Multiple sclerosis lesions affect intrinsic functional connectivity of the spinal cord.

PubMed

Conrad, Benjamin N; Barry, Robert L; Rogers, Baxter P; Maki, Satoshi; Mishra, Arabinda; Thukral, Saakshi; Sriram, Subramaniam; Bhatia, Aashim; Pawate, Siddharama; Gore, John C; Smith, Seth A

2018-06-01

Patients with multiple sclerosis present with focal lesions throughout the spinal cord. There is a clinical need for non-invasive measurements of spinal cord activity and functional organization in multiple sclerosis, given the cord's critical role in the disease. Recent reports of spontaneous blood oxygenation level-dependent fluctuations in the spinal cord using functional MRI suggest that, like the brain, cord activity at rest is organized into distinct, synchronized functional networks among grey matter regions, likely related to motor and sensory systems. Previous studies looking at stimulus-evoked activity in the spinal cord of patients with multiple sclerosis have demonstrated increased levels of activation as well as a more bilateral distribution of activity compared to controls. Functional connectivity studies of brain networks in multiple sclerosis have revealed widespread alterations, which may take on a dynamic trajectory over the course of the disease, with compensatory increases in connectivity followed by decreases associated with structural damage. We build upon this literature by examining functional connectivity in the spinal cord of patients with multiple sclerosis. Using ultra-high field 7 T imaging along with processing strategies for robust spinal cord functional MRI and lesion identification, the present study assessed functional connectivity within cervical cord grey matter of patients with relapsing-remitting multiple sclerosis (n = 22) compared to a large sample of healthy controls (n = 56). Patient anatomical images were rated for lesions by three independent raters, with consensus ratings revealing 19 of 22 patients presented with lesions somewhere in the imaged volume. Linear mixed models were used to assess effects of lesion location on functional connectivity. Analysis in control subjects demonstrated a robust pattern of connectivity among ventral grey matter regions as well as a distinct network among dorsal regions. A gender effect was also observed in controls whereby females demonstrated higher ventral network connectivity. Wilcoxon rank-sum tests detected no differences in average connectivity or power of low frequency fluctuations in patients compared to controls. The presence of lesions was, however, associated with local alterations in connectivity with differential effects depending on columnar location. The patient results suggest that spinal cord functional networks are generally intact in relapsing-remitting multiple sclerosis but that lesions are associated with focal abnormalities in intrinsic connectivity. These findings are discussed in light of the current literature on spinal cord functional MRI and the potential neurological underpinnings.

Decreased cerebellar-cerebral connectivity contributes to complex task performance

PubMed Central

Knops, André

2016-01-01

The cerebellum's role in nonmotor processes is now well accepted, but cerebellar interaction with cerebral targets is not well understood. Complex cognitive tasks activate cerebellar, parietal, and frontal regions, but the effective connectivity between these regions has never been tested. To this end, we used psycho-physiological interactions (PPI) analysis to test connectivity changes of cerebellar and parietal seed regions in complex (2-digit by 1-digit multiplication, e.g., 12 × 3) vs. simple (1-digit by 1-digit multiplication, e.g., 4 × 3) task conditions (“complex − simple”). For cerebellar seed regions (lobule VI, hemisphere and vermis), we found significantly decreased cerebellar-parietal, cerebellar-cingulate, and cerebellar-frontal connectivity in complex multiplication. For parietal seed regions (PFcm, PFop, PFm) we found significantly increased parietal-parietal and parietal-frontal connectivity in complex multiplication. These results suggest that decreased cerebellar-cerebral connectivity contributes to complex task performance. Interestingly, BOLD activity contrasts revealed partially overlapping parietal areas of increased BOLD activity but decreased cerebellar-parietal PPI connectivity. PMID:27334957

Mechanism of amido-thiourea catalyzed enantioselective imine hydrocyanation: transition state stabilization via multiple non-covalent interactions.

PubMed

Zuend, Stephan J; Jacobsen, Eric N

2009-10-28

An experimental and computational investigation of amido-thiourea promoted imine hydrocyanation has revealed a new and unexpected mechanism of catalysis. Rather than direct activation of the imine by the thiourea, as had been proposed previously in related systems, the data are consistent with a mechanism involving catalyst-promoted proton transfer from hydrogen isocyanide to imine to generate diastereomeric iminium/cyanide ion pairs that are bound to catalyst through multiple noncovalent interactions; these ion pairs collapse to form the enantiomeric alpha-aminonitrile products. This mechanistic proposal is supported by the observation of a statistically significant correlation between experimental and calculated enantioselectivities induced by eight different catalysts (P < 0.01). The computed models reveal a basis for enantioselectivity that involves multiple stabilizing and destabilizing interactions between substrate and catalyst, including thiourea-cyanide and amide-iminium interactions.

Comparative transcriptome analysis of pepper (Capsicum annuum) revealed common regulons in multiple stress conditions and hormone treatments.

PubMed

Lee, Sanghyeob; Choi, Doil

2013-09-01

Global transcriptome analysis revealed common regulons for biotic/abiotic stresses, and some of these regulons encoding signaling components in both stresses were newly identified in this study. In this study, we aimed to identify plant responses to multiple stress conditions and discover the common regulons activated under a variety of stress conditions. Global transcriptome analysis revealed that salicylic acid (SA) may affect the activation of abiotic stress-responsive genes in pepper. Our data indicate that methyl jasmonate (MeJA) and ethylene (ET)-responsive genes were primarily activated by biotic stress, while abscisic acid (ABA)-responsive genes were activated under both types of stresses. We also identified differentially expressed gene (DEG) responses to specific stress conditions. Biotic stress induces more DEGs than those induced by abiotic and hormone applications. The clustering analysis using DEGs indicates that there are common regulons for biotic or abiotic stress conditions. Although SA and MeJA have an antagonistic effect on gene expression levels, SA and MeJA show a largely common regulation as compared to the regulation at the DEG expression level induced by other hormones. We also monitored the expression profiles of DEG encoding signaling components. Twenty-two percent of these were commonly expressed in both stress conditions. The importance of this study is that several genes commonly regulated by both stress conditions may have future applications for creating broadly stress-tolerant pepper plants. This study revealed that there are complex regulons in pepper plant to both biotic and abiotic stress conditions.

Evidence from intrinsic activity that asymmetry of the human brain is controlled by multiple factors.

PubMed

Liu, Hesheng; Stufflebeam, Steven M; Sepulcre, Jorge; Hedden, Trey; Buckner, Randy L

2009-12-01

Cerebral lateralization is a fundamental property of the human brain and a marker of successful development. Here we provide evidence that multiple mechanisms control asymmetry for distinct brain systems. Using intrinsic activity to measure asymmetry in 300 adults, we mapped the most strongly lateralized brain regions. Both men and women showed strong asymmetries with a significant, but small, group difference. Factor analysis on the asymmetric regions revealed 4 separate factors that each accounted for significant variation across subjects. The factors were associated with brain systems involved in vision, internal thought (the default network), attention, and language. An independent sample of right- and left-handed individuals showed that hand dominance affects brain asymmetry but differentially across the 4 factors supporting their independence. These findings show the feasibility of measuring brain asymmetry using intrinsic activity fluctuations and suggest that multiple genetic or environmental mechanisms control cerebral lateralization.

Effect of hawthorn (Crataegus oxycantha) crude extract and chromatographic fractions on multiple activities in a cultured cardiomyocyte assay.

PubMed

Long, S R; Carey, R A; Crofoot, K M; Proteau, P J; Filtz, T M

2006-11-01

Extracts of hawthorn (Crataegus oxycantha) have become popular herbal supplements for their well-recognized cardiotonic effects. Many commercial preparations have been used successfully in the treatment of congestive heart failure, although the active principles within these extracts have yet to be conclusively identified. Several hawthorn preparations were studied and found to have negative chronotropic effects in a cultured neonatal murine cardiomyocyte assay using unpaced cells. As compared to conventional cardiac drugs (i.e., epinephrine, milrinone, ouabain, or propranolol), hawthorn extract has a unique activity profile. Hawthorn extract appears to be anti-arrhythmic and capable of inducing rhythmicity in quiescent cardiomyocytes. Hawthorn extract does not cause beta-adrenergic receptor blockade at concentrations which cause negative chronotropic effects. Commercial hawthorn preparations, extracts prepared from dried leaves and those made from dried berries have similar chronotropic activities. When crude extracts are separated using size-exclusion chromatography, several fractions retain multiple cardiac activities. Assays with chromatographic fractions reveal that multiple dissimilar cardioactive components may exist within the extract, making the identification of individual active constituents more challenging.

Productive engagement among older Americans: prevalence, patterns, and implications for public policy.

PubMed

Hinterlong, James E

2008-01-01

This study estimates the prevalence of productive engagement among adults aged 60 and over residing in the United States over a nine-year period. We analyze three waves of data from the Americans' Changing Lives Study, which allows the findings to describe the non-institutionalized older American population. Focusing upon five activities--formal paid employment, irregular paid work, unpaid volunteerism, caregiving, and informal assistance to others--we identify changes in the engagement rates, examine the extent to which engagement occurs through single or multiple concurrent activities, and document intra-individual patterns of engagement within and across forms of productive activity, including the continuity, initiation, and cessation of involvement. The findings reveal that late-life productive engagement is widespread, with the majority of older individuals involved in multiple forms of activity concurrently. Non-market-based activities such as caregiving, informal assistance, and volunteering are most prevalent. Initiation and cessation of activities are common and yield more complex patterns and lower rates of non-participation than are revealed in cross-sectional analyses. Time spent in productive engagement is highly variable and exhibits an overall decline across time. We conclude by highlighting policy strategies to increase the availability and quality of opportunities for productive engagement and promote planning for engagement in late life.

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.

Advanced analysis techniques for uranium assay

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

Geist, W. H.; Ensslin, Norbert; Carrillo, L. A.

2001-01-01

Uranium has a negligible passive neutron emission rate making its assay practicable only with an active interrogation method. The active interrogation uses external neutron sources to induce fission events in the uranium in order to determine the mass. This technique requires careful calibration with standards that are representative of the items to be assayed. The samples to be measured are not always well represented by the available standards which often leads to large biases. A technique of active multiplicity counting is being developed to reduce some of these assay difficulties. Active multiplicity counting uses the measured doubles and triples countmore » rates to determine the neutron multiplication (f4) and the product of the source-sample coupling ( C ) and the 235U mass (m). Since the 35U mass always appears in the multiplicity equations as the product of Cm, the coupling needs to be determined before the mass can be known. A relationship has been developed that relates the coupling to the neutron multiplication. The relationship is based on both an analytical derivation and also on empirical observations. To determine a scaling constant present in this relationship, known standards must be used. Evaluation of experimental data revealed an improvement over the traditional calibration curve analysis method of fitting the doubles count rate to the 235Um ass. Active multiplicity assay appears to relax the requirement that the calibration standards and unknown items have the same chemical form and geometry.« less

Multiple pilomatrixomas in a survivor of WNT-activated medulloblastoma leading to the discovery of a germline APC mutation and the diagnosis of familial adenomatous polyposis.

PubMed

Bendelsmith, Charles R; Skrypek, Mary M; Patel, Sachin R; Pond, Dinel A; Linabery, Amy M; Bendel, Anne E

2018-01-01

Because children diagnosed with WNT-activated medulloblastoma have a 10-year overall survival rate of 95%, active long-term follow-up is critically important in reducing mortality from other causes. Here, we describe an 11-year-old adopted female who developed multiple pilomatrixomas 3 years after diagnosis of WNT-activated medulloblastoma, an unusual finding that prompted deeper clinical investigation. A heterozygous germline APC gene mutation was discovered, consistent with familial adenomatous polyposis. Screening endoscopy revealed numerous precancerous polyps that were excised. This case highlights the importance of long-term follow-up of pediatric cancer survivors, including attention to unexpected symptoms, which might unveil an underlying cancer predisposition syndrome. © 2017 Wiley Periodicals, Inc.

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.

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…

Mechanism of Amido-Thiourea Catalyzed Enantioselective Imine Hydrocyanation: Transition State Stabilization via Multiple Non-Covalent Interactions

PubMed Central

Zuend, Stephan J.

2009-01-01

An experimental and computational investigation of amido-thiourea promoted imine hydrocyanation has revealed a new and unexpected mechanism of catalysis. Rather than direct activation of the imine by the thiourea, as had been proposed previously in related systems, the data are consistent with a mechanism involving catalyst-promoted proton transfer from hydrogen isocyanide to imine to generate diastereomeric iminium/cyanide ion pairs that are bound to catalyst through multiple non-covalent interactions; these ion pairs collapse to form the enantiomeric α-aminonitrile products. This mechanistic proposal is supported by the observation of a statistically significant correlation between experimental and calculated enantioselectivities induced by eight different catalysts (P ≪ 0.01). The computed models reveal a basis for enantioselectivity that involves multiple stabilizing and destabilizing interactions between substrate and catalyst, including thiourea-cyanide and amide-iminium interactions. PMID:19778044

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

A combined planning and self-efficacy intervention to promote physical activity: a multiple mediation analysis.

PubMed

Koring, Milena; Richert, Jana; Parschau, Linda; Ernsting, Anna; Lippke, Sonia; Schwarzer, Ralf

2012-01-01

Many individuals are motivated to improve their physical activity levels, but often fail to act upon their intention. Interventions fostering volitional strategies, such as action planning, coping planning, and self-efficacy beliefs, can help to translate intentions into behavior. This study examines the effectiveness and the mechanisms of a combined planning and self-efficacy intervention to promote physical activity among motivated individuals. Participants (N = 883) were randomly assigned to the intervention or to a waiting-list control condition. Multivariate analysis of variance revealed that the intervention resulted in significantly more physical activity, higher levels of action planning, coping planning, and volitional self-efficacy beliefs (p < 0.01). In addition, multiple mediation analysis showed that action planning, coping planning, and volitional self-efficacy mediate between the intervention and physical activity. The study shows that the intervention successfully fostered physical activity and unfolds the underlying self-regulatory mechanisms of the intervention's effectiveness.

Characteristics, location and origin of flare activity in a complex active region

NASA Technical Reports Server (NTRS)

Machado, M. E.; Gary, G. A.; Hagyard, M. J.; Hernandez, A. M.; Rovira, M. G.

1986-01-01

The observational characteristics of series of multiple-loop flares from a complex active region are summarized. The location of the highest observed photospheric magnetic shear is found to be the commonly observed site of flare onset, but not, in many cases, the magnetic region where the largest time-integrated energy release is observed. The observations thus reveal a consistent pattern of energy-release processes related to the magnetic-field topology.

Autoantigen La promotes efficient RNAi, antiviral response, and transposon silencing by facilitating multiple-turnover RISC catalysis

PubMed Central

Liu, Ying; Tan, Huiling; Tian, Hui; Liang, Chunyang; Chen, She; Liu, Qinghua

2011-01-01

SUMMARY The effector of RNA interference (RNAi) is the RNA-induced silencing complex (RISC). C3PO promotes the activation of RISC by degrading Argonaute2 (Ago2)-nicked passenger strand of duplex siRNA. Active RISC is a multiple-turnover enzyme that uses the guide strand of siRNA to direct Ago2-mediated sequence-specific cleavage of complementary mRNA. How this effector step of RNAi is regulated is currently unknown. Here, we used human Ago2 minimal RISC system to purify Sjögren’s syndrome antigen B (SSB)/autoantigen La as an activator of the RISC-mediated mRNA cleavage activity. Our reconstitution studies showed that La could promote multiple-turnover RISC catalysis by facilitating the release of cleaved mRNA from RISC. Moreover, we demonstrated that La was required for efficient RNAi, antiviral defense, and transposon silencing in vivo. Taken together, the findings of C3PO and La reveal a general concept that regulatory factors are required to remove Ago2-cleaved products to assemble or restore active RISC. PMID:22055194

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.

Factors affecting match performance in professional Australian football.

PubMed

Sullivan, Courtney; Bilsborough, Johann C; Cianciosi, Michael; Hocking, Joel; Cordy, Justin T; Coutts, Aaron J

2014-05-01

To determine the physical activity measures and skill-performance characteristics that contribute to coaches' perception of performance and player performance rank in professional Australian Football (AF). Prospective, longitudinal. Physical activity profiles were assessed via microtechnology (GPS and accelerometer) from 40 professional AF players from the same team during 15 Australian Football League games. Skill-performance measure and player-rank scores (Champion Data Rank) were provided by a commercial statistical provider. The physical-performance variables, skill involvements, and individual player performance scores were expressed relative to playing time for each quarter. A stepwise multiple regression was used to examine the contribution of physical activity and skill involvements to coaches' perception of performance and player rank in AF. Stepwise multiple-regression analysis revealed that 42.2% of the variance in coaches' perception of a player's performance could be explained by the skill-performance characteristics (player rank/min, effective kicks/min, pressure points/min, handballs/min, and running bounces/ min), with a small contribution from physical activity measures (accelerations/min) (adjusted R2 = .422, F6,282 = 36.054, P < .001). Multiple regression also revealed that 66.4% of the adjusted variance in player rank could be explained by total disposals/min, effective kicks/min, pressure points/min, kick clangers/min, marks/min, speed (m/min), and peak speed (adjusted R2 = .664, F7,281 = 82.289, P < .001). Increased physical activity throughout a match (speed [m/min] β - 0.097 and peak speed β - 0.116) negatively affects player rank in AF. Skill performance rather than increased physical activity is more important to coaches' perception of performance and player rank in professional AF.

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.

Phosphoinositide protein kinase PDPK1 is a crucial cell signaling mediator in multiple myeloma.

PubMed

Chinen, Yoshiaki; Kuroda, Junya; Shimura, Yuji; Nagoshi, Hisao; Kiyota, Miki; Yamamoto-Sugitani, Mio; Mizutani, Shinsuke; Sakamoto, Natsumi; Ri, Masaki; Kawata, Eri; Kobayashi, Tsutomu; Matsumoto, Yosuke; Horiike, Shigeo; Iida, Shinsuke; Taniwaki, Masafumi

2014-12-15

Multiple myeloma is a cytogenetically/molecularly heterogeneous hematologic malignancy that remains mostly incurable, and the identification of a universal and relevant therapeutic target molecule is essential for the further development of therapeutic strategy. Herein, we identified that 3-phosphoinositide-dependent protein kinase 1 (PDPK1), a serine threonine kinase, is expressed and active in all eleven multiple myeloma-derived cell lines examined regardless of the type of cytogenetic abnormality, the mutation state of RAS and FGFR3 genes, or the activation state of ERK and AKT. Our results revealed that PDPK1 is a pivotal regulator of molecules that are essential for myelomagenesis, such as RSK2, AKT, c-MYC, IRF4, or cyclin Ds, and that PDPK1 inhibition caused the growth inhibition and the induction of apoptosis with the activation of BIM and BAD, and augmented the in vitro cytotoxic effects of antimyeloma agents in myeloma cells. In the clinical setting, PDPK1 was active in myeloma cells of approximately 90% of symptomatic patients at diagnosis, and the smaller population of patients with multiple myeloma exhibiting myeloma cells without active PDPK1 showed a significantly less frequent proportion of the disease stage III by the International Staging System and a significantly more favorable prognosis, including the longer overall survival period and the longer progression-free survival period by bortezomib treatment, than patients with active PDPK1, suggesting that PDPK1 activation accelerates the disease progression and the resistance to treatment in multiple myeloma. Our study demonstrates that PDPK1 is a potent and a universally targetable signaling mediator in multiple myeloma regardless of the types of cytogenetic/molecular profiles. ©2014 American Association for Cancer Research.

Acute Motor-dominant Polyneuropathy as Guillain-Barré Syndrome and Multiple Mononeuropathies in a Patient with Sjögren's Syndrome.

PubMed

Tanaka, Kenichiro; Nakayasu, Hiroyuki; Suto, Yutaka; Takahashi, Shotaro; Konishi, Yoshihiro; Nishimura, Hirotake; Ueno, Rino; Kusunoki, Susumu; Nakashima, Kenji

A patient with xerostomia and xerophthalmia due to Sjögren's syndrome presented with acute motor-dominant polyneuropathy and multiple mononeuropathy with antiganglioside antibodies. Nerve conduction studies and a sural nerve biopsy revealed the neuropathy as a mixture of segmental demyelination and axonal degeneration. Positive results were obtained for several antiganglioside antibodies. Corticosteroid treatment proved effective. The neuropathy was considered to represent a mixture of polyneuropathy as Guillain-Barré syndrome and multiple mononeuropathy via Sjögren's syndrome. We speculate that Guillain-Barré syndrome occurred in the patient and Guillain-Barré syndrome itself activated multiple mononeuropathy via Sjögren's syndrome.

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.

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.

[Impact of physical activity level on alexithymia and coping strategies in an over-40 multiple sclerosis population: a pilot study].

PubMed

Mosson, M; Peter, L; Montel, S

2014-01-01

The aim of this study was to evaluate the impact of physical activity on alexithymia and coping strategies among people with multiple sclerosis aged over 40. The hypotheses were that physical activity should have a protective effect on alexithymia, and more particularly, on "emotional identification" and could influence coping strategies because it can be considered as a distractive coping strategy. Thirty-seven patients aged 40 years or older were asked to complete a form including an identification sheet and standardized questionnaires: the Bermond-Vorst Alexithymia Questionnaire (version B), the Coping with Health Injuries and Problem Questionnaire, the Fatigue Impact Scale, and the Hospital Anxiety and Depression Scale. The participants with a high or moderate level of physical activity used "information research" as a coping strategy better than those who had a lower level of physical activity. They also analyzed their emotions better. The results revealed an association between these variables and anxiety, depression and fatigue. This study provides insight for future research about the impact of physical activity on multiple sclerosis. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

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

Correlates of Successful Aging: Are They Universal?

ERIC Educational Resources Information Center

Litwin, Howard

2005-01-01

The analysis compared differing correlates of life satisfaction among three diverse population groups in Israel, examining background and health status variables, social environment factors, and activity indicators. Multiple regression analysis revealed that veteran Jewish-Israelis (n = 2,043) had the largest set of predictors, the strongest of…

Multiparameter Investigation of a 46,XX/46,XY Tetragametic Chimeric Phenotypical Male Patient with Bilateral Scrotal Ovotestes and Ovulatory Activity.

PubMed

van Bever, Yolande; Wolffenbuttel, Katja P; Brüggenwirth, Hennie T; Blom, Eric; de Klein, Annelies; Eussen, Bert H J; van der Windt, Florijn; Hannema, Sabine E; Dessens, Arianne B; Dorssers, Lambert C J; Biermann, Katharina; Hersmus, Remko; de Rijke, Yolanda B; Looijenga, Leendert H J

2018-01-01

We report on an adult male initially presenting with gynecomastia and a painless scrotal mass without additional genital anomalies. Hyperpigmentation of the skin following the Blaschko's lines was identified. He underwent gonadectomy because of suspected cancer. Histological analyses revealed an ovotestis with ovulatory activity confirmed by immunohistochemistry with multiple markers. Karyotyping of cultured peripheral blood lymphocytes and a buccal smear revealed a 46,XX/46,XY chimeric constitution with different percentages. Multiple molecular analyses as well as blood typing implied a tetragametic origin. After the unilateral gonadectomy, the patient developed recurrent painful cystic swellings of the remaining gonad. Because of the wish to preserve hormonal activity as well as future fertility, the patient underwent surgical resection of a cystic gonadal area. The removed tissue showed ovulation-related features in addition to both testicular and ovarian tissue, diagnosed as an ovotestis. Testosterone therapy was initiated to suppress the persistently elevated gonadotropins and thereby suppress ovarian activity. During treatment, the recurrent pain complaints and cystic swellings ceased, although gonadotropin levels were not fully suppressed. Based on these observations, the importance of a detailed genetic and pathological diagnosis and the clinical dilemmas including the pros and cons of personalized treatment with gonadal preservative surgery are discussed. © 2017 S. Karger AG, Basel.

Inappropriate ICD discharges due to "triple counting" during normal sinus rhythm.

PubMed

Khan, Ejaz; Voudouris, Apostolos; Shorofsky, Stephen R; Peters, Robert W

2006-11-01

To describe the clinical course of a patient with multiple ICD shocks in the setting of advanced renal failure and hyperkalemia. The patient was brought to the Electrophysiology Laboratory where the ICD was interrogated. The patient was found to be hyperkalemic (serum potassium 7.6 mg/dl). Analysis of stored intracardiac electrograms from the ICD revealed "triple counting" (twice during his QRS complex and once during the T wave) and multiple inappropriate shocks. Correction of his electrolyte abnormality normalized his electrogram and no further ICD activations were observed. Electrolyte abnormalities can distort the intracardiac electrogram in patients with ICD's and these changes can lead to multiple inappropriate shocks.

High School Online: Pedagogy, Preferences, and Practices of Three Online Teachers

ERIC Educational Resources Information Center

Kerr, Shantia

2011-01-01

This multiple case study explores how three online, high school teachers used technological tools to create meaningful learning activities for their students. Findings reveal that teachers use a wide variety of tools and approaches to online learning. Tools are categorized as content, communication, and management tools. Approaches include…

Developments in Transnational Research Linkages: Evidence from U.S. Higher-Education Activity

ERIC Educational Resources Information Center

Koehn, Peter H.

2014-01-01

In our knowledge-driven era, multiple and mutual benefits accrue from transnational research linkages. The article identifies important directions in transnational research collaborations involving U.S. universities revealed by key dimensions of 369 projects profiled on a U.S. higher-education association's database. Project initiators, principal…

Multiple elements of the allergic arm of the immune response modulate autoimmune demyelination

PubMed Central

Pedotti, Rosetta; DeVoss, Jason J.; Youssef, Sawsan; Mitchell, Dennis; Wedemeyer, Jochen; Madanat, Rami; Garren, Hideki; Fontoura, Paulo; Tsai, Mindy; Galli, Stephen J.; Sobel, Raymond A.; Steinman, Lawrence

2003-01-01

Analysis of mRNA from multiple sclerosis lesions revealed increased amounts of transcripts for several genes encoding molecules traditionally associated with allergic responses, including prostaglandin D synthase, histamine receptor type 1 (H1R), platelet activating factor receptor, Ig Fc ɛ receptor 1 (FcɛRI), and tryptase. We now demonstrate that, in the animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), mediated by T helper 1 (Th1) T cells, histamine receptor 1 and 2 (H1R and H2R) are present on inflammatory cells in brain lesions. Th1 cells reactive to myelin proteolipid protein expressed more H1R and less H2R than Th2 cells. Pyrilamine, an H1R antagonist, blocked EAE, and the platelet activating factor receptor antagonist CV6209 reduced the severity of EAE. EAE severity was also decreased in mice with disruption of the genes encoding Ig FcγRIII or both FcγRIII and FcɛRI. Prostaglandin D synthase and tryptase transcripts were elevated in EAE brain. Taken together, these data reveal extensive involvement of elements of the immune response associated with allergy in autoimmune demyelination. The pathogenesis of demyelination must now be viewed as encompassing elements of both Th1 responses and “allergic” responses. PMID:12576552

Attributions and self-efficacy for physical activity in multiple sclerosis.

PubMed

Nickel, D; Spink, K; Andersen, M; Knox, K

2014-01-01

Self-efficacy is an important predictor of health-related physical activity in multiple sclerosis (MS). While past experiences are believed to influence efficacy beliefs, the explanations individuals provide for these experiences also may be critical. Our objective was to test the hypothesis that perceived success or failure to accumulate 150 min of physical activity in the previous week would moderate the relationship between the attributional dimension of stability and self-efficacy to exercise in the future. Forty-two adults with MS participated in this cross-sectional descriptive study. Participants completed questions assessing physical activity, perceived outcome for meeting the recommended level of endurance activity, attributions for the outcome, and exercise self-efficacy. Results from hierarchical multiple regression revealed a significant main effect for perceived outcome predicting self-efficacy that was qualified by a significant interaction. The final model, which included perceived outcome, stability, and the interaction term, predicted 37% of the variance in exercise self-efficacy, F (3, 38) = 7.27, p = .001. Our findings suggest that the best prediction of self-efficacy in the MS population may include the interaction of specific attributional dimensions with success/failure at meeting the recommended physical activity dose. Attributions may be another target for interventions aimed at increasing the physical activity in MS.

Autoantigen La promotes efficient RNAi, antiviral response, and transposon silencing by facilitating multiple-turnover RISC catalysis.

PubMed

Liu, Ying; Tan, Huiling; Tian, Hui; Liang, Chunyang; Chen, She; Liu, Qinghua

2011-11-04

The effector of RNA interference (RNAi) is the RNA-induced silencing complex (RISC). C3PO promotes the activation of RISC by degrading the Argonaute2 (Ago2)-nicked passenger strand of duplex siRNA. Active RISC is a multiple-turnover enzyme that uses the guide strand of siRNA to direct the Ago2-mediated sequence-specific cleavage of complementary mRNA. How this effector step of RNAi is regulated is currently unknown. Here, we used the human Ago2 minimal RISC system to purify Sjögren's syndrome antigen B (SSB)/autoantigen La as an activator of the RISC-mediated mRNA cleavage activity. Our reconstitution studies showed that La could promote multiple-turnover RISC catalysis by facilitating the release of cleaved mRNA from RISC. Moreover, we demonstrated that La was required for efficient RNAi, antiviral defense, and transposon silencing in vivo. Taken together, the findings of C3PO and La reveal a general concept that regulatory factors are required to remove Ago2-cleaved products to assemble or restore active RISC. Copyright © 2011 Elsevier Inc. All rights reserved.

Cloud-based simulations on Google Exacycle reveal ligand modulation of GPCR activation pathways

NASA Astrophysics Data System (ADS)

Kohlhoff, Kai J.; Shukla, Diwakar; Lawrenz, Morgan; Bowman, Gregory R.; Konerding, David E.; Belov, Dan; Altman, Russ B.; Pande, Vijay S.

2014-01-01

Simulations can provide tremendous insight into the atomistic details of biological mechanisms, but micro- to millisecond timescales are historically only accessible on dedicated supercomputers. We demonstrate that cloud computing is a viable alternative that brings long-timescale processes within reach of a broader community. We used Google's Exacycle cloud-computing platform to simulate two milliseconds of dynamics of a major drug target, the G-protein-coupled receptor β2AR. Markov state models aggregate independent simulations into a single statistical model that is validated by previous computational and experimental results. Moreover, our models provide an atomistic description of the activation of a G-protein-coupled receptor and reveal multiple activation pathways. Agonists and inverse agonists interact differentially with these pathways, with profound implications for drug design.

Environmental influences on physical activity in rural Midwestern adults: a qualitative approach.

PubMed

Chrisman, Matthew; Nothwehr, Faryle; Yang, Ginger; Oleson, Jacob

2015-01-01

Qualitative research can be used to examine multiple factors associated with physical activity and help practitioners identify language used by the rural adult population when discussing this behavior. Three focus groups were conducted among 19 residents of multiple towns in a rural Midwestern county to examine the language and influences on rural physical activity. Focus group members were asked to define physical activity, exercise, community, and neighborhood. They were asked about the activities they engaged in and facilitators and barriers to those activities. A guidebook was developed to capture major themes and common patterns that emerged in the responses to the topics discussed. The data were reviewed for repeated statements and points that were agreed on by multiple participants. Important factors associated with physical activity include the importance of social support and modeling physical activity behavior. Also, the influence of pets and children was important for engaging these adults in physical activity. The focus group members engaged in walking and bicycling in their neighborhood streets and community trails, and desired to see community buildings be open to the public for exercise. This study revealed contextual issues and culturally relevant language for practitioners to use in tailoring physical activity measurement tools or designing interventions for a rural adult population. Social support (specifically, seeing others being active and using pets as motivators for being active) and policy attitudes may be targeted for interventions to increase physical activity in rural adults. © 2014 Society for Public Health Education.

Environmental Influences on Physical Activity in Rural Midwestern Adults: A Qualitative Approach

PubMed Central

Chrisman, Matthew; Nothwehr, Faryle; Yang, Ginger; Oleson, Jacob

2014-01-01

Qualitative research can be used to examine multiple factors associated with physical activity and help practitioners identify language used by the rural adult population when discussing this behavior. Three focus groups were conducted among 19 residents of multiple towns in a rural Midwestern county to examine the language and influences on rural physical activity. Focus group members were asked to define physical activity, exercise, community, and neighborhood. They were asked about the activities they engaged in and facilitators and barriers to those activities. A guidebook was developed to capture major themes and common patterns that emerged in the responses to the topics discussed. The data were reviewed for repeated statements and points that were agreed on by multiple participants. Important factors associated with physical activity include the importance of social support and modeling physical activity behavior. Also, the influence of pets and children was important for engaging these adults in physical activity. The focus group members engaged in walking and bicycling in their neighborhood streets and community trails, and desired to see community buildings be open to the public for exercise. This study revealed contextual issues and culturally relevant language for practitioners to use in tailoring physical activity measurement tools or designing interventions for a rural adult population. Social support (specifically, seeing others being active and using pets as motivators for being active) and policy attitudes may be targeted for interventions to increase physical activity in rural adults. PMID:24662894

Do religious activities among young-old immigrants act as a buffer against the effect of a lack of resources on well-being?

PubMed

Klokgieters, Silvia S; van Tilburg, Theo G; Deeg, Dorly J H; Huisman, Martijn

2018-01-30

Despite a large body of sociological and psychological literature suggesting that religious activities may mitigate the effects of stress, few studies have investigated the beneficial effects of religious activities among immigrants. Immigrants in particular may stand to benefit from these activities because they often report a religious affiliation and often occupy disadvantaged positions. This study investigates whether private and public religious activities reduce the negative effects of a lack of physical, social, and socio-economic resources on wellbeing among Turkish and Moroccan young-old immigrants in the Netherlands. Using data from the Longitudinal Study Amsterdam, cluster analysis revealed three patterns of absence of resources: physically disadvantaged, multiple disadvantages, and relatively advantaged. Linear regression analysis assessed associations between patterns of resources, religious activities and wellbeing. Persons who are physically disadvantaged or have multiple disadvantages have a lower level of wellbeing compared to persons who are relatively advantaged.  More engagement in private religious activities was associated with higher wellbeing. Among those with multiple disadvantages, however, more engagement in private religious activities was associated with lower wellbeing. Public religious activities were not associated with wellbeing in the disadvantaged group. Private religious activities are positively related to wellbeing among Turkish and Moroccan immigrants. In situations where resources are lacking, however, the relation between private religious activities and wellbeing is negative. The study's results highlight the importance of context, disadvantage and type of religious activity for wellbeing.

Complex Dynamics of Delay-Coupled Neural Networks

NASA Astrophysics Data System (ADS)

Mao, Xiaochen

2016-09-01

This paper reveals the complicated dynamics of a delay-coupled system that consists of a pair of sub-networks and multiple bidirectional couplings. Time delays are introduced into the internal connections and network-couplings, respectively. The stability and instability of the coupled network are discussed. The sufficient conditions for the existence of oscillations are given. Case studies of numerical simulations are given to validate the analytical results. Interesting and complicated neuronal activities are observed numerically, such as rest states, periodic oscillations, multiple switches of rest states and oscillations, and the coexistence of different types of oscillations.

Transitions in Learning: Evidence for Simultaneously Activated Strategies.

ERIC Educational Resources Information Center

Goldin-Meadow, Susan; And Others

Children rarely cite more than one strategy when asked to explain how they solved a particular arithmetic problem, hence their verbal explanations will not necessarily reveal whether they have considered multiple strategies on that problem. However, previous work has shown that, when asked to explain their performance on a task, children often use…

Sex and Violence: Words at Play in the Shakespeare Classroom

ERIC Educational Resources Information Center

Paquette, Maryellen G.

2007-01-01

Maryellen G. Paquette reveals the excitement and learning that can occur when high school students are presented with multiple opportunities to play. Activities that employ playful language and the whole body allow students to embody, name, and identify with complicated emotions and situations in Shakespeare's plays. In addition, play can be…

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

An autopsy case of chronic active Epstein-Barr virus infection (CAEBV): distribution of central nervous system (CNS) lesions.

PubMed

Kobayashi, Zen; Tsuchiya, Kuniaki; Takahashi, Makoto; Yokota, Osamu; Sasaki, Atsushi; Bhunchet, Ekapot; Arai, Tetsuaki; Akiyama, Haruhiko; Kamoshita, Masaharu; Kotera, Minoru; Mizusawa, Hidehiro

2008-12-15

A 27-year-old Japanese man developed recurrent respiratory and central nervous system (CNS) symptoms, and hemophagocytic syndromes with a clinical course of 6 years. CT demonstrated multiple nodular lesions in the bilateral lungs, and MRI revealed multiple abnormal intensity areas in the brain and spinal cord. Cerebrospinal fluid (CSF) examination disclosed mild pleocytosis and the presence of Epstein-Barr virus (EBV)-DNA detected by polymerase chain reaction (PCR). The patient died of a hemorrhagic shock associated with a hemophagocytic syndrome. A postmortem study revealed massive hemorrhage in the abdominal cavity and iliopsoas muscles, as well as diffuse infiltration of lymphocytes and/or macrophages into the lungs, liver, kidneys, spleen, cardiac muscle, bone marrow, and CNS. The severe involvement was demonstrated in the CNS, especially in the spinal cord and brainstem. The CD3 positive cells of the brainstem were EBV-encoded RNA 1 positive. This is the first autopsy case of chronic active EBV infection (CAEBV) in which severe and extensive CNS involvement was demonstrated.

A reversible component of mitochondrial respiratory dysfunction in apoptosis can be rescued by exogenous cytochrome c

PubMed Central

Mootha, Vamsi K.; Wei, Michael C.; Buttle, Karolyn F.; Scorrano, Luca; Panoutsakopoulou, Vily; Mannella, Carmen A.; Korsmeyer, Stanley J.

2001-01-01

Multiple apoptotic pathways release cytochrome c from the mitochondrial intermembrane space, resulting in the activation of downstream caspases. In vivo activation of Fas (CD95) resulted in increased permeability of the mitochondrial outer membrane and depletion of cytochrome c stores. Serial measurements of oxygen consumption, NADH redox state and membrane potential revealed a loss of respiratory state transitions. This tBID-induced respiratory failure did not require any caspase activity. At early time points, re-addition of exogenous cytochrome c markedly restored respiratory functions. Over time, however, mitochondria showed increasing irreversible respiratory dysfunction as well as diminished calcium buffering. Electron microscopy and tomographic reconstruction revealed asymmetric mitochondria with blebs of herniated matrix, distended inner membrane and partial loss of cristae structure. Thus, apoptogenic redistribution of cytochrome c is responsible for a distinct program of mitochondrial respiratory dysfunction, in addition to the activation of downstream caspases. PMID:11179211

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

Multiresolution multiscale active mask segmentation of fluorescence microscope images

NASA Astrophysics Data System (ADS)

Srinivasa, Gowri; Fickus, Matthew; Kovačević, Jelena

2009-08-01

We propose an active mask segmentation framework that combines the advantages of statistical modeling, smoothing, speed and flexibility offered by the traditional methods of region-growing, multiscale, multiresolution and active contours respectively. At the crux of this framework is a paradigm shift from evolving contours in the continuous domain to evolving multiple masks in the discrete domain. Thus, the active mask framework is particularly suited to segment digital images. We demonstrate the use of the framework in practice through the segmentation of punctate patterns in fluorescence microscope images. Experiments reveal that statistical modeling helps the multiple masks converge from a random initial configuration to a meaningful one. This obviates the need for an involved initialization procedure germane to most of the traditional methods used to segment fluorescence microscope images. While we provide the mathematical details of the functions used to segment fluorescence microscope images, this is only an instantiation of the active mask framework. We suggest some other instantiations of the framework to segment different types of images.

Development and application of a quantitative multiplexed small GTPase activity assay using targeted proteomics.

PubMed

Zhang, Cheng-Cheng; Li, Ru; Jiang, Honghui; Lin, Shujun; Rogalski, Jason C; Liu, Kate; Kast, Juergen

2015-02-06

Small GTPases are a family of key signaling molecules that are ubiquitously expressed in various types of cells. Their activity is often analyzed by western blot, which is limited by its multiplexing capability, the quality of isoform-specific antibodies, and the accuracy of quantification. To overcome these issues, a quantitative multiplexed small GTPase activity assay has been developed. Using four different binding domains, this assay allows the binding of up to 12 active small GTPase isoforms simultaneously in a single experiment. To accurately quantify the closely related small GTPase isoforms, a targeted proteomic approach, i.e., selected/multiple reaction monitoring, was developed, and its functionality and reproducibility were validated. This assay was successfully applied to human platelets and revealed time-resolved coactivation of multiple small GTPase isoforms in response to agonists and differential activation of these isoforms in response to inhibitor treatment. This widely applicable approach can be used for signaling pathway studies and inhibitor screening in many cellular systems.

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

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

Intrinsic frequency biases and profiles across human cortex.

PubMed

Mellem, Monika S; Wohltjen, Sophie; Gotts, Stephen J; Ghuman, Avniel Singh; Martin, Alex

2017-11-01

Recent findings in monkeys suggest that intrinsic periodic spiking activity in selective cortical areas occurs at timescales that follow a sensory or lower order-to-higher order processing hierarchy (Murray JD, Bernacchia A, Freedman DJ, Romo R, Wallis JD, Cai X, Padoa-Schioppa C, Pasternak T, Seo H, Lee D, Wang XJ. Nat Neurosci 17: 1661-1663, 2014). It has not yet been fully explored if a similar timescale hierarchy is present in humans. Additionally, these measures in the monkey studies have not addressed findings that rhythmic activity within a brain area can occur at multiple frequencies. In this study we investigate in humans if regions may be biased toward particular frequencies of intrinsic activity and if a full cortical mapping still reveals an organization that follows this hierarchy. We examined the spectral power in multiple frequency bands (0.5-150 Hz) from task-independent data using magnetoencephalography (MEG). We compared standardized power across bands to find regional frequency biases. Our results demonstrate a mix of lower and higher frequency biases across sensory and higher order regions. Thus they suggest a more complex cortical organization that does not simply follow this hierarchy. Additionally, some regions do not display a bias for a single band, and a data-driven clustering analysis reveals a regional organization with high standardized power in multiple bands. Specifically, theta and beta are both high in dorsal frontal cortex, whereas delta and gamma are high in ventral frontal cortex and temporal cortex. Occipital and parietal regions are biased more narrowly toward alpha power, and ventral temporal lobe displays specific biases toward gamma. Thus intrinsic rhythmic neural activity displays a regional organization but one that is not necessarily hierarchical. NEW & NOTEWORTHY The organization of rhythmic neural activity is not well understood. Whereas it has been postulated that rhythms are organized in a hierarchical manner across brain regions, our novel analysis allows comparison of full cortical maps across different frequency bands, which demonstrate that the rhythmic organization is more complex. Additionally, data-driven methods show that rhythms of multiple frequencies or timescales occur within a particular region and that this nonhierarchical organization is widespread. Copyright © 2017 the American Physiological Society.

Effect of Expiratory Resistive Loading in Expiratory Muscle Strength Training on Orbicularis Oris Muscle Activity

PubMed Central

Yanagisawa, Yukio; Matsuo, Yoshimi; Shuntoh, Hisato; Horiuchi, Noriaki

2014-01-01

[Purpose] The purpose of this study was to elucidate the effect of expiratory resistive loading on orbicularis oris muscle activity. [Subjects] Subjects were 23 healthy individuals (11 males, mean age 25.5±4.3 years; 12 females, mean age 25.0±3.0 years). [Methods] Surface electromyography was performed to measure the activity of the orbicularis oris muscle during maximum lip closure and resistive loading at different expiratory pressures. Measurement was performed at 10%, 30%, 50%, and 100% of maximum expiratory pressure (MEP) for all subjects. The t-test was used to compare muscle activity between maximum lip closure and 100% MEP, and analysis of variance followed by multiple comparisons was used to compare the muscle activities observed at different expiratory pressures. [Results] No significant difference in muscle activity was observed between maximum lip closure and 100% MEP. Analysis of variance with multiple comparisons revealed significant differences among the different expiratory pressures. [Conclusion] Orbicularis oris muscle activity increased with increasing expiratory resistive loading. PMID:24648644

Competition and cooperation among similar representations: toward a unified account of facilitative and inhibitory effects of lexical neighbors.

PubMed

Chen, Qi; Mirman, Daniel

2012-04-01

One of the core principles of how the mind works is the graded, parallel activation of multiple related or similar representations. Parallel activation of multiple representations has been particularly important in the development of theories and models of language processing, where coactivated representations (neighbors) have been shown to exhibit both facilitative and inhibitory effects on word recognition and production. Researchers generally ascribe these effects to interactive activation and competition, but there is no unified explanation for why the effects are facilitative in some cases and inhibitory in others. We present a series of simulations of a simple domain-general interactive activation and competition model that is broadly consistent with more specialized domain-specific models of lexical processing. The results showed that interactive activation and competition can indeed account for the complex pattern of reversals. Critically, the simulations revealed a core computational principle that determines whether neighbor effects are facilitative or inhibitory: strongly active neighbors exert a net inhibitory effect, and weakly active neighbors exert a net facilitative effect.

Kinetic Evidence of an Apparent Negative Activation Enthalpy in an Organocatalytic Process

PubMed Central

Han, Xiao; Lee, Richmond; Chen, Tao; Luo, Jie; Lu, Yixin; Huang, Kuo-Wei

2013-01-01

A combined kinetic and computational study on our tryptophan-based bifunctional thiourea catalyzed asymmetric Mannich reactions reveals an apparent negative activation enthalpy. The formation of the pre-transition state complex has been unambiguously confirmed and these observations provide an experimental support for the formation of multiple hydrogen bonding network between the substrates and the catalyst. Such interactions allow the creation of a binding cavity, a key factor to install high enantioselectivity. PMID:23990028

[Innate immunity in neuroimmunological disorders].

PubMed

Miyake, Sachiko

2013-05-01

Exogeneous pathogen-associated molecular patterns and endogenous danger signals bind to pattern recognition receptors and activate innate immunity cells, leading to proinflammatory cytokine production and activation of acquired immue cells. These are important factors in the pathogenesis of autoimmune-mediated neuroimmunological disorders such as multiple sclerosis. Furthermore, recent advances in the study of innate immunity revealed that innate immunity is a major players in the pathogenesis of some neuroimmunological diseases such as Behçet's disease and herpes simplex virus encephalitis.

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

Programmed Cell Death During Caenorhabditis elegans Development

PubMed Central

Conradt, Barbara; Wu, Yi-Chun; Xue, Ding

2016-01-01

Programmed cell death is an integral component of Caenorhabditis elegans development. Genetic and reverse genetic studies in C. elegans have led to the identification of many genes and conserved cell death pathways that are important for the specification of which cells should live or die, the activation of the suicide program, and the dismantling and removal of dying cells. Molecular, cell biological, and biochemical studies have revealed the underlying mechanisms that control these three phases of programmed cell death. In particular, the interplay of transcriptional regulatory cascades and networks involving multiple transcriptional regulators is crucial in activating the expression of the key death-inducing gene egl-1 and, in some cases, the ced-3 gene in cells destined to die. A protein interaction cascade involving EGL-1, CED-9, CED-4, and CED-3 results in the activation of the key cell death protease CED-3, which is tightly controlled by multiple positive and negative regulators. The activation of the CED-3 caspase then initiates the cell disassembly process by cleaving and activating or inactivating crucial CED-3 substrates; leading to activation of multiple cell death execution events, including nuclear DNA fragmentation, mitochondrial elimination, phosphatidylserine externalization, inactivation of survival signals, and clearance of apoptotic cells. Further studies of programmed cell death in C. elegans will continue to advance our understanding of how programmed cell death is regulated, activated, and executed in general. PMID:27516615

Endoscopic appearance of AIDS-related gastrointestinal lymphoma with c-MYC rearrangements: case report and literature review.

PubMed

Tanaka, Shohei; Nagata, Naoyoshi; Mine, Sohtaro; Igari, Toru; Kobayashi, Taiichiro; Sugihara, Jun; Honda, Haruhito; Teruya, Katsuji; Kikuchi, Yoshimi; Oka, Shinichi; Uemura, Naomi

2013-08-07

Acquired immune deficiency syndrome (AIDS)-related lymphoma (ARL) remains the main cause of AIDS-related deaths in the highly active anti-retroviral therapy (HAART) era. Recently, rearrangement of MYC is associated with poor prognosis in patients with diffuse large B-cell lymphoma. Here, we report a rare case of gastrointestinal (GI)-ARL with MYC rearrangements and coinfected with Epstein-Barr virus (EBV) infection presenting with various endoscopic findings. A 38-year-old homosexual man who presented with anemia and was diagnosed with an human immunodeficiency virus infection for the first time. GI endoscopy revealed multiple dish-like lesions, ulcerations, bloody spots, nodular masses with active bleeding in the stomach, erythematous flat lesions in the duodenum, and multiple nodular masses in the colon and rectum. Magnified endoscopy with narrow band imaging showed a honeycomb-like pattern without irregular microvessels in the dish-like lesions of the stomach. Biopsy specimens from the stomach, duodenum, colon, and rectum revealed diffuse large B-cell lymphoma concomitant with EBV infection that was detected by high tissue EBV-polymerase chain reaction levels and Epstein-Barr virus small RNAs in situ hybridization. Fluorescence in situ hybridization analysis revealed a fusion between the immunoglobulin heavy chain (IgH) and c-MYC genes, but not between the IgH and BCL2 loci. After 1-mo of treatment with HAART and R-CHOP, endoscopic appearance improved remarkably, and the histological features of the biopsy specimens revealed no evidence of lymphoma. However, he died from multiple organ failure on the 139(th) day after diagnosis. The cause of his poor outcome may be related to MYC rearrangement. The GI tract involvement in ARL is rarely reported, and its endoscopic findings are various and may be different from those in non-AIDS GI lymphoma; thus, we also conducted a literature review of GI-ARL cases.

Endoscopic appearance of AIDS-related gastrointestinal lymphoma with c-MYC rearrangements: Case report and literature review

PubMed Central

Tanaka, Shohei; Nagata, Naoyoshi; Mine, Sohtaro; Igari, Toru; Kobayashi, Taiichiro; Sugihara, Jun; Honda, Haruhito; Teruya, Katsuji; Kikuchi, Yoshimi; Oka, Shinichi; Uemura, Naomi

2013-01-01

Acquired immune deficiency syndrome (AIDS)-related lymphoma (ARL) remains the main cause of AIDS-related deaths in the highly active anti-retroviral therapy (HAART) era. Recently, rearrangement of MYC is associated with poor prognosis in patients with diffuse large B-cell lymphoma. Here, we report a rare case of gastrointestinal (GI)-ARL with MYC rearrangements and coinfected with Epstein-Barr virus (EBV) infection presenting with various endoscopic findings. A 38-year-old homosexual man who presented with anemia and was diagnosed with an human immunodeficiency virus infection for the first time. GI endoscopy revealed multiple dish-like lesions, ulcerations, bloody spots, nodular masses with active bleeding in the stomach, erythematous flat lesions in the duodenum, and multiple nodular masses in the colon and rectum. Magnified endoscopy with narrow band imaging showed a honeycomb-like pattern without irregular microvessels in the dish-like lesions of the stomach. Biopsy specimens from the stomach, duodenum, colon, and rectum revealed diffuse large B-cell lymphoma concomitant with EBV infection that was detected by high tissue EBV-polymerase chain reaction levels and Epstein-Barr virus small RNAs in situ hybridization. Fluorescence in situ hybridization analysis revealed a fusion between the immunoglobulin heavy chain (IgH) and c-MYC genes, but not between the IgH and BCL2 loci. After 1-mo of treatment with HAART and R-CHOP, endoscopic appearance improved remarkably, and the histological features of the biopsy specimens revealed no evidence of lymphoma. However, he died from multiple organ failure on the 139th day after diagnosis. The cause of his poor outcome may be related to MYC rearrangement. The GI tract involvement in ARL is rarely reported, and its endoscopic findings are various and may be different from those in non-AIDS GI lymphoma; thus, we also conducted a literature review of GI-ARL cases. PMID:23922484

Equatorial late-afternoon periodic TEC fluctuations observed by multiple GPS receivers

NASA Astrophysics Data System (ADS)

Tsugawa, T.; Maruyama, T.; Saito, S.; Ishii, M.

2009-12-01

We report, for the first time, equatorial periodic total electron content (TEC) fluctuations observed in the late afternoon by multiple GPS receivers. As a part of Southeast Asia low-latitude ionospheric network (SEALION), GPS receivers at Chiang Mai and Chumphon, Thailand, have been operated since 2005. We found that periodic TEC fluctuations (PTF) with the periods of 15-30 minutes are often observed at these two sites in the spring (Apr-May) late afternoon. Further investigations using multiple GPS receivers in Southeast Asia revealed that the PTFs propagate at 150-200 m/s away from the equator and their amplitudes depend on the satellite azimuth angle. Statistical study of the PTF activity at different latitudes and longitudes clarified that the PTFs are not observed at mid-latitudes, and their seasonal variations are different at different longitudes and at geomagnetically conjugate regions. These observational results indicate that the PTFs are caused by the atmospheric gravity waves (AGW) which are generated in the equatorial lower atmosphere and propagate away from the equator. Simultaneous GPS-TEC and ionosonde observations at Chumphon revealed that the day-to-day variations of PTF activities are well correlated with those of the rate of TEC change index (ROTI) and the occurrence of equatorial spread F (ESF) after the sunset, indicating the PTFs may be related with the onset of the ESF and plasma bubbles.

Feature diagnosticity and task context shape activity in human scene-selective cortex.

PubMed

Lowe, Matthew X; Gallivan, Jason P; Ferber, Susanne; Cant, Jonathan S

2016-01-15

Scenes are constructed from multiple visual features, yet previous research investigating scene processing has often focused on the contributions of single features in isolation. In the real world, features rarely exist independently of one another and likely converge to inform scene identity in unique ways. Here, we utilize fMRI and pattern classification techniques to examine the interactions between task context (i.e., attend to diagnostic global scene features; texture or layout) and high-level scene attributes (content and spatial boundary) to test the novel hypothesis that scene-selective cortex represents multiple visual features, the importance of which varies according to their diagnostic relevance across scene categories and task demands. Our results show for the first time that scene representations are driven by interactions between multiple visual features and high-level scene attributes. Specifically, univariate analysis of scene-selective cortex revealed that task context and feature diagnosticity shape activity differentially across scene categories. Examination using multivariate decoding methods revealed results consistent with univariate findings, but also evidence for an interaction between high-level scene attributes and diagnostic visual features within scene categories. Critically, these findings suggest visual feature representations are not distributed uniformly across scene categories but are shaped by task context and feature diagnosticity. Thus, we propose that scene-selective cortex constructs a flexible representation of the environment by integrating multiple diagnostically relevant visual features, the nature of which varies according to the particular scene being perceived and the goals of the observer. Copyright © 2015 Elsevier Inc. All rights reserved.

Cross-induction of detoxification genes by environmental xenobiotics and insecticides in the mosquito Aedes aegypti: impact on larval tolerance to chemical insecticides.

PubMed

Poupardin, Rodolphe; Reynaud, Stéphane; Strode, Clare; Ranson, Hilary; Vontas, John; David, Jean-Philippe

2008-05-01

The effect of exposure of Aedes aegypti larvae to sub-lethal doses of the pyrethroid insecticide permethrin, the organophosphate temephos, the herbicide atrazine, the polycyclic aromatic hydrocarbon fluoranthene and the heavy metal copper on their subsequent tolerance to insecticides, detoxification enzyme activities and expression of detoxification genes was investigated. Bioassays revealed a moderate increase in larval tolerance to permethrin following exposure to fluoranthene and copper while larval tolerance to temephos increased moderately after exposure to atrazine, copper and permethrin. Cytochrome P450 monooxygenases activities were induced in larvae exposed to permethrin, fluoranthene and copper while glutathione S-transferase activities were induced after exposure to fluoranthene and repressed after exposure to copper. Microarray screening of the expression patterns of all detoxification genes following exposure to each xenobiotic with the Aedes Detox Chip identified multiple genes induced by xenobiotics and insecticides. Further expression studies using real-time quantitative PCR confirmed the induction of multiple CYP genes and one carboxylesterase gene by insecticides and xenobiotics. Overall, this study reveals the potential of xenobiotics found in polluted mosquito breeding sites to affect their tolerance to insecticides, possibly through the cross-induction of particular detoxification genes. Molecular mechanisms involved and impact on mosquito control strategies are discussed.

Target proteins of ganoderic acid DM provides clues to various pharmacological mechanisms

PubMed Central

Liu, Jie; Shimizu, Kuniyoshi; Tanaka, Akinobu; Shinobu, Wakako; Ohnuki, Koichiro; Nakamura, Takanori; Kondo, Ryuichiro

2012-01-01

Ganoderma fungus (Ganodermataceae) is a multifunctional medicinal mushroom and has been traditionally used for the treatment of various types of disease. Ganoderic acid DM (1) is a representative triterpenoid isolated from G. lingzhi and exhibits various biological activities. However, a universal starting point that triggers multiple signaling pathways and results in multifunctionality of 1 is unknown. Here we demonstrate the important clues regarding the mechanisms underlying multi-medicinal action of 1. We examined structure–activity relationships between 1 and its analogs and found that the carbonyl group at C-3 was essential for cytotoxicity. Subsequently, we used 1-conjugated magnetic beads as a probe and identified tubulin as a specific 1-binding protein. Furthermore, 1 showed a similar Kd to that of vinblastine and also affected assembly of tubulin polymers. This study revealed multiple biological activities of 1 and may contribute to the design and development of new tubulin-inhibiting agents. PMID:23205267

A Corticothalamic Circuit Model for Sound Identification in Complex Scenes

PubMed Central

Otazu, Gonzalo H.; Leibold, Christian

2011-01-01

The identification of the sound sources present in the environment is essential for the survival of many animals. However, these sounds are not presented in isolation, as natural scenes consist of a superposition of sounds originating from multiple sources. The identification of a source under these circumstances is a complex computational problem that is readily solved by most animals. We present a model of the thalamocortical circuit that performs level-invariant recognition of auditory objects in complex auditory scenes. The circuit identifies the objects present from a large dictionary of possible elements and operates reliably for real sound signals with multiple concurrently active sources. The key model assumption is that the activities of some cortical neurons encode the difference between the observed signal and an internal estimate. Reanalysis of awake auditory cortex recordings revealed neurons with patterns of activity corresponding to such an error signal. PMID:21931668

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

Single Turnover at Molecular Polymerization Catalysts Reveals Spatiotemporally Resolved Reactions.

PubMed

Easter, Quinn T; Blum, Suzanne A

2017-10-23

Multiple active individual molecular ruthenium catalysts have been pinpointed within growing polynorbornene, thereby revealing information on the reaction dynamics and location that is unavailable through traditional ensemble experiments. This is the first single-turnover imaging of a molecular catalyst by fluorescence microscopy and allows detection of individual monomer reactions at an industrially important molecular ruthenium ring-opening metathesis polymerization (ROMP) catalyst under synthetically relevant conditions (e.g. unmodified industrial catalyst, ambient pressure, condensed phase, ca. 0.03 m monomer). These results further establish the key fundamentals of this imaging technique for characterizing the reactivity and location of active molecular catalysts even when they are the minor components. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Multiple Regions of a Cortical Network Commonly Encode the Meaning of Words in Multiple Grammatical Positions of Read Sentences.

PubMed

Anderson, Andrew James; Lalor, Edmund C; Lin, Feng; Binder, Jeffrey R; Fernandino, Leonardo; Humphries, Colin J; Conant, Lisa L; Raizada, Rajeev D S; Grimm, Scott; Wang, Xixi

2018-05-16

Deciphering how sentence meaning is represented in the brain remains a major challenge to science. Semantically related neural activity has recently been shown to arise concurrently in distributed brain regions as successive words in a sentence are read. However, what semantic content is represented by different regions, what is common across them, and how this relates to words in different grammatical positions of sentences is weakly understood. To address these questions, we apply a semantic model of word meaning to interpret brain activation patterns elicited in sentence reading. The model is based on human ratings of 65 sensory/motor/emotional and cognitive features of experience with words (and their referents). Through a process of mapping functional Magnetic Resonance Imaging activation back into model space we test: which brain regions semantically encode content words in different grammatical positions (e.g., subject/verb/object); and what semantic features are encoded by different regions. In left temporal, inferior parietal, and inferior/superior frontal regions we detect the semantic encoding of words in all grammatical positions tested and reveal multiple common components of semantic representation. This suggests that sentence comprehension involves a common core representation of multiple words' meaning being encoded in a network of regions distributed across the brain.

Fast and slow transitions in frontal ensemble activity during flexible sensorimotor behavior.

PubMed

Siniscalchi, Michael J; Phoumthipphavong, Victoria; Ali, Farhan; Lozano, Marc; Kwan, Alex C

2016-09-01

The ability to shift between repetitive and goal-directed actions is a hallmark of cognitive control. Previous studies have reported that adaptive shifts in behavior are accompanied by changes of neural activity in frontal cortex. However, neural and behavioral adaptations can occur at multiple time scales, and their relationship remains poorly defined. Here we developed an adaptive sensorimotor decision-making task for head-fixed mice, requiring them to shift flexibly between multiple auditory-motor mappings. Two-photon calcium imaging of secondary motor cortex (M2) revealed different ensemble activity states for each mapping. When adapting to a conditional mapping, transitions in ensemble activity were abrupt and occurred before the recovery of behavioral performance. By contrast, gradual and delayed transitions accompanied shifts toward repetitive responding. These results demonstrate distinct ensemble signatures associated with the start versus end of sensory-guided behavior and suggest that M2 leads in engaging goal-directed response strategies that require sensorimotor associations.

Active sensing in the categorization of visual patterns

PubMed Central

Yang, Scott Cheng-Hsin; Lengyel, Máté; Wolpert, Daniel M

2016-01-01

Interpreting visual scenes typically requires us to accumulate information from multiple locations in a scene. Using a novel gaze-contingent paradigm in a visual categorization task, we show that participants' scan paths follow an active sensing strategy that incorporates information already acquired about the scene and knowledge of the statistical structure of patterns. Intriguingly, categorization performance was markedly improved when locations were revealed to participants by an optimal Bayesian active sensor algorithm. By using a combination of a Bayesian ideal observer and the active sensor algorithm, we estimate that a major portion of this apparent suboptimality of fixation locations arises from prior biases, perceptual noise and inaccuracies in eye movements, and the central process of selecting fixation locations is around 70% efficient in our task. Our results suggest that participants select eye movements with the goal of maximizing information about abstract categories that require the integration of information from multiple locations. DOI: http://dx.doi.org/10.7554/eLife.12215.001 PMID:26880546

Identification of a primary target of thalidomide teratogenicity.

PubMed

Ito, Takumi; Ando, Hideki; Suzuki, Takayuki; Ogura, Toshihiko; Hotta, Kentaro; Imamura, Yoshimasa; Yamaguchi, Yuki; Handa, Hiroshi

2010-03-12

Half a century ago, thalidomide was widely prescribed to pregnant women as a sedative but was found to be teratogenic, causing multiple birth defects. Today, thalidomide is still used in the treatment of leprosy and multiple myeloma, although how it causes limb malformation and other developmental defects is unknown. Here, we identified cereblon (CRBN) as a thalidomide-binding protein. CRBN forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and Cul4A that is important for limb outgrowth and expression of the fibroblast growth factor Fgf8 in zebrafish and chicks. Thalidomide initiates its teratogenic effects by binding to CRBN and inhibiting the associated ubiquitin ligase activity. This study reveals a basis for thalidomide teratogenicity and may contribute to the development of new thalidomide derivatives without teratogenic activity.

Multiple acquired portosystemic shunts secondary to primary hypoplasia of the portal vein in a cat.

PubMed

Sugimoto, Satoko; Maeda, Shingo; Tsuboi, Masaya; Saeki, Kohei; Chambers, James K; Yonezawa, Tomohiro; Fukushima, Kenjiro; Fujiwara, Reina; Uchida, Kazuyuki; Tsujimoto, Hajime; Matsuki, Naoaki; Ohno, Koichi

2018-06-06

A 6-year 5-month-old spayed female Scottish Fold cat presented with a one-month history of gait abnormalities, increased salivation, and decreased activity. A blood test showed hyperammonemia and increased serum bile acids. Imaging tests revealed multiple shunt vessels indicating acquired portosystemic shunt. Histopathologic analysis of liver biopsy showed features consistent with liver hypoperfusion, such as a barely recognizable portal vein, increased numbers of small arterioles, and diffuse vacuolar degeneration of hepatocytes. These findings supported the diagnosis of primary hypoplasia of the portal vein/microvascular dysplasia, (PHPV/MVD). To our knowledge, this is the first case of feline PHPV/MVD that developed multiple acquired portosystemic shunts and presented with hepatic encephalopathy.

Ligand and receptor dynamics contribute to the mechanism of graded PPARγ agonism

PubMed Central

Hughes, Travis S.; Chalmers, Michael J.; Novick, Scott; Kuruvilla, Dana S.; Chang, Mi Ra; Kamenecka, Theodore M.; Rance, Mark; Johnson, Bruce A.; Burris, Thomas P.; Griffin, Patrick R.; Kojetin, Douglas J.

2011-01-01

SUMMARY Ligand binding to proteins is not a static process, but rather involves a number of complex dynamic transitions. A flexible ligand can change conformation upon binding its target. The conformation and dynamics of a protein can change to facilitate ligand binding. The conformation of the ligand, however, is generally presumed to have one primary binding mode, shifting the protein conformational ensemble from one state to another. We report solution NMR studies that reveal peroxisome proliferator-activated receptor γ (PPARγ) modulators can sample multiple binding modes manifesting in multiple receptor conformations in slow conformational exchange. Our NMR, hydrogen/deuterium exchange and docking studies reveal that ligand-induced receptor stabilization and binding mode occupancy correlate with the graded agonist response of the ligand. Our results suggest that ligand and receptor dynamics affect the graded transcriptional output of PPARγ modulators. PMID:22244763

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

Multiple division cycles and long-term survival of hepatocytes are distinctly regulated by extracellular signal-regulated kinases ERK1 and ERK2.

PubMed

Frémin, Christophe; Bessard, Anne; Ezan, Frédéric; Gailhouste, Luc; Régeard, Morgane; Le Seyec, Jacques; Gilot, David; Pagès, Gilles; Pouysségur, Jacques; Langouët, Sophie; Baffet, Georges

2009-03-01

We investigated the specific role of the mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase 1 (ERK1)/ERK2 pathway in the regulation of multiple cell cycles and long-term survival of normal hepatocytes. An early and sustained epidermal growth factor (EGF)-dependent MAPK activation greatly improved the potential of cell proliferation. In this condition, almost 100% of the hepatocytes proliferated, and targeting ERK1 or ERK2 via RNA interference revealed the specific involvement of ERK2 in this regulation. However, once their first cell cycle was performed, hepatocytes failed to undergo a second round of replication and stayed blocked in G1 phase. We demonstrated that sustained EGF-dependent activation of the MAPK/ERK kinase (MEK)/ERK pathway was involved in this blockage as specific transient inhibition of the cascade repotentiated hepatocytes to perform a new wave of replication and multiple cell cycles. We identified this mechanism by showing that this blockage was in part supported by ERK2-dependent p21 expression. Moreover, continuous MEK inhibition was associated with a lower apoptotic engagement, leading to an improvement of survival up to 3 weeks. Using RNA interference and ERK1 knockout mice, we extended these results by showing that this improved survival was due to the specific inhibition of ERK1 expression/phosphorylation and did not involve ERK2. Our results emphasize that transient MAPK inhibition allows multiple cell cycles in primary cultures of hepatocytes and that ERK2 has a key role in the regulation of S phase entry. Moreover, we revealed a major and distinct role of ERK1 in the regulation of hepatocyte survival. Taken together, our results represent an important advance in understanding long-term survival and cell cycle regulation of hepatocytes.

Structure of a group II intron in complex with its reverse transcriptase.

PubMed

Qu, Guosheng; Kaushal, Prem Singh; Wang, Jia; Shigematsu, Hideki; Piazza, Carol Lyn; Agrawal, Rajendra Kumar; Belfort, Marlene; Wang, Hong-Wei

2016-06-01

Bacterial group II introns are large catalytic RNAs related to nuclear spliceosomal introns and eukaryotic retrotransposons. They self-splice, yielding mature RNA, and integrate into DNA as retroelements. A fully active group II intron forms a ribonucleoprotein complex comprising the intron ribozyme and an intron-encoded protein that performs multiple activities including reverse transcription, in which intron RNA is copied into the DNA target. Here we report cryo-EM structures of an endogenously spliced Lactococcus lactis group IIA intron in its ribonucleoprotein complex form at 3.8-Å resolution and in its protein-depleted form at 4.5-Å resolution, revealing functional coordination of the intron RNA with the protein. Remarkably, the protein structure reveals a close relationship between the reverse transcriptase catalytic domain and telomerase, whereas the active splicing center resembles the spliceosomal Prp8 protein. These extraordinary similarities hint at intricate ancestral relationships and provide new insights into splicing and retromobility.

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

Systems Pharmacology Dissection of Traditional Chinese Medicine Wen-Dan Decoction for Treatment of Cardiovascular Diseases.

PubMed

Lan, Tao-Hua; Zhang, Lu-Lu; Wang, Yong-Hua; Wu, Huan-Lin; Xu, Dan-Ping

2018-01-01

Cardiovascular diseases (CVDs) have been recognized as first killer of human health. The underlying mechanisms of CVDs are extremely complicated and not fully revealed, leading to a challenge for CVDs treatment in modern medicine. Traditional Chinese medicine (TCM) characterized by multiple compounds and targets has shown its marked effects on CVDs therapy. However, system-level understanding of the molecular mechanisms is still ambiguous. In this study, a system pharmacology approach was developed to reveal the underlying molecular mechanisms of a clinically effective herb formula (Wen-Dan Decoction) in treating CVDs. 127 potential active compounds and their corresponding 283 direct targets were identified in Wen-Dan Decoction. The networks among active compounds, targets, and diseases were built to reveal the pharmacological mechanisms of Wen-Dan Decoction. A "CVDs pathway" consisted of several regulatory modules participating in therapeutic effects of Wen-Dan Decoction in CVDs. All the data demonstrates that Wen-Dan Decoction has multiscale beneficial activity in CVDs treatment, which provides a new way for uncovering the molecular mechanisms and new evidence for clinical application of Wen-Dan Decoction in cardiovascular disease.

Mechanosensing in hypothalamic osmosensory neurons.

PubMed

Prager-Khoutorsky, Masha

2017-11-01

Osmosensory neurons are specialized cells activated by increases in blood osmolality to trigger thirst, secretion of the antidiuretic hormone vasopressin, and elevated sympathetic tone during dehydration. In addition to multiple extrinsic factors modulating their activity, osmosensory neurons are intrinsically osmosensitive, as they are activated by increased osmolality in the absence of neighboring cells or synaptic contacts. This intrinsic osmosensitivity is a mechanical process associated with osmolality-induced changes in cell volume. This review summarises recent findings revealing molecular mechanisms underlying the mechanical activation of osmosensory neurons and highlighting important roles of microtubules, actin, and mechanosensitive ion channels in this process. Copyright © 2017 Elsevier Ltd. All rights reserved.

Will a category cue attract you? Motor output reveals dynamic competition across person construal.

PubMed

Freeman, Jonathan B; Ambady, Nalini; Rule, Nicholas O; Johnson, Kerri L

2008-11-01

People use social categories to perceive others, extracting category cues to glean membership. Growing evidence for continuous dynamics in real-time cognition suggests, contrary to prevailing social psychological accounts, that person construal may involve dynamic competition between simultaneously active representations. To test this, the authors examined social categorization in real-time by streaming the x, y coordinates of hand movements as participants categorized typical and atypical faces by sex. Though judgments of atypical targets were largely accurate, online motor output exhibited a continuous spatial attraction toward the opposite sex category, indicating dynamic competition between multiple social category alternatives. The authors offer a dynamic continuity account of social categorization and provide converging evidence across categorizations of real male and female faces (containing a typical or an atypical sex-specifying cue) and categorizations of computer-generated male and female faces (with subtly morphed sex-typical or sex-atypical features). In 3 studies, online motor output revealed continuous dynamics underlying person construal, in which multiple simultaneously and partially active category representations gradually cascade into social categorical judgments. Such evidence is challenging for discrete stage-based accounts. (c) 2008 APA, all rights reserved

Multiple Power-Saving MSSs Scheduling Methods for IEEE802.16e Broadband Wireless Networks

PubMed Central

2014-01-01

This work proposes two enhanced multiple mobile subscriber stations (MSSs) power-saving scheduling methods for IEEE802.16e broadband wireless networks. The proposed methods are designed for the Unsolicited Grant Service (UGS) of IEEE802.16e. To reduce the active periods of all power-saving MSSs, the base station (BS) allocates each MSS fewest possible transmission frames to retrieve its data from the BS. The BS interlaces the active periods of each MSS to increase the amount of scheduled MSSs and splits the overflowing transmission frames to maximize the bandwidth utilization. Simulation results reveal that interlacing the active periods of MSSs can increase the number of scheduled MSSs to more than four times of that in the Direct scheduling method. The bandwidth utilization can thus be improved by 60%–70%. Splitting the overflowing transmission frames can improve bandwidth utilization by more than 10% over that achieved using the method of interlacing active periods, with a sacrifice of only 1% of the sleep periods in the interlacing active period method. PMID:24523656

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.

EDS1 contributes to nonhost resistance of Arabidopsis thaliana against Erwinia amylovora.

PubMed

Moreau, Manon; Degrave, Alexandre; Vedel, Régine; Bitton, Frédérique; Patrit, Oriane; Renou, Jean-Pierre; Barny, Marie-Anne; Fagard, Mathilde

2012-03-01

Erwinia amylovora causes fire blight in rosaceous plants. In nonhost Arabidopsis thaliana, E. amylovora triggers necrotic symptoms associated with transient bacterial multiplication, suggesting either that A. thaliana lacks a susceptibility factor or that it actively restricts E. amylovora growth. Inhibiting plant protein synthesis at the time of infection led to an increase in necrosis and bacterial multiplication and reduced callose deposition, indicating that A. thaliana requires active protein synthesis to restrict E. amylovora growth. Analysis of the callose synthase-deficient pmr4-1 mutant indicated that lack of callose deposition alone did not lead to increased sensitivity to E. amylovora. Transcriptome analysis revealed that approximately 20% of the genes induced following E. amylovora infection are related to defense and signaling. Analysis of mutants affected in NDR1 and EDS1, two main components of the defense-gene activation observed, revealed that E. amylovora multiplied ten times more in the eds1-2 mutant than in the wild type but not in the ndr1-1 mutant. Analysis of mutants affected in three WRKY transcription factors showing EDS1-dependent activation identified WRKY46 and WRKY54 as positive regulators and WRKY70 as a negative regulator of defense against E. amylovora. Altogether, we show that EDS1 is a positive regulator of nonhost resistance against E. amylovora in A. thaliana and hypothesize that it controls the production of several effective defenses against E. amylovora through the action of WRKY46 and WRKY54, while WRKY70 acts as a negative regulator.

Modulation of brain activity by multiple lexical and word form variables in visual word recognition: A parametric fMRI study.

PubMed

Hauk, Olaf; Davis, Matthew H; Pulvermüller, Friedemann

2008-09-01

Psycholinguistic research has documented a range of variables that influence visual word recognition performance. Many of these variables are highly intercorrelated. Most previous studies have used factorial designs, which do not exploit the full range of values available for continuous variables, and are prone to skewed stimulus selection as well as to effects of the baseline (e.g. when contrasting words with pseudowords). In our study, we used a parametric approach to study the effects of several psycholinguistic variables on brain activation. We focussed on the variable word frequency, which has been used in numerous previous behavioural, electrophysiological and neuroimaging studies, in order to investigate the neuronal network underlying visual word processing. Furthermore, we investigated the variable orthographic typicality as well as a combined variable for word length and orthographic neighbourhood size (N), for which neuroimaging results are still either scarce or inconsistent. Data were analysed using multiple linear regression analysis of event-related fMRI data acquired from 21 subjects in a silent reading paradigm. The frequency variable correlated negatively with activation in left fusiform gyrus, bilateral inferior frontal gyri and bilateral insulae, indicating that word frequency can affect multiple aspects of word processing. N correlated positively with brain activity in left and right middle temporal gyri as well as right inferior frontal gyrus. Thus, our analysis revealed multiple distinct brain areas involved in visual word processing within one data set.

ANTIRADICAL AND ANTIMICROBIAL ACTIVITY OF PHENOLIC FRACTIONS OBTAINED FROM HONEYS.

PubMed

Mazol, Irena; Sroka, Zbigniew; Sowa, Alina; Ostrowska, Anna; Dryś, Andrzej; Gamian, Andrzej

2016-01-01

Honey is a natural product consisting of multiple components which determine its dietary and medicinal properties. In this work there were studied methanol fractions obtained from seven honeys from Lower Silesia (Poland) collected in different seasons of three successive years. Melissopalynologic studies revealed that two of them were polyfloral, and five were classified as monofloral (two buckwheat and three rapes). The amount of phenolic compounds in honeys varied from 0.09 to 0.38 mg per g of honey. Honeys harvested in 2010 were the richest in phenolic compounds and especially rich was buckwheat honey, comparing to 2011- 2012. Determination of antioxidant potential with the DPPH radical revealed that the strongest antiradical activity was exhibited by extracts obtained from polyfloral (1.22 TAU(515/mg)) and buckwheat (1.06 TAU(515lmg)) honeys, while the highest number of antiradical units was observed for rape honey (3.64 TAU(515/g)). Polyphenolic fractions exhibited various bactericidal activities against Klebsiella pneumoniae and Staphylococcus aureus and weak or no activity was observed against Pseudomonas aeruginosa.

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.

Structural distortions due to missense mutations in human formylglycine-generating enzyme leading to multiple sulfatase deficiency.

PubMed

Meshach Paul, D; Chadah, Tania; Senthilkumar, B; Sethumadhavan, Rao; Rajasekaran, R

2017-11-03

The major candidate for multiple sulfatase deficiency is a defective formylglycine-generating enzyme (FGE). Though adequately produced, mutations in FGE stall the activation of sulfatases and prevent their activity. Missense mutations, viz. E130D, S155P, A177P, W179S, C218Y, R224W, N259I, P266L, A279V, C336R, R345C, A348P, R349Q and R349W associated with multiple sulfatase deficiency are yet to be computationally studied. Aforementioned mutants were initially screened through ws-SNPs&GO 3D program. Mutant R345C acquired the highest score, and hence was studied in detail. Discrete molecular dynamics explored structural distortions due to amino acid substitution. Therein, comparative analyses of wild type and mutant were carried out. Changes in structural contours were observed between wild type and mutant. Mutant had low conformational fluctuation, high atomic mobility and more compactness than wild type. Moreover, free energy landscape showed mutant to vary in terms of its conformational space as compared to wild type. Subsequently, wild type and mutant were subjected to single-model analyses. Mutant had lesser intra molecular interactions than wild type suggesting variations pertaining to its secondary structure. Furthermore, simulated thermal denaturation showed dissimilar pattern of hydrogen bond dilution. Effects of these variations were observed as changes in elements of secondary structure. Docking studies of mutant revealed less favourable binding energy towards its substrate as compared to wild type. Therefore, theoretical explanations for structural distortions of mutant R345C leading to multiple sulfatase deficiency were revealed. The protocol of the study could be useful to examine the effectiveness of pharmacological chaperones prior to experimental studies.

Effects of dextromethorphan/quinidine on auditory event-related potentials in multiple sclerosis patients with pseudobulbar affect.

PubMed

Haiman, Guy; Pratt, Hillel; Miller, Ariel

2009-10-01

The purpose of this study was to characterize the brain activity and associated cortical structures involved in pseudobulbar affect (PBA), a condition characterized by uncontrollable episodes of laughing and/or crying in patients with multiple sclerosis before and after treatment with dextromethorphan/quinidine (DM/Q). Behavioral responses and event-related potentials (ERPs) in response to subjectively significant and neutral verbal stimuli were recorded from 2 groups: 6 multiple sclerosis patients with PBA before (PBA-preTx) and after (PBA-DM/Q) treatment with DM/Q and 6 healthy control (HC) subjects. Statistical nonparametric mapping comparisons of ERP source current density distributions between groups were conducted for subjectively significant and neutral stimuli separately before and after treatment with DM/Q. Treatment with DM/Q had a normalizing effect on the behavioral responses of PBA patients. Event-related potential waveform comparisons of PBA-preTx and PBA-DM/Q with HC, for both neutral and subjectively significant stimuli, revealed effects on early ERP components. Comparisons between PBA-preTx and HC, in response to subjectively significant stimuli, revealed both early and late effects. Source analysis comparisons between PBA-preTx and PBA-DM/Q indicated distinct activations in areas involved in emotional processing and high-level and associative visual processing in response to neutral stimuli and in areas involved in emotional, somatosensory, primary, and premotor processing in response to subjectively significant stimuli. In most cases, stimuli evoked higher current density in PBA-DM/Q compared with the other groups. In conclusion, differences in brain activity were observed before and after medication. Also, DM/Q administration resulted in normalization of behavioral and electrophysiological measures.

Relating speech production to tongue muscle compressions using tagged and high-resolution magnetic resonance imaging

NASA Astrophysics Data System (ADS)

Xing, Fangxu; Ye, Chuyang; Woo, Jonghye; Stone, Maureen; Prince, Jerry

2015-03-01

The human tongue is composed of multiple internal muscles that work collaboratively during the production of speech. Assessment of muscle mechanics can help understand the creation of tongue motion, interpret clinical observations, and predict surgical outcomes. Although various methods have been proposed for computing the tongue's motion, associating motion with muscle activity in an interdigitated fiber framework has not been studied. In this work, we aim to develop a method that reveals different tongue muscles' activities in different time phases during speech. We use fourdimensional tagged magnetic resonance (MR) images and static high-resolution MR images to obtain tongue motion and muscle anatomy, respectively. Then we compute strain tensors and local tissue compression along the muscle fiber directions in order to reveal their shortening pattern. This process relies on the support from multiple image analysis methods, including super-resolution volume reconstruction from MR image slices, segmentation of internal muscles, tracking the incompressible motion of tissue points using tagged images, propagation of muscle fiber directions over time, and calculation of strain in the line of action, etc. We evaluated the method on a control subject and two postglossectomy patients in a controlled speech task. The normal subject's tongue muscle activity shows high correspondence with the production of speech in different time instants, while both patients' muscle activities show different patterns from the control due to their resected tongues. This method shows potential for relating overall tongue motion to particular muscle activity, which may provide novel information for future clinical and scientific studies.

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

A large homozygous deletion in the SAMHD1 gene causes atypical Aicardi–Goutiéres syndrome associated with mtDNA deletions

PubMed Central

Leshinsky-Silver, Esther; Malinger, Gustavo; Ben-Sira, Liat; Kidron, Dvora; Cohen, Sarit; Inbar, Shani; Bezaleli, Tali; Levine, Arie; Vinkler, Chana; Lev, Dorit; Lerman-Sagie, Tally

2011-01-01

Aicardi–Goutiéres syndrome (AGS) is a genetic neurodegenerative disorder with clinical symptoms mimicking a congenital viral infection. Five causative genes have been described: three prime repair exonuclease1 (TREX1), ribonucleases H2A, B and C, and most recently SAM domain and HD domain 1 (SAMHD1). We performed a detailed clinical and molecular characterization of a family with autosomal recessive neurodegenerative disorder showing white matter destruction and calcifications, presenting in utero and associated with multiple mtDNA deletions. A muscle biopsy was normal and did not show any evidence of respiratory chain dysfunction. Southern blot analysis of tissue from a living child and affected fetuses demonstrated multiple mtDNA deletions. Molecular analysis of genes involved in mtDNA synthesis and maintenance (POLGα, POLGβ, Twinkle, ANT1, TK2, SUCLA1 and DGOUK) revealed normal sequences. Sequencing of TREX1 and ribonucleases H2A, B and C failed to reveal any mutations. Whole-genome homozygosity mapping revealed a candidate region containing the SAMHD1 gene. Sequencing of the gene in the affected child and two affected fetuses revealed a large deletion (9 kb), spanning the promoter, exon1 and intron 1. The parents were found to be heterozygous for this deletion. The identification of a homozygous large deletion in the SAMHD1 gene causing atypical AGS with multiple mtDNA deletions may add information regarding the involvement of mitochondria in self-activation of innate immunity by cell intrinsic components. PMID:21102625

Software forecasting as it is really done: A study of JPL software engineers

NASA Technical Reports Server (NTRS)

Griesel, Martha Ann; Hihn, Jairus M.; Bruno, Kristin J.; Fouser, Thomas J.; Tausworthe, Robert C.

1993-01-01

This paper presents a summary of the results to date of a Jet Propulsion Laboratory internally funded research task to study the costing process and parameters used by internally recognized software cost estimating experts. Protocol Analysis and Markov process modeling were used to capture software engineer's forecasting mental models. While there is significant variation between the mental models that were studied, it was nevertheless possible to identify a core set of cost forecasting activities, and it was also found that the mental models cluster around three forecasting techniques. Further partitioning of the mental models revealed clustering of activities, that is very suggestive of a forecasting lifecycle. The different forecasting methods identified were based on the use of multiple-decomposition steps or multiple forecasting steps. The multiple forecasting steps involved either forecasting software size or an additional effort forecast. Virtually no subject used risk reduction steps in combination. The results of the analysis include: the identification of a core set of well defined costing activities, a proposed software forecasting life cycle, and the identification of several basic software forecasting mental models. The paper concludes with a discussion of the implications of the results for current individual and institutional practices.

Comparing strategies to assess multiple behavior change in behavioral intervention studies.

PubMed

Drake, Bettina F; Quintiliani, Lisa M; Sapp, Amy L; Li, Yi; Harley, Amy E; Emmons, Karen M; Sorensen, Glorian

2013-03-01

Alternatives to individual behavior change methods have been proposed, however, little has been done to investigate how these methods compare. To explore four methods that quantify change in multiple risk behaviors targeting four common behaviors. We utilized data from two cluster-randomized, multiple behavior change trials conducted in two settings: small businesses and health centers. Methods used were: (1) summative; (2) z-score; (3) optimal linear combination; and (4) impact score. In the Small Business study, methods 2 and 3 revealed similar outcomes. However, physical activity did not contribute to method 3. In the Health Centers study, similar results were found with each of the methods. Multivitamin intake contributed significantly more to each of the summary measures than other behaviors. Selection of methods to assess multiple behavior change in intervention trials must consider study design, and the targeted population when determining the appropriate method/s to use.

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.

Infrared video tracking of Anopheles gambiae at insecticide-treated bed nets reveals rapid decisive impact after brief localised net contact

PubMed Central

Parker, Josephine E.A.; Angarita-Jaimes, Natalia; Abe, Mayumi; Towers, Catherine E.; Towers, David; McCall, Philip J.

2015-01-01

Long-lasting insecticidal bed nets (LLINs) protect humans from malaria transmission and are fundamental to malaria control worldwide, but little is known of how mosquitoes interact with nets. Elucidating LLIN mode of action is essential to maintain or improve efficacy, an urgent need as emerging insecticide resistance threatens their future. Tracking multiple free-flying Anopheles gambiae responding to human-occupied bed nets in a novel large-scale system, we characterised key behaviours and events. Four behavioural modes with different levels of net contact were defined: swooping, visiting, bouncing and resting. Approximately 75% of all activity occurred at the bed net roof where multiple brief contacts were focussed above the occupant’s torso. Total flight and net contact times were lower at LLINs than untreated nets but the essential character of the response was unaltered. LLINs did not repel mosquitoes but impacted rapidly: LLIN contact of less than 1 minute per mosquito during the first ten minutes reduced subsequent activity; after thirty minutes, activity at LLINs was negligible. Velocity measurements showed that mosquitoes detected nets, including unbaited untreated nets, prior to contact. This is the most complete characterisation of mosquito-LLIN interactions to date, and reveals many aspects of LLIN mode of action, important for developing the next generation of LLINs. PMID:26323965

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

Structural model of the dimeric Parkinson’s protein LRRK2 reveals a compact architecture involving distant interdomain contacts

PubMed Central

Guaitoli, Giambattista; Raimondi, Francesco; Gilsbach, Bernd K.; Gómez-Llorente, Yacob; Deyaert, Egon; Renzi, Fabiana; Li, Xianting; Schaffner, Adam; Jagtap, Pravin Kumar Ankush; Boldt, Karsten; von Zweydorf, Felix; Gotthardt, Katja; Lorimer, Donald D.; Yue, Zhenyu; Burgin, Alex; Janjic, Nebojsa; Sattler, Michael; Versées, Wim; Ueffing, Marius; Ubarretxena-Belandia, Iban; Kortholt, Arjan; Gloeckner, Christian Johannes

2016-01-01

Leucine-rich repeat kinase 2 (LRRK2) is a large, multidomain protein containing two catalytic domains: a Ras of complex proteins (Roc) G-domain and a kinase domain. Mutations associated with familial and sporadic Parkinson’s disease (PD) have been identified in both catalytic domains, as well as in several of its multiple putative regulatory domains. Several of these mutations have been linked to increased kinase activity. Despite the role of LRRK2 in the pathogenesis of PD, little is known about its overall architecture and how PD-linked mutations alter its function and enzymatic activities. Here, we have modeled the 3D structure of dimeric, full-length LRRK2 by combining domain-based homology models with multiple experimental constraints provided by chemical cross-linking combined with mass spectrometry, negative-stain EM, and small-angle X-ray scattering. Our model reveals dimeric LRRK2 has a compact overall architecture with a tight, multidomain organization. Close contacts between the N-terminal ankyrin and C-terminal WD40 domains, and their proximity—together with the LRR domain—to the kinase domain suggest an intramolecular mechanism for LRRK2 kinase activity regulation. Overall, our studies provide, to our knowledge, the first structural framework for understanding the role of the different domains of full-length LRRK2 in the pathogenesis of PD. PMID:27357661

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

Lovelace, Erica S.; Wagoner, Jessica; MacDonald, James

Silymarin (SM), a natural product, is touted as a liver protectant and preventer of both chronic inflammation and diseases. To define how SM elicits these effects at a systems level, we performed transcriptional profiling, metabolomics, and signaling studies in human liver and T cell lines. Multiple pathways associated with cellular stress and metabolism were modulated by SM treatment within 0.5 to four hours: activation of Activating Transcription Factor 4 (ATF-4) and adenosine monophosphate protein kinase (AMPK) and inhibition of mammalian target of rapamycin (mTOR) signaling, the latter being associated with induction of DNA-damage-inducible transcript 4 (DDIT4). Metabolomics analyses revealed suppressionmore » of glycolytic, TCA cycle, and amino acid metabolism by SM treatment. Antiinflammatory effects arose with prolonged (i.e. 24 hours) SM exposure, with suppression of multiple proinflammatory mRNAs and nuclear factor kappa B (NF-κB) and forkhead box O (FOXO) signaling. Studies with murine knock out cells revealed that SM inhibition of both mTOR and NF-κB was partially AMPK dependent, while SM inhibition of the mTOR pathway in part required DDIT4. Thus, SM activates stress and repair responses that culminate in an anti-inflammatory phenotype. Other natural products induced similar stress responses, which correlated with their ability to suppress inflammation. Therefore, natural products like SM may be useful as tools to define how metabolic, stress, and repair pathways regulate cellular inflammation.« less

A mixed-methods investigation of successful aging among older women engaged in sports-based versus exercise-based leisure time physical activities.

PubMed

Berlin, Kathryn; Kruger, Tina; Klenosky, David B

2018-01-01

This mixed-methods study compares active older women in different physically based leisure activities and explores the difference in subjective ratings of successful aging and quantifiable predictors of success. A survey was administered to 256 women, 60-92 years of age, engaged in a sports- or exercise-based activity. Quantitative data were analyzed through ANOVA and multiple regression. Qualitative data (n = 79) was analyzed using the approach associated with means-end theory. While participants quantitatively appeared similar in terms of successful aging, qualitative interviews revealed differences in activity motivation. Women involved in sports highlighted social/psychological benefits, while those involved in exercise-based activities stressed fitness outcomes.

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.

Acquired dysfibrinogenemia secondary to multiple myeloma.

PubMed

Kotlín, Roman; Sobotková, Alzbeta; Riedel, Tomás; Salaj, Peter; Suttnar, Jirí; Reicheltová, Zuzana; Májek, Pavel; Khaznadar, Tarek; Dyr, Jan E

2008-01-01

Abnormal coagulation properties indicative of a dysfibrinogen were found in the plasma of a 72-year-old male with multiple myeloma (IgGkappa, stage IIIA). The patient had high paraprotein concentration (85.75 g/l) and prolonged thrombin time (76.8 s), activated partial thromboplastin time (39.5 s), prothrombin time (23.5 s) and reptilase time (72.0 s). The fibrinogen level was increased. The fibrin polymerization induced by both thrombin and reptilase was impaired. Scanning electron microscopy revealed abnormal clot morphology. After six months of treatment, the paraprotein level decreased (19.48 g/l) and coagulation normalized as well as fibrin polymerization and fibrin clot morphology. It was found that the paraprotein interacts with the gamma-chain of fibrinogen. Acquired dysfibrinogenemia associated with multiple myeloma was diagnosed in the 72-year-old patient.

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.

Flow cytometric analysis reveals the high levels of platelet activation parameters in circulation of multiple sclerosis patients.

PubMed

Morel, Agnieszka; Rywaniak, Joanna; Bijak, Michał; Miller, Elżbieta; Niwald, Marta; Saluk, Joanna

2017-06-01

The epidemiological studies confirm an increased risk of cardiovascular disease in multiple sclerosis, especially prothrombotic events directly associated with abnormal platelet activity. The aim of our study was to investigate the level of blood platelet activation in the circulation of patients with chronic phase of multiple sclerosis (SP MS) and their reactivity in response to typical platelets' physiological agonists. We examined 85 SP MS patients diagnosed according to the revised McDonald's criteria and 50 healthy volunteers as a control group. The platelet activation and reactivity were assessed using flow cytometry analysis of the following: P-selectin expression (CD62P), activation of GP IIb/IIIa complex (PAC-1 binding), and formation of platelet microparticles (PMPs) and platelet aggregates (PA) in agonist-stimulated (ADP, collagen) and unstimulated whole blood samples. Furthermore, we measured the level of soluble P-selectin (sP-selectin) in plasma using ELISA method, to evaluate the in vivo level of platelet activation, both in healthy and SP MS subjects. We found a statistically significant increase in P-selectin expression, GP IIb/IIIa activation, and formation of PMPs and PA, as well as in unstimulated and agonist-stimulated (ADP, collagen) platelets in whole blood samples from patients with SP MS in comparison to the control group. We also determined the higher sP-selectin level in plasma of SP MS subjects than in the control group. Based on the obtained results, we might conclude that during the course of SP MS platelets are chronically activated and display hyperreactivity to physiological agonists, such as ADP or collagen.

Microplate fluorescence protease assays test the inhibition of select North American snake venoms' activities with an anti-proteinase library.

PubMed

Price, Joseph A

2015-09-01

Snake envenomation is a relatively neglected significant world health problem, designated an orphan disease by the WHO. While often effective, antivenins are insufficient. Could another approach greatly aid inhibition of the venom toxins? New fluorescent substrates for measuring protease activity in microplate assays suitable for high throughput screening were tested and found reproducible with snake venom. Representative North American venoms showed relatively strong proteinase and collagenase, but weaker elastase activities. Caseinolytic activity is inhibited by the nonspecific proteinase inhibitor 1,10-phenanthroline and by EDTA, as is collagenase activity, consistent with the action of metalloproteinases. Both general protease and collagenase assays CV average 3%, and Km measured were above normal working conditions. Using a library of anti -proteinase compounds with multiple venoms revealed high inhibitor activity by three agents with known multiple metalloproteinase inhibitor activity (Actinonin, GM6001, and NNGH), which incidentally supports the concept that much of the degradative activity of certain venoms is due to metalloproteinases with collagenase activity. These results together support the use of microplate proteinase assays, particularly this collagenase assay, in future drug repurposing studies leading to the development of new treatments for those envenomations that have a major proteolytic component in their pathophysiology. Copyright © 2015 Elsevier Ltd. All rights reserved.

Motor Skill Competence and Perceived Motor Competence: Which Best Predicts Physical Activity among Girls?

PubMed

Khodaverdi, Zeinab; Bahram, Abbas; Khalaji, Hassan; Kazemnejad, Anoshirvan

2013-10-01

The main purpose of this study was to determine which correlate, perceived motor competence or motor skill competence, best predicts girls' physical activity behavior. A sample of 352 girls (mean age=8.7, SD=0.3 yr) participated in this study. To assess motor skill competence and perceived motor competence, each child completed the Test of Gross Motor Development-2 and Physical Ability sub-scale of Marsh's Self-Description Questionnaire. Children's physical activity was assessed by the Physical Activity Questionnaire for Older Children. Multiple linear regression model was used to determine whether perceived motor competence or motor skill competence best predicts moderate-to-vigorous self-report physical activity. Multiple regression analysis indicated that motor skill competence and perceived motor competence predicted 21% variance in physical activity (R(2)=0.21, F=48.9, P=0.001), and motor skill competence (R(2)=0.15, ᵝ=0.33, P= 0.001) resulted in more variance than perceived motor competence (R(2)=0.06, ᵝ=0.25, P=0.001) in physical activity. Results revealed motor skill competence had more influence in comparison with perceived motor competence on physical activity level. We suggest interventional programs based on motor skill competence and perceived motor competence should be administered or implemented to promote physical activity in young girls.

The effects of sleep quality, physical activity, and environmental quality on the risk of falls in dementia.

PubMed

Eshkoor, Sima Ataollahi; Hamid, Tengku Aizan; Nudin, Siti Sa'adiah Hassan; Mun, Chan Yoke

2013-06-01

This study aimed to identify the effects of sleep quality, physical activity, environmental quality, age, ethnicity, sex differences, marital status, and educational level on the risk of falls in the elderly individuals with dementia. Data were derived from a group of 1210 Malaysian elderly individuals who were noninstitutionalized and demented. The multiple logistic regression model was applied to estimate the risk of falls in respondents. Approximately the prevalence of falls was 17% among the individuals. The results of multiple logistic regression analysis revealed that age (odds ratio [OR] = 1.03), ethnicity (OR = 1.76), sleep quality (OR = 1.46), and environmental quality (OR = 0.62) significantly affected the risk of falls in individuals (P < .05). Furthermore, sex differences, marital status, educational level, and physical activity were not significant predictors of falls in samples (P > .05). It was found that age, ethnic non-Malay, and sleep disruption increased the risk of falls in respondents, but high environmental quality reduced the risk of falls.

Exercise self-efficacy in older adults: social, affective, and behavioral influences.

PubMed

McAuley, Edward; Jerome, Gerald J; Marquez, David X; Elavsky, Steriani; Blissmer, Bryan

2003-01-01

A 6-month randomized controlled trial examined the effect of walking and stretching/toning activity on changes in self-efficacy to overcome barriers and engage in incremental periods of activity in older, formerly sedentary adults (N = 174, M age = 65.5 years). Additionally, we were interested in the extent to which social, affective, and behavioral influences contributed to self-efficacy at the end of the 6-month program. Multiple sample latent growth curve analyses revealed a nonsignificant curvilinear growth pattern for barriers efficacy with increases in efficacy occurring from baseline to 2 months and then declining at 4 and 6 months. In the case of efficacy related to continued activity participation, there was a significant growth pattern demonstrating declines in efficacy over the 4 time points. Structural modeling analyses revealed significant direct effects of physical activity, affect experienced during activity, and exercise social support on both types of self-efficacy. These relationships were not significantly different between modes of activity. The findings are discussed in terms of the need to target sources of efficacy information prior to program end and the implications that such an approach might have for long-term maintenance of physical activity in older adults.

Occidiofungin is an important component responsible for the antifungal activity of Burkholderia pyrrocinia strain Lyc2.

PubMed

Wang, X Q; Liu, A X; Guerrero, A; Liu, J; Yu, X Q; Deng, P; Ma, L; Baird, S M; Smith, L; Li, X D; Lu, S E

2016-03-01

To identify the taxonomy of tobacco rhizosphere-isolated strain Lyc2 and investigate the mechanisms of the antifungal activities, focusing on antimicrobials gene clusters identification and function analysis. Multilocus sequence typing and 16S rRNA analyses indicated that strain Lyc2 belongs to Burkholderia pyrrocinia. Bioassay results indicated strain Lyc2 showed significant antifungal activities against a broad range of plant and animal fungal pathogens and control efficacy on seedling damping off disease of cotton. A 55·2-kb gene cluster which was homologous to ocf gene clusters in Burkholderia contaminans MS14 was confirmed to be responsible for antifungal activities by random mutagenesis; HPLC was used to verify the production of antifungal compounds. Multiple antibiotic and secondary metabolized biosynthesis gene clusters predicated by antiSMASH revealed the broad spectrum of antimicrobials activities of the strain. Our results revealed the mechanisms of antifungal activities of strain Lyc2 and expand our knowledge about production of occidiofungin in the bacteria Burkholderia. Understanding the mechanisms of antifungal activities of strain Lyc2 has contributed to discovery of new antibiotics and expand our knowledge of production of occidiofungin in the bacteria Burkholderia. © 2015 The Society for Applied Microbiology.

The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints

PubMed Central

Llosa, Nicolas J.; Cruise, Michael; Tam, Ada; Wick, Elizabeth C.; Hechenbleikner, Elizabeth M.; Taube, Janis M.; Blosser, Lee; Fan, Hongni; Wang, Hao; Luber, Brandon; Zhang, Ming; Papadopoulos, Nickolas; Kinzler, Kenneth W.; Vogelstein, Bert; Sears, Cynthia L.; Anders, Robert A.; Pardoll, Drew M.; Housseau, Franck

2014-01-01

We examined the immune microenvironment of primary colorectal cancer (CRC) using immunohistochemistry, laser capture microdissection/qRT-PCR, flow cytometry and functional analysis of tumor infiltrating lymphocytes. A subset of CRC displayed high infiltration with activated CD8+ CTL as well as activated Th1 cells characterized by IFN-γ production and the Th1 transcription factor Tbet. Parallel analysis of tumor genotypes revealed that virtually all of the tumors with this active Th1/CTL microenvironment had defects in mismatch repair, as evidenced by microsatellite instability (MSI). Counterbalancing this active Th1/CTL microenvironment, MSI tumors selectively demonstrated highly up-regulated expression of multiple immune checkpoints, including five – PD-1, PD-L1, CTLA-4, LAG-3 and IDO – currently being targeted clinically with inhibitors. These findings link tumor genotype with the immune microenvironment, and explain why MSI tumors are not naturally eliminated despite a hostile Th1/CTL microenvironment. They further suggest that blockade of specific checkpoints may be selectively efficacious in the MSI subset of CRC. PMID:25358689

Direct interaction of menin leads to ubiquitin-proteasomal degradation of β-catenin.

PubMed

Kim, Byungho; Song, Tae-Yang; Jung, Kwan Young; Kim, Seul Gi; Cho, Eun-Jung

2017-10-07

Menin, encoded by the multiple endocrine neoplasia type 1 (MEN1) gene, is a tumor suppressor and transcription regulator. Menin interacts with various proteins as a scaffold protein and is proposed to play important roles in multiple physiological and pathological processes by controlling gene expression, proliferation, and apoptosis. The mechanisms underlying menin's suppression of tumorigenesis are largely elusive. In this study, we showed that menin was essential for the regulation of canonical Wnt/β-catenin signaling in cultured cells. The C-terminal domain of menin was able to directly interact with and promote ubiquitin-mediated degradation of β-catenin. We further revealed that overexpression of menin down-regulated the transcriptional activity of β-catenin and target gene expression. Moreover, menin efficiently inhibited β-catenin protein levels, transcriptional activity, and proliferation of human renal carcinoma cells with an activated β-catenin pathway. Taken together, our results provide novel molecular insights into the tumor suppressor activity of menin, which is partly mediated by proteasomal degradation of β-catenin and inhibition of Wnt/β-catenin signaling. Copyright © 2017 Elsevier Inc. All rights reserved.

Gender, Religiosity, Sexual Activity, Sexual Knowledge, and Attitudes Toward Controversial Aspects of Sexuality.

PubMed

Sümer, Zeynep Hatipoğlu

2015-12-01

The purpose of this study is to examine the role of gender, religiosity, sexual activity, and sexual knowledge in predicting attitudes toward controversial aspects of sexuality among Turkish university students. Participants were 162 female and 135 male undergraduate students who were recruited on a volunteer basis from an urban state university in Turkey. The SKAT-A Attitude Scale along with background information form, sexual activities inventory, and sexual knowledge scale were administered to the participants. Simultaneous multiple regression analyses revealed that religiosity, particularly attendance to religious services was the most significant predictor in explaining university students' attitudes toward masturbation, abortion, homosexuality, pornography, and sexual coercion.

Purification, developmental expression, and in silico characterization of α-amylase inhibitor from Echinochloa frumentacea.

PubMed

Panwar, Priyankar; Verma, A K; Dubey, Ashutosh

2018-05-01

Barnyard ( Echinochloa frumentacea ) and finger ( Eleusine coracana ) millet growing at northwestern Himalaya were explored for the α-amylase inhibitor (α-AI). The mature seeds of barnyard millet variety PRJ1 had maximum α-AI activity which increases in different developmental stage. α-AI was purified up to 22.25-fold from barnyard millet variety PRJ1. Semi-quantitative PCR of different developmental stages of barnyard millet seeds showed increased levels of the transcript from 7 to 28 days. Sequence analysis revealed that it contained 315 bp nucleotide which encodes 104 amino acid sequence with molecular weight 10.72 kDa. The predicted 3D structure of α-AI was 86.73% similar to a bifunctional inhibitor of ragi. In silico analysis of 71 α-AI protein sequences were carried out for biochemical features, homology search, multiple sequence alignment, phylogenetic tree construction, motif, and superfamily distribution of protein sequences. Analysis of multiple sequence alignment revealed the existence of conserved regions NPLP[S/G]CRWYVV[S/Q][Q/R]TCG[V/I] throughout sequences. Superfam analysis revealed that α-AI protein sequences were distributed among seven different superfamilies.

Functional anatomic studies of memory retrieval for auditory words and visual pictures.

PubMed

Buckner, R L; Raichle, M E; Miezin, F M; Petersen, S E

1996-10-01

Functional neuroimaging with positron emission tomography was used to study brain areas activated during memory retrieval. Subjects (n = 15) recalled items from a recent study episode (episodic memory) during two paired-associate recall tasks. The tasks differed in that PICTURE RECALL required pictorial retrieval, whereas AUDITORY WORD RECALL required word retrieval. Word REPETITION and REST served as two reference tasks. Comparing recall with repetition revealed the following observations. (1) Right anterior prefrontal activation (similar to that seen in several previous experiments), in addition to bilateral frontal-opercular and anterior cingulate activations. (2) An anterior subdivision of medial frontal cortex [pre-supplementary motor area (SMA)] was activated, which could be dissociated from a more posterior area (SMA proper). (3) Parietal areas were activated, including a posterior medial area near precuneus, that could be dissociated from an anterior parietal area that was deactivated. (4) Multiple medial and lateral cerebellar areas were activated. Comparing recall with rest revealed similar activations, except right prefrontal activation was minimal and activations related to motor and auditory demands became apparent (e.g., bilateral motor and temporal cortex). Directly comparing picture recall with auditory word recall revealed few notable activations. Taken together, these findings suggest a pathway that is commonly used during the episodic retrieval of picture and word stimuli under these conditions. Many areas in this pathway overlap with areas previously activated by a different set of retrieval tasks using stem-cued recall, demonstrating their generality. Examination of activations within individual subjects in relation to structural magnetic resonance images provided an-atomic information about the location of these activations. Such data, when combined with the dissociations between functional areas, provide an increasingly detailed picture of the brain pathways involved in episodic retrieval tasks.

Identification of Manganese Superoxide Dismutase from Sphingobacterium sp. T2 as a Novel Bacterial Enzyme for Lignin Oxidation.

PubMed

Rashid, Goran M M; Taylor, Charles R; Liu, Yangqingxue; Zhang, Xiaoyang; Rea, Dean; Fülöp, Vilmos; Bugg, Timothy D H

2015-10-16

The valorization of aromatic heteropolymer lignin is an important unsolved problem in the development of a biomass-based biorefinery, for which novel high-activity biocatalysts are needed. Sequencing of the genomic DNA of lignin-degrading bacterial strain Sphingobacterium sp. T2 revealed no matches to known lignin-degrading genes. Proteomic matches for two manganese superoxide dismutase proteins were found in partially purified extracellular fractions. Recombinant MnSOD1 and MnSOD2 were both found to show high activity for oxidation of Organosolv and Kraft lignin, and lignin model compounds, generating multiple oxidation products. Structure determination revealed that the products result from aryl-Cα and Cα-Cβ bond oxidative cleavage and O-demethylation. The crystal structure of MnSOD1 was determined to 1.35 Å resolution, revealing a typical MnSOD homodimer harboring a five-coordinate trigonal bipyramidal Mn(II) center ligated by three His, one Asp, and a water/hydroxide in each active site. We propose that the lignin oxidation reactivity of these enzymes is due to the production of a hydroxyl radical, a highly reactive oxidant. This is the first demonstration that MnSOD is a microbial lignin-oxidizing enzyme.

Ischemic stroke in patients with cancer: is it different from usual strokes?

PubMed

Lee, Eun-Jae; Nah, Hyun-Wook; Kwon, Joo-Young; Kang, Dong-Wha; Kwon, Sun U; Kim, Jong S

2014-06-01

It remains unclear whether the characteristics of ischemic stroke in patients with cancer (ISC) differ from usual ischemic strokes (non-ISC). Although a small number of studies have been conducted to characterize ISC, the status of cancer has rarely been considered seriously. We aimed to investigate the features of ISC according to the status of cancer, and compare their characteristics with those of non-ISC. We assessed and classified 204 ISC patients into two groups: 104 with active (ISC-active) and 100 with inactive (ISC-inactive) cancer. For each ISC patient, two age- and gender-matched ischemic stroke patients without history of cancer were selected as non-ISC control subjects. We compared the clinical/laboratory data, stroke mechanisms, and diffusion weighted imaging (DWI) lesion patterns between ISC-active and non-ISC patients, and between ISC-inactive and non-ISC patients. ISC-active patients demonstrated higher C-reactive protein (CRP) and D-dimer, more frequent cryptogenic stroke and patterns of multiple DWI lesions (in bilateral anterior or in anterior and posterior circulations), and less prevalent conventional risk factors than non-ISC patients, while ISC-inactive patients revealed no such marked differences. Among ISC-active patients, both elevated CRP and D-dimer levels were associated with cryptogenic mechanism and multiple lesion patterns. Furthermore, ISC-active patients with cryptogenic strokes tended to have multiple lesion patterns and metastasis. ISC-active, but not ISC-inactive, is distinct in terms of risk factors, stroke mechanisms, and lesion patterns. Chronic inflammation and an activated coagulation system may contribute to the pathogenic mechanism of strokes, the extent of each depending on the activity and severity of cancer. © 2013 The Authors. International Journal of Stroke © 2013 World Stroke Organization.

Variant hairy cell leukemia following papillary urothelial neoplasm of bladder.

PubMed

Beyan, Cengiz; Kaptan, Kürsat

2014-03-01

A 65 years old man was admitted with multiple lymphadenopathy, weight loss, night sweats and fatigue for 2 months. He had been treated for bladder cancer 2 years ago. Leukocyte count was 37.9 x10(9)/l. Peripheral blood smear had 91% lymphocytes. Lymphocytes had large nuclei with prominent nucleoli, heterogeneous appearance, and large cytoplasm with hairy projections. Flow cytometric immunophenotyping revealed CD20, CD22, CD24, CD45 and HLA-DR positivity. Atypical lymphocytes were stained with tartrate resistant acid phosphatase. Increased metabolic activity was detected in multiple lymph nodes, bone marrow and extremely enlarged spleen with positron emission tomography-computed tomography. Excisional biopsy of the left axillary lymph node revealed infiltration with diffuse B-cell leukemia/lymphoma. Immunohistochemistry showed CD20 positive atypical cells with weak expression of CD11c. The patient was diagnosed as a case of variant hairy cell leukemia and cladribine was administered. A probable second primary malignancy should be kept in mind in cases with a defined malignancy in the presence of unusual symptoms.

Probing protein flexibility reveals a mechanism for selective promiscuity

PubMed Central

Pabon, Nicolas A; Camacho, Carlos J

2017-01-01

Many eukaryotic regulatory proteins adopt distinct bound and unbound conformations, and use this structural flexibility to bind specifically to multiple partners. However, we lack an understanding of how an interface can select some ligands, but not others. Here, we present a molecular dynamics approach to identify and quantitatively evaluate the interactions responsible for this selective promiscuity. We apply this approach to the anticancer target PD-1 and its ligands PD-L1 and PD-L2. We discover that while unbound PD-1 exhibits a hard-to-drug hydrophilic interface, conserved specific triggers encoded in the cognate ligands activate a promiscuous binding pathway that reveals a flexible hydrophobic binding cavity. Specificity is then established by additional contacts that stabilize the PD-1 cavity into distinct bound-like modes. Collectively, our studies provide insight into the structural basis and evolution of multiple binding partners, and also suggest a biophysical approach to exploit innate binding pathways to drug seemingly undruggable targets. DOI: http://dx.doi.org/10.7554/eLife.22889.001 PMID:28432789

Dynamics of Multiple Trafficking Behaviors of Individual Synaptic Vesicles Revealed by Quantum-Dot Based Presynaptic Probe

PubMed Central

Lee, Suho; Jung, Kyung Jin; Jung, Hyun Suk; Chang, Sunghoe

2012-01-01

Although quantum dots (QDs) have provided invaluable information regarding the diffusive behaviors of postsynaptic receptors, their application in presynaptic terminals has been rather limited. In addition, the diffraction-limited nature of the presynaptic bouton has hampered detailed analyses of the behaviors of synaptic vesicles (SVs) at synapses. Here, we created a quantum-dot based presynaptic probe and characterized the dynamic behaviors of individual SVs. As previously reported, the SVs exhibited multiple exchanges between neighboring boutons. Actin disruption induced a dramatic decrease in the diffusive behaviors of SVs at synapses while microtubule disruption only reduced extrasynaptic mobility. Glycine-induced synaptic potentiation produced significant increases in synaptic and inter-boutonal trafficking of SVs, which were NMDA receptor- and actin-dependent while NMDA-induced synaptic depression decreased the mobility of the SVs at synapses. Together, our results show that sPH-AP-QD revealed previously unobserved trafficking properties of SVs around synapses, and the dynamic modulation of SV mobility could regulate presynaptic efficacy during synaptic activity. PMID:22666444

Efficacy of Synaptic Inhibition Depends on Multiple, Dynamically Interacting Mechanisms Implicated in Chloride Homeostasis

PubMed Central

Doyon, Nicolas; Prescott, Steven A.; Castonguay, Annie; Godin, Antoine G.; Kröger, Helmut; De Koninck, Yves

2011-01-01

Chloride homeostasis is a critical determinant of the strength and robustness of inhibition mediated by GABAA receptors (GABAARs). The impact of changes in steady state Cl− gradient is relatively straightforward to understand, but how dynamic interplay between Cl− influx, diffusion, extrusion and interaction with other ion species affects synaptic signaling remains uncertain. Here we used electrodiffusion modeling to investigate the nonlinear interactions between these processes. Results demonstrate that diffusion is crucial for redistributing intracellular Cl− load on a fast time scale, whereas Cl−extrusion controls steady state levels. Interaction between diffusion and extrusion can result in a somato-dendritic Cl− gradient even when KCC2 is distributed uniformly across the cell. Reducing KCC2 activity led to decreased efficacy of GABAAR-mediated inhibition, but increasing GABAAR input failed to fully compensate for this form of disinhibition because of activity-dependent accumulation of Cl−. Furthermore, if spiking persisted despite the presence of GABAAR input, Cl− accumulation became accelerated because of the large Cl− driving force that occurs during spikes. The resulting positive feedback loop caused catastrophic failure of inhibition. Simulations also revealed other feedback loops, such as competition between Cl− and pH regulation. Several model predictions were tested and confirmed by [Cl−]i imaging experiments. Our study has thus uncovered how Cl− regulation depends on a multiplicity of dynamically interacting mechanisms. Furthermore, the model revealed that enhancing KCC2 activity beyond normal levels did not negatively impact firing frequency or cause overt extracellular K− accumulation, demonstrating that enhancing KCC2 activity is a valid strategy for therapeutic intervention. PMID:21931544

[Neural basis of self-face recognition: social aspects].

PubMed

Sugiura, Motoaki

2012-07-01

Considering the importance of the face in social survival and evidence from evolutionary psychology of visual self-recognition, it is reasonable that we expect neural mechanisms for higher social-cognitive processes to underlie self-face recognition. A decade of neuroimaging studies so far has, however, not provided an encouraging finding in this respect. Self-face specific activation has typically been reported in the areas for sensory-motor integration in the right lateral cortices. This observation appears to reflect the physical nature of the self-face which representation is developed via the detection of contingency between one's own action and sensory feedback. We have recently revealed that the medial prefrontal cortex, implicated in socially nuanced self-referential process, is activated during self-face recognition under a rich social context where multiple other faces are available for reference. The posterior cingulate cortex has also exhibited this activation modulation, and in the separate experiment showed a response to attractively manipulated self-face suggesting its relevance to positive self-value. Furthermore, the regions in the right lateral cortices typically showing self-face-specific activation have responded also to the face of one's close friend under the rich social context. This observation is potentially explained by the fact that the contingency detection for physical self-recognition also plays a role in physical social interaction, which characterizes the representation of personally familiar people. These findings demonstrate that neuroscientific exploration reveals multiple facets of the relationship between self-face recognition and social-cognitive process, and that technically the manipulation of social context is key to its success.

Osthole: A Review on Its Bioactivities, Pharmacological Properties, and Potential as Alternative Medicine

PubMed Central

Zhang, Zhong-Rong; Leung, Wing Nang; Cheung, Ho Yee; Chan, Chun Wai

2015-01-01

This paper reviews the latest understanding of biological and pharmacological properties of osthole (7-methoxy-8-(3-methyl-2-butenyl)-2H-1-benzopyran-2-one), a natural product found in several medicinal plants such as Cnidium monnieri and Angelica pubescens. In vitro and in vivo experimental results have revealed that osthole demonstrates multiple pharmacological actions including neuroprotective, osteogenic, immunomodulatory, anticancer, hepatoprotective, cardiovascular protective, and antimicrobial activities. In addition, pharmacokinetic studies showed osthole uptake and utilization are fast and efficient in body. Moreover, the mechanisms of multiple pharmacological activities of osthole are very likely related to the modulatory effect on cyclic adenosine monophosphate (cAMP) and cyclic adenosine monophosphate (cGMP) level, though some mechanisms remain unclear. This review aims to summarize the pharmacological properties of osthole and give an overview of the underlying mechanisms, which showcase its potential as a multitarget alternative medicine. PMID:26246843

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

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

Sorption studies of nickel ions onto activated carbon

NASA Astrophysics Data System (ADS)

Joshi, Parth; Vyas, Meet; Patel, Chirag

2018-05-01

Activated porous carbons are made through pyrolysis and activation of carbonaceous natural as well as synthetic precursors. The use of low-cost activated carbon derived from azadirachta indica, an agricultural waste material, has been investigated as a replacement for the current expensive methods of removing nickel ions from wastewater. The temperature variation study showed that the nickel ions adsorption is endothermic and spontaneous with increased randomness at the solid solution interface. Significant effect on adsorption was observed on varying the pH of the nickel ion solutions. Therefore, this study revealed that azadirachta indica can serve as a good source of activated carbon with multiple and simultaneous metal ions removing potentials and may serve as a better replacement for commercial activated carbons in applications that warrant their use.

Systematic Determination of Replication Activity Type Highlights Interconnections between Replication, Chromatin Structure and Nuclear Localization

PubMed Central

Polten, Andreas; Hezroni, Hadas; Eldar, Yonina C.; Meshorer, Eran; Yakhini, Zohar; Simon, Itamar

2012-01-01

DNA replication is a highly regulated process, with each genomic locus replicating at a distinct time of replication (ToR). Advances in ToR measurement technology enabled several genome-wide profiling studies that revealed tight associations between ToR and general genomic features and a remarkable ToR conservation in mammals. Genome wide studies further showed that at the hundreds kb-to-megabase scale the genome can be divided into constant ToR regions (CTRs) in which the replication process propagates at a faster pace due to the activation of multiple origins and temporal transition regions (TTRs) in which the replication process propagates at a slower pace. We developed a computational tool that assigns a ToR to every measured locus and determines its replication activity type (CTR versus TTR). Our algorithm, ARTO (Analysis of Replication Timing and Organization), uses signal processing methods to fit a constant piece-wise linear curve to the measured raw data. We tested our algorithm and provide performance and usability results. A Matlab implementation of ARTO is available at http://bioinfo.cs.technion.ac.il/people/zohar/ARTO/. Applying our algorithm to ToR data measured in multiple mouse and human samples allowed precise genome-wide ToR determination and replication activity type characterization. Analysis of the results highlighted the plasticity of the replication program. For example, we observed significant ToR differences in 10–25% of the genome when comparing different tissue types. Our analyses also provide evidence for activity type differences in up to 30% of the probes. Integration of the ToR data with multiple aspects of chromosome organization characteristics suggests that ToR plays a role in shaping the regional chromatin structure. Namely, repressive chromatin marks, are associated with late ToR both in TTRs and CTRs. Finally, characterization of the differences between TTRs and CTRs, with matching ToR, revealed that TTRs are associated with compact chromatin and are located significantly closer to the nuclear envelope. Supplementary material is available. Raw and processed data were deposited in Geo (GSE17236). PMID:23145042

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.

Sex differences in neural and behavioral signatures of cooperation revealed by fNIRS hyperscanning

PubMed Central

Baker, Joseph M.; Liu, Ning; Cui, Xu; Vrticka, Pascal; Saggar, Manish; Hosseini, S. M. Hadi; Reiss, Allan L.

2016-01-01

Researchers from multiple fields have sought to understand how sex moderates human social behavior. While over 50 years of research has revealed differences in cooperation behavior of males and females, the underlying neural correlates of these sex differences have not been explained. A missing and fundamental element of this puzzle is an understanding of how the sex composition of an interacting dyad influences the brain and behavior during cooperation. Using fNIRS-based hyperscanning in 111 same- and mixed-sex dyads, we identified significant behavioral and neural sex-related differences in association with a computer-based cooperation task. Dyads containing at least one male demonstrated significantly higher behavioral performance than female/female dyads. Individual males and females showed significant activation in the right frontopolar and right inferior prefrontal cortices, although this activation was greater in females compared to males. Female/female dyad’s exhibited significant inter-brain coherence within the right temporal cortex, while significant coherence in male/male dyads occurred in the right inferior prefrontal cortex. Significant coherence was not observed in mixed-sex dyads. Finally, for same-sex dyads only, task-related inter-brain coherence was positively correlated with cooperation task performance. Our results highlight multiple important and previously undetected influences of sex on concurrent neural and behavioral signatures of cooperation. PMID:27270754

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.

Global Representations of Goal-Directed Behavior in Distinct Cell Types of Mouse Neocortex

PubMed Central

Allen, William E.; Kauvar, Isaac V.; Chen, Michael Z.; Richman, Ethan B.; Yang, Samuel J.; Chan, Ken; Gradinaru, Viviana; Deverman, Benjamin E.; Luo, Liqun; Deisseroth, Karl

2017-01-01

SUMMARY The successful planning and execution of adaptive behaviors in mammals may require long-range coordination of neural networks throughout cerebral cortex. The neuronal implementation of signals that could orchestrate cortex-wide activity remains unclear. Here, we develop and apply methods for cortex-wide Ca2+ imaging in mice performing decision-making behavior and identify a global cortical representation of task engagement encoded in the activity dynamics of both single cells and superficial neuropil distributed across the majority of dorsal cortex. The activity of multiple molecularly defined cell types was found to reflect this representation with type-specific dynamics. Focal optogenetic inhibition tiled across cortex revealed a crucial role for frontal cortex in triggering this cortex-wide phenomenon; local inhibition of this region blocked both the cortex-wide response to task-initiating cues and the voluntary behavior. These findings reveal cell-type-specific processes in cortex for globally representing goal-directed behavior and identify a major cortical node that gates the global broadcast of task-related information. PMID:28521139

The use of regression analysis in determining reference intervals for low hematocrit and thrombocyte count in multiple electrode aggregometry and platelet function analyzer 100 testing of platelet function.

PubMed

Kuiper, Gerhardus J A J M; Houben, Rik; Wetzels, Rick J H; Verhezen, Paul W M; Oerle, Rene van; Ten Cate, Hugo; Henskens, Yvonne M C; Lancé, Marcus D

2017-11-01

Low platelet counts and hematocrit levels hinder whole blood point-of-care testing of platelet function. Thus far, no reference ranges for MEA (multiple electrode aggregometry) and PFA-100 (platelet function analyzer 100) devices exist for low ranges. Through dilution methods of volunteer whole blood, platelet function at low ranges of platelet count and hematocrit levels was assessed on MEA for four agonists and for PFA-100 in two cartridges. Using (multiple) regression analysis, 95% reference intervals were computed for these low ranges. Low platelet counts affected MEA in a positive correlation (all agonists showed r 2 ≥ 0.75) and PFA-100 in an inverse correlation (closure times were prolonged with lower platelet counts). Lowered hematocrit did not affect MEA testing, except for arachidonic acid activation (ASPI), which showed a weak positive correlation (r 2 = 0.14). Closure time on PFA-100 testing was inversely correlated with hematocrit for both cartridges. Regression analysis revealed different 95% reference intervals in comparison with originally established intervals for both MEA and PFA-100 in low platelet or hematocrit conditions. Multiple regression analysis of ASPI and both tests on the PFA-100 for combined low platelet and hematocrit conditions revealed that only PFA-100 testing should be adjusted for both thrombocytopenia and anemia. 95% reference intervals were calculated using multiple regression analysis. However, coefficients of determination of PFA-100 were poor, and some variance remained unexplained. Thus, in this pilot study using (multiple) regression analysis, we could establish reference intervals of platelet function in anemia and thrombocytopenia conditions on PFA-100 and in thrombocytopenia conditions on MEA.

Multiple sexual partnerships and their correlates among Facebook users in Swaziland: an online cross-sectional study.

PubMed

Lukhele, Bhekumusa Wellington; Techasrivichien, Teeranee; Musumari, Patou Masika; El-Saaidi, Christina; Suguimoto, S Pilar; Ono-Kihara, Masako; Kihara, Masahiro

2016-09-01

Social networking sites (SNSs) have been suggested to facilitate risky sexual activities. However, it is unknown and of concern how SNSs such as Facebook shape risky sexual activities in developing settings such as Swaziland, the country hardest hit by HIV and AIDS. We conducted an online cross-sectional study in 2012 to explore the prevalence of multiple sexual partnerships (MSPs) and their correlates among Facebook users in Swaziland. The response rate was 44.1% (N = 882); relatively, an equal proportion of men 82.7% (341/414) and 82.9% (388/468) women had ever had sex. Of those sexually active, 44.9% of men and 30.7% of women reported having sex with someone they met on Facebook. Approximately half of the participants (61.6% men, 41.0% women and 50.6% total) reported MSPs over the past 12 months. Multiple logistic regression analysis revealed that time spent on Facebook, "finding it easier to initiate a romantic conversation on Facebook" and having had sex with someone met on Facebook were significantly associated with having MSPs (adjusted odds ratio = 1.6-3.8). The potential impact of risky sexual behaviour among Facebook users should be appropriately addressed particularly in high HIV-prevalent settings like Swaziland.

Comparative genome-wide analysis reveals that Burkholderia contaminans MS14 possesses multiple antimicrobial biosynthesis genes but not major genetic loci required for pathogenesis.

PubMed

Deng, Peng; Wang, Xiaoqiang; Baird, Sonya M; Showmaker, Kurt C; Smith, Leif; Peterson, Daniel G; Lu, Shien

2016-06-01

Burkholderia contaminans MS14 shows significant antimicrobial activities against plant and animal pathogenic fungi and bacteria. The antifungal agent occidiofungin produced by MS14 has great potential for development of biopesticides and pharmaceutical drugs. However, the use of Burkholderia species as biocontrol agent in agriculture is restricted due to the difficulties in distinguishing between plant growth-promoting bacteria and the pathogenic bacteria. The complete MS14 genome was sequenced and analyzed to find what beneficial and virulence-related genes it harbors. The phylogenetic relatedness of B. contaminans MS14 and other 17 Burkholderia species was also analyzed. To research MS14's potential virulence, the gene regions related to the antibiotic production, antibiotic resistance, and virulence were compared between MS14 and other Burkholderia genomes. The genome of B. contaminans MS14 was sequenced and annotated. The genomic analyses reveal the presence of multiple gene sets for antimicrobial biosynthesis, which contribute to its antimicrobial activities. BLAST results indicate that the MS14 genome harbors a large number of unique regions. MS14 is closely related to another plant growth-promoting Burkholderia strain B. lata 383 according to the average nucleotide identity data. Moreover, according to the phylogenetic analysis, plant growth-promoting species isolated from soils and mammalian pathogenic species are clustered together, respectively. MS14 has multiple antimicrobial activity-related genes identified from the genome, but it lacks key virulence-related gene loci found in the pathogenic strains. Additionally, plant growth-promoting Burkholderia species have one or more antimicrobial biosynthesis genes in their genomes as compared with nonplant growth-promoting soil-isolated Burkholderia species. On the other hand, pathogenic species harbor multiple virulence-associated gene loci that are not present in nonpathogenic Burkholderia species. The MS14 genome as well as Burkholderia species genome show considerable diversity. Multiple antimicrobial agent biosynthesis genes were identified in the genome of plant growth-promoting species of Burkholderia. In addition, by comparing to nonpathogenic Burkholderia species, pathogenic Burkholderia species have more characterized homologs of the gene loci known to contribute to pathogenicity and virulence to plant and animals. © 2016 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.

Age-related differences in brain network activation and co-activation during multiple object tracking.

PubMed

Dørum, Erlend S; Alnæs, Dag; Kaufmann, Tobias; Richard, Geneviève; Lund, Martina J; Tønnesen, Siren; Sneve, Markus H; Mathiesen, Nina C; Rustan, Øyvind G; Gjertsen, Øivind; Vatn, Sigurd; Fure, Brynjar; Andreassen, Ole A; Nordvik, Jan Egil; Westlye, Lars T

2016-11-01

Multiple object tracking (MOT) is a powerful paradigm for measuring sustained attention. Although previous fMRI studies have delineated the brain activation patterns associated with tracking and documented reduced tracking performance in aging, age-related effects on brain activation during MOT have not been characterized. In particular, it is unclear if the task-related activation of different brain networks is correlated, and also if this coordination between activations within brain networks shows differential effects of age. We obtained fMRI data during MOT at two load conditions from a group of younger ( n  = 25, mean age = 24.4 ± 5.1 years) and older ( n  = 21, mean age = 64.7 ± 7.4 years) healthy adults. Using a combination of voxel-wise and independent component analysis, we investigated age-related differences in the brain network activation. In order to explore to which degree activation of the various brain networks reflect unique and common mechanisms, we assessed the correlations between the brain networks' activations. Behavioral performance revealed an age-related reduction in MOT accuracy. Voxel and brain network level analyses converged on decreased load-dependent activations of the dorsal attention network (DAN) and decreased load-dependent deactivations of the default mode networks (DMN) in the old group. Lastly, we found stronger correlations in the task-related activations within DAN and within DMN components for younger adults, and stronger correlations between DAN and DMN components for older adults. Using MOT as means for measuring attentional performance, we have demonstrated an age-related attentional decline. Network-level analysis revealed age-related alterations in network recruitment consisting of diminished activations of DAN and diminished deactivations of DMN in older relative to younger adults. We found stronger correlations within DMN and within DAN components for younger adults and stronger correlations between DAN and DMN components for older adults, indicating age-related alterations in the coordinated network-level activation during attentional processing.

Renal Protective Role of Xiexin Decoction with Multiple Active Ingredients Involves Inhibition of Inflammation through Downregulation of the Nuclear Factor-κB Pathway in Diabetic Rats

PubMed Central

Wu, Jia-sheng; Shi, Rong; Zhong, Jie; Lu, Xiong; Ma, Bing-liang; Wang, Tian-ming; Zan, Bin; Ma, Yue-ming; Cheng, Neng-neng; Qiu, Fu-rong

2013-01-01

In Chinese medicine, Xiexin decoction (XXD) has been used for the clinical treatment of diabetes for at least 1700 years. The present study was conducted to investigate the effective ingredients of XXD and their molecular mechanisms of antidiabetic nephropathy in rats. Rats with diabetes induced by high-fat diet and streptozotocin were treated with XXD extract for 12 weeks. XXD significantly improved the glucolipid metabolism disorder, attenuated albuminuria and renal pathological changes, reduced renal advanced glycation end-products, inhibited receptor for advanced glycation end-product and inflammation factors expression, suppressed renal nuclear factor-κB pathway activity, and downregulated renal transforming growth factor-β1. The concentrations of multiple components in plasma from XXD were determined by liquid chromatography and tandem mass spectrometry. Pharmacokinetic/pharmacodynamic analysis using partial least square regression revealed that 8 ingredients of XXD were responsible for renal protective effects via actions on multiple molecular targets. Our study suggests that the renal protective role of XXD with multiple effective ingredients involves inhibition of inflammation through downregulation of the nuclear factor-κB pathway, reducing renal advanced glycation end-products and receptor for advanced glycation end-product in diabetic rats. PMID:23935673

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.

Local Plasticity of Al Thin Films as Revealed by X-Ray Microdiffraction

NASA Astrophysics Data System (ADS)

Spolenak, R.; Brown, W. L.; Tamura, N.; MacDowell, A. A.; Celestre, R. S.; Padmore, H. A.; Valek, B.; Bravman, J. C.; Marieb, T.; Fujimoto, H.; Batterman, B. W.; Patel, J. R.

2003-03-01

Grain-to-grain interactions dominate the plasticity of Al thin films and establish effective length scales smaller than the grain size. We have measured large strain distributions and their changes under plastic strain in 1.5-μm-thick Al0.5%Cu films using a 0.8-μm-diameter white x-ray probe at the Advanced Light Source. Strain distributions arise not only from the distribution of grain sizes and orientation, but also from the differences in grain shape and from stress environment. Multiple active glide plane domains have been found within single grains. Large grains behave like multiple smaller grains even before a dislocation substructure can evolve.

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.

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

Motor Skill Competence and Perceived Motor Competence: Which Best Predicts Physical Activity among Girls?

PubMed Central

Khodaverdi, Zeinab; Bahram, Abbas; Khalaji, Hassan; Kazemnejad, Anoshirvan

2013-01-01

Abstract Background The main purpose of this study was to determine which correlate, perceived motor competence or motor skill competence, best predicts girls’ physical activity behavior. Methods A sample of 352 girls (mean age=8.7, SD=0.3 yr) participated in this study. To assess motor skill competence and perceived motor competence, each child completed the Test of Gross Motor Development-2 and Physical Ability sub-scale of Marsh’s Self-Description Questionnaire. Children’s physical activity was assessed by the Physical Activity Questionnaire for Older Children. Multiple linear regression model was used to determine whether perceived motor competence or motor skill competence best predicts moderate-to-vigorous self-report physical activity. Results Multiple regression analysis indicated that motor skill competence and perceived motor competence predicted 21% variance in physical activity (R2=0.21, F=48.9, P=0.001), and motor skill competence (R2=0.15, ᵝ=0.33, P= 0.001) resulted in more variance than perceived motor competence (R2=0.06, ᵝ=0.25, P=0.001) in physical activity. Conclusion Results revealed motor skill competence had more influence in comparison with perceived motor competence on physical activity level. We suggest interventional programs based on motor skill competence and perceived motor competence should be administered or implemented to promote physical activity in young girls. PMID:26060623

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.

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.

The neural coding of creative idea generation across adolescence and early adulthood

PubMed Central

Kleibeuker, Sietske W.; Koolschijn, P. Cédric M. P.; Jolles, Dietsje D.; De Dreu, Carsten K. W.; Crone, Eveline A.

2013-01-01

Creativity is considered key to human prosperity, yet the neurocognitive principles underlying creative performance, and their development, are still poorly understood. To fill this void, we examined the neural correlates of divergent thinking in adults (25–30 years) and adolescents (15–17 years). Participants generated alternative uses (AU) or ordinary characteristics (OC) for common objects while brain activity was assessed using fMRI. Adults outperformed adolescents on the number of solutions for AU and OC trials. Contrasting neural activity for AU with OC trials revealed increased recruitment of left angular gyrus, left supramarginal gyrus, and bilateral middle temporal gyrus in both adults and adolescents. When only trials with multiple AU were included in the analysis, participants showed additional left inferior frontal gyrus (IFG)/middle frontal gyrus (MFG) activation for AU compared to OC trials. Correspondingly, individual difference analyses showed a positive correlation between activations for AU relative to OC trials in left IFG/MFG and divergent thinking performance and activations were more pronounced in adults than in adolescents. Taken together, the results of this study demonstrated that creative idea generation involves recruitment of mainly left lateralized parietal and temporal brain regions. Generating multiple creative ideas, a hallmark of divergent thinking, shows additional lateral PFC activation that is not yet optimized in adolescence. PMID:24416008

Antiproliferative activity of synthetic fatty acid amides from renewable resources.

PubMed

dos Santos, Daiane S; Piovesan, Luciana A; D'Oca, Caroline R Montes; Hack, Carolina R Lopes; Treptow, Tamara G M; Rodrigues, Marieli O; Vendramini-Costa, Débora B; Ruiz, Ana Lucia T G; de Carvalho, João Ernesto; D'Oca, Marcelo G Montes

2015-01-15

In the work, the in vitro antiproliferative activity of a series of synthetic fatty acid amides were investigated in seven cancer cell lines. The study revealed that most of the compounds showed antiproliferative activity against tested tumor cell lines, mainly on human glioma cells (U251) and human ovarian cancer cells with a multiple drug-resistant phenotype (NCI-ADR/RES). In addition, the fatty methyl benzylamide derived from ricinoleic acid (with the fatty acid obtained from castor oil, a renewable resource) showed a high selectivity with potent growth inhibition and cell death for the glioma cell line-the most aggressive CNS cancer. Copyright © 2014 Elsevier Ltd. All rights reserved.

Characterizing Student Perceptions of and Buy-In toward Common Formative Assessment Techniques

PubMed Central

Brazeal, Kathleen R.; Brown, Tanya L.; Couch, Brian A.

2016-01-01

Formative assessments (FAs) can occur as preclass assignments, in-class activities, or postclass homework. FAs aim to promote student learning by accomplishing key objectives, including clarifying learning expectations, revealing student thinking to the instructor, providing feedback to the student that promotes learning, facilitating peer interactions, and activating student ownership of learning. While FAs have gained prominence within the education community, we have limited knowledge regarding student perceptions of these activities. We used a mixed-methods approach to determine whether students recognize and value the role of FAs in their learning and how students perceive course activities to align with five key FA objectives. To address these questions, we administered a midsemester survey in seven introductory biology course sections that were using multiple FA techniques. Overall, responses to both open-ended and closed-ended questions revealed that the majority of students held positive perceptions of FAs and perceived FAs to facilitate their learning in a variety of ways. Students consistently considered FA activities to have accomplished particular objectives, but there was greater variation among FAs in how students perceived the achievement of other objectives. We further discuss potential sources of student resistance and implications of these results for instructor practice. PMID:27909023

Surgical correction of urethral dilatation in an intersex goat.

PubMed

Karras, S; Modransky, P; Welker, B

1992-11-15

Multiple congenital urethral abnormalities were successfully corrected in a polled goat kid. Anatomic genito-urinary abnormalities identified were paired testes with associated epididymis, ductus deferens, and active endometrial tissue. Blood karyotyping revealed the female state--XX sex chromosomes. This case exemplifies the complex interactions in addition to Y dominant Mendelian genetics that determine reproductive tract development in goats. The resultant intersex state is clinically recognized with greater frequency in polled progeny.

[Stress fractures of the ribs with acute thoracic pain in a young woman, diagnosed by the bone scan].

PubMed

Georgitzikis, Athanasios; Siopi, Dimitra; Doumas, Argyrios; Mitka, Ekaterini; Antoniadis, Antonios

2010-01-01

We report the unusual case of a 29 -year old woman with emotional instability who presented with acute onset chest pain after severe chronic cough. The chest X-ray and the serological tests were normal but the CT scanning, and the bone scanning revealed multiple bilateral rib stress fractures, caused by severe coughing and physical activity and worsened by the patient's emotional instability.

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

NASA Astrophysics Data System (ADS)

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

2017-07-01

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

Insights into the mode of action of anticandidal herbal monoterpenoid geraniol reveal disruption of multiple MDR mechanisms and virulence attributes in Candida albicans.

PubMed

Singh, Shweta; Fatima, Zeeshan; Hameed, Saif

2016-07-01

The anticandidal potential of Geraniol (Ger) against Candida albicans has already been established. The present study reveals deeper insights into the mechanisms of action of Ger. We observed that the repertoire of antifungal activity was not only limited to C. albicans and its clinical isolates but also against non-albicans species of Candida. The membrane tampering effect was visualized through transmission electron micrographs, depleted ergosterol levels and altered plasma membrane ATPase activity. Ger also affects cell wall as revealed by spot assays with cell wall-perturbing agents and scanning electron micrographs. Functional calcineurin pathway seems to be indispensable for the antifungal effect of Ger as calcineurin signaling mutant was hypersensitive to Ger while calcineurin overexpressing strain remained resistant. Ger also causes mitochondrial dysfunction, impaired iron homeostasis and genotoxicity. Furthermore, Ger inhibits both virulence attributes of hyphal morphogenesis and biofilm formation. Taken together, our results suggest that Ger is potential antifungal agent that warrants further investigation in clinical applications so that it could be competently employed in therapeutic strategies to treat Candida infections.

The influence of the interactions between anthropogenic activities and multiple ecological factors on land surface temperatures of urban forests

NASA Astrophysics Data System (ADS)

Ren, Y.

2017-12-01

Context Land surface temperatures (LSTs) spatio-temporal distribution pattern of urban forests are influenced by many ecological factors; the identification of interaction between these factors can improve simulations and predictions of spatial patterns of urban cold islands. This quantitative research requires an integrated method that combines multiple sources data with spatial statistical analysis. Objectives The purpose of this study was to clarify urban forest LST influence interaction between anthropogenic activities and multiple ecological factors using cluster analysis of hot and cold spots and Geogdetector model. We introduced the hypothesis that anthropogenic activity interacts with certain ecological factors, and their combination influences urban forests LST. We also assumed that spatio-temporal distributions of urban forest LST should be similar to those of ecological factors and can be represented quantitatively. Methods We used Jinjiang as a representative city in China as a case study. Population density was employed to represent anthropogenic activity. We built up a multi-source data (forest inventory, digital elevation models (DEM), population, and remote sensing imagery) on a unified urban scale to support urban forest LST influence interaction research. Through a combination of spatial statistical analysis results, multi-source spatial data, and Geogdetector model, the interaction mechanisms of urban forest LST were revealed. Results Although different ecological factors have different influences on forest LST, in two periods with different hot spots and cold spots, the patch area and dominant tree species were the main factors contributing to LST clustering in urban forests. The interaction between anthropogenic activity and multiple ecological factors increased LST in urban forest stands, linearly and nonlinearly. Strong interactions between elevation and dominant species were generally observed and were prevalent in either hot or cold spots areas in different years. Conclusions In conclusion, a combination of spatial statistics and GeogDetector models should be effective for quantitatively evaluating interactive relationships among ecological factors, anthropogenic activity and LST.

Simultaneous EUV and radio observations of bidirectional plasmoids ejection during magnetic reconnection

NASA Astrophysics Data System (ADS)

Kumar, Pankaj; Cho, Kyung-Suk

2013-09-01

We present a multiwavelength study of the X-class flare, which occurred in active region (AR) NOAA 11339 on 3 November 2011. The extreme ultraviolet (EUV) images recorded by SDO/AIA show the activation of a remote filament (located north of the AR) with footpoint brightenings about 50 min prior to the flare's occurrence. The kinked filament rises up slowly, and after reaching a projected height of ~49 Mm, it bends and falls freely near the AR, where the X-class flare was triggered. Dynamic radio spectrum from the Green Bank Solar Radio Burst Spectrometer (GBSRBS) shows simultaneous detection of both positive and negative drifting pulsating structures (DPSs) in the decimetric radio frequencies (500-1200 MHz) during the impulsive phase of the flare. The global negative DPSs in solar flares are generally interpreted as a signature of electron acceleration related to the upward-moving plasmoids in the solar corona. The EUV images from AIA 94 Å reveal the ejection of multiple plasmoids, which move simultaneously upward and downward in the corona during the magnetic reconnection. The estimated speeds of the upward- and downward-moving plasmoids are ~152-362 and ~83-254 km s-1, respectively. These observations strongly support the recent numerical simulations of the formation and interaction of multiple plasmoids due to tearing of the current-sheet structure. On the basis of our analysis, we suggest that the simultaneous detection of both the negative and positive DPSs is most likely generated by the interaction or coalescence of the multiple plasmoids moving upward and downward along the current-sheet structure during the magnetic reconnection process. Moreover, the differential emission measure (DEM) analysis of the active region reveals a hot flux-rope structure (visible in AIA 131 and 94 Å) prior to the flare initiation and ejection of the multitemperature plasmoids during the flare impulsive phase. Movie is available in electronic form at http://www.aanda.org

T helper 17.1 cells associate with multiple sclerosis disease activity: perspectives for early intervention.

PubMed

van Langelaar, Jamie; van der Vuurst de Vries, Roos M; Janssen, Malou; Wierenga-Wolf, Annet F; Spilt, Isis M; Siepman, Theodora A; Dankers, Wendy; Verjans, Georges M G M; de Vries, Helga E; Lubberts, Erik; Hintzen, Rogier Q; van Luijn, Marvin M

2018-05-01

Interleukin-17-expressing CD4+ T helper 17 (Th17) cells are considered as critical regulators of multiple sclerosis disease activity. However, depending on the species and pro-inflammatory milieu, Th17 cells are functionally heterogeneous, consisting of subpopulations that differentially produce interleukin-17, interferon-gamma and granulocyte macrophage colony-stimulating factor. In the current study, we studied distinct effector phenotypes of human Th17 cells and their correlation with disease activity in multiple sclerosis patients. T helper memory populations single- and double-positive for C-C chemokine receptor 6 (CCR6) and CXC chemokine receptor 3 (CXCR3) were functionally assessed in blood and/or cerebrospinal fluid from a total of 59 patients with clinically isolated syndrome, 35 untreated patients and 24 natalizumab-treated patients with relapsing-remitting multiple sclerosis, and nine patients with end-stage multiple sclerosis. Within the clinically isolated syndrome group, 23 patients had a second attack within 1 year and 26 patients did not experience subsequent attacks during a follow-up of >5 years. Low frequencies of T helper 1 (Th1)-like Th17 (CCR6+CXCR3+), and not Th17 (CCR6+CXCR3-) effector memory populations in blood strongly associated with a rapid diagnosis of clinically definite multiple sclerosis. In cerebrospinal fluid of clinically isolated syndrome and relapsing-remitting multiple sclerosis patients, Th1-like Th17 effector memory cells were abundant and showed increased production of interferon-gamma and granulocyte macrophage colony-stimulating factor compared to paired CCR6+ and CCR6-CD8+ T cell populations and their blood equivalents after short-term culturing. Their local enrichment was confirmed ex vivo using cerebrospinal fluid and brain single-cell suspensions. Across all pro-inflammatory T helper cells analysed in relapsing-remitting multiple sclerosis blood, Th1-like Th17 subpopulation T helper 17.1 (Th17.1; CCR6+CXCR3+CCR4-) expressed the highest very late antigen-4 levels and selectively accumulated in natalizumab-treated patients who remained free of clinical relapses. This was not found in patients who experienced relapses during natalizumab treatment. The enhanced potential of Th17.1 cells to infiltrate the central nervous system was supported by their predominance in cerebrospinal fluid of early multiple sclerosis patients and their preferential transmigration across human brain endothelial layers. These findings reveal a dominant contribution of Th1-like Th17 subpopulations, in particular Th17.1 cells, to clinical disease activity and provide a strong rationale for more specific and earlier use of T cell-targeted therapy in multiple sclerosis.

Microencephaloceles: another dual pathology of intractable temporal lobe epilepsy in childhood.

PubMed

Aquilina, Kristian; Clarke, Dave F; Wheless, James W; Boop, Frederick A

2010-04-01

Temporal lobe encephaloceles can be associated with temporal lobe epilepsy. The authors report on the case of an adolescent with multiple microencephaloceles, in the anterolateral middle fossa floor, identified at surgery (temporal lobectomy) for intractable partial-onset seizures of temporal origin. Magnetic resonance imaging revealed only hippocampal atrophy. Subdural electrodes demonstrated ictal activity arising primarily from the anterior and lateral temporal lobe, close to the microencephaloceles, spreading to the anterior and posterior mesial structures. Pathological examination revealed diffuse temporal gliosis involving the hippocampus, together with microdysgenesis of the amygdala. The literature on epilepsy secondary to encephaloceles is reviewed and the contribution of the microencephaloceles to the seizure disorder in this patient is discussed.

Feminist identity as a predictor of eating disorder diagnostic status.

PubMed

Green, Melinda A; Scott, Norman A; Riopel, Cori M; Skaggs, Anna K

2008-06-01

Passive Acceptance (PA) and Active Commitment (AC) subscales of the Feminist Identity Development Scale (FIDS) were examined as predictors of eating disorder diagnostic status as assessed by the Questionnaire for Eating Disorder Diagnoses (Q-EDD). Results of a hierarchical regression analysis revealed PA and AC scores were not statistically significant predictors of ED diagnostic status after controlling for diagnostic subtype. Results of a multiple regression analysis revealed FIDS as a statistically significant predictor of ED diagnostic status when failing to control for ED diagnostic subtype. Discrepancies suggest ED diagnostic subtype may serve as a moderator variable in the relationship between ED diagnostic status and FIDS. (c) 2008 Wiley Periodicals, Inc.

Deconvoluting Post-Transplant Immunity: Cell Subset-Specific Mapping Reveals Pathways for Activation and Expansion of Memory T, Monocytes and B Cells

PubMed Central

Grigoryev, Yevgeniy A.; Kurian, Sunil M.; Avnur, Zafi; Borie, Dominic; Deng, Jun; Campbell, Daniel; Sung, Joanna; Nikolcheva, Tania; Quinn, Anthony; Schulman, Howard; Peng, Stanford L.; Schaffer, Randolph; Fisher, Jonathan; Mondala, Tony; Head, Steven; Flechner, Stuart M.; Kantor, Aaron B.; Marsh, Christopher; Salomon, Daniel R.

2010-01-01

A major challenge for the field of transplantation is the lack of understanding of genomic and molecular drivers of early post-transplant immunity. The early immune response creates a complex milieu that determines the course of ensuing immune events and the ultimate outcome of the transplant. The objective of the current study was to mechanistically deconvolute the early immune response by purifying and profiling the constituent cell subsets of the peripheral blood. We employed genome-wide profiling of whole blood and purified CD4, CD8, B cells and monocytes in tandem with high-throughput laser-scanning cytometry in 10 kidney transplants sampled serially pre-transplant, 1, 2, 4, 8 and 12 weeks. Cytometry confirmed early cell subset depletion by antibody induction and immunosuppression. Multiple markers revealed the activation and proliferative expansion of CD45RO+CD62L− effector memory CD4/CD8 T cells as well as progressive activation of monocytes and B cells. Next, we mechanistically deconvoluted early post-transplant immunity by serial monitoring of whole blood using DNA microarrays. Parallel analysis of cell subset-specific gene expression revealed a unique spectrum of time-dependent changes and functional pathways. Gene expression profiling results were validated with 157 different probesets matching all 65 antigens detected by cytometry. Thus, serial blood cell monitoring reflects the profound changes in blood cell composition and immune activation early post-transplant. Each cell subset reveals distinct pathways and functional programs. These changes illuminate a complex, early phase of immunity and inflammation that includes activation and proliferative expansion of the memory effector and regulatory cells that may determine the phenotype and outcome of the kidney transplant. PMID:20976225

Deconvoluting post-transplant immunity: cell subset-specific mapping reveals pathways for activation and expansion of memory T, monocytes and B cells.

PubMed

Grigoryev, Yevgeniy A; Kurian, Sunil M; Avnur, Zafi; Borie, Dominic; Deng, Jun; Campbell, Daniel; Sung, Joanna; Nikolcheva, Tania; Quinn, Anthony; Schulman, Howard; Peng, Stanford L; Schaffer, Randolph; Fisher, Jonathan; Mondala, Tony; Head, Steven; Flechner, Stuart M; Kantor, Aaron B; Marsh, Christopher; Salomon, Daniel R

2010-10-14

A major challenge for the field of transplantation is the lack of understanding of genomic and molecular drivers of early post-transplant immunity. The early immune response creates a complex milieu that determines the course of ensuing immune events and the ultimate outcome of the transplant. The objective of the current study was to mechanistically deconvolute the early immune response by purifying and profiling the constituent cell subsets of the peripheral blood. We employed genome-wide profiling of whole blood and purified CD4, CD8, B cells and monocytes in tandem with high-throughput laser-scanning cytometry in 10 kidney transplants sampled serially pre-transplant, 1, 2, 4, 8 and 12 weeks. Cytometry confirmed early cell subset depletion by antibody induction and immunosuppression. Multiple markers revealed the activation and proliferative expansion of CD45RO(+)CD62L(-) effector memory CD4/CD8 T cells as well as progressive activation of monocytes and B cells. Next, we mechanistically deconvoluted early post-transplant immunity by serial monitoring of whole blood using DNA microarrays. Parallel analysis of cell subset-specific gene expression revealed a unique spectrum of time-dependent changes and functional pathways. Gene expression profiling results were validated with 157 different probesets matching all 65 antigens detected by cytometry. Thus, serial blood cell monitoring reflects the profound changes in blood cell composition and immune activation early post-transplant. Each cell subset reveals distinct pathways and functional programs. These changes illuminate a complex, early phase of immunity and inflammation that includes activation and proliferative expansion of the memory effector and regulatory cells that may determine the phenotype and outcome of the kidney transplant.

Distinct roles for multiple Src family kinases at fertilization.

PubMed

O'Neill, Forest J; Gillett, Jessica; Foltz, Kathy R

2004-12-01

Egg activation at fertilization requires the release of Ca2+ from the endoplasmic reticulum of the egg. Recent evidence indicates that Src family kinases (SFKs) function in the signaling pathway that initiates this Ca2+ release in the eggs of many deuterostomes. We have identified three SFKs expressed in starfish (Asterina miniata) eggs, designated AmSFK1, AmSFK2 and AmSFK3. Antibodies made against the unique domains of each AmSFK protein revealed that all three are expressed in eggs and localized primarily to the membrane fraction. Both AmSFK1 and AmSFK3 (but not AmSFK2) are necessary for egg activation, as determined by injection of starfish oocytes with dominant-interfering Src homology 2 (SH2) domains, which specifically delay and reduce the initial release of Ca2+ at fertilization. AmSFK3 exhibits a very rapid and transient kinase activity in response to fertilization, peaking at 30 seconds post sperm addition. AmSFK1 kinase activity also increases transiently at fertilization, but peaks later, at 2 minutes. These results indicate that there are multiple SFKs present in starfish eggs with distinct, perhaps sequential, signaling roles.

IKZF1 expression is a prognostic marker in newly diagnosed standard-risk multiple myeloma treated with lenalidomide and intensive chemotherapy: a study of the German Myeloma Study Group (DSMM).

PubMed

Krönke, J; Kuchenbauer, F; Kull, M; Teleanu, V; Bullinger, L; Bunjes, D; Greiner, A; Kolmus, S; Köpff, S; Schreder, M; Mügge, L-O; Straka, C; Engelhardt, M; Döhner, H; Einsele, H; Bassermann, F; Bargou, R; Knop, S; Langer, C

2017-06-01

Lenalidomide is an immunomodulatory compound with high clinical activity in multiple myeloma. Lenalidomide binding to the Cereblon (CRBN) E3 ubiquitin ligase results in targeted ubiquitination and degradation of the lymphoid transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) leading to growth inhibition of multiple myeloma cells. Recently, Basigin (BSG) was identified as another protein regulated by CRBN that is involved in the activity of lenalidomide. Here, we analyzed the prognostic value of IKZF1, IKZF3, CRBN and BSG mRNA expression levels in pretreatment plasma cells from 60 patients with newly diagnosed multiple myeloma uniformly treated with lenalidomide in combination with intensive chemotherapy within a clinical trial. We found that IKZF1 mRNA expression levels are significantly associated with progression-free survival (PFS). Patients in the lowest quartile (Q1) of IKZF1 expression had a superior PFS compared with patients in the remaining quartiles (Q2-Q4; 3-year PFS of 86 vs 51%, P=0.01). This translated into a significant better overall survival (100 vs 74%, P=0.03). Subgroup analysis revealed a significant impact of IKZF1, IKZF3 and BSG expression levels on PFS in cytogenetically defined standard-risk but not high-risk patients. Our data suggest a prognostic role of IKZF1, IKZF3 and BSG expression levels in lenalidomide-treated multiple myeloma.

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

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.

Characterizing multiple metal ion binding sites within a ribozyme by cadmium-induced EPR silencing

PubMed Central

Kisseleva, Natalia; Kraut, Stefanie; Jäschke, Andres; Schiemann, Olav

2007-01-01

In ribozyme catalysis, metal ions are generally known to make structural and∕or mechanistic contributions. The catalytic activity of a previously described Diels-Alderase ribozyme was found to depend on the concentration of divalent metal ions, and crystallographic data revealed multiple binding sites. Here, we elucidate the interactions of this ribozyme with divalent metal ions in solution using electron paramagnetic resonance (EPR) spectroscopy. Manganese ion titrations revealed five high-affinity Mn2+ binding sites with an upper Kd of 0.6±0.2 μM. In order to characterize each binding site individually, EPR-silent Cd2+ ions were used to saturate the other binding sites. This cadmium-induced EPR silencing showed that the Mn2+ binding sites possess different affinities. In addition, these binding sites could be assigned to three different types, including innersphere, outersphere, and a Mn2+ dimer. Based on simulations, the Mn2+-Mn2+ distance within the dimer was found to be ∼6 Å, which is in good agreement with crystallographic data. The EPR-spectroscopic characterization reveals no structural changes upon addition of a Diels-Alder product, supporting the concept of a preorganized catalytic pocket in the Diels-Alder ribozyme and the structural role of these ions. PMID:19404418

Activity loss by H46A mutation in Mycobacterium tuberculosis isocitrate lyase is due to decrease in structural plasticity and collective motions of the active site.

PubMed

Shukla, Rohit; Shukla, Harish; Tripathi, Timir

2018-01-01

Mycobacterium tuberculosis isocitrate lyase (MtbICL) is a crucial enzyme of the glyoxylate cycle and is a validated anti-tuberculosis drug target. Structurally distant, non-active site mutation (H46A) in MtbICL has been found to cause loss of enzyme activity. The aim of the present work was to explore the structural alterations induced by H46A mutation that caused the loss of enzyme activity. The structural and dynamic consequences of H46A mutation were studied using multiple computational methods such as docking, molecular dynamics simulation and residue interaction network analysis (RIN). Principal component analysis and cross correlation analysis revealed the difference in conformational flexibility and collective modes of motions between the wild-type and mutant enzyme, particularly in the active site region. RIN analysis revealed that the active site geometry was disturbed in the mutant enzyme. Thus, the dynamic perturbation of the active site led to enzyme transition from its active form to inactive form upon mutation. The computational analyses elucidated the mutant-specific conformational alterations, differential dominant motions, and anomalous residue level interactions that contributed to the abrogated function of mutant MtbICL. An understanding of interactions of mutant enzymes may help in modifying the existing drugs and designing improved drugs for successful control of tuberculosis. Copyright © 2017 Elsevier Ltd. All rights reserved.

Classroom sound can be used to classify teaching practices in college science courses.

PubMed

Owens, Melinda T; Seidel, Shannon B; Wong, Mike; Bejines, Travis E; Lietz, Susanne; Perez, Joseph R; Sit, Shangheng; Subedar, Zahur-Saleh; Acker, Gigi N; Akana, Susan F; Balukjian, Brad; Benton, Hilary P; Blair, J R; Boaz, Segal M; Boyer, Katharyn E; Bram, Jason B; Burrus, Laura W; Byrd, Dana T; Caporale, Natalia; Carpenter, Edward J; Chan, Yee-Hung Mark; Chen, Lily; Chovnick, Amy; Chu, Diana S; Clarkson, Bryan K; Cooper, Sara E; Creech, Catherine; Crow, Karen D; de la Torre, José R; Denetclaw, Wilfred F; Duncan, Kathleen E; Edwards, Amy S; Erickson, Karen L; Fuse, Megumi; Gorga, Joseph J; Govindan, Brinda; Green, L Jeanette; Hankamp, Paul Z; Harris, Holly E; He, Zheng-Hui; Ingalls, Stephen; Ingmire, Peter D; Jacobs, J Rebecca; Kamakea, Mark; Kimpo, Rhea R; Knight, Jonathan D; Krause, Sara K; Krueger, Lori E; Light, Terrye L; Lund, Lance; Márquez-Magaña, Leticia M; McCarthy, Briana K; McPheron, Linda J; Miller-Sims, Vanessa C; Moffatt, Christopher A; Muick, Pamela C; Nagami, Paul H; Nusse, Gloria L; Okimura, Kristine M; Pasion, Sally G; Patterson, Robert; Pennings, Pleuni S; Riggs, Blake; Romeo, Joseph; Roy, Scott W; Russo-Tait, Tatiane; Schultheis, Lisa M; Sengupta, Lakshmikanta; Small, Rachel; Spicer, Greg S; Stillman, Jonathon H; Swei, Andrea; Wade, Jennifer M; Waters, Steven B; Weinstein, Steven L; Willsie, Julia K; Wright, Diana W; Harrison, Colin D; Kelley, Loretta A; Trujillo, Gloriana; Domingo, Carmen R; Schinske, Jeffrey N; Tanner, Kimberly D

2017-03-21

Active-learning pedagogies have been repeatedly demonstrated to produce superior learning gains with large effect sizes compared with lecture-based pedagogies. Shifting large numbers of college science, technology, engineering, and mathematics (STEM) faculty to include any active learning in their teaching may retain and more effectively educate far more students than having a few faculty completely transform their teaching, but the extent to which STEM faculty are changing their teaching methods is unclear. Here, we describe the development and application of the machine-learning-derived algorithm Decibel Analysis for Research in Teaching (DART), which can analyze thousands of hours of STEM course audio recordings quickly, with minimal costs, and without need for human observers. DART analyzes the volume and variance of classroom recordings to predict the quantity of time spent on single voice (e.g., lecture), multiple voice (e.g., pair discussion), and no voice (e.g., clicker question thinking) activities. Applying DART to 1,486 recordings of class sessions from 67 courses, a total of 1,720 h of audio, revealed varied patterns of lecture (single voice) and nonlecture activity (multiple and no voice) use. We also found that there was significantly more use of multiple and no voice strategies in courses for STEM majors compared with courses for non-STEM majors, indicating that DART can be used to compare teaching strategies in different types of courses. Therefore, DART has the potential to systematically inventory the presence of active learning with ∼90% accuracy across thousands of courses in diverse settings with minimal effort.

Classroom sound can be used to classify teaching practices in college science courses

PubMed Central

Seidel, Shannon B.; Wong, Mike; Bejines, Travis E.; Lietz, Susanne; Perez, Joseph R.; Sit, Shangheng; Subedar, Zahur-Saleh; Acker, Gigi N.; Akana, Susan F.; Balukjian, Brad; Benton, Hilary P.; Blair, J. R.; Boaz, Segal M.; Boyer, Katharyn E.; Bram, Jason B.; Burrus, Laura W.; Byrd, Dana T.; Caporale, Natalia; Carpenter, Edward J.; Chan, Yee-Hung Mark; Chen, Lily; Chovnick, Amy; Chu, Diana S.; Clarkson, Bryan K.; Cooper, Sara E.; Creech, Catherine; Crow, Karen D.; de la Torre, José R.; Denetclaw, Wilfred F.; Duncan, Kathleen E.; Edwards, Amy S.; Erickson, Karen L.; Fuse, Megumi; Gorga, Joseph J.; Govindan, Brinda; Green, L. Jeanette; Hankamp, Paul Z.; Harris, Holly E.; He, Zheng-Hui; Ingalls, Stephen; Ingmire, Peter D.; Jacobs, J. Rebecca; Kamakea, Mark; Kimpo, Rhea R.; Knight, Jonathan D.; Krause, Sara K.; Krueger, Lori E.; Light, Terrye L.; Lund, Lance; Márquez-Magaña, Leticia M.; McCarthy, Briana K.; McPheron, Linda J.; Miller-Sims, Vanessa C.; Moffatt, Christopher A.; Muick, Pamela C.; Nagami, Paul H.; Nusse, Gloria L.; Okimura, Kristine M.; Pasion, Sally G.; Patterson, Robert; Riggs, Blake; Romeo, Joseph; Roy, Scott W.; Russo-Tait, Tatiane; Schultheis, Lisa M.; Sengupta, Lakshmikanta; Small, Rachel; Spicer, Greg S.; Stillman, Jonathon H.; Swei, Andrea; Wade, Jennifer M.; Waters, Steven B.; Weinstein, Steven L.; Willsie, Julia K.; Wright, Diana W.; Harrison, Colin D.; Kelley, Loretta A.; Trujillo, Gloriana; Domingo, Carmen R.; Schinske, Jeffrey N.; Tanner, Kimberly D.

2017-01-01

Active-learning pedagogies have been repeatedly demonstrated to produce superior learning gains with large effect sizes compared with lecture-based pedagogies. Shifting large numbers of college science, technology, engineering, and mathematics (STEM) faculty to include any active learning in their teaching may retain and more effectively educate far more students than having a few faculty completely transform their teaching, but the extent to which STEM faculty are changing their teaching methods is unclear. Here, we describe the development and application of the machine-learning–derived algorithm Decibel Analysis for Research in Teaching (DART), which can analyze thousands of hours of STEM course audio recordings quickly, with minimal costs, and without need for human observers. DART analyzes the volume and variance of classroom recordings to predict the quantity of time spent on single voice (e.g., lecture), multiple voice (e.g., pair discussion), and no voice (e.g., clicker question thinking) activities. Applying DART to 1,486 recordings of class sessions from 67 courses, a total of 1,720 h of audio, revealed varied patterns of lecture (single voice) and nonlecture activity (multiple and no voice) use. We also found that there was significantly more use of multiple and no voice strategies in courses for STEM majors compared with courses for non-STEM majors, indicating that DART can be used to compare teaching strategies in different types of courses. Therefore, DART has the potential to systematically inventory the presence of active learning with ∼90% accuracy across thousands of courses in diverse settings with minimal effort. PMID:28265087

Design and crystal structure of a native-like HIV-1 envelope trimer that engages multiple broadly neutralizing antibody precursors in vivo

DOE PAGES

Medina-Ramírez, Max; Garces, Fernando; Escolano, Amelia; ...

2017-08-28

Induction of broadly neutralizing antibodies (bNAbs) by HIV-1 envelope glycoprotein immunogens would be a major advance toward an effective vaccine. A critical step in this process is the activation of naive B cells expressing germline (gl) antibody precursors that have the potential to evolve into bNAbs. Here, we reengineered the BG505 SOSIP.664 glycoprotein to engage gl precursors of bNAbs that target either the trimer apex or the CD4-binding site. The resulting BG505 SOSIP.v4.1-GT1 trimer binds multiple bNAb gl precursors in vitro. Immunization experiments in knock-in mice expressing gl-VRC01 or gl-PGT121 show that this trimer activates B cells in vivo, resultingmore » in the secretion of specific antibodies into the sera. A crystal structure of the gl-targeting trimer at 3.2-Å resolution in complex with neutralizing antibodies 35O22 and 9H+109L reveals a native-like conformation and the successful incorporation of design features associated with binding of multiple gl-bNAb precursors.« less

Design and crystal structure of a native-like HIV-1 envelope trimer that engages multiple broadly neutralizing antibody precursors in vivo

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

Medina-Ramírez, Max; Garces, Fernando; Escolano, Amelia

Induction of broadly neutralizing antibodies (bNAbs) by HIV-1 envelope glycoprotein immunogens would be a major advance toward an effective vaccine. A critical step in this process is the activation of naive B cells expressing germline (gl) antibody precursors that have the potential to evolve into bNAbs. Here, we reengineered the BG505 SOSIP.664 glycoprotein to engage gl precursors of bNAbs that target either the trimer apex or the CD4-binding site. The resulting BG505 SOSIP.v4.1-GT1 trimer binds multiple bNAb gl precursors in vitro. Immunization experiments in knock-in mice expressing gl-VRC01 or gl-PGT121 show that this trimer activates B cells in vivo, resultingmore » in the secretion of specific antibodies into the sera. A crystal structure of the gl-targeting trimer at 3.2-Å resolution in complex with neutralizing antibodies 35O22 and 9H+109L reveals a native-like conformation and the successful incorporation of design features associated with binding of multiple gl-bNAb precursors.« less

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.

Episodic normal faulting and magmatism during the syn-spreading stage of the Baiyun sag in Pearl River Mouth Basin: response to the multi-phase seafloor spreading of the South China Sea

NASA Astrophysics Data System (ADS)

Deng, Peng; Mei, Lianfu; Liu, Jun; Zheng, Jinyun; Liu, Minghui; Cheng, Zijie; Guo, Fengtai

2018-03-01

Considerable post-breakup extensional deformation is recorded in the continental margins of the South China Sea (SCS). To recognize the nature and origin of the significant deformation during the syn-spreading stage (32-15.5 Ma) in the SCS, we comprehensively analyzed the geometry and kinematics of the faults and contemporaneous magmas in the Baiyun sag, northern margin of the SCS, using high-resolution regional three-dimensional seismic data. The kinematic analyses indicate that the faults in the Baiyun sag are recently formed following the onset of seafloor spreading in the SCS. The faults exhibit multiple episodes of growth history, with three active episodes, 32-29, 23.8-21 and 18.5-16.5 Ma, separated by periods of inactivity. Four volcanic groups comprising 98 volcanic mounds have been identified and described, located separately in the northwestern, the central, the southeastern and the northern slope areas. The occurrence of multiple palaeo-seafloors, complemented by the biostratigraphic and K-Ar dating data, reveals multiple extrusive events of the syn-spreading magmas in the Baiyun sag, with three active periods of 23.8-21, 18.5-17.5 and 17.5-16.5 Ma. This study confirms that the normal faulting has a shared genetic origin with the contemporaneous magmatism during the syn-spreading stage in the deep-offshore Baiyun sag, northern margin of the SCS. The episodic fault growth and magmatic extrusive events reveal that the Baiyun sag has undergone at least three episodic tectonic events during the syn-spreading stage, which evolved in response to the multi-stage seafloor spreading of the SCS.

Early and late components of EEG delay activity correlate differently with scene working memory performance

PubMed Central

Ng, Kenneth; Reichert, Chelsea P.

2017-01-01

Sustained and elevated activity during the working memory delay period has long been considered the primary neural correlate for maintaining information over short time intervals. This idea has recently been reinterpreted in light of findings generated from multiple neural recording modalities and levels of analysis. To further investigate the sustained or transient nature of activity, the temporal-spectral evolution (TSE) of delay period activity was examined in humans with high density EEG during performance of a Sternberg working memory paradigm with a relatively long six second delay and with novel scenes as stimuli. Multiple analyses were conducted using different trial window durations and different baseline periods for TSE computation. Sensor level analyses revealed transient rather than sustained activity during delay periods. Specifically, the consistent finding among the analyses was that high amplitude activity encompassing the theta range was found early in the first three seconds of the delay period. These increases in activity early in the delay period correlated positively with subsequent ability to distinguish new from old probe scenes. Source level signal estimation implicated a right parietal region of transient early delay activity that correlated positively with working memory ability. This pattern of results adds to recent evidence that transient rather than sustained delay period activity supports visual working memory performance. The findings are discussed in relation to synchronous and desynchronous intra- and inter-regional neural transmission, and choosing an optimal baseline for expressing temporal-spectral delay activity change. PMID:29016657

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.

Brain system for mental orientation in space, time, and person.

PubMed

Peer, Michael; Salomon, Roy; Goldberg, Ilan; Blanke, Olaf; Arzy, Shahar

2015-09-01

Orientation is a fundamental mental function that processes the relations between the behaving self to space (places), time (events), and person (people). Behavioral and neuroimaging studies have hinted at interrelations between processing of these three domains. To unravel the neurocognitive basis of orientation, we used high-resolution 7T functional MRI as 16 subjects compared their subjective distance to different places, events, or people. Analysis at the individual-subject level revealed cortical activation related to orientation in space, time, and person in a precisely localized set of structures in the precuneus, inferior parietal, and medial frontal cortex. Comparison of orientation domains revealed a consistent order of cortical activity inside the precuneus and inferior parietal lobes, with space orientation activating posterior regions, followed anteriorly by person and then time. Core regions at the precuneus and inferior parietal lobe were activated for multiple orientation domains, suggesting also common processing for orientation across domains. The medial prefrontal cortex showed a posterior activation for time and anterior for person. Finally, the default-mode network, identified in a separate resting-state scan, was active for all orientation domains and overlapped mostly with person-orientation regions. These findings suggest that mental orientation in space, time, and person is managed by a specific brain system with a highly ordered internal organization, closely related to the default-mode network.

Optical coherence tomography angiography indicates associations of the retinal vascular network and disease activity in multiple sclerosis.

PubMed

Feucht, Nikolaus; Maier, Mathias; Lepennetier, Gildas; Pettenkofer, Moritz; Wetzlmair, Carmen; Daltrozzo, Tanja; Scherm, Pauline; Zimmer, Claus; Hoshi, Muna-Miriam; Hemmer, Bernhard; Korn, Thomas; Knier, Benjamin

2018-01-01

Patients with multiple sclerosis (MS) and clinically isolated syndrome (CIS) may show alterations of retinal layer architecture as measured by optical coherence tomography. Little is known about changes in the retinal vascular network during MS. To characterize retinal vessel structures in patients with MS and CIS and to test for associations with MS disease activity. In all, 42 patients with MS or CIS and 50 healthy controls underwent retinal optical coherence tomography angiography (OCT-A) with analysis of the superficial and deep vascular plexuses and the choriocapillaries. We tested OCT-A parameters for associations with retinal layer volumes, history of optic neuritis (ON), and the retrospective disease activity. Inner retinal layer volumes correlated positively with the density of both the superficial and deep vascular plexuses. Eyes of MS/CIS patients with a history of ON revealed reduced vessel densities of the superficial and deep vascular plexuses as compared to healthy controls. Higher choriocapillary vessel densities were associated with ongoing inflammatory disease activity during 24 months prior to OCT-A examination in MS and CIS patients. Optic neuritis is associated with rarefaction of the superficial and deep retinal vessels. Alterations of the choriocapillaries might be linked to disease activity in MS.

A Multiplexed Assay That Monitors Effects of Multiple Compound Treatment Times Reveals Candidate Immune-Enhancing Compounds.

PubMed

Zhao, Ziyan; Henowitz, Liza; Zweifach, Adam

2018-05-01

We previously developed a flow cytometry assay that monitored lytic granule exocytosis in cytotoxic T lymphocytes stimulated by contacting beads coated with activating anti-CD3 antibodies. That assay was multiplexed in that responses of cells that did or did not receive the activating stimulus were distinguished via changes in light scatter accompanying binding of cells to beads, allowing us to discriminate compounds that activate responses on their own from compounds that enhance responses in cells that received the activating stimulus, all within a single sample. Here we add a second dimension of multiplexing by developing means to assess in a single sample the effects of treating cells with test compounds for different times. Bar-coding cells before adding them to test wells lets us determine compound treatment time while also monitoring activation status and response amplitude at the point of interrogation. This multiplexed assay is suitable for screening 96-well plates. We used it to screen compounds from the National Cancer Institute, identifying several compounds that enhance anti-LAMP1 responses. Multiple-treatment-time (MTT) screening enabled by bar-coding and read via high-throughput flow cytometry may be a generally useful method for facilitating the discovery of compounds of interest.

Modelling and simulation of biased agonism dynamics at a G protein-coupled receptor.

PubMed

Bridge, L J; Mead, J; Frattini, E; Winfield, I; Ladds, G

2018-04-07

Theoretical models of G protein-coupled receptor (GPCR) concentration-response relationships often assume an agonist producing a single functional response via a single active state of the receptor. These models have largely been analysed assuming steady-state conditions. There is now much experimental evidence to suggest that many GPCRs can exist in multiple receptor conformations and elicit numerous functional responses, with ligands having the potential to activate different signalling pathways to varying extents-a concept referred to as biased agonism, functional selectivity or pluri-dimensional efficacy. Moreover, recent experimental results indicate a clear possibility for time-dependent bias, whereby an agonist's bias with respect to different pathways may vary dynamically. Efforts towards understanding the implications of temporal bias by characterising and quantifying ligand effects on multiple pathways will clearly be aided by extending current equilibrium binding and biased activation models to include G protein activation dynamics. Here, we present a new model of time-dependent biased agonism, based on ordinary differential equations for multiple cubic ternary complex activation models with G protein cycle dynamics. This model allows simulation and analysis of multi-pathway activation bias dynamics at a single receptor for the first time, at the level of active G protein (α GTP ), towards the analysis of dynamic functional responses. The model is generally applicable to systems with N G G proteins and N* active receptor states. Numerical simulations for N G =N * =2 reveal new insights into the effects of system parameters (including cooperativities, and ligand and receptor concentrations) on bias dynamics, highlighting new phenomena including the dynamic inter-conversion of bias direction. Further, we fit this model to 'wet' experimental data for two competing G proteins (G i and G s ) that become activated upon stimulation of the adenosine A 1 receptor with adenosine derivative compounds. Finally, we show that our model can qualitatively describe the temporal dynamics of this competing G protein activation. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Evaluating Continuing Nursing Education: A Qualitative Study of Intention to Change Practice and Perceived Barriers to Knowledge Translation.

PubMed

Wellings, Cynthea A; Gendek, Marilyn A; Gallagher, Silvia E

Evaluating the effectiveness of continuing nursing education does not always include behavioral change and patient health outcomes. A qualitative analysis of open-ended evaluation questions from continuing nursing education activities was conducted. The aim was to evaluate learners' intentions to change their practice resulting from their learning and their perceived barriers to implementing practice changes. Results revealed the multiple, interconnected challenges involved in translating new learning into practice.

QSAR modeling for anti-human African trypanosomiasis activity of substituted 2-Phenylimidazopyridines

NASA Astrophysics Data System (ADS)

Masand, Vijay H.; El-Sayed, Nahed N. E.; Mahajan, Devidas T.; Mercader, Andrew G.; Alafeefy, Ahmed M.; Shibi, I. G.

2017-02-01

In the present work, sixty substituted 2-Phenylimidazopyridines previously reported with potent anti-human African trypanosomiasis (HAT) activity were selected to build genetic algorithm (GA) based QSAR models to determine the structural features that have significant correlation with the activity. Multiple QSAR models were built using easily interpretable descriptors that are directly associated with the presence or the absence of a structural scaffold, or a specific atom. All the QSAR models have been thoroughly validated according to the OECD principles. All the QSAR models are statistically very robust (R2 = 0.80-0.87) with high external predictive ability (CCCex = 0.81-0.92). The QSAR analysis reveals that the HAT activity has good correlation with the presence of five membered rings in the molecule.

Context Specificity of Stress-activated Mitogen-activated Protein (MAP) Kinase Signaling: The Story as Told by Caenorhabditis elegans*

PubMed Central

Andrusiak, Matthew G.; Jin, Yishi

2016-01-01

Stress-associated p38 and JNK mitogen-activated protein (MAP) kinase signaling cascades trigger specific cellular responses and are involved in multiple disease states. At the root of MAP kinase signaling complexity is the differential use of common components on a context-specific basis. The roundworm Caenorhabditis elegans was developed as a system to study genes required for development and nervous system function. The powerful genetics of C. elegans in combination with molecular and cellular dissections has led to a greater understanding of how p38 and JNK signaling affects many biological processes under normal and stress conditions. This review focuses on the studies revealing context specificity of different stress-activated MAPK components in C. elegans. PMID:26907690

Immunoglobulin G4-related acquired hemophilia: A case report

PubMed Central

Li, Xiaoyan; Duan, Wei; Zhu, Xiang; Xu, Jianying

2016-01-01

Acquired hemophilia A (AHA) is a relatively rare and life-threatening bleeding disorder whose pathogenesis is not completely understood. The present study reports a rare case of immunogubulin (IgG)4-related AHA with multisystemic involvement. A 55-year old male patient presented with symptoms of bronchial asthma and multiple subdermal hematomas. Chest computed tomography showed multiple diffuse nodular lesions with thickening of bronchovascular bundles, and scattered high-density spots in both lung lobes. Laboratory investigations showed increased activated partial prothrombin time (120.0 sec), a markedly decreased factor VIII (FVIII) activity (0.5%), a high-titer of FVIII inhibitor (27.2 Bethesda units/ml) and a marked increase in serum IgG4 (>4.03 g/l) level. Left inguinal lymph node biopsy revealed capsular thickening with marked lymphoplasmacytic infiltration, occlusive phlebitis and irregular fibrosis. Immunostaining revealed numerous IgG4-positive plasma cells (>100 cells/human plasma fibronectin) in the nodular lesions, with an IgG4/IgG ratio of >40%. The symptoms were markedly alleviated following corticosteroid therapy. The current study presents the first reported case of a rare IgG4-related AHA that presented with unusual clinical features and multisystemic involvement. The patient responded well to corticosteroid therapy. Documentation of such rare cases will help in characterizing the pathogenesis, and prompt recognition and timely treatment of this rare disorder. PMID:28105131

Broad Range Amino Acid Specificity of RNA-dependent Lipid Remodeling by Multiple Peptide Resistance Factors*

PubMed Central

Roy, Hervé; Ibba, Michael

2009-01-01

Aminoacylphosphatidylglycerol synthases (aaPGSs) are multiple peptide resistance factors that transfer amino acids from aminoacyl-tRNAs to phosphatidylglycerol (PG) in the cytoplasmic membrane. Aminoacylation of PG is used by bacteria to decrease the net negative charge of the cell envelope, diminishing affinity for charged molecules and allowing for adaptation to environmental changes. Lys-PGS, which transfers lysine to PG, is essential for the virulence of certain pathogens, providing resistance to both host cationic antimicrobial peptides and therapeutic antibiotics. Ala-PGS was also recently described, but little is known about the possible activities of other members of the highly diverse aaPGS family of proteins. Systematic deletion of the predicted membrane-inserted domains of several aaPGSs revealed that the carboxyl-terminal hydrophilic domain alone is sufficient for aminoacylphosphatidylglycerol transferase catalytic activity. In contrast to previously characterized aaPGSs, the Enterococcus faecium enzyme used an expanded repertoire of amino acids to modify PG with Ala, Arg, or Lys. Reexamination of previously characterized aaPGSs also revealed broader than anticipated substrate specificity, for example Bacillus subtilis Lys-PGS was shown to also catalyze Ala-PG synthesis. The relaxed substrate specificities of these aaPGSs allows for more elaborate remodeling of membrane lipids than previously thought, potentially providing bacteria that harbor these enzymes resistance to a broad spectrum of antibiotics and environmental stresses. PMID:19734140

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.

FDG-PET in the selection of brain lesions for biopsy

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

Hanson, M.W.; Glantz, M.J.; Hoffman, J.M.

1991-09-01

The CT-guided stereotaxic needle biopsy has become a widely used procedure in the diagnostic evaluation of intracranial lesions including tumors. Conventional CT or MR frequently defines the anatomic regions of abnormality, which may be multiple lesions or a single lesion that is heterogeneous in cellular composition owing to the topographic variation of cellular constituency or the combination of active disease, nonspecific inflammation, necrosis, and/or edema. In these cases, selection of the most appropriate site for a successful diagnostic needle biopsy can be difficult. In three patients, we have used (18F)fluorodeoxyglucose (FDG) positron emission tomography (PET) to determine the site mostmore » likely to provide a diagnostic biopsy result. In the first patient, who presented with confusion, multiple biopsies from the temporal lobe, based on MR abnormalities, revealed only reactive gliosis and edema. Repeat biopsy directed by PET revealed an anaplastic astrocytoma. In a second patient, PET allowed us to differentiate radiation effect from active metastatic breast cancer. In the third patient, who presented with a grand mal seizure, biopsy of a CT-defined hypodense region demonstrated lymphocytosis. Metabolism of FDG was normal or increased in areas of Aspergillus encephalitis at autopsy. These preliminary studies suggest a complementary role for FDG-PET and CT or MR in selected patients for defining the intracranial site most likely to yield a positive biopsy result.« less

A Steric-inhibition model for regulation of nucleotide exchange via the Dock180 family of GEFs.

PubMed

Lu, Mingjian; Kinchen, Jason M; Rossman, Kent L; Grimsley, Cynthia; Hall, Matthew; Sondek, John; Hengartner, Michael O; Yajnik, Vijay; Ravichandran, Kodi S

2005-02-22

CDM (CED-5, Dock180, Myoblast city) family members have been recently identified as novel, evolutionarily conserved guanine nucleotide exchange factors (GEFs) for Rho-family GTPases . They regulate multiple processes, including embryonic development, cell migration, apoptotic-cell engulfment, tumor invasion, and HIV-1 infection, in diverse model systems . However, the mechanism(s) of regulation of CDM proteins has not been well understood. Here, our studies on the prototype member Dock180 reveal a steric-inhibition model for regulating the Dock180 family of GEFs. At basal state, the N-terminal SH3 domain of Dock180 binds to the distant catalytic Docker domain and negatively regulates the function of Dock180. Further studies revealed that the SH3:Docker interaction sterically blocks Rac access to the Docker domain. Interestingly, ELMO binding to the SH3 domain of Dock180 disrupted the SH3:Docker interaction, facilitated Rac access to the Docker domain, and contributed to the GEF activity of the Dock180/ELMO complex. Additional genetic rescue studies in C. elegans suggested that the regulation of the Docker-domain-mediated GEF activity by the SH3 domain and its adjoining region is evolutionarily conserved. This steric-inhibition model may be a general mechanism for regulating multiple SH3-domain-containing Dock180 family members and may have implications for a variety of biological processes.

Exercise and academic performance among nursing and kinesiology students at US colleges.

PubMed

Bellar, David; Judge, Lawrence W; Petersen, Jeffrey; Bellar, Ann; Bryan, Charity L

2014-01-01

Lack of physical activity is a contributor to the obesity epidemic and is speculated to relate to reduced academic performance; however, this link has yet to be examined within the college population. The purpose of this study in a group of undergraduate students, was to determine if aerobic exercise activity was related to academic performance. The participants for this study included 740 students at multiple universities enrolled in nursing and kinesiology studies. The participants completed the Leisure and Physical Activity Questionnaire. Pearson's χ(2) analysis revealed differences in grade point average with aerobic activity (χ(2) = 44.29, P ≤ 0.001) as well as a trend toward differences in grade point average with weightlifting activity (χ(2) = 22.69, P = 0.61). Based on these findings it can be suggested that college students engage in greater aerobic exercise.

In vitro design of a novel lytic bacteriophage cocktail with therapeutic potential against organisms causing diabetic foot infections.

PubMed

Mendes, João J; Leandro, Clara; Mottola, Carla; Barbosa, Raquel; Silva, Filipa A; Oliveira, Manuela; Vilela, Cristina L; Melo-Cristino, José; Górski, Andrzej; Pimentel, Madalena; São-José, Carlos; Cavaco-Silva, Patrícia; Garcia, Miguel

2014-08-01

In patients with diabetes mellitus, foot infections pose a significant risk. These are complex infections commonly caused by Staphylococcus aureus, Pseudomonas aeruginosa and Acinetobacter baumannii, all of which are potentially susceptible to bacteriophages. Here, we characterized five bacteriophages that we had determined previously to have antimicrobial and wound-healing potential in chronic S. aureus, P. aeruginosa and A. baumannii infections. Morphological and genetic features indicated that the bacteriophages were lytic members of the family Myoviridae or Podoviridae and did not harbour any known bacterial virulence genes. Combinations of the bacteriophages had broad host ranges for the different target bacterial species. The activity of the bacteriophages against planktonic cells revealed effective, early killing at 4 h, followed by bacterial regrowth to pre-treatment levels by 24 h. Using metabolic activity as a measure of cell viability within established biofilms, we found significant cell impairment following bacteriophage exposure. Repeated treatment every 4 h caused a further decrease in cell activity. The greatest effects on both planktonic and biofilm cells occurred at a bacteriophage : bacterium input multiplicity of 10. These studies on both planktonic cells and established biofilms allowed us to better evaluate the effects of a high input multiplicity and a multiple-dose treatment protocol, and the findings support further clinical development of bacteriophage therapy. © 2014 The Authors.

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.

An APC/C-Cdh1 Biosensor Reveals the Dynamics of Cdh1 Inactivation at the G1/S Transition.

PubMed

Ondracka, Andrej; Robbins, Jonathan A; Cross, Frederick R

2016-01-01

B-type cyclin-dependent kinase activity must be turned off for mitotic exit and G1 stabilization. B-type cyclin degradation is mediated by the anaphase-promoting complex/cyclosome (APC/C); during and after mitotic exit, APC/C is dependent on Cdh1. Cdh1 is in turn phosphorylated and inactivated by cyclin-CDK at the Start transition of the new cell cycle. We developed a biosensor to assess the cell cycle dynamics of APC/C-Cdh1. Nuclear exit of the G1 transcriptional repressor Whi5 is a known marker of Start; APC/C-Cdh1 is inactivated 12 min after Whi5 nuclear exit with little measurable cell-to-cell timing variability. Multiple phosphorylation sites on Cdh1 act in a redundant manner to repress its activity. Reducing the number of phosphorylation sites on Cdh1 can to some extent be tolerated for cell viability, but it increases variability in timing of APC/C-Cdh1 inactivation. Mutants with minimal subsets of phosphorylation sites required for viability exhibit striking stochasticity in multiple responses including budding, nuclear division, and APC/C-Cdh1 activity itself. Multiple cyclin-CDK complexes, as well as the stoichiometric inhibitor Acm1, contribute to APC/C-Cdh1 inactivation; this redundant control is likely to promote rapid and reliable APC/C-Cdh1 inactivation immediately following the Start transition.

Is the structural diversity of tripeptides sufficient for developing functional food additives with satisfactory multiple bioactivities?

NASA Astrophysics Data System (ADS)

Wang, Jian-Hui; Liu, Yong-Le; Ning, Jing-Heng; Yu, Jian; Li, Xiang-Hong; Wang, Fa-Xiang

2013-05-01

Multifunctional peptides have attracted increasing attention in the food science community because of their therapeutic potential, low toxicity and rapid intestinal absorption. However, previous study demonstrated that the limited structural variations make it difficult to optimize dipeptide molecules in a good balance between desirable and undesirable properties (F. Tian, P. Zhou, F. Lv, R. Song, Z. Li, J. Pept. Sci. 13 (2007) 549-566). In the present work, we attempt to answer whether the structural diversity is sufficient for a tripeptide to have satisfactory multiple bioactivities. Statistical test, structural examination and energetic analysis confirm that peptides of three amino acids long can bind tightly to human angiotensin converting enzyme (ACE) and thus exert significant antihypertensive efficacy. Further quantitative structure-activity relationship (QSAR) modeling and prediction of all 8000 possible tripeptides reveal that their ACE-inhibitory potency exhibits a good (positive) relationship to antioxidative activity, but has only a quite modest correlation with bitterness. This means that it is possible to find certain tripeptide entities possessing the optimal combination of strong ACE-inhibitory potency, high antioxidative activity and weak bitter taste, which are the promising candidates for developing multifunctional food additives with satisfactory multiple bioactivities. The marked difference between dipeptide and tripeptide can be attributed to the fact that the structural diversity of peptides increases dramatically with a slight change in sequence length.

Dandelion root extract affects colorectal cancer proliferation and survival through the activation of multiple death signalling pathways

PubMed Central

Ovadje, Pamela; Ammar, Saleem; Guerrero, Jose-Antonio; Arnason, John Thor; Pandey, Siyaram

2016-01-01

Dandelion extracts have been studied extensively in recent years for its anti-depressant and anti-inflammatory activity. Recent work from our lab, with in-vitro systems, shows the anti-cancer potential of an aqueous dandelion root extract (DRE) in several cancer cell models, with no toxicity to non-cancer cells. In this study, we examined the cancer cell-killing effectiveness of an aqueous DRE in colon cancer cell models. Aqueous DRE induced programmed cell death (PCD) selectively in > 95% of colon cancer cells, irrespective of their p53 status, by 48 hours of treatment. The anti-cancer efficacy of this extract was confirmed in in-vivo studies, as the oral administration of DRE retarded the growth of human colon xenograft models by more than 90%. We found the activation of multiple death pathways in cancer cells by DRE treatment, as revealed by gene expression analyses showing the expression of genes implicated in programmed cell death. Phytochemical analyses of the extract showed complex multi-component composition of the DRE, including some known bioactive phytochemicals such as α-amyrin, β-amyrin, lupeol and taraxasterol. This suggested that this natural extract could engage and effectively target multiple vulnerabilities of cancer cells. Therefore, DRE could be a non-toxic and effective anti-cancer alternative, instrumental for reducing the occurrence of cancer cells drug-resistance. PMID:27564258

Inverse Association between Air Pressure and Rheumatoid Arthritis Synovitis

PubMed Central

Furu, Moritoshi; Nakabo, Shuichiro; Ohmura, Koichiro; Nakashima, Ran; Imura, Yoshitaka; Yukawa, Naoichiro; Yoshifuji, Hajime; Matsuda, Fumihiko; Ito, Hiromu; Fujii, Takao; Mimori, Tsuneyo

2014-01-01

Rheumatoid arthritis (RA) is a bone destructive autoimmune disease. Many patients with RA recognize fluctuations of their joint synovitis according to changes of air pressure, but the correlations between them have never been addressed in large-scale association studies. To address this point we recruited large-scale assessments of RA activity in a Japanese population, and performed an association analysis. Here, a total of 23,064 assessments of RA activity from 2,131 patients were obtained from the KURAMA (Kyoto University Rheumatoid Arthritis Management Alliance) database. Detailed correlations between air pressure and joint swelling or tenderness were analyzed separately for each of the 326 patients with more than 20 assessments to regulate intra-patient correlations. Association studies were also performed for seven consecutive days to identify the strongest correlations. Standardized multiple linear regression analysis was performed to evaluate independent influences from other meteorological factors. As a result, components of composite measures for RA disease activity revealed suggestive negative associations with air pressure. The 326 patients displayed significant negative mean correlations between air pressure and swellings or the sum of swellings and tenderness (p = 0.00068 and 0.00011, respectively). Among the seven consecutive days, the most significant mean negative correlations were observed for air pressure three days before evaluations of RA synovitis (p = 1.7×10−7, 0.00027, and 8.3×10−8, for swellings, tenderness and the sum of them, respectively). Standardized multiple linear regression analysis revealed these associations were independent from humidity and temperature. Our findings suggest that air pressure is inversely associated with synovitis in patients with RA. PMID:24454853

Design, synthesis and DNA-binding study of some novel morpholine linked thiazolidinone derivatives

NASA Astrophysics Data System (ADS)

War, Javeed Ahmad; Srivastava, Santosh Kumar; Srivastava, Savitri Devi

2017-02-01

The emergence of multiple drug resistance amongst bacterial strains resulted in many clinical drugs to be ineffective. Being vulnerable to bacterial infections any lack in the development of new antimicrobial drugs could pose a serious threat to public health. Here we report design and synthesis of a novel class of morpholine linked thiazolidinone hybrid molecules. The compounds were characterized by FT-IR, NMR and HRMS techniques. Susceptibility tests showed that most of the synthesized molecules were highly active against multiple bacterial strains. Compound 3f displayed MIC values which were better than the standard drug for most of the tested strains. DNA being a well defined target for many antimicrobial drugs was probed as possible target for these synthetic molecules. DNA-binding study of 3f with sm-DNA was probed through UV-vis absorption, fluorescence quenching, gel electrophoresis and molecular docking techniques. The studies revealed that compound 3f has strong affinity towards DNA and binds at the minor groove. The docking studies revealed that the compound 3f shows preferential binding towards A/T residues.

Design, synthesis and DNA-binding study of some novel morpholine linked thiazolidinone derivatives.

PubMed

War, Javeed Ahmad; Srivastava, Santosh Kumar; Srivastava, Savitri Devi

2017-02-15

The emergence of multiple drug resistance amongst bacterial strains resulted in many clinical drugs to be ineffective. Being vulnerable to bacterial infections any lack in the development of new antimicrobial drugs could pose a serious threat to public health. Here we report design and synthesis of a novel class of morpholine linked thiazolidinone hybrid molecules. The compounds were characterized by FT-IR, NMR and HRMS techniques. Susceptibility tests showed that most of the synthesized molecules were highly active against multiple bacterial strains. Compound 3f displayed MIC values which were better than the standard drug for most of the tested strains. DNA being a well defined target for many antimicrobial drugs was probed as possible target for these synthetic molecules. DNA-binding study of 3f with sm-DNA was probed through UV-vis absorption, fluorescence quenching, gel electrophoresis and molecular docking techniques. The studies revealed that compound 3f has strong affinity towards DNA and binds at the minor groove. The docking studies revealed that the compound 3f shows preferential binding towards A/T residues. Copyright © 2016 Elsevier B.V. All rights reserved.

[Psychopathological and psychosocial aspects of military crimes].

PubMed

Woś, Jarosław; Florkowski, Antoni; Zboralski, Krzysztof

2013-03-01

Crimes in the military, as well as criminal behaviors in the civilian community are determined by multiple factors. However, in case of military crimes committed by soldiers on active duty, an important part of forensic psychiatric opinion, is to assess whether occurring mental disorder resulted in inability to perform military duties. was to investigate the psychopathological and psychosocial determinants of criminal behavior in soldiers who committed military crime. The study included 122 soldiers who committed military crime. Material for this study consisted of forensic psychiatric opinions formed on the order of military prosecutor and the military judicial authorities. The results indicate that military crimes are determined by multiple factors. In most cases, the criminal behavior was associated with personality disorder (70%), alcohol problems (43%) and psychoactive substance use (30%). Psychosocial factors analysis revealed more frequent behavioral problems during childhood and adolescence (51%), history of parental alcohol problem (31%) and previous criminal record (29%). Forensic psychiatric examinations revealed that military crimes are more frequent in soldiers on compulsory military service, and in those with personality disorder or/and alcohol problems.

Concentrated energy addition for active drag reduction in hypersonic flow regime

NASA Astrophysics Data System (ADS)

Ashwin Ganesh, M.; John, Bibin

2018-01-01

Numerical optimization of hypersonic drag reduction technique based on concentrated energy addition is presented in this study. A reduction in wave drag is realized through concentrated energy addition in the hypersonic flowfield upstream of the blunt body. For the exhaustive optimization presented in this study, an in-house high precision inviscid flow solver has been developed. Studies focused on the identification of "optimum energy addition location" have revealed the existence of multiple minimum drag points. The wave drag coefficient is observed to drop from 0.85 to 0.45 when 50 Watts of energy is added to an energy bubble of 1 mm radius located at 74.7 mm upstream of the stagnation point. A direct proportionality has been identified between energy bubble size and wave drag coefficient. Dependence of drag coefficient on the upstream added energy magnitude is also revealed. Of the observed multiple minimum drag points, the energy deposition point (EDP) that offers minimum wave drag just after a sharp drop in drag is proposed as the most optimum energy addition location.

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

A novel de novo activating mutation in STAT3 identified in a patient with common variable immunodeficiency (CVID).

PubMed

Russell, Mark A; Pigors, Manuela; Houssen, Maha E; Manson, Ania; Kelsell, David; Longhurst, Hilary; Morgan, Noel G

2018-02-01

Common variable immunodeficiency (CVID) is characterised by repeated infection associated with primary acquired hypogammaglobulinemia. CVID frequently has a complex aetiology but, in certain cases, it has a monogenic cause. Recently, variants within the gene encoding the transcription factor STAT3 were implicated in monogenic CVID. Here, we describe a patient presenting with symptoms synonymous with CVID, who displayed reduced levels of IgG and IgA, repeated viral infections and multiple additional co-morbidities. Whole-exome sequencing revealed a de novo novel missense mutation in the coiled-coil domain of STAT3 (c.870A>T; p.K290N). Accordingly, the K290N variant of STAT3 was generated, and a STAT3 responsive dual-luciferase reporter assay revealed that the variant strongly enhances STAT3 transcriptional activity both under basal and stimulated (with IL-6) conditions. Overall, these data complement earlier studies in which CVID-associated STAT3 mutations are predicted to enhance transcriptional activity, suggesting that such patients may respond favourably to IL-6 receptor antagonists (e.g. tocilizumab). Copyright © 2017 Elsevier Inc. All rights reserved.

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

Presynaptic active zones of mammalian neuromuscular junctions: Nanoarchitecture and selective impairments in aging.

PubMed

Badawi, Yomna; Nishimune, Hiroshi

2018-02-01

Neurotransmitter release occurs at active zones, which are specialized regions of the presynaptic membrane. A dense collection of proteins at the active zone provides a platform for molecular interactions that promote recruitment, docking, and priming of synaptic vesicles. At mammalian neuromuscular junctions (NMJs), muscle-derived laminin β2 interacts with presynaptic voltage-gated calcium channels to organize active zones. The molecular architecture of presynaptic active zones has been revealed using super-resolution microscopy techniques that combine nanoscale resolution and multiple molecular identification. Interestingly, the active zones of adult NMJs are not stable structures and thus become impaired during aging due to the selective degeneration of specific active zone proteins. This review will discuss recent progress in the understanding of active zone nanoarchitecture and the mechanisms underlying active zone organization in mammalian NMJs. Furthermore, we will summarize the age-related degeneration of active zones at NMJs, and the role of exercise in maintaining active zones. Copyright © 2017 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

Homelessness among older african-american women: interpreting a serious social issue through the arts in community-based participatory action research.

PubMed

Feen-Calligan, Holly; Washington, Olivia G M; Moxley, David P

2009-01-01

This article describes the incorporation of the arts into a community-based participatory action research (CBPAR) project formulated to develop and test practices for helping homeless older African-American women. Studying how older African-American women become homeless has evolved into developing and testing promising interventions by the Leaving Homelessness Intervention Research Project (LHIRP). The women's participation in creative group activities helped them to communicate their experience with homelessness, express their concerns, develop personal strengths, and obtained mutual understanding. The use of multiple art forms has revealed a number of creative strengths among the participants, which have in turn inspired innovative artistic strategies and methodologies as part of the multiple methods that LHIRP incorporates. These interventions have been useful in helping participants resolve their homelessness. The role and benefit of the arts in CBPAR is described to show how creative activities help researchers and the public to better understand the complexities of homelessness.

Accelerated hydrolysis of substituted cellulose for potential biofuel production: kinetic study and modeling.

PubMed

Mu, Bingnan; Xu, Helan; Yang, Yiqi

2015-11-01

In this work, kinetics of substitution accelerated cellulose hydrolysis with multiple reaction stages was investigated to lay foundation for mechanism study and molecular design of substituting compounds. High-efficiency hydrolysis of cellulose is critical for cellulose-based bioethanol production. It is known that, substitution could substantially decrease activation energy and increase reaction rate of acidic hydrolysis of glycosidic bonds in cellulose. However, reaction kinetics and mechanism of the accelerated hydrolysis were not fully revealed. In this research, it was proved that substitution therefore accelerated hydrolysis only occurred in amorphous regions of cellulose fibers, and was a process with multiple reaction stages. With molar ratio of substitution less than 1%, the overall hydrolysis rate could be increased for around 10 times. We also quantified the relationship between the hydrolysis rate of individual reaction stage and its major influences, including molar ratio of substitution, activation energy of acidic hydrolysis, pH and temperature. Copyright © 2015 Elsevier Ltd. All rights reserved.

Theodore E. Woodward Award: Spare Me the Powerpoint and Bring Back the Medical Textbook

PubMed Central

Southwick, Frederick S.

2007-01-01

A tutorial for 4th year medical students revealed absent long-term retention of microbiology and infectious disease facts taught during the 2nd year. Students were suffering from the Ziegarnik effect, the loss of memory after completion of a task. PowerPoint lectures and PowerPoint notes combined with multiple-choice questions may have encouraged this outcome; this teaching format was also associated with minimal use of the course textbook. During the subsequent year, active learning techniques, Just-in-Time Teaching (JiTT) and Peer Instruction (PI) were used, and instructors specifically taught from the textbook. Essays and short answer questions were combined with multiple-choice questions to encourage understanding and recall. Performance on the National Board Shelf exam improved from the 59th percentile (2002–2004) to the 83rd percentile (2005), and textbook use increased from 1.6% to 79%. This experience demonstrates that strategies incorporating active learning and textbook use correlate with striking improvement in medical student performance. PMID:18528495

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

Multiple molecular dynamics simulations of human LOX-1 and Trp150Ala mutant reveal the structural determinants causing the full deactivation of the receptor.

PubMed

Iacovelli, Federico; Tucci, Fabio Giovanni; Macari, Gabriele; Falconi, Mattia

2017-10-01

Multiple classical molecular dynamics simulations have been applied to the human LOX-1 receptor to clarify the role of the Trp150Ala mutation in the loss of binding activity. Results indicate that the substitution of this crucial residue, located at the dimer interface, markedly disrupts the wild-type receptor dynamics. The mutation causes an irreversible rearrangement of the subunits interaction pattern that in the wild-type protein allows the maintaining of a specific symmetrical motion of the monomers. The subunits dislocation determines a loss of linearity of the arginines residues composing the basic spine and a consequent alteration of the long-range electrostatic attraction of the substrate. Moreover, the anomalous subunits arrangement observed in the mutated receptor also affects the integrity of the hydrophobic tunnel, actively involved in the short-range hydrophobic recognition of the substrate. The combined effect of these structural rearrangements generates the impairing of the receptor function. © 2017 Wiley Periodicals, Inc.

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.

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.

[Efflux systems in Serratia marcescens].

PubMed

Mardanova, A M; Bogomol'naia, L M; Romanova, Iu D; Sharipova, M R

2014-01-01

A widespread bacterium Serratia marcescens (family Enterobacteriaceae) is an opportunistic and exhibits multiple drug resistance. Active removal of antibiotics and other antimicrobials from pathogen and exhibits multiple drug resistance. Active removal of antibiotics and other antimicrobials from the cells by efflux systems is one of the mechanisms responsible for microbial resistance to these compounds. Among enterobacteria, efflux systems of Escherichia coli and Salmonella enterica var. Typhimurium have been studied most extensively. Few efflux systems that belong to different families have been reported for S. marcescens. In this review, we analyzed available literature about S. marcescens efflux systems and carried out the comparative analysis of the genes encoding the RND type systems in different Serratia species and in other enterobacteria. Bioinformatical analysis of the S. marcescens genome allowed us to identify the previously unknown efflux systems based on their homology with the relevant E. coli genes. Identification of additional efflux systems in S. marcescens genome will promote our understanding of physiology of these bacteria, will detect new molecular mechanisms of resistance and will reveal their resistance potential.

Genetic and epigenetic regulation of AHR gene expression in MCF-7 breast cancer cells: role of the proximal promoter GC-rich region

PubMed Central

Englert, Neal A.; Turesky, Robert J.; Han, Weiguo; Bessette, Erin E.; Spivack, Simon D.; Caggana, Michele; Spink, David C.; Spink, Barbara C.

2014-01-01

The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, contributes to carcinogenesis through its role in the regulation of cytochrome P450 1 (CYP1)-catalyzed metabolism of carcinogens. Here, we investigated genetic and epigenetic mechanisms that affect AhR expression. Analyses of the human AHR proximal promoter in MCF-7 human breast cancer cells using luciferase assays and electrophoretic mobility shift assays revealed multiple specificity protein (Sp) 1 binding sequences that are transcriptional activators in vitro. The regulation of AhR expression was evaluated in long-term estrogen exposed (LTEE) MCF-7 cells, which showed increased AhR expression, enhanced CYP1 inducibility, and increased capacity to form DNA adducts when exposed to the dietary carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. The increased AhR expression in LTEE cells was found not to result from increased mRNA stability, differential RNA processing, or decreased DNA methylation. Analysis of the AHR proximal promoter region using chromatin immunoprecipitation confirmed that enhanced expression of AhR in LTEE cells involves changes in histone modifications, notably decreased trimethylation of histone 3, lysine 27. Upon further examination of the GC-rich Sp1-binding region, we confirmed that it contains a polymorphic (GGGGC)n repeat. In a population of newborns from New York State, the allele frequency of (GGGGC)n was n = 4>5≫6, 2. Circular dichroism spectroscopy revealed the ability of sequences of this GC-rich region to form guanine-quadruplex structures in vitro. These studies revealed multiple levels at which AhR expression may be controlled, and offer additional insights into mechanisms regulating AhR expression that can ultimately impact carcinogenesis. PMID:22728919

A20 restricts ubiquitination of pro-interleukin-1β protein complexes and suppresses NLRP3 inflammasome activity

PubMed Central

Duong, Bao H.; Onizawa, Michio; Oses-Prieto, Juan A.; Advincula, Rommel; Burlingame, Alma; Malynn, Barbara A.; Ma, Averil

2015-01-01

SUMMARY Inappropriate inflammasome activation contributes to multiple human diseases, but the mechanisms by which inflammasomes are suppressed are poorly understood. The NFκB inhibitor A20 is a ubiquitin-modifying enzyme that may prevent human inflammatory diseases and lymphomas. Here, we report that A20-deficient macrophages, unlike normal cells, exhibit spontaneous NLRP3 inflammasome activity to LPS alone. The kinase RIPK3, but not the adaptor MyD88, is required for this response. In normal cells, A20 constitutively associates with caspase-1 and pro-IL-1β, and NLRP3 activation further promotes A20 recruitment to the inflammasome. Pro-IL-1β also co-immunoprecipitates with RIPK1, RIPK3, caspase-1 and caspase-8 in a complex that is modified with K63-linked and unanchored polyubiquitin. In A20-deficient macrophages, this pro-IL-1β-associated ubiquitination is markedly increased in a RIPK3-dependent manner. Mass spectrometric and mutational analyses reveal that K133 of pro-IL-1β is a physiological ubiquitination site that supports processing. Our study reveals a novel mechanism by which A20 prevents inflammatory diseases. PMID:25607459

Individual differences in mathematical competence predict parietal brain activation during mental calculation.

PubMed

Grabner, Roland H; Ansari, Daniel; Reishofer, Gernot; Stern, Elsbeth; Ebner, Franz; Neuper, Christa

2007-11-01

Functional neuroimaging studies have revealed that parietal brain circuits subserve arithmetic problem solving and that their recruitment dynamically changes as a function of training and development. The present study investigated whether the brain activation during mental calculation is also modulated by individual differences in mathematical competence. Twenty-five adult students were selected from a larger pool based on their performance on standardized tests of intelligence and arithmetic and divided into groups of individuals with relatively lower and higher mathematical competence. These groups did not differ in their non-numerical intelligence or age. In an fMRI block-design, participants had to verify the correctness of single-digit and multi-digit multiplication problems. Analyses revealed that the individuals with higher mathematical competence displayed stronger activation of the left angular gyrus while solving both types of arithmetic problems. Additional correlational analyses corroborated the association between individual differences in mathematical competence and angular gyrus activation, even when variability in task performance was controlled for. These findings demonstrate that the recruitment of the left angular gyrus during arithmetic problem solving underlies individual differences in mathematical ability and suggests a stronger reliance on automatic, language-mediated processes in more competent individuals.

Sonic hedgehog pathway activation increases mitochondrial abundance and activity in hippocampal neurons

PubMed Central

Yao, Pamela J.; Manor, Uri; Petralia, Ronald S.; Brose, Rebecca D.; Wu, Ryan T. Y.; Ott, Carolyn; Wang, Ya-Xian; Charnoff, Ari; Lippincott-Schwartz, Jennifer; Mattson, Mark P.

2017-01-01

Mitochondria are essential organelles whose biogenesis, structure, and function are regulated by many signaling pathways. We present evidence that, in hippocampal neurons, activation of the Sonic hedgehog (Shh) signaling pathway affects multiple aspects of mitochondria. Mitochondrial mass was increased significantly in neurons treated with Shh. Using biochemical and fluorescence imaging analyses, we show that Shh signaling activity reduces mitochondrial fission and promotes mitochondrial elongation, at least in part, via suppression of the mitochondrial fission protein dynamin-like GTPase Drp1. Mitochondria from Shh-treated neurons were more electron-dense, as revealed by electron microscopy, and had higher membrane potential and respiratory activity. We further show that Shh protects neurons against a variety of stresses, including the mitochondrial poison rotenone, amyloid β-peptide, hydrogen peroxide, and high levels of glutamate. Collectively our data suggest a link between Shh pathway activity and the physiological properties of mitochondria in hippocampal neurons. PMID:27932496

The role of sense of coherence and physical activity in positive and negative affect of Turkish adolescents.

PubMed

Oztekin, Ceyda; Tezer, Esin

2009-01-01

This study investigated the role of sense of coherence and total physical activity in positive and negative affect. Participants were 376 (169 female, 206 male, and 1 missing value) student volunteers from different faculties of Middle East Technical University. Three questionnaires: Sense of Coherence Scale (SOC), Physical Activity Assessment Questionnaire (PAAQ), and Positive and Negative Affect Schedule (PANAS) were administered to the students together with the demographic information sheet. Two separate stepwise multiple linear regression analyses were conducted to examine the predictive power of sense of coherence and total physical activity on positive and negative affect scores. Results revealed that both sense of coherence and total physical activity predicted the positive affect whereas only the sense of coherence predicted the negative affect on university students. Findings are discussed in light of sense of coherence, physical activity, and positive and negative affect literature.

Pupil size signals mental effort deployed during multiple object tracking and predicts brain activity in the dorsal attention network and the locus coeruleus.

PubMed

Alnæs, Dag; Sneve, Markus Handal; Espeseth, Thomas; Endestad, Tor; van de Pavert, Steven Harry Pieter; Laeng, Bruno

2014-04-01

Attentional effort relates to the allocation of limited-capacity attentional resources to meet current task demands and involves the activation of top-down attentional systems in the brain. Pupillometry is a sensitive measure of this intensity aspect of top-down attentional control. Studies relate pupillary changes in response to cognitive processing to activity in the locus coeruleus (LC), which is the main hub of the brain's noradrenergic system and it is thought to modulate the operations of the brain's attentional systems. In the present study, participants performed a visual divided attention task known as multiple object tracking (MOT) while their pupil sizes were recorded by use of an infrared eye tracker and then were tested again with the same paradigm while brain activity was recorded using fMRI. We hypothesized that the individual pupil dilations, as an index of individual differences in mental effort, as originally proposed by Kahneman (1973), would be a better predictor of LC activity than the number of tracked objects during MOT. The current results support our hypothesis, since we observed pupil-related activity in the LC. Moreover, the changes in the pupil correlated with activity in the superior colliculus and the right thalamus, as well as cortical activity in the dorsal attention network, which previous studies have shown to be strongly activated during visual tracking of multiple targets. Follow-up pupillometric analyses of the MOT task in the same individuals also revealed that individual differences to cognitive load can be remarkably stable over a lag of several years. To our knowledge this is the first study using pupil dilations as an index of attentional effort in the MOT task and also relating these to functional changes in the brain that directly implicate the LC-NE system in the allocation of processing resources.

Substrate-Induced Facilitated Dissociation of the Competitive Inhibitor from the Active Site of O-Acetyl Serine Sulfhydrylase Reveals a Competitive-Allostery Mechanism.

PubMed

Singh, Appu Kumar; Ekka, Mary Krishna; Kaushik, Abhishek; Pandya, Vaibhav; Singh, Ravi P; Banerjee, Shrijita; Mittal, Monica; Singh, Vijay; Kumaran, S

2017-09-19

By classical competitive antagonism, a substrate and competitive inhibitor must bind mutually exclusively to the active site. The competitive inhibition of O-acetyl serine sulfhydrylase (OASS) by the C-terminus of serine acetyltransferase (SAT) presents a paradox, because the C-terminus of SAT binds to the active site of OASS with an affinity that is 4-6 log-fold (10 4 -10 6 ) greater than that of the substrate. Therefore, we employed multiple approaches to understand how the substrate gains access to the OASS active site under physiological conditions. Single-molecule and ensemble approaches showed that the active site-bound high-affinity competitive inhibitor is actively dissociated by the substrate, which is not consistent with classical views of competitive antagonism. We employed fast-flow kinetic approaches to demonstrate that substrate-mediated dissociation of full length SAT-OASS (cysteine regulatory complex) follows a noncanonical "facilitated dissociation" mechanism. To understand the mechanism by which the substrate induces inhibitor dissociation, we resolved the crystal structures of enzyme·inhibitor·substrate ternary complexes. Crystal structures reveal a competitive allosteric binding mechanism in which the substrate intrudes into the inhibitor-bound active site and disengages the inhibitor before occupying the site vacated by the inhibitor. In summary, here we reveal a new type of competitive allosteric binding mechanism by which one of the competitive antagonists facilitates the dissociation of the other. Together, our results indicate that "competitive allostery" is the general feature of noncanonical "facilitated/accelerated dissociation" mechanisms. Further understanding of the mechanistic framework of "competitive allosteric" mechanism may allow us to design a new family of "competitive allosteric drugs/small molecules" that will have improved selectivity and specificity as compared to their competitive and allosteric counterparts.

Adaption of Ulva pertusa to multiple-contamination of heavy metals and nutrients: Biological mechanism of outbreak of Ulva sp. green tide.

PubMed

Ge, Changzi; Yu, Xiru; Kan, Manman; Qu, Chunfeng

2017-12-15

The multiple-contamination of heavy metals and nutrients worsens increasingly and Ulva sp. green tide occurs almost simultaneously. To reveal the biological mechanism for outbreak of the green tide, Ulva pertusa was exposed to seven-day-multiple-contamination. The relation between pH variation (V pH ), Chl a content, ratio of (Chl a content)/(Chl b content) (R chla/chlb ), SOD activity of U. pertusa (A SOD ) and contamination concentration is [Formula: see text] (p<0.05), C chla =0.88 ±0.09 -0.01 ±0.00 ×C Cd (p<0.05), [Formula: see text] (p<0.05), and [Formula: see text] (p<0.05), respectively. C ammonia , C Cd and C Zn is concentration of ammonia, Cd 2+ and Zn 2+ , respectively. Comparing the contamination concentrations of seawaters where Ulva sp. green tide occurred and the contamination concentrations set in the present work, U. pertusa can adapt to multiple-contaminations in these waters. Thus, the adaption to multiple-contamination may be one biological mechanism for the outbreak of Ulva sp. green tide. Copyright © 2017 Elsevier Ltd. All rights reserved.

Electrophysiological correlates of cocktail-party listening.

PubMed

Lewald, Jörg; Getzmann, Stephan

2015-10-01

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

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.

Selective ligand activity at Nur/retinoid X receptor complexes revealed by dimer-specific bioluminescence resonance energy transfer-based sensors

PubMed Central

Giner, Xavier C; Cotnoir-White, David; Mader, Sylvie; Lévesque, Daniel

2017-01-01

Retinoid X receptors (RXR) play a role as master regulators due to their capacity to form heterodimers with other nuclear receptors. Accordingly, retinoid signaling is involved in multiple biological processes, including development, cell differentiation, metabolism and cell death. However, the role and functions of RXR in different heterodimer complexes remain unsolved, mainly because most RXR drugs (called rexinoids) are not selective to specific heterodimer complexes. This also strongly limits the use of rexinoids for specific therapeutic approaches. In order to better characterize rexinoids at specific nuclear receptor complexes, we have developed and optimized luciferase protein complementation-based Bioluminescence Resonance Energy Transfer (BRET) assays, which can directly measure recruitment of a co-activator motif fused to yellow fluorescent protein (YFP) by specific nuclear receptor dimers. To validate the assays, we compared rexinoid modulation of co-activator recruitment by RXR homodimer, and heterodimers Nur77/RXR and Nurr1/RXR. Results reveal that some rexinoids display selective co-activator recruitment activities with homo- or hetero-dimer complexes. In particular, SR11237 (BMS649) has increased potency for recruitment of co-activator motif and transcriptional activity with the Nur77/RXR heterodimer compared to other complexes. This technology should prove useful to identify new compounds with specificity for individual dimeric species formed by nuclear receptors. PMID:26148973

Common brain regions underlying different arithmetic operations as revealed by conjunct fMRI-BOLD activation.

PubMed

Fehr, Thorsten; Code, Chris; Herrmann, Manfred

2007-10-03

The issue of how and where arithmetic operations are represented in the brain has been addressed in numerous studies. Lesion studies suggest that a network of different brain areas are involved in mental calculation. Neuroimaging studies have reported inferior parietal and lateral frontal activations during mental arithmetic using tasks of different complexities and using different operators (addition, subtraction, etc.). Indeed, it has been difficult to compare brain activation across studies because of the variety of different operators and different presentation modalities used. The present experiment examined fMRI-BOLD activity in participants during calculation tasks entailing different arithmetic operations -- addition, subtraction, multiplication and division -- of different complexities. Functional imaging data revealed a common activation pattern comprising right precuneus, left and right middle and superior frontal regions during all arithmetic operations. All other regional activations were operation specific and distributed in prominently frontal, parietal and central regions when contrasting complex and simple calculation tasks. The present results largely confirm former studies suggesting that activation patterns due to mental arithmetic appear to reflect a basic anatomical substrate of working memory, numerical knowledge and processing based on finger counting, and derived from a network originally related to finger movement. We emphasize that in mental arithmetic research different arithmetic operations should always be examined and discussed independently of each other in order to avoid invalid generalizations on arithmetics and involved brain areas.

A key requirement for CD300f in innate immune responses of eosinophils in colitis.

PubMed

Moshkovits, I; Reichman, H; Karo-Atar, D; Rozenberg, P; Zigmond, E; Haberman, Y; Ben Baruch-Morgenstern, N; Lampinen, M; Carlson, M; Itan, M; Denson, L A; Varol, C; Munitz, A

2017-01-01

Eosinophils are traditionally studied in the context of type 2 immune responses. However, recent studies highlight key innate immune functions for eosinophils especially in colonic inflammation. Surprisingly, molecular pathways regulating innate immune activities of eosinophil are largely unknown. We have recently shown that the CD300f is highly expressed by colonic eosinophils. Nonetheless, the role of CD300f in governing innate immune eosinophil activities is ill-defined. RNA sequencing of 162 pediatric Crohn's disease patients revealed upregulation of multiple Cd300 family members, which correlated with the presence of severe ulcerations and inflammation. Increased expression of CD300 family receptors was also observed in active ulcerative colitis (UC) and in mice following induction of experimental colitis. Specifically, the expression of CD300f was dynamically regulated in monocytes and eosinophils. Dextran sodium sulfate (DSS)-treated Cd300f -/- mice exhibit attenuated disease activity and histopathology in comparison with DSS-treated wild type (WT). Decreased disease activity in Cd300f -/- mice was accompanied with reduced inflammatory cell infiltration and nearly abolished production of pro-inflammatory cytokines. Monocyte depletion and chimeric bone marrow transfer experiments revealed a cell-specific requirement for CD300f in innate immune activation of eosinophils. Collectively, we uncover a new pathway regulating innate immune activities of eosinophils, a finding with significant implications in eosinophil-associated gastrointestinal diseases.

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.

Purification and characterization of multiple forms of the pineapple-stem-derived cysteine proteinases ananain and comosain.

PubMed Central

Napper, A D; Bennett, S P; Borowski, M; Holdridge, M B; Leonard, M J; Rogers, E E; Duan, Y; Laursen, R A; Reinhold, B; Shames, S L

1994-01-01

A mixture of ananain (EC 3.4.22.31) and comosain purified from crude pineapple stem extract was found to contain numerous closely related enzyme forms. Chromatographic separation of the major enzyme forms was achieved after treatment of the mixture with thiol-modifying reagents: reversible modification with 2-hydroxyethyl disulphide provided enzyme for kinetic studies, and irreversible alkylation with bromotrifluoroacetone or iodoacetamide gave enzyme for structural analyses by 19F-n.m.r. and electrospray mass spectrometry respectively. Structural and kinetic analyses revealed comosain to be closely related to stem bromelain (EC 3.4.22.32), whereas ananain differed markedly from both comosain and stem bromelain. Nevertheless, differences were seen between comosain and stem bromelain in amino acid composition and kinetic specificity towards the epoxide inhibitor E-64. Differences between five isolatable alternative forms of ananain were characterized by amidolytic activity, thiol stoichiometry and accurate mass determinations. Three of the enzyme forms displayed ananain-like amidolytic activity, whereas the other two forms were inactive. Thiol-stoichiometry determinations revealed that the active enzyme forms contained one free thiol, whereas the inactive forms lacked the reactive thiol required for enzyme activity. M.s. provided direct evidence for oxidation of the active-site thiol to the corresponding sulphinic acid. Images Figure 3 Figure 4 PMID:8053898

Elimination of active tad elements during the sexual phase of the Neurospora crassa life cycle.

PubMed

Anderson, C; Tang, Q; Kinsey, J A

2001-06-01

Tad is an active LINE-like retrotransposon isolated from the Adiopodoumé strain of Neurospora crassa. Extensive analysis of other Neurospora strains has revealed no other strain with active Tad, but all strains tested have multiple copies of defective Tad elements. We have examined the ability of Tad to survive during the sexual cycle of Neurospora and find that active Tad is rapidly eliminated. The characteristics of this elimination suggest that the repeat-induced point mutation (RIP) mechanism was responsible. By the use of transformation to switch the mating type of the Adiopodoumé strain we concluded that this strain is not defective in the RIP process. Analysis of defective Tad elements isolated from a variety of strains indicates that the major difference between these elements and active Tad is due to the presence of a large number of G-C to A-T transition mutations. This would be expected if the changes were due primarily to the RIP process. Mapping of a selection of defective Tad elements reveals that they are present on all of the chromosomes; however, many of the elements are not widely shared among strains. This suggests that repeated introduction and elimination of Tad elements has occurred. Mechanisms that might be responsible for this repeated introduction are discussed. Copyright 2001 Academic Press.

Upper extremity disorders in heavy industry workers in Greece.

PubMed

Tsouvaltzidou, Thomaella; Alexopoulos, Evangelos; Fragkakis, Ioannis; Jelastopulu, Eleni

2017-06-18

To investigate the disability due to musculoskeletal disorders of the upper extremities in heavy industry workers. The population under study consisted of 802 employees, both white- and blue-collar, working in a shipyard industry in Athens, Greece. Data were collected through the distribution of questionnaires and the recording of individual and job-related characteristics during the period 2006-2009. The questionnaires used were the Quick Disabilities of the Arm, Shoulder and Hand (QD) Outcome Measure, the Work Ability Index (WAI) and the Short-Form-36 (SF-36) Health Survey. The QD was divided into three parameters - movement restrictions in everyday activities, work and sports/music activities - and the SF-36 into two items, physical and emotional. Multiple linear regression analysis was performed by means of the SPSS v.22 for Windows Statistical Package. The answers given by the participants for the QD did not reveal great discomfort regarding the execution of manual tasks, with the majority of the participants scoring under 5%, meaning no disability. After conducting multiple linear regression, age revealed a positive association with the parameter of restrictions in everyday activities (b = 0.64, P = 0.000). Basic education showed a statistically significant association regarding restrictions during leisure activities, with b = 2.140 ( P = 0.029) for compulsory education graduates. WAI's final score displayed negative charging in the regression analysis of all three parameters, with b = -0.142 ( P = 0.0), b = -0.099 ( P = 0.055) and b = -0.376 ( P = 0.001) respectively, while the physical and emotional components of SF-36 associated with movement restrictions only in daily activities and work. The participants' specialty made no statistically significant associations with any of the three parameters of the QD. Increased musculoskeletal disorders of the upper extremity are associated with older age, lower basic education and physical and mental/emotional health and reduced working ability.

Detection of Mycobacterium tuberculosis peptides in the exosomes of patients with active and latent M. tuberculosis infection using MRM-MS.

PubMed

Kruh-Garcia, Nicole A; Wolfe, Lisa M; Chaisson, Lelia H; Worodria, William O; Nahid, Payam; Schorey, Jeff S; Davis, J Lucian; Dobos, Karen M

2014-01-01

The identification of easily measured, accurate diagnostic biomarkers for active tuberculosis (TB) will have a significant impact on global TB control efforts. Because of the host and pathogen complexities involved in TB pathogenesis, identifying a single biomarker that is adequately sensitive and specific continues to be a major hurdle. Our previous studies in models of TB demonstrated that exosomes, such as those released from infected macrophages, contain mycobacterial products, including many Mtb proteins. In this report, we describe the development of targeted proteomics assays employing multiplexed multiple reaction monitoring mass spectrometry (MRM-MS) in order to allow us to follow those proteins previously identified by western blot or shotgun mass spectrometry, and enhance biomarker discovery to include detection of Mtb proteins in human serum exosomes. Targeted MRM-MS assays were applied to exosomes isolated from human serum samples obtained from culture-confirmed active TB patients to detect 76 peptides representing 33 unique Mtb proteins. Our studies revealed the first identification of bacteria-derived biomarker candidates of active TB in exosomes from human serum. Twenty of the 33 proteins targeted for detection were found in the exosomes of TB patients, and included multiple peptides from 8 proteins (Antigen 85B, Antigen 85C, Apa, BfrB, GlcB, HspX, KatG, and Mpt64). Interestingly, all of these proteins are known mycobacterial adhesins and/or proteins that contribute to the intracellular survival of Mtb. These proteins will be included as target analytes in future validation studies as they may serve as markers for persistent active and latent Mtb infection. In summary, this work is the first step in identifying a unique and specific panel of Mtb peptide biomarkers encapsulated in exosomes and reveals complex biomarker patterns across a spectrum of TB disease states.

Detection of Mycobacterium tuberculosis Peptides in the Exosomes of Patients with Active and Latent M. tuberculosis Infection Using MRM-MS

PubMed Central

Kruh-Garcia, Nicole A.; Wolfe, Lisa M.; Chaisson, Lelia H.; Worodria, William O.; Nahid, Payam; Schorey, Jeff S.; Davis, J. Lucian; Dobos, Karen M.

2014-01-01

The identification of easily measured, accurate diagnostic biomarkers for active tuberculosis (TB) will have a significant impact on global TB control efforts. Because of the host and pathogen complexities involved in TB pathogenesis, identifying a single biomarker that is adequately sensitive and specific continues to be a major hurdle. Our previous studies in models of TB demonstrated that exosomes, such as those released from infected macrophages, contain mycobacterial products, including many Mtb proteins. In this report, we describe the development of targeted proteomics assays employing multiplexed multiple reaction monitoring mass spectrometry (MRM-MS) in order to allow us to follow those proteins previously identified by western blot or shotgun mass spectrometry, and enhance biomarker discovery to include detection of Mtb proteins in human serum exosomes. Targeted MRM-MS assays were applied to exosomes isolated from human serum samples obtained from culture-confirmed active TB patients to detect 76 peptides representing 33 unique Mtb proteins. Our studies revealed the first identification of bacteria-derived biomarker candidates of active TB in exosomes from human serum. Twenty of the 33 proteins targeted for detection were found in the exosomes of TB patients, and included multiple peptides from 8 proteins (Antigen 85B, Antigen 85C, Apa, BfrB, GlcB, HspX, KatG, and Mpt64). Interestingly, all of these proteins are known mycobacterial adhesins and/or proteins that contribute to the intracellular survival of Mtb. These proteins will be included as target analytes in future validation studies as they may serve as markers for persistent active and latent Mtb infection. In summary, this work is the first step in identifying a unique and specific panel of Mtb peptide biomarkers encapsulated in exosomes and reveals complex biomarker patterns across a spectrum of TB disease states. PMID:25080351

An improved ATAC-seq protocol reduces background and enables interrogation of frozen tissues.

PubMed

Corces, M Ryan; Trevino, Alexandro E; Hamilton, Emily G; Greenside, Peyton G; Sinnott-Armstrong, Nicholas A; Vesuna, Sam; Satpathy, Ansuman T; Rubin, Adam J; Montine, Kathleen S; Wu, Beijing; Kathiria, Arwa; Cho, Seung Woo; Mumbach, Maxwell R; Carter, Ava C; Kasowski, Maya; Orloff, Lisa A; Risca, Viviana I; Kundaje, Anshul; Khavari, Paul A; Montine, Thomas J; Greenleaf, William J; Chang, Howard Y

2017-10-01

We present Omni-ATAC, an improved ATAC-seq protocol for chromatin accessibility profiling that works across multiple applications with substantial improvement of signal-to-background ratio and information content. The Omni-ATAC protocol generates chromatin accessibility profiles from archival frozen tissue samples and 50-μm sections, revealing the activities of disease-associated DNA elements in distinct human brain structures. The Omni-ATAC protocol enables the interrogation of personal regulomes in tissue context and translational studies.

Tracing Multiple Generations of Active Galactic Nucleau Feedback in the Core of Abell 262

DTIC Science & Technology

2009-06-01

Virgo cluster reveal a series of filaments, which trace regions that are thought 1481 Report Documentation Page Form ApprovedOMB No. 0704-0188 Public...L. Sarazin4, L. D. Anderson3, Gopal-Krishna5, E. M. Douglass3, and N. E. Kassim1 1 Naval Research Laboratory, 4555 Overlook Avenue SW, Code 7213...Washington, DC 20375, USA 2 Interferometrics Inc., 13454 Sunrise Valley Drive, Suite 240, Herndon, VA 20171, USA 3 Institute for Astrophysical Research

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.

Dynamic changes in global microRNAome and transcriptome reveal complex miRNA-mRNA regulated host response to Japanese Encephalitis Virus in microglial cells

PubMed Central

Kumari, Bharti; Jain, Pratistha; Das, Shaoli; Ghosal, Suman; Hazra, Bibhabasu; Trivedi, Ashish Chandra; Basu, Anirban; Chakrabarti, Jayprokas; Vrati, Sudhanshu; Banerjee, Arup

2016-01-01

Microglia cells in the brain play essential role during Japanese Encephalitis Virus (JEV) infection and may lead to change in microRNA (miRNA) and mRNA profile. These changes may together control disease outcome. Using Affymetrix microarray platform, we profiled cellular miRNA and mRNA expression at multiple time points during viral infection in human microglial (CHME3) cells. In silico analysis of microarray data revealed a phased pattern of miRNAs expression, associated with JEV replication and provided unique signatures of infection. Target prediction and pathway enrichment analysis identified anti correlation between differentially expressed miRNA and the gene expression at multiple time point which ultimately affected diverse signaling pathways including Notch signaling pathways in microglia. Activation of Notch pathway during JEV infection was demonstrated in vitro and in vivo. The expression of a subset of miRNAs that target multiple genes in Notch signaling pathways were suppressed and their overexpression could affect JEV induced immune response. Further analysis provided evidence for the possible presence of cellular competing endogenous RNA (ceRNA) associated with innate immune response. Collectively, our data provide a uniquely comprehensive view of the changes in the host miRNAs induced by JEV during cellular infection and identify Notch pathway in modulating microglia mediated inflammation. PMID:26838068

Dynamic changes in global microRNAome and transcriptome reveal complex miRNA-mRNA regulated host response to Japanese Encephalitis Virus in microglial cells.

PubMed

Kumari, Bharti; Jain, Pratistha; Das, Shaoli; Ghosal, Suman; Hazra, Bibhabasu; Trivedi, Ashish Chandra; Basu, Anirban; Chakrabarti, Jayprokas; Vrati, Sudhanshu; Banerjee, Arup

2016-02-03

Microglia cells in the brain play essential role during Japanese Encephalitis Virus (JEV) infection and may lead to change in microRNA (miRNA) and mRNA profile. These changes may together control disease outcome. Using Affymetrix microarray platform, we profiled cellular miRNA and mRNA expression at multiple time points during viral infection in human microglial (CHME3) cells. In silico analysis of microarray data revealed a phased pattern of miRNAs expression, associated with JEV replication and provided unique signatures of infection. Target prediction and pathway enrichment analysis identified anti correlation between differentially expressed miRNA and the gene expression at multiple time point which ultimately affected diverse signaling pathways including Notch signaling pathways in microglia. Activation of Notch pathway during JEV infection was demonstrated in vitro and in vivo. The expression of a subset of miRNAs that target multiple genes in Notch signaling pathways were suppressed and their overexpression could affect JEV induced immune response. Further analysis provided evidence for the possible presence of cellular competing endogenous RNA (ceRNA) associated with innate immune response. Collectively, our data provide a uniquely comprehensive view of the changes in the host miRNAs induced by JEV during cellular infection and identify Notch pathway in modulating microglia mediated inflammation.

Trichuris suis ova therapy in relapsing multiple sclerosis is safe but without signals of beneficial effect.

PubMed

Voldsgaard, A; Bager, P; Garde, E; Åkeson, P; Leffers, A M; Madsen, C G; Kapel, C; Roepstorff, A; Thamsborg, S M; Melbye, M; Siebner, H; Søndergaard, H B; Sellebjerg, F; Sørensen, P Soelberg

2015-11-01

An observational study has suggested that relapsing-remitting multiple sclerosis patients with helminth infections have lower disease activity and progression than uninfected multiple sclerosis patients. To evaluate the safety and efficacy on MRI activity of treatment with TSO in relapsing MS. The study was an open-label, magnetic resonance imaging assessor-blinded, baseline-to-treatment study including ten patients with relapsing forms of multiple sclerosis. Median (range) age was 41 (24-55) years, disease duration 9 (4-34) years, Expanded Disability Status Scale score 2.5 (1-5.0), and number of relapses within the last two years 3 (2-5). Four patients received no disease modifying therapy, while six patients received IFN-β. After an observational period of 8 weeks, patients received 2500 ova from the helminth Trichuris suis orally every second week for 12 weeks. Patients were followed with serial magnetic resonance imaging, neurological examinations, laboratory safety tests and expression of immunological biomarker genes. Treatment with Trichuris suis orally was well-tolerated apart from some gastrointestinal symptoms. Magnetic resonance imaging revealed 6 new or enlarged T2 lesions in the run-in period, 7 lesions in the early period and 21 lesions in the late treatment period. Two patients suffered a relapse before treatment and two during treatment. Eight patients developed eosinophilia. The expression of cytokines and transcription factors did not change. In a small group of relapsing multiple sclerosis patients, Trichuris suis oral therapy was well tolerated but without beneficial effect. © The Author(s), 2015.

Mechanism of hole injection enhancement in light-emitting diodes by inserting multiple hole-reservoir layers in electron blocking layer

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

Zhao, Yukun; Wang, Shuai; Feng, Lungang

In this study, gallium nitride (GaN) based light-emitting diodes (LEDs) with single and multiple hole-reservoir layers (HRLs) inserted in the electron-blocking layer (EBL) have been investigated numerically and experimentally. According to simulation results, a better electron confinement and a higher hole injection level can be achieved by the multiple HRLs inserted in the EBL region. To further reveal the underlying mechanism of hole injection enhancement experimentally, the active regions were intentionally designed to emit photons with three different wavelengths of 440 nm, 460 nm, and 480 nm, respectively. Based on the experimental results of photoluminescence (PL) and time-resolved PL (TRPL) measurements conducted atmore » 298 K, the remarkable enhancement (148%) of PL intensities and significant increase in the decay times of the quantum wells close to p-GaN can be obtained. Therefore, the mechanism is proposed that carriers are able to reserve in the EBL region with multiple HRLs for a much longer time. Meanwhile, carriers could diffuse into the active region by tunnelling and/or thermo-electronic effect and then recombine efficiently, leading to the better carrier reservoir effect and higher hole injection in LEDs. As a result, by inserting multiple HRLs in the EBL region instead of single HRL, the experimental external quantum efficiency is enhanced by 19.8%, while the serious droop ratio is markedly suppressed from 37.0% to 27.6% at the high current injection of 100 A/cm{sup 2}.« less

Integrative proteomics, genomics, and translational immunology approaches reveal mutated forms of Proteolipid Protein 1 (PLP1) and mutant-specific immune response in multiple sclerosis.

PubMed

Qendro, Veneta; Bugos, Grace A; Lundgren, Debbie H; Glynn, John; Han, May H; Han, David K

2017-03-01

In order to gain mechanistic insights into multiple sclerosis (MS) pathogenesis, we utilized a multi-dimensional approach to test the hypothesis that mutations in myelin proteins lead to immune activation and central nervous system autoimmunity in MS. Mass spectrometry-based proteomic analysis of human MS brain lesions revealed seven unique mutations of PLP1; a key myelin protein that is known to be destroyed in MS. Surprisingly, in-depth genomic analysis of two MS patients at the genomic DNA and mRNA confirmed mutated PLP1 in RNA, but not in the genomic DNA. Quantification of wild type and mutant PLP RNA levels by qPCR further validated the presence of mutant PLP RNA in the MS patients. To seek evidence linking mutations in abundant myelin proteins and immune-mediated destruction of myelin, specific immune response against mutant PLP1 in MS patients was examined. Thus, we have designed paired, wild type and mutant peptide microarrays, and examined antibody response to multiple mutated PLP1 in sera from MS patients. Consistent with the idea of different patients exhibiting unique mutation profiles, we found that 13 out of 20 MS patients showed antibody responses against specific but not against all the mutant-PLP1 peptides. Interestingly, we found mutant PLP-directed antibody response against specific mutant peptides in the sera of pre-MS controls. The results from integrative proteomic, genomic, and immune analyses reveal a possible mechanism of mutation-driven pathogenesis in human MS. The study also highlights the need for integrative genomic and proteomic analyses for uncovering pathogenic mechanisms of human diseases. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Pervasive competition between threat and reward in the brain

PubMed Central

Choi, Jong Moon; Padmala, Srikanth; Spechler, Philip

2014-01-01

In the current functional MRI study, we investigated interactions between reward and threat processing. Visual cues at the start of each trial informed participants about the chance of winning monetary reward and/or receiving a mild aversive shock. We tested two competing hypothesis: according to the ‘salience hypothesis’, in the condition involving both reward and threat, enhanced activation would be observed because of increased salience; according to the ‘competition hypothesis’, the processing of reward and threat would trade-off against each other, leading to reduced activation. Analysis of skin conductance data during a delay phase revealed an interaction between reward and threat processing, such that the effect of reward was reduced during threat and the effect of threat was reduced during reward. Analysis of imaging data during the same task phase revealed interactions between reward and threat processing in several regions, including the midbrain/ventral tegmental area, caudate, putamen, bed nucleus of the stria terminalis, anterior insula, middle frontal gyrus and dorsal anterior cingulate cortex. Taken together, our findings reveal conditions during which reward and threat trade-off against each other across multiple sites. Such interactions are suggestive of competitive processes and may reflect the organization of opponent systems in the brain. PMID:23547242

Microbial Biofilm Voltammetry: Direct Electrochemical Characterization of Catalytic Electrode-Attached Biofilms▿ †

PubMed Central

Marsili, Enrico; Rollefson, Janet B.; Baron, Daniel B.; Hozalski, Raymond M.; Bond, Daniel R.

2008-01-01

While electrochemical characterization of enzymes immobilized on electrodes has become common, there is still a need for reliable quantitative methods for study of electron transfer between living cells and conductive surfaces. This work describes growth of thin (<20 μm) Geobacter sulfurreducens biofilms on polished glassy carbon electrodes, using stirred three-electrode anaerobic bioreactors controlled by potentiostats and nondestructive voltammetry techniques for characterization of viable biofilms. Routine in vivo analysis of electron transfer between bacterial cells and electrodes was performed, providing insight into the main redox-active species participating in electron transfer to electrodes. At low scan rates, cyclic voltammetry revealed catalytic electron transfer between cells and the electrode, similar to what has been observed for pure enzymes attached to electrodes under continuous turnover conditions. Differential pulse voltammetry and electrochemical impedance spectroscopy also revealed features that were consistent with electron transfer being mediated by an adsorbed catalyst. Multiple redox-active species were detected, revealing complexity at the outer surfaces of this bacterium. These techniques provide the basis for cataloging quantifiable, defined electron transfer phenotypes as a function of potential, electrode material, growth phase, and culture conditions and provide a framework for comparisons with other species or communities. PMID:18849456

The C-Terminal Tail of TRIM56 Dictates Antiviral Restriction of Influenza A and B Viruses by Impeding Viral RNA Synthesis

PubMed Central

Liu, Baoming; Li, Nan L.; Shen, Yang; Bao, Xiaoyong; Elbahesh, Husni; Webby, Richard J.

2016-01-01

ABSTRACT Accumulating data suggest that tripartite-motif-containing (TRIM) proteins participate in host responses to viral infections, either by acting as direct antiviral restriction factors or through regulating innate immune signaling of the host. Of >70 TRIMs, TRIM56 is a restriction factor of several positive-strand RNA viruses, including three members of the family Flaviviridae (yellow fever virus, dengue virus, and bovine viral diarrhea virus) and a human coronavirus (OC43), and this ability invariably depends upon the E3 ligase activity of TRIM56. However, the impact of TRIM56 on negative-strand RNA viruses remains unclear. Here, we show that TRIM56 puts a check on replication of influenza A and B viruses in cell culture but does not inhibit Sendai virus or human metapneumovirus, two paramyxoviruses. Interestingly, the anti-influenza virus activity was independent of the E3 ligase activity, B-box, or coiled-coil domain. Rather, deletion of a 63-residue-long C-terminal-tail portion of TRIM56 abrogated the antiviral function. Moreover, expression of this short C-terminal segment curtailed the replication of influenza viruses as effectively as that of full-length TRIM56. Mechanistically, TRIM56 was found to specifically impede intracellular influenza virus RNA synthesis. Together, these data reveal a novel antiviral activity of TRIM56 against influenza A and B viruses and provide insights into the mechanism by which TRIM56 restricts these medically important orthomyxoviruses. IMPORTANCE Options to treat influenza are limited, and drug-resistant influenza virus strains can emerge through minor genetic changes. Understanding novel virus-host interactions that alter influenza virus fitness may reveal new targets/approaches for therapeutic interventions. We show here that TRIM56, a tripartite-motif protein, is an intrinsic host restriction factor of influenza A and B viruses. Unlike its antiviral actions against positive-strand RNA viruses, the anti-influenza virus activity of TRIM56 was independent of the E3 ligase activity. Rather, expression of a short segment within the very C-terminal tail of TRIM56 inhibited the replication of influenza viruses as effectively as that of full-length TRIM56 by specifically targeting viral RNA synthesis. These data reveal the remarkable multifaceted activity of TRIM56, which has developed multiple domains to inhibit multiple viral families. They also raise the possibility of developing a broad-spectrum, TRIM56-based antiviral approach for addition to influenza prophylaxis and/or control strategies. PMID:26889027

Strategies that facilitate participation in family activities of children and adolescents with profound intellectual and multiple disabilities: parents' and personal assistants' experiences.

PubMed

Axelsson, Anna Karin; Imms, Christine; Wilder, Jenny

2014-01-01

Participation throughout one's life plays a significant role for development and emotional well-being. For this reason, there is a need to identify ways to facilitate participation in family activities for children and adolescents with profound intellectual and multiple disabilities (PIMD). The study design was qualitative and explorative, based on semi structured interviews with 11 parents and 9 personal assistants of children with PIMD. The interviews revealed participation-facilitating strategies relating to the children's/adolescent's proximal environment, such as "Availability and acceptability of the activity", "Good knowledge about the child" and a "A positive attitude of people close to the child", as well as strategies related to the children/adolescents themselves: "Sense of belonging", "Possible for the child/adolescent to understand", "Opportunities to influence" and "Feeling of being needed". Children and adolescents with PIMD are dependent on support obtained through their environment. The identified strategies, individually adapted through awareness and knowledge by the parents and the personal assistants, provide important evidence to assist our understanding in gaining understanding about how to improve participation in family activities of children and adolescents with PIMD. Participation-facilitating strategies related to the child/adolescent and his or her proximal environments are identified to improve participation in children and adolescents with profound intellectual and multiple disabilities (PIMD). Examples of strategies for the child's/adolescents' proximal environment include "good knowledge about the child/adolescent", and, for the child/adolescent, include creating "sense of belonging" and "opportunities to influence". Identifying and making these strategies explicit may assist in enhancing the participation of children and adolescents with PIMD in family activities. People in the child's/adolescent's proximal environment need to set the scene for participation.

Overlapping Networks Engaged during Spoken Language Production and Its Cognitive Control

PubMed Central

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

2014-01-01

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

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

PubMed

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

2014-06-25

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

Context Specificity of Stress-activated Mitogen-activated Protein (MAP) Kinase Signaling: The Story as Told by Caenorhabditis elegans.

PubMed

Andrusiak, Matthew G; Jin, Yishi

2016-04-08

Stress-associated p38 and JNK mitogen-activated protein (MAP) kinase signaling cascades trigger specific cellular responses and are involved in multiple disease states. At the root of MAP kinase signaling complexity is the differential use of common components on a context-specific basis. The roundwormCaenorhabditis eleganswas developed as a system to study genes required for development and nervous system function. The powerful genetics ofC. elegansin combination with molecular and cellular dissections has led to a greater understanding of how p38 and JNK signaling affects many biological processes under normal and stress conditions. This review focuses on the studies revealing context specificity of different stress-activated MAPK components inC. elegans. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Fundamental mechanisms of telomerase action in yeasts and mammals: understanding telomeres and telomerase in cancer cells.

PubMed

Armstrong, Christine A; Tomita, Kazunori

2017-03-01

Aberrant activation of telomerase occurs in 85-90% of all cancers and underpins the ability of cancer cells to bypass their proliferative limit, rendering them immortal. The activity of telomerase is tightly controlled at multiple levels, from transcriptional regulation of the telomerase components to holoenzyme biogenesis and recruitment to the telomere, and finally activation and processivity. However, studies using cancer cell lines and other model systems have begun to reveal features of telomeres and telomerase that are unique to cancer. This review summarizes our current knowledge on the mechanisms of telomerase recruitment and activation using insights from studies in mammals and budding and fission yeasts. Finally, we discuss the differences in telomere homeostasis between normal cells and cancer cells, which may provide a foundation for telomere/telomerase targeted cancer treatments. © 2017 The Authors.

Activity-Based Protein Profiling of Organophosphorus and Thiocarbamate Pesticides Reveals Multiple Serine Hydrolase Targets in Mouse Brain

PubMed Central

NOMURA, DANIEL K.; CASIDA, JOHN E.

2010-01-01

Organophosphorus (OP) and thiocarbamate (TC) agrochemicals are used worldwide as insecticides, herbicides, and fungicides, but their safety assessment in terms of potential off-targets remains incomplete. In this study, we used a chemoproteomic platform, termed activity-based protein profiling, to broadly define serine hydrolase targets in mouse brain of a panel of 29 OP and TC pesticides. Among the secondary targets identified, enzymes involved in degradation of endocannabinoid signaling lipids, monoacylglycerol lipase and fatty acid amide hydrolase, were inhibited by several OP and TC pesticides. Blockade of these two enzymes led to elevations in brain endocannabinoid levels and dysregulated brain arachidonate metabolism. Other secondary targets include enzymes thought to also play important roles in the nervous system and unannotated proteins. This study reveals a multitude of secondary targets for OP and TC pesticides and underscores the utility of chemoproteomic platforms in gaining insights into biochemical pathways that are perturbed by these toxicants. PMID:21341672

Single Molecule Analysis of Serotonin Transporter Regulation Using Antagonist-Conjugated Quantum Dots Reveals Restricted, p38 MAPK-Dependent Mobilization Underlying Uptake Activation

PubMed Central

Chang, Jerry C.; Tomlinson, Ian D.; Warnement, Michael R.; Ustione, Alessandro; Carneiro, Ana M. D.; Piston, David W.; Blakely, Randy D.; Rosenthal, Sandra J.

2012-01-01

The presynaptic serotonin (5-HT) transporter (SERT) is targeted by widely prescribed antidepressant medications. Altered SERT expression or regulation has been implicated in multiple neuropsychiatric disorders, including anxiety, depression and autism. Here, we implement a generalizable strategy that exploits antagonist-conjugated quantum dots (Qdots) to monitor, for the first time, single SERT proteins on the surface of serotonergic cells. We document two pools of SERT proteins defined by lateral mobility, one that exhibits relatively free diffusion, and a second, localized to cholesterol and GM1 ganglioside-enriched microdomains, that displays restricted mobility. Receptor-linked signalling pathways that enhance SERT activity mobilize transporters that, nonetheless, remain confined to membrane microdomains. Mobilization of transporters arise from a p38 MAPK-dependent untethering of the SERT C-terminus from the juxtamembrane actin cytoskeleton. Our studies establish the utility of ligand-conjugated Qdots for analysis of the behaviour of single membrane proteins and reveal a physical basis for signaling-mediated SERT regulation. PMID:22745492

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.

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

Lack of Free Choice Reveals the Cost of Having to Search for More Than One Object

PubMed Central

Ort, Eduard; Fahrenfort, Johannes J.; Olivers, Christian N. L.

2017-01-01

It is debated whether people can actively search for more than one object or whether this results in switch costs. Using a gaze-contingent eye-tracking paradigm, we revealed a crucial role for cognitive control in multiple-target search. We instructed participants to simultaneously search for two target objects presented among distractors. In one condition, both targets were available, which gave the observer free choice of what to search for and allowed for proactive control. In the other condition, only one of the two targets was available, so that the choice was imposed, and a reactive mechanism would be required. No switch costs emerged when target choice was free, but switch costs emerged reliably when targets were imposed. Bridging contradictory findings, the results are consistent with models of visual selection in which only one attentional template actively drives selection and in which the efficiency of switching targets depends on the type of cognitive control allowed for by the environment. PMID:28661761

Method of empirical dependences in estimation and prediction of activity of creatine kinase isoenzymes in cerebral ischemia

NASA Astrophysics Data System (ADS)

Sergeeva, Tatiana F.; Moshkova, Albina N.; Erlykina, Elena I.; Khvatova, Elena M.

2016-04-01

Creatine kinase is a key enzyme of energy metabolism in the brain. There are known cytoplasmic and mitochondrial creatine kinase isoenzymes. Mitochondrial creatine kinase exists as a mixture of two oligomeric forms - dimer and octamer. The aim of investigation was to study catalytic properties of cytoplasmic and mitochondrial creatine kinase and using of the method of empirical dependences for the possible prediction of the activity of these enzymes in cerebral ischemia. Ischemia was revealed to be accompanied with the changes of the activity of creatine kinase isoenzymes and oligomeric state of mitochondrial isoform. There were made the models of multiple regression that permit to study the activity of creatine kinase system in cerebral ischemia using a calculating method. Therefore, the mathematical method of empirical dependences can be applied for estimation and prediction of the functional state of the brain by the activity of creatine kinase isoenzymes in cerebral ischemia.

Age-related increase in brain activity during task-related and -negative networks and numerical inductive reasoning.

PubMed

Sun, Li; Liang, Peipeng; Jia, Xiuqin; Qi, Zhigang; Li, Kuncheng

2014-01-01

Recent neuroimaging studies have shown that elderly adults exhibit increased and decreased activation on various cognitive tasks, yet little is known about age-related changes in inductive reasoning. To investigate the neural basis for the aging effect on inductive reasoning, 15 young and 15 elderly subjects performed numerical inductive reasoning while in a magnetic resonance (MR) scanner. Functional magnetic resonance imaging (fMRI) analysis revealed that numerical inductive reasoning, relative to rest, yielded multiple frontal, temporal, parietal, and some subcortical area activations for both age groups. In addition, the younger participants showed significant regions of task-induced deactivation, while no deactivation occurred in the elderly adults. Direct group comparisons showed that elderly adults exhibited greater activity in regions of task-related activation and areas showing task-induced deactivation (TID) in the younger group. Our findings suggest an age-related deficiency in neural function and resource allocation during inductive reasoning.

A corticothalamic switch: controlling the thalamus with dynamic synapses

PubMed Central

Crandall, Shane R.; Cruikshank, Scott J.; Connors, Barry W.

2015-01-01

SUMMARY Corticothalamic neurons provide massive input to the thalamus. This top-down projection may allow cortex to regulate sensory processing by modulating the excitability of thalamic cells. Layer 6 corticothalamic neurons monosynaptically excite thalamocortical cells, but also indirectly inhibit them by driving inhibitory cells of the thalamic reticular nucleus. Whether corticothalamic activity generally suppresses or excites the thalamus remains unclear. Here we show that the corticothalamic influence is dynamic, with the excitatory-inhibitory balance shifting in an activity-dependent fashion. During low-frequency activity corticothalamic effects are mainly suppressive, whereas higher frequency activity (even a short bout of gamma frequency oscillations) converts the corticothalamic influence to enhancement. The mechanism of this switching depends upon distinct forms of short-term synaptic plasticity across multiple corticothalamic circuit components. Our results reveal an activity-dependent mechanism by which corticothalamic neurons can bidirectionally switch the excitability and sensory throughput of the thalamus, possibly to meet changing behavioral demands. PMID:25913856

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.

Impact craters on Venus - Initial analysis from Magellan

NASA Technical Reports Server (NTRS)

Phillips, Roger J.; Arvidson, Raymond E.; Boyce, Joseph M.; Campbell, Donald B.; Guest, John E.

1991-01-01

The general features of impact craters are described emphasizing two aspects: the effect of the atmosphere on crater and ejecta morphology and the implications of the distribution and appearance of the craters for the volcanic and tectonic resurfacing history of Venus. Magellan radar images reveal 135 craters about 15 km in diameter containing central peaks, multiple central peaks, and peak rings. Craters smaller than 15 km exhibit multiple floors or appear in clusters. Surface flows of material initially entrained in the atmosphere are characterized. Zones of low radar albedo originated from deformation of the surface by the shock or pressure wave associated with the incoming meteoroid surround many craters. A spectrum of surface ages on Venus ranging from 0 to 800 million years indicates that Venus must be a geologically active planet.

Gene Expression Profiling of Multiple Sclerosis Pathology Identifies Early Patterns of Demyelination Surrounding Chronic Active Lesions

PubMed Central

Hendrickx, Debbie A. E.; van Scheppingen, Jackelien; van der Poel, Marlijn; Bossers, Koen; Schuurman, Karianne G.; van Eden, Corbert G.; Hol, Elly M.; Hamann, Jörg; Huitinga, Inge

2017-01-01

In multiple sclerosis (MS), activated microglia and infiltrating macrophages phagocytose myelin focally in (chronic) active lesions. These demyelinating sites expand in time, but at some point turn inactive into a sclerotic scar. To identify molecular mechanisms underlying lesion activity and halt, we analyzed genome-wide gene expression in rim and peri-lesional regions of chronic active and inactive MS lesions, as well as in control tissue. Gene clustering revealed patterns of gene expression specifically associated with MS and with the presumed, subsequent stages of lesion development. Next to genes involved in immune functions, we found regulation of novel genes in and around the rim of chronic active lesions, such as NPY, KANK4, NCAN, TKTL1, and ANO4. Of note, the presence of many foamy macrophages in active rims was accompanied by a congruent upregulation of genes related to lipid binding, such as MSR1, CD68, CXCL16, and OLR1, and lipid uptake, such as CHIT1, GPNMB, and CCL18. Except CCL18, these genes were already upregulated in regions around active MS lesions, showing that such lesions are indeed expanding. In vitro downregulation of the scavenger receptors MSR1 and CXCL16 reduced myelin uptake. In conclusion, this study provides the gene expression profile of different aspects of MS pathology and indicates that early demyelination, mediated by scavenger receptors, is already present in regions around active MS lesions. Genes involved in early demyelination events in regions surrounding chronic active MS lesions might be promising therapeutic targets to stop lesion expansion. PMID:29312322

Gene Expression Profiling of Multiple Sclerosis Pathology Identifies Early Patterns of Demyelination Surrounding Chronic Active Lesions.

PubMed

Hendrickx, Debbie A E; van Scheppingen, Jackelien; van der Poel, Marlijn; Bossers, Koen; Schuurman, Karianne G; van Eden, Corbert G; Hol, Elly M; Hamann, Jörg; Huitinga, Inge

2017-01-01

In multiple sclerosis (MS), activated microglia and infiltrating macrophages phagocytose myelin focally in (chronic) active lesions. These demyelinating sites expand in time, but at some point turn inactive into a sclerotic scar. To identify molecular mechanisms underlying lesion activity and halt, we analyzed genome-wide gene expression in rim and peri-lesional regions of chronic active and inactive MS lesions, as well as in control tissue. Gene clustering revealed patterns of gene expression specifically associated with MS and with the presumed, subsequent stages of lesion development. Next to genes involved in immune functions, we found regulation of novel genes in and around the rim of chronic active lesions, such as NPY, KANK4, NCAN, TKTL1 , and ANO4 . Of note, the presence of many foamy macrophages in active rims was accompanied by a congruent upregulation of genes related to lipid binding, such as MSR1, CD68, CXCL16 , and OLR1 , and lipid uptake, such as CHIT1, GPNMB , and CCL18 . Except CCL18 , these genes were already upregulated in regions around active MS lesions, showing that such lesions are indeed expanding. In vitro downregulation of the scavenger receptors MSR1 and CXCL16 reduced myelin uptake. In conclusion, this study provides the gene expression profile of different aspects of MS pathology and indicates that early demyelination, mediated by scavenger receptors, is already present in regions around active MS lesions. Genes involved in early demyelination events in regions surrounding chronic active MS lesions might be promising therapeutic targets to stop lesion expansion.

All for one but not one for all: how multiple number representations are recruited in one numerical task.

PubMed

Wood, Guilherme; Nuerk, Hans-Christoph; Moeller, Korbinian; Geppert, Barbara; Schnitker, Ralph; Weber, Jochen; Willmes, Klaus

2008-01-02

Number processing recruits a complex network of multiple numerical representations. Usually the components of this network are examined in a between-task approach with the disadvantage of relying upon different instructions, tasks, and inhomogeneous stimulus sets across different studies. A within-task approach may avoid these disadvantages and access involved numerical representations more specifically. In the present study we employed a within-task approach to investigate numerical representations activated in the number bisection task (NBT) using parametric rapid event-related fMRI. Participants were to judge whether the central number of a triplet was also its arithmetic mean (e.g. 23_26_29) or not (e.g. 23_25_29). Activation in the left inferior parietal cortex was associated with the deployment of arithmetic fact knowledge, while activation of the intraparietal cortex indicated more intense magnitude processing, instrumental aspects of calculation and integration of the base-10 structure of two-digit numbers. These results replicate evidence from the literature. Furthermore, activation in the dorsolateral and ventrolateral prefrontal cortex revealed mechanisms of feature monitoring and inhibition as well as allocation of cognitive resources recruited to solve a specific triplet. We conclude that the network of numerical representations should rather be studied in a within-task approach than in varying between-task approaches.

Anti-herpes simplex virus type 1 activity of Houttuynoid A, a flavonoid from Houttuynia cordata Thunb.

PubMed

Li, Ting; Liu, Libao; Wu, Hongling; Chen, Shaodan; Zhu, Qinchang; Gao, Hao; Yu, Xiongtao; Wang, Yi; Su, Wenhan; Yao, Xinsheng; Peng, Tao

2017-08-01

Early events in herpes simplex virus type 1 (HSV-1) infection reactivate latent human immunodeficiency virus, Epstein-Barr virus, and human papillomavirus in the presence of acyclovir (ACV). The common use of nucleoside analog medications, such as ACV and pencyclovir, has resulted in the emergence of drug-resistant HSV-1 strains in clinical therapy. Therefore, new antiherpetics that can inhibit early events in HSV-1 infection should be developed. An example of this treatment is Houttuynia cordata Thunb. water extract, which can inhibit HSV-1 infection through multiple mechanisms. In this study, the anti-HSV-1 activity of Houttuynoid A, a new type of flavonoid isolated from H. cordata, was investigated. Three different assays confirmed that this compound could exhibit strong in vitro anti-HSV-1 activity. One assay verified that this compound could inhibit HSV-1 multiplication and prevent lesion formation in a HSV-1 infection mouse model. Mechanism analysis revealed that this compound could inactivate HSV-1 infectivity by blocking viral membrane fusion. Moreover, Houttuynoid A exhibited antiviral activities against other alpha herpes viruses, such as HSV-2 and varicella zoster virus (VZV). In conclusion, Houttuynoid A may be a useful antiviral agent for HSV-1. Copyright © 2017 Elsevier B.V. All rights reserved.

Meningeal hemangiopericytoma with delayed multiple distant metastases.

PubMed

Chang, Chiung-Chih; Chang, Yung-Yee; Lui, Chun-Chung; Huang, Chao-Cheng; Liu, Jia-Shou

2004-10-01

A 43-year-old housewife suffered from an occipital headache, and brain computed tomography (CT) showed an occipital meningeal tumor. She received a complete tumor excision and the tumor pathology was interpreted as atypical meningioma. Five years later, a subacute left neck pain with radiation to the left arm occurred. A tumor invading the second and third cervical vertebrae with compression on the dural sac was found. Angiography revealed hypervascular tumor staining supplied from the left vertebral artery. CT-guided biopsy was performed and nests of atypical spindle cells accompanied by staghorn vascular pattern were revealed histologically. Immunohistochemical studies showed positive vimentin staining but negative reactions to epithelial membrane antigen, cytokeratin low molecular weight, cytokeratin high molecular weight, CD34 and S-100 protein. Estimation of the Ki-67 proliferative (mitotic) index by using MIB-1 monoclonal antibody was 12%. Later on, a systemic survey revealed lesions in the left lung, liver and kidney. The diagnosis was revised to hemangiopericytoma. Distant metastasis is common in this tumor. However, the delayed multiple metastases without local recurrence were relatively rare. The clinical course in this patient also supported that a high mitotic activity may correlate with a poor prognosis even if the pathology is taken from the metastatic tissue, and that long-term follow-up is mandatory. Detailed immunohistochemical staining is helpful in avoiding misdiagnosis of meningioma.

Xrt And Shinx Joint Flare Study: Ar 11024

NASA Astrophysics Data System (ADS)

Engell, Alexander; Sylwester, J.; Siarkowski, M.

2010-05-01

From 12:00 UT on July 3 through July 7, 2009 SphinX (Solar Photometer IN X-rays) observes 130 flares with active region (AR) 11024 being the only AR on disk. XRT (X-Ray Telescope) is able to observe 64 of these flare events. The combination of both instruments results in a flare study revealing (1) a relationship between flux emergence and flare rate, (2) that the presence of active region loops typically results in different flare morphologies (single and multiple loop flares) then when there is a lack of an active region loop environment where more cusp and point-like flares are observed, (3) cusp and point-like flares often originate from the same location, and (4) a distribution of flare temperatures corresponding to the different flare morphologies. The differences between the observed flare morphologies may occur as the result of the heated plasma through the flaring process being confined by the proximity of loop structures as for the single and multiple loop flares, while for cusp and point-like flares they occur in an early-phase environment that lack loop presence. The continuing flux emergence of AR 11024 likely provides different magnetic interactions and may be the source responsible for all of the flares.

Psychometric properties of the Spanish version of the Passion Scale.

PubMed

Chamarro, Andrés; Penelo, Eva; Fornieles, Albert; Oberst, Ursula; Vallerand, Robert J; Fernández-Castro, Jordi

2015-01-01

Passion has been shown to be involved in psychological processes that emerge in diverse human activities like physical activity and sports, work, leisure, videogaming, pathological gambling, and interpersonal relationships. We aimed to present evidence of validity and internal consistency of the Passion Scale in Spanish based on the Dualistic Model of Passion, comprising harmonious and obsessive dimensions. The sample comprised 1,007 participants (350 females and 657 males), aged 16-65 (Md= 30.0 years). Exploratory Structural Equation Modeling (ESEM), measurement invariance and Multiple-Cause-Multiple-Indicator models (MIMIC) were used. Fit for the ESEM 2-factor solution was acceptable. Near full or partial measurement invariance across sex, type of activity, and age was supported. Relationships between both harmonious and obsessive dimensions and the external variables considered (age, sex, and criterion items) reasonably replicated those found in previous studies. Both scale scores showed adequate internal consistency (α = .81). Empirical evidence for the validity and internal consistency of the Spanish version of the Passion Scale is satisfactory and reveals that the scale is comparable to the English and French versions. Therefore, the Passion Scale can be used in research conducted in Spanish.

Adjustment modes in the trajectory of progressive multiple sclerosis: a qualitative study and conceptual model.

PubMed

Bogosian, Angeliki; Morgan, Myfanwy; Bishop, Felicity L; Day, Fern; Moss-Morris, Rona

2017-03-01

We examined cognitive and behavioural challenges and adaptations for people with progressive multiple sclerosis (MS) and developed a preliminary conceptual model of changes in adjustment over time. Using theoretical sampling, 34 semi-structured interviews were conducted with people with MS. Participants were between 41 and 77 years of age. Thirteen were diagnosed with primary progressive MS and 21 with secondary progressive MS. Data were analysed using a grounded theory approach. Participants described initially bracketing the illness off and carrying on their usual activities but this became problematic as the condition progressed and they employed different adjustment modes to cope with increased disabilities. Some scaled back their activities to live a more comfortable life, others identified new activities or adapted old ones, whereas at times, people disengaged from the adjustment process altogether and resigned to their condition. Relationships with partners, emotional reactions, environment and perception of the environment influenced adjustment, while people were often flexible and shifted among modes. Adjusting to a progressive condition is a fluid process. Future interventions can be tailored to address modifiable factors at different stages of the condition and may involve addressing emotional reactions concealing/revealing the condition and perceptions of the environment.

The application of multiple intelligence approach to the learning of human circulatory system

NASA Astrophysics Data System (ADS)

Kumalasari, Lita; Yusuf Hilmi, A.; Priyandoko, Didik

2017-11-01

The purpose of this study is to offer an alternative teaching approach or strategies which able to accommodate students’ different ability, intelligence and learning style. Also can gives a new idea for the teacher as a facilitator for exploring how to teach the student in creative ways and more student-center activities, for a lesson such as circulatory system. This study was carried out at one private school in Bandung involved eight students to see their responses toward the lesson that delivered by using Multiple Intelligence approach which is include Linguistic, Logical-Mathematical, Visual-Spatial, Musical, Bodily-Kinesthetic, Interpersonal, Intrapersonal, and Naturalistic. Students were test by using MI test based on Howard Gardner’s MI model to see their dominant intelligence. The result showed the percentage of top three ranks of intelligence are Bodily-Kinesthetic (73%), Visual-Spatial (68%), and Logical-Mathematical (61%). The learning process is given by using some different multimedia and activities to engaged their learning style and intelligence such as mini experiment, short clip, and questions. Student response is given by using self-assessment and the result is all students said the lesson gives them a knowledge and skills that useful for their life, they are clear with the explanation given, they didn’t find difficulties to understand the lesson and can complete the assignment given. At the end of the study, it is reveal that the students who are learned by Multiple Intelligence instructional approach have more enhance to the lesson given. It’s also found out that the students participated in the learning process which Multiple Intelligence approach was applied enjoyed the activities and have great fun.

Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination

PubMed Central

Anderberg, Charlotte; Cunha, Sara I.; Zhai, Zhenhua; Cortez, Eliane; Pardali, Evangelia; Johnson, Jill R.; Franco, Marcela; Páez-Ribes, Marta; Cordiner, Ross; Fuxe, Jonas; Johansson, Bengt R.; Goumans, Marie-José; Casanovas, Oriol; ten Dijke, Peter; Arthur, Helen M.

2013-01-01

Therapy-induced resistance remains a significant hurdle to achieve long-lasting responses and cures in cancer patients. We investigated the long-term consequences of genetically impaired angiogenesis by engineering multiple tumor models deprived of endoglin, a co-receptor for TGF-β in endothelial cells actively engaged in angiogenesis. Tumors from endoglin-deficient mice adapted to the weakened angiogenic response, and refractoriness to diminished endoglin signaling was accompanied by increased metastatic capability. Mechanistic studies in multiple mouse models of cancer revealed that deficiency for endoglin resulted in a tumor vasculature that displayed hallmarks of endothelial-to-mesenchymal transition, a process of previously unknown significance in cancer biology, but shown by us to be associated with a reduced capacity of the vasculature to avert tumor cell intra- and extravasation. Nevertheless, tumors deprived of endoglin exhibited a delayed onset of resistance to anti-VEGF (vascular endothelial growth factor) agents, illustrating the therapeutic utility of combinatorial targeting of multiple angiogenic pathways for the treatment of cancer. PMID:23401487

Feedback-related brain activity predicts learning from feedback in multiple-choice testing.

PubMed

Ernst, Benjamin; Steinhauser, Marco

2012-06-01

Different event-related potentials (ERPs) have been shown to correlate with learning from feedback in decision-making tasks and with learning in explicit memory tasks. In the present study, we investigated which ERPs predict learning from corrective feedback in a multiple-choice test, which combines elements from both paradigms. Participants worked through sets of multiple-choice items of a Swahili-German vocabulary task. Whereas the initial presentation of an item required the participants to guess the answer, corrective feedback could be used to learn the correct response. Initial analyses revealed that corrective feedback elicited components related to reinforcement learning (FRN), as well as to explicit memory processing (P300) and attention (early frontal positivity). However, only the P300 and early frontal positivity were positively correlated with successful learning from corrective feedback, whereas the FRN was even larger when learning failed. These results suggest that learning from corrective feedback crucially relies on explicit memory processing and attentional orienting to corrective feedback, rather than on reinforcement learning.

Quaternary organic solar cells enhanced by cocrystalline squaraines with power conversion efficiencies >10%

DOE PAGES

Goh, Tenghooi; Huang, Jing -Shun; Yager, Kevin G.; ...

2016-08-11

The incorporation of multiple donors into the bulk-heterojunction layer of organic polymer solar cells (PSCs) has been demonstrated as a practical and elegant strategy to improve photovoltaics performance. However, it is challenging to successfully design and blend multiple donors, while minimizing unfavorable interactions (e.g., morphological traps, recombination centers, etc.). Here, a new Förster resonance energy transfer-based design is shown utilizing the synergistic nature of three light active donors (two small molecules and a high-performance donor–acceptor polymer) with a fullerene acceptor to create highly efficient quaternary PSCs with power conversion efficiencies (PCEs) of up to 10.7%. Within this quaternary architecture, itmore » is revealed that the addition of small molecules in low concentrations broadens the absorption bandwidth, induces cocrystalline molecular conformations, and promotes rapid (picosecond) energy transfer processes. Finally, these results provide guidance for the design of multiple-donor systems using simple processing techniques to realize single-junction PSC designs with unprecedented PCEs.« less

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.

Contingent interaction during work and play tasks for mothers with multiple sclerosis and their daughters.

PubMed

Crist, P

1993-02-01

Occupational therapy has focused on activity as a catalyst for understanding human roles and interactions, regardless of whether disability or chronic illness is present. Parenting is an important interactional activity accompanied by specific role expectations. This investigation examined the interaction patterns of mothers with multiple sclerosis and their daughters. Thirty-one mothers with multiple sclerosis and their daughters aged 8 to 12 years were compared with 34 mothers without disabilities and their daughters aged 8 to 12 years. Videotaped mother-daughter interactions during a work task and a play task were scored by two raters for 11 different behaviors. These behaviors were collapsed into three behavioral composites--receptiveness, directiveness, and dissuasiveness--for statistical analysis. Statistical analysis revealed no significant differences between the two groups on the behavioral composites for either mothers or their daughters. The two tasks stimulated a different pattern of mother-daughter interactions. For both members of the dyad, interactions during the work task were more directive and less dissuasive than those in the play task. The clinical implication of this finding indicates the importance of understanding the influence of the task selected when observing interaction. Because of recent social and legal changes, understanding parenting and chronic illness is critical.

Rig-I regulates NF-κB activity through binding to Nf-κb1 3′-UTR mRNA

PubMed Central

Zhang, Hong-Xin; Liu, Zi-Xing; Sun, Yue-Ping; Lu, Shun-Yuan; Liu, Xue-Song; Huang, Qiu-Hua; Xie, Yin-Yin; Dang, Su-Ying; Zheng, Guang-Yong; Li, Yi-Xue; Kuang, Ying; Fei, Jian; Chen, Zhu; Wang, Zhu-Gang

2013-01-01

Retinoic acid inducible gene I (RIG-I) senses viral RNAs and triggers innate antiviral responses through induction of type I IFNs and inflammatory cytokines. However, whether RIG-I interacts with host cellular RNA remains undetermined. Here we report that Rig-I interacts with multiple cellular mRNAs, especially Nf-κb1. Rig-I is required for NF-κB activity via regulating Nf-κb1 expression at posttranscriptional levels. It interacts with the multiple binding sites within 3′-UTR of Nf-κb1 mRNA. Further analyses reveal that three distinct tandem motifs enriched in the 3′-UTR fragments can be recognized by Rig-I. The 3′-UTR binding with Rig-I plays a critical role in normal translation of Nf-κb1 by recruiting the ribosomal proteins [ribosomal protein L13 (Rpl13) and Rpl8] and rRNAs (18S and 28S). Down-regulation of Rig-I or Rpl13 significantly reduces Nf-κb1 and 3′-UTR–mediated luciferase expression levels. These findings indicate that Rig-I functions as a positive regulator for NF-κB signaling and is involved in multiple biological processes in addition to host antivirus immunity. PMID:23553835

Brain system for mental orientation in space, time, and person

PubMed Central

Peer, Michael; Salomon, Roy; Goldberg, Ilan; Blanke, Olaf; Arzy, Shahar

2015-01-01

Orientation is a fundamental mental function that processes the relations between the behaving self to space (places), time (events), and person (people). Behavioral and neuroimaging studies have hinted at interrelations between processing of these three domains. To unravel the neurocognitive basis of orientation, we used high-resolution 7T functional MRI as 16 subjects compared their subjective distance to different places, events, or people. Analysis at the individual-subject level revealed cortical activation related to orientation in space, time, and person in a precisely localized set of structures in the precuneus, inferior parietal, and medial frontal cortex. Comparison of orientation domains revealed a consistent order of cortical activity inside the precuneus and inferior parietal lobes, with space orientation activating posterior regions, followed anteriorly by person and then time. Core regions at the precuneus and inferior parietal lobe were activated for multiple orientation domains, suggesting also common processing for orientation across domains. The medial prefrontal cortex showed a posterior activation for time and anterior for person. Finally, the default-mode network, identified in a separate resting-state scan, was active for all orientation domains and overlapped mostly with person-orientation regions. These findings suggest that mental orientation in space, time, and person is managed by a specific brain system with a highly ordered internal organization, closely related to the default-mode network. PMID:26283353

Sirt3 binds to and deacetylates mitochondrial pyruvate carrier 1 to enhance its activity.

PubMed

Liang, Lei; Li, Qingguo; Huang, Liyong; Li, Dawei; Li, Xinxiang

2015-12-25

Mitochondrial pyruvate carrier (MPC), composed of MPC1 and MPC2, can modulate pyruvate oxidation in mitochondrial and MPC1 expression correlates with poor prognosis of multiple cancers. Here, we reported that MPC1 is acetylated and its main acetylation sites are: K45 and K46. Sirt3 binds to and deacetylates MPC1. High glucose decreases MPC1 acetylation level by increasing Sirt3-MPC1 binding. Furthermore, acetylation mimic mutation of MPC1 reduces it activity and abolishes its function in inhibition of colon cancer cell growth. These results reveal a novel post-translational regulation of MPC1 by Sirt3, which is important for its activity and colon cancer cell growth. Copyright © 2015 Elsevier Inc. All rights reserved.

SET1A/COMPASS and shadow enhancers in the regulation of homeotic gene expression

PubMed Central

Cao, Kaixiang; Collings, Clayton K.; Marshall, Stacy A.; Morgan, Marc A.; Rendleman, Emily J.; Wang, Lu; Sze, Christie C.; Sun, Tianjiao; Bartom, Elizabeth T.; Shilatifard, Ali

2017-01-01

The homeotic (Hox) genes are highly conserved in metazoans, where they are required for various processes in development, and misregulation of their expression is associated with human cancer. In the developing embryo, Hox genes are activated sequentially in time and space according to their genomic position within Hox gene clusters. Accumulating evidence implicates both enhancer elements and noncoding RNAs in controlling this spatiotemporal expression of Hox genes, but disentangling their relative contributions is challenging. Here, we identify two cis-regulatory elements (E1 and E2) functioning as shadow enhancers to regulate the early expression of the HoxA genes. Simultaneous deletion of these shadow enhancers in embryonic stem cells leads to impaired activation of HoxA genes upon differentiation, while knockdown of a long noncoding RNA overlapping E1 has no detectable effect on their expression. Although MLL/COMPASS (complex of proteins associated with Set1) family of histone methyltransferases is known to activate transcription of Hox genes in other contexts, we found that individual inactivation of the MLL1-4/COMPASS family members has little effect on early Hox gene activation. Instead, we demonstrate that SET1A/COMPASS is required for full transcriptional activation of multiple Hox genes but functions independently of the E1 and E2 cis-regulatory elements. Our results reveal multiple regulatory layers for Hox genes to fine-tune transcriptional programs essential for development. PMID:28487406

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.

Phosphotyrosine-mediated LAT assembly on membranes drives kinetic bifurcation in recruitment dynamics of the Ras activator SOS

DOE PAGES

Huang, William Y. C.; Yan, Qingrong; Lin, Wan-Chen; ...

2016-07-01

The assembly of cell surface receptors with downstream signaling molecules is a commonly occurring theme in multiple signaling systems. However, little is known about how these assemblies modulate reaction kinetics and the ultimate propagation of signals. Here, we reconstitute phosphotyrosine-mediated assembly of extended linker for the activation of T cells (LAT):growth factor receptor-bound protein 2 (Grb2):Son of Sevenless (SOS) networks, derived from the T-cell receptor signaling system, on supported membranes. Single-molecule dwell time distributions reveal two, well-differentiated kinetic species for both Grb2 and SOS on the LAT assemblies. The majority fraction of membrane-recruited Grb2 and SOS both exhibit fast kineticsmore » and single exponential dwell time distributions, with average dwell times of hundreds of milliseconds. The minor fraction exhibits much slower kinetics, extending the dwell times to tens of seconds. Considering this result in the context of the multistep process by which the Ras GEF (guanine nucleotide exchange factor) activity of SOS is activated indicates that kinetic stabilization from the LAT assembly may be important. This kinetic proofreading effect would additionally serve as a stochastic noise filter by reducing the relative probability of spontaneous SOS activation in the absence of receptor triggering. In conclusion, the generality of receptor-mediated assembly suggests that such effects may play a role in multiple receptor proximal signaling processes.« less

Psychological impact of sports activity in spinal cord injury patients.

PubMed

Gioia, M C; Cerasa, A; Di Lucente, L; Brunelli, S; Castellano, V; Traballesi, M

2006-12-01

To investigate whether sports activity is associated with better psychological profiles in patients with spinal cord injury (SCI) and to evaluate the effect of demographic factors on psychological benefits. The State-Trait Anxiety Inventory, Form X2 (STAI-X2), the Eysenck Personality Questionnaire for extraversion (EPQ-R (E)) and the questionnaire for depression (QD) were administered in a cross-sectional study of 137 males with spinal cord injury including 52 tetraplegics and 85 paraplegics. The subjects were divided into two groups according to sports activity participation (high frequency vs no sports participation). Moreover, multiple regression analysis was adopted to investigate the influence of demographic variables, such as age, educational level, occupational status and marital status, on psychological variables. Analysis of variance revealed significant differences among the groups for anxiety (STAI-X2), extraversion (EPQ-R (E)) and depression (QD). In particular, SCI patients who did not practice sports showed higher anxiety and depression scores and lower extraversion scores than sports participants. In addition, with respect to the paraplegics, the tetraplegic group showed the lowest depression scores. Following multiple regression analysis, only the sports activity factor remained as an independent factor of anxiety scores. These findings demonstrate that sports activity is associated with better psychological status in SCI patients, irrespective of tetraplegia and paraplegia, and that psychological benefits are not emphasized by demographic factors.

Age- and Activity-Related Differences in the Abundance of Myosin Essential and Regulatory Light Chains in Human Muscle

PubMed Central

Cobley, James N.; Ab. Malik, Zulezwan; Morton, James P.; Close, Graeme L.; Edwards, Ben J.; Burniston, Jatin G.

2016-01-01

Traditional methods for phenotyping skeletal muscle (e.g., immunohistochemistry) are labor-intensive and ill-suited to multixplex analysis, i.e., assays must be performed in a series. Addressing these concerns represents a largely unmet research need but more comprehensive parallel analysis of myofibrillar proteins could advance knowledge regarding age- and activity-dependent changes in human muscle. We report a label-free, semi-automated and time efficient LC-MS proteomic workflow for phenotyping the myofibrillar proteome. Application of this workflow in old and young as well as trained and untrained human skeletal muscle yielded several novel observations that were subsequently verified by multiple reaction monitoring (MRM). We report novel data demonstrating that human ageing is associated with lesser myosin light chain 1 content and greater myosin light chain 3 content, consistent with an age-related reduction in type II muscle fibers. We also disambiguate conflicting data regarding myosin regulatory light chain, revealing that age-related changes in this protein more closely reflect physical activity status than ageing per se. This finding reinforces the need to control for physical activity levels when investigating the natural process of ageing. Taken together, our data confirm and extend knowledge regarding age- and activity-related phenotypes. In addition, the MRM transitions described here provide a methodological platform that can be fine-tuned to suite multiple research needs and thus advance myofibrillar phenotyping. PMID:28248225

Phosphotyrosine-mediated LAT assembly on membranes drives kinetic bifurcation in recruitment dynamics of the Ras activator SOS

PubMed Central

Huang, William Y. C.; Yan, Qingrong; Lin, Wan-Chen; Chung, Jean K.; Hansen, Scott D.; Christensen, Sune M.; Tu, Hsiung-Lin; Kuriyan, John; Groves, Jay T.

2016-01-01

The assembly of cell surface receptors with downstream signaling molecules is a commonly occurring theme in multiple signaling systems. However, little is known about how these assemblies modulate reaction kinetics and the ultimate propagation of signals. Here, we reconstitute phosphotyrosine-mediated assembly of extended linker for the activation of T cells (LAT):growth factor receptor-bound protein 2 (Grb2):Son of Sevenless (SOS) networks, derived from the T-cell receptor signaling system, on supported membranes. Single-molecule dwell time distributions reveal two, well-differentiated kinetic species for both Grb2 and SOS on the LAT assemblies. The majority fraction of membrane-recruited Grb2 and SOS both exhibit fast kinetics and single exponential dwell time distributions, with average dwell times of hundreds of milliseconds. The minor fraction exhibits much slower kinetics, extending the dwell times to tens of seconds. Considering this result in the context of the multistep process by which the Ras GEF (guanine nucleotide exchange factor) activity of SOS is activated indicates that kinetic stabilization from the LAT assembly may be important. This kinetic proofreading effect would additionally serve as a stochastic noise filter by reducing the relative probability of spontaneous SOS activation in the absence of receptor triggering. The generality of receptor-mediated assembly suggests that such effects may play a role in multiple receptor proximal signaling processes. PMID:27370798

Phosphotyrosine-mediated LAT assembly on membranes drives kinetic bifurcation in recruitment dynamics of the Ras activator SOS.

PubMed

Huang, William Y C; Yan, Qingrong; Lin, Wan-Chen; Chung, Jean K; Hansen, Scott D; Christensen, Sune M; Tu, Hsiung-Lin; Kuriyan, John; Groves, Jay T

2016-07-19

The assembly of cell surface receptors with downstream signaling molecules is a commonly occurring theme in multiple signaling systems. However, little is known about how these assemblies modulate reaction kinetics and the ultimate propagation of signals. Here, we reconstitute phosphotyrosine-mediated assembly of extended linker for the activation of T cells (LAT):growth factor receptor-bound protein 2 (Grb2):Son of Sevenless (SOS) networks, derived from the T-cell receptor signaling system, on supported membranes. Single-molecule dwell time distributions reveal two, well-differentiated kinetic species for both Grb2 and SOS on the LAT assemblies. The majority fraction of membrane-recruited Grb2 and SOS both exhibit fast kinetics and single exponential dwell time distributions, with average dwell times of hundreds of milliseconds. The minor fraction exhibits much slower kinetics, extending the dwell times to tens of seconds. Considering this result in the context of the multistep process by which the Ras GEF (guanine nucleotide exchange factor) activity of SOS is activated indicates that kinetic stabilization from the LAT assembly may be important. This kinetic proofreading effect would additionally serve as a stochastic noise filter by reducing the relative probability of spontaneous SOS activation in the absence of receptor triggering. The generality of receptor-mediated assembly suggests that such effects may play a role in multiple receptor proximal signaling processes.

The helical domain of the EcoR124I motor subunit participates in ATPase activity and dsDNA translocation

PubMed Central

Shamayeva, Katsiaryna; Guzanova, Alena; Řeha, David; Csefalvay, Eva; Carey, Jannette; Weiserova, Marie

2017-01-01

Type I restriction-modification enzymes are multisubunit, multifunctional molecular machines that recognize specific DNA target sequences, and their multisubunit organization underlies their multifunctionality. EcoR124I is the archetype of Type I restriction-modification family IC and is composed of three subunit types: HsdS, HsdM, and HsdR. DNA cleavage and ATP-dependent DNA translocation activities are housed in the distinct domains of the endonuclease/motor subunit HsdR. Because the multiple functions are integrated in this large subunit of 1,038 residues, a large number of interdomain contacts might be expected. The crystal structure of EcoR124I HsdR reveals a surprisingly sparse number of contacts between helicase domain 2 and the C-terminal helical domain that is thought to be involved in assembly with HsdM. Only two potential hydrogen-bonding contacts are found in a very small contact region. In the present work, the relevance of these two potential hydrogen-bonding interactions for the multiple activities of EcoR124I is evaluated by analysing mutant enzymes using in vivo and in vitro experiments. Molecular dynamics simulations are employed to provide structural interpretation of the functional data. The results indicate that the helical C-terminal domain is involved in the DNA translocation, cleavage, and ATPase activities of HsdR, and a role in controlling those activities is suggested. PMID:28133570

Respiratory syncytial virus nonstructural proteins decrease levels of multiple members of the cellular interferon pathways.

PubMed

Swedan, Samer; Musiyenko, Alla; Barik, Sailen

2009-10-01

Viruses of the Paramyxoviridae family, such as the respiratory syncytial virus (RSV), suppress cellular innate immunity represented by type I interferon (IFN) for optimal growth in their hosts. The two unique nonstructural (NS) proteins, NS1 and NS2, of RSV suppress IFN synthesis, as well as IFN function, but their exact targets are still uncharacterized. Here, we investigate if either or both of the NS proteins affect the steady-state levels of key members of the IFN pathway. We found that both NS1 and NS2 decreased the levels of TRAF3, a strategic integrator of multiple IFN-inducing signals, although NS1 was more efficient. Only NS1 reduced IKKepsilon, a key protein kinase that specifically phosphorylates and activates IFN regulatory factor 3. Loss of the TRAF3 and IKKepsilon proteins appeared to involve a nonproteasomal mechanism. Interestingly, NS2 modestly increased IKKepsilon levels. In the IFN response pathway, NS2 decreased the levels of STAT2, the essential transcription factor for IFN-inducible antiviral genes. Preliminary mapping revealed that the C-terminal 10 residues of NS1 were essential for reducing IKKepsilon levels and the C-terminal 10 residues of NS2 were essential for increasing and reducing IKKepsilon and STAT2, respectively. In contrast, deletion of up to 20 residues of the C termini of NS1 and NS2 did not diminish their TRAF3-reducing activity. Coimmunoprecipitation studies revealed that NS1 and NS2 form a heterodimer. Clearly, the NS proteins of RSV, working individually and together, regulate key signaling molecules of both the IFN activation and response pathways.

Nevirapine Loaded Core Shell Gold Nanoparticles by Double Emulsion Solvent Evaporation: In vitro and In vivo Evaluation.

PubMed

Dalvi, Bhagyashree R; Siddiqui, Ejaz A; Syed, Asad S; Velhal, Shilpa M; Ahmad, Absar; Bandivdekar, Atmaram B; Devarajan, Padma V

2016-01-01

HIV/AIDS is a macrophage resident infection localized in the reticuloendothelial system and remote locations of brain and bone marrow. We present core shell nanoparticles of gold(AuNPs) and nevirapine(NVP) for targeted delivery to the multiple HIV reservoirs. The aim of the study was to design core shell NVP loaded AuNPs with high drug loading and to evaluate biodistribution of the nanoparticles in possible HIV reservoirs in vivo. A specific objective was to assess the possible synergy of AuNPs with NVP on anti-HIV activity in vitro. Core shell nanoparticles were prepared by double emulsion solvent evaporation method and characterized. Glyceryl monostearate-nevirapine-gold nanoparticles(GMS-NVP-AuNPs) revealed high entrapment efficiency (>70%), high loading (~40%), particle size <250 nm and zeta potential -35.9± 1.41mv and exhibited sustained release with good stability. Surface plasmon resonance indicated shell formation while SEM coupled EDAX confirmed the presence of Au. TEM confirmed formation of spherical core shell nanoparticles. GMS-NVP-AuNPs revealed low hemolysis (<10 %) and serum stability upto 6 h. GMS-NVP-AuNPs exhibited rapid, high and sustained accumulation in the possible HIV reservoir organs, including the major organs of liver, spleen, lymph nodes, thymus and also remote locations of brain, ovary and bone marrow. High cell viability and enhanced uptake in PBMC's and TZM-bl cells were observed. While uptake in PBMC's proposed monocytes/macrophages enabled brain delivery. GMS-NVP-AuNPs demonstrated synergistic anti-HIV activity. The superior anti-HIV activity in vitro coupled with extensive localization of the nanoparticles in multiple HIV reservoirs suggests great promise of the core shell GMS-NVP-AuNPs for improved therapy of HIV.

Improvement of Arabidopsis Biomass and Cold, Drought and Salinity Stress Tolerance by Modified Circadian Clock-Associated PSEUDO-RESPONSE REGULATORs.

PubMed

Nakamichi, Norihito; Takao, Saori; Kudo, Toru; Kiba, Takatoshi; Wang, Yin; Kinoshita, Toshinori; Sakakibara, Hitoshi

2016-05-01

Plant circadian clocks control the timing of a variety of genetic, metabolic and physiological processes. Recent studies revealed a possible molecular mechanism for circadian clock regulation. Arabidopsis thaliana (Arabidopsis) PSEUDO-RESPONSE REGULATOR (PRR) genes, including TIMING OF CAB EXPRESSION 1 (TOC1), encode clock-associated transcriptional repressors that act redundantly. Disruption of multiple PRR genes results in drastic phenotypes, including increased biomass and abiotic stress tolerance, whereas PRR single mutants show subtle phenotypic differences due to genetic redundancy. In this study, we demonstrate that constitutive expression of engineered PRR5 (PRR5-VP), which functions as a transcriptional activator, can increase biomass and abiotic stress tolerance, similar to prr multiple mutants. Concomitant analyses of relative growth rate, flowering time and photosynthetic activity suggested that increased biomass of PRR5-VP plants is mostly due to late flowering, rather than to alterations in photosynthetic activity or growth rate. In addition, genome-wide gene expression profiling revealed that genes related to cold stress and water deprivation responses were up-regulated in PRR5-VP plants. PRR5-VP plants were more resistant to cold, drought and salinity stress than the wild type, whereas ft tsf and gi, well-known late flowering and increased biomass mutants, were not. These findings suggest that attenuation of PRR function by a single transformation of PRR-VP is a valuable method for increasing biomass as well as abiotic stress tolerance in Arabidopsis. Because the PRR gene family is conserved in vascular plants, PRR-VP may regulate biomass and stress responses in many plants, but especially in long-day annual plants. © The Author 2016. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

EEG resolutions in detecting and decoding finger movements from spectral analysis

PubMed Central

Xiao, Ran; Ding, Lei

2015-01-01

Mu/beta rhythms are well-studied brain activities that originate from sensorimotor cortices. These rhythms reveal spectral changes in alpha and beta bands induced by movements of different body parts, e.g., hands and limbs, in electroencephalography (EEG) signals. However, less can be revealed in them about movements of different fine body parts that activate adjacent brain regions, such as individual fingers from one hand. Several studies have reported spatial and temporal couplings of rhythmic activities at different frequency bands, suggesting the existence of well-defined spectral structures across multiple frequency bands. In the present study, spectral principal component analysis (PCA) was applied on EEG data, obtained from a finger movement task, to identify cross-frequency spectral structures. Features from identified spectral structures were examined in their spatial patterns, cross-condition pattern changes, detection capability of finger movements from resting, and decoding performance of individual finger movements in comparison to classic mu/beta rhythms. These new features reveal some similar, but more different spatial and spectral patterns as compared with classic mu/beta rhythms. Decoding results further indicate that these new features (91%) can detect finger movements much better than classic mu/beta rhythms (75.6%). More importantly, these new features reveal discriminative information about movements of different fingers (fine body-part movements), which is not available in classic mu/beta rhythms. The capability in decoding fingers (and hand gestures in the future) from EEG will contribute significantly to the development of non-invasive BCI and neuroprosthesis with intuitive and flexible controls. PMID:26388720

metaseq: a Python package for integrative genome-wide analysis reveals relationships between chromatin insulators and associated nuclear mRNA.

PubMed

Dale, Ryan K; Matzat, Leah H; Lei, Elissa P

2014-08-01

Here we introduce metaseq, a software library written in Python, which enables loading multiple genomic data formats into standard Python data structures and allows flexible, customized manipulation and visualization of data from high-throughput sequencing studies. We demonstrate its practical use by analyzing multiple datasets related to chromatin insulators, which are DNA-protein complexes proposed to organize the genome into distinct transcriptional domains. Recent studies in Drosophila and mammals have implicated RNA in the regulation of chromatin insulator activities. Moreover, the Drosophila RNA-binding protein Shep has been shown to antagonize gypsy insulator activity in a tissue-specific manner, but the precise role of RNA in this process remains unclear. Better understanding of chromatin insulator regulation requires integration of multiple datasets, including those from chromatin-binding, RNA-binding, and gene expression experiments. We use metaseq to integrate RIP- and ChIP-seq data for Shep and the core gypsy insulator protein Su(Hw) in two different cell types, along with publicly available ChIP-chip and RNA-seq data. Based on the metaseq-enabled analysis presented here, we propose a model where Shep associates with chromatin cotranscriptionally, then is recruited to insulator complexes in trans where it plays a negative role in insulator activity. Published by Oxford University Press on behalf of Nucleic Acids Research 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Challenges and Support When Teaching Science Through an Integrated Inquiry and Literacy Approach

NASA Astrophysics Data System (ADS)

Ødegaard, Marianne; Haug, Berit; Mork, Sonja M.; Ove Sørvik, Gard

2014-12-01

In the Budding Science and Literacy project, we explored how working with an integrated inquiry-based science and literacy approach may challenge and support the teaching and learning of science at the classroom level. By studying the inter-relationship between multiple learning modalities and phases of inquiry, we wished to illuminate possible dynamics between science inquiry and literacy in an integrated science approach. Six teachers and their students were recruited from a professional development course for the current classroom study. The teachers were to try out the Budding Science teaching model. This paper presents an overall video analysis of our material demonstrating variations and patterns of inquiry-based science and literacy activities. Our analysis revealed that multiple learning modalities (read it, write it, do it, and talk it) are used in the integrated approach; oral activities dominate. The inquiry phases shifted throughout the students' investigations, but the consolidating phases of discussion and communication were given less space. The data phase of inquiry seems essential as a driving force for engaging in science learning in consolidating situations. The multiple learning modalities were integrated in all inquiry phases, but to a greater extent in preparation and data. Our results indicate that literacy activities embedded in science inquiry provide support for teaching and learning science; however, the greatest challenge for teachers is to find the time and courage to exploit the discussion and communication phases to consolidate the students' conceptual learning.

Process-Improvement Cost Model for the Emergency Department.

PubMed

Dyas, Sheila R; Greenfield, Eric; Messimer, Sherri; Thotakura, Swati; Gholston, Sampson; Doughty, Tracy; Hays, Mary; Ivey, Richard; Spalding, Joseph; Phillips, Robin

2015-01-01

The objective of this report is to present a simplified, activity-based costing approach for hospital emergency departments (EDs) to use with Lean Six Sigma cost-benefit analyses. The cost model complexity is reduced by removing diagnostic and condition-specific costs, thereby revealing the underlying process activities' cost inefficiencies. Examples are provided for evaluating the cost savings from reducing discharge delays and the cost impact of keeping patients in the ED (boarding) after the decision to admit has been made. The process-improvement cost model provides a needed tool in selecting, prioritizing, and validating Lean process-improvement projects in the ED and other areas of patient care that involve multiple dissimilar diagnoses.

Dynamic Neural Networks Supporting Memory Retrieval

PubMed Central

St. Jacques, Peggy L.; Kragel, Philip A.; Rubin, David C.

2011-01-01

How do separate neural networks interact to support complex cognitive processes such as remembrance of the personal past? Autobiographical memory (AM) retrieval recruits a consistent pattern of activation that potentially comprises multiple neural networks. However, it is unclear how such large-scale neural networks interact and are modulated by properties of the memory retrieval process. In the present functional MRI (fMRI) study, we combined independent component analysis (ICA) and dynamic causal modeling (DCM) to understand the neural networks supporting AM retrieval. ICA revealed four task-related components consistent with the previous literature: 1) Medial Prefrontal Cortex (PFC) Network, associated with self-referential processes, 2) Medial Temporal Lobe (MTL) Network, associated with memory, 3) Frontoparietal Network, associated with strategic search, and 4) Cingulooperculum Network, associated with goal maintenance. DCM analysis revealed that the medial PFC network drove activation within the system, consistent with the importance of this network to AM retrieval. Additionally, memory accessibility and recollection uniquely altered connectivity between these neural networks. Recollection modulated the influence of the medial PFC on the MTL network during elaboration, suggesting that greater connectivity among subsystems of the default network supports greater re-experience. In contrast, memory accessibility modulated the influence of frontoparietal and MTL networks on the medial PFC network, suggesting that ease of retrieval involves greater fluency among the multiple networks contributing to AM. These results show the integration between neural networks supporting AM retrieval and the modulation of network connectivity by behavior. PMID:21550407

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

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.

SOLAR MULTIPLE ERUPTIONS FROM A CONFINED MAGNETIC STRUCTURE

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

Lee, Jeongwoo; Chae, Jongchul; Liu, Chang

2016-09-20

How eruption can recur from a confined magnetic structure is discussed based on the Solar Dynamics Observatory observations of the NOAA active region 11444, which produced three eruptions within 1.5 hr on 2012 March 27. The active region (AR) had the positive-polarity magnetic fields in the center surrounded by the negative-polarity fields around. Since such a distribution of magnetic polarity tends to form a dome-like magnetic fan structure confined over the AR, the multiple eruptions were puzzling. Our investigation reveals that this event exhibits several properties distinct from other eruptions associated with magnetic fan structures: (i) a long filament encirclingmore » the AR was present before the eruptions; (ii) expansion of the open–closed boundary (OCB) of the field lines after each eruption was suggestive of the growing fan-dome structure, and (iii) the ribbons inside the closed magnetic polarity inversion line evolved in response to the expanding OCB. It thus appears that in spite of multiple eruptions the fan-dome structure remained undamaged, and the closing back field lines after each eruption rather reinforced the fan-dome structure. We argue that the multiple eruptions could occur in this AR in spite of its confined magnetic structure because the filament encircling the AR was adequate for slipping through the magnetic separatrix to minimize the damage to its overlying fan-dome structure. The result of this study provides a new insight into the productivity of eruptions from a confined magnetic structure.« less

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.

Adaptation of the length-active tension relationship in rabbit detrusor

PubMed Central

Almasri, Atheer M.; Bhatia, Hersch; Klausner, Adam P.; Ratz, Paul H.

2009-01-01

Studies have shown that the length-tension (L-T) relationships in airway and vascular smooth muscles are dynamic and can adapt to length changes over a period of time. Our prior studies have shown that the passive L-T relationship in rabbit detrusor smooth muscle (DSM) is also dynamic and that DSM exhibits adjustable passive stiffness (APS) characterized by a passive L-T curve that can shift along the length axis as a function of strain history and activation history. The present study demonstrates that the active L-T curve for DSM is also dynamic and that the peak active tension produced at a particular muscle length is a function of both strain and activation history. More specifically, this study reveals that the active L-T relationship, or curve, does not have a unique peak tension value with a single ascending and descending limb, but instead reveals that multiple ascending and descending limbs can be exhibited in the same DSM strip. This study also demonstrates that for DSM strips not stretched far enough to reveal a descending limb, the peak active tension produced by a maximal KCl-induced contraction at a short, passively slack muscle length of 3 mm was reduced by 58.6 ± 4.1% (n = 15) following stretches to and contractions at threefold the original muscle length, 9 mm. Moreover, five subsequent contractions at the short muscle length displayed increasingly greater tension; active tension produced by the sixth contraction was 91.5 ± 9.1% of that produced by the prestretch contraction at that length. Together, these findings indicate for the first time that DSM exhibits length adaptation, similar to vascular and airway smooth muscles. In addition, our findings demonstrate that preconditioning, APS and adaptation of the active L-T curve can each impact the maximum total tension observed at a particular DSM length. PMID:19675182

Multiple determinants controlling activation of yeast replication origins late in S phase.

PubMed

Friedman, K L; Diller, J D; Ferguson, B M; Nyland, S V; Brewer, B J; Fangman, W L

1996-07-01

Analysis of a 131-kb segment of the left arm of yeast chromosome XIV beginning 157 kb from the telomere reveals four highly active origins of replication that initiate replication late in S phase. Previous work has shown that telomeres act as determinants for late origin activation. However, at least two of the chromosome XIV origins maintain their late activation time when located on large circular plasmids, indicating that late replication is independent of telomeres. Analysis of the replication time of plasmid derivatives containing varying amounts of chromosome XIV DNA show that a minimum of three chromosomal elements, distinct from each tested origin, contribute to late activation time. These late determinants are functionally equivalent, because duplication of one set of contributing sequences can compensate for the removal of another set. Furthermore, insertion of an origin that is normally early activated into this domain results in a shift to late activation, suggesting that the chromosome XIV origins are not unique in their ability to respond to the late determinants.

Enhanced interlaminar excitation or reduced superficial layer inhibition in neocortex generates different spike-and-wave-like electrographic events in vitro

PubMed Central

Hall, Stephen P.; Traub, Roger D.; Adams, Natalie E.; Cunningham, Mark O.; Schofield, Ian; Jenkins, Alistair J.

2018-01-01

Acute in vitro models have revealed a great deal of information about mechanisms underlying many types of epileptiform activity. However, few examples exist that shed light on spike-and-wave (SpW) patterns of pathological activity. SpW are seen in many epilepsy syndromes, both generalized and focal, and manifest across the entire age spectrum. They are heterogeneous in terms of their severity, symptom burden, and apparent anatomical origin (thalamic, neocortical, or both), but any relationship between this heterogeneity and underlying pathology remains elusive. In this study we demonstrate that physiological delta-frequency rhythms act as an effective substrate to permit modeling of SpW of cortical origin and may help to address this issue. For a starting point of delta activity, multiple subtypes of SpW could be modeled computationally and experimentally by either enhancing the magnitude of excitatory synaptic events ascending from neocortical layer 5 to layers 2/3 or selectively modifying superficial layer GABAergic inhibition. The former generated SpW containing multiple field spikes with long interspike intervals, whereas the latter generated SpW with short-interval multiple field spikes. Both types had different laminar origins and each disrupted interlaminar cortical dynamics in a different manner. A small number of examples of human recordings from patients with different diagnoses revealed SpW subtypes with the same temporal signatures, suggesting that detailed quantification of the pattern of spikes in SpW discharges may be a useful indicator of disparate underlying epileptogenic pathologies. NEW & NOTEWORTHY Spike-and-wave-type discharges (SpW) are a common feature in many epilepsies. Their electrographic manifestation is highly varied, as are available genetic clues to associated underlying pathology. Using computational and in vitro models, we demonstrate that distinct subtypes of SpW are generated by lamina-selective disinhibition or enhanced interlaminar excitation. These subtypes could be detected in at least some noninvasive patient recordings, suggesting more detailed analysis of SpW may be useful in determining clinical pathology. PMID:28954894

Enhanced interlaminar excitation or reduced superficial layer inhibition in neocortex generates different spike-and-wave-like electrographic events in vitro.

PubMed

Hall, Stephen P; Traub, Roger D; Adams, Natalie E; Cunningham, Mark O; Schofield, Ian; Jenkins, Alistair J; Whittington, Miles A

2018-01-01

Acute in vitro models have revealed a great deal of information about mechanisms underlying many types of epileptiform activity. However, few examples exist that shed light on spike-and-wave (SpW) patterns of pathological activity. SpW are seen in many epilepsy syndromes, both generalized and focal, and manifest across the entire age spectrum. They are heterogeneous in terms of their severity, symptom burden, and apparent anatomical origin (thalamic, neocortical, or both), but any relationship between this heterogeneity and underlying pathology remains elusive. In this study we demonstrate that physiological delta-frequency rhythms act as an effective substrate to permit modeling of SpW of cortical origin and may help to address this issue. For a starting point of delta activity, multiple subtypes of SpW could be modeled computationally and experimentally by either enhancing the magnitude of excitatory synaptic events ascending from neocortical layer 5 to layers 2/3 or selectively modifying superficial layer GABAergic inhibition. The former generated SpW containing multiple field spikes with long interspike intervals, whereas the latter generated SpW with short-interval multiple field spikes. Both types had different laminar origins and each disrupted interlaminar cortical dynamics in a different manner. A small number of examples of human recordings from patients with different diagnoses revealed SpW subtypes with the same temporal signatures, suggesting that detailed quantification of the pattern of spikes in SpW discharges may be a useful indicator of disparate underlying epileptogenic pathologies. NEW & NOTEWORTHY Spike-and-wave-type discharges (SpW) are a common feature in many epilepsies. Their electrographic manifestation is highly varied, as are available genetic clues to associated underlying pathology. Using computational and in vitro models, we demonstrate that distinct subtypes of SpW are generated by lamina-selective disinhibition or enhanced interlaminar excitation. These subtypes could be detected in at least some noninvasive patient recordings, suggesting more detailed analysis of SpW may be useful in determining clinical pathology.

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.

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

RNA-Seq reveals virus–virus and virus–plant interactions in nature

PubMed Central

Kamitani, Mari; Nagano, Atsushi J.; Honjo, Mie N.; Kudoh, Hiroshi

2016-01-01

Abstract As research on plant viruses has focused mainly on crop diseases, little is known about these viruses in natural environments. To understand the ecology of viruses in natural systems, comprehensive information on virus–virus and virus–host interactions is required. We applied RNA-Seq to plants from a natural population of Arabidopsis halleri subsp. gemmifera to simultaneously determine the presence/absence of all sequence-reported viruses, identify novel viruses and quantify the host transcriptome. By introducing the criteria of read number and genome coverage, we detected infections by Turnip mosaic virus (TuMV), Cucumber mosaic virus and Brassica yellows virus. Active TuMV replication was observed by ultramicroscopy. De novo assembly further identified a novel partitivirus, Arabidopsis halleri partitivirus 1. Interestingly, virus reads reached a maximum level that was equivalent to that of the host's total mRNA, although asymptomatic infection was common. AhgAGO2, a key gene in host defence systems, was upregulated in TuMV-infected plants. Multiple infection was frequent in TuMV-infected leaves, suggesting that TuMV facilitates multiple infection, probably by suppressing host RNA silencing. Revealing hidden plant–virus interactions in nature can enhance our understanding of biological interactions and may have agricultural applications. PMID:27549115

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

Screening molecular associations with lipid membranes using natural abundance 13C cross-polarization magic-angle spinning NMR and principal component analysis.

PubMed

Middleton, David A; Hughes, Eleri; Madine, Jillian

2004-08-11

We describe an NMR approach for detecting the interactions between phospholipid membranes and proteins, peptides, or small molecules. First, 1H-13C dipolar coupling profiles are obtained from hydrated lipid samples at natural isotope abundance using cross-polarization magic-angle spinning NMR methods. Principal component analysis of dipolar coupling profiles for synthetic lipid membranes in the presence of a range of biologically active additives reveals clusters that relate to different modes of interaction of the additives with the lipid bilayer. Finally, by representing profiles from multiple samples in the form of contour plots, it is possible to reveal statistically significant changes in dipolar couplings, which reflect perturbations in the lipid molecules at the membrane surface or within the hydrophobic interior.

Examining the Associations Among Home-School Dissonance, Amotivation, and Classroom Disruptive Behavior for Urban High School Students.

PubMed

Brown-Wright, Lynda; Tyler, Kenneth M; Graves, Scott L; Thomas, Deneia; Stevens-Watkins, Danelle; Mulder, Shambra

2013-01-01

The current study examined the association among home-school dissonance, amotivation, and classroom disruptive behavior among 309 high school juniors and seniors at two urban high schools in the Southern region of the country. Students completed two subscales of the Patterns of Learning Activities Scales (PALS) and one subscale of the Academic Motivation Scale (AMS). ANCOVA analyses revealed significant differences in classroom disruptive behaviors for the gender independent variable. Controlling for gender in the multiple hierarchical regression analyses, it was revealed that home-school dissonance significantly predicted both amotivation and classroom disruptive behavior. In addition, a Sobel mediation analysis showed that amotivation was a significant mediator of the association between home-school dissonance and classroom disruptive behavior. Findings and limitations are discussed.

Examining the Associations Among Home–School Dissonance, Amotivation, and Classroom Disruptive Behavior for Urban High School Students

PubMed Central

Brown-Wright, Lynda; Tyler, Kenneth M.; Graves, Scott L.; Thomas, Deneia; Stevens-Watkins, Danelle; Mulder, Shambra

2015-01-01

The current study examined the association among home–school dissonance, amotivation, and classroom disruptive behavior among 309 high school juniors and seniors at two urban high schools in the Southern region of the country. Students completed two subscales of the Patterns of Learning Activities Scales (PALS) and one subscale of the Academic Motivation Scale (AMS). ANCOVA analyses revealed significant differences in classroom disruptive behaviors for the gender independent variable. Controlling for gender in the multiple hierarchical regression analyses, it was revealed that home–school dissonance significantly predicted both amotivation and classroom disruptive behavior. In addition, a Sobel mediation analysis showed that amotivation was a significant mediator of the association between home–school dissonance and classroom disruptive behavior. Findings and limitations are discussed. PMID:27081213

Label-free density difference amplification-based cell sorting.

PubMed

Song, Jihwan; Song, Minsun; Kang, Taewook; Kim, Dongchoul; Lee, Luke P

2014-11-01

The selective cell separation is a critical step in fundamental life sciences, translational medicine, biotechnology, and energy harvesting. Conventional cell separation methods are fluorescent activated cell sorting and magnetic-activated cell sorting based on fluorescent probes and magnetic particles on cell surfaces. Label-free cell separation methods such as Raman-activated cell sorting, electro-physiologically activated cell sorting, dielectric-activated cell sorting, or inertial microfluidic cell sorting are, however, limited when separating cells of the same kind or cells with similar sizes and dielectric properties, as well as similar electrophysiological phenotypes. Here we report a label-free density difference amplification-based cell sorting (dDACS) without using any external optical, magnetic, electrical forces, or fluidic activations. The conceptual microfluidic design consists of an inlet, hydraulic jump cavity, and multiple outlets. Incoming particles experience gravity, buoyancy, and drag forces in the separation chamber. The height and distance that each particle can reach in the chamber are different and depend on its density, thus allowing for the separation of particles into multiple outlets. The separation behavior of the particles, based on the ratio of the channel heights of the inlet and chamber and Reynolds number has been systematically studied. Numerical simulation reveals that the difference between the heights of only lighter particles with densities close to that of water increases with increasing the ratio of the channel heights, while decreasing Reynolds number can amplify the difference in the heights between the particles considered irrespective of their densities.

Too much of a good thing? How breadth of extracurricular participation relates to school-related affect and academic outcomes during adolescence.

PubMed

Knifsend, Casey A; Graham, Sandra

2012-03-01

Although adolescents often participate in multiple extracurricular activities, little research has examined how the breadth of activities in which an adolescent is involved relates to school-related affect and academic performance. Relying on a large, multi-ethnic sample (N = 864; 55.9% female), the current study investigated linear and non-linear relationships of 11th grade activity participation in four activity domains (academic/leadership groups, arts activities, clubs, and sports) to adolescents' sense of belonging at school, academic engagement, and grade point average, contemporarily and in 12th grade. Results of multiple regression models revealed curvilinear relationships for sense of belonging at school in 11th and 12th grade, grade point average in 11th grade, and academic engagement in 12th grade. Adolescents who were moderately involved (i.e., in two domains) reported a greater sense of belonging at school in 11th and 12th grade, a higher grade point average in 11th grade, and greater academic engagement in 12th grade, relative to those who were more or less involved. Furthermore, adolescents' sense of belonging at school in 11th grade mediated the relationship of domain participation in 11th grade to academic engagement in 12th grade. This study suggests that involvement in a moderate number of activity domains promotes positive school-related affect and greater academic performance. School policy implications and recommendations are discussed.

The Presence of a Stable Block bounded by Active Zones (Mobile Belts) in the southwestern North American Proterozoic craton

NASA Astrophysics Data System (ADS)

Goodell, P.; Martinez P, C.; Mahar, M. A.

2014-12-01

Bouguer gravity data, initial Sr isotope values, zircon U-Pb, and multiple occurrences of felsic Proterozoic rocks, have revealed an elevated, less deformed, felsic cratonic block in the northern Mexico. The block is situated in western Chihuahua and is bounded by active zones or mobile belts on three sides, and is here referred to as the Western Chihuahua Cratonic Block (WCCB). Bouguer gravity data clearly indicate a region of a highly negative anomaly (< -200 mgal) in contrast to adjoining areas. The region is large and the anomaly is relatively smooth over broad areas; the WCCB appears as a smaller version of the Colorado Plateau. The block is characterized by high initial Sr isotope ratios (<0.706). Several occurrences of Proterozoic rocks are located within or next to the WCCB, and they reveal the character of the Bouguer anomaly. On the east, at Los Filtros, Proterozoic rocks crop out in a basement cored uplift interpreted to having been derived from the WCCB during the Ouachita orogeny. At Sierra La Mojina boulders of 1.1 Ga granites are found in Permian conglomerates. And at Basasiachic, xenoliths of 1.1 Ga granites are present in ash flow tuffs. Establishment of the Precambrian character of the WCCB is of importance, and these multiple occurrences are evidence. Prior studies of the Sierra Madre Occidental suggest that the region was uplifted because of a vast Cenozoic batholith presumed to lie under the SLIP (Silicic Large Igneous Province), the Upper Volcanic Series. The present study challenges that conclusion and maintains the SMO is underlain by Proterozoic silicic crust. The geology of age dated samples supports this. The WCCB is surrounded on three sides by Active Zones or Mobile Belts, which have been active extensional and translational zones periodically over a long period of time. On the east are the Paleozoic Pedrogosa Basin, Mesozoic Chihuahua Trough and Cenozoic Rio Grande Rift, the first two of which also continue around the northern border of the block. On the west are the Paleozoic Sonora embayment and Mesozoic Sahuaripa basin. A possible model for the origin of the WCCB is that it was an integral part of the North American Proterozoic craton but has been displaced from North America by multiple episodes of extension associated with the mobile belts.

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.

In Australia: Multiple Intelligences in Multiple Settings.

ERIC Educational Resources Information Center

Vialle, Wilma

1997-01-01

In Australia, Gardner's multiple-intelligences theory has strongly influenced primary, preschool, and special education. A survey of 30 schools revealed that teachers use two basic approaches: teaching to, and teaching through, multiple intelligences. The first approach might develop children's music skills via playing an instrument. The second…

Peptides derived from transcription factor EB bind to calcineurin at a similar region as the NFAT-type motif

PubMed Central

Song, Ruiwen; Li, Jing; Zhang, Jin; Wang, Lu; Tong, Li; Wang, Ping; Yang, Huan; Wei, Qun; Cai, Huaibin; Luo, Jing

2018-01-01

Calcineurin (CN) is involved in many physiological processes and interacts with multiple substrates. Most of the substrates contain similar motifs recognized by CN. Recent studies revealed a new CN substrate, transcription factor EB (TFEB), which is involved in autophagy. We showed that a 15-mer QSYLENPTSYHLQQS peptide from TFEB (TFEB-YLENP) bound to CN. When the TFEB-YLENP peptide was changed to YLAVP, its affinity for CN increased and it had stronger CN inhibitory activity. Molecular dynamics simulations revealed that the TFEB-YLENP peptide has the same docking sites in CN as the 15-mer DQYLAVPQHPYQWAK motif of the nuclear factor of activated T cells, cytoplasmic 1 (NFATc1-YLAVP). Moreover expression of the NFATc1-YLAVP peptide suppressed the TFEB activation in starved Hela cells. Our studies first identified a CN binding site in TFEB and compared the inhibitory capability of various peptides derived from CN substrates. The data uncovered a diversity in recognition sequences that underlies the CN signaling within the cell. Studies of CN-substrate interactions should lay the groundwork for developing selective CN peptide inhibitors that target CN-substrate interaction in vitro experiments. PMID:28890387

The Rho GTPase effector ROCK regulates cyclin A, cyclin D1, and p27Kip1 levels by distinct mechanisms.

PubMed

Croft, Daniel R; Olson, Michael F

2006-06-01

The members of the Rho GTPase family are well known for their regulation of actin cytoskeletal structures. In addition, they influence progression through the cell cycle. The RhoA and RhoC proteins regulate numerous effector proteins, with a central and vital signaling role mediated by the ROCK I and ROCK II serine/threonine kinases. The requirement for ROCK function in the proliferation of numerous cell types has been revealed by studies utilizing ROCK-selective inhibitors such as Y-27632. However, the mechanisms by which ROCK signaling promotes cell cycle progression have not been thoroughly characterized. Using a conditionally activated ROCK-estrogen receptor fusion protein, we found that ROCK activation is sufficient to stimulate G1/S cell cycle progression in NIH 3T3 mouse fibroblasts. Further analysis revealed that ROCK acts via independent pathways to alter the levels of cell cycle regulatory proteins: cyclin D1 and p21(Cip1) elevation via Ras and the mitogen-activated protein kinase pathway, increased cyclin A via LIM kinase 2, and reduction of p27(Kip1) protein levels. Therefore, the influence of ROCK on cell cycle regulatory proteins occurs by multiple independent mechanisms.

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.

Population and clinical genetics of human transposable elements in the (post) genomic era

PubMed Central

Rishishwar, Lavanya; Wang, Lu; Clayton, Evan A.; Mariño-Ramírez, Leonardo; McDonald, John F.; Jordan, I. King

2017-01-01

ABSTRACT Recent technological developments—in genomics, bioinformatics and high-throughput experimental techniques—are providing opportunities to study ongoing human transposable element (TE) activity at an unprecedented level of detail. It is now possible to characterize genome-wide collections of TE insertion sites for multiple human individuals, within and between populations, and for a variety of tissue types. Comparison of TE insertion site profiles between individuals captures the germline activity of TEs and reveals insertion site variants that segregate as polymorphisms among human populations, whereas comparison among tissue types ascertains somatic TE activity that generates cellular heterogeneity. In this review, we provide an overview of these new technologies and explore their implications for population and clinical genetic studies of human TEs. We cover both recent published results on human TE insertion activity as well as the prospects for future TE studies related to human evolution and health. PMID:28228978

Na[superscript +] binding to meizothrombin desF1

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

Papaconstantinou, M.E.; Gandhi, P.S.; Chen, Z.

2009-06-10

Meizothrombin is the physiologically active intermediate generated by a single cleavage of prothrombin at R320 to separate the A and B chains. Recent evidence has suggested that meizothrombin, like thrombin, is a Na{sup +}-activated enzyme. In this study we present the first X-ray crystal structure of human meizothrombin desF1 solved in the presence of the active site inhibitor PPACK at 2.1 {angstrom} resolution. The structure reveals a Na{sup +} binding site whose architecture is practically identical to that of human thrombin. Stopped-flow measurements of Na{sup +} binding to meizothrombin desF1 document a slow phase of fluorescence change with a kmore » obs decreasing hyperbolically with increasing [Na{sup +}], consistent with the existence of three conformations in equilibrium, E*, E and E:Na{sup +}, as for human thrombin. Evidence that meizothrombin exists in multiple conformations provides valuable new information for studies of the mechanism of prothrombin activation.« less

Biological properties of 6-gingerol: a brief review.

PubMed

Wang, Shaopeng; Zhang, Caihua; Yang, Guang; Yang, Yanzong

2014-07-01

Numerous studies have revealed that regular consumption of certain fruits and vegetables can reduce the risk of many diseases. The rhizome of Zingiber officinale (ginger) is consumed worldwide as a spice and herbal medicine. It contains pungent phenolic substances collectively known as gingerols. 6-Gingerol is the major pharmacologically-active component of ginger. It is known to exhibit a variety of biological activities including anticancer, anti-inflammation, and anti-oxidation. 6-Gingerol has been found to possess anticancer activities via its effect on a variety of biological pathways involved in apoptosis, cell cycle regulation, cytotoxic activity, and inhibition of angiogenesis. Thus, due to its efficacy and regulation of multiple targets, as well as its safety for human use, 6-gingerol has received considerable interest as a potential therapeutic agent for the prevention and/or treatment of various diseases. Taken together, this review summarizes the various in vitro and in vivo pharmacological aspects of 6-gingerol and the underlying mechanisms.

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

Cellular Decision Making by Non-Integrative Processing of TLR Inputs.

PubMed

Kellogg, Ryan A; Tian, Chengzhe; Etzrodt, Martin; Tay, Savaş

2017-04-04

Cells receive a multitude of signals from the environment, but how they process simultaneous signaling inputs is not well understood. Response to infection, for example, involves parallel activation of multiple Toll-like receptors (TLRs) that converge on the nuclear factor κB (NF-κB) pathway. Although we increasingly understand inflammatory responses for isolated signals, it is not clear how cells process multiple signals that co-occur in physiological settings. We therefore examined a bacterial infection scenario involving co-stimulation of TLR4 and TLR2. Independent stimulation of these receptors induced distinct NF-κB dynamic profiles, although surprisingly, under co-stimulation, single cells continued to show ligand-specific dynamic responses characteristic of TLR2 or TLR4 signaling rather than a mixed response, comprising a cellular decision that we term "non-integrative" processing. Iterating modeling and microfluidic experiments revealed that non-integrative processing occurred through interaction of switch-like NF-κB activation, receptor-specific processing timescales, cell-to-cell variability, and TLR cross-tolerance mediated by multilayer negative feedback. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Crammed signaling motifs in the T-cell receptor.

PubMed

Borroto, Aldo; Abia, David; Alarcón, Balbino

2014-09-01

Although the T cell antigen receptor (TCR) is long known to contain multiple signaling subunits (CD3γ, CD3δ, CD3ɛ and CD3ζ), their role in signal transduction is still not well understood. The presence of at least one immunoreceptor tyrosine-based activation motif (ITAM) in each CD3 subunit has led to the idea that the multiplication of such elements essentially serves to amplify signals. However, the evolutionary conservation of non-ITAM sequences suggests that each CD3 subunit is likely to have specific non-redundant roles at some stage of development or in mature T cell function. The CD3ɛ subunit is paradigmatic because in a relatively short cytoplasmic sequence (∼55 amino acids) it contains several docking sites for proteins involved in intracellular trafficking and signaling, proteins whose relevance in T cell activation is slowly starting to be revealed. In this review we will summarize our current knowledge on the signaling effectors that bind directly to the TCR and we will propose a hierarchy in their response to TCR triggering. Copyright © 2014 Elsevier B.V. All rights reserved.

Induction of apoptosis in human multiple myeloma cell lines by ebselen via enhancing the endogenous reactive oxygen species production.

PubMed

Zhang, Liang; Zhou, Liwei; Du, Jia; Li, Mengxia; Qian, Chengyuan; Cheng, Yi; Peng, Yang; Xie, Jiayin; Wang, Dong

2014-01-01

Ebselen a selenoorganic compound showing glutathione peroxidase like activity is an anti-inflammatory and antioxidative agent. Its cytoprotective activity has been investigated in recent years. However, experimental evidence also shows that ebselen causes cell death in several cancer cell types whose mechanism has not yet been elucidated. In this study, we examined the effect of ebselen on multiple myeloma (MM) cell lines in vitro. The results showed that ebselen significantly enhanced the production of reactive oxygen species (ROS) accompanied by cell viability decrease and apoptosis rate increase. Further studies revealed that ebselen can induce Bax redistribution from the cytosol to mitochondria leading to mitochondrial membrane potential ΔΨm changes and cytochrome C release from the mitochondria to cytosol. Furtherly, we found that exogenous addition of N-acetyl cysteine (NAC) completely diminished the cell damage induced by ebselen. This result suggests that relatively high concentration of ebselen can induce MM cells apoptosis in culture by enhancing the production of endogenous ROS and triggering mitochondria mediated apoptotic pathway.

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

Acquired bilateral telangiectatic macules: a distinct clinical entity.

PubMed

Park, Ji-Hye; Lee, Dong Jun; Lee, Yoo-Jung; Jang, Yong Hyun; Kang, Hee Young; Kim, You Chan

2014-09-01

We evaluated 13 distinct patients with multiple telangiectatic pigmented macules confined mostly to the upper arms to determine if the clinical and histopathological features of these cases might represent a specific clinical entity. We retrospectively investigated the clinical, histopathologic, and immunohistochemical features of 13 patients with multiple telangiectatic pigmented macules on the upper arms who presented between January 2003 and December 2012. Epidermal pigmentation, melanogenic activity, melanocyte number, vascularity, epidermal thickness, and perivascular mast cell number of the specimens were evaluated. Clinically, the condition favored middle-aged men. On histopathologic examination, the lesional skin showed capillary proliferation and telangiectasia in the upper dermis. Histochemical and immunohistochemical analysis revealed basal hyperpigmentation and increased melanogenic activity in the lesional skin (P < .05). No significant difference in epidermal thickness or mast cell number was observed between the normal perilesional skin and the lesional skin. The clinical and histopathologic features of these lesions were relatively consistent in all patients. In addition, the features are quite distinct from other diseases. Based on clinical and histologic features, we suggest the name acquired bilateral telangiectatic macules for this new entity.

Multiple pore conformations driven by asynchronous movements of voltage sensors in a eukaryotic sodium channel

PubMed Central

Goldschen-Ohm, Marcel P.; Capes, Deborah L.; Oelstrom, Kevin M.; Chanda, Baron

2013-01-01

Voltage-dependent Na+ channels are crucial for electrical signalling in excitable cells. Membrane depolarization initiates asynchronous movements in four non-identical voltage-sensing domains of the Na+ channel. It remains unclear to what extent this structural asymmetry influences pore gating as compared with outwardly rectifying K+ channels, where channel opening results from a final concerted transition of symmetric pore gates. Here we combine single channel recordings, cysteine accessibility and voltage clamp fluorimetry to probe the relationships between voltage sensors and pore conformations in an inactivation deficient Nav1.4 channel. We observe three distinct conductance levels such that DI-III voltage sensor activation is kinetically correlated with formation of a fully open pore, whereas DIV voltage sensor movement underlies formation of a distinct subconducting pore conformation preceding inactivation in wild-type channels. Our experiments reveal that pore gating in sodium channels involves multiple transitions driven by asynchronous movements of voltage sensors. These findings shed new light on the mechanism of coupling between activation and fast inactivation in voltage-gated sodium channels. PMID:23322038

Electrochemical camera chip for simultaneous imaging of multiple metabolites in biofilms

PubMed Central

Bellin, Daniel L.; Sakhtah, Hassan; Zhang, Yihan; Price-Whelan, Alexa; Dietrich, Lars E. P.; Shepard, Kenneth L.

2016-01-01

Monitoring spatial distribution of metabolites in multicellular structures can enhance understanding of the biochemical processes and regulation involved in cellular community development. Here we report on an electrochemical camera chip capable of simultaneous spatial imaging of multiple redox-active phenazine metabolites produced by Pseudomonas aeruginosa PA14 colony biofilms. The chip features an 8 mm × 8 mm array of 1,824 electrodes multiplexed to 38 parallel output channels. Using this chip, we demonstrate potential-sweep-based electrochemical imaging of whole-biofilms at measurement rates in excess of 0.2 s per electrode. Analysis of mutants with various capacities for phenazine production reveals distribution of phenazine-1-carboxylic acid (PCA) throughout the colony, with 5-methylphenazine-1-carboxylic acid (5-MCA) and pyocyanin (PYO) localized to the colony edge. Anaerobic growth on nitrate confirms the O2-dependence of PYO production and indicates an effect of O2 availability on 5-MCA synthesis. This integrated-circuit-based technique promises wide applicability in detecting redox-active species from diverse biological samples. PMID:26813638

Molecular Cloning and Sequence Analysis of a Phenylalanine Ammonia-Lyase Gene from Dendrobium

PubMed Central

Cai, Yongping; Lin, Yi

2013-01-01

In this study, a phenylalanine ammonia-lyase (PAL) gene was cloned from Dendrobium candidum using homology cloning and RACE. The full-length sequence and catalytic active sites that appear in PAL proteins of Arabidopsis thaliana and Nicotiana tabacum are also found: PAL cDNA of D. candidum (designated Dc-PAL1, GenBank No. JQ765748) has 2,458 bps and contains a complete open reading frame (ORF) of 2,142 bps, which encodes 713 amino acid residues. The amino acid sequence of DcPAL1 has more than 80% sequence identity with the PAL genes of other plants, as indicated by multiple alignments. The dominant sites and catalytic active sites, which are similar to that showing in PAL proteins of Arabidopsis thaliana and Nicotiana tabacum, are also found in DcPAL1. Phylogenetic tree analysis revealed that DcPAL is more closely related to PALs from orchidaceae plants than to those of other plants. The differential expression patterns of PAL in protocorm-like body, leaf, stem, and root, suggest that the PAL gene performs multiple physiological functions in Dendrobium candidum. PMID:23638048

The human cytoplasmic dynein interactome reveals novel activators of motility

PubMed Central

Redwine, William B; DeSantis, Morgan E; Hollyer, Ian; Htet, Zaw Min; Tran, Phuoc Tien; Swanson, Selene K; Florens, Laurence; Washburn, Michael P; Reck-Peterson, Samara L

2017-01-01

In human cells, cytoplasmic dynein-1 is essential for long-distance transport of many cargos, including organelles, RNAs, proteins, and viruses, towards microtubule minus ends. To understand how a single motor achieves cargo specificity, we identified the human dynein interactome by attaching a promiscuous biotin ligase (‘BioID’) to seven components of the dynein machinery, including a subunit of the essential cofactor dynactin. This method reported spatial information about the large cytosolic dynein/dynactin complex in living cells. To achieve maximal motile activity and to bind its cargos, human dynein/dynactin requires ‘activators’, of which only five have been described. We developed methods to identify new activators in our BioID data, and discovered that ninein and ninein-like are a new family of dynein activators. Analysis of the protein interactomes for six activators, including ninein and ninein-like, suggests that each dynein activator has multiple cargos. DOI: http://dx.doi.org/10.7554/eLife.28257.001 PMID:28718761

Structure of the Mitochondrial Aminolevulinic Acid Synthase, a Key Heme Biosynthetic Enzyme.

PubMed

Brown, Breann L; Kardon, Julia R; Sauer, Robert T; Baker, Tania A

2018-04-03

5-Aminolevulinic acid synthase (ALAS) catalyzes the first step in heme biosynthesis. We present the crystal structure of a eukaryotic ALAS from Saccharomyces cerevisiae. In this homodimeric structure, one ALAS subunit contains covalently bound cofactor, pyridoxal 5'-phosphate (PLP), whereas the second is PLP free. Comparison between the subunits reveals PLP-coupled reordering of the active site and of additional regions to achieve the active conformation of the enzyme. The eukaryotic C-terminal extension, a region altered in multiple human disease alleles, wraps around the dimer and contacts active-site-proximal residues. Mutational analysis demonstrates that this C-terminal region that engages the active site is important for ALAS activity. Our discovery of structural elements that change conformation upon PLP binding and of direct contact between the C-terminal extension and the active site thus provides a structural basis for investigation of disruptions in the first step of heme biosynthesis and resulting human disorders. Copyright © 2018 Elsevier Ltd. All rights reserved.

Single-Cell Analysis Reveals that Insulation Maintains Signaling Specificity between Two Yeast MAPK Pathways with Common Components

PubMed Central

Patterson, Jesse C.; Klimenko, Evguenia S.; Thorner, Jeremy

2014-01-01

Eukaryotic cells use multiple mitogen-activated protein kinase (MAPK) cascades to evoke appropriate responses to external stimuli. In Saccharomyces cerevisiae, the MAPK Fus3 is activated by pheromone-binding G protein-coupled receptors to promote mating, whereas the MAPK Hog1 is activated by hyperosmotic stress to elicit the high osmolarity glycerol (HOG) response. Although these MAPK pathways share several upstream components, exposure to either pheromone or osmolyte alone triggers only the appropriate response. We used fluorescent localization- and transcription-specific reporters to assess activation of these pathways in individual cells on the minute and hour timescale, respectively. Dual activation of these two MAPK pathways occurred over a broad range of stimulant concentrations and temporal regimes in wild-type cells subjected to co-stimulation. Thus, signaling specificity is achieved through an “insulation” mechanism, not a “cross-inhibition” mechanism. Furthermore, we showed that there was a critical period during which Hog1 activity had to occur for proper insulation of the HOG pathway. PMID:20959523

Effect of a sport education program on motivation for physical education and leisure-time physical activity.

PubMed

Wallhead, Tristan L; Garn, Alex C; Vidoni, Carla

2014-12-01

The purpose of this study was to examine the effect of a high school sport education curriculum program on students' motivation for physical education and leisure-time physical activity. Participants were 568 high school students enrolled in the required physical education programs at 2 schools, 1 taught using sport education and the 2nd using a multiactivity model of instruction. A motivational profile survey, which included student psychological need satisfaction, autonomous motives, perceived effort and enjoyment in physical education, and physical activity intention and behavior, was completed by all participants prior to and at the end of the 2-year physical education program. Mixed-model analysis of variance tests revealed that the students in the sport education program reported greater increases in perceived effort and enjoyment of the program compared with the students taught within the multiactivity model. Hierarchical multiple regression analyses showed that these positive affective outcomes were facilitated by the development of more autonomous forms of motivation. RESULTS revealed limited support for the direct transfer of motivation from a sport education program to increases in leisure-time physical activity behavior. Sport education facilitates more internalized forms of student motivation in required physical education programs, but without the provision of an appropriately designed extracurricular outlet, the potential of transfer to leisure-time physical activity may not be achieved.

Research regarding biodegradable properties of food polymeric products under microorganism activity

NASA Astrophysics Data System (ADS)

Opran, Constantin; Lazar, Veronica; Fierascu, Radu Claudiu; Ditu, Lia Mara

2018-02-01

Aim of this research is the structural analysis by comparison of the biodegradable properties of two polymeric products made by non-biodegradable polymeric material (polypropylene TIPPLEN H949 A) and biodegradable polymeric material (ECOVIO IS 1335), under microorganism activity in order to give the best solution for the manufacture of food packaging biodegradable products. It presents the results of experimental determinations on comparative analysis of tensile strength for the two types of polymers. The sample weight variations after fungal biodegradation activity revealed that, after 3 months, there are no significant changes in polymeric substratum for non-biodegradable polymeric. The microscopically analysis showed that the fungal filaments did not strongly adhered on the non-biodegradable polymeric material, instead, both filamentous fungi strains adhered and covered the surface of the biodegradable sample with germinated filamentous conidia. The spectral analysis of polymer composition revealed that non-biodegradable polymer polypropylene spectra are identical for control and for samples that were exposed to fungal activity, suggesting that this type of sample was not degraded by the fungi strains. Instead, for biodegradable polymer sample, it was observed significant structural changes across multiple absorption bands, suggesting enzyme activity manifested mainly by Aspergillus niger strain. Structural analysis of interdisciplinary research results, lead, to achieving optimal injection molded technology emphasizing technological parameters, in order to obtain food packaging biodegradable products.

Virus-induced apoptosis and phosphorylation form of metacaspase in the marine coccolithophorid Emiliania huxleyi.

PubMed

Liu, Jingwen; Cai, Weicong; Fang, Xian; Wang, Xueting; Li, Guiling

2018-04-01

Lytic viral infection and programmed cell death (PCD) are thought to represent two distinct death mechanisms in phytoplankton, unicellular photoautotrophs that drift with ocean currents. PCD (apoptosis) is mainly brought about by the activation of caspases, a protease family with unique substrate selectivity. Here, we demonstrated that virus infection induced apoptosis of marine coccolithophorid Emiliania huxleyi BOF92 involving activation of metacaspase. E. huxleyi cells exhibited cell death process akin to that of apoptosis when exposed to virus infection. We observed typical hallmarks of apoptosis including cell shrinkage, associated nuclear morphological changes and DNA fragmentation. Immunoblotting revealed that antibody against human active-caspase-3 shared epitopes with a protein of ≈ 23 kDa; whose pattern of expression correlated with the onset of cell death. Moreover, analysis on two-dimensional gel electrophoresis revealed that two spots of active caspase-3 co-migrated with the different isoelectric points. Phosphatase treatment of cytosolic extracts containing active caspases-3 showed a mobility shift, suggesting that phosphorylated form of this enzyme might be present in the extracts. Computational prediction of phosphorylation sites based on the amino acid sequence of E. huxleyi metacaspase showed multiple phosphorylated sites for serine, threonine and tyrosine residues. This is the first report showing that phosphorylation modification of metacaspase in E. huxleyi might be required for certain biochemical and morphological changes during virus induced apoptosis.

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

Primary malignant melanoma of the gallbladder with multiple metastases: A case report.

PubMed

Wang, Jun-Ke; Su, Fei; Ma, Wen-Jie; Hu, Hai-Jie; Yang, Qin; Liu, Fei; Li, Quan-Sheng; Li, Fu-Yu

2017-11-01

Primary malignant melanoma of the gallbladder is an extremely rare tumor, with fewer than 40 cases reported in the literature worldwide. The majority of patients presented as a solitary lesion in the gallbladder. To our knowledge, only one case of primary malignant melanoma of the gallbladder with multiple metastases has been reported, which involved the stomach, duodenum, pancreas, jejunum and a mesenteric lymph node. We report a case of primary malignant melanoma of the gallbladder with metastases to the duodenal bulb, right adrenal and a celiac lymph node. Primary malignant melanoma of the gallbladder with multiple metastases. Gastrojejunostomy, cholecystectomy, and biopsy of the three metastatic lesions were performed. Histopathologic examination revealed melanin pigments were within the tumor cells of the four lesions, however, junctional activity was noted only in the gallbladder, supporting that the gallbladder was the primary site. No pigmented lesions were detected on the skin or eyes. The postoperative recovery was uneventful, and subsequently, chemotherapy with paclitaxel and carboplatin was administered. The patient survived for 16 months due to tumor. progression. The current case was unique due to the adrenal involvement. For patients with multiple metastases of malignant melanoma, gallbladder origin should be considered in the differential diagnosis from cutaneous origin.

Semaphorin4A Is Cytotoxic to Oligodendrocytes and Is Elevated in Microglia and Multiple Sclerosis

PubMed Central

Leitner, Dominique F.; Todorich, Bozho; Zhang, Xuesheng

2015-01-01

We have previously established that T cell immunoglobulin and mucin domain containing 2 (Tim2) is an H-ferritin receptor on oligodendrocytes (OLs). Tim2 also binds Semaphorin4A (Sema4A). Sema4A is expressed by lymphocytes, and its role in immune activation is known; however, its relationship to diseases that are known to have myelin damage has not been studied. In this study, we demonstrate that Sema4A is cytotoxic to OLs in culture: an effect accompanied by process collapse, membrane blebbing, and phosphatidylserine inversion. We further demonstrate that Sema4A preferentially binds to primary OLs but not astrocytes: an observation consistent with the lack of expression of Tim2 on astrocytes. We found that Sema4A protein levels are increased within multiple sclerosis plaques compared with normal-appearing white matter and that Sema4A induces lactate dehydrogenase release in a human OL cell line. The chief cellular source of Sema4A within the multiple sclerosis plaques appears to be infiltrating lymphocytes and microglia. Macrophages are known to express Sema4A, so we interrogated microglia as a potential source of Sema4A in the brain. We found that rat primary microglia express Sema4A which increased after lipopolysaccharide activation. Because activated microglia accumulate iron, we determined whether iron status influenced Sema4A and found that iron chelation decreased Sema4A and iron loading increased Sema4A in activated microglia. Overall, our data implicate Sema4A in the destruction of OLs and reveal that its expression is sensitive to iron levels. PMID:26024919

Electron Transfer as a Probe of the Interfacial Quantum Dot-Organic Molecule Interaction

NASA Astrophysics Data System (ADS)

Peterson, Mark D.

This dissertation describes a set of experimental and theoretical studies of the interaction between small organic molecules and the surfaces of semiconductor nanoparticles, also called quantum dots (QDs). Chapter 1 reviews the literature on the influence of ligands on exciton relaxation dynamics following photoexcitation of semiconductor QDs, and describes how ligands promote or inhibit processes such as emission, nonradiative relaxation, and charge transfer to redox active adsorbates. Chapter 2 investigates the specific interaction of alkylcarboxylated viologen derivatives with CdS QDs, and shows how a combination of steady-state photoluminescence (PL) and transient absorption (TA) experiments can be used to reveal the specific binding geometry of redox active organic molecules on QD surfaces. Chapter 3 expands on Chapter 2 by using PL and TA to provide information about the mechanisms through which methyl viologen (MV 2+) associates with CdS QDs to form a stable QD/MV2+ complex, suggesting two chemically distinct reactions. We use our understanding of the QD/molecule interaction to design a drug delivery system in Chapter 4, which employs PL and TA experiments to show that conformational changes in a redox active adsorbate may follow electron transfer, "activating" a biologically inert Schiff base to a protein inhibitor form. The protein inhibitor limits cell motility and may be used to prevent tumor metastasis in cancer patients. Chapter 5 discusses future applications of QD/molecule redox couples with an emphasis on efficient multiple charge-transfer reactions -- a process facilitated by the high degeneracy of band-edge states in QDs. These multiple charge-transfer reactions may potentially increase the thermodynamic efficiency of solar cells, and may also facilitate the splitting of water into fuel. Multiple exciton generation procedures, multi-electron transfer experiments, and future directions are discussed.

Curcumin activates human glutathione S-transferase P1 expression through antioxidant response element.

PubMed

Nishinaka, Toru; Ichijo, Yusuke; Ito, Maki; Kimura, Masayoshi; Katsuyama, Masato; Iwata, Kazumi; Miura, Takeshi; Terada, Tomoyuki; Yabe-Nishimura, Chihiro

2007-05-15

Curcumin is a plant-derived diferuloylmethane compound extracted from Curcuma longa, possessing antioxidative and anticarcinogenic properties. Antioxidants and oxidative stress are known to induce the expression of certain classes of detoxification enzymes. Since the upregulation of detoxifying enzymes affects the drug metabolism and cell defense system, it is important to understand the gene regulation by such agents. In this study, we demonstrated that curcumin could induce the expression of human glutathione S-transferase P1 (GSTP1). In HepG2 cells treated with 20muM curcumin, the level of GSTP1 mRNA was significantly increased. In luciferase reporter assays, curcumin augmented the promoter activity of a reporter construct carrying 336bp upstream of the 5'-flanking region of the GSTP1 gene. Mutation analyses revealed that the region including antioxidant response element (ARE), which overlaps AP1 in sequence, was essential to the response to curcumin. While the introduction of a wild-type Nrf2 expression construct augmented the promoter activity of the GSTP1 gene, co-expression of a dominant-negative Nrf2 abolished the responsiveness to curcumin. In addition, curcumin activated the expression of the luciferase gene from a reporter construct carrying multiple ARE consensus sequences but not one with multiple AP1 sites. In a gel mobility shift assay with an oligonucleotide with GSTP1 ARE, an increase in the amount of the binding complex was observed in the nuclear extracts of curcumin-treated HepG2 cells. These results suggested that ARE is the primary sequence for the curcumin-induced transactivation of the GSTP1 gene. The induction of GSTP1 may be one of the mechanisms underlying the multiple actions of curcumin.

Molecular evolution of multiple-level control of heme biosynthesis pathway in animal kingdom.

PubMed

Tzou, Wen-Shyong; Chu, Ying; Lin, Tzung-Yi; Hu, Chin-Hwa; Pai, Tun-Wen; Liu, Hsin-Fu; Lin, Han-Jia; Cases, Ildeofonso; Rojas, Ana; Sanchez, Mayka; You, Zong-Ye; Hsu, Ming-Wei

2014-01-01

Adaptation of enzymes in a metabolic pathway can occur not only through changes in amino acid sequences but also through variations in transcriptional activation, mRNA splicing and mRNA translation. The heme biosynthesis pathway, a linear pathway comprised of eight consecutive enzymes in animals, provides researchers with ample information for multiple types of evolutionary analyses performed with respect to the position of each enzyme in the pathway. Through bioinformatics analysis, we found that the protein-coding sequences of all enzymes in this pathway are under strong purifying selection, from cnidarians to mammals. However, loose evolutionary constraints are observed for enzymes in which self-catalysis occurs. Through comparative genomics, we found that in animals, the first intron of the enzyme-encoding genes has been co-opted for transcriptional activation of the genes in this pathway. Organisms sense the cellular content of iron, and through iron-responsive elements in the 5' untranslated regions of mRNAs and the intron-exon boundary regions of pathway genes, translational inhibition and exon choice in enzymes may be enabled, respectively. Pathway product (heme)-mediated negative feedback control can affect the transport of pathway enzymes into the mitochondria as well as the ubiquitin-mediated stability of enzymes. Remarkably, the positions of these controls on pathway activity are not ubiquitous but are biased towards the enzymes in the upstream portion of the pathway. We revealed that multiple-level controls on the activity of the heme biosynthesis pathway depend on the linear depth of the enzymes in the pathway, indicating a new strategy for discovering the molecular constraints that shape the evolution of a metabolic pathway.

Extracellular cyclophilin-A stimulates ERK1/2 phosphorylation in a cell-dependent manner but broadly stimulates nuclear factor kappa B

PubMed Central

2012-01-01

Background Although the peptidyl-prolyl isomerase, cyclophilin-A (peptidyl-prolyl isomerase, PPIA), has been studied for decades in the context of its intracellular functions, its extracellular roles as a major contributor to both inflammation and multiple cancers have more recently emerged. A wide range of activities have been ascribed to extracellular PPIA that include induction of cytokine and matrix metalloproteinase (MMP) secretion, which potentially underlie its roles in inflammation and tumorigenesis. However, there have been conflicting reports as to which particular signaling events are under extracellular PPIA regulation, which may be due to either cell-dependent responses and/or the use of commercial preparations recently shown to be highly impure. Methods We have produced and validated the purity of recombinant PPIA in order to subject it to a comparative analysis between different cell types. Specifically, we have used a combination of multiple methods such as luciferase reporter screens, translocation assays, phosphorylation assays, and nuclear magnetic resonance to compare extracellular PPIA activities in several different cell lines that included epithelial and monocytic cells. Results Our findings have revealed that extracellular PPIA activity is cell type-dependent and that PPIA signals via multiple cellular receptors beyond the single transmembrane receptor previously identified, Extracellular Matrix MetalloPRoteinase Inducer (EMMPRIN). Finally, while our studies provide important insight into the cell-specific responses, they also indicate that there are consistent responses such as nuclear factor kappa B (NFκB) signaling induced in all cell lines tested. Conclusions We conclude that although extracellular PPIA activates several common pathways, it also targets different receptors in different cell types, resulting in a complex, integrated signaling network that is cell type-specific. PMID:22631225

Structure of the Newcastle disease virus hemagglutinin-neuraminidase (HN) ectodomain reveals a four-helix bundle stalk

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

Yuan, Ping; Swanson, Kurt A.; Leser, George P.

2014-10-02

The paramyxovirus hemagglutinin-neuraminidase (HN) protein plays multiple roles in viral entry and egress, including binding to sialic acid receptors, activating the fusion (F) protein to activate membrane fusion and viral entry, and cleaving sialic acid from carbohydrate chains. HN is an oligomeric integral membrane protein consisting of an N-terminal transmembrane domain, a stalk region, and an enzymatically active neuraminidase (NA) domain. Structures of the HN NA domains have been solved previously; however, the structure of the stalk region has remained elusive. The stalk region contains specificity determinants for F interactions and activation, underlying the requirement for homotypic F and HNmore » interactions in viral entry. Mutations of the Newcastle disease virus HN stalk region have been shown to affect both F activation and NA activities, but a structural basis for understanding these dual affects on HN functions has been lacking. Here, we report the structure of the Newcastle disease virus HN ectodomain, revealing dimers of NA domain dimers flanking the N-terminal stalk domain. The stalk forms a parallel tetrameric coiled-coil bundle (4HB) that allows classification of extensive mutational data, providing insight into the functional roles of the stalk region. Mutations that affect both F activation and NA activities map predominantly to the 4HB hydrophobic core, whereas mutations that affect only F-protein activation map primarily to the 4HB surface. Two of four NA domains interact with the 4HB stalk, and residues at this interface in both the stalk and NA domain have been implicated in HN function.« less

Development and Validation of a Computational Model for Androgen Receptor Activity

PubMed Central

2016-01-01

Testing thousands of chemicals to identify potential androgen receptor (AR) agonists or antagonists would cost millions of dollars and take decades to complete using current validated methods. High-throughput in vitro screening (HTS) and computational toxicology approaches can more rapidly and inexpensively identify potential androgen-active chemicals. We integrated 11 HTS ToxCast/Tox21 in vitro assays into a computational network model to distinguish true AR pathway activity from technology-specific assay interference. The in vitro HTS assays probed perturbations of the AR pathway at multiple points (receptor binding, coregulator recruitment, gene transcription, and protein production) and multiple cell types. Confirmatory in vitro antagonist assay data and cytotoxicity information were used as additional flags for potential nonspecific activity. Validating such alternative testing strategies requires high-quality reference data. We compiled 158 putative androgen-active and -inactive chemicals from a combination of international test method validation efforts and semiautomated systematic literature reviews. Detailed in vitro assay information and results were compiled into a single database using a standardized ontology. Reference chemical concentrations that activated or inhibited AR pathway activity were identified to establish a range of potencies with reproducible reference chemical results. Comparison with existing Tier 1 AR binding data from the U.S. EPA Endocrine Disruptor Screening Program revealed that the model identified binders at relevant test concentrations (<100 μM) and was more sensitive to antagonist activity. The AR pathway model based on the ToxCast/Tox21 assays had balanced accuracies of 95.2% for agonist (n = 29) and 97.5% for antagonist (n = 28) reference chemicals. Out of 1855 chemicals screened in the AR pathway model, 220 chemicals demonstrated AR agonist or antagonist activity and an additional 174 chemicals were predicted to have potential weak AR pathway activity. PMID:27933809

Physical activity and exercise priorities in community dwelling people with multiple sclerosis: a Delphi study.

PubMed

Stennett, Andrea; De Souza, Lorraine; Norris, Meriel

2018-07-01

Exercise and physical activity have been found to be beneficial in managing disabilities caused by multiple sclerosis. Despite the known benefits, many people with multiple sclerosis are inactive. This study aimed to identify the prioritised exercise and physical activity practices of people with multiple sclerosis living in the community and the reasons why they are engaged in these activities. A four Round Delphi questionnaire scoped and determined consensus of priorities for the top 10 exercise and physical activities and the reasons why people with multiple sclerosis (n = 101) are engaged in these activities. Data were analysed using content analysis, descriptive statistics, and non-parametric tests. The top 10 exercise and physical activity practices and the top 10 reasons why people with multiple sclerosis (n = 70) engaged in these activities were identified and prioritised. Consensus was achieved for the exercise and physical activities (W = 0.744, p < .0001) and for the reasons they engaged in exercise and physical activity (W = 0.723, p < .0001). The exercise and physical activity practices and the reasons people with multiple sclerosis engaged in exercise and physical activity were diverse. These self-selected activities and reasons highlighted that people with multiple sclerosis might conceptualise exercise and physical activity in ways that may not be fully appreciated or understood by health professionals. Considerations of the views of people with multiple sclerosis may be essential if the goal of increasing physical activity in this population is to be achieved. Implications for Rehabilitation Health professionals should work collaboratively with people with multiple sclerosis to understand how they prioritise activities, the underlying reasons for their prioritisations and embed these into rehabilitation programmes. Health professionals should utilise activities prioritised by people with multiple sclerosis in the community as a way to support, promote, and sustain exercise and physical activity in this population. Rehabilitation interventions should include both the activities people with multiple sclerosis prioritise and the reasons why they engage in exercise and physical activity as another option for increasing physical activity levels and reducing sedentary behaviours.

IgA-kappa type multiple myeloma affecting proximal and distal renal tubules.

PubMed

Minemura, K; Ichikawa, K; Itoh, N; Suzuki, N; Hara, M; Shigematsu, S; Kobayashi, H; Hiramatsu, K; Hashizume, K

2001-09-01

A 45-year-old male was admitted because of chest pain, lumbago, and bilateral ankle pain. Examination disclosed hypophosphatemic osteomalacia, acquired Fanconi syndrome, and abnormalities in distal nephron such as distal renal tubular acidosis and renal diabetes insipidus. Further exploration revealed IgA kappa multiple myeloma excreting urinary Bence Jones protein (kappa-light chain). Renal biopsy revealed thick basement membranes and elec-tron-dense crystals in proximal tubular epithelial cells. Immunofluorescent studies revealed deposition of kappa-light chain in renal tubular epithelial cells that caused the renal tubular damage. Although the osteomalacia was relieved by medical treatment, the urinary Bence Jones protein and the renal tubular defects were not improved by the chemotherapy for the myeloma. The patient died of exacerbation of multiple myeloma at 50 years of age.

Proteomics investigation reveals cell death-associated proteins of basidiomycete fungus Trametes versicolor treated with Ferruginol.

PubMed

Chen, Yu-Han; Yeh, Ting-Feng; Chu, Fang-Hua; Hsu, Fu-Lan; Chang, Shang-Tzen

2015-01-14

Ferruginol has antifungal activity against wood-rot fungi (basidiomycetes). However, specific research on the antifungal mechanisms of ferruginol is scarce. Two-dimensional gel electrophoresis and fluorescent image analysis were employed to evaluate the differential protein expression of wood-rot fungus Trametes versicolor treated with or without ferruginol. Results from protein identification of tryptic peptides via liquid chromatography–electrospray ionization tandem mass spectrometry (LC–ESI-MS/MS) analyses revealed 17 protein assignments with differential expression. Downregulation of cytoskeleton β-tubulin 3 indicates that ferruginol has potential to be used as a microtubule-disrupting agent. Downregulation of major facilitator superfamily (MFS)–multiple drug resistance (MDR) transporter and peroxiredoxin TSA1 were observed, suggesting reduction in self-defensive capabilities of T. versicolor. In addition, the proteins involved in polypeptide sorting and DNA repair were also downregulated, while heat shock proteins and autophagy-related protein 7 were upregulated. These observations reveal that such cellular dysfunction and damage caused by ferruginol lead to growth inhibition and autophagic cell death of fungi.

[Correlation of brain electrical activity and motivation in healthy people].

PubMed

Bogovin, L V; Nakhamchen, D L; Kolosov, V P; Perel'man, Iu M

2014-01-01

Motivation dominates in the structure of the personality and is one of the basic notions which explains the dynamics of the behavior. The literature has little data about neurophysiology of motivation. The aim of the research was to study the correlation between the motivational sphere and electrical activity of the brain at the influence of different provocations. 24 healthy people at the age of 26-36 years were examined. The results of motivation tests turned out to be uniform (the motivation to success was of a moderate or high level, there were mean values of readiness to risk and low motivation to achievement and approval). Multiple correlations between different types of motivation and electrical activity of the brain at rest, at hyperventilation with room temperature air and at isocapnic cold air hyperventilation were revealed.

Effect of local and global geomagnetic activity on human cardiovascular homeostasis.

PubMed

Dimitrova, Svetla; Stoilova, Irina; Yanev, Toni; Cholakov, Ilia

2004-02-01

The authors investigated the effects of local and planetary geomagnetic activity on human physiology. They collected data in Sofia, Bulgaria, from a group of 86 volunteers during the periods of the autumnal and vernal equinoxes. They used the factors local/planetary geomagnetic activity, day of measurement, gender, and medication use to apply a four-factor multiple analysis of variance. They also used a post hoc analysis to establish the statistical significance of the differences between the average values of the measured physiological parameters in the separate factor levels. In addition, the authors performed correlation analysis between the physiological parameters examined and geophysical factors. The results revealed that geomagnetic changes had a statistically significant influence on arterial blood pressure. Participants expressed this reaction with weak local geomagnetic changes and when major and severe global geomagnetic storms took place.

Spherical loudspeaker array for local active control of sound.

PubMed

Rafaely, Boaz

2009-05-01

Active control of sound has been employed to reduce noise levels around listeners' head using destructive interference from noise-canceling sound sources. Recently, spherical loudspeaker arrays have been studied as multiple-channel sound sources, capable of generating sound fields with high complexity. In this paper, the potential use of a spherical loudspeaker array for local active control of sound is investigated. A theoretical analysis of the primary and secondary sound fields around a spherical sound source reveals that the natural quiet zones for the spherical source have a shell-shape. Using numerical optimization, quiet zones with other shapes are designed, showing potential for quiet zones with extents that are significantly larger than the well-known limit of a tenth of a wavelength for monopole sources. The paper presents several simulation examples showing quiet zones in various configurations.

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.

Pervasive competition between threat and reward in the brain.

PubMed

Choi, Jong Moon; Padmala, Srikanth; Spechler, Philip; Pessoa, Luiz

2014-06-01

In the current functional MRI study, we investigated interactions between reward and threat processing. Visual cues at the start of each trial informed participants about the chance of winning monetary reward and/or receiving a mild aversive shock. We tested two competing hypothesis: according to the 'salience hypothesis', in the condition involving both reward and threat, enhanced activation would be observed because of increased salience; according to the 'competition hypothesis', the processing of reward and threat would trade-off against each other, leading to reduced activation. Analysis of skin conductance data during a delay phase revealed an interaction between reward and threat processing, such that the effect of reward was reduced during threat and the effect of threat was reduced during reward. Analysis of imaging data during the same task phase revealed interactions between reward and threat processing in several regions, including the midbrain/ventral tegmental area, caudate, putamen, bed nucleus of the stria terminalis, anterior insula, middle frontal gyrus and dorsal anterior cingulate cortex. Taken together, our findings reveal conditions during which reward and threat trade-off against each other across multiple sites. Such interactions are suggestive of competitive processes and may reflect the organization of opponent systems in the brain. © The Author (2013). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Burnout, stress and satisfaction among Australian and New Zealand radiation oncology trainees.

PubMed

Leung, John; Rioseco, Pilar

2017-02-01

To evaluate the incidence of burnout among radiation oncology trainees in Australia and New Zealand and the stress and satisfaction factors related to burnout. A survey of trainees was conducted in mid-2015. There were 42 Likert scale questions on stress, 14 Likert scale questions on satisfaction and the Maslach Burnout Inventory-Human Services Survey assessed burnout. A principal component analysis identified specific stress and satisfaction areas. Categorical variables for the stress and satisfaction factors were computed. Associations between respondent's characteristics and stress and satisfaction subscales were examined by independent sample t-tests and analysis of variance. Effect sizes were calculated using Cohens's d when significant mean differences were observed. This was also done for respondent characteristics and the three burnout subscales. Multiple regression analyses were performed. The response rate was 81.5%. The principal component analysis for stress identified five areas: demands on time, professional development/training, delivery demands, interpersonal demands and administration/organizational issues. There were no significant differences by demographic group or area of interest after P-values were adjusted for the multiple tests conducted. The principal component analysis revealed two satisfaction areas: resources/professional activities and value/delivery of services. There were no significant differences by demographic characteristics or area of interest in the level of satisfaction after P-values were adjusted for the multiple tests conducted. The burnout results revealed 49.5% of respondents scored highly in emotional exhaustion and/or depersonalization and 13.1% had burnout in all three measures. Multiple regression analysis revealed the stress subscales 'demands on time' and 'interpersonal demands' were associated with emotional exhaustion. 'Interpersonal demands' was also associated with depersonalization and correlated negatively with personal accomplishment. The satisfaction of value/delivery of services subscale was associated with higher levels of personal accomplishment. There is a significant level of burnout among radiation oncology trainees in Australia and New Zealand. Further work addressing intervention would be appropriate to reduce levels of burnout. © 2016 The Authors. Journal of Medical Imaging and Radiation Oncology published by John Wiley & Sons Australia, Ltd on behalf of The Royal Australian and New Zealand College of Radiologists.

Developmental Regulation of an Adhesin Gene during Cellular Morphogenesis in the Fungal Pathogen Candida albicans▿ †

PubMed Central

Argimón, Silvia; Wishart, Jill A.; Leng, Roger; Macaskill, Susan; Mavor, Abigail; Alexandris, Thomas; Nicholls, Susan; Knight, Andrew W.; Enjalbert, Brice; Walmsley, Richard; Odds, Frank C.; Gow, Neil A. R.; Brown, Alistair J. P.

2007-01-01

Candida albicans expresses specific virulence traits that promote disease establishment and progression. These traits include morphological transitions between yeast and hyphal growth forms that are thought to contribute to dissemination and invasion and cell surface adhesins that promote attachment to the host. Here, we describe the regulation of the adhesin gene ALS3, which is expressed specifically during hyphal development in C. albicans. Using a combination of reporter constructs and regulatory mutants, we show that this regulation is mediated by multiple factors at the transcriptional level. The analysis of ALS3 promoter deletions revealed that this promoter contains two activation regions: one is essential for activation during hyphal development, while the second increases the amplitude of this activation. Further deletion analyses using the Renilla reniformis luciferase reporter delineate the essential activation region between positions −471 and −321 of the promoter. Further 5′ or 3′ deletions block activation. ALS3 transcription is repressed mainly by Nrg1 and Tup1, but Rfg1 contributes to this repression. Efg1, Tec1, and Bcr1 are essential for the transcriptional activation of ALS3, with Tec1 mediating its effects indirectly through Bcr1 rather than through the putative Tec1 sites in the ALS3 promoter. ALS3 transcription is not affected by Cph2, but Cph1 contributes to full ALS3 activation. The data suggest that multiple morphogenetic signaling pathways operate through the promoter of this adhesin gene to mediate its developmental regulation in this major fungal pathogen. PMID:17277173

Modelling the impact of correlations between condom use and sexual contact pattern on the dynamics of sexually transmitted infections.

PubMed

Yamamoto, Nao; Ejima, Keisuke; Nishiura, Hiroshi

2018-05-31

It is believed that sexually active people, i.e. people having multiple or concurrent sexual partners, are at a high risk of sexually transmitted infections (STI), but they are likely to be more aware of the risk and may exhibit greater fraction of the use of condom. The purpose of the present study is to examine the correlation between condom use and sexual contact pattern and clarify its impact on the transmission dynamics of STIs using a mathematical model. The definition of sexual contact pattern can be broad, but we focus on two specific aspects: (i) type of partnership (i.e. steady or casual partnership) and (ii) existence of concurrency (i.e. with single or multiple partners). Systematic review and meta-analysis of published studies are performed, analysing literature that epidemiologically examined the relationship between condom use and sexual contact pattern. Subsequently, we employ an epidemiological model and compute the reproduction number that accounts for with and without concurrency so that the corresponding coverage of condom use and its correlation with existence of concurrency can be explicitly investigated using the mathematical model. Combining the model with parameters estimated from the meta-analysis along with other assumed parameters, the impact of varying the proportion of population with multiple partners on the reproduction number is examined. Based on systematic review, we show that a greater number of people used condoms during sexual contact with casual partners than with steady partners. Furthermore, people with multiple partners use condoms more frequently than people with a single partner alone. Our mathematical model revealed a positive relationship between the effective reproduction number and the proportion of people with multiple partners. Nevertheless, the association was reversed to be negative by employing a slightly greater value of the relative risk of condom use for people with multiple partners than that empirically estimated. Depending on the correlation between condom use and the existence of concurrency, association between the proportion of people with multiple partners and the reproduction number can be reversed, suggesting the sexually active population is not necessary a primary target population to encourage condom use (i.e., sexually less active individuals could equivalently be a target in some cases).

Relation Between Magnetospheric State Parameters and the Occurrence of Plasma Depletion Events in the Nighttime Midlatitude F Region

NASA Technical Reports Server (NTRS)

Seker, Ilgin; Fung, Shing F.; Mathews, John D.

2011-01-01

Studies using all-sky imagers have revealed the presence of various ionospheric irregularities in the nighttime midlatitude F region. The most prevalent and well known of these are the medium-scale traveling ionospheric disturbances (MSTIDs) that usually occur when the geomagnetic activity is low and midlatitude spread F plumes that are often observed when the geomagnetic activity is high. The inverse and direct relations between geomagnetic activity and the occurrence rate of MSTIDs and midlatitude plumes, respectively, have been observed by several studies using different instruments; however, most of them focus on MSTIDs only and use only Kp to characterize geomagnetic activity. In order to understand the underlying causes of these two relations and to distinguish between MSTIDs and plumes, it is illuminating to better characterize the occurrence of MSTIDs and plumes using multiple magnetospheric state parameters. Here we statistically compare multiple geomagnetic driver and response parameters (such as Kp, AE, Dst, and solar wind parameters) with the occurrence rates of nighttime MSTIDs and plumes observed using an all ]sky imager at Arecibo Observatory (AO) between 2003 and 2008. We also present seasonal and annual variations of MSTIDs and plumes at AO. The results not only allow us to better distinguish MSTIDs and plumes, but also to shed further light on the generation mechanism and electrodynamics of these two different phenomena occurring at nighttime in the midlatitude F region.

Correlated components of ongoing EEG point to emotionally laden attention - a possible marker of engagement?

PubMed

Dmochowski, Jacek P; Sajda, Paul; Dias, Joao; Parra, Lucas C

2012-01-01

Recent evidence from functional magnetic resonance imaging suggests that cortical hemodynamic responses coincide in different subjects experiencing a common naturalistic stimulus. Here we utilize neural responses in the electroencephalogram (EEG) evoked by multiple presentations of short film clips to index brain states marked by high levels of correlation within and across subjects. We formulate a novel signal decomposition method which extracts maximally correlated signal components from multiple EEG records. The resulting components capture correlations down to a one-second time resolution, thus revealing that peak correlations of neural activity across viewings can occur in remarkable correspondence with arousing moments of the film. Moreover, a significant reduction in neural correlation occurs upon a second viewing of the film or when the narrative is disrupted by presenting its scenes scrambled in time. We also probe oscillatory brain activity during periods of heightened correlation, and observe during such times a significant increase in the theta band for a frontal component and reductions in the alpha and beta frequency bands for parietal and occipital components. Low-resolution EEG tomography of these components suggests that the correlated neural activity is consistent with sources in the cingulate and orbitofrontal cortices. Put together, these results suggest that the observed synchrony reflects attention- and emotion-modulated cortical processing which may be decoded with high temporal resolution by extracting maximally correlated components of neural activity.

Correlated Components of Ongoing EEG Point to Emotionally Laden Attention – A Possible Marker of Engagement?

PubMed Central

Dmochowski, Jacek P.; Sajda, Paul; Dias, Joao; Parra, Lucas C.

2012-01-01

Recent evidence from functional magnetic resonance imaging suggests that cortical hemodynamic responses coincide in different subjects experiencing a common naturalistic stimulus. Here we utilize neural responses in the electroencephalogram (EEG) evoked by multiple presentations of short film clips to index brain states marked by high levels of correlation within and across subjects. We formulate a novel signal decomposition method which extracts maximally correlated signal components from multiple EEG records. The resulting components capture correlations down to a one-second time resolution, thus revealing that peak correlations of neural activity across viewings can occur in remarkable correspondence with arousing moments of the film. Moreover, a significant reduction in neural correlation occurs upon a second viewing of the film or when the narrative is disrupted by presenting its scenes scrambled in time. We also probe oscillatory brain activity during periods of heightened correlation, and observe during such times a significant increase in the theta band for a frontal component and reductions in the alpha and beta frequency bands for parietal and occipital components. Low-resolution EEG tomography of these components suggests that the correlated neural activity is consistent with sources in the cingulate and orbitofrontal cortices. Put together, these results suggest that the observed synchrony reflects attention- and emotion-modulated cortical processing which may be decoded with high temporal resolution by extracting maximally correlated components of neural activity. PMID:22623915

High-level expression of two thermophilic β-mannanases in Yarrowialipolytica.

PubMed

YaPing, Wang; Ben, Rao; Ling, Zhang; Lixin, Ma

2017-05-01

Two thermophilic β-mannanases (ManA and ManB)were successfully expressed in Yarrowialipolytica using vector pINA1296I. The sequences of manA from Aspergillus niger CBS 513.88 and manB from Bacillus subtilis BCC41051 were optimized based on codon-usage bias in Y.lipolytica and synthesized by overlapping polymerase chain reaction (PCR). We utilized the pINA1296I vector, which allows inserting and expression of multiple copies of an expression cassette, to engineer recombinant strains containing multiple copies of manA or manB. Following verification of target-gene expression by quantitative PCR, fermentation experiments indicated that recombinant protein levels and enzyme activity increased along with increasing manA/manB copy number.After production in a 10 l fermenter, we obtained maximum enzyme activity from strains YLA6 and YLB6 of3024 U/mL and 1024 U/mL, respectively. Additionally, purification and characterization results revealed that the optimum pH and temperature for manA activity were pH∼5 and ∼70 °C, and for manB activity were pH∼7 and 60 °C, respectively. These results indicated that the thermo stabilities of these two enzymes were higher than most other mannanases, making them potentially useful for industrial applications. Copyright © 2017 Elsevier Inc. All rights reserved.

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

Association of TLR1, TLR2, TLR4, TLR6, and TIRAP polymorphisms with disease susceptibility.

PubMed

Noreen, Mamoona; Arshad, Muhammad

2015-06-01

Toll like receptors (TLRs) play a crucial role in regulation of innate as well as adaptive immunity. TLRs recognize a distinct but limited repertoire of conserved microbial products. Ligand binding to TLRs activates the signaling cascade and results in activation of multiple inflammatory genes. Variation in this immune response is under genetic control. Polymorphisms in genes associated with inflammatory pathway especially influence the outcome of diseases. TLR2 makes heterodimer with TLR1 or TLR6 and recognizes a wide variety of microbial ligands. In this review, we summarize studies of polymorphisms in genes encoding TLR1, TLR2, TLR4, TLR6, and most polymorphic adaptor protein, Mal/TIRAP, revealing their effect on susceptibility to diseases.

Effects of polygamy on the activity/rest rhythm of male fruit flies Drosophila melanogaster

NASA Astrophysics Data System (ADS)

Vartak, Vivek Rohidas; Varma, Vishwanath; Sharma, Vijay Kumar

2015-02-01

Although polygamy is common in insects, its extent varies enormously among natural populations. Mating systems influence the evolution of reproductive traits and the difference in extent of polygamy between males and females may be a key factor in determining traits which come under the influence of sexual selection. Fruit flies Drosophila melanogaster are promiscuous as both males and females mate with multiple partners. Mating has severe consequences on the physiology and behaviour of flies, and it affects their activity/rest rhythm in a sex-specific manner. In this study, we attempted to discern the effects of mating with multiple partners as opposed to a single partner, or of remaining unmated, on the activity/rest rhythm of flies under cyclic semi-natural (SN) and constant dark (DD) conditions. The results revealed that while evening activity of mated flies was significantly reduced compared to virgins, polygamous males showed a more severe reduction compared to monogamous males. In contrast, though mated females showed reduction in evening activity compared to virgins, activity levels were not different between polygamous and monogamous females. Although there was no detectable effect of mating on clock period, power of the activity/rest rhythm was significantly reduced in mated females with no difference seen between polygamous and monogamous individuals. These results suggest that courtship motivation, represented by evening activity, is successively reduced in males due to mating with one or more partners, while in females, it does not depend on the number of mating partners. Based on these results we conclude that polygamy affects the activity/rest rhythm of fruit flies D. melanogaster in a sex-dependent manner.

Spectrum and mechanisms of inflammasome activation by chitosan.

PubMed

Bueter, Chelsea L; Lee, Chrono K; Wang, Jennifer P; Ostroff, Gary R; Specht, Charles A; Levitz, Stuart M

2014-06-15

Chitosan, the deacetylated derivative of chitin, can be found in the cell wall of some fungi and is used in translational applications. We have shown that highly purified preparations of chitosan, but not chitin, activate the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome in primed mouse bone marrow-derived macrophages (BMMΦ), inducing a robust IL-1β response. In this article, we further define specific cell types that are activated and delineate mechanisms of activation. BMMΦ differentiated to promote a classically activated (M1) phenotype released more IL-1β in response to chitosan than intermediate or alternatively activated macrophages (M2). Chitosan, but not chitin, induced a robust IL-1β response in mouse dendritic cells, peritoneal macrophages, and human PBMCs. Three mechanisms for NLRP3 inflammasome activation may contribute: K(+) efflux, reactive oxygen species, and lysosomal destabilization. The contributions of these mechanisms were tested using a K(+) efflux inhibitor, high extracellular potassium, a mitochondrial reactive oxygen species inhibitor, lysosomal acidification inhibitors, and a cathepsin B inhibitor. These studies revealed that each of these pathways participated in optimal NLRP3 inflammasome activation by chitosan. Finally, neither chitosan nor chitin stimulated significant release from unprimed BMMΦ of any of 22 cytokines and chemokines assayed. This study has the following conclusions: 1) chitosan, but not chitin, stimulates IL-1β release from multiple murine and human cell types; 2) multiple nonredundant mechanisms appear to participate in inflammasome activation by chitosan; and 3) chitin and chitosan are relatively weak stimulators of inflammatory mediators from unprimed BMMΦ. These data have implications for understanding the nature of the immune response to microbes and biomaterials that contain chitin and chitosan. Copyright © 2014 by The American Association of Immunologists, Inc.

Atomic substitution reveals the structural basis for substrate adenine recognition and removal by adenine DNA glycosylase

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

Lee, Seongmin; Verdine, Gregory L.; Harvard)

2010-01-14

Adenine DNA glycosylase catalyzes the glycolytic removal of adenine from the promutagenic A {center_dot} oxoG base pair in DNA. The general features of DNA recognition by an adenine DNA glycosylase, Bacillus stearothermophilus MutY, have previously been revealed via the X-ray structure of a catalytically inactive mutant protein bound to an A:oxoG-containing DNA duplex. Although the structure revealed the substrate adenine to be, as expected, extruded from the DNA helix and inserted into an extrahelical active site pocket on the enzyme, the substrate adenine engaged in no direct contacts with active site residues. This feature was paradoxical, because other glycosylases havemore » been observed to engage their substrates primarily through direct contacts. The lack of direct contacts in the case of MutY suggested that either MutY uses a distinctive logic for substrate recognition or that the X-ray structure had captured a noncatalytically competent state in lesion recognition. To gain further insight into this issue, we crystallized wild-type MutY bound to DNA containing a catalytically inactive analog of 2'-deoxyadenosine in which a single 2'-H atom was replaced by fluorine. The structure of this fluorinated lesion-recognition complex (FLRC) reveals the substrate adenine buried more deeply into the active site pocket than in the prior structure and now engaged in multiple direct hydrogen bonding and hydrophobic interactions. This structure appears to capture the catalytically competent state of adenine DNA glycosylases, and it suggests a catalytic mechanism for this class of enzymes, one in which general acid-catalyzed protonation of the nucleobase promotes glycosidic bond cleavage.« less

Small G proteins Rac1 and Ras regulate serine/threonine protein phosphatase 5 (PP5)·extracellular signal-regulated kinase (ERK) complexes involved in the feedback regulation of Raf1.

PubMed

Mazalouskas, Matthew D; Godoy-Ruiz, Raquel; Weber, David J; Zimmer, Danna B; Honkanen, Richard E; Wadzinski, Brian E

2014-02-14

Serine/threonine protein phosphatase 5 (PP5, PPP5C) is known to interact with the chaperonin heat shock protein 90 (HSP90) and is involved in the regulation of multiple cellular signaling cascades that control diverse cellular processes, such as cell growth, differentiation, proliferation, motility, and apoptosis. Here, we identify PP5 in stable complexes with extracellular signal-regulated kinases (ERKs). Studies using mutant proteins reveal that the formation of PP5·ERK1 and PP5·ERK2 complexes partially depends on HSP90 binding to PP5 but does not require PP5 or ERK1/2 activity. However, PP5 and ERK activity regulates the phosphorylation state of Raf1 kinase, an upstream activator of ERK signaling. Whereas expression of constitutively active Rac1 promotes the assembly of PP5·ERK1/2 complexes, acute activation of ERK1/2 fails to influence the phosphatase-kinase interaction. Introduction of oncogenic HRas (HRas(V12)) has no effect on PP5-ERK1 binding but selectively decreases the interaction of PP5 with ERK2, in a manner that is independent of PP5 and MAPK/ERK kinase (MEK) activity, yet paradoxically requires ERK2 activity. Additional studies conducted with oncogenic variants of KRas4B reveal that KRas(L61), but not KRas(V12), also decreases the PP5-ERK2 interaction. The expression of wild type HRas or KRas proteins fails to reduce PP5-ERK2 binding, indicating that the effect is specific to HRas(V12) and KRas(L61) gain-of-function mutations. These findings reveal a novel, differential responsiveness of PP5-ERK1 and PP5-ERK2 interactions to select oncogenic Ras variants and also support a role for PP5·ERK complexes in regulating the feedback phosphorylation of PP5-associated Raf1.

The double-stranded break-forming activity of plant SPO11s and a novel rice SPO11 revealed by a Drosophila bioassay

PubMed Central

2012-01-01

Background SPO11 is a key protein for promoting meiotic recombination, by generating chromatin locus- and timing-specific DNA double-strand breaks (DSBs). The DSB activity of SPO11 was shown by genetic analyses, but whether SPO11 exerts DSB-forming activity by itself is still an unanswered question. DSB formation by SPO11 has not been detected by biochemical means, probably because of a lack of proper protein-folding, posttranslational modifications, and/or specific SPO11-interacting proteins required for this activity. In addition, plants have multiple SPO11-homologues. Results To determine whether SPO11 can cleave DNA by itself, and to identify which plant SPO11 homologue cleaves DNA, we developed a Drosophila bioassay system that detects the DSB signals generated by a plant SPO11 homologue expressed ectopically. We cytologically and genetically demonstrated the DSB activities of Arabidopsis AtSPO11-1 and AtSPO11-2, which are required for meiosis, in the absence of other plant proteins. Using this bioassay, we further found that a novel SPO11-homologue, OsSPO11D, which has no counterpart in Arabidopsis, displays prominent DSB-forming activity. Quantitative analyses of the rice SPO11 transcripts revealed the specific increase in OsSPO11D mRNA in the anthers containing meiotic pollen mother cells. Conclusions The Drosophila bioassay system successfully demonstrated that some plant SPO11 orthologues have intrinsic DSB activities. Furthermore, we identified a novel SPO11 homologue, OsSPO11D, with robust DSB activity and a possible meiotic function. PMID:22248237

Pseudomonas syringae pv. actinidiae Type III Effectors Localized at Multiple Cellular Compartments Activate or Suppress Innate Immune Responses in Nicotiana benthamiana.

PubMed

Choi, Sera; Jayaraman, Jay; Segonzac, Cécile; Park, Hye-Jee; Park, Hanbi; Han, Sang-Wook; Sohn, Kee Hoon

2017-01-01

Bacterial phytopathogen type III secreted (T3S) effectors have been strongly implicated in altering the interaction of pathogens with host plants. Therefore, it is useful to characterize the whole effector repertoire of a pathogen to understand the interplay of effectors in plants. Pseudomonas syringae pv. actinidiae is a causal agent of kiwifruit canker disease. In this study, we generated an Agrobacterium -mediated transient expression library of YFP-tagged T3S effectors from two strains of Psa , Psa -NZ V13 and Psa -NZ LV5, in order to gain insight into their mode of action in Nicotiana tabacum and N. benthamiana . Determining the subcellular localization of effectors gives an indication of the possible host targets of effectors. A confocal microscopy assay detecting YFP-tagged Psa effectors revealed that the nucleus, cytoplasm and cell periphery are major targets of Psa effectors. Agrobacterium -mediated transient expression of multiple Psa effectors induced HR-like cell death (HCD) in Nicotiana spp., suggesting that multiple Psa effectors may be recognized by Nicotiana spp.. Virus-induced gene silencing (VIGS) of several known plant immune regulators, EDS1 , NDR1 , or SGT1 specified the requirement of SGT1 in HCD induced by several Psa effectors in N. benthamiana . In addition, the suppression activity of Psa effectors on HCD-inducing proteins and PTI was assessed. Psa effectors showed differential suppression activities on each HCD inducer or PTI. Taken together, our Psa effector repertoire analysis highlights the great diversity of T3S effector functions in planta .

Pseudomonas syringae pv. actinidiae Type III Effectors Localized at Multiple Cellular Compartments Activate or Suppress Innate Immune Responses in Nicotiana benthamiana

PubMed Central

Choi, Sera; Jayaraman, Jay; Segonzac, Cécile; Park, Hye-Jee; Park, Hanbi; Han, Sang-Wook; Sohn, Kee Hoon

2017-01-01

Bacterial phytopathogen type III secreted (T3S) effectors have been strongly implicated in altering the interaction of pathogens with host plants. Therefore, it is useful to characterize the whole effector repertoire of a pathogen to understand the interplay of effectors in plants. Pseudomonas syringae pv. actinidiae is a causal agent of kiwifruit canker disease. In this study, we generated an Agrobacterium-mediated transient expression library of YFP-tagged T3S effectors from two strains of Psa, Psa-NZ V13 and Psa-NZ LV5, in order to gain insight into their mode of action in Nicotiana tabacum and N. benthamiana. Determining the subcellular localization of effectors gives an indication of the possible host targets of effectors. A confocal microscopy assay detecting YFP-tagged Psa effectors revealed that the nucleus, cytoplasm and cell periphery are major targets of Psa effectors. Agrobacterium-mediated transient expression of multiple Psa effectors induced HR-like cell death (HCD) in Nicotiana spp., suggesting that multiple Psa effectors may be recognized by Nicotiana spp.. Virus-induced gene silencing (VIGS) of several known plant immune regulators, EDS1, NDR1, or SGT1 specified the requirement of SGT1 in HCD induced by several Psa effectors in N. benthamiana. In addition, the suppression activity of Psa effectors on HCD-inducing proteins and PTI was assessed. Psa effectors showed differential suppression activities on each HCD inducer or PTI. Taken together, our Psa effector repertoire analysis highlights the great diversity of T3S effector functions in planta. PMID:29326748

Bitter Taste Stimuli Induce Differential Neural Codes in Mouse Brain

PubMed Central

Wilson, David M.; Boughter, John D.; Lemon, Christian H.

2012-01-01

A growing literature suggests taste stimuli commonly classified as “bitter” induce heterogeneous neural and perceptual responses. Here, the central processing of bitter stimuli was studied in mice with genetically controlled bitter taste profiles. Using these mice removed genetic heterogeneity as a factor influencing gustatory neural codes for bitter stimuli. Electrophysiological activity (spikes) was recorded from single neurons in the nucleus tractus solitarius during oral delivery of taste solutions (26 total), including concentration series of the bitter tastants quinine, denatonium benzoate, cycloheximide, and sucrose octaacetate (SOA), presented to the whole mouth for 5 s. Seventy-nine neurons were sampled; in many cases multiple cells (2 to 5) were recorded from a mouse. Results showed bitter stimuli induced variable gustatory activity. For example, although some neurons responded robustly to quinine and cycloheximide, others displayed concentration-dependent activity (p<0.05) to quinine but not cycloheximide. Differential activity to bitter stimuli was observed across multiple neurons recorded from one animal in several mice. Across all cells, quinine and denatonium induced correlated spatial responses that differed (p<0.05) from those to cycloheximide and SOA. Modeling spatiotemporal neural ensemble activity revealed responses to quinine/denatonium and cycloheximide/SOA diverged during only an early, at least 1 s wide period of the taste response. Our findings highlight how temporal features of sensory processing contribute differences among bitter taste codes and build on data suggesting heterogeneity among “bitter” stimuli, data that challenge a strict monoguesia model for the bitter quality. PMID:22844505

Deciphering the biochemical and molecular mechanism underlying the in vitro and in vivo chemotherapeutic efficacy of ruthenium quercetin complex in colon cancer.

PubMed

Roy, Souvik; Das, Rituparna; Ghosh, Balaram; Chakraborty, Tania

2018-06-01

Flavonoids are the most investigated phytochemicals due to their pharmacological and therapeutic activities. Their ability to chelate with metal ions has resulted in the emergence of a new category of molecules with a broader spectrum of pharmacological activities. In this study, the ruthenium quercetin complex has been synthesized and anticancer activity has been evaluated on a well-defined model of DMH followed by DSS induced rat colon cancer and on human colon cancer cell line HT-29. The characterizations accomplished through UV-visible, NMR, IR, Mass spectra and XRD techniques, and antioxidant activity was assessed by DPPH, FRAP, and ABTS methods. In vitro study confirmed that the complex increased p53 expression, reduced VEGF and mTOR expression, apoptosis induction, and DNA fragmentation in the HT-29 cells. Acute and subacute toxicity study was also assessed and results from in vivo study revealed that complex was efficient to suppress ACF multiplicity and hyperplastic lesions and elevated the CAT, SOD, and glutathione levels. Furthermore, the complex was found to decrease cell proliferation and increased apoptotic events in tumor cells correlates upregulation of p53 and Bax and downregulation of Bcl2 expression. Our findings from the in vitro and in vivo study support the continued investigation of ruthenium quercetin complex possesses a potential chemotherapeutic activity against colon cancer and was efficient in reducing ACF multiplicity, hyperplastic lesions in the colon tissues of rats by inducing apoptosis. © 2018 Wiley Periodicals, Inc.

Striatal and Hippocampal Entropy and Recognition Signals in Category Learning: Simultaneous Processes Revealed by Model-Based fMRI

PubMed Central

Davis, Tyler; Love, Bradley C.; Preston, Alison R.

2012-01-01

Category learning is a complex phenomenon that engages multiple cognitive processes, many of which occur simultaneously and unfold dynamically over time. For example, as people encounter objects in the world, they simultaneously engage processes to determine their fit with current knowledge structures, gather new information about the objects, and adjust their representations to support behavior in future encounters. Many techniques that are available to understand the neural basis of category learning assume that the multiple processes that subserve it can be neatly separated between different trials of an experiment. Model-based functional magnetic resonance imaging offers a promising tool to separate multiple, simultaneously occurring processes and bring the analysis of neuroimaging data more in line with category learning’s dynamic and multifaceted nature. We use model-based imaging to explore the neural basis of recognition and entropy signals in the medial temporal lobe and striatum that are engaged while participants learn to categorize novel stimuli. Consistent with theories suggesting a role for the anterior hippocampus and ventral striatum in motivated learning in response to uncertainty, we find that activation in both regions correlates with a model-based measure of entropy. Simultaneously, separate subregions of the hippocampus and striatum exhibit activation correlated with a model-based recognition strength measure. Our results suggest that model-based analyses are exceptionally useful for extracting information about cognitive processes from neuroimaging data. Models provide a basis for identifying the multiple neural processes that contribute to behavior, and neuroimaging data can provide a powerful test bed for constraining and testing model predictions. PMID:22746951

Brain hyper-connectivity and operation-specific deficits during arithmetic problem solving in children with developmental dyscalculia

PubMed Central

Rosenberg-Lee, Miriam; Ashkenazi, Sarit; Chen, Tianwen; Young, Christina B.; Geary, David C.; Menon, Vinod

2014-01-01

Developmental dyscalculia (DD) is marked by specific deficits in processing numerical and mathematical information despite normal intelligence (IQ) and reading ability. We examined how brain circuits used by young children with DD to solve simple addition and subtraction problems differ from those used by typically developing (TD) children who were matched on age, IQ, reading ability, and working memory. Children with DD were slower and less accurate during problem solving than TD children, and were especially impaired on their ability to solve subtraction problems. Children with DD showed significantly greater activity in multiple parietal, occipito-temporal and prefrontal cortex regions while solving addition and subtraction problems. Despite poorer performance during subtraction, children with DD showed greater activity in multiple intra-parietal sulcus (IPS) and superior parietal lobule subdivisions in the dorsal posterior parietal cortex as well as fusiform gyrus in the ventral occipito-temporal cortex. Critically, effective connectivity analyses revealed hyper-connectivity, rather than reduced connectivity, between the IPS and multiple brain systems including the lateral fronto-parietal and default mode networks in children with DD during both addition and subtraction. These findings suggest the IPS and its functional circuits are a major locus of dysfunction during both addition and subtraction problem solving in DD, and that inappropriate task modulation and hyper-connectivity, rather than under-engagement and under-connectivity, are the neural mechanisms underlying problem solving difficulties in children with DD. We discuss our findings in the broader context of multiple levels of analysis and performance issues inherent in neuroimaging studies of typical and atypical development. PMID:25098903

Brain hyper-connectivity and operation-specific deficits during arithmetic problem solving in children with developmental dyscalculia.

PubMed

Rosenberg-Lee, Miriam; Ashkenazi, Sarit; Chen, Tianwen; Young, Christina B; Geary, David C; Menon, Vinod

2015-05-01

Developmental dyscalculia (DD) is marked by specific deficits in processing numerical and mathematical information despite normal intelligence (IQ) and reading ability. We examined how brain circuits used by young children with DD to solve simple addition and subtraction problems differ from those used by typically developing (TD) children who were matched on age, IQ, reading ability, and working memory. Children with DD were slower and less accurate during problem solving than TD children, and were especially impaired on their ability to solve subtraction problems. Children with DD showed significantly greater activity in multiple parietal, occipito-temporal and prefrontal cortex regions while solving addition and subtraction problems. Despite poorer performance during subtraction, children with DD showed greater activity in multiple intra-parietal sulcus (IPS) and superior parietal lobule subdivisions in the dorsal posterior parietal cortex as well as fusiform gyrus in the ventral occipito-temporal cortex. Critically, effective connectivity analyses revealed hyper-connectivity, rather than reduced connectivity, between the IPS and multiple brain systems including the lateral fronto-parietal and default mode networks in children with DD during both addition and subtraction. These findings suggest the IPS and its functional circuits are a major locus of dysfunction during both addition and subtraction problem solving in DD, and that inappropriate task modulation and hyper-connectivity, rather than under-engagement and under-connectivity, are the neural mechanisms underlying problem solving difficulties in children with DD. We discuss our findings in the broader context of multiple levels of analysis and performance issues inherent in neuroimaging studies of typical and atypical development. © 2014 John Wiley & Sons Ltd.

Coping and Sexual Harassment: How Victims Cope across Multiple Settings.

PubMed

Scarduzio, Jennifer A; Sheff, Sarah E; Smith, Mathew

2018-02-01

The ways sexual harassment occurs both online and in face-to-face settings has become more complicated. Sexual harassment that occurs in cyberspace or online sexual harassment adds complexity to the experiences of victims, current research understandings, and the legal dimensions of this phenomenon. Social networking sites (SNS) are a type of social media that offer unique opportunities to users and sometimes the communication that occurs on SNS can cross the line from flirtation into online sexual harassment. Victims of sexual harassment employ communicative strategies such as coping to make sense of their experiences of sexual harassment. The current study qualitatively examined problem-focused, active emotion-focused, and passive emotion-focused coping strategies employed by sexual harassment victims across multiple settings. We conducted 26 in-depth interviews with victims that had experienced sexual harassment across multiple settings (e.g., face-to-face and SNS). The findings present 16 types of coping strategies-five problem-focused, five active emotion-focused, and six passive emotion-focused. The victims used an average of three types of coping strategies during their experiences. Theoretical implications extend research on passive emotion-focused coping strategies by discussing powerlessness and how victims blame other victims. Furthermore, theoretically the findings reveal that coping is a complex, cyclical process and that victims shift among types of coping strategies over the course of their experience. Practical implications are offered for victims and for SNS sites.

SUMOylation of ATRIP potentiates DNA damage signaling by boosting multiple protein interactions in the ATR pathway

PubMed Central

Wu, Ching-Shyi; Ouyang, Jian; Mori, Eiichiro; Nguyen, Hai Dang; Maréchal, Alexandre; Hallet, Alexander; Chen, David J.; Zou, Lee

2014-01-01

The ATR (ATM [ataxia telangiectasia-mutated]- and Rad3-related) checkpoint is a crucial DNA damage signaling pathway. While the ATR pathway is known to transmit DNA damage signals through the ATR–Chk1 kinase cascade, whether post-translational modifications other than phosphorylation are important for this pathway remains largely unknown. Here, we show that protein SUMOylation plays a key role in the ATR pathway. ATRIP, the regulatory partner of ATR, is modified by SUMO2/3 at K234 and K289. An ATRIP mutant lacking the SUMOylation sites fails to localize to DNA damage and support ATR activation efficiently. Surprisingly, the ATRIP SUMOylation mutant is compromised in the interaction with a protein group, rather than a single protein, in the ATR pathway. Multiple ATRIP-interacting proteins, including ATR, RPA70, TopBP1, and the MRE11–RAD50–NBS1 complex, exhibit reduced binding to the ATRIP SUMOylation mutant in cells and display affinity for SUMO2 chains in vitro, suggesting that they bind not only ATRIP but also SUMO. Fusion of a SUMO2 chain to the ATRIP SUMOylation mutant enhances its interaction with the protein group and partially suppresses its localization and functional defects, revealing that ATRIP SUMOylation promotes ATR activation by providing a unique type of protein glue that boosts multiple protein interactions along the ATR pathway. PMID:24990965

Anticancer kinase inhibitors impair intracellular viral trafficking and exert broad-spectrum antiviral effects.

PubMed

Bekerman, Elena; Neveu, Gregory; Shulla, Ana; Brannan, Jennifer; Pu, Szu-Yuan; Wang, Stanley; Xiao, Fei; Barouch-Bentov, Rina; Bakken, Russell R; Mateo, Roberto; Govero, Jennifer; Nagamine, Claude M; Diamond, Michael S; De Jonghe, Steven; Herdewijn, Piet; Dye, John M; Randall, Glenn; Einav, Shirit

2017-04-03

Global health is threatened by emerging viral infections, which largely lack effective vaccines or therapies. Targeting host pathways that are exploited by multiple viruses could offer broad-spectrum solutions. We previously reported that AAK1 and GAK, kinase regulators of the host adaptor proteins AP1 and AP2, are essential for hepatitis C virus (HCV) infection, but the underlying mechanism and relevance to other viruses or in vivo infections remained unknown. Here, we have discovered that AP1 and AP2 cotraffic with HCV particles in live cells. Moreover, we found that multiple viruses, including dengue and Ebola, exploit AAK1 and GAK during entry and infectious virus production. In cultured cells, treatment with sunitinib and erlotinib, approved anticancer drugs that inhibit AAK1 or GAK activity, or with more selective compounds inhibited intracellular trafficking of HCV and multiple unrelated RNA viruses with a high barrier to resistance. In murine models of dengue and Ebola infection, sunitinib/erlotinib combination protected against morbidity and mortality. We validated sunitinib- and erlotinib-mediated inhibition of AAK1 and GAK activity as an important mechanism of antiviral action. Additionally, we revealed potential roles for additional kinase targets. These findings advance our understanding of virus-host interactions and establish a proof of principle for a repurposed, host-targeted approach to combat emerging viruses.

Anticancer kinase inhibitors impair intracellular viral trafficking and exert broad-spectrum antiviral effects

PubMed Central

Bekerman, Elena; Shulla, Ana; Brannan, Jennifer; Wang, Stanley; Barouch-Bentov, Rina; Bakken, Russell R.; Mateo, Roberto; Govero, Jennifer; Nagamine, Claude M.; Diamond, Michael S.; De Jonghe, Steven; Herdewijn, Piet; Dye, John M.; Randall, Glenn

2017-01-01

Global health is threatened by emerging viral infections, which largely lack effective vaccines or therapies. Targeting host pathways that are exploited by multiple viruses could offer broad-spectrum solutions. We previously reported that AAK1 and GAK, kinase regulators of the host adaptor proteins AP1 and AP2, are essential for hepatitis C virus (HCV) infection, but the underlying mechanism and relevance to other viruses or in vivo infections remained unknown. Here, we have discovered that AP1 and AP2 cotraffic with HCV particles in live cells. Moreover, we found that multiple viruses, including dengue and Ebola, exploit AAK1 and GAK during entry and infectious virus production. In cultured cells, treatment with sunitinib and erlotinib, approved anticancer drugs that inhibit AAK1 or GAK activity, or with more selective compounds inhibited intracellular trafficking of HCV and multiple unrelated RNA viruses with a high barrier to resistance. In murine models of dengue and Ebola infection, sunitinib/erlotinib combination protected against morbidity and mortality. We validated sunitinib- and erlotinib-mediated inhibition of AAK1 and GAK activity as an important mechanism of antiviral action. Additionally, we revealed potential roles for additional kinase targets. These findings advance our understanding of virus-host interactions and establish a proof of principle for a repurposed, host-targeted approach to combat emerging viruses. PMID:28240606

Logic programming reveals alteration of key transcription factors in multiple myeloma.

PubMed

Miannay, Bertrand; Minvielle, Stéphane; Roux, Olivier; Drouin, Pierre; Avet-Loiseau, Hervé; Guérin-Charbonnel, Catherine; Gouraud, Wilfried; Attal, Michel; Facon, Thierry; Munshi, Nikhil C; Moreau, Philippe; Campion, Loïc; Magrangeas, Florence; Guziolowski, Carito

2017-08-23

Innovative approaches combining regulatory networks (RN) and genomic data are needed to extract biological information for a better understanding of diseases, such as cancer, by improving the identification of entities and thereby leading to potential new therapeutic avenues. In this study, we confronted an automatically generated RN with gene expression profiles (GEP) from a cohort of multiple myeloma (MM) patients and normal individuals using global reasoning on the RN causality to identify key-nodes. We modeled each patient by his or her GEP, the RN and the possible automatically detected repairs needed to establish a coherent flow of the information that explains the logic of the GEP. These repairs could represent cancer mutations leading to GEP variability. With this reasoning, unmeasured protein states can be inferred, and we can simulate the impact of a protein perturbation on the RN behavior to identify therapeutic targets. We showed that JUN/FOS and FOXM1 activities are altered in almost all MM patients and identified two survival markers for MM patients. Our results suggest that JUN/FOS-activation has a strong impact on the RN in view of the whole GEP, whereas FOXM1-activation could be an interesting way to perturb an MM subgroup identified by our method.

The Relation Between Magnetospheric State Parameters and the Occurrence of Plasma Depletion Events in the Night-Time Mid-Latitude F-Region

NASA Technical Reports Server (NTRS)

Seker, Ilgin; Fung, Shing F.; Mathews, John D.

2010-01-01

Studies using all-sky imagers have revealed the presence of various ionospheric irregularities in the night-time mid-latitude F-region. The most prevalent and well known of these are the Medium Scale Traveling Ionospheric Disturbances (MSTIDs) that usually occur when the geomagnetic activity is low, and mid-latitude spread-F plumes that are often observed when the geomagnetic activity is high. The inverse and direct relations between geomagnetic activity (particularly Kp) and the occurrence rate of MSTIDs and midlatitude plumes, respectively, have been observed by several studies using different instruments. In order to understand the underlying causes of these two relations, it is illuminating to better characterize the occurrence of MSTIDs and plumes using multiple magnetospheric state parameters. Here we statistically compare multiple geomagnetic driver and response parameters (such as Kp, AE, Dst, and solar wind parameters) with the occurrence rates of night-time MSTIDs and plumes observed using an all-sky imager at Arecibo Observatory (AO) between 2003 and 2008. The results not only allow us to better distinguish MSTIDs and plumes, but also shed further light on the generation mechanism and electrodynamics of these two different phenomena occurring at night-time in the mid-latitude F-region.

Aging causes decreased resistance to multiple stresses and a failure to activate specific stress response pathways.

PubMed

Dues, Dylan J; Andrews, Emily K; Schaar, Claire E; Bergsma, Alexis L; Senchuk, Megan M; Van Raamsdonk, Jeremy M

2016-04-01

In this work, we examine the relationship between stress resistance and aging. We find that resistance to multiple types of stress peaks during early adulthood and then declines with age. To dissect the underlying mechanisms, we use C. elegans transcriptional reporter strains that measure the activation of different stress responses including: the heat shock response, mitochondrial unfolded protein response, endoplasmic reticulum unfolded protein response, hypoxia response, SKN-1-mediated oxidative stress response, and the DAF-16-mediated stress response. We find that the decline in stress resistance with age is at least partially due to a decreased ability to activate protective mechanisms in response to stress. In contrast, we find that any baseline increase in stress caused by the advancing age is too mild to detectably upregulate any of the stress response pathways. Further exploration of how worms respond to stress with increasing age revealed that the ability to mount a hormetic response to heat stress is also lost with increasing age. Overall, this work demonstrates that resistance to all types of stress declines with age. Based on our data, we speculate that the decrease in stress resistance with advancing age results from a genetically-programmed inactivation of stress response pathways, not accumulation of damage.

Bromate Reduction by Rhodococcus sp. Br-6 in the Presence of Multiple Redox Mediators.

PubMed

Tamai, Naoko; Ishii, Takahiro; Sato, Yusuke; Fujiya, Hiroko; Muramatsu, Yasuyuki; Okabe, Nobuaki; Amachi, Seigo

2016-10-04

A bromate (BrO 3 - )-reducing bacterium, designated Rhodococcus sp. strain Br-6, was isolated from soil. The strain reduced 250 μM bromate completely within 4 days under growth conditions transitioning from aerobic to anaerobic conditions, while no reduction was observed under aerobic and anaerobic growth conditions. Bromate was reduced to bromide (Br - ) stoichiometrically, and acetate was required as an electron donor. Interestingly, bromate reduction by strain Br-6 was significantly dependent on both ferric iron and a redox dye 2,6-dichloroindophenol (DCIP). Cell free extract of strain Br-6 showed a dicumarol-sensitive diaphorase activity, which catalyzes the reduction of DCIP in the presence of NADH. Following abiotic experiments showed that the reduced form of DCIP was reoxidized by ferric iron, and that the resulting ferrous iron reduced bromate abiotically. Furthermore, activity staining of the cell free extract revealed that one of diaphorase isoforms possessed a bromate-reducing activity. Our results demonstrate that strain Br-6 utilizes multiple redox mediators, that is, DCIP and ferric iron, for bromate reduction. Since the apparent rate of bromate reduction by this strain (60 μM day -1 ) was 3 orders of magnitude higher than that of known bromate-reducing bacteria, it could be applicable to removal of this probable human carcinogen from drinking water.

Prediction processes during multiple object tracking (MOT): involvement of dorsal and ventral premotor cortices

PubMed Central

Atmaca, Silke; Stadler, Waltraud; Keitel, Anne; Ott, Derek V M; Lepsien, Jöran; Prinz, Wolfgang

2013-01-01

Background The multiple object tracking (MOT) paradigm is a cognitive task that requires parallel tracking of several identical, moving objects following nongoal-directed, arbitrary motion trajectories. Aims The current study aimed to investigate the employment of prediction processes during MOT. As an indicator for the involvement of prediction processes, we targeted the human premotor cortex (PM). The PM has been repeatedly implicated to serve the internal modeling of future actions and action effects, as well as purely perceptual events, by means of predictive feedforward functions. Materials and methods Using functional magnetic resonance imaging (fMRI), BOLD activations recorded during MOT were contrasted with those recorded during the execution of a cognitive control task that used an identical stimulus display and demanded similar attentional load. A particular effort was made to identify and exclude previously found activation in the PM-adjacent frontal eye fields (FEF). Results We replicated prior results, revealing occipitotemporal, parietal, and frontal areas to be engaged in MOT. Discussion The activation in frontal areas is interpreted to originate from dorsal and ventral premotor cortices. The results are discussed in light of our assumption that MOT engages prediction processes. Conclusion We propose that our results provide first clues that MOT does not only involve visuospatial perception and attention processes, but prediction processes as well. PMID:24363971

Aging causes decreased resistance to multiple stresses and a failure to activate specific stress response pathways

PubMed Central

Bergsma, Alexis L.; Senchuk, Megan M.; Van Raamsdonk, Jeremy M.

2016-01-01

In this work, we examine the relationship between stress resistance and aging. We find that resistance to multiple types of stress peaks during early adulthood and then declines with age. To dissect the underlying mechanisms, we use C. elegans transcriptional reporter strains that measure the activation of different stress responses including: the heat shock response, mitochondrial unfolded protein response, endoplasmic reticulum unfolded protein response, hypoxia response, SKN-1-mediated oxidative stress response, and the DAF-16-mediated stress response. We find that the decline in stress resistance with age is at least partially due to a decreased ability to activate protective mechanisms in response to stress. In contrast, we find that any baseline increase in stress caused by the advancing age is too mild to detectably upregulate any of the stress response pathways. Further exploration of how worms respond to stress with increasing age revealed that the ability to mount a hormetic response to heat stress is also lost with increasing age. Overall, this work demonstrates that resistance to all types of stress declines with age. Based on our data, we speculate that the decrease in stress resistance with advancing age results from a genetically-programmed inactivation of stress response pathways, not accumulation of damage. PMID:27053445

Symptom variability, affect and physical activity in ambulatory persons with multiple sclerosis: Understanding patterns and time-bound relationships.

PubMed

Kasser, Susan L; Goldstein, Amanda; Wood, Phillip K; Sibold, Jeremy

2017-04-01

Individuals with multiple sclerosis (MS) experience a clinical course that is highly variable with daily fluctuations in symptoms significantly affecting functional ability and quality of life. Yet, understanding how MS symptoms co-vary and associate with physical and psychological health is unclear. The purpose of the study was to explore variability patterns and time-bound relationships across symptoms, affect, and physical activity in individuals with MS. The study employed a multivariate, replicated, single-subject repeated-measures (MRSRM) design and involved four individuals with MS. Mood, fatigue, pain, balance confidence, and losses of balance were measured daily over 28 days by self-report. Physical activity was also measured daily over this same time period via accelerometry. Dynamic factor analysis (DFA) was used to determine the dimensionality and lagged relationships across the variables. Person-specific models revealed considerable time-dependent co-variation patterns as well as pattern variation across subjects. Results also offered insight into distinct variability structures at varying levels of disability. Modeling person-level variability may be beneficial for addressing the heterogeneity of experiences in individuals with MS and for understanding temporal and dynamic interrelationships among perceived symptoms, affect, and health outcomes in this group. Copyright © 2016 Elsevier Inc. All rights reserved.

Nothing in Evolution Makes Sense Except in the Light of Genomics: Read-Write Genome Evolution as an Active Biological Process.

PubMed

Shapiro, James A

2016-06-08

The 21st century genomics-based analysis of evolutionary variation reveals a number of novel features impossible to predict when Dobzhansky and other evolutionary biologists formulated the neo-Darwinian Modern Synthesis in the middle of the last century. These include three distinct realms of cell evolution; symbiogenetic fusions forming eukaryotic cells with multiple genome compartments; horizontal organelle, virus and DNA transfers; functional organization of proteins as systems of interacting domains subject to rapid evolution by exon shuffling and exonization; distributed genome networks integrated by mobile repetitive regulatory signals; and regulation of multicellular development by non-coding lncRNAs containing repetitive sequence components. Rather than single gene traits, all phenotypes involve coordinated activity by multiple interacting cell molecules. Genomes contain abundant and functional repetitive components in addition to the unique coding sequences envisaged in the early days of molecular biology. Combinatorial coding, plus the biochemical abilities cells possess to rearrange DNA molecules, constitute a powerful toolbox for adaptive genome rewriting. That is, cells possess "Read-Write Genomes" they alter by numerous biochemical processes capable of rapidly restructuring cellular DNA molecules. Rather than viewing genome evolution as a series of accidental modifications, we can now study it as a complex biological process of active self-modification.

Nothing in Evolution Makes Sense Except in the Light of Genomics: Read–Write Genome Evolution as an Active Biological Process

PubMed Central

Shapiro, James A.

2016-01-01

The 21st century genomics-based analysis of evolutionary variation reveals a number of novel features impossible to predict when Dobzhansky and other evolutionary biologists formulated the neo-Darwinian Modern Synthesis in the middle of the last century. These include three distinct realms of cell evolution; symbiogenetic fusions forming eukaryotic cells with multiple genome compartments; horizontal organelle, virus and DNA transfers; functional organization of proteins as systems of interacting domains subject to rapid evolution by exon shuffling and exonization; distributed genome networks integrated by mobile repetitive regulatory signals; and regulation of multicellular development by non-coding lncRNAs containing repetitive sequence components. Rather than single gene traits, all phenotypes involve coordinated activity by multiple interacting cell molecules. Genomes contain abundant and functional repetitive components in addition to the unique coding sequences envisaged in the early days of molecular biology. Combinatorial coding, plus the biochemical abilities cells possess to rearrange DNA molecules, constitute a powerful toolbox for adaptive genome rewriting. That is, cells possess “Read–Write Genomes” they alter by numerous biochemical processes capable of rapidly restructuring cellular DNA molecules. Rather than viewing genome evolution as a series of accidental modifications, we can now study it as a complex biological process of active self-modification. PMID:27338490

Spatio-Temporal Pattern Mining on Trajectory Data Using Arm

NASA Astrophysics Data System (ADS)

Khoshahval, S.; Farnaghi, M.; Taleai, M.

2017-09-01

Preliminary mobile was considered to be a device to make human connections easier. But today the consumption of this device has been evolved to a platform for gaming, web surfing and GPS-enabled application capabilities. Embedding GPS in handheld devices, altered them to significant trajectory data gathering facilities. Raw GPS trajectory data is a series of points which contains hidden information. For revealing hidden information in traces, trajectory data analysis is needed. One of the most beneficial concealed information in trajectory data is user activity patterns. In each pattern, there are multiple stops and moves which identifies users visited places and tasks. This paper proposes an approach to discover user daily activity patterns from GPS trajectories using association rules. Finding user patterns needs extraction of user's visited places from stops and moves of GPS trajectories. In order to locate stops and moves, we have implemented a place recognition algorithm. After extraction of visited points an advanced association rule mining algorithm, called Apriori was used to extract user activity patterns. This study outlined that there are useful patterns in each trajectory that can be emerged from raw GPS data using association rule mining techniques in order to find out about multiple users' behaviour in a system and can be utilized in various location-based applications.

How does curcumin work with poor bioavailability? Clues from experimental and theoretical studies

NASA Astrophysics Data System (ADS)

Shen, Liang; Liu, Cui-Cui; An, Chun-Yan; Ji, Hong-Fang

2016-02-01

Curcumin is a natural product with multiple biological activities and numerous potential therapeutic applications. However, its poor systemic bioavailability fails to explain the potent pharmacological effects and hinders its clinical application. Using experimental and theoretical approaches, we compared curcumin and its degradation products for its biological activities against Alzheimer’s disease (AD), including the superoxide anion radical (O2.-)-scavenging activity, Aβ fibrils (fAβ) formation-inhibiting activity, and enzymatic inhibition activity. We showed that compared to the parent compound curcumin, the degradation products mixture possessed higher O2.--scavenging activity and stronger inhibition against fAβ formation. The docking simulations revealed that the bioactive degradation products should make important contribution to the experimentally observed enzymatic inhibition activities of curcumin. Given that curcumin is readily degraded under physiological condition, our findings strongly suggested that the degradation products should make important contribution to the diverse biological activities of curcumin. Our novel findings not only provide novel insights into the complex pharmacology of curcumin due to its poor bioavailability, but also open new avenues for developing therapeutic applications of this natural product.

Polycystic kidneys in the red panda (Ailurus fulgens).

PubMed

Makungu, Modesta; du Plessis, Wencke M; Barrows, Michelle; Koeppel, Katja N; Groenewald, Hermanus B

2013-09-01

An intact adult male 14.3-yr-old red panda (Ailurus fulgens) presented for health examination with a history of slowly progressing loss of body condition. Abdominal radiographs revealed a truncated abdomen with poor serosal abdominal detail and multiple areas of spondylosis with some collapsed intervertebral disc spaces. On computed tomography, multiple ovoid hypoattenuating lesions were seen in the left and right kidneys. Gross pathology and histopathology revealed multiple cystic lesions in the kidneys concurrent with pancreatic cysts on histopathology. To the best of the authors' knowledge, polycystic kidneys have not been reported in this species.

Genome-wide chromatin footprinting reveals changes in replication origin architecture induced by pre-RC assembly

PubMed Central

MacAlpine, Heather K.; Lubelsky, Yoav; Hartemink, Alexander J.

2015-01-01

Start sites of DNA replication are marked by the origin recognition complex (ORC), which coordinates Mcm2–7 helicase loading to form the prereplicative complex (pre-RC). Although pre-RC assembly is well characterized in vitro, the process is poorly understood within the local chromatin environment surrounding replication origins. To reveal how the chromatin architecture modulates origin selection and activation, we “footprinted” nucleosomes, transcription factors, and replication proteins at multiple points during the Saccharomyces cerevisiae cell cycle. Our nucleotide-resolution protein occupancy profiles resolved a precise ORC-dependent footprint at 269 origins in G2. A separate class of inefficient origins exhibited protein occupancy only in G1, suggesting that stable ORC chromatin association in G2 is a determinant of origin efficiency. G1 nucleosome remodeling concomitant with pre-RC assembly expanded the origin nucleosome-free region and enhanced activation efficiency. Finally, the local chromatin environment restricts the loading of the Mcm2–7 double hexamer either upstream of or downstream from the ARS consensus sequence (ACS). PMID:25593310

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.

The Jet-driven Outflow in the Radio Galaxy SDSS J1517+3353: Implications for Double-peaked Narrow-line Active Galactic Nucleus

NASA Astrophysics Data System (ADS)

Rosario, D. J.; Shields, G. A.; Taylor, G. B.; Salviander, S.; Smith, K. L.

2010-06-01

We report on the study of an intriguing active galaxy that was selected as a potential multiple supermassive black hole merger in the early-type host SDSS J151709.20+335324.7 (z = 0.135) from a complete search for double-peaked [O III] lines from the SDSS spectroscopic quasi-stellar object (QSO) database. Ground-based SDSS imaging reveals two blue structures on either side of the photometric center of the host galaxy, separated from each other by about 5.7 kpc. From a combination of SDSS fiber and Keck/HIRES long-slit spectroscopy, it is demonstrated that, in addition to these two features, a third distinct structure surrounds the nucleus of the host galaxy. All three structures exhibit highly ionized line emission with line ratios characteristic of Seyfert II active galactic nuclei. The analysis of spatially resolved emission-line profiles from the HIRES spectrum reveal three distinct kinematic subcomponents, one at rest and the other two moving at -350 km s-1 and 500 km s-1 with respect to the systemic velocity of the host galaxy. A comparison of imaging and spectral data confirm a strong association between the kinematic components and the spatial knots, which implies a highly disturbed and complex active region in this object. A comparative analysis of the broadband positions, colors, kinematics, and spectral properties of the knots in this system lead to two plausible explanations: (1) a multiple active galactic nucleus (AGN) produced due to a massive dry merger, or (2) a very powerful radio jet-driven outflow. Subsequent VLA radio imaging reveals a clear jet aligned with the emission-line gas, confirming the latter explanation. We use the broadband radio measurements to examine the impact of the jet on the interstellar medium of the host galaxy, and find that the energy in the radio lobes can heat a significant fraction of the gas to the virial temperature. Finally, we discuss tests that may help future surveys distinguish between jet-driven kinematics and true black-hole binaries. J1517+3353 is a remarkable laboratory for AGN feedback and warrants deeper follow-up study. In the Appendix, we present high-resolution radio imaging of a second AGN with double-peaked [O III] lines, SDSS J112939.78+605742.6, which shows a sub-arcsecond radio jet. If the double-peaked nature of the narrow lines in radio-loud AGNs are generally due to radio jet interactions, we suggest that extended radio structure should be expected in most of such systems.

Age-related increase in brain activity during task-related and -negative networks and numerical inductive reasoning

PubMed Central

Sun, Li; Liang, Peipeng; Jia, Xiuqin; Qi, Zhigang; Li, Kuncheng

2014-01-01

Objective: Recent neuroimaging studies have shown that elderly adults exhibit increased and decreased activation on various cognitive tasks, yet little is known about age-related changes in inductive reasoning. Methods: To investigate the neural basis for the aging effect on inductive reasoning, 15 young and 15 elderly subjects performed numerical inductive reasoning while in a magnetic resonance (MR) scanner. Results: Functional magnetic resonance imaging (fMRI) analysis revealed that numerical inductive reasoning, relative to rest, yielded multiple frontal, temporal, parietal, and some subcortical area activations for both age groups. In addition, the younger participants showed significant regions of task-induced deactivation, while no deactivation occurred in the elderly adults. Direct group comparisons showed that elderly adults exhibited greater activity in regions of task-related activation and areas showing task-induced deactivation (TID) in the younger group. Conclusions: Our findings suggest an age-related deficiency in neural function and resource allocation during inductive reasoning. PMID:25337240

Some Lipid Droplets Are More Equal Than Others: Different Metabolic Lipid Droplet Pools in Hepatic Stellate Cells.

PubMed

Molenaar, Martijn R; Vaandrager, Arie B; Helms, J Bernd

2017-01-01

Hepatic stellate cells (HSCs) are professional lipid-storing cells and are unique in their property to store most of the retinol (vitamin A) as retinyl esters in large-sized lipid droplets. Hepatic stellate cell activation is a critical step in the development of chronic liver disease, as activated HSCs cause fibrosis. During activation, HSCs lose their lipid droplets containing triacylglycerols, cholesteryl esters, and retinyl esters. Lipidomic analysis revealed that the dynamics of disappearance of these different classes of neutral lipids are, however, very different from each other. Although retinyl esters steadily decrease during HSC activation, triacylglycerols have multiple pools one of which becomes transiently enriched in polyunsaturated fatty acids before disappearing. These observations are consistent with the existence of preexisting "original" lipid droplets with relatively slow turnover and rapidly recycling lipid droplets that transiently appear during activation of HSCs. Elucidation of the molecular machinery involved in the regulation of these distinct lipid droplet pools may open new avenues for the treatment of liver fibrosis.

Apoptogenic effects of β-sitosterol glucoside from Castanopsis indica leaves.

PubMed

Dolai, Narayan; Kumar, Ashish; Islam, Aminul; Haldar, Pallab K

2016-01-01

β-Sitosterol glucoside (BSSG) is a natural biologically active substance isolated from the Castanopsis indica leaves. This study explored the apoptogenic mechanistic studies of BSSG against Ehrlich's ascites carcinoma (EAC) treated mice through morphological study, comet assay, flow cytometry (FACS) and Western blotting assay method. AO/EB staining and FACS analysis showed that BSSG possessed apoptosis induction activities on EAC cells. Dose dependent induction of DNA damage was observed after BSSG treatment. Increase the expression of apoptotic protein p53 and p21 in EAC, multiple downstream factors contributing to apoptosis pathway. The increase of caspase-9 and caspase-3 activities revealed that caspase was a key mediator of the apoptotic pathway induced by BSSG, and up-regulation of Bax and down-regulation of anti-apoptotic protein Bcl-2 resulted in the decrease of Bcl-2/Bax ratio. Owing to the combination of significant antitumour activity by inducing apoptosis, BSSG holds the promise of being an interesting chemo-preventive agent active in cancer therapy.

One-way membrane trafficking of SOS in receptor-triggered Ras activation.

PubMed

Christensen, Sune M; Tu, Hsiung-Lin; Jun, Jesse E; Alvarez, Steven; Triplet, Meredith G; Iwig, Jeffrey S; Yadav, Kamlesh K; Bar-Sagi, Dafna; Roose, Jeroen P; Groves, Jay T

2016-09-01

SOS is a key activator of the small GTPase Ras. In cells, SOS-Ras signaling is thought to be initiated predominantly by membrane recruitment of SOS via the adaptor Grb2 and balanced by rapidly reversible Grb2-SOS binding kinetics. However, SOS has multiple protein and lipid interactions that provide linkage to the membrane. In reconstituted-membrane experiments, these Grb2-independent interactions were sufficient to retain human SOS on the membrane for many minutes, during which a single SOS molecule could processively activate thousands of Ras molecules. These observations raised questions concerning how receptors maintain control of SOS in cells and how membrane-recruited SOS is ultimately released. We addressed these questions in quantitative assays of reconstituted SOS-deficient chicken B-cell signaling systems combined with single-molecule measurements in supported membranes. These studies revealed an essentially one-way trafficking process in which membrane-recruited SOS remains trapped on the membrane and continuously activates Ras until being actively removed via endocytosis.

One-way membrane trafficking of SOS in receptor-triggered Ras activation

PubMed Central

Christensen, Sune M.; Tu, Hsiung-Lin; Jun, Jesse E.; Alvarez, Steven; Triplet, Meredith G.; Iwig, Jeffrey S.; Yadav, Kamlesh K.; Bar-Sagi, Dafna; Roose, Jeroen P.; Groves, Jay T.

2016-01-01

SOS is a key activator of the small GTPase Ras. In cells, SOS-Ras signaling is thought to be initiated predominantly by membrane-recruitment of SOS via the adaptor Grb2 and balanced by rapidly reversible Grb2:SOS binding kinetics. However, SOS has multiple protein and lipid interactions that provide linkage to the membrane. In reconstituted membrane experiments, these Grb2-independent interactions are sufficient to retain SOS on the membrane for many minutes, during which a single SOS molecule can processively activate thousands of Ras molecules. These observations raise questions concerning how receptors maintain control of SOS in cells and how membrane-recruited SOS is ultimately released. We addressed these questions in quantitative reconstituted SOS-deficient chicken B cell signaling systems combined with single molecule measurements in supported membranes. These studies reveal an essentially one-way trafficking process in which membrane-recruited SOS remains trapped on the membrane and continuously activates Ras until it is actively removed via endocytosis. PMID:27501536

Lightning activity related to satellite and radar observations of a mesoscale convective system over Texas on 7 8 April 2002

NASA Astrophysics Data System (ADS)

Dotzek, Nikolai; Rabin, Robert M.; Carey, Lawrence D.; MacGorman, Donald R.; McCormick, Tracy L.; Demetriades, Nicholas W.; Murphy, Martin J.; Holle, Ronald L.

2005-07-01

A multi-sensor study of the leading-line, trailing-stratiform (LLTS) mesoscale convective system (MCS) that developed over Texas in the afternoon of 7 April 2002 is presented. The analysis relies mainly on operationally available data sources such as GOES East satellite imagery, WSR-88D radar data and NLDN cloud-to-ground flash data. In addition, total lightning information in three dimensions from the LDAR II network in the Dallas-Ft. Worth region is used. GOES East satellite imagery revealed several ring-like cloud top structures with a diameter of about 100 km during MCS formation. The Throckmorton tornadic supercell, which had formed just ahead of the developing linear MCS, was characterized by a high CG+ percentage below a V-shaped cloud top overshoot north of the tornado swath. There were indications of the presence of a tilted electrical dipole in this storm. Also this supercell had low average CG- first stroke currents and flash multiplicities. Interestingly, especially the average CG+ flash multiplicity in the Throckmorton storm showed oscillations with an estimated period of about 15 min. Later on, in the mature LLTS MCS, the radar versus lightning activity comparison revealed two dominant discharge regions at the back of the convective leading edge and a gentle descent of the upper intracloud lightning region into the trailing stratiform region, apparently coupled to hydrometeor sedimentation. There was evidence for an inverted dipole in the stratiform region of the LLTS MCS, and CG+ flashes from the stratiform region had high first return stroke peak currents.

1,3-Bis(3,5-dichlorophenyl) urea compound 'COH-SR4' inhibits proliferation and activates apoptosis in melanoma.

PubMed

Singhal, Sharad S; Figarola, James; Singhal, Jyotsana; Leake, Kathryn; Nagaprashantha, Lokesh; Lincoln, Christopher; Gabriel Gugiu, B; Horne, David; Jove, Richard; Awasthi, Sanjay; Rahbar, Samuel

2012-12-01

The current clinical interventions in malignant melanomas are met with poor response to therapy due to dynamic regulation of multiple melanoma signaling pathways consequent to administration of single target agents. In this context of limited response to single target agents, novel candidate molecules capable of effectively inducing tumor inhibition along with targeting multiple critical nodes of melanoma signaling assume translational significance. In this regard, we investigated the anti-cancer effects of a novel dichlorophenyl urea compound called COH-SR4 in melanoma. The SR4 treatment decreased the survival and inhibited the clonogenic potential of melanomas along with inducing apoptosis in vitro cultures. SR4 treatments lead to inhibition of GST activity along with causing G2/M phase cell cycle arrest. Oral administration of 4 mg/kg SR4 leads to effective inhibition of tumor burdens in both syngeneic and nude mouse models of melanoma. The SR4 treatment was well tolerated and no overt toxicity was observed. The histopathological examination of resected tumor sections revealed decreased blood vessels, decrease in the levels of angiogenesis marker, CD31, and proliferation marker, Ki67, along with an increase in pAMPK levels. Western blot analyses of resected tumor lysates revealed increased PARP cleavage, Bim, pAMPK along with decreased pAkt, vimentin, fibronectin, CDK4 and cyclin B1. Thus, SR4 represents a novel candidate for the further development of mono and combinatorial therapies to effectively target aggressive and therapeutically refractory melanomas. 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

Biosensor reveals multiple sources for mitochondrial NAD⁺.

PubMed

Cambronne, Xiaolu A; Stewart, Melissa L; Kim, DongHo; Jones-Brunette, Amber M; Morgan, Rory K; Farrens, David L; Cohen, Michael S; Goodman, Richard H

2016-06-17

Nicotinamide adenine dinucleotide (NAD(+)) is an essential substrate for sirtuins and poly(adenosine diphosphate-ribose) polymerases (PARPs), which are NAD(+)-consuming enzymes localized in the nucleus, cytosol, and mitochondria. Fluctuations in NAD(+) concentrations within these subcellular compartments are thought to regulate the activity of NAD(+)-consuming enzymes; however, the challenge in measuring compartmentalized NAD(+) in cells has precluded direct evidence for this type of regulation. We describe the development of a genetically encoded fluorescent biosensor for directly monitoring free NAD(+) concentrations in subcellular compartments. We found that the concentrations of free NAD(+) in the nucleus, cytoplasm, and mitochondria approximate the Michaelis constants for sirtuins and PARPs in their respective compartments. Systematic depletion of enzymes that catalyze the final step of NAD(+) biosynthesis revealed cell-specific mechanisms for maintaining mitochondrial NAD(+) concentrations. Copyright © 2016, American Association for the Advancement of Science.

Regulation of Ras Exchange Factors and Cellular Localization of Ras Activation by Lipid Messengers in T Cells

PubMed Central

Jun, Jesse E.; Rubio, Ignacio; Roose, Jeroen P.

2013-01-01

The Ras-MAPK signaling pathway is highly conserved throughout evolution and is activated downstream of a wide range of receptor stimuli. Ras guanine nucleotide exchange factors (RasGEFs) catalyze GTP loading of Ras and play a pivotal role in regulating receptor-ligand induced Ras activity. In T cells, three families of functionally important RasGEFs are expressed: RasGRF, RasGRP, and Son of Sevenless (SOS)-family GEFs. Early on it was recognized that Ras activation is critical for T cell development and that the RasGEFs play an important role herein. More recent work has revealed that nuances in Ras activation appear to significantly impact T cell development and selection. These nuances include distinct biochemical patterns of analog versus digital Ras activation, differences in cellular localization of Ras activation, and intricate interplays between the RasGEFs during distinct T cell developmental stages as revealed by various new mouse models. In many instances, the exact nature of these nuances in Ras activation or how these may result from fine-tuning of the RasGEFs is not understood. One large group of biomolecules critically involved in the control of RasGEFs functions are lipid second messengers. Multiple, yet distinct lipid products are generated following T cell receptor (TCR) stimulation and bind to different domains in the RasGRP and SOS RasGEFs to facilitate the activation of the membrane-anchored Ras GTPases. In this review we highlight how different lipid-based elements are generated by various enzymes downstream of the TCR and other receptors and how these dynamic and interrelated lipid products may fine-tune Ras activation by RasGEFs in developing T cells. PMID:24027568

Physical Activity and Its Correlates in Youth with Multiple Sclerosis.

PubMed

Grover, Stephanie A; Sawicki, Carolyn P; Kinnett-Hopkins, Dominique; Finlayson, Marcia; Schneiderman, Jane E; Banwell, Brenda; Till, Christine; Motl, Robert W; Yeh, E Ann

2016-12-01

To investigate physical activity levels in youth with multiple sclerosis and monophasic acquired demyelinating syndromes ([mono-ADS], ie, children without relapsing disease) compared with healthy controls and to determine factors that contribute to engagement in physical activity. We hypothesized that greater physical activity goal setting and physical activity self-efficacy would be associated with greater levels of vigorous physical activity in youth with multiple sclerosis. A total of 68 consecutive patients (27 multiple sclerosis, 41 mono-ADS) and 37 healthy controls completed fatigue, depression, Physical Activity Self-Efficacy Scale, perceived disability, Exercise Goal-Setting scale, and physical activity questionnaires, and wore an accelerometer for 7 days. All patients had no ambulatory limitations (Expanded Disability Status Scale, scores all <4). Youth with multiple sclerosis engaged in fewer minutes per day of vigorous (P = .009) and moderate and vigorous physical activity (P = .048) than did patients with mono-ADS and healthy controls. A lower proportion of the group with multiple sclerosis (63%) reported participating in any strenuous physical activity than the mono-ADS (85%) and healthy control (89%) groups (P = .020). When we adjusted for age and sex, the Physical Activity Self-Efficacy Scale and Exercise Goal-Setting scale were associated positively with vigorous physical activity in the group with multiple sclerosis. Fatigue and depression did not predict physical activity or accelerometry metrics. Youth with multiple sclerosis participate in less physical activity than their counterparts with mono-ADS and healthy controls. Physical activity self-efficacy and exercise goal setting serve as potentially modifiable correlates of physical activity, and are measures suited to future interventions aimed to increase physical activity in youth with multiple sclerosis. Copyright © 2016 Elsevier Inc. All rights reserved.

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.

The 2016 M7.8 Kaikōura earthquake revealed by multiple seismic wavefield simulations: slow rupture propagation on a geometrically complex fault network

NASA Astrophysics Data System (ADS)

Kaneko, Y.; Francois-Holden, C.; Hamling, I. J.; D'Anastasio, E.; Fry, B.

2017-12-01

The 2016 M7.8 Kaikōura (New Zealand) earthquake generated ground motions over 1g across a 200-km long region, resulted in multiple onshore and offshore fault ruptures, a profusion of triggered landslides, and a regional tsunami. Here we examine the rupture evolution during the Kaikōura earthquake multiple kinematic modelling methods based on local strong-motion and high-rate GPS data. Our kinematic models constrained by near-source data capture, in detail, a complex pattern of slowly (Vr < 2km/s) propagating rupture from the south to north, with over half of the moment release occurring in the northern source region, mostly on the Kekerengu fault, 60 seconds after the origin time. Interestingly, both models indicate rupture re-activation on the Kekerengu fault with the time separation of 11 seconds. We further conclude that most near-source waveforms can be explained by slip on the crustal faults, with little (<8%) or no contribution from the subduction interface.

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.

Inhibition of estrogen-responsive gene activation by the retinoid X receptor beta: evidence for multiple inhibitory pathways.

PubMed

Segars, J H; Marks, M S; Hirschfeld, S; Driggers, P H; Martinez, E; Grippo, J F; Brown, M; Wahli, W; Ozato, K

1993-04-01

The retinoid X receptor beta (RXR beta; H-2RIIBP) forms heterodimers with various nuclear hormone receptors and binds multiple hormone response elements, including the estrogen response element (ERE). In this report, we show that endogenous RXR beta contributes to ERE binding activity in nuclear extracts of the human breast cancer cell line MCF-7. To define a possible regulatory role of RXR beta regarding estrogen-responsive transcription in breast cancer cells, RXR beta and a reporter gene driven by the vitellogenin A2 ERE were transfected into estrogen-treated MCF-7 cells. RXR beta inhibited ERE-driven reporter activity in a dose-dependent and element-specific fashion. This inhibition occurred in the absence of the RXR ligand 9-cis retinoic acid. The RXR beta-induced inhibition was specific for estrogen receptor (ER)-mediated ERE activation because inhibition was observed in ER-negative MDA-MB-231 cells only following transfection of the estrogen-activated ER. No inhibition of the basal reporter activity was observed. The inhibition was not caused by simple competition of RXR beta with the ER for ERE binding, since deletion mutants retaining DNA binding activity but lacking the N-terminal or C-terminal domain failed to inhibit reporter activity. In addition, cross-linking studies indicated the presence of an auxiliary nuclear factor present in MCF-7 cells that contributed to RXR beta binding of the ERE. Studies using known heterodimerization partners of RXR beta confirmed that RXR beta/triiodothyronine receptor alpha heterodimers avidly bind the ERE but revealed the existence of another triiodothyronine-independent pathway of ERE inhibition. These results indicate that estrogen-responsive genes may be negatively regulated by RXR beta through two distinct pathways.

Trivanillic polyphenols with anticancer cytostatic effects through the targeting of multiple kinases and intracellular Ca2+ release

PubMed Central

Lamoral-Theys, Delphine; Wauthoz, Nathalie; Heffeter, Petra; Mathieu, Véronique; Jungwirth, Utte; Lefranc, Florence; Nève, Jean; Dubois, Jacques; Dufrasne, François; Amighi, Karim; Berger, Walter; Gailly, Philippe; Kiss, Robert

2012-01-01

Abstract Cancer cells exhibit de-regulation of multiple cellular signalling pathways and treatments of various types of cancers with polyphenols are promising. We recently reported the synthesis of a series of 33 novel divanillic and trivanillic polyphenols that displayed anticancer activity, at least in vitro, through inhibiting various kinases. This study revealed that minor chemical modifications of a trivanillate scaffold could convert cytotoxic compounds into cytostatic ones. Compound 13c, a tri-chloro derivative of trivanillic ester, displayed marked inhibitory activities against FGF-, VEGF-, EGF- and Src-related kinases, all of which are implicated not only in angiogenesis but also in the biological aggressiveness of various cancer types. The pan-anti-kinase activity of 13c occurs at less than one-tenth of its mean IC50in vitro growth inhibitory concentrations towards a panel of 12 cancer cell lines. Of the 26 kinases for which 13c inhibited their activity by >75%, eight (Yes, Fyn, FGF-R1, EGFR, Btk, Mink, Ret and Itk) are implicated in control of the actin cytoskeleton organization to varying degrees. Compound 13c accordingly impaired the typical organization of the actin cytoskeleton in human U373 glioblastoma cells. The pan-anti-kinase activity and actin cytoskeleton organization impairment provoked by 13c concomitantly occurs with calcium homeostasis impairment but without provoking MDR phenotype activation. All of these anticancer properties enabled 13c to confer therapeutic benefits in vivo in a mouse melanoma pseudometastatic lung model. These data argue in favour of further chemically modifying trivanillates to produce novel and potent anticancer drugs. PMID:21810170

A Novel Agonist of the TRIF Pathway Induces a Cellular State Refractory to Replication of Zika, Chikungunya, and Dengue Viruses

PubMed Central

Pryke, Kara M.; Abraham, Jinu; Sali, Tina M.; Gall, Bryan J.; Archer, Iris; Liu, Andrew; Bambina, Shelly; Baird, Jason; Gough, Michael; Chakhtoura, Marita; Haddad, Elias K.; Kirby, Ilsa T.; Nilsen, Aaron; Streblow, Daniel N.; Hirsch, Alec J.; Smith, Jessica L.

2017-01-01

ABSTRACT The ongoing concurrent outbreaks of Zika, Chikungunya, and dengue viruses in Latin America and the Caribbean highlight the need for development of broad-spectrum antiviral treatments. The type I interferon (IFN) system has evolved in vertebrates to generate tissue responses that actively block replication of multiple known and potentially zoonotic viruses. As such, its control and activation through pharmacological agents may represent a novel therapeutic strategy for simultaneously impairing growth of multiple virus types and rendering host populations resistant to virus spread. In light of this strategy’s potential, we undertook a screen to identify novel interferon-activating small molecules. Here, we describe 1-(2-fluorophenyl)-2-(5-isopropyl-1,3,4-thiadiazol-2-yl)-1,2-dihydrochromeno[2,3-c]pyrrole-3,9-dione, which we termed AV-C. Treatment of human cells with AV-C activates innate and interferon-associated responses that strongly inhibit replication of Zika, Chikungunya, and dengue viruses. By utilizing genome editing, we investigated the host proteins essential to AV-C-induced cellular states. This showed that the compound requires a TRIF-dependent signaling cascade that culminates in IFN regulatory factor 3 (IRF3)-dependent expression and secretion of type I interferon to elicit antiviral responses. The other canonical IRF3-terminal adaptor proteins STING and IPS-1/MAVS were dispensable for AV-C-induced phenotypes. However, our work revealed an important inhibitory role for IPS-1/MAVS, but not TRIF, in flavivirus replication, implying that TRIF-directed viral evasion may not occur. Additionally, we show that in response to AV-C, primary human peripheral blood mononuclear cells secrete proinflammatory cytokines that are linked with establishment of adaptive immunity to viral pathogens. Ultimately, synthetic innate immune activators such as AV-C may serve multiple therapeutic purposes, including direct antimicrobial responses and facilitation of pathogen-directed adaptive immunity. PMID:28465426

Potential control of multiple sclerosis by cannabis and the endocannabinoid system.

PubMed

Pryce, Gareth; Baker, David

2012-08-01

For many years, multiple sclerosis (MS) patients have been self-medicating with illegal street cannabis to alleviate symptoms associated with MS. Data from animal models of MS and clinical studies have supported the anecdotal data that cannabis can improve symptoms such as limb spasticity, which are commonly associated with progressive MS, by the modulation of excessive neuronal signalling. This has lead to cannabis-based medicines being approved for the treatment of pain and spasticity in MS for the first time. Experimental studies into the biology of the endocannabinoid system have revealed that cannabinoids have activity, not only in symptom relief but also potentially in neuroprotective strategies which may slow disease progression and thus delay the onset of symptoms such as spasticity. This review appraises the current knowledge of cannabinoid biology particularly as it pertains to MS and outlines potential future therapeutic strategies for the treatment of disease progression in MS.

Wearable photoplethysmography device prototype for wireless cardiovascular monitoring

NASA Astrophysics Data System (ADS)

Kviesis-Kipge, E.; Grabovskis, A.; Marcinkevics, Z.; Mecnika, V.; Rubenis, O.

2014-05-01

The aim of the study was to develop a prototype system of the smart garment for real time telemetric monitoring of human cardiovascular activity. Two types of photoplethysmography (PPG) sensors for low noise and artefact free signal recording from various sites of the human body that were suitable for integration into smart textile were investigated. The reflectance sensors with single and multiple photodiodes based on "pulse-duration-based signal conversion" signal acquisition principle were designed and evaluated. The technical parameters of the system were measured both on bench and in vivo. Overall, both types of PPG sensors showed acceptable signal quality SNR 86.56±3.00 dB, dynamic range 89.84 dB. However, in-vivo condition tests revealed lower noise and higher accuracy achieved by applying the multiple photodiodes sensor. We concluded that the proposed PPG device prototype is simple and reliable, and therefore, can be utilized in low-cost smart garments.

Relationships Among Substance Use, Multiple Sexual Partners, and Condomless Sex.

PubMed

Zhao, Yunchuan Lucy; Kim, Heejung; Peltzer, Jill

2017-04-01

Male and female students manifest different behaviors in condomless sex. This cross-sectional, exploratory, correlational study examined the differences in risk factors for condomless sex between male and female high school students, using secondary data from 4,968 sexually active males and females participating in the 2011 National Youth Risk Behavior Survey. Results in descriptive statistics and multivariate binary logistic regressions revealed that condomless sex was reported as 39.70% in general. A greater proportion of females engaged in condomless sex (23.26%) than did males (16.44%). Physical abuse by sex partners was a common reason for failure to use condoms regardless of gender. Lower condom use was found in (1) those experiencing forced sex by a partner in males, (2) female smokers, and (3) female with multiple sex partners. Thus, sexual health education should address the different risk factors and consider gender characteristics to reduce condomless sex.

Counselor Education Doctoral Students' Experiences with Multiple Roles and Relationships

ERIC Educational Resources Information Center

Dickens, Kristen N.; Ebrahim, Christine H.; Herlihy, Barbara

2016-01-01

Interpretive phenomenological analysis was used to explore 10 counselor education doctoral students' lived experiences with multiple roles and relationships. Four superordinate themes were found: power differential, need for education, transformation, and learning from experiences. Findings revealed that multiple roles and relationships offer…

Dual allosteric activation mechanisms in monomeric human glucokinase

PubMed Central

Whittington, A. Carl; Larion, Mioara; Bowler, Joseph M.; Ramsey, Kristen M.; Brüschweiler, Rafael; Miller, Brian G.

2015-01-01

Cooperativity in human glucokinase (GCK), the body’s primary glucose sensor and a major determinant of glucose homeostatic diseases, is fundamentally different from textbook models of allostery because GCK is monomeric and contains only one glucose-binding site. Prior work has demonstrated that millisecond timescale order-disorder transitions within the enzyme’s small domain govern cooperativity. Here, using limited proteolysis, we map the site of disorder in unliganded GCK to a 30-residue active-site loop that closes upon glucose binding. Positional randomization of the loop, coupled with genetic selection in a glucokinase-deficient bacterium, uncovers a hyperactive GCK variant with substantially reduced cooperativity. Biochemical and structural analysis of this loop variant and GCK variants associated with hyperinsulinemic hypoglycemia reveal two distinct mechanisms of enzyme activation. In α-type activation, glucose affinity is increased, the proteolytic susceptibility of the active site loop is suppressed and the 1H-13C heteronuclear multiple quantum coherence (HMQC) spectrum of 13C-Ile–labeled enzyme resembles the glucose-bound state. In β-type activation, glucose affinity is largely unchanged, proteolytic susceptibility of the loop is enhanced, and the 1H-13C HMQC spectrum reveals no perturbation in ensemble structure. Leveraging both activation mechanisms, we engineer a fully noncooperative GCK variant, whose functional properties are indistinguishable from other hexokinase isozymes, and which displays a 100-fold increase in catalytic efficiency over wild-type GCK. This work elucidates specific structural features responsible for generating allostery in a monomeric enzyme and suggests a general strategy for engineering cooperativity into proteins that lack the structural framework typical of traditional allosteric systems. PMID:26283387

Chronic fatigue syndrome: exercise performance related to immune dysfunction.

PubMed

Nijs, Jo; Meeus, Mira; McGregor, Neil R; Meeusen, Romain; de Schutter, Guy; van Hoof, Elke; de Meirleir, Kenny

2005-10-01

To date, the exact cause of abnormal exercise response in chronic fatigue syndrome (CFS) remains to be revealed, but evidence addressing intracellular immune deregulation in CFS is growing. Therefore, the aim of this cross-sectional study was to examine the interactions between several intracellular immune variables and exercise performance in CFS patients. After venous blood sampling, subjects (16 CFS patients) performed a maximal exercise stress test on a bicycle ergometer with continuous monitoring of cardiorespiratory variables. The following immune variables were assessed: the ratio of 37 kDa Ribonuclease (RNase) L to the 83 kDa native RNase L (using a radiolabeled ligand/receptor assay), RNase L enzymatic activity (enzymatic assay), protein kinase R activity assay (comparison Western blot), elastase activity (enzymatic-colorimetric assay), the percent of monocytes, and nitric oxide determination (for monocytes and lymphocytes; flow cytometry, live cell assay). Forward stepwise multiple regression analysis revealed 1) that elastase activity was the only factor related to the reduction in oxygen uptake at a respiratory exchange ratio (RER) of 1.0 (regression model: R = 0.53, F (1,14) = 15.5, P < 0.002; elastase activity P < 0.002); 2) that the protein kinase R activity was the principle factor related to the reduction in workload at RER = 1.0; and 3) that elastase activity was the principle factor related to the reduction in percent of target heart rate achieved. These data provide evidence for an association between intracellular immune deregulation and exercise performance in patients with CFS. To establish a causal relationship, further study of these interactions using a prospective longitudinal design is required.

Dual allosteric activation mechanisms in monomeric human glucokinase.

PubMed

Whittington, A Carl; Larion, Mioara; Bowler, Joseph M; Ramsey, Kristen M; Brüschweiler, Rafael; Miller, Brian G

2015-09-15

Cooperativity in human glucokinase (GCK), the body's primary glucose sensor and a major determinant of glucose homeostatic diseases, is fundamentally different from textbook models of allostery because GCK is monomeric and contains only one glucose-binding site. Prior work has demonstrated that millisecond timescale order-disorder transitions within the enzyme's small domain govern cooperativity. Here, using limited proteolysis, we map the site of disorder in unliganded GCK to a 30-residue active-site loop that closes upon glucose binding. Positional randomization of the loop, coupled with genetic selection in a glucokinase-deficient bacterium, uncovers a hyperactive GCK variant with substantially reduced cooperativity. Biochemical and structural analysis of this loop variant and GCK variants associated with hyperinsulinemic hypoglycemia reveal two distinct mechanisms of enzyme activation. In α-type activation, glucose affinity is increased, the proteolytic susceptibility of the active site loop is suppressed and the (1)H-(13)C heteronuclear multiple quantum coherence (HMQC) spectrum of (13)C-Ile-labeled enzyme resembles the glucose-bound state. In β-type activation, glucose affinity is largely unchanged, proteolytic susceptibility of the loop is enhanced, and the (1)H-(13)C HMQC spectrum reveals no perturbation in ensemble structure. Leveraging both activation mechanisms, we engineer a fully noncooperative GCK variant, whose functional properties are indistinguishable from other hexokinase isozymes, and which displays a 100-fold increase in catalytic efficiency over wild-type GCK. This work elucidates specific structural features responsible for generating allostery in a monomeric enzyme and suggests a general strategy for engineering cooperativity into proteins that lack the structural framework typical of traditional allosteric systems.

The influence of alcohol consumption on sickness presenteeism and impaired daily activities. The WIRUS screening study

PubMed Central

Aas, Randi Wågø; Haveraaen, Lise; Sagvaag, Hildegunn

2017-01-01

Background Alcohol use is a global health issue and may influence activity performance in a variety of domains, including the occupational and domestic spheres. The aim of the study was to examine the influence of annual drinking frequency and binge drinking (≥6 units at one occasion) on activity impairments both at work (sickness presenteeism) and outside the workplace. Methods Employees (n = 3278), recruited from 14 Norwegian private and public companies, responded to a questionnaire containing questions from the Alcohol Use Disorders Identification Test (AUDIT) and the Workplace Productivity and Activity Impairment questionnaire (WPAI). Results Multiple hierarchical regression analyses revealed that binge drinking was associated with both sickness presenteeism and impaired daily activities, even after controlling for gender, age, educational level, living status and employment sector. Annual drinking frequency was associated with impaired daily activities, but not sickness presenteeism. Conclusions Binge drinking seems to have a stronger influence on activity performance both at work and outside the workplace than drinking frequency. Interventions targeting alcohol consumption should benefit from focusing on binge drinking behavior. PMID:29040323

The influence of alcohol consumption on sickness presenteeism and impaired daily activities. The WIRUS screening study.

PubMed

Aas, Randi Wågø; Haveraaen, Lise; Sagvaag, Hildegunn; Thørrisen, Mikkel Magnus

2017-01-01

Alcohol use is a global health issue and may influence activity performance in a variety of domains, including the occupational and domestic spheres. The aim of the study was to examine the influence of annual drinking frequency and binge drinking (≥6 units at one occasion) on activity impairments both at work (sickness presenteeism) and outside the workplace. Employees (n = 3278), recruited from 14 Norwegian private and public companies, responded to a questionnaire containing questions from the Alcohol Use Disorders Identification Test (AUDIT) and the Workplace Productivity and Activity Impairment questionnaire (WPAI). Multiple hierarchical regression analyses revealed that binge drinking was associated with both sickness presenteeism and impaired daily activities, even after controlling for gender, age, educational level, living status and employment sector. Annual drinking frequency was associated with impaired daily activities, but not sickness presenteeism. Binge drinking seems to have a stronger influence on activity performance both at work and outside the workplace than drinking frequency. Interventions targeting alcohol consumption should benefit from focusing on binge drinking behavior.

Reciprocal and activity-dependent regulation of surface AMPA and NMDA receptors in cultured neurons

PubMed Central

Li, Guo Hua; Jackson, Michael F; Orser, Beverley A; MacDonald, John F

2010-01-01

Activation of NMDA receptors (NMDARs) can modulate excitatory synaptic transmission in the central nervous system by dynamically altering the number of synaptic AMPA receptors (AMPARs). The surface expression of NMDARs themselves is also subject to modulation in an activity-dependent manner. In addition to NMDAR-induced changes in AMPAR expression, AMPARs have also been found to regulate their own surface expression, independently of NMDARs. However, whether or not AMPARs and NMDARs might reciprocally regulate their surface expression has not previously been systematically explored. We utilized surface biotinylation assays and stimulation protocols intended to selectively stimulate various glutamate receptor subpopulations (e.g. AMPARs vs NMDARs; synaptic vs extrasynaptic). We reveal that activation of synaptic NMDARs increases the surface expression of both NMDAR and AMPAR subunits, while activation of extrasynaptic NMDAR produces the opposite effect. Surprisingly, we find that selective activation of AMPARs reduces the surface expression of not only AMPARs but also of NMDARs. These results suggest that both AMPARs and NMDARs at synaptic sites are subject to modulation by multiple signalling pathways in an activity-dependent way. PMID:21383896

Metabolomic analysis reveals key metabolites related to the rapid adaptation of Saccharomyce cerevisiae to multiple inhibitors of furfural, acetic acid, and phenol.

PubMed

Wang, Xin; Li, Bing-Zhi; Ding, Ming-Zhu; Zhang, Wei-Wen; Yuan, Ying-Jin

2013-03-01

During hydrolysis of lignocellulosic biomass, a broad range of inhibitors are generated, which interfere with yeast growth and bioethanol production. In order to improve the strain tolerance to multiple inhibitors--acetic acid, furfural, and phenol (three representative lignocellulose-derived inhibitors) and uncover the underlying tolerant mechanism, an adaptation experiment was performed in which the industrial Saccharomyces cerevisiae was cultivated repeatedly in a medium containing multiple inhibitors. The adaptation occurred quickly, accompanied with distinct increase in growth rate, glucose utilization rate, furfural metabolism rate, and ethanol yield, only after the first transfer. A similar rapid adaptation was also observed for the lab strains of BY4742 and BY4743. The metabolomic analysis was employed to investigate the responses of the industrial S. cereviaise to three inhibitors during the adaptation. The results showed that higher levels of 2-furoic acid, 2, 3-butanediol, intermediates in glycolytic pathway, and amino acids derived from glycolysis, were discovered in the adapted strains, suggesting that enhanced metabolic activity in these pathways may relate to resistance against inhibitors. Additionally, through single-gene knockouts, several genes related to alanine metabolism, GABA shunt, and glycerol metabolism were verified to be crucial for the resistance to multiple inhibitors. This study provides new insights into the tolerance mechanism against multiple inhibitors, and guides for the improvement of tolerant ethanologenic yeast strains for lignocellulose-bioethanol fermentation.

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

Common and distinct neural correlates of inhibitory dysregulation: Stroop fMRI study of cocaine addiction and intermittent explosive disorder

PubMed Central

Moeller, Scott J.; Froböse, Monja I.; Konova, Anna B.; Misyrlis, Michail; Parvaz, Muhammad A.; Goldstein, Rita Z.; Alia-Klein, Nelly

2014-01-01

Despite the high prevalence and consequences associated with externalizing psychopathologies, little is known about their underlying neurobiological mechanisms. Studying multiple externalizing disorders, each characterized by compromised inhibition, could reveal both common and distinct mechanisms of impairment. The present study therefore compared individuals with intermittent explosive disorder (IED) (N=11), individuals with cocaine use disorder (CUD) (N=21), and healthy controls (N=17) on task performance and functional magnetic resonance imaging (fMRI) activity during an event-related color-word Stroop task; self-reported trait anger expression was also collected in all participants. Results revealed higher error-related activity in the two externalizing psychopathologies as compared with controls in two subregions of the dorsolateral prefrontal cortex (DLPFC) (a region known to be involved in exerting cognitive control during this task), suggesting a neural signature of inhibitory-related error processing common to these psychopathologies. Interestingly, in one DLPFC subregion, error-related activity was especially high in IED, possibly indicating a specific neural correlate of clinically high anger expression. Supporting this interpretation, error-related DLPFC activity in this same subregion positively correlated with trait anger expression across all participants. These collective results help to illuminate common and distinct neural signatures of impaired self-control, and could suggest novel therapeutic targets for increasing self-control in clinical aggression specifically and/or in various externalizing psychopathologies more generally. PMID:25106072

HIBCH mutations can cause Leigh-like disease with combined deficiency of multiple mitochondrial respiratory chain enzymes and pyruvate dehydrogenase.

PubMed

Ferdinandusse, Sacha; Waterham, Hans R; Heales, Simon J R; Brown, Garry K; Hargreaves, Iain P; Taanman, Jan-Willem; Gunny, Roxana; Abulhoul, Lara; Wanders, Ronald J A; Clayton, Peter T; Leonard, James V; Rahman, Shamima

2013-12-04

Deficiency of 3-hydroxy-isobutyryl-CoA hydrolase (HIBCH) caused by HIBCH mutations is a rare cerebral organic aciduria caused by disturbance of valine catabolism. Multiple mitochondrial respiratory chain (RC) enzyme deficiencies can arise from a number of mechanisms, including defective maintenance or expression of mitochondrial DNA. Impaired biosynthesis of iron-sulphur clusters and lipoic acid can lead to pyruvate dehydrogenase complex (PDHc) deficiency in addition to multiple RC deficiencies, known as the multiple mitochondrial dysfunctions syndrome. Two brothers born to distantly related Pakistani parents presenting in early infancy with a progressive neurodegenerative disorder, associated with basal ganglia changes on brain magnetic resonance imaging, were investigated for suspected Leigh-like mitochondrial disease. The index case had deficiencies of multiple RC enzymes and PDHc in skeletal muscle and fibroblasts respectively, but these were normal in his younger brother. The observation of persistently elevated hydroxy-C4-carnitine levels in the younger brother led to suspicion of HIBCH deficiency, which was investigated by biochemical assay in cultured skin fibroblasts and molecular genetic analysis. Specific spectrophotometric enzyme assay revealed HIBCH activity to be below detectable limits in cultured skin fibroblasts from both brothers. Direct Sanger sequence analysis demonstrated a novel homozygous pathogenic missense mutation c.950G

Thermodynamic coupling between activation and inactivation gating in potassium channels revealed by free energy molecular dynamics simulations.

PubMed

Pan, Albert C; Cuello, Luis G; Perozo, Eduardo; Roux, Benoît

2011-12-01

The amount of ionic current flowing through K(+) channels is determined by the interplay between two separate time-dependent processes: activation and inactivation gating. Activation is concerned with the stimulus-dependent opening of the main intracellular gate, whereas inactivation is a spontaneous conformational transition of the selectivity filter toward a nonconductive state occurring on a variety of timescales. A recent analysis of multiple x-ray structures of open and partially open KcsA channels revealed the mechanism by which movements of the inner activation gate, formed by the inner helices from the four subunits of the pore domain, bias the conformational changes at the selectivity filter toward a nonconductive inactivated state. This analysis highlighted the important role of Phe103, a residue located along the inner helix, near the hinge position associated with the opening of the intracellular gate. In the present study, we use free energy perturbation molecular dynamics simulations (FEP/MD) to quantitatively elucidate the thermodynamic basis for the coupling between the intracellular gate and the selectivity filter. The results of the FEP/MD calculations are in good agreement with experiments, and further analysis of the repulsive, van der Waals dispersive, and electrostatic free energy contributions reveals that the energetic basis underlying the absence of inactivation in the F103A mutation in KcsA is the absence of the unfavorable steric interaction occurring with the large Ile100 side chain in a neighboring subunit when the intracellular gate is open and the selectivity filter is in a conductive conformation. Macroscopic current analysis shows that the I100A mutant indeed relieves inactivation in KcsA, but to a lesser extent than the F103A mutant.

Structures of BmrR-Drug Complexes Reveal a Rigid Multidrug Binding Pocket And Transcription Activation Through Tyrosine Expulsion

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

Newberry, K.J.; Huffman, J.L.; Miller, M.C.

2009-05-22

BmrR is a member of the MerR family and a multidrug binding transcription factor that up-regulates the expression of the bmr multidrug efflux transporter gene in response to myriad lipophilic cationic compounds. The structural mechanism by which BmrR binds these chemically and structurally different drugs and subsequently activates transcription is poorly understood. Here, we describe the crystal structures of BmrR bound to rhodamine 6G (R6G) or berberine (Ber) and cognate DNA. These structures reveal each drug stacks against multiple aromatic residues with their positive charges most proximal to the carboxylate group of Glu-253 and that, unlike other multidrug binding pockets,more » that of BmrR is rigid. Substitution of Glu-253 with either alanine (E253A) or glutamine (E253Q) results in unpredictable binding affinities for R6G, Ber, and tetraphenylphosphonium. Moreover, these drug binding studies reveal that the negative charge of Glu-253 is not important for high affinity binding to Ber and tetraphenylphosphonium but plays a more significant, but unpredictable, role in R6G binding. In vitro transcription data show that E253A and E253Q are constitutively active, and structures of the drug-free E253A-DNA and E253Q-DNA complexes support a transcription activation mechanism requiring the expulsion of Tyr-152 from the multidrug binding pocket. In sum, these data delineate the mechanism by which BmrR binds lipophilic, monovalent cationic compounds and suggest the importance of the redundant negative electrostatic nature of this rigid drug binding pocket that can be used to discriminate against molecules that are not substrates of the Bmr multidrug efflux pump.« less

Dyslexia in a French-Spanish bilingual girl: behavioural and neural modulations following a visual attention span intervention.

PubMed

Valdois, Sylviane; Peyrin, Carole; Lassus-Sangosse, Delphine; Lallier, Marie; Démonet, Jean-François; Kandel, Sonia

2014-04-01

We report the case study of a French-Spanish bilingual dyslexic girl, MP, who exhibited a severe visual attention (VA) span deficit but preserved phonological skills. Behavioural investigation showed a severe reduction of reading speed for both single items (words and pseudo-words) and texts in the two languages. However, performance was more affected in French than in Spanish. MP was administered an intensive VA span intervention programme. Pre-post intervention comparison revealed a positive effect of intervention on her VA span abilities. The intervention further transferred to reading. It primarily resulted in faster identification of the regular and irregular words in French. The effect of intervention was rather modest in Spanish that only showed a tendency for faster word reading. Text reading improved in the two languages with a stronger effect in French but pseudo-word reading did not improve in either French or Spanish. The overall results suggest that VA span intervention may primarily enhance the fast global reading procedure, with stronger effects in French than in Spanish. MP underwent two fMRI sessions to explore her brain activations before and after VA span training. Prior to the intervention, fMRI assessment showed that the striate and extrastriate visual cortices alone were activated but none of the regions typically involved in VA span. Post-training fMRI revealed increased activation of the superior and inferior parietal cortices. Comparison of pre- and post-training activations revealed significant activation increase of the superior parietal lobes (BA 7) bilaterally. Thus, we show that a specific VA span intervention not only modulates reading performance but further results in increased brain activity within the superior parietal lobes known to housing VA span abilities. Furthermore, positive effects of VA span intervention on reading suggest that the ability to process multiple visual elements simultaneously is one cause of successful reading acquisition. Copyright © 2013 Elsevier Ltd. All rights reserved.

Venoms of Heteropteran Insects: A Treasure Trove of Diverse Pharmacological Toolkits

PubMed Central

Walker, Andrew A.; Weirauch, Christiane; Fry, Bryan G.; King, Glenn F.

2016-01-01

The piercing-sucking mouthparts of the true bugs (Insecta: Hemiptera: Heteroptera) have allowed diversification from a plant-feeding ancestor into a wide range of trophic strategies that include predation and blood-feeding. Crucial to the success of each of these strategies is the injection of venom. Here we review the current state of knowledge with regard to heteropteran venoms. Predaceous species produce venoms that induce rapid paralysis and liquefaction. These venoms are powerfully insecticidal, and may cause paralysis or death when injected into vertebrates. Disulfide-rich peptides, bioactive phospholipids, small molecules such as N,N-dimethylaniline and 1,2,5-trithiepane, and toxic enzymes such as phospholipase A2, have been reported in predatory venoms. However, the detailed composition and molecular targets of predatory venoms are largely unknown. In contrast, recent research into blood-feeding heteropterans has revealed the structure and function of many protein and non-protein components that facilitate acquisition of blood meals. Blood-feeding venoms lack paralytic or liquefying activity but instead are cocktails of pharmacological modulators that disable the host haemostatic systems simultaneously at multiple points. The multiple ways venom is used by heteropterans suggests that further study will reveal heteropteran venom components with a wide range of bioactivities that may be recruited for use as bioinsecticides, human therapeutics, and pharmacological tools. PMID:26907342

The SlFSR Gene Controls Fruit Shelf-Life in Tomato.

PubMed

Zhang, Lincheng; Zhu, Mingku; Ren, Lijun; Li, Anzhou; Chen, Guoping; Hu, Zongli

2018-04-04

Fruit ripening represents a process changing flavor and appearance and also a process dramatically increasing fruit softening. Fruit softening and textural variations are mainly resulted from the disrupted cell wall of fruit throughout ripening, whereas, the exact mechanisms and specific modifications of cell wall remain unclear. Plant-specific GRAS proteins play a critical role in development and growth. To date, few GRAS genes have been functionally categorized in tomato. The expression of a novel GRAS gene revealed herein is designated as SlFSR (fruitshelf-liferegulator), specifically increased during fruit ripening, whereas significantly decreased in tomato mutant rin (ripening inhibitor). RNAi repression of SlFSR resulted in reduced expression of multiple cell wall modification-related genes, decreased PG (polygalacturonase), TBG (tomato β-galactosidase), CEL (cellulase) and XYL (β-D-xylosidase) activities, and significantly prolonged fruit shelf-life. Furthermore, overexpression of SlFSR in mutant rin gave rise to up-regulated expression of multiple cell wall modification-related genes, such as PG, TBG4, CEL2, XYL1, PL, PE, MAN1, EXP1 and XTH5, and significantly shortened fruit shelf-life. Our findings make it possible to reveal the genetic mechanisms underlying fruit cell wall metabolisms and suggest that SlFSR gene is another biotechnological targeted control of tomato fruit shelf-life.

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

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

Multiple Modes of Communication between Neurons and Oligodendrocyte Precursor Cells.

PubMed

Maldonado, Paloma P; Angulo, María Cecilia

2015-06-01

The surprising discovery of bona fide synapses between neurons and oligodendrocytes precursor cells (OPCs) 15 years ago placed these progenitors as real partners of neurons in the CNS. The role of these synapses has not been established yet, but a main hypothesis is that neuron-OPC synaptic activity is a signaling pathway controlling OPC proliferation/differentiation, influencing the myelination process. However, new evidences describing non-synaptic mechanisms of communication between neurons and OPCs have revealed that neuron-OPC interactions are more complex than expected. The activation of extrasynaptic receptors by ambient neurotransmitter or local spillover and the ability of OPCs to sense neuronal activity through a potassium channel suggest that distinct modes of communication mediate different functions of OPCs in the CNS. This review discusses different mechanisms used by OPCs to interact with neurons and their potential roles during postnatal development and in brain disorders. © The Author(s) 2014.

Innate immune activity conditions the effect of regulatory variants upon monocyte gene expression.

PubMed

Fairfax, Benjamin P; Humburg, Peter; Makino, Seiko; Naranbhai, Vivek; Wong, Daniel; Lau, Evelyn; Jostins, Luke; Plant, Katharine; Andrews, Robert; McGee, Chris; Knight, Julian C

2014-03-07

To systematically investigate the impact of immune stimulation upon regulatory variant activity, we exposed primary monocytes from 432 healthy Europeans to interferon-γ (IFN-γ) or differing durations of lipopolysaccharide and mapped expression quantitative trait loci (eQTLs). More than half of cis-eQTLs identified, involving hundreds of genes and associated pathways, are detected specifically in stimulated monocytes. Induced innate immune activity reveals multiple master regulatory trans-eQTLs including the major histocompatibility complex (MHC), coding variants altering enzyme and receptor function, an IFN-β cytokine network showing temporal specificity, and an interferon regulatory factor 2 (IRF2) transcription factor-modulated network. Induced eQTL are significantly enriched for genome-wide association study loci, identifying context-specific associations to putative causal genes including CARD9, ATM, and IRF8. Thus, applying pathophysiologically relevant immune stimuli assists resolution of functional genetic variants.

High-resolution analysis of locomotor activity rhythms in disconnected, a visual-system mutant of Drosophila melanogaster.

PubMed

Dowse, H B; Dushay, M S; Hall, J C; Ringo, J M

1989-07-01

Free-running locomotor activity and eclosion rhythms of Drosophila melanogaster, mutant at the disconnected (disco) locus, are substantially different from the wild-type phenotype. Initial periodogram analysis revealed little or no rhythmicity (Dushay et al., 1989). We have reanalyzed the locomotor activity data using high-resolution signal analysis (maximum-entropy spectral analysis, or MESA). These analyses, corroborated by autocorrelograms, uncovered significant residual circadian rhythmicity and strong ultradian rhythms in most of the animals tested. In this regard the disco mutants are much like flies expressing mutant alleles of the period gene, as well as wild-type flies reared throughout life in constant darkness. We hypothesize that light normally triggers the coupling of multiple ultradian oscillators into a functional circadian clock and that this process is disrupted in disco flies as a result of the neural lesion.

Distributed task coding throughout the multiple demand network of the human frontal-insular cortex.

PubMed

Stiers, Peter; Mennes, Maarten; Sunaert, Stefan

2010-08-01

The large variety of tasks that humans can perform is governed by a small number of key frontal-insular regions that are commonly active during task performance. Little is known about how this network distinguishes different tasks. We report on fMRI data in twelve participants while they performed four cognitive tasks. Of 20 commonly active frontal-insular regions in each hemisphere, five showed a BOLD response increase with increased task demands, regardless of the task. Although active in all tasks, each task invoked a unique response pattern across the voxels in each area that proved reliable in split-half multi-voxel correlation analysis. Consequently, voxels differed in their preference for one or more of the tasks. Voxel-based functional connectivity analyses revealed that same preference voxels distributed across all areas of the network constituted functional sub-networks that characterized the task being executed. Copyright 2010 Elsevier Inc. All rights reserved.

Young Children's Energy Expenditure and Moderate-to-vigorous Physical Activity on Weekdays and Weekends.

PubMed

Lee, Jung Eun; Stodden, David F; Gao, Zan

2016-09-01

Few studies have examined young children's leisure- and school-based energy expenditure (EE) and moderateto-vigorous physical activity (MVPA). The purpose of this study was to explore children's estimated EE rates and time spent in MVPA in 3 time segments: at-school, after-school, and weekends. A total of 187 second and third grade children from 2 elementary schools participated in the study. Accelerometers were used to assess children's 5-day EE and MVPA. Multiple 2 (Grade) × 2 (Gender) ANOVAs with repeated measures (Time) were conducted to examine the differences in the outcome variables. Significant time effects on EE and MVPA were revealed. Children's EE rate and minutes in MVPA per day were higher during after school and weekends than at school. Although children were more active outside of school, their MVPA during weekdays and weekends still fell far short of the recommended level of 60 minutes/day.

Quantitative structure-activity relationships of selective antagonists of glucagon receptor using QuaSAR descriptors.

PubMed

Manoj Kumar, Palanivelu; Karthikeyan, Chandrabose; Hari Narayana Moorthy, Narayana Subbiah; Trivedi, Piyush

2006-11-01

In the present paper, quantitative structure activity relationship (QSAR) approach was applied to understand the affinity and selectivity of a novel series of triaryl imidazole derivatives towards glucagon receptor. Statistically significant and highly predictive QSARs were derived for glucagon receptor inhibition by triaryl imidazoles using QuaSAR descriptors of molecular operating environment (MOE) employing computer-assisted multiple regression procedure. The generated QSAR models revealed that factors related to hydrophobicity, molecular shape and geometry predominantly influences glucagon receptor binding affinity of the triaryl imidazoles indicating the relevance of shape specific steric interactions between the molecule and the receptor. Further, QSAR models formulated for selective inhibition of glucagon receptor over p38 mitogen activated protein (MAP) kinase of the compounds in the series highlights that the same structural features, which influence the glucagon receptor affinity, also contribute to their selective inhibition.

Rapid learning in visual cortical networks.

PubMed

Wang, Ye; Dragoi, Valentin

2015-08-26

Although changes in brain activity during learning have been extensively examined at the single neuron level, the coding strategies employed by cell populations remain mysterious. We examined cell populations in macaque area V4 during a rapid form of perceptual learning that emerges within tens of minutes. Multiple single units and LFP responses were recorded as monkeys improved their performance in an image discrimination task. We show that the increase in behavioral performance during learning is predicted by a tight coordination of spike timing with local population activity. More spike-LFP theta synchronization is correlated with higher learning performance, while high-frequency synchronization is unrelated with changes in performance, but these changes were absent once learning had stabilized and stimuli became familiar, or in the absence of learning. These findings reveal a novel mechanism of plasticity in visual cortex by which elevated low-frequency synchronization between individual neurons and local population activity accompanies the improvement in performance during learning.

Wavelength dependence of biological damage induced by UV radiation on bacteria.

PubMed

Santos, Ana L; Oliveira, Vanessa; Baptista, Inês; Henriques, Isabel; Gomes, Newton C M; Almeida, Adelaide; Correia, António; Cunha, Ângela

2013-01-01

The biological effects of UV radiation of different wavelengths (UVA, UVB and UVC) were assessed in nine bacterial isolates displaying different UV sensitivities. Biological effects (survival and activity) and molecular markers of oxidative stress [DNA strand breakage (DSB), generation of reactive oxygen species (ROS), oxidative damage to proteins and lipids, and the activity of antioxidant enzymes catalase and superoxide dismutase] were quantified and statistically analyzed in order to identify the major determinants of cell inactivation under the different spectral regions. Survival and activity followed a clear wavelength dependence, being highest under UVA and lowest under UVC. The generation of ROS, as well as protein and lipid oxidation, followed the same pattern. DNA damage (DSB) showed the inverse trend. Multiple stepwise regression analysis revealed that survival under UVA, UVB and UVC wavelengths was best explained by DSB, oxidative damage to lipids, and intracellular ROS levels, respectively.

Active PHO5 chromatin encompasses variable numbers of nucleosomes at individual promoters.

PubMed

Jessen, Walter J; Hoose, Scott A; Kilgore, Jessica A; Kladde, Michael P

2006-03-01

Transcriptional activation is often associated with chromatin remodeling. However, little is known about the dynamics of remodeling of nucleosome arrays in vivo. Upon induction of Saccharomyces cerevisiae PHO5, a novel kinetic assay of DNA methyltransferase accessibility showed that nucleosomes adjacent to the histone-free upstream activating sequence (UASp1) are disrupted earlier and at higher frequency in the cell population than are those more distal. Individually cloned molecules, each representing the chromatin state of a full promoter from a single cell, revealed multiple promoter classes with either no remodeling or variable numbers of disrupted nucleosomes. Individual promoters in the remodeled fraction were highly enriched for contiguous blocks of disrupted nucleosomes, the majority of which overlapped the UAS region. These results support a probabilistic model in which chromatin remodeling at PHO5 spreads from sites of transactivator association with DNA and attenuates with distance.

Decoding thalamic afferent input using microcircuit spiking activity

PubMed Central

Sederberg, Audrey J.; Palmer, Stephanie E.

2015-01-01

A behavioral response appropriate to a sensory stimulus depends on the collective activity of thousands of interconnected neurons. The majority of cortical connections arise from neighboring neurons, and thus understanding the cortical code requires characterizing information representation at the scale of the cortical microcircuit. Using two-photon calcium imaging, we densely sampled the thalamically evoked response of hundreds of neurons spanning multiple layers and columns in thalamocortical slices of mouse somatosensory cortex. We then used a biologically plausible decoder to characterize the representation of two distinct thalamic inputs, at the level of the microcircuit, to reveal those aspects of the activity pattern that are likely relevant to downstream neurons. Our data suggest a sparse code, distributed across lamina, in which a small population of cells carries stimulus-relevant information. Furthermore, we find that, within this subset of neurons, decoder performance improves when noise correlations are taken into account. PMID:25695647

Decoding thalamic afferent input using microcircuit spiking activity.

PubMed

Sederberg, Audrey J; Palmer, Stephanie E; MacLean, Jason N

2015-04-01

A behavioral response appropriate to a sensory stimulus depends on the collective activity of thousands of interconnected neurons. The majority of cortical connections arise from neighboring neurons, and thus understanding the cortical code requires characterizing information representation at the scale of the cortical microcircuit. Using two-photon calcium imaging, we densely sampled the thalamically evoked response of hundreds of neurons spanning multiple layers and columns in thalamocortical slices of mouse somatosensory cortex. We then used a biologically plausible decoder to characterize the representation of two distinct thalamic inputs, at the level of the microcircuit, to reveal those aspects of the activity pattern that are likely relevant to downstream neurons. Our data suggest a sparse code, distributed across lamina, in which a small population of cells carries stimulus-relevant information. Furthermore, we find that, within this subset of neurons, decoder performance improves when noise correlations are taken into account. Copyright © 2015 the American Physiological Society.

Plasmacytoma Infiltrating Leiomyoma in Multiple Myeloma

DTIC Science & Technology

2018-01-19

genital tract. Here, we report the case of a 55 year-old female with a history of multiple myeloma who presented with a six month history of...history of multiple myeloma who presented with a six month history of postmenopausal vaginal bleeding. Speculum exam revealed a mass protruding through

Increased experience amplifies the activation of task-irrelevant category representations.

PubMed

Wu, Rachel; Pruitt, Zoe; Zinszer, Benjamin D; Cheung, Olivia S

2017-02-01

Prior research has demonstrated the benefits (i.e., task-relevant attentional selection) and costs (i.e., task-irrelevant attentional capture) of prior knowledge on search for an individual target or multiple targets from a category. This study investigated whether the level of experience with particular categories predicts the degree of task-relevant and task-irrelevant activation of item and category representations. Adults with varying levels of dieting experience (measured via 3 subscales of Disinhibition, Restraint, Hunger; Stunkard & Messick, Journal of Psychosomatic Research, 29(1), 71-83, 1985) searched for targets defined as either a specific food item (e.g., carrots), or a category (i.e., any healthy or unhealthy food item). Apart from the target-present trials, in the target-absent "foil" trials, when searching for a specific item (e.g., carrots), irrelevant items from the target's category (e.g., squash) were presented. The ERP (N2pc) results revealed that the activation of task-relevant representations (measured via Exemplar and Category N2pc amplitudes) did not differ based on the degree of experience. Critically, however, increased dieting experience, as revealed by lower Disinhibition scores, predicted activation of task-irrelevant representations (i.e., attentional capture of foils from the target item category). Our results suggest that increased experience with particular categories encourages the rapid activation of category representations even when category information is task irrelevant, and that the N2pc in foil trials could potentially serve as an indication of experience level in future studies on categorization.

Combination of DTI and fMRI reveals the white matter changes correlating with the decline of default-mode network activity in Alzheimer's disease

NASA Astrophysics Data System (ADS)

Wu, Xianjun; Di, Qian; Li, Yao; Zhao, Xiaojie

2009-02-01

Recently, evidences from fMRI studies have shown that there was decreased activity among the default-mode network in Alzheimer's disease (AD), and DTI researches also demonstrated that demyelinations exist in white matter of AD patients. Therefore, combining these two MRI methods may help to reveal the relationship between white matter damages and alterations of the resting state functional connectivity network. In the present study, we tried to address this issue by means of correlation analysis between DTI and resting state fMRI images. The default-mode networks of AD and normal control groups were compared to find the areas with significantly declined activity firstly. Then, the white matter regions whose fractional anisotropy (FA) value correlated with this decline were located through multiple regressions between the FA values and the BOLD response of the default networks. Among these correlating white matter regions, those whose FA values also declined were found by a group comparison between AD patients and healthy elderly control subjects. Our results showed that the areas with decreased activity among default-mode network included left posterior cingulated cortex (PCC), left medial temporal gyrus et al. And the damaged white matter areas correlated with the default-mode network alterations were located around left sub-gyral temporal lobe. These changes may relate to the decreased connectivity between PCC and medial temporal lobe (MTL), and thus correlate with the deficiency of default-mode network activity.

Expression of Human CTP Synthetase in Saccharomyces cerevisiae Reveals Phosphorylation by Protein Kinase A*

PubMed Central

Han, Gil-Soo; Sreenivas, Avula; Choi, Mal-Gi; Chang, Yu-Fang; Martin, Shelley S.; Baldwin, Enoch P.; Carman, George M.

2005-01-01

CTP synthetase (EC 6.3.4.2, UTP: ammonia ligase (ADP-forming)) is an essential enzyme in all organisms; it generates the CTP required for the synthesis of nucleic acids and membrane phospholipids. In this work we showed that the human CTP synthetase genes, CTPS1 and CTPS2, were functional in Saccharomyces cerevisiae and complemented the lethal phenotype of the ura7Δ ura8Δ mutant lacking CTP synthetase activity. The expression of the CTPS1-and CTPS2-encoded human CTP synthetase enzymes in the ura7Δ ura8Δ mutant was shown by immunoblot analysis of CTP synthetase proteins, the measurement of CTP synthetase activity, and the synthesis of CTP in vivo. Phosphoamino acid and phosphopeptide mapping analyses of human CTP synthetase 1 isolated from 32Pi-labeled cells revealed that the enzyme was phosphorylated on multiple serine residues in vivo. Activation of protein kinase A activity in yeast resulted in transient increases (2-fold) in the phosphorylation of human CTP synthetase 1 and the cellular level of CTP. Human CTP synthetase 1 was also phosphorylated by mammalian protein kinase A in vitro. Using human CTP synthetase 1 purified from Escherichia coli as a substrate, protein kinase A activity was dose- and time-dependent, and dependent on the concentrations of CTP synthetase1 and ATP. These studies showed that S. cerevisiae was useful for the analysis of human CTP synthetase phosphorylation. PMID:16179339

Silymarin Suppresses Cellular Inflammation By Inducing Reparative Stress Signaling.

PubMed

Lovelace, Erica S; Wagoner, Jessica; MacDonald, James; Bammler, Theo; Bruckner, Jacob; Brownell, Jessica; Beyer, Richard P; Zink, Erika M; Kim, Young-Mo; Kyle, Jennifer E; Webb-Robertson, Bobbie-Jo M; Waters, Katrina M; Metz, Thomas O; Farin, Federico; Oberlies, Nicholas H; Polyak, Stephen J

2015-08-28

Silymarin, a characterized extract of the seeds of milk thistle (Silybum marianum), suppresses cellular inflammation. To define how this occurs, transcriptional profiling, metabolomics, and signaling studies were performed in human liver and T cell lines. Cellular stress and metabolic pathways were modulated within 4 h of silymarin treatment: activation of Activating Transcription Factor 4 (ATF-4) and adenosine monophosphate protein kinase (AMPK) and inhibition of mammalian target of rapamycin (mTOR) signaling, the latter being associated with induction of DNA-damage-inducible transcript 4 (DDIT4). Metabolomics analyses revealed silymarin suppression of glycolytic, tricarboxylic acid (TCA) cycle, and amino acid metabolism. Anti-inflammatory effects arose with prolonged (i.e., 24 h) silymarin exposure, with suppression of multiple pro-inflammatory mRNAs and signaling pathways including nuclear factor kappa B (NF-κB) and forkhead box O (FOXO). Studies with murine knock out cells revealed that silymarin inhibition of both mTOR and NF-κB was partially AMPK dependent, whereas silymarin inhibition of mTOR required DDIT4. Other natural products induced similar stress responses, which correlated with their ability to suppress inflammation. Thus, natural products activate stress and repair responses that culminate in an anti-inflammatory cellular phenotype. Natural products like silymarin may be useful as tools to define how metabolic, stress, and repair pathways regulate cellular inflammation.

Silymarin Suppresses Cellular Inflammation By Inducing Reparative Stress Signaling

PubMed Central

Lovelace, Erica S.; Wagoner, Jessica; MacDonald, James; Bammler, Theo; Bruckner, Jacob; Brownell, Jessica; Beyer, Richard; Zink, Erika M.; Kim, Young-Mo; Kyle, Jennifer E.; Webb-Robertson, Bobbie-Jo; Waters, Katrina M.; Metz, Thomas O.; Farin, Federico; Oberlies, Nicholas H.; Polyak, Stephen J.

2016-01-01

Silymarin, a characterized extract of the seeds of milk thistle (Silybum marianum), suppresses cellular inflammation. To define how this occurs, transcriptional profiling, metabolomics, and signaling studies were performed in human liver and T cell lines. Cellular stress and metabolic pathways were modulated within 4 h of silymarin treatment: activation of Activating Transcription Factor 4 (ATF-4) and adenosine monophosphate protein kinase (AMPK) and inhibition of mammalian target of rapamycin (mTOR) signaling, the latter being associated with induction of DNA-damage-inducible transcript 4 (DDIT4). Metabolomics analyses revealed silymarin suppression of glycolytic, tricarboxylic acid (TCA) cycle, and amino acid metabolism. Anti-inflammatory effects arose with prolonged (i.e. 24 h) silymarin exposure, with suppression of multiple pro-inflammatory mRNAs and signaling pathways including nuclear factor kappa B (NF-κB) and forkhead box O (FOXO). Studies with murine knock out cells revealed that silymarin inhibition of both mTOR and NF-κB was partially AMPK dependent, while silymarin inhibition of mTOR required DDIT4. Other natural products induced similar stress responses, which correlated with their ability to suppress inflammation. Thus, natural products activate stress and repair responses that culminate in an anti-inflammatory cellular phenotype. Natural products like silymarin may be useful as tools to define how metabolic, stress, and repair pathways regulate cellular inflammation. PMID:26186142

Caged Naloxone Reveals Opioid Signaling Deactivation Kinetics

PubMed Central

Banghart, Matthew R.; Shah, Ruchir C.; Lavis, Luke D.

2013-01-01

The spatiotemporal dynamics of opioid signaling in the brain remain poorly defined. Photoactivatable opioid ligands provide a means to quantitatively measure these dynamics and their underlying mechanisms in brain tissue. Although activation kinetics can be assessed using caged agonists, deactivation kinetics are obscured by slow clearance of agonist in tissue. To reveal deactivation kinetics of opioid signaling we developed a caged competitive antagonist that can be quickly photoreleased in sufficient concentrations to render agonist dissociation effectively irreversible. Carboxynitroveratryl-naloxone (CNV-NLX), a caged analog of the competitive opioid antagonist NLX, was readily synthesized from commercially available NLX in good yield and found to be devoid of antagonist activity at heterologously expressed opioid receptors. Photolysis in slices of rat locus coeruleus produced a rapid inhibition of the ionic currents evoked by multiple agonists of the μ-opioid receptor (MOR), but not of α-adrenergic receptors, which activate the same pool of ion channels. Using the high-affinity peptide agonist dermorphin, we established conditions under which light-driven deactivation rates are independent of agonist concentration and thus intrinsic to the agonist-receptor complex. Under these conditions, some MOR agonists yielded deactivation rates that are limited by G protein signaling, whereas others appeared limited by agonist dissociation. Therefore, the choice of agonist determines which feature of receptor signaling is unmasked by CNV-NLX photolysis. PMID:23960100

AMP-activated protein kinase-mediated feedback phosphorylation controls the Ca2+/calmodulin (CaM) dependence of Ca2+/CaM-dependent protein kinase kinase β.

PubMed

Nakanishi, Akihiro; Hatano, Naoya; Fujiwara, Yuya; Sha'ri, Arian; Takabatake, Shota; Akano, Hiroki; Kanayama, Naoki; Magari, Masaki; Nozaki, Naohito; Tokumitsu, Hiroshi

2017-12-01

The Ca 2+ /calmodulin-dependent protein kinase kinase β (CaMKKβ)/5'-AMP-activated protein kinase (AMPK) phosphorylation cascade affects various Ca 2+ -dependent metabolic pathways and cancer growth. Unlike recombinant CaMKKβ that exhibits higher basal activity (autonomous activity), activation of the CaMKKβ/AMPK signaling pathway requires increased intracellular Ca 2+ concentrations. Moreover, the Ca 2+ /CaM dependence of CaMKKβ appears to arise from multiple phosphorylation events, including autophosphorylation and activities furnished by other protein kinases. However, the effects of proximal downstream kinases on CaMKKβ activity have not yet been evaluated. Here, we demonstrate feedback phosphorylation of CaMKKβ at multiple residues by CaMKKβ-activated AMPK in addition to autophosphorylation in vitro , leading to reduced autonomous, but not Ca 2+ /CaM-activated, CaMKKβ activity. MS analysis and site-directed mutagenesis of AMPK phosphorylation sites in CaMKKβ indicated that Thr 144 phosphorylation by activated AMPK converts CaMKKβ into a Ca 2+ /CaM-dependent enzyme as shown by completely Ca 2+ /CaM-dependent CaMKK activity of a phosphomimetic T144E CaMKKβ mutant. CaMKKβ mutant analysis indicated that the C-terminal domain (residues 471-587), including the autoinhibitory region, plays an important role in stabilizing an inactive conformation in a Thr 144 phosphorylation-dependent manner. Furthermore, immunoblot analysis with anti-phospho-Thr 144 antibody revealed phosphorylation of Thr 144 in CaMKKβ in transfected COS-7 cells that was further enhanced by exogenous expression of AMPKα. These results indicate that AMPK-mediated feedback phosphorylation of CaMKKβ regulates the CaMKKβ/AMPK signaling cascade and may be physiologically important for intracellular maintenance of Ca 2+ -dependent AMPK activation by CaMKKβ. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Use of the Godin leisure-time exercise questionnaire in multiple sclerosis research: a comprehensive narrative review.

PubMed

Sikes, Elizabeth Morghen; Richardson, Emma V; Cederberg, Katie J; Sasaki, Jeffer E; Sandroff, Brian M; Motl, Robert W

2018-01-17

The Godin Leisure-Time Exercise Questionnaire has been a commonly applied measure of physical activity in research among persons with multiple sclerosis over the past decade. This paper provides a comprehensive description of its application and inclusion in research on physical activity in multiple sclerosis. This comprehensive, narrative review included papers that were published between 1985 and 2017, written in English, involved participants with multiple sclerosis as a primary population, measured physical activity, and cited one of the two original Godin papers. There is a broad scope of research that has included the Godin Leisure-Time Exercise Questionnaire in persons with multiple sclerosis. Overall, 8 papers evaluated its psychometric properties, 21 evaluated patterns of physical activity, 24 evaluated correlates or determinants of physical activity, 28 evaluated outcomes or consequences of physical activity, and 15 evaluated physical activity interventions. The Godin Leisure-Time Exercise Questionnaire is a valid self-report measure of physical activity in persons with multiple sclerosis, and further is an appropriate, simple, and effective tool for describing patterns of physical activity, examining correlates and outcomes of physical activity, and provides a sensitive outcome for measuring change in physical activity after an intervention. Implications for rehabilitation There is increasing interest in physical activity and its benefits in multiple sclerosis. The study of physical activity requires appropriate and standardized measures. The Godin Leisure-Time Exercise Questionnaire is a common self-report measure of physical activity for persons with multiple sclerosis. Godin Leisure-Time Exercise Questionnaire scores are reliable measures of physical activity in persons with multiple sclerosis. The Godin Leisure-Time Exercise Questionnaire further is an appropriate, simple, and effective tool for describing patterns of physical activity, examining correlates and outcomes of physical activity participation, and is an advantageous primary outcome for measuring change in physical activity in response to an intervention.

Hemophagocytic syndrome in a cat with multiple myeloma.

PubMed

Dunbar, Mark D; Lyles, Sarah

2013-03-01

An 11-year-old, castrated male, Domestic Medium Hair cat was presented to the University of Florida Small Animal Hospital with a 2-week history of upper respiratory infection and increased serum globulins, as reported by the referring veterinarian. Physical examination was unremarkable other than melanosis of the left iris, with no evidence of ocular, nasal, or respiratory disease. Laboratory abnormalities included moderate nonregenerative anemia, mild leukopenia, mild hyperfibrinogenemia, severe hyperglobulinemia, mild hypoalbuminemia, and hypocholesterolemia. Abdominal radiographs and ultrasonographic examination revealed mild splenomegaly with no other abnormalities. Thoracic radiographs revealed no abnormalities. Cytologic evaluation of fine-needle aspirates from the spleen, liver, and bone marrow revealed numerous plasma cells and many vacuolated macrophages exhibiting marked phagocytosis of mature erythrocytes and platelets, occasionally metarubricytes and leukocytes, and rarely plasma cells. The cytologic interpretation was multiple myeloma and associated hemophagocytic syndrome (HPS). Serum protein electrophoresis revealed a monoclonal gammopathy, providing further evidence for a multiple myeloma. To the authors' knowledge, this is the first report of HPS secondary to neoplasia in a cat. © 2012 American Society for Veterinary Clinical Pathology.

Disseminated sinus histiocytosis with massive lymphadenopathy: its pathologic aspects.

PubMed

Buchino, J J; Byrd, R P; Kmetz, D R

1982-01-01

Sinus histiocytosis with massive lymphadenopathy (SHML) is generally regarded as a benign, self-limited, pseudolymphomatous process requiring little or no therapy. We studied a 13-year-old black boy with a ten-year clinical course of SHML that had varying, intermittent sites of extranodal involvement, including bone, submandibular gland, trachea, eye, and spinal cord. At the time of death, which was attributed to SHML, additional extranodal sites of involvement included thymus, kidney, heart, liver, and base of brain. Microscopic examination of the SHML lesions at the time of autopsy revealed varying stages of development, from proliferation to involution. This case illustrates that SHML may involve multiple organ systems, can kill, and that histologic evaluation of disease activity at one site cannot be used as an indicator of activity at another.

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.

Immunocompetence analysis of the aquatic snail Lymnaea stagnalis exposed to urban wastewaters.

PubMed

Boisseaux, Paul; Noury, Patrice; Delorme, Nicolas; Perrier, Lucile; Thomas-Guyon, Helene; Garric, Jeanne

2018-04-02

Wastewater treatment plant effluents from urban area are a well-known source of chronic multiple micropollution to the downstream living organisms. In this study, ecologically relevant laboratory-bred freshwater gastropods, Lymnaea stagnalis, were exposed for 29 days to raw effluents of a wastewater treatment plant in Lyon area (France). A time-course analysis of individual markers of immunocompetence (hemocyte density and viability, hemocyte NADPH activity, phenol oxidase activity, and capacity of phagocytosis) has shown slight trends of inflammatory-like responses induced by the 100% effluents. So far, no short-term hazard for L. stagnalis can be revealed. However, over the long term, such environmental stress-stimulating immune responses could provoke deleterious life history trade-offs because the immune system is known to be highly energy-consuming.

Structural and Functional Impacts of ER Coactivator Sequential Recruitment.

PubMed

Yi, Ping; Wang, Zhao; Feng, Qin; Chou, Chao-Kai; Pintilie, Grigore D; Shen, Hong; Foulds, Charles E; Fan, Guizhen; Serysheva, Irina; Ludtke, Steven J; Schmid, Michael F; Hung, Mien-Chie; Chiu, Wah; O'Malley, Bert W

2017-09-07

Nuclear receptors recruit multiple coactivators sequentially to activate transcription. This "ordered" recruitment allows different coactivator activities to engage the nuclear receptor complex at different steps of transcription. Estrogen receptor (ER) recruits steroid receptor coactivator-3 (SRC-3) primary coactivator and secondary coactivators, p300/CBP and CARM1. CARM1 recruitment lags behind the binding of SRC-3 and p300 to ER. Combining cryo-electron microscopy (cryo-EM) structure analysis and biochemical approaches, we demonstrate that there is a close crosstalk between early- and late-recruited coactivators. The sequential recruitment of CARM1 not only adds a protein arginine methyltransferase activity to the ER-coactivator complex, it also alters the structural organization of the pre-existing ERE/ERα/SRC-3/p300 complex. It induces a p300 conformational change and significantly increases p300 HAT activity on histone H3K18 residues, which, in turn, promotes CARM1 methylation activity on H3R17 residues to enhance transcriptional activity. This study reveals a structural role for a coactivator sequential recruitment and biochemical process in ER-mediated transcription. Copyright © 2017 Elsevier Inc. All rights reserved.

Structural basis for Mob1-dependent activation of the core Mst–Lats kinase cascade in Hippo signaling

DOE PAGES

Ni, Lisheng; Zheng, Yonggang; Hara, Mayuko; ...

2015-06-24

The Mst–Lats kinase cascade is central to the Hippo tumor-suppressive pathway that controls organ size and tissue homeostasis. The adaptor protein Mob1 promotes Lats activation by Mst, but the mechanism remains unknown. Here, we show that human Mob1 binds to autophosphorylated docking motifs in active Mst2. This binding enables Mob1 phosphorylation by Mst2. Phosphorylated Mob1 undergoes conformational activation and binds to Lats1. We determine the crystal structures of phospho-Mst2–Mob1 and phospho-Mob1–Lats1 complexes, revealing the structural basis of both phosphorylation-dependent binding events. Further biochemical and functional analyses demonstrate that Mob1 mediates Lats1 activation through dynamic scaffolding and allosteric mechanisms. Thus, Mob1more » acts as a phosphorylation-regulated coupler of kinase activation by virtue of its ability to engage multiple ligands. We propose that stepwise, phosphorylation-triggered docking interactions of nonkinase elements enhance the specificity and robustness of kinase signaling cascades.« less

The regulation of the SARK promoter activity by hormones and environmental signals.

PubMed

Delatorre, Carla A; Cohen, Yuval; Liu, Li; Peleg, Zvi; Blumwald, Eduardo

2012-09-01

The Senescence Associated Receptor Protein Kinase (P(SARK)) promoter, fused to isopentenyltransferase (IPT) gene has been shown to promote drought tolerance in crops. We dissected P(SARK) in order to understand the various elements associated with its activation and suppression. The activity of P(SARK) was higher in mature and early senescing leaves, and abiotic stress induced its activity in mature leaves. Bioinformatics analysis suggests the interactions of multiple cis-acting elements in the control of P(SARK) activity. In vitro gel shift assays and yeast one hybrid system revealed interactions of P(SARK) with transcription factors related to abscisic acid and cytokinin response. Deletion analysis of P(SARK), fused to GUS-reporter gene was used to identify specific regions regulating transcription under senescence or during drought stress. Effects of exogenous hormonal treatments were characterized in entire plants and in leaf disk assays, and regions responsive to various hormones were defined. Our results indicate a complex interaction of plant hormones and additional factors modulating P(SARK) activity under stress resulting in a transient induction of expression. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

LWD-TCP complex activates the morning gene CCA1 in Arabidopsis.

PubMed

Wu, Jing-Fen; Tsai, Huang-Lung; Joanito, Ignasius; Wu, Yi-Chen; Chang, Chin-Wen; Li, Yi-Hang; Wang, Ying; Hong, Jong Chan; Chu, Jhih-Wei; Hsu, Chao-Ping; Wu, Shu-Hsing

2016-10-13

A double-negative feedback loop formed by the morning genes CIRCADIAN CLOCK ASSOCIATED1 (CCA1)/LATE ELONGATED HYPOCOTYL (LHY) and the evening gene TIMING OF CAB EXPRESSION1 (TOC1) contributes to regulation of the circadian clock in Arabidopsis. A 24-h circadian cycle starts with the peak expression of CCA1 at dawn. Although CCA1 is targeted by multiple transcriptional repressors, including PSEUDO-RESPONSE REGULATOR9 (PRR9), PRR7, PRR5 and CCA1 HIKING EXPEDITION (CHE), activators of CCA1 remain elusive. Here we use mathematical modelling to infer a co-activator role for LIGHT-REGULATED WD1 (LWD1) in CCA1 expression. We show that the TEOSINTE BRANCHED 1-CYCLOIDEA-PCF20 (TCP20) and TCP22 proteins act as LWD-interacting transcriptional activators. The concomitant binding of LWD1 and TCP20/TCP22 to the TCP-binding site in the CCA1 promoter activates CCA1. Our study reveals activators of the morning gene CCA1 and provides an action mechanism that ensures elevated expression of CCA1 at dawn to sustain a robust clock.

LWD–TCP complex activates the morning gene CCA1 in Arabidopsis

PubMed Central

Wu, Jing-Fen; Tsai, Huang-Lung; Joanito, Ignasius; Wu, Yi-Chen; Chang, Chin-Wen; Li, Yi-Hang; Wang, Ying; Hong, Jong Chan; Chu, Jhih-Wei; Hsu, Chao-Ping; Wu, Shu-Hsing

2016-01-01

A double-negative feedback loop formed by the morning genes CIRCADIAN CLOCK ASSOCIATED1 (CCA1)/LATE ELONGATED HYPOCOTYL (LHY) and the evening gene TIMING OF CAB EXPRESSION1 (TOC1) contributes to regulation of the circadian clock in Arabidopsis. A 24-h circadian cycle starts with the peak expression of CCA1 at dawn. Although CCA1 is targeted by multiple transcriptional repressors, including PSEUDO-RESPONSE REGULATOR9 (PRR9), PRR7, PRR5 and CCA1 HIKING EXPEDITION (CHE), activators of CCA1 remain elusive. Here we use mathematical modelling to infer a co-activator role for LIGHT-REGULATED WD1 (LWD1) in CCA1 expression. We show that the TEOSINTE BRANCHED 1-CYCLOIDEA-PCF20 (TCP20) and TCP22 proteins act as LWD-interacting transcriptional activators. The concomitant binding of LWD1 and TCP20/TCP22 to the TCP-binding site in the CCA1 promoter activates CCA1. Our study reveals activators of the morning gene CCA1 and provides an action mechanism that ensures elevated expression of CCA1 at dawn to sustain a robust clock. PMID:27734958

Structural mechanism of ligand activation in human calcium-sensing receptor

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

Geng, Yong; Mosyak, Lidia; Kurinov, Igor

2016-07-19

Human calcium-sensing receptor (CaSR) is a G-protein-coupled receptor (GPCR) that maintains extracellular Ca 2+homeostasis through the regulation of parathyroid hormone secretion. It functions as a disulfide-tethered homodimer composed of three main domains, the Venus Flytrap module, cysteine-rich domain, and seven-helix transmembrane region. Here, we present the crystal structures of the entire extracellular domain of CaSR in the resting and active conformations. We provide direct evidence that L-amino acids are agonists of the receptor. In the active structure, L-Trp occupies the orthosteric agonist-binding site at the interdomain cleft and is primarily responsible for inducing extracellular domain closure to initiate receptor activation.more » Our structures reveal multiple binding sites for Ca 2+and PO 4 3-ions. Both ions are crucial for structural integrity of the receptor. While Ca 2+ions stabilize the active state, PO 4 3-ions reinforce the inactive conformation. The activation mechanism of CaSR involves the formation of a novel dimer interface between subunits.« less

The dyad palindromic glutathione transferase P enhancer binds multiple factors including AP1.

PubMed Central

Diccianni, M B; Imagawa, M; Muramatsu, M

1992-01-01

Glutathione Transferase P (GST-P) gene expression is dominantly regulated by an upstream enhancer (GPEI) consisting of a dyad of palindromically oriented imperfect TPA (12-O-tetradecanoyl-phorbol-13-acetate)-responsive elements (TRE). GPEI is active in AP1-lacking F9 cells as well in AP1-containing HeLa cells. Despite GPEI's similarity to a TRE, c-jun co-transfection has only a minimal effect on transactivation. Antisense c-jun and c-fos co-transfection experiments further demonstrate the lack of a role for AP1 in GPEI mediated trans-activation in F9 cells, although endogenously present AP1 can influence GPEI in HeLa cells. Co-transfection of delta fosB with c-jun, which forms an inactive c-Jun/delta FosB heterodimer that binds TRE sequences, inhibits GPEI-mediated transcription in AP1-lacking F9 cells as well as AP1-containing HeLa cells. These data suggest novel factor(s) other than AP1 are influencing GPEI. Binding studies reveal multiple nucleoproteins bind to GPEI. These factors are likely responsible for the high level of GPEI-mediated transcription observed in the absence of AP1 and during hepatocarcinogenesis. Images PMID:1408831

The dyad palindromic glutathione transferase P enhancer binds multiple factors including AP1.

PubMed

Diccianni, M B; Imagawa, M; Muramatsu, M

1992-10-11

Glutathione Transferase P (GST-P) gene expression is dominantly regulated by an upstream enhancer (GPEI) consisting of a dyad of palindromically oriented imperfect TPA (12-O-tetradecanoyl-phorbol-13-acetate)-responsive elements (TRE). GPEI is active in AP1-lacking F9 cells as well in AP1-containing HeLa cells. Despite GPEI's similarity to a TRE, c-jun co-transfection has only a minimal effect on transactivation. Antisense c-jun and c-fos co-transfection experiments further demonstrate the lack of a role for AP1 in GPEI mediated trans-activation in F9 cells, although endogenously present AP1 can influence GPEI in HeLa cells. Co-transfection of delta fosB with c-jun, which forms an inactive c-Jun/delta FosB heterodimer that binds TRE sequences, inhibits GPEI-mediated transcription in AP1-lacking F9 cells as well as AP1-containing HeLa cells. These data suggest novel factor(s) other than AP1 are influencing GPEI. Binding studies reveal multiple nucleoproteins bind to GPEI. These factors are likely responsible for the high level of GPEI-mediated transcription observed in the absence of AP1 and during hepatocarcinogenesis.

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

Aberrant Upregulation of Astroglial Ceramide Potentiates Oligodendrocyte Injury

PubMed Central

Kim, SunJa; Steelman, Andrew J.; Zhang, Yumin; Kinney, Hannah C.; Li, Jianrong

2015-01-01

Oligodendroglial injury is a pathological hallmark of many human white matter diseases, including multiple sclerosis and periventricular leukomalacia. Critical regulatory mechanisms of oligodendroglia destruction, however, remain incompletely understood. Ceramide, a bioactive sphingolipid pivotal to sphingolipid metabolism pathways, regulates cell death in response to diverse stimuli and has been implicated in neurodegenerative disorders. We report here that ceramide accumulates in reactive astrocytes in active lesions of multiple sclerosis and periventricular leukomalacia, as well as in animal models of demyelination. Serine palmitoyltransferase, the rate-limiting enzyme for ceramide de novo biosynthesis, was consistently upregulated in reactive astrocytes in the cuprizone mouse model of demyelination. Mass spectrometry confirmed the upregulation of specific ceramides during demyelination and revealed a concomitant increase of sphingosine as well as a suppression of sphingosine-1-phosphate, a potent signaling molecule with key roles in cell survival and mitogenesis. Importantly, this altered sphingolipid metabolism during demyelination was restored upon active remyelination. In culture, ceramide acted synergistically with tumor necrosis factor leading to apoptotic death of oligodendroglia in an astrocyte-dependent manner. Taken together, our findings implicate that disturbed sphingolipid pathways in reactive astrocytes may indirectly contribute to oligodendroglial injury in cerebral white matter disorders. PMID:21615590

Unifying mechanism for different fibrotic diseases

PubMed Central

Wernig, Gerlinde; Chen, Shih-Yu; Cui, Lu; Van Neste, Camille; Tsai, Jonathan M.; Kambham, Neeraja; Vogel, Hannes; Natkunam, Yaso; Gilliland, D. Gary; Nolan, Garry; Weissman, Irving L.

2017-01-01

Fibrotic diseases are not well-understood. They represent a number of different diseases that are characterized by the development of severe organ fibrosis without any obvious cause, such as the devastating diseases idiopathic pulmonary fibrosis (IPF) and scleroderma. These diseases have a poor prognosis comparable with endstage cancer and are uncurable. Given the phenotypic differences, it was assumed that the different fibrotic diseases also have different pathomechanisms. Here, we demonstrate that many endstage fibrotic diseases, including IPF; scleroderma; myelofibrosis; kidney-, pancreas-, and heart-fibrosis; and nonalcoholic steatohepatosis converge in the activation of the AP1 transcription factor c-JUN in the pathologic fibroblasts. Expression of the related AP1 transcription factor FRA2 was restricted to pulmonary artery hypertension. Induction of c-Jun in mice was sufficient to induce severe fibrosis in multiple organs and steatohepatosis, which was dependent on sustained c-Jun expression. Single cell mass cytometry revealed that c-Jun activates multiple signaling pathways in mice, including pAkt and CD47, which were also induced in human disease. αCD47 antibody treatment and VEGF or PI3K inhibition reversed various organ c-Jun–mediated fibroses in vivo. These data suggest that c-JUN is a central molecular mediator of most fibrotic conditions. PMID:28424250

Strength, Multijoint Coordination, and Sensorimotor Processing Are Independent Contributors to Overall Balance Ability

PubMed Central

Lawrence, Emily L.; Cesar, Guilherme M.; Bromfield, Martha R.; Peterson, Richard; Valero-Cuevas, Francisco J.; Sigward, Susan M.

2015-01-01

For young adults, balance is essential for participation in physical activities but is often disrupted following lower extremity injury. Clinical outcome measures such as single limb balance (SLB), Y-balance (YBT), and the single limb hop and balance (SLHB) tests are commonly used to quantify balance ability following injury. Given the varying demands across tasks, it is likely that such outcome measures provide useful, although task-specific, information. But the extent to which they are independent and contribute to understanding the multiple contributors to balance is not clear. Therefore, the purpose of this study was to investigate the associations among these measures as they relate to the different contributors to balance. Thirty-seven recreationally active young adults completed measures including Vertical Jump, YBT, SLB, SLHB, and the new Lower Extremity Dexterity test. Principal components analysis revealed that these outcome measures could be thought of as quantifying the strength, multijoint coordination, and sensorimotor processing contributors to balance. Our results challenge the practice of using a single outcome measure to quantify the naturally multidimensional mechanisms for everyday functions such as balance. This multidimensional approach to, and interpretation of, multiple contributors to balance may lead to more effective, specialized training and rehabilitation regimens. PMID:26665007

Novel 3-Substituted 7-Phenylpyrrolo[3,2-f]quinolin-9(6H)-ones as Single Entities with Multitarget Antiproliferative Activity.

PubMed

Carta, Davide; Bortolozzi, Roberta; Hamel, Ernest; Basso, Giuseppe; Moro, Stefano; Viola, Giampietro; Ferlin, Maria Grazia

2015-10-22

A series of chemically modified 7-phenylpyrrolo[3,2-f]quinolinones was synthesized and evaluated as anticancer agents. Among them, the most cytotoxic (subnanomolar GI50 values) amidic derivative 5f was shown to act as an inhibitor of tubulin polymerization (IC50, 0.99 μM) by binding to the colchicine site with high affinity. Moreover, 5f induced cell cycle arrest in the G2/M phase of the cell cycle in a concentration dependent manner, followed by caspase-dependent apoptotic cell death. Compound 5f also showed lower toxicity in nontumoral cells, suggesting selectivity toward cancer cells. Additional experiments revealed that 5f inhibited the enzymatic activity of multiple kinases, including AURKA, FLT3, GSK3A, MAP3K, MEK, RSK2, RSK4, PLK4, ULK1, and JAK1. Computational studies showed that 5f can be properly accommodated in the colchicine binding site of tubulin as well as in the ATP binding clefts of all examined kinases. Our data indicate that the excellent antiproliferative profile of 5f may be derived from its interactions with multiple cellular targets.

Targeting cancer by binding iron: Dissecting cellular signaling pathways

PubMed Central

Lui, Goldie Y.L.; Kovacevic, Zaklina; Richardson, Vera; Merlot, Angelica M.; Kalinowski, Danuta S.; Richardson, Des R.

2015-01-01

Newer and more potent therapies are urgently needed to effectively treat advanced cancers that have developed resistance and metastasized. One such strategy is to target cancer cell iron metabolism, which is altered compared to normal cells and may facilitate their rapid proliferation. This is supported by studies reporting the anti-neoplastic activities of the clinically available iron chelators, desferrioxamine and deferasirox. More recently, ligands of the di-2-pyridylketone thiosemicarbazone (DpT) class have demonstrated potent and selective anti-proliferative activity across multiple cancer-types in vivo, fueling studies aimed at dissecting their molecular mechanisms of action. In the past five years alone, significant advances have been made in understanding how chelators not only modulate cellular iron metabolism, but also multiple signaling pathways implicated in tumor progression and metastasis. Herein, we discuss recent research on the targeting of iron in cancer cells, with a focus on the novel and potent DpT ligands. Several key studies have revealed that iron chelation can target the AKT, ERK, JNK, p38, STAT3, TGF-β, Wnt and autophagic pathways to subsequently inhibit cellular proliferation, the epithelial-mesenchymal transition (EMT) and metastasis. These developments emphasize that these novel therapies could be utilized clinically to effectively target cancer. PMID:26125440

A site-saturated mutagenesis study of pentaerythritol tetranitrate reductase reveals that residues 181 and 184 influence ligand binding, stereochemistry and reactivity.

PubMed

Toogood, Helen S; Fryszkowska, Anna; Hulley, Martyn; Sakuma, Michiyo; Mansell, David; Stephens, Gill M; Gardiner, John M; Scrutton, Nigel S

2011-03-21

We have conducted a site-specific saturation mutagenesis study of H181 and H184 of flavoprotein pentaerythritol tetranitrate reductase (PETN reductase) to probe the role of these residues in substrate binding and catalysis with a variety of α,β-unsaturated alkenes. Single mutations at these residues were sufficient to dramatically increase the enantiopurity of products formed by reduction of 2-phenyl-1-nitropropene. In addition, many mutants exhibited a switch in reactivity to predominantly catalyse nitro reduction, as opposed to CC reduction. These mutants showed an enhancement in a minor side reaction and formed 2-phenylpropanal oxime from 2-phenyl-1-nitropropene. The multiple binding conformations of hydroxy substituted nitro-olefins in PETN reductase were examined by using both structural and catalytic techniques. These compounds were found to bind in both active and inhibitory complexes; this highlights the plasticity of the active site and the ability of the H181/H184 couple to coordinate with multiple functional groups. These properties demonstrate the potential to use PETN reductase as a scaffold in the development of industrially useful biocatalysts. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Intrinsic and synaptic properties of vertical cells of the mouse dorsal cochlear nucleus

PubMed Central

Kuo, Sidney P.; Lu, Hsin-Wei

2012-01-01

Multiple classes of inhibitory interneurons shape the activity of principal neurons of the dorsal cochlear nucleus (DCN), a primary target of auditory nerve fibers in the mammalian brain stem. Feedforward inhibition mediated by glycinergic vertical cells (also termed tuberculoventral or corn cells) is thought to contribute importantly to the sound-evoked response properties of principal neurons, but the cellular and synaptic properties that determine how vertical cells function are unclear. We used transgenic mice in which glycinergic neurons express green fluorescent protein (GFP) to target vertical cells for whole cell patch-clamp recordings in acute slices of DCN. We found that vertical cells express diverse intrinsic spiking properties and could fire action potentials at high, sustained spiking rates. Using paired recordings, we directly examined synapses made by vertical cells onto fusiform cells, a primary DCN principal cell type. Vertical cell synapses produced unexpectedly small-amplitude unitary currents in fusiform cells, and additional experiments indicated that multiple vertical cells must be simultaneously active to inhibit fusiform cell spike output. Paired recordings also revealed that a major source of inhibition to vertical cells comes from other vertical cells. PMID:22572947

The impact of physical activity on endothelial function in middle-aged and elderly subjects: the Ikaria study.

PubMed

Siasos, Gerasimos; Chrysohoou, Christina; Tousoulis, Dimitris; Oikonomou, Evangelos; Panagiotakos, Demosthenes; Zaromitidou, Marina; Zisimos, Konstantinos; Marinos, Georgios; Mazaris, Savvas; Kampaksis, Manolis; Papavassiliou, Athanasios G; Pitsavos, Christos; Stefanadis, Christodoulos

2013-01-01

Exercise training and physical activity (PA) have substantial vascular and cardiac health benefits. Ikaria Island has been recognised as having one of the highest longevity rates worldwide and a high percentage of healthy ageing. We examined the relationship between endothelial function and levels of habitual PA to evaluate the factors related to healthy ageing in this population. The study was conducted on a subgroup population of the IKARIA study consisting of 185 middle-aged (40-65 years) and 142 elderly subjects (66-91 years). Endothelial function was evaluated by ultrasound measurement of flow-mediated dilatation (FMD). PA was evaluated using the shortened version of the self-reported International Physical Activity Questionnaire (IPAQ). Subjects in the low PA group (<500 MET/ min/week) were considered as physically inactive and the rest as active. In the overall study population FMD was inversely associated with age (r=-0.24, p<0.001) and middle-aged subjects had higher FMD compared with the elderly (6.26 ± 3.31% vs. 5.21 ± 2.95%, p=0.003). Multiple linear regression analysis revealed that among middle-aged subjects the physically active had higher FMD compared with the physically inactive. Physically active subjects in the middle-aged group showed higher FMD compared with the physically active elderly (p=0.008). However, there was no difference in FMD values between middle-aged inactive subjects and the elderly physically active (p=NS). The present study revealed that increased PA was associated with improved endothelial function in middle-aged subjects and that PA in elderly subjects can ameliorate the devastating effects of ageing on arterial wall properties.

Screening Active Compounds from Garcinia Species Native to China Reveals Novel Compounds Targeting the STAT/JAK Signaling Pathway

PubMed Central

Xu, Linfeng; Lao, Yuanzhi; Zhao, Yanhui; Qin, Jian; Fu, Wenwei; Zhang, Yingjia; Xu, Hongxi

2015-01-01

Natural compounds from medicinal plants are important resources for drug development. In a panel of human tumor cells, we screened a library of the natural products from Garcinia species which have anticancer potential to identify new potential therapeutic leads and discovered that caged xanthones were highly effective at suppressing multiple cancer cell lines. Their anticancer activities mainly depended on apoptosis pathways. For compounds in sensitive cancer line, their mechanisms of mode of action were evaluated. 33-Hydroxyepigambogic acid and 35-hydroxyepigambogic acid exhibited about 1 μM IC50 values against JAK2/JAK3 kinases and less than 1 μM IC50 values against NCI-H1650 cell which autocrined IL-6. Thus these two compounds provided a new antitumor molecular scaffold. Our report describes 33-hydroxyepigambogic acid and 35-hydroxyepigambogic acid that inhibited NCI-H1650 cell growth by suppressing constitutive STAT3 activation via direct inhibition of JAK kinase activity. PMID:26090459

crm-1 facilitates BMP signaling to control body size in Caenorhabditis elegans.

PubMed

Fung, Wong Yan; Fat, Ko Frankie Chi; Eng, Cheah Kathryn Song; Lau, Chow King

2007-11-01

We have identified in Caenorhabditis elegans a homologue of the vertebrate Crim1, crm-1, which encodes a putative transmembrane protein with multiple cysteine-rich (CR) domains known to have bone morphogenetic proteins (BMPs) binding activity. Using the body morphology of C. elegans as an indicator, we showed that attenuation of crm-1 activity leads to a small body phenotype reminiscent of that of BMP pathway mutants. We showed that the crm-1 loss-of-function phenotype can be rescued by constitutive supply of sma-4 activity. crm-1 can enhance BMP signaling and this activity is dependent on the presence of the DBL-1 ligand and its receptors. crm-1 is expressed in neurons at the ventral nerve cord, where the DBL-1 ligand is produced. However, ectopic expression experiments reveal that crm-1 gene products act outside the DBL-1 producing cells and function non-autonomously to facilitate dbl/sma pathway signaling to control body size.

Multiple Mechanisms of Anti-Cancer Effects Exerted by Astaxanthin

PubMed Central

Zhang, Li; Wang, Handong

2015-01-01

Astaxanthin (ATX) is a xanthophyll carotenoid which has been approved by the United States Food and Drug Administration (USFDA) as food colorant in animal and fish feed. It is widely found in algae and aquatic animals and has powerful anti-oxidative activity. Previous studies have revealed that ATX, with its anti-oxidative property, is beneficial as a therapeutic agent for various diseases without any side effects or toxicity. In addition, ATX also shows preclinical anti-tumor efficacy both in vivo and in vitro in various cancer models. Several researches have deciphered that ATX exerts its anti-proliferative, anti-apoptosis and anti-invasion influence via different molecules and pathways including signal transducer and activator of transcription 3 (STAT3), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and peroxisome proliferator-activated receptor gamma (PPARγ). Hence, ATX shows great promise as chemotherapeutic agents in cancer. Here, we review the rapidly advancing field of ATX in cancer therapy as well as some molecular targets of ATX. PMID:26184238

Phonology and arithmetic in the language-calculation network.

PubMed

Andin, Josefine; Fransson, Peter; Rönnberg, Jerker; Rudner, Mary

2015-04-01

Arithmetic and language processing involve similar neural networks, but the relative engagement remains unclear. In the present study we used fMRI to compare activation for phonological, multiplication and subtraction tasks, keeping the stimulus material constant, within a predefined language-calculation network including left inferior frontal gyrus and angular gyrus (AG) as well as superior parietal lobule and the intraparietal sulcus bilaterally. Results revealed a generally left lateralized activation pattern within the language-calculation network for phonology and a bilateral activation pattern for arithmetic, and suggested regional differences between tasks. In particular, we found a more prominent role for phonology than arithmetic in pars opercularis of the left inferior frontal gyrus but domain generality in pars triangularis. Parietal activation patterns demonstrated greater engagement of the visual and quantity systems for calculation than language. This set of findings supports the notion of a common, but regionally differentiated, language-calculation network. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Crystallographic structure of a small molecule SIRT1 activator-enzyme complex

NASA Astrophysics Data System (ADS)

Dai, Han; Case, April W.; Riera, Thomas V.; Considine, Thomas; Lee, Jessica E.; Hamuro, Yoshitomo; Zhao, Huizhen; Jiang, Yong; Sweitzer, Sharon M.; Pietrak, Beth; Schwartz, Benjamin; Blum, Charles A.; Disch, Jeremy S.; Caldwell, Richard; Szczepankiewicz, Bruce; Oalmann, Christopher; Yee Ng, Pui; White, Brian H.; Casaubon, Rebecca; Narayan, Radha; Koppetsch, Karsten; Bourbonais, Francis; Wu, Bo; Wang, Junfeng; Qian, Dongming; Jiang, Fan; Mao, Cheney; Wang, Minghui; Hu, Erding; Wu, Joe C.; Perni, Robert B.; Vlasuk, George P.; Ellis, James L.

2015-07-01

SIRT1, the founding member of the mammalian family of seven NAD+-dependent sirtuins, is composed of 747 amino acids forming a catalytic domain and extended N- and C-terminal regions. We report the design and characterization of an engineered human SIRT1 construct (mini-hSIRT1) containing the minimal structural elements required for lysine deacetylation and catalytic activation by small molecule sirtuin-activating compounds (STACs). Using this construct, we solved the crystal structure of a mini-hSIRT1-STAC complex, which revealed the STAC-binding site within the N-terminal domain of hSIRT1. Together with hydrogen-deuterium exchange mass spectrometry (HDX-MS) and site-directed mutagenesis using full-length hSIRT1, these data establish a specific STAC-binding site and identify key intermolecular interactions with hSIRT1. The determination of the interface governing the binding of STACs with human SIRT1 facilitates greater understanding of STAC activation of this enzyme, which holds significant promise as a therapeutic target for multiple human diseases.

Pinus Roxburghii essential oil anticancer activity and chemical composition evaluation.

PubMed

Sajid, Arfaa; Manzoor, Qaisar; Iqbal, Munawar; Tyagi, Amit Kumar; Sarfraz, Raja Adil; Sajid, Anam

2018-01-01

The present study was conducted to appraise the anticancer activity of Pinus roxburghii essential oil along with chemical composition evaluation. MTT assay revealed cytotoxicity induction in colon, leukemia, multiple myeloma, pancreatic, head and neck and lung cancer cells exposed to essential oil. Cancer cell death was also observed through live/dead cell viability assay and FACS analysis. Apoptosis induced by essential oil was confirmed by cleavage of PARP and caspase-3 that suppressed the colony-forming ability of tumor cells and 50 % inhibition occurred at a dose of 25 μg/mL. Moreover, essential oil inhibited the activation of inflammatory transcription factor NF-κB and inhibited expression of NF-κB regulated gene products linked to cell survival (survivin, c-FLIP, Bcl-2, Bcl-xL, c-Myc, c-IAP2), proliferation (Cyclin D1) and metastasis (MMP-9). P. roxburghii essential oil has considerable anticancer activity and could be used as anticancer agent, which needs further investigation to identify and purify the bioactive compounds followed by in vivo studies.

Intestinal alkaline phosphatase: multiple biological roles in maintenance of intestinal homeostasis and modulation by diet.

PubMed

Lallès, Jean-Paul

2010-06-01

The diverse nature of intestinal alkaline phosphatase (IAP) functions has remained elusive, and it is only recently that four additional major functions of IAP have been revealed. The present review analyzes the earlier literature on the dietary factors modulating IAP activity in light of these new findings. IAP regulates lipid absorption across the apical membrane of enterocytes, participates in the regulation of bicarbonate secretion and of duodenal surface pH, limits bacterial transepithelial passage, and finally controls bacterial endotoxin-induced inflammation by dephosphorylation, thus detoxifying intestinal lipopolysaccharide. Many dietary components, including fat, protein, and carbohydrate, modulate IAP expression or activity and may be combined to sustain a high level of IAP activity. In conclusion, IAP has a pivotal role in intestinal homeostasis and its activity could be increased through the diet. This is especially true in pathological situations (e.g., inflammatory bowel diseases) in which the involvement of commensal bacteria is suspected and when intestinal AP is too low to detoxify a sufficient amount of bacterial lipopolysaccharide.

Structure and activation of pro-activin A

PubMed Central

Wang, Xuelu; Fischer, Gerhard; Hyvönen, Marko

2016-01-01

Activins are growth factors with multiple roles in the development and homeostasis. Like all TGF-β family of growth factors, activins are synthesized as large precursors from which mature dimeric growth factors are released proteolytically. Here we have studied the activation of activin A and determined crystal structures of the unprocessed precursor and of the cleaved pro-mature complex. Replacing the natural furin cleavage site with a HRV 3C protease site, we show how the protein gains its bioactivity after proteolysis and is as active as the isolated mature domain. The complex remains associated in conditions used for biochemical analysis with a dissociation constant of 5 nM, but the pro-domain can be actively displaced from the complex by follistatin. Our high-resolution structures of pro-activin A share features seen in the pro-TGF-β1 and pro-BMP-9 structures, but reveal a new oligomeric arrangement, with a domain-swapped, cross-armed conformation for the protomers in the dimeric protein. PMID:27373274

Stepwise Adaptations to Low Temperature as Revealed by Multiple Mutants of Psychrophilic α-Amylase from Antarctic Bacterium*

PubMed Central

Cipolla, Alexandre; D'Amico, Salvino; Barumandzadeh, Roya; Matagne, André; Feller, Georges

2011-01-01

The mutants Mut5 and Mut5CC from a psychrophilic α-amylase bear representative stabilizing interactions found in the heat-stable porcine pancreatic α-amylase but lacking in the cold-active enzyme from an Antarctic bacterium. From an evolutionary perspective, these mutants can be regarded as structural intermediates between the psychrophilic and the mesophilic enzymes. We found that these engineered interactions improve all the investigated parameters related to protein stability as follows: compactness; kinetically driven stability; thermodynamic stability; resistance toward chemical denaturation, and the kinetics of unfolding/refolding. Concomitantly to this improved stability, both mutants have lost the kinetic optimization to low temperature activity displayed by the parent psychrophilic enzyme. These results provide strong experimental support to the hypothesis assuming that the disappearance of stabilizing interactions in psychrophilic enzymes increases the amplitude of concerted motions required by catalysis and the dynamics of active site residues at low temperature, leading to a higher activity. PMID:21900238

Structural basis for gating and activation of RyR1

PubMed Central

des Georges, Amédée; Clarke, Oliver B.; Zalk, Ran; Yuan, Qi; Condon, Kendall J.; Grassucci, Robert A.; Hendrickson, Wayne A.; Marks, Andrew R.; Frank, Joachim

2016-01-01

Summary The type-1 ryanodine receptor (RyR1) is an intracellular calcium (Ca2+) release channel required for skeletal muscle contraction. Here we present cryo-EM reconstructions of RyR1 in multiple functional states revealing the structural basis of channel gating and ligand-dependent activation. Binding sites for the channel activators Ca2+, ATP and caffeine were identified at interdomain interfaces of the C-terminal domain. Either ATP or Ca2+ alone induce conformational changes in the cytoplasmic assembly (‘priming’), without pore dilation. In contrast, in the presence of all three activating ligands, high-resolution reconstructions of open and closed states of RyR1 were obtained from the same sample, enabling analyses of conformational changes associated with gating. Gating involves global conformational changes in the cytosolic assembly accompanied by local changes in the transmembrane domain, which include bending of the S6 transmembrane segment and consequent pore dilation, displacement and deformation of the S4-S5 linker, and conformational changes in the pseudo-voltage-sensor domain. PMID:27662087