteins of marine mammals revealed unexpected variations in the number and types of hemoglobins (Hbs) present in coastal bottlenose dolphins, Tursiops truncatus. We obtained blood samples from free-ranging coastal bottlenose dolphins as a component of capture-release studies. We found that the oxygen-binding functions of bottlenose dolphin blood are poised between effector-saturated and unsaturated levels, enabling exercise-dependent shifts in oxygen transfer functions. Isolated bottlenose dolphin Hbs showed elevated pH sensitivities (Bohr effects) and appreciably lower oxygen affinities than adult human Hb in the absence of allosteric effectors. These properties may be an adaptive modification that enhances oxygen delivery during diving episodes when oxygen tensions and effector levels are low. The Hbs of individual dolphins showed similar oxygen affinities, responses to effectors, and expression of heme-heme interaction in oxygen binding, but differed in their redox potentials and rates of autoxidation. The heterogeneity suggested by these functional variations in Hbs of individual dolphins was born out by variations in the molecular weights and numbers of their alpha and beta globin chains. Although coastal bottlenose dolphins were expected to have a single type of Hb, the mass differences observed revealed considerable genetic diversity. There were multiple Hb forms in some individuals and differences in Hb patterns among individuals within the same community.

Revealing time bunching effect in single-molecule enzyme conformational dynamics.

PubMed

Lu, H Peter

2011-04-21

In this perspective, we focus our discussion on how the single-molecule spectroscopy and statistical analysis are able to reveal enzyme hidden properties, taking the study of T4 lysozyme as an example. Protein conformational fluctuations and dynamics play a crucial role in biomolecular functions, such as in enzymatic reactions. Single-molecule spectroscopy is a powerful approach to analyze protein conformational dynamics under physiological conditions, providing dynamic perspectives on a molecular-level understanding of protein structure-function mechanisms. Using single-molecule fluorescence spectroscopy, we have probed T4 lysozyme conformational motions under the hydrolysis reaction of a polysaccharide of E. coli B cell walls by monitoring the fluorescence resonant energy transfer (FRET) between a donor-acceptor probe pair tethered to T4 lysozyme domains involving open-close hinge-bending motions. Based on the single-molecule spectroscopic results, molecular dynamics simulation, a random walk model analysis, and a novel 2D statistical correlation analysis, we have revealed a time bunching effect in protein conformational motion dynamics that is critical to enzymatic functions. Bunching effect implies that conformational motion times tend to bunch in a finite and narrow time window. We show that convoluted multiple Poisson rate processes give rise to the bunching effect in the enzymatic reaction dynamics. Evidently, the bunching effect is likely common in protein conformational dynamics involving in conformation-gated protein functions. In this perspective, we will also discuss a new approach of 2D regional correlation analysis capable of analyzing fluctuation dynamics of complex multiple correlated and anti-correlated fluctuations under a non-correlated noise background. Using this new method, we are able to map out any defined segments along the fluctuation trajectories and determine whether they are correlated, anti-correlated, or non-correlated; after which, a cross correlation analysis can be applied for each specific segment to obtain a detailed fluctuation dynamics analysis.

RNA Splicing: Regulation and Dysregulation in the Heart.

PubMed

van den Hoogenhof, Maarten M G; Pinto, Yigal M; Creemers, Esther E

2016-02-05

RNA splicing represents a post-transcriptional mechanism to generate multiple functional RNAs or proteins from a single transcript. The evolution of RNA splicing is a prime example of the Darwinian function follows form concept. A mutation that leads to a new mRNA (form) that encodes for a new functional protein (function) is likely to be retained, and this way, the genome has gradually evolved to encode for genes with multiple isoforms, thereby creating an enormously diverse transcriptome. Advances in technologies to characterize RNA populations have led to a better understanding of RNA processing in health and disease. In the heart, alternative splicing is increasingly being recognized as an important layer of post-transcriptional gene regulation. Moreover, the recent identification of several cardiac splice factors, such as RNA-binding motif protein 20 and SF3B1, not only provided important insight into the mechanisms underlying alternative splicing but also revealed how these splicing factors impact functional properties of the heart. Here, we review our current knowledge of alternative splicing in the heart, with a particular focus on the major and minor spliceosome, the factors controlling RNA splicing, and the role of alternative splicing in cardiac development and disease. © 2016 American Heart Association, Inc.

Mesalamine-induced myocarditis following diagnosis of Crohn's disease: a case report.

PubMed

Galvão Braga, Carlos; Martins, Juliana; Arantes, Carina; Ramos, Vítor; Vieira, Catarina; Salgado, Alberto; Magalhães, Sónia; Correia, Adelino

2013-09-01

Mesalamine is a common treatment for Crohn's disease, and can be rarely associated with myocarditis through a mechanism of drug hypersensitivity. We present the case of a 19-year-old male who developed chest pain two weeks after beginning mesalamine therapy. The electrocardiogram showed slight ST-segment elevation with upward concavity in the inferolateral leads; blood tests demonstrated elevated troponin I and the echocardiogram revealed moderately depressed left ventricular systolic function with global hypocontractility. Cardiac magnetic resonance imaging confirmed the diagnosis of myocarditis, revealing multiple areas of subepicardial fibrosis. The onset of symptoms after mesalamine, and improvement of chest pain, cardiac biomarkers and left ventricular systolic function after discontinuing the drug, suggest that our patient suffered from a rare drug-hypersensitivity reaction to mesalamine. Copyright © 2012 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

Ras activation by SOS: Allosteric regulation by altered fluctuation dynamics

PubMed Central

Iversen, Lars; Tu, Hsiung-Lin; Lin, Wan-Chen; Christensen, Sune M.; Abel, Steven M.; Iwig, Jeff; Wu, Hung-Jen; Gureasko, Jodi; Rhodes, Christopher; Petit, Rebecca S.; Hansen, Scott D.; Thill, Peter; Yu, Cheng-Han; Stamou, Dimitrios; Chakraborty, Arup K.; Kuriyan, John; Groves, Jay T.

2014-01-01

Activation of the small guanosine triphosphatase H-Ras by the exchange factor Son of Sevenless (SOS) is an important hub for signal transduction. Multiple layers of regulation, through protein and membrane interactions, govern activity of SOS. We characterized the specific activity of individual SOS molecules catalyzing nucleotide exchange in H-Ras. Single-molecule kinetic traces revealed that SOS samples a broad distribution of turnover rates through stochastic fluctuations between distinct, long-lived (more than 100 seconds), functional states. The expected allosteric activation of SOS by Ras–guanosine triphosphate (GTP) was conspicuously absent in the mean rate. However, fluctuations into highly active states were modulated by Ras-GTP. This reveals a mechanism in which functional output may be determined by the dynamical spectrum of rates sampled by a small number of enzymes, rather than the ensemble average. PMID:24994643

The Role of Microglia and Matrix Metalloproteinases Involvement in Neuroinflammation and Gliomas

PubMed Central

Könnecke, Helen; Bechmann, Ingo

2013-01-01

Matrix metalloproteinases (MMPs) are involved in the pathogenesis of neuroinflammatory diseases (such as multiple sclerosis) as well as in the expansion of malignant gliomas because they facilitate penetration of anatomical barriers (such as the glia limitans) and migration within the neuropil. This review elucidates pathomechanisms and summarizes the current knowledge of the involvement of MMPs in neuroinflammation and glioma, invasion highlighting microglia as major sources of MMPs. The induction of expression, suppression, and multiple pathways of function of MMPs in these scenarios will also be discussed. Understanding the induction and action of MMPs might provide valuable information and reveal attractive targets for future therapeutic strategies. PMID:24023566

Structural and functional diversity of CLAVATA3/ESR (CLE)-like genes from the potato cyst nematode Globodera rostochiensis.

PubMed

Lu, Shun-Wen; Chen, Shiyan; Wang, Jianying; Yu, Hang; Chronis, Demosthenis; Mitchum, Melissa G; Wang, Xiaohong

2009-09-01

Plant CLAVATA3/ESR-related (CLE) peptides have diverse roles in plant growth and development. Here, we report the isolation and functional characterization of five new CLE genes from the potato cyst nematode Globodera rostochiensis. Unlike typical plant CLE peptides that contain a single CLE motif, four of the five Gr-CLE genes encode CLE proteins with multiple CLE motifs. These Gr-CLE genes were found to be specifically expressed within the dorsal esophageal gland cell of nematode parasitic stages, suggesting a role for their encoded proteins in plant parasitism. Overexpression phenotypes of Gr-CLE genes in Arabidopsis mimicked those of plant CLE genes, and Gr-CLE proteins could rescue the Arabidopsis clv3-2 mutant phenotype when expressed within meristems. A short root phenotype was observed when synthetic GrCLE peptides were exogenously applied to roots of Arabidopsis or potato similar to the overexpression of Gr-CLE genes in Arabidopsis and potato hairy roots. These results reveal that G. rostochiensis CLE proteins with either single or multiple CLE motifs function similarly to plant CLE proteins and that CLE signaling components are conserved in both Arabidopsis and potato roots. Furthermore, our results provide evidence to suggest that the evolution of multiple CLE motifs may be an important mechanism for generating functional diversity in nematode CLE proteins to facilitate parasitism.

Changes in reflectance anisotropy of wheat crop during different phenophases

NASA Astrophysics Data System (ADS)

Lunagaria, Manoj M.; Patel, Haridas R.

2017-04-01

The canopy structure of wheat changes significantly with growth stages and leads to changes in reflectance anisotropy. Bidirectional reflectance distribution function characterises the reflectance anisotropy of the targets, which can be approximated. Spectrodirectional reflectance measurements on wheat crop were acquired using a field goniometer system. The bidirectional reflectance spectra were acquired at 54 view angles to cover the hemispheric span up to 60° view zenith. The observations were made during early growth stages till maturity of the crop. The anisotropy was not constant for all wavelengths and anisotropic factors clearly revealed spectral dependence, which was more pronounced in near principal plane. In near infrared, wheat canopy expressed less reflectance anisotropy because of higher multiple scattering. The broad hotspot signature was noticeable in reflectance of canopy whenever view and solar angles were close. Distinct changes in bidirectional reflectance distribution function were observed during booting to flowering stages as the canopy achieves more uniformity, height and head emergence. The function clearly reveals bowl shape during heading to early milking growth stages of the crop. Late growth stages show less prominent gap and shadow effects. Anisotropy index revealed that wheat exhibits changes in reflectance anisotropy with phenological development and with spectral bands.

Schwann cell-specific JAM-C-deficient mice reveal novel expression and functions for JAM-C in peripheral nerves

PubMed Central

Colom, Bartomeu; Poitelon, Yannick; Huang, Wenlong; Woodfin, Abigail; Averill, Sharon; Del Carro, Ubaldo; Zambroni, Desirée; Brain, Susan D.; Perretti, Mauro; Ahluwalia, Amrita; Priestley, John V.; Chavakis, Triantafyllos; Imhof, Beat A.; Feltri, M. Laura; Nourshargh, Sussan

2012-01-01

Junctional adhesion molecule-C (JAM-C) is an adhesion molecule expressed at junctions between adjacent endothelial and epithelial cells and implicated in multiple inflammatory and vascular responses. In addition, we recently reported on the expression of JAM-C in Schwann cells (SCs) and its importance for the integrity and function of peripheral nerves. To investigate the role of JAM-C in neuronal functions further, mice with a specific deletion of JAM-C in SCs (JAM-C SC KO) were generated. Compared to wild-type (WT) controls, JAM-C SC KO mice showed electrophysiological defects, muscular weakness, and hypersensitivity to mechanical stimuli. In addressing the underlying cause of these defects, nerves from JAM-C SC KO mice were found to have morphological defects in the paranodal region, exhibiting increased nodal length as compared to WTs. The study also reports on previously undetected expressions of JAM-C, namely on perineural cells, and in line with nociception defects of the JAM-C SC KO animals, on finely myelinated sensory nerve fibers. Collectively, the generation and characterization of JAM-C SC KO mice has provided unequivocal evidence for the involvement of SC JAM-C in the fine organization of peripheral nerves and in modulating multiple neuronal responses.—Colom, B., Poitelon, Y., Huang, W., Woodfin, A., Averill, S., Del Carro, U., Zambroni, D., Brain, S. D., Perretti, M., Ahluwalia, A., Priestley, J. V., Chavakis, T., Imhof, B. A., Feltri, M. L., Nourshargh, S. Schwann cell-specific JAM-C-deficient mice reveal novel expression and functions for JAM-C in peripheral nerves. PMID:22090315

Structure-guided discovery of the metabolite carboxy-SAM that modulates tRNA function.

PubMed

Kim, Jungwook; Xiao, Hui; Bonanno, Jeffrey B; Kalyanaraman, Chakrapani; Brown, Shoshana; Tang, Xiangying; Al-Obaidi, Nawar F; Patskovsky, Yury; Babbitt, Patricia C; Jacobson, Matthew P; Lee, Young-Sam; Almo, Steven C

2013-06-06

The identification of novel metabolites and the characterization of their biological functions are major challenges in biology. X-ray crystallography can reveal unanticipated ligands that persist through purification and crystallization. These adventitious protein-ligand complexes provide insights into new activities, pathways and regulatory mechanisms. We describe a new metabolite, carboxy-S-adenosyl-l-methionine (Cx-SAM), its biosynthetic pathway and its role in transfer RNA modification. The structure of CmoA, a member of the SAM-dependent methyltransferase superfamily, revealed a ligand consistent with Cx-SAM in the catalytic site. Mechanistic analyses showed an unprecedented role for prephenate as the carboxyl donor and the involvement of a unique ylide intermediate as the carboxyl acceptor in the CmoA-mediated conversion of SAM to Cx-SAM. A second member of the SAM-dependent methyltransferase superfamily, CmoB, recognizes Cx-SAM and acts as a carboxymethyltransferase to convert 5-hydroxyuridine into 5-oxyacetyl uridine at the wobble position of multiple tRNAs in Gram-negative bacteria, resulting in expanded codon-recognition properties. CmoA and CmoB represent the first documented synthase and transferase for Cx-SAM. These findings reveal new functional diversity in the SAM-dependent methyltransferase superfamily and expand the metabolic and biological contributions of SAM-based biochemistry. These discoveries highlight the value of structural genomics approaches in identifying ligands within the context of their physiologically relevant macromolecular binding partners, and in revealing their functions.

Multiple-wavelength neutron holography with pulsed neutrons

PubMed Central

Hayashi, Kouichi; Ohoyama, Kenji; Happo, Naohisa; Matsushita, Tomohiro; Hosokawa, Shinya; Harada, Masahide; Inamura, Yasuhiro; Nitani, Hiroaki; Shishido, Toetsu; Yubuta, Kunio

2017-01-01

Local structures around impurities in solids provide important information for understanding the mechanisms of material functions, because most of them are controlled by dopants. For this purpose, the x-ray absorption fine structure method, which provides radial distribution functions around specific elements, is most widely used. However, a similar method using neutron techniques has not yet been developed. If one can establish a method of local structural analysis with neutrons, then a new frontier of materials science can be explored owing to the specific nature of neutron scattering—that is, its high sensitivity to light elements and magnetic moments. Multiple-wavelength neutron holography using the time-of-flight technique with pulsed neutrons has great potential to realize this. We demonstrated multiple-wavelength neutron holography using a Eu-doped CaF2 single crystal and obtained a clear three-dimensional atomic image around trivalent Eu substituted for divalent Ca, revealing an interesting feature of the local structure that allows it to maintain charge neutrality. The new holography technique is expected to provide new information on local structures using the neutron technique. PMID:28835917

Multiple-wavelength neutron holography with pulsed neutrons.

PubMed

Hayashi, Kouichi; Ohoyama, Kenji; Happo, Naohisa; Matsushita, Tomohiro; Hosokawa, Shinya; Harada, Masahide; Inamura, Yasuhiro; Nitani, Hiroaki; Shishido, Toetsu; Yubuta, Kunio

2017-08-01

Local structures around impurities in solids provide important information for understanding the mechanisms of material functions, because most of them are controlled by dopants. For this purpose, the x-ray absorption fine structure method, which provides radial distribution functions around specific elements, is most widely used. However, a similar method using neutron techniques has not yet been developed. If one can establish a method of local structural analysis with neutrons, then a new frontier of materials science can be explored owing to the specific nature of neutron scattering-that is, its high sensitivity to light elements and magnetic moments. Multiple-wavelength neutron holography using the time-of-flight technique with pulsed neutrons has great potential to realize this. We demonstrated multiple-wavelength neutron holography using a Eu-doped CaF 2 single crystal and obtained a clear three-dimensional atomic image around trivalent Eu substituted for divalent Ca, revealing an interesting feature of the local structure that allows it to maintain charge neutrality. The new holography technique is expected to provide new information on local structures using the neutron technique.

Consumer diversity across kingdoms supports multiple functions in a coastal ecosystem

PubMed Central

Hensel, Marc J. S.; Silliman, Brian R.

2013-01-01

The global biodiversity crisis impairs the valuable benefits ecosystems provide humans. These nature-generated benefits are defined by a multitude of different ecosystem functions that operate simultaneously. Although several studies have simulated species loss in communities and tracked the response of single functions such as productivity or nutrient cycling, these studies have involved relatively similar taxa, and seldom are strikingly different functions examined. With the exception of highly managed ecosystems such as agricultural fields, rarely are we interested in only one function being performed well. Instead, we rely on ecosystems to deliver several different functions at the same time. Here, we experimentally investigated the extinction impacts of dominant consumers in a salt marsh. These consumers are remarkably phylogenetically diverse, spanning two kingdoms (i.e., Animalia and Fungi). Our field studies reveal that a diverse consumer assemblage significantly enhances simultaneous functioning of disparate ecosystem processes (i.e., productivity, decomposition, and infiltration). Extreme functional and phylogenetic differences among consumers underlie this relationship. Each marsh consumer affected at least one different ecosystem function, and each individual function was affected by no more than two consumers. The implications of these findings are profound: If we want ecosystems to perform many different functions well, it is not just number of species that matter. Rather, the presence of species representing markedly different ecologies and biology is also essential to maximizing multiple functions. Moreover, this work emphasizes the need to incorporate both microcomponents and macrocomponents of food webs to accurately predict biodiversity declines on integrated-ecosystem functioning. PMID:24297926

A poly(acrylonitrile)-functionalized porous aromatic framework synthesized by atom-transfer radical polymerization for the extraction of uranium from seawater

DOE PAGES

Yue, Yanfeng; Zhang, Chenxi; Tang, Qing; ...

2015-10-30

In order to ensure a sustainable reserve of fuel for nuclear power generation, tremendous research efforts have been devoted to developing advanced sorbent materials for extracting uranium from seawater. In this work, a porous aromatic framework (PAF) was surface-functionalized with poly(acrylonitrile) through atom-transfer radical polymerization (ATRP). Batches of this adsorbent were conditioned with potassium hydroxide (KOH) at room temperature or 80 °C prior to contact with a uranium-spiked seawater simulant, with minimal differences in uptake observed as a function of conditioning temperature. A maximum capacity of 4.81 g-U/kg-ads was obtained following 42 days contact with uranium-spiked filtered environmental seawater, whichmore » demonstrates a comparable adsorption rate. A kinetic investigation revealed extremely rapid uranyl uptake, with more than 80% saturation reached within 14 days. Furthermore, relying on the semiordered structure of the PAF adsorbent, density functional theory (DFT) calculations reveal cooperative interactions between multiple adsorbent groups yield a strong driving force for uranium binding.« less

Segregated Fronto-Cerebellar Circuits Revealed by Intrinsic Functional Connectivity

PubMed Central

Buckner, Randy L.

2009-01-01

Multiple, segregated fronto-cerebellar circuits have been characterized in nonhuman primates using transneuronal tracing techniques including those that target prefrontal areas. Here, we used functional connectivity MRI (fcMRI) in humans (n = 40) to identify 4 topographically distinct fronto-cerebellar circuits that target 1) motor cortex, 2) dorsolateral prefrontal cortex, 3) medial prefrontal cortex, and 4) anterior prefrontal cortex. All 4 circuits were replicated and dissociated in an independent data set (n = 40). Direct comparison of right- and left-seeded frontal regions revealed contralateral lateralization in the cerebellum for each of the segregated circuits. The presence of circuits that involve prefrontal regions confirms that the cerebellum participates in networks important to cognition including a specific fronto-cerebellar circuit that interacts with the default network. Overall, the extent of the cerebellum associated with prefrontal cortex included a large portion of the posterior hemispheres consistent with a prominent role of the cerebellum in nonmotor functions. We conclude by providing a provisional map of the topography of the cerebellum based on functional correlations with the frontal cortex. PMID:19592571

Recovering complete and draft population genomes from metagenome datasets

DOE PAGES

Sangwan, Naseer; Xia, Fangfang; Gilbert, Jack A.

2016-03-08

Assembly of metagenomic sequence data into microbial genomes is of fundamental value to improving our understanding of microbial ecology and metabolism by elucidating the functional potential of hard-to-culture microorganisms. Here, we provide a synthesis of available methods to bin metagenomic contigs into species-level groups and highlight how genetic diversity, sequencing depth, and coverage influence binning success. Despite the computational cost on application to deeply sequenced complex metagenomes (e.g., soil), covarying patterns of contig coverage across multiple datasets significantly improves the binning process. We also discuss and compare current genome validation methods and reveal how these methods tackle the problem ofmore » chimeric genome bins i.e., sequences from multiple species. Finally, we explore how population genome assembly can be used to uncover biogeographic trends and to characterize the effect of in situ functional constraints on the genome-wide evolution.« less

Recovering complete and draft population genomes from metagenome datasets

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

Sangwan, Naseer; Xia, Fangfang; Gilbert, Jack A.

Assembly of metagenomic sequence data into microbial genomes is of fundamental value to improving our understanding of microbial ecology and metabolism by elucidating the functional potential of hard-to-culture microorganisms. Here, we provide a synthesis of available methods to bin metagenomic contigs into species-level groups and highlight how genetic diversity, sequencing depth, and coverage influence binning success. Despite the computational cost on application to deeply sequenced complex metagenomes (e.g., soil), covarying patterns of contig coverage across multiple datasets significantly improves the binning process. We also discuss and compare current genome validation methods and reveal how these methods tackle the problem ofmore » chimeric genome bins i.e., sequences from multiple species. Finally, we explore how population genome assembly can be used to uncover biogeographic trends and to characterize the effect of in situ functional constraints on the genome-wide evolution.« less

On testing an unspecified function through a linear mixed effects model with multiple variance components

PubMed Central

Wang, Yuanjia; Chen, Huaihou

2012-01-01

Summary We examine a generalized F-test of a nonparametric function through penalized splines and a linear mixed effects model representation. With a mixed effects model representation of penalized splines, we imbed the test of an unspecified function into a test of some fixed effects and a variance component in a linear mixed effects model with nuisance variance components under the null. The procedure can be used to test a nonparametric function or varying-coefficient with clustered data, compare two spline functions, test the significance of an unspecified function in an additive model with multiple components, and test a row or a column effect in a two-way analysis of variance model. Through a spectral decomposition of the residual sum of squares, we provide a fast algorithm for computing the null distribution of the test, which significantly improves the computational efficiency over bootstrap. The spectral representation reveals a connection between the likelihood ratio test (LRT) in a multiple variance components model and a single component model. We examine our methods through simulations, where we show that the power of the generalized F-test may be higher than the LRT, depending on the hypothesis of interest and the true model under the alternative. We apply these methods to compute the genome-wide critical value and p-value of a genetic association test in a genome-wide association study (GWAS), where the usual bootstrap is computationally intensive (up to 108 simulations) and asymptotic approximation may be unreliable and conservative. PMID:23020801

On testing an unspecified function through a linear mixed effects model with multiple variance components.

PubMed

Wang, Yuanjia; Chen, Huaihou

2012-12-01

We examine a generalized F-test of a nonparametric function through penalized splines and a linear mixed effects model representation. With a mixed effects model representation of penalized splines, we imbed the test of an unspecified function into a test of some fixed effects and a variance component in a linear mixed effects model with nuisance variance components under the null. The procedure can be used to test a nonparametric function or varying-coefficient with clustered data, compare two spline functions, test the significance of an unspecified function in an additive model with multiple components, and test a row or a column effect in a two-way analysis of variance model. Through a spectral decomposition of the residual sum of squares, we provide a fast algorithm for computing the null distribution of the test, which significantly improves the computational efficiency over bootstrap. The spectral representation reveals a connection between the likelihood ratio test (LRT) in a multiple variance components model and a single component model. We examine our methods through simulations, where we show that the power of the generalized F-test may be higher than the LRT, depending on the hypothesis of interest and the true model under the alternative. We apply these methods to compute the genome-wide critical value and p-value of a genetic association test in a genome-wide association study (GWAS), where the usual bootstrap is computationally intensive (up to 10(8) simulations) and asymptotic approximation may be unreliable and conservative. © 2012, The International Biometric Society.

Imaging Voltage in Genetically Defined Neuronal Subpopulations with a Cre Recombinase-Targeted Hybrid Voltage Sensor.

PubMed

Bayguinov, Peter O; Ma, Yihe; Gao, Yu; Zhao, Xinyu; Jackson, Meyer B

2017-09-20

Genetically encoded voltage indicators create an opportunity to monitor electrical activity in defined sets of neurons as they participate in the complex patterns of coordinated electrical activity that underlie nervous system function. Taking full advantage of genetically encoded voltage indicators requires a generalized strategy for targeting the probe to genetically defined populations of cells. To this end, we have generated a mouse line with an optimized hybrid voltage sensor (hVOS) probe within a locus designed for efficient Cre recombinase-dependent expression. Crossing this mouse with Cre drivers generated double transgenics expressing hVOS probe in GABAergic, parvalbumin, and calretinin interneurons, as well as hilar mossy cells, new adult-born neurons, and recently active neurons. In each case, imaging in brain slices from male or female animals revealed electrically evoked optical signals from multiple individual neurons in single trials. These imaging experiments revealed action potentials, dynamic aspects of dendritic integration, and trial-to-trial fluctuations in response latency. The rapid time response of hVOS imaging revealed action potentials with high temporal fidelity, and enabled accurate measurements of spike half-widths characteristic of each cell type. Simultaneous recording of rapid voltage changes in multiple neurons with a common genetic signature offers a powerful approach to the study of neural circuit function and the investigation of how neural networks encode, process, and store information. SIGNIFICANCE STATEMENT Genetically encoded voltage indicators hold great promise in the study of neural circuitry, but realizing their full potential depends on targeting the sensor to distinct cell types. Here we present a new mouse line that expresses a hybrid optical voltage sensor under the control of Cre recombinase. Crossing this line with Cre drivers generated double-transgenic mice, which express this sensor in targeted cell types. In brain slices from these animals, single-trial hybrid optical voltage sensor recordings revealed voltage changes with submillisecond resolution in multiple neurons simultaneously. This imaging tool will allow for the study of the emergent properties of neural circuits and permit experimental tests of the roles of specific types of neurons in complex circuit activity. Copyright © 2017 the authors 0270-6474/17/379305-15$15.00/0.

Effect of posttranslational modifications on enzyme function and assembly.

PubMed

Ryšlavá, Helena; Doubnerová, Veronika; Kavan, Daniel; Vaněk, Ondřej

2013-10-30

The detailed examination of enzyme molecules by mass spectrometry and other techniques continues to identify hundreds of distinct PTMs. Recently, global analyses of enzymes using methods of contemporary proteomics revealed widespread distribution of PTMs on many key enzymes distributed in all cellular compartments. Critically, patterns of multiple enzymatic and nonenzymatic PTMs within a single enzyme are now functionally evaluated providing a holistic picture of a macromolecule interacting with low molecular mass compounds, some of them being substrates, enzyme regulators, or activated precursors for enzymatic and nonenzymatic PTMs. Multiple PTMs within a single enzyme molecule and their mutual interplays are critical for the regulation of catalytic activity. Full understanding of this regulation will require detailed structural investigation of enzymes, their structural analogs, and their complexes. Further, proteomics is now integrated with molecular genetics, transcriptomics, and other areas leading to systems biology strategies. These allow the functional interrogation of complex enzymatic networks in their natural environment. In the future, one might envisage the use of robust high throughput analytical techniques that will be able to detect multiple PTMs on a global scale of individual proteomes from a number of carefully selected cells and cellular compartments. This article is part of a Special Issue entitled: Posttranslational Protein modifications in biology and Medicine. Copyright © 2013 Elsevier B.V. All rights reserved.

The causes of hypopituitarism in the absence of abnormal pituitary imaging.

PubMed

Wilson, V; Mallipedhi, A; Stephens, J W; Redfern, R M; Price, D E

2014-01-01

Hypopituitarism in the absence of a history of pituitary pathology or abnormal pituitary imaging is rare. To identify the cause of hypopituitarism in individuals in whom pituitary imaging was normal. Retrospective analysis of electronic patient record. A review of the pituitary function in the 506 patients on the Morriston Hospital pituitary database revealed 230 had some degree of hypopituitarism and of these, 21 (9%) had normal pituitary imaging. Of this group, six patients had a past medical history of subarachnoid haemorrhage, head injury or meningitis, and mainly suffered from a deficiency of antidiuretic hormone. One patient had a stroke resulting in multiple anterior hormone deficiencies and six individuals had idiopathic cranial diabetes insipidus (DI). Subsequent investigations of the remaining eight patients with normal pituitary imaging revealed that two had neurosarcoidosis both of whom had panhypopituitarism. Four patients had haemochromatosis which resulted in gonadotropin deficiency in two, DI in one and panhypopituitarism in the other. There were two individuals with confirmed hypopituitarism and multiple hormone deficiencies in which no cause could be identified. These results show that hypopituitarism in the absence of pituitary pathology or an identifiable cause is rare. In patients with multiple anterior pituitary hormone deficiencies haemochromatosis and sarcoidosis should be considered.

Circular RNA profiling reveals that circular RNAs from ANXA2 can be used as new biomarkers for multiple sclerosis.

PubMed

Iparraguirre, Leire; Muñoz-Culla, Maider; Prada-Luengo, Iñigo; Castillo-Triviño, Tamara; Olascoaga, Javier; Otaegui, David

2017-09-15

Multiple sclerosis is an autoimmune disease, with higher prevalence in women, in whom the immune system is dysregulated. This dysregulation has been shown to correlate with changes in transcriptome expression as well as in gene-expression regulators, such as non-coding RNAs (e.g. microRNAs). Indeed, some of these have been suggested as biomarkers for multiple sclerosis even though few biomarkers have reached the clinical practice. Recently, a novel family of non-coding RNAs, circular RNAs, has emerged as a new player in the complex network of gene-expression regulation. MicroRNA regulation function through a 'sponge system' and a RNA splicing regulation function have been proposed for the circular RNAs. This regulating role together with their high stability in biofluids makes them seemingly good candidates as biomarkers. Given the dysregulation of both protein-coding and non-coding transcriptome that have been reported in multiple sclerosis patients, we hypothesised that circular RNA expression may also be altered. Therefore, we carried out expression profiling of 13.617 circular RNAs in peripheral blood leucocytes from multiple sclerosis patients and healthy controls finding 406 differentially expressed (P-value < 0.05, Fold change > 1.5) and demonstrate after validation that, circ_0005402 and circ_0035560 are underexpressed in multiple sclerosis patients and could be used as biomarkers of the disease. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

MultiSETTER: web server for multiple RNA structure comparison.

PubMed

Čech, Petr; Hoksza, David; Svozil, Daniel

2015-08-12

Understanding the architecture and function of RNA molecules requires methods for comparing and analyzing their tertiary and quaternary structures. While structural superposition of short RNAs is achievable in a reasonable time, large structures represent much bigger challenge. Therefore, we have developed a fast and accurate algorithm for RNA pairwise structure superposition called SETTER and implemented it in the SETTER web server. However, though biological relationships can be inferred by a pairwise structure alignment, key features preserved by evolution can be identified only from a multiple structure alignment. Thus, we extended the SETTER algorithm to the alignment of multiple RNA structures and developed the MultiSETTER algorithm. In this paper, we present the updated version of the SETTER web server that implements a user friendly interface to the MultiSETTER algorithm. The server accepts RNA structures either as the list of PDB IDs or as user-defined PDB files. After the superposition is computed, structures are visualized in 3D and several reports and statistics are generated. To the best of our knowledge, the MultiSETTER web server is the first publicly available tool for a multiple RNA structure alignment. The MultiSETTER server offers the visual inspection of an alignment in 3D space which may reveal structural and functional relationships not captured by other multiple alignment methods based either on a sequence or on secondary structure motifs.

Association between the Type of Workplace and Lung Function in Copper Miners

PubMed Central

Gruszczyński, Leszek; Wojakowska, Anna; Ścieszka, Marek; Turczyn, Barbara; Schmidt, Edward

2016-01-01

The aim of the analysis was to retrospectively assess changes in lung function in copper miners depending on the type of workplace. In the groups of 225 operators, 188 welders, and 475 representatives of other jobs, spirometry was performed at the start of employment and subsequently after 10, 20, and 25 years of work. Spirometry Longitudinal Data Analysis software was used to estimate changes in group means for FEV1 and FVC. Multiple linear regression analysis was used to assess an association between workplace and lung function. Lung function assessed on the basis of calculation of longitudinal FEV1 (FVC) decline was similar in all studied groups. However, multiple linear regression model used in cross-sectional analysis revealed an association between workplace and lung function. In the group of welders, FEF75 was lower in comparison to operators and other miners as early as after 10 years of work. Simultaneously, in smoking welders, the FEV1/FVC ratio was lower than in nonsmokers (p < 0,05). The interactions between type of workplace and smoking (p < 0,05) in their effect on FVC, FEV1, PEF, and FEF50 were shown. Among underground working copper miners, the group of smoking welders is especially threatened by impairment of lung ventilatory function. PMID:27274987

Correlates of Social Functioning in Autism Spectrum Disorder: The Role of Social Cognition

PubMed Central

Bishop-Fitzpatrick, Lauren; Mazefsky, Carla A.; Eack, Shaun M.; Minshew, Nancy J.

2017-01-01

Background Individuals with autism spectrum disorder (ASD) experience marked challenges with social function by definition, but few modifiable predictors of social functioning in ASD have been identified in extant research. This study hypothesized that deficits in social cognition and motor function may help to explain poor social functioning in individuals with ASD. Method Cross-sectional data from 108 individuals with ASD and without intellectual disability ages 9 through 27.5 were used to assess the relationship between social cognition and motor function, and social functioning. Results Results of hierarchical multiple regression analyses revealed that greater social cognition, but not motor function, was significantly associated with better social functioning when controlling for sex, age, and intelligence quotient. Post-hoc analyses revealed that, better performance on second-order false belief tasks was associated with higher levels of socially adaptive behavior and lower levels of social problems. Conclusions Our findings support the development and testing of interventions that target social cognition in order to improve social functioning in individuals with ASD. Interventions that teach generalizable skills to help people with ASD better understand social situations and develop competency in advanced perspective taking have the potential to create more durable change because their effects can be applied to a wide and varied set of situations and not simply a prescribed set of rehearsed situations. PMID:28839456

Fungal proteomics: from identification to function.

PubMed

Doyle, Sean

2011-08-01

Some fungi cause disease in humans and plants, while others have demonstrable potential for the control of insect pests. In addition, fungi are also a rich reservoir of therapeutic metabolites and industrially useful enzymes. Detailed analysis of fungal biochemistry is now enabled by multiple technologies including protein mass spectrometry, genome and transcriptome sequencing and advances in bioinformatics. Yet, the assignment of function to fungal proteins, encoded either by in silico annotated, or unannotated genes, remains problematic. The purpose of this review is to describe the strategies used by many researchers to reveal protein function in fungi, and more importantly, to consolidate the nomenclature of 'unknown function protein' as opposed to 'hypothetical protein' - once any protein has been identified by protein mass spectrometry. A combination of approaches including comparative proteomics, pathogen-induced protein expression and immunoproteomics are outlined, which, when used in combination with a variety of other techniques (e.g. functional genomics, microarray analysis, immunochemical and infection model systems), appear to yield comprehensive and definitive information on protein function in fungi. The relative advantages of proteomic, as opposed to transcriptomic-only, analyses are also described. In the future, combined high-throughput, quantitative proteomics, allied to transcriptomic sequencing, are set to reveal much about protein function in fungi. © 2011 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.

Contribution of Theory of Mind, Executive Functioning, and Pragmatics to Socialization Behaviors of Children with High-Functioning Autism.

PubMed

Berenguer, Carmen; Miranda, Ana; Colomer, Carla; Baixauli, Inmaculada; Roselló, Belén

2018-02-01

Social difficulties are a key aspect of autism, but the intervening factors are still poorly understood. This study had two objectives: to compare the profile of ToM skills, executive functioning (EF), and pragmatic competence (PC) of children with high-functioning autism (HFA) and children with typical development (TD), and analyze their mediator role in social functioning. The participants were 52 children with HFA and 37 children with TD matched on age, intelligence quotient, and expressive vocabulary. Significant differences were found on measures of ToM, both explicit and applied, EF, and PC between children with HFA and TD. Multiple mediation analysis revealed that applied ToM skills and PC mediated the relations between autism symptoms and social functioning. Implications for social cognitive interventions to address these findings are discussed.

Whole-Genome Duplication and the Functional Diversification of Teleost Fish Hemoglobins

PubMed Central

Opazo, Juan C.; Butts, G. Tyler; Nery, Mariana F.; Storz, Jay F.; Hoffmann, Federico G.

2013-01-01

Subsequent to the two rounds of whole-genome duplication that occurred in the common ancestor of vertebrates, a third genome duplication occurred in the stem lineage of teleost fishes. This teleost-specific genome duplication (TGD) is thought to have provided genetic raw materials for the physiological, morphological, and behavioral diversification of this highly speciose group. The extreme physiological versatility of teleost fish is manifest in their diversity of blood–gas transport traits, which reflects the myriad solutions that have evolved to maintain tissue O2 delivery in the face of changing metabolic demands and environmental O2 availability during different ontogenetic stages. During the course of development, regulatory changes in blood–O2 transport are mediated by the expression of multiple, functionally distinct hemoglobin (Hb) isoforms that meet the particular O2-transport challenges encountered by the developing embryo or fetus (in viviparous or oviparous species) and in free-swimming larvae and adults. The main objective of the present study was to assess the relative contributions of whole-genome duplication, large-scale segmental duplication, and small-scale gene duplication in producing the extraordinary functional diversity of teleost Hbs. To accomplish this, we integrated phylogenetic reconstructions with analyses of conserved synteny to characterize the genomic organization and evolutionary history of the globin gene clusters of teleosts. These results were then integrated with available experimental data on functional properties and developmental patterns of stage-specific gene expression. Our results indicate that multiple α- and β-globin genes were present in the common ancestor of gars (order Lepisoteiformes) and teleosts. The comparative genomic analysis revealed that teleosts possess a dual set of TGD-derived globin gene clusters, each of which has undergone lineage-specific changes in gene content via repeated duplication and deletion events. Phylogenetic reconstructions revealed that paralogous genes convergently evolved similar functional properties in different teleost lineages. Consistent with other recent studies of globin gene family evolution in vertebrates, our results revealed evidence for repeated evolutionary transitions in the developmental regulation of Hb synthesis. PMID:22949522

Case report: paradoxical ventricular septal motion in the setting of primary right ventricular myocardial failure.

PubMed

Maslow, Andrew; Schwartz, Carl; Mahmood, Feroze; Singh, Arun; Heerdt, Paul M

2009-07-01

In this report, a case of right ventricular (RV) failure, hemodynamic instability, and systemic organ failure is described to highlight how paradoxical ventricular systolic septal motion (PVSM), or a rightward systolic displacement of the interventricular septum, may contribute to RV ejection. Multiple inotropic medications and vasopressors were administered to treat right heart failure and systemic hypotension in a patient following combined aortic and mitral valve replacement. In the early postoperative period, echocardiographic evaluation revealed adequate left ventricular systolic function, akinesis of the RV myocardial tissues, and PVSM. In the presence of PVSM, RV fractional area of contraction was > or =35% despite akinesis of the primary RV myocardial walls. The PVSM appeared to contribute toward RV ejection. As a result, the need for multiple inotropes was re-evaluated, in considering that end-organ dysfunction was the result of systemic hypotension and prolonged vasopressor administration. After discontinuation of phosphodiesterase inhibitors, native vascular tone returned and the need for vasopressors declined. This was followed by recovery of systemic organ function. Echocardiographic re-evaluation two years later, revealed persistent akinesis of the RV myocardial tissues and PVSM, the latter appearing to contribute toward RV ejection. This case highlights the importance of left to RV interactions, and how PVSM may mediate these hemodynamic interactions.

Genes uniquely expressed in human growth plate chondrocytes uncover a distinct regulatory network.

PubMed

Li, Bing; Balasubramanian, Karthika; Krakow, Deborah; Cohn, Daniel H

2017-12-20

Chondrogenesis is the earliest stage of skeletal development and is a highly dynamic process, integrating the activities and functions of transcription factors, cell signaling molecules and extracellular matrix proteins. The molecular mechanisms underlying chondrogenesis have been extensively studied and multiple key regulators of this process have been identified. However, a genome-wide overview of the gene regulatory network in chondrogenesis has not been achieved. In this study, employing RNA sequencing, we identified 332 protein coding genes and 34 long non-coding RNA (lncRNA) genes that are highly selectively expressed in human fetal growth plate chondrocytes. Among the protein coding genes, 32 genes were associated with 62 distinct human skeletal disorders and 153 genes were associated with skeletal defects in knockout mice, confirming their essential roles in skeletal formation. These gene products formed a comprehensive physical interaction network and participated in multiple cellular processes regulating skeletal development. The data also revealed 34 transcription factors and 11,334 distal enhancers that were uniquely active in chondrocytes, functioning as transcriptional regulators for the cartilage-selective genes. Our findings revealed a complex gene regulatory network controlling skeletal development whereby transcription factors, enhancers and lncRNAs participate in chondrogenesis by transcriptional regulation of key genes. Additionally, the cartilage-selective genes represent candidate genes for unsolved human skeletal disorders.

Content Representation in the Human Medial Temporal Lobe

PubMed Central

Liang, Jackson C.; Wagner, Anthony D.

2013-01-01

Current theories of medial temporal lobe (MTL) function focus on event content as an important organizational principle that differentiates MTL subregions. Perirhinal and parahippocampal cortices may play content-specific roles in memory, whereas hippocampal processing is alternately hypothesized to be content specific or content general. Despite anatomical evidence for content-specific MTL pathways, empirical data for content-based MTL subregional dissociations are mixed. Here, we combined functional magnetic resonance imaging with multiple statistical approaches to characterize MTL subregional responses to different classes of novel event content (faces, scenes, spoken words, sounds, visual words). Univariate analyses revealed that responses to novel faces and scenes were distributed across the anterior–posterior axis of MTL cortex, with face responses distributed more anteriorly than scene responses. Moreover, multivariate pattern analyses of perirhinal and parahippocampal data revealed spatially organized representational codes for multiple content classes, including nonpreferred visual and auditory stimuli. In contrast, anterior hippocampal responses were content general, with less accurate overall pattern classification relative to MTL cortex. Finally, posterior hippocampal activation patterns consistently discriminated scenes more accurately than other forms of content. Collectively, our findings indicate differential contributions of MTL subregions to event representation via a distributed code along the anterior–posterior axis of MTL that depends on the nature of event content. PMID:22275474

Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons.

PubMed

Griesi-Oliveira, K; Acab, A; Gupta, A R; Sunaga, D Y; Chailangkarn, T; Nicol, X; Nunez, Y; Walker, M F; Murdoch, J D; Sanders, S J; Fernandez, T V; Ji, W; Lifton, R P; Vadasz, E; Dietrich, A; Pradhan, D; Song, H; Ming, G-L; Gu, X; Haddad, G; Marchetto, M C N; Spitzer, N; Passos-Bueno, M R; State, M W; Muotri, A R

2015-11-01

An increasing number of genetic variants have been implicated in autism spectrum disorders (ASDs), and the functional study of such variants will be critical for the elucidation of autism pathophysiology. Here, we report a de novo balanced translocation disruption of TRPC6, a cation channel, in a non-syndromic autistic individual. Using multiple models, such as dental pulp cells, induced pluripotent stem cell (iPSC)-derived neuronal cells and mouse models, we demonstrate that TRPC6 reduction or haploinsufficiency leads to altered neuronal development, morphology and function. The observed neuronal phenotypes could then be rescued by TRPC6 complementation and by treatment with insulin-like growth factor-1 or hyperforin, a TRPC6-specific agonist, suggesting that ASD individuals with alterations in this pathway may benefit from these drugs. We also demonstrate that methyl CpG binding protein-2 (MeCP2) levels affect TRPC6 expression. Mutations in MeCP2 cause Rett syndrome, revealing common pathways among ASDs. Genetic sequencing of TRPC6 in 1041 ASD individuals and 2872 controls revealed significantly more nonsynonymous mutations in the ASD population, and identified loss-of-function mutations with incomplete penetrance in two patients. Taken together, these findings suggest that TRPC6 is a novel predisposing gene for ASD that may act in a multiple-hit model. This is the first study to use iPSC-derived human neurons to model non-syndromic ASD and illustrate the potential of modeling genetically complex sporadic diseases using such cells.

Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons

PubMed Central

Griesi-Oliveira, Karina; Acab, Allan; Gupta, Abha R.; Sunaga, Daniele Yumi; Chailangkarn, Thanathom; Nicol, Xavier; Nunez, Yanelli; Walker, Michael F.; Murdoch, John D.; Sanders, Stephan J.; Fernandez, Thomas V.; Ji, Weizhen; Lifton, Richard P.; Vadasz, Estevão; Dietrich, Alexander; Pradhan, Dennis; Song, Hongjun; Ming, Guo-li; Guoe, Xiang; Haddad, Gabriel; Marchetto, Maria C. N.; Spitzer, Nicholas; Passos-Bueno, Maria Rita; State, Matthew W.; Muotri, Alysson R.

2014-01-01

An increasing number of genetic variants have been implicated in autism spectrum disorders (ASD), and the functional study of such variants will be critical for the elucidation of autism pathophysiology. Here, we report a de novo balanced translocation disruption of TRPC6, a cation channel, in a non-syndromic autistic individual. Using multiple models, such as dental pulp cells, iPSC-derived neuronal cells and mouse models, we demonstrate that TRPC6 reduction or haploinsufficiency leads to altered neuronal development, morphology, and function. The observed neuronal phenotypes could then be rescued by TRPC6 complementation and by treatment with IGF1 or hyperforin, a TRPC6-specific agonist, suggesting that ASD individuals with alterations in this pathway might benefit from these drugs. We also demonstrate that MeCP2 levels affect TRPC6 expression. Mutations in MeCP2 cause Rett syndrome, revealing common pathways among ASDs. Genetic sequencing of TRPC6 in 1041 ASD individuals and 2872 controls revealed significantly more nonsynonymous mutations in the ASD population, and identified loss-of-function mutations with incomplete penetrance in two patients. Taken together, these findings suggest that TRPC6 is a novel predisposing gene for ASD that may act in a multiple-hit model. This is the first study to use iPSC-derived human neurons to model non-syndromic ASD and illustrate the potential of modeling genetically complex sporadic diseases using such cells. PMID:25385366

Aberrant functioning of the theory-of-mind network in children and adolescents with autism.

PubMed

Kana, Rajesh K; Maximo, Jose O; Williams, Diane L; Keller, Timothy A; Schipul, Sarah E; Cherkassky, Vladimir L; Minshew, Nancy J; Just, Marcel Adam

2015-01-01

Theory-of-mind (ToM), the ability to infer people's thoughts and feelings, is a pivotal skill in effective social interactions. Individuals with autism spectrum disorders (ASD) have been found to have altered ToM skills, which significantly impacts the quality of their social interactions. Neuroimaging studies have reported altered activation of the ToM cortical network, especially in adults with autism, yet little is known about the brain responses underlying ToM in younger individuals with ASD. This functional magnetic resonance imaging (fMRI) study investigated the neural mechanisms underlying ToM in high-functioning children and adolescents with ASD and matched typically developing (TD) peers. fMRI data were acquired from 13 participants with ASD and 13 TD control participants while they watched animations involving two "interacting" geometrical shapes. Participants with ASD showed significantly reduced activation, relative to TD controls, in regions considered part of the ToM network, the mirror network, and the cerebellum. Functional connectivity analyses revealed underconnectivity between frontal and posterior regions during task performance in the ASD participants. Overall, the findings of this study reveal disruptions in the brain circuitry underlying ToM in ASD at multiple levels, including decreased activation and decreased functional connectivity.

Discriminative analysis of non-linear brain connectivity for leukoaraiosis with resting-state fMRI

NASA Astrophysics Data System (ADS)

Lai, Youzhi; Xu, Lele; Yao, Li; Wu, Xia

2015-03-01

Leukoaraiosis (LA) describes diffuse white matter abnormalities on CT or MR brain scans, often seen in the normal elderly and in association with vascular risk factors such as hypertension, or in the context of cognitive impairment. The mechanism of cognitive dysfunction is still unclear. The recent clinical studies have revealed that the severity of LA was not corresponding to the cognitive level, and functional connectivity analysis is an appropriate method to detect the relation between LA and cognitive decline. However, existing functional connectivity analyses of LA have been mostly limited to linear associations. In this investigation, a novel measure utilizing the extended maximal information coefficient (eMIC) was applied to construct non-linear functional connectivity in 44 LA subjects (9 dementia, 25 mild cognitive impairment (MCI) and 10 cognitively normal (CN)). The strength of non-linear functional connections for the first 1% of discriminative power increased in MCI compared with CN and dementia, which was opposed to its linear counterpart. Further functional network analysis revealed that the changes of the non-linear and linear connectivity have similar but not completely the same spatial distribution in human brain. In the multivariate pattern analysis with multiple classifiers, the non-linear functional connectivity mostly identified dementia, MCI and CN from LA with a relatively higher accuracy rate than the linear measure. Our findings revealed the non-linear functional connectivity provided useful discriminative power in classification of LA, and the spatial distributed changes between the non-linear and linear measure may indicate the underlying mechanism of cognitive dysfunction in LA.

Dynamic transcriptomic m6A decoration: writers, erasers, readers and functions in RNA metabolism.

PubMed

Yang, Ying; Hsu, Phillip J; Chen, Yu-Sheng; Yang, Yun-Gui

2018-05-22

N 6 -methyladenosine (m 6 A) is a chemical modification present in multiple RNA species, being most abundant in mRNAs. Studies on enzymes or factors that catalyze, recognize, and remove m 6 A have revealed its comprehensive roles in almost every aspect of mRNA metabolism, as well as in a variety of physiological processes. This review describes the current understanding of the m 6 A modification, particularly the functions of its writers, erasers, readers in RNA metabolism, with an emphasis on its role in regulating the isoform dosage of mRNAs.

Neurocognition and community outcome in schizophrenia: long-term predictive validity.

PubMed

Fujii, Daryl E; Wylie, A Michael

2003-02-01

The present study examined the predictive validity of neuropsychological measures to functional outcome in 26 schizophrenic patients 15-plus year post-testing. Outcome measures included score on the Resource Associated Functional Level Scale (RAFLS), number of state hospital admissions, and total duration of state hospital inpatient stay. Results of several stepwise multiple regressions revealed that verbal memory significantly predicted RAFLS score, accounting for nearly half of the variance. Trails B significantly predicted duration of state hospital inpatient status. Discussion focused on the utility of these measures for clinicians and system planners. Copyright 2002 Elsevier Science B.V.

Treatment with insulin analogs and prevalence of cardiovascular complications in patients with type 1 diabetes.

PubMed

Hasslacher, Christoph; Lorenzo Bermejo, Justo

2017-11-01

A lower incidence of cardiovascular events has been reported in type 2 diabetes patients treated with insulin analogs (IAs). Corresponding data on people affected by type 1 diabetes are not available yet. We investigated demographic and clinical data from 509 type 1 diabetics, who were treated in an outpatient clinic from 2006 to 2012. Multiple logistic regression was used to investigate the relationship between the type of insulin treatment and the prevalence of cardiovascular (CV) complications, that is, presence of coronary heart, cerebrovascular and peripheral arterial diseases, adjusting for potential confounders. Results from multiple logistic regression revealed that patients with impaired renal function [estimated glomerular filtration rate (eGFR) < 90 ml/min] show lower CV complication rates when treated with IAs (25%) compared with patients treated with human insulin (HI; 28%) and HI/IA (38%, p = 0.06). CV complication rates in the complete patient collective amounted to 17% (IA), 21% (HI) and 21% (HI/IA, p = 0.08). Examination of CV complications according to the type of IA revealed the lowest complication rates in type 1 diabetics treated with insulin lispro (5.9%) and glargine (16%). However, complication rate differences among insulin treatments did not reach statistical significance. The present cross-sectional study shows a borderline significantly lower CV morbidity in people with type 1 diabetes and impaired renal function when treated with IA compared with HI treatment after adjustment for multiple potential confounders [odds ratio (OR) = 0.78, which translates into a 22% lower complication rate]. Validation of these preliminary findings in confirmatory, prospective studies may have important clinical implications.

A combined computational-experimental analyses of selected metabolic enzymes in Pseudomonas species.

PubMed

Perumal, Deepak; Lim, Chu Sing; Chow, Vincent T K; Sakharkar, Kishore R; Sakharkar, Meena K

2008-09-10

Comparative genomic analysis has revolutionized our ability to predict the metabolic subsystems that occur in newly sequenced genomes, and to explore the functional roles of the set of genes within each subsystem. These computational predictions can considerably reduce the volume of experimental studies required to assess basic metabolic properties of multiple bacterial species. However, experimental validations are still required to resolve the apparent inconsistencies in the predictions by multiple resources. Here, we present combined computational-experimental analyses on eight completely sequenced Pseudomonas species. Comparative pathway analyses reveal that several pathways within the Pseudomonas species show high plasticity and versatility. Potential bypasses in 11 metabolic pathways were identified. We further confirmed the presence of the enzyme O-acetyl homoserine (thiol) lyase (EC: 2.5.1.49) in P. syringae pv. tomato that revealed inconsistent annotations in KEGG and in the recently published SYSTOMONAS database. These analyses connect and integrate systematic data generation, computational data interpretation, and experimental validation and represent a synergistic and powerful means for conducting biological research.

To Stroop or Not to Stroop: Sex-Related Differences in Brain-Behavior Associations During Early Childhood

PubMed Central

Cuevas, Kimberly; Calkins, Susan D.; Bell, Martha Ann

2015-01-01

Executive functions (EFs) are linked with optimal cognitive and social-emotional development. Despite behavioral evidence of sex differences in early childhood EF, little is known about potential sex differences in corresponding brain-behavior associations. The present study examined changes in 4-year-olds’ 6–9 Hz EEG power in response to increased executive processing demands (i.e., “Stroop-like” vs. “non-Stroop” day-night tasks). Although there were no sex differences in task performance, an examination of multiple scalp electrode sites revealed that boys exhibited more widespread changes in EEG power as compared to girls. Further, multiple regression analyses controlling for maternal education and non-EF performance indicated that individual differences in boys’ and girls’ EF performance were associated with different frontal neural correlates (i.e., different frontal scalp sites and different measures of EEG power). These data reveal valuable information concerning sex differences in the neural systems underlying executive processing during early childhood. PMID:26681615

Multi-color electron microscopy by element-guided identification of cells, organelles and molecules.

PubMed

Scotuzzi, Marijke; Kuipers, Jeroen; Wensveen, Dasha I; de Boer, Pascal; Hagen, Kees C W; Hoogenboom, Jacob P; Giepmans, Ben N G

2017-04-07

Cellular complexity is unraveled at nanometer resolution using electron microscopy (EM), but interpretation of macromolecular functionality is hampered by the difficulty in interpreting grey-scale images and the unidentified molecular content. We perform large-scale EM on mammalian tissue complemented with energy-dispersive X-ray analysis (EDX) to allow EM-data analysis based on elemental composition. Endogenous elements, labels (gold and cadmium-based nanoparticles) as well as stains are analyzed at ultrastructural resolution. This provides a wide palette of colors to paint the traditional grey-scale EM images for composition-based interpretation. Our proof-of-principle application of EM-EDX reveals that endocrine and exocrine vesicles exist in single cells in Islets of Langerhans. This highlights how elemental mapping reveals unbiased biomedical relevant information. Broad application of EM-EDX will further allow experimental analysis on large-scale tissue using endogenous elements, multiple stains, and multiple markers and thus brings nanometer-scale 'color-EM' as a promising tool to unravel molecular (de)regulation in biomedicine.

Multi-color electron microscopy by element-guided identification of cells, organelles and molecules

PubMed Central

Scotuzzi, Marijke; Kuipers, Jeroen; Wensveen, Dasha I.; de Boer, Pascal; Hagen, Kees (C.) W.; Hoogenboom, Jacob P.; Giepmans, Ben N. G.

2017-01-01

Cellular complexity is unraveled at nanometer resolution using electron microscopy (EM), but interpretation of macromolecular functionality is hampered by the difficulty in interpreting grey-scale images and the unidentified molecular content. We perform large-scale EM on mammalian tissue complemented with energy-dispersive X-ray analysis (EDX) to allow EM-data analysis based on elemental composition. Endogenous elements, labels (gold and cadmium-based nanoparticles) as well as stains are analyzed at ultrastructural resolution. This provides a wide palette of colors to paint the traditional grey-scale EM images for composition-based interpretation. Our proof-of-principle application of EM-EDX reveals that endocrine and exocrine vesicles exist in single cells in Islets of Langerhans. This highlights how elemental mapping reveals unbiased biomedical relevant information. Broad application of EM-EDX will further allow experimental analysis on large-scale tissue using endogenous elements, multiple stains, and multiple markers and thus brings nanometer-scale ‘color-EM’ as a promising tool to unravel molecular (de)regulation in biomedicine. PMID:28387351

Hypoxia and Mucosal Inflammation

PubMed Central

Colgan, Sean P.; Campbell, Eric L.; Kominsky, Douglas J.

2016-01-01

Sites of inflammation are defined by significant changes in metabolic activity. Recent studies have suggested that O2 metabolism and hypoxia play a prominent role in inflammation so-called “inflammatory hypoxia,” which results from a combination of recruited inflammatory cells (e.g., neutrophils and monocytes), the local proliferation of multiple cell types, and the activation of multiple O2-consuming enzymes during inflammation. These shifts in energy supply and demand result in localized regions of hypoxia and have revealed the important function off the transcription factor HIF (hypoxia-inducible factor) in the regulation of key target genes that promote inflammatory resolution. Analysis of these pathways has provided multiple opportunities for understanding basic mechanisms of inflammation and has defined new targets for intervention. Here, we review recent work addressing tissue hypoxia and metabolic control of inflammation and immunity. PMID:27193451

Amyloid Fibrils as Building Blocks for Natural and Artificial Functional Materials.

PubMed

Knowles, Tuomas P J; Mezzenga, Raffaele

2016-08-01

Proteinaceous materials based on the amyloid core structure have recently been discovered at the origin of biological functionality in a remarkably diverse set of roles, and attention is increasingly turning towards such structures as the basis of artificial self-assembling materials. These roles contrast markedly with the original picture of amyloid fibrils as inherently pathological structures. Here we outline the salient features of this class of functional materials, both in the context of the functional roles that have been revealed for amyloid fibrils in nature, as well as in relation to their potential as artificial materials. We discuss how amyloid materials exemplify the emergence of function from protein self-assembly at multiple length scales. We focus on the connections between mesoscale structure and material function, and demonstrate how the natural examples of functional amyloids illuminate the potential applications for future artificial protein based materials. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The genome and phenome of the green alga Chloroidium sp. UTEX 3007 reveal adaptive traits for desert acclimatization.

PubMed

Nelson, David R; Khraiwesh, Basel; Fu, Weiqi; Alseekh, Saleh; Jaiswal, Ashish; Chaiboonchoe, Amphun; Hazzouri, Khaled M; O'Connor, Matthew J; Butterfoss, Glenn L; Drou, Nizar; Rowe, Jillian D; Harb, Jamil; Fernie, Alisdair R; Gunsalus, Kristin C; Salehi-Ashtiani, Kourosh

2017-06-17

To investigate the phenomic and genomic traits that allow green algae to survive in deserts, we characterized a ubiquitous species, Chloroidium sp. UTEX 3007 , which we isolated from multiple locations in the United Arab Emirates (UAE). Metabolomic analyses of Chloroidium sp. UTEX 3007 indicated that the alga accumulates a broad range of carbon sources, including several desiccation tolerance-promoting sugars and unusually large stores of palmitate. Growth assays revealed capacities to grow in salinities from zero to 60 g/L and to grow heterotrophically on >40 distinct carbon sources. Assembly and annotation of genomic reads yielded a 52.5 Mbp genome with 8153 functionally annotated genes. Comparison with other sequenced green algae revealed unique protein families involved in osmotic stress tolerance and saccharide metabolism that support phenomic studies. Our results reveal the robust and flexible biology utilized by a green alga to successfully inhabit a desert coastline.

Concanavalin-A conjugated fine-multiple emulsion loaded with 6-mercaptopurine.

PubMed

Khopade, A J; Jain, N K

2000-01-01

Fine-multiple (water-in-oil-in-water) emulsions were prepared by two-step emulsification using sonication. They were coated with concanavalin-A (Con-A) by three methods. The one involving covalent coupling of Con-A to the multiple emulsion incorporated anchor was better compared with lipid derivatized Con-A anchoring or the glutaraldehyde-based cross-linking method, as shown by the faster rate of dextran-induced aggregation. The selected multiple emulsions were characterized by physical properties such as droplet size, encapsulation efficiency, and zeta potential. Stability parameters such as droplet size, creaming, leakage, and aggregation as a function of relative turbidity were monitored over a 1-month period, which revealed good stability of the formulations. The release profile of 6-mercaptopurine followed zero-order kinetics. Pharmacokinetic studies showed an increase in half-life and bioavailability from multiple emulsion formulations administered intravenously. There was prolonged retention of drug in various tissues of rats when treated with Con-A-coated multiple emulsion as compared with uncoated one. Our study demonstrates the suitability of fine-multiple emulsion for intravenous administration and the potential for prolonged retention of drugs and targeting in biological systems.

Changes in Cortical Activity During Real and Imagined Movements: an ERP Study

PubMed Central

Machado, Sergio; Arias-Carrión, Oscar; Paes, Flávia; Ribeiro, Pedro; Cagy, Mauricio; Piedade, Roberto; Almada, Leonardo Ferreira; Anghinah, Renato; Basile, Luis; Moro, Maria Francesca; Orsini, Marco; Silva, Julio Guilherme; Silva, Adriana Cardoso; Nardi, Antonio E.

2013-01-01

This study aims to compare the topographic distribution of cortical activation between real and imagined movement through event-related potential (ERP). We are specifically interested in identifying, the topographic distribution of activated areas, the intensity of activated areas, and the temporal occurrence of these activations on preparation and motor response phases. Twelve healthy and right handed subjects were instructed to perform a task under real and imagery conditions. The task was performed simultaneously to electroencephalographic (EEG) recording. When compared the conditions, we found a statistically significant difference in favor of real condition revealed by performing an unpaired t-test with multiple corrections of Bonferroni, demonstrating negative activity on electrode C3 and positive activity on the electrode C4 only in motor response phase. These findings revealed similar functional connections established during real and imagery conditions, suggesting that there are common neural substrate and similar properties of functional integration shared by conditions. PMID:24358049

Changes in Cortical Activity During Real and Imagined Movements: an ERP Study.

PubMed

Machado, Sergio; Arias-Carrión, Oscar; Paes, Flávia; Ribeiro, Pedro; Cagy, Mauricio; Piedade, Roberto; Almada, Leonardo Ferreira; Anghinah, Renato; Basile, Luis; Moro, Maria Francesca; Orsini, Marco; Silva, Julio Guilherme; Silva, Adriana Cardoso; Nardi, Antonio E

2013-11-15

This study aims to compare the topographic distribution of cortical activation between real and imagined movement through event-related potential (ERP). We are specifically interested in identifying, the topographic distribution of activated areas, the intensity of activated areas, and the temporal occurrence of these activations on preparation and motor response phases. Twelve healthy and right handed subjects were instructed to perform a task under real and imagery conditions. The task was performed simultaneously to electroencephalographic (EEG) recording. When compared the conditions, we found a statistically significant difference in favor of real condition revealed by performing an unpaired t-test with multiple corrections of Bonferroni, demonstrating negative activity on electrode C3 and positive activity on the electrode C4 only in motor response phase. These findings revealed similar functional connections established during real and imagery conditions, suggesting that there are common neural substrate and similar properties of functional integration shared by conditions.

Molecular kinetics. Ras activation by SOS: allosteric regulation by altered fluctuation dynamics.

PubMed

Iversen, Lars; Tu, Hsiung-Lin; Lin, Wan-Chen; Christensen, Sune M; Abel, Steven M; Iwig, Jeff; Wu, Hung-Jen; Gureasko, Jodi; Rhodes, Christopher; Petit, Rebecca S; Hansen, Scott D; Thill, Peter; Yu, Cheng-Han; Stamou, Dimitrios; Chakraborty, Arup K; Kuriyan, John; Groves, Jay T

2014-07-04

Activation of the small guanosine triphosphatase H-Ras by the exchange factor Son of Sevenless (SOS) is an important hub for signal transduction. Multiple layers of regulation, through protein and membrane interactions, govern activity of SOS. We characterized the specific activity of individual SOS molecules catalyzing nucleotide exchange in H-Ras. Single-molecule kinetic traces revealed that SOS samples a broad distribution of turnover rates through stochastic fluctuations between distinct, long-lived (more than 100 seconds), functional states. The expected allosteric activation of SOS by Ras-guanosine triphosphate (GTP) was conspicuously absent in the mean rate. However, fluctuations into highly active states were modulated by Ras-GTP. This reveals a mechanism in which functional output may be determined by the dynamical spectrum of rates sampled by a small number of enzymes, rather than the ensemble average. Copyright © 2014, American Association for the Advancement of Science.

Association between Social Activities and Cognitive Function among the Elderly in China: A Cross-Sectional Study.

PubMed

Fu, Chang; Li, Zhen; Mao, Zongfu

2018-01-30

Participation in social activities is one of important factors for older adults' health. The present study aims to examine the cross-sectional association between social activities and cognitive function among Chinese elderly. A total of 8966 individuals aged 60 and older from the 2015 China Health and Retirement Longitudinal Study were obtained for this study. Telephone interviews of cognitive status, episodic memory, and visuospatial abilities were assessed by questionnaire. We used the sum of all three of the above measures to represent the respondent's cognitive status as a whole. Types and frequencies of participation in social groups were used to measure social activities. Multiple linear regression analysis was used to explore the relationship between social activities and cognitive function. After adjustment for demographics, smoking, drinking, depression, hypertension, diabetes, basic activities of daily living, instrumental activities of daily living, and self-rated health, multiple linear regression analysis revealed that interaction with friends, participating in hobby groups, and sports groups were associated with better cognitive function among both men and women ( p < 0.05); doing volunteer work was associated with better cognitive function among women but not among men ( p < 0.05). These findings suggest that there is a cross-sectional association between participation in social activities and cognitive function among Chinese elderly. Longitudinal studies are needed to examine the effects of social activities on cognitive function.

Association between Social Activities and Cognitive Function among the Elderly in China: A Cross-Sectional Study

PubMed Central

Fu, Chang; Li, Zhen; Mao, Zongfu

2018-01-01

Participation in social activities is one of important factors for older adults’ health. The present study aims to examine the cross-sectional association between social activities and cognitive function among Chinese elderly. A total of 8966 individuals aged 60 and older from the 2015 China Health and Retirement Longitudinal Study were obtained for this study. Telephone interviews of cognitive status, episodic memory, and visuospatial abilities were assessed by questionnaire. We used the sum of all three of the above measures to represent the respondent’s cognitive status as a whole. Types and frequencies of participation in social groups were used to measure social activities. Multiple linear regression analysis was used to explore the relationship between social activities and cognitive function. After adjustment for demographics, smoking, drinking, depression, hypertension, diabetes, basic activities of daily living, instrumental activities of daily living, and self-rated health, multiple linear regression analysis revealed that interaction with friends, participating in hobby groups, and sports groups were associated with better cognitive function among both men and women (p < 0.05); doing volunteer work was associated with better cognitive function among women but not among men (p < 0.05). These findings suggest that there is a cross-sectional association between participation in social activities and cognitive function among Chinese elderly. Longitudinal studies are needed to examine the effects of social activities on cognitive function. PMID:29385773

The impact of subjective cognitive fatigue and depression on cognitive function in patients with multiple sclerosis.

PubMed

Golan, Daniel; Doniger, Glen M; Wissemann, Karl; Zarif, Myassar; Bumstead, Barbara; Buhse, Marijean; Fafard, Lori; Lavi, Idit; Wilken, Jeffrey; Gudesblatt, Mark

2018-02-01

The association between subjective cognitive fatigue and objective cognitive dysfunction in patients with multiple sclerosis (PwMS) has been studied, with conflicting results. To explore the impact of fatigue on cognitive function, while controlling for the influence of depression, disability, comorbidities, and psychotropic medications. PwMS completed a computerized cognitive testing battery with age- and education-adjusted cognitive domain scores. Disability (Expanded Disability Status Scale (EDSS)), cognitive fatigue, and depression were concurrently evaluated. In all, 699 PwMS were included. Both cognitive fatigue and depression were significantly and negatively correlated with the same cognitive domains: information processing speed, executive function, attention, motor function, and memory (-0.15 ⩽ r ⩽ -0.14 for cognitive fatigue; -0.24 ⩽ r ⩽ -0.19 for depression). Multivariate analysis revealed significant but small independent correlations only between depression and neuropsychological test results, while cognitive fatigue had no independent correlation with objective cognitive function except for a trend toward impaired motor function in highly fatigued PwMS. Depression and cognitive fatigue accounted for no more than 6% of the variance in objective cognitive domain scores. Cognitive fatigue is not independently related to objective cognitive impairment. Depression may influence cognitive function of PwMS primarily when it is severe. Cognitive impairment in PwMS should not be ascribed to fatigue or mild depression.

Signal Diversity of Receptor for Advanced Glycation End Products.

PubMed

Sakaguchi, Masakiyo; Kinoshita, Rie; Putranto, Endy Widya; Ruma, I Made Winarsa; Sumardika, I Wayan; Youyi, Chen; Tomonobu, Naoko; Yamamoto, Ken-Ichi; Murata, Hitoshi

2017-12-01

The receptor for advanced glycation end products (RAGE) is involved in inflammatory pathogenesis. It functions as a receptor to multiple ligands such as AGEs, HMGB1 and S100 proteins, activating multiple intracellular signaling pathways with each ligand binding. The molecular events by which ligand-activated RAGE controls diverse signaling are not well understood, but some progress was made recently. Accumulating evidence revealed that RAGE has multiple binding partners within the cytoplasm and on the plasma membrane. It was first pointed out in 2008 that RAGE's cytoplasmic tail is able to recruit Diaphanous-1 (Dia-1), resulting in the acquisition of increased cellular motility through Rac1/Cdc42 activation. We also observed that within the cytosol, RAGE's cytoplasmic tail behaves similarly to a Toll-like receptor (TLR4)-TIR domain, interacting with TIRAP and MyD88 adaptor molecules that in turn activate multiple downstream signals. Subsequent studies demonstrated the presence of an alternative adaptor molecule, DAP10, on the plasma membrane. The coupling of RAGE with DAP10 is critical for enhancing the RAGE-mediated survival signal. Interestingly, RAGE interaction on the membrane was not restricted to DAP10 alone. The chemotactic G-protein-coupled receptors (GPCRs) formyl peptide receptors1 and 2 (FPR1 and FPR2) also interacted with RAGE on the plasma membrane. Binding interaction between leukotriene B4 receptor 1 (BLT1) and RAGE was also demonstrated. All of the interactions affected the RAGE signal polarity. These findings indicate that functional interactions between RAGE and various molecules within the cytoplasmic area or on the membrane area coordinately regulate multiple ligand-mediated RAGE responses, leading to typical cellular phenotypes in several pathological settings. Here we review RAGE's signaling diversity, to contribute to the understanding of the elaborate functions of RAGE in physiological and pathological contexts.

How does the multifaceted plant hormone salicylic acid combat disease in plants and are similar mechanisms utilized in humans?

PubMed

Dempsey, D'Maris Amick; Klessig, Daniel F

2017-03-23

Salicylic acid (SA) is an important plant hormone that regulates many aspects of plant growth and development, as well as resistance to (a)biotic stress. Efforts to identify SA effector proteins have revealed that SA binds to and alters the activity of multiple plant proteins-this represents a shift from the paradigm that hormones mediate their functions via one or a few receptors. SA and its derivatives also have multiple targets in animals; some of these proteins, like their plant counterparts, are associated with pathological processes. Together, these findings suggest that SA exerts its defense-associated effects in both kingdoms via a large number of targets.

Hierarchical Feedback Modules and Reaction Hubs in Cell Signaling Networks

PubMed Central

Xu, Jianfeng; Lan, Yueheng

2015-01-01

Despite much effort, identification of modular structures and study of their organizing and functional roles remain a formidable challenge in molecular systems biology, which, however, is essential in reaching a systematic understanding of large-scale cell regulation networks and hence gaining capacity of exerting effective interference to cell activity. Combining graph theoretic methods with available dynamics information, we successfully retrieved multiple feedback modules of three important signaling networks. These feedbacks are structurally arranged in a hierarchical way and dynamically produce layered temporal profiles of output signals. We found that global and local feedbacks act in very different ways and on distinct features of the information flow conveyed by signal transduction but work highly coordinately to implement specific biological functions. The redundancy embodied with multiple signal-relaying channels and feedback controls bestow great robustness and the reaction hubs seated at junctions of different paths announce their paramount importance through exquisite parameter management. The current investigation reveals intriguing general features of the organization of cell signaling networks and their relevance to biological function, which may find interesting applications in analysis, design and control of bio-networks. PMID:25951347

Empirically Defined Patterns of Executive Function Deficits in Schizophrenia and Their Relation to Everyday Functioning: A Person-Centered Approach

PubMed Central

Iampietro, Mary; Giovannetti, Tania; Drabick, Deborah A. G.; Kessler, Rachel K.

2013-01-01

Executive function (EF) deficits in schizophrenia (SZ) are well documented, although much less is known about patterns of EF deficits and their association to differential impairments in everyday functioning. The present study empirically defined SZ groups based on measures of various EF abilities and then compared these EF groups on everyday action errors. Participants (n=45) completed various subtests from the Delis–Kaplan Executive Function System (D-KEFS) and the Naturalistic Action Test (NAT), a performance-based measure of everyday action that yields scores reflecting total errors and a range of different error types (e.g., omission, perseveration). Results of a latent class analysis revealed three distinct EF groups, characterized by (a) multiple EF deficits, (b) relatively spared EF, and (c) perseverative responding. Follow-up analyses revealed that the classes differed significantly on NAT total errors, total commission errors, and total perseveration errors; the two classes with EF impairment performed comparably on the NAT but performed worse than the class with relatively spared EF. In sum, people with SZ demonstrate variable patterns of EF deficits, and distinct aspects of these EF deficit patterns (i.e., poor mental control abilities) may be associated with everyday functioning capabilities. PMID:23035705

Interhemispheric correlations of slow spontaneous neuronal fluctuations revealed in human sensory cortex

PubMed Central

Nir, Yuval; Mukamel, Roy; Dinstein, Ilan; Privman, Eran; Harel, Michal; Fisch, Lior; Gelbard-Sagiv, Hagar; Kipervasser, Svetlana; Andelman, Fani; Neufeld, Miri Y; Kramer, Uri; Arieli, Amos; Fried, Itzhak; Malach, Rafael

2009-01-01

Animal studies have shown robust electrophysiological activity in the sensory cortex in the absence of stimuli or tasks. Similarly, recent human functional magnetic resonance imaging (fMRI) revealed widespread, spontaneously emerging cortical fluctuations. However, it is unknown what neuronal dynamics underlie this spontaneous activity in the human brain. Here we studied this issue by combining bilateral single-unit, local field potentials (LFPs) and intracranial electrocorticography (ECoG) recordings in individuals undergoing clinical monitoring. We found slow (<0.1 Hz, following 1/f-like profiles) spontaneous fluctuations of neuronal activity with significant interhemispheric correlations. These fluctuations were evident mainly in neuronal firing rates and in gamma (40–100 Hz) LFP power modulations. Notably, the interhemispheric correlations were enhanced during rapid eye movement and stage 2 sleep. Multiple intracranial ECoG recordings revealed clear selectivity for functional networks in the spontaneous gamma LFP power modulations. Our results point to slow spontaneous modulations in firing rate and gamma LFP as the likely correlates of spontaneous fMRI fluctuations in the human sensory cortex. PMID:19160509

An Integrated Cell Purification and Genomics Strategy Reveals Multiple Regulators of Pancreas Development

PubMed Central

Benitez, Cecil M.; Qu, Kun; Sugiyama, Takuya; Pauerstein, Philip T.; Liu, Yinghua; Tsai, Jennifer; Gu, Xueying; Ghodasara, Amar; Arda, H. Efsun; Zhang, Jiajing; Dekker, Joseph D.; Tucker, Haley O.; Chang, Howard Y.; Kim, Seung K.

2014-01-01

The regulatory logic underlying global transcriptional programs controlling development of visceral organs like the pancreas remains undiscovered. Here, we profiled gene expression in 12 purified populations of fetal and adult pancreatic epithelial cells representing crucial progenitor cell subsets, and their endocrine or exocrine progeny. Using probabilistic models to decode the general programs organizing gene expression, we identified co-expressed gene sets in cell subsets that revealed patterns and processes governing progenitor cell development, lineage specification, and endocrine cell maturation. Purification of Neurog3 mutant cells and module network analysis linked established regulators such as Neurog3 to unrecognized gene targets and roles in pancreas development. Iterative module network analysis nominated and prioritized transcriptional regulators, including diabetes risk genes. Functional validation of a subset of candidate regulators with corresponding mutant mice revealed that the transcription factors Etv1, Prdm16, Runx1t1 and Bcl11a are essential for pancreas development. Our integrated approach provides a unique framework for identifying regulatory genes and functional gene sets underlying pancreas development and associated diseases such as diabetes mellitus. PMID:25330008

Microtubule-Actin Cross-Linking Factor 1: Domains, Interaction Partners, and Tissue-Specific Functions.

PubMed

Goryunov, Dmitry; Liem, Ronald K H

2016-01-01

The cytoskeleton of most eukaryotic cells is composed of three principal filamentous components: actin filaments, microtubules (MTs), and intermediate filaments. It is a highly dynamic system that plays crucial roles in a wide range of cellular processes, including migration, adhesion, cytokinesis, morphogenesis, intracellular traffic and signaling, and structural flexibility. Among the large number of cytoskeleton-associated proteins characterized to date, microtubule-actin cross-linking factor 1 (MACF1) is arguably the most versatile integrator and modulator of cytoskeleton-related processes. MACF1 belongs to the plakin family of proteins, and within it, to the spectraplakin subfamily. These proteins are characterized by the ability to bridge MT and actin cytoskeletal networks in a dynamic fashion, which underlies their involvement in the regulation of cell migration, axonal extension, and vesicular traffic. Studying MACF1 functions has provided insights not only into the regulation of the cytoskeleton but also into molecular mechanisms of both normal cellular physiology and cellular pathology. Multiple MACF1 isoforms exist, composed of a large variety of alternatively spliced domains. Each of these domains mediates a specific set of interactions and functions. These functions are manifested in tissue and cell-specific phenotypes observed in conditional MACF1 knockout mice. The conditional models described to date reveal critical roles of MACF1 in mammalian skin, nervous system, heart muscle, and intestinal epithelia. Complete elimination of MACF1 is early embryonic lethal, indicating an essential role for MACF1 in early development. Further studies of MACF1 domains and their interactions will likely reveal multiple new roles of this protein in various tissues. © 2016 Elsevier Inc. All rights reserved.

Subtyping cognitive profiles in Autism Spectrum Disorder using a Functional Random Forest algorithm.

PubMed

Feczko, E; Balba, N M; Miranda-Dominguez, O; Cordova, M; Karalunas, S L; Irwin, L; Demeter, D V; Hill, A P; Langhorst, B H; Grieser Painter, J; Van Santen, J; Fombonne, E J; Nigg, J T; Fair, D A

2018-05-15

DSM-5 Autism Spectrum Disorder (ASD) comprises a set of neurodevelopmental disorders characterized by deficits in social communication and interaction and repetitive behaviors or restricted interests, and may both affect and be affected by multiple cognitive mechanisms. This study attempts to identify and characterize cognitive subtypes within the ASD population using our Functional Random Forest (FRF) machine learning classification model. This model trained a traditional random forest model on measures from seven tasks that reflect multiple levels of information processing. 47 ASD diagnosed and 58 typically developing (TD) children between the ages of 9 and 13 participated in this study. Our RF model was 72.7% accurate, with 80.7% specificity and 63.1% sensitivity. Using the random forest model, the FRF then measures the proximity of each subject to every other subject, generating a distance matrix between participants. This matrix is then used in a community detection algorithm to identify subgroups within the ASD and TD groups, and revealed 3 ASD and 4 TD putative subgroups with unique behavioral profiles. We then examined differences in functional brain systems between diagnostic groups and putative subgroups using resting-state functional connectivity magnetic resonance imaging (rsfcMRI). Chi-square tests revealed a significantly greater number of between group differences (p < .05) within the cingulo-opercular, visual, and default systems as well as differences in inter-system connections in the somato-motor, dorsal attention, and subcortical systems. Many of these differences were primarily driven by specific subgroups suggesting that our method could potentially parse the variation in brain mechanisms affected by ASD. Copyright © 2017. Published by Elsevier Inc.

Mitogen-activated protein kinase cascades in signaling plant growth and development.

PubMed

Xu, Juan; Zhang, Shuqun

2015-01-01

Mitogen-activated protein kinase (MAPK) cascades are ubiquitous signaling modules in eukaryotes. Early research of plant MAPKs has been focused on their functions in immunity and stress responses. Recent studies reveal that they also play essential roles in plant growth and development downstream of receptor-like protein kinases (RLKs). With only a limited number of MAPK components, multiple functional pathways initiated from different receptors often share the same MAPK components or even a complete MAPK cascade. In this review, we discuss how MAPK cascades function as molecular switches in response to spatiotemporal-specific ligand-receptor interactions and the availability of downstream substrates. In addition, we discuss other possible mechanisms governing the functional specificity of plant MAPK cascades, a question central to our understanding of MAPK functions. Copyright © 2014 Elsevier Ltd. All rights reserved.

Mapping causal functional contributions derived from the clinical assessment of brain damage after stroke

PubMed Central

Zavaglia, Melissa; Forkert, Nils D.; Cheng, Bastian; Gerloff, Christian; Thomalla, Götz; Hilgetag, Claus C.

2015-01-01

Lesion analysis reveals causal contributions of brain regions to mental functions, aiding the understanding of normal brain function as well as rehabilitation of brain-damaged patients. We applied a novel lesion inference technique based on game theory, Multi-perturbation Shapley value Analysis (MSA), to a large clinical lesion dataset. We used MSA to analyze the lesion patterns of 148 acute stroke patients together with their neurological deficits, as assessed by the National Institutes of Health Stroke Scale (NIHSS). The results revealed regional functional contributions to essential behavioral and cognitive functions as reflected in the NIHSS, particularly by subcortical structures. There were also side specific differences of functional contributions between the right and left hemispheric brain regions which may reflect the dominance of the left hemispheric syndrome aphasia in the NIHSS. Comparison of MSA to established lesion inference methods demonstrated the feasibility of the approach for analyzing clinical data and indicated its capability for objectively inferring functional contributions from multiple injured, potentially interacting sites, at the cost of having to predict the outcome of unknown lesion configurations. The analysis of regional functional contributions to neurological symptoms measured by the NIHSS contributes to the interpretation of this widely used standardized stroke scale in clinical practice as well as clinical trials and provides a first approximation of a ‘map of stroke’. PMID:26448908

Mapping causal functional contributions derived from the clinical assessment of brain damage after stroke.

PubMed

Zavaglia, Melissa; Forkert, Nils D; Cheng, Bastian; Gerloff, Christian; Thomalla, Götz; Hilgetag, Claus C

2015-01-01

Lesion analysis reveals causal contributions of brain regions to mental functions, aiding the understanding of normal brain function as well as rehabilitation of brain-damaged patients. We applied a novel lesion inference technique based on game theory, Multi-perturbation Shapley value Analysis (MSA), to a large clinical lesion dataset. We used MSA to analyze the lesion patterns of 148 acute stroke patients together with their neurological deficits, as assessed by the National Institutes of Health Stroke Scale (NIHSS). The results revealed regional functional contributions to essential behavioral and cognitive functions as reflected in the NIHSS, particularly by subcortical structures. There were also side specific differences of functional contributions between the right and left hemispheric brain regions which may reflect the dominance of the left hemispheric syndrome aphasia in the NIHSS. Comparison of MSA to established lesion inference methods demonstrated the feasibility of the approach for analyzing clinical data and indicated its capability for objectively inferring functional contributions from multiple injured, potentially interacting sites, at the cost of having to predict the outcome of unknown lesion configurations. The analysis of regional functional contributions to neurological symptoms measured by the NIHSS contributes to the interpretation of this widely used standardized stroke scale in clinical practice as well as clinical trials and provides a first approximation of a 'map of stroke'.

Endoreplication and polyploidy: insights into development and disease

PubMed Central

Fox, Donald T.; Duronio, Robert J.

2013-01-01

Polyploid cells have genomes that contain multiples of the typical diploid chromosome number and are found in many different organisms. Studies in a variety of animal and plant developmental systems have revealed evolutionarily conserved mechanisms that control the generation of polyploidy and have recently begun to provide clues to its physiological function. These studies demonstrate that cellular polyploidy plays important roles during normal development and also contributes to human disease, particularly cancer. PMID:23222436

The relative effects on math performance of single- versus multiple-ratio schedules: a case study1

PubMed Central

Lovitt, Tom C.; Esveldt, Karen A.

1970-01-01

This series of four experiments sought to assess the comparative effects of multiple- versus single-ratio schedules on a pupil's responding to mathematics materials. Experiment I, which alternated between single- and multiple-ratio contingencies, revealed that during the latter phase the subject responded at a higher rate. Similar findings were revealed by Exp. II. The third experiment, which manipulated frequency of reinforcement rather than multiple ratios, revealed that the alteration had a minimal effect on the subject's response rate. A final experiment, conducted to assess further the effects of multiple ratios, provided data similar to those of Exp. I and II. PMID:16795267

The association between sexual satisfaction and body image in women.

PubMed

Pujols, Yasisca; Seal, Brooke N; Meston, Cindy M

2010-02-01

Although sexual functioning has been linked to sexual satisfaction, it only partially explains the degree to which women report being sexually satisfied. Other factors include quality of life, relational variables, and individual factors such as body image. Of the few studies that have investigated the link between body image and sexual satisfaction, most have considered body image to be a single construct and have shown mixed results. The present study assessed multiple body image variables in order to better understand which aspects of body image influence multiple domains of sexual satisfaction, including sexual communication, compatibility, contentment, personal concern, and relational concern in a community sample of women. Women between the ages of 18 and 49 years in sexual relationships (N = 154) participated in an Internet survey that assessed sexual functioning, five domains of sexual satisfaction, and several body image variables. Body image variables included the sexual attractiveness, weight concern, and physical condition subscales of the Body Esteem Scale, the appearance-based subscale of the Cognitive Distractions During Sexual Activity Scale, and body mass index. Total score of the Sexual Satisfaction Scale for Women was the main outcome measure. Sexual functioning was measured by a modified Female Sexual Function Index. Consistent with expectations, correlations indicated significant positive relationships between sexual functioning, sexual satisfaction, and all body image variables. A multiple regression analysis revealed that sexual satisfaction was predicted by high body esteem and low frequency of appearance-based distracting thoughts during sexual activity, even after controlling for sexual functioning status. Several aspects of body image, including weight concern, physical condition, sexual attractiveness, and thoughts about the body during sexual activity predict sexual satisfaction in women. The findings suggest that women who experience low sexual satisfaction may benefit from treatments that target these specific aspects of body image.

Comprehensive single cell-resolution analysis of the role of chromatin regulators in early C. elegans embryogenesis.

PubMed

Krüger, Angela V; Jelier, Rob; Dzyubachyk, Oleh; Zimmerman, Timo; Meijering, Erik; Lehner, Ben

2015-02-15

Chromatin regulators are widely expressed proteins with diverse roles in gene expression, nuclear organization, cell cycle regulation, pluripotency, physiology and development, and are frequently mutated in human diseases such as cancer. Their inhibition often results in pleiotropic effects that are difficult to study using conventional approaches. We have developed a semi-automated nuclear tracking algorithm to quantify the divisions, movements and positions of all nuclei during the early development of Caenorhabditis elegans and have used it to systematically study the effects of inhibiting chromatin regulators. The resulting high dimensional datasets revealed that inhibition of multiple regulators, including F55A3.3 (encoding FACT subunit SUPT16H), lin-53 (RBBP4/7), rba-1 (RBBP4/7), set-16 (MLL2/3), hda-1 (HDAC1/2), swsn-7 (ARID2), and let-526 (ARID1A/1B) affected cell cycle progression and caused chromosome segregation defects. In contrast, inhibition of cir-1 (CIR1) accelerated cell division timing in specific cells of the AB lineage. The inhibition of RNA polymerase II also accelerated these division timings, suggesting that normal gene expression is required to delay cell cycle progression in multiple lineages in the early embryo. Quantitative analyses of the dataset suggested the existence of at least two functionally distinct SWI/SNF chromatin remodeling complex activities in the early embryo, and identified a redundant requirement for the egl-27 and lin-40 MTA orthologs in the development of endoderm and mesoderm lineages. Moreover, our dataset also revealed a characteristic rearrangement of chromatin to the nuclear periphery upon the inhibition of multiple general regulators of gene expression. Our systematic, comprehensive and quantitative datasets illustrate the power of single cell-resolution quantitative tracking and high dimensional phenotyping to investigate gene function. Furthermore, the results provide an overview of the functions of essential chromatin regulators during the early development of an animal. Copyright © 2014 Elsevier Inc. All rights reserved.

Systems Level Analyses Reveal Multiple Regulatory Activities of CodY Controlling Metabolism, Motility and Virulence in Listeria monocytogenes

PubMed Central

Lobel, Lior; Herskovits, Anat A.

2016-01-01

Bacteria sense and respond to many environmental cues, rewiring their regulatory network to facilitate adaptation to new conditions/niches. Global transcription factors that co-regulate multiple pathways simultaneously are essential to this regulatory rewiring. CodY is one such global regulator, controlling expression of both metabolic and virulence genes in Gram-positive bacteria. Branch chained amino acids (BCAAs) serve as a ligand for CodY and modulate its activity. Classically, CodY was considered to function primarily as a repressor under rich growth conditions. However, our previous studies of the bacterial pathogen Listeria monocytogenes revealed that CodY is active also when the bacteria are starved for BCAAs. Under these conditions, CodY loses the ability to repress genes (e.g., metabolic genes) and functions as a direct activator of the master virulence regulator gene, prfA. This observation raised the possibility that CodY possesses multiple functions that allow it to coordinate gene expression across a wide spectrum of metabolic growth conditions, and thus better adapt bacteria to the mammalian niche. To gain a deeper understanding of CodY’s regulatory repertoire and identify direct target genes, we performed a genome wide analysis of the CodY regulon and DNA binding under both rich and minimal growth conditions, using RNA-Seq and ChIP-Seq techniques. We demonstrate here that CodY is indeed active (i.e., binds DNA) under both conditions, serving as a repressor and activator of different genes. Further, we identified new genes and pathways that are directly regulated by CodY (e.g., sigB, arg, his, actA, glpF, gadG, gdhA, poxB, glnR and fla genes), integrating metabolism, stress responses, motility and virulence in L. monocytogenes. This study establishes CodY as a multifaceted factor regulating L. monocytogenes physiology in a highly versatile manner. PMID:26895237

Flexible modulation of network connectivity related to cognition in Alzheimer's disease.

PubMed

McLaren, Donald G; Sperling, Reisa A; Atri, Alireza

2014-10-15

Functional neuroimaging tools, such as fMRI methods, may elucidate the neural correlates of clinical, behavioral, and cognitive performance. Most functional imaging studies focus on regional task-related activity or resting state connectivity rather than how changes in functional connectivity across conditions and tasks are related to cognitive and behavioral performance. To investigate the promise of characterizing context-dependent connectivity-behavior relationships, this study applies the method of generalized psychophysiological interactions (gPPI) to assess the patterns of associative-memory-related fMRI hippocampal functional connectivity in Alzheimer's disease (AD) associated with performance on memory and other cognitively demanding neuropsychological tests and clinical measures. Twenty-four subjects with mild AD dementia (ages 54-82, nine females) participated in a face-name paired-associate encoding memory study. Generalized PPI analysis was used to estimate the connectivity between the hippocampus and the whole brain during encoding. The difference in hippocampal-whole brain connectivity between encoding novel and encoding repeated face-name pairs was used in multiple-regression analyses as an independent predictor for 10 behavioral, neuropsychological and clinical tests. The analysis revealed connectivity-behavior relationships that were distributed, dynamically overlapping, and task-specific within and across intrinsic networks; hippocampal-whole brain connectivity-behavior relationships were not isolated to single networks, but spanned multiple brain networks. Importantly, these spatially distributed performance patterns were unique for each measure. In general, out-of-network behavioral associations with encoding novel greater than repeated face-name pairs hippocampal-connectivity were observed in the default-mode network, while correlations with encoding repeated greater than novel face-name pairs hippocampal-connectivity were observed in the executive control network (p<0.05, cluster corrected). Psychophysiological interactions revealed significantly more extensive and robust associations between paired-associate encoding task-dependent hippocampal-whole brain connectivity and performance on memory and behavioral/clinical measures than previously revealed by standard activity-behavior analysis. Compared to resting state and task-activation methods, gPPI analyses may be more sensitive to reveal additional complementary information regarding subtle within- and between-network relations. The patterns of robust correlations between hippocampal-whole brain connectivity and behavioral measures identified here suggest that there are 'coordinated states' in the brain; that the dynamic range of these states is related to behavior and cognition; and that these states can be observed and quantified, even in individuals with mild AD. Copyright © 2014 Elsevier Inc. All rights reserved.

Ensemble gene function prediction database reveals genes important for complex I formation in Arabidopsis thaliana.

PubMed

Hansen, Bjoern Oest; Meyer, Etienne H; Ferrari, Camilla; Vaid, Neha; Movahedi, Sara; Vandepoele, Klaas; Nikoloski, Zoran; Mutwil, Marek

2018-03-01

Recent advances in gene function prediction rely on ensemble approaches that integrate results from multiple inference methods to produce superior predictions. Yet, these developments remain largely unexplored in plants. We have explored and compared two methods to integrate 10 gene co-function networks for Arabidopsis thaliana and demonstrate how the integration of these networks produces more accurate gene function predictions for a larger fraction of genes with unknown function. These predictions were used to identify genes involved in mitochondrial complex I formation, and for five of them, we confirmed the predictions experimentally. The ensemble predictions are provided as a user-friendly online database, EnsembleNet. The methods presented here demonstrate that ensemble gene function prediction is a powerful method to boost prediction performance, whereas the EnsembleNet database provides a cutting-edge community tool to guide experimentalists. © 2017 The Authors. New Phytologist © 2017 New Phytologist Trust.

Functional characterization of the turkey macrophage migration inhibitory factor.

PubMed

Park, Myeongseon; Kim, Sungwon; Fetterer, Raymond H; Dalloul, Rami A

2016-08-01

Macrophage migration inhibitory factor (MIF) is a soluble protein that inhibits the random migration of macrophages and plays a pivotal immunoregulatory function in innate and adaptive immunity. The aim of this study was to clone the turkey MIF (TkMIF) gene, express the active protein, and characterize its basic function. The full-length TkMIF gene was amplified from total RNA extracted from turkey spleen, followed by cloning into a prokaryotic (pET11a) expression vector. Sequence analysis revealed that TkMIF consists of 115 amino acids with 12.5 kDa molecular weight. Multiple sequence alignment revealed 100%, 65%, 95% and 92% identity with chicken, duck, eagle and zebra finch MIFs, respectively. Recombinant TkMIF (rTkMIF) was expressed in Escherichia coli and purified through HPLC and endotoxin removal. SDS-PAGE analysis revealed an approximately 13.5 kDa of rTkMIF monomer containing T7 tag in soluble form. Western blot analysis showed that anti-chicken MIF (ChMIF) polyclonal antisera detected a monomer form of TkMIF at approximately 13.5 kDa size. Further functional analysis revealed that rTkMIF inhibits migration of both mononuclear cells and splenocytes in a dose-dependent manner, but was abolished by the addition of anti-ChMIF polyclonal antisera. qRT-PCR analysis revealed elevated transcripts of pro-inflammatory cytokines by rTkMIF in LPS-stimulated monocytes. rTkMIF also led to increased levels of IFN-γ and IL-17F transcripts in Con A-activated splenocytes, while IL-10 and IL-13 transcripts were decreased. Overall, the sequences of both the turkey and chicken MIF have high similarity and comparable biological functions with respect to migration inhibitory activities of macrophages and enhancement of pro-inflammatory cytokine expression, suggesting that turkey and chicken MIFs would be biologically cross-reactive. Copyright © 2016 Elsevier Ltd. All rights reserved.

A genetic screen for vascular mutants in zebrafish reveals dynamic roles for Vegf/Plcg1 signaling during artery development.

PubMed

Covassin, L D; Siekmann, A F; Kacergis, M C; Laver, E; Moore, J C; Villefranc, J A; Weinstein, B M; Lawson, N D

2009-05-15

In this work we describe a forward genetic approach to identify mutations that affect blood vessel development in the zebrafish. By applying a haploid screening strategy in a transgenic background that allows direct visualization of blood vessels, it was possible to identify several classes of mutant vascular phenotypes. Subsequent characterization of mutant lines revealed that defects in Vascular endothelial growth factor (Vegf) signaling specifically affected artery development. Comparison of phenotypes associated with different mutations within a functional zebrafish Vegf receptor-2 ortholog (referred to as kdr-like, kdrl) revealed surprisingly varied effects on vascular development. In parallel, we identified an allelic series of mutations in phospholipase c gamma 1 (plcg1). Together with in vivo structure-function analysis, our results suggest a requirement for Plcg1 catalytic activity downstream of receptor tyrosine kinases. We further find that embryos lacking both maternal and zygotic plcg1 display more severe defects in artery differentiation but are otherwise similar to zygotic mutants. Finally, we demonstrate through mosaic analysis that plcg1 functions autonomously in endothelial cells. Together our genetic analyses suggest that Vegf/Plcg1 signaling acts at multiple time points and in different signaling contexts to mediate distinct aspects of artery development.

A genetic screen for vascular mutants in zebrafish reveals dynamic roles for Vegf/Plcg1 signaling during artery development

PubMed Central

Covassin, L. D.; Siekmann, A. F.; Kacergis, M. C.; Laver, E.; Moore, J. C.; Villefranc, J. A.; Weinstein, B. M.; Lawson, N. D.

2009-01-01

In this work we describe a forward genetic approach to identify mutations that affect blood vessel development in the zebrafish. By applying a haploid screening strategy in a transgenic background that allows direct visualization of blood vessels, it was possible to identify several classes of mutant vascular phenotypes. Subsequent characterization of mutant lines revealed that defects in Vascular endothelial growth factor (Vegf) signaling specifically affected artery development. Comparison of phenotypes associated with different mutations within a functional zebrafish Vegf receptor-2 ortholog (referred to as kdr-like, kdrl) revealed surprisingly varied effects on vascular development. In parallel, we identified an allelic series of mutations in phospholipase c gamma 1 (plcg1). Together with in vivo structure-function analysis, our results suggest a requirement for Plcg1 catalytic activity downstream of receptor tyrosine kinases. We further find that embryos lacking both maternal and zygotic plcg1 display more severe defects in artery differentiation but are otherwise similar to zygotic mutants. Finally, we demonstrate through mosaic analysis that plcg1 functions autonomously in endothelial cells. Together our genetic analyses suggest that Vegf/Plcg1 signaling acts at multiple time points and in different signaling contexts to mediate distinct aspects of artery development. PMID:19269286

Bio-mimicking of Proline-Rich Motif Applied to Carbon Nanotube Reveals Unexpected Subtleties Underlying Nanoparticle Functionalization

NASA Astrophysics Data System (ADS)

Zhang, Yuanzhao; Jimenez-Cruz, Camilo A.; Wang, Jian; Zhou, Bo; Yang, Zaixing; Zhou, Ruhong

2014-11-01

Here, we report computational studies of the SH3 protein domain interacting with various single-walled carbon nanotubes (SWCNT) either bare or functionalized by mimicking the proline-rich motif (PRM) ligand (PPPVPPRR) and compare it to the SH3-PRM complex binding. With prolines or a single arginine attached, the SWCNT gained slightly on specificity when compared with the bare control, whereas with multi-arginine systems the specificity dropped dramatically to our surprise. Although the electrostatic interaction provided by arginines is crucial in the recognition between PRM and SH3 domain, our results suggest that attaching multiple arginines to the SWCNT has a detrimental effect on the binding affinity. Detailed analysis of the MD trajectories found two main factors that modulate the specificity of the binding: the existence of competing acidic patches at the surface of SH3 that leads to ``trapping and clamping'' by the arginines, and the rigidity of the SWCNT introducing entropic penalties in the proper binding. Further investigation revealed that the same ``clamping'' phenomenon exits in the PRM-SH3 system, which has not been reported in previous literature. The competing effects between nanoparticle and its functionalization components revealed by our model system should be of value to current and future nanomedicine designs.

A simple method for assessment of muscle force, velocity, and power producing capacities from functional movement tasks.

PubMed

Zivkovic, Milena Z; Djuric, Sasa; Cuk, Ivan; Suzovic, Dejan; Jaric, Slobodan

2017-07-01

A range of force (F) and velocity (V) data obtained from functional movement tasks (e.g., running, jumping, throwing, lifting, cycling) performed under variety of external loads have typically revealed strong and approximately linear F-V relationships. The regression model parameters reveal the maximum F (F-intercept), V (V-intercept), and power (P) producing capacities of the tested muscles. The aim of the present study was to evaluate the level of agreement between the routinely used "multiple-load model" and a simple "two-load model" based on direct assessment of the F-V relationship from only 2 external loads applied. Twelve participants were tested on the maximum performance vertical jumps, cycling, bench press throws, and bench pull performed against a variety of different loads. All 4 tested tasks revealed both exceptionally strong relationships between the parameters of the 2 models (median R = 0.98) and a lack of meaningful differences between their magnitudes (fixed bias below 3.4%). Therefore, addition of another load to the standard tests of various functional tasks typically conducted under a single set of mechanical conditions could allow for the assessment of the muscle mechanical properties such as the muscle F, V, and P producing capacities.

Bio-mimicking of Proline-Rich Motif Applied to Carbon Nanotube Reveals Unexpected Subtleties Underlying Nanoparticle Functionalization

PubMed Central

Zhang, Yuanzhao; Jimenez-Cruz, Camilo A.; Wang, Jian; Zhou, Bo; Yang, Zaixing; Zhou, Ruhong

2014-01-01

Here, we report computational studies of the SH3 protein domain interacting with various single-walled carbon nanotubes (SWCNT) either bare or functionalized by mimicking the proline-rich motif (PRM) ligand (PPPVPPRR) and compare it to the SH3-PRM complex binding. With prolines or a single arginine attached, the SWCNT gained slightly on specificity when compared with the bare control, whereas with multi-arginine systems the specificity dropped dramatically to our surprise. Although the electrostatic interaction provided by arginines is crucial in the recognition between PRM and SH3 domain, our results suggest that attaching multiple arginines to the SWCNT has a detrimental effect on the binding affinity. Detailed analysis of the MD trajectories found two main factors that modulate the specificity of the binding: the existence of competing acidic patches at the surface of SH3 that leads to “trapping and clamping” by the arginines, and the rigidity of the SWCNT introducing entropic penalties in the proper binding. Further investigation revealed that the same “clamping” phenomenon exits in the PRM-SH3 system, which has not been reported in previous literature. The competing effects between nanoparticle and its functionalization components revealed by our model system should be of value to current and future nanomedicine designs. PMID:25427563

Temporal Dynamics Assessment of Spatial Overlap Pattern of Functional Brain Networks Reveals Novel Functional Architecture of Cerebral Cortex.

PubMed

Jiang, Xi; Li, Xiang; Lv, Jinglei; Zhao, Shijie; Zhang, Shu; Zhang, Wei; Zhang, Tuo; Han, Junwei; Guo, Lei; Liu, Tianming

2018-06-01

Various studies in the brain mapping field have demonstrated that there exist multiple concurrent functional networks that are spatially overlapped and interacting with each other during specific task performance to jointly realize the total brain function. Assessing such spatial overlap patterns of functional networks (SOPFNs) based on functional magnetic resonance imaging (fMRI) has thus received increasing interest for brain function studies. However, there are still two crucial issues to be addressed. First, the SOPFNs are assessed over the entire fMRI scan assuming the temporal stationarity, while possibly time-dependent dynamics of the SOPFNs is not sufficiently explored. Second, the SOPFNs are assessed within individual subjects, while group-wise consistency of the SOPFNs is largely unknown. To address the two issues, we propose a novel computational framework of group-wise sparse representation of whole-brain fMRI temporal segments to assess the temporal dynamic spatial patterns of SOPFNs that are consistent across different subjects. Experimental results based on the recently publicly released Human Connectome Project grayordinate task fMRI data demonstrate that meaningful SOPFNs exhibiting dynamic spatial patterns across different time periods are effectively and robustly identified based on the reconstructed concurrent functional networks via the proposed framework. Specifically, those SOPFNs locate significantly more on gyral regions than on sulcal regions across different time periods. These results reveal novel functional architecture of cortical gyri and sulci. Moreover, these results help better understand functional dynamics mechanisms of cerebral cortex in the future.

Locomotive syndrome is associated not only with physical capacity but also degree of depression.

PubMed

Ikemoto, Tatsunori; Inoue, Masayuki; Nakata, Masatoshi; Miyagawa, Hirofumi; Shimo, Kazuhiro; Wakabayashi, Toshiko; Arai, Young-Chang P; Ushida, Takahiro

2016-05-01

Reports of locomotive syndrome (LS) have recently been increasing. Although physical performance measures for LS have been well investigated to date, studies including psychiatric assessment are still scarce. Hence, the aim of this study was to investigate both physical and mental parameters in relation to presence and severity of LS using a 25-question geriatric locomotive function scale (GLFS-25) questionnaire. 150 elderly people aged over 60 years who were members of our physical-fitness center and displayed well-being were enrolled in this study. Firstly, using the previously determined GLFS-25 cutoff value (=16 points), subjects were divided into two groups accordingly: an LS and non-LS group in order to compare each parameter (age, grip strength, timed-up-and-go test (TUG), one-leg standing with eye open, back muscle and leg muscle strength, degree of depression and cognitive impairment) between the groups using the Mann-Whitney U-test followed by multiple logistic regression analysis. Secondly, a multiple linear regression was conducted to determine which variables showed the strongest correlation with severity of LS. We confirmed 110 people for non-LS (73%) and 40 people for LS using the GLFS-25 cutoff value. Comparative analysis between LS and non-LS revealed significant differences in parameters in age, grip strength, TUG, one-leg standing, back muscle strength and degree of depression (p < 0.006, after Bonferroni correction). Multiple logistic regression revealed that functional decline in grip strength, TUG and one-leg standing and degree of depression were significantly associated with LS. On the other hand, we observed that the significant contributors towards the GLFS-25 score were TUG and degree of depression in multiple linear regression analysis. The results indicate that LS is associated with not only the capacity of physical performance but also the degree of depression although most participants fell under the criteria of LS. Copyright © 2016 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.

Neuropsychological performance measures as intermediate phenotypes for attention-deficit/hyperactivity disorder: A multiple mediation analysis

PubMed Central

KAMRADT, JACLYN M.; NIGG, JOEL T.; FRIDERICI, KAREN H.; NIKOLAS, MOLLY A.

2016-01-01

Genetic influences on dopaminergic neurotransmission have been implicated in attention-deficit hyperactivity disorder (ADHD) and are theorized to impact cognitive functioning via alterations in frontal–striatal circuitry. Neuropsychological functioning has been proposed to account for the potential associations between dopamine candidate genes and ADHD. However, to date, this mediation hypothesis has not been directly tested. Participants were 498 youth ages 6–17 years (mean M = 10.8 years, SD = 2.4 years, 55.0% male). All youth completed a multistage, multiple-informant assessment procedure to identify ADHD and non-ADHD cases, as well as a comprehensive neuropsychological battery. Youth provided a saliva sample for DNA analyses; the 480 base pair variable number of tandem repeat polymorphism of the dopamine active transporter 1 gene (DAT1) and the 120 base pair promoter polymorphism of the dopamine receptor D4 gene (DRD4) were genotyped. Multiple mediation analysis revealed significant indirect associations between DAT1 genotype and inattention, hyperactivity–impulsivity, and oppositionality, with specific indirect effects through response inhibition. The results highlight the role of neurocognitive task performance, particularly response inhibition, as a potential intermediate phenotype for ADHD, further elucidating the relationship between genetic polymorphisms and externalizing psychopathology. PMID:27049476

A pilot study examining functional brain activity 6 months after memory retraining in MS: the MEMREHAB trial.

PubMed

Dobryakova, Ekaterina; Wylie, Glenn R; DeLuca, John; Chiaravalloti, Nancy D

2014-09-01

Cognitive impairment in individuals with multiple sclerosis (MS) is now well recognized. One of the most common cognitive deficits is found in memory functioning, largely due to impaired acquisition. We examined functional brain activity 6 months after memory retraining in individuals with MS. The current report presents long term follow-up results from a randomized clinical trial on a memory rehabilitation protocol known as the modified Story Memory Technique. Behavioral memory performance and brain activity of all participants were evaluated at baseline, immediately after treatment, and 6 months after treatment. Results revealed that previously observed increases in patterns of cerebral activation during learning immediately after memory training were maintained 6 months post training.

DISCO Interacting Protein 2 regulates axonal bifurcation and guidance of Drosophila mushroom body neurons.

PubMed

Nitta, Yohei; Yamazaki, Daisuke; Sugie, Atsushi; Hiroi, Makoto; Tabata, Tetsuya

2017-01-15

Axonal branching is one of the key processes within the enormous complexity of the nervous system to enable a single neuron to send information to multiple targets. However, the molecular mechanisms that control branch formation are poorly understood. In particular, previous studies have rarely addressed the mechanisms underlying axonal bifurcation, in which axons form new branches via splitting of the growth cone. We demonstrate that DISCO Interacting Protein 2 (DIP2) is required for precise axonal bifurcation in Drosophila mushroom body (MB) neurons by suppressing ectopic bifurcation and regulating the guidance of sister axons. We also found that DIP2 localize to the plasma membrane. Domain function analysis revealed that the AMP-synthetase domains of DIP2 are essential for its function, which may involve exerting a catalytic activity that modifies fatty acids. Genetic analysis and subsequent biochemical analysis suggested that DIP2 is involved in the fatty acid metabolization of acyl-CoA. Taken together, our results reveal a function of DIP2 in the developing nervous system and provide a potential functional relationship between fatty acid metabolism and axon morphogenesis. Copyright © 2016 Elsevier Inc. All rights reserved.

An Improved Method for TAL Effectors DNA-Binding Sites Prediction Reveals Functional Convergence in TAL Repertoires of Xanthomonas oryzae Strains

PubMed Central

Pérez-Quintero, Alvaro L.; Rodriguez-R, Luis M.; Dereeper, Alexis; López, Camilo; Koebnik, Ralf; Szurek, Boris; Cunnac, Sebastien

2013-01-01

Transcription Activators-Like Effectors (TALEs) belong to a family of virulence proteins from the Xanthomonas genus of bacterial plant pathogens that are translocated into the plant cell. In the nucleus, TALEs act as transcription factors inducing the expression of susceptibility genes. A code for TALE-DNA binding specificity and high-resolution three-dimensional structures of TALE-DNA complexes were recently reported. Accurate prediction of TAL Effector Binding Elements (EBEs) is essential to elucidate the biological functions of the many sequenced TALEs as well as for robust design of artificial TALE DNA-binding domains in biotechnological applications. In this work a program with improved EBE prediction performances was developed using an updated specificity matrix and a position weight correction function to account for the matching pattern observed in a validation set of TALE-DNA interactions. To gain a systems perspective on the large TALE repertoires from X. oryzae strains, this program was used to predict rice gene targets for 99 sequenced family members. Integrating predictions and available expression data in a TALE-gene network revealed multiple candidate transcriptional targets for many TALEs as well as several possible instances of functional convergence among TALEs. PMID:23869221

Multidimensional Predictors of Fatigue among Octogenarians and Centenarians

PubMed Central

Cho, Jinmyoung; Martin, Peter; Margrett, Jennifer; MacDonald, Maurice; Johnson, Mary Ann; Poon, Leonard W.

2012-01-01

Background Fatigue is a common and frequently observed complaint among older adults. However, knowledge about the nature and correlates of fatigue in old age is very limited. Objective: This study examined the relationship of functional indicators, psychological and situational factors and fatigue for 210 octogenarians and centenarians from the Georgia Centenarian Study. Methods Three indicators of functional capacity (self-rated health, instrumental activities of daily living, physical activities of daily living), two indicators of psychological well-being (positive and negative affect), two indicators of situational factors (social network and social support), and a multidimensional fatigue scale were used. Blocked multiple regression analyses were computed to examine significant factors related to fatigue. In addition, multi-group analysis in structural equation modeling was used to investigate residential differences (i.e., long-term care facilities vs. private homes) in the relationship between significant factors and fatigue. Results Blocked multiple regression analyses indicated that two indicators of functional capacity, self-rated health and instrumental activities of daily living, both positive and negative affect, and social support were significant predictors of fatigue among oldest-old adults. The multiple group analysis in structural equation modeling revealed a significant difference among oldest-old adults based on residential status. Conclusion The results suggest that we should not consider fatigue as merely an unpleasant physical symptom, but rather adopt a perspective that different factors such as psychosocial aspects can influence fatigue in advanced later life. PMID:22094445

Multidimensional predictors of fatigue among octogenarians and centenarians.

PubMed

Cho, Jinmyoung; Martin, Peter; Margrett, Jennifer; MacDonald, Maurice; Johnson, Mary Ann; Poon, Leonard W; Jazwinski, S M; Green, R C; Gearing, M; Woodard, J L; Tenover, J S; Siegler, I C; Rott, C; Rodgers, W L; Hausman, D; Arnold, J; Davey, A

2012-01-01

Fatigue is a common and frequently observed complaint among older adults. However, knowledge about the nature and correlates of fatigue in old age is very limited. This study examined the relationship of functional indicators, psychological and situational factors and fatigue for 210 octogenarians and centenarians from the Georgia Centenarian Study. Three indicators of functional capacity (self-rated health, instrumental activities of daily living, physical activities of daily living), two indicators of psychological well-being (positive and negative affect), two indicators of situational factors (social network and social support), and a multidimensional fatigue scale were used. Blocked multiple regression analyses were computed to examine significant factors related to fatigue. In addition, multi-group analysis in structural equation modeling was used to investigate residential differences (i.e., long-term care facilities vs. private homes) in the relationship between significant factors and fatigue. Blocked multiple regression analyses indicated that two indicators of functional capacity, self-rated health and instrumental activities of daily living, both positive and negative affect, and social support were significant predictors of fatigue among oldest-old adults. The multiple group analysis in structural equation modeling revealed a significant difference among oldest-old adults based on residential status. The results suggest that we should not consider fatigue as merely an unpleasant physical symptom, but rather adopt a perspective that different factors such as psychosocial aspects can influence fatigue in advanced later life. Copyright © 2011 S. Karger AG, Basel.

Identifying and exploiting trait-relevant tissues with multiple functional annotations in genome-wide association studies

PubMed Central

Zhang, Shujun

2018-01-01

Genome-wide association studies (GWASs) have identified many disease associated loci, the majority of which have unknown biological functions. Understanding the mechanism underlying trait associations requires identifying trait-relevant tissues and investigating associations in a trait-specific fashion. Here, we extend the widely used linear mixed model to incorporate multiple SNP functional annotations from omics studies with GWAS summary statistics to facilitate the identification of trait-relevant tissues, with which to further construct powerful association tests. Specifically, we rely on a generalized estimating equation based algorithm for parameter inference, a mixture modeling framework for trait-tissue relevance classification, and a weighted sequence kernel association test constructed based on the identified trait-relevant tissues for powerful association analysis. We refer to our analytic procedure as the Scalable Multiple Annotation integration for trait-Relevant Tissue identification and usage (SMART). With extensive simulations, we show how our method can make use of multiple complementary annotations to improve the accuracy for identifying trait-relevant tissues. In addition, our procedure allows us to make use of the inferred trait-relevant tissues, for the first time, to construct more powerful SNP set tests. We apply our method for an in-depth analysis of 43 traits from 28 GWASs using tissue-specific annotations in 105 tissues derived from ENCODE and Roadmap. Our results reveal new trait-tissue relevance, pinpoint important annotations that are informative of trait-tissue relationship, and illustrate how we can use the inferred trait-relevant tissues to construct more powerful association tests in the Wellcome trust case control consortium study. PMID:29377896

Resolving protein structure-function-binding site relationships from a binding site similarity network perspective.

PubMed

Mudgal, Richa; Srinivasan, Narayanaswamy; Chandra, Nagasuma

2017-07-01

Functional annotation is seldom straightforward with complexities arising due to functional divergence in protein families or functional convergence between non-homologous protein families, leading to mis-annotations. An enzyme may contain multiple domains and not all domains may be involved in a given function, adding to the complexity in function annotation. To address this, we use binding site information from bound cognate ligands and catalytic residues, since it can help in resolving fold-function relationships at a finer level and with higher confidence. A comprehensive database of 2,020 fold-function-binding site relationships has been systematically generated. A network-based approach is employed to capture the complexity in these relationships, from which different types of associations are deciphered, that identify versatile protein folds performing diverse functions, same function associated with multiple folds and one-to-one relationships. Binding site similarity networks integrated with fold, function, and ligand similarity information are generated to understand the depth of these relationships. Apart from the observed continuity in the functional site space, network properties of these revealed versatile families with topologically different or dissimilar binding sites and structural families that perform very similar functions. As a case study, subtle changes in the active site of a set of evolutionarily related superfamilies are studied using these networks. Tracing of such similarities in evolutionarily related proteins provide clues into the transition and evolution of protein functions. Insights from this study will be helpful in accurate and reliable functional annotations of uncharacterized proteins, poly-pharmacology, and designing enzymes with new functional capabilities. Proteins 2017; 85:1319-1335. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Self-organized criticality in a cold plasma

NASA Astrophysics Data System (ADS)

Alex, Prince; Carreras, Benjamin Andres; Arumugam, Saravanan; Sinha, Suraj Kumar

2017-12-01

We present direct evidence for the existence of self-organized critical behavior in cold plasma. A multiple anodic double layer structure generated in a double discharge plasma setup shows critical behavior for the anode bias above a threshold value. Analysis of the floating potential fluctuations reveals the existence of long-range time correlations and power law behavior in the tail of the probability distribution function of the fluctuations. The measured Hurst exponent and the power law tail in the rank function are strong indication of the self-organized critical behavior of the system and hence provide a condition under which complexities arise in cold plasma.

Revealed and stated preference valuation and transfer: A within-sample comparison of water quality improvement values

NASA Astrophysics Data System (ADS)

Ferrini, Silvia; Schaafsma, Marije; Bateman, Ian

2014-06-01

Benefit transfer (BT) methods are becoming increasingly important for environmental policy, but the empirical findings regarding transfer validity are mixed. A novel valuation survey was designed to obtain both stated preference (SP) and revealed preference (RP) data concerning river water quality values from a large sample of households. Both dichotomous choice and payment card contingent valuation (CV) and travel cost (TC) data were collected. Resulting valuations were directly compared and used for BT analyses using both unit value and function transfer approaches. WTP estimates are found to pass the convergence validity test. BT results show that the CV data produce lower transfer errors, below 20% for both unit value and function transfer, than TC data especially when using function transfer. Further, comparison of WTP estimates suggests that in all cases, differences between methods are larger than differences between study areas. Results show that when multiple studies are available, using welfare estimates from the same area but based on a different method consistently results in larger errors than transfers across space keeping the method constant.

The heptanucleotide motif GAGACGC is a key component of a cis-acting promoter element that is critical for SnSAG1 expression in Sarcocystis neurona.

PubMed

Gaji, Rajshekhar Y; Howe, Daniel K

2009-07-01

The apicomplexan parasite Sarcocystis neurona undergoes a complex process of intracellular development, during which many genes are temporally regulated. The described study was undertaken to begin identifying the basic promoter elements that control gene expression in S. neurona. Sequence analysis of the 5'-flanking region of five S. neurona genes revealed a conserved heptanucleotide motif GAGACGC that is similar to the WGAGACG motif described upstream of multiple genes in Toxoplasma gondii. The promoter region for the major surface antigen gene SnSAG1, which contains three heptanucleotide motifs within 135 bases of the transcription start site, was dissected by functional analysis using a dual luciferase reporter assay. These analyses revealed that a minimal promoter fragment containing all three motifs was sufficient to drive reporter molecule expression, with the presence and orientation of the 5'-most heptanucleotide motif being absolutely critical for promoter function. Further studies should help to identify additional sequence elements important for promoter function and for controlling gene expression during intracellular development by this apicomplexan pathogen.

The Thiamine-Pyrophosphate-Motif

NASA Technical Reports Server (NTRS)

Ciszak, Ewa; Dominiak, Paulina

2004-01-01

Thiamin pyrophosphate (TPP), a derivative of vitamin B1, is a cofactor for enzymes performing catalysis in pathways of energy production including the well known decarboxylation of a-keto acid dehydrogenases followed by transketolation. TPP-dependent enzymes constitute a structurally and functionally diverse group exhibiting multimeric subunit organization, multiple domains and two chemically equivalent catalytic centers. Annotation of functional TPP-dependcnt enzymes, therefore, has not been trivial due to low sequence similarity related to this complex organization. Our approach to analysis of structures of known TPP-dependent enzymes reveals for the first time features common to this group, which we have termed the TPP-motif. The TPP-motif consists of specific spatial arrangements of structural elements and their specific contacts to provide for a flip-flop, or alternate site, enzymatic mechanism of action. Analysis of structural elements entrained in the flip-flop action displayed by TPP-dependent enzymes reveals a novel definition of the common amino acid sequences. These sequences allow for annotation of TPP-dependent enzymes, thus advancing functional proteomics. Further details of three-dimensional structures of TPP-dependent enzymes will be discussed.

The Effect of Executive Function on Science Achievement Among Normally Developing 10-Year Olds

NASA Astrophysics Data System (ADS)

Lederman, Sheri G.

Executive function (EF) is an umbrella term used to identify a set of discrete but interrelated cognitive abilities that enable individuals to engage in goal-directed, future-oriented action in response to a novel context. Developmental studies indicate that EF is predictive of reading and math achievement in middle childhood. The purpose of this study was to identify the association between EF and science achievement among normally developing 10 year olds. A sample of fifth grade students from a Northeastern suburban community participated in tests of EF, science, and intelligence. Consistent with adult models of EF, principal components analysis identified a three-factor model of EF organization in middle childhood, including cognitive flexibility, working memory, and inhibition. Multiple regression analyses revealed that executive function processes of cognitive flexibility, working memory, and inhibition were all predictive of science performance. Post hoc analyses revealed that high-performing science students differed significantly from low-performing students in both cognitive flexibility and working memory. These findings suggest that complex academic demands specific to science achievement rely on the emergence and maturation of EF components.

Impulsivity and the Modular Organization of Resting-State Neural Networks

PubMed Central

Davis, F. Caroline; Knodt, Annchen R.; Sporns, Olaf; Lahey, Benjamin B.; Zald, David H.; Brigidi, Bart D.; Hariri, Ahmad R.

2013-01-01

Impulsivity is a complex trait associated with a range of maladaptive behaviors, including many forms of psychopathology. Previous research has implicated multiple neural circuits and neurotransmitter systems in impulsive behavior, but the relationship between impulsivity and organization of whole-brain networks has not yet been explored. Using graph theory analyses, we characterized the relationship between impulsivity and the functional segregation (“modularity”) of the whole-brain network architecture derived from resting-state functional magnetic resonance imaging (fMRI) data. These analyses revealed remarkable differences in network organization across the impulsivity spectrum. Specifically, in highly impulsive individuals, regulatory structures including medial and lateral regions of the prefrontal cortex were isolated from subcortical structures associated with appetitive drive, whereas these brain areas clustered together within the same module in less impulsive individuals. Further exploration of the modular organization of whole-brain networks revealed novel shifts in the functional connectivity between visual, sensorimotor, cortical, and subcortical structures across the impulsivity spectrum. The current findings highlight the utility of graph theory analyses of resting-state fMRI data in furthering our understanding of the neurobiological architecture of complex behaviors. PMID:22645253

The complex and specific pMHC interactions with diverse HIV-1 TCR clonotypes reveal a structural basis for alterations in CTL function

NASA Astrophysics Data System (ADS)

Xia, Zhen; Chen, Huabiao; Kang, Seung-Gu; Huynh, Tien; Fang, Justin W.; Lamothe, Pedro A.; Walker, Bruce D.; Zhou, Ruhong

2014-02-01

Immune control of viral infections is modulated by diverse T cell receptor (TCR) clonotypes engaging peptide-MHC class I complexes on infected cells, but the relationship between TCR structure and antiviral function is unclear. Here we apply in silico molecular modeling with in vivo mutagenesis studies to investigate TCR-pMHC interactions from multiple CTL clonotypes specific for a well-defined HIV-1 epitope. Our molecular dynamics simulations of viral peptide-HLA-TCR complexes, based on two independent co-crystal structure templates, reveal that effective and ineffective clonotypes bind to the terminal portions of the peptide-MHC through similar salt bridges, but their hydrophobic side-chain packings can be very different, which accounts for the major part of the differences among these clonotypes. Non-specific hydrogen bonding to viral peptide also accommodates greater epitope variants. Furthermore, free energy perturbation calculations for point mutations on the viral peptide KK10 show excellent agreement with in vivo mutagenesis assays, with new predictions confirmed by additional experiments. These findings indicate a direct structural basis for heterogeneous CTL antiviral function.

Characterizing Solution Surface Loop Conformational Flexibility of the GM2 Activator Protein

PubMed Central

2015-01-01

GM2AP has a β-cup topology with numerous X-ray structures showing multiple conformations for some of the surface loops, revealing conformational flexibility that may be related to function, where function is defined as either membrane binding associated with ligand binding and extraction or interaction with other proteins. Here, site-directed spin labeling (SDSL) electron paramagnetic resonance (EPR) spectroscopy and molecular dynamic (MD) simulations are used to characterize the mobility and conformational flexibility of various structural regions of GM2AP. A series of 10 single cysteine amino acid substitutions were generated, and the constructs were chemically modified with the methanethiosulfonate spin label. Continuous wave (CW) EPR line shapes were obtained and subsequently simulated using the microscopic order macroscopic disorder (MOMD) program. Line shapes for sites that have multiple conformations in the X-ray structures required two spectral components, whereas spectra of the remaining sites were adequately fit with single-component parameters. For spin labeled sites L126C and I66C, spectra were acquired as a function of temperature, and simulations provided for the determination of thermodynamic parameters associated with conformational change. Binding to GM2 ligand did not alter the conformational flexibility of the loops, as evaluated by EPR and NMR spectroscopies. These results confirm that the conformational flexibility observed in the surface loops of GM2AP crystals is present in solution and that the exchange is slow on the EPR time scale (>ns). Furthermore, MD simulation results are presented and agree well with the conformational heterogeneity revealed by SDSL. PMID:25127419

Identification and Analyses of AUX-IAA target genes controlling multiple pathways in developing fiber cells of Gossypium hirsutum L

PubMed Central

Nigam, Deepti; Sawant, Samir V

2013-01-01

Technological development led to an increased interest in systems biological approaches in plants to characterize developmental mechanism and candidate genes relevant to specific tissue or cell morphology. AUX-IAA proteins are important plant-specific putative transcription factors. There are several reports on physiological response of this family in Arabidopsis but in cotton fiber the transcriptional network through which AUX-IAA regulated its target genes is still unknown. in-silico modelling of cotton fiber development specific gene expression data (108 microarrays and 22,737 genes) using Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNe) reveals 3690 putative AUX-IAA target genes of which 139 genes were known to be AUX-IAA co-regulated within Arabidopsis. Further AUX-IAA targeted gene regulatory network (GRN) had substantial impact on the transcriptional dynamics of cotton fiber, as showed by, altered TF networks, and Gene Ontology (GO) biological processes and metabolic pathway associated with its target genes. Analysis of the AUX-IAA-correlated gene network reveals multiple functions for AUX-IAA target genes such as unidimensional cell growth, cellular nitrogen compound metabolic process, nucleosome organization, DNA-protein complex and process related to cell wall. These candidate networks/pathways have a variety of profound impacts on such cellular functions as stress response, cell proliferation, and cell differentiation. While these functions are fairly broad, their underlying TF networks may provide a global view of AUX-IAA regulated gene expression and a GRN that guides future studies in understanding role of AUX-IAA box protein and its targets regulating fiber development. PMID:24497725

Revealing the source of the radial flow patterns in proton-proton collisions using hard probes

NASA Astrophysics Data System (ADS)

Ortiz, Antonio; Bencédi, Gyula; Bello, Héctor

2017-06-01

In this work, we propose a tool to reveal the origin of the collective-like phenomena observed in proton-proton collisions. We exploit the fundamental difference between the underlying mechanisms, color reconnection and hydrodynamics, which produce radial flow patterns in Pythia 8 and Epos 3, respectively. Specifically, we proceed by examining the strength of the coupling between the soft and hard components which, by construction, is larger in Pythia 8 than in Epos 3. We study the transverse momentum ({p}{{T}}) distributions of charged pions, kaons and (anti) protons in inelastic pp collisions at \\sqrt{s}=7 TeV produced at mid-rapidity. Specific selections are made on an event-by-event basis as a function of the charged particle multiplicity and the transverse momentum of the leading jet ({p}{{T}}{jet}) reconstructed using the FastJet algorithm at mid-pseudorapidity (| η | < 1). From our studies, quantitative and qualitative differences between Pythia 8 and Epos 3 are found in the {p}{{T}} spectra when (for a given multiplicity class) the leading jet {p}{{T}} is increased. In addition, we show that for low-multiplicity events the presence of jets can produce radial flow-like behavior. Motivated by our findings, we propose to perform a similar analysis using experimental data from RHIC and LHC.

What have we learned about GPER function in physiology and disease from knockout mice?

PubMed

Prossnitz, Eric R; Hathaway, Helen J

2015-09-01

Estrogens, predominantly 17β-estradiol, exert diverse effects throughout the body in both normal and pathophysiology, during development and in reproductive, metabolic, endocrine, cardiovascular, nervous, musculoskeletal and immune systems. Estrogen and its receptors also play important roles in carcinogenesis and therapy, particularly for breast cancer. In addition to the classical nuclear estrogen receptors (ERα and ERβ) that traditionally mediate predominantly genomic signaling, the G protein-coupled estrogen receptor GPER has become recognized as a critical mediator of rapid signaling in response to estrogen. Mouse models, and in particular knockout (KO) mice, represent an important approach to understand the functions of receptors in normal physiology and disease. Whereas ERα KO mice display multiple significant defects in reproduction and mammary gland development, ERβ KO phenotypes are more limited, and GPER KO exhibit no reproductive deficits. However, the study of GPER KO mice over the last six years has revealed that GPER deficiency results in multiple physiological alterations including obesity, cardiovascular dysfunction, insulin resistance and glucose intolerance. In addition, the lack of estrogen-mediated effects in numerous tissues of GPER KO mice, studied in vivo or ex vivo, including those of the cardiovascular, endocrine, nervous and immune systems, reveals GPER as a genuine mediator of estrogen action. Importantly, GPER KO mice have also demonstrated roles for GPER in breast carcinogenesis and metastasis. In combination with the supporting effects of GPER-selective ligands and GPER knockdown approaches, GPER KO mice demonstrate the therapeutic potential of targeting GPER activity in diseases as diverse as obesity, diabetes, multiple sclerosis, hypertension, atherosclerosis, myocardial infarction, stroke and cancer. Copyright © 2015. Published by Elsevier Ltd.

Preference-based Health status in a German outpatient cohort with multiple sclerosis

PubMed Central

2013-01-01

Background To prospectively determine health status and health utility and its predictors in patients with multiple sclerosis (MS). Methods A total of 144 MS patients (mean age: 41.0 ±11.3y) with different subtypes (patterns of progression) and severities of MS were recruited in an outpatient university clinic in Germany. Patients completed a questionnaire at baseline (n = 144), 6 months (n = 65) and 12 months (n = 55). Health utilities were assessed using the EuroQol instrument (EQ-5D, EQ VAS). Health status was assessed by several scales (Expanded Disability Severity Scale (EDSS), Modified Fatigue Impact Scale (M-FIS), Functional Assessment of MS (FAMS), Beck Depression Inventory (BDI-II) and Multiple Sclerosis Functional Composite (MSFC)). Additionally, demographic and socioeconomic parameters were assessed. Multivariate linear and logistic regressions were applied to reveal independent predictors of health status. Results Health status is substantially diminished in MS patients and the EQ VAS was considerably lower than that of the general German population. No significant change in health-status parameters was observed over a 12-months period. Multivariate analyses revealed M-FIS, BDI-II, MSFC, and EDSS to be significant predictors of reduced health status. Socioeconomic and socio-demographic parameters such as working status, family status, number of household inhabitants, age, and gender did not prove significant in multivariate analyses. Conclusion MS considerably impairs patients’ health status. Guidelines aiming to improve self-reported health status should include treatment options for depression and fatigue. Physicians should be aware of depression and fatigue as co-morbidities. Future studies should consider the minimal clinical difference when health status is a primary outcome. PMID:24089999

Human Myo19 is a novel myosin that associates with mitochondria

PubMed Central

Quintero, Omar A.; DiVito, Melinda M.; Adikes, Rebecca C.; Kortan, Melisa B.; Case, Lindsay B.; Lier, Audun J.; Panaretos, Niki S.; Slater, Stephanie Q.; Rengarajan, Michelle; Feliu, Marianela; Cheney, Richard E.

2009-01-01

Summary Mitochondria are pleomorphic organelles [1, 2] that have central roles in cell physiology. Defects in their localization and dynamics lead to human disease [3-5]. Myosins are actin-based motors that power processes such as muscle contraction, cytokinesis, and organelle transport [6]. Here we report the initial characterization of myosin-XIX (Myo19), the founding member of a novel class of myosin that associates with mitochondria. The 970aa heavy chain consists of a motor domain, three IQ motifs, and a short tail. Myo19 mRNA is expressed in multiple tissues and antibodies to human Myo19 detect a ∼109kD band in multiple cell lines. Both endogenous Myo19 and GFP-Myo19 exhibit striking localization to mitochondria. Deletion analysis reveals that the Myo19 tail is necessary and sufficient for mitochondrial localization. Expressing full-length GFP-Myo19 in A549 cells reveals a remarkable gain-of-function where the majority of the mitochondria move continuously. Moving mitochondria travel for many microns with an obvious leading end and distorted shape. The motility and shape-change are sensitive to latrunculin B, indicating that both are actin-dependent. Expressing the GFP-Myo19 tail in CAD cells resulted in decreased mitochondrial run lengths in neurites. These results suggest that this novel myosin functions as an actin-based motor for mitochondrial movement in vertebrate cells. PMID:19932026

PLOD2 regulated by transcription factor FOXA1 promotes metastasis in NSCLC

PubMed Central

Du, Hongzhi; Chen, Yulong; Hou, Xiaoying; Huang, Yue; Wei, Xiaohui; Yu, Xiaowen; Feng, Shuyun; Wu, Yao; Zhan, Meixiao; Shi, Xin; Lin, Sensen; Lu, Ligong; Yuan, Shengtao; Sun, Li

2017-01-01

In multiple types of tumors, fibrotic collagen is regarded as the 'highway' for cancer cell migration, which is mainly modified by lysyl hydroxylase 2 (PLOD2). The previous findings have demonstrated that the expression of PLOD2 was regulated by multiple factors, including HIF-1α, TGF-β and microRNA-26a/b. Although PLOD2 was confirmed to be related to poor prognosis in lung adenocarcinoma, the regulatory mechanism and function of PLOD2 in human lung adenocarcinoma is poorly understood. On the other hand, upregulation or hyperactivation of epidermal growth factor receptor is considered as a prognostic marker in many cancers, especially in non-small-cell lung cancer (NSCLC). In this study, we found that PLOD2 was elevated in NSCLC specimens and positively links to NSCLC poor prognosis. Gain- and loss-of-function studies and orthotopic implantation metastasis model pinpointed that PLOD2 promotes NSCLC metastasis directly by enhancing migration and indirectly by inducing collagen reorganization. In addition, we revealed that PLOD2 was regulated by PI3K/AKT-FOXA1 axis. The transcription factor FOXA1 directly bound to the PLOD2 promoter, and turned on PLOD2 transcription. In summary, our findings revealed a regulatory mechanism of NSCLC metastasis through EGFR-PI3K/AKT-FOXA1-PLOD2 pathway, and provided PLOD2 as a therapeutic target for NSCLC treatment. PMID:29072684

Transcriptomic profile induced in bone marrow mesenchymal stromal cells after interaction with multiple myeloma cells: implications in myeloma progression and myeloma bone disease

PubMed Central

Garcia-Gomez, Antonio; Las Rivas, Javier De; Ocio, Enrique M.; Díaz-Rodríguez, Elena; Montero, Juan C.; Martín, Montserrat; Blanco, Juan F.; Sanchez-Guijo, Fermín M.; Pandiella, Atanasio; San Miguel, Jesús F.; Garayoa, Mercedes

2014-01-01

Despite evidence about the implication of the bone marrow (BM) stromal microenvironment in multiple myeloma (MM) cell growth and survival, little is known about the effects of myelomatous cells on BM stromal cells. Mesenchymal stromal cells (MSCs) from healthy donors (dMSCs) or myeloma patients (pMSCs) were co-cultured with the myeloma cell line MM.1S, and the transcriptomic profile of MSCs induced by this interaction was analyzed. Deregulated genes after co-culture common to both d/pMSCs revealed functional involvement in tumor microenvironment cross-talk, myeloma growth induction and drug resistance, angiogenesis and signals for osteoclast activation and osteoblast inhibition. Additional genes induced by co-culture were exclusively deregulated in pMSCs and predominantly associated to RNA processing, the ubiquitine-proteasome pathway, cell cycle regulation, cellular stress and non-canonical Wnt signaling. The upregulated expression of five genes after co-culture (CXCL1, CXCL5 and CXCL6 in d/pMSCs, and Neuregulin 3 and Norrie disease protein exclusively in pMSCs) was confirmed, and functional in vitro assays revealed putative roles in MM pathophysiology. The transcriptomic profile of pMSCs co-cultured with myeloma cells may better reflect that of MSCs in the BM of myeloma patients, and provides new molecular insights to the contribution of these cells to MM pathophysiology and to myeloma bone disease. PMID:25268740

Brain activation of semantic category-based grouping in multiple identity tracking task

PubMed Central

Wei, Liuqing; Lyu, Chuang; Hu, Siyuan; Li, Zhen

2017-01-01

Using Multiple Identity Tracking task and the functional magnetic resonance imaging (fMRI) technology, the present study aimed to isolate and visualize the functional anatomy of neural systems involved in the semantic category-based grouping process. Three experiment conditions were selected and compared: the category-based targets grouping (TG) condition, the targets-distractors grouping (TDG) condition and the homogenous condition. In the TG condition, observers could utilize the categorical distinction between targets and distractors, to construct a uniform presentation of targets, that is, to form a group of the targets to facilitate tracking. In the TDG condition, half the targets and half the distractors belonged to the same category. Observers had to inhibit the grouping of targets and distractors in one category to complete tracking. In the homogenous condition, where targets and distractors consisted of the same objects, no grouping could be formed. The “TG-Homogenous” contrast (p<0.01) revealed the activation of the left fusiform and the pars triangularis of inferior frontal gyrus (IFG). The “TG-TDG” contrast only revealed the activation of the left anterior cingulate gyrus (ACC). The fusiform and IFG pars triangularis might participate in the representation of semantic knowledge, IFG pars triangularis might relate intensely with the classification of semantic categories. The ACC might be responsible for the initiation and maintenance of grouping representation. PMID:28505166

STARD6 on steroids: solution structure, multiple timescale backbone dynamics and ligand binding mechanism

NASA Astrophysics Data System (ADS)

Létourneau, Danny; Bédard, Mikaël; Cabana, Jérôme; Lefebvre, Andrée; Lehoux, Jean-Guy; Lavigne, Pierre

2016-06-01

START domain proteins are conserved α/β helix-grip fold that play a role in the non-vesicular and intracellular transport of lipids and sterols. The mechanism and conformational changes permitting the entry of the ligand into their buried binding sites is not well understood. Moreover, their functions and the identification of cognate ligands is still an active area of research. Here, we report the solution structure of STARD6 and the characterization of its backbone dynamics on multiple time-scales through 15N spin-relaxation and amide exchange studies. We reveal for the first time the presence of concerted fluctuations in the Ω1 loop and the C-terminal helix on the microsecond-millisecond time-scale that allows for the opening of the binding site and ligand entry. We also report that STARD6 binds specifically testosterone. Our work represents a milestone for the study of ligand binding mechanism by other START domains and the elucidation of the biological function of STARD6.

Global Existence Results for Viscoplasticity at Finite Strain

NASA Astrophysics Data System (ADS)

Mielke, Alexander; Rossi, Riccarda; Savaré, Giuseppe

2018-01-01

We study a model for rate-dependent gradient plasticity at finite strain based on the multiplicative decomposition of the strain tensor, and investigate the existence of global-in-time solutions to the related PDE system. We reveal its underlying structure as a generalized gradient system, where the driving energy functional is highly nonconvex and features the geometric nonlinearities related to finite-strain elasticity as well as the multiplicative decomposition of finite-strain plasticity. Moreover, the dissipation potential depends on the left-invariant plastic rate, and thus depends on the plastic state variable. The existence theory is developed for a class of abstract, nonsmooth, and nonconvex gradient systems, for which we introduce suitable notions of solutions, namely energy-dissipation-balance and energy-dissipation-inequality solutions. Hence, we resort to the toolbox of the direct method of the calculus of variations to check that the specific energy and dissipation functionals for our viscoplastic models comply with the conditions of the general theory.

Object Perception Impairments Predict Instrumental Activities of Daily Living Dependence in Alzheimer's Disease

PubMed Central

JEFFERSON, ANGELA L.; BARAKAT, LAMIA P.; GIOVANNETTI, TANIA; PAUL, ROBERT H.; GLOSSER, GUILA

2009-01-01

This study examined the contribution of object perception and spatial localization to functional dependence among Alzheimer's disease (AD) patients. Forty patients with probable AD completed measures assessing verbal recognition memory, working memory, object perception, spatial localization, semantic knowledge, and global cognition. Primary caregivers completed a measure of activities of daily living (ADLs) that included instrumental and basic self-care subscales (i.e., IADLs and BADLs, respectively). Stepwise multiple regressions revealed that global cognition accounted for significant portions of variance among the ADL total, IADL, and BADL scores. However, when global cognition was removed from the model, object perception was the only significant cognitive predictor of the ADL total and IADL subscale scores, accounting for 18.5% and 19.3% of the variance, respectively. When considering multiple cognitive components simultaneously, object perception and the integrity of the inferotemporal cortex is important in the completion of functional abilities in general and IADLs in particular among AD patients. PMID:16822730

Natively Unfolded FG Repeats Stabilize the Structure of the Nuclear Pore Complex.

PubMed

Onischenko, Evgeny; Tang, Jeffrey H; Andersen, Kasper R; Knockenhauer, Kevin E; Vallotton, Pascal; Derrer, Carina P; Kralt, Annemarie; Mugler, Christopher F; Chan, Leon Y; Schwartz, Thomas U; Weis, Karsten

2017-11-02

Nuclear pore complexes (NPCs) are ∼100 MDa transport channels assembled from multiple copies of ∼30 nucleoporins (Nups). One-third of these Nups contain phenylalanine-glycine (FG)-rich repeats, forming a diffusion barrier, which is selectively permeable for nuclear transport receptors that interact with these repeats. Here, we identify an additional function of FG repeats in the structure and biogenesis of the yeast NPC. We demonstrate that GLFG-containing FG repeats directly bind to multiple scaffold Nups in vitro and act as NPC-targeting determinants in vivo. Furthermore, we show that the GLFG repeats of Nup116 function in a redundant manner with Nup188, a nonessential scaffold Nup, to stabilize critical interactions within the NPC scaffold needed for late steps of NPC assembly. Our results reveal a previously unanticipated structural role for natively unfolded GLFG repeats as Velcro to link NPC subcomplexes and thus add a new layer of connections to current models of the NPC architecture. Copyright © 2017 Elsevier Inc. All rights reserved.

Examination of Cognitive Fatigue in Multiple Sclerosis using Functional Magnetic Resonance Imaging and Diffusion Tensor Imaging

PubMed Central

Genova, Helen M.; Rajagopalan, Venkateswaran; DeLuca, John; Das, Abhijit; Binder, Allison; Arjunan, Aparna; Chiaravalloti, Nancy; Wylie, Glenn

2013-01-01

The present study investigated the neural correlates of cognitive fatigue in Multiple Sclerosis (MS), looking specifically at the relationship between self-reported fatigue and objective measures of cognitive fatigue. In Experiment 1, functional magnetic resonance imaging (fMRI) was used to examine where in the brain BOLD activity covaried with “state” fatigue, assessed during performance of a task designed to induce cognitive fatigue while in the scanner. In Experiment 2, diffusion tensor imaging (DTI) was used to examine where in the brain white matter damage correlated with increased “trait” fatigue in individuals with MS, assessed by the Fatigue Severity Scale (FSS) completed outside the scanning session. During the cognitively fatiguing task, the MS group had increased brain activity associated with fatigue in the caudate as compared with HCs. DTI findings revealed that reduced fractional anisotropy in the anterior internal capsule was associated with increased self-reported fatigue on the FSS. Results are discussed in terms of identifying a “fatigue-network” in MS. PMID:24223850

Examination of cognitive fatigue in multiple sclerosis using functional magnetic resonance imaging and diffusion tensor imaging.

PubMed

Genova, Helen M; Rajagopalan, Venkateswaran; Deluca, John; Das, Abhijit; Binder, Allison; Arjunan, Aparna; Chiaravalloti, Nancy; Wylie, Glenn

2013-01-01

The present study investigated the neural correlates of cognitive fatigue in Multiple Sclerosis (MS), looking specifically at the relationship between self-reported fatigue and objective measures of cognitive fatigue. In Experiment 1, functional magnetic resonance imaging (fMRI) was used to examine where in the brain BOLD activity covaried with "state" fatigue, assessed during performance of a task designed to induce cognitive fatigue while in the scanner. In Experiment 2, diffusion tensor imaging (DTI) was used to examine where in the brain white matter damage correlated with increased "trait" fatigue in individuals with MS, assessed by the Fatigue Severity Scale (FSS) completed outside the scanning session. During the cognitively fatiguing task, the MS group had increased brain activity associated with fatigue in the caudate as compared with HCs. DTI findings revealed that reduced fractional anisotropy in the anterior internal capsule was associated with increased self-reported fatigue on the FSS. Results are discussed in terms of identifying a "fatigue-network" in MS.

"Multiple partial recognitions in dynamic equilibrium" in the binding sites of proteins form the molecular basis of promiscuous recognition of structurally diverse ligands.

PubMed

Kohda, Daisuke

2018-04-01

Promiscuous recognition of ligands by proteins is as important as strict recognition in numerous biological processes. In living cells, many short, linear amino acid motifs function as targeting signals in proteins to specify the final destination of the protein transport. In general, the target signal is defined by a consensus sequence containing wild-characters, and hence represented by diverse amino acid sequences. The classical lock-and-key or induced-fit/conformational selection mechanism may not cover all aspects of the promiscuous recognition. On the basis of our crystallographic and NMR studies on the mitochondrial Tom20 protein-presequence interaction, we proposed a new hypothetical mechanism based on "a rapid equilibrium of multiple states with partial recognitions". This dynamic, multiple recognition mode enables the Tom20 receptor to recognize diverse mitochondrial presequences with nearly equal affinities. The plant Tom20 is evolutionally unrelated to the animal Tom20 in our study, but is a functional homolog of the animal/fungal Tom20. NMR studies by another research group revealed that the presequence binding by the plant Tom20 was not fully explained by simple interaction modes, suggesting the presence of a similar dynamic, multiple recognition mode. Circumstantial evidence also suggested that similar dynamic mechanisms may be applicable to other promiscuous recognitions of signal peptides by the SRP54/Ffh and SecA proteins.

Reconstitution of active human core Mediator complex reveals a critical role of the MED14 subunit.

PubMed

Cevher, Murat A; Shi, Yi; Li, Dan; Chait, Brian T; Malik, Sohail; Roeder, Robert G

2014-12-01

The evolutionarily conserved Mediator complex is a critical coactivator for RNA polymerase II (Pol II)-mediated transcription. Here we report the reconstitution of a functional 15-subunit human core Mediator complex and its characterization by functional assays and chemical cross-linking coupled to MS (CX-MS). Whereas the reconstituted head and middle modules can stably associate, basal and coactivator functions are acquired only after incorporation of MED14 into the bimodular complex. This results from a dramatically enhanced ability of MED14-containing complexes to associate with Pol II. Altogether, our analyses identify MED14 as both an architectural and a functional backbone of the Mediator complex. We further establish a conditional requirement for metazoan-specific MED26 that becomes evident in the presence of heterologous nuclear factors. This general approach paves the way for systematic dissection of the multiple layers of functionality associated with the Mediator complex.

Further education improves cognitive reserve and triggers improvement in selective cognitive functions in older adults: The Tasmanian Healthy Brain Project.

PubMed

Thow, Megan E; Summers, Mathew J; Saunders, Nichole L; Summers, Jeffery J; Ritchie, Karen; Vickers, James C

2018-01-01

The strong link between early-life education and subsequent reduced risk of dementia suggests that education in later life could enhance cognitive function and may reduce age-related cognitive decline and protect against dementia. Episodic memory, working memory, executive function, and language processing performances were assessed annually over 4 years in 359 healthy older adults who attended university for a minimum of 12 months (intervention) and were compared against 100 healthy adult controls. Multiple group latent growth curve modeling revealed a significant improvement in language processing capacity over time in the intervention group. No changes were detected for episodic memory, working memory, or executive function. These results suggest that complex mental stimulation resulting from late-life further education results in improved crystallized knowledge but no changes to fluid cognitive functions.

Behavioral testing strategies in a localized animal model of multiple sclerosis.

PubMed

Buddeberg, Bigna S; Kerschensteiner, Martin; Merkler, Doron; Stadelmann, Christine; Schwab, Martin E

2004-08-01

To assess neurological impairments quantitatively in an animal model of multiple sclerosis (MS), we have used a targeted model of experimental autoimmune encephalomyelitis (EAE), which leads to the formation of anatomically defined lesions in the spinal cord. Deficits in the hindlimb locomotion are therefore well defined and highly reproducible, in contrast to the situation in generalized EAE with disseminated lesions. Behavioral tests for hindlimb sensorimotor functions, originally established for traumatic spinal cord injury, revealed temporary or persistent deficits in open field locomotion, the grid walk, the narrow beam and the measurement of the foot exorotation angle. Such refined behavioral testing in EAE will be crucial for the analysis of new therapeutic approaches for MS that seek to improve or prevent neurological impairment.

Perceptual grouping in the human brain: common processing of different cues.

PubMed

Seymour, Kiley; Karnath, Hans-Otto; Himmelbach, Marc

2008-12-03

The perception of global scenes and objects consisting of multiple constituents is based on the integration of local elements or features. Gestalt grouping cues, such as proximity or similarity, can aid this process. Using functional MRI we investigated whether grouping guided by different gestalt cues rely on distinct networks in the brain or share a common network. Our study revealed that gestalt grouping involved the inferior parietal cortex, middle temporal gyrus and prefrontal cortex irrespective of the specific cue used. These findings agree with observations in neurological patients, which suggest that inferior parietal regions may aid the integration of local features into a global gestalt. Damage to this region results in simultanagnosia, a deficit in perceiving multiple objects and global scenes.

An in vivo model of functional and vascularized human brain organoids.

PubMed

Mansour, Abed AlFatah; Gonçalves, J Tiago; Bloyd, Cooper W; Li, Hao; Fernandes, Sarah; Quang, Daphne; Johnston, Stephen; Parylak, Sarah L; Jin, Xin; Gage, Fred H

2018-06-01

Differentiation of human pluripotent stem cells to small brain-like structures known as brain organoids offers an unprecedented opportunity to model human brain development and disease. To provide a vascularized and functional in vivo model of brain organoids, we established a method for transplanting human brain organoids into the adult mouse brain. Organoid grafts showed progressive neuronal differentiation and maturation, gliogenesis, integration of microglia, and growth of axons to multiple regions of the host brain. In vivo two-photon imaging demonstrated functional neuronal networks and blood vessels in the grafts. Finally, in vivo extracellular recording combined with optogenetics revealed intragraft neuronal activity and suggested graft-to-host functional synaptic connectivity. This combination of human neural organoids and an in vivo physiological environment in the animal brain may facilitate disease modeling under physiological conditions.

Matrix factorization reveals aging-specific co-expression gene modules in the fat and muscle tissues in nonhuman primates

NASA Astrophysics Data System (ADS)

Wang, Yongcui; Zhao, Weiling; Zhou, Xiaobo

2016-10-01

Accurate identification of coherent transcriptional modules (subnetworks) in adipose and muscle tissues is important for revealing the related mechanisms and co-regulated pathways involved in the development of aging-related diseases. Here, we proposed a systematically computational approach, called ICEGM, to Identify the Co-Expression Gene Modules through a novel mathematical framework of Higher-Order Generalized Singular Value Decomposition (HO-GSVD). ICEGM was applied on the adipose, and heart and skeletal muscle tissues in old and young female African green vervet monkeys. The genes associated with the development of inflammation, cardiovascular and skeletal disorder diseases, and cancer were revealed by the ICEGM. Meanwhile, genes in the ICEGM modules were also enriched in the adipocytes, smooth muscle cells, cardiac myocytes, and immune cells. Comprehensive disease annotation and canonical pathway analysis indicated that immune cells, adipocytes, cardiomyocytes, and smooth muscle cells played a synergistic role in cardiac and physical functions in the aged monkeys by regulation of the biological processes associated with metabolism, inflammation, and atherosclerosis. In conclusion, the ICEGM provides an efficiently systematic framework for decoding the co-expression gene modules in multiple tissues. Analysis of genes in the ICEGM module yielded important insights on the cooperative role of multiple tissues in the development of diseases.

Aging effects on DNA methylation modules in human brain and blood tissue

PubMed Central

2012-01-01

Background Several recent studies reported aging effects on DNA methylation levels of individual CpG dinucleotides. But it is not yet known whether aging-related consensus modules, in the form of clusters of correlated CpG markers, can be found that are present in multiple human tissues. Such a module could facilitate the understanding of aging effects on multiple tissues. Results We therefore employed weighted correlation network analysis of 2,442 Illumina DNA methylation arrays from brain and blood tissues, which enabled the identification of an age-related co-methylation module. Module preservation analysis confirmed that this module can also be found in diverse independent data sets. Biological evaluation showed that module membership is associated with Polycomb group target occupancy counts, CpG island status and autosomal chromosome location. Functional enrichment analysis revealed that the aging-related consensus module comprises genes that are involved in nervous system development, neuron differentiation and neurogenesis, and that it contains promoter CpGs of genes known to be down-regulated in early Alzheimer's disease. A comparison with a standard, non-module based meta-analysis revealed that selecting CpGs based on module membership leads to significantly increased gene ontology enrichment, thus demonstrating that studying aging effects via consensus network analysis enhances the biological insights gained. Conclusions Overall, our analysis revealed a robustly defined age-related co-methylation module that is present in multiple human tissues, including blood and brain. We conclude that blood is a promising surrogate for brain tissue when studying the effects of age on DNA methylation profiles. PMID:23034122

Homozygous inactivation of CHEK2 is linked to a familial case of multiple primary lung cancer with accompanying cancers in other organs

PubMed Central

Kukita, Yoji; Okami, Jiro; Yoneda-Kato, Noriko; Nakamae, Ikuko; Kawabata, Takeshi; Higashiyama, Masahiko; Kato, Junya; Kodama, Ken; Kato, Kikuya

2016-01-01

In clinical practice, there are a number of cancer patients with clear family histories, but the patients lack mutations in known familial cancer syndrome genes. Recent advances in genomic technologies have enhanced the possibility of identifying causative genes in such cases. Two siblings, an elder sister and a younger brother, were found to have multiple primary lung cancers at the age of 60. The former subsequently developed breast cancer and had a history of uterine myoma. The latter had initially developed prostate cancer at the age of 59 and had a history of colon cancer. Single-nucleotide polymorphism (SNP) genotyping revealed that ∼10% of the genomes were homozygous in both patients. Exome sequencing revealed nonsynonymous mutations in five genes in the runs of homozygosity: CHEK2, FCGRT, INPP5J, MYO18B, and SFI1. Evolutionary conservation of primary protein structures suggested the functional importance of the CHEK2 mutation, p.R474C. This mutation altered the tertiary structure of CHK2 by disrupting the salt bridge between p.R474 and p.E394. No such structural changes were observed with the other mutated genes. Subsequent cell-based transfection analysis revealed that CHK2 p.R474C was unstable and scarcely activated. We concluded that the homozygous CHEK2 variant was contributory in this case of familial cancer. Although homozygous inactivation of CHEK2 in mice led to cancers in multiple organs, accumulation of additional human cases is needed to establish its pathogenic role in humans. PMID:27900359

Homozygous inactivation of CHEK2 is linked to a familial case of multiple primary lung cancer with accompanying cancers in other organs.

PubMed

Kukita, Yoji; Okami, Jiro; Yoneda-Kato, Noriko; Nakamae, Ikuko; Kawabata, Takeshi; Higashiyama, Masahiko; Kato, Junya; Kodama, Ken; Kato, Kikuya

2016-11-01

In clinical practice, there are a number of cancer patients with clear family histories, but the patients lack mutations in known familial cancer syndrome genes. Recent advances in genomic technologies have enhanced the possibility of identifying causative genes in such cases. Two siblings, an elder sister and a younger brother, were found to have multiple primary lung cancers at the age of 60. The former subsequently developed breast cancer and had a history of uterine myoma. The latter had initially developed prostate cancer at the age of 59 and had a history of colon cancer. Single-nucleotide polymorphism (SNP) genotyping revealed that ∼10% of the genomes were homozygous in both patients. Exome sequencing revealed nonsynonymous mutations in five genes in the runs of homozygosity: CHEK2 , FCGRT , INPP5J , MYO18B , and SFI1 . Evolutionary conservation of primary protein structures suggested the functional importance of the CHEK2 mutation, p.R474C. This mutation altered the tertiary structure of CHK2 by disrupting the salt bridge between p.R474 and p.E394. No such structural changes were observed with the other mutated genes. Subsequent cell-based transfection analysis revealed that CHK2 p.R474C was unstable and scarcely activated. We concluded that the homozygous CHEK2 variant was contributory in this case of familial cancer. Although homozygous inactivation of CHEK2 in mice led to cancers in multiple organs, accumulation of additional human cases is needed to establish its pathogenic role in humans.

STAYGREEN (CsSGR) is a candidate for the anthracnose (Colletotrichum orbiculare) resistance locus cla in Gy14 cucumber.

PubMed

Pan, Junsong; Tan, Junyi; Wang, Yuhui; Zheng, Xiangyang; Owens, Ken; Li, Dawei; Li, Yuhong; Weng, Yiqun

2018-04-21

Map-based cloning identified a candidate gene for resistance to the anthracnose fungal pathogen Colletotrichum orbiculare in cucumber, which reveals a novel function for the highly conserved STAYGREEN family genes for host disease resistance in plants. Colletotrichum orbiculare is a hemibiotrophic fungal pathogen that causes anthracnose disease in cucumber and other cucurbit crops. No host resistance genes against the anthracnose pathogens have been cloned in crop plants. Here, we reported fine mapping and cloning of a resistance gene to the race 1 anthracnose pathogen in cucumber inbred lines Gy14 and WI 2757. Phenotypic and QTL analysis in multiple populations revealed that a single recessive gene, cla, was underlying anthracnose resistance in both lines, but WI2757 carried an additional minor-effect QTL. Fine mapping using 150 Gy14 × 9930 recombinant inbred lines and 1043 F 2 individuals delimited the cla locus into a 32 kb region in cucumber Chromosome 5 with three predicted genes. Multiple lines of evidence suggested that the cucumber STAYGREEN (CsSGR) gene is a candidate for the anthracnose resistance locus. A single nucleotide mutation in the third exon of CsSGR resulted in the substitution of Glutamine in 9930 to Arginine in Gy14 in CsSGR protein which seems responsible for the differential anthracnose inoculation responses between Gy14 and 9930. Quantitative real-time PCR analysis indicated that CsSGR was significantly upregulated upon anthracnose pathogen inoculation in the susceptible 9930, while its expression was much lower in the resistant Gy14. Investigation of allelic diversities in natural cucumber populations revealed that the resistance allele in almost all improved cultivars or breeding lines of the U.S. origin was derived from PI 197087. This work reveals an unknown function for the highly conserved STAYGREEN (SGR) family genes for host disease resistance in plants.

Microbial diversity and activity in the Nematostella vectensis holobiont: insights from 16S rRNA gene sequencing, isolate genomes, and a pilot-scale survey of gene expression.

PubMed

Har, Jia Y; Helbig, Tim; Lim, Ju H; Fernando, Samodha C; Reitzel, Adam M; Penn, Kevin; Thompson, Janelle R

2015-01-01

We have characterized the molecular and genomic diversity of the microbiota of the starlet sea anemone Nematostella vectensis, a cnidarian model for comparative developmental and functional biology and a year-round inhabitant of temperate salt marshes. Molecular phylogenetic analysis of 16S rRNA gene clone libraries revealed four ribotypes associated with N. vectensis at multiple locations and times. These associates include two novel ribotypes within the ε-Proteobacterial order Campylobacterales and the Spirochetes, respectively, each sharing <85% identity with cultivated strains, and two γ-Proteobacterial ribotypes sharing >99% 16S rRNA identity with Endozoicomonas elysicola and Pseudomonas oleovorans, respectively. Species-specific PCR revealed that these populations persisted in N. vectensis asexually propagated under laboratory conditions. cDNA indicated expression of the Campylobacterales and Endozoicomonas 16S rRNA in anemones from Sippewissett Marsh, MA. A collection of bacteria from laboratory raised N. vectensis was dominated by isolates from P. oleovorans and Rhizobium radiobacter. Isolates from field-collected anemones revealed an association with Limnobacter and Stappia isolates. Genomic DNA sequencing was carried out on 10 cultured bacterial isolates representing field- and laboratory-associates, i.e., Limnobacter spp., Stappia spp., P. oleovorans and R. radiobacter. Genomes contained multiple genes identified as virulence (host-association) factors while S. stellulata and L. thiooxidans genomes revealed pathways for mixotrophic sulfur oxidation. A pilot metatranscriptome of laboratory-raised N. vectensis was compared to the isolate genomes and indicated expression of ORFs from L. thiooxidans with predicted functions of motility, nutrient scavenging (Fe and P), polyhydroxyalkanoate synthesis for carbon storage, and selective permeability (porins). We hypothesize that such activities may mediate acclimation and persistence of bacteria in a N. vectensis holobiont defined by both internal and external gradients of chemicals and nutrients in a dynamic coastal habitat.

Microbial diversity and activity in the Nematostella vectensis holobiont: insights from 16S rRNA gene sequencing, isolate genomes, and a pilot-scale survey of gene expression

PubMed Central

Har, Jia Y.; Helbig, Tim; Lim, Ju H.; Fernando, Samodha C.; Reitzel, Adam M.; Penn, Kevin; Thompson, Janelle R.

2015-01-01

We have characterized the molecular and genomic diversity of the microbiota of the starlet sea anemone Nematostella vectensis, a cnidarian model for comparative developmental and functional biology and a year-round inhabitant of temperate salt marshes. Molecular phylogenetic analysis of 16S rRNA gene clone libraries revealed four ribotypes associated with N. vectensis at multiple locations and times. These associates include two novel ribotypes within the ε-Proteobacterial order Campylobacterales and the Spirochetes, respectively, each sharing <85% identity with cultivated strains, and two γ-Proteobacterial ribotypes sharing >99% 16S rRNA identity with Endozoicomonas elysicola and Pseudomonas oleovorans, respectively. Species-specific PCR revealed that these populations persisted in N. vectensis asexually propagated under laboratory conditions. cDNA indicated expression of the Campylobacterales and Endozoicomonas 16S rRNA in anemones from Sippewissett Marsh, MA. A collection of bacteria from laboratory raised N. vectensis was dominated by isolates from P. oleovorans and Rhizobium radiobacter. Isolates from field-collected anemones revealed an association with Limnobacter and Stappia isolates. Genomic DNA sequencing was carried out on 10 cultured bacterial isolates representing field- and laboratory-associates, i.e., Limnobacter spp., Stappia spp., P. oleovorans and R. radiobacter. Genomes contained multiple genes identified as virulence (host-association) factors while S. stellulata and L. thiooxidans genomes revealed pathways for mixotrophic sulfur oxidation. A pilot metatranscriptome of laboratory-raised N. vectensis was compared to the isolate genomes and indicated expression of ORFs from L. thiooxidans with predicted functions of motility, nutrient scavenging (Fe and P), polyhydroxyalkanoate synthesis for carbon storage, and selective permeability (porins). We hypothesize that such activities may mediate acclimation and persistence of bacteria in a N. vectensis holobiont defined by both internal and external gradients of chemicals and nutrients in a dynamic coastal habitat. PMID:26388838

Cdx ParaHox genes acquired distinct developmental roles after gene duplication in vertebrate evolution.

PubMed

Marlétaz, Ferdinand; Maeso, Ignacio; Faas, Laura; Isaacs, Harry V; Holland, Peter W H

2015-08-01

The functional consequences of whole genome duplications in vertebrate evolution are not fully understood. It remains unclear, for instance, why paralogues were retained in some gene families but extensively lost in others. Cdx homeobox genes encode conserved transcription factors controlling posterior development across diverse bilaterians. These genes are part of the ParaHox gene cluster. Multiple Cdx copies were retained after genome duplication, raising questions about how functional divergence, overlap, and redundancy respectively contributed to their retention and evolutionary fate. We examined the degree of regulatory and functional overlap between the three vertebrate Cdx genes using single and triple morpholino knock-down in Xenopus tropicalis followed by RNA-seq. We found that one paralogue, Cdx4, has a much stronger effect on gene expression than the others, including a strong regulatory effect on FGF and Wnt genes. Functional annotation revealed distinct and overlapping roles and subtly different temporal windows of action for each gene. The data also reveal a colinear-like effect of Cdx genes on Hox genes, with repression of Hox paralogy groups 1 and 2, and activation increasing from Hox group 5 to 11. We also highlight cases in which duplicated genes regulate distinct paralogous targets revealing pathway elaboration after whole genome duplication. Despite shared core pathways, Cdx paralogues have acquired distinct regulatory roles during development. This implies that the degree of functional overlap between paralogues is relatively low and that gene expression pattern alone should be used with caution when investigating the functional evolution of duplicated genes. We therefore suggest that developmental programmes were extensively rewired after whole genome duplication in the early evolution of vertebrates.

Acetylproteomic Analysis Reveals Functional Implications of Lysine Acetylation in Human Spermatozoa (sperm)*

PubMed Central

Yu, Heguo; Diao, Hua; Wang, Chunmei; Lin, Yan; Yu, Fudong; Lu, Hui; Xu, Wei; Li, Zheng; Shi, Huijuan; Zhao, Shimin; Zhou, Yuchuan; Zhang, Yonglian

2015-01-01

Male infertility is a medical condition that has been on the rise globally. Lysine acetylation of human sperm, an essential posttranslational modification involved in the etiology of sperm abnormality, is not fully understood. Therefore, we first generated a qualified pan-anti-acetyllysine monoclonal antibody to characterize the global lysine acetylation of uncapacitated normal human sperm with a proteomics approach. With high enrichment ratios that were up to 31%, 973 lysine-acetylated sites that matched to 456 human sperm proteins, including 671 novel lysine acetylation sites and 205 novel lysine-acetylated proteins, were identified. These proteins exhibited conserved motifs XXXKYXXX, XXXKFXXX, and XXXKHXXX, were annotated to function in multiple metabolic processes, and were localized predominantly in the mitochondrion and cytoplasmic fractions. Between the uncapacitated and capacitated sperm, different acetylation profiles in regard to functional proteins involved in sperm capacitation, sperm-egg recognition, sperm-egg plasma fusion, and fertilization were observed, indicating that acetylation of functional proteins may be required during sperm capacitation. Bioinformatics analysis revealed association of acetylated proteins with diseases and drugs. Novel acetylation of voltage-dependent anion channel proteins was also found. With clinical sperm samples, we observed differed lysine acetyltransferases and lysine deacetylases expression between normal sperm and abnormal sperm of asthenospermia or necrospermia. Furthermore, with sperm samples impaired by epigallocatechin gallate to mimic asthenospermia, we observed that inhibition of sperm motility was partly through the blockade of voltage-dependent anion channel 2 Lys-74 acetylation combined with reduced ATP levels and mitochondrial membrane potential. Taken together, we obtained a qualified pan-anti-acetyllysine monoclonal antibody, analyzed the acetylproteome of uncapacitated human sperm, and revealed associations between functional protein acetylation and sperm functions. PMID:25680958

Secondary traumatization in parents following the disclosure of extrafamilial child sexual abuse: initial effects.

PubMed

Manion, I G; McIntyre, J; Firestone, P; Ligezinska, M; Ensom, R; Wells, G

1996-11-01

Disclosure or discovery of extrafamilial sexual abuse (ESA) has the potential to traumatize the entire family system. Little controlled research has examined the initial reactions of parents to this type of trauma. The present study evaluated the adjustment of 93 parents (63 mothers and 30 fathers) within 3 months of the disclosure of ESA. Parents' functioning was compared to that of a nonclinical comparison group of 136 parents (74 mothers, 62 fathers). Parent adjustment was assessed using self-report measures of psychological distress, parent competence, family functioning, marital functioning, life stressors, and environmental support. Results revealed that mothers of sexually abused children, in comparison to mothers of nonabused children, experienced greater overall emotional distress, poorer family functioning, and lower satisfaction in their parenting role. Fathers of sexually abused children also experienced greater overall emotional distress relative to comparison fathers but their level of distress remained below that of mothers. Standard and hierarchical multiple regressions on maternal self-reports revealed that mothers' satisfaction with their parenting role and their perceived level of environmental support predicted their emotional functioning. Abuse-related variables did not contribute to the prediction of emotional functioning. These results emphasize the need to expand our focus beyond the child victims to the traumatized families and to normalize the potential for all close family members to be vulnerable to experience adjustment difficulties following ESA.

Genetic architecture and balancing selection: the life and death of differentiated variants.

PubMed

Llaurens, Violaine; Whibley, Annabel; Joron, Mathieu

2017-05-01

Balancing selection describes any form of natural selection, which results in the persistence of multiple variants of a trait at intermediate frequencies within populations. By offering up a snapshot of multiple co-occurring functional variants and their interactions, systems under balancing selection can reveal the evolutionary mechanisms favouring the emergence and persistence of adaptive variation in natural populations. We here focus on the mechanisms by which several functional variants for a given trait can arise, a process typically requiring multiple epistatic mutations. We highlight how balancing selection can favour specific features in the genetic architecture and review the evolutionary and molecular mechanisms shaping this architecture. First, balancing selection affects the number of loci underlying differentiated traits and their respective effects. Control by one or few loci favours the persistence of differentiated functional variants by limiting intergenic recombination, or its impact, and may sometimes lead to the evolution of supergenes. Chromosomal rearrangements, particularly inversions, preventing adaptive combinations from being dissociated are increasingly being noted as features of such systems. Similarly, due to the frequency of heterozygotes maintained by balancing selection, dominance may be a key property of adaptive variants. High heterozygosity and limited recombination also influence associated genetic load, as linked recessive deleterious mutations may be sheltered. The capture of deleterious elements in a locus under balancing selection may reinforce polymorphism by further promoting heterozygotes. Finally, according to recent genomewide scans, balanced polymorphism might be more pervasive than generally thought. We stress the need for both functional and ecological studies to characterize the evolutionary mechanisms operating in these systems. © 2017 John Wiley & Sons Ltd.

Force-independent distribution of correlated neural inputs to hand muscles during three-digit grasping.

PubMed

Poston, Brach; Danna-Dos Santos, Alessander; Jesunathadas, Mark; Hamm, Thomas M; Santello, Marco

2010-08-01

The ability to modulate digit forces during grasping relies on the coordination of multiple hand muscles. Because many muscles innervate each digit, the CNS can potentially choose from a large number of muscle coordination patterns to generate a given digit force. Studies of single-digit force production tasks have revealed that the electromyographic (EMG) activity scales uniformly across all muscles as a function of digit force. However, the extent to which this finding applies to the coordination of forces across multiple digits is unknown. We addressed this question by asking subjects (n = 8) to exert isometric forces using a three-digit grip (thumb, index, and middle fingers) that allowed for the quantification of hand muscle coordination within and across digits as a function of grasp force (5, 20, 40, 60, and 80% maximal voluntary force). We recorded EMG from 12 muscles (6 extrinsic and 6 intrinsic) of the three digits. Hand muscle coordination patterns were quantified in the amplitude and frequency domains (EMG-EMG coherence). EMG amplitude scaled uniformly across all hand muscles as a function of grasp force (muscle x force interaction: P = 0.997; cosines of angle between muscle activation pattern vector pairs: 0.897-0.997). Similarly, EMG-EMG coherence was not significantly affected by force (P = 0.324). However, coherence was stronger across extrinsic than that across intrinsic muscle pairs (P = 0.0039). These findings indicate that the distribution of neural drive to multiple hand muscles is force independent and may reflect the anatomical properties or functional roles of hand muscle groups.

Basonuclin 2 has a function in the multiplication of embryonic craniofacial mesenchymal cells and is orthologous to disco proteins

PubMed Central

Vanhoutteghem, Amandine; Maciejewski-Duval, Anna; Bouche, Cyril; Delhomme, Brigitte; Hervé, Françoise; Daubigney, Fabrice; Soubigou, Guillaume; Araki, Masatake; Araki, Kimi; Yamamura, Ken-ichi; Djian, Philippe

2009-01-01

Basonuclin 2 is a recently discovered zinc finger protein of unknown function. Its paralog, basonuclin 1, is associated with the ability of keratinocytes to multiply. The basonuclin zinc fingers are closely related to those of the Drosophila proteins disco and discorelated, but the relation between disco proteins and basonuclins has remained elusive because the function of the disco proteins in larval head development seems to have no relation to that of basonuclin 1 and because the amino acid sequence of disco, apart from the zinc fingers, also has no similarity to that of the basonuclins. We have generated mice lacking basonuclin 2. These mice die within 24 h of birth with a cleft palate and abnormalities of craniofacial bones and tongue. In the embryonic head, expression of the basonuclin 2 gene is restricted to mesenchymal cells in the palate, at the periphery of the tongue, and in the mesenchymal sheaths that surround the brain and the osteocartilagineous structures. In late embryos, the rate of multiplication of these mesenchymal cells is greatly diminished. Therefore, basonuclin 2 is essential for the multiplication of craniofacial mesenchymal cells during embryogenesis. Non-Drosophila insect databases available since 2008 reveal that the basonuclins and the disco proteins share much more extensive sequence and gene structure similarity than noted when only Drosophila sequences were examined. We conclude that basonuclin 2 is both structurally and functionally the vertebrate ortholog of the disco proteins. We also note the possibility that some human craniofacial abnormalities are due to a lack of basonuclin 2. PMID:19706529

Health related quality of life in parents of six to eight year old children with Down syndrome.

PubMed

Marchal, Jan Pieter; Maurice-Stam, Heleen; Hatzmann, Janneke; van Trotsenburg, A S Paul; Grootenhuis, Martha A

2013-11-01

Raising a child with Down syndrome (DS) has been found to be associated with lowered health related quality of life (HRQoL) in the domains cognitive functioning, social functioning, daily activities and vitality. We aimed to explore which socio-demographics, child functioning and psychosocial variables were related to these HRQoL domains in parents of children with DS. Parents of 98 children with DS completed the TNO-AZL adult quality of life questionnaire (TAAQOL) and a questionnaire assessing socio-demographic, child functioning and psychosocial predictors. Using multiple linear regression analyses for each category of predictors, we selected relevant predictors for the final models. The final multiple linear regression models revealed that cognitive functioning was best predicted by the sleep of the child (β=.29, p<.01) and by the parent having given up a hobby (β=-.29, p<.01), social functioning by the quality of the partner relation (β=.34, p<.001), daily activities by the parent having to care for an ill friend or family member (β=-.31, p<.01), and vitality by the parent having enough personal time (β=.32, p<.01). Overall, psychosocial variables rather than socio-demographics or child functioning showed most consistent and powerful relations to the HRQoL domains of cognitive functioning, social functioning, daily activities and vitality. These psychosocial variables mainly related to social support and time pressure. Systematic screening of parents to detect problems timely, and interventions targeting the supportive network and the demands in time are recommended. Copyright © 2013 Elsevier Ltd. All rights reserved.

The Multiple-Demand System in the Novelty of Musical Improvisation: Evidence from an MRI Study on Composers.

PubMed

Lu, Jing; Yang, Hua; He, Hui; Jeon, Seun; Hou, Changyue; Evans, Alan C; Yao, Dezhong

2017-01-01

The multiple-demand (MD) system has proven to be associated with creating structured mental programs in comprehensive behaviors, but the functional mechanisms of this system have not been clarified in the musical domain. In this study, we explored the hypothesis that the MD system is involved in a comprehensive music-related behavior known as musical improvisation. Under a functional magnetic resonance imaging (fMRI) paradigm, 29 composers were recruited to improvise melodies through visual imagery tasks according to familiar and unfamiliar cues. We found that the main regions of the MD system were significantly activated during both musical improvisation conditions. However, only a greater involvement of the intraparietal sulcus (IPS) within the MD system was shown when improvising with unfamiliar cues. Our results revealed that the MD system strongly participated in musical improvisation through processing the novelty of melodies, working memory, and attention. In particular, improvising with unfamiliar cues required more musical transposition manipulations. Moreover, both functional and structural analyses indicated evidence of neuroplasticity in MD regions that could be associated with musical improvisation training. These findings can help unveil the functional mechanisms of the MD system in musical cognition, as well as improve our understanding of musical improvisation.

The Multiple-Demand System in the Novelty of Musical Improvisation: Evidence from an MRI Study on Composers

PubMed Central

Lu, Jing; Yang, Hua; He, Hui; Jeon, Seun; Hou, Changyue; Evans, Alan C.; Yao, Dezhong

2017-01-01

The multiple-demand (MD) system has proven to be associated with creating structured mental programs in comprehensive behaviors, but the functional mechanisms of this system have not been clarified in the musical domain. In this study, we explored the hypothesis that the MD system is involved in a comprehensive music-related behavior known as musical improvisation. Under a functional magnetic resonance imaging (fMRI) paradigm, 29 composers were recruited to improvise melodies through visual imagery tasks according to familiar and unfamiliar cues. We found that the main regions of the MD system were significantly activated during both musical improvisation conditions. However, only a greater involvement of the intraparietal sulcus (IPS) within the MD system was shown when improvising with unfamiliar cues. Our results revealed that the MD system strongly participated in musical improvisation through processing the novelty of melodies, working memory, and attention. In particular, improvising with unfamiliar cues required more musical transposition manipulations. Moreover, both functional and structural analyses indicated evidence of neuroplasticity in MD regions that could be associated with musical improvisation training. These findings can help unveil the functional mechanisms of the MD system in musical cognition, as well as improve our understanding of musical improvisation. PMID:29311776

Discounting of Monetary Rewards that are Both Delayed and Probabilistic: Delay and Probability Combine Multiplicatively, not Additively

PubMed Central

Vanderveldt, Ariana; Green, Leonard; Myerson, Joel

2014-01-01

The value of an outcome is affected both by the delay until its receipt (delay discounting) and by the likelihood of its receipt (probability discounting). Despite being well-described by the same hyperboloid function, delay and probability discounting involve fundamentally different processes, as revealed, for example, by the differential effects of reward amount. Previous research has focused on the discounting of delayed and probabilistic rewards separately, with little research examining more complex situations in which rewards are both delayed and probabilistic. In two experiments, participants made choices between smaller rewards that were both immediate and certain and larger rewards that were both delayed and probabilistic. Analyses revealed significant interactions between delay and probability factors inconsistent with an additive model. In contrast, a hyperboloid discounting model in which delay and probability were combined multiplicatively provided an excellent fit to the data. These results suggest that the hyperboloid is a good descriptor of decision making in complicated monetary choice situations like those people encounter in everyday life. PMID:24933696

Native architecture of the Chlamydomonas chloroplast revealed by in situ cryo-electron tomography

PubMed Central

Engel, Benjamin D; Schaffer, Miroslava; Kuhn Cuellar, Luis; Villa, Elizabeth; Plitzko, Jürgen M; Baumeister, Wolfgang

2015-01-01

Chloroplast function is orchestrated by the organelle's intricate architecture. By combining cryo-focused ion beam milling of vitreous Chlamydomonas cells with cryo-electron tomography, we acquired three-dimensional structures of the chloroplast in its native state within the cell. Chloroplast envelope inner membrane invaginations were frequently found in close association with thylakoid tips, and the tips of multiple thylakoid stacks converged at dynamic sites on the chloroplast envelope, implicating lipid transport in thylakoid biogenesis. Subtomogram averaging and nearest neighbor analysis revealed that RuBisCO complexes were hexagonally packed within the pyrenoid, with ∼15 nm between their centers. Thylakoid stacks and the pyrenoid were connected by cylindrical pyrenoid tubules, physically bridging the sites of light-dependent photosynthesis and light-independent carbon fixation. Multiple parallel minitubules were bundled within each pyrenoid tubule, possibly serving as conduits for the targeted one-dimensional diffusion of small molecules such as ATP and sugars between the chloroplast stroma and the pyrenoid matrix. DOI: http://dx.doi.org/10.7554/eLife.04889.001 PMID:25584625

[Disease concept, etiology and mechanisms of multiple sclerosis].

PubMed

Kira, Jun-Ichi

2014-11-01

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system(CNS). MS is assumed to be caused by a complex interplay between genes and environments. Autoimmune mechanisms targeting CNS myelin has long been proposed, yet it has not been proved. Th17 cells producing interleukin-17 and Th1 cells producing interferon-gamma are postulated to play major roles in initiating inflammation while regulatory T cell functions are dampened. The forth nationwide survey of MS in Japan revealed that MS prevalence showed four-folds increase over 30 years and the increase was especially prominent in female. Thus, westernized life style and improved sanitation are suspected to increase MS susceptibility. Genome-wide association studies in Western MS patients disclosed more than 100 disease-susceptibility genes, most of which are immune-related genes. It therefore supports immune-mediated mechanisms to be operative. Detailed magnetic resonance imaging studies revealed an early atrophy of the cerebral gray matter where T cell infiltration is pathologically scarce. Therefore, neurodegenerative process also takes place in the early course beside neuroinflammation.

Geo-Chip analysis reveals reduced functional diversity of the bacterial community at a dumping site for dredged Elbe sediment.

PubMed

Störmer, Rebecca; Wichels, Antje; Gerdts, Gunnar

2013-12-15

The dumping of dredged sediments represents a major stressor for coastal ecosystems. The impact on the ecosystem function is determined by its complexity not easy to assess. In the present study, we evaluated the potential of bacterial community analyses to act as ecological indicators in environmental monitoring programmes. We investigated the functional structure of bacterial communities, applying functional gene arrays (GeoChip4.2). The relationship between functional genes and environmental factors was analysed using distance-based multivariate multiple regression. Apparently, both the function and structure of the bacterial communities are impacted by dumping activities. The bacterial community at the dumping centre displayed a significant reduction of its entire functional diversity compared with that found at a reference site. DDX compounds separated bacterial communities of the dumping site from those of un-impacted sites. Thus, bacterial community analyses show great potential as ecological indicators in environmental monitoring. Copyright © 2013 Elsevier Ltd. All rights reserved.

Health-related quality of life and psychosocial functioning in children with Tourette syndrome: parent-child agreement and comparison to healthy norms.

PubMed

Gutierrez-Colina, Ana M; Eaton, Cyd K; Lee, Jennifer L; LaMotte, Julia; Blount, Ronald L

2015-03-01

This study aimed to evaluate the degree of agreement between parent proxy- and child self-report on measures of child psychosocial functioning and health-related quality of life in children with Tourette syndrome. Participants included 28 children with Tourette syndrome and their parents. All participants provided ratings of children's level of quality of life and psychosocial functioning. Results revealed strong, positive relationships between child self- and parent proxy-reports on all quality of life and psychosocial functioning domains. Parents perceived significantly higher levels of depression compared to their children, whereas children reported significantly lower Physical quality of life compared to their parents. Results suggest that assessment of quality of life and psychosocial functioning should include multiple reporters whenever feasible. Caution should be used when exclusively relying on parent proxy-reports of quality of life and psychosocial functioning, as these reports may not accurately reflect children's difficulties or perceptions of their functioning. © The Author(s) 2014.

Executive functioning as a predictor of children's mathematics ability: inhibition, switching, and working memory.

PubMed

Bull, R; Scerif, G

2001-01-01

Children's mathematical skills were considered in relation to executive functions. Using multiple measures--including the Wisconsin Card Sorting Task (WCST), dual-task performance, Stroop task, and counting span-it was found that mathematical ability was significantly correlated with all measures of executive functioning, with the exception of dual-task performance. Furthermore, regression analyses revealed that each executive function measure predicted unique variance in mathematics ability. These results are discussed in terms of a central executive with diverse functions (Shallice & Burgess, 1996) and with recent evidence from Miyake, et al. (2000) showing the unity and diversity among executive functions. It is proposed that the particular difficulties for children of lower mathematical ability are lack of inhibition and poor working memory, which result in problems with switching and evaluation of new strategies for dealing with a particular task. The practical and theoretical implications of these results are discussed, along with suggestions for task changes and longitudinal studies that would clarify theoretical and developmental issues related to executive functioning.

Disentangling the multigenic and pleiotropic nature of molecular function

PubMed Central

2015-01-01

Background Biological processes at the molecular level are usually represented by molecular interaction networks. Function is organised and modularity identified based on network topology, however, this approach often fails to account for the dynamic and multifunctional nature of molecular components. For example, a molecule engaging in spatially or temporally independent functions may be inappropriately clustered into a single functional module. To capture biologically meaningful sets of interacting molecules, we use experimentally defined pathways as spatial/temporal units of molecular activity. Results We defined functional profiles of Saccharomyces cerevisiae based on a minimal set of Gene Ontology terms sufficient to represent each pathway's genes. The Gene Ontology terms were used to annotate 271 pathways, accounting for pathway multi-functionality and gene pleiotropy. Pathways were then arranged into a network, linked by shared functionality. Of the genes in our data set, 44% appeared in multiple pathways performing a diverse set of functions. Linking pathways by overlapping functionality revealed a modular network with energy metabolism forming a sparse centre, surrounded by several denser clusters comprised of regulatory and metabolic pathways. Signalling pathways formed a relatively discrete cluster connected to the centre of the network. Genetic interactions were enriched within the clusters of pathways by a factor of 5.5, confirming the organisation of our pathway network is biologically significant. Conclusions Our representation of molecular function according to pathway relationships enables analysis of gene/protein activity in the context of specific functional roles, as an alternative to typical molecule-centric graph-based methods. The pathway network demonstrates the cooperation of multiple pathways to perform biological processes and organises pathways into functionally related clusters with interdependent outcomes. PMID:26678917

Discovering functional DNA elements using population genomic information: a proof of concept using human mtDNA.

PubMed

Schrider, Daniel R; Kern, Andrew D

2014-06-09

Identifying the complete set of functional elements within the human genome would be a windfall for multiple areas of biological research including medicine, molecular biology, and evolution. Complete knowledge of function would aid in the prioritization of loci when searching for the genetic bases of disease or adaptive phenotypes. Because mutations that disrupt function are disfavored by natural selection, purifying selection leaves a detectable signature within functional elements; accordingly, this signal has been exploited for over a decade through the use of genomic comparisons of distantly related species. While this is so, the functional complement of the genome changes extensively across time and between lineages; therefore, evidence of the current action of purifying selection in humans is essential. Because the removal of deleterious mutations by natural selection also reduces within-species genetic diversity within functional loci, dense population genetic data have the potential to reveal genomic elements that are currently functional. Here, we assess the potential of this approach by examining an ultradeep sample of human mitochondrial genomes (n = 16,411). We show that the high density of polymorphism in this data set precisely delineates regions experiencing purifying selection. Furthermore, we show that the number of segregating alleles at a site is strongly correlated with its divergence across species after accounting for known mutational biases in human mitochondrial DNA (ρ = 0.51; P < 2.2 × 10(-16)). These two measures track one another at a remarkably fine scale across many loci-a correlation that is purely the result of natural selection. Our results demonstrate that genetic variation has the potential to reveal with surprising precision which regions in the genome are currently performing important functions and likely to have deleterious fitness effects when mutated. As more complete human genomes are sequenced, similar power to reveal purifying selection may be achievable in the human nuclear genome. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

The genome and phenome of the green alga Chloroidium sp. UTEX 3007 reveal adaptive traits for desert acclimatization

PubMed Central

Nelson, David R; Khraiwesh, Basel; Fu, Weiqi; Alseekh, Saleh; Jaiswal, Ashish; Chaiboonchoe, Amphun; Hazzouri, Khaled M; O’Connor, Matthew J; Butterfoss, Glenn L; Drou, Nizar; Rowe, Jillian D; Harb, Jamil; Fernie, Alisdair R; Gunsalus, Kristin C; Salehi-Ashtiani, Kourosh

2017-01-01

To investigate the phenomic and genomic traits that allow green algae to survive in deserts, we characterized a ubiquitous species, Chloroidium sp. UTEX 3007, which we isolated from multiple locations in the United Arab Emirates (UAE). Metabolomic analyses of Chloroidium sp. UTEX 3007 indicated that the alga accumulates a broad range of carbon sources, including several desiccation tolerance-promoting sugars and unusually large stores of palmitate. Growth assays revealed capacities to grow in salinities from zero to 60 g/L and to grow heterotrophically on >40 distinct carbon sources. Assembly and annotation of genomic reads yielded a 52.5 Mbp genome with 8153 functionally annotated genes. Comparison with other sequenced green algae revealed unique protein families involved in osmotic stress tolerance and saccharide metabolism that support phenomic studies. Our results reveal the robust and flexible biology utilized by a green alga to successfully inhabit a desert coastline. DOI: http://dx.doi.org/10.7554/eLife.25783.001 PMID:28623667

The neurogenetics of alternative splicing

PubMed Central

Vuong, Celine K.; Black, Douglas L.; Zheng, Sika

2016-01-01

Alternative precursor-mRNA splicing is a key mechanism for regulating gene expression in mammals and is controlled by specialized RNA-binding proteins. The misregulation of splicing is implicated in multiple neurological disorders. We describe recent mouse genetic studies of alternative splicing that reveal its critical role in both neuronal development and the function of mature neurons. We discuss the challenges in understanding the extensive genetic programmes controlled by proteins that regulate splicing, both during development and in the adult brain. PMID:27094079

Reliability assessment of multiple quantum well avalanche photodiodes

NASA Technical Reports Server (NTRS)

Yun, Ilgu; Menkara, Hicham M.; Wang, Yang; Oguzman, Isamil H.; Kolnik, Jan; Brennan, Kevin F.; May, Gray S.; Wagner, Brent K.; Summers, Christopher J.

1995-01-01

The reliability of doped-barrier AlGaAs/GsAs multi-quantum well avalanche photodiodes fabricated by molecular beam epitaxy is investigated via accelerated life tests. Dark current and breakdown voltage were the parameters monitored. The activation energy of the degradation mechanism and median device lifetime were determined. Device failure probability as a function of time was computed using the lognormal model. Analysis using the electron beam induced current method revealed the degradation to be caused by ionic impurities or contamination in the passivation layer.

Mathematical Modeling of Loop Heat Pipes with Multiple Capillary Pumps and Multiple Condensers. Part 1; Stead State Stimulations

NASA Technical Reports Server (NTRS)

Hoang, Triem T.; OConnell, Tamara; Ku, Jentung

2004-01-01

Loop Heat Pipes (LHPs) have proven themselves as reliable and robust heat transport devices for spacecraft thermal control systems. So far, the LHPs in earth-orbit satellites perform very well as expected. Conventional LHPs usually consist of a single capillary pump for heat acquisition and a single condenser for heat rejection. Multiple pump/multiple condenser LHPs have shown to function very well in ground testing. Nevertheless, the test results of a dual pump/condenser LHP also revealed that the dual LHP behaved in a complicated manner due to the interaction between the pumps and condensers. Thus it is redundant to say that more research is needed before they are ready for 0-g deployment. One research area that perhaps compels immediate attention is the analytical modeling of LHPs, particularly the transient phenomena. Modeling a single pump/single condenser LHP is difficult enough. Only a handful of computer codes are available for both steady state and transient simulations of conventional LHPs. No previous effort was made to develop an analytical model (or even a complete theory) to predict the operational behavior of the multiple pump/multiple condenser LHP systems. The current research project offered a basic theory of the multiple pump/multiple condenser LHP operation. From it, a computer code was developed to predict the LHP saturation temperature in accordance with the system operating and environmental conditions.

Translational Upregulation of an Individual p21Cip1 Transcript Variant by GCN2 Regulates Cell Proliferation and Survival under Nutrient Stress

PubMed Central

Lehman, Stacey L.; Cerniglia, George J.; Johannes, Gregg J.; Ye, Jiangbin; Ryeom, Sandra; Koumenis, Constantinos

2015-01-01

Multiple transcripts encode for the cell cycle inhibitor p21Cip1. These transcripts produce identical proteins but differ in their 5’ untranslated regions (UTRs). Although several stresses that induce p21 have been characterized, the mechanisms regulating the individual transcript variants and their functional significance are unknown. Here we demonstrate through 35S labeling, luciferase reporter assays, and polysome transcript profiling that activation of the Integrated Stress Response (ISR) kinase GCN2 selectively upregulates the translation of a p21 transcript variant containing 5’ upstream open reading frames (uORFs) through phosphorylation of the eukaryotic translation initiation factor eIF2α. Mutational analysis reveals that the uORFs suppress translation under basal conditions, but promote translation under stress. Functionally, ablation of p21 ameliorates G1/S arrest and reduces cell survival in response to GCN2 activation. These findings uncover a novel mechanism of p21 post-transcriptional regulation, offer functional significance for the existence of multiple p21 transcripts, and support a key role for GCN2 in regulating the cell cycle under stress. PMID:26102367

Divergent Expression Patterns and Function Implications of Four nanos Genes in a Hermaphroditic Fish, Epinephelus coioides.

PubMed

Sun, Zhi-Hui; Wang, Yang; Lu, Wei-Jia; Li, Zhi; Liu, Xiao-Chun; Li, Shui-Sheng; Zhou, Li; Gui, Jian-Fang

2017-03-23

Multiple nanos genes have been characterized in several fishes, but the functional implications of their various expression patterns remain unclear. In this study, we identified and characterized four nanos genes from a hermaphroditic fish orange-spotted grouper, Epinephelus coioides . Ecnanos1a and Ecnanos1b show divergent expression patterns, and the dynamic expression change of Ecnanos1a in pituitaries during sex change is associated with testis differentiation and spermatogenesis. Ecnanos2 and Ecnanos3 might be germline stem cells (GSCs) and primordial germ cells (PGCs)-specific markers, respectively. Significantly, Ecnanos3 3'-untranslated region (UTR) is necessary for PGC specific expression, where a non-canonical "GCACGTTT" sequence is required for miR-430-mediated repression of Ecnanos3 RNA. Furthermore, grouper Dead end (Dnd) can relieve miR-430 repression in PGCs by associating with a 23 bp U-rich region (URR) in Ecnanos3 3'-UTR. The current study revealed the functional association of multiple nanos genes with PGC formation and germ cell development in orange-spotted grouper, and opened up new possibilities for developing biotechnologies through utilizing the associations between Ecnanos3 and PGCs or between Ecnanos2 and GSCs in the hermaphroditic fish.

Quantitative assessment of upper extremities motor function in multiple sclerosis.

PubMed

Daunoraviciene, Kristina; Ziziene, Jurgita; Griskevicius, Julius; Pauk, Jolanta; Ovcinikova, Agne; Kizlaitiene, Rasa; Kaubrys, Gintaras

2018-05-18

Upper extremity (UE) motor function deficits are commonly noted in multiple sclerosis (MS) patients and assessing it is challenging because of the lack of consensus regarding its definition. Instrumented biomechanical analysis of upper extremity movements can quantify coordination with different spatiotemporal measures and facilitate disability rating in MS patients. To identify objective quantitative parameters for more accurate evaluation of UE disability and relate it to existing clinical scores. Thirty-four MS patients and 24 healthy controls (CG) performed a finger-to-nose test as fast as possible and, in addition, clinical evaluation kinematic parameters of UE were measured by using inertial sensors. Generally, a higher disability score was associated with an increase of several temporal parameters, like slower task performance. The time taken to touch their nose was longer when the task was fulfilled with eyes closed. Time to peak angular velocity significantly changed in MS patients (EDSS > 5.0). The inter-joint coordination significantly decreases in MS patients (EDSS 3.0-5.5). Spatial parameters indicated that maximal ROM changes were in elbow flexion. Our findings have revealed that spatiotemporal parameters are related to the UE motor function and MS disability level. Moreover, they facilitate clinical rating by supporting clinical decisions with quantitative data.

Direct Evidence for the Formation of Diastereoisomeric Benzylpenicilloyl Haptens from Benzylpenicillin and Benzylpenicillenic Acid in PatientsS⃞

PubMed Central

Meng, Xiaoli; Jenkins, Rosalind E.; Berry, Neil G.; Maggs, James L.; Farrell, John; Lane, Catherine S.; Stachulski, Andrew V.; French, Neil S.; Naisbitt, Dean J.; Pirmohamed, Munir

2011-01-01

Covalent binding to proteins to form neoantigens is thought to be central to the pathogenesis of penicillin hypersensitivity reactions. We have undertaken detailed mass spectrometric studies to define the mechanism and protein chemistry of hapten formation from benzylpenicillin (BP) and its rearrangement product, benzylpenicillenic acid (PA). Mass spectrometric analysis of human serum albumin exposed to BP and PA in vitro revealed that at low concentrations (drug protein molar ratio 0.001:1) and during short time incubations BP and PA selectively target different residues, Lys199 and Lys525, respectively. Molecular modeling showed that the selectivity was a function of noncovalent interaction before covalent modification. With increased exposure to higher concentrations of BP and PA, multiple epitopes were detected on albumin, demonstrating that the multiplicity of hapten formation is a function of time and concentration. More importantly, we have demonstrated direct evidence that PA is a hapten accounting for the diastereoisomeric BP antigen formation in albumin isolated from the blood of patients receiving penicillin. Furthermore, PA was found to be more potent than BP with respect to stimulation of T cells from patients with penicillin hypersensitivity, illustrating the functional relevance of diastereoisomeric hapten formation. PMID:21680886

A case of multiple system atrophy-parkinsonian type with stuttering- and palilalia-like dysfluencies and putaminal atrophy.

PubMed

Kikuchi, Yoshikazu; Umezaki, Toshiro; Uehara, Taira; Yamaguchi, Hiroo; Yamashita, Koji; Hiwatashi, Akio; Sawatsubashi, Motohiro; Adachi, Kazuo; Yamaguchi, Yumi; Murakami, Daisuke; Kira, Jun-Ichi; Nakagawa, Takashi

2017-11-14

Both developmental and acquired stuttering are related to the function of the basal ganglia-thalamocortical loop, which includes the putamen. Here, we present a case of stuttering- and palilalia-like dysfluencies that manifested as an early symptom of multiple system atrophy-parkinsonian type (MSA-P) and bilateral atrophy of the putamen. The patient was a 72-year-old man with no history of developmental stuttering who presented with a stutter for consultation with our otorhinolaryngology department. The patient was diagnosed with MSA-P based on parkinsonism, autonomic dysfunction, and bilateral putaminal atrophy revealed by T2-weighted magnetic resonance imaging. Treatment with levodopa improved both the motor functional deficits related to MSA-P and stuttering-like dysfluencies while reading; however, the palilalia-like dysfluencies were much less responsive to levodopa therapy. The patient died of aspiration pneumonia two years after his first consultation at our hospital. In conclusion, adult-onset stuttering- and palilalia-like dysfluencies warrant careful examination of the basal ganglia-thalamocortical loop, and especially the putamen, using neuroimaging techniques. Acquired stuttering may be related to deficits in dopaminergic function. Copyright © 2017 Elsevier Inc. All rights reserved.

The relationship between vascular endothelial dysfunction and treatment frequency in neovascular age-related macular degeneration.

PubMed

Ueda-Consolvo, Tomoko; Hayashi, Atsushi; Ozaki, Mayumi; Nakamura, Tomoko; Yagou, Takaaki; Abe, Shinya

2017-07-01

To assess the correlation between endothelial dysfunction and frequency of antivascular endothelial growth factor (anti-VEGF) treatment for neovascular age-related macular degeneration (nAMD). We examined 64 consecutive patients with nAMD who were evaluated for endothelial function by use of peripheral arterial tonometry (EndoPAT 2000; Itamar Medical, Caesarea, Israel) at Toyama University Hospital from January 2015. We tallied the number of anti-VEGF treatments between January 2014 and December 2015 and determined the correlation between the number of anti-VEGF injections and endothelial function expressed as the reactive hyperemia index (RHI). Multiple regression analysis was also performed to identify the independent predictors of a larger number of injections. The mean number of anti-VEGF injections was 8.2 ± 3.3. The mean lnRHI was 0.47 ± 0.17. The lnRHI correlated with the number of anti-VEGF injections (r = -0.56; P = 0.030). The multiple regression analysis revealed that endothelial function, neovascular subtypes, and treatment regimens were associated with the number of injections. Endothelial dysfunction may affect the efficacy of anti-VEGF therapy. Neovascular subtypes may also predict a larger number of injections.

Next-Generation Connexin and Pannexin Cell Biology.

PubMed

Esseltine, Jessica L; Laird, Dale W

2016-12-01

Connexins and pannexins are two families of large-pore channel forming proteins that are capable of passing small signaling molecules. While connexins serve the seminal task of direct gap junctional intercellular communication, pannexins are far less understood but function primarily as single membrane channels in autocrine and paracrine signaling. Advancements in connexin and pannexin biology in recent years has revealed that in addition to well-described classical functions at the plasma membrane, exciting new evidence suggests that connexins and pannexins participate in alternative pathways involving multiple intracellular compartments. Here we briefly highlight classical functions of connexins and pannexins but focus our attention mostly on the transformative findings that suggest that these channel-forming proteins may serve roles far beyond our current understandings. Copyright © 2016 Elsevier Ltd. All rights reserved.

Exercise-induced pulmonary artery hypertension in a patient with compensated cardiac disease: hemodynamic and functional response to sildenafil therapy.

PubMed

Nikolaidis, Lazaros; Memon, Nabeel; O'Murchu, Brian

2015-02-01

We describe the case of a 54-year-old man who presented with exertional dyspnea and fatigue that had worsened over the preceding 2 years, despite a normally functioning bioprosthetic aortic valve and stable, mild left ventricular dysfunction (left ventricular ejection fraction, 0.45). His symptoms could not be explained by physical examination, an extensive biochemical profile, or multiple cardiac and pulmonary investigations. However, abnormal cardiopulmonary exercise test results and a right heart catheterization-combined with the use of a symptom-limited, bedside bicycle ergometer-revealed that the patient's exercise-induced pulmonary artery hypertension was out of proportion to his compensated left heart disease. A trial of sildenafil therapy resulted in objective improvements in hemodynamic values and functional class.

Functional Multiple-Set Canonical Correlation Analysis

ERIC Educational Resources Information Center

Hwang, Heungsun; Jung, Kwanghee; Takane, Yoshio; Woodward, Todd S.

2012-01-01

We propose functional multiple-set canonical correlation analysis for exploring associations among multiple sets of functions. The proposed method includes functional canonical correlation analysis as a special case when only two sets of functions are considered. As in classical multiple-set canonical correlation analysis, computationally, the…

Bmp signaling regulates a dose-dependent transcriptional program to control facial skeletal development.

PubMed

Bonilla-Claudio, Margarita; Wang, Jun; Bai, Yan; Klysik, Elzbieta; Selever, Jennifer; Martin, James F

2012-02-01

We performed an in depth analysis of Bmp4, a critical regulator of development, disease, and evolution, in cranial neural crest (CNC). Conditional Bmp4 overexpression, using a tetracycline-regulated Bmp4 gain-of-function allele, resulted in facial skeletal changes that were most dramatic after an E10.5 Bmp4 induction. Expression profiling uncovered a signature of Bmp4-induced genes (BIG) composed predominantly of transcriptional regulators that control self-renewal, osteoblast differentiation and negative Bmp autoregulation. The complimentary experiment, CNC inactivation of Bmp2, Bmp4 and Bmp7, resulted in complete or partial loss of multiple CNC-derived skeletal elements, revealing a crucial requirement for Bmp signaling in membranous bone and cartilage development. Importantly, the BIG signature was reduced in Bmp loss-of-function mutants, indicating Bmp-regulated target genes are modulated by Bmp dose. Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation. These data support the hypothesis that Bmp signaling regulates craniofacial skeletal development by balancing self-renewal and differentiation pathways in CNC progenitors.

Trophic segregation of a fish assemblage along lateral depth gradients in a subtropical coastal lagoon revealed by stable isotope analyses.

PubMed

Mont'Alverne, R; Pereyra, P E R; Garcia, A M

2016-07-01

Stable isotopes were used to evaluate the hypothesis that fish assemblages occurring in shallow and deep areas of a large coastal lagoon are structured in partially segregated trophic modules with consumers showing contrasting reliance on benthic or pelagic food sources. The results revealed that fishes in deep areas were mainly dependent on particulate organic matter in the sediment (SOM), whereas emergent macrophytes were as important as SOM to fish consumers in shallow areas. Conceptual trophic diagrams depicting relationships among basal food sources and consumers in different regions of the lagoon highlighted the greater use of multiple basal food sources by more feeding mode functional guilds in shallow water compared with the use of predominantly benthic resources (SOM) in deep areas. The findings appear to corroborate the initial hypothesis and offer complementary perspectives in understanding the role of spatial ecology in structuring coastal ecosystem function and productivity. © 2016 The Fisheries Society of the British Isles.

Cell and region specificity of Aryl hydrocarbon Receptor (AhR) system in the testis and the epididymis.

PubMed

Wajda, A; Łapczuk, J; Grabowska, M; Pius-Sadowska, E; Słojewski, M; Laszczynska, M; Urasinska, E; Machalinski, B; Drozdzik, M

2017-04-01

Aryl hydrocarbon receptor (AhR) plays multiple important functions in adaptive responses. Exposure to AhR ligands may produce an altered metabolic activity controlled by the AhR pathways, and consequently affect drug/toxin responses, hormonal status and cellular homeostasis. This research revealed species-, cell- and region-specific pattern of the AhR system expression in the rat and human testis and epididymis, complementing the existing knowledge, especially within the epididymal segments. The study showed that AhR level in the rat and human epididymis is higher than in the testis. The downregulation of AhR expression after TCDD treatment was revealed in the spermatogenic cells at different stages and the epididymal epithelial cells, but not in the Sertoli and Leydig cells. Hence, this basic research provides information about the AhR function in the testis and epididymis, which may provide an insight into deleterious effects of drugs, hormones and environmental pollutants on male fertility. Copyright © 2017 Elsevier Inc. All rights reserved.

Single-Molecule Imaging of an in Vitro-Evolved RNA Aptamer Reveals Homogeneous Ligand Binding Kinetics

PubMed Central

2009-01-01

Many studies of RNA folding and catalysis have revealed conformational heterogeneity, metastable folding intermediates, and long-lived states with distinct catalytic activities. We have developed a single-molecule imaging approach for investigating the functional heterogeneity of in vitro-evolved RNA aptamers. Monitoring the association of fluorescently labeled ligands with individual RNA aptamer molecules has allowed us to record binding events over the course of multiple days, thus providing sufficient statistics to quantitatively define the kinetic properties at the single-molecule level. The ligand binding kinetics of the highly optimized RNA aptamer studied here displays a remarkable degree of uniformity and lack of memory. Such homogeneous behavior is quite different from the heterogeneity seen in previous single-molecule studies of naturally derived RNA and protein enzymes. The single-molecule methods we describe may be of use in analyzing the distribution of functional molecules in heterogeneous evolving populations or even in unselected samples of random sequences. PMID:19572753

Host genetic determinants of microbiota-dependent nutrition revealed by genome-wide analysis of Drosophila melanogaster

PubMed Central

Dobson, Adam J.; Chaston, John M.; Newell, Peter D.; Donahue, Leanne; Hermann, Sara L.; Sannino, David R.; Westmiller, Stephanie; Wong, Adam C.-N.; Clark, Andrew G.; Lazzaro, Brian P.; Douglas, Angela E.

2015-01-01

Animals bear communities of gut microorganisms with substantial effects on animal nutrition, but the host genetic basis of these effects is unknown. Here, we use Drosophila to demonstrate substantial among-genotype variation in the effects of eliminating the gut microbiota on five host nutritional indices (weight, and protein, lipid, glucose and glycogen contents); this includes variation in both the magnitude and direction of microbiota-dependent effects. Genome-wide associations to identify the genetic basis of the microbiota-dependent variation reveal polymorphisms in largely non-overlapping sets of genes associated with variation in the nutritional traits, including strong representation of conserved genes functioning in signaling. Key genes identified by the GWA study are validated by loss-of-function mutations that altered microbiota-dependent nutritional effects. We conclude that the microbiota interacts with the animal at multiple points in the signaling and regulatory networks that determine animal nutrition. These interactions with the microbiota are likely conserved across animals, including humans. PMID:25692519

Using in vivo probabilistic tractography to reveal two segregated dorsal ‘language-cognitive’ pathways in the human brain☆

PubMed Central

Cloutman, Lauren L.; Binney, Richard J.; Morris, David M.; Parker, Geoffrey J.M.; Lambon Ralph, Matthew A.

2013-01-01

Primate studies have recently identified the dorsal stream as constituting multiple dissociable pathways associated with a range of specialized cognitive functions. To elucidate the nature and number of dorsal pathways in the human brain, the current study utilized in vivo probabilistic tractography to map the structural connectivity associated with subdivisions of the left supramarginal gyrus (SMG). The left SMG is a prominent region within the dorsal stream, which has recently been parcellated into five structurally-distinct regions which possess a dorsal–ventral (and rostral-caudal) organisation, postulated to reflect areas of functional specialisation. The connectivity patterns reveal a dissociation of the arcuate fasciculus into at least two segregated pathways connecting frontal-parietal-temporal regions. Specifically, the connectivity of the inferior SMG, implicated as an acoustic-motor speech interface, is carried by an inner/ventro-dorsal arc of fibres, whilst the pathways of the posterior superior SMG, implicated in object use and cognitive control, forms a parallel outer/dorso-dorsal crescent. PMID:23937853

Repetition priming influences distinct brain systems: evidence from task-evoked data and resting-state correlations.

PubMed

Wig, Gagan S; Buckner, Randy L; Schacter, Daniel L

2009-05-01

Behavioral dissociations suggest that a single experience can separately influence multiple processing components. Here we used a repetition priming functional magnetic resonance imaging paradigm that directly contrasted the effects of stimulus and decision changes to identify the underlying brain systems. Direct repetition of stimulus features caused marked reductions in posterior regions of the inferior temporal lobe that were insensitive to whether the decision was held constant or changed between study and test. By contrast, prefrontal cortex showed repetition effects that were sensitive to the exact stimulus-to-decision mapping. Analysis of resting-state functional connectivity revealed that the dissociated repetition effects are embedded within distinct brain systems. Regions that were sensitive to changes in the stimulus correlated with perceptual cortices, whereas the decision changes attenuated activity in regions correlated with middle-temporal regions and a frontoparietal control system. These results thus explain the long-known dissociation between perceptual and conceptual components of priming by revealing how a single experience can separately influence distinct, concurrently active brain systems.

Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation

PubMed Central

Epelman, Slava; Lavine, Kory J.; Beaudin, Anna E.; Sojka, Dorothy K.; Carrero, Javier A.; Calderon, Boris; Brija, Thaddeus; Gautier, Emmanuel L.; Ivanov, Stoyan; Satpathy, Ansuman T.; Schilling, Joel D.; Schwendener, Reto; Sergin, Ismail; Razani, Babak; Forsberg, E. Camilla; Yokoyama, Wayne; Unanue, Emil R.; Colonna, Marco; Randolph, Gwendalyn J.; Mann, Douglas L.

2014-01-01

Summary Cardiac macrophages are crucial for tissue repair after cardiac injury but have not been well characterized. Here we identify four populations of cardiac macrophages. At steady state, resident macrophages were primarily maintained through local proliferation. However, after macrophage depletion or during cardiac inflammation, Ly6chi monocytes contributed to all four macrophage populations, whereas resident macrophages also expanded numerically through proliferation. Genetic fate mapping revealed that yolk-sac and fetal monocyte progenitors gave rise to the majority of cardiac macrophages, and the heart was among a minority of organs in which substantial numbers of yolk-sac macrophages persisted in adulthood. CCR2 expression and dependence distinguished cardiac macrophages of adult monocyte versus embryonic origin. Transcriptional and functional data revealed that monocyte-derived macrophages coordinate cardiac inflammation, while playing redundant but lesser roles in antigen sampling and efferocytosis. These data highlight the presence of multiple cardiac macrophage subsets, with different functions, origins and strategies to regulate compartment. PMID:24439267

Diversity of sharp-wave-ripple LFP signatures reveals differentiated brain-wide dynamical events.

PubMed

Ramirez-Villegas, Juan F; Logothetis, Nikos K; Besserve, Michel

2015-11-17

Sharp-wave-ripple (SPW-R) complexes are believed to mediate memory reactivation, transfer, and consolidation. However, their underlying neuronal dynamics at multiple scales remains poorly understood. Using concurrent hippocampal local field potential (LFP) recordings and functional MRI (fMRI), we study local changes in neuronal activity during SPW-R episodes and their brain-wide correlates. Analysis of the temporal alignment between SPW and ripple components reveals well-differentiated SPW-R subtypes in the CA1 LFP. SPW-R-triggered fMRI maps show that ripples aligned to the positive peak of their SPWs have enhanced neocortical metabolic up-regulation. In contrast, ripples occurring at the trough of their SPWs relate to weaker neocortical up-regulation and absent subcortical down-regulation, indicating differentiated involvement of neuromodulatory pathways in the ripple phenomenon mediated by long-range interactions. To our knowledge, this study provides the first evidence for the existence of SPW-R subtypes with differentiated CA1 activity and metabolic correlates in related brain areas, possibly serving different memory functions.

Diversity of sharp-wave–ripple LFP signatures reveals differentiated brain-wide dynamical events

PubMed Central

Ramirez-Villegas, Juan F.; Logothetis, Nikos K.; Besserve, Michel

2015-01-01

Sharp-wave–ripple (SPW-R) complexes are believed to mediate memory reactivation, transfer, and consolidation. However, their underlying neuronal dynamics at multiple scales remains poorly understood. Using concurrent hippocampal local field potential (LFP) recordings and functional MRI (fMRI), we study local changes in neuronal activity during SPW-R episodes and their brain-wide correlates. Analysis of the temporal alignment between SPW and ripple components reveals well-differentiated SPW-R subtypes in the CA1 LFP. SPW-R–triggered fMRI maps show that ripples aligned to the positive peak of their SPWs have enhanced neocortical metabolic up-regulation. In contrast, ripples occurring at the trough of their SPWs relate to weaker neocortical up-regulation and absent subcortical down-regulation, indicating differentiated involvement of neuromodulatory pathways in the ripple phenomenon mediated by long-range interactions. To our knowledge, this study provides the first evidence for the existence of SPW-R subtypes with differentiated CA1 activity and metabolic correlates in related brain areas, possibly serving different memory functions. PMID:26540729

Chronic triceps insufficiency managed with extensor carpi radialis longus and palmaris longus tendon grafts.

PubMed

Singh, Dhanpal; Kumar, K Arun; Dinesh, Mc; Raj, Ranju

2012-03-01

Chronic triceps insufficiency, causing prolonged disability, occurs due to a missed diagnosis of an acute rupture. We report a 25 year old male with history of a significant fall sustaining multiple injuries. Since then, he had inability in extending his right elbow for which he sought intervention after a year. Diagnosis of triceps rupture was made clinicoradiologically and surgery was planned. Intraoperative findings revealed a deficient triceps with a fleck of avulsed bone from olecranon. Ipsilateral double tendon graft including extensor carpi radialis longus and palmaris longus were anchored to triceps and secured with the olecranon. Six-months follow revealed a complete active extension of elbow and a full function at the donor site.

The role of social frailty in explaining the association between hearing problems and mild cognitive impairment in older adults.

PubMed

Bae, Seongryu; Lee, Sangyoon; Lee, Sungchul; Jung, Songee; Makino, Keitaro; Park, Hyuntae; Shimada, Hiroyuki

2018-06-01

We examined the role of social frailty in the association between hearing problems and mild cognitive impairment (MCI), and investigated which cognitive impairment domains are most strongly involved. Participants were 4251 older adults (mean age 72.5 ± 5.2 years, 46.1% male) who met the study inclusion criteria. Hearing problems were measured using the Hearing Handicap Inventory for the Elderly. Social frailty was identified using responses to five questions. Participants were divided into four groups depending on the presence of social frailty and hearing problems: control, social frailty, hearing problem, and co-occurrence. We assessed memory, attention, executive function, and processing speed using the National Center for Geriatrics and Gerontology-Functional Assessment Tool. Participants were categorized into normal cognition, single- and multiple-domain MCI, depending on the number of impaired cognitive domains. Participants with multiple-domain MCI exhibited the highest odds ratios (OR) of the co-occurrence group (OR: 3.89, 95% confidence intervals [CI]: 1.96-7.72), followed by the social frailty (OR: 2.65, 95% CI: 1.49-4.67), and hearing problem (OR: 1.90, 95% CI: 1.08-3.34) groups, compared with the control group. However, single-domain MCI was not significantly associated with any group. Cognitive domain analysis revealed that impaired executive function and processing speed were associated with the co-occurrence, hearing problem, and social frailty groups, respectively. Social frailty and hearing problems were independently associated with multiple-domain MCI. Comorbid conditions were more strongly associated with multiple-domain MCI. Longitudinal studies are needed to elucidate the causal role of social frailty in the association between hearing impairment and MCI. Copyright © 2018 Elsevier B.V. All rights reserved.

Metabolic Coevolution in the Bacterial Symbiosis of Whiteflies and Related Plant Sap-Feeding Insects.

PubMed

Luan, Jun-Bo; Chen, Wenbo; Hasegawa, Daniel K; Simmons, Alvin M; Wintermantel, William M; Ling, Kai-Shu; Fei, Zhangjun; Liu, Shu-Sheng; Douglas, Angela E

2015-09-15

Genomic decay is a common feature of intracellular bacteria that have entered into symbiosis with plant sap-feeding insects. This study of the whitefly Bemisia tabaci and two bacteria (Portiera aleyrodidarum and Hamiltonella defensa) cohoused in each host cell investigated whether the decay of Portiera metabolism genes is complemented by host and Hamiltonella genes, and compared the metabolic traits of the whitefly symbiosis with other sap-feeding insects (aphids, psyllids, and mealybugs). Parallel genomic and transcriptomic analysis revealed that the host genome contributes multiple metabolic reactions that complement or duplicate Portiera function, and that Hamiltonella may contribute multiple cofactors and one essential amino acid, lysine. Homologs of the Bemisia metabolism genes of insect origin have also been implicated in essential amino acid synthesis in other sap-feeding insect hosts, indicative of parallel coevolution of shared metabolic pathways across multiple symbioses. Further metabolism genes coded in the Bemisia genome are of bacterial origin, but phylogenetically distinct from Portiera, Hamiltonella and horizontally transferred genes identified in other sap-feeding insects. Overall, 75% of the metabolism genes of bacterial origin are functionally unique to one symbiosis, indicating that the evolutionary history of metabolic integration in these symbioses is strongly contingent on the pattern of horizontally acquired genes. Our analysis, further, shows that bacteria with genomic decay enable host acquisition of complex metabolic pathways by multiple independent horizontal gene transfers from exogenous bacteria. Specifically, each horizontally acquired gene can function with other genes in the pathway coded by the symbiont, while facilitating the decay of the symbiont gene coding the same reaction. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Distinct Domains of CheA Confer Unique Functions in Chemotaxis and Cell Length in Azospirillum brasilense Sp7.

PubMed

Gullett, Jessica M; Bible, Amber; Alexandre, Gladys

2017-07-01

Chemotaxis is the movement of cells in response to gradients of diverse chemical cues. Motile bacteria utilize a conserved chemotaxis signal transduction system to bias their motility and navigate through a gradient. A central regulator of chemotaxis is the histidine kinase CheA. This cytoplasmic protein interacts with membrane-bound receptors, which assemble into large polar arrays, to propagate the signal. In the alphaproteobacterium Azospirillum brasilense , Che1 controls transient increases in swimming speed during chemotaxis, but it also biases the cell length at division. However, the exact underlying molecular mechanisms for Che1-dependent control of multiple cellular behaviors are not known. Here, we identify specific domains of the CheA1 histidine kinase implicated in modulating each of these functions. We show that CheA1 is produced in two isoforms: a membrane-anchored isoform produced as a fusion with a conserved seven-transmembrane domain of unknown function (TMX) at the N terminus and a soluble isoform similar to prototypical CheA. Site-directed and deletion mutagenesis combined with behavioral assays confirm the role of CheA1 in chemotaxis and implicate the TMX domain in mediating changes in cell length. Fluorescence microscopy further reveals that the membrane-anchored isoform is distributed around the cell surface while the soluble isoform localizes at the cell poles. Together, the data provide a mechanism for the role of Che1 in controlling multiple unrelated cellular behaviors via acquisition of a new domain in CheA1 and production of distinct functional isoforms. IMPORTANCE Chemotaxis provides a significant competitive advantage to bacteria in the environment, and this function has been transferred laterally multiple times, with evidence of functional divergence in different genomic contexts. The molecular principles that underlie functional diversification of chemotaxis in various genomic contexts are unknown. Here, we provide a molecular mechanism by which a single CheA protein controls two unrelated functions: chemotaxis and cell length. Acquisition of this multifunctionality is seemingly a recent evolutionary event. The findings illustrate a mechanism by which chemotaxis function may be co-opted to regulate additional cellular functions. Copyright © 2017 American Society for Microbiology.

Distinct Domains of CheA Confer Unique Functions in Chemotaxis and Cell Length in Azospirillum brasilense Sp7

PubMed Central

Gullett, Jessica M.

2017-01-01

ABSTRACT Chemotaxis is the movement of cells in response to gradients of diverse chemical cues. Motile bacteria utilize a conserved chemotaxis signal transduction system to bias their motility and navigate through a gradient. A central regulator of chemotaxis is the histidine kinase CheA. This cytoplasmic protein interacts with membrane-bound receptors, which assemble into large polar arrays, to propagate the signal. In the alphaproteobacterium Azospirillum brasilense, Che1 controls transient increases in swimming speed during chemotaxis, but it also biases the cell length at division. However, the exact underlying molecular mechanisms for Che1-dependent control of multiple cellular behaviors are not known. Here, we identify specific domains of the CheA1 histidine kinase implicated in modulating each of these functions. We show that CheA1 is produced in two isoforms: a membrane-anchored isoform produced as a fusion with a conserved seven-transmembrane domain of unknown function (TMX) at the N terminus and a soluble isoform similar to prototypical CheA. Site-directed and deletion mutagenesis combined with behavioral assays confirm the role of CheA1 in chemotaxis and implicate the TMX domain in mediating changes in cell length. Fluorescence microscopy further reveals that the membrane-anchored isoform is distributed around the cell surface while the soluble isoform localizes at the cell poles. Together, the data provide a mechanism for the role of Che1 in controlling multiple unrelated cellular behaviors via acquisition of a new domain in CheA1 and production of distinct functional isoforms. IMPORTANCE Chemotaxis provides a significant competitive advantage to bacteria in the environment, and this function has been transferred laterally multiple times, with evidence of functional divergence in different genomic contexts. The molecular principles that underlie functional diversification of chemotaxis in various genomic contexts are unknown. Here, we provide a molecular mechanism by which a single CheA protein controls two unrelated functions: chemotaxis and cell length. Acquisition of this multifunctionality is seemingly a recent evolutionary event. The findings illustrate a mechanism by which chemotaxis function may be co-opted to regulate additional cellular functions. PMID:28416707

Non-coding RNAs as regulators of gene expression and epigenetics

PubMed Central

Kaikkonen, Minna U.; Lam, Michael T.Y.; Glass, Christopher K.

2011-01-01

Genome-wide studies have revealed that mammalian genomes are pervasively transcribed. This has led to the identification and isolation of novel classes of non-coding RNAs (ncRNAs) that influence gene expression by a variety of mechanisms. Here we review the characteristics and functions of regulatory ncRNAs in chromatin remodelling and at multiple levels of transcriptional and post-transcriptional regulation. We also describe the potential roles of ncRNAs in vascular biology and in mediating epigenetic modifications that might play roles in cardiovascular disease susceptibility. The emerging recognition of the diverse functions of ncRNAs in regulation of gene expression suggests that they may represent new targets for therapeutic intervention. PMID:21558279

Parametric effects of syntactic-semantic conflict in Broca's area during sentence processing.

PubMed

Thothathiri, Malathi; Kim, Albert; Trueswell, John C; Thompson-Schill, Sharon L

2012-03-01

The hypothesized role of Broca's area in sentence processing ranges from domain-general executive function to domain-specific computation that is specific to certain syntactic structures. We examined this issue by manipulating syntactic structure and conflict between syntactic and semantic cues in a sentence processing task. Functional neuroimaging revealed that activation within several Broca's area regions of interest reflected the parametric variation in syntactic-semantic conflict. These results suggest that Broca's area supports sentence processing by mediating between multiple incompatible constraints on sentence interpretation, consistent with this area's well-known role in conflict resolution in other linguistic and non-linguistic tasks. Copyright © 2011 Elsevier Inc. All rights reserved.

Learning about learning: Mining human brain sub-network biomarkers from fMRI data

PubMed Central

Dereli, Nazli; Dang, Xuan-Hong; Bassett, Danielle S.; Wymbs, Nicholas F.; Grafton, Scott T.; Singh, Ambuj K.

2017-01-01

Modeling the brain as a functional network can reveal the relationship between distributed neurophysiological processes and functional interactions between brain structures. Existing literature on functional brain networks focuses mainly on a battery of network properties in “resting state” employing, for example, modularity, clustering, or path length among regions. In contrast, we seek to uncover functionally connected subnetworks that predict or correlate with cohort differences and are conserved within the subjects within a cohort. We focus on differences in both the rate of learning as well as overall performance in a sensorimotor task across subjects and develop a principled approach for the discovery of discriminative subgraphs of functional connectivity based on imaging acquired during practice. We discover two statistically significant subgraph regions: one involving multiple regions in the visual cortex and another involving the parietal operculum and planum temporale. High functional coherence in the former characterizes sessions in which subjects take longer to perform the task, while high coherence in the latter is associated with high learning rate (performance improvement across trials). Our proposed methodology is general, in that it can be applied to other cognitive tasks, to study learning or to differentiate between healthy patients and patients with neurological disorders, by revealing the salient interactions among brain regions associated with the observed global state. The discovery of such significant discriminative subgraphs promises a better data-driven understanding of the dynamic brain processes associated with high-level cognitive functions. PMID:29016686

Learning about learning: Mining human brain sub-network biomarkers from fMRI data.

PubMed

Bogdanov, Petko; Dereli, Nazli; Dang, Xuan-Hong; Bassett, Danielle S; Wymbs, Nicholas F; Grafton, Scott T; Singh, Ambuj K

2017-01-01

Modeling the brain as a functional network can reveal the relationship between distributed neurophysiological processes and functional interactions between brain structures. Existing literature on functional brain networks focuses mainly on a battery of network properties in "resting state" employing, for example, modularity, clustering, or path length among regions. In contrast, we seek to uncover functionally connected subnetworks that predict or correlate with cohort differences and are conserved within the subjects within a cohort. We focus on differences in both the rate of learning as well as overall performance in a sensorimotor task across subjects and develop a principled approach for the discovery of discriminative subgraphs of functional connectivity based on imaging acquired during practice. We discover two statistically significant subgraph regions: one involving multiple regions in the visual cortex and another involving the parietal operculum and planum temporale. High functional coherence in the former characterizes sessions in which subjects take longer to perform the task, while high coherence in the latter is associated with high learning rate (performance improvement across trials). Our proposed methodology is general, in that it can be applied to other cognitive tasks, to study learning or to differentiate between healthy patients and patients with neurological disorders, by revealing the salient interactions among brain regions associated with the observed global state. The discovery of such significant discriminative subgraphs promises a better data-driven understanding of the dynamic brain processes associated with high-level cognitive functions.

Conflicting Demands of Abstract and Specific Visual Object Processing Resolved by Fronto-Parietal Networks

PubMed Central

McMenamin, Brenton W.; Marsolek, Chad J.; Morseth, Brianna K.; Speer, MacKenzie F.; Burton, Philip C.; Burgund, E. Darcy

2016-01-01

Object categorization and exemplar identification place conflicting demands on the visual system, yet humans easily perform these fundamentally contradictory tasks. Previous studies suggest the existence of dissociable visual processing subsystems to accomplish the two abilities – an abstract category (AC) subsystem that operates effectively in the left hemisphere, and a specific exemplar (SE) subsystem that operates effectively in the right hemisphere. This multiple subsystems theory explains a range of visual abilities, but previous studies have not explored what mechanisms exist for coordinating the function of multiple subsystems and/or resolving the conflicts that would arise between them. We collected functional MRI data while participants performed two variants of a cue-probe working memory task that required AC or SE processing. During the maintenance phase of the task, the bilateral intraparietal sulcus (IPS) exhibited hemispheric asymmetries in functional connectivity consistent with exerting proactive control over the two visual subsystems: greater connectivity to the left hemisphere during the AC task, and greater connectivity to the right hemisphere during the SE task. Moreover, probe-evoked activation revealed activity in a broad fronto-parietal network (containing IPS) associated with reactive control when the two visual subsystems were in conflict, and variations in this conflict signal across trials was related to the visual similarity of the cue/probe stimulus pairs. Although many studies have confirmed the existence of multiple visual processing subsystems, this study is the first to identify the mechanisms responsible for coordinating their operations. PMID:26883940

Emotional face processing and flat affect in schizophrenia: functional and structural neural correlates.

PubMed

Lepage, M; Sergerie, K; Benoit, A; Czechowska, Y; Dickie, E; Armony, J L

2011-09-01

There is a general consensus in the literature that schizophrenia causes difficulties with facial emotion perception and discrimination. Functional brain imaging studies have observed reduced limbic activity during facial emotion perception but few studies have examined the relation to flat affect severity. A total of 26 people with schizophrenia and 26 healthy controls took part in this event-related functional magnetic resonance imaging study. Sad, happy and neutral faces were presented in a pseudo-random order and participants indicated the gender of the face presented. Manual segmentation of the amygdala was performed on a structural T1 image. Both the schizophrenia group and the healthy control group rated the emotional valence of facial expressions similarly. Both groups exhibited increased brain activity during the perception of emotional faces relative to neutral ones in multiple brain regions, including multiple prefrontal regions bilaterally, the right amygdala, right cingulate cortex and cuneus. Group comparisons, however, revealed increased activity in the healthy group in the anterior cingulate, right parahippocampal gyrus and multiple visual areas. In schizophrenia, the severity of flat affect correlated significantly with neural activity in several brain areas including the amygdala and parahippocampal region bilaterally. These results suggest that many of the brain regions involved in emotional face perception, including the amygdala, are equally recruited in both schizophrenia and controls, but flat affect can also moderate activity in some other brain regions, notably in the left amygdala and parahippocampal gyrus bilaterally. There were no significant group differences in the volume of the amygdala.

Multiple-Localization and Hub Proteins

PubMed Central

Ota, Motonori; Gonja, Hideki; Koike, Ryotaro; Fukuchi, Satoshi

2016-01-01

Protein-protein interactions are fundamental for all biological phenomena, and protein-protein interaction networks provide a global view of the interactions. The hub proteins, with many interaction partners, play vital roles in the networks. We investigated the subcellular localizations of proteins in the human network, and found that the ones localized in multiple subcellular compartments, especially the nucleus/cytoplasm proteins (NCP), the cytoplasm/cell membrane proteins (CMP), and the nucleus/cytoplasm/cell membrane proteins (NCMP), tend to be hubs. Examinations of keywords suggested that among NCP, those related to post-translational modifications and transcription functions are the major contributors to the large number of interactions. These types of proteins are characterized by a multi-domain architecture and intrinsic disorder. A survey of the typical hub proteins with prominent numbers of interaction partners in the type revealed that most are either transcription factors or co-regulators involved in signaling pathways. They translocate from the cytoplasm to the nucleus, triggered by the phosphorylation and/or ubiquitination of intrinsically disordered regions. Among CMP and NCMP, the contributors to the numerous interactions are related to either kinase or ubiquitin ligase activity. Many of them reside on the cytoplasmic side of the cell membrane, and act as the upstream regulators of signaling pathways. Overall, these hub proteins function to transfer external signals to the nucleus, through the cell membrane and the cytoplasm. Our analysis suggests that multiple-localization is a crucial concept to characterize groups of hub proteins and their biological functions in cellular information processing. PMID:27285823

Conflicting demands of abstract and specific visual object processing resolved by frontoparietal networks.

PubMed

McMenamin, Brenton W; Marsolek, Chad J; Morseth, Brianna K; Speer, MacKenzie F; Burton, Philip C; Burgund, E Darcy

2016-06-01

Object categorization and exemplar identification place conflicting demands on the visual system, yet humans easily perform these fundamentally contradictory tasks. Previous studies suggest the existence of dissociable visual processing subsystems to accomplish the two abilities-an abstract category (AC) subsystem that operates effectively in the left hemisphere and a specific exemplar (SE) subsystem that operates effectively in the right hemisphere. This multiple subsystems theory explains a range of visual abilities, but previous studies have not explored what mechanisms exist for coordinating the function of multiple subsystems and/or resolving the conflicts that would arise between them. We collected functional MRI data while participants performed two variants of a cue-probe working memory task that required AC or SE processing. During the maintenance phase of the task, the bilateral intraparietal sulcus (IPS) exhibited hemispheric asymmetries in functional connectivity consistent with exerting proactive control over the two visual subsystems: greater connectivity to the left hemisphere during the AC task, and greater connectivity to the right hemisphere during the SE task. Moreover, probe-evoked activation revealed activity in a broad frontoparietal network (containing IPS) associated with reactive control when the two visual subsystems were in conflict, and variations in this conflict signal across trials was related to the visual similarity of the cue-probe stimulus pairs. Although many studies have confirmed the existence of multiple visual processing subsystems, this study is the first to identify the mechanisms responsible for coordinating their operations.

Encoding Time in Feedforward Trajectories of a Recurrent Neural Network Model.

PubMed

Hardy, N F; Buonomano, Dean V

2018-02-01

Brain activity evolves through time, creating trajectories of activity that underlie sensorimotor processing, behavior, and learning and memory. Therefore, understanding the temporal nature of neural dynamics is essential to understanding brain function and behavior. In vivo studies have demonstrated that sequential transient activation of neurons can encode time. However, it remains unclear whether these patterns emerge from feedforward network architectures or from recurrent networks and, furthermore, what role network structure plays in timing. We address these issues using a recurrent neural network (RNN) model with distinct populations of excitatory and inhibitory units. Consistent with experimental data, a single RNN could autonomously produce multiple functionally feedforward trajectories, thus potentially encoding multiple timed motor patterns lasting up to several seconds. Importantly, the model accounted for Weber's law, a hallmark of timing behavior. Analysis of network connectivity revealed that efficiency-a measure of network interconnectedness-decreased as the number of stored trajectories increased. Additionally, the balance of excitation (E) and inhibition (I) shifted toward excitation during each unit's activation time, generating the prediction that observed sequential activity relies on dynamic control of the E/I balance. Our results establish for the first time that the same RNN can generate multiple functionally feedforward patterns of activity as a result of dynamic shifts in the E/I balance imposed by the connectome of the RNN. We conclude that recurrent network architectures account for sequential neural activity, as well as for a fundamental signature of timing behavior: Weber's law.

Versatile functional roles of horizontal cells in the retinal circuit.

PubMed

Chaya, Taro; Matsumoto, Akihiro; Sugita, Yuko; Watanabe, Satoshi; Kuwahara, Ryusuke; Tachibana, Masao; Furukawa, Takahisa

2017-07-17

In the retinal circuit, environmental light signals are converted into electrical signals that can be decoded properly by the brain. At the first synapse of the visual system, information flow from photoreceptors to bipolar cells is modulated by horizontal cells (HCs), however, their functional contribution to retinal output and individual visual function is not fully understood. In the current study, we investigated functional roles for HCs in retinal ganglion cell (RGC) response properties and optokinetic responses by establishing a HC-depleted mouse line. We observed that HC depletion impairs the antagonistic center-surround receptive field formation of RGCs, supporting a previously reported HC function revealed by pharmacological approaches. In addition, we found that HC loss reduces both the ON and OFF response diversities of RGCs, impairs adjustment of the sensitivity to ambient light at the retinal output level, and alters spatial frequency tuning at an individual level. Taken together, our current study suggests multiple functional aspects of HCs crucial for visual processing.

Predictors of Posttraumatic Stress Symptoms Among Adolescent and Young Adult Survivors of Childhood Cancer: Importance of Monitoring Survivors' Experiences of Family Functioning.

PubMed

Kamibeppu, Kiyoko; Murayama, Shiho; Ozono, Shuichi; Sakamoto, Naoko; Iwai, Tsuyako; Asami, Keiko; Maeda, Naoko; Inada, Hiroko; Kakee, Naoko; Okamura, Jun; Horibe, Keizo; Ishida, Yasushi

2015-11-01

The purpose of this study was to identify factors associated with posttraumatic stress symptoms (PTSS) among Japanese long-term childhood cancer survivors (CCSs). Subjects comprised 185 adolescent and young adult (AYA) CCSs who completed anonymous self-report questionnaires. Attending physicians also completed an anonymous disease/treatment data sheet. Mean age of survivors was approximately 8 years at diagnosis and 23 years at participation. Multiple regression analysis showed that family functioning, satisfaction with social support, being female, and interactions between family functioning and gender and age at the time of diagnosis were associated with PTSS among survivors. This study revealed family functioning as the most predictive factor of PTSS among AYA CCSs in Japan. Even when the survivor may have unchangeable risk factors, family functioning can potentially moderate the effects on PTSS. Thus, it is crucial for health professionals to carefully monitor and attend to survivors' experiences of family functioning to mitigate PTSS. © The Author(s) 2015.

Seismic receiver function interpretation: Ps splitting or anisotropic underplating?

NASA Astrophysics Data System (ADS)

Liu, Z.; Park, J. J.

2016-12-01

Crustal anisotropy is crucial to understanding the evolutionary history of Earth's lithosphere. Shear-wave splitting of Moho P-to-s converted phases in receiver functions has often been used to infer crustal anisotropy. In addition to estimating birefringence directly, the harmonic variations of Moho Ps phases in delay times can be used to infer splitting parameters of averaged anisotropy in the crust. However, crustal anisotropy may localize at various levels within the crust due to complex deformational processes. Layered anisotropy requires careful investigation of the distribution of anisotropy before interpreting Moho Ps splitting. In this study, we show results from stations ARU in Russia, KIP in Hawaiian Islands and LSA in Tibetan Plateau, where layered anisotropy is well constrained by intra-crust Ps conversions at high frequencies using harmonic decomposition of multiple-taper correlation receiver functions. Anisotropic velocity models are inferred by forward-modeling decomposed RF waveforms. Our results of ARU and KIP show that the harmonic behavior of Moho Ps phases can be explained by a uniformly anisotropic crust model at lower cut-off frequencies, but higher-resolution RF-signals reveal a thin, highly anisotropic layer at the base of the crust. Station LSA tells a similar story with a twist: a modest Ps birefringence is revealed at high frequencies to stem from multiple thin (5-10-km) layers of localized anisotropy within the middle crust, but no strongly-sheared basal layer is inferred. We suggest that the harmonic variation of Moho Ps phases should always be investigated as a result of anisotropic layering using RFs with frequency content above 1Hz, rather than simply reporting averaged anisotropy of the whole crust.

Diversity as Opportunity: Insights from 600 Million Years of AHR Evolution.

PubMed

Hahn, Mark E; Karchner, Sibel I; Merson, Rebeka R

2017-02-01

The aryl hydrocarbon receptor (AHR) was for many years of interest only to pharmacologists and toxicologists. However, this protein has fundamental roles in biology that are being revealed through studies in diverse animal species. The AHR is an ancient protein. AHR homologs exist in most major groups of modern bilaterian animals, including deuterostomes (chordates, hemichordates, echinoderms) and the two major clades of protostome invertebrates [ecdysozoans (e.g. arthropods and nematodes) and lophotrochozoans (e.g. molluscs and annelids)]. AHR homologs also have been identified in cnidarians such as the sea anemone Nematostella and in the genome of Trichoplax , a placozoan. Bilaterians, cnidarians, and placozoans form the clade Eumetazoa , whose last common ancestor lived approximately 600 million years ago (MYA). The presence of AHR homologs in modern representatives of all these groups indicates that the original eumetazoan animal possessed an AHR homolog. Studies in invertebrates and vertebrates reveal parallel functions of AHR in the development and function of sensory neural systems, suggesting that these may be ancestral roles. Vertebrate animals are characterized by the expansion and diversification of AHRs, via gene and genome duplications, from the ancestral protoAHR into at least five classes of AHR-like proteins: AHR, AHR1, AHR2, AHR3, and AHRR. The evolution of multiple AHRs in vertebrates coincided with the acquisition of high-affinity binding of halogenated and polynuclear aromatic hydrocarbons and the emergence of adaptive functions involving regulation of xenobiotic-metabolizing enzymes and roles in adaptive immunity. The existence of multiple AHRs may have facilitated subfunction partitioning and specialization of specific AHR types in some taxa. Additional research in diverse model and non-model species will continue to enrich our understanding of AHR and its pleiotropic roles in biology and toxicology.

Diversity as Opportunity: Insights from 600 Million Years of AHR Evolution

PubMed Central

Hahn, Mark E.; Karchner, Sibel I.; Merson, Rebeka R.

2017-01-01

The aryl hydrocarbon receptor (AHR) was for many years of interest only to pharmacologists and toxicologists. However, this protein has fundamental roles in biology that are being revealed through studies in diverse animal species. The AHR is an ancient protein. AHR homologs exist in most major groups of modern bilaterian animals, including deuterostomes (chordates, hemichordates, echinoderms) and the two major clades of protostome invertebrates [ecdysozoans (e.g. arthropods and nematodes) and lophotrochozoans (e.g. molluscs and annelids)]. AHR homologs also have been identified in cnidarians such as the sea anemone Nematostella and in the genome of Trichoplax, a placozoan. Bilaterians, cnidarians, and placozoans form the clade Eumetazoa, whose last common ancestor lived approximately 600 million years ago (MYA). The presence of AHR homologs in modern representatives of all these groups indicates that the original eumetazoan animal possessed an AHR homolog. Studies in invertebrates and vertebrates reveal parallel functions of AHR in the development and function of sensory neural systems, suggesting that these may be ancestral roles. Vertebrate animals are characterized by the expansion and diversification of AHRs, via gene and genome duplications, from the ancestral protoAHR into at least five classes of AHR-like proteins: AHR, AHR1, AHR2, AHR3, and AHRR. The evolution of multiple AHRs in vertebrates coincided with the acquisition of high-affinity binding of halogenated and polynuclear aromatic hydrocarbons and the emergence of adaptive functions involving regulation of xenobiotic-metabolizing enzymes and roles in adaptive immunity. The existence of multiple AHRs may have facilitated subfunction partitioning and specialization of specific AHR types in some taxa. Additional research in diverse model and non-model species will continue to enrich our understanding of AHR and its pleiotropic roles in biology and toxicology. PMID:28286876

Analysis of Serine Codon Conservation Reveals Diverse Phenotypic Constraints on Hepatitis C Virus Glycoprotein Evolution

PubMed Central

Koutsoudakis, George; Urbanowicz, Richard A.; Mirza, Deeman; Ginkel, Corinne; Riebesehl, Nina; Calland, Noémie; Albecka, Anna; Price, Louisa; Hudson, Natalia; Descamps, Véronique; Backx, Matthijs; McClure, C. Patrick; Duverlie, Gilles; Pecheur, Eve-Isabelle; Dubuisson, Jean; Perez-del-Pulgar, Sofia; Forns, Xavier; Steinmann, Eike; Tarr, Alexander W.; Pietschmann, Thomas

2014-01-01

Serine is encoded by two divergent codon types, UCN and AGY, which are not interchangeable by a single nucleotide substitution. Switching between codon types therefore occurs via intermediates (threonine or cysteine) or via simultaneous tandem substitutions. Hepatitis C virus (HCV) chronically infects 2 to 3% of the global population. The highly variable glycoproteins E1 and E2 decorate the surface of the viral envelope, facilitate cellular entry, and are targets for host immunity. Comparative sequence analysis of globally sampled E1E2 genes, coupled with phylogenetic analysis, reveals the signatures of multiple archaic codon-switching events at seven highly conserved serine residues. Limited detection of intermediate phenotypes indicates that associated fitness costs restrict their fixation in divergent HCV lineages. Mutational pathways underlying codon switching were probed via reverse genetics, assessing glycoprotein functionality using multiple in vitro systems. These data demonstrate selection against intermediate phenotypes can act at the structural/functional level, with some intermediates displaying impaired virion assembly and/or decreased capacity for target cell entry. These effects act in residue/isolate-specific manner. Selection against intermediates is also provided by humoral targeting, with some intermediates exhibiting increased epitope exposure and enhanced neutralization sensitivity, despite maintaining a capacity for target cell entry. Thus, purifying selection against intermediates limits their frequencies in globally sampled strains, with divergent functional constraints at the protein level restricting the fixation of deleterious mutations. Overall our study provides an experimental framework for identification of barriers limiting viral substitutional evolution and indicates that serine codon-switching represents a genomic “fossil record” of historical purifying selection against E1E2 intermediate phenotypes. PMID:24173227

Multiple Classes of Immune-Related Proteases Associated with the Cell Death Response in Pepper Plants

PubMed Central

Bae, Chungyun; Kim, Su-min; Lee, Dong Ju; Choi, Doil

2013-01-01

Proteases regulate a large number of biological processes in plants, such as metabolism, physiology, growth, and defense. In this study, we carried out virus-induced gene silencing assays with pepper cDNA clones to elucidate the biological roles of protease superfamilies. A total of 153 representative protease genes from pepper cDNA were selected and cloned into a Tobacco rattle virus-ligation independent cloning vector in a loss-of-function study. Silencing of 61 proteases resulted in altered phenotypes, such as the inhibition of shoot growth, abnormal leaf shape, leaf color change, and lethality. Furthermore, the silencing experiments revealed that multiple proteases play a role in cell death and immune response against avirulent and virulent pathogens. Among these 153 proteases, 34 modulated the hypersensitive cell death response caused by infection with an avirulent pathogen, and 16 proteases affected disease symptom development caused by a virulent pathogen. Specifically, we provide experimental evidence for the roles of multiple protease genes in plant development and immune defense following pathogen infection. With these results, we created a broad sketch of each protease function. This information will provide basic information for further understanding the roles of the protease superfamily in plant growth, development, and defense. PMID:23696830

Non-linear relationship of cell hit and transformation probabilities in a low dose of inhaled radon progenies.

PubMed

Balásházy, Imre; Farkas, Arpád; Madas, Balázs Gergely; Hofmann, Werner

2009-06-01

Cellular hit probabilities of alpha particles emitted by inhaled radon progenies in sensitive bronchial epithelial cell nuclei were simulated at low exposure levels to obtain useful data for the rejection or support of the linear-non-threshold (LNT) hypothesis. In this study, local distributions of deposited inhaled radon progenies in airway bifurcation models were computed at exposure conditions characteristic of homes and uranium mines. Then, maximum local deposition enhancement factors at bronchial airway bifurcations, expressed as the ratio of local to average deposition densities, were determined to characterise the inhomogeneity of deposition and to elucidate their effect on resulting hit probabilities. The results obtained suggest that in the vicinity of the carinal regions of the central airways the probability of multiple hits can be quite high, even at low average doses. Assuming a uniform distribution of activity there are practically no multiple hits and the hit probability as a function of dose exhibits a linear shape in the low dose range. The results are quite the opposite in the case of hot spots revealed by realistic deposition calculations, where practically all cells receive multiple hits and the hit probability as a function of dose is non-linear in the average dose range of 10-100 mGy.

The dead seed coat functions as a long-term storage for active hydrolytic enzymes

PubMed Central

Raviv, Buzi; Aghajanyan, Lusine; Granot, Gila; Makover, Vardit; Frenkel, Omer; Gutterman, Yitzchak

2017-01-01

Seed development culminates in programmed cell death (PCD) and hardening of organs enclosing the embryo (e.g., pericarp, seed coat) providing essentially a physical shield for protection during storage in the soil. We examined the proposal that dead organs enclosing embryos are unique entities that store and release upon hydration active proteins that might increase seed persistence in soil, germination and seedling establishment. Proteome analyses of dead seed coats of Brassicaceae species revealed hundreds of proteins being stored in the seed coat and released upon hydration, many are stress-associated proteins such as nucleases, proteases and chitinases. Functional analysis revealed that dead seed coats function as long-term storage for multiple active hydrolytic enzymes (e.g., nucleases) that can persist in active forms for decades. Substances released from the dead seed coat of the annual desert plant Anastatica hierochuntica displayed strong antimicrobial activity. Our data highlighted a previously unrecognized feature of dead organs enclosing embryos (e.g., seed coat) functioning not only as a physical shield for embryo protection but also as a long-term storage for active proteins and other substances that are released upon hydration to the “seedsphere” and could contribute to seed persistence in the soil, germination and seedling establishment. PMID:28700755

The dead seed coat functions as a long-term storage for active hydrolytic enzymes.

PubMed

Raviv, Buzi; Aghajanyan, Lusine; Granot, Gila; Makover, Vardit; Frenkel, Omer; Gutterman, Yitzchak; Grafi, Gideon

2017-01-01

Seed development culminates in programmed cell death (PCD) and hardening of organs enclosing the embryo (e.g., pericarp, seed coat) providing essentially a physical shield for protection during storage in the soil. We examined the proposal that dead organs enclosing embryos are unique entities that store and release upon hydration active proteins that might increase seed persistence in soil, germination and seedling establishment. Proteome analyses of dead seed coats of Brassicaceae species revealed hundreds of proteins being stored in the seed coat and released upon hydration, many are stress-associated proteins such as nucleases, proteases and chitinases. Functional analysis revealed that dead seed coats function as long-term storage for multiple active hydrolytic enzymes (e.g., nucleases) that can persist in active forms for decades. Substances released from the dead seed coat of the annual desert plant Anastatica hierochuntica displayed strong antimicrobial activity. Our data highlighted a previously unrecognized feature of dead organs enclosing embryos (e.g., seed coat) functioning not only as a physical shield for embryo protection but also as a long-term storage for active proteins and other substances that are released upon hydration to the "seedsphere" and could contribute to seed persistence in the soil, germination and seedling establishment.

Insight, symptoms and executive functions in schizophrenia.

PubMed

Simon, Andor E; Berger, Gregor E; Giacomini, Véronique; Ferrero, François; Mohr, Sylvia

2006-09-01

We investigated the relationship of insight with executive functions and symptoms in a group of stabilised inpatients with schizophrenia. Executive functions using an extensive battery constituted of several tests as well as psychopathology were assessed in 38 inpatients with a DSM-IV diagnosis of schizophrenia. Insight was assessed with the Scale to assess Unawareness of Mental Disorder (SUMD). A principal component analysis of the insight dimensions revealed a three-factor model which accounted for 98% of the variance. Of particular interest is the finding that a composite factor that accounted for 74% of the variance covered insight dimensions that represent a higher degree of insight (awareness of mental disorder, its social consequences, and attribution of symptoms). Only an association between letter fluency and this composite factor was found, which was weakly mediated by depressive symptoms. A stepwise multiple regression analysis revealed a relationship between antipsychotic dose and awareness of medication effect. No association of illness duration and insight was found. The findings of partial association between dimensions of insight and measures of executive function supports the growing evidence that insight is a multidimensional phenomenon. Accordingly, they emphasise that in the framework of therapeutic interventions, enhancement of higher levels of insight needs to take into account that patients suffering from schizophrenia have differential impairment in insight dimensions.

Photovoltaic devices based on quantum dot functionalized nanowire arrays embedded in an organic matrix

NASA Astrophysics Data System (ADS)

Kung, Patrick; Harris, Nicholas; Shen, Gang; Wilbert, David S.; Baughman, William; Balci, Soner; Dawahre, Nabil; Butler, Lee; Rivera, Elmer; Nikles, David; Kim, Seongsin M.

2012-01-01

Quantum dot (QD) functionalized nanowire arrays are attractive structures for low cost high efficiency solar cells. QDs have the potential for higher quantum efficiency, increased stability and lifetime compared to traditional dyes, as well as the potential for multiple electron generation per photon. Nanowire array scaffolds constitute efficient, low resistance electron transport pathways which minimize the hopping mechanism in the charge transport process of quantum dot solar cells. However, the use of liquid electrolytes as a hole transport medium within such scaffold device structures have led to significant degradation of the QDs. In this work, we first present the synthesis uniform single crystalline ZnO nanowire arrays and their functionalization with InP/ZnS core-shell quantum dots. The structures are characterized using electron microscopy, optical absorption, photoluminescence and Raman spectroscopy. Complementing photoluminescence, transmission electron microanalysis is used to reveal the successful QD attachment process and the atomistic interface between the ZnO and the QD. Energy dispersive spectroscopy reveals the co-localized presence of indium, phosphorus, and sulphur, suggestive of the core-shell nature of the QDs. The functionalized nanowire arrays are subsequently embedded in a poly-3(hexylthiophene) hole transport matrix with a high degree of polymer infiltration to complete the device structure prior to measurement.

Do current European policies support soil multifunctionality?

NASA Astrophysics Data System (ADS)

Helming, Katharina; Glaesner, Nadia; de Vries, Wim

2017-04-01

Soils are multifunctional. Maximising one function, e.g. production of biomass, is often at the costs of the other functions, e.g. water purification, carbon sequestration, nutrient recycling, habitat provision. Sustainable soil management actually means the minimization of trade-offs between multiple soil functions. While Europe does not have a policy that explicitly focuses on soil functions, a number of policies exist in the agricultural, environmental and climate domains that may affect soil functions, in particular food production, water purification, climate change mitigation, biodiversity conservation. The objective of this study was to identify gaps and overlaps in existing EU legislation that is related to soil functions. We conducted a cross-policy analysis of 19 legislative policies at European level. Results revealed two key findings: (i) soil functions are addressed in existing legislation but with the approach to their conservation rather than their improvement. (ii) Different legislations addressed isolated soil functions but there is no policy in place that actually addressed the soil multifunctionality, which is the integrated balancing of the multitude of functions. Because soil degradation is ongoing in Europe, it raises the question whether existing legislation is sufficient for maintaining soil resources and achieving sustainable soil management. Addressing soil functions individually in various directives fails to account for the multifunctionality of soil. Here, research has a role to play to better reveal the interacting processes between soil functions and their sensitivity to soil management decisions and to translate such understanding into policy recommendation. We conclude the presentation with some insights into a research approach that integrates the soil systems into the socio-economic systems to improve the understanding of soil management pressures, soil functional reactions and their impacts on societal value systems, including resource efficiency, ecosystem services and intergenerational equity.

Circular RNA expression in basal cell carcinoma.

PubMed

Sand, Michael; Bechara, Falk G; Sand, Daniel; Gambichler, Thilo; Hahn, Stephan A; Bromba, Michael; Stockfleth, Eggert; Hessam, Schapoor

2016-05-01

Circular RNAs (circRNAs), are nonprotein coding RNAs consisting of a circular loop with multiple miRNA, binding sites called miRNA response elements (MREs), functioning as miRNA sponges. This study was performed to identify differentially expressed circRNAs and their MREs in basal cell carcinoma (BCC). Microarray circRNA expression profiles were acquired from BCC and control followed by qRT-PCR validation. Bioinformatical target prediction revealed multiple MREs. Sequence analysis was performed concerning MRE interaction potential with the BCC miRNome. We identified 23 upregulated and 48 downregulated circRNAs with 354 miRNA response elements capable of sequestering miRNA target sequences of the BCC miRNome. The present study describes a variety of circRNAs that are potentially involved in the molecular pathogenesis of BCC.

Neurocognitive Basis of Racial Ingroup Bias in Empathy.

PubMed

Han, Shihui

2018-05-01

Racial discrimination in social behavior, although disapproved of by many contemporary cultures, has been widely reported. Because empathy plays a key functional role in social behavior, brain imaging researchers have extensively investigated the neurocognitive underpinnings of racial ingroup bias in empathy. This research has revealed consistent evidence for increased neural responses to the perceived pain of same-race compared with other-race individuals in multiple brain regions and across multiple time-windows. Researchers have also examined neurocognitive, sociocultural, and environmental influences on racial ingroup bias in empathic neural responses, as well as explored possible interventions to reduce racial ingroup bias in empathic brain activity. These findings have important implications for understanding racial ingroup favoritism in social behavior and for improving interracial communication. Copyright © 2018 Elsevier Ltd. All rights reserved.

Lactobacillus sakei: A Starter for Sausage Fermentation, a Protective Culture for Meat Products

PubMed Central

Zagorec, Monique; Champomier-Vergès, Marie-Christine

2017-01-01

Among lactic acid bacteria of meat products, Lactobacillus sakei is certainly the most studied species due to its role in the fermentation of sausage and its prevalence during cold storage of raw meat products. Consequently, the physiology of this bacterium regarding functions involved in growth, survival, and metabolism during meat storage and processing are well known. This species exhibits a wide genomic diversity that can be observed when studying different strains and on which probably rely its multiple facets in meat products: starter, spoiler, or protective culture. The emerging exploration of the microbial ecology of meat products also revealed the multiplicity of bacterial interactions L. sakei has to face and their various consequences on microbial quality and safety at the end of storage. PMID:28878171

Sarcoidosis and multiple myeloma: Concurrent presentation of an unusual association

PubMed Central

Nair, Vidya; Prajapat, Deepak; Talwar, Deepak

2016-01-01

Literature on concurrent association of sarcoidosis with lymphoproliferative malignancies other than lymphoma e.g. multiple myeloma is meager. The rarity of the situation prompted us to report this patient who was a 51-year-old woman with a 2-years history of breathlessness, cough with expectoration, chest pain and backache. Initial evaluation revealed mild anemia, increased alkaline phosphatase with chest skiagram showing both lower zone non homogenous opacities with calcified hilar lymph nodes. CECT chest showed mediastinal with bilateral hilar lymphadenopathy, parenchymal fibrosis, traction bronchiectasis, ground glass opacities, septal and peribronchovascular thickening affecting mid and lower lung zones bilaterally. MRI Dorsolumbar spine was suggestive of marrow infiltrative disorder. EBUS FNA of intrathoracic nodes, EBB and TBLB confirmed sarcoidosis. PET CT revealed hyper metabolic activity in lung, multiple lymph nodes and lytic bone lesions. Serum protein electrophoresis and immunofixation revealed a monoclonal paraprotein, immunoglobulin IgG kappa type. Bone marrow biopsy revealed an increase in plasma cells (15%), but no granulomas. Diagnosis of Indolent or multiple myeloma with sarcoidosis was established. 12 cases of sarcoidosis and multiple myeloma have been reported in literature, and mostly preceding the onset of multiple myeloma by many years, in our case both were diagnosed concurrently. PMID:26933313

Employment barriers, skills, and aspirations among unemployed job seekers with and without social anxiety disorder.

PubMed

Himle, Joseph A; Weaver, Addie; Bybee, Deborah; O'Donnell, Lisa; Vlnka, Sarah; Laviolette, Wayne; Steinberger, Edward; Golenberg, Zipora; Levine, Debra Siegel

2014-07-01

The literature has consistently demonstrated that social anxiety disorder has substantial negative impacts on occupational functioning. However, to date, no empirical work has focused on understanding the specific nature of vocational problems among persons with social anxiety disorder. This study examined the association between perceived barriers to employment, employment skills, and job aspirations and social anxiety among adults seeking vocational rehabilitation services. Data from intake assessments (June 2010-December 2011) of 265 low-income, unemployed adults who initiated vocational rehabilitation services in urban Michigan were examined to assess perceived barriers to employment, employment skills, job aspirations, and demographic characteristics among participants who did or did not screen positive for social anxiety disorder. Bivariate and multiple logistic regression analyses were performed. After adjustment for other factors, the multiple logistic regression analysis revealed that perceiving more employment barriers involving experience and skills, reporting fewer skills related to occupations requiring social skills, and having less education were significantly associated with social anxiety disorder. Participants who screened positive for social anxiety disorder were significantly less likely to aspire to social jobs. Employment-related characteristics that were likely to have an impact on occupational functioning were significantly different between persons with and without social anxiety problems. Identifying these differences in employment barriers, skills, and job aspirations revealed important information for designing psychosocial interventions for treatment of social anxiety disorder. The findings underscored the need for vocational services professionals to assess and address social anxiety among their clients.

Aggressive Behaviors in Young Siblings: Associations with Executive Functions and Maternal Characteristics.

PubMed

Spann, Catherine A; Gagne, Jeffrey R

2016-04-01

Aggressive behaviors in early childhood are associated with multiple undesirable outcomes, including juvenile delinquency, academic failure, and substance abuse. This investigation employed a family study design to examine child, mother and sibling predictors of early-emerging aggressive behaviors. These predictors included several indices of executive functioning within children, depression symptoms and education level of mothers, and inhibitory control (IC) of siblings. The sample consisted of 95 families (191 children; boys = 100) with at least two, typically developing children between 30 and 66 months of age (M(age) = 45.93 months, SD = 12.40). Measures included laboratory-assessed working memory and IC, parent-reported aggressive behaviors, as well as self-reported maternal depression symptoms and education. Results revealed that children showed substantial sibling similarity in aggressive behaviors. Using multilevel regression analyses, low child IC and greater maternal depression symptoms were associated with increased child aggressive behaviors. Child working memory, maternal education, and sibling IC did not uniquely predict child aggressive behaviors. Moderation analyses revealed an interaction between maternal depression symptoms and maternal education, such that the effect of depression symptoms on child aggressive behaviors was particularly evident amongst highly educated mothers. The current analysis moved beyond a main effects model of maternal depression and extended previous findings on the importance of child IC to aggressive behaviors by using a multiple-child-per-family framework. A promising direction for future research includes assessing whether efforts to increase child IC are successful in reducing child aggressive behaviors.

The effects of rehearsal on the functional neuroanatomy of episodic autobiographical and semantic remembering: an fMRI study

PubMed Central

Svoboda, Eva; Levine, Brian

2009-01-01

This study examined the effects of rehearsal on the neural substrates supporting episodic autobiographical and semantic memory. Stimuli were collected prospectively using audio recordings, thereby bringing under experimental control ecologically-valid, naturalistic autobiographical stimuli. Participants documented both autobiographical and semantic stimuli over a period of 6 to 8 months, followed by a rehearsal manipulation during the three days preceding scanning. During fMRI scanning participants were exposed to recordings that they were hearing for the first, second or eighth time. Rehearsal increased the rated vividness with which information was remembered, particularly for autobiographical events. Neuroimaging findings revealed rehearsal-related suppression of activation in regions supporting episodic autobiographical and semantic memory. Episodic autobiographical and semantic memory produced distinctly different patterns of regional activation that held even after eight repetitions. Region of interest analyses further indicated a functional anatomical dissociation in response to rehearsal and memory conditions. These findings revealed that the hippocampus was specifically engaged by episodic autobiographical memory, whereas both memory conditions engaged the parahippocampal cortex. Our data suggest that when retrieval cues are potent enough to engage a vivid episodic recollection, the episodic/semantic dissociation within medial temporal lobe structures endure even with multiple stimulus repetitions. These findings support the Multiple Trace Theory (MTT) which predicts that the hippocampus is engaged in the retrieval of rich episodic recollection regardless of repeated reactivation such as that occurring with the passage of time. PMID:19279244

Allosteric Modulation of Metabotropic Glutamate Receptors

PubMed Central

Sheffler, Douglas J.; Gregory, Karen J.; Rook, Jerri M.; Conn, P. Jeffrey

2013-01-01

The development of receptor subtype-selective ligands by targeting allosteric sites of G protein-coupled receptors (GPCRs) has proven highly successful in recent years. One GPCR family that has greatly benefited from this approach is the metabotropic glutamate receptors (mGlus). These family C GPCRs participate in the neuromodulatory actions of glutamate throughout the CNS, where they play a number of key roles in regulating synaptic transmission and neuronal excitability. A large number of mGlu subtype-selective allosteric modulators have been identified, the majority of which are thought to bind within the transmembrane regions of the receptor. These modulators can either enhance or inhibit mGlu functional responses and, together with mGlu knockout mice, have furthered the establishment of the physiologic roles of many mGlu subtypes. Numerous pharmacological and receptor mutagenesis studies have been aimed at providing a greater mechanistic understanding of the interaction of mGlu allosteric modulators with the receptor, which have revealed evidence for common allosteric binding sites across multiple mGlu subtypes and the presence for multiple allosteric sites within a single mGlu subtype. Recent data have also revealed that mGlu allosteric modulators can display functional selectivity toward particular signal transduction cascades downstream of an individual mGlu subtype. Studies continue to validate the therapeutic utility of mGlu allosteric modulators as a potential therapeutic approach for a number of disorders including anxiety, schizophrenia, Parkinson’s disease, and Fragile X syndrome. PMID:21907906

The complex and specific pMHC interactions with diverse HIV-1 TCR clonotypes reveal a structural basis for alterations in CTL function

PubMed Central

Xia, Zhen; Chen, Huabiao; Kang, Seung-gu; Huynh, Tien; Fang, Justin W.; Lamothe, Pedro A.; Walker, Bruce D.; Zhou, Ruhong

2014-01-01

Immune control of viral infections is modulated by diverse T cell receptor (TCR) clonotypes engaging peptide-MHC class I complexes on infected cells, but the relationship between TCR structure and antiviral function is unclear. Here we apply in silico molecular modeling with in vivo mutagenesis studies to investigate TCR-pMHC interactions from multiple CTL clonotypes specific for a well-defined HIV-1 epitope. Our molecular dynamics simulations of viral peptide-HLA-TCR complexes, based on two independent co-crystal structure templates, reveal that effective and ineffective clonotypes bind to the terminal portions of the peptide-MHC through similar salt bridges, but their hydrophobic side-chain packings can be very different, which accounts for the major part of the differences among these clonotypes. Non-specific hydrogen bonding to viral peptide also accommodates greater epitope variants. Furthermore, free energy perturbation calculations for point mutations on the viral peptide KK10 show excellent agreement with in vivo mutagenesis assays, with new predictions confirmed by additional experiments. These findings indicate a direct structural basis for heterogeneous CTL antiviral function. PMID:24522437

The nuclear receptor PPARγ individually responds to serotonin- and fatty acid-metabolites

PubMed Central

Waku, Tsuyoshi; Shiraki, Takuma; Oyama, Takuji; Maebara, Kanako; Nakamori, Rinna; Morikawa, Kosuke

2010-01-01

The nuclear receptor, peroxisome proliferator-activated receptor γ (PPARγ), recognizes various synthetic and endogenous ligands by the ligand-binding domain. Fatty-acid metabolites reportedly activate PPARγ through conformational changes of the Ω loop. Here, we report that serotonin metabolites act as endogenous agonists for PPARγ to regulate macrophage function and adipogenesis by directly binding to helix H12. A cyclooxygenase inhibitor, indomethacin, is a mimetic agonist of these metabolites. Crystallographic analyses revealed that an indole acetate functions as a common moiety for the recognition by the sub-pocket near helix H12. Intriguingly, a serotonin metabolite and a fatty-acid metabolite each bind to distinct sub-pockets, and the PPARγ antagonist, T0070907, blocked the fatty-acid agonism, but not that of the serotonin metabolites. Mutational analyses on receptor-mediated transcription and coactivator binding revealed that each metabolite individually uses coregulator and/or heterodimer interfaces in a ligand-type-specific manner. Furthermore, the inhibition of the serotonin metabolism reduced the expression of the endogenous PPARγ-target gene. Collectively, these results suggest a novel agonism, in which PPARγ functions as a multiple sensor in response to distinct metabolites. PMID:20717101

Convergent and divergent pathways decoding hierarchical additive mechanisms in treating cerebral ischemia-reperfusion injury.

PubMed

Zhang, Ying-Ying; Li, Hai-Xia; Chen, Yin-Ying; Fang, Hong; Yu, Ya-Nan; Liu, Jun; Jing, Zhi-Wei; Wang, Zhong; Wang, Yong-Yan

2014-03-01

Cerebral ischemia is considered to be a highly complex disease resulting from the complicated interplay of multiple pathways. Disappointedly, most of the previous studies were limited to a single gene or a single pathway. The extent to which all involved pathways are translated into fusing mechanisms of a combination therapy is of fundamental importance. We report an integrative strategy to reveal the additive mechanism that a combination (BJ) of compound baicalin (BA) and jasminoidin (JA) fights against cerebral ischemia based on variation of pathways and functional communities. We identified six pathways of BJ group that shared diverse additive index from 0.09 to 1, which assembled broad cross talks from seven pathways of BA and 16 pathways of JA both at horizontal and vertical levels. Besides a total of 60 overlapping functions as a robust integration background among the three groups based on significantly differential subnetworks, additive mechanism with strong confidence by networks altered functions. These results provide strong evidence that the additive mechanism is more complex than previously appreciated, and an integrative analysis of pathways may suggest an important paradigm for revealing pharmacological mechanisms underlying drug combinations. © 2013 John Wiley & Sons Ltd.

Maximal Neighbor Similarity Reveals Real Communities in Networks

PubMed Central

Žalik, Krista Rizman

2015-01-01

An important problem in the analysis of network data is the detection of groups of densely interconnected nodes also called modules or communities. Community structure reveals functions and organizations of networks. Currently used algorithms for community detection in large-scale real-world networks are computationally expensive or require a priori information such as the number or sizes of communities or are not able to give the same resulting partition in multiple runs. In this paper we investigate a simple and fast algorithm that uses the network structure alone and requires neither optimization of pre-defined objective function nor information about number of communities. We propose a bottom up community detection algorithm in which starting from communities consisting of adjacent pairs of nodes and their maximal similar neighbors we find real communities. We show that the overall advantage of the proposed algorithm compared to the other community detection algorithms is its simple nature, low computational cost and its very high accuracy in detection communities of different sizes also in networks with blurred modularity structure consisting of poorly separated communities. All communities identified by the proposed method for facebook network and E-Coli transcriptional regulatory network have strong structural and functional coherence. PMID:26680448

Time-delay-induced dynamical behaviors for an ecological vegetation growth system driven by cross-correlated multiplicative and additive noises.

PubMed

Wang, Kang-Kang; Ye, Hui; Wang, Ya-Jun; Li, Sheng-Hong

2018-05-14

In this paper, the modified potential function, the stationary probability distribution function (SPDF), the mean growth time and the mean degeneration time for a vegetation growth system with time delay are investigated, where the vegetation system is assumed to be disturbed by cross-correlated multiplicative and additive noises. The results reveal some fact that the multiplicative and additive noises can both reduce the stability and speed up the decline of the vegetation system, while the strength of the noise correlation and time delay can both enhance the stability of the vegetation and slow down the depression process of the ecological system. On the other hand, with regard to the impacts of noises and time delay on the mean development and degeneration processes of the ecological system, it is discovered that 1) in the development process of the vegetation population, the increase of the noise correlation strength and time delay will restrain the regime shift from the barren state to the boom one, while the increase of the additive noise can lead to the fast regime shift from the barren state to the boom one. 2) Conversely, in the depression process of the ecological system, the increase of the strength of the correlation noise and time delay will prevent the regime shift from the boom state to the barren one. Comparatively, the increase of the additive and multiplicative noises can accelerate the regime shift from the boom state to the barren state.

Structure of an Arrestin2-clathrin Complex Reveals a Novel Clathrin Binding Domain that Modulates Receptor Trafficking

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

Kang, D.; Kern, R; Puthenveedu, M

2009-01-01

Non-visual arrestins play a pivotal role as adaptor proteins in regulating the signaling and trafficking of multiple classes of receptors. Although arrestin interaction with clathrin, AP-2, and phosphoinositides contributes to receptor trafficking, little is known about the configuration and dynamics of these interactions. Here, we identify a novel interface between arrestin2 and clathrin through x-ray diffraction analysis. The intrinsically disordered clathrin binding box of arrestin2 interacts with a groove between blades 1 and 2 in the clathrin {beta}-propeller domain, whereas an 8-amino acid splice loop found solely in the long isoform of arrestin2 (arrestin2L) interacts with a binding pocket formedmore » by blades 4 and 5 in clathrin. The apposition of the two binding sites in arrestin2L suggests that they are exclusive and may function in higher order macromolecular structures. Biochemical analysis demonstrates direct binding of clathrin to the splice loop in arrestin2L, whereas functional analysis reveals that both binding domains contribute to the receptor-dependent redistribution of arrestin2L to clathrin-coated pits. Mutagenesis studies reveal that the clathrin binding motif in the splice loop is (L/I){sub 2}GXL. Taken together, these data provide a framework for understanding the dynamic interactions between arrestin2 and clathrin and reveal an essential role for this interaction in arrestin-mediated endocytosis.« less

The Association Between Sexual Satisfaction and Body Image in Women

PubMed Central

Pujols, Yasisca; Meston, Cindy M.; Seal, Brooke N.

2010-01-01

Introduction Although sexual functioning has been linked to sexual satisfaction, it only partially explains the degree to which women report being sexually satisfied. Other factors include quality of life, relational variables, and individual factors such as body image. Of the few studies that have investigated the link between body image and sexual satisfaction, most have considered body image to be a single construct and have shown mixed results. Aim The present study assessed multiple body image variables in order to better understand which aspects of body image influence multiple domains of sexual satisfaction, including sexual communication, compatibility, contentment, personal concern, and relational concern in a community sample of women. Methods Women between the ages of 18 and 49 years in sexual relationships (N = 154) participated in an Internet survey that assessed sexual functioning, five domains of sexual satisfaction, and several body image variables. Main Outcome Measures Body image variables included the sexual attractiveness, weight concern, and physical condition subscales of the Body Esteem Scale, the appearance-based subscale of the Cognitive Distractions During Sexual Activity Scale, and body mass index. Total score of the Sexual Satisfaction Scale for Women was the main outcome measure. Sexual functioning was measured by a modified Female Sexual Function Index. Results Consistent with expectations, correlations indicated significant positive relationships between sexual functioning, sexual satisfaction, and all body image variables. A multiple regression analysis revealed that sexual satisfaction was predicted by high body esteem and low frequency of appearance-based distracting thoughts during sexual activity, even after controlling for sexual functioning status. Conclusion Several aspects of body image, including weight concern, physical condition, sexual attractiveness, and thoughts about the body during sexual activity predict sexual satisfaction in women. The findings suggest that women who experience low sexual satisfaction may benefit from treatments that target these specific aspects of body image. PMID:19968771

Nucleotide substitutions revealing specific functions of Polycomb group genes.

PubMed

Bajusz, Izabella; Sipos, László; Pirity, Melinda K

2015-04-01

POLYCOMB group (PCG) proteins belong to the family of epigenetic regulators of genes playing important roles in differentiation and development. Mutants of PcG genes were isolated first in the fruit fly, Drosophila melanogaster, resulting in spectacular segmental transformations due to the ectopic expression of homeotic genes. Homologs of Drosophila PcG genes were also identified in plants and in vertebrates and subsequent experiments revealed the general role of PCG proteins in the maintenance of the repressed state of chromatin through cell divisions. The past decades of gene targeting experiments have allowed us to make significant strides towards understanding how the network of PCG proteins influences multiple aspects of cellular fate determination during development. Being involved in the transmission of specific expression profiles of different cell lineages, PCG proteins were found to control wide spectra of unrelated epigenetic processes in vertebrates, such as stem cell plasticity and renewal, genomic imprinting and inactivation of X-chromosome. PCG proteins also affect regulation of metabolic genes being important for switching programs between pluripotency and differentiation. Insight into the precise roles of PCG proteins in normal physiological processes has emerged from studies employing cell culture-based systems and genetically modified animals. Here we summarize the findings obtained from PcG mutant fruit flies and mice generated to date with a focus on PRC1 and PRC2 members altered by nucleotide substitutions resulting in specific alleles. We also include a compilation of lessons learned from these models about the in vivo functions of this complex protein family. With multiple knockout lines, sophisticated approaches to study the consequences of peculiar missense point mutations, and insights from complementary gain-of-function systems in hand, we are now in a unique position to significantly advance our understanding of the molecular basis of in vivo functions of PcG proteins. Copyright © 2015 Elsevier Inc. All rights reserved.

Emerging Importance of Helicases in Plant Stress Tolerance: Characterization of Oryza sativa Repair Helicase XPB2 Promoter and Its Functional Validation in Tobacco under Multiple Stresses

PubMed Central

Raikwar, Shailendra; Srivastava, Vineet K.; Gill, Sarvajeet S.; Tuteja, Renu; Tuteja, Narendra

2015-01-01

Genetic material always remains at the risk of spontaneous or induced damage which challenges the normal functioning of DNA molecule, thus, DNA repair is vital to protect the organisms against genetic damage. Helicases, the unique molecular motors, are emerged as prospective molecules to engineer stress tolerance in plants and are involved in nucleic acid metabolism including DNA repair. The repair helicase, XPB is an evolutionary conserved protein present in different organisms, including plants. Availability of few efficient promoters for gene expression in plants provoked us to study the promoter of XPB for better understanding of gene regulation under stress conditions. Here, we report the in silico analysis of novel stress inducible promoter of Oryza sativa XPB2 (OsXPB2). The in vivo validation of functionality/activity of OsXPB2 promoter under abiotic and hormonal stress conditions was performed by Agrobacterium-mediated transient assay in tobacco leaves using OsXPB2::GUS chimeric construct. The present research revealed that OsXPB2 promoter contains cis-elements accounting for various abiotic stresses (salt, dehydration, or cold) and hormone (Auxin, ABA, or MeJA) induced GUS expression/activity in the promoter-reporter assay. The promoter region of OsXPB2 contains CACG, GTAACG, CACGTG, CGTCA CCGCCGCGCT cis acting-elements which are reported to be salt, dehydration, cold, MeJA, or ABA responsive, respectively. Functional analysis was done by Agrobacterium-mediated transient assay using agroinfiltration in tobacco leaves, followed by GUS staining and fluorescence quantitative analyses. The results revealed high induction of GUS activity under multiple abiotic stresses as compared to mock treated control. The present findings suggest that OsXPB2 promoter is a multi-stress inducible promoter and has potential applications in sustainable crop production under abiotic stresses by regulating desirable pattern of gene expression. PMID:26734018

Emerging Importance of Helicases in Plant Stress Tolerance: Characterization of Oryza sativa Repair Helicase XPB2 Promoter and Its Functional Validation in Tobacco under Multiple Stresses.

PubMed

Raikwar, Shailendra; Srivastava, Vineet K; Gill, Sarvajeet S; Tuteja, Renu; Tuteja, Narendra

2015-01-01

Genetic material always remains at the risk of spontaneous or induced damage which challenges the normal functioning of DNA molecule, thus, DNA repair is vital to protect the organisms against genetic damage. Helicases, the unique molecular motors, are emerged as prospective molecules to engineer stress tolerance in plants and are involved in nucleic acid metabolism including DNA repair. The repair helicase, XPB is an evolutionary conserved protein present in different organisms, including plants. Availability of few efficient promoters for gene expression in plants provoked us to study the promoter of XPB for better understanding of gene regulation under stress conditions. Here, we report the in silico analysis of novel stress inducible promoter of Oryza sativa XPB2 (OsXPB2). The in vivo validation of functionality/activity of OsXPB2 promoter under abiotic and hormonal stress conditions was performed by Agrobacterium-mediated transient assay in tobacco leaves using OsXPB2::GUS chimeric construct. The present research revealed that OsXPB2 promoter contains cis-elements accounting for various abiotic stresses (salt, dehydration, or cold) and hormone (Auxin, ABA, or MeJA) induced GUS expression/activity in the promoter-reporter assay. The promoter region of OsXPB2 contains CACG, GTAACG, CACGTG, CGTCA CCGCCGCGCT cis acting-elements which are reported to be salt, dehydration, cold, MeJA, or ABA responsive, respectively. Functional analysis was done by Agrobacterium-mediated transient assay using agroinfiltration in tobacco leaves, followed by GUS staining and fluorescence quantitative analyses. The results revealed high induction of GUS activity under multiple abiotic stresses as compared to mock treated control. The present findings suggest that OsXPB2 promoter is a multi-stress inducible promoter and has potential applications in sustainable crop production under abiotic stresses by regulating desirable pattern of gene expression.

Harvesting multiple electron-hole pairs generated through plasmonic excitation of Au nanoparticles.

PubMed

Kim, Youngsoo; Smith, Jeremy G; Jain, Prashant K

2018-05-07

Multi-electron redox reactions, although central to artificial photosynthesis, are kinetically sluggish. Amidst the search for synthetic catalysts for such processes, plasmonic nanoparticles have been found to catalyse multi-electron reduction of CO 2 under visible light. This example motivates the need for a general, insight-driven framework for plasmonic catalysis of such multi-electron chemistry. Here, we elucidate the principles underlying the extraction of multiple redox equivalents from a plasmonic photocatalyst. We measure the kinetics of electron harvesting from a gold nanoparticle photocatalyst as a function of photon flux. Our measurements, supported by theoretical modelling, reveal a regime where two-electron transfer from the excited gold nanoparticle becomes prevalent. Multiple electron harvesting becomes possible under continuous-wave, visible-light excitation of moderate intensity due to strong interband transitions in gold and electron-hole separation accomplished using a hole scavenger. These insights will help expand the utility of plasmonic photocatalysis beyond CO 2 reduction to other challenging multi-electron, multi-proton transformations such as N 2 fixation.

Complete structural characterization of ceramides as [M – H]− ions by multiple-stage linear ion trap mass spectrometry

PubMed Central

Hsu, Fong-Fu

2016-01-01

Ceramide is a huge lipid family consisting of diversified structures including various modifications in the fatty acyl chain and the long chain base (LCB). In this contribution, negative-ion ESI linear ion-trap multiple-stage mass spectrometric method (LIT MSn) towards complete structural determination of ceramides in ten major families characterized as the [M – H]− ions is described. Multiple sets of fragment ions reflecting the fatty acyl chain and LCB were observed in the CID MS2 spectrum, while the sequential MS3 and MS4 spectra contain structural information for locating the double bond and the functional groups, permitting realization of the fragmentation processes. Thereby, differentiation of ceramide molecules varied by chain length, the LCB (sphingosine, phytosphigosine, 6-hydroxy-sphingosine), and by the modification (α-hydroxy-, β-hydroxy-, ω-hydroxy-FA) can be achieved; and many isomeric structures in the biological specimen can be revealed in detail. PMID:27523779

[Functional mapping using subdural electrodes combined with monitoring during awake craniotomy enabled preservation of function and extensive resection of a glioma adjacent to the parietal lobe language sites: a case report].

PubMed

Takebayashi, Kento; Saito, Taiichi; Nitta, Masayuki; Tamura, Manabu; Maruyama, Takashi; Muragaki, Yoshihiro; Okada, Yoshikazu

2015-01-01

Surgical resection of gliomas located in the dominant parietal lobe is difficult because this lesion is surrounded by multiple functional areas. Although functional mapping during awake craniotomy is very useful for resection of gliomas adjacent to eloquent areas, the limited time available makes it difficult to sufficiently evaluate multiple functions, such as language, calculative ability, distinction of right and left sides, and finger recognition. Here, we report a case of anaplastic oligodendroglioma, which was successfully treated with a combination of functional mapping using subdural electrodes and monitoring under awake craniotomy for glioma. A 32-year-old man presented with generalized seizure. Magnetic resonance imaging revealed a non-enhanced tumor in the left angular and supramarginal gyri. In addition, the tumor showed high accumulation on 11C-methionine positron emission tomography(PET)(tumor/normal brain tissue ratio=3.20). Preparatory mapping using subdural electrodes showed absence of brain function on the tumor lesion. Surgical removal was performed using cortical mapping during awake craniotomy with an updated navigation system using intraoperative magnetic resonance imaging(MRI). The tumor was resected until aphasia was detected by functional monitoring, and the extent of tumor resection was 93%. The patient showed transient transcortical aphasia and Gerstmann's syndrome after surgery but eventually recovered. The pathological diagnosis was anaplastic oligodendroglioma, and the patient was administered chemo-radiotherapy. The patient has been progression free for more than 2 years. The combination of subdural electrode mapping and monitoring during awake craniotomy is useful in order to achieve preservation of function and extensive resection for gliomas in the dominant parietal lobe.

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

Gifford, Brendan Joel; Kilina, Svetlana; Htoon, Han

Recent spectroscopic studies have revealed the appearance of multiple low-energy peaks in the fluorescence of single-walled carbon nanotubes (SWCNTs) upon their covalent functionalization by aryl groups. The photophysical nature of these low energy optical bands is of significant interest in the quest to understand their appearance and to achieve their precise control via chemical modification of SWCNTs. This theoretical study explains the specific energy dependence of emission features introduced in chemically functionalized (6,5) SWCNTs with aryl bromides at different conformations and in various dielectric media. Calculations using density functional theory (DFT) and time dependent DFT (TD-DFT) show that the specificmore » isomer geometry—the relative position of functional groups on the carbon-ring of the nanotube—is critical for controlling the energies and intensities of optical transitions introduced by functionalization, while the dielectric environment and the chemical composition of functional groups play less significant roles. Furthermore, the predominant effects on optical properties as a result of functionalization conformation are rationalized by exciton localization on the surface of the SWCNT near the dopant sp3-defect but not onto the functional group itself.« less

SMAD Signaling Is Required for Structural Integrity of the Female Reproductive Tract and Uterine Function During Early Pregnancy in Mice1

PubMed Central

Rodriguez, Amanda; Tripurani, Swamy K.; Burton, Jason C.; Clementi, Caterina; Larina, Irina; Pangas, Stephanie A.

2016-01-01

Pregnancy is a complex physiological process tightly controlled by the interplay among hormones, morphogens, transcription factors, and signaling pathways. Although recent studies using genetically engineered mouse models have revealed that ligands and receptors of transforming growth factor beta (TGFbeta) and bone morphogenetic protein (BMP) signaling pathways are essential for multiple reproductive events during pregnancy, the functional role of SMAD transcription factors, which serve as the canonical signaling platform for the TGFbeta/BMP pathways, in the oviduct and uterus is undefined. Here, we used a mouse model containing triple conditional deletion of the BMP receptor signaling Smads (Smad1 and Smad5) and Smad4, the central mediator of both TGFbeta and BMP signaling, to investigate the role of the SMADs in reproductive tract structure and function in cells from the Amhr2 lineage. Unlike the respective single- or double-knockouts, female Smad1flox/flox Smad5flox/flox Smad4flox/flox Amhr2cre/+conditional knockout (i.e., Smad1/5/4-Amhr2-cre KO) mice are sterile. We discovered that Smad1/5/4-Amhr2-cre KO females have malformed oviducts that subsequently develop oviductal diverticuli. These oviducts showed dysregulation of multiple genes essential for oviduct and smooth muscle development. In addition, uteri from Smad1/5/4-Amhr2-cre KO females exhibit multiple defects in stroma, epithelium, and smooth muscle layers and fail to assemble a closed uterine lumen upon embryo implantation, with defective uterine decidualization that led to pregnancy loss at early to mid-gestation. Taken together, our study uncovers a new role for the SMAD transcription factors in maintaining the structural and functional integrity of oviduct and uterus, required for establishment and maintenance of pregnancy. PMID:27335065

VoxelStats: A MATLAB Package for Multi-Modal Voxel-Wise Brain Image Analysis.

PubMed

Mathotaarachchi, Sulantha; Wang, Seqian; Shin, Monica; Pascoal, Tharick A; Benedet, Andrea L; Kang, Min Su; Beaudry, Thomas; Fonov, Vladimir S; Gauthier, Serge; Labbe, Aurélie; Rosa-Neto, Pedro

2016-01-01

In healthy individuals, behavioral outcomes are highly associated with the variability on brain regional structure or neurochemical phenotypes. Similarly, in the context of neurodegenerative conditions, neuroimaging reveals that cognitive decline is linked to the magnitude of atrophy, neurochemical declines, or concentrations of abnormal protein aggregates across brain regions. However, modeling the effects of multiple regional abnormalities as determinants of cognitive decline at the voxel level remains largely unexplored by multimodal imaging research, given the high computational cost of estimating regression models for every single voxel from various imaging modalities. VoxelStats is a voxel-wise computational framework to overcome these computational limitations and to perform statistical operations on multiple scalar variables and imaging modalities at the voxel level. VoxelStats package has been developed in Matlab(®) and supports imaging formats such as Nifti-1, ANALYZE, and MINC v2. Prebuilt functions in VoxelStats enable the user to perform voxel-wise general and generalized linear models and mixed effect models with multiple volumetric covariates. Importantly, VoxelStats can recognize scalar values or image volumes as response variables and can accommodate volumetric statistical covariates as well as their interaction effects with other variables. Furthermore, this package includes built-in functionality to perform voxel-wise receiver operating characteristic analysis and paired and unpaired group contrast analysis. Validation of VoxelStats was conducted by comparing the linear regression functionality with existing toolboxes such as glim_image and RMINC. The validation results were identical to existing methods and the additional functionality was demonstrated by generating feature case assessments (t-statistics, odds ratio, and true positive rate maps). In summary, VoxelStats expands the current methods for multimodal imaging analysis by allowing the estimation of advanced regional association metrics at the voxel level.

Role of Alexithymia, Anxiety, and Depression in Predicting Self-Efficacy in Academic Students

PubMed Central

2017-01-01

Objective. Little research is available on the predictive factors of self-efficacy in college students. The aim of the present study is to examine the role of alexithymia, anxiety, and depression in predicting self-efficacy in academic students. Design. In a cross-sectional study, a total of 133 students at Babol University of Medical Sciences (Medicine, Dentistry, and Paramedicine) participated in the study between 2014 and 2015. All participants completed the Toronto Alexithymia Scale (TAS-20), College Academic Self-Efficacy Scale (CASES), and 14 items on anxiety and depression derived from the 28 items of the General Health Questionnaire (28-GHQ). Results. Pearson correlation coefficients revealed negative significant relationships between alexithymia and the three subscales with student self-efficacy. There was no significant correlation between anxiety/depression symptoms and student self-efficacy. A backward multiple regression analysis revealed that alexithymia was a negative significant predictor of self-efficacy in academic students (B = −0.512, P < 0.001). The prevalence of alexithymia was 21.8% in students. Multiple backward logistic analysis regression revealed that number of passed semesters, gender, mother's education, father's education, and doctoral level did not accurately predict alexithymia in college students. Conclusion. As alexithymia is prevalent in college students and affects self-efficacy and academic functioning, we suggest it should be routinely evaluated by mental physicians at universities. PMID:28154839

Role of Alexithymia, Anxiety, and Depression in Predicting Self-Efficacy in Academic Students.

PubMed

Faramarzi, Mahbobeh; Khafri, Soraya

2017-01-01

Objective . Little research is available on the predictive factors of self-efficacy in college students. The aim of the present study is to examine the role of alexithymia, anxiety, and depression in predicting self-efficacy in academic students. Design . In a cross-sectional study, a total of 133 students at Babol University of Medical Sciences (Medicine, Dentistry, and Paramedicine) participated in the study between 2014 and 2015. All participants completed the Toronto Alexithymia Scale (TAS-20), College Academic Self-Efficacy Scale (CASES), and 14 items on anxiety and depression derived from the 28 items of the General Health Questionnaire (28-GHQ). Results . Pearson correlation coefficients revealed negative significant relationships between alexithymia and the three subscales with student self-efficacy. There was no significant correlation between anxiety/depression symptoms and student self-efficacy. A backward multiple regression analysis revealed that alexithymia was a negative significant predictor of self-efficacy in academic students ( B = -0.512, P < 0.001). The prevalence of alexithymia was 21.8% in students. Multiple backward logistic analysis regression revealed that number of passed semesters, gender, mother's education, father's education, and doctoral level did not accurately predict alexithymia in college students. Conclusion . As alexithymia is prevalent in college students and affects self-efficacy and academic functioning, we suggest it should be routinely evaluated by mental physicians at universities.

Free energy landscape and transition pathways from Watson–Crick to Hoogsteen base pairing in free duplex DNA

PubMed Central

Yang, Changwon; Kim, Eunae; Pak, Youngshang

2015-01-01

Houghton (HG) base pairing plays a central role in the DNA binding of proteins and small ligands. Probing detailed transition mechanism from Watson–Crick (WC) to HG base pair (bp) formation in duplex DNAs is of fundamental importance in terms of revealing intrinsic functions of double helical DNAs beyond their sequence determined functions. We investigated a free energy landscape of a free B-DNA with an adenosine–thymine (A–T) rich sequence to probe its conformational transition pathways from WC to HG base pairing. The free energy landscape was computed with a state-of-art two-dimensional umbrella molecular dynamics simulation at the all-atom level. The present simulation showed that in an isolated duplex DNA, the spontaneous transition from WC to HG bp takes place via multiple pathways. Notably, base flipping into the major and minor grooves was found to play an important role in forming these multiple transition pathways. This finding suggests that naked B-DNA under normal conditions has an inherent ability to form HG bps via spontaneous base opening events. PMID:26250116

Neurocognitive functioning in children with developmental dyslexia and attention-deficit/hyperactivity disorder: Multiple deficits and diagnostic accuracy.

PubMed

Moura, Octávio; Pereira, Marcelino; Alfaiate, Cláudia; Fernandes, Eva; Fernandes, Boavida; Nogueira, Susana; Moreno, Joana; Simões, Mário R

2017-04-01

This study aimed to investigate the neurocognitive functioning of children with developmental dyslexia (DD) and attention-deficit/hyperactivity disorder (ADHD). Four groups of children between the ages of 8 and 10 years participated in the study: typically developing children (TDC; N = 34), children with DD-only (N = 32), children with ADHD-only (N = 32), and children with DD+ADHD (N = 18). Children with DD and ADHD exhibited significant weaknesses on almost all neurocognitive measures compared with TDC. Large effect sizes were observed for naming speed and phonological awareness. The comorbid group showed deficits consistent with both DD and ADHD without additional impairments. Results from binary logistic regression and receiver-operating characteristic (ROC) curve analyses suggested that some neurocognitive measures revealed an adequate sensitivity for the clinical diagnosis of both neurodevelopmental disorders. Specifically, naming speed and phonological awareness were the strongest predictors to correctly discriminate both disorders. Taken together, the results lend support to the multiple cognitive deficit hypothesis showing a considerable overlap of neurocognitive deficits between both disorders.

Function of the CRISPR-Cas System of the Human Pathogen Clostridium difficile

PubMed Central

Boudry, Pierre; Semenova, Ekaterina; Monot, Marc; Datsenko, Kirill A.; Lopatina, Anna; Sekulovic, Ognjen; Ospina-Bedoya, Maicol; Fortier, Louis-Charles; Severinov, Konstantin; Dupuy, Bruno

2015-01-01

ABSTRACT Clostridium difficile is the cause of most frequently occurring nosocomial diarrhea worldwide. As an enteropathogen, C. difficile must be exposed to multiple exogenous genetic elements in bacteriophage-rich gut communities. CRISPR (clustered regularly interspaced short palindromic repeats)-Cas (CRISPR-associated) systems allow bacteria to adapt to foreign genetic invaders. Our recent data revealed active expression and processing of CRISPR RNAs from multiple type I-B CRISPR arrays in C. difficile reference strain 630. Here, we demonstrate active expression of CRISPR arrays in strain R20291, an epidemic C. difficile strain. Through genome sequencing and host range analysis of several new C. difficile phages and plasmid conjugation experiments, we provide evidence of defensive function of the CRISPR-Cas system in both C. difficile strains. We further demonstrate that C. difficile Cas proteins are capable of interference in a heterologous host, Escherichia coli. These data set the stage for mechanistic and physiological analyses of CRISPR-Cas-mediated interactions of important global human pathogen with its genetic parasites. PMID:26330515

Alkaline Phosphatase, an Unconventional Immune Protein.

PubMed

Rader, Bethany A

2017-01-01

Recent years have seen an increase in the number of studies focusing on alkaline phosphatases (APs), revealing an expanding complexity of function of these enzymes. Of the four human AP (hAP) proteins, most is known about tissue non-specific AP (TNAP) and intestinal AP (IAP). This review highlights current understanding of TNAP and IAP in relation to human health and disease. TNAP plays a role in multiple processes, including bone mineralization, vitamin B6 metabolism, and neurogenesis, is the genetic cause of hypophosphatasia, influences inflammation through regulation of purinergic signaling, and has been implicated in Alzheimer's disease. IAP regulates fatty acid absorption and has been implicated in the regulation of diet-induced obesity and metabolic syndrome. IAP and TNAP can dephosphorylate bacterial-derived lipopolysaccharide, and IAP has been identified as a potential regulator of the composition of the intestinal microbiome, an evolutionarily conserved function. Endogenous and recombinant bovine APs and recombinant hAPs are currently being explored for their potential as pharmacological agents to treat AP-associated diseases and mitigate multiple sources of inflammation. Continued research on these versatile proteins will undoubtedly provide insight into human pathophysiology, biochemistry, and the human holobiont.

Multitrophic functional diversity predicts ecosystem functioning in experimental assemblages of estuarine consumers.

PubMed

Lefcheck, Jonathan S; Duffy, J Emmett

2015-11-01

The use of functional traits to explain how biodiversity affects ecosystem functioning has attracted intense interest, yet few studies have a priori altered functional diversity, especially in multitrophic communities. Here, we manipulated multivariate functional diversity of estuarine grazers and predators within multiple levels of species richness to test how species richness and functional diversity predicted ecosystem functioning in a multitrophic food web. Community functional diversity was a better predictor than species richness for the majority of ecosystem properties, based on generalized linear mixed-effects models. Combining inferences from eight traits into a single multivariate index increased prediction accuracy of these models relative to any individual trait. Structural equation modeling revealed that functional diversity of both grazers and predators was important in driving final biomass within trophic levels, with stronger effects observed for predators. We also show that different species drove different ecosystem responses, with evidence for both sampling effects and complementarity. Our study extends experimental investigations of functional trait diversity to a multilevel food web, and demonstrates that functional diversity can be more accurate and effective than species richness in predicting community biomass in a food web context.

How does a planet excite multiple spiral arms?

NASA Astrophysics Data System (ADS)

Bae, Jaehan; Zhu, Zhaohuan

2018-01-01

Protoplanetary disk simulations show that a single planet excites multiple spiral arms in the background disk, potentially supported by the multi-armed spirals revealed with recent high-resolution observations in some disks. The existence of multiple spiral arms is of importance in many aspects. It is empirically found that the arm-to-arm separation increases as a function of the planetary mass, so one can use the morphology of observed spiral arms to infer the mass of unseen planets. In addition, a spiral arm opens a radial gap as it steepens into a shock, so when a planet excites multiple spiral arms it can open multiple gaps in the disk. Despite the important implications, however, the formation mechanism of multiple spiral arms has not been fully understood by far.In this talk, we explain how a planet excites multiple spiral arms. The gravitational potential of a planet can be decomposed into a Fourier series, a sum of individual azimuthal modes having different azimuthal wavenumbers. Using a linear wave theory, we first demonstrate that appropriate sets of Fourier decomposed waves can be in phase, raising a possibility that constructive interference among the waves can produce coherent structures - spiral arms. More than one spiral arm can form since such constructive interference can occur at different positions in the disk for different sets of waves. We then verify this hypothesis using a suite of two-dimensional hydrodynamic simulations. Finally, we present non-linear behavior in the formation of multiple spiral arms.

Strains, functions, and dynamics in the expanded Human Microbiome Project

PubMed Central

Lloyd-Price, Jason; Mahurkar, Anup; Rahnavard, Gholamali; Crabtree, Jonathan; Orvis, Joshua; Hall, A. Brantley; Brady, Arthur; Creasy, Heather H.; McCracken, Carrie; Giglio, Michelle G.; McDonald, Daniel; Franzosa, Eric A.; Knight, Rob; White, Owen; Huttenhower, Curtis

2018-01-01

Summary The characterization of baseline microbial and functional diversity in the human microbiome has enabled studies of microbiome-related disease, microbial population diversity, biogeography, and molecular function. The NIH Human Microbiome Project (HMP) has provided one of the broadest such characterizations to date. Here, we introduce an expanded second phase of the study, abbreviated HMP1-II, comprising 1,631 new metagenomic samples (2,355 total) targeting diverse body sites with multiple time points in 265 individuals. We applied updated profiling and assembly methods to these data to provide new characterizations of microbiome personalization. Strain identification revealed distinct subspecies clades specific to body sites; it also quantified species with phylogenetic diversity under-represented in isolate genomes. Body-wide functional profiling classified pathways into universal, human-enriched, and body site-enriched subsets. Finally, temporal analysis decomposed microbial variation into rapidly variable, moderately variable, and stable subsets. This study furthers our knowledge of baseline human microbial diversity, thus enabling an understanding of personalized microbiome function and dynamics. PMID:28953883

Reconstitution of active human core Mediator complex reveals a pivotal role of the MED14 subunit

PubMed Central

Cevher, Murat A.; Shi, Yi; Li, Dan; Chait, Brian T.; Malik, Sohail; Roeder, Robert G.

2014-01-01

The evolutionarily conserved Mediator complex is a critical coactivator for RNA polymerase II (Pol II)-mediated transcription. Here, we report the reconstitution of a functional 15-subunit human core Mediator complex and its characterization by functional assays and chemical cross-linking coupled to mass spectrometry (CX-MS). Whereas the reconstituted head and middle modules can stably associate, only with incorporation of MED14 into the bi-modular complex does it acquire basal and coactivator functions. This results from a dramatically enhanced ability of MED14-containing complexes to associate with Pol II. Altogether, our analyses identify MED14 as both an architectural and a functional backbone of the Mediator complex. We further establish a conditional requirement for metazoan-specific MED26 that becomes evident in the presence of heterologous nuclear factors. This general approach paves the way for systematically dissecting the multiple layers of functionalities associated with the Mediator complex. PMID:25383669

Rehabilitation-triggered cortical plasticity after stroke: in vivo imaging at multiple scales (Conference Presentation)

NASA Astrophysics Data System (ADS)

Allegra Mascaro, Anna Letizia; Conti, Emilia; Lai, Stefano; Spalletti, Cristina; Di Giovanna, Antonino Paolo; Alia, Claudia; Panarese, Alessandro; Sacconi, Leonardo; Micera, Silvestro; Caleo, Matteo; Pavone, Francesco S.

2017-02-01

Neurorehabilitation protocols based on the use of robotic devices provide a highly repeatable therapy and have recently shown promising clinical results. Little is known about how rehabilitation molds the brain to promote motor recovery of the affected limb. We used a custom-made robotic platform that provides quantitative assessment of forelimb function in a retraction test. Complementary imaging techniques allowed us to access to the multiple facets of robotic rehabilitation-induced cortical plasticity after unilateral photothrombotic stroke in mice Primary Motor Cortex (Caudal Forelimb Area - CFA). First, we analyzed structural features of vasculature and dendritic reshaping in the peri-infarct area with two-photon fluorescence microscopy. Longitudinal analysis of dendritic branches and spines of pyramidal neurons suggests that robotic rehabilitation promotes the stabilization of peri-infarct cortical excitatory circuits, which is not accompanied by consistent vascular reorganization towards pre-stroke conditions. To investigate if this structural stabilization was linked to functional remapping, we performed mesoscale wide-field imaging on GCaMP6 mice while performing the motor task on the robotic platform. We revealed temporal and spatial features of the motor-triggered cortical activation, shining new light on rehabilitation-induced functional remapping of the ipsilesional cortex. Finally, by using an all-optical approach that combines optogenetic activation of the contralesional hemisphere and wide-field functional imaging of peri-infarct area, we dissected the effect of robotic rehabilitation on inter-hemispheric cortico-cortical connectivity.

CLAVATA1 Dominant-Negative Alleles Reveal Functional Overlap between Multiple Receptor Kinases That Regulate Meristem and Organ Development

PubMed Central

Diévart, Anne; Dalal, Monica; Tax, Frans E.; Lacey, Alexzandria D.; Huttly, Alison; Li, Jianming; Clark, Steven E.

2003-01-01

The CLAVATA1 (CLV1) receptor kinase controls stem cell number and differentiation at the Arabidopsis shoot and flower meristems. Other components of the CLV1 signaling pathway include the secreted putative ligand CLV3 and the receptor-like protein CLV2. We report evidence indicating that all intermediate and strong clv1 alleles are dominant negative and likely interfere with the activity of unknown receptor kinase(s) that have functional overlap with CLV1. clv1 dominant-negative alleles show major differences from dominant-negative alleles characterized to date in animal receptor kinase signaling systems, including the lack of a dominant-negative effect of kinase domain truncation and the ability of missense mutations in the extracellular domain to act in a dominant-negative manner. We analyzed chimeric receptor kinases by fusing CLV1 and BRASSINOSTEROID INSENSITIVE1 (BRI1) coding sequences and expressing these in clv1 null backgrounds. Constructs containing the CLV1 extracellular domain and the BRI1 kinase domain were strongly dominant negative in the regulation of meristem development. Furthermore, we show that CLV1 expressed within the pedicel can partially replace the function of the ERECTA receptor kinase. We propose the presence of multiple receptors that regulate meristem development in a functionally related manner whose interactions are driven by the extracellular domains and whose activation requires the kinase domain. PMID:12724544

Protection by dimethyl fumarate against diabetic cardiomyopathy in type 1 diabetic mice likely via activation of nuclear factor erythroid-2 related factor 2.

PubMed

Hu, Xinyue; Rajesh, Mohanraj; Zhang, Jian; Zhou, Shanshan; Wang, Shudong; Sun, Jian; Tan, Yi; Zheng, Yang; Cai, Lu

2018-05-01

Oxidative stress and inflammation play key roles in the development of diabetic cardiomyopathy (DCM). Dimethyl fumarate (DMF), an FDA approved medicine for relapsing multiple sclerosis, has manifested its antioxidant and anti-inflammatory function mostly in the central nervous system. In this study, we investigated whether DMF could attenuate the development of DCM. Type 1 diabetes mouse model was established using multiple low-dose streptozotocin, and the diabetic mice were treated with DMF (10 mg/kg body weight) for 3 months. Cardiac functions were determined using echocardiography. Oxidative stress, pro-inflammatory cytokines and pro-fibrotic markers were determined with commercially available kits, real-time quantitative PCR or western blot techniques. DCM was characterized by diminished cardiac function, accompanied by oxidative stress and enhanced expression of pro-inflammatory cytokines. Diabetic cardiac tissue exhibited marked fibrosis, revealed by extracellular matrix deposition as determined by Sirius red staining of the myocardial tissues. Furthermore, Nrf2 and its downstream effectors were repressed in diabetic myocardium. On the contrary, diabetic animals treated with DMF exhibited blunted oxidative stress, inflammation, fibrosis and this correlated with Nrf2 activation. Our findings suggest that DMF could potentially thwart diabetes-induced myocardial tissue injury, likely via activation of Nrf2 function, providing firm impetus for future repurposing of DMF in the management of DCM. Copyright © 2018 Elsevier B.V. All rights reserved.

Genes Upregulated in Winter Wheat (Triticum aestivum L.) during Mild Freezing and Subsequent Thawing Suggest Sequential Activation of Multiple Response Mechanisms.

PubMed

Skinner, Daniel Z

2015-01-01

Exposing fully cold-acclimated wheat plants to a mild freeze-thaw cycle of -3 °C for 24h followed by +3 °C for 24 or 48 h results in dramatically improved tolerance of subsequent exposure to sub-freezing temperatures. Gene enrichment analysis of crown tissue from plants collected before or after the -3 °C freeze or after thawing at +3 °C for 24 or 48 h revealed that many biological processes and molecular functions were activated during the freeze-thaw cycle in an increasing cascade of responses such that over 150 processes or functions were significantly enhanced by the end of the 48 h, post-freeze thaw. Nearly 2,000 individual genes were upregulated more than 2-fold over the 72 h course of freezing and thawing, but more than 70% of these genes were upregulated during only one of the time periods examined, suggesting a series of genes and gene functions were involved in activation of the processes that led to enhanced freezing tolerance. This series of functions appeared to include extensive cell signaling, activation of stress response mechanisms and the phenylpropanoid biosynthetic pathway, extensive modification of secondary metabolites, and physical restructuring of cell membranes. By identifying plant lines that are especially able to activate these multiple mechanisms it may be possible to develop lines with enhanced winterhardiness.

Functional remission and employment among patients with schizophrenia in Malaysia.

PubMed

Dahlan, Rahima; Midin, Marhani; Shah, Shamsul Azhar; Nik Jaafar, Nik Ruzyanei; Abdul Rahman, Fairuz Nazri; Baharudin, Azlin; Das, Srijit; Sidi, Hatta

2014-01-01

The study aimed to determine the rates of functional remission and employment as well as the factors associated with functional remission among patients with Schizophrenia, receiving community psychiatric service in an urban setting in Malaysia. From a total of 250 patients randomly selected, 155 fulfilled the study requirement and were assessed on their functional remission status using the Personal and Social Performance Scale. The relationships between functional remission and socio-demographic factors, clinical factors, social support, symptom remission and rates of hospitalization were examined. The results revealed that 74% (n=115) of the respondents had functional remission with only 20% (n=31) currently employed. Functional remission was found to be significantly associated with good social support (84.4% versus 36.4% p<0.001, OR=9.487 [95% CI=4.008-22.457]); shorter illness duration of less than 10 years (81.2% versus 66.7% p=0.038, OR=2.167 [95% CI=1.035-4.535]); good medication compliance (79.1% versus 50.0% p=0.002, OR=3.778 [95% CI=1.570-9.090]); hospital admissions of lower than 3 per year (80.5% versus 44.4% p<0.001 OR=5.150 [95% CI=2.145-12.365]) and; symptomatic remission (87.3% versus 37.4% p<0.001 [95% CI=0.070 (0.029-0.168]). A multiple regression analysis revealed only social support, lower hospitalization rate and symptom remission, as significant predictors of functional remission. A majority of patients with Schizophrenia in this study achieved functional remission, however, only a small percentage of them were employed. Functional remission was influenced by severity of illness and levels of social support in these patients. Copyright © 2014 Elsevier Inc. All rights reserved.

Mammalian skin cell biology: at the interface between laboratory and clinic.

PubMed

Watt, Fiona M

2014-11-21

Mammalian skin research represents the convergence of three complementary disciplines: cell biology, mouse genetics, and dermatology. The skin provides a paradigm for current research in cell adhesion, inflammation, and tissue stem cells. Here, I discuss recent insights into the cell biology of skin. Single-cell analysis has revealed that human epidermal stem cells are heterogeneous and differentiate in response to multiple extrinsic signals. Live-cell imaging, optogenetics, and cell ablation experiments show skin cells to be remarkably dynamic. High-throughput, genome-wide approaches have yielded unprecedented insights into the circuitry that controls epidermal stem cell fate. Last, integrative biological analysis of human skin disorders has revealed unexpected functions for elements of the skin that were previously considered purely structural. Copyright © 2014, American Association for the Advancement of Science.

The brain in time: insights from neuromagnetic recordings.

PubMed

Hari, Riitta; Parkkonen, Lauri; Nangini, Cathy

2010-03-01

The millisecond time resolution of magnetoencephalography (MEG) is instrumental for investigating the brain basis of sensory processing, motor planning, cognition, and social interaction. We review the basic principles, recent progress, and future potential of MEG in noninvasive tracking of human brain activity. Cortical activation sequences from tens to hundreds of milliseconds can be followed during, e.g., perception, motor action, imitation, and language processing by recording both spontaneous and evoked brain signals. Moreover, tagging of sensory input can be used to reveal neuronal mechanisms of binaural interaction and perception of ambiguous images. The results support the emerging ideas of multiple, hierarchically organized temporal scales in human brain function. Instrumentation and data analysis methods are rapidly progressing, enabling attempts to decode the four-dimensional spatiotemporal signal patterns to reveal correlates of behavior and mental contents.

Sequencing of Pax6 Loci from the Elephant Shark Reveals a Family of Pax6 Genes in Vertebrate Genomes, Forged by Ancient Duplications and Divergences

PubMed Central

Gautier, Philippe; Loosli, Felix; Tay, Boon-Hui; Tay, Alice; Murdoch, Emma; Coutinho, Pedro; van Heyningen, Veronica; Brenner, Sydney; Venkatesh, Byrappa; Kleinjan, Dirk A.

2013-01-01

Pax6 is a developmental control gene essential for eye development throughout the animal kingdom. In addition, Pax6 plays key roles in other parts of the CNS, olfactory system, and pancreas. In mammals a single Pax6 gene encoding multiple isoforms delivers these pleiotropic functions. Here we provide evidence that the genomes of many other vertebrate species contain multiple Pax6 loci. We sequenced Pax6-containing BACs from the cartilaginous elephant shark (Callorhinchus milii) and found two distinct Pax6 loci. Pax6.1 is highly similar to mammalian Pax6, while Pax6.2 encodes a paired-less Pax6. Using synteny relationships, we identify homologs of this novel paired-less Pax6.2 gene in lizard and in frog, as well as in zebrafish and in other teleosts. In zebrafish two full-length Pax6 duplicates were known previously, originating from the fish-specific genome duplication (FSGD) and expressed in divergent patterns due to paralog-specific loss of cis-elements. We show that teleosts other than zebrafish also maintain duplicate full-length Pax6 loci, but differences in gene and regulatory domain structure suggest that these Pax6 paralogs originate from a more ancient duplication event and are hence renamed as Pax6.3. Sequence comparisons between mammalian and elephant shark Pax6.1 loci highlight the presence of short- and long-range conserved noncoding elements (CNEs). Functional analysis demonstrates the ancient role of long-range enhancers for Pax6 transcription. We show that the paired-less Pax6.2 ortholog in zebrafish is expressed specifically in the developing retina. Transgenic analysis of elephant shark and zebrafish Pax6.2 CNEs with homology to the mouse NRE/Pα internal promoter revealed highly specific retinal expression. Finally, morpholino depletion of zebrafish Pax6.2 resulted in a “small eye” phenotype, supporting a role in retinal development. In summary, our study reveals that the pleiotropic functions of Pax6 in vertebrates are served by a divergent family of Pax6 genes, forged by ancient duplication events and by independent, lineage-specific gene losses. PMID:23359656

Microarray RNA expression analysis of cerebral white matter lesions reveals changes in multiple functional pathways.

PubMed

Simpson, Julie E; Hosny, Ola; Wharton, Stephen B; Heath, Paul R; Holden, Hazel; Fernando, Malee S; Matthews, Fiona; Forster, Gill; O'Brien, John T; Barber, Robert; Kalaria, Raj N; Brayne, Carol; Shaw, Pamela J; Lewis, Claire E; Ince, Paul G

2009-02-01

White matter lesions (WML) in brain aging are linked to dementia and depression. Ischemia contributes to their pathogenesis but other mechanisms may contribute. We used RNA microarray analysis with functional pathway grouping as an unbiased approach to investigate evidence for additional pathogenetic mechanisms. WML were identified by MRI and pathology in brains donated to the Medical Research Council Cognitive Function and Ageing Study Cognitive Function and Aging Study. RNA was extracted to compare WML with nonlesional white matter samples from cases with lesions (WM[L]), and from cases with no lesions (WM[C]) using RNA microarray and pathway analysis. Functional pathways were validated for selected genes by quantitative real-time polymerase chain reaction and immunocytochemistry. We identified 8 major pathways in which multiple genes showed altered RNA transcription (immune regulation, cell cycle, apoptosis, proteolysis, ion transport, cell structure, electron transport, metabolism) among 502 genes that were differentially expressed in WML compared to WM[C]. In WM[L], 409 genes were altered involving the same pathways. Genes selected to validate this microarray data all showed the expected changes in RNA levels and immunohistochemical expression of protein. WML represent areas with a complex molecular phenotype. From this and previous evidence, WML may arise through tissue ischemia but may also reflect the contribution of additional factors like blood-brain barrier dysfunction. Differential expression of genes in WM[L] compared to WM[C] indicate a "field effect" in the seemingly normal surrounding white matter.

Functional Brain Networks Develop from a “Local to Distributed” Organization

PubMed Central

Power, Jonathan D.; Dosenbach, Nico U. F.; Church, Jessica A.; Miezin, Francis M.; Schlaggar, Bradley L.; Petersen, Steven E.

2009-01-01

The mature human brain is organized into a collection of specialized functional networks that flexibly interact to support various cognitive functions. Studies of development often attempt to identify the organizing principles that guide the maturation of these functional networks. In this report, we combine resting state functional connectivity MRI (rs-fcMRI), graph analysis, community detection, and spring-embedding visualization techniques to analyze four separate networks defined in earlier studies. As we have previously reported, we find, across development, a trend toward ‘segregation’ (a general decrease in correlation strength) between regions close in anatomical space and ‘integration’ (an increased correlation strength) between selected regions distant in space. The generalization of these earlier trends across multiple networks suggests that this is a general developmental principle for changes in functional connectivity that would extend to large-scale graph theoretic analyses of large-scale brain networks. Communities in children are predominantly arranged by anatomical proximity, while communities in adults predominantly reflect functional relationships, as defined from adult fMRI studies. In sum, over development, the organization of multiple functional networks shifts from a local anatomical emphasis in children to a more “distributed” architecture in young adults. We argue that this “local to distributed” developmental characterization has important implications for understanding the development of neural systems underlying cognition. Further, graph metrics (e.g., clustering coefficients and average path lengths) are similar in child and adult graphs, with both showing “small-world”-like properties, while community detection by modularity optimization reveals stable communities within the graphs that are clearly different between young children and young adults. These observations suggest that early school age children and adults both have relatively efficient systems that may solve similar information processing problems in divergent ways. PMID:19412534

Functional brain networks develop from a "local to distributed" organization.

PubMed

Fair, Damien A; Cohen, Alexander L; Power, Jonathan D; Dosenbach, Nico U F; Church, Jessica A; Miezin, Francis M; Schlaggar, Bradley L; Petersen, Steven E

2009-05-01

The mature human brain is organized into a collection of specialized functional networks that flexibly interact to support various cognitive functions. Studies of development often attempt to identify the organizing principles that guide the maturation of these functional networks. In this report, we combine resting state functional connectivity MRI (rs-fcMRI), graph analysis, community detection, and spring-embedding visualization techniques to analyze four separate networks defined in earlier studies. As we have previously reported, we find, across development, a trend toward 'segregation' (a general decrease in correlation strength) between regions close in anatomical space and 'integration' (an increased correlation strength) between selected regions distant in space. The generalization of these earlier trends across multiple networks suggests that this is a general developmental principle for changes in functional connectivity that would extend to large-scale graph theoretic analyses of large-scale brain networks. Communities in children are predominantly arranged by anatomical proximity, while communities in adults predominantly reflect functional relationships, as defined from adult fMRI studies. In sum, over development, the organization of multiple functional networks shifts from a local anatomical emphasis in children to a more "distributed" architecture in young adults. We argue that this "local to distributed" developmental characterization has important implications for understanding the development of neural systems underlying cognition. Further, graph metrics (e.g., clustering coefficients and average path lengths) are similar in child and adult graphs, with both showing "small-world"-like properties, while community detection by modularity optimization reveals stable communities within the graphs that are clearly different between young children and young adults. These observations suggest that early school age children and adults both have relatively efficient systems that may solve similar information processing problems in divergent ways.

Minimum Action Path Theory Reveals the Details of Stochastic Transitions Out of Oscillatory States

NASA Astrophysics Data System (ADS)

de la Cruz, Roberto; Perez-Carrasco, Ruben; Guerrero, Pilar; Alarcon, Tomas; Page, Karen M.

2018-03-01

Cell state determination is the outcome of intrinsically stochastic biochemical reactions. Transitions between such states are studied as noise-driven escape problems in the chemical species space. Escape can occur via multiple possible multidimensional paths, with probabilities depending nonlocally on the noise. Here we characterize the escape from an oscillatory biochemical state by minimizing the Freidlin-Wentzell action, deriving from it the stochastic spiral exit path from the limit cycle. We also use the minimized action to infer the escape time probability density function.

DISC1 genetics, biology and psychiatric illness

PubMed Central

THOMSON, Pippa A.; MALAVASI, Elise L.V.; GRÜNEWALD, Ellen; SOARES, Dinesh C.; BORKOWSKA, Malgorzata; MILLAR, J. Kirsty

2012-01-01

Psychiatric disorders are highly heritable, and in many individuals likely arise from the combined effects of genes and the environment. A substantial body of evidence points towards DISC1 being one of the genes that influence risk of schizophrenia, bipolar disorder and depression, and functional studies of DISC1 consequently have the potential to reveal much about the pathways that lead to major mental illness. Here, we review the evidence that DISC1 influences disease risk through effects upon multiple critical pathways in the developing and adult brain. PMID:23550053

Like a slippery fish, a little slime is a good thing: the glycocalyx revealed.

PubMed

Biddle, Chuck

2013-12-01

The glycocalyx is a dynamic network of multiple membrane-bound complexes lining the vascular endothelium. Its role in maintaining vascular homeostasis includes regulating vascular permeability as well as a range of vital functions, such as mechanotransduction, hemostasis, modulation of inflammatory processes, and serving as an antiatherogenic. Revisionist thinking about the Starling principle is discussed in terms of the major influence of the glycocalyx on capillary and tissue fluid homeostasis. The clinical and pathophysiologic threats to the glycocalyx are reviewed as well as strategies to maintain its integrity.

Minimum Action Path Theory Reveals the Details of Stochastic Transitions Out of Oscillatory States.

PubMed

de la Cruz, Roberto; Perez-Carrasco, Ruben; Guerrero, Pilar; Alarcon, Tomas; Page, Karen M

2018-03-23

Cell state determination is the outcome of intrinsically stochastic biochemical reactions. Transitions between such states are studied as noise-driven escape problems in the chemical species space. Escape can occur via multiple possible multidimensional paths, with probabilities depending nonlocally on the noise. Here we characterize the escape from an oscillatory biochemical state by minimizing the Freidlin-Wentzell action, deriving from it the stochastic spiral exit path from the limit cycle. We also use the minimized action to infer the escape time probability density function.

Protein function prediction--the power of multiplicity.

PubMed

Rentzsch, Robert; Orengo, Christine A

2009-04-01

Advances in experimental and computational methods have quietly ushered in a new era in protein function annotation. This 'age of multiplicity' is marked by the notion that only the use of multiple tools, multiple evidence and considering the multiple aspects of function can give us the broad picture that 21st century biology will need to link and alter micro- and macroscopic phenotypes. It might also help us to undo past mistakes by removing errors from our databases and prevent us from producing more. On the downside, multiplicity is often confusing. We therefore systematically review methods and resources for automated protein function prediction, looking at individual (biochemical) and contextual (network) functions, respectively.

A full-potential approach to the relativistic single-site Green's function

DOE PAGES

Liu, Xianglin; Wang, Yang; Eisenbach, Markus; ...

2016-07-07

One major purpose of studying the single-site scattering problem is to obtain the scattering matrices and differential equation solutions indispensable to multiple scattering theory (MST) calculations. On the other hand, the single-site scattering itself is also appealing because it reveals the physical environment experienced by electrons around the scattering center. In this study, we demonstrate a new formalism to calculate the relativistic full-potential single-site Green's function. We implement this method to calculate the single-site density of states and electron charge densities. Lastly, the code is rigorously tested and with the help of Krein's theorem, the relativistic effects and full potentialmore » effects in group V elements and noble metals are thoroughly investigated.« less

Food-derived immunomodulatory peptides.

PubMed

Santiago-López, Lourdes; Hernández-Mendoza, Adrián; Vallejo-Cordoba, Belinda; Mata-Haro, Verónica; González-Córdova, Aarón F

2016-08-01

Food proteins contain specific amino acid sequences within their structures that may positively impact bodily functions and have multiple immunomodulatory effects. The functional properties of these specific sequences, also referred to as bioactive peptides, are revealed only after the degradation of native proteins during digestion processes. Currently, milk proteins have been the most explored source of bioactive peptides, which presents an interesting opportunity for the dairy industry. However, plant- and animal-derived proteins have also been shown to be important sources of bioactive peptides. This review summarizes the in vitro and in vivo evidence of the role of various food proteins as sources of immunomodulatory peptides and discusses the possible pathways involving these properties. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

Perceived Neighborhood Safety and Adolescent School Functioning

PubMed Central

Martin-Storey, Alexa; Crosnoe, Robert

2014-01-01

This study examined the association between adolescents’ perceptions of their neighborhoods’ safety and multiple elements of their functioning in school with data on 15 year olds from the NICHD Study of Early Child Care and Youth Development (n = 924). In general, perceived neighborhood safety was more strongly associated with aspects of schooling that were more psychosocial in nature (e.g., school attachment) than those that were more cognitive (e.g., test scores). Examination of neighborhood and family moderators of these associations revealed that perceived neighborhood safety was negatively associated with grades for youth from low-income families but was positively associated with school attachment for youth from such families when they lived in neighborhoods rated by observers as high in physical disorder. PMID:25045245

Resolving TYK2 locus genotype-to-phenotype differences in autoimmunity

PubMed Central

Dendrou, Calliope A.; Cortes, Adrian; Shipman, Lydia; Evans, Hayley G.; Attfield, Kathrine E.; Jostins, Luke; Barber, Thomas; Kaur, Gurman; Kuttikkatte, Subita Balaram; Leach, Oliver A.; Desel, Christiane; Faergeman, Soren L.; Cheeseman, Jane; Neville, Matt J.; Sawcer, Stephen; Compston, Alastair; Johnson, Adam R.; Everett, Christine; Bell, John I.; Karpe, Fredrik; Ultsch, Mark; Eigenbrot, Charles; McVean, Gil; Fugger, Lars

2017-01-01

Thousands of genetic variants have been identified that contribute to the development of complex diseases, but determining how to fully elucidate their biological consequences for translation into clinical benefit is challenging. Conflicting evidence regarding the functional impact of genetic variants in the tyrosine kinase 2 (TYK2) gene, which is differentially associated with common autoimmune diseases, currently obscures the potential of TYK2 as a therapeutic target. We aimed to resolve this conflict by performing genetic meta-analysis across disorders, subsequent molecular, cellular, in vivo and structural functional follow-up and epidemiological studies. Our data revealed a protective homozygous effect that defined a signaling optimum between autoimmunity and immunodeficiency and identified TYK2 as a potential drug target for multiple autoimmune disorders. PMID:27807284

Exploring the impact of mentoring functions on job satisfaction and organizational commitment of new staff nurses

PubMed Central

2010-01-01

Background Although previous studies proved that the implementation of mentoring program is beneficial for enhancing the nursing skills and attitudes, few researchers devoted to exploring the impact of mentoring functions on job satisfaction and organizational commitment of new nurses. In this research we aimed at examining the effects of mentoring functions on the job satisfaction and organizational commitment of new nurses in Taiwan's hospitals. Methods We employed self-administered questionnaires to collect research data and select new nurses from three regional hospitals as samples in Taiwan. In all, 306 nurse samples were obtained. We adopted a multiple regression analysis to test the impact of the mentoring functions. Results Results revealed that career development and role modeling functions have positive effects on the job satisfaction and organizational commitment of new nurses; however, the psychosocial support function was incapable of providing adequate explanation for these work outcomes. Conclusion It is suggested in this study that nurse managers should improve the career development and role modeling functions of mentoring in order to enhance the job satisfaction and organizational commitment of new nurses. PMID:20712873

Bayesian model reveals latent atrophy factors with dissociable cognitive trajectories in Alzheimer's disease.

PubMed

Zhang, Xiuming; Mormino, Elizabeth C; Sun, Nanbo; Sperling, Reisa A; Sabuncu, Mert R; Yeo, B T Thomas

2016-10-18

We used a data-driven Bayesian model to automatically identify distinct latent factors of overlapping atrophy patterns from voxelwise structural MRIs of late-onset Alzheimer's disease (AD) dementia patients. Our approach estimated the extent to which multiple distinct atrophy patterns were expressed within each participant rather than assuming that each participant expressed a single atrophy factor. The model revealed a temporal atrophy factor (medial temporal cortex, hippocampus, and amygdala), a subcortical atrophy factor (striatum, thalamus, and cerebellum), and a cortical atrophy factor (frontal, parietal, lateral temporal, and lateral occipital cortices). To explore the influence of each factor in early AD, atrophy factor compositions were inferred in beta-amyloid-positive (Aβ+) mild cognitively impaired (MCI) and cognitively normal (CN) participants. All three factors were associated with memory decline across the entire clinical spectrum, whereas the cortical factor was associated with executive function decline in Aβ+ MCI participants and AD dementia patients. Direct comparison between factors revealed that the temporal factor showed the strongest association with memory, whereas the cortical factor showed the strongest association with executive function. The subcortical factor was associated with the slowest decline for both memory and executive function compared with temporal and cortical factors. These results suggest that distinct patterns of atrophy influence decline across different cognitive domains. Quantification of this heterogeneity may enable the computation of individual-level predictions relevant for disease monitoring and customized therapies. Factor compositions of participants and code used in this article are publicly available for future research.

Two-photon excited autofluorescence imaging of freshly isolated frog retinas.

PubMed

Lu, Rong-Wen; Li, Yi-Chao; Ye, Tong; Strang, Christianne; Keyser, Kent; Curcio, Christine A; Yao, Xin-Cheng

2011-06-01

The purpose of this study was to investigate cellular sources of autofluorescence signals in freshly isolated frog (Rana pipiens) retinas. Equipped with an ultrafast laser, a laser scanning two-photon excitation fluorescence microscope was employed for sub-cellular resolution examination of both sliced and flat-mounted retinas. Two-photon imaging of retinal slices revealed autofluorescence signals over multiple functional layers, including the photoreceptor layer (PRL), outer nuclear layer (ONL), outer plexiform layer (OPL), inner nuclear layer (INL), inner plexiform layer (IPL), and ganglion cell layer (GCL). Using flat-mounted retinas, depth-resolved imaging of individual retinal layers further confirmed multiple sources of autofluorescence signals. Cellular structures were clearly observed at the PRL, ONL, INL, and GCL. At the PRL, the autofluorescence was dominantly recorded from the intracellular compartment of the photoreceptors; while mixed intracellular and extracellular autofluorescence signals were observed at the ONL, INL, and GCL. High resolution autofluorescence imaging clearly revealed mosaic organization of rod and cone photoreceptors; and sub-cellular bright autofluorescence spots, which might relate to connecting cilium, was observed in the cone photoreceptors only. Moreover, single-cone and double-cone outer segments could be directly differentiated.

Dissecting Impulsivity and its Relationships to Drug Addictions

PubMed Central

Ashenhurst, James R.; Cervantes, M. Catalina; James, Alexander S.; Groman, Stephanie M.; Pennington, Zachary T.

2015-01-01

Addictions are often characterized as forms of impulsive behavior. That said, it is often noted that impulsivity is a multidimensional construct, spanning several psychological domains. This review describes the relationship between varieties of impulsivity and addiction-related behaviors, the nature of the causal relationship between the two and the underlying neurobiological mechanisms that promote impulsive behaviors. We conclude that the available data strongly supports the notion that impulsivity is both a risk factor for, and a consequence of, drug and alcohol consumption. While the evidence indicating that subtypes of impulsive behavior are uniquely informative – either biologically or with respect to their relationships to addictions – is convincing, multiple lines of study link “distinct” subtypes of impulsivity to low dopamine D2 receptor function and perturbed serotonergic transmission, revealing shared mechanisms between the subtypes. Therefore, a common biological framework involving monoaminergic transmitters in key frontostriatal circuits may link multiple forms of impulsivity to drug self-administration and addiction-related behaviors. Further dissection of these relationships is needed before the next phase of genetic and genomic discovery will be able to reveal the biological sources of the vulnerability for addiction indexed by impulsivity. PMID:24654857

The m6A pathway facilitates sex determination in Drosophila

PubMed Central

Kan, Lijuan; Grozhik, Anya V.; Vedanayagam, Jeffrey; Patil, Deepak P.; Pang, Nan; Lim, Kok-Seong; Huang, Yi-Chun; Joseph, Brian; Lin, Ching-Jung; Despic, Vladimir; Guo, Jian; Yan, Dong; Kondo, Shu; Deng, Wu-Min; Dedon, Peter C.; Jaffrey, Samie R.; Lai, Eric C.

2017-01-01

The conserved modification N6-methyladenosine (m6A) modulates mRNA processing and activity. Here, we establish the Drosophila system to study the m6A pathway. We first apply miCLIP to map m6A across embryogenesis, characterize its m6A ‘writer’ complex, validate its YTH ‘readers’ CG6422 and YT521-B, and generate mutants in five m6A factors. While m6A factors with additional roles in splicing are lethal, m6A-specific mutants are viable but present certain developmental and behavioural defects. Notably, m6A facilitates the master female determinant Sxl, since multiple m6A components enhance female lethality in Sxl sensitized backgrounds. The m6A pathway regulates Sxl processing directly, since miCLIP data reveal Sxl as a major intronic m6A target, and female-specific Sxl splicing is compromised in multiple m6A pathway mutants. YT521-B is a dominant m6A effector for Sxl regulation, and YT521-B overexpression can induce female-specific Sxl splicing. Overall, our transcriptomic and genetic toolkit reveals in vivo biologic function for the Drosophila m6A pathway. PMID:28675155

Predicting early adolescent gang involvement from middle school adaptation.

PubMed

Dishion, Thomas J; Nelson, Sarah E; Yasui, Miwa

2005-03-01

This study examined the role of adaptation in the first year of middle school (Grade 6, age 11) to affiliation with gangs by the last year of middle school (Grade 8, age 13). The sample consisted of 714 European American (EA) and African American (AA) boys and girls. Specifically, academic grades, reports of antisocial behavior, and peer relations in 6th grade were used to predict multiple measures of gang involvement by 8th grade. The multiple measures of gang involvement included self-, peer, teacher, and counselor reports. Unexpectedly, self-report measures of gang involvement did not correlate highly with peer and school staff reports. The results, however, were similar for other and self-report measures of gang involvement. Mean level analyses revealed statistically reliable differences in 8th-grade gang involvement as a function of the youth gender and ethnicity. Structural equation prediction models revealed that peer nominations of rejection, acceptance, academic failure, and antisocial behavior were predictive of gang involvement for most youth. These findings suggest that the youth level of problem behavior and the school ecology (e.g., peer rejection, school failure) require attention in the design of interventions to prevent the formation of gangs among high-risk young adolescents.

A Hidden Markov Model for Single Particle Tracks Quantifies Dynamic Interactions between LFA-1 and the Actin Cytoskeleton

PubMed Central

Das, Raibatak; Cairo, Christopher W.; Coombs, Daniel

2009-01-01

The extraction of hidden information from complex trajectories is a continuing problem in single-particle and single-molecule experiments. Particle trajectories are the result of multiple phenomena, and new methods for revealing changes in molecular processes are needed. We have developed a practical technique that is capable of identifying multiple states of diffusion within experimental trajectories. We model single particle tracks for a membrane-associated protein interacting with a homogeneously distributed binding partner and show that, with certain simplifying assumptions, particle trajectories can be regarded as the outcome of a two-state hidden Markov model. Using simulated trajectories, we demonstrate that this model can be used to identify the key biophysical parameters for such a system, namely the diffusion coefficients of the underlying states, and the rates of transition between them. We use a stochastic optimization scheme to compute maximum likelihood estimates of these parameters. We have applied this analysis to single-particle trajectories of the integrin receptor lymphocyte function-associated antigen-1 (LFA-1) on live T cells. Our analysis reveals that the diffusion of LFA-1 is indeed approximately two-state, and is characterized by large changes in cytoskeletal interactions upon cellular activation. PMID:19893741

Linear and nonlinear stiffness and friction in biological rhythmic movements.

PubMed

Beek, P J; Schmidt, R C; Morris, A W; Sim, M Y; Turvey, M T

1995-11-01

Biological rhythmic movements can be viewed as instances of self-sustained oscillators. Auto-oscillatory phenomena must involve a nonlinear friction function, and usually involve a nonlinear elastic function. With respect to rhythmic movements, the question is: What kinds of nonlinear friction and elastic functions are involved? The nonlinear friction functions of the kind identified by Rayleigh (involving terms such as theta3) and van der Pol (involving terms such as theta2theta), and the nonlinear elastic functions identified by Duffing (involving terms such as theta3), constitute elementary nonlinear components for the assembling of self-sustained oscillators, Recently, additional elementary nonlinear friction and stiffness functions expressed, respectively, through terms such as theta2theta3 and thetatheta2, and a methodology for evaluating the contribution of the elementary components to any given cyclic activity have been identified. The methodology uses a quantification of the continuous deviation of oscillatory motion from ideal (harmonic) motion. Multiple regression of this quantity on the elementary linear and nonlinear terms reveals the individual contribution of each term to the oscillator's non-harmonic behavior. In the present article the methodology was applied to the data from three experiments in which human subjects produced pendular rhythmic movements under manipulations of rotational inertia (experiment 1), rotational inertia and frequency (experiment 2), and rotational inertia and amplitude (experiment 3). The analysis revealed that the pendular oscillators assembled in the three experiments were compositionally rich, braiding linear and nonlinear friction and elastic functions in a manner that depended on the nature of the task.

Uncovering Local Trends in Genetic Effects of Multiple Phenotypes via Functional Linear Models.

PubMed

Vsevolozhskaya, Olga A; Zaykin, Dmitri V; Barondess, David A; Tong, Xiaoren; Jadhav, Sneha; Lu, Qing

2016-04-01

Recent technological advances equipped researchers with capabilities that go beyond traditional genotyping of loci known to be polymorphic in a general population. Genetic sequences of study participants can now be assessed directly. This capability removed technology-driven bias toward scoring predominantly common polymorphisms and let researchers reveal a wealth of rare and sample-specific variants. Although the relative contributions of rare and common polymorphisms to trait variation are being debated, researchers are faced with the need for new statistical tools for simultaneous evaluation of all variants within a region. Several research groups demonstrated flexibility and good statistical power of the functional linear model approach. In this work we extend previous developments to allow inclusion of multiple traits and adjustment for additional covariates. Our functional approach is unique in that it provides a nuanced depiction of effects and interactions for the variables in the model by representing them as curves varying over a genetic region. We demonstrate flexibility and competitive power of our approach by contrasting its performance with commonly used statistical tools and illustrate its potential for discovery and characterization of genetic architecture of complex traits using sequencing data from the Dallas Heart Study. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Reduced cognitive function, increased blood-brain-barrier transport and inflammatory responses, and altered brain metabolites in LDLr -/-and C57BL/6 mice fed a western diet

PubMed Central

Lee, Linda L.; Puchowicz, Michelle; Golub, Mari S.; Befroy, Douglas E.; Wilson, Dennis W.; Anderson, Steven; Cline, Gary; Bini, Jason; Borkowski, Kamil; Knotts, Trina A.; Rutledge, John C.

2018-01-01

Recent work suggests that diet affects brain metabolism thereby impacting cognitive function. Our objective was to determine if a western diet altered brain metabolism, increased blood-brain barrier (BBB) transport and inflammation, and induced cognitive impairment in C57BL/6 (WT) mice and low-density lipoprotein receptor null (LDLr -/-) mice, a model of hyperlipidemia and cognitive decline. We show that a western diet and LDLr -/- moderately influence cognitive processes as assessed by Y-maze and radial arm water maze. Also, western diet significantly increased BBB transport, as well as microvessel factor VIII in LDLr -/- and microglia IBA1 staining in WT, both indicators of activation and neuroinflammation. Interestingly, LDLr -/- mice had a significant increase in 18F- fluorodeoxyglucose uptake irrespective of diet and brain 1H-magnetic resonance spectroscopy showed increased lactate and lipid moieties. Metabolic assessments of whole mouse brain by GC/MS and LC/MS/MS showed that a western diet altered brain TCA cycle and β-oxidation intermediates, levels of amino acids, and complex lipid levels and elevated proinflammatory lipid mediators. Our study reveals that the western diet has multiple impacts on brain metabolism, physiology, and altered cognitive function that likely manifest via multiple cellular pathways. PMID:29444171

Divergent Expression Patterns and Function Implications of Four nanos Genes in a Hermaphroditic Fish, Epinephelus coioides

PubMed Central

Sun, Zhi-Hui; Wang, Yang; Lu, Wei-Jia; Li, Zhi; Liu, Xiao-Chun; Li, Shui-Sheng; Zhou, Li; Gui, Jian-Fang

2017-01-01

Multiple nanos genes have been characterized in several fishes, but the functional implications of their various expression patterns remain unclear. In this study, we identified and characterized four nanos genes from a hermaphroditic fish orange-spotted grouper, Epinephelus coioides. Ecnanos1a and Ecnanos1b show divergent expression patterns, and the dynamic expression change of Ecnanos1a in pituitaries during sex change is associated with testis differentiation and spermatogenesis. Ecnanos2 and Ecnanos3 might be germline stem cells (GSCs) and primordial germ cells (PGCs)-specific markers, respectively. Significantly, Ecnanos3 3′-untranslated region (UTR) is necessary for PGC specific expression, where a non-canonical “GCACGTTT” sequence is required for miR-430-mediated repression of Ecnanos3 RNA. Furthermore, grouper Dead end (Dnd) can relieve miR-430 repression in PGCs by associating with a 23 bp U-rich region (URR) in Ecnanos3 3′-UTR. The current study revealed the functional association of multiple nanos genes with PGC formation and germ cell development in orange-spotted grouper, and opened up new possibilities for developing biotechnologies through utilizing the associations between Ecnanos3 and PGCs or between Ecnanos2 and GSCs in the hermaphroditic fish. PMID:28333083

Schwann cell-specific JAM-C-deficient mice reveal novel expression and functions for JAM-C in peripheral nerves.

PubMed

Colom, Bartomeu; Poitelon, Yannick; Huang, Wenlong; Woodfin, Abigail; Averill, Sharon; Del Carro, Ubaldo; Zambroni, Desirée; Brain, Susan D; Perretti, Mauro; Ahluwalia, Amrita; Priestley, John V; Chavakis, Triantafyllos; Imhof, Beat A; Feltri, M Laura; Nourshargh, Sussan

2012-03-01

Junctional adhesion molecule-C (JAM-C) is an adhesion molecule expressed at junctions between adjacent endothelial and epithelial cells and implicated in multiple inflammatory and vascular responses. In addition, we recently reported on the expression of JAM-C in Schwann cells (SCs) and its importance for the integrity and function of peripheral nerves. To investigate the role of JAM-C in neuronal functions further, mice with a specific deletion of JAM-C in SCs (JAM-C SC KO) were generated. Compared to wild-type (WT) controls, JAM-C SC KO mice showed electrophysiological defects, muscular weakness, and hypersensitivity to mechanical stimuli. In addressing the underlying cause of these defects, nerves from JAM-C SC KO mice were found to have morphological defects in the paranodal region, exhibiting increased nodal length as compared to WTs. The study also reports on previously undetected expressions of JAM-C, namely on perineural cells, and in line with nociception defects of the JAM-C SC KO animals, on finely myelinated sensory nerve fibers. Collectively, the generation and characterization of JAM-C SC KO mice has provided unequivocal evidence for the involvement of SC JAM-C in the fine organization of peripheral nerves and in modulating multiple neuronal responses.

Efficacy of a Computer-Assisted Cognitive Rehabilitation Intervention in Relapsing-Remitting Multiple Sclerosis Patients: A Multicenter Randomized Controlled Trial

PubMed Central

Kosmidis, Mary H.; Zampakis, Petros; Malefaki, Sonia; Ntoskou, Katerina; Nousia, Anastasia; Bakirtzis, Christos; Papathanasopoulos, Panagiotis

2017-01-01

Cognitive impairment is frequently encountered in multiple sclerosis (MS) affecting between 40–65% of individuals, irrespective of disease duration and severity of physical disability. In the present multicenter randomized controlled trial, fifty-eight clinically stable RRMS patients with mild to moderate cognitive impairment and relatively low disability status were randomized to receive either computer-assisted (RehaCom) functional cognitive training with an emphasis on episodic memory, information processing speed/attention, and executive functions for 10 weeks (IG; n = 32) or standard clinical care (CG; n = 26). Outcome measures included a flexible comprehensive neuropsychological battery of tests sensitive to MS patient deficits and feedback regarding personal benefit gained from the intervention on four verbal questions. Only the IG group showed significant improvements in verbal and visuospatial episodic memory, processing speed/attention, and executive functioning from pre - to postassessment. Moreover, the improvement obtained on attention was retained over 6 months providing evidence on the long-term benefits of this intervention. Group by time interactions revealed significant improvements in composite cognitive domain scores in the IG relative to the demographically and clinically matched CG for verbal episodic memory, processing speed, verbal fluency, and attention. Treated patients rated the intervention positively and were more confident about their cognitive abilities following treatment. PMID:29463950

Spatial organization of transcription machinery and its segregation from the replisome in fast-growing bacterial cells

PubMed Central

Cagliero, Cedric; Zhou, Yan Ning; Jin, Ding Jun

2014-01-01

In a fast-growing Escherichia coli cell, most RNA polymerase (RNAP) is allocated to rRNA synthesis forming transcription foci at clusters of rrn operons or bacterial nucleolus, and each of the several nascent nucleoids contains multiple pairs of replication forks. The composition of transcription foci has not been determined. In addition, how the transcription machinery is three-dimensionally organized to promote cell growth in concord with replication machinery in the nucleoid remains essentially unknown. Here, we determine the spatial and functional landscapes of transcription and replication machineries in fast-growing E. coli cells using super-resolution-structured illumination microscopy. Co-images of RNAP and DNA reveal spatial compartmentation and duplication of the transcription foci at the surface of the bacterial chromosome, encompassing multiple nascent nucleoids. Transcription foci cluster with NusA and NusB, which are the rrn anti-termination system and are associated with nascent rRNAs. However, transcription foci tend to separate from SeqA and SSB foci, which track DNA replication forks and/or the replisomes, demonstrating that transcription machinery and replisome are mostly located in different chromosomal territories to maintain harmony between the two major cellular functions in fast-growing cells. Our study suggests that bacterial chromosomes are spatially and functionally organized, analogous to eukaryotes. PMID:25416798

Disturbed Glucose Metabolism in Rat Neurons Exposed to Cerebrospinal Fluid Obtained from Multiple Sclerosis Subjects

PubMed Central

Mathur, Deepali; María-Lafuente, Eva; Ureña-Peralta, Juan R.; Sorribes, Lucas; Hernández, Alberto; Casanova, Bonaventura; López-Rodas, Gerardo; Coret-Ferrer, Francisco; Burgal-Marti, Maria

2017-01-01

Axonal damage is widely accepted as a major cause of permanent functional disability in Multiple Sclerosis (MS). In relapsing-remitting MS, there is a possibility of remyelination by myelin producing cells and restoration of neurological function. The purpose of this study was to delineate the pathophysiological mechanisms underpinning axonal injury through hitherto unknown factors present in cerebrospinal fluid (CSF) that may regulate axonal damage, remyelinate the axon and make functional recovery possible. We employed primary cultures of rat unmyelinated cerebellar granule neurons and treated them with CSF obtained from MS and Neuromyelitis optica (NMO) patients. We performed microarray gene expression profiling to study changes in gene expression in treated neurons as compared to controls. Additionally, we determined the influence of gene-gene interaction upon the whole metabolic network in our experimental conditions using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) program. Our findings revealed the downregulated expression of genes involved in glucose metabolism in MS-derived CSF-treated neurons and upregulated expression of genes in NMO-derived CSF-treated neurons. We conclude that factors in the CSF of these patients caused a perturbation in metabolic gene(s) expression and suggest that MS appears to be linked with metabolic deformity. PMID:29267205

Genetic Particle Swarm Optimization-Based Feature Selection for Very-High-Resolution Remotely Sensed Imagery Object Change Detection.

PubMed

Chen, Qiang; Chen, Yunhao; Jiang, Weiguo

2016-07-30

In the field of multiple features Object-Based Change Detection (OBCD) for very-high-resolution remotely sensed images, image objects have abundant features and feature selection affects the precision and efficiency of OBCD. Through object-based image analysis, this paper proposes a Genetic Particle Swarm Optimization (GPSO)-based feature selection algorithm to solve the optimization problem of feature selection in multiple features OBCD. We select the Ratio of Mean to Variance (RMV) as the fitness function of GPSO, and apply the proposed algorithm to the object-based hybrid multivariate alternative detection model. Two experiment cases on Worldview-2/3 images confirm that GPSO can significantly improve the speed of convergence, and effectively avoid the problem of premature convergence, relative to other feature selection algorithms. According to the accuracy evaluation of OBCD, GPSO is superior at overall accuracy (84.17% and 83.59%) and Kappa coefficient (0.6771 and 0.6314) than other algorithms. Moreover, the sensitivity analysis results show that the proposed algorithm is not easily influenced by the initial parameters, but the number of features to be selected and the size of the particle swarm would affect the algorithm. The comparison experiment results reveal that RMV is more suitable than other functions as the fitness function of GPSO-based feature selection algorithm.

Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans

PubMed Central

Romeo, Stefano; Yin, Wu; Kozlitina, Julia; Pennacchio, Len A.; Boerwinkle, Eric; Hobbs, Helen H.; Cohen, Jonathan C.

2008-01-01

The relative activity of lipoprotein lipase (LPL) in different tissues controls the partitioning of lipoprotein-derived fatty acids between sites of fat storage (adipose tissue) and oxidation (heart and skeletal muscle). Here we used a reverse genetic strategy to test the hypothesis that 4 angiopoietin-like proteins (ANGPTL3, -4, -5, and -6) play key roles in triglyceride (TG) metabolism in humans. We re-sequenced the coding regions of the genes encoding these proteins and identified multiple rare nonsynonymous (NS) sequence variations that were associated with low plasma TG levels but not with other metabolic phenotypes. Functional studies revealed that all mutant alleles of ANGPTL3 and ANGPTL4 that were associated with low plasma TG levels interfered either with the synthesis or secretion of the protein or with the ability of the ANGPTL protein to inhibit LPL. A total of 1% of the Dallas Heart Study population and 4% of those participants with a plasma TG in the lowest quartile had a rare loss-of-function mutation in ANGPTL3, ANGPTL4, or ANGPTL5. Thus, ANGPTL3, ANGPTL4, and ANGPTL5, but not ANGPTL6, play nonredundant roles in TG metabolism, and multiple alleles at these loci cumulatively contribute to variability in plasma TG levels in humans. PMID:19075393

Comparative Genomics and Reverse Genetics Analysis Reveal Indispensable Functions of the Serine Acetyltransferase Gene Family in Arabidopsis[W][OA

PubMed Central

Watanabe, Mutsumi; Mochida, Keiichi; Kato, Tomohiko; Tabata, Satoshi; Yoshimoto, Naoko; Noji, Masaaki; Saito, Kazuki

2008-01-01

Ser acetyltransferase (SERAT), which catalyzes O-acetyl-Ser (OAS) formation, plays a key role in sulfur assimilation and Cys synthesis. Despite several studies on SERATs from various plant species, the in vivo function of multiple SERAT genes in plant cells remains unaddressed. Comparative genomics studies with the five genes of the SERAT gene family in Arabidopsis thaliana indicated that all three Arabidopsis SERAT subfamilies are conserved across five plant species with available genome sequences. Single and multiple knockout mutants of all Arabidopsis SERAT gene family members were analyzed. All five quadruple mutants with a single gene survived, with three mutants showing dwarfism. However, the quintuple mutant lacking all SERAT genes was embryo-lethal. Thus, all five isoforms show functional redundancy in vivo. The developmental and compartment-specific roles of each SERAT isoform were also demonstrated. Mitochondrial SERAT2;2 plays a predominant role in cellular OAS formation, while plastidic SERAT2;1 contributes less to OAS formation and subsequent Cys synthesis. Three cytosolic isoforms, SERAT1;1, SERAT3;1, and SERAT3;2, may play a major role during seed development. Thus, the evolutionally conserved SERAT gene family is essential in cellular processes, and the substrates and products of SERAT must be exchangeable between the cytosol and organelles. PMID:18776059

Comparative metagenomic and metatranscriptomic analyses of microbial communities in acid mine drainage.

PubMed

Chen, Lin-xing; Hu, Min; Huang, Li-nan; Hua, Zheng-shuang; Kuang, Jia-liang; Li, Sheng-jin; Shu, Wen-sheng

2015-07-01

The microbial communities in acid mine drainage have been extensively studied to reveal their roles in acid generation and adaption to this environment. Lacking, however, are integrated community- and organism-wide comparative gene transcriptional analyses that could reveal the response and adaptation mechanisms of these extraordinary microorganisms to different environmental conditions. In this study, comparative metagenomics and metatranscriptomics were performed on microbial assemblages collected from four geochemically distinct acid mine drainage (AMD) sites. Taxonomic analysis uncovered unexpectedly high microbial biodiversity of these extremely acidophilic communities, and the abundant taxa of Acidithiobacillus, Leptospirillum and Acidiphilium exhibited high transcriptional activities. Community-wide comparative analyses clearly showed that the AMD microorganisms adapted to the different environmental conditions via regulating the expression of genes involved in multiple in situ functional activities, including low-pH adaptation, carbon, nitrogen and phosphate assimilation, energy generation, environmental stress resistance, and other functions. Organism-wide comparative analyses of the active taxa revealed environment-dependent gene transcriptional profiles, especially the distinct strategies used by Acidithiobacillus ferrivorans and Leptospirillum ferrodiazotrophum in nutrients assimilation and energy generation for survival under different conditions. Overall, these findings demonstrate that the gene transcriptional profiles of AMD microorganisms are closely related to the site physiochemical characteristics, providing clues into the microbial response and adaptation mechanisms in the oligotrophic, extremely acidic environments.

The evolution of pattern camouflage strategies in waterfowl and game birds.

PubMed

Marshall, Kate L A; Gluckman, Thanh-Lan

2015-05-01

Visual patterns are common in animals. A broad survey of the literature has revealed that different patterns have distinct functions. Irregular patterns (e.g., stipples) typically function in static camouflage, whereas regular patterns (e.g., stripes) have a dual function in both motion camouflage and communication. Moreover, irregular and regular patterns located on different body regions ("bimodal" patterning) can provide an effective compromise between camouflage and communication and/or enhanced concealment via both static and motion camouflage. Here, we compared the frequency of these three pattern types and traced their evolutionary history using Bayesian comparative modeling in aquatic waterfowl (Anseriformes: 118 spp.), which typically escape predators by flight, and terrestrial game birds (Galliformes: 170 spp.), which mainly use a "sit and hide" strategy to avoid predation. Given these life histories, we predicted that selection would favor regular patterning in Anseriformes and irregular or bimodal patterning in Galliformes and that pattern function complexity should increase over the course of evolution. Regular patterns were predominant in Anseriformes whereas regular and bimodal patterns were most frequent in Galliformes, suggesting that patterns with multiple functions are broadly favored by selection over patterns with a single function in static camouflage. We found that the first patterns to evolve were either regular or bimodal in Anseriformes and either irregular or regular in Galliformes. In both orders, irregular patterns could evolve into regular patterns but not the reverse. Our hypothesis of increasing complexity in pattern camouflage function was supported in Galliformes but not in Anseriformes. These results reveal a trajectory of pattern evolution linked to increasing function complexity in Galliformes although not in Anseriformes, suggesting that both ecology and function complexity can have a profound influence on pattern evolution.

The evolution of pattern camouflage strategies in waterfowl and game birds

PubMed Central

Marshall, Kate L A; Gluckman, Thanh-Lan

2015-01-01

Visual patterns are common in animals. A broad survey of the literature has revealed that different patterns have distinct functions. Irregular patterns (e.g., stipples) typically function in static camouflage, whereas regular patterns (e.g., stripes) have a dual function in both motion camouflage and communication. Moreover, irregular and regular patterns located on different body regions (“bimodal” patterning) can provide an effective compromise between camouflage and communication and/or enhanced concealment via both static and motion camouflage. Here, we compared the frequency of these three pattern types and traced their evolutionary history using Bayesian comparative modeling in aquatic waterfowl (Anseriformes: 118 spp.), which typically escape predators by flight, and terrestrial game birds (Galliformes: 170 spp.), which mainly use a “sit and hide” strategy to avoid predation. Given these life histories, we predicted that selection would favor regular patterning in Anseriformes and irregular or bimodal patterning in Galliformes and that pattern function complexity should increase over the course of evolution. Regular patterns were predominant in Anseriformes whereas regular and bimodal patterns were most frequent in Galliformes, suggesting that patterns with multiple functions are broadly favored by selection over patterns with a single function in static camouflage. We found that the first patterns to evolve were either regular or bimodal in Anseriformes and either irregular or regular in Galliformes. In both orders, irregular patterns could evolve into regular patterns but not the reverse. Our hypothesis of increasing complexity in pattern camouflage function was supported in Galliformes but not in Anseriformes. These results reveal a trajectory of pattern evolution linked to increasing function complexity in Galliformes although not in Anseriformes, suggesting that both ecology and function complexity can have a profound influence on pattern evolution. PMID:26045950

Curli mediate bacterial adhesion to fibronectin via tensile multiple bonds

NASA Astrophysics Data System (ADS)

Oh, Yoo Jin; Hubauer-Brenner, Michael; Gruber, Hermann J.; Cui, Yidan; Traxler, Lukas; Siligan, Christine; Park, Sungsu; Hinterdorfer, Peter

2016-09-01

Many enteric bacteria including pathogenic Escherichia coli and Salmonella strains produce curli fibers that bind to host surfaces, leading to bacterial internalization into host cells. By using a nanomechanical force-sensing approach, we obtained real-time information about the distribution of molecular bonds involved in the adhesion of curliated bacteria to fibronectin. We found that curliated E. coli and fibronectin formed dense quantized and multiple specific bonds with high tensile strength, resulting in tight bacterial binding. Nanomechanical recognition measurements revealed that approximately 10 bonds were disrupted either sequentially or simultaneously under force load. Thus the curli formation of bacterial surfaces leads to multi-bond structural components of fibrous nature, which may explain the strong mechanical binding of curliated bacteria to host cells and unveil the functions of these proteins in bacterial internalization and invasion.

Screening of differentially expressed genes between multiple trauma patients with and without sepsis.

PubMed

Ji, S C; Pan, Y T; Lu, Q Y; Sun, Z Y; Liu, Y Z

2014-03-17

The purpose of this study was to identify critical genes associated with septic multiple trauma by comparing peripheral whole blood samples from multiple trauma patients with and without sepsis. A microarray data set was downloaded from the Gene Expression Omnibus (GEO) database. This data set included 70 samples, 36 from multiple trauma patients with sepsis and 34 from multiple trauma patients without sepsis (as a control set). The data were preprocessed, and differentially expressed genes (DEGs) were then screened for using packages of the R language. Functional analysis of DEGs was performed with DAVID. Interaction networks were then established for the most up- and down-regulated genes using HitPredict. Pathway-enrichment analysis was conducted for genes in the networks using WebGestalt. Fifty-eight DEGs were identified. The expression levels of PLAU (down-regulated) and MMP8 (up-regulated) presented the largest fold-changes, and interaction networks were established for these genes. Further analysis revealed that PLAT (plasminogen activator, tissue) and SERPINF2 (serpin peptidase inhibitor, clade F, member 2), which interact with PLAU, play important roles in the pathway of the component and coagulation cascade. We hypothesize that PLAU is a major regulator of the component and coagulation cascade, and down-regulation of PLAU results in dysfunction of the pathway, causing sepsis.

Multiple filters affect tree species assembly in mid-latitude forest communities.

PubMed

Kubota, Y; Kusumoto, B; Shiono, T; Ulrich, W

2018-05-01

Species assembly patterns of local communities are shaped by the balance between multiple abiotic/biotic filters and dispersal that both select individuals from species pools at the regional scale. Knowledge regarding functional assembly can provide insight into the relative importance of the deterministic and stochastic processes that shape species assembly. We evaluated the hierarchical roles of the α niche and β niches by analyzing the influence of environmental filtering relative to functional traits on geographical patterns of tree species assembly in mid-latitude forests. Using forest plot datasets, we examined the α niche traits (leaf and wood traits) and β niche properties (cold/drought tolerance) of tree species, and tested non-randomness (clustering/over-dispersion) of trait assembly based on null models that assumed two types of species pools related to biogeographical regions. For most plots, species assembly patterns fell within the range of random expectation. However, particularly for cold/drought tolerance-related β niche properties, deviation from randomness was frequently found; non-random clustering was predominant in higher latitudes with harsh climates. Our findings demonstrate that both randomness and non-randomness in trait assembly emerged as a result of the α and β niches, although we suggest the potential role of dispersal processes and/or species equalization through trait similarities in generating the prevalence of randomness. Clustering of β niche traits along latitudinal climatic gradients provides clear evidence of species sorting by filtering particular traits. Our results reveal that multiple filters through functional niches and stochastic processes jointly shape geographical patterns of species assembly across mid-latitude forests.

Clustered metallothionein genes are co-regulated in rice and ectopic expression of OsMT1e-P confers multiple abiotic stress tolerance in tobacco via ROS scavenging

PubMed Central

2012-01-01

Background Metallothioneins (MT) are low molecular weight, cysteine rich metal binding proteins, found across genera and species, but their function(s) in abiotic stress tolerance are not well documented. Results We have characterized a rice MT gene, OsMT1e-P, isolated from a subtractive library generated from a stressed salinity tolerant rice genotype, Pokkali. Bioinformatics analysis of the rice genome sequence revealed that this gene belongs to a multigenic family, which consists of 13 genes with 15 protein products. OsMT1e-P is located on chromosome XI, away from the majority of other type I genes that are clustered on chromosome XII. Various members of this MT gene cluster showed a tight co-regulation pattern under several abiotic stresses. Sequence analysis revealed the presence of conserved cysteine residues in OsMT1e-P protein. Salinity stress was found to regulate the transcript abundance of OsMT1e-P in a developmental and organ specific manner. Using transgenic approach, we found a positive correlation between ectopic expression of OsMT1e-P and stress tolerance. Our experiments further suggest ROS scavenging to be the possible mechanism for multiple stress tolerance conferred by OsMT1e-P. Conclusion We present an overview of MTs, describing their gene structure, genome localization and expression patterns under salinity and development in rice. We have found that ectopic expression of OsMT1e-P enhances tolerance towards multiple abiotic stresses in transgenic tobacco and the resultant plants could survive and set viable seeds under saline conditions. Taken together, the experiments presented here have indicated that ectopic expression of OsMT1e-P protects against oxidative stress primarily through efficient scavenging of reactive oxygen species. PMID:22780875

Clustered metallothionein genes are co-regulated in rice and ectopic expression of OsMT1e-P confers multiple abiotic stress tolerance in tobacco via ROS scavenging.

PubMed

Kumar, Gautam; Kushwaha, Hemant Ritturaj; Panjabi-Sabharwal, Vaishali; Kumari, Sumita; Joshi, Rohit; Karan, Ratna; Mittal, Shweta; Pareek, Sneh L Singla; Pareek, Ashwani

2012-07-10

Metallothioneins (MT) are low molecular weight, cysteine rich metal binding proteins, found across genera and species, but their function(s) in abiotic stress tolerance are not well documented. We have characterized a rice MT gene, OsMT1e-P, isolated from a subtractive library generated from a stressed salinity tolerant rice genotype, Pokkali. Bioinformatics analysis of the rice genome sequence revealed that this gene belongs to a multigenic family, which consists of 13 genes with 15 protein products. OsMT1e-P is located on chromosome XI, away from the majority of other type I genes that are clustered on chromosome XII. Various members of this MT gene cluster showed a tight co-regulation pattern under several abiotic stresses. Sequence analysis revealed the presence of conserved cysteine residues in OsMT1e-P protein. Salinity stress was found to regulate the transcript abundance of OsMT1e-P in a developmental and organ specific manner. Using transgenic approach, we found a positive correlation between ectopic expression of OsMT1e-P and stress tolerance. Our experiments further suggest ROS scavenging to be the possible mechanism for multiple stress tolerance conferred by OsMT1e-P. We present an overview of MTs, describing their gene structure, genome localization and expression patterns under salinity and development in rice. We have found that ectopic expression of OsMT1e-P enhances tolerance towards multiple abiotic stresses in transgenic tobacco and the resultant plants could survive and set viable seeds under saline conditions. Taken together, the experiments presented here have indicated that ectopic expression of OsMT1e-P protects against oxidative stress primarily through efficient scavenging of reactive oxygen species.

Local loss and spatial homogenization of plant diversity reduce ecosystem multifunctionality.

PubMed

Hautier, Yann; Isbell, Forest; Borer, Elizabeth T; Seabloom, Eric W; Harpole, W Stanley; Lind, Eric M; MacDougall, Andrew S; Stevens, Carly J; Adler, Peter B; Alberti, Juan; Bakker, Jonathan D; Brudvig, Lars A; Buckley, Yvonne M; Cadotte, Marc; Caldeira, Maria C; Chaneton, Enrique J; Chu, Chengjin; Daleo, Pedro; Dickman, Christopher R; Dwyer, John M; Eskelinen, Anu; Fay, Philip A; Firn, Jennifer; Hagenah, Nicole; Hillebrand, Helmut; Iribarne, Oscar; Kirkman, Kevin P; Knops, Johannes M H; La Pierre, Kimberly J; McCulley, Rebecca L; Morgan, John W; Pärtel, Meelis; Pascual, Jesus; Price, Jodi N; Prober, Suzanne M; Risch, Anita C; Sankaran, Mahesh; Schuetz, Martin; Standish, Rachel J; Virtanen, Risto; Wardle, Glenda M; Yahdjian, Laura; Hector, Andy

2018-01-01

Biodiversity is declining in many local communities while also becoming increasingly homogenized across space. Experiments show that local plant species loss reduces ecosystem functioning and services, but the role of spatial homogenization of community composition and the potential interaction between diversity at different scales in maintaining ecosystem functioning remains unclear, especially when many functions are considered (ecosystem multifunctionality). We present an analysis of eight ecosystem functions measured in 65 grasslands worldwide. We find that more diverse grasslands-those with both species-rich local communities (α-diversity) and large compositional differences among localities (β-diversity)-had higher levels of multifunctionality. Moreover, α- and β-diversity synergistically affected multifunctionality, with higher levels of diversity at one scale amplifying the contribution to ecological functions at the other scale. The identity of species influencing ecosystem functioning differed among functions and across local communities, explaining why more diverse grasslands maintained greater functionality when more functions and localities were considered. These results were robust to variation in environmental drivers. Our findings reveal that plant diversity, at both local and landscape scales, contributes to the maintenance of multiple ecosystem services provided by grasslands. Preserving ecosystem functioning therefore requires conservation of biodiversity both within and among ecological communities.

Responses of stream microbes to multiple anthropogenic stressors in a mesocosm study.

PubMed

Nuy, Julia K; Lange, Anja; Beermann, Arne J; Jensen, Manfred; Elbrecht, Vasco; Röhl, Oliver; Peršoh, Derek; Begerow, Dominik; Leese, Florian; Boenigk, Jens

2018-08-15

Stream ecosystems are affected by multiple anthropogenic stressors worldwide. Even though effects of many single stressors are comparatively well studied, the effects of multiple stressors are difficult to predict. In particular bacteria and protists, which are responsible for the majority of ecosystem respiration and element flows, are infrequently studied with respect to multiple stressors responses. We conducted a stream mesocosm experiment to characterize the responses of single and multiple stressors on microbiota. Two functionally important stream habitats, leaf litter and benthic phototrophic rock biofilms, were exposed to three stressors in a full factorial design: fine sediment deposition, increased chloride concentration (salinization) and reduced flow velocity. We analyzed the microbial composition in the two habitat types of the mesocosms using an amplicon sequencing approach. Community analysis on different taxonomic levels as well as principle component analyses (PCoAs) based on realtive abundances of operational taxonomic units (OTUs) showed treatment specific shifts in the eukaryotic biofilm community. Analysis of variance (ANOVA) revealed that Bacillariophyta responded positively salinity and sediment increase, while the relative read abundance of chlorophyte taxa decreased. The combined effects of multiple stressors were mainly antagonistic. Therefore, the community composition in multiply stressed environments resembled the composition of the unstressed control community in terms of OTU occurrence and relative abundances. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in neurodevelopment.

PubMed

Wang, Ping; Lin, Mingyan; Pedrosa, Erika; Hrabovsky, Anastasia; Zhang, Zheng; Guo, Wenjun; Lachman, Herbert M; Zheng, Deyou

2015-01-01

Disruptive mutation in the CHD8 gene is one of the top genetic risk factors in autism spectrum disorders (ASDs). Previous analyses of genome-wide CHD8 occupancy and reduced expression of CHD8 by shRNA knockdown in committed neural cells showed that CHD8 regulates multiple cell processes critical for neural functions, and its targets are enriched with ASD-associated genes. To further understand the molecular links between CHD8 functions and ASD, we have applied the CRISPR/Cas9 technology to knockout one copy of CHD8 in induced pluripotent stem cells (iPSCs) to better mimic the loss-of-function status that would exist in the developing human embryo prior to neuronal differentiation. We then carried out transcriptomic and bioinformatic analyses of neural progenitors and neurons derived from the CHD8 mutant iPSCs. Transcriptome profiling revealed that CHD8 hemizygosity (CHD8 (+/-)) affected the expression of several thousands of genes in neural progenitors and early differentiating neurons. The differentially expressed genes were enriched for functions of neural development, β-catenin/Wnt signaling, extracellular matrix, and skeletal system development. They also exhibited significant overlap with genes previously associated with autism and schizophrenia, as well as the downstream transcriptional targets of multiple genes implicated in autism. Providing important insight into how CHD8 mutations might give rise to macrocephaly, we found that seven of the twelve genes associated with human brain volume or head size by genome-wide association studies (e.g., HGMA2) were dysregulated in CHD8 (+/-) neural progenitors or neurons. We have established a renewable source of CHD8 (+/-) iPSC lines that would be valuable for investigating the molecular and cellular functions of CHD8. Transcriptomic profiling showed that CHD8 regulates multiple genes implicated in ASD pathogenesis and genes associated with brain volume.

Structural Insight into How Bacteria Prevent Interference between Multiple Divergent Type IV Secretion Systems

PubMed Central

Phan, Isabelle Q. H.; Scheib, Holger; Subramanian, Sandhya; Edwards, Thomas E.; Lehman, Stephanie S.; Piitulainen, Hanna; Sayeedur Rahman, M.; Rennoll-Bankert, Kristen E.; Staker, Bart L.; Taira, Suvi; Stacy, Robin; Myler, Peter J.; Azad, Abdu F.

2015-01-01

ABSTRACT Prokaryotes use type IV secretion systems (T4SSs) to translocate substrates (e.g., nucleoprotein, DNA, and protein) and/or elaborate surface structures (i.e., pili or adhesins). Bacterial genomes may encode multiple T4SSs, e.g., there are three functionally divergent T4SSs in some Bartonella species (vir, vbh, and trw). In a unique case, most rickettsial species encode a T4SS (rvh) enriched with gene duplication. Within single genomes, the evolutionary and functional implications of cross-system interchangeability of analogous T4SS protein components remains poorly understood. To lend insight into cross-system interchangeability, we analyzed the VirB8 family of T4SS channel proteins. Crystal structures of three VirB8 and two TrwG Bartonella proteins revealed highly conserved C-terminal periplasmic domain folds and dimerization interfaces, despite tremendous sequence divergence. This implies remarkable structural constraints for VirB8 components in the assembly of a functional T4SS. VirB8/TrwG heterodimers, determined via bacterial two-hybrid assays and molecular modeling, indicate that differential expression of trw and vir systems is the likely barrier to VirB8-TrwG interchangeability. We also determined the crystal structure of Rickettsia typhi RvhB8-II and modeled its coexpressed divergent paralog RvhB8-I. Remarkably, while RvhB8-I dimerizes and is structurally similar to other VirB8 proteins, the RvhB8-II dimer interface deviates substantially from other VirB8 structures, potentially preventing RvhB8-I/RvhB8-II heterodimerization. For the rvh T4SS, the evolution of divergent VirB8 paralogs implies a functional diversification that is unknown in other T4SSs. Collectively, our data identify two different constraints (spatiotemporal for Bartonella trw and vir T4SSs and structural for rvh T4SSs) that mediate the functionality of multiple divergent T4SSs within a single bacterium. PMID:26646013

FANCA safeguards interphase and mitosis during hematopoiesis in vivo

PubMed Central

Abdul-Sater, Zahi; Cerabona, Donna; Sierra Potchanant, Elizabeth; Sun, Zejin; Enzor, Rikki; He, Ying; Robertson, Kent; Goebel, W. Scott; Nalepa, Grzegorz

2015-01-01

Fanconi anemia (FA/BRCA) signaling network controls multiple genome-housekeeping checkpoints, from interphase DNA repair to mitosis. The in vivo role of abnormal cell division in FA remains unknown. Here, we quantified the origins of genomic instability in FA patients and mice in vivo and ex vivo. We found that both mitotic errors and interphase DNA damage significantly contribute to genomic instability during FA-deficient hematopoiesis and in non-hematopoietic human and murine FA primary cells. Super-resolution microscopy coupled with functional assays revealed that FANCA shuttles to the pericentriolar material (PCM) to regulate spindle assembly at mitotic entry. Loss of FA signaling rendered cells hypersensitive to spindle chemotherapeutics and allowed escape from the chemotherapy-induced spindle assembly checkpoint. In support of these findings, direct comparison of DNA cross-linking and antimitotic chemotherapeutics in primary FANCA−/− cells revealed genomic instability originating through divergent cell cycle checkpoint aberrations. Our data indicate that the FA/BRCA signaling functions as an in vivo gatekeeper of genomic integrity throughout interphase and mitosis, which may have implications for future targeted therapies in FA and FA-deficient cancers. PMID:26366677

IR spectrum of the protonated neurotransmitter 2-phenylethylamine: dispersion and anharmonicity of the NH3(+)-π interaction.

PubMed

Bouchet, Aude; Schütz, Markus; Chiavarino, Barbara; Crestoni, Maria Elisa; Fornarini, Simonetta; Dopfer, Otto

2015-10-21

The structure and dynamics of the highly flexible side chain of (protonated) phenylethylamino neurotransmitters are essential for their function. The geometric, vibrational, and energetic properties of the protonated neutrotransmitter 2-phenylethylamine (H(+)PEA) are characterized in the N-H stretch range by infrared photodissociation (IRPD) spectroscopy of cold ions using rare gas tagging (Rg = Ne and Ar) and anharmonic calculations at the B3LYP-D3/(aug-)cc-pVTZ level including dispersion corrections. A single folded gauche conformer (G) protonated at the basic amino group and stabilized by an intramolecular NH(+)-π interaction is observed. The dispersion-corrected density functional theory calculations reveal the important effects of dispersion on the cation-π interaction and the large vibrational anharmonicity of the NH3(+) group involved in the NH(+)-π hydrogen bond. They allow for assigning overtone and combination bands and explain anomalous intensities observed in previous IR multiple-photon dissociation spectra. Comparison with neutral PEA reveals the large effects of protonation on the geometric and electronic structure.

CD8 T cell memory: it takes all kinds

PubMed Central

Hamilton, Sara E.; Jameson, Stephen C.

2012-01-01

Understanding the mechanisms that regulate the differentiation and maintenance of CD8+ memory T cells is fundamental to the development of effective T cell-based vaccines. Memory cell differentiation is influenced by the cytokines that accompany T cell priming, the history of previous antigen encounters, and the tissue sites into which memory cells migrate. These cues combine to influence the developing CD8+ memory pool, and recent work has revealed the importance of multiple transcription factors, metabolic molecules, and surface receptors in revealing the type of memory cell that is generated. Paired with increasingly meticulous subsetting and sorting of memory populations, we now know the CD8+ memory pool to be phenotypically and functionally heterogeneous in nature. This includes both recirculating and tissue-resident memory populations, and cells with varying degrees of inherent longevity and protective function. These data point to the importance of tailored vaccine design. Here we discuss how the diversity of the memory CD8+ T cell pool challenges the notion that “one size fits all” for pathogen control, and how distinct memory subsets may be suited for distinct aspects of protective immunity. PMID:23230436

Morphological and functional aspects of progenitors perturbed in cortical malformations

PubMed Central

Bizzotto, Sara; Francis, Fiona

2015-01-01

In this review, we discuss molecular and cellular mechanisms important for the function of neuronal progenitors during development, revealed by their perturbation in different cortical malformations. We focus on a class of neuronal progenitors, radial glial cells (RGCs), which are renowned for their unique morphological and behavioral characteristics, constituting a key element during the development of the mammalian cerebral cortex. We describe how the particular morphology of these cells is related to their roles in the orchestration of cortical development and their influence on other progenitor types and post-mitotic neurons. Important for disease mechanisms, we overview what is currently known about RGC cellular components, cytoskeletal mechanisms, signaling pathways and cell cycle characteristics, focusing on how defects lead to abnormal development and cortical malformation phenotypes. The multiple recent entry points from human genetics and animal models are contributing to our understanding of this important cell type. Combining data from phenotypes in the mouse reveals molecules which potentially act in common pathways. Going beyond this, we discuss future directions that may provide new data in this expanding area. PMID:25729350

Functional Expression of an Orchid Fragrance Gene in Lactococcus lactis

PubMed Central

Song, Adelene Ai Lian; Abdullah, Janna O.; Abdullah, Mohd Puad; Shafee, Norazizah; Rahim, Raha A.

2012-01-01

Vanda Mimi Palmer (VMP), an orchid hybrid of Vanda tesselata and Vanda Tan Chay Yan is a highly scented tropical orchid which blooms all year round. Previous studies revealed that VMP produces a variety of isoprenoid volatiles during daylight. Isoprenoids are well known to contribute significantly to the scent of most fragrant plants. They are a large group of secondary metabolites which may possess valuable characteristics such as flavor, fragrance and toxicity and are produced via two pathways, the mevalonate (MVA) pathway or/and the 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway. In this study, a sesquiterpene synthase gene denoted VMPSTS, previously isolated from a floral cDNA library of VMP was cloned and expressed in Lactococcus lactis to characterize the functionality of the protein. L. lactis, a food grade bacterium which utilizes the mevalonate pathway for isoprenoid production was found to be a suitable host for the characterization of plant terpene synthases. Through recombinant expression of VMPSTS, it was revealed that VMPSTS produced multiple sesquiterpenes and germacrene D dominates its profile. PMID:22408409

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.

Trypanosoma brucei Metacaspase 4 Is a Pseudopeptidase and a Virulence Factor*

PubMed Central

Proto, William R.; Castanys-Munoz, Esther; Black, Alana; Tetley, Laurence; Moss, Catherine X.; Juliano, Luiz; Coombs, Graham H.; Mottram, Jeremy C.

2011-01-01

Metacaspases are caspase family cysteine peptidases found in plants, fungi, and protozoa but not mammals. Trypanosoma brucei is unusual in having five metacaspases (MCA1–MCA5), of which MCA1 and MCA4 have active site substitutions, making them possible non-enzymatic homologues. Here we demonstrate that recombinant MCA4 lacks detectable peptidase activity despite maintaining a functional peptidase structure. MCA4 is expressed primarily in the bloodstream form of the parasite and associates with the flagellar membrane via dual myristoylation/palmitoylation. Loss of function phenotyping revealed critical roles for MCA4; rapid depletion by RNAi caused lethal disruption to the parasite's cell cycle, yet the generation of MCA4 null mutant parasites (Δmca4) was possible. Δmca4 had normal growth in axenic culture but markedly reduced virulence in mice. Further analysis revealed that MCA4 is released from the parasite and is specifically processed by MCA3, the only metacaspase that is both palmitoylated and enzymatically active. Accordingly, we have identified that the multiple metacaspases in T. brucei form a membrane-associated proteolytic cascade to generate a pseudopeptidase virulence factor. PMID:21949125

Taguchi's off line method and Multivariate loss function approach for quality management and optimization of process parameters -A review

NASA Astrophysics Data System (ADS)

Bharti, P. K.; Khan, M. I.; Singh, Harbinder

2010-10-01

Off-line quality control is considered to be an effective approach to improve product quality at a relatively low cost. The Taguchi method is one of the conventional approaches for this purpose. Through this approach, engineers can determine a feasible combination of design parameters such that the variability of a product's response can be reduced and the mean is close to the desired target. The traditional Taguchi method was focused on ensuring good performance at the parameter design stage with one quality characteristic, but most products and processes have multiple quality characteristics. The optimal parameter design minimizes the total quality loss for multiple quality characteristics. Several studies have presented approaches addressing multiple quality characteristics. Most of these papers were concerned with maximizing the parameter combination of signal to noise (SN) ratios. The results reveal the advantages of this approach are that the optimal parameter design is the same as the traditional Taguchi method for the single quality characteristic; the optimal design maximizes the amount of reduction of total quality loss for multiple quality characteristics. This paper presents a literature review on solving multi-response problems in the Taguchi method and its successful implementation in various industries.

A Flexible High-Performance Photoimaging Device Based on Bioinspired Hierarchical Multiple-Patterned Plasmonic Nanostructures.

PubMed

Lee, Yoon Ho; Lee, Tae Kyung; Kim, Hongki; Song, Inho; Lee, Jiwon; Kang, Saewon; Ko, Hyunhyub; Kwak, Sang Kyu; Oh, Joon Hak

2018-03-01

In insect eyes, ommatidia with hierarchical structured cornea play a critical role in amplifying and transferring visual signals to the brain through optic nerves, enabling the perception of various visual signals. Here, inspired by the structure and functions of insect ommatidia, a flexible photoimaging device is reported that can simultaneously detect and record incoming photonic signals by vertically stacking an organic photodiode and resistive memory device. A single-layered, hierarchical multiple-patterned back reflector that can exhibit various plasmonic effects is incorporated into the organic photodiode. The multiple-patterned flexible organic photodiodes exhibit greatly enhanced photoresponsivity due to the increased light absorption in comparison with the flat systems. Moreover, the flexible photoimaging device shows a well-resolved spatiotemporal mapping of optical signals with excellent operational and mechanical stabilities at low driving voltages below half of the flat systems. Theoretical calculation and scanning near-field optical microscopy analyses clearly reveal that multiple-patterned electrodes have much stronger surface plasmon coupling than flat and single-patterned systems. The developed methodology provides a versatile and effective route for realizing high-performance optoelectronic and photonic systems. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

High density genotyping of STAT4 gene reveals multiple haplotypic associations with Systemic Lupus Erythematosus in different racial groups

PubMed Central

Namjou, Bahram; Sestak, Andrea L.; Armstrong, Don L.; Zidovetzki, Raphael; Kelly, Jennifer A.; Jacob, Noam; Ciobanu, Voicu; Kaufman, Kenneth M.; Ojwang, Joshua O.; Ziegler, Julie; Quismorio, Francesco; Reiff, Andreas; Myones, Barry L.; Guthridge, Joel M.; Nath, Swapan K.; Bruner, Gail R.; Mehrian-Shai, Ruth; Silverman, Earl; Klein-Gitelman, Marisa; McCurdy, Deborah; Wagner-Weiner, Linda; Nocton, James J.; Putterman, Chaim; Bae, Sang-Cheol; Kim, Yun Jung; Petri, Michelle; Reveille, John D.; Vyse, Timothy J.; Gilkeson, Gary S.; Kamen, Diane L.; Alarcón-Riquelme, Marta E.; Gaffney, Patrick M.; Moser, Kathy L; Merrill, Joan T.; Scofield, R. Hal; James, Judith A.; Langefeld, Carl D.; Harley, John B.; Jacob, Chaim O.

2009-01-01

Objective Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disorder with complex etiology and a strong genetic component. Recently, gene products involved in the interferon pathway have been under intense investigation in SLE pathogenesis. STAT1 and STAT4 are transcription factors that play key roles in the interferon and Th1 signaling pathways, making them attractive candidates for SLE susceptibility. Methods Fifty-six single-nucleotide polymorphisms (SNPs) across STAT1 and STAT4 genes on chromosome 2 were genotyped using Illumina platform as a part of extensive association study in a large collection of 9923 lupus cases and controls from different racial groups. DNA from patients and controls was obtained from peripheral blood. Principal component analyses and population based case-control association analyses were performed and the p values, FDR q values and Odds ratios with 95% confidence intervals (95% CIs) were calculated. Results We observed strong genetic associations with SLE and multiple SNPs located within the STAT4 gene in different ethnicities (Fisher combined p= 7.02×10−25). In addition to strong confirmation of the association in the 3rd intronic region of this gene reported previously, we identified additional haplotypic association across STAT4 gene and in particular a common risk haplotype that is found in multiple racial groups. In contrast, only a relatively weak suggestive association was observed with STAT1, probably due to the proximity to STAT4. Conclusion Our findings indicate that the STAT4 gene is likely to be a crucial component in SLE pathogenesis among multiple racial groups. The functional effects of this association, when revealed, might improve our understanding of the disease and provide new therapeutic targets. PMID:19333953

Interactive effects of multiple stressors revealed by sequencing total (DNA) and active (RNA) components of experimental sediment microbial communities.

PubMed

Birrer, Simone C; Dafforn, Katherine A; Simpson, Stuart L; Kelaher, Brendan P; Potts, Jaimie; Scanes, Peter; Johnston, Emma L

2018-05-15

Coastal waterways are increasingly exposed to multiple stressors, e.g. contaminants that can be delivered via pulse or press exposures. Therefore, it is crucial that ecological impacts can be differentiated among stressors to manage ecosystem threats. We investigated microbial community development in sediments exposed to press and pulse stressors. Press exposures were created with in situ mesocosm sediments containing a range of 'metal' concentrations (sediment contaminated with multiple metal(loid)s) and organic enrichment (fertiliser), while the pulse exposure was simulated by a single dose of organic fertiliser. All treatments and exposure concentrations were crossed in a fully factorial field experiment. We used amplicon sequencing to compare the sensitivity of the 1) total (DNA) and active (RNA) component of 2) bacterial (16S rRNA) and eukaryotic (18S rRNA) communities to contaminant exposures. Overall microbial community change was greater when exposed to press than pulse stressors, with the bacterial community responding more strongly than the eukaryotes. The total bacterial community represents a more time-integrated measure of change and proved to be more sensitive to multiple stressors than the active community. Metals and organic enrichment treatments interacted such that the effect of metals was weaker when the sediment was organically enriched. Taxa-level analyses revealed that press enrichment resulted in potential functional changes, mainly involving nitrogen cycling. Furthermore, enrichment generally reduced the abundance of active eukaryotes in the sediment. As well as demonstrating interactive impacts of metals and organic enrichment, this study highlights the sensitivity of next-generation sequencing for ecosystem biomonitoring of interacting stressors and identifies opportunities for more targeted application. Copyright © 2018 Elsevier B.V. All rights reserved.

Development of multiple myeloma in a patient with chronic hepatitis C: A case report and review of the literature

PubMed Central

Lakatos, Peter Laszlo; Fekete, Sandor; Horanyi, Margit; Fischer, Simon; Abonyi, Margit E

2006-01-01

An association between chronic hepatitis C virus (HCV) infection and essential mixed cryoglobulinaemia and non-Hodgkin lymphoma (NHL) has been suggested. However, a causative role of HCV in these conditions has not been established. The authors report a case of a 50 year-old woman with chronic hepatitis C (CHC) who has been followed up since 1998 due to a high viral load, genotype 1b and moderately elevated liver function tests (LFTs). Laboratory data and liver biopsy revealed moderate activity (grade: 5/18, stage: 1/6). In April 1999, one-year interferon therapy was started. HCV-RNA became negative with normalization of LFTs. However, the patient relapsed during treatment. In September 2002, the patient was admitted for chronic back pain. A CT examination demonstrated degenerative changes. In March 2003, multiple myeloma was diagnosed (IgG-kappa, bone ma-rrow biopsy: 50% plasma cell infiltration). MRI revealed a compression fracture of the 5th lumbar vertebral body and an abdominal mass in the right lower quadrant, infiltrating the canalis spinalis. Treatment with vincristine, adriamycin and dexamethasone (VAD) was started and bisphosphonate was administered regularly. In January 2004, after six cycles of VAD therapy, the multiple myeloma regressed. Thalidomide, as a second line trea-tment of refractory multiple myeloma (MM) was initiated, and followed by peginterferon-α2b and ribavirin against the HCV infection in June. In June 2005, LFTs returned to normal, while HCV-RNA was negative, demonstrating an end of treatment response. Although a pathogenic role of HCV infection in malignant lymphoproliferative disorders has not been established, NHL and possibly MM may develop in CHC patients, supporting a role of a complex follow-up in these patients. PMID:16610042

Functional magnetic resonance imaging reflects changes in brain functioning with sedation.

PubMed

Starbuck, Victoria N; Kay, Gary G; Platenberg, R. Craig; Lin, Chin-Shoou; Zielinski, Brandon A

2000-12-01

Functional magnetic resonance imaging (fMRI) studies have demonstrated localized brain activation during cognitive tasks. Brain activation increases with task complexity and decreases with familiarity. This study investigates how sleepiness alters the relationship between brain activation and task familiarity. We hypothesize that sleepiness prevents the reduction in activation associated with practice. Twenty-nine individuals rated their sleepiness using the Stanford Sleepiness Scale before fMRI. During imaging, subjects performed the Paced Auditory Serial Addition Test, a continuous mental arithmetic task. A positive correlation was observed between self-rated sleepiness and frontal brain activation. Fourteen subjects participated in phase 2. Sleepiness was induced by evening dosing with chlorpheniramine (CP) (8 mg or 12 mg) and terfenadine (60 mg) in the morning for 3 days before the second fMRI scan. The Multiple Sleep Latency Test (MSLT) was also performed. Results revealed a significant increase in fMRI activation in proportion to the dose of CP. In contrast, for all subjects receiving placebo there was a reduction in brain activation. MSLT revealed significant daytime sleepiness for subjects receiving CP. These findings suggest that sleepiness interferes with efficiency of brain functioning. The sleepy or sedated brain shows increased oxygen utilization during performance of a familiar cognitive task. Thus, the beneficial effect of prior task exposure is lost under conditions of sedation. Copyright 2000 John Wiley & Sons, Ltd.

The Microtubule-Associated Protein MAP18 Affects ROP2 GTPase Activity during Root Hair Growth1[OPEN

PubMed Central

Kang, Erfang; Zheng, Mingzhi; Zhang, Yan; Yuan, Ming; Fu, Ying

2017-01-01

Establishment and maintenance of the polar site are important for root hair tip growth. We previously reported that Arabidopsis (Arabidopsis thaliana) MICROTUBULE-ASSOCIATED PROTEIN18 (MAP18) functions in controlling the direction of pollen tube growth and root hair elongation. Additionally, the Rop GTPase ROP2 was reported as a positive regulator of both root hair initiation and tip growth in Arabidopsis. Both loss of function of ROP2 and knockdown of MAP18 lead to a decrease in root hair length, whereas overexpression of either MAP18 or ROP2 causes multiple tips or a branching hair phenotype. However, it is unclear whether MAP18 and ROP2 coordinately regulate root hair growth. In this study, we demonstrate that MAP18 and ROP2 interact genetically and functionally. MAP18 interacts physically with ROP2 in vitro and in vivo and preferentially binds to the inactive form of the ROP2 protein. MAP18 promotes ROP2 activity during root hair tip growth. Further investigation revealed that MAP18 competes with RhoGTPase GDP DISSOCIATION INHIBITOR1/SUPERCENTIPEDE1 for binding to ROP2, in turn affecting the localization of active ROP2 in the plasma membrane of the root hair tip. These results reveal a novel function of MAP18 in the regulation of ROP2 activation during root hair growth. PMID:28314794

Basic leucine zipper transcription factor SlbZIP1 mediates salt and drought stress tolerance in tomato.

PubMed

Zhu, Mingku; Meng, Xiaoqing; Cai, Jing; Li, Ge; Dong, Tingting; Li, Zongyun

2018-05-08

Basic region/leucine zipper (bZIP) transcription factors perform as crucial regulators in ABA-mediated stress response in plants. Nevertheless, the functions for most bZIP family members in tomato remain to be deciphered. Here we examined the functional characterization of SlbZIP1 under salt and drought stresses in tomato. Silencing of SlbZIP1 in tomato resulted in reduced expression of multiple ABA biosynthesis- and signal transduction-related genes in transgenic plants. In stress assays, SlbZIP1-RNAi transgenic plants exhibited reduced tolerance to salt and drought stresses compared with WT plants, as are evaluated by multiple physiological parameters associated with stress responses, such as decreased ABA, chlorophyll contents and CAT activity, and increased MDA content. In addition, RNA-seq analysis of transgenic plants revealed that the transcription levels of multiple genes encoding defense proteins related to responses to abiotic stress (e.g. endochitinase, peroxidases, and lipid transfer proteins) and biotic stress (e.g. pathogenesis-related proteins) were downregulated in SlbZIP1-RNAi plants, suggesting that SlbZIP1 plays a role in regulating the genes related to biotic and abiotic stress response. Collectively, the data suggest that SlbZIP1 exerts an essential role in salt and drought stress tolerance through modulating an ABA-mediated pathway, and SlbZIP1 may hold potential applications in the engineering of salt- and drought-tolerant tomato cultivars.

Neuroimaging studies of social cognition in schizophrenia.

PubMed

Fujiwara, Hironobu; Yassin, Walid; Murai, Toshiya

2015-05-01

Impaired social cognition is considered a core contributor to unfavorable psychosocial functioning in schizophrenia. Rather than being a unitary process, social cognition is a collection of multifaceted processes that recruit multiple brain structures, thus structural and functional neuroimaging techniques are ideal methodologies for revealing the underlying pathophysiology of impaired social cognition. Many neuroimaging studies have suggested that in addition to white-matter deficits, schizophrenia is associated with decreased gray-matter volume in multiple brain areas, especially fronto-temporal and limbic regions. However, few schizophrenia studies have examined associations between brain abnormalities and social cognitive disabilities. During the last decade, we have investigated structural brain abnormalities in schizophrenia using high-resolution magnetic resonance imaging, and our findings have been confirmed by us and others. By assessing different types of social cognitive abilities, structural abnormalities in multiple brain regions have been found to be associated with disabilities in social cognition, such as recognition of facial emotion, theory of mind, and empathy. These structural deficits have also been associated with alexithymia and quality of life in ways that are closely related to the social cognitive disabilities found in schizophrenia. Here, we overview a series of neuroimaging studies from our laboratory that exemplify current research into this topic, and discuss how it can be further tackled using recent advances in neuroimaging technology. © 2014 The Authors. Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology.

Multi-Party Privacy-Preserving Set Intersection with Quasi-Linear Complexity

NASA Astrophysics Data System (ADS)

Cheon, Jung Hee; Jarecki, Stanislaw; Seo, Jae Hong

Secure computation of the set intersection functionality allows n parties to find the intersection between their datasets without revealing anything else about them. An efficient protocol for such a task could have multiple potential applications in commerce, health care, and security. However, all currently known secure set intersection protocols for n>2 parties have computational costs that are quadratic in the (maximum) number of entries in the dataset contributed by each party, making secure computation of the set intersection only practical for small datasets. In this paper, we describe the first multi-party protocol for securely computing the set intersection functionality with both the communication and the computation costs that are quasi-linear in the size of the datasets. For a fixed security parameter, our protocols require O(n2k) bits of communication and Õ(n2k) group multiplications per player in the malicious adversary setting, where k is the size of each dataset. Our protocol follows the basic idea of the protocol proposed by Kissner and Song, but we gain efficiency by using different representations of the polynomials associated with users' datasets and careful employment of algorithms that interpolate or evaluate polynomials on multiple points more efficiently. Moreover, the proposed protocol is robust. This means that the protocol outputs the desired result even if some corrupted players leave during the execution of the protocol.

Multisubstrate Isotope Labeling and Metagenomic Analysis of Active Soil Bacterial Communities

PubMed Central

Verastegui, Y.; Cheng, J.; Engel, K.; Kolczynski, D.; Mortimer, S.; Lavigne, J.; Montalibet, J.; Romantsov, T.; Hall, M.; McConkey, B. J.; Rose, D. R.; Tomashek, J. J.; Scott, B. R.

2014-01-01

ABSTRACT Soil microbial diversity represents the largest global reservoir of novel microorganisms and enzymes. In this study, we coupled functional metagenomics and DNA stable-isotope probing (DNA-SIP) using multiple plant-derived carbon substrates and diverse soils to characterize active soil bacterial communities and their glycoside hydrolase genes, which have value for industrial applications. We incubated samples from three disparate Canadian soils (tundra, temperate rainforest, and agricultural) with five native carbon (12C) or stable-isotope-labeled (13C) carbohydrates (glucose, cellobiose, xylose, arabinose, and cellulose). Indicator species analysis revealed high specificity and fidelity for many uncultured and unclassified bacterial taxa in the heavy DNA for all soils and substrates. Among characterized taxa, Actinomycetales (Salinibacterium), Rhizobiales (Devosia), Rhodospirillales (Telmatospirillum), and Caulobacterales (Phenylobacterium and Asticcacaulis) were bacterial indicator species for the heavy substrates and soils tested. Both Actinomycetales and Caulobacterales (Phenylobacterium) were associated with metabolism of cellulose, and Alphaproteobacteria were associated with the metabolism of arabinose; members of the order Rhizobiales were strongly associated with the metabolism of xylose. Annotated metagenomic data suggested diverse glycoside hydrolase gene representation within the pooled heavy DNA. By screening 2,876 cloned fragments derived from the 13C-labeled DNA isolated from soils incubated with cellulose, we demonstrate the power of combining DNA-SIP, multiple-displacement amplification (MDA), and functional metagenomics by efficiently isolating multiple clones with activity on carboxymethyl cellulose and fluorogenic proxy substrates for carbohydrate-active enzymes. PMID:25028422

A novel approach to tracking antigen-experienced CD4 T cells into functional compartments via tandem deep and shallow TCR clonotyping.

PubMed

Estorninho, Megan; Gibson, Vivienne B; Kronenberg-Versteeg, Deborah; Liu, Yuk-Fun; Ni, Chester; Cerosaletti, Karen; Peakman, Mark

2013-12-01

Extensive diversity in the human repertoire of TCRs for Ag is both a cornerstone of effective adaptive immunity that enables host protection against a multiplicity of pathogens and a weakness that gives rise to potential pathological self-reactivity. The complexity arising from diversity makes detection and tracking of single Ag-specific CD4 T cells (ASTs) involved in these immune responses challenging. We report a tandem, multistep process to quantify rare TCRβ-chain variable sequences of ASTs in large polyclonal populations. The approach combines deep high-throughput sequencing (HTS) within functional CD4 T cell compartments, such as naive/memory cells, with shallow, multiple identifier-based HTS of ASTs identified by activation marker upregulation after short-term Ag stimulation in vitro. We find that clonotypes recognizing HLA class II-restricted epitopes of both pathogen-derived Ags and self-Ags are oligoclonal and typically private. Clonotype tracking within an individual reveals private AST clonotypes resident in the memory population, as would be expected, representing clonal expansions (identical nucleotide sequence; "ultraprivate"). Other AST clonotypes share CDR3β amino acid sequences through convergent recombination and are found in memory populations of multiple individuals. Tandem HTS-based clonotyping will facilitate studying AST dynamics, epitope spreading, and repertoire changes that arise postvaccination and following Ag-specific immunotherapies for cancer and autoimmune disease.

Variable and complex food web structures revealed by exploring missing trophic links between birds and biofilm.

PubMed

Kuwae, Tomohiro; Miyoshi, Eiichi; Hosokawa, Shinya; Ichimi, Kazuhiko; Hosoya, Jun; Amano, Tatsuya; Moriya, Toshifumi; Kondoh, Michio; Ydenberg, Ronald C; Elner, Robert W

2012-04-01

Food webs are comprised of a network of trophic interactions and are essential to elucidating ecosystem processes and functions. However, the presence of unknown, but critical networks hampers understanding of complex and dynamic food webs in nature. Here, we empirically demonstrate a missing link, both critical and variable, by revealing that direct predator-prey relationships between shorebirds and biofilm are widespread and mediated by multiple ecological and evolutionary determinants. Food source mixing models and energy budget estimates indicate that the strength of the missing linkage is dependent on predator traits (body mass and foraging action rate) and the environment that determines food density. Morphological analyses, showing that smaller bodied species possess more developed feeding apparatus to consume biofilm, suggest that the linkage is also phylogenetically dependent and affords a compelling re-interpretation of niche differentiation. We contend that exploring missing links is a necessity for revealing true network structure and dynamics. © 2012 Blackwell Publishing Ltd/CNRS.

Functional identification of pathogenic autoantibody responses in patients with multiple sclerosis

PubMed Central

Elliott, Christina; Lindner, Maren; Arthur, Ariel; Brennan, Kathryn; Jarius, Sven; Hussey, John; Chan, Andrew; Stroet, Anke; Olsson, Tomas; Willison, Hugh; Barnett, Susan C.; Meinl, Edgar

2012-01-01

Pathological and clinical studies implicate antibody-dependent mechanisms in the immunopathogenesis of multiple sclerosis. We tested this hypothesis directly by investigating the ability of patient-derived immunoglobulins to mediate demyelination and axonal injury in vitro. Using a myelinating culture system, we developed a sensitive and reproducible bioassay to detect and quantify these effects and applied this to investigate the pathogenic potential of immunoglobulin G preparations obtained from patients with multiple sclerosis (n = 37), other neurological diseases (n = 10) and healthy control donors (n = 13). This identified complement-dependent demyelinating immunoglobulin G responses in approximately 30% of patients with multiple sclerosis, which in two cases was accompanied by significant complement-dependent antibody mediated axonal loss. No pathogenic immunoglobulin G responses were detected in patients with other neurological disease or healthy controls, indicating that the presence of these demyelinating/axopathic autoantibodies is specific for a subset of patients with multiple sclerosis. Immunofluorescence microscopy revealed immunoglobulin G preparations with demyelinating activity contained antibodies that specifically decorated the surface of myelinating oligodendrocytes and their contiguous myelin sheaths. No other binding was observed indicating that the response is restricted to autoantigens expressed by terminally differentiated myelinating oligodendrocytes. In conclusion, our study identifies axopathic and/or demyelinating autoantibody responses in a subset of patients with multiple sclerosis. This observation underlines the mechanistic heterogeneity of multiple sclerosis and provides a rational explanation why some patients benefit from antibody depleting treatments. PMID:22561643

Functional connectivity in the resting brain as biological correlate of the Affective Neuroscience Personality Scales.

PubMed

Deris, Nadja; Montag, Christian; Reuter, Martin; Weber, Bernd; Markett, Sebastian

2017-02-15

According to Jaak Panksepp's Affective Neuroscience Theory and the derived self-report measure, the Affective Neuroscience Personality Scales (ANPS), differences in the responsiveness of primary emotional systems form the basis of human personality. In order to investigate neuronal correlates of personality, the underlying neuronal circuits of the primary emotional systems were analyzed in the present fMRI-study by associating the ANPS to functional connectivity in the resting brain. N=120 healthy participants were invited for the present study. The results were reinvestigated in an independent, smaller sample of N=52 participants. A seed-based whole brain approach was conducted with seed-regions bilaterally in the basolateral and superficial amygdalae. The selection of seed-regions was based on meta-analytic data on affective processing and the Juelich histological atlas. Multiple regression analyses on the functional connectivity maps revealed associations with the SADNESS-scale in both samples. Functional resting-state connectivity between the left basolateral amygdala and a cluster in the postcentral gyrus, and between the right basolateral amygdala and clusters in the superior parietal lobe and subgyral in the parietal lobe was associated with SADNESS. No other ANPS-scale revealed replicable results. The present findings give first insights into the neuronal basis of the SADNESS-scale of the ANPS and support the idea of underlying neuronal circuits. In combination with previous research on genetic associations of the ANPS functional resting-state connectivity is discussed as a possible endophenotype of personality. Copyright © 2016 Elsevier Inc. All rights reserved.

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.

Exciton Localization and Optical Emission in Aryl-Functionalized Carbon Nanotubes

DOE PAGES

Gifford, Brendan Joel; Kilina, Svetlana; Htoon, Han; ...

2017-10-26

Recent spectroscopic studies have revealed the appearance of multiple low-energy peaks in the fluorescence of single-walled carbon nanotubes (SWCNTs) upon their covalent functionalization by aryl groups. The photophysical nature of these low energy optical bands is of significant interest in the quest to understand their appearance and to achieve their precise control via chemical modification of SWCNTs. This theoretical study explains the specific energy dependence of emission features introduced in chemically functionalized (6,5) SWCNTs with aryl bromides at different conformations and in various dielectric media. Calculations using density functional theory (DFT) and time dependent DFT (TD-DFT) show that the specificmore » isomer geometry—the relative position of functional groups on the carbon-ring of the nanotube—is critical for controlling the energies and intensities of optical transitions introduced by functionalization, while the dielectric environment and the chemical composition of functional groups play less significant roles. Furthermore, the predominant effects on optical properties as a result of functionalization conformation are rationalized by exciton localization on the surface of the SWCNT near the dopant sp3-defect but not onto the functional group itself.« less

Beyond triglyceride synthesis: the dynamic functional roles of MGAT and DGAT enzymes in energy metabolism.

PubMed

Shi, Yuguang; Cheng, Dong

2009-07-01

Monoacyglycerol acyltransferases (MGATs) and diacylglycerol acyltransferases (DGATs) catalyze two consecutive steps of enzyme reactions in the synthesis of triacylglycerols (TAGs). The metabolic complexity of TAG synthesis is reflected by the presence of multiple isoforms of MGAT and DGAT enzymes that differ in catalytic properties, subcellular localization, tissue distribution, and physiological functions. MGAT and DGAT enzymes play fundamental roles in the metabolism of monoacylglycerol (MAG), diacylglycerol (DAG), and triacylglycerol (TAG) that are involved in many aspects of physiological functions, such as intestinal fat absorption, lipoprotein assembly, adipose tissue formation, signal transduction, satiety, and lactation. The recent progress in the phenotypic characterization of mice deficient in MGAT and DGAT enzymes and the development of chemical inhibitors have revealed important roles of these enzymes in the regulation of energy homeostasis and insulin sensitivity. Consequently, selective inhibition of MGAT or DGAT enzymes by synthetic compounds may provide novel treatment for obesity and its related metabolic complications.

Origin and function of myofibroblasts in kidney fibrosis.

PubMed

LeBleu, Valerie S; Taduri, Gangadhar; O'Connell, Joyce; Teng, Yingqi; Cooke, Vesselina G; Woda, Craig; Sugimoto, Hikaru; Kalluri, Raghu

2013-08-01

Myofibroblasts are associated with organ fibrosis, but their precise origin and functional role remain unknown. We used multiple genetically engineered mice to track, fate map and ablate cells to determine the source and function of myofibroblasts in kidney fibrosis. Through this comprehensive analysis, we identified that the total pool of myofibroblasts is split, with 50% arising from local resident fibroblasts through proliferation. The nonproliferating myofibroblasts derive through differentiation from bone marrow (35%), the endothelial-to-mesenchymal transition program (10%) and the epithelial-to-mesenchymal transition program (5%). Specific deletion of Tgfbr2 in α-smooth muscle actin (αSMA)(+) cells revealed the importance of this pathway in the recruitment of myofibroblasts through differentiation. Using genetic mouse models and a fate-mapping strategy, we determined that vascular pericytes probably do not contribute to the emergence of myofibroblasts or fibrosis. Our data suggest that targeting diverse pathways is required to substantially inhibit the composite accumulation of myofibroblasts in kidney fibrosis.

Origin and Function of Myofibroblasts in Kidney Fibrosis

PubMed Central

LeBleu, Valerie S.; Taduri, Gangadhar; O’Connell, Joyce; Teng, Yingqi; Cooke, Vesselina G.; Woda, Craig; Sugimoto, Hikaru; Kalluri, Raghu

2014-01-01

Myofibroblasts are associated with organ fibrosis but their precise origin and functional role remain unknown. We employed multiple genetically engineered mice to track, fate-map and ablate cells to determine the source and function of myofibroblasts in kidney fibrosis. Such comprehensive analysis identified that the total pool of myofibroblasts is split, with 50% arising from local resident fibroblasts via proliferation. The non-proliferating myofibroblasts derive via differentiation from bone marrow (35%), endothelial to mesenchymal transition (EndMT) program (10%) and epithelial to mesenchymal transition (EMT) program (5%). Specific deletion of Tgfbr2 in αSMA+ cells revealed the importance of this pathway in recruitment of myofibroblasts via differentiation. Using genetic mouse models and fate-mapping strategy we determined that vascular pericytes likely do not contribute to the emergence of myofibroblasts or fibrosis. This study suggests that targeting diverse pathways is required to significantly inhibit composite accumulation of myofibroblasts in kidney fibrosis. PMID:23817022

Manipulating multiple order parameters via oxygen vacancies: The case of E u0.5B a0.5Ti O3 -δ

NASA Astrophysics Data System (ADS)

Li, Weiwei; He, Qian; Wang, Le; Zeng, Huizhong; Bowlan, John; Ling, Langsheng; Yarotski, Dmitry A.; Zhang, Wenrui; Zhao, Run; Dai, Jiahong; Gu, Junxing; Shen, Shipeng; Guo, Haizhong; Pi, Li; Wang, Haiyan; Wang, Yongqiang; Velasco-Davalos, Ivan A.; Wu, Yangjiang; Hu, Zhijun; Chen, Bin; Li, Run-Wei; Sun, Young; Jin, Kuijuan; Zhang, Yuheng; Chen, Hou-Tong; Ju, Sheng; Ruediger, Andreas; Shi, Daning; Borisevich, Albina Y.; Yang, Hao

2017-09-01

Controlling functionalities, such as magnetism or ferroelectricity, by means of oxygen vacancies (VO) is a key issue for the future development of transition-metal oxides. Progress in this field is currently addressed through VO variations and their impact on mainly one order parameter. Here we reveal a mechanism for tuning both magnetism and ferroelectricity simultaneously by using VO. Combining experimental and density-functional theory studies of E u0.5B a0.5Ti O3 -δ , we demonstrate that oxygen vacancies create T i3 +3 d1 defect states, mediating the ferromagnetic coupling between the localized Eu 4 f7 spins, and increase an off-center displacement of Ti ions, enhancing the ferroelectric Curie temperature. The dual function of Ti sites also promises a magnetoelectric coupling in the E u0.5B a0.5Ti O3 -δ .

Academic and emotional functioning in early adolescence: longitudinal relations, patterns, and prediction by experience in middle school.

PubMed

Roeser, R W; Eccles, J S; Sameroff, A J

1998-01-01

Adopting a motivational perspective on adolescent development, these two companion studies examined the longitudinal relations between early adolescents' school motivation (competence beliefs and values), achievement, emotional functioning (depressive symptoms and anger), and middle school perceptions using both variable- and person-centered analytic techniques. Data were collected from 1041 adolescents and their parents at the beginning of seventh and the end of eight grade in middle school. Controlling for demographic factors, regression analyses in Study 1 showed reciprocal relations between school motivation and positive emotional functioning over time. Furthermore, adolescents' perceptions of the middle school learning environment (support for competence and autonomy, quality of relationships with teachers) predicted their eighth grade motivation, achievement, and emotional functioning after accounting for demographic and prior adjustment measures. Cluster analyses in Study 2 revealed several different patterns of school functioning and emotional functioning during seventh grade that were stable over 2 years and that were predictably related to adolescents' reports of their middle school environment. Discussion focuses on the developmental significance of schooling for multiple adjustment outcomes during adolescence.

Non-coding effects of circular RNA CCDC66 promote colon cancer growth and metastasis

PubMed Central

Hsiao, Kuei-Yang; Lin, Ya-Chi; Gupta, Sachin Kumar; Chang, Ning; Yen, Laising; Sun, H. Sunny; Tsai, Shaw-Jenq

2018-01-01

Circular RNA (circRNA) is a class of non-coding RNA whose functions remain mostly unknown. Recent studies indicate circRNA may be involved in disease pathogenesis, but direct evidence is scarce. Here we characterize the functional role of a novel circRNA, circCCDC66, in colorectal cancer (CRC). RNA-Seq data from matched normal and tumor colon tissue samples identified numerous circRNAs specifically elevated in cancer cells, several of which were verified by quantitative RT-PCR. CircCCDC66 expression was elevated in polyps and colon cancer and was associated with poor prognosis. Gain-of-function and loss-of-function studies in CRC cell-lines demonstrated that circCCDC66 controlled multiple pathological processes, including cell proliferation, migration, invasion, and anchorage-independent growth. In-depth characterization revealed that circCCDC66 exerts its function via regulation of a subset of oncogenes, and knockdown of circCCDC66 inhibited tumor growth and cancer invasion in xenograft and orthotopic mouse models, respectively. Taken together, these findings highlight a novel oncogenic function of circRNA in cancer progression and metastasis. PMID:28249903

Latent class analysis reveals clinically relevant atopy phenotypes in 2 birth cohorts.

PubMed

Hose, Alexander J; Depner, Martin; Illi, Sabina; Lau, Susanne; Keil, Thomas; Wahn, Ulrich; Fuchs, Oliver; Pfefferle, Petra Ina; Schmaußer-Hechfellner, Elisabeth; Genuneit, Jon; Lauener, Roger; Karvonen, Anne M; Roduit, Caroline; Dalphin, Jean-Charles; Riedler, Josef; Pekkanen, Juha; von Mutius, Erika; Ege, Markus J

2017-06-01

Phenotypes of childhood-onset asthma are characterized by distinct trajectories and functional features. For atopy, definition of phenotypes during childhood is less clear. We sought to define phenotypes of atopic sensitization over the first 6 years of life using a latent class analysis (LCA) integrating 3 dimensions of atopy: allergen specificity, time course, and levels of specific IgE (sIgE). Phenotypes were defined by means of LCA in 680 children of the Multizentrische Allergiestudie (MAS) and 766 children of the Protection against allergy: Study in Rural Environments (PASTURE) birth cohorts and compared with classical nondisjunctive definitions of seasonal, perennial, and food sensitization with respect to atopic diseases and lung function. Cytokine levels were measured in the PASTURE cohort. The LCA classified predominantly by type and multiplicity of sensitization (food vs inhalant), allergen combinations, and sIgE levels. Latent classes were related to atopic disease manifestations with higher sensitivity and specificity than the classical definitions. LCA detected consistently in both cohorts a distinct group of children with severe atopy characterized by high seasonal sIgE levels and a strong propensity for asthma; hay fever; eczema; and impaired lung function, also in children without an established asthma diagnosis. Severe atopy was associated with an increased IL-5/IFN-γ ratio. A path analysis among sensitized children revealed that among all features of severe atopy, only excessive sIgE production early in life affected asthma risk. LCA revealed a set of benign, symptomatic, and severe atopy phenotypes. The severe phenotype emerged as a latent condition with signs of a dysbalanced immune response. It determined high asthma risk through excessive sIgE production and directly affected impaired lung function. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Genome-wide characterization of the WRKY gene family in radish (Raphanus sativus L.) reveals its critical functions under different abiotic stresses.

PubMed

Karanja, Bernard Kinuthia; Fan, Lianxue; Xu, Liang; Wang, Yan; Zhu, Xianwen; Tang, Mingjia; Wang, Ronghua; Zhang, Fei; Muleke, Everlyne M'mbone; Liu, Liwang

2017-11-01

The radish WRKY gene family was genome-widely identified and played critical roles in response to multiple abiotic stresses. The WRKY is among the largest transcription factors (TFs) associated with multiple biological activities for plant survival, including control response mechanisms against abiotic stresses such as heat, salinity, and heavy metals. Radish is an important root vegetable crop and therefore characterization and expression pattern investigation of WRKY transcription factors in radish is imperative. In the present study, 126 putative WRKY genes were retrieved from radish genome database. Protein sequence and annotation scrutiny confirmed that RsWRKY proteins possessed highly conserved domains and zinc finger motif. Based on phylogenetic analysis results, RsWRKYs candidate genes were divided into three groups (Group I, II and III) with the number 31, 74, and 20, respectively. Additionally, gene structure analysis revealed that intron-exon patterns of the WRKY genes are highly conserved in radish. Linkage map analysis indicated that RsWRKY genes were distributed with varying densities over nine linkage groups. Further, RT-qPCR analysis illustrated the significant variation of 36 RsWRKY genes under one or more abiotic stress treatments, implicating that they might be stress-responsive genes. In total, 126 WRKY TFs were identified from the R. sativus genome wherein, 35 of them showed abiotic stress-induced expression patterns. These results provide a genome-wide characterization of RsWRKY TFs and baseline for further functional dissection and molecular evolution investigation, specifically for improving abiotic stress resistances with an ultimate goal of increasing yield and quality of radish.

Functional Coding Variation in Recombinant Inbred Mouse Lines Reveals Novel Serotonin Transporter-Associated Phenotypes

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

Carneiro, Ana; Airey, David; Thompson, Brent

The human serotonin (5-hydroxytryptamine, 5-HT) transporter (hSERT, SLC6A4) figures prominently in the etiology or treatment of many prevalent neurobehavioral disorders including anxiety, alcoholism, depression, autism and obsessive-compulsive disorder (OCD). Here we utilize naturally occurring polymorphisms in recombinant inbred (RI) lines to identify novel phenotypes associated with altered SERT function. The widely used mouse strain C57BL/6J, harbors a SERT haplotype defined by two nonsynonymous coding variants (Gly39 and Lys152 (GK)). At these positions, many other mouse lines, including DBA/2J, encode Glu39 and Arg152 (ER haplotype), assignments found also in hSERT. Synaptosomal 5-HT transport studies revealed reduced uptake associated with the GKmore » variant. Heterologous expression studies confirmed a reduced SERT turnover rate for the GK variant. Experimental and in silico approaches using RI lines (C57Bl/6J X DBA/2J=BXD) identifies multiple anatomical, biochemical and behavioral phenotypes specifically impacted by GK/ER variation. Among our findings are multiple traits associated with anxiety and alcohol consumption, as well as of the control of dopamine (DA) signaling. Further bioinformatic analysis of BXD phenotypes, combined with biochemical evaluation of SERT knockout mice, nominates SERT-dependent 5-HT signaling as a major determinant of midbrain iron homeostasis that, in turn, dictates ironregulated DA phenotypes. Our studies provide a novel example of the power of coordinated in vitro, in vivo and in silico approaches using murine RI lines to elucidate and quantify the system-level impact of gene variation.« less

Unusual Variability of the Drosophila Melanogaster Ref(2)p Protein Which Controls the Multiplication of Sigma Rhabdovirus

PubMed Central

Dru, P.; Bras, F.; Dezelee, S.; Gay, P.; Petitjean, A. M.; Pierre-Deneubourg, A.; Teninges, D.; Contamine, D.

1993-01-01

The ref(2)P gene of Drosophila melanogaster was identified by the discovery of two alleles, P(o) and P(p), respectively, permissive and restrictive for sigma rhabdovirus multiplication. A surprising variability of this gene was first noticed by the observation of size differences between the transcripts of permissive and restrictive alleles. In this paper, another restrictive allele, P(n), clearly distinct from P(p), is described: it exhibits a weaker antiviral effect than P(p) and differs from P(p) by its molecular structure. Five types of alleles were distinguished on the basis of their molecular structure, as revealed by S1 nuclease analysis of 17 D. melanogaster strains; three alleles were permissive and two restrictive. Comparison of the sequences of four haplotypes revealed numerous point mutations, two deletions (21 and 24 bp) and a complex event involving a 3-bp deletion, all affected the coding region. The unusual variability of the ref(2)P locus was confirmed by the high ratio of amino acid replacements to synonymous mutations (7:1), as compared to that of other genes, such as the Adh (2:42). Nevertheless, nucleotide sequence comparison with the Drosophila erecta ref(2)P gene shows that selective pressures are exerted to maintain the existence of a functional protein. The effects of this high variability on the ref(2)P protein are discussed in relation to its specific antiviral properties and to its function in D. melanogaster, where it is required for male fertility. PMID:8462852

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

Wang, Jing; Ma, Zihao; Carr, Steven A.

Coexpression of mRNAs under multiple conditions is commonly used to infer cofunctionality of their gene products despite well-known limitations of this “guilt-by-association” (GBA) approach. Recent advancements in mass spectrometry-based proteomic technologies have enabled global expression profiling at the protein level; however, whether proteome profiling data can outperform transcriptome profiling data for coexpression based gene function prediction has not been systematically investigated. Here, we address this question by constructing and analyzing mRNA and protein coexpression networks for three cancer types with matched mRNA and protein profiling data from The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC).more » Our analyses revealed a marked difference in wiring between the mRNA and protein coexpression networks. Whereas protein coexpression was driven primarily by functional similarity between coexpressed genes, mRNA coexpression was driven by both cofunction and chromosomal colocalization of the genes. Functionally coherent mRNA modules were more likely to have their edges preserved in corresponding protein networks than functionally incoherent mRNA modules. Proteomic data strengthened the link between gene expression and function for at least 75% of Gene Ontology (GO) biological processes and 90% of KEGG pathways. A web application Gene2Net (http://cptac.gene2net.org) developed based on the three protein coexpression networks revealed novel gene-function relationships, such as linking ERBB2 (HER2) to lipid biosynthetic process in breast cancer, identifying PLG as a new gene involved in complement activation, and identifying AEBP1 as a new epithelial-mesenchymal transition (EMT) marker. Our results demonstrate that proteome profiling outperforms transcriptome profiling for coexpression based gene function prediction. Proteomics should be integrated if not preferred in gene function and human disease studies. Molecular & Cellular Proteomics 16: 10.1074/mcp.M116.060301, 121–134, 2017.« less

Multiple Renal Artery Pseudoaneurysms in Patients Undergoing Renal Artery Embolization Following Partial Nephrectomy: Correlation with RENAL Nephrometry Scores

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

Gupta, Nakul; Patel, Anish; Ensor, Joe

PurposeTo describe the incidence of multiple renal artery pseudoaneurysms (PSA) in patients referred for renal artery embolization following partial nephrectomy and to study its relationship to RENAL nephrometry scores.Materials and MethodsThe medical records of 25 patients referred for renal artery embolization after partial nephrectomy were retrospectively reviewed for the following parameters: size and number of tumors, RENAL nephrometry scores, angiographic abnormalities, technical and clinical outcomes, and estimated glomerular filtration rates (eGFRs) after embolization.ResultsTwenty-four patients had primary renal tumors, while 1 patient had a pancreatic tumor invading the kidney. Multiple tumors were resected in 4 patients. Most patients (92 %) were symptomatic,more » presenting with gross hematuria, flank pain, or both. Angiography revealed PSA with (n = 5) or without (n = 20) AV fistulae. Sixteen patients (64 %) had multiple PSA involving multiple renal vessels. Higher RENAL nephrometry scores were associated with an increasing likelihood of multiple PSA. Multiple vessels were embolized in 14 patients (56 %). Clinical success was achieved after one (n = 22) or two (n = 3) embolization sessions in all patients. Post-embolization eGFR values at different time points after embolization were not significantly different from the post-operative eGFR.ConclusionA majority of patients requiring renal artery embolization following partial nephrectomy have multiple pseudoaneurysms, often requiring selective embolization of multiple vessels. Higher RENAL nephrometry score is associated with an increasing likelihood of multiple pseudoaneurysms. We found transarterial embolization to be a safe and effective treatment option with no long-term adverse effect on renal function in all but one patient with a solitary kidney.« less

Reptile Toll-like receptor 5 unveils adaptive evolution of bacterial flagellin recognition.

PubMed

Voogdt, Carlos G P; Bouwman, Lieneke I; Kik, Marja J L; Wagenaar, Jaap A; van Putten, Jos P M

2016-01-07

Toll-like receptors (TLR) are ancient innate immune receptors crucial for immune homeostasis and protection against infection. TLRs are present in mammals, birds, amphibians and fish but have not been functionally characterized in reptiles despite the central position of this animal class in vertebrate evolution. Here we report the cloning, characterization, and function of TLR5 of the reptile Anolis carolinensis (Green Anole lizard). The receptor (acTLR5) displays the typical TLR protein architecture with 22 extracellular leucine rich repeats flanked by a N- and C-terminal leucine rich repeat domain, a membrane-spanning region, and an intracellular TIR domain. The receptor is phylogenetically most similar to TLR5 of birds and most distant to fish TLR5. Transcript analysis revealed acTLR5 expression in multiple lizard tissues. Stimulation of acTLR5 with TLR ligands demonstrated unique responsiveness towards bacterial flagellin in both reptile and human cells. Comparison of acTLR5 and human TLR5 using purified flagellins revealed differential sensitivity to Pseudomonas but not Salmonella flagellin, indicating development of species-specific flagellin recognition during the divergent evolution of mammals and reptiles. Our discovery of reptile TLR5 fills the evolutionary gap regarding TLR conservation across vertebrates and provides novel insights in functional evolution of host-microbe interactions.

Reptile Toll-like receptor 5 unveils adaptive evolution of bacterial flagellin recognition

PubMed Central

Voogdt, Carlos G. P.; Bouwman, Lieneke I.; Kik, Marja J. L.; Wagenaar, Jaap A.; van Putten, Jos P. M.

2016-01-01

Toll-like receptors (TLR) are ancient innate immune receptors crucial for immune homeostasis and protection against infection. TLRs are present in mammals, birds, amphibians and fish but have not been functionally characterized in reptiles despite the central position of this animal class in vertebrate evolution. Here we report the cloning, characterization, and function of TLR5 of the reptile Anolis carolinensis (Green Anole lizard). The receptor (acTLR5) displays the typical TLR protein architecture with 22 extracellular leucine rich repeats flanked by a N- and C-terminal leucine rich repeat domain, a membrane-spanning region, and an intracellular TIR domain. The receptor is phylogenetically most similar to TLR5 of birds and most distant to fish TLR5. Transcript analysis revealed acTLR5 expression in multiple lizard tissues. Stimulation of acTLR5 with TLR ligands demonstrated unique responsiveness towards bacterial flagellin in both reptile and human cells. Comparison of acTLR5 and human TLR5 using purified flagellins revealed differential sensitivity to Pseudomonas but not Salmonella flagellin, indicating development of species-specific flagellin recognition during the divergent evolution of mammals and reptiles. Our discovery of reptile TLR5 fills the evolutionary gap regarding TLR conservation across vertebrates and provides novel insights in functional evolution of host-microbe interactions. PMID:26738735

Association of Leukoaraiosis With Convalescent Rehabilitation Outcome in Patients With Ischemic Stroke.

PubMed

Senda, Joe; Ito, Keiichi; Kotake, Tomomitsu; Kanamori, Masahiko; Kishimoto, Hideo; Kadono, Izumi; Suzuki, Yoshiro; Katsuno, Masahisa; Nishida, Yoshihiro; Ishiguro, Naoki; Sobue, Gen

2016-01-01

We investigated the factors influencing inpatient convalescent rehabilitation outcomes in patients with ischemic stroke, particularly severity of leukoaraiosis on magnetic resonance imaging. Participants included 520 patients with ischemic stroke (317 men and 203 women; mean age, 72.8±8.4 years) who were transferred from acute care hospitals for inpatient convalescent rehabilitation. Ischemic stroke subtypes included lacunar infarction (n=41), atherothrombosis (n=223), artery-to-artery embolism (n=67), cardiogenic embolism (n=97), undetermined embolism (n=76), and uncategorized ischemic stroke (n=16). Leukoaraiosis was graded according to periventricular hyperintensity (PVH) and deep white matter hyperintensity on magnetic resonance imaging. Functional Independence Measure scores were assessed on admission and at discharge. Multiple regression analysis revealed that rehabilitation outcomes, measured as total Functional Independence Measure scores, were significantly associated with leukoaraiosis estimated by PVH grade. This association was observed after adjustment for factors such as severity, age, and poststroke history. In all patients, PVH grades were associated with Functional Independence Measure motor scores (P<0.001), whereas in patients with artery-to-artery embolism or cardiogenic embolism and deep white matter hyperintensity grades were associated with Functional Independence Measure cognitive scores (P<0.05). Our study revealed that the degree of leukoaraiosis was associated with inpatient convalescent rehabilitation outcome in patients with ischemic stroke. Furthermore, the PVH grade was associated with motor function outcome, whereas the deep white matter hyperintensity grade correlated with cognitive function outcome, likely because the progression patterns and anatomic backgrounds of PVH and deep white matter hyperintensity differ according to ischemic stroke subtype. © 2015 American Heart Association, Inc.

Novel multi-system functional gains via task specific training in spinal cord injured male rats.

PubMed

Ward, Patricia J; Herrity, April N; Smith, Rebecca R; Willhite, Andrea; Harrison, Benjamin J; Petruska, Jeffrey C; Harkema, Susan J; Hubscher, Charles H

2014-05-01

Locomotor training (LT) after spinal cord injury (SCI) is a rehabilitative therapy used to enhance locomotor recovery. There is evidence, primarily anecdotal, also associating LT with improvements in bladder function and reduction in some types of SCI-related pain. In the present study, we determined if a step training paradigm could improve outcome measures of locomotion, bladder function, and pain/allodynia. After a T10 contusive SCI trained animals (adult male Wistar rats), trained animals began quadrupedal step training beginning 2 weeks post-SCI for 1 h/day. End of study experiments (3 months of training) revealed significant changes in limb kinematics, gait, and hindlimb flexor-extensor bursting patterns relative to non-trained controls. Importantly, micturition function, evaluated with terminal transvesical cystometry, was significantly improved in the step trained group (increased voiding efficiency, intercontraction interval, and contraction amplitude). Because both SCI and LT affect neurotrophin signaling, and neurotrophins are involved with post-SCI plasticity in micturition pathways, we measured bladder neurotrophin mRNA. Training regulated the expression of nerve growth factor (NGF) but not BDNF or NT3. Bladder NGF mRNA levels were inversely related to bladder function in the trained group. Monitoring of overground locomotion and neuropathic pain throughout the study revealed significant improvements, beginning after 3 weeks of training, which in both cases remained consistent for the study duration. These novel findings, improving non-locomotor in addition to locomotor functions, demonstrate that step training post-SCI could contribute to multiple quality of life gains, targeting patient-centered high priority deficits.

Quantifying small molecule phenotypic effects using mitochondrial morpho-functional fingerprinting and machine learning.

PubMed

Blanchet, Lionel; Smeitink, Jan A M; van Emst-de Vries, Sjenet E; Vogels, Caroline; Pellegrini, Mina; Jonckheere, An I; Rodenburg, Richard J T; Buydens, Lutgarde M C; Beyrath, Julien; Willems, Peter H G M; Koopman, Werner J H

2015-01-26

In primary fibroblasts from Leigh Syndrome (LS) patients, isolated mitochondrial complex I deficiency is associated with increased reactive oxygen species levels and mitochondrial morpho-functional changes. Empirical evidence suggests these aberrations constitute linked therapeutic targets for small chemical molecules. However, the latter generally induce multiple subtle effects, meaning that in vitro potency analysis or single-parameter high-throughput cell screening are of limited use to identify these molecules. We combine automated image quantification and artificial intelligence to discriminate between primary fibroblasts of a healthy individual and a LS patient based upon their mitochondrial morpho-functional phenotype. We then evaluate the effects of newly developed Trolox variants in LS patient cells. This revealed that Trolox ornithylamide hydrochloride best counterbalanced mitochondrial morpho-functional aberrations, effectively scavenged ROS and increased the maximal activity of mitochondrial complexes I, IV and citrate synthase. Our results suggest that Trolox-derived antioxidants are promising candidates in therapy development for human mitochondrial disorders.

Functional and mechanistic diversity of distal transcription enhancers

PubMed Central

Bulger, Michael; Groudine, Mark

2013-01-01

Biological differences among metazoans, and between cell types in a given organism, arise in large part due to differences in gene expression patterns. The sequencing of multiple metazoan genomes, coupled with recent advances in genome-wide analysis of histone modifications and transcription factor binding, has revealed that among regulatory DNA sequences, gene-distal enhancers appear to exhibit the greatest diversity and cell-type specificity. Moreover, such elements are emerging as important targets for mutations that can give rise to disease and to genetic variability that underlies evolutionary change. Studies of long-range interactions between distal genomic sequences in the nucleus indicate that enhancers are often important determinants of nuclear organization, contributing to a general model for enhancer function that involves direct enhancer-promoter contact. In a number of systems, however, mechanisms for enhancer function are emerging that do not fit solely within such a model, suggesting that enhancers as a class of DNA regulatory element may be functionally and mechanistically diverse. PMID:21295696

Microglia promote learning-dependent synapse formation through BDNF

PubMed Central

Parkhurst, Christopher N.; Yang, Guang; Ninan, Ipe; Savas, Jeffrey N.; Yates, John R.; Lafaille, Juan J.; Hempstead, Barbara L.; Littman, Dan R.; Gan, Wen-Biao

2014-01-01

SUMMARY Microglia are the resident macrophages of the central nervous system and their functions have been extensively studied in various brain pathologies. The physiological roles of microglia in brain plasticity and function, however, remain unclear. To address this question, we generated CX3CR1CreER mice expressing tamoxifen-inducible Cre recombinase that allow for specific manipulation of gene function in microglia. Using CX3CR1CreER to drive diphtheria toxin receptor expression in microglia, we found that microglia could be specifically depleted from the brain upon diphtheria toxin administration. Mice depleted of microglia show deficits in multiple learning tasks and a significant reduction in motor learning-dependent synapse formation. Furthermore, Cre-dependent removal of brain-derived neurotrophic factor (BDNF) from microglia largely recapitulated the effects of microglia depletion. Microglial BDNF increases neuronal TrkB phosphorylation, a key mediator of synaptic plasticity. Together, our findings reveal important physiological functions of microglia in learning and memory by promoting learning-related synapse formation through BDNF signaling. PMID:24360280

Essential roles of Gab1 tyrosine phosphorylation in growth factor-mediated signaling and angiogenesis.

PubMed

Wang, Weiye; Xu, Suowen; Yin, Meimei; Jin, Zheng Gen

2015-02-15

Growth factors and their downstream receptor tyrosine kinases (RTKs) mediate a number of biological processes controlling cell function. Adaptor (docking) proteins, which consist exclusively of domains and motifs that mediate molecular interactions, link receptor activation to downstream effectors. Recent studies have revealed that Grb2-associated-binders (Gab) family members (including Gab1, Gab2, and Gab3), when phosphorylated on tyrosine residues, provide binding sites for multiple effector proteins, such as Src homology-2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2) and phosphatidylinositol 3-kinase (PI3K) regulatory subunit p85, thereby playing important roles in transducing RTKs-mediated signals into pathways with diversified biological functions. Here, we provide an up-to-date overview on the domain structure and biological functions of Gab1, the most intensively studied Gab family protein, in growth factor signaling and biological functions, with a special focus on angiogenesis. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

The evolutionary landscape of intergenic trans-splicing events in insects

PubMed Central

Kong, Yimeng; Zhou, Hongxia; Yu, Yao; Chen, Longxian; Hao, Pei; Li, Xuan

2015-01-01

To explore the landscape of intergenic trans-splicing events and characterize their functions and evolutionary dynamics, we conduct a mega-data study of a phylogeny containing eight species across five orders of class Insecta, a model system spanning 400 million years of evolution. A total of 1,627 trans-splicing events involving 2,199 genes are identified, accounting for 1.58% of the total genes. Homology analysis reveals that mod(mdg4)-like trans-splicing is the only conserved event that is consistently observed in multiple species across two orders, which represents a unique case of functional diversification involving trans-splicing. Thus, evolutionarily its potential for generating proteins with novel function is not broadly utilized by insects. Furthermore, 146 non-mod trans-spliced transcripts are found to resemble canonical genes from different species. Trans-splicing preserving the function of ‘breakup' genes may serve as a general mechanism for relaxing the constraints on gene structure, with profound implications for the evolution of genes and genomes. PMID:26521696

Quantifying small molecule phenotypic effects using mitochondrial morpho-functional fingerprinting and machine learning

NASA Astrophysics Data System (ADS)

Blanchet, Lionel; Smeitink, Jan A. M.; van Emst-de Vries, Sjenet E.; Vogels, Caroline; Pellegrini, Mina; Jonckheere, An I.; Rodenburg, Richard J. T.; Buydens, Lutgarde M. C.; Beyrath, Julien; Willems, Peter H. G. M.; Koopman, Werner J. H.

2015-01-01

In primary fibroblasts from Leigh Syndrome (LS) patients, isolated mitochondrial complex I deficiency is associated with increased reactive oxygen species levels and mitochondrial morpho-functional changes. Empirical evidence suggests these aberrations constitute linked therapeutic targets for small chemical molecules. However, the latter generally induce multiple subtle effects, meaning that in vitro potency analysis or single-parameter high-throughput cell screening are of limited use to identify these molecules. We combine automated image quantification and artificial intelligence to discriminate between primary fibroblasts of a healthy individual and a LS patient based upon their mitochondrial morpho-functional phenotype. We then evaluate the effects of newly developed Trolox variants in LS patient cells. This revealed that Trolox ornithylamide hydrochloride best counterbalanced mitochondrial morpho-functional aberrations, effectively scavenged ROS and increased the maximal activity of mitochondrial complexes I, IV and citrate synthase. Our results suggest that Trolox-derived antioxidants are promising candidates in therapy development for human mitochondrial disorders.

Cryogenic terahertz spectrum of (+)-methamphetamine hydrochloride and assignment using solid-state density functional theory.

PubMed

Hakey, Patrick M; Allis, Damian G; Ouellette, Wayne; Korter, Timothy M

2009-04-30

The cryogenic terahertz spectrum of (+)-methamphetamine hydrochloride from 10.0 to 100.0 cm(-1) is presented, as is the complete structural analysis and vibrational assignment of the compound using solid-state density functional theory. This cryogenic investigation reveals multiple spectral features that were not previously reported in room-temperature terahertz studies of the title compound. Modeling of the compound employed eight density functionals utilizing both solid-state and isolated-molecule methods. The results clearly indicate the necessity of solid-state simulations for the accurate assignment of solid-state THz spectra. Assignment of the observed spectral features to specific atomic motions is based on the BP density functional, which provided the best-fit solid-state simulation of the experimental spectrum. The seven experimental spectral features are the result of thirteen infrared-active vibrational modes predicted at a BP/DNP level of theory with more than 90% of the total spectral intensity associated with external crystal vibrations.

Posttranslational modification of autophagy-related proteins in macroautophagy

PubMed Central

Xie, Yangchun; Kang, Rui; Sun, Xiaofang; Zhong, Meizuo; Huang, Jin; Klionsky, Daniel J.; Tang, Daolin

2014-01-01

Macroautophagy is an intracellular catabolic process involved in the formation of multiple membrane structures ranging from phagophores to autophagosomes and autolysosomes. Dysfunction of macroautophagy is implicated in both physiological and pathological conditions. To date, 38 autophagy-related (ATG) genes have been identified as controlling these complicated membrane dynamics during macroautophagy in yeast; approximately half of these genes are clearly conserved up to human, and there are additional genes whose products function in autophagy in higher eukaryotes that are not found in yeast. The function of the ATG proteins, in particular their ability to interact with a number of macroautophagic regulators, is modulated by posttranslational modifications (PTMs) such as phosphorylation, glycosylation, ubiquitination, acetylation, lipidation, and proteolysis. In this review, we summarize our current knowledge of the role of ATG protein PTMs and their functional relevance in macroautophagy. Unraveling how these PTMs regulate ATG protein function during macroautophagy will not only reveal fundamental mechanistic insights into the regulatory process, but also provide new therapeutic targets for the treatment of autophagy-associated diseases. PMID:25484070

The bornavirus-derived human protein EBLN1 promotes efficient cell cycle transit, microtubule organisation and genome stability.

PubMed

Myers, Katie N; Barone, Giancarlo; Ganesh, Anil; Staples, Christopher J; Howard, Anna E; Beveridge, Ryan D; Maslen, Sarah; Skehel, J Mark; Collis, Spencer J

2016-10-14

It was recently discovered that vertebrate genomes contain multiple endogenised nucleotide sequences derived from the non-retroviral RNA bornavirus. Strikingly, some of these elements have been evolutionary maintained as open reading frames in host genomes for over 40 million years, suggesting that some endogenised bornavirus-derived elements (EBL) might encode functional proteins. EBLN1 is one such element established through endogenisation of the bornavirus N gene (BDV N). Here, we functionally characterise human EBLN1 as a novel regulator of genome stability. Cells depleted of human EBLN1 accumulate DNA damage both under non-stressed conditions and following exogenously induced DNA damage. EBLN1-depleted cells also exhibit cell cycle abnormalities and defects in microtubule organisation as well as premature centrosome splitting, which we attribute in part, to improper localisation of the nuclear envelope protein TPR. Our data therefore reveal that human EBLN1 possesses important cellular functions within human cells, and suggest that other EBLs present within vertebrate genomes may also possess important cellular functions.

Endocannabinoid signaling and synaptic function.

PubMed

Castillo, Pablo E; Younts, Thomas J; Chávez, Andrés E; Hashimotodani, Yuki

2012-10-04

Endocannabinoids are key modulators of synaptic function. By activating cannabinoid receptors expressed in the central nervous system, these lipid messengers can regulate several neural functions and behaviors. As experimental tools advance, the repertoire of known endocannabinoid-mediated effects at the synapse, and their underlying mechanism, continues to expand. Retrograde signaling is the principal mode by which endocannabinoids mediate short- and long-term forms of plasticity at both excitatory and inhibitory synapses. However, growing evidence suggests that endocannabinoids can also signal in a nonretrograde manner. In addition to mediating synaptic plasticity, the endocannabinoid system is itself subject to plastic changes. Multiple points of interaction with other neuromodulatory and signaling systems have now been identified. In this Review, we focus on new advances in synaptic endocannabinoid signaling in the mammalian brain. The emerging picture not only reinforces endocannabinoids as potent regulators of synaptic function but also reveals that endocannabinoid signaling is mechanistically more complex and diverse than originally thought. Copyright © 2012 Elsevier Inc. All rights reserved.

Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes and progenitors

PubMed Central

Villani, Alexandra-Chloé; Satija, Rahul; Reynolds, Gary; Sarkizova, Siranush; Shekhar, Karthik; Fletcher, James; Griesbeck, Morgane; Butler, Andrew; Zheng, Shiwei; Lazo, Suzan; Jardine, Laura; Dixon, David; Stephenson, Emily; Nilsson, Emil; Grundberg, Ida; McDonald, David; Filby, Andrew; Li, Weibo; De Jager, Philip L.; Rozenblatt-Rosen, Orit; Lane, Andrew A.; Haniffa, Muzlifah; Regev, Aviv; Hacohen, Nir

2017-01-01

Dendritic cells (DCs) and monocytes play a central role in pathogen sensing, phagocytosis and antigen presentation and consist of multiple specialized subtypes. However, their identities and interrelationships are not fully understood. Using unbiased single-cell RNA sequencing (RNA-seq) of ~2400 cells, we identified six human DCs and four monocyte subtypes in human blood. Our study reveals: a new DC subset that shares properties with plasmacytoid DCs (pDCs) but potently activates T cells, thus redefining pDCs; a new subdivision within the CD1C+ subset of DCs; the relationship between blastic plasmacytoid DC neoplasia cells and healthy DCs; and circulating progenitor of conventional DCs (cDCs). Our revised taxonomy will enable more accurate functional and developmental analyses as well as immune monitoring in health and disease. PMID:28428369

Statistical discovery of site inter-dependencies in sub-molecular hierarchical protein structuring

PubMed Central

2012-01-01

Background Much progress has been made in understanding the 3D structure of proteins using methods such as NMR and X-ray crystallography. The resulting 3D structures are extremely informative, but do not always reveal which sites and residues within the structure are of special importance. Recently, there are indications that multiple-residue, sub-domain structural relationships within the larger 3D consensus structure of a protein can be inferred from the analysis of the multiple sequence alignment data of a protein family. These intra-dependent clusters of associated sites are used to indicate hierarchical inter-residue relationships within the 3D structure. To reveal the patterns of associations among individual amino acids or sub-domain components within the structure, we apply a k-modes attribute (aligned site) clustering algorithm to the ubiquitin and transthyretin families in order to discover associations among groups of sites within the multiple sequence alignment. We then observe what these associations imply within the 3D structure of these two protein families. Results The k-modes site clustering algorithm we developed maximizes the intra-group interdependencies based on a normalized mutual information measure. The clusters formed correspond to sub-structural components or binding and interface locations. Applying this data-directed method to the ubiquitin and transthyretin protein family multiple sequence alignments as a test bed, we located numerous interesting associations of interdependent sites. These clusters were then arranged into cluster tree diagrams which revealed four structural sub-domains within the single domain structure of ubiquitin and a single large sub-domain within transthyretin associated with the interface among transthyretin monomers. In addition, several clusters of mutually interdependent sites were discovered for each protein family, each of which appear to play an important role in the molecular structure and/or function. Conclusions Our results demonstrate that the method we present here using a k-modes site clustering algorithm based on interdependency evaluation among sites obtained from a sequence alignment of homologous proteins can provide significant insights into the complex, hierarchical inter-residue structural relationships within the 3D structure of a protein family. PMID:22793672

Statistical discovery of site inter-dependencies in sub-molecular hierarchical protein structuring.

PubMed

Durston, Kirk K; Chiu, David Ky; Wong, Andrew Kc; Li, Gary Cl

2012-07-13

Much progress has been made in understanding the 3D structure of proteins using methods such as NMR and X-ray crystallography. The resulting 3D structures are extremely informative, but do not always reveal which sites and residues within the structure are of special importance. Recently, there are indications that multiple-residue, sub-domain structural relationships within the larger 3D consensus structure of a protein can be inferred from the analysis of the multiple sequence alignment data of a protein family. These intra-dependent clusters of associated sites are used to indicate hierarchical inter-residue relationships within the 3D structure. To reveal the patterns of associations among individual amino acids or sub-domain components within the structure, we apply a k-modes attribute (aligned site) clustering algorithm to the ubiquitin and transthyretin families in order to discover associations among groups of sites within the multiple sequence alignment. We then observe what these associations imply within the 3D structure of these two protein families. The k-modes site clustering algorithm we developed maximizes the intra-group interdependencies based on a normalized mutual information measure. The clusters formed correspond to sub-structural components or binding and interface locations. Applying this data-directed method to the ubiquitin and transthyretin protein family multiple sequence alignments as a test bed, we located numerous interesting associations of interdependent sites. These clusters were then arranged into cluster tree diagrams which revealed four structural sub-domains within the single domain structure of ubiquitin and a single large sub-domain within transthyretin associated with the interface among transthyretin monomers. In addition, several clusters of mutually interdependent sites were discovered for each protein family, each of which appear to play an important role in the molecular structure and/or function. Our results demonstrate that the method we present here using a k-modes site clustering algorithm based on interdependency evaluation among sites obtained from a sequence alignment of homologous proteins can provide significant insights into the complex, hierarchical inter-residue structural relationships within the 3D structure of a protein family.

Increased sensitivity to age-related differences in brain functional connectivity during continuous multiple object tracking compared to resting-state.

PubMed

Dørum, Erlend S; Kaufmann, Tobias; Alnæs, Dag; Andreassen, Ole A; Richard, Geneviève; Kolskår, Knut K; Nordvik, Jan Egil; Westlye, Lars T

2017-03-01

Age-related differences in cognitive agility vary greatly between individuals and cognitive functions. This heterogeneity is partly mirrored in individual differences in brain network connectivity as revealed using resting-state functional magnetic resonance imaging (fMRI), suggesting potential imaging biomarkers for age-related cognitive decline. However, although convenient in its simplicity, the resting state is essentially an unconstrained paradigm with minimal experimental control. Here, based on the conception that the magnitude and characteristics of age-related differences in brain connectivity is dependent on cognitive context and effort, we tested the hypothesis that experimentally increasing cognitive load boosts the sensitivity to age and changes the discriminative network configurations. To this end, we obtained fMRI data from younger (n=25, mean age 24.16±5.11) and older (n=22, mean age 65.09±7.53) healthy adults during rest and two load levels of continuous multiple object tracking (MOT). Brain network nodes and their time-series were estimated using independent component analysis (ICA) and dual regression, and the edges in the brain networks were defined as the regularized partial temporal correlations between each of the node pairs at the individual level. Using machine learning based on a cross-validated regularized linear discriminant analysis (rLDA) we attempted to classify groups and cognitive load from the full set of edge-wise functional connectivity indices. While group classification using resting-state data was highly above chance (approx. 70% accuracy), functional connectivity (FC) obtained during MOT strongly increased classification performance, with 82% accuracy for the young and 95% accuracy for the old group at the highest load level. Further, machine learning revealed stronger differentiation between rest and task in young compared to older individuals, supporting the notion of network dedifferentiation in cognitive aging. Task-modulation in edgewise FC was primarily observed between attention- and sensorimotor networks; with decreased negative correlations between attention- and default mode networks in older adults. These results demonstrate that the magnitude and configuration of age-related differences in brain functional connectivity are partly dependent on cognitive context and load, which emphasizes the importance of assessing brain connectivity differences across a range of cognitive contexts beyond the resting-state. Copyright © 2017 Elsevier Inc. All rights reserved.

Visual discrimination in the pigeon (Columba livia): effects of selective lesions of the nucleus rotundus

NASA Technical Reports Server (NTRS)

Laverghetta, A. V.; Shimizu, T.

1999-01-01

The nucleus rotundus is a large thalamic nucleus in birds and plays a critical role in many visual discrimination tasks. In order to test the hypothesis that there are functionally distinct subdivisions in the nucleus rotundus, effects of selective lesions of the nucleus were studied in pigeons. The birds were trained to discriminate between different types of stationary objects and between different directions of moving objects. Multiple regression analyses revealed that lesions in the anterior, but not posterior, division caused deficits in discrimination of small stationary stimuli. Lesions in neither the anterior nor posterior divisions predicted effects in discrimination of moving stimuli. These results are consistent with a prediction led from the hypothesis that the nucleus is composed of functional subdivisions.

Raman studies of single-walled carbon nanotubes synthesized by pulsed laser ablation at room temperature

NASA Astrophysics Data System (ADS)

Dixit, Saurabh; Shukla, A. K.

2018-06-01

In this article, single-walled carbon nanotubes (SWCNTs) are synthesized at room temperature using pulsed laser ablation of ferrocene mixed graphitic target. Radial breathing mode (RBM) reveals the presence of semiconducting SWCNTs of multiple diameters. Quantum confinement model is developed for Raman line-shape of G - feature. It is invoked here that G-feature is the manifestation of TO phonons in the semiconducting SWCNTs. Disorder in the SWCNTs is studied here as a function of the concentration of ferrocene in the graphitic target using X-ray diffraction analysis, oscillator strength of G - feature and D mode and Raman line-shape model of G - feature. Furthermore, phonon softening of G - feature of semiconducting SWCNTs is observed as a function of the diameter of nanotube.

Engineering microbial consortia to enhance biomining and bioremediation.

PubMed

Brune, Karl D; Bayer, Travis S

2012-01-01

In natural environments microorganisms commonly exist as communities of multiple species that are capable of performing more varied and complicated tasks than clonal populations. Synthetic biologists have engineered clonal populations with characteristics such as differentiation, memory, and pattern formation, which are usually associated with more complex multicellular organisms. The prospect of designing microbial communities has alluring possibilities for environmental, biomedical, and energy applications, and is likely to reveal insight into how natural microbial consortia function. Cell signaling and communication pathways between different species are likely to be key processes for designing novel functions in synthetic and natural consortia. Recent efforts to engineer synthetic microbial interactions will be reviewed here, with particular emphasis given to research with significance for industrial applications in the field of biomining and bioremediation of acid mine drainage.

Timing, sequencing, and executive control in repetitive movement production.

PubMed

Krampe, Ralf Th; Mayr, Ulrich; Kliegl, Reinhold

2005-06-01

The authors demonstrate that the timing and sequencing of target durations require low-level timing and executive control. Sixteen young (M-sub(age) = 19 years) and 16 older (M-sub(age) = 70 years) adults participated in 2 experiments. In Experiment 1, individual mean-variance functions for low-level timing (isochronous tapping) and the sequencing of multiple targets (rhythm production) revealed (a) a dissociation of low-level timing and sequencing in both age groups, (b) negligible age differences for low-level timing, and (c) large age differences for sequencing. Experiment 2 supported the distinction between low-level timing and executive functions: Selection against a dominant rhythm and switching between rhythms impaired performances in both age groups and induced pronounced perseveration of the dominant pattern in older adults. ((c) 2005 APA, all rights reserved).

Lithium Down-regulates Histone Deacetylase 1 (HDAC1) and Induces Degradation of Mutant Huntingtin*

PubMed Central

Wu, Shuai; Zheng, Shui-Di; Huang, Hong-Ling; Yan, Li-Chong; Yin, Xiao-Fei; Xu, Hai-Neng; Zhang, Kang-Jian; Gui, Jing-Hua; Chu, Liang; Liu, Xin-Yuan

2013-01-01

Lithium is an effective mood stabilizer that has been clinically used to treat bipolar disorder for several decades. Recent studies have suggested that lithium possesses robust neuroprotective and anti-tumor properties. Thus far, a large number of lithium targets have been discovered. Here, we report for the first time that HDAC1 is a target of lithium. Lithium significantly down-regulated HDAC1 at the translational level by targeting HDAC1 mRNA. We also showed that depletion of HDAC1 is essential for the neuroprotective effects of lithium and for the lithium-mediated degradation of mutant huntingtin through the autophagic pathway. Our studies explain the multiple functions of lithium and reveal a novel mechanism for the function of lithium in neurodegeneration. PMID:24165128

HIV-1 nucleocapsid protein localizes efficiently to the nucleus and nucleolus.

PubMed

Yu, Kyung Lee; Lee, Sun Hee; Lee, Eun Soo; You, Ji Chang

2016-05-01

The HIV-1 nucleocapsid (NC) is an essential viral protein containing two highly conserved retroviral-type zinc finger (ZF) motifs, which functions in multiple stages of the HIV-1 life cycle. Although a number of functions for NC either in its mature form or as a domain of Gag have been revealed, little is known about the intracellular localization of NC and, moreover, its role in Gag protein trafficking. Here, we have investigated various forms of HIV-1 NC protein for its cellular localization and found that the NC has a strong nuclear and nucleolar localization activity. The linker region, composed of a stretch of basic amino acids between the two ZF motifs, was necessary and sufficient for the activity. Copyright © 2016 Elsevier Inc. All rights reserved.

Engineering microbial consortia to enhance biomining and bioremediation

PubMed Central

Brune, Karl D.; Bayer, Travis S.

2012-01-01

In natural environments microorganisms commonly exist as communities of multiple species that are capable of performing more varied and complicated tasks than clonal populations. Synthetic biologists have engineered clonal populations with characteristics such as differentiation, memory, and pattern formation, which are usually associated with more complex multicellular organisms. The prospect of designing microbial communities has alluring possibilities for environmental, biomedical, and energy applications, and is likely to reveal insight into how natural microbial consortia function. Cell signaling and communication pathways between different species are likely to be key processes for designing novel functions in synthetic and natural consortia. Recent efforts to engineer synthetic microbial interactions will be reviewed here, with particular emphasis given to research with significance for industrial applications in the field of biomining and bioremediation of acid mine drainage. PMID:22679443

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.

Anticholinergic load negatively correlates with recovery of cognitive activities of daily living for geriatric patients after stroke in the convalescent stage.

PubMed

Kose, E; Hirai, T; Seki, T; Hidaka, S; Hamamoto, T

2018-05-16

Anticholinergic drugs are associated with risks of falls, confusion and cognitive dysfunction. However, the effect of anticholinergic drug use on rehabilitation outcomes after a stroke is poorly documented. We therefore aimed to establish whether the anticholinergic load was associated with functional recovery among geriatric patients convalescing after stroke. Consecutive geriatric stroke patients admitted and discharged from a convalescence rehabilitation ward between 2010 and 2016 were included in this retrospective cohort study. Anticholinergic load was assessed by the Anticholinergic Risk Scale (ARS), and functional recovery was assessed by the Functional Independence Measure (FIM). The primary outcome was cognitive FIM (FIM-C) gain, but we also assessed the interaction of other putative factors identified from univariate analysis. Multivariate analyses were performed, adjusting for confounding factors. We included 418 participants (171 males, 247 females) with a median age of 78 years (interquartile range, 72-84 years). Multiple regression analysis revealed that ARS change, length of stay, and epilepsy were independently and negatively correlated with cognitive FIM gain. Multiple logistic regression analysis indicated that the "Comprehension" and "Memory" items of the cognitive FIM gain were independently and negatively associated with anticholinergic load. A causal relationship cannot be established, but increased ARS scores during hospitalization may predict limited cognitive functional improvement in geriatric patients after stroke. Alternatively, cognitive impairment may lead to increased use of anticholinergic drugs. © 2018 John Wiley & Sons Ltd.

A study of satisfaction of medical students on their mentoring programs at one medical school in Korea

PubMed Central

2017-01-01

Purpose The purpose of this study was to investigate the awareness levels of medical students regarding the characteristics of each function within a mentoring program conducted within Kyung Hee University and to ultimately suggest points for reformation. Medical students’ awareness levels were determined using a 29-item questionnaire. Methods The questionnaire was conducted on 347 medical students, excluding 25 students who either marked multiple answers or did not reply. The assessment of the program was based on a questionnaire with the use of a 5-point Likert scale using SPSS version 22.0. Multiple regression was conducted to examine the relationship between the satisfaction level, regarding functions of mentoring programs, and characteristics of mentoring programs. Interviews were conducted to supplement additional information that was hard to gain from the questionnaire. Results The results on demographic and functional characteristics revealed that there was no statistically significant differences in satisfaction levels across gender, whereas there were significant differences across grade levels. In addition, there were significant differences in the frequency of meetings and topics of conversation while the length of meetings and meeting place were not significantly different. Conclusion For the improved mentoring programs for medical students, the program should focus on the frequency of meetings and the topics of conversation. Furthermore, mentoring programs of high quality can be expected if professors take interview results into consideration. Also, students want to be provided with psychosocial advice from mentors in various ways such as role model function. PMID:29207456

Posttraumatic headache: biopsychosocial comparisons with multiple control groups.

PubMed

Tatrow, Kristin; Blanchard, Edward B; Hickling, Edward J; Silverman, Daniel J

2003-01-01

This study examined somatic, psychological, and cognitive functioning of subjects with posttraumatic headache in comparison with multiple control groups. Posttraumatic headache is not as widely studied as other forms of headache (eg, tension-type, migraine). Previous research has suggested poor psychological functioning in patients with posttraumatic headache in comparison with other groups of patients with pain; however, this group has yet to be compared with a group of persons who have experienced trauma but are headache-free. Nineteen subjects with posttraumatic headache were studied, with full assessments available for 14 participants. Comparison groups, containing 16 participants each, included another headache group, a nonheadache group, and a trauma (motor vehicle accident) survivor nonheadache group. Participants completed several measures assessing somatic, psychological, and cognitive functioning. Findings revealed that the posttraumatic headache group exhibited significantly poorer functioning than the comparison groups on several measures including the Psychosomatic Symptom Checklist, Postconcussion Syndrome Checklist, axis II psychiatric diagnoses, Minnesota Multiphasic Personality Inventory, and the Daily Hassles Scale (frequency and total). Additionally, they scored higher on the following: number of axis I psychiatric diagnoses, the Daily Hassles Scale (intensity), Beck Depression Inventory, State-Trait Anxiety Inventory, and State-Trait Anger Expression Inventory. The posttraumatic headache group was similar to the other trauma group on the Posttraumatic Stress Disorder Symptom Checklist and the Life-Trauma Checklist. This study confirmed the distress seen in this understudied population of persons with headache and highlights areas of focus for proper assessment and treatment of those with headache and who have had an accident.

Pericytes of Multiple Organs Do Not Behave as Mesenchymal Stem Cells In Vivo.

PubMed

Guimarães-Camboa, Nuno; Cattaneo, Paola; Sun, Yunfu; Moore-Morris, Thomas; Gu, Yusu; Dalton, Nancy D; Rockenstein, Edward; Masliah, Eliezer; Peterson, Kirk L; Stallcup, William B; Chen, Ju; Evans, Sylvia M

2017-03-02

Pericytes are widely believed to function as mesenchymal stem cells (MSCs), multipotent tissue-resident progenitors with great potential for regenerative medicine. Cultured pericytes isolated from distinct tissues can differentiate into multiple cell types in vitro or following transplantation in vivo. However, the cell fate plasticity of endogenous pericytes in vivo remains unclear. Here, we show that the transcription factor Tbx18 selectively marks pericytes and vascular smooth muscle cells in multiple organs of adult mouse. Fluorescence-activated cell sorting (FACS)-purified Tbx18-expressing cells behaved as MSCs in vitro. However, lineage-tracing experiments using an inducible Tbx18-CreERT2 line revealed that pericytes and vascular smooth muscle cells maintained their identity in aging and diverse pathological settings and did not significantly contribute to other cell lineages. These results challenge the current view of endogenous pericytes as multipotent tissue-resident progenitors and suggest that the plasticity observed in vitro or following transplantation in vivo arises from artificial cell manipulations ex vivo. Copyright © 2016 Elsevier Inc. All rights reserved.

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.

Cortical travelling waves: mechanisms and computational principles

PubMed Central

Muller, Lyle; Chavane, Frédéric; Reynolds, John

2018-01-01

Multichannel recording technologies have revealed travelling waves of neural activity in multiple sensory, motor and cognitive systems. These waves can be spontaneously generated by recurrent circuits or evoked by external stimuli. They travel along brain networks at multiple scales, transiently modulating spiking and excitability as they pass. Here, we review recent experimental findings that have found evidence for travelling waves at single-area (mesoscopic) and whole-brain (macroscopic) scales. We place these findings in the context of the current theoretical understanding of wave generation and propagation in recurrent networks. During the large low-frequency rhythms of sleep or the relatively desynchronized state of the awake cortex, travelling waves may serve a variety of functions, from long-term memory consolidation to processing of dynamic visual stimuli. We explore new avenues for experimental and computational understanding of the role of spatiotemporal activity patterns in the cortex. PMID:29563572

Boosting healthy heart employer-sponsored health dissemination efforts: identification and information-sharing intentions.

PubMed

Stephens, Keri K; Pastorek, Angie; Crook, Brittani; Mackert, Michael; Donovan, Erin E; Shalev, Heidi

2015-01-01

Health information dissemination options have expanded to include workplaces and employer-sponsored efforts. This study focuses on a core relational concept found in workplaces, organizational identification-the feeling of belongingness-and the impact of partnering with employers and health clinics in health information dissemination. We use social-identity theory and multiple identification to test our predictions from a sample of working adults representing more than 100 different employers. We found that when people strongly identify with their employer, they have increased health behavioral intentions and they intend to talk about the health information with coworkers. The significant models explain more than 50% and 30% of the variance in these two outcomes. The experimental results examining single and multiple organizational sources revealed no differences on any outcomes. These findings offer a contribution to health information dissemination research by articulating how identification with an employer functions to affect behavioral intentions.

Churg–Strauss syndrome in a patient previously diagnosed with multiple sclerosis

PubMed Central

Sarkar, Pamela; Ibitoye, Richard Tolulope; Promnitz, Douglas Anthony

2011-01-01

A lady in her 70s with a background of multiple sclerosis (MS) and late-onset asthma was admitted with a 2-week history of cough and shortness of breath, progressive right-sided weakness and functional decline. Investigation revealed eosinophilia, elevated myeloperoxidase antineutrophil cytoplasmic antibody, CT sinuses showed long-standing inflammatory changes consistent with sinonasal polyposis and MRI head showed lesions consistent with vasculitis. She then developed left-sided weakness and increased wheeze. Review of her case notes demonstrated that, the eosinophilia was long-standing, her asthma was severe and steroid-dependent, and her neurologic syndrome was atypical for MS. Intravenous methylprednisolone then cyclophosphamide were administered. She demonstrated remarkable improvement, becoming more alert, with improvement in left-sided weakness. A diagnosis of Churg–Strauss syndrome was established. She was discharged to a nursing home with outpatient rheumatology follow-up. The diagnosis of MS was revisited. PMID:22679315

Spectroscopic evidence for two-gap superconductivity in the quasi-1D chalcogenide Nb2Pd0.81S5

NASA Astrophysics Data System (ADS)

Park, Eunsung; Lee, Sangyun; Ronning, Filip; Thompson, Joe D.; Zhang, Qiu; Balicas, Luis; Lu, Xin; Park, Tuson

2018-04-01

Low-dimensional electronic systems with confined electronic wave functions have attracted interest due to their propensity toward novel quantum phases and their use in wide range of nanotechnologies. The newly discovered chalcogenide Nb2PdS5 possesses a quasi-one-dimensional electronic structure and becomes superconducting. Here, we report spectroscopic evidence for two-band superconductivity, where soft point-contact spectroscopic measurements in the superconducting (SC) state reveal Andreev reflection in the differential conductance G. Multiple peaks in G are observed at 1.8 K and explained by the two-band Blonder–Tinkham–Klapwijk model with two gaps Δ1  =  0.61 meV and Δ2  =  1.20 meV. The progressive evolution of G with temperature and magnetic field corroborates the multiple nature of the SC gaps.

Small RNAs Reflect Grandparental Environments in Apomictic Dandelion

PubMed Central

Morgado, Lionel; Preite, Veronica; Oplaat, Carla; Anava, Sarit; Ferreira de Carvalho, Julie; Rechavi, Oded; Johannes, Frank; Verhoeven, Koen J.F.

2017-01-01

Abstract Plants can show long-term effects of environmental stresses and in some cases a stress “memory” has been reported to persist across generations, potentially mediated by epigenetic mechanisms. However, few documented cases exist of transgenerational effects that persist for multiple generations and it remains unclear if or how epigenetic mechanisms are involved. Here, we show that the composition of small regulatory RNAs in apomictic dandelion lineages reveals a footprint of drought stress and salicylic acid treatment experienced two generations ago. Overall proportions of 21 and 24 nt RNA pools were shifted due to grandparental treatments. While individual genes did not show strong up- or downregulation of associated sRNAs, the subset of genes that showed the strongest shifts in sRNA abundance was significantly enriched for several GO terms including stress-specific functions. This suggests that a stress-induced signal was transmitted across multiple unexposed generations leading to persistent changes in epigenetic gene regulation. PMID:28472380

Comparisons of mathematics achievement of grade 8 students in the United States and the Russian Federation.

PubMed

Bazarova, Saodat I; Engelhard, George

2004-01-01

Using the Mantel-Haenszel (MH) Procedure, we analyzed data for 7,087 American and 4,022 Russian Grade 8 students from the Third International Mathematics and Science Study (TIMSS) to compare mathematics achievement in the two countries on each of the 124 multiple-choice items. The results of the analyses indicate that the performance of the students on individual multiple-choice mathematics items vary by country. The results also suggest that the relationship between country and item performance differ as a function of content area. A total score of a country's achievement does not provide the whole picture of achievement dynamics; it averages out potentially important information on student achievement and the causes of their performance relative to other countries. The dynamics of achievement across countries will not be revealed unless the analyses are done at the item level.

Applications of the Phytomedicine Echinacea purpurea (Purple Coneflower) in Infectious Diseases

PubMed Central

Hudson, James B.

2012-01-01

Extracts of Echinacea purpurea (EP, purple coneflower) have been used traditionally in North America for the treatment of various types of infections and wounds, and they have become very popular herbal medicines globally. Recent studies have revealed that certain standardized preparations contain potent and selective antiviral and antimicrobial activities. In addition, they display multiple immune-modulatory activities, comprising stimulation of certain immune functions such as phagocytic activity of macrophages and suppression of the proinflammatory responses of epithelial cells to viruses and bacteria, which are manifested as alterations in secretion of various cytokines and chemokines. These immune modulations result from upregulation or downregulation of the relevant genes and their transcription factors. All these bioactivities can be demonstrated at noncytotoxic concentrations of extract and appear to be due to multiple components rather than the individual chemical compounds that characterize Echinacea extracts. Potential applications of the bioactive extracts may go beyond their traditional uses. PMID:22131823

Predicting invasive species impacts: a community module functional response approach reveals context dependencies.

PubMed

Paterson, Rachel A; Dick, Jaimie T A; Pritchard, Daniel W; Ennis, Marilyn; Hatcher, Melanie J; Dunn, Alison M

2015-03-01

Predatory functional responses play integral roles in predator-prey dynamics, and their assessment promises greater understanding and prediction of the predatory impacts of invasive species. Other interspecific interactions, however, such as parasitism and higher-order predation, have the potential to modify predator-prey interactions and thus the predictive capability of the comparative functional response approach. We used a four-species community module (higher-order predator; focal native or invasive predators; parasites of focal predators; native prey) to compare the predatory functional responses of native Gammarus duebeni celticus and invasive Gammarus pulex amphipods towards three invertebrate prey species (Asellus aquaticus, Simulium spp., Baetis rhodani), thus, quantifying the context dependencies of parasitism and a higher-order fish predator on these functional responses. Our functional response experiments demonstrated that the invasive amphipod had a higher predatory impact (lower handling time) on two of three prey species, which reflects patterns of impact observed in the field. The community module also revealed that parasitism had context-dependent influences, for one prey species, with the potential to further reduce the predatory impact of the invasive amphipod or increase the predatory impact of the native amphipod in the presence of a higher-order fish predator. Partial consumption of prey was similar for both predators and occurred increasingly in the order A. aquaticus, Simulium spp. and B. rhodani. This was associated with increasing prey densities, but showed no context dependencies with parasitism or higher-order fish predator. This study supports the applicability of comparative functional responses as a tool to predict and assess invasive species impacts incorporating multiple context dependencies. © 2014 The Authors. Journal of Animal Ecology © 2014 British Ecological Society.

Dissociable Temporo-Parietal Memory Networks Revealed by Functional Connectivity during Episodic Retrieval

PubMed Central

Hirose, Satoshi; Kimura, Hiroko M.; Jimura, Koji; Kunimatsu, Akira; Abe, Osamu; Ohtomo, Kuni; Miyashita, Yasushi; Konishi, Seiki

2013-01-01

Episodic memory retrieval most often recruits multiple separate processes that are thought to involve different temporal regions. Previous studies suggest dissociable regions in the left lateral parietal cortex that are associated with the retrieval processes. Moreover, studies using resting-state functional connectivity (RSFC) have provided evidence for the temporo-parietal memory networks that may support the retrieval processes. In this functional MRI study, we tested functional significance of the memory networks by examining functional connectivity of brain activity during episodic retrieval in the temporal and parietal regions of the memory networks. Recency judgments, judgments of the temporal order of past events, can be achieved by at least two retrieval processes, relational and item-based. Neuroimaging results revealed several temporal and parietal activations associated with relational/item-based recency judgments. Significant RSFC was observed between one parahippocampal region and one left lateral parietal region associated with relational recency judgments, and between four lateral temporal regions and another left lateral parietal region associated with item-based recency judgments. Functional connectivity during task was found to be significant between the parahippocampal region and the parietal region in the RSFC network associated with relational recency judgments. However, out of the four tempo-parietal RSFC networks associated with item-based recency judgments, only one of them (between the left posterior lateral temporal region and the left lateral parietal region) showed significant functional connectivity during task. These results highlight the contrasting roles of the parahippocampal and the lateral temporal regions in recency judgments, and suggest that only a part of the tempo-parietal RSFC networks are recruited to support particular retrieval processes. PMID:24009657

Which experimental systems should we use for human microbiome science?

PubMed

Douglas, Angela E

2018-03-01

Microbiome science is revealing that the phenotype and health of animals, including humans, depend on the sustained function of their resident microorganisms. In this essay, I argue for thoughtful choice of model systems for human microbiome science. A greater variety of experimental systems, including wider use of invertebrate models, would benefit biomedical research, while systems ill-suited to experimental and genetic manipulation can be used to address very limited sets of scientific questions. Microbiome science benefits from the coordinated use of multiple systems, which is facilitated by networks of researchers with expertise in different experimental systems.

Human genetic variation and the gut microbiome in disease.

PubMed

Hall, Andrew Brantley; Tolonen, Andrew C; Xavier, Ramnik J

2017-11-01

Taxonomic and functional changes to the composition of the gut microbiome have been implicated in multiple human diseases. Recent microbiome genome-wide association studies reveal that variants in many human genes involved in immunity and gut architecture are associated with an altered composition of the gut microbiome. Although many factors can affect the microbial organisms residing in the gut, a number of recent findings support the hypothesis that certain host genetic variants predispose an individual towards microbiome dysbiosis. This condition, in which the normal microbiome population structure is disturbed, is a key feature in disorders of metabolism and immunity.

Pearson disease in an infant presenting with severe hypoplastic anemia, normal pancreatic function, and progressive liver failure.

PubMed

Shapira, Adi; Konopnicki, Muriel; Hammad-Saied, Mohammed; Shabad, Evelyn

2014-07-01

Pearson disease is a rare, usually fatal, mitochondrial disorder affecting primarily the bone marrow and the exocrine pancreas. We report a previously healthy 10-week-old girl who presented with profound macrocytic anemia followed by pancytopenia, synthetic liver dysfunction with liver steatosis, and metabolic acidosis with high lactate levels. She had no pancreatic involvement. Multiple cytoplasmic vacuoles in myelocytes and monocytes were seen upon microscopic evaluation of the bone marrow. Genetic analysis of the mitochondrial genome revealed a 5 kbp deletion, thus establishing the diagnosis of Pearson disease.

Epigenetic modulation by TFII-I during embryonic stem cell differentiation.

PubMed

Bayarsaihan, Dashzeveg; Makeyev, Aleksandr V; Enkhmandakh, Badam

2012-10-01

TFII-I transcription factors play an essential role during early vertebrate embryogenesis. Genome-wide mapping studies by ChIP-seq and ChIP-chip revealed that TFII-I primes multiple genomic loci in mouse embryonic stem cells and embryonic tissues. Moreover, many TFII-I-bound regions co-localize with H3K4me3/K27me3 bivalent chromatin within the promoters of lineage-specific genes. This minireview provides a summary of current knowledge regarding the function of TFII-I in epigenetic control of stem cell differentiation. Copyright © 2012 Wiley Periodicals, Inc.

Differences between child and adult large-scale functional brain networks for reading tasks.

PubMed

Liu, Xin; Gao, Yue; Di, Qiqi; Hu, Jiali; Lu, Chunming; Nan, Yun; Booth, James R; Liu, Li

2018-02-01

Reading is an important high-level cognitive function of the human brain, requiring interaction among multiple brain regions. Revealing differences between children's large-scale functional brain networks for reading tasks and those of adults helps us to understand how the functional network changes over reading development. Here we used functional magnetic resonance imaging data of 17 adults (19-28 years old) and 16 children (11-13 years old), and graph theoretical analyses to investigate age-related changes in large-scale functional networks during rhyming and meaning judgment tasks on pairs of visually presented Chinese characters. We found that: (1) adults had stronger inter-regional connectivity and nodal degree in occipital regions, while children had stronger inter-regional connectivity in temporal regions, suggesting that adults rely more on visual orthographic processing whereas children rely more on auditory phonological processing during reading. (2) Only adults showed between-task differences in inter-regional connectivity and nodal degree, whereas children showed no task differences, suggesting the topological organization of adults' reading network is more specialized. (3) Children showed greater inter-regional connectivity and nodal degree than adults in multiple subcortical regions; the hubs in children were more distributed in subcortical regions while the hubs in adults were more distributed in cortical regions. These findings suggest that reading development is manifested by a shift from reliance on subcortical to cortical regions. Taken together, our study suggests that Chinese reading development is supported by developmental changes in brain connectivity properties, and some of these changes may be domain-general while others may be specific to the reading domain. © 2017 Wiley Periodicals, Inc.

Obese Japanese Patients with Stroke Have Higher Functional Recovery in Convalescent Rehabilitation Wards: A Retrospective Cohort Study.

PubMed

Nishioka, Shinta; Wakabayashi, Hidetaka; Yoshida, Tomomi; Mori, Natsumi; Watanabe, Riko; Nishioka, Emi

2016-01-01

A protective effect of excessive body mass index (BMI) on mortality or functional outcome in patients with stroke is not well established in the Asian population. This study aimed to explore whether obese patients with stroke have advantages for functional improvement in Japanese rehabilitation wards. This retrospective cohort study included consecutive patients with stroke admitted and discharged from convalescent rehabilitation wards between 2011 and 2015. Demographic data, BMI, Functional Independence Measure (FIM) score, and nutritional status were analyzed. Participants were classified into 4 groups according to BMI (underweight <18.5 kg/m(2), standard 18.5-<23 kg/m(2), overweight 23-<27.5 kg/m(2), obese ≥27.5 kg/m(2)). The primary outcome was the FIM gain, and the secondary outcome was the FIM score at discharge. Multiple regression analysis was performed to analyze the relationship between BMI and functional recovery. In total, 897 participants (males 484, females 413; mean age 71.6 years) were analyzed and classified as underweight (134), standard (432), overweight (277), and obese (54). The median FIM gain and the FIM score at discharge were 30 and 114, respectively. The FIM gain in the obese group was significantly higher than those in the other groups. Multiple regression analysis revealed that obesity was independently correlated with the FIM gain, and those at discharge after adjusting for confounders such as age, gender, and FIM score on admission. Obese Japanese convalescent patients with stroke may have some advantages for functional recovery in rehabilitation wards. Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Cerebral responses to innocuous somatic pressure stimulation following aerobic exercise rehabilitation in chronic pain patients: a functional magnetic resonance imaging study

PubMed Central

Micalos, Peter S; Korgaonkar, Mayuresh S; Drinkwater, Eric J; Cannon, Jack; Marino, Frank E

2014-01-01

Objective The purpose of this research was to assess the functional brain activity and perceptual rating of innocuous somatic pressure stimulation before and after exercise rehabilitation in patients with chronic pain. Materials and methods Eleven chronic pain patients and eight healthy pain-free controls completed 12 weeks of supervised aerobic exercise intervention. Perceptual rating of standardized somatic pressure stimulation (2 kg) on the right anterior mid-thigh and brain responses during functional magnetic resonance imaging (fMRI) were assessed at pre- and postexercise rehabilitation. Results There was a significant difference in the perceptual rating of innocuous somatic pressure stimulation between the chronic pain and control groups (P=0.02) but no difference following exercise rehabilitation. Whole brain voxel-wise analysis with correction for multiple comparisons revealed trends for differences in fMRI responses between the chronic pain and control groups in the superior temporal gyrus (chronic pain > control, corrected P=0.30), thalamus, and caudate (control > chronic, corrected P=0.23). Repeated measures of the regions of interest (5 mm radius) for blood oxygen level-dependent signal response revealed trend differences for superior temporal gyrus (P=0.06), thalamus (P=0.04), and caudate (P=0.21). Group-by-time interactions revealed trend differences in the caudate (P=0.10) and superior temporal gyrus (P=0.29). Conclusion Augmented perceptual and brain responses to innocuous somatic pressure stimulation were shown in the chronic pain group compared to the control group; however, 12-weeks of exercise rehabilitation did not significantly attenuate these responses. PMID:25210471

Novel candidate genes of the PARK7 interactome as mediators of apoptosis and acetylation in multiple sclerosis: An in silico analysis.

PubMed

Vavougios, George D; Zarogiannis, Sotirios G; Krogfelt, Karen Angeliki; Gourgoulianis, Konstantinos; Mitsikostas, Dimos Dimitrios; Hadjigeorgiou, Georgios

2018-01-01

currently only 4 studies have explored the potential role of PARK7's dysregulation in MS pathophysiology Currently, no study has evaluated the potential role of the PARK7 interactome in MS. The aim of our study was to assess the differential expression of PARK7 mRNA in peripheral blood mononuclears (PBMCs) donated from MS versus healthy patients using data mining techniques. The PARK7 interactome data from the GDS3920 profile were scrutinized for differentially expressed genes (DEGs); Gene Enrichment Analysis (GEA) was used to detect significantly enriched biological functions. 27 differentially expressed genes in the MS dataset were detected; 12 of these (NDUFA4, UBA2, TDP2, NPM1, NDUFS3, SUMO1, PIAS2, KIAA0101, RBBP4, NONO, RBBP7 AND HSPA4) are reported for the first time in MS. Stepwise Linear Discriminant Function Analysis constructed a predictive model (Wilk's λ = 0.176, χ 2 = 45.204, p = 1.5275e -10 ) with 2 variables (TIDP2, RBBP4) that achieved 96.6% accuracy when discriminating between patients and controls. Gene Enrichment Analysis revealed that induction and regulation of programmed / intrinsic cell death represented the most salient Gene Ontology annotations. Cross-validation on systemic lupus erythematosus and ischemic stroke datasets revealed that these functions are unique to the MS dataset. Based on our results, novel potential target genes are revealed; these differentially expressed genes regulate epigenetic and apoptotic pathways that may further elucidate underlying mechanisms of autorreactivity in MS. Copyright © 2017 Elsevier B.V. All rights reserved.