Involvement of Receptor Activator of Nuclear Factor-κB Ligand (RANKL)-induced Incomplete Cytokinesis in the Polyploidization of Osteoclasts*

PubMed Central

Takegahara, Noriko; Kim, Hyunsoo; Mizuno, Hiroki; Sakaue-Sawano, Asako; Miyawaki, Atsushi; Tomura, Michio; Kanagawa, Osami; Ishii, Masaru; Choi, Yongwon

2016-01-01

Osteoclasts are specialized polyploid cells that resorb bone. Upon stimulation with receptor activator of nuclear factor-κB ligand (RANKL), myeloid precursors commit to becoming polyploid, largely via cell fusion. Polyploidization of osteoclasts is necessary for their bone-resorbing activity, but the mechanisms by which polyploidization is controlled remain to be determined. Here, we demonstrated that in addition to cell fusion, incomplete cytokinesis also plays a role in osteoclast polyploidization. In in vitro cultured osteoclasts derived from mice expressing the fluorescent ubiquitin-based cell cycle indicator (Fucci), RANKL induced polyploidy by incomplete cytokinesis as well as cell fusion. Polyploid cells generated by incomplete cytokinesis had the potential to subsequently undergo cell fusion. Nuclear polyploidy was also observed in osteoclasts in vivo, suggesting the involvement of incomplete cytokinesis in physiological polyploidization. Furthermore, RANKL-induced incomplete cytokinesis was reduced by inhibition of Akt, resulting in impaired multinucleated osteoclast formation. Taken together, these results reveal that RANKL-induced incomplete cytokinesis contributes to polyploidization of osteoclasts via Akt activation. PMID:26670608

A new framework of statistical inferences based on the valid joint sampling distribution of the observed counts in an incomplete contingency table.

PubMed

Tian, Guo-Liang; Li, Hui-Qiong

2017-08-01

Some existing confidence interval methods and hypothesis testing methods in the analysis of a contingency table with incomplete observations in both margins entirely depend on an underlying assumption that the sampling distribution of the observed counts is a product of independent multinomial/binomial distributions for complete and incomplete counts. However, it can be shown that this independency assumption is incorrect and can result in unreliable conclusions because of the under-estimation of the uncertainty. Therefore, the first objective of this paper is to derive the valid joint sampling distribution of the observed counts in a contingency table with incomplete observations in both margins. The second objective is to provide a new framework for analyzing incomplete contingency tables based on the derived joint sampling distribution of the observed counts by developing a Fisher scoring algorithm to calculate maximum likelihood estimates of parameters of interest, the bootstrap confidence interval methods, and the bootstrap testing hypothesis methods. We compare the differences between the valid sampling distribution and the sampling distribution under the independency assumption. Simulation studies showed that average/expected confidence-interval widths of parameters based on the sampling distribution under the independency assumption are shorter than those based on the new sampling distribution, yielding unrealistic results. A real data set is analyzed to illustrate the application of the new sampling distribution for incomplete contingency tables and the analysis results again confirm the conclusions obtained from the simulation studies.

CpG methylation of a silent controlling element in the murine Avy allele is incomplete and unresponsive to methyl donor supplementation.

PubMed

Cropley, Jennifer E; Suter, Catherine M; Beckman, Kenneth B; Martin, David I K

2010-02-04

The viable yellow allele of agouti (A(vy)) is remarkable for its unstable and partially heritable epigenetic state, which produces wide variation in phenotypes of isogenic mice. In the A(vy) allele an inserted intracisternal A particle (IAP) acts as a controlling element which deregulates expression of agouti by transcription from the LTR of the IAP; the phenotypic state has been linked to CpG methylation of the LTR. Phenotypic variation between A(vy) mice indicates that the epigenetic state of the IAP is unstable in the germline. We have made a detailed examination of somatic methylation of the IAP using bisulphite allelic sequencing, and find that the promoter is incompletely methylated even when it is transcriptionally silent. In utero exposure to supplementary methyl donors, which alters the spectrum of A(vy) phenotypes, does not increase the density of CpG methylation in the silent LTR. Our findings suggest that, contrary to previous supposition, methyl donor supplementation acts through an indirect mechanism to silence A(vy). The incomplete cytosine methylation we observe at the somatically silent A(vy) allele may reflect its unstable germline state, and the influence of epigenetic modifications underlying CpG methylation.

CpG Methylation of a Silent Controlling Element in the Murine Avy Allele Is Incomplete and Unresponsive to Methyl Donor Supplementation

PubMed Central

Cropley, Jennifer E.; Suter, Catherine M.; Beckman, Kenneth B.; Martin, David I. K.

2010-01-01

Background The viable yellow allele of agouti (Avy) is remarkable for its unstable and partially heritable epigenetic state, which produces wide variation in phenotypes of isogenic mice. In the Avy allele an inserted intracisternal A particle (IAP) acts as a controlling element which deregulates expression of agouti by transcription from the LTR of the IAP; the phenotypic state has been linked to CpG methylation of the LTR. Phenotypic variation between Avy mice indicates that the epigenetic state of the IAP is unstable in the germline. Principal Findings We have made a detailed examination of somatic methylation of the IAP using bisulphite allelic sequencing, and find that the promoter is incompletely methylated even when it is transcriptionally silent. In utero exposure to supplementary methyl donors, which alters the spectrum of Avy phenotypes, does not increase the density of CpG methylation in the silent LTR. Conclusions Our findings suggest that, contrary to previous supposition, methyl donor supplementation acts through an indirect mechanism to silence Avy. The incomplete cytosine methylation we observe at the somatically silent Avy allele may reflect its unstable germline state, and the influence of epigenetic modifications underlying CpG methylation. PMID:20140227

Tributyltin differentially promotes development of a phenotypically distinct adipocyte.

PubMed

Regnier, Shane M; El-Hashani, Essam; Kamau, Wakanene; Zhang, Xiaojie; Massad, Nicole L; Sargis, Robert M

2015-09-01

Environmental endocrine disrupting chemicals (EDCs) are increasingly implicated in the pathogenesis of obesity. Evidence implicates various EDCs as being proadipogenic, including tributyltin (TBT), which activates the peroxisome proliferator activated receptor-γ (PPARγ). However, the conditions required for TBT-induced adipogenesis and its functional consequences are incompletely known. The costimulatory conditions necessary for preadipocyte-to-adipocyte differentiation were compared between TBT and the pharmacological PPARγ agonist troglitazone (Trog) in the 3T3-L1 cell line; basal and insulin-stimulated glucose uptake were assessed using radiolabeled 2-deoxyglucose. TBT enhanced expression of the adipocyte marker C/EBPα with coexposure to either isobutylmethylxanthine or insulin in the absence of other adipogenic stimuli. Examination of several adipocyte-specific proteins revealed that TBT and Trog differentially affected protein expression despite comparable PPARγ stimulation. In particular, TBT reduced adiponectin expression upon maximal adipogenic stimulation. Under submaximal stimulation, TBT and Trog differentially promoted adipocyte-specific gene expression despite similar lipid accumulation. Moreover, TBT attenuated Trog-induced adipocyte gene expression under conditions of cotreatment. Finally, TBT-induced adipocytes exhibited altered glucose metabolism, with increased basal glucose uptake. TBT-induced adipocytes are functionally distinct from those generated by a pharmacological PPARγ agonist, suggesting that obesogen-induced adipogenesis may generate dysfunctional adipocytes with the capacity to deleteriously affect global energy homeostasis. © 2015 The Obesity Society.

Negotiating identity and self-image: perceptions of falls in ambulatory individuals with spinal cord injury - a qualitative study.

PubMed

Jørgensen, Vivien; Roaldsen, Kirsti Skavberg

2017-04-01

Explore and describe experiences and perceptions of falls, risk of falling, and fall-related consequences in individuals with incomplete spinal cord injury (SCI) who are still walking. A qualitative interview study applying interpretive content analysis with an inductive approach. Specialized rehabilitation hospital. A purposeful sample of 15 individuals (10 men), 23 to 78 years old, 2-34 years post injury with chronic incomplete traumatic SCI, and walking ⩾75% of time for mobility needs. Individual, semi-structured face-to-face interviews were recorded, condensed, and coded to find themes and subthemes. One overarching theme was revealed: "Falling challenges identity and self-image as normal" which comprised two main themes "Walking with incomplete SCI involves minimizing fall risk and fall-related concerns without compromising identity as normal" and "Walking with incomplete SCI implies willingness to increase fall risk in order to maintain identity as normal". Informants were aware of their increased fall risk and took precautions, but willingly exposed themselves to risky situations when important to self-identity. All informants expressed some conditional fall-related concerns, and a few experienced concerns limiting activity and participation. Ambulatory individuals with incomplete SCI considered falls to be a part of life. However, falls interfered with the informants' identities and self-images as normal, healthy, and well-functioning. A few expressed dysfunctional concerns about falling, and interventions should target these.

Transient inflammatory response mediated by interleukin-1β is required for proper regeneration in zebrafish fin fold.

PubMed

Hasegawa, Tomoya; Hall, Christopher J; Crosier, Philip S; Abe, Gembu; Kawakami, Koichi; Kudo, Akira; Kawakami, Atsushi

2017-02-23

Cellular responses to injury are crucial for complete tissue regeneration, but their underlying processes remain incompletely elucidated. We have previously reported that myeloid-defective zebrafish mutants display apoptosis of regenerative cells during fin fold regeneration. Here, we found that the apoptosis phenotype is induced by prolonged expression of interleukin 1 beta ( il1b ). Myeloid cells are considered to be the principal source of Il1b, but we show that epithelial cells express il1b in response to tissue injury and initiate the inflammatory response, and that its resolution by macrophages is necessary for survival of regenerative cells. We further show that Il1b plays an essential role in normal fin fold regeneration by regulating expression of regeneration-induced genes. Our study reveals that proper levels of Il1b signaling and tissue inflammation, which are tuned by macrophages, play a crucial role in tissue regeneration.

HIV-1 gp120 Upregulates Brain-Derived Neurotrophic Factor (BDNF) Expression in BV2 Cells via the Wnt/β-Catenin Signaling Pathway.

PubMed

Wang, Yongdi; Liao, Jinxu; Tang, Shao-Jun; Shu, Jianhong; Zhang, Wenping

2017-06-01

HIV-1 gp120 plays a critical role in the pathogenesis of HIV-associated pain, but the underlying molecular mechanisms are incompletely understood. This study aims to determine the effect and possible mechanism of HIV-1 gp120 on BDNF expression in BV2 cells (a murine-derived microglial cell line). We observed that gp120 (10 ng/ml) activated BV2 cells in cultures and upregulated proBDNF/mBDNF. Furthermore, gp120-treated BV2 also accumulated Wnt3a and β-catenin, suggesting the activation of the Wnt/β-catenin pathway. We demonstrated that activation of the pathway by Wnt3a upregulated BDNF expression. In contrast, inhibition of the Wnt/β-catenin pathway by either DKK1 or IWR-1 attenuated BDNF upregulation induced by gp120 or Wnt3a. These findings collectively suggest that gp120 stimulates BDNF expression in BV2 cells via the Wnt/β-catenin signaling pathway.

The identification of transcription factors expressed in the notochord of Ciona intestinalis adds new potential players to the Brachyury gene regulatory network

PubMed Central

José-Edwards, Diana S.; Kerner, Pierre; Kugler, Jamie E.; Deng, Wei; Jiang, Di; Di Gregorio, Anna

2013-01-01

The notochord is the distinctive characteristic of chordates; however, the knowledge of the complement of transcription factors governing the development of this structure is still incomplete. Here we present the expression patterns of seven transcription factor genes detected in the notochord of the ascidian Ciona intestinalis at various stages of embryonic development. Four of these transcription factors, Fos-a, NFAT5, AFF and Klf15, have not been directly associated with the notochord in previous studies, while the others, including Spalt-like-a, Lmx-like and STAT5/6-b, display evolutionarily conserved expression in this structure as well as in other domains. We examined the hierarchical relationships between these genes and the transcription factor Brachyury, which is necessary for notochord development in all chordates. We found that Ciona Brachyury regulates the expression of most, although not all, of these genes. These results shed light on the genetic regulatory program underlying notochord formation in Ciona and possibly other chordates. PMID:21594950

Mechanisms Underlying HIV-Associated Noninfectious Lung Disease.

PubMed

Presti, Rachel M; Flores, Sonia C; Palmer, Brent E; Atkinson, Jeffrey J; Lesko, Catherine R; Lau, Bryan; Fontenot, Andrew P; Roman, Jesse; McDyer, John F; Twigg, Homer L

2017-11-01

Pulmonary disease remains a primary source of morbidity and mortality in persons living with HIV (PLWH), although the advent of potent combination antiretroviral therapy has resulted in a shift from predominantly infectious to noninfectious pulmonary complications. PLWH are at high risk for COPD, pulmonary hypertension, and lung cancer even in the era of combination antiretroviral therapy. The underlying mechanisms of this are incompletely understood, but recent research in both human and animal models suggests that oxidative stress, expression of matrix metalloproteinases, and genetic instability may result in lung damage, which predisposes PLWH to these conditions. Some of the factors that drive these processes include tobacco and other substance use, direct HIV infection and expression of specific HIV proteins, inflammation, and shifts in the microbiome toward pathogenic and opportunistic organisms. Further studies are needed to understand the relative importance of these factors to the development of lung disease in PLWH. Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Clostridium thermocellum DSM 1313 transcriptional responses to redox perturbation

DOE PAGES

Sander, Kyle B.; Wilson, Charlotte M.; M. Rodriquez, Jr.; ...

2015-12-12

Clostridium thermocellum is a promising consolidated bioprocessing candidate organism capable of directly converting lignocellulosic biomass to ethanol. Current ethanol yields, productivities, and growth inhibitions are industrial deployment impediments for commodity fuel production by this bacterium. Redox imbalance under certain conditions and in engineered strains may contribute to incomplete substrate utilization and may direct fermentation products to undesirable overflow metabolites. As a result, towards a better understanding of redox metabolism in C. thermocellum, we established continuous growth conditions and analyzed global gene expression during addition of two stress chemicals (methyl viologen and hydrogen peroxide) which changed the fermentation redox potential.

Negotiating identity and self-image: perceptions of falls in ambulatory individuals with spinal cord injury – a qualitative study

PubMed Central

Jørgensen, Vivien; Roaldsen, Kirsti Skavberg

2016-01-01

Objective: Explore and describe experiences and perceptions of falls, risk of falling, and fall-related consequences in individuals with incomplete spinal cord injury (SCI) who are still walking. Design: A qualitative interview study applying interpretive content analysis with an inductive approach. Setting: Specialized rehabilitation hospital. Subjects: A purposeful sample of 15 individuals (10 men), 23 to 78 years old, 2-34 years post injury with chronic incomplete traumatic SCI, and walking ⩾75% of time for mobility needs. Methods: Individual, semi-structured face-to-face interviews were recorded, condensed, and coded to find themes and subthemes. Results: One overarching theme was revealed: “Falling challenges identity and self-image as normal” which comprised two main themes “Walking with incomplete SCI involves minimizing fall risk and fall-related concerns without compromising identity as normal” and “Walking with incomplete SCI implies willingness to increase fall risk in order to maintain identity as normal”. Informants were aware of their increased fall risk and took precautions, but willingly exposed themselves to risky situations when important to self-identity. All informants expressed some conditional fall-related concerns, and a few experienced concerns limiting activity and participation. Conclusion: Ambulatory individuals with incomplete SCI considered falls to be a part of life. However, falls interfered with the informants’ identities and self-images as normal, healthy, and well-functioning. A few expressed dysfunctional concerns about falling, and interventions should target these. PMID:27170274

Genetic manipulation of murine embryonic stem cells with enhanced green fluorescence protein and sulfatase-modifying factor I genes.

PubMed

Zhao, Guoying; Karageorgos, Litsa; Hutchinson, Rhonda G; Hopwood, John J; Hemsley, Kim

2010-05-01

Mucopolysaccharidosis type IIIA (MPS IIIA) is a lysosomal storage disorder (LSD) in which an absence of sulfamidase results in incomplete degradation and subsequent accumulation of its substrate, heparan sulfate. Most neurodegenerative LSD remain untreatable. However, therapy options, such as gene, enzyme end cell therapy, are under investigation. Previously, we have constructed an embryonic stem (ES) cell line (NS21) that over-expresses human sulphamidase as a potential treatment for murine MPS IIIA. In the present study the sulfatase-modifying factor I (SUMF1) and enhanced green fluorescence protein (eGFP) genes were co-introduced under a cytomegalovirus (CMV) promoter into NS21 cells, to enhance further sulfamidase activity and provide a marker for in vivo cell tracking, respectively. eGFP was also introduced under the control of the human elongation factor-1alpha (hEF-1alpha) promoter to compare the stability of transgene expression. During differentiation of ES cells into glial precursors, SUMF1 was down-regulated and was hardly detectable by day 18 of differentiation. Likewise, eGFP expression was heterogeneous and highly unstable. Use of a human EF-1alpha promoter resulted in more homogeneous eGFP expression, with approximately 50% of cells eGFP positive following differentiation into glial precursors. Compared with NS21 cells, the outgrowth of eGFP-expressing cells was not as confluent when differentiated into glial precursors. Our data suggest that SUMF1 enhances sulfamidase activity in ES cells, hEF-1alpha is a stronger promoter than CMV for ES cells and over-expression of eGFP may affect cell growth and contribute to unstable gene expression.

Tributyltin Differentially Promotes Development of a Phenotypically Distinct Adipocyte

PubMed Central

Regnier, Shane M.; El-Hashani, Essam; Kamau, Wakanene; Zhang, Xiaojie; Massad, Nicole L.; Sargis, Robert M.

2015-01-01

Objective Environmental endocrine disrupting chemicals (EDCs) are increasingly implicated in the pathogenesis of obesity. Evidence implicates various EDCs as being pro-adipogenic, including tributyltin (TBT), which activates the peroxisome proliferator activated receptor-γ (PPARγ). However, the conditions required for TBT-induced adipogenesis and its functional consequences are incompletely known. Methods The co-stimulatory conditions necessary for preadipocyte-to-adipocyte differentiation were compared between TBT and the pharmacological PPARγ agonist troglitazone (Trog) in the 3T3-L1 cell line; basal and insulin-stimulated glucose uptake were assessed using radiolabeled 2-deoxyglucose. Results TBT enhanced expression of the adipocyte marker C/EBPα with co-exposure to either isobutylmethylxanthine or insulin in the absence of other adipogenic stimuli. Examination of several adipocyte-specific proteins revealed that TBT and Trog differentially affected protein expression despite comparable PPARγ stimulation. In particular, TBT reduced adiponectin expression upon maximal adipogenic stimulation. Under submaximal stimulation, TBT and Trog differentially promoted adipocyte-specific gene expression despite similar lipid accumulation. Moreover, TBT attenuated Trog-induced adipocyte gene expression under conditions of co-treatment. Finally, TBT-induced adipocytes exhibited altered glucose metabolism, with increased basal glucose uptake. Conclusions TBT-induced adipocytes are functionally distinct from those generated by a pharmacological PPARγ agonist, suggesting that obesogen-induced adipogenesis may generate dysfunctional adipocytes with the capacity to deleteriously affect global energy homeostasis. PMID:26243053

Transcription factor Afmac1 controls copper import machinery in Aspergillus fumigatus.

PubMed

Kusuya, Yoko; Hagiwara, Daisuke; Sakai, Kanae; Yaguchi, Takashi; Gonoi, Tohru; Takahashi, Hiroki

2017-08-01

Copper (Cu) is an essential metal for all living organisms, although it is toxic in excess. Filamentous fungus must acquire copper from its environment for growth. Despite its essentiality for growth, the mechanisms that maintain copper homeostasis are not fully understood in filamentous fungus. To gain insights into copper homeostasis, we investigated the roles of a copper transcription factor Afmac1 in the life-threatening fungus Aspergillus fumigatus, a homolog of the yeast MAC1. We observed that the Afmac1 deletion mutant exhibited not only significantly slower growth, but also incomplete conidiation including a short chain of conidia and defective melanin. Moreover, the expressions of the copper transporters, ctrA1, ctrA2, and ctrC, and metalloreductases, Afu8g01310 and fre7, were repressed in ∆Afmac1 cells, while those expressions were induced under copper depletion conditions in wild-type. The expressions of pksP and wetA, which are, respectively, involved in biosynthesis of conidia-specific melanin and the late stage of conidiogenesis, were decreased in the ∆Afmac1 strain under minimal media condition. Taken together, these results indicate that copper acquisition through AfMac1 functions in growth as well as conidiation.

Sparse coding for flexible, robust 3D facial-expression synthesis.

PubMed

Lin, Yuxu; Song, Mingli; Quynh, Dao Thi Phuong; He, Ying; Chen, Chun

2012-01-01

Computer animation researchers have been extensively investigating 3D facial-expression synthesis for decades. However, flexible, robust production of realistic 3D facial expressions is still technically challenging. A proposed modeling framework applies sparse coding to synthesize 3D expressive faces, using specified coefficients or expression examples. It also robustly recovers facial expressions from noisy and incomplete data. This approach can synthesize higher-quality expressions in less time than the state-of-the-art techniques.

Transcriptome assembly and digital gene expression atlas of the rainbow trout

USDA-ARS?s Scientific Manuscript database

Background: Transcriptome analysis is a preferred method for gene discovery, marker development and gene expression profiling in non-model organisms. Previously, we sequenced a transcriptome reference using Sanger-based and 454-pyrosequencing, however, a transcriptome assembly is still incomplete an...

A novel gene whose expression in Medicago truncatula roots is suppressed in response to colonization by vesicular-arbuscular mycorrhizal (VAM) fungi and to phosphate nutrition.

PubMed

Burleigh, S H; Harrison, M J

1997-05-01

A cDNA clone (Mt4) was isolated as a result of a differential screen to identify genes showing altered expression during the interaction between Medicago truncatula and the vesicular-arbuscular mycorrhizal (VAM) fungus Glomus versiforme. Mt4 represents a M. truncatula mRNA that contains numerous short open reading frames, the two longest of which are predicted to encode polypeptides of 51 amino acids each. One of these open reading frames shares a short region of identity with a phosphate starvation-inducible gene from tomato. Mt4 gene expression is regulated in response to colonization by mycorrhizal fungi: transcripts were detected in non-colonized roots and levels decreased in both M. truncatula and M. sativa (alfalfa) roots after colonization by G. versiforme. Transcript levels also decreased during the incomplete interaction between G. versiforme and a M. sativa mycorrhizal minus (myc-) line, indicating that the down-regulation of this gene occurs early during the interaction between the fungus and its host plant. Phosphate levels in the nutrient media also affected the expression of the Mt4 gene: transcripts were present in the roots of plants grown under phosphate-deficient conditions, but were undetectable in the roots of plants grown under phosphate sufficient conditions. Furthermore, expression was only observed when plants were grown under nitrogen-sufficient conditions. Northern blot analyses indicate that Mt4 transcripts are present primarily in roots and barely detectable in stems or leaves. Thus, Mt4 represents a M. truncatula gene whose expression is regulated in response to both colonization by mycorrhizal fungi and to the phosphate status of the plant.

Interleukin-22 promotes aerobic glycolysis associated with tumor progression via targeting hexokinase-2 in human colon cancer cells.

PubMed

Liu, Yulin; Xiang, Fan; Huang, Yongming; Shi, Liang; Hu, Chaojie; Yang, Yiming; Wang, Di; He, Nan; Tao, Kaixiong; Wu, Ke; Wang, Guobin

2017-04-11

Interleukin-22 has been explored extensively in human cancer, but its functions and underlying mechanisms are incompletely understood. Here, we show that aberrant interleukin-22 expression facilitates aerobic glycolysis in colon cancer cells. Elevated interleukin-22 mRNA expression was observed and positively correlated with hexokinase-2 in colon cancer tissues. In vitro, interleukin-22 enhanced glucose consumption and lactate production via targeting hexokinase-2 in colon cancer cells. Moreover, the transcriptional factor c-Myc and signal transducer and activator of transcription 3 were involved in interleukin-22-induced up-regulation of hexokinase-2. We further demonstrated that hexokinase-2 partly accounted for interleukin-22-mediated cellular proliferation in DLD-1 cells. In vivo, our data demonstrated that interleukin-22 significantly promoted tumor growth along with elevated expression of c-Myc and hexokinase-2 in mice. In summary, our findings provide a new perspective on the pro-inflammatory cytokine interleukin-22 in promoting aerobic glycolysis associated with tumor progression in human colon cancer cells.

Transient inflammatory response mediated by interleukin-1β is required for proper regeneration in zebrafish fin fold

PubMed Central

Hasegawa, Tomoya; Hall, Christopher J; Crosier, Philip S; Abe, Gembu; Kawakami, Koichi; Kudo, Akira; Kawakami, Atsushi

2017-01-01

Cellular responses to injury are crucial for complete tissue regeneration, but their underlying processes remain incompletely elucidated. We have previously reported that myeloid-defective zebrafish mutants display apoptosis of regenerative cells during fin fold regeneration. Here, we found that the apoptosis phenotype is induced by prolonged expression of interleukin 1 beta (il1b). Myeloid cells are considered to be the principal source of Il1b, but we show that epithelial cells express il1b in response to tissue injury and initiate the inflammatory response, and that its resolution by macrophages is necessary for survival of regenerative cells. We further show that Il1b plays an essential role in normal fin fold regeneration by regulating expression of regeneration-induced genes. Our study reveals that proper levels of Il1b signaling and tissue inflammation, which are tuned by macrophages, play a crucial role in tissue regeneration. DOI: http://dx.doi.org/10.7554/eLife.22716.001 PMID:28229859

The identification of transcription factors expressed in the notochord of Ciona intestinalis adds new potential players to the brachyury gene regulatory network.

PubMed

José-Edwards, Diana S; Kerner, Pierre; Kugler, Jamie E; Deng, Wei; Jiang, Di; Di Gregorio, Anna

2011-07-01

The notochord is the distinctive characteristic of chordates; however, the knowledge of the complement of transcription factors governing the development of this structure is still incomplete. Here we present the expression patterns of seven transcription factor genes detected in the notochord of the ascidian Ciona intestinalis at various stages of embryonic development. Four of these transcription factors, Fos-a, NFAT5, AFF and Klf15, have not been directly associated with the notochord in previous studies, while the others, including Spalt-like-a, Lmx-like, and STAT5/6-b, display evolutionarily conserved expression in this structure as well as in other domains. We examined the hierarchical relationships between these genes and the transcription factor Brachyury, which is necessary for notochord development in all chordates. We found that Ciona Brachyury regulates the expression of most, although not all, of these genes. These results shed light on the genetic regulatory program underlying notochord formation in Ciona and possibly other chordates. Copyright © 2011 Wiley-Liss, Inc.

GATA2 null mutation associated with incomplete penetrance in a family with Emberger syndrome.

PubMed

Brambila-Tapia, Aniel Jessica Leticia; García-Ortiz, José Elías; Brouillard, Pascal; Nguyen, Ha-Long; Vikkula, Miikka; Ríos-González, Blanca Estela; Sandoval-Muñiz, Roberto de Jesús; Sandoval-Talamantes, Ana Karen; Bobadilla-Morales, Lucina; Corona-Rivera, Jorge Román; Arnaud-Lopez, Lisette

2017-09-01

GATA2 mutations are associated with several conditions, including Emberger syndrome which is the association of primary lymphedema with hematological anomalies and an increased risk for myelodysplasia and leukemia. To describe a family with Emberger syndrome with incomplete penetrance. A DNA sequencing of GATA2 gene was performed in the parents and offspring (five individuals in total). The family consisted of 5 individuals with a GATA2 null mutation (c.130G>T, p.Glu44*); three of them were affected (two of which were deceased) while two remained unaffected at the age of 40 and 13 years old. The three affected siblings (two boys and one girl) presented with lymphedema of the lower limbs, recurrent warts, epistaxis and recurrent infections. Two died due to hematological abnormalities (AML and pancytopenia). In contrast, the two other family members who carry the same mutation (the mother and one brother) have not presented any symptoms and their blood tests remain normal. Incomplete penetrance may indicate that GATA2 haploinsufficiency is not enough to produce the phenotype of Emberger syndrome. It could be useful to perform whole exome or genome sequencing, in cases where incomplete penetrance or high variable expressivity is described, in order to probably identify specific gene interactions that drastically modify the phenotype. In addition, skewed gene expression by an epigenetic mechanism of gene regulation should also be considered.

Gene expression in the liver of rainbow trout, Oncorhynchus mykiss, during the stress response

USGS Publications Warehouse

Momoda, T.S.; Schwindt, A.R.; Feist, G.W.; Gerwick, L.; Bayne, C.J.; Schreck, C.B.

2007-01-01

To better appreciate the mechanisms underlying the physiology of the stress response, an oligonucleotide microarray and real-time RT-PCR (QRT-PCR) were used to study gene expression in the livers of rainbow trout (Oncorhynchus mykiss). For increased confidence in the discovery of candidate genes responding to stress, we conducted two separate experiments using fish from different year classes. In both experiments, fish exposed to a 3 h stressor were compared to control (unstressed) fish. In the second experiment some additional fish were exposed to only 0.5 h of stress and others were sampled 21 h after experiencing a 3 h stressor. This 21 h post-stress treatment was a means to study gene expression during recovery from stress. The genes we report as differentially expressed are those that responded similarly in both experiments, suggesting that they are robust indicators of stress. Those genes are a major histocompatibility complex class 1 molecule (MHC1), JunB, glucose 6-phosphatase (G6Pase), and nuclear protein 1 (Nupr1). Interestingly, Nupr1 gene expression was still elevated 21 h after stress, which indicates that recovery was incomplete at that time.

Usage of the Heterologous Expression of the Antimicrobial Gene afp From Aspergillus giganteus for Increasing Fungal Resistance in Olive.

PubMed

Narvaez, Isabel; Khayreddine, Titouh; Pliego, Clara; Cerezo, Sergio; Jiménez-Díaz, Rafael M; Trapero-Casas, José L; López-Herrera, Carlos; Arjona-Girona, Isabel; Martín, Carmen; Mercado, José A; Pliego-Alfaro, Fernando

2018-01-01

The antifungal protein (AFP) produced by Aspergillus giganteus , encoded by the afp gene, has been used to confer resistance against a broad range of fungal pathogens in several crops. In this research, transgenic olive plants expressing the afp gene under the control of the constitutive promoter CaMV35S were generated and their disease response against two root infecting fungal pathogens, Verticillium dahliae and Rosellinia necatrix , was evaluated. Embryogenic cultures derived from a mature zygotic embryo of cv. 'Picual' were used for A. tumefaciens transformation. Five independent transgenic lines were obtained, showing a variable level of afp expression in leaves and roots. None of these transgenic lines showed enhanced resistance to Verticillium wilt. However, some of the lines displayed a degree of incomplete resistance to white root rot caused by R. necatrix compared with disease reaction of non-transformed plants or transgenic plants expressing only the GUS gene. The level of resistance to this pathogen correlated with that of the afp expression in root and leaves. Our results indicate that the afp gene can be useful for enhanced partial resistance to R. necatrix in olive, but this gene does not protect against V. dahliae .

An Allelic Series of Trp63 Mutations Defines TAp63 as a Modifier of EEC Syndrome

PubMed Central

Lindahl, Emma Vernersson; Garcia, Elvin L.; Mills, Alea A.

2014-01-01

Human Ectrodactyly, Ectodermal dysplasia, Clefting (EEC) syndrome is an autosomal dominant developmental disorder defined by limb deformities, skin defects, and craniofacial clefting. Although associated with heterozygous missense mutations in TP63, the genetic basis underlying the variable expressivity and incomplete penetrance of EEC is unknown. Here we show that mice heterozygous for an allele encoding the Trp63 p.Arg318His mutation, which corresponds to the human TP63 p.Arg279His mutation found in patients with EEC, have features of human EEC. Using an allelic series, we discovered that whereas clefting and skin defects are caused by loss of Trp63 function, limb anomalies are due to gain- and/or dominant-negative effects of Trp63. Furthermore, we identify TAp63 as a strong modifier of EEC-associated phenotypes with regard to both penetrance and expressivity. PMID:23775923

Peroxisome proliferator-activated receptor-gamma co-activator 1alpha-mediated metabolic remodeling of skeletal myocytes mimics exercise training and reverses lipid-induced mitochondrial inefficiency.

PubMed

Koves, Timothy R; Li, Ping; An, Jie; Akimoto, Takayuki; Slentz, Dorothy; Ilkayeva, Olga; Dohm, G Lynis; Yan, Zhen; Newgard, Christopher B; Muoio, Deborah M

2005-09-30

Peroxisome proliferator-activated receptor-gamma co-activator 1alpha (PGC1alpha) is a promiscuous co-activator that plays a key role in regulating mitochondrial biogenesis and fuel homeostasis. Emergent evidence links decreased skeletal muscle PGC1alpha activity and coincident impairments in mitochondrial performance to the development of insulin resistance in humans. Here we used rodent models to demonstrate that muscle mitochondrial efficiency is compromised by diet-induced obesity and is subsequently rescued by exercise training. Chronic high fat feeding caused accelerated rates of incomplete fatty acid oxidation and accumulation of beta-oxidative intermediates. The capacity of muscle mitochondria to fully oxidize a heavy influx of fatty acid depended on factors such as fiber type and exercise training and was positively correlated with expression levels of PGC1alpha. Likewise, an efficient lipid-induced substrate switch in cultured myocytes depended on adenovirus-mediated increases in PGC1alpha expression. Our results supported a novel paradigm in which a high lipid supply, occurring under conditions of low PGC1alpha, provokes a disconnect between mitochondrial beta-oxidation and tricarboxylic acid cycle activity. Conversely, the metabolic remodeling that occurred in response to PGC1alpha overexpression favored a shift from incomplete to complete beta-oxidation. We proposed that PGC1alpha enables muscle mitochondria to better cope with a high lipid load, possibly reflecting a fundamental metabolic benefit of exercise training.

The structure of a gene co-expression network reveals biological functions underlying eQTLs.

PubMed

Villa-Vialaneix, Nathalie; Liaubet, Laurence; Laurent, Thibault; Cherel, Pierre; Gamot, Adrien; SanCristobal, Magali

2013-01-01

What are the commonalities between genes, whose expression level is partially controlled by eQTL, especially with regard to biological functions? Moreover, how are these genes related to a phenotype of interest? These issues are particularly difficult to address when the genome annotation is incomplete, as is the case for mammalian species. Moreover, the direct link between gene expression and a phenotype of interest may be weak, and thus difficult to handle. In this framework, the use of a co-expression network has proven useful: it is a robust approach for modeling a complex system of genetic regulations, and to infer knowledge for yet unknown genes. In this article, a case study was conducted with a mammalian species. It showed that the use of a co-expression network based on partial correlation, combined with a relevant clustering of nodes, leads to an enrichment of biological functions of around 83%. Moreover, the use of a spatial statistics approach allowed us to superimpose additional information related to a phenotype; this lead to highlighting specific genes or gene clusters that are related to the network structure and the phenotype. Three main results are worth noting: first, key genes were highlighted as a potential focus for forthcoming biological experiments; second, a set of biological functions, which support a list of genes under partial eQTL control, was set up by an overview of the global structure of the gene expression network; third, pH was found correlated with gene clusters, and then with related biological functions, as a result of a spatial analysis of the network topology.

European option pricing under the Student's t noise with jumps

NASA Astrophysics Data System (ADS)

Wang, Xiao-Tian; Li, Zhe; Zhuang, Le

2017-03-01

In this paper we present a new approach to price European options under the Student's t noise with jumps. Through the conditional delta hedging strategy and the minimal mean-square-error hedging, a closed-form solution of the European option value is obtained under the incomplete information case. In particular, we propose a Value-at-Risk-type procedure to estimate the volatility parameter σ such that the pricing error is in accord with the risk preferences of investors. In addition, the numerical results of us show that options are not priced in some cases in an incomplete information market.

Transcriptomic Analysis of Lung Tissue from Cigarette Smoke-Induced Emphysema Murine Models and Human Chronic Obstructive Pulmonary Disease Show Shared and Distinct Pathways.

PubMed

Yun, Jeong H; Morrow, Jarrett; Owen, Caroline A; Qiu, Weiliang; Glass, Kimberly; Lao, Taotao; Jiang, Zhiqiang; Perrella, Mark A; Silverman, Edwin K; Zhou, Xiaobo; Hersh, Craig P

2017-07-01

Although cigarette smoke (CS) is the primary risk factor for chronic obstructive pulmonary disease (COPD), the underlying molecular mechanisms for the significant variability in developing COPD in response to CS are incompletely understood. We performed lung gene expression profiling of two different wild-type murine strains (C57BL/6 and NZW/LacJ) and two genetic models with mutations in COPD genome-wide association study genes (HHIP and FAM13A) after 6 months of chronic CS exposure and compared the results to human COPD lung tissues. We identified gene expression patterns that correlate with severity of emphysema in murine and human lungs. Xenobiotic metabolism and nuclear erythroid 2-related factor 2-mediated oxidative stress response were commonly regulated molecular response patterns in C57BL/6, Hhip +/- , and Fam13a -/- murine strains exposed chronically to CS. The CS-resistant Fam13a -/- mouse and NZW/LacJ strain revealed gene expression response pattern differences. The Fam13a -/- strain diverged in gene expression compared with C57BL/6 control only after CS exposure. However, the NZW/LacJ strain had a unique baseline expression pattern, enriched for nuclear erythroid 2-related factor 2-mediated oxidative stress response and xenobiotic metabolism, and converged to a gene expression pattern similar to the more susceptible wild-type C57BL/6 after CS exposure. These results suggest that distinct molecular pathways may account for resistance to emphysema. Surprisingly, there were few genes commonly modulated in mice and humans. Our study suggests that gene expression responses to CS may be largely species and model dependent, yet shared pathways could provide biologically significant insights underlying individual susceptibility to CS.

Src is activated by the nuclear receptor peroxisome proliferator-activated receptor β/δ in ultraviolet radiation-induced skin cancer.

PubMed

Montagner, Alexandra; Delgado, Maria B; Tallichet-Blanc, Corinne; Chan, Jeremy S K; Sng, Ming K; Mottaz, Hélén; Degueurce, Gwendoline; Lippi, Yannick; Moret, Catherine; Baruchet, Michael; Antsiferova, Maria; Werner, Sabine; Hohl, Daniel; Saati, Talal Al; Farmer, Pierre J; Tan, Nguan S; Michalik, Liliane; Wahli, Walter

2014-01-01

Although non-melanoma skin cancer (NMSC) is the most common human cancer and its incidence continues to rise worldwide, the mechanisms underlying its development remain incompletely understood. Here, we unveil a cascade of events involving peroxisome proliferator-activated receptor (PPAR) β/δ and the oncogene Src, which promotes the development of ultraviolet (UV)-induced skin cancer in mice. UV-induced PPARβ/δ activity, which directly stimulated Src expression, increased Src kinase activity and enhanced the EGFR/Erk1/2 signalling pathway, resulting in increased epithelial-to-mesenchymal transition (EMT) marker expression. Consistent with these observations, PPARβ/δ-null mice developed fewer and smaller skin tumours, and a PPARβ/δ antagonist prevented UV-dependent Src stimulation. Furthermore, the expression of PPARβ/δ positively correlated with the expression of SRC and EMT markers in human skin squamous cell carcinoma (SCC), and critically, linear models applied to several human epithelial cancers revealed an interaction between PPARβ/δ and SRC and TGFβ1 transcriptional levels. Taken together, these observations motivate the future evaluation of PPARβ/δ modulators to attenuate the development of several epithelial cancers.

Src is activated by the nuclear receptor peroxisome proliferator-activated receptor β/δ in ultraviolet radiation-induced skin cancer

PubMed Central

Montagner, Alexandra; Delgado, Maria B; Tallichet-Blanc, Corinne; Chan, Jeremy S K; Sng, Ming K; Mottaz, Hélène; Degueurce, Gwendoline; Lippi, Yannick; Moret, Catherine; Baruchet, Michael; Antsiferova, Maria; Werner, Sabine; Hohl, Daniel; Al Saati, Talal; Farmer, Pierre J; Tan, Nguan S; Michalik, Liliane; Wahli, Walter

2014-01-01

Although non-melanoma skin cancer (NMSC) is the most common human cancer and its incidence continues to rise worldwide, the mechanisms underlying its development remain incompletely understood. Here, we unveil a cascade of events involving peroxisome proliferator-activated receptor (PPAR) β/δ and the oncogene Src, which promotes the development of ultraviolet (UV)-induced skin cancer in mice. UV-induced PPARβ/δ activity, which directly stimulated Src expression, increased Src kinase activity and enhanced the EGFR/Erk1/2 signalling pathway, resulting in increased epithelial-to-mesenchymal transition (EMT) marker expression. Consistent with these observations, PPARβ/δ-null mice developed fewer and smaller skin tumours, and a PPARβ/δ antagonist prevented UV-dependent Src stimulation. Furthermore, the expression of PPARβ/δ positively correlated with the expression of SRC and EMT markers in human skin squamous cell carcinoma (SCC), and critically, linear models applied to several human epithelial cancers revealed an interaction between PPARβ/δ and SRC and TGFβ1 transcriptional levels. Taken together, these observations motivate the future evaluation of PPARβ/δ modulators to attenuate the development of several epithelial cancers. PMID:24203162

The effectiveness of clinical hypnosis in the digestive endoscopy: a multiple case report.

PubMed

Domínguez-Ortega, Luis; Rodríguez-Muñoz, Sarbelio

2010-10-01

The aim of this study is to evaluate the efficacy and viability of hypnosis before and during a gastrointestinal endoscopy. Six Gastroscopies and 22 colonoscopies were carried out under hypnosis in a group of patients. The patients ranged in age from 20 and 67 years and have a history of previously incomplete and poorly tolerated examinations or expressed an active demand for sedation. For 6 of the patients who underwent a gastroscopy under hypnosis, the procedure was successfully completed, reaching the second part of the duodenum without difficulty for the endoscopist. Colonoscopy of the cecum was completed in 19 of 20 patients. All patients, except 1, considered their tolerance level as "good." Hypnosis facilitated an adequate endoscopy intervention without any discomfort in 85% of the cases examined. Avoidance of anaesthesia reduces risk to the patient. Hence, hypnosis for gastrointestinal endoscopy appears to provide a promising strategy.

Activity map of the tammar X chromosome shows that marsupial X inactivation is incomplete and escape is stochastic

PubMed Central

2010-01-01

Background X chromosome inactivation is a spectacular example of epigenetic silencing. In order to deduce how this complex system evolved, we examined X inactivation in a model marsupial, the tammar wallaby (Macropus eugenii). In marsupials, X inactivation is known to be paternal, incomplete and tissue-specific, and occurs in the absence of an XIST orthologue. Results We examined expression of X-borne genes using quantitative PCR, revealing a range of dosage compensation for different loci. To assess the frequency of 1X- or 2X-active fibroblasts, we investigated expression of 32 X-borne genes at the cellular level using RNA-FISH. In female fibroblasts, two-color RNA-FISH showed that genes were coordinately expressed from the same X (active X) in nuclei in which both loci were inactivated. However, loci on the other X escape inactivation independently, with each locus showing a characteristic frequency of 1X-active and 2X-active nuclei, equivalent to stochastic escape. We constructed an activity map of the tammar wallaby inactive X chromosome, which identified no relationship between gene location and extent of inactivation, nor any correlation with the presence or absence of a Y-borne paralog. Conclusions In the tammar wallaby, one X (presumed to be maternal) is expressed in all cells, but genes on the other (paternal) X escape inactivation independently and at characteristic frequencies. The paternal and incomplete X chromosome inactivation in marsupials, with stochastic escape, appears to be quite distinct from the X chromosome inactivation process in eutherians. We find no evidence for a polar spread of inactivation from an X inactivation center. PMID:21182760

Usage of the Heterologous Expression of the Antimicrobial Gene afp From Aspergillus giganteus for Increasing Fungal Resistance in Olive

PubMed Central

Narvaez, Isabel; Khayreddine, Titouh; Pliego, Clara; Cerezo, Sergio; Jiménez-Díaz, Rafael M.; Trapero-Casas, José L.; López-Herrera, Carlos; Arjona-Girona, Isabel; Martín, Carmen; Mercado, José A.; Pliego-Alfaro, Fernando

2018-01-01

The antifungal protein (AFP) produced by Aspergillus giganteus, encoded by the afp gene, has been used to confer resistance against a broad range of fungal pathogens in several crops. In this research, transgenic olive plants expressing the afp gene under the control of the constitutive promoter CaMV35S were generated and their disease response against two root infecting fungal pathogens, Verticillium dahliae and Rosellinia necatrix, was evaluated. Embryogenic cultures derived from a mature zygotic embryo of cv. ‘Picual’ were used for A. tumefaciens transformation. Five independent transgenic lines were obtained, showing a variable level of afp expression in leaves and roots. None of these transgenic lines showed enhanced resistance to Verticillium wilt. However, some of the lines displayed a degree of incomplete resistance to white root rot caused by R. necatrix compared with disease reaction of non-transformed plants or transgenic plants expressing only the GUS gene. The level of resistance to this pathogen correlated with that of the afp expression in root and leaves. Our results indicate that the afp gene can be useful for enhanced partial resistance to R. necatrix in olive, but this gene does not protect against V. dahliae. PMID:29875785

Limit Pricing with Incomplete Information: Answers to Frequently Asked Questions

ERIC Educational Resources Information Center

Sorenson, Timothy L.

2004-01-01

Strategic pricing is an important and exciting topic in industrial organization and the economics of strategy. A wide range of texts use what has become a standard version of the Milgrom and Roberts (1982a) limit-pricing model to convey the essential ideas of strategic pricing under incomplete information. In addition to providing a formal, but…

Difference of protein 53 expression based on radiation therapy response in cervical cancer

NASA Astrophysics Data System (ADS)

Pasaribu, H. P.; Lubis, L. I.; Dina, S.; Simanjuntak, R. Y.; Siregar, H. S.; Rivany, R.

2018-03-01

Cervical cancer is one of most common gynecological cancer in women and the leading cause of death in developing countries. An analytic study with the case-control design was conducted to determine the difference of p53 expression based on radiation therapy response in cervical cancer. The study was performed in Obstetric and Gynecology Department and Pathology Department of Adam Malik General Hospital Medan from January to February 2017. 15 paraffin blocks of acervical cancer patient with incomplete response were obtained as study samples, and 15 paraffin blocks of acervical cancer patient with complete response were obtained as control samples, The samples were collected by consecutive sampling, andan immunohistochemical assessment of p53 expression was done to assessapoptosis count and radiation response. Data were analyzed using Kruskal-Wallis with confidence interval 83.5% and p<0.05 was considered statistically significant. The study found that an increase of p53 expressionin samples with abundant apoptosis (≥5 apoptosis cells/5 HPF), p=0.033, and in incomplete response group, p=0.046. It means that p53 expression before radiation therapy can be used as an early marker for radiation therapy response in cervical cancer.

An integrated PCR colony hybridization approach to screen cDNA libraries for full-length coding sequences.

PubMed

Pollier, Jacob; González-Guzmán, Miguel; Ardiles-Diaz, Wilson; Geelen, Danny; Goossens, Alain

2011-01-01

cDNA-Amplified Fragment Length Polymorphism (cDNA-AFLP) is a commonly used technique for genome-wide expression analysis that does not require prior sequence knowledge. Typically, quantitative expression data and sequence information are obtained for a large number of differentially expressed gene tags. However, most of the gene tags do not correspond to full-length (FL) coding sequences, which is a prerequisite for subsequent functional analysis. A medium-throughput screening strategy, based on integration of polymerase chain reaction (PCR) and colony hybridization, was developed that allows in parallel screening of a cDNA library for FL clones corresponding to incomplete cDNAs. The method was applied to screen for the FL open reading frames of a selection of 163 cDNA-AFLP tags from three different medicinal plants, leading to the identification of 109 (67%) FL clones. Furthermore, the protocol allows for the use of multiple probes in a single hybridization event, thus significantly increasing the throughput when screening for rare transcripts. The presented strategy offers an efficient method for the conversion of incomplete expressed sequence tags (ESTs), such as cDNA-AFLP tags, to FL-coding sequences.

Integrin β4 Signaling Promotes Mammary Tumor Cell Adhesion to Brain Microvascular Endothelium by Inducing ErbB2-mediated Secretion of VEGF

PubMed Central

Fan, Jie; Cai, Bin; Zeng, Min; Hao, Yanyan

2015-01-01

Prior studies have indicated that the β4 integrin promotes mammary tumor invasion and metastasis by combining with ErbB2 and amplifying its signaling capacity. However, the effector pathways and cellular functions by which the β4 integrin exerts these effects are incompletely understood. To examine if β4 signaling plays a role during mammary tumor cell adhesion to microvascular endothelium, we have examined ErbB2-transformed mammary tumor cells expressing either a wild-type (WT) or a signaling-defective form of β4 (1355T). We report that WT cells adhere to brain microvascular endothelium in vitro to a significantly larger extent as compared to 1355T cells. Interestingly, integrin β4 signaling does not exert a direct effect on adhesion to the endothelium or the underlying basement membrane. Rather, it enhances ErbB2-dependent expression of VEGF by tumor cells. VEGF in turn disrupts the tight and adherens junctions of endothelial monolayers, enabling the exposure of underlying basement membrane and increasing the adhesion of tumor cells to the intercellular junctions of endothelium. Inhibition of ErbB2 on tumor cells or the VEGFR-2 on endothelial cells suppresses mammary tumor cell adhesion to microvascular endothelium. Our results indicate that β4 signaling regulates VEGF expression by the mammary tumor cells thereby enhancing their adhesion to microvascular endothelium. PMID:21556948

Mining functionally relevant gene sets for analyzing physiologically novel clinical expression data.

PubMed

Turcan, Sevin; Vetter, Douglas E; Maron, Jill L; Wei, Xintao; Slonim, Donna K

2011-01-01

Gene set analyses have become a standard approach for increasing the sensitivity of transcriptomic studies. However, analytical methods incorporating gene sets require the availability of pre-defined gene sets relevant to the underlying physiology being studied. For novel physiological problems, relevant gene sets may be unavailable or existing gene set databases may bias the results towards only the best-studied of the relevant biological processes. We describe a successful attempt to mine novel functional gene sets for translational projects where the underlying physiology is not necessarily well characterized in existing annotation databases. We choose targeted training data from public expression data repositories and define new criteria for selecting biclusters to serve as candidate gene sets. Many of the discovered gene sets show little or no enrichment for informative Gene Ontology terms or other functional annotation. However, we observe that such gene sets show coherent differential expression in new clinical test data sets, even if derived from different species, tissues, and disease states. We demonstrate the efficacy of this method on a human metabolic data set, where we discover novel, uncharacterized gene sets that are diagnostic of diabetes, and on additional data sets related to neuronal processes and human development. Our results suggest that our approach may be an efficient way to generate a collection of gene sets relevant to the analysis of data for novel clinical applications where existing functional annotation is relatively incomplete.

MicroRNA-124 expression counteracts pro-survival stress responses in glioblastoma.

PubMed

Mucaj, V; Lee, S S; Skuli, N; Giannoukos, D N; Qiu, B; Eisinger-Mathason, T S K; Nakazawa, M S; Shay, J E S; Gopal, P P; Venneti, S; Lal, P; Minn, A J; Simon, M C; Mathew, L K

2015-04-23

Glioblastomas are aggressive adult brain tumors, characterized by inadequately organized vasculature and consequent nutrient and oxygen (O2)-depleted areas. Adaptation to low nutrients and hypoxia supports glioblastoma cell survival, progression and therapeutic resistance. However, specific mechanisms promoting cellular survival under nutrient and O2 deprivation remain incompletely understood. Here, we show that miR-124 expression is negatively correlated with a hypoxic gene signature in glioblastoma patient samples, suggesting that low miR-124 levels contribute to pro-survival adaptive pathways in this disease. As miR-124 expression is repressed in various cancer types (including glioblastoma), we quantified miR-124 abundance in normoxic and hypoxic regions in glioblastoma patient tissue, and investigated whether ectopic miR-124 expression compromises cell survival during tumor ischemia. Our results indicate that miR-124 levels are further diminished in hypoxic/ischemic regions within individual glioblastoma patient samples, compared with regions replete in O2 and nutrients. Importantly, we also show that increased miR-124 expression affects the ability of tumor cells to survive under O2 and/or nutrient deprivation. Moreover, miR-124 re-expression increases cell death in vivo and enhances the survival of mice bearing intracranial xenograft tumors. miR-124 exerts this phenotype in part by directly regulating TEAD1, MAPK14/p38α and SERP1, factors involved in cell proliferation and survival under stress. Simultaneous suppression of these miR-124 targets results in similar levels of cell death as caused by miR-124 restoration. Importantly, we further demonstrate that SERP1 reintroduction reverses the hypoxic cell death elicited by miR-124, indicating the importance of SERP1 in promoting tumor cell survival. In support of our experimental data, we observed a significant correlation between high SERP1 levels and poor patient outcome in glioblastoma patients. Collectively, among the many pro-tumorigeneic properties of miR-124 repression in glioblastoma, we delineated a novel role in promoting tumor cell survival under stressful microenvironments, thereby supporting tumor progression.

MicroRNA-124 expression counteracts pro-survival stress responses in glioblastoma

PubMed Central

Mucaj, Vera; Lee, Samuel S.; Skuli, Nicolas; Giannoukos, Dionysios N.; Qiu, Bo; Eisinger-Mathason, T.S. Karin; Nakazawa, Michael S.; Shay, Jessica E.S.; Gopal, Pallavi P.; Venneti, Sriram; Lal, Priti; Minn, Andy J.; Simon, M. Celeste; Mathew, Lijoy K.

2014-01-01

Glioblastomas are aggressive adult brain tumors, characterized by inadequately organized vasculature and consequent nutrient and oxygen (O2)-depleted areas. Adaptation to low nutrients and hypoxia supports glioblastoma cell survival, progression, and therapeutic resistance. However, specific mechanisms promoting cellular survival under nutrient and O2 deprivation remain incompletely understood. Here, we show that miR-124 expression is negatively correlated with a hypoxic gene signature in glioblastoma patient samples, suggesting that low miR-124 levels contribute to pro-survival adaptive pathways in this disease. Since miR-124 expression is repressed in various cancers (including glioblastoma), we quantified miR-124 abundance in normoxic and hypoxic regions in glioblastoma patient tissue, and investigated whether ectopic miR-124 expression compromises cell survival, during tumor ischemia. Our results indicate that miR-124 levels are further diminished in hypoxic/ischemic regions within individual glioblastoma patient samples, compared to regions replete in O2 and nutrients. Importantly, we also show that increased miR-124 expression affects the ability of tumor cells to survive under O2 and/or nutrient deprivation. Moreover, miR-124 re-expression increases cell death in vivo, and enhances the survival of mice bearing intracranial xenograft tumors. miR-124 exerts this phenotype in part by directly regulating TEAD1, MAPK14/p38α and SERP1, factors involved in cell proliferation and survival under stress. Simultaneous suppression of these miR-124 targets results in similar levels of cell death as caused by miR-124 restoration. Importantly, we further demonstrate that SERP1 re-introduction reverses the hypoxic cell death elicited by miR-124, indicating the importance of SERP1 in promoting tumor cell survival. In support of our experimental data, we observed a significant correlation between high SERP1 levels and poor patient outcome in glioblastoma patients. Collectively, among the many pro-tumorigeneic properties of miR-124 repression in glioblastoma, we delineated a novel role in promoting tumor cell survival under stressful microenvironments, thereby supporting tumor progression. PMID:24954504

Group prioritisation with unknown expert weights in incomplete linguistic context

NASA Astrophysics Data System (ADS)

Cheng, Dong; Cheng, Faxin; Zhou, Zhili; Wang, Juan

2017-09-01

In this paper, we study a group prioritisation problem in situations when the expert weights are completely unknown and their judgement preferences are linguistic and incomplete. Starting from the theory of relative entropy (RE) and multiplicative consistency, an optimisation model is provided for deriving an individual priority vector without estimating the missing value(s) of an incomplete linguistic preference relation. In order to address the unknown expert weights in the group aggregating process, we define two new kinds of expert weight indicators based on RE: proximity entropy weight and similarity entropy weight. Furthermore, a dynamic-adjusting algorithm (DAA) is proposed to obtain an objective expert weight vector and capture the dynamic properties involved in it. Unlike the extant literature of group prioritisation, the proposed RE approach does not require pre-allocation of expert weights and can solve incomplete preference relations. An interesting finding is that once all the experts express their preference relations, the final expert weight vector derived from the DAA is fixed irrespective of the initial settings of expert weights. Finally, an application example is conducted to validate the effectiveness and robustness of the RE approach.

Brain Natriuretic Peptide Stimulates Lipid Metabolism through Its Receptor NPR1 and the Glycerolipid Metabolism Pathway in Chicken Adipocytes.

PubMed

Huang, H Y; Zhao, G P; Liu, R R; Li, Q H; Zheng, M Q; Li, S F; Liang, Z; Zhao, Z H; Wen, J

2015-11-03

Brain natriuretic peptide (BNP) is related to lipid metabolism in mammals, but its effect and the molecular mechanisms underlying it in chickens are incompletely understood. We found that the level of natriuretic peptide precursor B (NPPB, which encodes BNP) mRNA expression in high-abdominal-fat chicken groups was significantly higher than that of low-abdominal-fat groups. Partial correlations indicated that changes in the weight of abdominal fat were positively correlated with NPPB mRNA expression level. In vitro, compared with the control group, preadipocytes with NPPB interference showed reduced levels of proliferation, differentiation, and glycerin in media. Treatments of cells with BNP led to enhanced proliferation and differentiation of cells and glycerin concentration, and mRNA expression of its receptor natriuretic peptide receptor 1 (NPR1) was upregulated significantly. In cells exposed to BNP, 482 differentially expressed genes were identified compared with controls without BNP. Four genes known to be related to lipid metabolism (diacylglycerol kinase; lipase, endothelial; 1-acylglycerol-3-phosphate O-acyltransferase 1; and 1-acylglycerol-3-phosphate O-acyltransferase 2) were enriched in the glycerolipid metabolism pathway and expressed differentially. In conclusion, BNP stimulates the proliferation, differentiation, and lipolysis of preadipocytes through upregulation of the levels of expression of its receptor NPR1 and key genes enriched in the glycerolipid metabolic pathway.

Multidrug Resistance in Breast Cancer: From In Vitro Models to Clinical Studies

PubMed Central

Wind, N. S.; Holen, I.

2011-01-01

The development of multidrug resistance (MDR) and subsequent relapse on therapy is a widespread problem in breast cancer, but our understanding of the underlying molecular mechanisms is incomplete. Numerous studies have aimed to establish the role of drug transporter pumps in MDR and to link their expression to response to chemotherapy. The ATP-binding cassette (ABC) transporters are central to breast cancer MDR, and increases in ABC expression levels have been shown to correlate with decreases in response to various chemotherapy drugs and a reduction in overall survival. But as there is a large degree of redundancy between different ABC transporters, this correlation has not been seen in all studies. This paper provides an introduction to the key molecules associated with breast cancer MDR and summarises evidence of their potential roles reported from model systems and clinical studies. We provide possible explanations for why despite several decades of research, the precise role of ABC transporters in breast cancer MDR remains elusive. PMID:22332018

Genetic, Hormonal, and Physiological Analysis of Late Maturity α-Amylase in Wheat1[W][OA

PubMed Central

Barrero, Jose M.; Mrva, Kolumbina; Talbot, Mark J.; White, Rosemary G.; Taylor, Jennifer; Gubler, Frank; Mares, Daryl J.

2013-01-01

Late maturity α-amylase (LMA) is a genetic defect that is commonly found in bread wheat (Triticum aestivum) cultivars and can result in commercially unacceptably high levels of α-amylase in harvest-ripe grain in the absence of rain or preharvest sprouting. This defect represents a serious problem for wheat farmers, and apart from the circumstantial evidence that gibberellins are somehow involved in the expression of LMA, the mechanisms or genes underlying LMA are unknown. In this work, we use a doubled haploid population segregating for constitutive LMA to physiologically analyze the appearance of LMA during grain development and to profile the transcriptomic and hormonal changes associated with this phenomenon. Our results show that LMA is a consequence of a very narrow and transitory peak of expression of genes encoding high-isoelectric point α-amylase during grain development and that the LMA phenotype seems to be a partial or incomplete gibberellin response emerging from a strongly altered hormonal environment. PMID:23321420

Inhibiting platelet-derived growth factor beta reduces Ewing's sarcoma growth and metastasis in a novel orthotopic human xenograft model.

PubMed

Wang, Yong Xin; Mandal, Deendayal; Wang, Suizhau; Hughes, Dennis; Pollock, Raphael E; Lev, Dina; Kleinerman, Eugenie; Hayes-Jordan, Andrea

2009-01-01

Despite aggressive therapy, Ewing's sarcoma (ES) patients have a poor five-year overall survival of only 20-40%. Pulmonary metastasis is the most common form of demise in these patients. The pathogenesis of pulmonary metastasis is poorly understood and few orthotopic models exist that allow study of spontaneous pulmonary metastasis in ES. We have developed a novel orthotopic xenograft model in which spontaneous pulmonary metastases develop. While the underlying biology of ES is incompletely understood, in addition to the EWS-FLI-1 mutation, it is known that platelet-derived growth factor receptor beta (PDGFR-beta) is highly expressed in ES. Hypothesizing that PDGFR-beta expression is indicative of a specific role for this receptor protein in ES progression, the effect of PDGFR-beta inhibition on ES growth and metastasis was assessed in this novel orthotopic ES model. Silencing PDGFR-beta reduced spontaneous growth and metastasis in ES. Preclinical therapeutically relevant findings such as these may ultimately lead to new treatment initiatives in ES.

Molecular mechanism of monoamine oxidase A gene regulation under inflammation and ischemia-like conditions: key roles of the transcription factors GATA2, Sp1 and TBP.

PubMed

Gupta, Vinayak; Khan, Abrar A; Sasi, Binu K; Mahapatra, Nitish R

2015-07-01

Monoamine oxidase A (MAOA) plays important roles in the pathogenesis of several neurological and cardiovascular disorders. The mechanism of transcriptional regulation of MAOA under basal and pathological conditions, however, remains incompletely understood. Here, we report systematic identification and characterization of cis elements and transcription factors that govern the expression of MAOA gene. Extensive computational analysis of MAOA promoter, followed by 5'-promoter deletion/reporter assays, revealed that the -71/-40 bp domain was sufficient for its basal transcription. Gel-shift and chromatin immunoprecipitation assays provided evidence of interactions of the transcription factors GATA-binding protein 2 (GATA2), Sp1 and TATA-binding protein (TBP) with this proximal promoter region. Consistently, over-expression of GATA2, Sp1 and TBP augmented MAOA promoter activity in a coordinated manner. In corroboration, siRNA-mediated down-regulation of GATA2/Sp1/TBP repressed the endogenous MAOA expression as well as transfected MAOA promoter activity. Tumor necrosis factor-α and forskolin activated MAOA transcription that was reversed by Sp1 siRNA; in support, tumor necrosis factor-α- and forskolin-induced activities were enhanced by ectopic over-expression of Sp1. On the other hand, MAOA transcription was diminished upon exposure of neuroblasts or cardiac myoblasts to ischemia-like conditions because of reduced binding of GATA2/Sp1/TBP with MAOA promoter. In conclusion, this study revealed previously unknown roles of GATA2, Sp1 and TBP in modulating MAOA expression under basal as well as pathophysiological conditions such as inflammation and ischemia, thus providing new insights into the molecular basis of aberrant MAOA expression in neuronal/cardiovascular disease states. Dysregulation of monoamine oxidase A (MAOA) have been implicated in several behavioral and neuronal disease states. Here, we identified three crucial transcription factors (GATA2, Sp1 and TBP) that regulate MAOA gene expression in a coordinated manner. Aberrant MAOA expression under pathophysiological conditions including inflammation and ischemia is mediated by altered binding of GATA2/Sp1/TBP with MAOA proximal promoter. Thus, these findings provide new insights into pathogenesis of several common diseases. GATA2, GATA-binding protein 2; Sp1, specificity protein 1; TBP, TATA-binding protein. © 2015 International Society for Neurochemistry.

Stochastic Online Learning in Dynamic Networks under Unknown Models

DTIC Science & Technology

2016-08-02

Repeated Game with Incomplete Information, IEEE International Conference on Acoustics, Speech, and Signal Processing. 20-MAR-16, Shanghai, China...in a game theoretic framework for the application of multi-seller dynamic pricing with unknown demand models. We formulated the problem as an...infinitely repeated game with incomplete information and developed a dynamic pricing strategy referred to as Competitive and Cooperative Demand Learning

Rough Set Approach to Incomplete Multiscale Information System

PubMed Central

Yang, Xibei; Qi, Yong; Yu, Dongjun; Yu, Hualong; Song, Xiaoning; Yang, Jingyu

2014-01-01

Multiscale information system is a new knowledge representation system for expressing the knowledge with different levels of granulations. In this paper, by considering the unknown values, which can be seen everywhere in real world applications, the incomplete multiscale information system is firstly investigated. The descriptor technique is employed to construct rough sets at different scales for analyzing the hierarchically structured data. The problem of unravelling decision rules at different scales is also addressed. Finally, the reduct descriptors are formulated to simplify decision rules, which can be derived from different scales. Some numerical examples are employed to substantiate the conceptual arguments. PMID:25276852

MicroRNA203a suppresses glioma tumorigenesis through an ATM-dependent interferon response pathway

PubMed Central

Yang, Chuan He; Wang, Yinan; Sims, Michelle; Cai, Chun; He, Ping; Häcker, Hans; Yue, Junming; Cheng, Jinjun; Boop, Frederick A.; Pfeffer, Lawrence M.

2017-01-01

Glioblastoma (GBM) is a deadly and incurable brain tumor. Although microRNAs (miRNAs) play critical roles in regulating the cancer cell phenotype, the underlying mechanisms of how they regulate tumorigenesis are incompletely understood. We previously showed that miR-203a is expressed at relatively low levels in GBM patients, and ectopic miR-203a expression in GBM cell lines inhibited cell proliferation and migration, increased sensitivity to apoptosis induced by interferon (IFN) or temozolomide in vitro, and inhibited GBM tumorigenesis in vivo. Here we show that ectopic expression of miR-203a in GBM cell lines promotes the IFN response pathway as evidenced by increased IFN production and IFN-stimulated gene (ISG) expression, and high basal tyrosine phosphorylation of multiple STAT proteins. Importantly, we identified that miR-203a directly suppressed the protein levels of ataxia-telangiectasia mutated (ATM) kinase that negatively regulates IFN production. We found that high ATM expression in GBM correlates with poor patient survival and that ATM expression is inversely correlated with miR-203a expression. Knockout of ATM expression and inhibition of ATM function in GBM cell lines inhibited cell proliferation and migration, increased sensitivity to apoptosis induced by therapeutic agents in vitro, and markedly suppressed GBM tumor growth and promoted animal survival. In contrast, restoring ATM levels in GBM cells ectopically expressing miR-203a increased tumorigenicity and decreased animal survival. Our study suggests that low miR-203a expression in GBM suppresses the interferon response through an ATM-dependent pathway. PMID:29348882

MicroRNA203a suppresses glioma tumorigenesis through an ATM-dependent interferon response pathway.

PubMed

Yang, Chuan He; Wang, Yinan; Sims, Michelle; Cai, Chun; He, Ping; Häcker, Hans; Yue, Junming; Cheng, Jinjun; Boop, Frederick A; Pfeffer, Lawrence M

2017-12-22

Glioblastoma (GBM) is a deadly and incurable brain tumor. Although microRNAs (miRNAs) play critical roles in regulating the cancer cell phenotype, the underlying mechanisms of how they regulate tumorigenesis are incompletely understood. We previously showed that miR-203a is expressed at relatively low levels in GBM patients, and ectopic miR-203a expression in GBM cell lines inhibited cell proliferation and migration, increased sensitivity to apoptosis induced by interferon (IFN) or temozolomide in vitro , and inhibited GBM tumorigenesis in vivo . Here we show that ectopic expression of miR-203a in GBM cell lines promotes the IFN response pathway as evidenced by increased IFN production and IFN-stimulated gene (ISG) expression, and high basal tyrosine phosphorylation of multiple STAT proteins. Importantly, we identified that miR-203a directly suppressed the protein levels of ataxia-telangiectasia mutated (ATM) kinase that negatively regulates IFN production. We found that high ATM expression in GBM correlates with poor patient survival and that ATM expression is inversely correlated with miR-203a expression. Knockout of ATM expression and inhibition of ATM function in GBM cell lines inhibited cell proliferation and migration, increased sensitivity to apoptosis induced by therapeutic agents in vitro , and markedly suppressed GBM tumor growth and promoted animal survival. In contrast, restoring ATM levels in GBM cells ectopically expressing miR-203a increased tumorigenicity and decreased animal survival. Our study suggests that low miR-203a expression in GBM suppresses the interferon response through an ATM-dependent pathway.

Reduced hippocampal damage and epileptic seizures after status epilepticus in mice lacking proapoptotic Puma

PubMed Central

Engel, Tobias; Murphy, Brona M.; Hatazaki, Seiji; Jimenez-Mateos, Eva M.; Concannon, Caoimhin G.; Woods, Ina; Prehn, Jochen H. M.; Henshall, David C.

2010-01-01

The functional significance of neuronal death for pathogenesis of epilepsy and the underlying molecular mechanisms thereof remain incompletely understood. The p53 transcription factor has been implicated in seizure damage, but its target genes and the influence of cell death under its control on epilepsy development are unknown. In the present study, we report that status epilepticus (SE) triggered by intra-amygdala kainic acid in mice causes rapid p53 accumulation and subsequent hippocampal damage. Expression of p53-up-regulated mediator of apoptosis (Puma), a proapoptotic Bcl-2 homology domain 3-only protein under p53 control, was increased within a few hours of SE. Induction of Puma was blocked by pharmacologic inhibition of p53, and hippocampal damage was also reduced. Puma induction was also blocked in p53-deficient mice subject to SE. Compared to Puma-expressing mice, Puma-deficient mice had significantly smaller hippocampal lesions after SE. Long-term, continuous telemetric EEG monitoring revealed a ∼60% reduction in the frequency of epileptic seizures in the Puma-deficient mice compared to Puma-expressing mice. These are the first data showing genetic deletion of a proapoptotic protein acting acutely to influence neuronal death subsequently alters the phenotype of epilepsy in the long-term, supporting the concept that apoptotic pathway activation is a trigger of epileptogenesis.—Engel, T., Murphy, B. M., Hatazaki, S., Jimenez-Mateos, E. M., Concannon, C. G., Woods, I., Prehn, J. H. M., Henshall, D. C. Reduced hippocampal damage and epileptic seizures after status epilepticus in mice lacking proapoptotic Puma. PMID:19890018

Micro-terminator: 'Hasta la vista, lncRNA!'.

PubMed

Diederichs, Sven

2015-04-01

Transcriptional termination is an important yet incompletely understood aspect of gene expression. Proudfoot, Jopling and colleagues now identify a new Microprocessor-mediated mechanism of transcriptional termination, which acts specifically on long noncoding transcripts that serve as microRNA precursors.

Adult epidermal Notch activity induces dermal accumulation of T cells and neural crest derivatives through upregulation of jagged 1.

PubMed

Ambler, Carrie A; Watt, Fiona M

2010-11-01

Notch signalling regulates epidermal differentiation and tumour formation via non-cell autonomous mechanisms that are incompletely understood. This study shows that epidermal Notch activation via a 4-hydroxy-tamoxifen-inducible transgene caused epidermal thickening, focal detachment from the underlying dermis and hair clumping. In addition, there was dermal accumulation of T lymphocytes and stromal cells, some of which localised to the blisters at the epidermal-dermal boundary. The T cell infiltrate was responsible for hair clumping but not for other Notch phenotypes. Notch-induced stromal cells were heterogeneous, expressing markers of neural crest, melanocytes, smooth muscle and peripheral nerve. Although Slug1 expression was expanded in the epidermis, the stromal cells did not arise through epithelial-mesenchymal transition. Epidermal Notch activation resulted in upregulation of jagged 1 in both epidermis and dermis. When Notch was activated in the absence of epidermal jagged 1, jagged 1 was not upregulated in the dermis, and epidermal thickening, blister formation, accumulation of T cells and stromal cells were inhibited. Gene expression profiling revealed that epidermal Notch activation resulted in upregulation of several growth factors and cytokines, including TNFα, the expression of which was dependent on epidermal jagged 1. We conclude that jagged 1 is a key mediator of non-cell autonomous Notch signalling in skin.

Role of ATF4 in skeletal muscle atrophy.

PubMed

Adams, Christopher M; Ebert, Scott M; Dyle, Michael C

2017-05-01

Here, we discuss recent work focused on the role of activating transcription factor 4 (ATF4) in skeletal muscle atrophy. Muscle atrophy involves and requires widespread changes in skeletal muscle gene expression; however, the transcriptional regulatory proteins responsible for those changes are not yet well defined. Recent work indicates that some forms of muscle atrophy require ATF4, a stress-inducible bZIP transcription factor subunit that helps to mediate a broad range of stress responses in mammalian cells. ATF4 expression in skeletal muscle fibers is sufficient to induce muscle fiber atrophy and required for muscle atrophy during several stress conditions, including aging, fasting, and limb immobilization. By helping to activate specific genes in muscle fibers, ATF4 contributes to the expression of numerous mRNAs, including at least two mRNAs (Gadd45a and p21) that encode mediators of muscle fiber atrophy. Gadd45a promotes muscle fiber atrophy by activating the protein kinase MEKK4. p21 promotes atrophy by reducing expression of spermine oxidase, a metabolic enzyme that helps to maintain muscle fiber size under nonstressed conditions. In skeletal muscle fibers, ATF4 is critical component of a complex and incompletely understood molecular signaling network that causes muscle atrophy during aging, fasting, and immobilization.

Chronic low-frequency stimulation transforms cat masticatory muscle fibers into jaw-slow fibers.

PubMed

Kang, Lucia H D; Hoh, Joseph F Y

2011-09-01

Cat masticatory muscle during regeneration expresses masticatory-specific myofibrillar proteins upon innervation by a fast muscle nerve but acquires the jaw-slow phenotype when innervated by a slow muscle nerve. Here, we test the hypothesis that chronic low-frequency stimulation simulating impulses from the slow nerve can result in masticatory-to-slow fiber-type transformation. In six cats, the temporalis muscle was continuously stimulated directly at 10 Hz for up to 12 weeks using a stimulator affixed to the skull. Stimulated muscles were analyzed by immunohistochemistry using, among others, monoclonal antibodies against masticatory-specific myosin heavy chain (MyHC), myosin binding protein-C, and tropomyosins. Under the electrodes, stimulation induced muscle regeneration, which generated slow fibers. Deep to the electrodes, at two to three weeks, two distinct populations of masticatory fibers began to express slow MyHC: 1) evenly distributed fibers that completely suppressed masticatory-specific proteins but transiently co-expressed fetal MyHCs, and 2) incompletely transformed fibers that express slow and masticatory but not fetal MyHCs. SDS-PAGE confirmed de novo expression of slow MyHC and β-tropomyosin in the stimulated muscles. We conclude that chronic low-frequency stimulation induces masticatory-to-slow fiber-type conversion. The two populations of transforming masticatory fibers may differ in their mode of activation or lineage of their myogenic cells.

Regulatory role of resveratrol, a microRNA-controlling compound, in HNRNPA1 expression, which is associated with poor prognosis in breast cancer.

PubMed

Otsuka, Kurataka; Yamamoto, Yusuke; Ochiya, Takahiro

2018-05-15

Certain lifestyles, such as unhealthy eating habits, are associated with an increased risk for several diseases, including cancer. Recently, some naturally occurring compounds, such as resveratrol, have been shown to regulate microRNA (miRNA) expression in a positive manner; this regulatory activity is likely to be advantageous for cancer prevention and treatment. Resveratrol, a multi-functional polyphenolic phytoalexin, has been known to exert anti-tumorigenic and anti-inflammatory effects and to regulate miRNA expression. However, our understanding of the underlying molecular mechanisms whereby resveratrol controls cancer cell growth via the regulation of miRNA and oncogenic target gene expression to inhibit disease progression remains incomplete. Here we show that resveratrol controls breast cancer cell proliferation by inducing tumor-suppressive miRNAs ( miR-34a , miR-424 , and miR-503 ) via the p53 pathway and then by suppressing heterogeneous nuclear ribonucleoprotein A1 ( HNRNPA1 ), which is associated with tumorigenesis and tumor progression. Notably, HNRNPA1 was directly regulated by miR-424 and miR-503 , the expression of which were mediated by resveratrol. Moreover, we found that resveratrol exerts broad effects on the HNRNPA1 -related pre-mRNA splicing pathway. Our data provide novel insights into the regulatory roles of resveratrol for preventing and treating of diseases.

Regulatory role of resveratrol, a microRNA-controlling compound, in HNRNPA1 expression, which is associated with poor prognosis in breast cancer

PubMed Central

Otsuka, Kurataka; Yamamoto, Yusuke; Ochiya, Takahiro

2018-01-01

Certain lifestyles, such as unhealthy eating habits, are associated with an increased risk for several diseases, including cancer. Recently, some naturally occurring compounds, such as resveratrol, have been shown to regulate microRNA (miRNA) expression in a positive manner; this regulatory activity is likely to be advantageous for cancer prevention and treatment. Resveratrol, a multi-functional polyphenolic phytoalexin, has been known to exert anti-tumorigenic and anti-inflammatory effects and to regulate miRNA expression. However, our understanding of the underlying molecular mechanisms whereby resveratrol controls cancer cell growth via the regulation of miRNA and oncogenic target gene expression to inhibit disease progression remains incomplete. Here we show that resveratrol controls breast cancer cell proliferation by inducing tumor-suppressive miRNAs (miR-34a, miR-424, and miR-503) via the p53 pathway and then by suppressing heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1), which is associated with tumorigenesis and tumor progression. Notably, HNRNPA1 was directly regulated by miR-424 and miR-503, the expression of which were mediated by resveratrol. Moreover, we found that resveratrol exerts broad effects on the HNRNPA1-related pre-mRNA splicing pathway. Our data provide novel insights into the regulatory roles of resveratrol for preventing and treating of diseases. PMID:29872500

Identification and characterization of an alternative promoter of the human PGC-1{alpha} gene

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

Yoshioka, Toyo; Inagaki, Kenjiro; Noguchi, Tetsuya, E-mail: noguchi@med.kobe-u.ac.jp

2009-04-17

The transcriptional regulator peroxisome proliferator-activated receptor-{gamma} coactivator-1{alpha} (PGC-1{alpha}) controls mitochondrial biogenesis and energy homeostasis. Although physical exercise induces PGC-1{alpha} expression in muscle, the underlying mechanism of this effect has remained incompletely understood. We recently identified a novel muscle-enriched isoform of PGC-1{alpha} transcript (designated PGC-1{alpha}-b) that is derived from a previously unidentified first exon. We have now cloned and characterized the human PGC-1{alpha}-b promoter. The muscle-specific transcription factors MyoD and MRF4 transactivated this promoter through interaction with a proximal E-box motif. Furthermore, either forced expression of Ca{sup 2+}- and calmodulin-dependent protein kinase IV (CaMKIV), calcineurin A, or the p38 mitogen-activated proteinmore » kinase (p38 MAPK) kinase MKK6 or the intracellular accumulation of cAMP activated the PGC-1{alpha}-b promoter in cultured myoblasts through recruitment of cAMP response element (CRE)-binding protein (CREB) to a putative CRE located downstream of the E-box. Our results thus reveal a potential molecular basis for isoform-specific regulation of PGC-1{alpha} expression in contracting muscle.« less

Coordinated regulation of neuronal mRNA steady-state levels through developmentally controlled intron retention

PubMed Central

Yap, Karen; Lim, Zhao Qin; Khandelia, Piyush; Friedman, Brad; Makeyev, Eugene V.

2012-01-01

Differentiated cells acquire unique structural and functional traits through coordinated expression of lineage-specific genes. An extensive battery of genes encoding components of the synaptic transmission machinery and specialized cytoskeletal proteins is activated during neurogenesis, but the underlying regulation is not well understood. Here we show that genes encoding critical presynaptic proteins are transcribed at a detectable level in both neurons and nonneuronal cells. However, in nonneuronal cells, the splicing of 3′-terminal introns within these genes is repressed by the polypyrimidine tract-binding protein (Ptbp1). This inhibits the export of incompletely spliced mRNAs to the cytoplasm and triggers their nuclear degradation. Clearance of these intron-containing transcripts occurs independently of the nonsense-mediated decay (NMD) pathway but requires components of the nuclear RNA surveillance machinery, including the nuclear pore-associated protein Tpr and the exosome complex. When Ptbp1 expression decreases during neuronal differentiation, the regulated introns are spliced out, thus allowing the accumulation of translation-competent mRNAs in the cytoplasm. We propose that this mechanism counters ectopic and precocious expression of functionally linked neuron-specific genes and ensures their coherent activation in the appropriate developmental context. PMID:22661231

Coordinated regulation of neuronal mRNA steady-state levels through developmentally controlled intron retention.

PubMed

Yap, Karen; Lim, Zhao Qin; Khandelia, Piyush; Friedman, Brad; Makeyev, Eugene V

2012-06-01

Differentiated cells acquire unique structural and functional traits through coordinated expression of lineage-specific genes. An extensive battery of genes encoding components of the synaptic transmission machinery and specialized cytoskeletal proteins is activated during neurogenesis, but the underlying regulation is not well understood. Here we show that genes encoding critical presynaptic proteins are transcribed at a detectable level in both neurons and nonneuronal cells. However, in nonneuronal cells, the splicing of 3'-terminal introns within these genes is repressed by the polypyrimidine tract-binding protein (Ptbp1). This inhibits the export of incompletely spliced mRNAs to the cytoplasm and triggers their nuclear degradation. Clearance of these intron-containing transcripts occurs independently of the nonsense-mediated decay (NMD) pathway but requires components of the nuclear RNA surveillance machinery, including the nuclear pore-associated protein Tpr and the exosome complex. When Ptbp1 expression decreases during neuronal differentiation, the regulated introns are spliced out, thus allowing the accumulation of translation-competent mRNAs in the cytoplasm. We propose that this mechanism counters ectopic and precocious expression of functionally linked neuron-specific genes and ensures their coherent activation in the appropriate developmental context.

Role of Adrenomedullin in Breast Cancer Bone Metastasis and Chemoresistance

DTIC Science & Technology

2008-05-01

osteoblast proliferation but does not induce bone matrix protein (bone sialoprotein , type I collagen, osteocalcin, and osteopontin) mRNA expression...are incompletely understood. AM treatment stimulates osteoblast proliferation but does not induce bone matrix protein (bone sialoprotein , type I

Normalization of relative and incomplete temporal expressions in clinical narratives.

PubMed

Sun, Weiyi; Rumshisky, Anna; Uzuner, Ozlem

2015-09-01

To improve the normalization of relative and incomplete temporal expressions (RI-TIMEXes) in clinical narratives. We analyzed the RI-TIMEXes in temporally annotated corpora and propose two hypotheses regarding the normalization of RI-TIMEXes in the clinical narrative domain: the anchor point hypothesis and the anchor relation hypothesis. We annotated the RI-TIMEXes in three corpora to study the characteristics of RI-TMEXes in different domains. This informed the design of our RI-TIMEX normalization system for the clinical domain, which consists of an anchor point classifier, an anchor relation classifier, and a rule-based RI-TIMEX text span parser. We experimented with different feature sets and performed an error analysis for each system component. The annotation confirmed the hypotheses that we can simplify the RI-TIMEXes normalization task using two multi-label classifiers. Our system achieves anchor point classification, anchor relation classification, and rule-based parsing accuracy of 74.68%, 87.71%, and 57.2% (82.09% under relaxed matching criteria), respectively, on the held-out test set of the 2012 i2b2 temporal relation challenge. Experiments with feature sets reveal some interesting findings, such as: the verbal tense feature does not inform the anchor relation classification in clinical narratives as much as the tokens near the RI-TIMEX. Error analysis showed that underrepresented anchor point and anchor relation classes are difficult to detect. We formulate the RI-TIMEX normalization problem as a pair of multi-label classification problems. Considering only RI-TIMEX extraction and normalization, the system achieves statistically significant improvement over the RI-TIMEX results of the best systems in the 2012 i2b2 challenge. © The Author 2015. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Optogenetic Acidification of Synaptic Vesicles and Lysosomes

PubMed Central

Grauel, M. Katharina; Wozny, Christian; Bentz, Claudia; Blessing, Anja; Rosenmund, Tanja; Jentsch, Thomas J.; Schmitz, Dietmar; Hegemann, Peter; Rosenmund, Christian

2016-01-01

Acidification is required for the function of many intracellular organelles, but methods to acutely manipulate their intraluminal pH have not been available. Here we present a targeting strategy to selectively express the light-driven proton pump Arch3 on synaptic vesicles. Our new tool, pHoenix, can functionally replace endogenous proton pumps, enabling optogenetic control of vesicular acidification and neurotransmitter accumulation. Under physiological conditions, glutamatergic vesicles are nearly full, as additional vesicle acidification with pHoenix only slightly increased the quantal size. By contrast, we found that incompletely filled vesicles exhibited a lower release probability than full vesicles, suggesting preferential exocytosis of vesicles with high transmitter content. Our subcellular targeting approach can be transferred to other organelles, as demonstrated for a pHoenix variant that allows light-activated acidification of lysosomes. PMID:26551543

Optogenetic acidification of synaptic vesicles and lysosomes.

PubMed

Rost, Benjamin R; Schneider, Franziska; Grauel, M Katharina; Wozny, Christian; Bentz, Claudia; Blessing, Anja; Rosenmund, Tanja; Jentsch, Thomas J; Schmitz, Dietmar; Hegemann, Peter; Rosenmund, Christian

2015-12-01

Acidification is required for the function of many intracellular organelles, but methods to acutely manipulate their intraluminal pH have not been available. Here we present a targeting strategy to selectively express the light-driven proton pump Arch3 on synaptic vesicles. Our new tool, pHoenix, can functionally replace endogenous proton pumps, enabling optogenetic control of vesicular acidification and neurotransmitter accumulation. Under physiological conditions, glutamatergic vesicles are nearly full, as additional vesicle acidification with pHoenix only slightly increased the quantal size. By contrast, we found that incompletely filled vesicles exhibited a lower release probability than full vesicles, suggesting preferential exocytosis of vesicles with high transmitter content. Our subcellular targeting approach can be transferred to other organelles, as demonstrated for a pHoenix variant that allows light-activated acidification of lysosomes.

Photocounting distributions for exponentially decaying sources.

PubMed

Teich, M C; Card, H C

1979-05-01

Exact photocounting distributions are obtained for a pulse of light whose intensity is exponentially decaying in time, when the underlying photon statistics are Poisson. It is assumed that the starting time for the sampling interval (which is of arbitrary duration) is uniformly distributed. The probability of registering n counts in the fixed time T is given in terms of the incomplete gamma function for n >/= 1 and in terms of the exponential integral for n = 0. Simple closed-form expressions are obtained for the count mean and variance. The results are expected to be of interest in certain studies involving spontaneous emission, radiation damage in solids, and nuclear counting. They will also be useful in neurobiology and psychophysics, since habituation and sensitization processes may sometimes be characterized by the same stochastic model.

Assessing the Robustness of Graph Statistics for Network Analysis Under Incomplete Information

DTIC Science & Technology

strategy for dismantling these networks based on their network structure. However, these strategies typically assume complete information about the...combat them with missing information . This thesis analyzes the performance of a variety of network statistics in the context of incomplete information by...leveraging simulation to remove nodes and edges from networks and evaluating the effect this missing information has on our ability to accurately

Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective GABAA Receptor Modulators?

PubMed Central

Vinkers, Christiaan H.; Olivier, Berend

2012-01-01

Despite decades of basic and clinical research, our understanding of how benzodiazepines tend to lose their efficacy over time (tolerance) is at least incomplete. In appears that tolerance develops relatively quickly for the sedative and anticonvulsant actions of benzodiazepines, whereas tolerance to anxiolytic and amnesic effects probably does not develop at all. In light of this evidence, we review the current evidence for the neuroadaptive mechanisms underlying benzodiazepine tolerance, including changes of (i) the GABAA receptor (subunit expression and receptor coupling), (ii) intracellular changes stemming from transcriptional and neurotrophic factors, (iii) ionotropic glutamate receptors, (iv) other neurotransmitters (serotonin, dopamine, and acetylcholine systems), and (v) the neurosteroid system. From the large variance in the studies, it appears that either different (simultaneous) tolerance mechanisms occur depending on the benzodiazepine effect, or that the tolerance-inducing mechanism depends on the activated GABAA receptor subtypes. Importantly, there is no convincing evidence that tolerance occurs with α subunit subtype-selective compounds acting at the benzodiazepine site. PMID:22536226

FARO server: Meta-analysis of gene expression by matching gene expression signatures to a compendium of public gene expression data.

PubMed

Manijak, Mieszko P; Nielsen, Henrik B

2011-06-11

Although, systematic analysis of gene annotation is a powerful tool for interpreting gene expression data, it sometimes is blurred by incomplete gene annotation, missing expression response of key genes and secondary gene expression responses. These shortcomings may be partially circumvented by instead matching gene expression signatures to signatures of other experiments. To facilitate this we present the Functional Association Response by Overlap (FARO) server, that match input signatures to a compendium of 242 gene expression signatures, extracted from more than 1700 Arabidopsis microarray experiments. Hereby we present a publicly available tool for robust characterization of Arabidopsis gene expression experiments which can point to similar experimental factors in other experiments. The server is available at http://www.cbs.dtu.dk/services/faro/.

Achieving large dynamic range control of gene expression with a compact RNA transcription–translation regulator

PubMed Central

2017-01-01

Abstract RNA transcriptional regulators are emerging as versatile components for genetic network construction. However, these regulators suffer from incomplete repression in their OFF state, making their dynamic range less than that of their protein counterparts. This incomplete repression causes expression leak, which impedes the construction of larger synthetic regulatory networks as leak propagation can interfere with desired network function. To address this, we demonstrate how naturally derived antisense RNA-mediated transcriptional regulators can be configured to regulate both transcription and translation in a single compact RNA mechanism that functions in Escherichia coli. Using in vivo gene expression assays, we show that a combination of transcriptional termination and ribosome binding site sequestration increases repression from 85% to 98%, or activation from 10-fold to over 900-fold, in response to cognate antisense RNAs. We also show that orthogonal repressive versions of this mechanism can be created through engineering minimal antisense RNAs. Finally, to demonstrate the utility of this mechanism, we use it to reduce network leak in an RNA-only cascade. We anticipate these regulators will find broad use as synthetic biology moves beyond parts engineering to the design and construction of more sophisticated regulatory networks. PMID:28387839

Sensitivity to imputation models and assumptions in receiver operating characteristic analysis with incomplete data

PubMed Central

Karakaya, Jale; Karabulut, Erdem; Yucel, Recai M.

2015-01-01

Modern statistical methods using incomplete data have been increasingly applied in a wide variety of substantive problems. Similarly, receiver operating characteristic (ROC) analysis, a method used in evaluating diagnostic tests or biomarkers in medical research, has also been increasingly popular problem in both its development and application. While missing-data methods have been applied in ROC analysis, the impact of model mis-specification and/or assumptions (e.g. missing at random) underlying the missing data has not been thoroughly studied. In this work, we study the performance of multiple imputation (MI) inference in ROC analysis. Particularly, we investigate parametric and non-parametric techniques for MI inference under common missingness mechanisms. Depending on the coherency of the imputation model with the underlying data generation mechanism, our results show that MI generally leads to well-calibrated inferences under ignorable missingness mechanisms. PMID:26379316

Optimization of Soluble Expression and Purification of Recombinant Human Rhinovirus Type-14 3C Protease Using Statistically Designed Experiments: Isolation and Characterization of the Enzyme.

PubMed

Antoniou, Georgia; Papakyriacou, Irineos; Papaneophytou, Christos

2017-10-01

Human rhinovirus (HRV) 3C protease is widely used in recombinant protein production for various applications such as biochemical characterization and structural biology projects to separate recombinant fusion proteins from their affinity tags in order to prevent interference between these tags and the target proteins. Herein, we report the optimization of expression and purification conditions of glutathione S-transferase (GST)-tagged HRV 3C protease by statistically designed experiments. Soluble expression of GST-HRV 3C protease was initially optimized by response surface methodology (RSM), and a 5.5-fold increase in enzyme yield was achieved. Subsequently, we developed a new incomplete factorial (IF) design that examines four variables (bacterial strain, expression temperature, induction time, and inducer concentration) in a single experiment. The new design called Incomplete Factorial-Strain/Temperature/Time/Inducer (IF-STTI) was validated using three GST-tagged proteins. In all cases, IF-STTI resulted in only 10% lower expression yields than those obtained by RSM. Purification of GST-HRV 3C was optimized by an IF design that examines simultaneously the effect of the amount of resin, incubation time of cell lysate with resin, and glycerol and DTT concentration in buffers, and a further 15% increase in protease recovery was achieved. Purified GST-HRV 3C protease was active at both 4 and 25 °C in a variety of buffers.

HDL and Glut1 inhibition reverse a hypermetabolic state in mouse models of myeloproliferative disorders

PubMed Central

Gautier, Emmanuel L.; Westerterp, Marit; Bhagwat, Neha; Cremers, Serge; Shih, Alan; Abdel-Wahab, Omar; Lütjohann, Dieter; Randolph, Gwendalyn J.; Levine, Ross L.; Tall, Alan R.

2013-01-01

A high metabolic rate in myeloproliferative disorders is a common complication of neoplasms, but the underlying mechanisms are incompletely understood. Using three different mouse models of myeloproliferative disorders, including mice with defective cholesterol efflux pathways and two models based on expression of human leukemia disease alleles, we uncovered a mechanism by which proliferating and inflammatory myeloid cells take up and oxidize glucose during the feeding period, contributing to energy dissipation and subsequent loss of adipose mass. In vivo, lentiviral inhibition of Glut1 by shRNA prevented myeloproliferation and adipose tissue loss in mice with defective cholesterol efflux pathway in leukocytes. Thus, Glut1 was necessary to sustain proliferation and potentially divert glucose from fat storage. We also showed that overexpression of the human ApoA-I transgene to raise high-density lipoprotein (HDL) levels decreased Glut1 expression, dampened myeloproliferation, and prevented fat loss. These experiments suggest that inhibition of Glut-1 and HDL cholesterol–raising therapies could provide novel therapeutic approaches to treat the energy imbalance observed in myeloproliferative disorders. PMID:23319699

Cell Cycle Regulation of Stem Cells by MicroRNAs.

PubMed

Mens, Michelle M J; Ghanbari, Mohsen

2018-06-01

MicroRNAs (miRNAs) are a class of small non-coding RNA molecules involved in the regulation of gene expression. They are involved in the fine-tuning of fundamental biological processes such as proliferation, differentiation, survival and apoptosis in many cell types. Emerging evidence suggests that miRNAs regulate critical pathways involved in stem cell function. Several miRNAs have been suggested to target transcripts that directly or indirectly coordinate the cell cycle progression of stem cells. Moreover, previous studies have shown that altered expression levels of miRNAs can contribute to pathological conditions, such as cancer, due to the loss of cell cycle regulation. However, the precise mechanism underlying miRNA-mediated regulation of cell cycle in stem cells is still incompletely understood. In this review, we discuss current knowledge of miRNAs regulatory role in cell cycle progression of stem cells. We describe how specific miRNAs may control cell cycle associated molecules and checkpoints in embryonic, somatic and cancer stem cells. We further outline how these miRNAs could be regulated to influence cell cycle progression in stem cells as a potential clinical application.

Outage Probability of MRC for κ-μ Shadowed Fading Channels under Co-Channel Interference.

PubMed

Chen, Changfang; Shu, Minglei; Wang, Yinglong; Yang, Ming; Zhang, Chongqing

2016-01-01

In this paper, exact closed-form expressions are derived for the outage probability (OP) of the maximal ratio combining (MRC) scheme in the κ-μ shadowed fading channels, in which both the independent and correlated shadowing components are considered. The scenario assumes the received desired signals are corrupted by the independent Rayleigh-faded co-channel interference (CCI) and background white Gaussian noise. To this end, first, the probability density function (PDF) of the κ-μ shadowed fading distribution is obtained in the form of a power series. Then the incomplete generalized moment-generating function (IG-MGF) of the received signal-to-interference-plus-noise ratio (SINR) is derived in the closed form. By using the IG-MGF results, closed-form expressions for the OP of MRC scheme are obtained over the κ-μ shadowed fading channels. Simulation results are included to validate the correctness of the analytical derivations. These new statistical results can be applied to the modeling and analysis of several wireless communication systems, such as body centric communications.

Outage Probability of MRC for κ-μ Shadowed Fading Channels under Co-Channel Interference

PubMed Central

Chen, Changfang; Shu, Minglei; Wang, Yinglong; Yang, Ming; Zhang, Chongqing

2016-01-01

In this paper, exact closed-form expressions are derived for the outage probability (OP) of the maximal ratio combining (MRC) scheme in the κ-μ shadowed fading channels, in which both the independent and correlated shadowing components are considered. The scenario assumes the received desired signals are corrupted by the independent Rayleigh-faded co-channel interference (CCI) and background white Gaussian noise. To this end, first, the probability density function (PDF) of the κ-μ shadowed fading distribution is obtained in the form of a power series. Then the incomplete generalized moment-generating function (IG-MGF) of the received signal-to-interference-plus-noise ratio (SINR) is derived in the closed form. By using the IG-MGF results, closed-form expressions for the OP of MRC scheme are obtained over the κ-μ shadowed fading channels. Simulation results are included to validate the correctness of the analytical derivations. These new statistical results can be applied to the modeling and analysis of several wireless communication systems, such as body centric communications. PMID:27851817

Nonparametric Bayesian Dictionary Learning for Analysis of Noisy and Incomplete Images

PubMed Central

Zhou, Mingyuan; Chen, Haojun; Paisley, John; Ren, Lu; Li, Lingbo; Xing, Zhengming; Dunson, David; Sapiro, Guillermo; Carin, Lawrence

2013-01-01

Nonparametric Bayesian methods are considered for recovery of imagery based upon compressive, incomplete, and/or noisy measurements. A truncated beta-Bernoulli process is employed to infer an appropriate dictionary for the data under test and also for image recovery. In the context of compressive sensing, significant improvements in image recovery are manifested using learned dictionaries, relative to using standard orthonormal image expansions. The compressive-measurement projections are also optimized for the learned dictionary. Additionally, we consider simpler (incomplete) measurements, defined by measuring a subset of image pixels, uniformly selected at random. Spatial interrelationships within imagery are exploited through use of the Dirichlet and probit stick-breaking processes. Several example results are presented, with comparisons to other methods in the literature. PMID:21693421

Analysis of Autoregulation at the Level of Pre-mRNA Splicing of the Suppressor-of-White-Apricot Gene in Drosophila

PubMed Central

Zachar, Z.; Chou, T. B.; Kramer, J.; Mims, I. P.; Bingham, P. M.

1994-01-01

The Drosophila suppressor-of-white-apricot [su(w(a))] protein regulates/modulates at least two somatic RNA processing events. It is a potent regulator of its own expression. We report here new studies of this autoregulatory circuit. Among other things, our studies show the following. First, new evidence that su(w(a)) expression is autoregulated at the level of pre-mRNA splicing is reported. su(w(a)) protein represses accumulation of the fully spliced su(w(a)) mRNA encoding it and promotes accumulation of high levels of incompletely spliced su(w(a)) pre-mRNA. Second, the fully spliced su(w(a)) mRNA is sufficient for all known su(w(a)) genetic functions indicating that it encodes the sole su(w(a)) protein. Third, the incompletely spliced su(w(a)) pre-mRNAs resulting from autoregulation are not translated (probably as a result of nuclear retention) and apparently represent nonfunctional by-products. Fourth, the special circumstances of su(w(a)) expression during oogenesis allows maternal deposition exclusively of fully spliced su(w(a)) mRNA. Fifth, su(w(a)) protein immunolocalizes to nuclei consistent with its being a direct regulator of pre-mRNA processing. We discuss the implications of our results for mechanisms of splicing regulation and for developmental control of su(w(a)) expression. PMID:8056305

Nitric oxide–mediated regulation of ferroportin-1 controls macrophage iron homeostasis and immune function in Salmonella infection

PubMed Central

Nairz, Manfred; Schleicher, Ulrike; Schroll, Andrea; Sonnweber, Thomas; Theurl, Igor; Ludwiczek, Susanne; Talasz, Heribert; Brandacher, Gerald; Moser, Patrizia L.; Muckenthaler, Martina U.; Fang, Ferric C.; Bogdan, Christian

2013-01-01

Nitric oxide (NO) generated by inducible NO synthase 2 (NOS2) affects cellular iron homeostasis, but the underlying molecular mechanisms and implications for NOS2-dependent pathogen control are incompletely understood. In this study, we found that NO up-regulated the expression of ferroportin-1 (Fpn1), the major cellular iron exporter, in mouse and human cells. Nos2−/− macrophages displayed increased iron content due to reduced Fpn1 expression and allowed for an enhanced iron acquisition by the intracellular bacterium Salmonella typhimurium. Nos2 gene disruption or inhibition of NOS2 activity led to an accumulation of iron in the spleen and splenic macrophages. Lack of NO formation resulted in impaired nuclear factor erythroid 2-related factor-2 (Nrf2) expression, resulting in reduced Fpn1 transcription and diminished cellular iron egress. After infection of Nos2−/− macrophages or mice with S. typhimurium, the increased iron accumulation was paralleled by a reduced cytokine (TNF, IL-12, and IFN-γ) expression and impaired pathogen control, all of which were restored upon administration of the iron chelator deferasirox or hyperexpression of Fpn1 or Nrf2. Thus, the accumulation of iron in Nos2−/− macrophages counteracts a proinflammatory host immune response, and the protective effect of NO appears to partially result from its ability to prevent iron overload in macrophages PMID:23630227

Adult epidermal Notch activity induces dermal accumulation of T cells and neural crest derivatives through upregulation of jagged 1

PubMed Central

Ambler, Carrie A.; Watt, Fiona M.

2010-01-01

Notch signalling regulates epidermal differentiation and tumour formation via non-cell autonomous mechanisms that are incompletely understood. This study shows that epidermal Notch activation via a 4-hydroxy-tamoxifen-inducible transgene caused epidermal thickening, focal detachment from the underlying dermis and hair clumping. In addition, there was dermal accumulation of T lymphocytes and stromal cells, some of which localised to the blisters at the epidermal-dermal boundary. The T cell infiltrate was responsible for hair clumping but not for other Notch phenotypes. Notch-induced stromal cells were heterogeneous, expressing markers of neural crest, melanocytes, smooth muscle and peripheral nerve. Although Slug1 expression was expanded in the epidermis, the stromal cells did not arise through epithelial-mesenchymal transition. Epidermal Notch activation resulted in upregulation of jagged 1 in both epidermis and dermis. When Notch was activated in the absence of epidermal jagged 1, jagged 1 was not upregulated in the dermis, and epidermal thickening, blister formation, accumulation of T cells and stromal cells were inhibited. Gene expression profiling revealed that epidermal Notch activation resulted in upregulation of several growth factors and cytokines, including TNFα, the expression of which was dependent on epidermal jagged 1. We conclude that jagged 1 is a key mediator of non-cell autonomous Notch signalling in skin. PMID:20940224

MicroRNAs enriched in hematopoietic stem cells differentially regulate long-term hematopoietic output.

PubMed

O'Connell, Ryan M; Chaudhuri, Aadel A; Rao, Dinesh S; Gibson, William S J; Balazs, Alejandro B; Baltimore, David

2010-08-10

The production of blood cells depends on a rare hematopoietic stem-cell (HSC) population, but the molecular mechanisms underlying HSC biology remain incompletely understood. Here, we identify a subset of microRNAs (miRNAs) that is enriched in HSCs compared with other bone-marrow cells. An in vivo gain-of-function screen found that three of these miRNAs conferred a competitive advantage to engrafting hematopoietic cells, whereas other HSC miRNAs attenuated production of blood cells. Overexpression of the most advantageous miRNA, miR-125b, caused a dose-dependent myeloproliferative disorder that progressed to a lethal myeloid leukemia in mice and also enhanced hematopoietic engraftment in human immune system mice. Our study identifies an evolutionarily conserved subset of miRNAs that is expressed in HSCs and functions to modulate hematopoietic output.

Isgur-Karl model revisited

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

Galeta, Leonardo; Pirjol, Dan; Schat, Carlos

2009-12-01

We show how to match the Isgur-Karl model to the spin-flavor quark operator expansion used in the 1/N{sub c} studies of the nonstrange negative parity L=1 excited baryons. Using the transformation properties of states and interactions under the permutation group S{sub 3} we are able to express the operator coefficients as overlap integrals, without making any assumption on the spatial dependence of the quark wave functions. The general mass operator leads to parameter free mass relations and constraints on the mixing angles that are valid beyond the usual harmonic oscillator approximation. The Isgur-Karl model with harmonic oscillator wave functions providesmore » a simple counterexample that demonstrates explicitly that the alternative operator basis for the 1/N{sub c} expansion for excited baryons recently proposed by Matagne and Stancu is incomplete.« less

KLF6 contributes to myeloid cell plasticity in the pathogenesis of intestinal inflammation

PubMed Central

Goodman, Wendy A.; Omenetti, Sara; Date, Dipali; Di Martino, Luca; De Salvo, Carlo; Kim, Gun-Dong; Chowdhry, Saleem; Bamias, Giorgos; Cominelli, Fabio; Pizarro, Theresa T.; Mahabeleshwar, Ganapati H.

2016-01-01

Inflammatory bowel disease (IBD) is associated with dysregulated macrophage responses, such that quiescent macrophages acquire a pro-inflammatory activation state and contribute to chronic intestinal inflammation. The transcriptional events governing macrophage activation and gene expression in the context of chronic inflammation such as IBD remain incompletely understood. Here, we identify Kruppel-like transcription factor-6 (KLF6) as a critical regulator of pathogenic myeloid cell activation in human and experimental IBD. We found that KLF6 was significantly upregulated in myeloid cells and intestinal tissue from IBD patients and experimental models of IBD, particularly in actively inflamed regions of the colon. Using complementary gain- and loss-of-function studies, we observed that KLF6 promotes pro-inflammatory gene expression through enhancement of NFκB signaling, while simultaneously suppressing anti-inflammatory gene expression through repression of STAT3 signaling. To study the in vivo role of myeloid KLF6, we treated myeloid-specific KLF6-knockout mice (Mac-KLF6-KO) with dextran sulfate-sodium (DSS) and found that Mac-KLF6-KO mice were protected against chemically-induced colitis; this highlights the central role of myeloid KLF6 in promoting intestinal inflammation. Collectively, our results point to a novel gene regulatory program underlying pathogenic, pro-inflammatory macrophage activation in the setting of chronic intestinal inflammation. PMID:26838049

Downregulation of MicroRNA miR-526a by Enterovirus Inhibits RIG-I-Dependent Innate Immune Response

PubMed Central

Xu, Changzhi; He, Xiang; Zheng, Zirui; Zhang, Zhe; Wei, Congwen; Guan, Kai; Hou, Lihua; Zhang, Buchang; Zhu, Lin; Cao, Yuan; Zhang, Yanhong; Cao, Ye; Ma, Shengli; Wang, Penghao; Zhang, Pingping; Xu, Quanbin; Ling, Youguo

2014-01-01

ABSTRACT Retinoic acid-inducible gene I (RIG-I) is an intracellular RNA virus sensor that induces type I interferon-mediated host-protective innate immunity against viral infection. Although cylindromatosis (CYLD) has been shown to negatively regulate innate antiviral response by removing K-63-linked polyubiquitin from RIG-I, the regulation of its expression and the underlying regulatory mechanisms are still incompletely understood. Here we show that RIG-I activity is regulated by inhibition of CYLD expression mediated by the microRNA miR-526a. We found that viral infection specifically upregulates miR-526a expression in macrophages via interferon regulatory factor (IRF)-dependent mechanisms. In turn, miR-526a positively regulates virus-triggered type I interferon (IFN-I) production, thus suppressing viral replication, the underlying mechanism of which is the enhancement of RIG-I K63-linked ubiquitination by miR-526a via suppression of the expression of CYLD. Remarkably, virus-induced miR-526a upregulation and CYLD downregulation are blocked by enterovirus 71 (EV71) 3C protein, while ectopic miR-526a expression inhibits the replication of EV71 virus. The collective results of this study suggest a novel mechanism of the regulation of RIG-I activity during RNA virus infection by miR-526a and suggest a novel mechanism for the evasion of the innate immune response controlled by EV71. IMPORTANCE RNA virus infection upregulates the expression of miR-526a in macrophages through IRF-dependent pathways. In turn, miR-526a positively regulates virus-triggered type I IFN production and inhibits viral replication, the underlying mechanism of which is the enhancement of RIG-I K-63 ubiquitination by miR-526a via suppression of the expression of CYLD. Remarkably, virus-induced miR-526a upregulation and CYLD downregulation are blocked by enterovirus 71 (EV71) 3C protein; cells with overexpressed miR-526a were highly resistant to EV71 infection. The collective results of this study suggest a novel mechanism of the regulation of RIG-I activity during RNA virus infection by miR-526a and propose a novel mechanism for the evasion of the innate immune response controlled by EV71. PMID:25056901

A variant of nested dissection for solving n by n grid problems

NASA Technical Reports Server (NTRS)

George, A.; Poole, W. G., Jr.; Voigt, R. G.

1976-01-01

Nested dissection orderings are known to be very effective for solving the sparse positive definite linear systems which arise from n by n grid problems. In this paper nested dissection is shown to be the final step of incomplete nested dissection, an ordering which corresponds to the premature termination of dissection. Analyses of the arithmetic and storage requirements for incomplete nested dissection are given, and the ordering is shown to be competitive with nested dissection under certain conditions.

Revitalizing Personalized Medicine: Respecting Biomolecular Complexities Beyond Gene Expression

PubMed Central

Jayachandran, D; Ramkrishna, U; Skiles, J; Renbarger, J; Ramkrishna, D

2014-01-01

Despite recent advancements in “omic” technologies, personalized medicine has not realized its fullest potential due to isolated and incomplete application of gene expression tools. In many instances, pharmacogenomics is being interchangeably used for personalized medicine, when actually it is one of the many facets of personalized medicine. Herein, we highlight key issues that are hampering the advancement of personalized medicine and highlight emerging predictive tools that can serve as a decision support mechanism for physicians to personalize treatments. PMID:24739991

Chronic Ethanol consumption modulates growth factor release, mucosal cytokine production and microRNA expression in nonhuman primates

PubMed Central

Asquith, Mark; Pasala, Sumana; Engelmann, Flora; Haberthur, Kristen; Meyer, Christine; Park, Byung; Grant, Kathleen A.; Messaoudi, Ilhem

2013-01-01

BACKGROUND Chronic alcohol consumption has been associated with enhanced susceptibility to both systemic and mucosal infections. However, the exact mechanisms underlying this enhanced susceptibility remain incompletely understood. METHODS Using a nonhuman primate model of ethanol self-administration, we examined the impact of chronic alcohol exposure on immune homeostasis, cytokine and growth factor production in peripheral blood, lung and intestinal mucosa following twelve months of chronic ethanol exposure. RESULTS Ethanol exposure inhibited activation-induced production of growth factors HGF, G-CSF and VEGF by peripheral blood mononuclear cells (PBMC). Moreover, ethanol significantly reduced the frequency of colonic Th1 and Th17 cells in a dose-dependent manner. In contrast, we did not observe differences in lymphocyte frequency or soluble factor production in the lung of ethanol-consuming animals. To uncover mechanisms underlying reduced growth factor and Th1/Th17 cytokine production, we compared expression levels of microRNAs in PBMC and intestinal mucosa. Our analysis revealed ethanol-dependent upregulation of distinct microRNAs in affected tissues (miR-181a and miR-221 in PBMC; miR-155 in colon). Moreover, we were able to detect reduced expression of the transcription factors STAT3 and ARNT, which regulate expression of VEGF, G-CSF and HGF and contain targets for these microRNAs. To confirm and extend these observations, PBMC were transfected with either mimics or antagomirs of miR181 and 221and protein levels of the transcription factors and growth factors were determined. Transfection of microRNA mimics led to a reduction in both STAT-3/ARNT as well as VEGF/HGF/G-CSF levels. The opposite outcome was observed when microRNA antagomirs were transfected CONCLUSION Chronic ethanol consumption significantly disrupts both peripheral and mucosal immune homeostasis, and this dysregulation may be mediated by changes in microRNA expression. PMID:24329418

"Antelope": a hybrid-logic model checker for branching-time Boolean GRN analysis

PubMed Central

2011-01-01

Background In Thomas' formalism for modeling gene regulatory networks (GRNs), branching time, where a state can have more than one possible future, plays a prominent role. By representing a certain degree of unpredictability, branching time can model several important phenomena, such as (a) asynchrony, (b) incompletely specified behavior, and (c) interaction with the environment. Introducing more than one possible future for a state, however, creates a difficulty for ordinary simulators, because infinitely many paths may appear, limiting ordinary simulators to statistical conclusions. Model checkers for branching time, by contrast, are able to prove properties in the presence of infinitely many paths. Results We have developed Antelope ("Analysis of Networks through TEmporal-LOgic sPEcifications", http://turing.iimas.unam.mx:8080/AntelopeWEB/), a model checker for analyzing and constructing Boolean GRNs. Currently, software systems for Boolean GRNs use branching time almost exclusively for asynchrony. Antelope, by contrast, also uses branching time for incompletely specified behavior and environment interaction. We show the usefulness of modeling these two phenomena in the development of a Boolean GRN of the Arabidopsis thaliana root stem cell niche. There are two obstacles to a direct approach when applying model checking to Boolean GRN analysis. First, ordinary model checkers normally only verify whether or not a given set of model states has a given property. In comparison, a model checker for Boolean GRNs is preferable if it reports the set of states having a desired property. Second, for efficiency, the expressiveness of many model checkers is limited, resulting in the inability to express some interesting properties of Boolean GRNs. Antelope tries to overcome these two drawbacks: Apart from reporting the set of all states having a given property, our model checker can express, at the expense of efficiency, some properties that ordinary model checkers (e.g., NuSMV) cannot. This additional expressiveness is achieved by employing a logic extending the standard Computation-Tree Logic (CTL) with hybrid-logic operators. Conclusions We illustrate the advantages of Antelope when (a) modeling incomplete networks and environment interaction, (b) exhibiting the set of all states having a given property, and (c) representing Boolean GRN properties with hybrid CTL. PMID:22192526

Minimax Rate-optimal Estimation of High-dimensional Covariance Matrices with Incomplete Data*

PubMed Central

Cai, T. Tony; Zhang, Anru

2016-01-01

Missing data occur frequently in a wide range of applications. In this paper, we consider estimation of high-dimensional covariance matrices in the presence of missing observations under a general missing completely at random model in the sense that the missingness is not dependent on the values of the data. Based on incomplete data, estimators for bandable and sparse covariance matrices are proposed and their theoretical and numerical properties are investigated. Minimax rates of convergence are established under the spectral norm loss and the proposed estimators are shown to be rate-optimal under mild regularity conditions. Simulation studies demonstrate that the estimators perform well numerically. The methods are also illustrated through an application to data from four ovarian cancer studies. The key technical tools developed in this paper are of independent interest and potentially useful for a range of related problems in high-dimensional statistical inference with missing data. PMID:27777471

Minimax Rate-optimal Estimation of High-dimensional Covariance Matrices with Incomplete Data.

PubMed

Cai, T Tony; Zhang, Anru

2016-09-01

Missing data occur frequently in a wide range of applications. In this paper, we consider estimation of high-dimensional covariance matrices in the presence of missing observations under a general missing completely at random model in the sense that the missingness is not dependent on the values of the data. Based on incomplete data, estimators for bandable and sparse covariance matrices are proposed and their theoretical and numerical properties are investigated. Minimax rates of convergence are established under the spectral norm loss and the proposed estimators are shown to be rate-optimal under mild regularity conditions. Simulation studies demonstrate that the estimators perform well numerically. The methods are also illustrated through an application to data from four ovarian cancer studies. The key technical tools developed in this paper are of independent interest and potentially useful for a range of related problems in high-dimensional statistical inference with missing data.

An Examination of Factors and Attitudes that Influence Reporting Fraudulent Claims in an Academic Environment

ERIC Educational Resources Information Center

Carmichael, Anna M.; Krueger, Lacy E.

2014-01-01

The study examined potential factors and attitudes associated with providing fraudulent academic claims. A total of 319 students completed an online survey which involved reading a vignette about an incomplete assignment. Participants reported whether they would contact their instructor to gain an extension, expressed their confidence in the…

Design and Implementation of Technology Enabled Affective Learning Using Fusion of Bio-Physical and Facial Expression

ERIC Educational Resources Information Center

Ray, Arindam; Chakrabarti, Amlan

2016-01-01

Technology Enabled Learning is a cognitive, constructive, systematic, collaborative learning procedure, which transforms teaching-learning pedagogy where role of emotion is very often neglected. Emotion plays significant role in the cognitive process of human being, so the transformation is incomplete without capturing the learner's emotional…

Genome-wide association identifies a deletion in the 3’ untranslated region of Striatin in a canine model of arrhythmogenic right ventricular cardiomyopathy

USDA-ARS?s Scientific Manuscript database

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial cardiac disease characterized by rapid ventricular tachycardia and sudden cardiac death. It is most frequently inherited as an autosomal dominant trait with incomplete and age-related penetrance and variable clinical expression. Th...

Quantifying structural uncertainty on fault networks using a marked point process within a Bayesian framework

NASA Astrophysics Data System (ADS)

Aydin, Orhun; Caers, Jef Karel

2017-08-01

Faults are one of the building-blocks for subsurface modeling studies. Incomplete observations of subsurface fault networks lead to uncertainty pertaining to location, geometry and existence of faults. In practice, gaps in incomplete fault network observations are filled based on tectonic knowledge and interpreter's intuition pertaining to fault relationships. Modeling fault network uncertainty with realistic models that represent tectonic knowledge is still a challenge. Although methods that address specific sources of fault network uncertainty and complexities of fault modeling exists, a unifying framework is still lacking. In this paper, we propose a rigorous approach to quantify fault network uncertainty. Fault pattern and intensity information are expressed by means of a marked point process, marked Strauss point process. Fault network information is constrained to fault surface observations (complete or partial) within a Bayesian framework. A structural prior model is defined to quantitatively express fault patterns, geometries and relationships within the Bayesian framework. Structural relationships between faults, in particular fault abutting relations, are represented with a level-set based approach. A Markov Chain Monte Carlo sampler is used to sample posterior fault network realizations that reflect tectonic knowledge and honor fault observations. We apply the methodology to a field study from Nankai Trough & Kumano Basin. The target for uncertainty quantification is a deep site with attenuated seismic data with only partially visible faults and many faults missing from the survey or interpretation. A structural prior model is built from shallow analog sites that are believed to have undergone similar tectonics compared to the site of study. Fault network uncertainty for the field is quantified with fault network realizations that are conditioned to structural rules, tectonic information and partially observed fault surfaces. We show the proposed methodology generates realistic fault network models conditioned to data and a conceptual model of the underlying tectonics.

STAT3 Knockdown Reduces Pancreatic Cancer Cell Invasiveness and Matrix Metalloproteinase-7 Expression in Nude Mice

PubMed Central

Huang, Ke jian; Wu, Wei dong; Jiang, Tao; Cao, Jun; Feng, Zhen zhong; Qiu, Zheng jun

2011-01-01

Aims Transducer and activator of transcription-3 (STAT3) plays an important role in tumor cell invasion and metastasis. The aim of the present study was to investigate the effects of STAT3 knockdown in nude mouse xenografts of pancreatic cancer cells and underlying gene expression. Methods A STAT3 shRNA lentiviral vector was constructed and infected into SW1990 cells. qRT-PCR and western immunoblot were performed to detect gene expression. Nude mouse xenograft assays were used to assess changes in phenotypes of these stable cells in vivo. HE staining was utilized to evaluate tumor cell invasion and immunohistochemistry was performed to analyze gene expression. Results STAT3 shRNA successfully silenced expression of STAT3 mRNA and protein in SW1990 cells compared to control cells. Growth rate of the STAT3-silenced tumor cells in nude mice was significantly reduced compared to in the control vector tumors and parental cells-generated tumors. Tumor invasion into the vessel and muscle were also suppressed in the STAT3-silenced tumors compared to controls. Collagen IV expression was complete and continuous surrounding the tumors of STAT3-silenced SW1990 cells, whereas collagen IV expression was incomplete and discontinuous surrounding the control tumors. Moreover, microvessel density was significantly lower in STAT3-silenced tumors than parental or control tumors of SW1990 cells. In addition, MMP-7 expression was reduced in STAT3-silenced tumors compared to parental SW1990 xenografts and controls. In contrast, expression of IL-1β and IgT7α was not altered. Conclusion These data clearly demonstrate that STAT3 plays an important role in regulation of tumor growth, invasion, and angiogenesis, which could be act by reducing MMP-7 expression in pancreatic cancer cells. PMID:21991388

Novel strategies to enforce an epithelial phenotype in mesenchymal cells

PubMed Central

Dragoi, Ana-Maria; Swiss, Rachel; Gao, Beile; Agaisse, Hervé

2014-01-01

E-cadherin downregulation in cancer cells is associated with epithelial-to-mesenchymal transition (EMT) and metastatic prowess, but the underlying mechanisms are incompletely characterized. In this study, we probed E-cadherin expression at the plasma membrane as a functional assay to identify genes involved in E-cadherin downregulation. The assay was based on the E-cadherin-dependent invasion properties of the intracellular pathogen Listeria monocytogenes. On the basis of a functional readout, automated microscopy and computer-assisted image analysis were used to screen siRNAs targeting 7,000 human genes. The validity of the screen was supported by its definion of several known regulators of E-cadherin expression, including ZEB1, HDAC1 and MMP14. We identified three new regulators (FLASH, CASP7 and PCGF1), the silencing of which was sufficient to restore high levels of E-cadherin transcription. Additionally, we identified two new regulators (FBXL5 and CAV2), the silencing of which was sufficient to increase E-cadherin expression at a post-transcriptional level. FLASH silencing regulated the expression of E-cadherin and other ZEB1-dependent genes, through post-transcriptional regulation of ZEB1, but it also regulated the expression of numerous ZEB1-independent genes with functions predicted to contribute to a restoration of the epithelial phenotype. Finally, we also report the identification of siRNA duplexes that potently restored the epithelial phenotype by mimicking the activity of known and putative microRNAs. Our findings suggest new ways to enforce epithelial phenotypes as a general strategy to treat cancer by blocking invasive and metastatic phenotypes associated with EMT. PMID:24845104

Deletion of the miR-143/145 Cluster Leads to Hydronephrosis in Mice

PubMed Central

Medrano, Silvia; Sequeira-Lopez, Maria Luisa S.; Gomez, R. Ariel

2015-01-01

Obstructive nephropathy, the leading cause of kidney failure in children, can be anatomic or functional. The underlying causes of functional hydronephrosis are not well understood. miRNAs, which are small noncoding RNAs, regulate gene expression at the post-transcriptional level. We found that miR-145-5p, a member of the miR-143/145 cluster that is highly expressed in smooth muscle cells of the renal vasculature, was present in the pelvicalyceal system and the ureter. To evaluate whether the miR-143/145 cluster is involved in urinary tract function we performed morphologic, functional, and gene expression studies in mice carrying a whole-body deletion of miR-143/145. miR-143/145–deficient mice developed hydronephrosis, characterized by severe papillary atrophy and dilatation of the pelvicalyceal system without obvious physical obstruction. Moreover, mutant mice showed abnormal ureteral peristalsis. The number of ureter contractions was significantly higher in miR-143/145–deficient mice. Peristalsis was replaced by incomplete, short, and more frequent contractions that failed to completely propagate in a proximal-distal direction. Microarray analysis showed 108 differentially expressed genes in ureters of miR-143/145–deficient mice. Ninety genes were up-regulated and 18 genes were down-regulated, including genes with potential regulatory roles in smooth muscle contraction and extracellular matrix-receptor interaction. We show that miR-143/145 are important for the normal peristalsis of the ureter and report an association between the expression of these miRNAs and hydronephrosis. PMID:25307343

Substance-specific importance of EGFR for vascular smooth muscle cells motility in primary culture.

PubMed

Schreier, Barbara; Schwerdt, Gerald; Heise, Christian; Bethmann, Daniel; Rabe, Sindy; Mildenberger, Sigrid; Gekle, Michael

2016-07-01

Besides their importance for the vascular tone, vascular smooth muscle cells (VSMC) also contribute to pathophysiological vessel alterations. Various G-protein coupled receptor ligands involved in vascular dysfunction and remodeling can transactivate the epidermal growth factor receptor (EGFR) of VSMC, yet the importance of EGFR transactivation for the VSMC phenotype is incompletely understood. The aims of this study were (i) to characterize further the importance of the VSMC-EGFR for proliferation, migration and marker gene expression for inflammation, fibrosis and reactive oxygen species (ROS) homeostasis and (ii) to test the hypothesis that vasoactive substances (endothelin-1, phenylephrine, thrombin, vasopressin and ATP) rely differentially on the EGFR with respect to the abovementioned phenotypic alterations. In primary, aortic VSMC from mice without conditional deletion of the EGFR, proliferation, migration, marker gene expression (inflammation, fibrosis and ROS homeostasis) and cell signaling (ERK 1/2, intracellular calcium) were analyzed. VSMC-EGFR loss reduced collective cell migration and single cell migration probability, while no difference between the genotypes in single cell velocity, chemotaxis or marker gene expression could be observed under control conditions. EGF promoted proliferation, collective cell migration, chemokinesis and chemotaxis and leads to a proinflammatory gene expression profile in wildtype but not in knockout VSMC. Comparing the impact of five vasoactive substances (all reported to transactivate EGFR and all leading to an EGFR dependent increase in ERK1/2 phosphorylation), we demonstrate that the importance of EGFR for their action is substance-dependent and most apparent for crowd migration but plays a minor role for gene expression regulation. Copyright © 2016 Elsevier B.V. All rights reserved.

miR-125b is downregulated in systemic lupus erythematosus patients and inhibits autophagy by targeting UVRAG.

PubMed

Cao, Wenting; Qian, Ge; Luo, Wen; Liu, Xin; Pu, Yunjing; Hu, Guilan; Han, Lulu; Yuan, Limei; A, Xiao; Deng, Danqi

2018-03-01

Systemic lupus erythematosus (SLE) is a severe autoimmune disease and the pathogenesis remains incompletely understood. This study aimed to investigate the role of miR-125b in the pathogenesis of SLE and explore the underlying mechanism. Compared to healthy controls, the expression of miR-125b decreased in peripheral blood mononuclear cells (PBMCs) of SLE patients. In addition, PBMCs exposed to ultraviolet B had lower miR-125b level compared to those unexposed to radiation. We identified UV radiation resistance associated gene (UVRAG) as a target of miR-125b. Jurkat cells treated with miR-125b-5p agomir showed reduced levels of ATG7, Beclin-1 and LC3 II and decreased autophagy. In contrast, Jurkat cells treated with miR-125b-5p antagomir showed increased levels of ATG7, Beclin-1 and LC3 II and increased autophagy. Furthermore, Jurkat cells transfected with UVRAG expression vector showed higher expression of ATG7, Beclin-1 and LC3 II and increased autophagy. Conversely, cells transfected with UVRAG siRNA had lower expression of ATG7, Beclin-1 and LC3 II and decreased autophagy. Taken together, our data demonstrate that Ultraviolet B radiation can downregulate miR-125b-5p and increase UVRAG expression and autophagy activity in PBMCs of SLE patients. These findings help explain how ultraviolet B exacerbates SLE and suggest that UVRAG is a potential therapeutic target for SLE. Copyright © 2018. Published by Elsevier Masson SAS.

Non-input analysis for incomplete trapping irreversible tracer with PET.

PubMed

Ohya, Tomoyuki; Kikuchi, Tatsuya; Fukumura, Toshimitsu; Zhang, Ming-Rong; Irie, Toshiaki

2013-07-01

When using metabolic trapping type tracers, the tracers are not always trapped in the target tissue; i.e., some are completely trapped in the target, but others can be eliminated from the target tissue at a measurable rate. The tracers that can be eliminated are termed 'incomplete trapping irreversible tracers'. These incomplete trapping irreversible tracers may be clinically useful when the tracer β-value, the ratio of the tracer (metabolite) elimination rate to the tracer efflux rate, is under approximately 0.1. In this study, we propose a non-input analysis for incomplete trapping irreversible tracers based on the shape analysis (Shape), a non-input analysis used for irreversible tracers. A Monte Carlo simulation study based on experimental monkey data with two actual PET tracers (a complete trapping irreversible tracer [(11)C]MP4A and an incomplete trapping irreversible tracer [(18)F]FEP-4MA) was performed to examine the effects of the environmental error and the tracer elimination rate on the estimation of the k3-parameter (corresponds to metabolic rate) using Shape (original) and modified Shape (M-Shape) analysis. The simulation results were also compared with the experimental results obtained with the two PET tracers. When the tracer β-value was over 0.03, the M-Shape method was superior to the Shape method for the estimation of the k3-parameter. The simulation results were also in reasonable agreement with the experimental ones. M-Shape can be used as the non-input analysis of incomplete trapping irreversible tracers for PET study. Copyright © 2013 Elsevier Inc. All rights reserved.

Incomplete Infection of Secondarily Infected Potato Plants – an Environment Dependent Underestimated Mechanism in Plant Virology

PubMed Central

Bertschinger, Lukas; Bühler, Lukas; Dupuis, Brice; Duffy, Brion; Gessler, Cesare; Forbes, Gregory A.; Keller, Ernst R.; Scheidegger, Urs C.; Struik, Paul C.

2017-01-01

The common assumption in potato virus epidemiology is that all daughter tubers produced by plants coming from infected mother tubers (secondary infection) will become infected via systemic translocation of the virus during growth. We hypothesize that depending on the prevalent environmental conditions, only a portion of the daughter tubers of a plant that is secondarily infected by viruses may become infected. To test this hypothesis experimental data from standardized field experiments were produced in three contrasting environments at 112, 3280, and 4000 m a.s.l. in Peru during two growing seasons. In these experiments, the percentage of infected daughter tubers produced by seed tubers that were infected with either potato potexvirus X (PVX), potato Andean mottle comovirus (APMoV), potato potyvirus Y (PVY) (jointly infected with PVX) or potato leafroll luteovirus (PLRV) was determined. Incomplete autoinfection was found in all cases, as the percentage of virus infected daughter tubers harvested from secondarily infected plants was invariably less than 100%, with the lowest percentage of infection being 30%. Changing the growing site to higher altitudes decreased autoinfection for all viruses. Therefore, the assumption of complete autoinfection of secondarily infected plants were rejected, while the hypothesis of environmentally dependent incomplete autoinfection was accepted. The findings help explain the occurrence of traditional seed management practices in the Andes and may help to develop locally adapted seed systems in environments of the world that have no steady access to healthy seed tubers coming from a formally certified seed system. The results obtained almost three decades ago are discussed in light of most recent knowledge on epigenetic regulation of host plant – virus interactions which allow for speculating about the underlying biological principles of the incomplete autoinfection. A research roadmap is proposed for achieving explicit experimental proof for the epigenetic regulation of incomplete autoinfection in the pathosystem under study. PMID:28217131

Regulation of adipose branched-chain amin acid catabolism enzyme expression and cross-adipose amino acid flux in human obesity

USDA-ARS?s Scientific Manuscript database

Elevated blood branched-chain amin acids (BCAA)are often assoicated with insulin resistance and type2 diabetes, which might result from a reduced cellular utilization and/or incomplete BCAA oxidation. White adipose tissue (WAT) has become appreciated as a potential player in whole body BCAA metaboli...

Children's Drawings--Resource for Development and Observation of Perception of Numbers of Children

ERIC Educational Resources Information Center

Pavlovicová, Gabriela; Švecová, Valéria

2011-01-01

Children's drawings are one of the most appropriate approach to knowing children, their individuality and also their perceptions. Child is not always able to express their thoughts precisely, because their vocabulary is still incomplete and is gained just lately. In our paper we concentrate on drawing as a communication means, with which we can…

A role for nephrin, a renal protein, in vertebrate skeletal muscle cell fusion

PubMed Central

Sohn, Regina Lee; Huang, Ping; Kawahara, Genri; Mitchell, Matthew; Guyon, Jeffrey; Kalluri, Raghu; Kunkel, Louis M.; Gussoni, Emanuela

2009-01-01

Skeletal muscle is formed via fusion of myoblasts, a well-studied process in Drosophila. In vertebrates however, this process is less well understood, and whether there is evolutionary conservation with the proteins studied in flies is under investigation. Sticks and stones (Sns), a cell surface protein found on Drosophila myoblasts, has structural homology to nephrin. Nephrin is a protein expressed in kidney that is part of the filtration barrier formed by podocytes. No previous study has established any role for nephrin in skeletal muscle. We show, using two models, zebrafish and mice, that the absence of nephrin results in poorly developed muscles and incompletely fused myotubes, respectively. Although nephrin-knockout (nephrinKO) myoblasts exhibit prolonged activation of MAPK/ERK pathway during myogenic differentiation, expression of myogenin does not seem to be altered. Nevertheless, MAPK pathway blockade does not rescue myoblast fusion. Co-cultures of unaffected human fetal myoblasts with nephrinKO myoblasts or myotubes restore the formation of mature myotubes; however, the contribution of nephrinKO myoblasts is minimal. These studies suggest that nephrin plays a role in secondary fusion of myoblasts into nascent myotubes, thus establishing a possible functional conservation with Drosophila Sns. PMID:19470472

Inhibition of TRPC3 downregulates airway hyperresponsiveness, remodeling of OVA-sensitized mouse.

PubMed

Wang, Lingwei; Li, Jie; Zhang, Jian; He, Qi; Weng, Xuanwen; Huang, Yanmei; Guan, Minjie; Qiu, Chen

2017-02-26

Airway hyperresponsiveness (AHR), airway remodeling and inflammation are the fundamental pathological alterations that occur in asthma. Transient receptor potential canonical 3 (TRPC3) has been implicated in diverse functions of airway smooth muscle cells (ASMCs) in asthma. However, the underlying mechanisms remain incompletely understood. We investigated the mRNA and protein expression of TRPC3 in ASMCs from normal and OVA-sensitized mouse. And the effects of inhibition or knockdown of TRPC3 with Ethyl-1- (4- (2,3,3-trichloroacrylamide) phenyl) -5 - (trifluoromethyl) -1H -pyrazole -4-carboxylate (Pyr3) and lentiviral shRNA on OVA-sensitized mouse AHR, airway remodeling, circulating inflammatory cytokines, cell proliferation and migration. We found that TRPC3 mRNA and protein expression levels were significantly increased in ASMCs from OVA-sensitized mouse. Inhibiting TRPC3 with continuous subcutaneous administration of Pyr3 decreased enhanced pause (Penh) of OVA-sensitized mouse. Meanwhile, both Pyr3 and lentiviral shRNA treatment of ASMCs in OVA-sensitized mouse significantly decreased their proliferation and migration. These results suggest that TRPC3 plays a critical role in asthma and represents a promising new target for asthma treatment. Copyright © 2016 Elsevier Inc. All rights reserved.

AML1-ETO requires enhanced C/D box snoRNA/RNP formation to induce self-renewal and leukaemia.

PubMed

Zhou, Fengbiao; Liu, Yi; Rohde, Christian; Pauli, Cornelius; Gerloff, Dennis; Köhn, Marcel; Misiak, Danny; Bäumer, Nicole; Cui, Chunhong; Göllner, Stefanie; Oellerich, Thomas; Serve, Hubert; Garcia-Cuellar, Maria-Paz; Slany, Robert; Maciejewski, Jaroslaw P; Przychodzen, Bartlomiej; Seliger, Barbara; Klein, Hans-Ulrich; Bartenhagen, Christoph; Berdel, Wolfgang E; Dugas, Martin; Taketo, Makoto Mark; Farouq, Daneyal; Schwartz, Schraga; Regev, Aviv; Hébert, Josée; Sauvageau, Guy; Pabst, Caroline; Hüttelmaier, Stefan; Müller-Tidow, Carsten

2017-07-01

Leukaemogenesis requires enhanced self-renewal, which is induced by oncogenes. The underlying molecular mechanisms remain incompletely understood. Here, we identified C/D box snoRNAs and rRNA 2'-O-methylation as critical determinants of leukaemic stem cell activity. Leukaemogenesis by AML1-ETO required expression of the groucho-related amino-terminal enhancer of split (AES). AES functioned by inducing snoRNA/RNP formation via interaction with the RNA helicase DDX21. Similarly, global loss of C/D box snoRNAs with concomitant loss of rRNA 2'-O-methylation resulted in decreased leukaemia self-renewal potential. Genomic deletion of either C/D box snoRNA SNORD14D or SNORD35A suppressed clonogenic potential of leukaemia cells in vitro and delayed leukaemogenesis in vivo. We further showed that AML1-ETO9a, MYC and MLL-AF9 all enhanced snoRNA formation. Expression levels of C/D box snoRNAs in AML patients correlated closely with in vivo frequency of leukaemic stem cells. Collectively, these findings indicate that induction of C/D box snoRNA/RNP function constitutes an important pathway in leukaemogenesis.

Towards Using Reo for Compliance-Aware Business Process Modeling

NASA Astrophysics Data System (ADS)

Arbab, Farhad; Kokash, Natallia; Meng, Sun

Business process modeling and implementation of process supporting infrastructures are two challenging tasks that are not fully aligned. On the one hand, languages such as Business Process Modeling Notation (BPMN) exist to capture business processes at the level of domain analysis. On the other hand, programming paradigms and technologies such as Service-Oriented Computing (SOC) and web services have emerged to simplify the development of distributed web systems that underly business processes. BPMN is the most recognized language for specifying process workflows at the early design steps. However, it is rather declarative and may lead to the executable models which are incomplete or semantically erroneous. Therefore, an approach for expressing and analyzing BPMN models in a formal setting is required. In this paper we describe how BPMN diagrams can be represented by means of a semantically precise channel-based coordination language called Reo which admits formal analysis using model checking and bisimulation techniques. Moreover, since additional requirements may come from various regulatory/legislative documents, we discuss the opportunities offered by Reo and its mathematical abstractions for expressing process-related constraints such as Quality of Service (QoS) or time-aware conditions on process states.

BIM-23A760 influences key functional endpoints in pituitary adenomas and normal pituitaries: molecular mechanisms underlying the differential response in adenomas

PubMed Central

Ibáñez-Costa, Alejandro; López-Sánchez, Laura M.; Gahete, Manuel D.; Rivero-Cortés, Esther; Vázquez-Borrego, Mari C.; Gálvez, María A.; de la Riva, Andrés; Venegas-Moreno, Eva; Jiménez-Reina, Luis; Moreno-Carazo, Alberto; Tinahones, Francisco J.; Maraver-Selfa, Silvia; Japón, Miguel A.; García-Arnés, Juan A.; Soto-Moreno, Alfonso; Webb, Susan M.; Kineman, Rhonda D.; Culler, Michael D.; Castaño, Justo P.; Luque, Raúl M.

2017-01-01

Chimeric somatostatin/dopamine compounds such as BIM-23A760, an sst2/sst5/D2 receptors-agonist, have emerged as promising new approaches to treat pituitary adenomas. However, information on direct in vitro effects of BIM-23A760 in normal and tumoral pituitaries remains incomplete. The objective of this study was to analyze BIM-23A760 effects on functional parameters (Ca2+ signaling, hormone expression/secretion, cell viability and apoptosis) in pituitary adenomas (n = 74), and to compare with the responses of normal primate and human pituitaries (n = 3–5). Primate and human normal pituitaries exhibited similar sst2/sst5/D2 expression patterns, wherein BIM-23A760 inhibited the expression/secretion of several pituitary hormones (specially GH/PRL), which was accompanied by increased sst2/sst5/D2 expression in primates and decreased Ca2+ concentration in human cells. In tumoral pituitaries, BIM-23A760 also inhibited Ca2+ concentration, hormone secretion/expression and proliferation. However, BIM-23A760 elicited stimulatory effects in a subset of GHomas, ACTHomas and NFPAs in terms of Ca2+ signaling and/or hormone secretion, which was associated with the relative somatostatin/dopamine-receptors levels, especially sst5 and sst5TMD4. The chimeric sst2/sst5/D2 compound BIM-23A760 affects multiple, clinically relevant parameters on pituitary adenomas and may represent a valuable therapeutic tool. The relative ssts/D2 expression profile, particularly sst5 and/or sst5TMD4 levels, might represent useful molecular markers to predict the ultimate response of pituitary adenomas to BIM-23A760. PMID:28181484

Stress alters the expression of cancer-related genes in the prostate.

PubMed

Flores, Ivan E; Sierra-Fonseca, Jorge A; Davalos, Olinamyr; Saenz, Luis A; Castellanos, Maria M; Zavala, Jaidee K; Gosselink, Kristin L

2017-09-05

Prostate cancer is a major contributor to mortality worldwide, and significant efforts are being undertaken to decipher specific cellular and molecular pathways underlying the disease. Chronic stress is known to suppress reproductive function and promote tumor progression in several cancer models, but our understanding of the mechanisms through which stress contributes to cancer development and progression is incomplete. We therefore examined the relationship between stress, modulation of the gonadotropin-releasing hormone (GnRH) system, and changes in the expression of cancer-related genes in the rat prostate. Adult male rats were acutely or repeatedly exposed to restraint stress, and compared to unstressed controls and groups that were allowed 14 days of recovery from the stress. Prostate tissue was collected and frozen for gene expression analyses by PCR array before the rats were transcardially perfused; and brain tissues harvested and immunohistochemically stained for Fos to determine neuronal activation. Acute stress elevated Fos expression in the paraventricular nucleus of the hypothalamus (PVH), an effect that habituated with repeated stress exposure. Data from the PCR arrays showed that repeated stress significantly increases the transcript levels of several genes associated with cellular proliferation, including proto-oncogenes. Data from another array platform showed that both acute and repeated stress can induce significant changes in metastatic gene expression. The functional diversity of genes with altered expression, which includes transcription factors, growth factor receptors, apoptotic genes, and extracellular matrix components, suggests that stress is able to induce aberrant changes in pathways that are deregulated in prostate cancer. Our findings further support the notion that stress can affect cancer outcomes, perhaps by interfering with neuroendocrine mechanisms involved in the control of reproduction.

BIM-23A760 influences key functional endpoints in pituitary adenomas and normal pituitaries: molecular mechanisms underlying the differential response in adenomas.

PubMed

Ibáñez-Costa, Alejandro; López-Sánchez, Laura M; Gahete, Manuel D; Rivero-Cortés, Esther; Vázquez-Borrego, Mari C; Gálvez, María A; de la Riva, Andrés; Venegas-Moreno, Eva; Jiménez-Reina, Luis; Moreno-Carazo, Alberto; Tinahones, Francisco J; Maraver-Selfa, Silvia; Japón, Miguel A; García-Arnés, Juan A; Soto-Moreno, Alfonso; Webb, Susan M; Kineman, Rhonda D; Culler, Michael D; Castaño, Justo P; Luque, Raúl M

2017-02-09

Chimeric somatostatin/dopamine compounds such as BIM-23A760, an sst2/sst5/D 2 receptors-agonist, have emerged as promising new approaches to treat pituitary adenomas. However, information on direct in vitro effects of BIM-23A760 in normal and tumoral pituitaries remains incomplete. The objective of this study was to analyze BIM-23A760 effects on functional parameters (Ca 2+ signaling, hormone expression/secretion, cell viability and apoptosis) in pituitary adenomas (n = 74), and to compare with the responses of normal primate and human pituitaries (n = 3-5). Primate and human normal pituitaries exhibited similar sst2/sst5/D2 expression patterns, wherein BIM-23A760 inhibited the expression/secretion of several pituitary hormones (specially GH/PRL), which was accompanied by increased sst2/sst5/D2 expression in primates and decreased Ca 2+ concentration in human cells. In tumoral pituitaries, BIM-23A760 also inhibited Ca 2+ concentration, hormone secretion/expression and proliferation. However, BIM-23A760 elicited stimulatory effects in a subset of GHomas, ACTHomas and NFPAs in terms of Ca 2+ signaling and/or hormone secretion, which was associated with the relative somatostatin/dopamine-receptors levels, especially sst5 and sst5TMD4. The chimeric sst2/sst5/D 2 compound BIM-23A760 affects multiple, clinically relevant parameters on pituitary adenomas and may represent a valuable therapeutic tool. The relative ssts/D 2 expression profile, particularly sst5 and/or sst5TMD4 levels, might represent useful molecular markers to predict the ultimate response of pituitary adenomas to BIM-23A760.

Reactant conversion in homogeneous turbulence: Mathematical modeling, computational validations and practical applications

NASA Technical Reports Server (NTRS)

Madnia, C. K.; Frankel, S. H.; Givi, P.

1992-01-01

Closed form analytical expressions are obtained for predicting the limited rate of reactant conversion in a binary reaction of the type F + rO yields (1 + r) Product in unpremixed homogeneous turbulence. These relations are obtained by means of a single point Probability Density Function (PDF) method based on the Amplitude Mapping Closure. It is demonstrated that with this model, the maximum rate of the reactants' decay can be conveniently expressed in terms of definite integrals of the Parabolic Cylinder Functions. For the cases with complete initial segregation, it is shown that the results agree very closely with those predicted by employing a Beta density of the first kind for an appropriately defined Shvab-Zeldovich scalar variable. With this assumption, the final results can also be expressed in terms of closed form analytical expressions which are based on the Incomplete Beta Functions. With both models, the dependence of the results on the stoichiometric coefficient and the equivalence ratio can be expressed in an explicit manner. For a stoichiometric mixture, the analytical results simplify significantly. In the mapping closure, these results are expressed in terms of simple trigonometric functions. For the Beta density model, they are in the form of Gamma Functions. In all the cases considered, the results are shown to agree well with data generated by Direct Numerical Simulations (DNS). Due to the simplicity of these expressions and because of nice mathematical features of the Parabolic Cylinder and the Incomplete Beta Functions, these models are recommended for estimating the limiting rate of reactant conversion in homogeneous reacting flows. These results also provide useful insights in assessing the extent of validity of turbulence closures in the modeling of unpremixed reacting flows. Some discussions are provided on the extension of the model for treating more complicated reacting systems including realistic kinetics schemes and multi-scalar mixing with finite rate chemical reactions in more complex configurations.

Global Dosage Compensation Is Ubiquitous in Lepidoptera, but Counteracted by the Masculinization of the Z Chromosome

PubMed Central

Huylmans, Ann Kathrin; Macon, Ariana; Vicoso, Beatriz

2017-01-01

Abstract While chromosome-wide dosage compensation of the X chromosome has been found in many species, studies in ZW clades have indicated that compensation of the Z is more localized and/or incomplete. In the ZW Lepidoptera, some species show complete compensation of the Z chromosome, while others lack full equalization, but what drives these inconsistencies is unclear. Here, we compare patterns of male and female gene expression on the Z chromosome of two closely related butterfly species, Papilio xuthus and Papilio machaon, and in multiple tissues of two moths species, Plodia interpunctella and Bombyx mori, which were previously found to differ in the extent to which they equalize Z-linked gene expression between the sexes. We find that, while some species and tissues seem to have incomplete dosage compensation, this is in fact due to the accumulation of male-biased genes and the depletion of female-biased genes on the Z chromosome. Once this is accounted for, the Z chromosome is fully compensated in all four species, through the up-regulation of Z expression in females and in some cases additional down-regulation in males. We further find that both sex-biased genes and Z-linked genes have increased rates of expression divergence in this clade, and that this can lead to fast shifts in patterns of gene expression even between closely related species. Taken together, these results show that the uneven distribution of sex-biased genes on sex chromosomes can confound conclusions about dosage compensation and that Z chromosome-wide dosage compensation is not only possible but ubiquitous among Lepidoptera. PMID:28957502

Central excitability contributes to supramaximal volitional contractions in human incomplete spinal cord injury

PubMed Central

Thompson, Christopher K; Lewek, Michael D; Jayaraman, Arun; Hornby, T George

2011-01-01

Abstract Despite greater muscle fatigue in individuals with spinal cord injury (SCI) when compared to neurologically intact subjects using neuromuscular electrical stimulation (NMES) protocols, few studies have investigated the extent of volitional fatigue in motor incomplete SCI. Using an established protocol of 20 repeated, intermittent, maximal volitional effort (MVE) contractions, we previously demonstrated that subjects with incomplete SCI unexpectedly demonstrated a 15% increase in peak knee extensor torques within the first five MVEs with minimal evidence of fatigue after 20 contraction. In the present study, we investigated potential segmental mechanisms underlying this supramaximal torque generation. Changes in twitch properties and maximum compound muscle action potentials (M-waves) were assessed prior to and following one, three and five MVEs, revealing a significant 17% increase only in maximum twitch torques after a single MVE. Despite this post-activation potentiation of the muscle, use of conventional NMES protocols to elicit repeated muscular contractions resulted in a significant decrease in evoked torque generation, suggesting limited the muscular contributions to the observed phenomenon. To evaluate potential central mechanisms underlying the augmented torques, non-linear responses to wide-pulse width (1 ms), low-intensity, variable-frequency (25–100 Hz) NMES were also tested prior to and following repeated MVEs. When variable-frequency NMES was applied following the repeated MVEs, augmented and prolonged torques were observed and accompanied by sustained quadriceps electromyographic activity often lasting >2s after stimulus termination. Such data suggest a potential contribution of elevated spinal excitability to the reserve in volitional force generation in incomplete SCI. PMID:21610138

GW501516-activated PPARβ/δ promotes liver fibrosis via p38-JNK MAPK-induced hepatic stellate cell proliferation.

PubMed

Kostadinova, Radina; Montagner, Alexandra; Gouranton, Erwan; Fleury, Sébastien; Guillou, Hervé; Dombrowicz, David; Desreumaux, Pierre; Wahli, Walter

2012-10-10

After liver injury, the repair process comprises activation and proliferation of hepatic stellate cells (HSCs), which produce extracellular matrix (ECM) proteins. Peroxisome proliferator-activated receptor beta/delta (PPARβ/δ) is highly expressed in these cells, but its function in liver repair remains incompletely understood. This study investigated whether activation of PPARβ/δ with the ligand GW501516 influenced the fibrotic response to injury from chronic carbon tetrachloride (CCl4) treatment in mice. Wild type and PPARβ/δ-null mice were treated with CCl4 alone or CCl4 co-administered with GW501516. To unveil mechanisms underlying the PPARβ/δ-dependent effects, we analyzed the proliferative response of human LX-2 HSCs to GW501516 in the presence or absence of PPARβ/δ. We found that GW501516 treatment enhanced the fibrotic response. Compared to the other experimental groups, CCl4/GW501516-treated wild type mice exhibited increased expression of various profibrotic and pro-inflammatory genes, such as those involved in extracellular matrix deposition and macrophage recruitment. Importantly, compared to healthy liver, hepatic fibrotic tissues from alcoholic patients showed increased expression of several PPAR target genes, including phosphoinositide-dependent kinase-1, transforming growth factor beta-1, and monocyte chemoattractant protein-1. GW501516 stimulated HSC proliferation that caused enhanced fibrotic and inflammatory responses, by increasing the phosphorylation of p38 and c-Jun N-terminal kinases through the phosphoinositide-3 kinase/protein kinase-C alpha/beta mixed lineage kinase-3 pathway. This study clarified the mechanism underlying GW501516-dependent promotion of hepatic repair by stimulating proliferation of HSCs via the p38 and JNK MAPK pathways.

Suppression of c-Myc induces apoptosis via an AMPK/mTOR-dependent pathway by 4-O-methyl-ascochlorin in leukemia cells.

PubMed

Shin, Jae-Moon; Jeong, Yun-Jeong; Cho, Hyun-Ji; Magae, Junji; Bae, Young-Seuk; Chang, Young-Chae

2016-05-01

4-O-Methyl-ascochlorin (MAC) is a methylated derivative of the prenyl-phenol antibiotic ascochlorin, which was isolated from an incomplete fungus, Ascochyta viciae. Although the effects of MAC on apoptosis have been reported, the underlying mechanisms remain unknown. Here, we show that MAC promoted apoptotic cell death and downregulated c-Myc expression in K562 human leukemia cells. The effect of MAC on apoptosis was similar to that of 10058-F4 (a c-Myc inhibitor) or c-Myc siRNA, suggesting that the downregulation of c-Myc expression plays a role in the apoptotic effect of MAC. Further investigation showed that MAC downregulated c-Myc by inhibiting protein synthesis. MAC promoted the phosphorylation of AMP-activated protein kinase (AMPK) and inhibited the phosphorylation of mammalian target of rapamycin (mTOR) and its target proteins, including p70S6 K and 4E-BP-1. Treatment of cells with AICAR (an AMPK activator), rapamycin (an mTOR inhibitor), or mTOR siRNA downregulated c-Myc expression and induced apoptosis to a similar extent to that of MAC. These results suggest that the effect of MAC on apoptosis induction in human leukemia cells is mediated by the suppression of c-Myc protein synthesis via an AMPK/mTOR-dependent mechanism.

CpsR, a GntR family regulator, transcriptionally regulates capsular polysaccharide biosynthesis and governs bacterial virulence in Streptococcus pneumoniae.

PubMed

Wu, Kaifeng; Xu, Hongmei; Zheng, Yuqiang; Wang, Libin; Zhang, Xuemei; Yin, Yibing

2016-07-08

Transcriptional regulation of capsule expression is critical for pneumococcal transition from carriage to infection, yet the underlying mechanism remains incompletely understood. Here, we describe the regulation of capsular polysaccharide, one of the most important pneumococcal virulence factor by a GntR family regulator, CpsR. Electrophoretic mobility-shift assays have shown the direct interaction between CpsR and the cps promoter (cpsp), and their interaction could be competitively interfered by glucose. DNase I footprinting assays localized the binding site to a region -146 to -114 base pairs relative to the transcriptional start site of the cps locus in S. pneumoniae D39. We found that CpsR negatively controlled the transcription of the cps locus and hence CPS production, which was confirmed by fine-tuning expression of CpsR in a ΔcpsR complemented strain. Increased expression of CpsR in complemented strain led to a decreased resistance to the whole-blood-mediated killing, suggesting a protective role for CpsR-cpsp interaction in the establishment of invasive infection. Finally, animal experiments showed that CpsR-cpsp interaction was necessary for both pneumococcal colonization and invasive infection. Taken together, our results provide a thorough insight into the regulation of capsule production mediated by CpsR and its important roles in pneumococcal pathogenesis.

OXPHOS-Mediated Induction of NAD+ Promotes Complete Oxidation of Fatty Acids and Interdicts Non-Alcoholic Fatty Liver Disease.

PubMed

Akie, Thomas E; Liu, Lijun; Nam, Minwoo; Lei, Shi; Cooper, Marcus P

2015-01-01

OXPHOS is believed to play an important role in non-alcoholic fatty liver disease (NAFLD), however, precise mechanisms whereby OXPHOS influences lipid homeostasis are incompletely understood. We previously reported that ectopic expression of LRPPRC, a protein that increases cristae density and OXPHOS, promoted fatty acid oxidation in cultured primary hepatocytes. To determine the biological significance of that observation and define underlying mechanisms, we have ectopically expressed LRPPRC in mouse liver in the setting of NAFLD. Interestingly, ectopic expression of LRPPRC in mouse liver completely interdicted NAFLD, including inflammation. Consistent with mitigation of NAFLD, two markers of hepatic insulin resistance--ROS and PKCε activity--were both modestly reduced. As reported by others, improvement of NAFLD was associated with improved whole-body insulin sensitivity. Regarding hepatic lipid homeostasis, the ratio of NAD+ to NADH was dramatically increased in mouse liver replete with LRPPRC. Pharmacological activators and inhibitors of the cellular respiration respectively increased and decreased the [NAD+]/[NADH] ratio, indicating respiration-mediated control of the [NAD+]/[NADH] ratio. Supporting a prominent role for NAD+, increasing the concentration of NAD+ stimulated complete oxidation of fatty acids. Importantly, NAD+ rescued impaired fatty acid oxidation in hepatocytes deficient for either OXPHOS or SIRT3. These data are consistent with a model whereby augmented hepatic OXPHOS increases NAD+, which in turn promotes complete oxidation of fatty acids and protects against NAFLD.

eGFP expression under the Uchl1 promoter labels corticospinal motor neurons and a subpopulation of degeneration resistant spinal motor neurons in ALS mouse models

NASA Astrophysics Data System (ADS)

Yasvoina, Marina V.

Current understanding of basic cellular and molecular mechanisms for motor neuron vulnerability during motor neuron disease initiation and progression is incomplete. The complex cytoarchitecture and cellular heterogeneity of the cortex and spinal cord greatly impedes our ability to visualize, isolate, and study specific neuron populations in both healthy and diseased states. We generated a novel reporter line, the Uchl1-eGFP mouse, in which cortical and spinal components of motor neuron circuitry are genetically labeled with eGFP under the Uchl1 promoter. A series of cellular and anatomical analyses combined with retrograde labeling, molecular marker expression, and electrophysiology were employed to determine identity of eGFP expressing cells in the motor cortex and the spinal cord of novel Uchl1-eGFP reporter mice. We conclude that eGFP is expressed in corticospinal motor neurons (CSMN) in the motor cortex and a subset of S-type alpha and gamma spinal motor neurons (SMN) in the spinal cord. hSOD1G93A and Alsin-/- mice, mouse models for amyotrophic lateral sclerosis (ALS), were bred to Uchl1-eGFP reporter mouse line to investigate the pathophysiology and underlying mechanisms of CSMN degeneration in vivo. Evidence suggests early and progressive degeneration of CSMN and SMN in the hSOD1G93A transgenic mice. We show an early increase of autophagosome formation in the apical dendrites of vulnerable CSMN in hSOD1G93A-UeGFP mice, which is localized to the apical dendrites. In addition, labeling S-type alpha and gamma SMN in the hSOD1G93A-UeGFP mice provide a unique opportunity to study basis of their resistance to degeneration. Mice lacking alsin show moderate clinical phenotype and mild CSMN axon degeneration in the spinal cord, which suggests vulnerability of CSMN. Therefore, we investigated the CSMN cellular and axon defects in aged Alsin-/- mice bred to Uchl1-eGFP reporter mouse line. We show that while CSMN are preserved and lack signs of degeneration, CSMN axons are vulnerable and show significant loss.

Effects of Missing Data Methods in SEM under Conditions of Incomplete and Nonnormal Data

ERIC Educational Resources Information Center

Li, Jian; Lomax, Richard G.

2017-01-01

Using Monte Carlo simulations, this research examined the performance of four missing data methods in SEM under different multivariate distributional conditions. The effects of four independent variables (sample size, missing proportion, distribution shape, and factor loading magnitude) were investigated on six outcome variables: convergence rate,…

X chromosome regulation: diverse patterns in development, tissues and disease

PubMed Central

Deng, Xinxian; Berletch, Joel B.; Nguyen, Di K.; Disteche, Christine M.

2014-01-01

Genes on the mammalian X chromosome are present in one copy in males and two copies in females. The complex mechanisms that regulate the X chromosome lead to evolutionary and physiological variability in gene expression between species, the sexes, individuals, developmental stages, tissues and cell types. In early development, delayed and incomplete X chromosome inactivation (XCI) in some species causes variability in gene expression. Additional diversity stems from escape from XCI and from mosaicism or XCI skewing in females. This causes sex-specific differences that manifest as differential gene expression and associated phenotypes. Furthermore, the complexity and diversity of X dosage regulation affect the severity of diseases caused by X-linked mutations. PMID:24733023

Nature Disaster Risk Evaluation with a Group Decision Making Method Based on Incomplete Hesitant Fuzzy Linguistic Preference Relations.

PubMed

Tang, Ming; Liao, Huchang; Li, Zongmin; Xu, Zeshui

2018-04-13

Because the natural disaster system is a very comprehensive and large system, the disaster reduction scheme must rely on risk analysis. Experts' knowledge and experiences play a critical role in disaster risk assessment. The hesitant fuzzy linguistic preference relation is an effective tool to express experts' preference information when comparing pairwise alternatives. Owing to the lack of knowledge or a heavy workload, information may be missed in the hesitant fuzzy linguistic preference relation. Thus, an incomplete hesitant fuzzy linguistic preference relation is constructed. In this paper, we firstly discuss some properties of the additive consistent hesitant fuzzy linguistic preference relation. Next, the incomplete hesitant fuzzy linguistic preference relation, the normalized hesitant fuzzy linguistic preference relation, and the acceptable hesitant fuzzy linguistic preference relation are defined. Afterwards, three procedures to estimate the missing information are proposed. The first one deals with the situation in which there are only n-1 known judgments involving all the alternatives; the second one is used to estimate the missing information of the hesitant fuzzy linguistic preference relation with more known judgments; while the third procedure is used to deal with ignorance situations in which there is at least one alternative with totally missing information. Furthermore, an algorithm for group decision making with incomplete hesitant fuzzy linguistic preference relations is given. Finally, we illustrate our model with a case study about flood disaster risk evaluation. A comparative analysis is presented to testify the advantage of our method.

Effects of ibuprofen, diclofenac and paracetamol on hatch and motor behavior in developing zebrafish (Danio rerio).

PubMed

Xia, Liang; Zheng, Liang; Zhou, Jun Liang

2017-09-01

Non-steroidal anti-inflammatory drugs (NSAIDs) which are widely used as pain relief medicines are causing increasing environmental concern due to their incomplete removal in wastewater treatment plant and potential toxicity on endocrine, kidney and reproduction in teleost fish. This study focused on the effects of widely used ibuprofen, diclofenac and paracetamol on the hatch and motor ability of early-stage zebrafish, by exposing embryos to the target chemicals at 5, 50 and 500 μg/L starting from 6 h postfertilization (hpf). A significant reduction in hatch rate at 55 hpf was caused by both ibuprofen (-63%) and diclofenac (-58%) at 500 μg/L. Exposure to high concentration of ibuprofen significantly decreased the spontaneous movement by 25%, and reduced the free swimming distance, duration and speed under dark condition by 41%, 29% and 30%, respectively. High concentration of diclofenac also caused 23% decrease in spontaneous movement, and reduced the swimming distance as well as active duration by 17% and 13% under light stimulation. In comparison, the exposure to paracetamol did not cause any notable effect. Among neuron related genes tested, the expression of neurog1 was down-regulated from ibuprofen and diclofenac exposure by 19% and 26%, while the expression of neurod1 was up-regulated only by ibuprofen (31%). These findings indicated that ibuprofen and diclofenac significantly affected embryo locomotivity and were potentially neurotoxic, thus posing threats to zebrafish development. Copyright © 2017 Elsevier Ltd. All rights reserved.

Incomplete Mixing and Reactions - A Lagrangian Approach in a Pure Shear Flow

NASA Astrophysics Data System (ADS)

Paster, A.; Aquino, T.; Bolster, D.

2014-12-01

Incomplete mixing of reactive solutes is well known to slow down reaction rates relative to what would be expected from assuming perfect mixing. As reactions progress in a system and deplete reactant concentrations, initial fluctuations in the concentrations of reactions can be amplified relative to mean background concentrations and lead to spatial segregation of reactants. As the system evolves, in the absence of sufficient mixing, this segregation will increase, leading to a persistence of incomplete mixing that fundamentally changes the effective rate at which overall reactions will progress. On the other hand, non-uniform fluid flows are known to affect mixing between interacting solutes. Thus a natural question arises: Can non-uniform flows sufficiently enhance mixing to suppress incomplete mixing effects, and if so, under what conditions? In this work we address this question by considering one of the simplest possible flows, a laminar pure shear flow, which is known to significantly enhance mixing relative to diffusion alone. To study this system we adapt a novel Lagrangian particle-based random walk method, originally designed to simulate reactions in purely diffusive systems, to the case of advection and diffusion in a shear flow. To interpret the results we develop a semi-analytical solution, by proposing a closure approximation that aims to capture the effect of incomplete mixing. The results obtained via the Lagrangian model and the semi-analytical solutions consistently highlight that if shear effects in the system are not sufficiently strong, incomplete mixing effects initially similar to purely diffusive systems will occur, slowing down the overall reaction rate. Then, at some later time, dependent on the strength of the shear, the system will return to behaving as if it were well-mixed, but represented by a reduced effective reaction rate. If shear effects are sufficiently strong, the incomplete mixing regime never emerges and the system can behave as well-mixed at all times.

Incomplete Mixing and Reactions - A Lagrangian Approach in a Pure Shear Flow

NASA Astrophysics Data System (ADS)

Paster, Amir; Bolster, Diogo; Aquino, Tomas

2015-04-01

Incomplete mixing of reactive solutes is well known to slow down reaction rates relative to what would be expected from assuming perfect mixing. As reactions progress in a system and deplete reactant concentrations, initial fluctuations in the concentrations of reactions can be amplified relative to mean background concentrations and lead to spatial segregation of reactants. As the system evolves, in the absence of sufficient mixing, this segregation will increase, leading to a persistence of incomplete mixing that fundamentally changes the effective rate at which overall reactions will progress. On the other hand, nonuniform fluid flows are known to affect mixing between interacting solutes. Thus a natural question arises: Can non-uniform flows sufficiently enhance mixing to suppress incomplete mixing effects, and if so, under what conditions? In this work we address this question by considering one of the simplest possible flows, a laminar pure shear flow, which is known to significantly enhance mixing relative to diffusion alone. To study this system we adapt a novel Lagrangian particle-based random walk method, originally designed to simulate reactions in purely diffusive systems, to the case of advection and diffusion in a shear flow. To interpret the results we develop a semi-analytical solution, by proposing a closure approximation that aims to capture the effect of incomplete mixing. The results obtained via the Lagrangian model and the semi-analytical solutions consistently highlight that if shear effects in the system are not sufficiently strong, incomplete mixing effects initially similar to purely diffusive systems will occur, slowing down the overall reaction rate. Then, at some later time, dependent on the strength of the shear, the system will return to behaving as if it were well-mixed, but represented by a reduced effective reaction rate. If shear effects are sufficiently strong, the incomplete mixing regime never emerges and the system can behave as well-mixed at all times.

Solving the muon g -2 anomaly in deflected anomaly mediated SUSY breaking with messenger-matter interactions

NASA Astrophysics Data System (ADS)

Wang, Fei; Wang, Wenyu; Yang, Jin Min

2017-10-01

We propose to introduce general messenger-matter interactions in the deflected anomaly mediated supersymmetry (SUSY) breaking (AMSB) scenario to explain the gμ-2 anomaly. Scenarios with complete or incomplete grand unified theory (GUT) multiplet messengers are discussed, respectively. The introduction of incomplete GUT mulitiplets can be advantageous in various aspects. We found that the gμ-2 anomaly can be solved in both scenarios under current constraints including the gluino mass bounds, while the scenarios with incomplete GUT representation messengers are more favored by the gμ-2 data. We also found that the gluino is upper bounded by about 2.5 TeV (2.0 TeV) in scenario A and 3.0 TeV (2.7 TeV) in scenario B if the generalized deflected AMSB scenarios are used to fully account for the gμ-2 anomaly at 3 σ (2 σ ) level. Such a gluino should be accessible in the future LHC searches. Dark matter (DM) constraints, including DM relic density and direct detection bounds, favor scenario B with incomplete GUT multiplets. Much of the allowed parameter space for scenario B could be covered by the future DM direct detection experiments.

Inference and sample size calculation for clinical trials with incomplete observations of paired binary outcomes.

PubMed

Zhang, Song; Cao, Jing; Ahn, Chul

2017-02-20

We investigate the estimation of intervention effect and sample size determination for experiments where subjects are supposed to contribute paired binary outcomes with some incomplete observations. We propose a hybrid estimator to appropriately account for the mixed nature of observed data: paired outcomes from those who contribute complete pairs of observations and unpaired outcomes from those who contribute either pre-intervention or post-intervention outcomes. We theoretically prove that if incomplete data are evenly distributed between the pre-intervention and post-intervention periods, the proposed estimator will always be more efficient than the traditional estimator. A numerical research shows that when the distribution of incomplete data is unbalanced, the proposed estimator will be superior when there is moderate-to-strong positive within-subject correlation. We further derive a closed-form sample size formula to help researchers determine how many subjects need to be enrolled in such studies. Simulation results suggest that the calculated sample size maintains the empirical power and type I error under various design configurations. We demonstrate the proposed method using a real application example. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Increased Phosphoenolpyruvate Carboxykinase (PEPCK) Gene Expression and Steatosis During Hepatitis C Virus (HCV) Subgenome Replication: Role of Nonstructural Component-5A (NS5A) and CCAAT/Enhancer Binding Protein ß (C/EBPß)

USDA-ARS?s Scientific Manuscript database

Chronic hepatitis C virus (HCV) infection greatly increases the risk for type 2 diabetes and nonalcoholic steatohepatitis; however, the pathogenic mechanisms remain incompletely understood. Here we report gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) transcription and associated tra...

Time-dependent biodistribution and transgene expression of a recombinant human adenovirus serotype 5-luciferase vector as a surrogate agent for rAd5-FMDV vaccines in cattle

USDA-ARS?s Scientific Manuscript database

Replication-defective recombinant adenovirus 5 (rAd5) vectors carrying foot-and-mouth disease virus (FMDV) transgenes elicit a robust immune response to FMDV challenge in cattle; however vaccine function mechanisms are incompletely understood. Recent efforts addressing critical interactions of rAd5 ...

Social Interactions under Incomplete Information: Games, Equilibria, and Expectations

NASA Astrophysics Data System (ADS)

Yang, Chao

My dissertation research investigates interactions of agents' behaviors through social networks when some information is not shared publicly, focusing on solutions to a series of challenging problems in empirical research, including heterogeneous expectations and multiple equilibria. The first chapter, "Social Interactions under Incomplete Information with Heterogeneous Expectations", extends the current literature in social interactions by devising econometric models and estimation tools with private information in not only the idiosyncratic shocks but also some exogenous covariates. For example, when analyzing peer effects in class performances, it was previously assumed that all control variables, including individual IQ and SAT scores, are known to the whole class, which is unrealistic. This chapter allows such exogenous variables to be private information and models agents' behaviors as outcomes of a Bayesian Nash Equilibrium in an incomplete information game. The distribution of equilibrium outcomes can be described by the equilibrium conditional expectations, which is unique when the parameters are within a reasonable range according to the contraction mapping theorem in function spaces. The equilibrium conditional expectations are heterogeneous in both exogenous characteristics and the private information, which makes estimation in this model more demanding than in previous ones. This problem is solved in a computationally efficient way by combining the quadrature method and the nested fixed point maximum likelihood estimation. In Monte Carlo experiments, if some exogenous characteristics are private information and the model is estimated under the mis-specified hypothesis that they are known to the public, estimates will be biased. Applying this model to municipal public spending in North Carolina, significant negative correlations between contiguous municipalities are found, showing free-riding effects. The Second chapter "A Tobit Model with Social Interactions under Incomplete Information", is an application of the first chapter to censored outcomes, corresponding to the situation when agents" behaviors are subjected to some binding restrictions. In an interesting empirical analysis for property tax rates set by North Carolina municipal governments, it is found that there is a significant positive correlation among near-by municipalities. Additionally, some private information about its own residents is used by a municipal government to predict others' tax rates, which enriches current empirical work about tax competition. The third chapter, "Social Interactions under Incomplete Information with Multiple Equilibria", extends the first chapter by investigating effective estimation methods when the condition for a unique equilibrium may not be satisfied. With multiple equilibria, the previous model is incomplete due to the unobservable equilibrium selection. Neither conventional likelihoods nor moment conditions can be used to estimate parameters without further specifications. Although there are some solutions to this issue in the current literature, they are based on strong assumptions such as agents with the same observable characteristics play the same strategy. This paper relaxes those assumptions and extends the all-solution method used to estimate discrete choice games to a setting with both discrete and continuous choices, bounded and unbounded outcomes, and a general form of incomplete information, where the existence of a pure strategy equilibrium has been an open question for a long time. By the use of differential topology and functional analysis, it is found that when all exogenous characteristics are public information, there are a finite number of equilibria. With privately known exogenous characteristics, the equilbria can be represented by a compact set in a Banach space and be approximated by a finite set. As a result, a finite-state probability mass function can be used to specify a probability measure for equilibrium selection, which completes the model. From Monte Carlo experiments about two types of binary choice models, it is found that assuming equilibrium uniqueness can bring in estimation biases when the true value of interaction intensity is large and there are multiple equilibria in the data generating process.

MicroRNA and mesial temporal lobe epilepsy with hippocampal sclerosis: Whole miRNome profiling of human hippocampus.

PubMed

Bencurova, Petra; Baloun, Jiri; Musilova, Katerina; Radova, Lenka; Tichy, Boris; Pail, Martin; Zeman, Martin; Brichtova, Eva; Hermanova, Marketa; Pospisilova, Sarka; Mraz, Marek; Brazdil, Milan

2017-10-01

Mesial temporal lobe epilepsy (mTLE) is a severe neurological disorder characterized by recurrent seizures. mTLE is frequently accompanied by neurodegeneration in the hippocampus resulting in hippocampal sclerosis (HS), the most common morphological correlate of drug resistance in mTLE patients. Incomplete knowledge of pathological changes in mTLE+HS complicates its therapy. The pathological mechanism underlying mTLE+HS may involve abnormal gene expression regulation, including posttranscriptional networks involving microRNAs (miRNAs). miRNA expression deregulation has been reported in various disorders, including epilepsy. However, the miRNA profile of mTLE+HS is not completely known and needs to be addressed. Here, we have focused on hippocampal miRNA profiling in 33 mTLE+HS patients and nine postmortem controls to reveal abnormally expressed miRNAs. In this study, we significantly reduced technology-related bias (the most common source of false positivity in miRNA profiling data) by combining two different miRNA profiling methods, namely next generation sequencing and miRNA-specific quantitative real-time polymerase chain reaction. These methods combined have identified and validated 20 miRNAs with altered expression in the human epileptic hippocampus; 19 miRNAs were up-regulated and one down-regulated in mTLE+HS patients. Nine of these miRNAs have not been previously associated with epilepsy, and 19 aberrantly expressed miRNAs potentially regulate the targets and pathways linked with epilepsy (such as potassium channels, γ-aminobutyric acid, neurotrophin signaling, and axon guidance). This study extends current knowledge of miRNA-mediated gene expression regulation in mTLE+HS by identifying miRNAs with altered expression in mTLE+HS, including nine novel abnormally expressed miRNAs and their putative targets. These observations further encourage the potential of microRNA-based biomarkers or therapies. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

Reconciliation of Decision-Making Heuristics Based on Decision Trees Topologies and Incomplete Fuzzy Probabilities Sets

PubMed Central

Doubravsky, Karel; Dohnal, Mirko

2015-01-01

Complex decision making tasks of different natures, e.g. economics, safety engineering, ecology and biology, are based on vague, sparse, partially inconsistent and subjective knowledge. Moreover, decision making economists / engineers are usually not willing to invest too much time into study of complex formal theories. They require such decisions which can be (re)checked by human like common sense reasoning. One important problem related to realistic decision making tasks are incomplete data sets required by the chosen decision making algorithm. This paper presents a relatively simple algorithm how some missing III (input information items) can be generated using mainly decision tree topologies and integrated into incomplete data sets. The algorithm is based on an easy to understand heuristics, e.g. a longer decision tree sub-path is less probable. This heuristic can solve decision problems under total ignorance, i.e. the decision tree topology is the only information available. But in a practice, isolated information items e.g. some vaguely known probabilities (e.g. fuzzy probabilities) are usually available. It means that a realistic problem is analysed under partial ignorance. The proposed algorithm reconciles topology related heuristics and additional fuzzy sets using fuzzy linear programming. The case study, represented by a tree with six lotteries and one fuzzy probability, is presented in details. PMID:26158662

Reconciliation of Decision-Making Heuristics Based on Decision Trees Topologies and Incomplete Fuzzy Probabilities Sets.

PubMed

Doubravsky, Karel; Dohnal, Mirko

2015-01-01

Complex decision making tasks of different natures, e.g. economics, safety engineering, ecology and biology, are based on vague, sparse, partially inconsistent and subjective knowledge. Moreover, decision making economists / engineers are usually not willing to invest too much time into study of complex formal theories. They require such decisions which can be (re)checked by human like common sense reasoning. One important problem related to realistic decision making tasks are incomplete data sets required by the chosen decision making algorithm. This paper presents a relatively simple algorithm how some missing III (input information items) can be generated using mainly decision tree topologies and integrated into incomplete data sets. The algorithm is based on an easy to understand heuristics, e.g. a longer decision tree sub-path is less probable. This heuristic can solve decision problems under total ignorance, i.e. the decision tree topology is the only information available. But in a practice, isolated information items e.g. some vaguely known probabilities (e.g. fuzzy probabilities) are usually available. It means that a realistic problem is analysed under partial ignorance. The proposed algorithm reconciles topology related heuristics and additional fuzzy sets using fuzzy linear programming. The case study, represented by a tree with six lotteries and one fuzzy probability, is presented in details.

31 CFR 1.28 - Training, rules of conduct, penalties for non-compliance.

Code of Federal Regulations, 2013 CFR

2013-07-01

... be maintained under the provisions of the Privacy Act of 1974, including information on First Amendment Activities, information that is inaccurate, irrelevant or so incomplete as to risk unfairness to...

31 CFR 1.28 - Training, rules of conduct, penalties for non-compliance.

Code of Federal Regulations, 2012 CFR

2012-07-01

... be maintained under the provisions of the Privacy Act of 1974, including information on First Amendment Activities, information that is inaccurate, irrelevant or so incomplete as to risk unfairness to...

31 CFR 1.28 - Training, rules of conduct, penalties for non-compliance.

Code of Federal Regulations, 2014 CFR

2014-07-01

... be maintained under the provisions of the Privacy Act of 1974, including information on First Amendment Activities, information that is inaccurate, irrelevant or so incomplete as to risk unfairness to...

31 CFR 1.28 - Training, rules of conduct, penalties for non-compliance.

Code of Federal Regulations, 2011 CFR

2011-07-01

... be maintained under the provisions of the Privacy Act of 1974, including information on First Amendment Activities, information that is inaccurate, irrelevant or so incomplete as to risk unfairness to...

37 CFR 41.109 - Access to and copies of Office records.

Code of Federal Regulations, 2010 CFR

2010-07-01

... accorded benefit under subpart E of this part. (c) Missing or incomplete copies. If a party does not... TRADEMARK OFFICE, DEPARTMENT OF COMMERCE PRACTICE BEFORE THE BOARD OF PATENT APPEALS AND INTERFERENCES...

GSK-3Beta-Dependent Activation of GEF-H1/ROCK Signaling Promotes LPS-Induced Lung Vascular Endothelial Barrier Dysfunction and Acute Lung Injury.

PubMed

Yi, Lei; Huang, Xiaoqin; Guo, Feng; Zhou, Zengding; Chang, Mengling; Huan, Jingning

2017-01-01

The bacterial endotoxin or lipopolysaccharide (LPS) leads to the extensive vascular endothelial cells (EC) injury under septic conditions. Guanine nucleotide exchange factor-H1 (GEF-H1)/ROCK signaling not only involved in LPS-induced overexpression of pro-inflammatory mediator in ECs but also implicated in LPS-induced endothelial hyper-permeability. However, the mechanisms behind LPS-induced GEF-H1/ROCK signaling activation in the progress of EC injury remain incompletely understood. GEF-H1 localized on microtubules (MT) and is suppressed in its MT-bound state. MT disassembly promotes GEF-H1 release from MT and stimulates downstream ROCK-specific GEF activity. Since glycogen synthase kinase (GSK-3beta) participates in regulating MT dynamics under pathologic conditions, we examined the pivotal roles for GSK-3beta in modulating LPS-induced activation of GEF-H1/ROCK, increase of vascular endothelial permeability and severity of acute lung injury (ALI). In this study, we found that LPS induced human pulmonary endothelial cell (HPMEC) monolayers disruption accompanied by increase in GSK-3beta activity, activation of GEF-H1/ROCK signaling and decrease in beta-catenin and ZO-1 expression. Inhibition of GSK-3beta reduced HPMEC monolayers hyper-permeability and GEF-H1/ROCK activity in response to LPS. GSK-3beta/GEF-H1/ROCK signaling is implicated in regulating the expression of beta-catenin and ZO-1. In vivo , GSK-3beta inhibition attenuated LPS-induced activation of GEF-H1/ROCK pathway, lung edema and subsequent ALI. These findings present a new mechanism of GSK-3beta-dependent exacerbation of lung micro-vascular hyper-permeability and escalation of ALI via activation of GEF-H1/ROCK signaling and disruption of intracellular junctional proteins under septic condition.

Reduced PU.1 expression underlies aberrant neutrophil maturation and function in β-thalassemia mice and patients.

PubMed

Siwaponanan, Panjaree; Siegers, Jurre Ynze; Ghazali, Razi; Ng, Thian; McColl, Bradley; Ng, Garrett Zhen-Wei; Sutton, Philip; Wang, Nancy; Ooi, Isabelle; Thiengtavor, Chayada; Fucharoen, Suthat; Chaichompoo, Pornthip; Svasti, Saovaros; Wijburg, Odilia; Vadolas, Jim

2017-06-08

β-Thalassemia is associated with several abnormalities of the innate immune system. Neutrophils in particular are defective, predisposing patients to life-threatening bacterial infections. The molecular and cellular mechanisms involved in impaired neutrophil function remain incompletely defined. We used the Hbb th3/+ β-thalassemia mouse and hemoglobin E (HbE)/β-thalassemia patients to investigate dysregulated neutrophil activity. Mature neutrophils from Hbb th3/+ mice displayed a significant reduction in chemotaxis, opsonophagocytosis, and production of reactive oxygen species, closely mimicking the defective immune functions observed in β-thalassemia patients. In Hbb th3/+ mice, the expression of neutrophil CXCR2, CD11b, and reduced NAD phosphate oxidase components (p22phox, p67phox, and gp91phox) were significantly reduced. Morphological analysis of Hbb th3/+ neutrophils showed that a large percentage of mature phenotype neutrophils (Ly6G hi Ly6C low ) appeared as band form cells, and a striking expansion of immature (Ly6G low Ly6C low ) hyposegmented neutrophils, consisting mainly of myelocytes and metamyelocytes, was noted. Intriguingly, expression of an essential mediator of neutrophil terminal differentiation, the ets transcription factor PU.1, was significantly decreased in Hbb th3/+ neutrophils. In addition, in vivo infection with Streptococcus pneumoniae failed to induce PU.1 expression or upregulate neutrophil effector functions in Hbb th3/+ mice. Similar changes to neutrophil morphology and PU.1 expression were observed in splenectomized and nonsplenectomized HbE/β-thalassemia patients. This study provides a mechanistic insight into defective neutrophil maturation in β-thalassemia patients, which contributes to deficiencies in neutrophil effector functions. © 2017 by The American Society of Hematology.

EphA2 Promotes Infiltrative Invasion of Glioma Stem Cells in vivo through Crosstalk with Akt and Regulates Stem Properties

PubMed Central

Miao, Hui; Gale, Nickolas W.; Guo, Hong; Qian, Juan; Petty, Aaron; Kaspar, James; Murphy, Andrew J.; Valenzuela, David M.; Yancopoulos, George; Hambardzumyan, Dolores; Lathia, Justin D.; Rich, Jeremy N.; Lee, Jeongwu; Wang, Bingcheng

2014-01-01

Diffuse infiltrative invasion is a major cause for the dismal prognosis of glioblastoma (GBM), but the underlying mechanisms remain incompletely understood. Using human glioblastoma stem cells (GSCs) that recapitulate the invasive propensity of primary GBM, we find that EphA2 critically regulates GBM invasion in vivo. EphA2 was expressed in all seven GSC lines examined, and overexpression of EphA2 enhanced intracranial invasion. The effects required Akt-mediated phosphorylation of EphA2 on serine 897. In vitro the Akt-EphA2 signaling axis is maintained in the absence of ephrin-A ligands and is disrupted upon ligand stimulation. To test whether ephrin-As in tumor microenvironment can regulate GSC invasion, the newly established Efna1;Efna3;Efna4 triple knockout mice (TKO) were used in an ex vivo brain slice invasion assay. We observed significantly increased GSC invasion through the brain slices of TKO mice relative to wild type littermates. Mechanistically EphA2 knockdown suppressed stem properties of GSCs, causing diminished self-renewal, reduced stem marker expression and decreased tumorigenicity. In a subset of GSCs, the reduced stem properties were associated with lower Sox2 expression. Overexpression of EphA2 promoted stem properties in a kinase-independent manner and increased Sox2 expression. In addition to suppressing invasion, disrupting Akt-EphA2 crosstalk attenuated stem marker expression and neurosphere formation while having minimal effects on tumorigenesis, suggesting that the Akt-EphA2 signaling axis contributes to the stem properties. Taken together, the results show that EphA2 endows invasiveness of GSCs in vivo in cooperation with Akt and contributes to the maintenance of stem properties. PMID:24488013

EphA2 promotes infiltrative invasion of glioma stem cells in vivo through cross-talk with Akt and regulates stem cell properties.

PubMed

Miao, H; Gale, N W; Guo, H; Qian, J; Petty, A; Kaspar, J; Murphy, A J; Valenzuela, D M; Yancopoulos, G; Hambardzumyan, D; Lathia, J D; Rich, J N; Lee, J; Wang, B

2015-01-29

Diffuse infiltrative invasion is a major cause for the dismal prognosis of glioblastoma multiforme (GBM), but the underlying mechanisms remain incompletely understood. Using human glioma stem cells (GSCs) that recapitulate the invasive propensity of primary GBM, we find that EphA2 critically regulates GBM invasion in vivo. EphA2 was expressed in all seven GSC lines examined, and overexpression of EphA2 enhanced intracranial invasion. The effects required Akt-mediated phosphorylation of EphA2 on serine 897. In vitro the Akt-EphA2 signaling axis is maintained in the absence of ephrin-A ligands and is disrupted upon ligand stimulation. To test whether ephrin-As in tumor microenvironment can regulate GSC invasion, the newly established Efna1;Efna3;Efna4 triple knockout mice (TKO) were used in an ex vivo brain slice invasion assay. We observed significantly increased GSC invasion through the brain slices of TKO mice relative to wild-type (WT) littermates. Mechanistically EphA2 knockdown suppressed stem cell properties of GSCs, causing diminished self-renewal, reduced stem marker expression and decreased tumorigenicity. In a subset of GSCs, the reduced stem cell properties were associated with lower Sox2 expression. Overexpression of EphA2 promoted stem cell properties in a kinase-independent manner and increased Sox2 expression. Disruption of Akt-EphA2 cross-talk attenuated stem cell marker expression and neurosphere formation while having minimal effects on tumorigenesis. Taken together, the results show that EphA2 endows invasiveness of GSCs in vivo in cooperation with Akt and regulates glioma stem cell properties.

Gene regulation mediating fiber-type transformation in skeletal muscle cells is partly glucose- and ChREBP-dependent.

PubMed

Hanke, Nina; Scheibe, Renate J; Manukjan, Georgi; Ewers, David; Umeda, Patrick K; Chang, Kin-Chow; Kubis, Hans-Peter; Gros, Gerolf; Meissner, Joachim D

2011-03-01

Adaptations in the oxidative capacity of skeletal muscle cells can occur under several physiological or pathological conditions. We investigated the effect of increasing extracellular glucose concentration on the expression of markers of energy metabolism in primary skeletal muscle cells and the C2C12 muscle cell line. Growth of myotubes in 25mM glucose (high glucose, HG) compared with 5.55mM led to increases in the expression and activity of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a marker of glycolytic energy metabolism, while oxidative markers peroxisome proliferator-activated receptor γ coactivator 1α and citrate synthase decreased. HG induced metabolic adaptations as are seen during a slow-to-fast fiber transformation. Furthermore, HG increased fast myosin heavy chain (MHC) IId/x but did not change slow MHCI/β expression. Protein phosphatase 2A (PP2A) was shown to mediate the effects of HG on GAPDH and MHCIId/x. Carbohydrate response element-binding protein (ChREBP), a glucose-dependent transcription factor downstream of PP2A, partially mediated the effects of glucose on metabolic markers. The glucose-induced increase in PP2A activity was associated with an increase in p38 mitogen-activated protein kinase activity, which presumably mediates the increase in MHCIId/x promoter activity. Liver X receptor, another possible mediator of glucose effects, induced only an incomplete metabolic shift, mainly increasing the expression of the glycolytic marker. Taken together, HG induces a partial slow-to-fast transformation comprising metabolic enzymes together with an increased expression of MHCIId/x. This work demonstrates a functional role for ChREBP in determining the metabolic type of muscle fibers and highlights the importance of glucose as a signaling molecule in muscle. Copyright © 2011 Elsevier B.V. All rights reserved.

Overexpression of a partial fragment of the salt-responsive gene OsNUC1 enhances salt adaptation in transgenic Arabidopsis thaliana and rice (Oryza sativa L.) during salt stress.

PubMed

Sripinyowanich, Siriporn; Chamnanmanoontham, Nontalee; Udomchalothorn, Thanikarn; Maneeprasopsuk, Somporn; Santawee, Panudda; Buaboocha, Teerapong; Qu, Li-Jia; Gu, Hongya; Chadchawan, Supachitra

2013-12-01

The rice (Oryza sativa L.) nucleolin gene, OsNUC1, transcripts were expressed in rice leaves, flowers, seeds and roots but differentially expressed within and between two pairs of salt-sensitive and salt-resistant rice lines when subjected to salt stress. Salt-resistant lines exhibited higher OsNUC1 transcript expression levels than salt-sensitive lines during 0.5% (w/v) NaCl salt stress for 6d. Two sizes of OsNUC1 full-length cDNA were found in the rice genome database and northern blot analysis confirmed their existence in rice tissues. The longer transcript (OsNUC1-L) putatively encodes for a protein with a serine rich N-terminal, RNA recognition motifs in the central domain and a glycine- and arginine-rich repeat in the C-terminal domain, while the shorter one (OsNUC1-S) putatively encodes for the similar protein without the N-terminus. Without salt stress, OsNUC1-L expressing Arabidopsis thaliana Atnuc1-L1 plants displayed a substantial but incomplete revertant phenotype, whereas OsNUC1-S expression only induced a weak effect. However, under 0.5% (w/v) NaCl salt stress they displayed a higher relative growth rate, longer root length and a lower H2O2 level than the wild type plants, suggesting a higher salt resistance. Moreover, they displayed elevated AtSOS1 and AtP5CS1 transcript levels. We propose that OsNUC1-S plays an important role in salt resistance during salt stress, a new role for nucleolin in plants. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Dynamic Modularity of Host Protein Interaction Networks in Salmonella Typhi Infection

PubMed Central

Dhal, Paltu Kumar; Barman, Ranjan Kumar; Saha, Sudipto; Das, Santasabuj

2014-01-01

Background Salmonella Typhi is a human-restricted pathogen, which causes typhoid fever and remains a global health problem in the developing countries. Although previously reported host expression datasets had identified putative biomarkers and therapeutic targets of typhoid fever, the underlying molecular mechanism of pathogenesis remains incompletely understood. Methods We used five gene expression datasets of human peripheral blood from patients suffering from S. Typhi or other bacteremic infections or non-infectious disease like leukemia. The expression datasets were merged into human protein interaction network (PIN) and the expression correlation between the hubs and their interacting proteins was measured by calculating Pearson Correlation Coefficient (PCC) values. The differences in the average PCC for each hub between the disease states and their respective controls were calculated for studied datasets. The individual hubs and their interactors with expression, PCC and average PCC values were treated as dynamic subnetworks. The hubs that showed unique trends of alterations specific to S. Typhi infection were identified. Results We identified S. Typhi infection-specific dynamic subnetworks of the host, which involve 81 hubs and 1343 interactions. The major enriched GO biological process terms in the identified subnetworks were regulation of apoptosis and biological adhesions, while the enriched pathways include cytokine signalling in the immune system and downstream TCR signalling. The dynamic nature of the hubs CCR1, IRS2 and PRKCA with their interactors was studied in detail. The difference in the dynamics of the subnetworks specific to S. Typhi infection suggests a potential molecular model of typhoid fever. Conclusions Hubs and their interactors of the S. Typhi infection-specific dynamic subnetworks carrying distinct PCC values compared with the non-typhoid and other disease conditions reveal new insight into the pathogenesis of S. Typhi. PMID:25144185

Endangered species act : the U.S. Fish and Wildlife service has incomplete information about effects on listed species from section 7 consultations.

DOT National Transportation Integrated Search

2009-05-01

The western United States, including vast stretches of federal land, is home to more than a third of the 1,317 species listed under the Endangered Species Act. Under section 7 of the act, federal agencies must ensure that any actions they authorize, ...

Joint sparse learning for 3-D facial expression generation.

PubMed

Song, Mingli; Tao, Dacheng; Sun, Shengpeng; Chen, Chun; Bu, Jiajun

2013-08-01

3-D facial expression generation, including synthesis and retargeting, has received intensive attentions in recent years, because it is important to produce realistic 3-D faces with specific expressions in modern film production and computer games. In this paper, we present joint sparse learning (JSL) to learn mapping functions and their respective inverses to model the relationship between the high-dimensional 3-D faces (of different expressions and identities) and their corresponding low-dimensional representations. Based on JSL, we can effectively and efficiently generate various expressions of a 3-D face by either synthesizing or retargeting. Furthermore, JSL is able to restore 3-D faces with holes by learning a mapping function between incomplete and intact data. Experimental results on a wide range of 3-D faces demonstrate the effectiveness of the proposed approach by comparing with representative ones in terms of quality, time cost, and robustness.

Hfe and Hjv exhibit overlapping functions for iron signaling to hepcidin.

PubMed

Kent, Patricia; Wilkinson, Nicole; Constante, Marco; Fillebeen, Carine; Gkouvatsos, Konstantinos; Wagner, John; Buffler, Marzell; Becker, Christiane; Schümann, Klaus; Santos, Manuela M; Pantopoulos, Kostas

2015-05-01

Functional inactivation of HFE or hemojuvelin (HJV) is causatively linked to adult or juvenile hereditary hemochromatosis, respectively. Systemic iron overload results from inadequate expression of hepcidin, the iron regulatory hormone. While HJV regulates hepcidin by amplifying bone morphogenetic protein (BMP) signaling, the role of HFE in the hepcidin pathway remains incompletely understood. We investigated the pathophysiological implications of combined Hfe and Hjv ablation in mice. Isogenic Hfe (-)/(-) and Hjv (-)/(-) mice were crossed to generate double Hfe (-)/(-) Hjv (-)/(-) progeny. Wild-type control and mutant mice of all genotypes were analyzed for serum, hepatic, and splenic iron content, expression of iron metabolism proteins, and expression of hepcidin and Smad signaling in the liver, in response to a standard or an iron-enriched diet. As expected, Hfe (-)/(-) and Hjv (-)/(-) mice developed relatively mild or severe iron overload, respectively, which corresponded to the degree of hepcidin inhibition. The double Hfe (-)/(-) Hjv (-)/(-) mice exhibited an indistinguishable phenotype to single Hjv (-)/(-) counterparts with regard to suppression of hepcidin, serum and hepatic iron overload, splenic iron deficiency, tissue iron metabolism, and Smad signaling, under both dietary regimens. We conclude that the hemochromatotic phenotype caused by disruption of Hjv is not further aggravated by combined Hfe/Hjv deficiency. Our results provide genetic evidence that Hfe and Hjv operate in the same pathway for the regulation of hepcidin expression and iron metabolism. Combined disruption of Hfe and Hjv phenocopies single Hjv deficiency. Single Hjv(-)/(-) and double Hfe(-)/(-)Hjv(-)/(-) mice exhibit comparable iron overload. Hfe and Hjv regulate hepcidin via the same pathway.

Deletion of OTX2 in neural ectoderm delays anterior pituitary development

PubMed Central

Mortensen, Amanda H.; Schade, Vanessa; Lamonerie, Thomas; Camper, Sally A.

2015-01-01

OTX2 is a homeodomain transcription factor that is necessary for normal head development in mouse and man. Heterozygosity for loss-of-function alleles causes an incompletely penetrant, haploinsufficiency disorder. Affected individuals exhibit a spectrum of features that range from developmental defects in eye and/or pituitary development to acephaly. To investigate the mechanism underlying the pituitary defects, we used different cre lines to inactivate Otx2 in early head development and in the prospective anterior and posterior lobes. Mice homozygous for Otx2 deficiency in early head development and pituitary oral ectoderm exhibit craniofacial defects and pituitary gland dysmorphology, but normal pituitary cell specification. The morphological defects mimic those observed in humans and mice with OTX2 heterozygous mutations. Mice homozygous for Otx2 deficiency in the pituitary neural ectoderm exhibited altered patterning of gene expression and ablation of FGF signaling. The posterior pituitary lobe and stalk, which normally arise from neural ectoderm, were extremely hypoplastic. Otx2 expression was intact in Rathke's pouch, the precursor to the anterior lobe, but the anterior lobe was hypoplastic. The lack of FGF signaling from the neural ectoderm was sufficient to impair anterior lobe growth, but not the differentiation of hormone-producing cells. This study demonstrates that Otx2 expression in the neural ectoderm is important intrinsically for the development of the posterior lobe and pituitary stalk, and it has significant extrinsic effects on anterior pituitary growth. Otx2 expression early in head development is important for establishing normal craniofacial features including development of the brain, eyes and pituitary gland. PMID:25315894

Iron overload causes osteoporosis in thalassemia major patients through interaction with transient receptor potential vanilloid type 1 (TRPV1) channels

PubMed Central

Rossi, Francesca; Perrotta, Silverio; Bellini, Giulia; Luongo, Livio; Tortora, Chiara; Siniscalco, Dario; Francese, Matteo; Torella, Marco; Nobili, Bruno; Di Marzo, Vincenzo; Maione, Sabatino

2014-01-01

The pathogenesis of bone resorption in β-thalassemia major is multifactorial and our understanding of the underlying molecular and cellular mechanisms remains incomplete. Considering the emerging importance of the endocannabinoid/endovanilloid system in bone metabolism, it may be instructive to examine a potential role for this system in the development of osteoporosis in patients with β-thalassemia major and its relationship with iron overload and iron chelation therapy. This study demonstrates that, in thalassemic-derived osteoclasts, tartrate-resistant acid phosphatase expression inversely correlates with femoral and lumbar bone mineral density, and directly correlates with ferritin levels and liver iron concentration. The vanilloid agonist resiniferatoxin dramatically reduces cathepsin K levels and osteoclast numbers in vitro, without affecting tartrate-resistant acid phosphatase expression. The iron chelators deferoxamine, deferiprone and deferasirox decrease both tartrate-resistant acid phosphatase and cathepsin K expression, as well as osteoclast activity. Taken together, these data show that transient receptor potential vanilloid type 1 activation/desensitization influences tartrate-resistant acid phosphatase expression and activity, and this effect is dependent on iron, suggesting a pivotal role for iron overload in the dysregulation of bone metabolism in patients with thalassemia major. Our applied pharmacology provides evidence for the potential of iron chelators to abrogate these effects by reducing osteoclast activity. Whether iron chelation therapy is capable of restoring bone health in humans requires further study, but the potential to provide dual benefits for patients with β-thalassemia major –preventing iron-overload and alleviating associated osteoporotic changes – is exciting. PMID:25216685

AAV-mediated targeting of gene expression to the peri-infarct region in rat cortical stroke model.

PubMed

Mätlik, Kert; Abo-Ramadan, Usama; Harvey, Brandon K; Arumäe, Urmas; Airavaara, Mikko

2014-10-30

For stroke patients the recovery of cognitive and behavioral functions is often incomplete. Functional recovery is thought to be mediated largely by connectivity rearrangements in the peri-infarct region. A method for manipulating gene expression in this region would be useful for identifying new recovery-enhancing treatments. We have characterized a way of targeting adeno-associated virus (AAV) vectors to the peri-infarct region of cortical ischemic lesion in rats 2days after middle cerebral artery occlusion (MCAo). We used magnetic resonance imaging (MRI) to show that the altered properties of post-ischemic brain tissue facilitate the spreading of intrastriatally injected nanoparticles toward the infarct. We show that subcortical injection of green fluorescent protein-encoding dsAAV7-GFP resulted in transduction of cells in and around the white matter tract underlying the lesion, and in the cortex proximal to the lesion. A similar result was achieved with dsAAV7 vector encoding the cerebral dopamine neurotrophic factor (CDNF), a protein with therapeutic potential. Viral vector-mediated intracerebral gene delivery has been used before in rodent models of ischemic injury. However, the method of targeting gene expression to the peri-infarct region, after the initial phase of ischemic cell death, has not been described before. We demonstrate a straightforward and robust way to target AAV vector-mediated over-expression of genes to the peri-infarct region in a rat stroke model. This method will be useful for studying the action of specific proteins in peri-infarct region during the recovery process. Copyright © 2014 Elsevier B.V. All rights reserved.

Transfer of chromosome 3 fragments suppresses tumorigenicity of an ovarian cancer cell line monoallelic for chromosome 3p.

PubMed

Cody, N A L; Ouellet, V; Manderson, E N; Quinn, M C J; Filali-Mouhim, A; Tellis, P; Zietarska, M; Provencher, D M; Mes-Masson, A-M; Chevrette, M; Tonin, P N

2007-01-25

Multiple chromosome 3p tumor suppressor genes (TSG) have been proposed in the pathogenesis of ovarian cancer based on complex patterns of 3p loss. To attain functional evidence in support of TSGs and identify candidate regions, we applied a chromosome transfer method involving cell fusions of the tumorigenic OV90 human ovarian cancer cell line, monoallelic for 3p and an irradiated mouse cell line containing a human chromosome 3 in order to derive OV90 hybrids containing normal 3p fragments. The resulting hybrids showed complete or incomplete suppression of tumorigenicity in nude mouse xenograft assays, and varied in their ability to form colonies in soft agarose and three-dimensional spheroids in a manner consistent with alteration of their in vivo tumorigenic phenotypes. Expression microarray analysis identified a set of common differentially expressed genes, such as SPARC, DAB2 and VEGF, some of which have been shown implicated in ovarian cancer. Genotyping assays revealed that they harbored normal 3p fragments, some of which overlapped candidate TSG regions (3p25-p26, 3p24 and 3p14-pcen) identified previously in loss of heterozygosity analyses of ovarian cancers. However, only the 3p12-pcen region was acquired in common by all hybrids where expression microarray analysis identified differentially expressed genes. The correlation of 3p12-pcen transfer and tumor suppression with a concerted re-programming of the cellular transcriptome suggest that the putative TSG may have affected key underlying events in ovarian cancer.

Larval spicules, cilia, and symmetry as remnants of indirect development in the direct developing sea urchin Heliocidaris erythrogramma.

PubMed

Emlet, R B

1995-02-01

Nonfeeding larvae of the echinoid Heliocidaris erythrogramma were raised in culture and examined for expression of a larval skeleton and for the arrangement of the ciliated band. Opaque larvae were fixed, cleared, and examined under polarized light for evidence of calcification. By 35 hr after fertilization (at 22 degrees C), a pair of triradiate spicules was present at the posterior end of the larvae. Each member of this pair formed a fenestrated spicule as it grew laterally. This pair and another pair which formed subsequently, were arranged across a plane of bilateral symmetry orthagonal to the juvenile oral aboral axis. These paired larval spicules can be identified as reduced expressions of postoral and posterodorsal rods found in plutei, and their expression indicates that the juvenile rudiment of H. erythrogramma forms on the left side and that larval body axes are conserved in this modified larva. By 44 hr the ciliated band formed as an incomplete transverse loop of three segments at the posterior end and on the dorsal surface of the ovoid larva. Cilia in these segments grew to lengths of 45-50 microns, longer than other swimming and feeding cilia reported for echinoderm larvae. Band segments are interpreted as expressions of epaulettes (specialized swimming bands) rather than the feeding ciliated band of the pluteus. The ciliated band segments and the larval spicules are both bilaterally symmetrical with respect to the same plane and indicate conserved larval bilateral symmetry despite the major asymmetry of the fates of cells on either side of this plane in their contribution to juvenile development.

Hypoxia-inducible factors promote alveolar development and regeneration.

PubMed

Vadivel, Arul; Alphonse, Rajesh S; Etches, Nicholas; van Haaften, Timothy; Collins, Jennifer J P; O'Reilly, Megan; Eaton, Farah; Thébaud, Bernard

2014-01-01

Understanding how alveoli and the underlying capillary network develop and how these mechanisms are disrupted in disease states is critical for developing effective therapies for lung regeneration. Recent evidence suggests that lung angiogenesis promotes lung development and repair. Vascular endothelial growth factor (VEGF) preserves lung angiogenesis and alveolarization in experimental O2-induced arrested alveolar growth in newborn rats, but combined VEGF+angiopoietin 1 treatment is necessary to correct VEGF-induced vessel leakiness. Hypoxia-inducible factors (HIFs) are transcription factors that activate multiple O2-sensitive genes, including those encoding for angiogenic growth factors, but their role during postnatal lung growth is incompletely understood. By inducing the expression of a range of angiogenic factors in a coordinated fashion, HIF may orchestrate efficient and safe angiogenesis superior to VEGF. We hypothesized that HIF inhibition impairs alveolarization and that HIF activation regenerates irreversible O2-induced arrested alveolar growth. HIF inhibition by intratracheal dominant-negative adenovirus (dnHIF-1α)-mediated gene transfer or chetomin decreased lung HIF-1α, HIF-2α, and VEGF expression and led to air space enlargement and arrested lung vascular growth. In experimental O2-induced arrested alveolar growth in newborn rats, the characteristic features of air space enlargement and loss of lung capillaries were associated with decreased lung HIF-1α and HIF-2α expression. Intratracheal administration of Ad.HIF-1α restored HIF-1α, endothelial nitric oxide synthase, VEGF, VEGFR2, and Tie2 expression and preserved and rescued alveolar growth and lung capillary formation in this model. HIFs promote normal alveolar development and may be useful targets for alveolar regeneration.

Hypoxia increases the heterogeneity of melanoma cell populations and affects the response to vemurafenib.

PubMed

Pucciarelli, Daniela; Lengger, Nina; Takáčová, Martina; Csaderova, Lucia; Bartosova, Maria; Breiteneder, Heimo; Pastorekova, Silvia; Hafner, Christine

2016-04-01

A hypoxic microenvironment is one of the predominant reasons for incomplete response to melanoma treatment. Vemurafenib, which targets the mutated BRAF-V600 kinase, improves melanoma patient survival, however, resistance invariably develops. The present study evaluated the effect of hypoxia on three BRAF-V600E mutant melanoma cell lines, M14, A375 and 518A2, treated with vemurafenib. Compared with the other two cell lines, hypoxic vemurafenib-treated A375 cells exhibited an enhanced cell proliferation rate and migratory capacity compared with normoxic vemurafenib-treated A375 cells. Immunoblotting analyses revealed that the expression levels of hypoxia inducible factor (HIF)1α and carbonic anhydrase IX were reduced in vemurafenib‑treated M14 and 518A2 cells, however, not in A375 cells. The expression levels of the mitogen‑activated protein kinase, Janus kinase-signal transducer and activator of transcription, and phosphatidylinositol-4,5-bisphosphate 3‑kinase signaling pathway proteins revealed a cell‑type specific response to vemurafenib and hypoxia. Knockdown experiments of HIF1α performed in hypoxic A375 cells decreased the expression of phosphorylated (p‑)protein kinase B, which was restored following vemurafenib treatment, and increased the expression of p‑extracellular‑signal‑regulated kinases. Therefore, three melanoma cell lines responded to vemurafenib under hypoxia in a cell type‑specific manner, suggesting that a subset of cells provides a treatment-resistant pool, from which disease relapse may originate. These data confirmed that vemurafenib may be successful in treating the proliferating cells, whereas the non‑proliferating subpopulation must be addressed by a combination of vemurafenib with other treatment strategies.

Modulation of frontostriatal interaction aligns with reduced primary reward processing under serotonergic drugs.

PubMed

Abler, Birgit; Grön, Georg; Hartmann, Antonie; Metzger, Coraline; Walter, Martin

2012-01-25

Recently, functional interactions between anteroventral prefrontal cortex and nucleus accumbens (NAcc) have been shown to relate to behavior counteracting reward-desiring (Diekhof and Gruber, 2010). Downregulation of the reward system by serotonin has also been suggested as the mode of action accounting for unsatisfactory effects of serotonin reuptake inhibitors (SSRIs) such as insufficient alleviation or even increase of anhedonia, and loss of interest. However, understanding of the in vivo mechanisms of SSRI-related alteration of the human reward system is still incomplete. Using functional magnetic resonance imaging (fMRI) within a double-blind cross-over within-subjects study design and administering the SSRI paroxetine, the dopamine/norepinephrine reuptake inhibitor bupropione, and placebo for 7 d each, we investigated a group of 18 healthy male subjects. Under paroxetine, subjects showed significantly decreased activation of the bilateral NAcc during processing of primary rewards (erotic videos), but not under bupropion. Similar to the previous study, analysis of psychophysiological interactions revealed that this downregulation relied on negative interactions between left and right NAcc fMRI signals and the bilateral anteroventral prefrontal cortex that now were significantly enhanced under paroxetine and reduced under bupropion. Individual drug-dependent modulations of interacting brain regions were significantly associated with individual expressions of impulsivity as a personality trait. Our results corroborate and extend previous insights on interregional crosstalk from secondary to primary rewards and demonstrate parallels between active inhibitory control of and serotonergic effects on the dopaminergic reward system's activity.

Identification of a novel PPARβ/δ/miR-21-3p axis in UV-induced skin inflammation.

PubMed

Degueurce, Gwendoline; D'Errico, Ilenia; Pich, Christine; Ibberson, Mark; Schütz, Frédéric; Montagner, Alexandra; Sgandurra, Marie; Mury, Lionel; Jafari, Paris; Boda, Akash; Meunier, Julien; Rezzonico, Roger; Brembilla, Nicolò Costantino; Hohl, Daniel; Kolios, Antonios; Hofbauer, Günther; Xenarios, Ioannis; Michalik, Liliane

2016-08-01

Although excessive exposure to UV is widely recognized as a major factor leading to skin perturbations and cancer, the complex mechanisms underlying inflammatory skin disorders resulting from UV exposure remain incompletely characterized. The nuclear hormone receptor PPARβ/δ is known to control mouse cutaneous repair and UV-induced skin cancer development. Here, we describe a novel PPARβ/δ-dependent molecular cascade involving TGFβ1 and miR-21-3p, which is activated in the epidermis in response to UV exposure. We establish that the passenger miRNA miR-21-3p, that we identify as a novel UV-induced miRNA in the epidermis, plays a pro-inflammatory function in keratinocytes and that its high level of expression in human skin is associated with psoriasis and squamous cell carcinomas. Finally, we provide evidence that inhibition of miR-21-3p reduces UV-induced cutaneous inflammation in ex vivo human skin biopsies, thereby underlining the clinical relevance of miRNA-based topical therapies for cutaneous disorders. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

Learning under uncertainty in smart home environments.

PubMed

Zhang, Shuai; McClean, Sally; Scotney, Bryan; Nugent, Chris

2008-01-01

Technologies and services for the home environment can provide levels of independence for elderly people to support 'ageing in place'. Learning inhabitants' patterns of carrying out daily activities is a crucial component of these technological solutions with sensor technologies being at the core of such smart environments. Nevertheless, identifying high-level activities from low-level sensor events can be a challenge, as information may be unreliable resulting in incomplete data. Our work addresses the issues of learning in the presence of incomplete data along with the identification and the prediction of inhabitants and their activities under such uncertainty. We show via the evaluation results that our approach also offers the ability to assess the impact of various sensors in the activity recognition process. The benefit of this work is that future predictions can be utilised in a proposed intervention mechanism in a real smart home environment.

Chronic ethanol consumption modulates growth factor release, mucosal cytokine production, and microRNA expression in nonhuman primates.

PubMed

Asquith, Mark; Pasala, Sumana; Engelmann, Flora; Haberthur, Kristen; Meyer, Christine; Park, Byung; Grant, Kathleen A; Messaoudi, Ilhem

2014-04-01

Chronic alcohol consumption has been associated with enhanced susceptibility to both systemic and mucosal infections. However, the exact mechanisms underlying this enhanced susceptibility remain incompletely understood. Using a nonhuman primate model of ethanol (EtOH) self-administration, we examined the impact of chronic alcohol exposure on immune homeostasis, cytokine, and growth factor production in peripheral blood, lung, and intestinal mucosa following 12 months of chronic EtOH exposure. EtOH exposure inhibited activation-induced production of growth factors hepatocyte growth factor (HGF), granulocyte colony-stimulating factor (G-CSF), and vascular-endothelial growth factor (VEGF) by peripheral blood mononuclear cells (PBMC). Moreover, EtOH significantly reduced the frequency of colonic Th1 and Th17 cells in a dose-dependent manner. In contrast, we did not observe differences in lymphocyte frequency or soluble factor production in the lung of EtOH-consuming animals. To uncover mechanisms underlying reduced growth factor and Th1/Th17 cytokine production, we compared expression levels of microRNAs in PBMC and intestinal mucosa. Our analysis revealed EtOH-dependent up-regulation of distinct microRNAs in affected tissues (miR-181a and miR-221 in PBMC; miR-155 in colon). Moreover, we were able to detect reduced expression of the transcription factors STAT3 and ARNT, which regulate expression of VEGF, G-CSF, and HGF and contain targets for these microRNAs. To confirm and extend these observations, PBMC were transfected with either mimics or antagomirs of miR-181 and miR-221, and protein levels of the transcription factors and growth factors were determined. Transfection of microRNA mimics led to a reduction in both STAT3/ARNT as well as VEGF/HGF/G-CSF levels. The opposite outcome was observed when microRNA antagomirs were transfected. Chronic EtOH consumption significantly disrupts both peripheral and mucosal immune homeostasis, and this dysregulation may be mediated by changes in microRNA expression. Copyright © 2013 by the Research Society on Alcoholism.

Comparative analysis of gene expression between semigametic Pima 57-6 and non-semigametic Pima S-1 in cotton by differential display

USDA-ARS?s Scientific Manuscript database

Semigamy in cotton is a type of facultative apomixis controlled by a single incompletely dominant gene (Se) in which the sperm and egg nuclei fail to fuse after the sperm nucleus has entered the embryo sac, giving rise to diploid, haploid or even chimeral embryos comprised of paternal and maternal o...

Transgenic Expression of the Vitamin D Receptor Restricted to the Ileum, Cecum, and Colon of Vitamin D Receptor Knockout Mice Rescues Vitamin D Receptor-Dependent Rickets.

PubMed

Dhawan, Puneet; Veldurthy, Vaishali; Yehia, Ghassan; Hsaio, Connie; Porta, Angela; Kim, Ki-In; Patel, Nishant; Lieben, Liesbet; Verlinden, Lieve; Carmeliet, Geert; Christakos, Sylvia

2017-11-01

Although the intestine plays the major role in 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] action on calcium homeostasis, the mechanisms involved remain incompletely understood. The established model of 1,25(OH)2D3-regulated intestinal calcium absorption postulates a critical role for the duodenum. However, the distal intestine is where 70% to 80% of ingested calcium is absorbed. To test directly the role of 1,25(OH)2D3 and the vitamin D receptor (VDR) in the distal intestine, three independent knockout (KO)/transgenic (TG) lines expressing VDR exclusively in the ileum, cecum, and colon were generated by breeding VDR KO mice with TG mice expressing human VDR (hVDR) under the control of the 9.5-kb caudal type homeobox 2 promoter. Mice from one TG line (KO/TG3) showed low VDR expression in the distal intestine (<50% of the levels observed in KO/TG1, KO/TG2, and wild-type mice). In the KO/TG mice, hVDR was not expressed in the duodenum, jejunum, kidney, or other tissues. Growth arrest, elevated parathyroid hormone level, and hypocalcemia of the VDR KO mice were prevented in mice from KO/TG lines 1 and 2. Microcomputed tomography analysis revealed that the expression of hVDR in the distal intestine of KO/TG1 and KO/TG2 mice rescued the bone defects associated with systemic VDR deficiency, including growth plate abnormalities and altered trabecular and cortical parameters. KO/TG3 mice showed rickets, but less severely than VDR KO mice. These findings show that expression of VDR exclusively in the distal intestine can prevent abnormalities in calcium homeostasis and bone mineralization associated with systemic VDR deficiency. Copyright © 2017 Endocrine Society.

Analytical solution for reactive solute transport considering incomplete mixing within a reference elementary volume

NASA Astrophysics Data System (ADS)

Chiogna, Gabriele; Bellin, Alberto

2013-05-01

The laboratory experiments of Gramling et al. (2002) showed that incomplete mixing at the pore scale exerts a significant impact on transport of reactive solutes and that assuming complete mixing leads to overestimation of product concentration in bimolecular reactions. Successively, several attempts have been made to model this experiment, either considering spatial segregation of the reactants, non-Fickian transport applying a Continuous Time Random Walk (CTRW) or an effective upscaled time-dependent kinetic reaction term. Previous analyses of these experimental results showed that, at the Darcy scale, conservative solute transport is well described by a standard advection dispersion equation, which assumes complete mixing at the pore scale. However, reactive transport is significantly affected by incomplete mixing at smaller scales, i.e., within a reference elementary volume (REV). We consider here the family of equilibrium reactions for which the concentration of the reactants and the product can be expressed as a function of the mixing ratio, the concentration of a fictitious non reactive solute. For this type of reactions we propose, in agreement with previous studies, to model the effect of incomplete mixing at scales smaller than the Darcy scale assuming that the mixing ratio is distributed within an REV according to a Beta distribution. We compute the parameters of the Beta model by imposing that the mean concentration is equal to the value that the concentration assumes at the continuum Darcy scale, while the variance decays with time as a power law. We show that our model reproduces the concentration profiles of the reaction product measured in the Gramling et al. (2002) experiments using the transport parameters obtained from conservative experiments and an instantaneous reaction kinetic. The results are obtained applying analytical solutions both for conservative and for reactive solute transport, thereby providing a method to handle the effect of incomplete mixing on multispecies reactive solute transport, which is simpler than other previously developed methods.

Analytical Solution for Reactive Solute Transport Considering Incomplete Mixing

NASA Astrophysics Data System (ADS)

Bellin, A.; Chiogna, G.

2013-12-01

The laboratory experiments of Gramling et al. (2002) showed that incomplete mixing at the pore scale exerts a significant impact on transport of reactive solutes and that assuming complete mixing leads to overestimation of product concentration in bimolecular reactions. We consider here the family of equilibrium reactions for which the concentration of the reactants and the product can be expressed as a function of the mixing ratio, the concentration of a fictitious non reactive solute. For this type of reactions we propose, in agreement with previous studies, to model the effect of incomplete mixing at scales smaller than the Darcy scale assuming that the mixing ratio is distributed within an REV according to a Beta distribution. We compute the parameters of the Beta model by imposing that the mean concentration is equal to the value that the concentration assumes at the continuum Darcy scale, while the variance decays with time as a power law. We show that our model reproduces the concentration profiles of the reaction product measured in the Gramling et al. (2002) experiments using the transport parameters obtained from conservative experiments and an instantaneous reaction kinetic. The results are obtained applying analytical solutions both for conservative and for reactive solute transport, thereby providing a method to handle the effect of incomplete mixing on multispecies reactive solute transport, which is simpler than other previously developed methods. Gramling, C. M., C. F. Harvey, and L. C. Meigs (2002), Reactive transport in porous media: A comparison of model prediction with laboratory visualization, Environ. Sci. Technol., 36(11), 2508-2514.

Finite barrier corrections to the PGH solution of Kramers' turnover theory

NASA Astrophysics Data System (ADS)

Pollak, Eli; Ianconescu, Reuven

2014-04-01

Kramers [Physica 7, 284 (1940)], in his seminal paper, derived expressions for the rate of crossing a barrier in the underdamped limit of weak friction and the moderate to strong friction limit. The challenge of obtaining a uniform expression for the rate, valid for all damping strengths is known as Kramers turnover theory. Two different solutions have been presented. Mel'nikov and Meshkov [J. Chem. Phys. 85, 1018 (1986)] (MM) considered the motion of the particle, treating the friction as a perturbation parameter. Pollak, Grabert, and Hänggi [J. Chem. Phys. 91, 4073 (1989)] (PGH), considered the motion along the unstable mode which is separable from the bath in the barrier region. In practice, the two theories differ in the way an energy loss parameter is estimated. In this paper, we show that previous numerical attempts to resolve the quality of the two approaches were incomplete and that at least for a cubic potential with Ohmic friction, the quality of agreement of both expressions with numerical simulation is similar over a large range of friction strengths and temperatures. Mel'nikov [Phys. Rev. E 48, 3271 (1993)], in a later paper, improved his theory by introducing finite barrier corrections. In this paper we note that previous numerical tests of the finite barrier corrections were also incomplete. They did not employ the exact rate expression, but a harmonic approximation to it. The central part of this paper, is to include finite barrier corrections also within the PGH formalism. Tests on a cubic potential demonstrate that finite barrier corrections significantly improve the agreement of both MM and PGH theories when compared with numerical simulations.

Desensitization and Incomplete Recovery of Hepatic Target Genes After Chronic Thyroid Hormone Treatment and Withdrawal in Male Adult Mice

PubMed Central

Ohba, Kenji; Singh, Brijesh Kumar; Sinha, Rohit Anthony; Lesmana, Ronny; Liao, Xiao-Hui; Ghosh, Sujoy; Refetoff, Samuel

2016-01-01

Clinical symptoms may vary and not necessarily reflect serum thyroid hormone (TH) levels during acute and chronic hyperthyroidism as well as recovery from hyperthyroidism. We thus examined changes in hepatic gene expression and serum TH/TSH levels in adult male mice treated either with a single T3 (20 μg per 100 g body weight) injection (acute T3) or daily injections for 14 days (chronic T3) followed by 10 days of withdrawal. Gene expression arrays from livers harvested at these time points showed that among positively-regulated target genes, 320 were stimulated acutely and 429 chronically by T3. Surprisingly, only 69 of 680 genes (10.1%) were induced during both periods, suggesting desensitization of the majority of acutely stimulated target genes. About 90% of positively regulated target genes returned to baseline expression levels after 10 days of withdrawal; however, 67 of 680 (9.9%) did not return to baseline despite normalization of serum TH/TSH levels. Similar findings also were observed for negatively regulated target genes. Chromatin immunoprecipitation analysis of representative positively regulated target genes suggested that acetylation of H3K9/K14 was associated with acute stimulation, whereas trimethylation of H3K4 was associated with chronic stimulation. In an in vivo model of chronic intrahepatic hyperthyroidism since birth, adult male monocarboxylate transporter-8 knockout mice also demonstrated desensitization of most acutely stimulated target genes that were examined. In summary, we have identified transcriptional desensitization and incomplete recovery of gene expression during chronic hyperthyroidism and recovery. Our findings may be a potential reason for discordance between clinical symptoms and serum TH levels observed in these conditions. PMID:26866609

Identification and Characterization of Staphylococcus aureus Strains with an Incomplete Hemolytic Phenotype.

PubMed

Zhang, Haifang; Zheng, Yi; Gao, Huasheng; Xu, Ping; Wang, Min; Li, Aiqing; Miao, Minhui; Xie, Xiaofang; Deng, Yimai; Zhou, Huiqin; Du, Hong

2016-01-01

Staphylococcus aureus is a common pathogen causing both hospital and community-acquired infections. Hemolysin is one of the important virulence factors for S. aureus and causes the typical β-hemolytic phenotype which is called complete hemolytic phenotype as well. Recently, S. aureus with an incomplete hemolytic phenotype (SIHP) was isolated from clinical samples. To study the microbiologic characteristics of SIHP, the special hemolytic phenotype of SIHP was verified on the sheep blood agar plates supplied by different manufacturers. Expression of hemolysin genes hla, hlb, hlgC , and hld of SIHP was detected by qRT-PCR and it was showed that expression of hlb in SIHP was obviously increased compared to the control S. aureus strains with complete hemolytic phenotype (SCHP), while the expression of hla, hlgC , and hld in SIHP was significantly decreased. In addition, the α-hemolysin encoded by gene hla was decreased obviously in SIHP compared to SCHP by western blot. All 60 SIHP strains were identified to be the methicillin resistant S. aureus (MRSA), and moreover these SIHP strains all contains mecA gene. The virulence gene tst were all present in SIHP, and the intracellular survival ability of SIHP was much greater than that of the gene tst negative S. aureus . We also found that IL-2, IL-6, and IL-17A secreted in the supernatant of SIHP infected macrophages increased significantly compared to tst negative control strains infected ones. MLST analysis showed that all of SIHP strains were classified into ST5 clone. To our knowledge, this study firstly showed that SIHP strains are a kind of methicillin resistant strains which express β-hemolysin highly and possess a potential high virulence, and it was suggested that SIHP should be paid more attention in hospital.

Discrimination Learning in Children

ERIC Educational Resources Information Center

Ochocki, Thomas E.; And Others

1975-01-01

Examined the learning performance of 192 fourth-, fifth-, and sixth-grade children on either a two or four choice simultaneous color discrimination task. Compared the use of verbal reinforcement and/or punishment, under conditions of either complete or incomplete instructions. (Author/SDH)

Direct activation of chordoblasts by retinoic acid is required for segmented centra mineralization during zebrafish spine development.

PubMed

Pogoda, Hans-Martin; Riedl-Quinkertz, Iris; Löhr, Heiko; Waxman, Joshua S; Dale, Rodney M; Topczewski, Jacek; Schulte-Merker, Stefan; Hammerschmidt, Matthias

2018-05-08

Zebrafish mutants with increased retinoic acid (RA) signaling due to the loss of the RA-inactivating enzyme Cyp26b1 develop a hyper-mineralized spine with gradually fusing vertebral body precursors (centra). However, the underlying cellular mechanisms remain incompletely understood. Here, we show that cells of the notochord epithelium named chordoblasts are sensitive to RA signaling. Chordoblasts are uniformly distributed along the anteroposterior axis and initially generate the continuous collagenous notochord sheath. However, subsequently and iteratively, subsets of these cells undergo further RA-dependent differentiation steps, acquire a stellate-like shape, downregulate expression of the collagen gene col2a1a , switch on cyp26b1 expression and trigger metameric sheath mineralization. This mineralization fails to appear upon chordoblast-specific cell ablation or RA signal transduction blockade. Together, our data reveal that, despite their different developmental origins, the activities and regulation of chordoblasts are very similar to those of osteoblasts, including their RA-induced transition from osteoid-producing cells to osteoid-mineralizing ones. Furthermore, our data point to a requirement for locally controlled RA activity within the chordoblast layer in order to generate the segmented vertebral column. © 2018. Published by The Company of Biologists Ltd.

Unravelling the effects of mechanical physiological conditioning on cardiac adipose tissue-derived progenitor cells in vitro and in silico.

PubMed

Llucià-Valldeperas, Aida; Bragós, Ramon; Soler-Botija, Carolina; Roura, Santiago; Gálvez-Montón, Carolina; Prat-Vidal, Cristina; Perea-Gil, Isaac; Bayes-Genis, Antoni

2018-01-11

Mechanical conditioning is incompletely characterized for stimulating therapeutic cells within the physiological range. We sought to unravel the mechanism of action underlying mechanical conditioning of adipose tissue-derived progenitor cells (ATDPCs), both in vitro and in silico. Cardiac ATDPCs, grown on 3 different patterned surfaces, were mechanically stretched for 7 days at 1 Hz. A custom-designed, magnet-based, mechanical stimulator device was developed to apply ~10% mechanical stretching to monolayer cell cultures. Gene and protein analyses were performed for each cell type and condition. Cell supernatants were also collected to analyze secreted proteins and construct an artificial neural network. Gene and protein modulations were different for each surface pattern. After mechanostimulation, cardiac ATDPCs increased the expression of structural genes and there was a rising trend on cardiac transcription factors. Finally, secretome analyses revealed upregulation of proteins associated with both myocardial infarction and cardiac regeneration, such as regulators of the immune response, angiogenesis or cell adhesion. To conclude, mechanical conditioning of cardiac ATDPCs enhanced the expression of early and late cardiac genes in vitro. Additionally, in silico analyses of secreted proteins showed that mechanical stimulation of cardiac ATDPCs was highly associated with myocardial infarction and repair.

Id4 functions downstream of Bmp signaling to restrict TCF function in endocardial cells during atrioventricular valve development.

PubMed

Ahuja, Suchit; Dogra, Deepika; Stainier, Didier Y R; Reischauer, Sven

2016-04-01

The atrioventricular canal (AVC) connects the atrial and ventricular chambers of the heart and its formation is critical for the development of the cardiac valves, chamber septation and formation of the cardiac conduction system. Consequently, problems in AVC formation can lead to congenital defects ranging from cardiac arrhythmia to incomplete cardiac septation. While our knowledge about early heart tube formation is relatively comprehensive, much remains to be investigated about the genes that regulate AVC formation. Here we identify a new role for the basic helix-loop-helix factor Id4 in zebrafish AVC valve development and function. id4 is first expressed in the AVC endocardium and later becomes more highly expressed in the atrial chamber. TALEN induced inactivation of id4 causes retrograde blood flow at the AV canal under heat induced stress conditions, indicating defects in AV valve function. At the molecular level, we found that id4 inactivation causes misexpression of several genes important for AVC and AV valve formation including bmp4 and spp1. We further show that id4 appears to control the number of endocardial cells that contribute to the AV valves by regulating Wnt signaling in the developing AVC endocardium. Copyright © 2016 Elsevier Inc. All rights reserved.

A single rapamycin dose protects against late-stage experimental cerebral malaria via modulation of host immunity, endothelial activation and parasite sequestration.

PubMed

Mejia, Pedro; Treviño-Villarreal, J Humberto; Reynolds, Justin S; De Niz, Mariana; Thompson, Andrew; Marti, Matthias; Mitchell, James R

2017-11-09

Maladaptive immune responses during cerebral malaria (CM) result in high mortality despite opportune anti-malarial chemotherapy. Rapamycin, an FDA-approved immunomodulator, protects against experimental cerebral malaria (ECM) in mice through effects on the host. However, the potential for reduced adaptive immunity with chronic use, combined with an incomplete understanding of mechanisms underlying protection, limit translational potential as an adjunctive therapy in CM. The results presented herein demonstrate that a single dose of rapamycin, provided as late as day 4 or 5 post-infection, protected mice from ECM neuropathology and death through modulation of distinct host responses to infection. Rapamycin prevented parasite cytoadherence in peripheral organs, including white adipose tissue, via reduction of CD36 expression. Rapamycin also altered the splenic immune response by reducing the number of activated T cells with migratory phenotype, while increasing local cytotoxic T cell activation. Finally, rapamycin reduced brain endothelial ICAM-1 expression concomitant with reduced brain pathology. Together, these changes potentially contributed to increased parasite elimination while reducing CD8 T cell migration to the brain. Rapamycin exerts pleotropic effects on host immunity, vascular activation and parasite sequestration that rescue mice from ECM, and thus support the potential clinical use of rapamycin as an adjunctive therapy in CM.

Barriers for Deriving Transgene-Free Pig iPS Cells with Episomal Vectors.

PubMed

Du, Xuguang; Feng, Tao; Yu, Dawei; Wu, Yuanyuan; Zou, Huiying; Ma, Shuangyu; Feng, Chong; Huang, Yongye; Ouyang, Hongsheng; Hu, Xiaoxiang; Pan, Dengke; Li, Ning; Wu, Sen

2015-11-01

To date no authentic embryonic stem cell (ESC) line or germline-competent-induced pluripotent stem cell (iPSC) line has been established for large animals. Despite this fact, there is an impression in the field that large animal ESCs or iPSCs are as good as mouse counterparts. Clarification of this issue is important for a healthy advancement of the stem cell field. Elucidation of the causes of this failure in obtaining high quality iPSCs/ESCs may offer essential clues for eventual establishment of authentic ESCs for large animals including humans. To this end, we first generated porcine iPSCs using nonintegrating replicating episomal plasmids. Although these porcine iPSCs met most pluripotency criteria, they could neither generate cloned piglets through nuclear transfer, nor contribute to later stage chimeras through morula injections or aggregations. We found that the reprogramming genes in iPSCs could not be removed even under negative selection, indicating they are required to maintain self-renewal. The persistent expression of these genes in porcine iPSCs in turn caused differentiation defects in vivo. Therefore, incomplete reprogramming manifested by a reliance on sustained expression of exogenous-reprogramming factors appears to be the main reason for the inability of porcine iPSCs to form iPSC-derived piglets. © 2015 AlphaMed Press.

SAS-1 Is a C2 Domain Protein Critical for Centriole Integrity in C. elegans

PubMed Central

Delattre, Marie; Balestra, Fernando R.; Blanchoud, Simon; Finger, Susanne; Knott, Graham; Müller-Reichert, Thomas; Gönczy, Pierre

2014-01-01

Centrioles are microtubule-based organelles important for the formation of cilia, flagella and centrosomes. Despite progress in understanding the underlying assembly mechanisms, how centriole integrity is ensured is incompletely understood, including in sperm cells, where such integrity is particularly critical. We identified C. elegans sas-1 in a genetic screen as a locus required for bipolar spindle assembly in the early embryo. Our analysis reveals that sperm-derived sas-1 mutant centrioles lose their integrity shortly after fertilization, and that a related defect occurs when maternal sas-1 function is lacking. We establish that sas-1 encodes a C2 domain containing protein that localizes to centrioles in C. elegans, and which can bind and stabilize microtubules when expressed in human cells. Moreover, we uncover that SAS-1 is related to C2CD3, a protein required for complete centriole formation in human cells and affected in a type of oral-facial-digital (OFD) syndrome. PMID:25412110

Emerging Roles of microRNAs in Ischemic Stroke: As Possible Therapeutic Agents

PubMed Central

Khoshnam, Seyed Esmaeil; Winlow, William; Farbood, Yaghoob; Moghaddam, Hadi Fathi; Farzaneh, Maryam

2017-01-01

Stroke is one of the leading causes of death and physical disability worldwide. The consequences of stroke injuries are profound and persistent, causing in considerable burden to both the individual patient and society. Current treatments for ischemic stroke injuries have proved inadequate, partly owing to an incomplete understanding of the cellular and molecular changes that occur following ischemic stroke. MicroRNAs (miRNA) are endogenously expressed RNA molecules that function to inhibit mRNA translation and have key roles in the pathophysiological processes contributing to ischemic stroke injuries. Potential therapeutic areas to compensate these pathogenic processes include promoting angiogenesis, neurogenesis and neuroprotection. Several miRNAs, and their target genes, are recognized to be involved in these recoveries and repair mechanisms. The capacity of miRNAs to simultaneously regulate several target genes underlies their unique importance in ischemic stroke therapeutics. In this Review, we focus on the role of miRNAs as potential diagnostic and prognostic biomarkers, as well as promising therapeutic agents in cerebral ischemic stroke. PMID:28480877

Leptin Action on GABAergic Neurons Prevents Obesity and Reduces Inhibitory Tone to POMC Neurons

PubMed Central

Vong, Linh; Ye, Chianping; Yang, Zongfang; Choi, Brian; Chua, Streamson; Lowell, Bradford B.

2011-01-01

SUMMARY Leptin acts in the brain to prevent obesity. The underlying neurocircuitry responsible for this is poorly understood, in part due to incomplete knowledge regarding first order, leptin-responsive neurons. To address this, we and others have been removing leptin receptors from candidate first order neurons. While functionally relevant neurons have been identified, the observed effects have been small suggesting that most first order neurons remain unidentified. Here we take an alternative approach and test whether first order neurons are inhibitory (GABAergic, VGAT+) or excitatory (glutamatergic, VGLUT2+). Remarkably, the vast majority of leptin’s anti-obesity effects are mediated by GABAergic neurons; glutamatergic neurons play only a minor role. Leptin, working directly on presynaptic GABAergic neurons, many of which appear not to express AgRP, reduces inhibitory tone to postsynaptic POMC neurons. As POMC neurons prevent obesity, their disinhibition by leptin action on presynaptic GABAergic neurons likely mediates, at least in part, leptin’s anti-obesity effects. PMID:21745644

Dietary tryptophan alleviates dextran sodium sulfate-induced colitis through aryl hydrocarbon receptor in mice.

PubMed

Islam, Jahidul; Sato, Shoko; Watanabe, Kouichi; Watanabe, Takaya; Ardiansyah; Hirahara, Keisuke; Aoyama, Yukihide; Tomita, Shuhei; Aso, Hisashi; Komai, Michio; Shirakawa, Hitoshi

2017-04-01

Ulcerative colitis is the typical progression of chronic inflammatory bowel disease. Amino acids, particularly tryptophan, have been reported to exert a protective effect against colitis induced by dextran sodium sulfate (DSS), but the precise underlying mechanisms remain incompletely clarified. Tryptophan metabolites are recognized to function as endogenous ligands for aryl hydrocarbon receptor (Ahr), which is a critical regulator of inflammation and immunity. Thus, we conducted this study to investigate whether dietary tryptophan supplementation protects against DSS-induced colitis by acting through Ahr. Female wild-type (WT) and Ahr-deficient (knockout; KO) mice (10-12 weeks old) were divided into four groups and fed either a control or 0.5% tryptophan diet. The tryptophan diet ameliorated DSS-induced colitis symptoms and severity in WT mice but not in KO mice, and the diet reduced the mRNA expression of Il-6, Tnfα, Il-1β and the chemokines Ccl2, Cxcl1 and Cxcl2 in the WT groups. Furthermore, Il-22 and Stat3 mRNA expression in the colon was elevated in WT mice fed with the tryptophan diet, which mainly protected epithelial layer integrity, and Ahr also modulated immune homeostasis by regulating Foxp3 and Il-17 mRNA expression. These data suggest that tryptophan-containing diet might ameliorate DSS-induced acute colitis and regulate epithelial homeostasis through Ahr. Thus, tryptophan could serve as a promising preventive agent in the treatment of ulcerative colitis. Copyright © 2017 Elsevier Inc. All rights reserved.

Inhibition of TRPC3 downregulates airway hyperresponsiveness, remodeling of OVA-sensitized mouse

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

Wang, Lingwei; Li, Jie; Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou

Airway hyperresponsiveness (AHR), airway remodeling and inflammation are the fundamental pathological alterations that occur in asthma. Transient receptor potential canonical 3 (TRPC3) has been implicated in diverse functions of airway smooth muscle cells (ASMCs) in asthma. However, the underlying mechanisms remain incompletely understood. We investigated the mRNA and protein expression of TRPC3 in ASMCs from normal and OVA-sensitized mouse. And the effects of inhibition or knockdown of TRPC3 with Ethyl-1- (4- (2,3,3-trichloroacrylamide) phenyl) −5 - (trifluoromethyl) -1H -pyrazole -4-carboxylate (Pyr3) and lentiviral shRNA on OVA-sensitized mouse AHR, airway remodeling, circulating inflammatory cytokines, cell proliferation and migration. We found that TRPC3 mRNAmore » and protein expression levels were significantly increased in ASMCs from OVA-sensitized mouse. Inhibiting TRPC3 with continuous subcutaneous administration of Pyr3 decreased enhanced pause (Penh) of OVA-sensitized mouse. Meanwhile, both Pyr3 and lentiviral shRNA treatment of ASMCs in OVA-sensitized mouse significantly decreased their proliferation and migration. These results suggest that TRPC3 plays a critical role in asthma and represents a promising new target for asthma treatment. - Highlights: • Penh, airway remodeling and the gene expression and protein of TRPC3 are increased in OVA-sensitized mice. • Inhibition of TRPC3 suppresses the OVA-sensitized mice Penh and airway remodeling. • Inhibition of TRPC3 decreases OVA-sensitized mice ASMC proliferation and migration.« less

Postdoctoral recruitment in neuropsychology: a review and call for inter-organizational action.

PubMed

Belanger, Heather G; Vanderploeg, Rodney D; Silva, Marc A; Cimino, Cynthia R; Roper, Brad L; Bodin, Doug

2013-01-01

The history of centralized matches for postgraduate selection is briefly discussed with a focus on the match instituted by the Association of Postdoctoral Programs in Clinical Neuropsychology (APPCN) in 2001] Survey data, conducted both by APPCN and independently, are summarized. In general, despite incomplete participation and an estimated 30% rate of "exploding offers", applicants are somewhat satisfied with the match according to recent surveys (although satisfaction varies depending on whether an applicant matched). Given the high rate of withdrawal, the history of other specialties with suboptimal participation, and the concerns most commonly expressed by participants about this issue in survey data, there is cause for concern. We assert that incomplete participation in the match hurts applicants and programs. We propose that focused efforts are needed involving multiple organizations to enhance the match, including the Clinical Neuropsychology Synarchy (CNS) as our specialty council and the multiple organizations represented on the CNS.

Manifestation of Incompleteness in Obsessive-Compulsive Disorder (OCD) as Reduced Functionality and Extended Activity beyond Task Completion

PubMed Central

Zor, Rama; Szechtman, Henry; Hermesh, Haggai; Fineberg, Naomi A.; Eilam, David

2011-01-01

Background This study focused on hypotheses regarding the source of incompleteness in obsessive-compulsive disorder (OCD). For this, we had to document the behavioral manifestation of incompleteness in compulsive rituals, predicting that an exaggerated focus on acts that are appropriate for the task will support the hypothesis on heightened responsibility/perfectionism. In contrast, activity past the expected terminal act for the motor task would support the “stop signal deficiency” hypothesis. Methodology and Principal Findings We employed video-telemetry to analyze 39 motor OCD rituals and compared each with a similar task performed by a non-OCD individual, in order to objectively and explicitly determine the functional end of the activity. We found that 75% of OCD rituals comprised a “tail,” which is a section that follows the functional end of the task that the patients ascribed to their activity. The other 25% tailless rituals comprised a relatively high number and higher rate of repetition of non-functional acts. Thus, in rituals with tail, incompleteness was manifested by the mere presence of the tail whereas in tailless rituals, incompleteness was manifested by the reduced functionality of the task due to an inflated execution and repetition of non-functional acts. Conclusions The prevalence of activity after the functional end (“tail”) and the elevated non-functionality in OCD motor rituals support the “lack of stop signal” theories as the underlying mechanism in OCD. Furthermore, the presence and content of the tail might have a therapeutic potential in cognitive-behavior therapy. PMID:21966460

The consequences of hospital autonomization in Colombia: a transaction cost economics analysis.

PubMed

Castano, Ramon; Mills, Anne

2013-03-01

Granting autonomy to public hospitals in developing countries has been common over recent decades, and implies a shift from hierarchical to contract-based relationships with health authorities. Theory on transactions costs in contractual relationships suggests they stem from relationship-specific investments and contract incompleteness. Transaction cost economics argues that the parties involved in exchanges seek to reduce transaction costs. The objective of this research was to analyse the relationships observed between purchasers and the 22 public hospitals of the city of Bogota, Colombia, in order to understand the role of relationship-specific investments and contract incompleteness as sources of transaction costs, through a largely qualitative study. We found that contract-based relationships showed relevant transaction costs associated mainly with contract incompleteness, not with relationship-specific investments. Regarding relationships between insurers and local hospitals for primary care services, compulsory contracting regulations locked-in the parties to the contracts. For high-complexity services (e.g. inpatient care), no restrictions applied and relationships suggested transaction-cost minimizing behaviour. Contract incompleteness was found to be a source of transaction costs on its own. We conclude that transaction costs seemed to play a key role in contract-based relationships, and contract incompleteness by itself appeared to be a source of transaction costs. The same findings are likely in other contexts because of difficulties in defining, observing and verifying the contracted products and the underlying information asymmetries. The role of compulsory contracting might be context-specific, although it is likely to emerge in other settings due to the safety-net role of public hospitals.

Double propensity-score adjustment: A solution to design bias or bias due to incomplete matching.

PubMed

Austin, Peter C

2017-02-01

Propensity-score matching is frequently used to reduce the effects of confounding when using observational data to estimate the effects of treatments. Matching allows one to estimate the average effect of treatment in the treated. Rosenbaum and Rubin coined the term "bias due to incomplete matching" to describe the bias that can occur when some treated subjects are excluded from the matched sample because no appropriate control subject was available. The presence of incomplete matching raises important questions around the generalizability of estimated treatment effects to the entire population of treated subjects. We describe an analytic solution to address the bias due to incomplete matching. Our method is based on using optimal or nearest neighbor matching, rather than caliper matching (which frequently results in the exclusion of some treated subjects). Within the sample matched on the propensity score, covariate adjustment using the propensity score is then employed to impute missing potential outcomes under lack of treatment for each treated subject. Using Monte Carlo simulations, we found that the proposed method resulted in estimates of treatment effect that were essentially unbiased. This method resulted in decreased bias compared to caliper matching alone and compared to either optimal matching or nearest neighbor matching alone. Caliper matching alone resulted in design bias or bias due to incomplete matching, while optimal matching or nearest neighbor matching alone resulted in bias due to residual confounding. The proposed method also tended to result in estimates with decreased mean squared error compared to when caliper matching was used.

Double propensity-score adjustment: A solution to design bias or bias due to incomplete matching

PubMed Central

2016-01-01

Propensity-score matching is frequently used to reduce the effects of confounding when using observational data to estimate the effects of treatments. Matching allows one to estimate the average effect of treatment in the treated. Rosenbaum and Rubin coined the term “bias due to incomplete matching” to describe the bias that can occur when some treated subjects are excluded from the matched sample because no appropriate control subject was available. The presence of incomplete matching raises important questions around the generalizability of estimated treatment effects to the entire population of treated subjects. We describe an analytic solution to address the bias due to incomplete matching. Our method is based on using optimal or nearest neighbor matching, rather than caliper matching (which frequently results in the exclusion of some treated subjects). Within the sample matched on the propensity score, covariate adjustment using the propensity score is then employed to impute missing potential outcomes under lack of treatment for each treated subject. Using Monte Carlo simulations, we found that the proposed method resulted in estimates of treatment effect that were essentially unbiased. This method resulted in decreased bias compared to caliper matching alone and compared to either optimal matching or nearest neighbor matching alone. Caliper matching alone resulted in design bias or bias due to incomplete matching, while optimal matching or nearest neighbor matching alone resulted in bias due to residual confounding. The proposed method also tended to result in estimates with decreased mean squared error compared to when caliper matching was used. PMID:25038071

On incomplete sampling under birth-death models and connections to the sampling-based coalescent.

PubMed

Stadler, Tanja

2009-11-07

The constant rate birth-death process is used as a stochastic model for many biological systems, for example phylogenies or disease transmission. As the biological data are usually not fully available, it is crucial to understand the effect of incomplete sampling. In this paper, we analyze the constant rate birth-death process with incomplete sampling. We derive the density of the bifurcation events for trees on n leaves which evolved under this birth-death-sampling process. This density is used for calculating prior distributions in Bayesian inference programs and for efficiently simulating trees. We show that the birth-death-sampling process can be interpreted as a birth-death process with reduced rates and complete sampling. This shows that joint inference of birth rate, death rate and sampling probability is not possible. The birth-death-sampling process is compared to the sampling-based population genetics model, the coalescent. It is shown that despite many similarities between these two models, the distribution of bifurcation times remains different even in the case of very large population sizes. We illustrate these findings on an Hepatitis C virus dataset from Egypt. We show that the transmission times estimates are significantly different-the widely used Gamma statistic even changes its sign from negative to positive when switching from the coalescent to the birth-death process.

Modeling Aggressive Medulloblastoma Using Human Induced Pluripotent Stem Cells

DTIC Science & Technology

2017-09-01

and Myc in turn induces expression of AT1R creating a positive feedback loop and development of aggression tumor phenotype. The therapeutic...strengths are the relevant expertise of the applicant and his collaborating team, the novel paracrine positive feedback loop in EC-tumor cell...to as MYC-driven MB. The molecular mechanisms that drive MYC hyper -activation in MB remain incompletely understood. MB cells in actual tumors interact

Suppression of lysyl-tRNA synthetase, KRS, causes incomplete epithelial-mesenchymal transition and ineffective cell‑extracellular matrix adhesion for migration.

PubMed

Nam, Seo Hee; Kang, Minkyung; Ryu, Jihye; Kim, Hye-Jin; Kim, Doyeun; Kim, Dae Gyu; Kwon, Nam Hoon; Kim, Sunghoon; Lee, Jung Weon

2016-04-01

The cell-adhesion properties of cancer cells can be targeted to block cancer metastasis. Although cytosolic lysyl-tRNA synthetase (KRS) functions in protein synthesis, KRS on the plasma membrane is involved in cancer metastasis. We hypothesized that KRS is involved in cell adhesion-related signal transduction for cellular migration. To test this hypothesis, colon cancer cells with modulated KRS protein levels were analyzed for cell-cell contact and cell-substrate adhesion properties and cellular behavior. Although KRS suppression decreased expression of cell-cell adhesion molecules, cells still formed colonies without being scattered, supporting an incomplete epithelial mesenchymal transition. Noteworthy, KRS-suppressed cells still exhibited focal adhesions on laminin, with Tyr397-phopshorylated focal adhesion kinase (FAK), but they lacked laminin-adhesion-mediated extracellular signal-regulated kinase (ERK) and paxillin activation. KRS, p67LR and integrin α6β1 were found to interact, presumably to activate ERK for paxillin expression and Tyr118 phosphorylation even without involvement of FAK, so that specific inhibition of ERK or KRS in parental HCT116 cells blocked cell-cell adhesion and cell-substrate properties for focal adhesion formation and signaling activity. Together, these results indicate that KRS can promote cell-cell and cell-ECM adhesion for migration.

15 CFR 30.47 - Clearance or departure of carriers under bond on incomplete manifest.

Code of Federal Regulations, 2014 CFR

2014-01-01

... (a)(1), (2), and (3) of this section. (1) For manifests submitted electronically through AES, the... through the AES, the condition of the bond shall be that the manifest and all required filing citations...

Activity-based protein profiling for biochemical pathway discovery in cancer

PubMed Central

Nomura, Daniel K.; Dix, Melissa M.; Cravatt, Benjamin F.

2011-01-01

Large-scale profiling methods have uncovered numerous gene and protein expression changes that correlate with tumorigenesis. However, determining the relevance of these expression changes and which biochemical pathways they affect has been hindered by our incomplete understanding of the proteome and its myriad functions and modes of regulation. Activity-based profiling platforms enable both the discovery of cancer-relevant enzymes and selective pharmacological probes to perturb and characterize these proteins in tumour cells. When integrated with other large-scale profiling methods, activity-based proteomics can provide insight into the metabolic and signalling pathways that support cancer pathogenesis and illuminate new strategies for disease diagnosis and treatment. PMID:20703252

Reply to ‘Comment on “On the Clausius equality and inequality”’

NASA Astrophysics Data System (ADS)

Anacleto, Joaquim; Pereira, Mário G.; Ferreira, J. M.

2013-01-01

We address Bizarro's comment on a paper by Anacleto (2011 Eur. J. Phys. 32 279). Bizarro claims that (i) Anacleto's approach is either incomplete or incorrect; (ii) one problem is the definition of dissipative work; and (iii) additional ambiguities and misconceptions may stem from his explanations. We contend that (i) both authors present exactly the same definition of dissipative work; and (ii) it is possible to obtain a more general expression to evaluate the entropy change that comprises the expressions developed by both authors—indicating that Anacleto's approach is correct and coherent, and that the criticism of the paper is therefore unfounded.

Brain iron homeostasis, the choroid plexus, and localization of iron transport proteins.

PubMed

Rouault, Tracey A; Zhang, De-Liang; Jeong, Suh Young

2009-12-01

Maintenance of appropriate iron homeostasis in the brain is important, but the mechanisms involved in brain iron uptake are incompletely understood. Here, we have analyzed where messenger RNAs that encode iron transport proteins are expressed in the brain, using the Allen Brain atlas, and we conclude that several important iron transporters are highly expressed in the choroid plexus. Based on recent estimates of the surface area of the choroid plexus and on MRI imaging studies of manganese uptake in the brain, we propose that the choroid plexus may have a much greater role than has been previously appreciated in brain iron transport.

Mapping-by-sequencing of Ligon-lintless-1 (Li 1 ) reveals a cluster of neighboring genes with correlated expression in developing fibers of Upland cotton (Gossypium hirsutum L.).

PubMed

Thyssen, Gregory N; Fang, David D; Turley, Rickie B; Florane, Christopher; Li, Ping; Naoumkina, Marina

2015-09-01

Mapping-by-sequencing and SNP marker analysis were used to fine map the Ligon-lintless-1 ( Li 1 ) short fiber mutation in tetraploid cotton to a 255-kb region that contains 16 annotated proteins. The Ligon-lintless-1 (Li 1 ) mutant of cotton (Gossypium hirsutum L.) has been studied as a model for cotton fiber development since its identification in 1929; however, the causative mutation has not been identified yet. Here we report the fine genetic mapping of the mutation to a 255-kb region that contains only 16 annotated genes in the reference Gossypium raimondii genome. We took advantage of the incompletely dominant dwarf vegetative phenotype to identify 100 mutants (Li 1 /Li 1 ) and 100 wild-type (li 1 /li 1 ) homozygotes from a mapping population of 2567 F2 plants, which we bulked and deep sequenced. Since only homozygotes were sequenced, we were able to use a high stringency in SNP calling to rapidly narrow down the region harboring the Li 1 locus, and designed subgenome-specific SNP markers to test the population. We characterized the expression of all sixteen genes in the region by RNA sequencing of elongating fibers and by RT-qPCR at seven time points spanning fiber development. One of the most highly expressed genes found in this interval in wild-type fiber cells is 40-fold under-expressed at the day of anthesis (DOA) in the mutant fiber cells.  This gene is a major facilitator superfamily protein, part of the large family of proteins that includes auxin and sugar transporters. Interestingly, nearly all genes in this region were most highly expressed at DOA and showed a high degree of co-expression. Further characterization is required to determine if transport of hormones or carbohydrates is involved in both the dwarf and lintless phenotypes of Li 1 plants.

Review of Reliability-Based Design Optimization Approach and Its Integration with Bayesian Method

NASA Astrophysics Data System (ADS)

Zhang, Xiangnan

2018-03-01

A lot of uncertain factors lie in practical engineering, such as external load environment, material property, geometrical shape, initial condition, boundary condition, etc. Reliability method measures the structural safety condition and determine the optimal design parameter combination based on the probabilistic theory. Reliability-based design optimization (RBDO) is the most commonly used approach to minimize the structural cost or other performance under uncertainty variables which combines the reliability theory and optimization. However, it cannot handle the various incomplete information. The Bayesian approach is utilized to incorporate this kind of incomplete information in its uncertainty quantification. In this paper, the RBDO approach and its integration with Bayesian method are introduced.

7 CFR 1709.108 - Supporting data for determining community eligibility.

Code of Federal Regulations, 2010 CFR

2010-01-01

... areas. A comparison of the historical residential energy cost or expenditure information for the local... lieu of historical residential energy costs or expenditure information under the following circumstances: (1) Where historical community energy cost data are unavailable (unserved areas), incomplete or...

Sequestration of mitochondrial iron by silica particles initiates a biological effect.

EPA Science Inventory

Summary Inhalation of particulate matter has presented a challenge to human health for thousands of years. The underlying mechanism for biological effect following particle exposure is incompletely understood. We tested the postulate that particle sequestration of cell and mit...

Characterization of a Brome mosaic virus strain and its use as a vector for gene silencing in monocotyledonous hosts.

PubMed

Ding, Xin Shun; Schneider, William L; Chaluvadi, Srinivasa Rao; Mian, M A Rouf; Nelson, Richard S

2006-11-01

Virus-induced gene silencing (VIGS) is used to analyze gene function in dicotyledonous plants but less so in monocotyledonous plants (particularly rice and corn), partially due to the limited number of virus expression vectors available. Here, we report the cloning and modification for VIGS of a virus from Festuca arundinacea Schreb. (tall fescue) that caused systemic mosaic symptoms on barley, rice, and a specific cultivar of maize (Va35) under greenhouse conditions. Through sequencing, the virus was determined to be a strain of Brome mosaic virus (BMV). The virus was named F-BMV (F for Festuca), and genetic determinants that controlled the systemic infection of rice were mapped to RNAs 1 and 2 of the tripartite genome. cDNA from RNA 3 of the Russian strain of BMV (R-BMV) was modified to accept inserts from foreign genes. Coinoculation of RNAs 1 and 2 from F-BMV and RNA 3 from R-BMV expressing a portion of a plant gene to leaves of barley, rice, and maize plants resulted in visual silencing-like phenotypes. The visual phenotypes were correlated with decreased target host transcript levels in the corresponding leaves. The VIGS visual phenotype varied from maintained during silencing of actin 1 transcript expression to transient with incomplete penetration through affected tissue during silencing of phytoene desaturase expression. F-BMV RNA 3 was modified to allow greater accumulation of virus while minimizing virus pathogenicity. The modified vector C-BMV(A/G) (C for chimeric) was shown to be useful for VIGS. These BMV vectors will be useful for analysis of gene function in rice and maize for which no VIGS system is reported.

Adverse remodeling of the electrophysiological response to ischemia-reperfusion in human heart failure is associated with remodeling of metabolic gene expression.

PubMed

Ng, Fu Siong; Holzem, Katherine M; Koppel, Aaron C; Janks, Deborah; Gordon, Fabiana; Wit, Andrew L; Peters, Nicholas S; Efimov, Igor R

2014-10-01

Ventricular arrhythmias occur more frequently in heart failure during episodes of ischemia-reperfusion although the mechanisms underlying this in humans are unclear. We assessed, in explanted human hearts, the remodeled electrophysiological response to acute ischemia-reperfusion in heart failure and its potential causes, including the remodeling of metabolic gene expression. We optically mapped coronary-perfused left ventricular wedge preparations from 6 human end-stage failing hearts (F) and 6 donor hearts rejected for transplantation (D). Preparations were subjected to 30 minutes of global ischemia, followed by 30 minutes of reperfusion. Failing hearts had exaggerated electrophysiological responses to ischemia-reperfusion, with greater action potential duration shortening (P<0.001 at 8-minute ischemia; P=0.001 at 12-minute ischemia) and greater conduction slowing during ischemia, delayed recovery of electric excitability after reperfusion (F, 4.8±1.8 versus D, 1.0±0 minutes; P<0.05), and incomplete restoration of action potential duration and conduction velocity early after reperfusion. Expression of 46 metabolic genes was probed using custom-designed TaqMan arrays, using extracted RNA from 15 failing and 9 donor hearts. Ten genes important in cardiac metabolism were downregulated in heart failure, with SLC27A4 and KCNJ11 significantly downregulated at a false discovery rate of 0%. We demonstrate, for the first time in human hearts, that the electrophysiological response to ischemia-reperfusion in heart failure is accelerated during ischemia with slower recovery after reperfusion. This can enhance spatial conduction and repolarization gradients across the ischemic border and increase arrhythmia susceptibility. This adverse response was associated with downregulation of expression of cardiac metabolic genes. © 2014 American Heart Association, Inc.

Denitrification gene expression in clay-soil bacterial community

NASA Astrophysics Data System (ADS)

Pastorelli, R.; Landi, S.

2009-04-01

Our contribution in the Italian research project SOILSINK was focused on microbial denitrification gene expression in Mediterranean agricultural soils. In ecosystems with high inputs of nitrogen, such as agricultural soils, denitrification causes a net loss of nitrogen since nitrate is reduced to gaseous forms, which are released into the atmosphere. Moreover, incomplete denitrification can lead to emission of nitrous oxide, a potent greenhouse gas which contributes to global warming and destruction of ozone layer. A critical role in denitrification is played by microorganisms and the ability to denitrify is widespread among a variety of phylogenetically unrelated organisms. Data reported here are referred to wheat cultivation in a clay-rich soil under different environmental impact management (Agugliano, AN, Italy). We analysed the RNA directly extracted from soil to provide information on in situ activities of specific populations. The expression of genes coding for two nitrate reductases (narG and napA), two nitrite reductases (nirS and nirK), two nitric oxide reductases (cnorB and qnorB) and nitrous oxide reductase (nosZ) was analyzed by reverse transcription (RT)-nested PCR. Only napA, nirS, nirK, qnorB and nosZ were detected and fragments sequenced showed high similarity with the corresponding gene sequences deposited in GenBank database. These results suggest the suitability of the method for the qualitative detection of denitrifying bacteria in environmental samples and they offered us the possibility to perform the denaturing gradient gel electrophoresis (DGGE) analyzes for denitrification genes.. Earlier conclusions showed nirK gene is more widely distributed in soil environment than nirS gene. The results concerning the nosZ expression indicated that microbial activity was clearly present only in no-tilled and no-fertilized soils.

Using co-expression analysis and stress-based screens to uncover Arabidopsis peroxisomal proteins involved in drought response

DOE PAGES

Li, Jiying; Hu, Jianping; Bassham, Diane

2015-09-14

Peroxisomes are essential organelles that house a wide array of metabolic reactions important for plant growth and development. However, our knowledge regarding the role of peroxisomal proteins in various biological processes, including plant stress response, is still incomplete. Recent proteomic studies of plant peroxisomes significantly increased the number of known peroxisomal proteins and greatly facilitated the study of peroxisomes at the systems level. The objectives of this study were to determine whether genes that encode peroxisomal proteins with related functions are co-expressed in Arabidopsis and identify peroxisomal proteins involved in stress response using in silico analysis and mutant screens. Usingmore » microarray data from online databases, we performed hierarchical clustering analysis to generate a comprehensive view of transcript level changes for Arabidopsis peroxisomal genes during development and under abiotic and biotic stress conditions. Many genes involved in the same metabolic pathways exhibited co-expression, some genes known to be involved in stress response are regulated by the corresponding stress conditions, and function of some peroxisomal proteins could be predicted based on their coexpression pattern. Since drought caused expression changes to the highest number of genes that encode peroxisomal proteins, we subjected a subset of Arabidopsis peroxisomal mutants to a drought stress assay. Mutants of the LON2 protease and the photorespiratory enzyme hydroxypyruvate reductase 1 (HPR1) showed enhanced susceptibility to drought, suggesting the involvement of peroxisomal quality control and photorespiration in drought resistance. Lastly, our study provided a global view of how genes that encode peroxisomal proteins respond to developmental and environmental cues and began to reveal additional peroxisomal proteins involved in stress response, thus opening up new avenues to investigate the role of peroxisomes in plant adaptation to environmental stresses.« less

Hindbrain Catecholamine Neurons Activate Orexin Neurons During Systemic Glucoprivation in Male Rats.

PubMed

Li, Ai-Jun; Wang, Qing; Elsarelli, Megan M; Brown, R Lane; Ritter, Sue

2015-08-01

Hindbrain catecholamine neurons are required for elicitation of feeding responses to glucose deficit, but the forebrain circuitry required for these responses is incompletely understood. Here we examined interactions of catecholamine and orexin neurons in eliciting glucoprivic feeding. Orexin neurons, located in the perifornical lateral hypothalamus (PeFLH), are heavily innervated by hindbrain catecholamine neurons, stimulate food intake, and increase arousal and behavioral activation. Orexin neurons may therefore contribute importantly to appetitive responses, such as food seeking, during glucoprivation. Retrograde tracing results showed that nearly all innervation of the PeFLH from the hindbrain originated from catecholamine neurons and some raphe nuclei. Results also suggested that many catecholamine neurons project collaterally to the PeFLH and paraventricular hypothalamic nucleus. Systemic administration of the antiglycolytic agent, 2-deoxy-D-glucose, increased food intake and c-Fos expression in orexin neurons. Both responses were eliminated by a lesion of catecholamine neurons innervating orexin neurons using the retrogradely transported immunotoxin, anti-dopamine-β-hydroxylase saporin, which is specifically internalized by dopamine-β-hydroxylase-expressing catecholamine neurons. Using designer receptors exclusively activated by designer drugs in transgenic rats expressing Cre recombinase under the control of tyrosine hydroxylase promoter, catecholamine neurons in cell groups A1 and C1 of the ventrolateral medulla were activated selectively by peripheral injection of clozapine-N-oxide. Clozapine-N-oxide injection increased food intake and c-Fos expression in PeFLH orexin neurons as well as in paraventricular hypothalamic nucleus neurons. In summary, catecholamine neurons are required for the activation of orexin neurons during glucoprivation. Activation of orexin neurons may contribute to appetitive responses required for glucoprivic feeding.

HMGB1 induces an inflammatory response in endothelial cells via the RAGE-dependent endoplasmic reticulum stress pathway

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

Luo, Ying; Li, Shu-Jun; Yang, Jian

Highlights: •Mechanisms of inflammatory response induced by HMGB1 are incompletely understood. •We found that endoplasmic reticulum stress mediate the inflammatory response induced by HMGB1. •RAGE-mediated ERS pathways are involved in those processes. •We reported a new mechanism for HMGB1 induced inflammatory response. -- Abstract: The high mobility group 1B protein (HMGB1) mediates chronic inflammatory responses in endothelial cells, which play a critical role in atherosclerosis. However, the underlying mechanism is unknown. The goal of our study was to identify the effects of HMGB1 on the RAGE-induced inflammatory response in endothelial cells and test the possible involvement of the endoplasmic reticulummore » stress pathway. Our results showed that incubation of endothelial cells with HMGB1 (0.01–1 μg/ml) for 24 h induced a dose-dependent activation of endoplasmic reticulum stress transducers, as assessed by PERK and IRE1 protein expression. Moreover, HMGB1 also promoted nuclear translocation of ATF6. HMGB1-mediated ICAM-1 and P-selectin production was dramatically suppressed by PERK siRNA or IRE1 siRNA. However, non-targeting siRNA had no such effects. HMGB1-induced increases in ICAM-1 and P-selectin expression were also inhibited by a specific eIF2α inhibitor (salubrinal) and a specific JNK inhibitor (SP600125). Importantly, a blocking antibody specifically targeted against RAGE (anti-RAGE antibody) decreased ICAM-1, P-selectin and endoplasmic reticulum stress molecule (PERK, eIF2α, IRE1 and JNK) protein expression levels. Collectively, these novel findings suggest that HMGB1 promotes an inflammatory response by inducing the expression of ICAM-1 and P-selectin via RAGE-mediated stimulation of the endoplasmic reticulum stress pathway.« less

High-Intensity Locomotor Exercise Increases Brain-Derived Neurotrophic Factor in Individuals with Incomplete Spinal Cord Injury.

PubMed

Leech, Kristan A; Hornby, T George

2017-03-15

High-intensity locomotor exercise is suggested to contribute to improved recovery of locomotor function after neurological injury. This may be secondary to exercise-intensity-dependent increases in neurotrophin expression demonstrated previously in control subjects. However, rigorous examination of intensity-dependent changes in neurotrophin levels is lacking in individuals with motor incomplete spinal cord injury (SCI). Therefore, the primary aim of this study was to evaluate the effect of locomotor exercise intensity on peripheral levels of brain-derived neurotrophic factor (BDNF) in individuals with incomplete SCI. We also explored the impact of the Val66Met single-nucleotide polymorphism (SNP) on the BDNF gene on intensity-dependent changes. Serum concentrations of BDNF and insulin-like growth factor-1 (IGF-1), as well as measures of cardiorespiratory dynamics, were evaluated across different levels of exercise intensity achieved during a graded-intensity, locomotor exercise paradigm in 11 individuals with incomplete SCI. Our results demonstrate a significant increase in serum BDNF at high, as compared to moderate, exercise intensities (p = 0.01) and 15 and 30 min post-exercise (p < 0.01 for both), with comparison to changes at low intensity approaching significance (p = 0.05). Serum IGF-1 demonstrated no intensity-dependent changes. Significant correlations were observed between changes in BDNF and specific indicators of exercise intensity (e.g., rating of perceived exertion; R = 0.43; p = 0.02). Additionally, the data suggest that Val66Met SNP carriers may not exhibit intensity-dependent changes in serum BDNF concentration. Given the known role of BDNF in experience-dependent neuroplasticity, these preliminary results suggest that exercise intensity modulates serum BDNF concentrations and may be an important parameter of physical rehabilitation interventions after neurological injury.

High-Intensity Locomotor Exercise Increases Brain-Derived Neurotrophic Factor in Individuals with Incomplete Spinal Cord Injury

PubMed Central

Leech, Kristan A.

2017-01-01

Abstract High-intensity locomotor exercise is suggested to contribute to improved recovery of locomotor function after neurological injury. This may be secondary to exercise-intensity–dependent increases in neurotrophin expression demonstrated previously in control subjects. However, rigorous examination of intensity-dependent changes in neurotrophin levels is lacking in individuals with motor incomplete spinal cord injury (SCI). Therefore, the primary aim of this study was to evaluate the effect of locomotor exercise intensity on peripheral levels of brain-derived neurotrophic factor (BDNF) in individuals with incomplete SCI. We also explored the impact of the Val66Met single-nucleotide polymorphism (SNP) on the BDNF gene on intensity-dependent changes. Serum concentrations of BDNF and insulin-like growth factor-1 (IGF-1), as well as measures of cardiorespiratory dynamics, were evaluated across different levels of exercise intensity achieved during a graded-intensity, locomotor exercise paradigm in 11 individuals with incomplete SCI. Our results demonstrate a significant increase in serum BDNF at high, as compared to moderate, exercise intensities (p = 0.01) and 15 and 30 min post-exercise (p < 0.01 for both), with comparison to changes at low intensity approaching significance (p = 0.05). Serum IGF-1 demonstrated no intensity-dependent changes. Significant correlations were observed between changes in BDNF and specific indicators of exercise intensity (e.g., rating of perceived exertion; R = 0.43; p = 0.02). Additionally, the data suggest that Val66Met SNP carriers may not exhibit intensity-dependent changes in serum BDNF concentration. Given the known role of BDNF in experience-dependent neuroplasticity, these preliminary results suggest that exercise intensity modulates serum BDNF concentrations and may be an important parameter of physical rehabilitation interventions after neurological injury. PMID:27526567

Lipid Partitioning, Incomplete Fatty Acid Oxidation, and Insulin Signal Transduction in Primary Human Muscle Cells: Effects of Severe Obesity, Fatty Acid Incubation, and Fatty Acid Translocase/CD36 Overexpression

PubMed Central

Bell, Jill A.; Reed, Melissa A.; Consitt, Leslie A.; Martin, Ola J.; Haynie, Kimberly R.; Hulver, Matthew W.; Muoio, Deborah M.; Dohm, G. Lynis

2010-01-01

Context: Intracellular lipid partitioning toward storage and the incomplete oxidation of fatty acids (FA) have been linked to insulin resistance. Objective: To gain insight into how intracellular lipid metabolism is related to insulin signal transduction, we examined the effects of severe obesity, excess FA, and overexpression of the FA transporter, FA translocase (FAT)/CD36, in primary human skeletal myocytes. Design, Setting, and Patients: Insulin signal transduction, FA oxidation, and metabolism were measured in skeletal muscle cells harvested from lean and severely obese women. To emulate the obesity phenotype in our cell culture system, we incubated cells from lean individuals with excess FA or overexpressed FAT/CD36 using recombinant adenoviral technology. Results: Complete oxidation of FA was significantly reduced, whereas total lipid accumulation, FA esterification into lipid intermediates, and incomplete oxidation were up-regulated in the muscle cells of severely obese subjects. Insulin signal transduction was reduced in the muscle cells from severely obese subjects compared to lean controls. Incubation of muscle cells from lean subjects with lipids reduced insulin signal transduction and increased lipid storage and incomplete FA oxidation. CD36 overexpression increased FA transport capacity, but did not impair complete FA oxidation and insulin signal transduction in muscle cells from lean subjects. Conclusions: Cultured myocytes from severely obese women express perturbations in FA metabolism and insulin signaling reminiscent of those observed in vivo. The obesity phenotype can be recapitulated in muscle cells from lean subjects via exposure to excess lipid, but not by overexpressing the FAT/CD36 FA transporter. PMID:20427507

Differentiation of C2C12 myoblasts expressing lamin A mutated at a site responsible for Emery-Dreifuss muscular dystrophy is improved by inhibition of the MEK-ERK pathway and stimulation of the PI3-kinase pathway

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

Favreau, Catherine; Delbarre, Erwan; Courvalin, Jean-Claude

2008-04-01

Mutation R453W in A-type lamins, that are major nuclear envelope proteins, generates Emery-Dreifuss muscular dystrophy. We previously showed that mouse myoblasts expressing R453W-lamin A incompletely exit the cell cycle and differentiate into myocytes with a low level of multinucleation. Here we attempted to improve differentiation by treating these cells with a mixture of PD98059, an extracellular-regulated kinase (ERK) kinase (also known as mitogen-activated kinase, MEK) inhibitor, and insulin-like growth factor-II, an activator of phosphoinositide 3-kinase. We show that mouse myoblasts expressing R453W-lamin A were sensitive to the drug treatment as shown by (i) an increase in multinucleation, (ii) downregulation ofmore » proliferation markers (cyclin D1, hyperphosphorylated Rb), (iii) upregulation of myogenin, and (iv) sustained activation of p21 and cyclin D3. However, nuclear matrix anchorage of p21 and cyclin D3 in a complex with hypophosphorylated Rb that is critical to trigger cell cycle arrest and myogenin induction was deficient and incompletely restored by drug treatment. As the turn-over of R453W-lamin A at the nuclear envelope was greatly enhanced, we propose that R453W-lamin A impairs the capacity of the nuclear lamina to serve as scaffold for substrates of the MEK-ERK pathway and for MyoD-induced proteins that play a role in the differentiation process.« less

A-MADMAN: Annotation-based microarray data meta-analysis tool

PubMed Central

Bisognin, Andrea; Coppe, Alessandro; Ferrari, Francesco; Risso, Davide; Romualdi, Chiara; Bicciato, Silvio; Bortoluzzi, Stefania

2009-01-01

Background Publicly available datasets of microarray gene expression signals represent an unprecedented opportunity for extracting genomic relevant information and validating biological hypotheses. However, the exploitation of this exceptionally rich mine of information is still hampered by the lack of appropriate computational tools, able to overcome the critical issues raised by meta-analysis. Results This work presents A-MADMAN, an open source web application which allows the retrieval, annotation, organization and meta-analysis of gene expression datasets obtained from Gene Expression Omnibus. A-MADMAN addresses and resolves several open issues in the meta-analysis of gene expression data. Conclusion A-MADMAN allows i) the batch retrieval from Gene Expression Omnibus and the local organization of raw data files and of any related meta-information, ii) the re-annotation of samples to fix incomplete, or otherwise inadequate, metadata and to create user-defined batches of data, iii) the integrative analysis of data obtained from different Affymetrix platforms through custom chip definition files and meta-normalization. Software and documentation are available on-line at . PMID:19563634

The incomplete anti-Rh antibody agglutination mechanism of trypsinized ORh+ red cells.

PubMed Central

Margni, R A; Leoni, J; Bazzurro, M

1977-01-01

The capacity for binding to trypsinized and non-trypsinized ORh+ red cells, of the IgG incomplete anti-Rh antibody and its F(ab')2 and Fc fragments has been investigated. An analysis has also been made of the capacity of non-specific human IgG, aggregated non-specific human IgG, human IgM (19S) and IgM (7S), and of fragments Fcgamma, Fcmu and Fc5mu to inhibit the agglutination of trypsinized ORh+ red cells by the IgG incomplete anti-Rh antibody. The results obtained indicate that these antibodies behave in a similar manner to that of nonprecipitating antibodies, and that the agglutination of trypsinized red cells seems to be a mixed reaction due to the interaction of an Fab fragment with its Rh antigenic determinant present in the surface of a red cell and the Fc of the same molecule with a receptor for Fc present in adjacent red cells. The trypsin treatment apparently results in the liberation of occult Fc receptors. It has also been demonstrated that in the agglutination of ORh+ red cells by IgG incomplete anti-Rh antibody in the presence of albumin, interaction must occur in some manner between the albumin and the Fc fragment since the F(ab')2 fragment does not give rise to agglutination under such conditions. Images Figure 1 PMID:415968

Sample size considerations for paired experimental design with incomplete observations of continuous outcomes.

PubMed

Zhu, Hong; Xu, Xiaohan; Ahn, Chul

2017-01-01

Paired experimental design is widely used in clinical and health behavioral studies, where each study unit contributes a pair of observations. Investigators often encounter incomplete observations of paired outcomes in the data collected. Some study units contribute complete pairs of observations, while the others contribute either pre- or post-intervention observations. Statistical inference for paired experimental design with incomplete observations of continuous outcomes has been extensively studied in literature. However, sample size method for such study design is sparsely available. We derive a closed-form sample size formula based on the generalized estimating equation approach by treating the incomplete observations as missing data in a linear model. The proposed method properly accounts for the impact of mixed structure of observed data: a combination of paired and unpaired outcomes. The sample size formula is flexible to accommodate different missing patterns, magnitude of missingness, and correlation parameter values. We demonstrate that under complete observations, the proposed generalized estimating equation sample size estimate is the same as that based on the paired t-test. In the presence of missing data, the proposed method would lead to a more accurate sample size estimate comparing with the crude adjustment. Simulation studies are conducted to evaluate the finite-sample performance of the generalized estimating equation sample size formula. A real application example is presented for illustration.

Predictors of seizure freedom after incomplete resection in children.

PubMed

Perry, M S; Dunoyer, C; Dean, P; Bhatia, S; Bavariya, A; Ragheb, J; Miller, I; Resnick, T; Jayakar, P; Duchowny, M

2010-10-19

Incomplete resection of the epileptogenic zone (EZ) is the most important predictor of poor outcome after resective surgery for intractable epilepsy. We analyzed the contribution of preoperative and perioperative variables including MRI and EEG data as predictors of seizure-free (SF) outcome after incomplete resection. We retrospectively reviewed patients <18 years of age with incomplete resection for epilepsy with 2 years of follow-up. Fourteen preoperative and perioperative variables were compared in SF and non-SF (NSF) patients. We compared lesional patients, categorized by reason for incompleteness, to lesional patients with complete resection. We analyzed for effect of complete EEG resection on SF outcome in patients with incompletely resected MRI lesions and vice versa. Eighty-three patients with incomplete resection were included with 41% becoming SF. Forty-eight lesional patients with complete resection were included. Thirty-eight percent (57/151) of patients with incomplete resection and 34% (47/138) with complete resection were excluded secondary to lack of follow-up or incomplete records. Contiguous MRI lesions were predictive of seizure freedom after incomplete resection. Fifty-seven percent of patients incomplete by MRI alone, 52% incomplete by EEG alone, and 24% incomplete by both became SF compared to 77% of patients with complete resection (p = 0.0005). Complete resection of the MRI- and EEG-defined EZ is the best predictor of seizure freedom, though patients incomplete by EEG or MRI alone have better outcome compared to patients incomplete by both. More than one-third of patients with incomplete resection become SF, with contiguous MRI lesions a predictor of SF outcome.

Distributed control systems with incomplete and uncertain information

NASA Astrophysics Data System (ADS)

Tang, Jingpeng

Scientific and engineering advances in wireless communication, sensors, propulsion, and other areas are rapidly making it possible to develop unmanned air vehicles (UAVs) with sophisticated capabilities. UAVs have come to the forefront as tools for airborne reconnaissance to search for, detect, and destroy enemy targets in relatively complex environments. They potentially reduce risk to human life, are cost effective, and are superior to manned aircraft for certain types of missions. It is desirable for UAVs to have a high level of intelligent autonomy to carry out mission tasks with little external supervision and control. This raises important issues involving tradeoffs between centralized control and the associated potential to optimize mission plans, and decentralized control with great robustness and the potential to adapt to changing conditions. UAV capabilities have been extended several ways through armament (e.g., Hellfire missiles on Predator UAVs), increased endurance and altitude (e.g., Global Hawk), and greater autonomy. Some known barriers to full-scale implementation of UAVs are increased communication and control requirements as well as increased platform and system complexity. One of the key problems is how UAV systems can handle incomplete and uncertain information in dynamic environments. Especially when the system is composed of heterogeneous and distributed UAVs, the overall system complexity is increased under such conditions. Presented through the use of published papers, this dissertation lays the groundwork for the study of methodologies for handling incomplete and uncertain information for distributed control systems. An agent-based simulation framework is built to investigate mathematical approaches (optimization) and emergent intelligence approaches. The first paper provides a mathematical approach for systems of UAVs to handle incomplete and uncertain information. The second paper describes an emergent intelligence approach for UAVs, again in handling incomplete and uncertain information. The third paper combines mathematical and emergent intelligence approaches.

Dehydration upon admission is a risk factor for incomplete recovery of renal function in children with haemolytic uremic syndrome.

PubMed

Ojeda, José M; Kohout, Isolda; Cuestas, Eduardo

2013-01-01

Haemolytic uremic syndrome (HUS) is the most common cause of acute renal failure and the second leading cause of chronic renal failure in children. The factors that affect incomplete renal function recovery prior to hospital admission are poorly understood. To analyse the risk factors that determine incomplete recovery of renal function prior to hospitalisation in children with HUS. A retrospective case-control study. age, sex, duration of diarrhoea, bloody stools, vomiting, fever, dehydration, previous use of antibiotics, and incomplete recovery of renal function (proteinuria, hypertension, reduced creatinine clearance, and chronic renal failure during follow-up). Patients of both sexes under 15 years of age were included. Of 36 patients, 23 were males (65.3%; 95%CI: 45.8 to 80.9), with an average age of 2.5 ± 1.4 years. Twenty-one patients required dialysis (58%; 95% CI: 40.8 to 75.8), and 13 (36.1%; 95% CI: 19.0 to 53.1) did not recover renal function. In the bivariate model, the only significant risk factor was dehydration (defined as weight loss >5%) [(OR: 5.3; 95% CI: 1.4 to 12.3; P=.0220]. In the multivariate analysis (Cox multiple regression), only dehydration was marginally significant (HR: 95.823; 95% CI: 93.175 to 109.948; P=.085). Our data suggest that dehydration prior to admission may be a factor that increases the risk of incomplete recovery of renal function during long-term follow-up in children who develop HUS D+. Consequently, in patients with diarrhoea who are at risk of HUS, dehydration should be strongly avoided during outpatient care to preserve long-term renal function. These results must be confirmed by larger prospective studies.

Psychology Textbooks: Examining Their Accuracy

ERIC Educational Resources Information Center

Steuer, Faye B.; Ham, K. Whitfield, II

2008-01-01

Sales figures and recollections of psychologists indicate textbooks play a central role in psychology students' education, yet instructors typically must select texts under time pressure and with incomplete information. Although selection aids are available, none adequately address the accuracy of texts. We describe a technique for sampling…

Diamagnetic Corrections and Pascal's Constants

ERIC Educational Resources Information Center

Bain, Gordon A.; Berry, John F.

2008-01-01

Measured magnetic susceptibilities of paramagnetic substances must typically be corrected for their underlying diamagnetism. This correction is often accomplished by using tabulated values for the diamagnetism of atoms, ions, or whole molecules. These tabulated values can be problematic since many sources contain incomplete and conflicting data.…

Circadian Rhythm and Cartilage Extracellular Matrix Genes in Osseointegration: A Genome-Wide Screening of Implant Failure by Vitamin D Deficiency

PubMed Central

Mengatto, Cristiane Machado; Mussano, Federico; Honda, Yoshitomo; Colwell, Christopher S.; Nishimura, Ichiro

2011-01-01

Background Successful dental and orthopedic implants require the establishment of an intimate association with bone tissue; however, the mechanistic explanation of how biological systems accomplish osseointegration is still incomplete. We sought to identify critical gene networks involved in osseointegration by exploring the implant failure model under vitamin D deficiency. Methodology Adult male Sprague-Dawley rats were exposed to control or vitamin D-deficient diet prior to the osteotomy surgery in the femur bone and the placement of T-shaped Ti4Al6V implant. Two weeks after the osteotomy and implant placement, tissue formed at the osteotomy site or in the hollow chamber of T-shaped implant was harvested and total RNA was evaluated by whole genome microarray analyses. Principal Findings Two-way ANOVA of microarray data identified 103 genes that were significantly (>2 fold) modulated by the implant placement and vitamin D deficiency. Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses assigned the highest z-score to the circadian rhythm pathway including neuronal PAS domain 2 (NPAS2), and period homolog 2 (Per2). NPAS2 and Aryl hydrocarbon receptor nuclear translocator-like (ARNTL/Bmal 1) were upregulated around implant and diminished by vitamin D deficiency, whereas the expression pattern of Per2 was complementary. Hierarchical cluster analysis further revealed that NPAS2 was in a group predominantly composed of cartilage extracellular matrix (ECM) genes. Whereas the expression of bone ECM genes around implant was not significantly affected by vitamin D deficiency, cartilage ECM genes were modulated by the presence of the implant and vitamin D status. In a proof-of-concept in vitro study, the expression of cartilage type II and X collagens was found upregulated when mouse mesenchymal stem cells were cultured on implant disk with 1,25D supplementation. Conclusions This study suggests that the circadian rhythm system and cartilage extracellular matrix may be involved in the establishment of osseointegration under vitamin D regulation. PMID:21264318

Essays on incomplete contracts in regulatory activities

NASA Astrophysics Data System (ADS)

Saavedra, Eduardo Humberto

This dissertation consists of three essays. The first essay, The Hold-Up Problem in Public Infrastructure Franchising, characterizes the equilibria of the investment decisions in public infrastructure franchising under incomplete contracting and ex-post renegotiation. The parties (government and a firm) are unable to credibly commit to the contracted investment plan, so that a second step investment is renegotiated by the parties at the revision stage. As expected, the possibility of renegotiation affects initial non-verifiable investments. The main conclusion of this essay is that not only underinvestment but also overinvestment in infrastructure may arise in equilibrium, compared to the complete contracting case. The second essay, Alternative Institutional Arrangements in Network Utilities: An Incomplete Contracting Approach, presents a theoretical assessment of the efficiency implications of privatizing natural monopolies which are vertically related to potential competitive firms. Based on the incomplete contracts and asymmetric information paradigm. I develop a model that analyzes the relative advantages of different institutional arrangements---alternative ownership and market structures in the industry--- in terms of their allocative and productive efficiencies. The main policy conclusion of this essay is that both ownership and the existence of conglomerates in network industries matter. Among other conclusions, this essay provides an economic rationale for a mixed economy in which the network is public and vertical separation of the industry when the natural monopoly is under private ownership. The last essay, Opportunistic Behavior and Legal Disputes in the Chilean Electricity Sector, analyzes post-contractual disputes in this newly privatized industry. It discusses the presumption that opportunistic behavior and disputes arise due to inadequate market design, ambiguous regulation, and institutional weaknesses. This chapter also assesses the presumption that a large number of legal disputes are inhibited by the nonexistence of institutions able to verify and enforce contracts. An in-depth analysis of six cases of open conflict provides support for such a presumption and highlights the crucial role of an adequate market design.

[Potential under-registration of occupational accidents in the Mexican Institute of Social Security].

PubMed

Salinas-Tovar, José Santiago; López-Rojas, Pablo; Soto-Navarro, María Oralia; Caudillo-Araujo, David Efraín; Sánchez-Román, Francisco Raúl; Borja-Aburto, Victor Hugo

2004-01-01

To assess the potential under-registration of work-related accidents in the Mexican Institute of Social Security. A countrywide cross-sectional study was carried out with information collected from 27 district offices of the Mexican Institute of Social Security (MISS), on workers seen at MISS emergency rooms during November 2001 because of a probable accident at work. We compared these reports to official records of work-related accidents to estimate the proportion of incomplete reports. Data analysis consisted of descriptive statistics for each variable; the annual estimation of incomplete reporting proportions was made by multiplying by twelve months; 95% confidence intervals were estimated using Poisson's exact method for a proportion. Data from 27 out of 37 MISS district offices revealed that 7211 cases were not recognized as work accidents, accounting for an underestimation of 26.3%, ranging between 0 and 68% among the different district offices. The accidents that were most frequently left unregistered were mild and blunt injuries. Under-registration can affect worker compensation plans and the financial balance of the institution's occupational risk insurance. Research is needed to investigate and eliminate the causes of under-registration. Employers, the industry, and health institutions should be involved in this effort. The English version of this paper is available at: http://www.insp.mx/salud/index.html.

Variable expression of podocyte-related markers in the glomeruloid bodies in Wilms tumor.

PubMed

Kanemoto, Katsuyoshi; Takahashi, Shori; Shu, Yujing; Usui, Joichi; Tomari, Shinsuke; Yan, Kunimasa; Hamazaki, Yutaka; Nagata, Michio

2003-09-01

Several podocyte-related markers are organized to express in glomerular differentiation. However, whether expression of them is virtually synchronized and a reliable indicator of the state of differentiation is unknown. The present study investigated, by immunohistochemistry, the divergent expression of several podocyte markers in the improperly differentiated glomeruloid bodies from four cases of Wilms tumors. The glomeruloid bodies were classified into immature (IGB) or mature forms (MGB) based on morphology and epithelial features. Podocytes in IGB expressed WT1, synaptopodin, podocalyxin, and nephrin, and their expression was stronger in MGB. In contrast, Pax2 was strong in IGB and diminished in MGB. p27 was first expressed in MGB. The expression pattern in each molecule mimics normal glomerulogenesis. Podocytes in MGB showed persistent expression of bcl-2 and cytokeratin with synaptopodin, podocalyxin, and nephrin by serial section, a finding unusual for normal glomerulogenesis. Moreover, parietal cells in MGB also occasionally expressed these podocyte markers. The ultrastructure revealed that podocytes in MGB showed tight junctions without foot process formations, which indicated incomplete differentiation. These results suggest that a set of podocyte differentiation markers are occasionally diversely expressed, and raise the possibility that expression of these markers is insufficient to determine the state of terminal differentiation in podocytes.

Molecular mechanisms of continuous light inhibition of Atlantic salmon parr-smolt transformation

USGS Publications Warehouse

Stefansson, S.O.; Nilsen, Tom O.; Ebbesson, Lars O.E.; Wargelius, A.; Madsen, Steffen S.; Bjornsson, B. Th; McCormick, S.D.

2007-01-01

Atlantic salmon (Salmo salar) rely on changes in photoperiod for the synchronization of the developmental events constituting the parr-smolt transformation. In the absence of photoperiod cues, parr-smolt transformation is incomplete, and such 'pseudo-smolts' normally fail to adapt to seawater. The present study addresses the endocrine and molecular mechanisms controlling the development of hypo-osmoregulatory ability and how artificial photoperiod can disrupt these changes. Juvenile Atlantic salmon reared under constant light (LL) from first feeding, were separated into two groups, and exposed to either LL or simulated natural photoperiod (LDN) from October, eight months prior to the expected completion of smoltification. Juveniles reared on LL grew well, but failed to show the smolt-related reduction in condition factor in spring. Gill mRNA levels of Na+, K+-ATPase (NKA) isoform ??1a decreased in LDN fish through completion of parr-smolt transformation, while levels remained unchanged in the LL group. In contrast, ??1b expression increased 6-fold in the LDN group between February and May, again with no change in the LL group. Further, Na+, K+, 2Cl- co-transporter (NKCC) showed a transient increase in expression in smolts on LDN between February and May, while no changes in mRNA levels were seen in juveniles under LL. Consequently, gill NKA activity and NKA ?? and NKCC protein abundance were significantly lower in juveniles on LL than in smolts on LDN. LL fish in spring had lower circulating levels of thyroid hormones (THs), growth hormone (GH) and cortisol. Gill GH-receptor mRNA levels, determined by quantitative PCR, were less than 50% of controls. In contrast, circulating levels of IGF-1 and gill IGF-1 receptor expression, were comparable to controls. Our findings show that continuous light prevents the completion of parr-smolt transformation at a very basic level, disrupting the natural up-regulation of key elements of the endocrine system involved in the regulation of the parr-smolt transformation, and consequently inhibiting the smoltification-related increase in expression, abundance and activity of gill ion transport proteins. ?? 2007 Elsevier B.V. All rights reserved.

Blockade of αEβ7 integrin suppresses accumulation of CD8+ and Th9 lymphocytes from patients with IBD in the inflamed gut in vivo.

PubMed

Zundler, Sebastian; Schillinger, Daniela; Fischer, Anika; Atreya, Raja; López-Posadas, Rocío; Watson, Alastair; Neufert, Clemens; Atreya, Imke; Neurath, Markus F

2017-11-01

Therapeutically targeting lymphocyte adhesion is of increasing relevance in IBD. Yet, central aspects of the action of antiadhesion compounds are incompletely understood. We investigated the role of αEβ7 and α4β7 integrins and their blockade by vedolizumab and etrolizumab for trafficking of IBD T lymphocytes in an in vivo model of homing to and retention in the inflamed gut. We explored integrin expression in patients with IBD by flow cytometry and immunohistochemistry, while regulation of integrins was studied in T cell cultures. The functional relevance of integrins was assessed by adhesion assays and a recently established humanised mouse model in dextran sodium sulfate-treated immunodeficient mice. High expression of αEβ7 was noted on CD8 + and CD4 + Th9 cells, while α4β7 was expressed on CD8 + , Th2 and Th17 cells. T cell receptor stimulation and transforming growth factor β were key inducers of αEβ7 on human T cells, while butyric acid suppressed αEβ7. In comparison to α4β7 blockade via vedolizumab, blockade of β7 via etrolizumab surrogate antibody superiorly reduced colonic numbers of CD8 + and Th9 cells in vivo after 3 hours, while no difference was noted after 0.5 hours. AEβ7 expression was higher on CD8 + T cells from patients with IBD under vedolizumab therapy. AEβ7 is of key relevance for gut trafficking of IBD CD8 + T cells and CD4 + Th9 cells in vivo and mainly retention might account for this effect. These findings indicate that blockade of αEβ7 in addition to α4β7 may be particularly effective in intestinal disorders with expansion of CD8 + and Th9 cells such as IBD. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Acute exposure to wood smoke from incomplete combustion--indications of cytotoxicity.

PubMed

Muala, Ala; Rankin, Gregory; Sehlstedt, Maria; Unosson, Jon; Bosson, Jenny A; Behndig, Annelie; Pourazar, Jamshid; Nyström, Robin; Pettersson, Esbjörn; Bergvall, Christoffer; Westerholm, Roger; Jalava, Pasi I; Happo, Mikko S; Uski, Oskari; Hirvonen, Maija-Riitta; Kelly, Frank J; Mudway, Ian S; Blomberg, Anders; Boman, Christoffer; Sandström, Thomas

2015-10-29

Smoke from combustion of biomass fuels is a major risk factor for respiratory disease, but the underlying mechanisms are poorly understood. The aim of this study was to determine whether exposure to wood smoke from incomplete combustion would elicit airway inflammation in humans. Fourteen healthy subjects underwent controlled exposures on two separate occasions to filtered air and wood smoke from incomplete combustion with PM1 concentration at 314 μg/m(3) for 3 h in a chamber. Bronchoscopy with bronchial wash (BW), bronchoalveolar lavage (BAL) and endobronchial mucosal biopsies was performed after 24 h. Differential cell counts and soluble components were analyzed, with biopsies stained for inflammatory markers using immunohistochemistry. In parallel experiments, the toxicity of the particulate matter (PM) generated during the chamber exposures was investigated in vitro using the RAW264.7 macrophage cell line. Significant reductions in macrophage, neutrophil and lymphocyte numbers were observed in BW (p < 0.01, <0.05, <0.05, respectively) following the wood smoke exposure, with a reduction in lymphocytes numbers in BAL fluid (<0.01. This unexpected cellular response was accompanied by decreased levels of sICAM-1, MPO and MMP-9 (p < 0.05, <0.05 and <0.01). In contrast, significant increases in submucosal and epithelial CD3+ cells, epithelial CD8+ cells and submucosal mast cells (p < 0.01, <0.05, <0.05 and <0.05, respectively), were observed after wood smoke exposure. The in vitro data demonstrated that wood smoke particles generated under these incomplete combustion conditions induced cell death and DNA damage, with only minor inflammatory responses. Short-term exposure to sooty PAH rich wood smoke did not induce an acute neutrophilic inflammation, a classic hallmark of air pollution exposure in humans. While minor proinflammatory lymphocytic and mast cells effects were observed in the bronchial biopsies, significant reductions in BW and BAL cells and soluble components were noted. This unexpected observation, combined with the in vitro data, suggests that wood smoke particles from incomplete combustion could be potentially cytotoxic. Additional research is required to establish the mechanism of this dramatic reduction in airway leukocytes and to clarify how this acute response contributes to the adverse health effects attributed to wood smoke exposure. NCT01488500.

Incidence of dentinal defects after root canal preparation: reciprocating versus rotary instrumentation.

PubMed

Bürklein, Sebastian; Tsotsis, Polymnia; Schäfer, Edgar

2013-04-01

The purpose of this study was to evaluate the incidence of dentinal defects after root canal preparation with reciprocating instruments (Reciproc and WaveOne) and rotary instruments. One hundred human central mandibular incisors were randomly assigned to 5 groups (n = 20 teeth per group). The root canals were instrumented by using the reciprocating single-file systems Reciproc and WaveOne and the full-sequence rotary Mtwo and ProTaper instruments. One group was left unprepared as control. Roots were sectioned horizontally at 3, 6, and 9 mm from the apex and evaluated under a microscope by using 25-fold magnification. The presence of dentinal defects (complete/incomplete cracks and craze lines) was noted and analyzed by using the chi-square test. No defects were observed in the controls. All canal preparation created dentinal defects. Overall, instrumentation with Reciproc was associated with more complete cracks than the full-sequence files (P = .021). Although both reciprocating files produced more incomplete cracks apically (3 mm) compared with the rotary files (P = .001), no statistically significant differences were obtained concerning the summarized values of all cross sections (P > .05). Under the conditions of this study, root canal preparation with both rotary and reciprocating instruments resulted in dentinal defects. At the apical level of the canals, reciprocating files produced significantly more incomplete dentinal cracks than full-sequence rotary systems (P < .05). Copyright © 2013 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

Finite-size effects of hysteretic dynamics in multilayer graphene on a ferroelectric

DOE PAGES

Morozovska, Anna N.; Pusenkova, Anastasiia S.; Varenyk, Oleksandr V.; ...

2015-06-11

The origin and influence of finite-size effects on the nonlinear dynamics of space charge stored by multilayer graphene on a ferroelectric and resistivity of graphene channel were analyzed. In this paper, we develop a self-consistent approach combining the solution of electrostatic problems with the nonlinear Landau-Khalatnikov equations for a ferroelectric. The size-dependent behaviors are governed by the relations between the thicknesses of multilayer graphene, ferroelectric film, and the dielectric layer. The appearance of charge and electroresistance hysteresis loops and their versatility stem from the interplay of polarization reversal dynamics and its incomplete screening in an alternating electric field. These featuresmore » are mostly determined by the dielectric layer thickness. The derived analytical expressions for electric fields and space-charge-density distribution in a multilayer system enable knowledge-driven design of graphene-on-ferroelectric heterostructures with advanced performance. We further investigate the effects of spatially nonuniform ferroelectric domain structures on the graphene layers’ conductivity and predict its dramatic increase under the transition from multi- to single-domain state in a ferroelectric. Finally, this intriguing effect can open possibilities for the graphene-based sensors and explore the underlying physical mechanisms in the operation of graphene field-effect transistor with ferroelectric gating.« less

Characterization of biofilm formation by Salmonella enterica at the air-liquid interface in aquatic environments.

PubMed

Medrano-Félix, José Andrés; Chaidez, Cristóbal; Mena, Kristina D; Soto-Galindo, María Del Socorro; Castro-Del Campo, Nohelia

2018-03-15

Survival of bacterial pathogens in different environments is due, in part, to their ability to form biofilms. Four wild-type Salmonella enterica strains, two Oranienburg and two Saintpaul isolated from river water and animal feces, were tested for biofilm formation at the air-liquid interface under stressful conditions (pH and salinity treatments such as pH 3, NaCl 4.5 w/v; pH 7, NaCl 4.5 w/v; pH 10, NaCl 4.5 w/v; pH 3, Nacl 0.5 w/v; pH 7, NaCl 0.5 w/v; and pH 10, NaCl 0.5 w/v); Salmonella Typhimurium DT104 was used as a control strain. Salmonella Oranienburg and Saintpaul from feces were moderately hydrophobic and motile, while S. Saintpaul from water and the control strain S. Typhimurium showed high hydrophobicity, which helped them form more resistant biofilms than S. Oranienburg. Under stressful conditions, all strains experienced difficulties in forming biofilms. Salmonella Saintpaul and Typhimurium expressed the red dry and rough (RDAR) morphotype and were able to form biofilm at air-liquid interface, contrarily to Oranienburg that showed incomplete rough morphology. This study contributes to the knowledge of biofilm formation as a survival strategy for Salmonella in aquatic environments.

Scaling laws for AC gas breakdown and implications for universality

NASA Astrophysics Data System (ADS)

Loveless, Amanda M.; Garner, Allen L.

2017-10-01

The reduced dependence on secondary electron emission and electrode surface properties makes radiofrequency (RF) and microwave (MW) plasmas advantageous over direct current (DC) plasmas for various applications, such as microthrusters. Theoretical models relating molecular constants to alternating current (AC) breakdown often fail due to incomplete understanding of both the constants and the mechanisms involved. This work derives simple analytic expressions for RF and MW breakdown, demonstrating the transition between these regimes at their high and low frequency limits, respectively. We further show that the limiting expressions for DC, RF, and MW breakdown voltage all have the same universal scaling dependence on pressure and gap distance at high pressure, agreeing with experiment.

49 CFR 555.12 - Petition for exemption.

Code of Federal Regulations, 2010 CFR

2010-10-01

... under the laws of which it is organized, and the name of each alterer, incomplete vehicle manufacturer... sought; (g) Specify any part of the information and data submitted that the petitioner requests be...). (1) The information and data which petitioner requests be withheld from public disclosure must be...

49 CFR 555.12 - Petition for exemption.

Code of Federal Regulations, 2014 CFR

2014-10-01

... under the laws of which it is organized, and the name of each alterer, incomplete vehicle manufacturer... sought; (g) Specify any part of the information and data submitted that the petitioner requests be...). (1) The information and data which petitioner requests be withheld from public disclosure must be...

49 CFR 555.12 - Petition for exemption.

Code of Federal Regulations, 2012 CFR

2012-10-01

... under the laws of which it is organized, and the name of each alterer, incomplete vehicle manufacturer... sought; (g) Specify any part of the information and data submitted that the petitioner requests be...). (1) The information and data which petitioner requests be withheld from public disclosure must be...

49 CFR 555.12 - Petition for exemption.

Code of Federal Regulations, 2013 CFR

2013-10-01

... under the laws of which it is organized, and the name of each alterer, incomplete vehicle manufacturer... sought; (g) Specify any part of the information and data submitted that the petitioner requests be...). (1) The information and data which petitioner requests be withheld from public disclosure must be...

49 CFR 555.12 - Petition for exemption.

Code of Federal Regulations, 2011 CFR

2011-10-01

... under the laws of which it is organized, and the name of each alterer, incomplete vehicle manufacturer... sought; (g) Specify any part of the information and data submitted that the petitioner requests be...). (1) The information and data which petitioner requests be withheld from public disclosure must be...

Eph and Ephrin function in dispersal and epithelial insertion of pigmented immunocytes in sea urchin embryos

PubMed Central

Krupke, Oliver A; Zysk, Ivona; Mellott, Dan O; Burke, Robert D

2016-01-01

The mechanisms that underlie directional cell migration are incompletely understood. Eph receptors usually guide migrations of cells by exclusion from regions expressing Ephrin. In sea urchin embryos, pigmented immunocytes are specified in vegetal epithelium, transition to mesenchyme, migrate, and re-enter ectoderm, distributing in dorsal ectoderm and ciliary band, but not ventral ectoderm. Immunocytes express Sp-Eph and Sp-Efn is expressed throughout dorsal and ciliary band ectoderm. Interfering with expression or function of Sp-Eph results in rounded immunocytes entering ectoderm but not adopting a dendritic form. Expressing Sp-Efn throughout embryos permits immunocyte insertion in ventral ectoderm. In mosaic embryos, immunocytes insert preferentially in ectoderm expressing Sp-Efn. We conclude that Sp-Eph signaling is necessary and sufficient for epithelial insertion. As well, we propose that immunocytes disperse when Sp-Eph enhances adhesion, causing haptotactic movement to regions of higher ligand abundance. This is a distinctive example of Eph/Ephrin signaling acting positively to pattern migrating cells. DOI: http://dx.doi.org/10.7554/eLife.16000.001 PMID:27474796

Arc expression identifies the lateral amygdala fear memory trace

PubMed Central

Gouty-Colomer, L A; Hosseini, B; Marcelo, I M; Schreiber, J; Slump, D E; Yamaguchi, S; Houweling, A R; Jaarsma, D; Elgersma, Y; Kushner, S A

2016-01-01

Memories are encoded within sparsely distributed neuronal ensembles. However, the defining cellular properties of neurons within a memory trace remain incompletely understood. Using a fluorescence-based Arc reporter, we were able to visually identify the distinct subset of lateral amygdala (LA) neurons activated during auditory fear conditioning. We found that Arc-expressing neurons have enhanced intrinsic excitability and are preferentially recruited into newly encoded memory traces. Furthermore, synaptic potentiation of thalamic inputs to the LA during fear conditioning is learning-specific, postsynaptically mediated and highly localized to Arc-expressing neurons. Taken together, our findings validate the immediate-early gene Arc as a molecular marker for the LA neuronal ensemble recruited during fear learning. Moreover, these results establish a model of fear memory formation in which intrinsic excitability determines neuronal selection, whereas learning-related encoding is governed by synaptic plasticity. PMID:25802982

Semantic Borders and Incomplete Understanding.

PubMed

Silva-Filho, Waldomiro J; Dazzani, Maria Virgínia

2016-03-01

In this article, we explore a fundamental issue of Cultural Psychology, that is our "capacity to make meaning", by investigating a thesis from contemporary philosophical semantics, namely, that there is a decisive relationship between language and rationality. Many philosophers think that for a person to be described as a rational agent he must understand the semantic content and meaning of the words he uses to express his intentional mental states, e.g., his beliefs and thoughts. Our argument seeks to investigate the thesis developed by Tyler Burge, according to which our mastery or understanding of the semantic content of the terms which form our beliefs and thoughts is an "incomplete understanding". To do this, we discuss, on the one hand, the general lines of anti-individualism or semantic externalism and, on the other, criticisms of the Burgean notion of incomplete understanding - one radical and the other moderate. We defend our understanding that the content of our beliefs must be described in the light of the limits and natural contingencies of our cognitive capacities and the normative nature of our rationality. At heart, anti-individualism leads us to think about the fact that we are social creatures, living in contingent situations, with important, but limited, cognitive capacities, and that we receive the main, and most important, portion of our knowledge simply from what others tell us. Finally, we conclude that this discussion may contribute to the current debate about the notion of borders.

Zebrafish mab21l2 is specifically expressed in the presumptive eye and tectum from early somitogenesis onwards.

PubMed

Kudoh, T; Dawid, I B

2001-11-01

Random screening for tissue specific genes in zebrafish by in situ hybridization led us to isolate a gene which showed highly restricted expression in the developing eyes and midbrain at somitogenesis stages. This gene was very similar to mouse and human mab21l2. The characteristic expression pattern of mab21l2 facilitates a detailed description of the morphogenesis of the eyes and midbrain in the zebrafish. In the eye field, mab21l2 expression illustrates the transformation of the eye field to form two separate eyes in the anterior neural plate. Mab21l2 staining in the cyclopic mutants, cyc and oep, exhibited incomplete splitting of the eye primodium. In the midbrain, mab21l2 is expressed in the tectum, and its expression follows the expansion of the tectal region. In mutants affecting the mid-hindbrain boundary (MHB), mab21l2 expression is affected differentially. In the noi/pax2.1 mutant, mab21l2 is down-regulated and the size of the tectum remains small, whereas in the ace/fgf8 mutant, mab21l2 expression persists although the shape of the tectum is altered.

Gene Expression Profiling of the Hypoxia Signaling Pathway in Hypoxia-Inducible Factor 1α Null Mouse Embryonic Fibroblasts

PubMed Central

Vengellur, Ajith; Woods, Barbara G.; Ryan, Heather E.; Johnson, Randall S.; Lapres, John J.

2003-01-01

Hypoxia is defined as a deficiency of oxygen reaching the tissues of the body, and it plays a critical role in development and pathological conditions, such as cancer. Once tumors outgrow their blood supply, their central portion becomes hypoxic and the tumor stimulates angiogenesis through the activation of the hypoxia-inducible factors (HIFs). HIFs are transcription factors that are regulated in an oxygen-dependent manner by a group of prolyl hydroxylases (known as PHDs or HPHs). Our understanding of hypoxia signaling is limited by our incomplete knowledge of HIF target genes. cDNA microarrays and a cell line lacking a principal HIF protein, HIF1α, were used to identify a more complete set of hypoxia-regulated genes. The microarrays identified a group of 286 clones that were significantly influenced by hypoxia and 54 of these were coordinately regulated by cobalt chloride. The expression profile of HIF1α −/− cells also identified a group of downregulated genes encoding enzymes involved in protecting cells from oxidative stress, offering an explanation for the increased sensitivity of HIF1α −/− cells to agents that promote this type of response. The microarray studies confirmed the hypoxia-induced expression of the HIF regulating prolyl hydroxylase, PHD2. An analysis of the members of the PHD family revealed that they are differentially regulated by cobalt chloride and hypoxia. These results suggest that HIF1α is the predominant isoform in fibroblasts and that it regulates a wide battery of genes critical for normal cellular function and survival under various stresses. PMID:14686790

Mechanism of Hyperkalemia-Induced Metabolic Acidosis.

PubMed

Harris, Autumn N; Grimm, P Richard; Lee, Hyun-Wook; Delpire, Eric; Fang, Lijuan; Verlander, Jill W; Welling, Paul A; Weiner, I David

2018-05-01

Background Hyperkalemia in association with metabolic acidosis that are out of proportion to changes in glomerular filtration rate defines type 4 renal tubular acidosis (RTA), the most common RTA observed, but the molecular mechanisms underlying the associated metabolic acidosis are incompletely understood. We sought to determine whether hyperkalemia directly causes metabolic acidosis and, if so, the mechanisms through which this occurs. Methods We studied a genetic model of hyperkalemia that results from early distal convoluted tubule (DCT)-specific overexpression of constitutively active Ste20/SPS1-related proline-alanine-rich kinase (DCT-CA-SPAK). Results DCT-CA-SPAK mice developed hyperkalemia in association with metabolic acidosis and suppressed ammonia excretion; however, titratable acid excretion and urine pH were unchanged compared with those in wild-type mice. Abnormal ammonia excretion in DCT-CA-SPAK mice associated with decreased proximal tubule expression of the ammonia-generating enzymes phosphate-dependent glutaminase and phosphoenolpyruvate carboxykinase and overexpression of the ammonia-recycling enzyme glutamine synthetase. These mice also had decreased expression of the ammonia transporter family member Rhcg and decreased apical polarization of H + -ATPase in the inner stripe of the outer medullary collecting duct. Correcting the hyperkalemia by treatment with hydrochlorothiazide corrected the metabolic acidosis, increased ammonia excretion, and normalized ammoniagenic enzyme and Rhcg expression in DCT-CA-SPAK mice. In wild-type mice, induction of hyperkalemia by administration of the epithelial sodium channel blocker benzamil caused hyperkalemia and suppressed ammonia excretion. Conclusions Hyperkalemia decreases proximal tubule ammonia generation and collecting duct ammonia transport, leading to impaired ammonia excretion that causes metabolic acidosis. Copyright © 2018 by the American Society of Nephrology.

Heat-shock protein 40 is the key farnesylation target in meristem size control, abscisic acid signaling, and drought resistance.

PubMed

Barghetti, Andrea; Sjögren, Lars; Floris, Maïna; Paredes, Esther Botterweg; Wenkel, Stephan; Brodersen, Peter

2017-11-15

Protein farnesylation is central to molecular cell biology. In plants, protein farnesyl transferase mutants are pleiotropic and exhibit defective meristem organization, hypersensitivity to the hormone abscisic acid, and increased drought resistance. The precise functions of protein farnesylation in plants remain incompletely understood because few relevant farnesylated targets have been identified. Here, we show that defective farnesylation of a single factor-heat-shock protein 40 (HSP40), encoded by the J2 and J3 genes-is sufficient to confer ABA hypersensitivity, drought resistance, late flowering, and enlarged meristems, indicating that altered function of chaperone client proteins underlies most farnesyl transferase mutant phenotypes. We also show that expression of an abiotic stress-related microRNA (miRNA) regulon controlled by the transcription factor SPL7 requires HSP40 farnesylation. Expression of a truncated SPL7 form mimicking its activated proteolysis fragment of the membrane-bound SPL7 precursor partially restores accumulation of SPL7-dependent miRNAs in farnesyl transferase mutants. These results implicate the pathway directing SPL7 activation from its membrane-bound precursor as an important target of farnesylated HSP40, consistent with our demonstration that HSP40 farnesylation facilitates its membrane association. The results also suggest that altered gene regulation via select miRNAs contributes to abiotic stress-related phenotypes of farnesyl transferase mutants. © 2017 Barghetti et al.; Published by Cold Spring Harbor Laboratory Press.

NOGGIN IS REQUIRED FOR NORMAL LOBE PATTERNING AND DUCTAL BUDDING IN THE MOUSE PROSTATE

PubMed Central

Cook, Crist; Vezina, Chad M.; Hicks, Sarah M.; Shaw, Aubie; Yu, Min; Peterson, Richard E.; Bushman, Wade

2008-01-01

Mesenchymal expression of the BMP antagonist NOGGIN during prostate development plays a critical role in pre-natal ventral prostate development and opposes BMP4-mediated inhibition of cell proliferation during postnatal ductal development. Morphologic examination of newborn Noggin-/- male fetuses revealed genitourinary anomalies including cryptorchidism, incomplete separation of the hindgut from the urogenital sinus (UGS), absence of the ventral mesenchymal pad and a complete loss of ventral prostate (VP) budding. Examination of lobe-specific marker expression in the E14 Noggin-/- UGS rescued by transplantation under the renal capsule of a male nude mouse confirmed a complete loss of VP determination. More modest effects were observed in the other lobes, including decreased number of ductal buds in the dorsal and lateral prostates of newborn Noggin-/- males. BMP4 and BMP7 have been shown to inhibit ductal budding and outgrowth by negatively regulating epithelial cell proliferation. We show here that NOGGIN can neutralize budding inhibition by BMP4 and rescues branching morphogenesis of BMP4-exposed UGS in organ culture and show that the effects of BMP4 and NOGGIN activities converge on P63+ epithelial cells located at nascent duct tips. Together, these studies show that the BMP-NOGGIN axis regulates patterning of the ventral prostate, regulates ductal budding, and controls proliferation of P63+ epithelial cells in the nascent ducts of developing mouse prostate. PMID:18028901

Global Liver Proteome Analysis Using iTRAQ Reveals AMPK-mTOR-Autophagy Signaling Is Altered by Intrauterine Growth Restriction in Newborn Piglets.

PubMed

Long, Baisheng; Yin, Cong; Fan, Qiwen; Yan, Guokai; Wang, Zhichang; Li, Xiuzhi; Chen, Changqing; Yang, Xingya; Liu, Lu; Zheng, Zilong; Shi, Min; Yan, Xianghua

2016-04-01

Intrauterine growth restriction (IUGR) impairs fetal growth and development, perturbs nutrient metabolism, and increases the risk of developing diseases in postnatal life. However, the underlying mechanisms by which IUGR affects fetal liver development and metabolism remain incompletely understood. Here, we applied a high-throughput proteomics approach and biochemical analysis to investigate the impact of IUGR on the liver of newborn piglets. As a result, we identified 78 differentially expressed proteins in the three biological replicates, including 31 significantly up-regulated proteins and 47 significantly down-regulated proteins. Among them, a majority of differentially expressed proteins were related to nutrient metabolism and mitochondrial function. Additionally, many significantly down-regulated proteins participated in the mTOR signaling pathway and the phagosome maturation signaling pathway. Further analysis suggested that glucose concentration and hepatic glycogen storage were both reduced in IUGR newborn piglets, which may contribute to AMPK activation and mTORC1 inhibition. However, AMPK activation and mTORC1 inhibition failed to induce autophagy in the liver of IUGR neonatal pigs. A possible reason is that PP2Ac, a potential candidate in autophagy regulation, is significantly down-regulated in the liver of IUGR newborn piglets. These findings may provide implications for preventing and treating IUGR in human beings and domestic animals.

Antagonism of dopamine D2 receptors alters phosphorylation of Fyn in the rat medial prefrontal cortex

PubMed Central

Mao, Li-Min; Wang, John Q.

2017-01-01

Several Src family kinase (SFK) members are expressed in the mammalian brain and serve as key kinases in the regulation of a variety of cellular and synaptic events. These SFKs may be subject to the modulation by dopamine, although this topic has been investigated incompletely. In this study, we explored whether dopamine D2 receptors (D2R) regulate SFKs in adult rat brains in vivo. We investigated the role of D2Rs in two forebrain areas, the medial prefrontal cortex (mPFC) and hippocampus, since dopamine plays a pivotal role in regulating activity of mPFC and hippocampal neurons and D2Rs are expressed in these regions. We found that a systemic injection of a D2R selective antagonist eticlopride elevated phosphorylation of SFKs at a conserved autophosphorylation site, an event correlated with activation of SFKs, in the mPFC. Similarly, antagonism of D2Rs by haloperidol increased SFK phosphorylation. In contrast, eticlopride and haloperidol did not alter SFK phosphorylation in the hippocampus. The effect of eticlopride was time-dependent and relatively delayed. Among two common SFK members enriched at synaptic sites, eticlopride selectively altered phosphorylation of Fyn but not Src. Our data suggest that D2Rs exert an inhibitory effect on the activity-related phosphorylation of Fyn in the mPFC under normal conditions. PMID:28176147

Degradation of Alzheimer's amyloid fibrils by microglia requires delivery of ClC-7 to lysosomes

PubMed Central

Majumdar, Amitabha; Capetillo-Zarate, Estibaliz; Cruz, Dana; Gouras, Gunnar K.; Maxfield, Frederick R.

2011-01-01

Incomplete lysosomal acidification in microglia inhibits the degradation of fibrillar forms of Alzheimer's amyloid β peptide (fAβ). Here we show that in primary microglia a chloride transporter, ClC-7, is not delivered efficiently to lysosomes, causing incomplete lysosomal acidification. ClC-7 protein is synthesized by microglia but it is mistargeted and appears to be degraded by an endoplasmic reticulum–associated degradation pathway. Activation of microglia with macrophage colony-stimulating factor induces trafficking of ClC-7 to lysosomes, leading to lysosomal acidification and increased fAβ degradation. ClC-7 associates with another protein, Ostm1, which plays an important role in its correct lysosomal targeting. Expression of both ClC-7 and Ostm1 is increased in activated microglia, which can account for the increased delivery of ClC-7 to lysosomes. Our findings suggest a novel mechanism of lysosomal pH regulation in activated microglia that is required for fAβ degradation. PMID:21441306

Sex Chromosome Dosage Compensation in Heliconius Butterflies: Global yet Still Incomplete?

PubMed Central

Walters, James R.; Hardcastle, Thomas J.; Jiggins, Chris D.

2015-01-01

The evolution of heterogametic sex chromosomes is often—but not always—accompanied by the evolution of dosage compensating mechanisms that mitigate the impact of sex-specific gene dosage on levels of gene expression. One emerging view of this process is that such mechanisms may only evolve in male-heterogametic (XY) species but not in female-heterogametic (ZW) species, which will consequently exhibit “incomplete” sex chromosome dosage compensation. However, recent results suggest that at least some Lepidoptera (moths and butterflies) may prove to be an exception to this prediction. Studies in bombycoid moths indicate the presence of a chromosome-wide epigenetic mechanism that effectively balances Z chromosome gene expression between the sexes by reducing Z-linked expression in males. In contrast, strong sex chromosome dosage effects without any reduction in male Z-linked expression were previously reported in a pyralid moth, suggesting a lack of any such dosage compensating mechanism. Here we report an analysis of sex chromosome dosage compensation in Heliconius butterflies, sampling multiple individuals for several different adult tissues (head, abdomen, leg, mouth, and antennae). Methodologically, we introduce a novel application of linear mixed-effects models to assess dosage compensation, offering a unified statistical framework that can estimate effects specific to chromosome, to sex, and their interactions (i.e., a dosage effect). Our results show substantially reduced Z-linked expression relative to autosomes in both sexes, as previously observed in bombycoid moths. This observation is consistent with an increasing body of evidence that some lepidopteran species possess an epigenetic dosage compensating mechanism that reduces Z chromosome expression in males to levels comparable with females. However, this mechanism appears to be imperfect in Heliconius, resulting in a modest dosage effect that produces an average 5–20% increase in male expression relative to females on the Z chromosome, depending on the tissue. Thus our results in Heliconius reflect a mixture of previous patterns reported for Lepidoptera. In Heliconius, a moderate pattern of incomplete dosage compensation persists apparently despite the presence of an epigenetic dosage compensating mechanism. The chromosomal distributions of sex-biased genes show an excess of male-biased and a dearth of female-biased genes on the Z chromosome relative to autosomes, consistent with predictions of sexually antagonistic evolution. PMID:26338190

Posttranscriptional regulation of adrenal TH gene expression contributes to the maladaptive responses triggered by insulin-induced recurrent hypoglycemia.

PubMed

Kudrick, Necla; Chan, Owen; La Gamma, Edmund F; Kim, Juhye Lena; Tank, Arnold William; Sterling, Carol; Nankova, Bistra B

2015-02-01

Acute metabolic stress such as insulin-induced hypoglycemia triggers a counterregulatory response during which the release of catecholamines (epinephrine), the activation of tyrosine hydroxylase (TH) enzyme and subsequent compensatory catecholamine biosynthesis occur in the adrenal medulla. However, recurrent exposure to hypoglycemia (RH), a consequence of tight glycemic control in individuals with type 1 and type 2 diabetes compromises this physiological response. The molecular mechanisms underlying the maladaptive response to repeated glucose deprivation are incompletely understood. We hypothesize that impaired epinephrine release following RH reflects altered regulation of adrenal catecholamine biosynthesis. To test this hypothesis, we compared the effect of single daily (RH) and twice-daily episodes of insulin-induced hypoglycemia (2RH) on adrenal epinephrine release and production in normal rats. Control animals received saline injections under similar conditions (RS and 2RS, respectively). Following 3 days of treatment, we assessed the counterregulatory hormonal responses during a hypoglycemic clamp. Changes in adrenal TH gene expression were also analyzed. The counterregulatory responses, relative TH transcription and TH mRNA levels and Ser40-TH phosphorylation (marker for enzyme activation) were induced to a similar extent in RS, 2RS, and RH groups. In contrast, epinephrine and glucagon responses were attenuated in the 2RH group and this was associated with a limited elevation of adrenal TH mRNA, rapid inactivation of TH enzyme and no significant changes in TH protein. Our results suggest that novel posttranscriptional mechanisms controlling TH mRNA and activated TH enzyme turnover contribute to the impaired epinephrine responses and may provide new therapeutic targets to prevent HAAF. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Posttranscriptional regulation of adrenal TH gene expression contributes to the maladaptive responses triggered by insulin-induced recurrent hypoglycemia

PubMed Central

Kudrick, Necla; Chan, Owen; La Gamma, Edmund F; Kim, Juhye Lena; Tank, Arnold William; Sterling, Carol; Nankova, Bistra B

2015-01-01

Acute metabolic stress such as insulin-induced hypoglycemia triggers a counterregulatory response during which the release of catecholamines (epinephrine), the activation of tyrosine hydroxylase (TH) enzyme and subsequent compensatory catecholamine biosynthesis occur in the adrenal medulla. However, recurrent exposure to hypoglycemia (RH), a consequence of tight glycemic control in individuals with type 1 and type 2 diabetes compromises this physiological response. The molecular mechanisms underlying the maladaptive response to repeated glucose deprivation are incompletely understood. We hypothesize that impaired epinephrine release following RH reflects altered regulation of adrenal catecholamine biosynthesis. To test this hypothesis, we compared the effect of single daily (RH) and twice-daily episodes of insulin-induced hypoglycemia (2RH) on adrenal epinephrine release and production in normal rats. Control animals received saline injections under similar conditions (RS and 2RS, respectively). Following 3 days of treatment, we assessed the counterregulatory hormonal responses during a hypoglycemic clamp. Changes in adrenal TH gene expression were also analyzed. The counterregulatory responses, relative TH transcription and TH mRNA levels and Ser40-TH phosphorylation (marker for enzyme activation) were induced to a similar extent in RS, 2RS, and RH groups. In contrast, epinephrine and glucagon responses were attenuated in the 2RH group and this was associated with a limited elevation of adrenal TH mRNA, rapid inactivation of TH enzyme and no significant changes in TH protein. Our results suggest that novel posttranscriptional mechanisms controlling TH mRNA and activated TH enzyme turnover contribute to the impaired epinephrine responses and may provide new therapeutic targets to prevent HAAF. PMID:25713330

Search Planning Under Incomplete Information Using Stochastic Optimization and Regression

DTIC Science & Technology

2011-09-01

solve since they involve un- certainty and unknown parameters (see for example Shapiro et al., 2009; Wallace & Ziemba , 2005). One application area is...M16130.2E. 43 Wallace, S. W., & Ziemba , W. T. (2005). Applications of stochastic programming. Philadelphia, PA: Society for Industrial and Applied

PILOT-SCALE STUDIES ON THE EFFECT OF BROMINE ADDITION ON THE EMISSIONS OF CHLORINATED ORGANIC COMBUSTION BY-PRODUCTS

EPA Science Inventory

The addition of brominated organic compounds to the feed of a pilot-scale incinerator burning chlorinated waste has been found previously, under some circumstances, to enhance emissions of volatile and semivolatile organic chlorinated products of incomplete combustion (PiCs) incl...

Alaska Division of Geological and Geophysical Surveys

Science.gov Websites

; Divison of Geological & Geophysical Surveys> Engineering Geology Coastal Hazards Alaska's extensive shorelines are incompletely mapped and under-instrumented for the evaluation of coastal dynamics. The Coastal communities Updates to the Alaska Coastal Profile Tool including data in Norton Sound and St. Lawrence Island

49 CFR 529.5 - Requirements for intermediate manufacturers.

Code of Federal Regulations, 2012 CFR

2012-10-01

... TRAFFIC SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION MANUFACTURERS OF MULTISTAGE AUTOMOBILES § 529... automobile cause it to exceed the maximum curb weight or maximum frontal area set forth in the document furnished it by the incomplete automobile manufacturer under § 529.4(c)(1) or by a previous intermediate...

49 CFR 529.5 - Requirements for intermediate manufacturers.

Code of Federal Regulations, 2014 CFR

2014-10-01

... TRAFFIC SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION MANUFACTURERS OF MULTISTAGE AUTOMOBILES § 529... automobile cause it to exceed the maximum curb weight or maximum frontal area set forth in the document furnished it by the incomplete automobile manufacturer under § 529.4(c)(1) or by a previous intermediate...

49 CFR 529.5 - Requirements for intermediate manufacturers.

Code of Federal Regulations, 2013 CFR

2013-10-01

... TRAFFIC SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION MANUFACTURERS OF MULTISTAGE AUTOMOBILES § 529... automobile cause it to exceed the maximum curb weight or maximum frontal area set forth in the document furnished it by the incomplete automobile manufacturer under § 529.4(c)(1) or by a previous intermediate...

49 CFR 529.5 - Requirements for intermediate manufacturers.

Code of Federal Regulations, 2011 CFR

2011-10-01

... TRAFFIC SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION MANUFACTURERS OF MULTISTAGE AUTOMOBILES § 529... automobile cause it to exceed the maximum curb weight or maximum frontal area set forth in the document furnished it by the incomplete automobile manufacturer under § 529.4(c)(1) or by a previous intermediate...

49 CFR 529.5 - Requirements for intermediate manufacturers.

Code of Federal Regulations, 2010 CFR

2010-10-01

... TRAFFIC SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION MANUFACTURERS OF MULTISTAGE AUTOMOBILES § 529... automobile cause it to exceed the maximum curb weight or maximum frontal area set forth in the document furnished it by the incomplete automobile manufacturer under § 529.4(c)(1) or by a previous intermediate...

Knowledge Affords Distinctive Processing in Memory

ERIC Educational Resources Information Center

Hunt, R. Reed; Rawson, Katherine A.

2011-01-01

The effect of knowledge on memory generally is processing. However, both conceptual and empirical reasons exist to suspect that the organizational account is incomplete. Recently a revised version of that account has been proposed under the rubric of distinctiveness theory (Rawson & Van Overschelde, 2008). The goal of the experiments reported…

The Pennies-as-Electrons Analogy

ERIC Educational Resources Information Center

Ashmann, Scott

2009-01-01

Everyday experiences familiarize students with the ways in which electricity is used, but often the underlying concepts remain a mystery. Teachers often use analogies to help students relate the flow of electrons to other common systems, but many times these analogies are incomplete and lead to more student misconceptions. However, the "pass the…

Groundwater withdrawals under drought: reconciling GRACE and land surface models in the United States High Plains Aquifer

USDA-ARS?s Scientific Manuscript database

Advanced Land Surface Models (LSM) offer a powerful tool for studying hydrological variability. Highly managed systems, however, present a challenge for these models, which typically have simplified or incomplete representations of human water use. Here we examine recent groundwater declines in the ...

Using microarrays to identify positional candidate genes for QTL: the case study of ACTH response in pigs.

PubMed

Jouffe, Vincent; Rowe, Suzanne; Liaubet, Laurence; Buitenhuis, Bart; Hornshøj, Henrik; SanCristobal, Magali; Mormède, Pierre; de Koning, D J

2009-07-16

Microarray studies can supplement QTL studies by suggesting potential candidate genes in the QTL regions, which by themselves are too large to provide a limited selection of candidate genes. Here we provide a case study where we explore ways to integrate QTL data and microarray data for the pig, which has only a partial genome sequence. We outline various procedures to localize differentially expressed genes on the pig genome and link this with information on published QTL. The starting point is a set of 237 differentially expressed cDNA clones in adrenal tissue from two pig breeds, before and after treatment with adrenocorticotropic hormone (ACTH). Different approaches to localize the differentially expressed (DE) genes to the pig genome showed different levels of success and a clear lack of concordance for some genes between the various approaches. For a focused analysis on 12 genes, overlapping QTL from the public domain were presented. Also, differentially expressed genes underlying QTL for ACTH response were described. Using the latest version of the draft sequence, the differentially expressed genes were mapped to the pig genome. This enabled co-location of DE genes and previously studied QTL regions, but the draft genome sequence is still incomplete and will contain many errors. A further step to explore links between DE genes and QTL at the pathway level was largely unsuccessful due to the lack of annotation of the pig genome. This could be improved by further comparative mapping analyses but this would be time consuming. This paper provides a case study for the integration of QTL data and microarray data for a species with limited genome sequence information and annotation. The results illustrate the challenges that must be addressed but also provide a roadmap for future work that is applicable to other non-model species.

Higher Order Chromatin Modulator Cohesin SA1 Is an Early Biomarker for Colon Carcinogenesis: Race-Specific Implications.

PubMed

Wali, Ramesh K; Momi, Navneet; Dela Cruz, Mart; Calderwood, Audrey H; Stypula-Cyrus, Yolanda; Almassalha, Luay; Chhaparia, Anuj; Weber, Christopher R; Radosevich, Andrew; Tiwari, Ashish K; Latif, Bilal; Backman, Vadim; Roy, Hemant K

2016-11-01

Alterations in high order chromatin, with concomitant modulation in gene expression, are one of the earliest events in the development of colorectal cancer. Cohesins are a family of proteins that modulate high-order chromatin, although the role in colorectal cancer remains incompletely understood. We, therefore, assessed the role of cohesin SA1 in colorectal cancer biology and as a biomarker focusing in particular on the increased incidence/mortality of colorectal cancer among African-Americans. Immunohistochemistry on tissue arrays revealed dramatically decreased SA1 expression in both adenomas (62%; P = 0.001) and adenocarcinomas (75%; P = 0.0001). RT-PCR performed in endoscopically normal rectal biopsies (n = 78) revealed a profound decrease in SA1 expression in adenoma-harboring patients (field carcinogenesis) compared with those who were neoplasia-free (47%; P = 0.03). From a racial perspective, colorectal cancer tissues from Caucasians had 56% higher SA1 expression than in African-Americans. This was mirrored in field carcinogenesis where healthy Caucasians expressed more SA1 at baseline compared with matched African-American subjects (73%; P = 0.003). However, as a biomarker for colorectal cancer risk, the diagnostic performance as assessed by area under ROC curve was greater in African-Americans (AUROC = 0.724) than in Caucasians (AUROC = 0.585). From a biologic perspective, SA1 modulation of high-order chromatin was demonstrated with both biophotonic (nanocytology) and chromatin accessibility [micrococcal nuclease (MNase)] assays in SA1-knockdown HT29 colorectal cancer cells. The functional consequences were underscored by increased proliferation (WST-1; P = 0.0002, colony formation; P = 0.001) in the SA1-knockdown HT29 cells. These results provide the first evidence indicating a tumor suppressor role of SA1 in early colon carcinogenesis and as a risk stratification biomarker giving potential insights into biologic basis of racial disparities in colorectal cancer. Cancer Prev Res; 9(11); 844-54. ©2016 AACR. ©2016 American Association for Cancer Research.

Reciprocal Feedback Between miR-181a and E2/ERα in Myometrium Enhances Inflammation Leading to Labor

PubMed Central

Wang, Gang; Liu, Wei-Na; Kinser, Holly; Franco, Hector L.

2016-01-01

Context: The initiation of term and preterm labor is associated with an up-regulated inflammatory response in myometrium; however, the underlying signaling pathways remain incompletely defined. Objective: To define the regulatory mechanisms that mediate the increased myometrial inflammatory response leading to labor, we investigated the roles of microRNAs (miRNA/miR). Design and Setting: Human myometrial tissues, isolated smooth muscle cells, and animal models were used to study miR-181a regulation of uterine inflammatory pathways and contractility. Patients: Myometrial tissues from 15 term pregnant women undergoing elective cesarean section (not in labor) and 10 term pregnant women undergoing emergency cesarean section (in labor) were used. Results: Expression of the highly conserved microRNA, miR-181a, was significantly decreased in mouse and human myometrium during late gestation. By contrast, the putative miR-181a targets, TNF-α, and estrogen receptor (ER)-α, and the validated target, c-Fos, key factors in the inflammatory response leading to parturition, were coordinately up-regulated. In studies using human myometrial cells, overexpression of miR-181a mimics repressed basal as well as IL-1β-induced TNF-α, C-C motif chemokine ligand 2 and 8 expression, whereas the expression of the antiinflammatory cytokine, IL-10, was increased. Overexpression of miR-181a dramatically inhibited both spontaneous and IL-1β-induced contraction of human myometrial cells. Notably, miR-181a directly targeted ERα and decreased its expression, whereas estradiol-17β reciprocally inhibited expression of mature miR-181a in myometrial cells. Conclusions: Thus, increased estradiol-17β/ERα signaling in myometrium near term inhibits miR-181a, resulting in a further increase in ERα and proinflammatory signaling. This escalating feedback loop provides novel targets and therapeutic strategies for the prevention of preterm labor and its consequences. PMID:27459534

Bone marrow mesenchymal stem cells accelerate the hyperglycemic refractory wound healing by inhibiting an excessive inflammatory response.

PubMed

Nan, Wenbin; Xu, Zhihao; Chen, Zhibin; Yuan, Xin; Lin, Juntang; Feng, Huigen; Lian, Jie; Chen, Hongli

2017-05-01

The aim of the present study was to evaluate the healing effect of bone marrow-derived mesenchymal stem cells administered to hyperglycemia model mice with skin wounds, and to explore the underlying mechanism contributing to their effects in promoting refractory wound healing. A full‑thickness skin wound mouse model was established, and refers to a wound of the skin and subcutaneous tissue. The mice were randomly divided into three groups: Blank control group, hyperglycemic group and a hyperglycemic group treated with stem cells. Wound healing was monitored and the wound‑healing rate was determined at 3, 6, 9, and 12 days following trauma. The structure of the organization of new skin tissue was observed by hematoxylin and eosin staining, and expression levels of the inflammatory cytokines interleukin (IL)‑6 and tumor necrosis factor (TNF)‑α were determined from 1 to 6 days following trauma. The wound healing of the hyperglycemic group was slower than that of the blank group, and the hyperglycemic mice treated with stem cells presented faster healing than the hyperglycemia group. The horny layer and granular layer of the skin were thinner and incomplete in the new skin tissue of the hyperglycemic group, whereas the new skin wound tissue basal layer was flat and demonstrated better fusion with the wound edge in the other two groups. The expression of inflammatory cytokines (IL‑6 and TNF‑α) was significantly increased in all three groups, with continuously higher expression in the hyperglycemic group and decreased expression in the other two groups over time. Hyperglycemia refractory wounds are likely related to the excessive expression of inflammatory cytokines surrounding the wound area. Stem cells may be able to alleviate the excessive inflammatory reaction in the wound tissue of hyperglycemic mice, so as to promote wound healing.

Lhx2 Determines Odorant Receptor Expression Frequency in Mature Olfactory Sensory Neurons

PubMed Central

Zhang, Guangfan; Titlow, William B.; Biecker, Stephanie M.; Stromberg, Arnold J.

2016-01-01

Abstract A developmental program of epigenetic repression prepares each mammalian olfactory sensory neuron (OSN) to strongly express one allele from just one of hundreds of odorant receptor (OR) genes, but what completes this process of OR gene choice by driving the expression of this allele is incompletely understood. Conditional deletion experiments in mice demonstrate that Lhx2 is necessary for normal expression frequencies of nearly all ORs and all trace amine-associated receptors, irrespective of whether the deletion of Lhx2 is initiated in immature or mature OSNs. Given previous evidence that Lhx2 binds OR gene control elements, these findings indicate that Lhx2 is directly involved in driving OR expression. The data also support the conclusion that OR expression is necessary to allow immature OSNs to complete differentiation and become mature. In contrast to the robust effects of conditional deletion of Lhx2, the loss of Emx2 has much smaller effects and more often causes increased expression frequencies. Lhx2:Emx2 double mutants show opposing effects on Olfr15 expression that reveal independent effects of these two transcription factors. While Lhx2 is necessary for OR expression that supports OR gene choice, Emx2 can act differently; perhaps by helping to control the availability of OR genes for expression. PMID:27822500

Neural expression and post-transcriptional dosage compensation of the steroid metabolic enzyme 17β-HSD type 4

PubMed Central

2010-01-01

Background Steroids affect many tissues, including the brain. In the zebra finch, the estrogenic steroid estradiol (E2) is especially effective at promoting growth of the neural circuit specialized for song. In this species, only the males sing and they have a much larger and more interconnected song circuit than females. Thus, it was surprising that the gene for 17β-hydroxysteroid dehydrogenase type 4 (HSD17B4), an enzyme that converts E2 to a less potent estrogen, had been mapped to the Z sex chromosome. As a consequence, it was likely that HSD17B4 was differentially expressed in males (ZZ) and females (ZW) because dosage compensation of Z chromosome genes is incomplete in birds. If a higher abundance of HSD17B4 mRNA in males than females was translated into functional enzyme in the brain, then contrary to expectation, males could produce less E2 in their brains than females. Results Here, we used molecular and biochemical techniques to confirm the HSD17B4 Z chromosome location in the zebra finch and to determine that HSD17B4 mRNA and activity were detectable in the early developing and adult brain. As expected, HSD17B4 mRNA expression levels were higher in males compared to females. This provides further evidence of the incomplete Z chromosome inactivation mechanisms in birds. We detected HSD17B4 mRNA in regions that suggested a role for this enzyme in the early organization and adult function of song nuclei. We did not, however, detect significant sex differences in HSD17B4 activity levels in the adult brain. Conclusions Our results demonstrate that the HSD17B4 gene is expressed and active in the zebra finch brain as an E2 metabolizing enzyme, but that dosage compensation of this Z-linked gene may occur via post-transcriptional mechanisms. PMID:20359329

Predictors of incomplete immunization coverage among one to five years old children in Togo.

PubMed

Landoh, Dadja Essoya; Ouro-Kavalah, Farihétou; Yaya, Issifou; Kahn, Anna-Lea; Wasswa, Peter; Lacle, Anani; Nassoury, Danladi Ibrahim; Gitta, Sheba Nakacubo; Soura, Abdramane Bassiahi

2016-09-13

Incompleteness of vaccination coverage among children is a major public health concern because itcontinues to sustain a high prevalence of vaccine-preventable diseases in some countries. In Togo, very few data on the factors associated with incomplete vaccination coverage among children have been published. We determined the prevalence of incomplete immunization coverage in children aged one to five years in Togo and associated factors. This was a cross-sectional study using secondary data from the 2010 Multiple Indicator Cluster Surveys (MICS4) conducted in 2010 among children aged 1 to 5 years in Togo. This survey was conducted over a period of two months from September to November, 2010. During Togo'sMICS4 survey, 2067 children met the inclusion criteria for our study. Female children accounted for 50.9 % (1051/2067) of the sample and 1372 (66.4 %) lived in rural areas. The majority of children (92.2 %; 1905/2067) lived with both parents and 30 % of the head of households interviewed were not schooled (620/2067). At the time of the survey, 36.2 % (750/2067) of the children had not received all vaccines recommended by Expanded Program on Immunization (EPI). In multivariate analysis, factors associated with incompleteness of immunization at 1 year were: health region of residences (Maritime aOR = 0.650; p = 0.043; Savanes: aOR = 0.324; p <0.001), non-schooled mother (aOR = 1.725; p = 0.002),standard of living (poor: aOR = 1.668; p = 0.013; medium: aOR = 1.393; p = 0.090) and the following characteristics of the household heads: sex (aOR = 1.465; p = 0.034), marital status (aOR = 1.591; p = 0.032), education level(non-educated: aOR = 1.435; p = 0.027. The incomplete immunization coverage among children in Togo remains high. It is necessary to strengthen health promotion among the population in order to improve the use of immunization services that are essential to reduce morbidity and mortality among under five years old children.

Using Answer Set Programming to Integrate RNA Expression with Signalling Pathway Information to Infer How Mutations Affect Ageing

PubMed Central

Papatheodorou, Irene; Ziehm, Matthias; Wieser, Daniela; Alic, Nazif; Partridge, Linda; Thornton, Janet M.

2012-01-01

A challenge of systems biology is to integrate incomplete knowledge on pathways with existing experimental data sets and relate these to measured phenotypes. Research on ageing often generates such incomplete data, creating difficulties in integrating RNA expression with information about biological processes and the phenotypes of ageing, including longevity. Here, we develop a logic-based method that employs Answer Set Programming, and use it to infer signalling effects of genetic perturbations, based on a model of the insulin signalling pathway. We apply our method to RNA expression data from Drosophila mutants in the insulin pathway that alter lifespan, in a foxo dependent fashion. We use this information to deduce how the pathway influences lifespan in the mutant animals. We also develop a method for inferring the largest common sub-paths within each of our signalling predictions. Our comparisons reveal consistent homeostatic mechanisms across both long- and short-lived mutants. The transcriptional changes observed in each mutation usually provide negative feedback to signalling predicted for that mutation. We also identify an S6K-mediated feedback in two long-lived mutants that suggests a crosstalk between these pathways in mutants of the insulin pathway, in vivo. By formulating the problem as a logic-based theory in a qualitative fashion, we are able to use the efficient search facilities of Answer Set Programming, allowing us to explore larger pathways, combine molecular changes with pathways and phenotype and infer effects on signalling in in vivo, whole-organism, mutants, where direct signalling stimulation assays are difficult to perform. Our methods are available in the web-service NetEffects: http://www.ebi.ac.uk/thornton-srv/software/NetEffects. PMID:23251396

Using answer set programming to integrate RNA expression with signalling pathway information to infer how mutations affect ageing.

PubMed

Papatheodorou, Irene; Ziehm, Matthias; Wieser, Daniela; Alic, Nazif; Partridge, Linda; Thornton, Janet M

2012-01-01

A challenge of systems biology is to integrate incomplete knowledge on pathways with existing experimental data sets and relate these to measured phenotypes. Research on ageing often generates such incomplete data, creating difficulties in integrating RNA expression with information about biological processes and the phenotypes of ageing, including longevity. Here, we develop a logic-based method that employs Answer Set Programming, and use it to infer signalling effects of genetic perturbations, based on a model of the insulin signalling pathway. We apply our method to RNA expression data from Drosophila mutants in the insulin pathway that alter lifespan, in a foxo dependent fashion. We use this information to deduce how the pathway influences lifespan in the mutant animals. We also develop a method for inferring the largest common sub-paths within each of our signalling predictions. Our comparisons reveal consistent homeostatic mechanisms across both long- and short-lived mutants. The transcriptional changes observed in each mutation usually provide negative feedback to signalling predicted for that mutation. We also identify an S6K-mediated feedback in two long-lived mutants that suggests a crosstalk between these pathways in mutants of the insulin pathway, in vivo. By formulating the problem as a logic-based theory in a qualitative fashion, we are able to use the efficient search facilities of Answer Set Programming, allowing us to explore larger pathways, combine molecular changes with pathways and phenotype and infer effects on signalling in in vivo, whole-organism, mutants, where direct signalling stimulation assays are difficult to perform. Our methods are available in the web-service NetEffects: http://www.ebi.ac.uk/thornton-srv/software/NetEffects.

A Novel Assay for Antibody-Dependent Cell-Mediated Cytotoxicity against HIV-1- or SIV-Infected Cells Reveals Incomplete Overlap with Antibodies Measured by Neutralization and Binding Assays

PubMed Central

Alpert, Michael D.; Heyer, Lisa N.; Williams, David E. J.; Harvey, Jackson D.; Greenough, Thomas; Allhorn, Maria

2012-01-01

The resistance of human immunodeficiency virus type 1 (HIV-1) to antibody-mediated immunity often prevents the detection of antibodies that neutralize primary isolates of HIV-1. However, conventional assays for antibody functions other than neutralization are suboptimal. Current methods for measuring the killing of virus-infected cells by antibody-dependent cell-mediated cytotoxicity (ADCC) are limited by the number of natural killer (NK) cells obtainable from individual donors, donor-to-donor variation, and the use of nonphysiological targets. We therefore developed an ADCC assay based on NK cell lines that express human or macaque CD16 and a CD4+ T-cell line that expresses luciferase from a Tat-inducible promoter upon HIV-1 or simian immunodeficiency virus (SIV) infection. NK cells and virus-infected targets are mixed in the presence of serial plasma dilutions, and ADCC is measured as the dose-dependent loss of luciferase activity. Using this approach, ADCC titers were measured in plasma samples from HIV-infected human donors and SIV-infected macaques. For the same plasma samples paired with the same test viruses, this assay was approximately 2 orders of magnitude more sensitive than optimized assays for neutralizing antibodies—frequently allowing the measurement of ADCC in the absence of detectable neutralization. Although ADCC correlated with other measures of Env-specific antibodies, neutralizing and gp120 binding titers did not consistently predict ADCC activity. Hence, this assay affords a sensitive method for measuring antibodies capable of directing ADCC against HIV- or SIV-infected cells expressing native conformations of the viral envelope glycoprotein and reveals incomplete overlap of the antibodies that direct ADCC and those measured in neutralization and binding assays. PMID:22933282

T cell-depleted splenocytes from mice pre-immunized with neuroantigen in incomplete Freund's adjuvant involved in protection from experimental autoimmune encephalomyelitis.

PubMed

Zheng, Hui; Zhang, Han; Liu, Feng; Qi, Yuanyuan; Jiang, Hong

2014-01-01

Mice immunized with neuroantigens in incomplete Freund's adjuvant (IFA) are resistant to subsequent induction of experimental autoimmune encephalomyelitis (EAE). The mechanisms involved in this protection are complex. Studies on relevant CD4(+) or CD8(+) T cells, including effective and regulatory T cells, have been performed by others. In this work, the effects of CD4(-)-, CD8(-)- splenocytes on protection from EAE in C57BL/6 mice which were immunized with myelin oligodendrocyte glycoprotein 35-55 (MOG)35-55 in IFA were evaluated. We observed that MOG-reactive CD4(+) T cells failed to be activated and proliferate when CD4(-)-, CD8(-)- splenocytes from MOG/IFA-immunized mice were regarded as antigen-presenting cells (APC). It was shown that these APC expressed lower levels of major histocompatibility complex class II (MHC-II), CD80, and CD86 than naïve cells. In addition, CD4(-)-, CD8(-)- splenocytes from MOG/IFA-immunized mice showed significantly higher levels of IL-10 mRNA expression. When the immunized-mice were induced to develop EAE, these cells secreted significantly higher levels of IL-10 and produced lower levels of IL-6, leading to decreased secretion of IL-17 and IFN-γ from MOG-specific CD4(+) T cells. The transfer of CD4(-)-, CD8(-)- splenocytes from MOG/IFA-immunized mice was able to ameliorate the subsequent induction of EAE in recipient mice. Thus, MOG/IFA immunization can modulate CD4(-)-, CD8(-)- splenocytes by reducing the expression of antigen-presenting molecules and altering the levels of secreted cytokines. Our study reveals an additional mechanism involved in the protective effects of MOG/IFA pre-immunization in an EAE model. Copyright © 2013 Elsevier B.V. All rights reserved.

The Roles of Sexual and Viability Selection in the Evolution of Incomplete Reproductive Isolation: From Allopatry to Sympatry.

PubMed

Cotto, Olivier; Servedio, Maria R

2017-11-01

In recent years, theoretical models have introduced the concept that ongoing hybridization between "good" species can occur because incomplete reproductive isolation can be a selected optimum. They furthermore show that positive frequency-dependent sexual selection, which is naturally generated by some of the underlying processes that lead to assortative mating, plays a key role in the evolution of incomplete reproductive isolation. This occurs, however, through different mechanisms in sympatric versus allopatric scenarios. We investigate the evolution of incomplete reproductive isolation by sexual selection in scenarios ranging from sympatry to allopatry, to examine how these mechanisms interact. We consider an ecological scenario in which there are two habitats used during foraging and individuals can breed either within a habitat or in a common mating pool. We find that when trait divergence is maintained, sexual selection drives the evolution of choosiness in opposite ways in the common mating pool versus within each habitat. Specifically, strong choosiness is favored in the common mating pool, whereas intermediate choosiness is favored within habitat; the interaction of these forces determines whether intermediate reproductive isolation ultimately evolves in the system. We further find cases where the evolution of stronger choosiness occurs but leads to the loss of divergence. Overall, our study shows that contrasting forces on the evolution of reproductive isolation can occur in different mating areas, and we propose a new avenue for understanding the diversity in levels of reproductive isolation within and across species.

The effect of hypoxia on the critical flicker fusion threshold in pilots.

PubMed

Truszczyński, Olaf; Wojtkowiak, Mieczysław; Biernacki, Marcin; Kowalczuk, Krzysztof

2009-01-01

Human reactions to environmental changes have been the subject of numerous investigations related to pathophysiology, aviation psychology, aviation, and sports. The present study aimed at evaluating the perception of light stimulus via the Critical Flicker Fusion threshold (CFF) measurements among aviation pilots. The study was carried out under hypoxic conditions corresponding to 5000 m altitude, for a period of 30 min, without the use of supplemental oxygen. Fourteen volunteer pilots, 23-30 years of age, were examined in the hypobaric chamber (HC). The measurements were performed at normobaria and at the initial and final phase of hypoxia. Heart rate (HR) and blood oxygen saturation (SaO2) were monitored. The high altitude hypoxia was found to produce a decrease in the CFF threshold F(3.39) = 3.207, p < 0.05, and SaO2 F(3.39) = 52.651, p < 0.001, as well as HR increase F(3.39) = 7.356, p < 0.001. The results indicate that the higher the decrease in SaO2 under hypoxic conditions, the higher the decrease in CFF r = .567 p < 0.05. Likewise, the higher the increase in HR, the higher the decrease in CFF r = -0.491 p < 0.05. Under hypoxic conditions, the perceptual ability of the pilots is gradually decreasing. This has been confirmed by the findings of the physiological examinations. The authors express an opinion that it would be advisable to introduce CFF measurement into the hypobaric chamber tests as it allows individual assessment of the pilot's perceptual ability under conditions of incomplete physiological compensation of the high altitude hypoxia.

Metabolomic and 13C-Metabolic Flux Analysis of a Xylose-Consuming Saccharomyces cerevisiae Strain Expressing Xylose Isomerase

PubMed Central

Wasylenko, Thomas M.; Stephanopoulos, Gregory

2016-01-01

Over the past two decades significant progress has been made in the engineering of xylose-consuming Saccharomyces cerevisiae strains for production of lignocellulosic biofuels. However, the ethanol productivities achieved on xylose are still significantly lower than those observed on glucose for reasons that are not well understood. We have undertaken an analysis of central carbon metabolite pool sizes and metabolic fluxes on glucose and on xylose under aerobic and anaerobic conditions in a strain capable of rapid xylose assimilation via xylose isomerase in order to investigate factors that may limit the rate of xylose fermentation. We find that during xylose utilization the flux through the non-oxidative PPP is high but the flux through the oxidative PPP is low, highlighting an advantage of the strain employed in this study. Furthermore, xylose fails to elicit the full carbon catabolite repression response that is characteristic of glucose fermentation in S. cerevisiae. We present indirect evidence that the incomplete activation of the fermentation program on xylose results in a bottleneck in lower glycolysis, leading to inefficient re-oxidation of NADH produced in glycolysis. PMID:25311863

Severe infectious diseases of childhood as monogenic inborn errors of immunity

PubMed Central

Casanova, Jean-Laurent

2015-01-01

This paper reviews the developments that have occurred in the field of human genetics of infectious diseases from the second half of the 20th century onward. In particular, it stresses and explains the importance of the recently described monogenic inborn errors of immunity underlying resistance or susceptibility to specific infections. The monogenic component of the genetic theory provides a plausible explanation for the occurrence of severe infectious diseases during primary infection. Over the last 20 y, increasing numbers of life-threatening infectious diseases striking otherwise healthy children, adolescents, and even young adults have been attributed to single-gene inborn errors of immunity. These studies were inspired by seminal but neglected findings in plant and animal infections. Infectious diseases typically manifest as sporadic traits because human genotypes often display incomplete penetrance (most genetically predisposed individuals remain healthy) and variable expressivity (different infections can be allelic at the same locus). Infectious diseases of childhood, once thought to be archetypal environmental diseases, actually may be among the most genetically determined conditions of mankind. This nascent and testable notion has interesting medical and biological implications. PMID:26621750

Prothrombotic changes in diabetes mellitus.

PubMed

Morel, Olivier; Jesel, Laurence; Abbas, Malak; Morel, Nicolas

2013-07-01

Although our understanding of vascular pathology has greatly improved in recent years, the cellular and molecular mechanisms underlying the enhanced thrombotic propensity in type 2 diabetes mellitus (T2DM) remain incompletely characterized. Detrimental interactions between activated vascular cells (i.e., platelets, leukocytes, endothelial cells) and the vulnerable atheromatous plaque are a major determinant of the increased atherothrombotic burden in T2DM patients. Endothelial damage and accelerated senescence, impairment of the endothelial progenitor cell repair system, plaque neovascularization and inflammation, decreased clearance of detrimental molecules within the plaque, and increased expression of matrix metalloproteinases may collectively contribute to intraplaque hemorrhage and subsequent rupture. Notably, recent data demonstrates the central importance of the tissue factor-microparticle-mediated pathway in diabetic thrombophilia and cardiovascular complications. Acting as detrimental amplifiers of various biological responses (including thrombogenicity and plaque remodeling), microparticles have also emerged as a key marker of global vascular damage in T2DM patients. Available evidence suggests that targeting the tissue factor-microparticle pathway may be a promising approach for reducing the burden of the atherosclerotic complications of diabetes. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Ketamine produces antidepressant-like effects through phosphorylation-dependent nuclear export of histone deacetylase 5 (HDAC5) in rats

PubMed Central

Choi, Miyeon; Lee, Seung Hoon; Wang, Sung Eun; Ko, Seung Yeon; Song, Mihee; Choi, June-Seek; Duman, Ronald S.; Son, Hyeon

2015-01-01

Ketamine produces rapid antidepressant-like effects in animal assays for depression, although the molecular mechanisms underlying these behavioral actions remain incomplete. Here, we demonstrate that ketamine rapidly stimulates histone deacetylase 5 (HDAC5) phosphorylation and nuclear export in rat hippocampal neurons through calcium/calmodulin kinase II- and protein kinase D-dependent pathways. Consequently, ketamine enhanced the transcriptional activity of myocyte enhancer factor 2 (MEF2), which leads to regulation of MEF2 target genes. Transfection of a HDAC5 phosphorylation-defective mutant (Ser259/Ser498 replaced by Ala259/Ala498, HDAC5-S/A), resulted in resistance to ketamine-induced nuclear export, suppression of ketamine-mediated MEF2 transcriptional activity, and decreased expression of MEF2 target genes. Behaviorally, viral-mediated hippocampal knockdown of HDAC5 blocked or occluded the antidepressant effects of ketamine both in unstressed and stressed animals. Taken together, our results reveal a novel role of HDAC5 in the actions of ketamine and suggest that HDAC5 could be a potential mechanism contributing to the therapeutic actions of ketamine. PMID:26647181

Mitochondrial Dynamics Mediated by Mitofusin 1 Is Required for POMC Neuron Glucose-Sensing and Insulin Release Control.

PubMed

Ramírez, Sara; Gómez-Valadés, Alicia G; Schneeberger, Marc; Varela, Luis; Haddad-Tóvolli, Roberta; Altirriba, Jordi; Noguera, Eduard; Drougard, Anne; Flores-Martínez, Álvaro; Imbernón, Mónica; Chivite, Iñigo; Pozo, Macarena; Vidal-Itriago, Andrés; Garcia, Ainhoa; Cervantes, Sara; Gasa, Rosa; Nogueiras, Ruben; Gama-Pérez, Pau; Garcia-Roves, Pablo M; Cano, David A; Knauf, Claude; Servitja, Joan-Marc; Horvath, Tamas L; Gomis, Ramon; Zorzano, Antonio; Claret, Marc

2017-06-06

Proopiomelanocortin (POMC) neurons are critical sensors of nutrient availability implicated in energy balance and glucose metabolism control. However, the precise mechanisms underlying nutrient sensing in POMC neurons remain incompletely understood. We show that mitochondrial dynamics mediated by Mitofusin 1 (MFN1) in POMC neurons couple nutrient sensing with systemic glucose metabolism. Mice lacking MFN1 in POMC neurons exhibited defective mitochondrial architecture remodeling and attenuated hypothalamic gene expression programs during the fast-to-fed transition. This loss of mitochondrial flexibility in POMC neurons bidirectionally altered glucose sensing, causing abnormal glucose homeostasis due to defective insulin secretion by pancreatic β cells. Fed mice lacking MFN1 in POMC neurons displayed enhanced hypothalamic mitochondrial oxygen flux and reactive oxygen species generation. Central delivery of antioxidants was able to normalize the phenotype. Collectively, our data posit MFN1-mediated mitochondrial dynamics in POMC neurons as an intrinsic nutrient-sensing mechanism and unveil an unrecognized link between this subset of neurons and insulin release. Copyright © 2017 Elsevier Inc. All rights reserved.

RRE-dependent HIV-1 Env RNA effects on Gag protein expression, assembly and release

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

López, Claudia S., E-mail: lopezcl@ohsu.edu; Sloan, Rachel; Cylinder, Isabel

The HIV-1 Gag proteins are translated from the full-length HIV-1 viral RNA (vRNA), whereas the envelope (Env) protein is translated from incompletely spliced Env mRNAs. Nuclear export of vRNAs and Env mRNAs is mediated by the Rev accessory protein which binds to the rev-responsive element (RRE) present on these RNAs. Evidence has shown there is a direct or indirect interaction between the Gag protein, and the cytoplasmic tail (CT) of the Env protein. Our current work shows that env gene expression impacts HIV-1 Gag expression and function in two ways. At the protein level, full-length Env expression altered Gag proteinmore » expression, while Env CT-deletion proteins did not. At the RNA level, RRE-containing Env mRNA expression reduced Gag expression, processing, and virus particle release from cells. Our results support models in which Gag is influenced by the Env CT, and Env mRNAs compete with vRNAs for nuclear export. - Highlights: • At the protein level, full-length HIV-1 Env alters Gag protein expression. • HIV-1 Env RNA expression reduces Gag levels and virus release. • Env RNA effects on Gag are dependent on the RRE. • RRE-containing Env RNAs compete with vRNAs for nuclear export.« less

Thrust modeling for hypersonic engines

NASA Technical Reports Server (NTRS)

Riggins, D. W.; Mcclinton, C. R.

1995-01-01

Expressions for the thrust losses of a scramjet engine are developed in terms of irreversible entropy increases and the degree of incomplete combustion. A method is developed which allows the calculation of the lost vehicle thrust due to different loss mechanisms within a given flow-field. This analysis demonstrates clearly the trade-off between mixing enhancement and resultant increased flow losses in scramjet combustors. An engine effectiveness parameter is defined in terms of thrust loss. Exergy and the thrust-potential method are related and compared.

Regulation of transmission line capacity and reliability in electric networks

NASA Astrophysics Data System (ADS)

Celebi, Metin

This thesis is composed of two essays that analyze the incentives and optimal regulation of a monopolist line owner in providing capacity and reliability. Similar analyses in the economic literature resulted in under-investment by an unregulated line owner when line reliability was treated as an exogenous variable. However, reliability should be chosen on the basis of economic principles as well, taking into account not only engineering principles but also the preferences of electricity users. When reliability is treated as a choice variable, both over- and under-investment by the line owner becomes possible. The result depends on the cross-cost elasticity of line construction and on the interval in which the optimal choices of capacity take place. We present some sufficient conditions that lead to definite results about the incentives of the line owner. We also characterize the optimal regulation of the line owner under incomplete information. Our analysis shows that the existence of a line is justified for the social planner when the reliability of other lines on the network is not too high, or when the marginal cost of generation at the expensive generating plant is high. The expectation of higher demand in the future makes the regulator less likely to build the line if it will be congested and reliability of other lines is high enough. It is always optimal to have a congested line under complete information, but not necessarily under incomplete information.

Kruppel-like factor 2 (KLF2) regulates proinflammatory activation of monocytes

PubMed Central

Das, Hiranmoy; Kumar, Ajay; Lin, Zhiyong; Patino, Willmar D.; Hwang, Paul M.; Feinberg, Mark W.; Majumder, Pradip K.; Jain, Mukesh K.

2006-01-01

The mechanisms regulating activation of monocytes remain incompletely understood. Herein we provide evidence that Kruppel-like factor 2 (KLF2) inhibits proinflammatory activation of monocytes. In vitro, KLF2 expression in monocytes is reduced by cytokine activation or differentiation. Consistent with this observation, KLF2 expression in circulating monocytes is reduced in patients with chronic inflammatory conditions such as coronary artery disease. Adenoviral overexpression of KLF2 inhibits the LPS-mediated induction of proinflammatory factors, cytokines, and chemokines and reduces phagocytosis. Conversely, short interfering RNA-mediated reduction in KLF2 increased inflammatory gene expression. Reconstitution of immunodeficient mice with KLF2-overexpressing monocytes significantly reduced carrageenan-induced acute paw edema formation. Mechanistically, KLF2 inhibits the transcriptional activity of both NF-κB and activator protein 1, in part by means of recruitment of transcriptional coactivator p300/CBP-associated factor. These observations identify KLF2 as a novel negative regulator of monocytic activation. PMID:16617118

Multi-level omics analysis in a murine model of dystrophin loss and therapeutic restoration.

PubMed

Roberts, Thomas C; Johansson, Henrik J; McClorey, Graham; Godfrey, Caroline; Blomberg, K Emelie M; Coursindel, Thibault; Gait, Michael J; Smith, C I Edvard; Lehtiö, Janne; El Andaloussi, Samir; Wood, Matthew J A

2015-12-01

Duchenne muscular dystrophy (DMD) is a classical monogenic disorder, a model disease for genomic studies and a priority candidate for regenerative medicine and gene therapy. Although the genetic cause of DMD is well known, the molecular pathogenesis of disease and the response to therapy are incompletely understood. Here, we describe analyses of protein, mRNA and microRNA expression in the tibialis anterior of the mdx mouse model of DMD. Notably, 3272 proteins were quantifiable and 525 identified as differentially expressed in mdx muscle (P < 0.01). Therapeutic restoration of dystrophin by exon skipping induced widespread shifts in protein and mRNA expression towards wild-type expression levels, whereas the miRNome was largely unaffected. Comparison analyses between datasets showed that protein and mRNA ratios were only weakly correlated (r = 0.405), and identified a multitude of differentially affected cellular pathways, upstream regulators and predicted miRNA-target interactions. This study provides fundamental new insights into gene expression and regulation in dystrophic muscle. © The Author 2015. Published by Oxford University Press.

Expression and mutational analysis of Cip/Kip family in early glottic cancer.

PubMed

Kim, D-K; Lee, J H; Lee, O J; Park, C H

2015-02-01

Genetic alteration of cyclin-dependent kinase inhibitors has been associated with carcinogenesis mechanisms in various organs. This study aimed to evaluate the expression and mutational analysis of Cip/Kip family cyclin-dependent kinase inhibitors (p21CIP1/WAF1, p27KIP1 and p57KIP2) in early glottic cancer. Expressions of Cip/Kip family and p53 were determined by quantitative reverse transcription polymerase chain reaction and densitometry. For the analysis of p21 inactivation, sequence alteration was assessed using single-strand conformational polymorphism polymerase chain reaction. Additionally, the inactivation mechanism of p27 and p57 were investigated using DNA methylation analysis. Reduced expression of p27 and p57 were detected in all samples, whereas the expression of p21 was incompletely down-regulated in 6 of 11 samples. Additionally, single-strand conformational polymorphism polymerase chain reaction analysis showed the p53 mutation at exon 6. Methylation of p27 and p57 was detected by DNA methylation assay. Our results suggest that the Cip/Kip family may have a role as a molecular mechanism of carcinogenesis in early glottic cancer.

Osteosarcoma tissues and cell lines from patients with differing serum alkaline phosphatase concentrations display minimal differences in gene expression patterns

PubMed Central

de Sá Rodrigues, L. C.; Holmes, K. E.; Thompson, V.; Piskun, C. M.; Lana, S. E.; Newton, M. A.; Stein, T. J.

2016-01-01

Serum alkaline phosphatase (ALP) concentration is a prognostic factor for osteosarcoma in multiple studies, although its biological significance remains incompletely understood. To determine whether gene expression patterns differed in osteosarcoma from patients with differing serum ALP concentrations, microarray analysis was performed on 18 primary osteosarcoma samples and six osteosarcoma cell lines from dogs with normal and increased serum ALP concentration. No differences in gene expression patterns were noted between tumours or cell lines with differing serum ALP concentration using a gene-specific two-sample t-test. Using a more sensitive empirical Bayes procedure, defective in cullin neddylation 1 domain containing 1 (DCUN1D1) was increased in both the tissue and cell lines of the normal ALP group. Using quantitative PCR (qPCR), differences in DCUN1D1 expression between the two groups failed to reach significance. The homogeneity of gene expression patterns of osteosarcoma associated differing serum ALP concentrations are consistent with previous studies suggesting serum ALP concentration is not associated with intrinsic differences of osteosarcoma cells. PMID:25643733

Devascularization of Head and Neck Paragangliomas by Direct Percutaneous Embolization

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

Ozyer, Umut, E-mail: umut_ozyer@yahoo.com; Harman, Ali; Yildirim, Erkan

2010-10-15

Preoperative transarterial embolization of head and neck paragangliomas using particulate agents has proven beneficial for decreasing intraoperative blood loss. However, the procedure is often incomplete owing to extensive vascular structure and arteriovenous shunts. We report our experience with embolization of these lesions by means of direct puncture and intratumoral injection of n-butyl cyanoacrylate (NBCA) or Onyx. Ten patients aged 32-82 years who were referred for preoperative embolization of seven carotid body tumors and three jugular paragangliomas were retrospectively analyzed. Intratumoral injections were primarily performed in four cases with multiple small-caliber arterial feeders and adjunctive to transarterial embolization in six casesmore » with incomplete devascularization. Punctures were performed under ultrasound and injections were performed under roadmap fluoroscopic guidance. Detailed angiographies were performed before and after embolization procedures. Control angiograms showed complete or near-complete devascularization in all tumors. Three tumors with multiple small-caliber arterial feeders were treated with primary NBCA injections. One tumor necessitated transarterial embolization after primary injection of Onyx. Six tumors showed regional vascularization from the vasa vasorum or small-caliber branches of the external carotid artery following the transarterial approach. These regions were embolized with NBCA injections. No technical or clinical complications related to embolization procedures occurred. All except one of the tumors were surgically removed following embolization. In conclusion, preoperative devascularization with percutaneous direct injection of NBCA or Onyx is feasible, safe, and effective in head and neck paragangliomas with multiple small-caliber arterial feeders and in cases of incomplete devascularization following transarterial embolization.« less

Association of ectrodactyly and distal phocomelia.

PubMed

Delrue, M A; Lacombe, D

2002-01-01

Ectrodactyly and phocomelia are well known limbs malformations. They can be a part of various syndromes, and are more often transmitted with dominant autosomal Inheritance with variable expression and Incomplete penetrance. Different loci have been Identified for ectrodactyly (SHFM1 at 7q21.3q22.1, SHFM2 at Xq26, SHFM3 at 10q24q25, SHFM4 at 3q27), and two genes are known (DSS1 for SHFM1, p63 for SHFM4). We report the case of a 33 year-old female affected with the association of ectrodactyly and phocomelia. It could be a "new" association, or a mild or partial expression of the syndrome Including ectrodactyly, phocomelia, deafness and sinusal arythmia.

Investigation of defect rate of lap laser welding of stainless steel railway vehicles car body

NASA Astrophysics Data System (ADS)

Wang, Hongxiao

2015-02-01

In order to resolve the disadvantages such as poor appearance quality, poor tightness, low efficiency of resistance spot welding of stainless steel rail vehicles, partial penetration lap laser welding process was investigated widely. But due to the limitation of processing technology, there will be local incomplete fusion in the lap laser welding seam. Defect rate is the ratio of the local incomplete fusion length to the weld seam length. The tensile shear strength under different defect rate and its effect on the car body static strength are not clear. It is necessary to find the biggest defect rate by numerical analysis of effects of different defect rates on the laser welding stainless steel rail vehicle body structure strength ,and tests of laser welding shear tensile strength.

On the uncertainty of interdisciplinarity measurements due to incomplete bibliographic data.

PubMed

Calatrava Moreno, María Del Carmen; Auzinger, Thomas; Werthner, Hannes

The accuracy of interdisciplinarity measurements is directly related to the quality of the underlying bibliographic data. Existing indicators of interdisciplinarity are not capable of reflecting the inaccuracies introduced by incorrect and incomplete records because correct and complete bibliographic data can rarely be obtained. This is the case for the Rao-Stirling index, which cannot handle references that are not categorized into disciplinary fields. We introduce a method that addresses this problem. It extends the Rao-Stirling index to acknowledge missing data by calculating its interval of uncertainty using computational optimization. The evaluation of our method indicates that the uncertainty interval is not only useful for estimating the inaccuracy of interdisciplinarity measurements, but it also delivers slightly more accurate aggregated interdisciplinarity measurements than the Rao-Stirling index.

Dynamic variation in sapwood specific conductivity in six woody species.

Treesearch

J.C. Domec; F.C. Meinzer; B.L. Gartner; J. Housset

2007-01-01

Relationships between pressure gradients and flow rates in the xylem are incompletely understood because steady-state conductivity coefficients are inadequate for predicting and interpreting flow under the non-steady-state conditions more prevalent in intact trees. The goal of this study was to determine the magnitude of deviation of trunk sapwood specific conductivity...

Inactivation of E.coli 0157:H7 in crop soil by amending with fast and slow pryolysis-generated biochars

USDA-ARS?s Scientific Manuscript database

Biochar, generated by pyrolysis (i.e., heating biomass under low-oxygen conditions), results in incomplete combustion, producing a fine, grainy, highly porous material, 200 – 1,000 um in diameter. Benefits of biochar production include generation of bio-fuels, useful soil amendments for fertilizing...

78 FR 28198 - Interim Procedures for Considering Requests Under the Commercial Availability Provision of the...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-14

..., Response, Rebuttal, and Request to Remove or Restrict) must be in English. If any attachments are in a language other than English, then a complete translation must be provided. Each submission must be... that lacks the applicable certifications will be considered an incomplete submission that CITA will...

Inferring duplications, losses, transfers and incomplete lineage sorting with nonbinary species trees.

PubMed

Stolzer, Maureen; Lai, Han; Xu, Minli; Sathaye, Deepa; Vernot, Benjamin; Durand, Dannie

2012-09-15

Gene duplication (D), transfer (T), loss (L) and incomplete lineage sorting (I) are crucial to the evolution of gene families and the emergence of novel functions. The history of these events can be inferred via comparison of gene and species trees, a process called reconciliation, yet current reconciliation algorithms model only a subset of these evolutionary processes. We present an algorithm to reconcile a binary gene tree with a nonbinary species tree under a DTLI parsimony criterion. This is the first reconciliation algorithm to capture all four evolutionary processes driving tree incongruence and the first to reconcile non-binary species trees with a transfer model. Our algorithm infers all optimal solutions and reports complete, temporally feasible event histories, giving the gene and species lineages in which each event occurred. It is fixed-parameter tractable, with polytime complexity when the maximum species outdegree is fixed. Application of our algorithms to prokaryotic and eukaryotic data show that use of an incomplete event model has substantial impact on the events inferred and resulting biological conclusions. Our algorithms have been implemented in Notung, a freely available phylogenetic reconciliation software package, available at http://www.cs.cmu.edu/~durand/Notung. mstolzer@andrew.cmu.edu.

Robust pulmonary lobe segmentation against incomplete fissures

NASA Astrophysics Data System (ADS)

Gu, Suicheng; Zheng, Qingfeng; Siegfried, Jill; Pu, Jiantao

2012-03-01

As important anatomical landmarks of the human lung, accurate lobe segmentation may be useful for characterizing specific lung diseases (e.g., inflammatory, granulomatous, and neoplastic diseases). A number of investigations showed that pulmonary fissures were often incomplete in image depiction, thereby leading to the computerized identification of individual lobes a challenging task. Our purpose is to develop a fully automated algorithm for accurate identification of individual lobes regardless of the integrity of pulmonary fissures. The underlying idea of the developed lobe segmentation scheme is to use piecewise planes to approximate the detected fissures. After a rotation and a global smoothing, a number of small planes were fitted using local fissures points. The local surfaces are finally combined for lobe segmentation using a quadratic B-spline weighting strategy to assure that the segmentation is smooth. The performance of the developed scheme was assessed by comparing with a manually created reference standard on a dataset of 30 lung CT examinations. These examinations covered a number of lung diseases and were selected from a large chronic obstructive pulmonary disease (COPD) dataset. The results indicate that our scheme of lobe segmentation is efficient and accurate against incomplete fissures.

Incomplete offspring sex bias in Australian populations of the butterfly Eurema hecabe

PubMed Central

Kemp, D J; Thomson, F E; Edwards, W; Iturbe-Ormaetxe, I

2017-01-01

Theory predicts unified sex ratios for most organisms, yet biases may be engendered by selfish genetic elements such as endosymbionts that kill or feminize individuals with male genotypes. Although rare, feminization is established for Wolbachia-infected Eurema butterflies. This paradigm is presently confined to islands in the southern Japanese archipelago, where feminized phenotypes produce viable all-daughter broods. Here, we characterize sex bias for E. hecabe in continental Australia. Starting with 186 wild-caught females, we reared >6000 F1–F3 progeny in pedigree designs that incorporated selective antibiotic treatments. F1 generations expressed a consistent bias across 2 years and populations that was driven by an ~5% incidence of broods comprising ⩾80% daughters. Females from biased lineages continued to overproduce daughters over two generations of outcrossing to wild males. Treatment with antibiotics of differential strength influenced sex ratio only in biased lineages by inducing an equivalent incomplete degree of son overproduction. Brood sex ratios were nevertheless highly variable within lineages and across generations. Intriguingly, the cytogenetic signature of female karyotype was uniformly absent, even among phenotypic females in unbiased lineages. Molecular evidence supported the existence of a single Wolbachia strain at high prevalence, yet this was not clearly linked to brood sex bias. In sum, we establish an inherited, experimentally reversible tendency for incomplete offspring bias. Key features of our findings clearly depart from the Japanese feminization paradigm and highlight the potential for more subtle degrees of sex distortion in arthropods. PMID:27731327

Bi-level Multi-Source Learning for Heterogeneous Block-wise Missing Data

PubMed Central

Xiang, Shuo; Yuan, Lei; Fan, Wei; Wang, Yalin; Thompson, Paul M.; Ye, Jieping

2013-01-01

Bio-imaging technologies allow scientists to collect large amounts of high-dimensional data from multiple heterogeneous sources for many biomedical applications. In the study of Alzheimer's Disease (AD), neuroimaging data, gene/protein expression data, etc., are often analyzed together to improve predictive power. Joint learning from multiple complementary data sources is advantageous, but feature-pruning and data source selection are critical to learn interpretable models from high-dimensional data. Often, the data collected has block-wise missing entries. In the Alzheimer’s Disease Neuroimaging Initiative (ADNI), most subjects have MRI and genetic information, but only half have cerebrospinal fluid (CSF) measures, a different half has FDG-PET; only some have proteomic data. Here we propose how to effectively integrate information from multiple heterogeneous data sources when data is block-wise missing. We present a unified “bi-level” learning model for complete multi-source data, and extend it to incomplete data. Our major contributions are: (1) our proposed models unify feature-level and source-level analysis, including several existing feature learning approaches as special cases; (2) the model for incomplete data avoids imputing missing data and offers superior performance; it generalizes to other applications with block-wise missing data sources; (3) we present efficient optimization algorithms for modeling complete and incomplete data. We comprehensively evaluate the proposed models including all ADNI subjects with at least one of four data types at baseline: MRI, FDG-PET, CSF and proteomics. Our proposed models compare favorably with existing approaches. PMID:23988272

Bi-level multi-source learning for heterogeneous block-wise missing data.

PubMed

Xiang, Shuo; Yuan, Lei; Fan, Wei; Wang, Yalin; Thompson, Paul M; Ye, Jieping

2014-11-15

Bio-imaging technologies allow scientists to collect large amounts of high-dimensional data from multiple heterogeneous sources for many biomedical applications. In the study of Alzheimer's Disease (AD), neuroimaging data, gene/protein expression data, etc., are often analyzed together to improve predictive power. Joint learning from multiple complementary data sources is advantageous, but feature-pruning and data source selection are critical to learn interpretable models from high-dimensional data. Often, the data collected has block-wise missing entries. In the Alzheimer's Disease Neuroimaging Initiative (ADNI), most subjects have MRI and genetic information, but only half have cerebrospinal fluid (CSF) measures, a different half has FDG-PET; only some have proteomic data. Here we propose how to effectively integrate information from multiple heterogeneous data sources when data is block-wise missing. We present a unified "bi-level" learning model for complete multi-source data, and extend it to incomplete data. Our major contributions are: (1) our proposed models unify feature-level and source-level analysis, including several existing feature learning approaches as special cases; (2) the model for incomplete data avoids imputing missing data and offers superior performance; it generalizes to other applications with block-wise missing data sources; (3) we present efficient optimization algorithms for modeling complete and incomplete data. We comprehensively evaluate the proposed models including all ADNI subjects with at least one of four data types at baseline: MRI, FDG-PET, CSF and proteomics. Our proposed models compare favorably with existing approaches. © 2013 Elsevier Inc. All rights reserved.

FOXO1 opposition of CD8+ T cell effector programming confers early memory properties and phenotypic diversity.

PubMed

Delpoux, Arnaud; Lai, Chen-Yen; Hedrick, Stephen M; Doedens, Andrew L

2017-10-17

The factors and steps controlling postinfection CD8 + T cell terminal effector versus memory differentiation are incompletely understood. Whereas we found that naive TCF7 (alias "Tcf-1") expression is FOXO1 independent, early postinfection we report bimodal, FOXO1-dependent expression of the memory-essential transcription factor TCF7 in pathogen-specific CD8 + T cells. We determined the early postinfection TCF7 high population is marked by low TIM3 expression and bears memory signature hallmarks before the appearance of established memory precursor marker CD127 (IL-7R). These cells exhibit diminished TBET, GZMB, mTOR signaling, and cell cycle progression. Day 5 postinfection, TCF7 high cells express higher memory-associated BCL2 and EOMES, as well as increased accumulation potential and capacity to differentiate into memory phenotype cells. TCF7 retroviral transduction opposes GZMB expression and the formation of KLRG1 pos phenotype cells, demonstrating an active role for TCF7 in extinguishing the effector program and forestalling terminal differentiation. Past the peak of the cellular immune response, we report a gradient of FOXO1 and TCF7 expression, which functions to oppose TBET and orchestrate a continuum of effector-to-memory phenotypes.

Prediction of clinical outcome using blood flow volume in the superior mesenteric artery in patients with pseudomyxoma peritonei treated by cytoreductive surgery.

PubMed

Dohan, A; Barral, M; Eveno, C; Lo Dico, R; Kaci, R; Pasteur-Rousseau, A; Soyer, P; Pocard, M; Bonnin, P

2017-10-01

Pseudomyxoma peritonei (PMP) is a rare carcinomatosis limited to the peritoneal cavity, mainly supplied by the superior mesenteric artery (SMA). The only curative treatment is cytoreductive surgery (CRS) associated with hyperthermic intraperitoneal chemotherapy. This study aimed to evaluate the ability of blood flow volume (BFV) recorded in the SMA using Doppler ultrasonography pre-operatively to predict the extent and resectability of the disease and post-operatively to assess clinical outcome. BFV was measured in the SMA of forty-nine patients before and the year following CRS. Patients were categorized in 3 groups according to clinical and surgical outcomes: group-1 (n = 22): patient with completed CRS, group-2 (n = 16): incomplete resection with slowly progressive disease (alive at 2 years without severe clinical symptoms), group-3 (n = 11): incomplete resection and with severe clinical symptoms or dead within two years. Pre-operative mean SMA BFV was higher in group-2 (510 mL/min, p = 0.027) and in group-3 (572 mL/min, p = 0.004) than in group-1 (378 mL/min). After surgery, BFV dropped to normal values (203 mL/min, p = 0.001) in group-1, and to 423 mL/min (p = 0.047) in group-2. It remained elevated in group-3 (626 mL/min, p = 0.566). BFV allowed stratification of 1) resectability before CRS (group-2 and -3 vs group-1, area under the ROC curve: 0.794 [0.650-0.939]), and 2) non progression after incomplete CRS (group-3 vs group-2, area under the ROC curve: 0.827 [0.565-1.00]. Pre-operative BFV in the SMA correlates with extent and resectability of PMP. After incomplete surgery, post-operative BFV might aid in identifying patients who may benefit of post-operative therapy. Copyright © 2017 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Some Families of the Incomplete H-Functions and the Incomplete \\overline H -Functions and Associated Integral Transforms and Operators of Fractional Calculus with Applications

NASA Astrophysics Data System (ADS)

Srivastava, H. M.; Saxena, R. K.; Parmar, R. K.

2018-01-01

Our present investigation is inspired by the recent interesting extensions (by Srivastava et al. [35]) of a pair of the Mellin-Barnes type contour integral representations of their incomplete generalized hypergeometric functions p γ q and p Γ q by means of the incomplete gamma functions γ( s, x) and Γ( s, x). Here, in this sequel, we introduce a family of the relatively more general incomplete H-functions γ p,q m,n ( z) and Γ p,q m,n ( z) as well as their such special cases as the incomplete Fox-Wright generalized hypergeometric functions p Ψ q (γ) [ z] and p Ψ q (Γ) [ z]. The main object of this paper is to study and investigate several interesting properties of these incomplete H-functions, including (for example) decomposition and reduction formulas, derivative formulas, various integral transforms, computational representations, and so on. We apply some substantially general Riemann-Liouville and Weyl type fractional integral operators to each of these incomplete H-functions. We indicate the easilyderivable extensions of the results presented here that hold for the corresponding incomplete \\overline H -functions as well. Potential applications of many of these incomplete special functions involving (for example) probability theory are also indicated.

Cigarette Smoke-Related Hydroquinone Dysregulates MCP-1, VEGF and PEDF Expression in Retinal Pigment Epithelium in Vitro and in Vivo

PubMed Central

Pons, Marianne; Marin-Castaño, Maria E.

2011-01-01

Background Age-related macular degeneration (AMD) is the leading cause of legal blindness in the elderly population. Debris (termed drusen) below the retinal pigment epithelium (RPE) have been recognized as a risk factor for dry AMD and its progression to wet AMD, which is characterized by choroidal neovascularization (CNV). The underlying mechanism of how drusen might elicit CNV remains undefined. Cigarette smoking, oxidative damage to the RPE and inflammation are postulated to be involved in the pathophysiology of the disease. To better understand the cellular mechanism(s) linking oxidative stress and inflammation to AMD, we examined the expression of pro-inflammatory monocyte chemoattractant protein-1 (MCP-1), pro-angiogenic vascular endothelial growth factor (VEGF) and anti-angiogenic pigment epithelial derived factor (PEDF) in RPE from smoker patients with AMD. We also evaluated the effects of hydroquinone (HQ), a major pro-oxidant in cigarette smoke on MCP-1, VEGF and PEDF expression in cultured ARPE-19 cells and RPE/choroids from C57BL/6 mice. Principal Findings MCP-1, VEGF and PEDF expression was examined by real-time PCR, Western blot, and ELISA. Low levels of MCP-1 protein were detected in RPE from AMD smoker patients relative to controls. Both MCP-1 mRNA and protein were downregulated in ARPE-19 cells and RPE/choroids from C57BL/6 mice after 5 days and 3 weeks of exposure to HQ-induced oxidative injury. VEGF protein expression was increased and PEDF protein expression was decreased in RPE from smoker patients with AMD versus controls resulting in increased VEGF/PEDF ratio. Treatment with HQ for 5 days and 3 weeks increased the VEGF/PEDF ratio in vitro and in vivo. Conclusion We propose that impaired RPE-derived MCP-1-mediated scavenging macrophages recruitment and phagocytosis might lead to incomplete clearance of proinflammatory debris and infiltration of proangiogenic macrophages which along with increased VEGF/PEDF ratio favoring angiogenesis might promote drusen accumulation and progression to CNV in smoker patients with dry AMD. PMID:21386905

Identification and Classification of New Transcripts in Dorper and Small-Tailed Han Sheep Skeletal Muscle Transcriptomes.

PubMed

Chao, Tianle; Wang, Guizhi; Wang, Jianmin; Liu, Zhaohua; Ji, Zhibin; Hou, Lei; Zhang, Chunlan

2016-01-01

High-throughput mRNA sequencing enables the discovery of new transcripts and additional parts of incompletely annotated transcripts. Compared with the human and cow genomes, the reference annotation level of the sheep genome is still low. An investigation of new transcripts in sheep skeletal muscle will improve our understanding of muscle development. Therefore, applying high-throughput sequencing, two cDNA libraries from the biceps brachii of small-tailed Han sheep and Dorper sheep were constructed, and whole-transcriptome analysis was performed to determine the unknown transcript catalogue of this tissue. In this study, 40,129 transcripts were finally mapped to the sheep genome. Among them, 3,467 transcripts were determined to be unannotated in the current reference sheep genome and were defined as new transcripts. Based on protein-coding capacity prediction and comparative analysis of sequence similarity, 246 transcripts were classified as portions of unannotated genes or incompletely annotated genes. Another 1,520 transcripts were predicted with high confidence to be long non-coding RNAs. Our analysis also revealed 334 new transcripts that displayed specific expression in ruminants and uncovered a number of new transcripts without intergenus homology but with specific expression in sheep skeletal muscle. The results confirmed a complex transcript pattern of coding and non-coding RNA in sheep skeletal muscle. This study provided important information concerning the sheep genome and transcriptome annotation, which could provide a basis for further study.

Novel Antibiofilm Chemotherapy Targets Exopolysaccharide Synthesis and Stress Tolerance in Streptococcus mutans To Modulate Virulence Expression In Vivo

PubMed Central

Falsetta, Megan L.; Klein, Marlise I.; Lemos, José A.; Silva, Bruno B.; Agidi, Senyo; Scott-Anne, Kathy K.

2012-01-01

Fluoride is the mainstay of dental caries prevention, and yet current applications offer incomplete protection and may not effectively address the infectious character of the disease. Therefore, we evaluated the effectiveness of a novel combination therapy (CT; 2 mM myricetin, 4 mM tt-farnesol, 250 ppm of fluoride) that supplements fluoride with naturally occurring, food-derived, antibiofilm compounds. Treatment regimens simulating those experienced clinically (twice daily for ≤60 s) were used both in vitro over a saliva-coated hydroxyapatite biofilm model and in vivo with a rodent model of dental caries. The effectiveness of CT was evaluated based on the incidence and severity of carious lesions (compared to fluoride or vehicle control). We found that CT was superior to fluoride (positive control, P < 0.05); topical applications dramatically reduced caries development in Sprague-Dawley rats, all without altering the Streptococcus mutans or total populations within the plaque. We subsequently identified the underlying mechanisms through which applications of CT modulate biofilm virulence. CT targets expression of key Streptococcus mutans genes during biofilm formation in vitro and in vivo. These are associated with exopolysaccharide matrix synthesis (gtfB) and the ability to tolerate exogenous stress (e.g., sloA), which are essential for cariogenic biofilm assembly. We also identified a unique gene (SMU.940) that was severely repressed and may represent a potentially novel target; its inactivation disrupted exopolysaccharide accumulation and matrix development. Altogether, CT may be clinically more effective than current anticaries modalities, targeting expression of bacterial virulence associated with pathogenesis of the disease. These observations may have relevance for development of enhanced therapies against other biofilm-dependent infections. PMID:22985885

CD40 Ligand Promotes Mac-1 Expression, Leukocyte Recruitment, and Neointima Formation after Vascular Injury

PubMed Central

Li, Guohong; Sanders, John M.; Bevard, Melissa H.; Sun, ZhiQi; Chumley, James W.; Galkina, Elena V.; Ley, Klaus; Sarembock, Ian J.

2008-01-01

High levels of circulating soluble CD40 ligand (sCD40L) are frequently found in patients with hypercholesterolemia, diabetes, ischemic stroke, or acute coronary syndromes, predicting an increased rate of atherosclerotic plaque rupture and restenosis after coronary/carotid interventions. Clinical restenosis is characterized in part by exaggerated neointima formation, but the underlying mechanism remains incompletely understood. This study investigated the role of elevated sCD40L in neointima formation in response to vascular injury in an atherogenic animal model and explored the molecular mechanisms involved. apoE−/− mice fed a Western diet developed severe hypercholesterolemia, significant hyperglycemia, and high levels of plasma sCD40L. Neointima formation after carotid denudation injury was exaggerated in the apoE−/− mice. In vivo, blocking CD40L with anti-CD40L monoclonal antibody attenuated the early accumulation of Ly-6G+ neutrophils and Gr-1+ monocytes (at 3 days) and the late accumulation of Mac-2+ macrophages (at 28 days) in the denudated arteries; it also reduced the exaggerated neointima formation at 28 days. In vitro, recombinant CD40L stimulated platelet P-selectin and neutrophil Mac-1 expression and platelet-neutrophil co-aggregation and adhesive interaction. These effects were abrogated by anti-CD40L or anti-Mac-1 monoclonal antibody. Moreover, recombinant CD40L stimulated neutrophil oxidative burst and release of matrix metalloproteinase-9 in vitro. We conclude that elevated sCD40L promotes platelet-leukocyte activation and recruitment and neointima formation after arterial injury, potentially through enhancement of platelet P-selectin and leukocyte Mac-1 expression and oxidative activity. PMID:18349125

Regulation of Extracellular Matrix Remodeling Proteins by Osteoblasts in Titanium Nanoparticle-Induced Aseptic Loosening Model.

PubMed

Xie, Jing; Hou, Yanhua; Fu, Na; Cai, Xiaoxiao; Li, Guo; Peng, Qiang; Lin, Yunfeng

2015-10-01

Titanium (Ti)-wear particles, formed at the bone-implant interface, are responsible for aseptic loosening, which is a main cause of total joint replacement failure. There have been many studies on Ti particle-induced function changes in mono-cultured osteoblasts and synovial cells. However, little is known on extracellular matrix remodeling displayed by osteoblasts when in coexistence with Synovial cells. To further mimic the bone-implant interface environment, we firstly established a nanoscaled-Ti particle-induced aseptic loosening system by co-culturing osteoblasts and Synovial cells. We then explored the impact of the Synovial cells on Ti particle-engulfed osteoblasts in the mimicked flamed niche. The matrix metalloproteinases and lysyl oxidases expression levels, two protein families which are critical in osseointegration, were examined under induction by tumor necrosis factor-alpha. It was found that the co-culture between the osteoblasts and Synovial cells markedly increased the migration and proliferation of the osteoblasts, even in the Ti-particle engulfed osteoblasts. Importantly, the Ti-particle engulfed osteoblasts, induced by TNF-alpha after the co-culture, enhanced the release of the matrix metalloproteinases and reduced the expressions of lysyl oxidases. The regulation of extracellular matrix remodeling at the protein level was further assessed by investigations on gene expression of the matrix metalloproteinases and lysyl oxidases, which also suggested that the regulation started at the genetic level. Our research work has therefore revealed the critical role of multi cell-type interactions in the extracellular matrix remodeling within the peri-prosthetic tissues, which provides new insights on aseptic loosening and brings new clues about incomplete osseointegration between the implantation materials and their surrounding bones.

The cell cycle regulator ecdysoneless cooperates with H-Ras to promote oncogenic transformation of human mammary epithelial cells.

PubMed

Bele, Aditya; Mirza, Sameer; Zhang, Ying; Ahmad Mir, Riyaz; Lin, Simon; Kim, Jun Hyun; Gurumurthy, Channabasavaiah Basavaraju; West, William; Qiu, Fang; Band, Hamid; Band, Vimla

2015-01-01

The mammalian ortholog of Drosophila ecdysoneless (Ecd) gene product regulates Rb-E2F interaction and is required for cell cycle progression. Ecd is overexpressed in breast cancer and its overexpression predicts shorter survival in patients with ErbB2-positive tumors. Here, we demonstrate Ecd knock down (KD) in human mammary epithelial cells (hMECs) induces growth arrest, similar to the impact of Ecd Knock out (KO) in mouse embryonic fibroblasts. Furthermore, whole-genome mRNA expression analysis of control vs. Ecd KD in hMECs demonstrated that several of the top 40 genes that were down-regulated were E2F target genes. To address the role of Ecd in mammary oncogenesis, we overexpressed Ecd and/or mutant H-Ras in hTERT-immortalized hMECs. Cell cycle analyses revealed hMECs overexpressing Ecd+Ras showed incomplete arrest in G1 phase upon growth factor deprivation, and more rapid cell cycle progression in growth factor-containing medium. Analyses of cell migration, invasion, acinar structures in 3-D Matrigel and anchorage-independent growth demonstrated that Ecd+Ras-overexpressing cells exhibit substantially more dramatic transformed phenotype as compared to cells expressing vector, Ras or Ecd. Under conditions of nutrient deprivation, Ecd+Ras-overexpressing hMECs exhibited better survival, with substantial upregulation of the autophagy marker LC3 both at the mRNA and protein levels. Significantly, while hMECs expressing Ecd or mutant Ras alone did not form tumors in NOD/SCID mice, Ecd+Ras-overexpressing hMECs formed tumors, clearly demonstrating oncogenic cooperation between Ecd and mutant Ras. Collectively, we demonstrate an important co-oncogenic role of Ecd in the progression of mammary oncogenesis through promoting cell survival.

Nuclear Export and Expression of Human T-Cell Leukemia Virus Type 1 tax/rex mRNA Are RxRE/Rex Dependent

PubMed Central

Bai, X. T.; Sinha-Datta, U.; Ko, N. L.; Bellon, M.

2012-01-01

Human T-cell leukemia virus type 1 (HTLV-1) is a complex retrovirus associated with the lymphoproliferative disease adult T-cell leukemia/lymphoma (ATL) and the neurodegenerative disorder tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM). Replication of HTLV-1 is under the control of two major trans-acting proteins, Tax and Rex. Previous studies suggested that Tax activates transcription from the viral long terminal repeat (LTR) through recruitment of cellular CREB and transcriptional coactivators. Other studies reported that Rex acts posttranscriptionally and allows the cytoplasmic export of unspliced or incompletely spliced viral mRNAs carrying gag/pol and env only. As opposed to HIV's Rev-responsive element (RRE), the Rex-responsive element (RxRE) is present in all viral mRNAs in HTLV-1. However, based on indirect observations, it is believed that nuclear export and expression of the doubly spliced tax/rex RNA are Rex independent. In this study, we demonstrate that Rex does stimulate Tax expression, through nuclear-cytoplasmic export of the tax/rex RNA, even though a Rex-independent basal export mechanism exists. This effect was dependent upon the RxRE element and the RNA-binding activity of Rex. In addition, Rex-mediated export of tax/rex RNA was CRM1 dependent and inhibited by leptomycin B treatment. RNA immunoprecipitation (RNA-IP) experiments confirmed Rex binding to the tax/rex RNA in both transfected cells with HTLV-1 molecular clones and HTLV-1-infected T cells. Since both Rex and p30 interact with the tax/rex RNA and with one another, this may offer a temporal and dynamic regulation of HTLV-1 replication. Our results shed light on HTLV-1 replication and reveal a more complex regulatory network than previously anticipated. PMID:22318152

The cell cycle regulator ecdysoneless cooperates with H-Ras to promote oncogenic transformation of human mammary epithelial cells

PubMed Central

Bele, Aditya; Mirza, Sameer; Zhang, Ying; Ahmad Mir, Riyaz; Lin, Simon; Kim, Jun Hyun; Gurumurthy, Channabasavaiah Basavaraju; West, William; Qiu, Fang; Band, Hamid; Band, Vimla

2015-01-01

The mammalian ortholog of Drosophila ecdysoneless (Ecd) gene product regulates Rb-E2F interaction and is required for cell cycle progression. Ecd is overexpressed in breast cancer and its overexpression predicts shorter survival in patients with ErbB2-positive tumors. Here, we demonstrate Ecd knock down (KD) in human mammary epithelial cells (hMECs) induces growth arrest, similar to the impact of Ecd Knock out (KO) in mouse embryonic fibroblasts. Furthermore, whole-genome mRNA expression analysis of control vs. Ecd KD in hMECs demonstrated that several of the top 40 genes that were down-regulated were E2F target genes. To address the role of Ecd in mammary oncogenesis, we overexpressed Ecd and/or mutant H-Ras in hTERT-immortalized hMECs. Cell cycle analyses revealed hMECs overexpressing Ecd+Ras showed incomplete arrest in G1 phase upon growth factor deprivation, and more rapid cell cycle progression in growth factor-containing medium. Analyses of cell migration, invasion, acinar structures in 3-D Matrigel and anchorage-independent growth demonstrated that Ecd+Ras-overexpressing cells exhibit substantially more dramatic transformed phenotype as compared to cells expressing vector, Ras or Ecd. Under conditions of nutrient deprivation, Ecd+Ras-overexpressing hMECs exhibited better survival, with substantial upregulation of the autophagy marker LC3 both at the mRNA and protein levels. Significantly, while hMECs expressing Ecd or mutant Ras alone did not form tumors in NOD/SCID mice, Ecd+Ras-overexpressing hMECs formed tumors, clearly demonstrating oncogenic cooperation between Ecd and mutant Ras. Collectively, we demonstrate an important co-oncogenic role of Ecd in the progression of mammary oncogenesis through promoting cell survival. PMID:25616580

Myocardial dysfunction occurs prior to changes in ventricular geometry in mice with chronic kidney disease (CKD).

PubMed

Winterberg, Pamela D; Jiang, Rong; Maxwell, Josh T; Wang, Bo; Wagner, Mary B

2016-03-01

Uremic cardiomyopathy is responsible for high morbidity and mortality rates among patients with chronic kidney disease (CKD), but the underlying mechanisms contributing to this complex phenotype are incompletely understood. Myocardial deformation analyses (ventricular strain) of patients with mild CKD have recently been reported to predict adverse clinical outcome. We aimed to determine if early myocardial dysfunction in a mouse model of CKD could be detected using ventricular strain analyses. CKD was induced in 5-week-old male 129X1/SvJ mice through partial nephrectomy (5/6Nx) with age-matched mice undergoing bilateral sham surgeries serving as controls. Serial transthoracic echocardiography was performed over 16 weeks following induction of CKD. Invasive hemodynamic measurements were performed at 8 weeks. Gene expression and histology was performed on hearts at 8 and 16 weeks. CKD mice developed decreased longitudinal strain (-25 ± 4.2% vs. -29 ± 2.3%; P = 0.01) and diastolic dysfunction (E/A ratio 1.2 ± 0.15 vs. 1.9 ± 0.18; P < 0.001) compared to controls as early as 2 weeks following 5/6Nx. In contrast, ventricular hypertrophy was not apparent until 4 weeks. Hearts from CKD mice developed progressive fibrosis at 8 and 16 weeks with gene signatures suggestive of evolving heart failure with elevated expression of natriuretic peptides. Uremic cardiomyopathy in this model is characterized by early myocardial dysfunction which preceded observable changes in ventricular geometry. The model ultimately resulted in myocardial fibrosis and increased expression of natriuretic peptides suggestive of progressive heart failure. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Dorsal Medial Habenula Regulation of Mood-Related Behaviors and Primary Reinforcement by Tachykinin-Expressing Habenula Neurons

PubMed Central

Hsu, Yun-Wei A.

2016-01-01

Abstract Animal models have been developed to investigate aspects of stress, anxiety, and depression, but our understanding of the circuitry underlying these models remains incomplete. Prior studies of the habenula, a poorly understood nucleus in the dorsal diencephalon, suggest that projections to the medial habenula (MHb) regulate fear and anxiety responses, whereas the lateral habenula (LHb) is involved in the expression of learned helplessness, a model of depression. Tissue-specific deletion of the transcription factor Pou4f1 in the dorsal MHb (dMHb) results in a developmental lesion of this subnucleus. These dMHb-ablated mice show deficits in voluntary exercise, a possible correlate of depression. Here we explore the role of the dMHb in mood-related behaviors and intrinsic reinforcement. Lesions of the dMHb do not elicit changes in contextual conditioned fear. However, dMHb-lesioned mice exhibit shorter immobility time in the tail suspension test, another model of depression. dMHb-lesioned mice also display increased vulnerability to the induction of learned helplessness. However, this effect is not due specifically to the dMHb lesion, but appears to result from Pou4f1 haploinsufficiency elsewhere in the nervous system. Pou4f1 haploinsufficiency does not produce the other phenotypes associated with dMHb lesions. Using optogenetic intracranial self-stimulation, intrinsic reinforcement by the dMHb can be mapped to a specific population of neurokinin-expressing habenula neurons. Together, our data show that the dMHb is involved in the regulation of multiple mood-related behaviors, but also support the idea that these behaviors do not reflect a single functional pathway. PMID:27482535

Plectin regulates the signaling and trafficking of the HIV-1 co-receptor CXCR4 and plays a role in HIV-1 infection

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

Ding Yun; Department of Neurobiology and Neurotoxicology, Meharry Medical College, Nashville, TN 37208; Zhang Li

2008-02-01

The CXC chemokine CXCL12 and its cognate receptor CXCR4 play an important role in inflammation, human immunodeficiency virus (HIV) infection and cancer metastasis. The signal transduction and intracellular trafficking of CXCR4 are involved in these functions, but the underlying mechanisms remain incompletely understood. In the present study, we demonstrated that the CXCR4 formed a complex with the cytolinker protein plectin in a ligand-dependent manner in HEK293 cells stably expressing CXCR4. The glutathione-S-transferase (GST)-CXCR4 C-terminal fusion proteins co-precipitated with the full-length and the N-terminal fragments of plectin isoform 1 but not with the N-terminal deletion mutants of plectin isoform 1, therebymore » suggesting an interaction between the N-terminus of plectin and the C-terminus of CXCR4. This interaction was confirmed by confocal microscopic reconstructions showing co-distribution of these two proteins in the internal vesicles after ligand-induced internalization of CXCR4 in HEK293 cells stably expressing CXCR4. Knockdown of plectin with RNA interference (RNAi) significantly inhibited ligand-dependent CXCR4 internalization and attenuated CXCR4-mediated intracellular calcium mobilization and activation of extracellular signal regulated kinase 1/2 (ERK1/2). CXCL12-induced chemotaxis of HEK293 cells stably expressing CXCR4 and of Jurkat T cells was inhibited by the plectin RNAi. Moreover, CXCR4 tropic HIV-1 infection in MAGI (HeLa-CD4-LTR-Gal) cells was inhibited by the RNAi of plectin. Thus, plectin appears to interact with CXCR4 and plays an important role in CXCR4 signaling and trafficking and HIV-1 infection.« less

Dorsal Medial Habenula Regulation of Mood-Related Behaviors and Primary Reinforcement by Tachykinin-Expressing Habenula Neurons.

PubMed

Hsu, Yun-Wei A; Morton, Glenn; Guy, Elizabeth G; Wang, Si D; Turner, Eric E

2016-01-01

Animal models have been developed to investigate aspects of stress, anxiety, and depression, but our understanding of the circuitry underlying these models remains incomplete. Prior studies of the habenula, a poorly understood nucleus in the dorsal diencephalon, suggest that projections to the medial habenula (MHb) regulate fear and anxiety responses, whereas the lateral habenula (LHb) is involved in the expression of learned helplessness, a model of depression. Tissue-specific deletion of the transcription factor Pou4f1 in the dorsal MHb (dMHb) results in a developmental lesion of this subnucleus. These dMHb-ablated mice show deficits in voluntary exercise, a possible correlate of depression. Here we explore the role of the dMHb in mood-related behaviors and intrinsic reinforcement. Lesions of the dMHb do not elicit changes in contextual conditioned fear. However, dMHb-lesioned mice exhibit shorter immobility time in the tail suspension test, another model of depression. dMHb-lesioned mice also display increased vulnerability to the induction of learned helplessness. However, this effect is not due specifically to the dMHb lesion, but appears to result from Pou4f1 haploinsufficiency elsewhere in the nervous system. Pou4f1 haploinsufficiency does not produce the other phenotypes associated with dMHb lesions. Using optogenetic intracranial self-stimulation, intrinsic reinforcement by the dMHb can be mapped to a specific population of neurokinin-expressing habenula neurons. Together, our data show that the dMHb is involved in the regulation of multiple mood-related behaviors, but also support the idea that these behaviors do not reflect a single functional pathway.

Paradoxical leanness in the imprinting-centre deletion mouse model for Prader–Willi syndrome

PubMed Central

Golding, David M; Rees, Daniel J; Davies, Jennifer R; Relkovic, Dinko; Furby, Hannah V; Guschina, Irina A; Hopkins, Anna L; Davies, Jeffrey S; Resnick, James L; Isles, Anthony R

2016-01-01

Prader–Willi syndrome (PWS), a neurodevelopmental disorder caused by loss of paternal gene expression from 15q11–q13, is characterised by growth retardation, hyperphagia and obesity. However, as single gene mutation mouse models for this condition display an incomplete spectrum of the PWS phenotype, we have characterised the metabolic impairment in a mouse model for ‘full’ PWS, in which deletion of the imprinting centre (IC) abolishes paternal gene expression from the entire PWS cluster. We show that PWS-ICdel mice displayed postnatal growth retardation, with reduced body weight, hyperghrelinaemia and marked abdominal leanness; proportionate retroperitoneal, epididymal/omental and inguinal white adipose tissue (WAT) weights being reduced by 82%, 84% and 67%, respectively. PWS-ICdel mice also displayed a 48% reduction in proportionate interscapular brown adipose tissue (isBAT) weight with significant ‘beiging’ of abdominal WAT, and a 2°C increase in interscapular surface body temperature. Maintenance of PWS-ICdel mice under thermoneutral conditions (30°C) suppressed the thermogenic activity in PWS-ICdel males, but failed to elevate the abdominal WAT weight, possibly due to a normalisation of caloric intake. Interestingly, PWS-ICdel mice also showed exaggerated food hoarding behaviour with standard and high-fat diets, but despite becoming hyperphagic when switched to a high-fat diet, PWS-ICdel mice failed to gain weight. This evidence indicates that, unlike humans with PWS, loss of paternal gene expression from the PWS cluster in mice results in abdominal leanness. Although reduced subcutaneous insulation may lead to exaggerated heat loss and thermogenesis, abdominal leanness is likely to arise from a reduced lipid storage capacity rather than increased energy utilisation in BAT. PMID:27799465

Paradoxical leanness in the imprinting-centre deletion mouse model for Prader-Willi syndrome.

PubMed

Golding, David M; Rees, Daniel J; Davies, Jennifer R; Relkovic, Dinko; Furby, Hannah V; Guschina, Irina A; Hopkins, Anna L; Davies, Jeffrey S; Resnick, James L; Isles, Anthony R; Wells, Timothy

2017-01-01

Prader-Willi syndrome (PWS), a neurodevelopmental disorder caused by loss of paternal gene expression from 15q11-q13, is characterised by growth retardation, hyperphagia and obesity. However, as single gene mutation mouse models for this condition display an incomplete spectrum of the PWS phenotype, we have characterised the metabolic impairment in a mouse model for 'full' PWS, in which deletion of the imprinting centre (IC) abolishes paternal gene expression from the entire PWS cluster. We show that PWS-IC del mice displayed postnatal growth retardation, with reduced body weight, hyperghrelinaemia and marked abdominal leanness; proportionate retroperitoneal, epididymal/omental and inguinal white adipose tissue (WAT) weights being reduced by 82%, 84% and 67%, respectively. PWS-IC del mice also displayed a 48% reduction in proportionate interscapular brown adipose tissue (isBAT) weight with significant 'beiging' of abdominal WAT, and a 2°C increase in interscapular surface body temperature. Maintenance of PWS-IC del mice under thermoneutral conditions (30°C) suppressed the thermogenic activity in PWS-IC del males, but failed to elevate the abdominal WAT weight, possibly due to a normalisation of caloric intake. Interestingly, PWS-IC del mice also showed exaggerated food hoarding behaviour with standard and high-fat diets, but despite becoming hyperphagic when switched to a high-fat diet, PWS-IC del mice failed to gain weight. This evidence indicates that, unlike humans with PWS, loss of paternal gene expression from the PWS cluster in mice results in abdominal leanness. Although reduced subcutaneous insulation may lead to exaggerated heat loss and thermogenesis, abdominal leanness is likely to arise from a reduced lipid storage capacity rather than increased energy utilisation in BAT. © 2017 The authors.

Failsafe modes in incomplete minority game

NASA Astrophysics Data System (ADS)

Yao, Xiaobo; Wan, Shaolong; Chen, Wen

2009-09-01

We make a failsafe extension to the incomplete minority game model, give a brief analysis on how incompleteness will effect system efficiency. Simulations that limited incompleteness in strategies can improve the system efficiency. Among three failsafe modes, the “Back-to-Best” mode brings most significant improvement and keeps the system efficiency in a long range of incompleteness. A simple analytic formula has a trend which matches simulation results. The IMMG model is used to study the effect of distribution, and we find that there is one junction point in each series of curves, at which system efficiency is not influenced by the distribution of incompleteness. When pIbar > the concentration of incompleteness weakens the effect. On the other side of , concentration will be helpful. When pI is close to zero agents using incomplete strategies have on average better profits than those using standard strategies, and the “Back-to-Best” agents have a wider range of pI to win.

Incomplete lung recovery following sub-acute inhalation of combustion-derived ultrafine particles in mice.

PubMed

Noël, A; Xiao, R; Perveen, Z; Zaman, H M; Rouse, R L; Paulsen, D B; Penn, A L

2016-02-24

Particulate matter (PM) is one of the six criteria pollutant classes for which National Ambient Air Quality Standards have been set by the United States Environmental Protection Agency. Exposures to PM have been correlated with increased cardio-pulmonary morbidity and mortality. Butadiene soot (BDS), generated from the incomplete combustion of 1,3-butadiene (BD), is both a model PM mixture and a real-life example of a petrochemical product of incomplete combustion. There are numerous events, including wildfires, accidents at refineries and tank car explosions that result in sub-acute exposure to high levels of airborne particles, with the people exposed facing serious health problems. These real-life events highlight the need to investigate the health effects induced by short-term exposure to elevated levels of PM, as well as to assess whether, and if so, how well these adverse effects are resolved over time. In the present study, we investigated the extent of recovery of mouse lungs 10 days after inhalation exposures to environmentally-relevant levels of BDS aerosols had ended. Female BALB/c mice exposed to either HEPA-filtered air or to BDS (5 mg/m(3) in HEPA filtered air, 4 h/day, 21 consecutive days) were sacrificed immediately, or 10 days after the final BDS exposure. Bronchoalveolar lavage fluid (BALF) was collected for cytology and cytokine analysis. Lung proteins and RNA were extracted for protein and gene expression analysis. Lung histopathology evaluation also was performed. Sub-acute exposures of mice to hydrocarbon-rich ultrafine particles induced: (1) BALF neutrophil elevation; (2) lung mucosal inflammation, and (3) increased BALF IL-1β concentration; with all three outcomes returning to baseline levels 10 days post-exposure. In contrast, (4) lung connective tissue inflammation persisted 10 days post-exposure; (5) we detected time-dependent up-regulation of biotransformation and oxidative stress genes, with incomplete return to baseline levels; and (6) we observed persistent particle alveolar load following 10 days of recovery. These data show that 10 days after a 21-day exposure to 5 mg/m(3) of BDS has ended, incomplete lung recovery promotes a pro-biotransformation, pro-oxidant, and pro-inflammatory milieu, which may be a starting point for potential long-term cardio-pulmonary effects.

HIF-inducible miR-191 promotes migration in breast cancer through complex regulation of TGFβ-signaling in hypoxic microenvironment.

PubMed

Nagpal, Neha; Ahmad, Hafiz M; Chameettachal, Shibu; Sundar, Durai; Ghosh, Sourabh; Kulshreshtha, Ritu

2015-04-13

The molecular mechanisms of hypoxia induced breast cell migration remain incompletely understood. Our results show that hypoxia through hypoxia-inducible factor (HIF) brings about a time-dependent increase in the level of an oncogenic microRNA, miR-191 in various breast cancer cell lines. miR-191 enhances breast cancer aggressiveness by promoting cell proliferation, migration and survival under hypoxia. We further established that miR-191 is a critical regulator of transforming growth factor beta (TGFβ)-signaling and promotes cell migration by inducing TGFβ2 expression under hypoxia through direct binding and indirectly by regulating levels of a RNA binding protein, human antigen R (HuR). The levels of several TGFβ pathway genes (like VEGFA, SMAD3, CTGF and BMP4) were found to be higher in miR-191 overexpressing cells. Lastly, anti-miR-191 treatment given to breast tumor spheroids led to drastic reduction in spheroid tumor volume. This stands as a first report of identification of a microRNA mediator that links hypoxia and the TGFβ signaling pathways, both of which are involved in regulation of breast cancer metastasis. Together, our results show a critical role of miR-191 in hypoxia-induced cancer progression and suggest that miR-191 inhibition may offer a novel therapy for hypoxic breast tumors.

Why Work with Undergraduate Researchers? Differences in Research Advisors' Motivations and Outcomes by Career Stage.

PubMed

Hayward, Charles N; Laursen, Sandra L; Thiry, Heather

2017-01-01

Undergraduate research is often hailed as a solution to increasing the number and quality of science, technology, engineering, and mathematics graduates needed to fill the high-tech jobs of the future. Student benefits of research are well documented but the emerging literature on advisors' perspectives is incomplete: only a few studies have included the graduate students and postdocs who often serve as research advisors, and not much is known about why research advisors choose to work with undergraduate researchers. We report the motivations for advising undergraduate researchers, and the related costs and benefits of doing so, from 30 interviews with research advisors at various career stages. Many advisors stated intrinsic motivations, but a small group of early-career advisors expressed only instrumental motivations. We explore what this means for how advisors work with student researchers, the benefits students may or may not gain from the experience, and the implications for training and retaining research advisors who can provide high-quality research experiences for undergraduate students. © 2017 C. N. Hayward et al. CBE—Life Sciences Education © 2017 The American Society for Cell Biology. This article is distributed by The American Society for Cell Biology under license from the author(s). It is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

Analyzing the impacts of three types of biochar on soil carbon fractions and physiochemical properties in a corn-soybean rotation

USDA-ARS?s Scientific Manuscript database

Biochar is a soil amendment produced from incomplete pyrolysis of organic materials in the absence of oxygen. In most previous studies, the impacts of biochar on soil physical properties and organic carbon was investigated under controlled conditions such as laboratory or greenhouse environments. Th...

75 FR 70881 - Designation of a Chief Compliance Officer; Required Compliance Policies; and Annual Report of a...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-19

... and reasonable belief, the annual report is accurate and complete. Liability for false, incomplete, or... belief of the chief compliance officer, and under penalty of law, the information contained in the annual... supervise or false statements to the Commission. The Commission could seek an injunction against future...

Research in computer science

NASA Technical Reports Server (NTRS)

Ortega, J. M.

1984-01-01

The research efforts of University of Virginia students under a NASA sponsored program are summarized and the status of the program is reported. The research includes: testing method evaluations for N version programming; a representation scheme for modeling three dimensional objects; fault tolerant protocols for real time local area networks; performance investigation of Cyber network; XFEM implementation; and vectorizing incomplete Cholesky conjugate gradients.

21 CFR 101.17 - Food labeling warning, notice, and safe handling statements.

Code of Federal Regulations, 2010 CFR

2010-04-01

... bear the following warning: WARNING—Avoid spraying in eyes. Contents under pressure. Do not puncture or... warning required by paragraph (a)(1) of this section. (4) The words “Avoid spraying in eyes” may be... containing dry or incompletely hydrated psyllium husk, also known as psyllium seed husk, and bearing a health...

Vitamin D and Fractures in People with Intellectual Disability

ERIC Educational Resources Information Center

Vanlint, S.; Nugent, M.

2006-01-01

Background: People with intellectual disability (ID) are thought to be at an increased risk of fractures. The extent of this increase in risk has been incompletely documented in the literature, and the underlying reasons remain to be elucidated. Methods: The aims of our study were to document the vitamin D status and fracture incidence in an…

The mirror system in human and nonhuman primates.

PubMed

Orban, Guy A

2014-04-01

The description of the mirror neuron system provided by Cook et al. is incomplete for the macaque, and incorrect for humans. This is relevant to exaptation versus associative learning as the underlying mechanism generating mirror neurons, and to the sensorimotor learning as evidence for the authors' viewpoint. The proposed additional testing of the mirror system in rodents is unrealistic.

Diapause response to photoperiod in an Arizona population of Lygus hesperus (Hemiptera: Miridae)

USDA-ARS?s Scientific Manuscript database

The western tarnished plant bug (Lygus hesperus Knight) is an important crop pest in the western U.S. that overwinters in an adult diapause. However, knowledge of L. hesperus diapause is incomplete. Eggs from field-collected adults were reared under photoperiods of 10:14, 11:13, 12:12, and 13:10 (L:...

Decryption with incomplete cyphertext and multiple-information encryption in phase space.

PubMed

Xu, Xiaobin; Wu, Quanying; Liu, Jun; Situ, Guohai

2016-01-25

Recently, we have demonstrated that information encryption in phase space offers security enhancement over the traditional encryption schemes operating in real space. However, there is also an important issue with this technique: increasing the cost for data transmitting and storage. To address this issue, here we investigate the problem of decryption using incomplete cyphertext. We show that the analytic solution under the traditional framework set the lower limit of decryption performance. More importantly, we demonstrate that one just needs a small amount of cyphertext to recover the plaintext signal faithfully using compressive sensing, meaning that the amount of data that needs to transmit and store can be significantly reduced. This leads to multiple information encryption so that we can use the system bandwidth more effectively. We also provide an optical experimental result to demonstrate the plaintext recovered in phase space.

49 CFR 568.4 - Requirements for incomplete vehicle manufacturers.

Code of Federal Regulations, 2014 CFR

2014-10-01

... manufacturing operation on the incomplete vehicle. (3) Identification of the incomplete vehicle(s) to which the document applies. The identification shall be by vehicle identification number (VIN) or groups of VINs to... 49 Transportation 6 2014-10-01 2014-10-01 false Requirements for incomplete vehicle manufacturers...

49 CFR 568.4 - Requirements for incomplete vehicle manufacturers.

Code of Federal Regulations, 2011 CFR

2011-10-01

... manufacturing operation on the incomplete vehicle. (3) Identification of the incomplete vehicle(s) to which the document applies. The identification shall be by vehicle identification number (VIN) or groups of VINs to... 49 Transportation 6 2011-10-01 2011-10-01 false Requirements for incomplete vehicle manufacturers...

49 CFR 568.4 - Requirements for incomplete vehicle manufacturers.

Code of Federal Regulations, 2010 CFR

2010-10-01

... manufacturing operation on the incomplete vehicle. (3) Identification of the incomplete vehicle(s) to which the document applies. The identification shall be by vehicle identification number (VIN) or groups of VINs to... 49 Transportation 6 2010-10-01 2010-10-01 false Requirements for incomplete vehicle manufacturers...

49 CFR 529.4 - Requirements for incomplete automobile manufacturers.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 49 Transportation 6 2012-10-01 2012-10-01 false Requirements for incomplete automobile... AUTOMOBILES § 529.4 Requirements for incomplete automobile manufacturers. (a) Except as provided in paragraph (c) of this section, §§ 529.5 and 529.6, each incomplete automobile manufacturer is considered, with...

49 CFR 529.4 - Requirements for incomplete automobile manufacturers.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 49 Transportation 6 2010-10-01 2010-10-01 false Requirements for incomplete automobile... AUTOMOBILES § 529.4 Requirements for incomplete automobile manufacturers. (a) Except as provided in paragraph (c) of this section, §§ 529.5 and 529.6, each incomplete automobile manufacturer is considered, with...

49 CFR 529.4 - Requirements for incomplete automobile manufacturers.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 49 Transportation 6 2014-10-01 2014-10-01 false Requirements for incomplete automobile... AUTOMOBILES § 529.4 Requirements for incomplete automobile manufacturers. (a) Except as provided in paragraph (c) of this section, §§ 529.5 and 529.6, each incomplete automobile manufacturer is considered, with...

49 CFR 529.4 - Requirements for incomplete automobile manufacturers.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 49 Transportation 6 2013-10-01 2013-10-01 false Requirements for incomplete automobile... AUTOMOBILES § 529.4 Requirements for incomplete automobile manufacturers. (a) Except as provided in paragraph (c) of this section, §§ 529.5 and 529.6, each incomplete automobile manufacturer is considered, with...

49 CFR 529.4 - Requirements for incomplete automobile manufacturers.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 49 Transportation 6 2011-10-01 2011-10-01 false Requirements for incomplete automobile... AUTOMOBILES § 529.4 Requirements for incomplete automobile manufacturers. (a) Except as provided in paragraph (c) of this section, §§ 529.5 and 529.6, each incomplete automobile manufacturer is considered, with...

Incomplete synthesis of N-glycans in congenital dyserythropoietic anemia type II caused by a defect in the gene encoding. alpha. -mannosidase II

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

Fukuda, M.N.; Masri, K.A.; Dell, A.

1990-10-01

Congenital dyserythropoietic anemia type II, or hereditary erythroblastic multinuclearity with a positive acidified-serum-lysis test (HEMPAS), is a genetic anemia in humans inherited by an autosomally recessive mode. The enzyme defect in most HEMPAS patients has previously been proposed as a lowered activity of N-acetylglucosaminyltransferase II, resulting in a lack of polylactosamine on proteins and leading to the accumulation of polylactosaminyl lipids. A recent HEMPAS case, G.C., has now been analyzed by cell-surface labeling, fast-atom-bombardment mass spectrometry of glycopeptides, and activity assay of glycosylation enzymes. Significantly decreased glycosylation of polylactosaminoglycan proteins and incompletely processed asparagine-linked oligosaccharides were detected in the erythrocytemore » membranes of G.C. These results suggest that G.C. cells contain a mutation in {alpha}-ManII-encoding gene that results in inefficient expression of {alpha}-ManII mRNA, either through reduced transcription or message instability. This report demonstrates that HEMPAS is caused by a defective gene encoding an enzyme necessary for the synthesis of asparagine-linked oligosaccharides.« less

The threshold signal:noise ratio in the perception of fragmented figures.

PubMed

Merkul'ev, A V; Pronin, S V; Semenov, L A; Foreman, N; Chikhman, V N; Shelepin, Yu E

2006-01-01

Perception thresholds were measured for fragmented outline figures (the Gollin test). A new approach to the question of the perception of incomplete images was developed. In this approach, figure fragmentation consisted of masking with multiplicative texture-like noise--this interference was termed "invisible" masking. The first series of studies established that the "similarity" between the amplitude-frequency spectra of test figures and "invisible" masks, expressed as a linear correlation coefficient, had significant effects on the recognition thresholds of these figures. The second series of experiments showed that progressing formation of the figures was accompanied by increases in the correlation between their spatial-frequency characteristics and the corresponding characteristics of the incomplete figure, while the correlation with the "invisible" mask decreased. It is suggested that the ratio of the correlation coefficients, characterizing the "similarity" of the fragmented figure with the intact figure and the "invisible" mask, corresponds to the signal:noise ratio. The psychophysical recognition threshold for figures for naive subjects not familiar with the test image alphabet was reached after the particular level of fragmentation at which this ratio was unity.

A prefoldin-associated WD-repeat protein (WDR92) is required for the correct architectural assembly of motile cilia

PubMed Central

Patel-King, Ramila S.; King, Stephen M.

2016-01-01

WDR92 is a highly conserved WD-repeat protein that has been proposed to be involved in apoptosis and also to be part of a prefoldin-like cochaperone complex. We found that WDR92 has a phylogenetic signature that is generally compatible with it playing a role in the assembly or function of specifically motile cilia. To test this hypothesis, we performed an RNAi-based knockdown of WDR92 gene expression in the planarian Schmidtea mediterranea and were able to achieve a robust reduction in mRNA expression to levels undetectable under our standard RT-PCR conditions. We found that this treatment resulted in a dramatic reduction in the rate of organismal movement that was caused by a switch in the mode of locomotion from smooth, cilia-driven gliding to muscle-based, peristaltic contractions. Although the knockdown animals still assembled cilia of normal length and in similar numbers to controls, these structures had reduced beat frequency and did not maintain hydrodynamic coupling. By transmission electron microscopy we observed that many cilia had pleiomorphic defects in their architecture, including partial loss of dynein arms, incomplete closure of the B-tubule, and occlusion or replacement of the central pair complex by accumulated electron-dense material. These observations suggest that WDR92 is part of a previously unrecognized cytoplasmic chaperone system that is specifically required to fold key components necessary to build motile ciliary axonemes. PMID:26912790

Cellular and Molecular Mechanisms of REM Sleep Homeostatic Drive: A Plausible Component for Behavioral Plasticity

PubMed Central

Datta, Subimal; Oliver, Michael D.

2017-01-01

Homeostatic regulation of REM sleep drive, as measured by an increase in the number of REM sleep transitions, plays a key role in neuronal and behavioral plasticity (i.e., learning and memory). Deficits in REM sleep homeostatic drive (RSHD) are implicated in the development of many neuropsychiatric disorders. Yet, the cellular and molecular mechanisms underlying this RSHD remain to be incomplete. To further our understanding of this mechanism, the current study was performed on freely moving rats to test a hypothesis that a positive interaction between extracellular-signal-regulated kinase 1 and 2 (ERK1/2) activity and brain-derived neurotrophic factor (BDNF) signaling in the pedunculopontine tegmentum (PPT) is a causal factor for the development of RSHD. Behavioral results of this study demonstrated that a short period (<90 min) of selective REM sleep restriction (RSR) exhibited a strong RSHD. Molecular analyses revealed that this increased RSHD increased phosphorylation and activation of ERK1/2 and BDNF expression in the PPT. Additionally, pharmacological results demonstrated that the application of the ERK1/2 activation inhibitor U0126 into the PPT prevented RSHD and suppressed BDNF expression in the PPT. These results, for the first time, suggest that the positive interaction between ERK1/2 and BDNF in the PPT is a casual factor for the development of RSHD. These findings provide a novel direction in understanding how RSHD-associated specific molecular changes can facilitate neuronal plasticity and memory processing. PMID:28959190

Genome-Guided Analysis and Whole Transcriptome Profiling of the Mesophilic Syntrophic Acetate Oxidising Bacterium Syntrophaceticus schinkii

PubMed Central

Manzoor, Shahid; Bongcam-Rudloff, Erik; Schnürer, Anna; Müller, Bettina

2016-01-01

Syntrophaceticus schinkii is a mesophilic, anaerobic bacterium capable of oxidising acetate to CO2 and H2 in intimate association with a methanogenic partner, a syntrophic relationship which operates close to the energetic limits of microbial life. Syntrophaceticus schinkii has been identified as a key organism in engineered methane-producing processes relying on syntrophic acetate oxidation as the main methane-producing pathway. However, due to strict cultivation requirements and difficulties in reconstituting the thermodynamically unfavourable acetate oxidation, the physiology of this functional group is poorly understood. Genome-guided and whole transcriptome analyses performed in the present study provide new insights into habitat adaptation, syntrophic acetate oxidation and energy conservation. The working draft genome of Syntrophaceticus schinkii indicates limited metabolic capacities, with lack of organic nutrient uptake systems, chemotactic machineries, carbon catabolite repression and incomplete biosynthesis pathways. Ech hydrogenase, [FeFe] hydrogenases, [NiFe] hydrogenases, F1F0-ATP synthase and membrane-bound and cytoplasmic formate dehydrogenases were found clearly expressed, whereas Rnf and a predicted oxidoreductase/heterodisulphide reductase complex, both found encoded in the genome, were not expressed under syntrophic growth condition. A transporter sharing similarities to the high-affinity acetate transporters of aceticlastic methanogens was also found expressed, suggesting that Syntrophaceticus schinkii can potentially compete with methanogens for acetate. Acetate oxidation seems to proceed via the Wood-Ljungdahl pathway as all genes involved in this pathway were highly expressed. This study shows that Syntrophaceticus schinkii is a highly specialised, habitat-adapted organism relying on syntrophic acetate oxidation rather than metabolic versatility. By expanding its complement of respiratory complexes, it might overcome limiting bioenergetic barriers, and drive efficient energy conservation from reactions operating close to the thermodynamic equilibrium, which might enable S. schinkii to occupy the same niche as the aceticlastic methanogens. The knowledge gained here will help specify process conditions supporting efficient and robust biogas production and will help identify mechanisms important for the syntrophic lifestyle. PMID:27851830

Dwarfism and Altered Craniofacial Development in Rabbits Is Caused by a 12.1 kb Deletion at the HMGA2 Locus.

PubMed

Carneiro, Miguel; Hu, Dou; Archer, John; Feng, Chungang; Afonso, Sandra; Chen, Congying; Blanco-Aguiar, José A; Garreau, Hervé; Boucher, Samuel; Ferreira, Paula G; Ferrand, Nuno; Rubin, Carl-Johan; Andersson, Leif

2017-02-01

The dwarf phenotype characterizes the smallest of rabbit breeds and is governed largely by the effects of a single dwarfing allele with an incompletely dominant effect on growth. Dwarf rabbits typically weigh under 1 kg and have altered craniofacial morphology. The dwarf allele is recessive lethal and dwarf homozygotes die within a few days of birth. The dwarf phenotype is expressed in heterozygous individuals and rabbits from dwarf breeds homozygous for the wild-type allele are normal, although smaller when compared to other breeds. Here, we show that the dwarf allele constitutes a ∼12.1 kb deletion overlapping the promoter region and first three exons of the HMGA2 gene leading to inactivation of this gene. HMGA2 has been frequently associated with variation in body size across species. Homozygotes for null alleles are viable in mice but not in rabbits and probably not in humans. RNA-sequencing analysis of rabbit embryos showed that very few genes (4-29 genes) were differentially expressed among the three HMGA2/dwarf genotypes, suggesting that dwarfism and inviability in rabbits are caused by modest changes in gene expression. Our results show that HMGA2 is critical for normal expression of IGF2BP2, which encodes an RNA-binding protein. Finally, we report a catalog of regions of elevated genetic differentiation between dwarf and normal-size rabbits, including LCORL-NCAPG, STC2, HOXD cluster, and IGF2BP2 Levels and patterns of genetic diversity at the LCORL-NCAPG locus further suggest that small size in dwarf breeds was enhanced by crosses with wild rabbits. Overall, our results imply that small size in dwarf rabbits results from a large effect, loss-of-function (LOF) mutation in HMGA2 combined with polygenic selection. Copyright © 2017 by the Genetics Society of America.

Dwarfism and Altered Craniofacial Development in Rabbits Is Caused by a 12.1 kb Deletion at the HMGA2 Locus

PubMed Central

Hu, Dou; Archer, John; Feng, Chungang; Afonso, Sandra; Chen, Congying; Blanco-Aguiar, José A.; Garreau, Hervé; Boucher, Samuel; Ferreira, Paula G.; Ferrand, Nuno; Rubin, Carl-Johan

2017-01-01

The dwarf phenotype characterizes the smallest of rabbit breeds and is governed largely by the effects of a single dwarfing allele with an incompletely dominant effect on growth. Dwarf rabbits typically weigh under 1 kg and have altered craniofacial morphology. The dwarf allele is recessive lethal and dwarf homozygotes die within a few days of birth. The dwarf phenotype is expressed in heterozygous individuals and rabbits from dwarf breeds homozygous for the wild-type allele are normal, although smaller when compared to other breeds. Here, we show that the dwarf allele constitutes a ∼12.1 kb deletion overlapping the promoter region and first three exons of the HMGA2 gene leading to inactivation of this gene. HMGA2 has been frequently associated with variation in body size across species. Homozygotes for null alleles are viable in mice but not in rabbits and probably not in humans. RNA-sequencing analysis of rabbit embryos showed that very few genes (4–29 genes) were differentially expressed among the three HMGA2/dwarf genotypes, suggesting that dwarfism and inviability in rabbits are caused by modest changes in gene expression. Our results show that HMGA2 is critical for normal expression of IGF2BP2, which encodes an RNA-binding protein. Finally, we report a catalog of regions of elevated genetic differentiation between dwarf and normal-size rabbits, including LCORL-NCAPG, STC2, HOXD cluster, and IGF2BP2. Levels and patterns of genetic diversity at the LCORL-NCAPG locus further suggest that small size in dwarf breeds was enhanced by crosses with wild rabbits. Overall, our results imply that small size in dwarf rabbits results from a large effect, loss-of-function (LOF) mutation in HMGA2 combined with polygenic selection. PMID:27986804

Farnesoid X receptor induces Takeda G-protein receptor 5 cross-talk to regulate bile acid synthesis and hepatic metabolism.

PubMed

Pathak, Preeti; Liu, Hailiang; Boehme, Shannon; Xie, Cen; Krausz, Kristopher W; Gonzalez, Frank; Chiang, John Y L

2017-06-30

The bile acid-activated receptors, nuclear farnesoid X receptor (FXR) and the membrane Takeda G-protein receptor 5 (TGR5), are known to improve glucose and insulin sensitivity in obese and diabetic mice. However, the metabolic roles of these two receptors and the underlying mechanisms are incompletely understood. Here, we studied the effects of the dual FXR and TGR5 agonist INT-767 on hepatic bile acid synthesis and intestinal secretion of glucagon-like peptide-1 (GLP-1) in wild-type, Fxr -/- , and Tgr5 -/- mice. INT-767 efficaciously stimulated intracellular Ca 2+ levels, cAMP activity, and GLP-1 secretion and improved glucose and lipid metabolism more than did the FXR-selective obeticholic acid and TGR5-selective INT-777 agonists. Interestingly, INT-767 reduced expression of the genes in the classic bile acid synthesis pathway but induced those in the alternative pathway, which is consistent with decreased taurocholic acid and increased tauromuricholic acids in bile. Furthermore, FXR activation induced expression of FXR target genes, including fibroblast growth factor 15, and unexpectedly Tgr5 and prohormone convertase 1/3 gene expression in the ileum. We identified an FXR-responsive element on the Tgr5 gene promoter. Fxr -/- and Tgr5 -/- mice exhibited reduced GLP-1 secretion, which was stimulated by INT-767 in the Tgr5 -/- mice but not in the Fxr -/- mice. Our findings uncovered a novel mechanism in which INT-767 activation of FXR induces Tgr5 gene expression and increases Ca 2+ levels and cAMP activity to stimulate GLP-1 secretion and improve hepatic glucose and lipid metabolism in high-fat diet-induced obese mice. Activation of both FXR and TGR5 may therefore represent an effective therapy for managing hepatic steatosis, obesity, and diabetes. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Seismic sample areas defined from incomplete catalogues: an application to the Italian territory

NASA Astrophysics Data System (ADS)

Mulargia, F.; Tinti, S.

1985-11-01

The comprehensive understanding of earthquake source-physics under real conditions requires the study not of single faults as separate entities but rather of a seismically active region as a whole, accounting for the interaction among different structures. We define "seismic sample area" the most convenient region to be used as a natural laboratory for the study of seismic source physics. This coincides with the region where the average large magnitude seismicity is the highest. To this end, time and space future distributions of large earthquakes are to be estimated. Using catalog seismicity as an input, the rate of occurrence is not constant but appears generally biased by incompleteness in some parts of the catalog and possible nonstationarities in seismic activity. We present a statistical procedure which is capable, under a few mild assumptions, of both detecting nonstationarities in seismicity and finding the incomplete parts of a seismic catalog. The procedure is based on Kolmogorov-Smirnov nonparametric statistics, and can be applied without a priori assuming the parent distribution of the events. The efficiency of this procedure allows the analysis of small data sets. An application to the Italian territory is presented, using the most recent version of the ENEL seismic catalog. Seismic activity takes place in six well defined areas but only five of them have a number of events sufficient for analysis. Barring a few exceptions, seismicity is found stationary throughout the whole catalog span 1000-1980. The eastern Alps region stands out as the best "sample area", with the highest average probability of event occurrence per time and area unit. Final objective of this characterization is to stimulate a program of intensified research.

Vitiligo blood transcriptomics provides new insights into disease mechanisms and identifies potential novel therapeutic targets.

PubMed

Dey-Rao, Rama; Sinha, Animesh A

2017-01-28

Significant gaps remain regarding the pathomechanisms underlying the autoimmune response in vitiligo (VL), where the loss of self-tolerance leads to the targeted killing of melanocytes. Specifically, there is incomplete information regarding alterations in the systemic environment that are relevant to the disease state. We undertook a genome-wide profiling approach to examine gene expression in the peripheral blood of VL patients and healthy controls in the context of our previously published VL-skin gene expression profile. We used several in silico bioinformatics-based analyses to provide new insights into disease mechanisms and suggest novel targets for future therapy. Unsupervised clustering methods of the VL-blood dataset demonstrate a "disease-state"-specific set of co-expressed genes. Ontology enrichment analysis of 99 differentially expressed genes (DEGs) uncovers a down-regulated immune/inflammatory response, B-Cell antigen receptor (BCR) pathways, apoptosis and catabolic processes in VL-blood. There is evidence for both type I and II interferon (IFN) playing a role in VL pathogenesis. We used interactome analysis to identify several key blood associated transcriptional factors (TFs) from within (STAT1, STAT6 and NF-kB), as well as "hidden" (CREB1, MYC, IRF4, IRF1, and TP53) from the dataset that potentially affect disease pathogenesis. The TFs overlap with our reported lesional-skin transcriptional circuitry, underscoring their potential importance to the disease. We also identify a shared VL-blood and -skin transcriptional "hot spot" that maps to chromosome 6, and includes three VL-blood dysregulated genes (PSMB8, PSMB9 and TAP1) described as potential VL-associated genetic susceptibility loci. Finally, we provide bioinformatics-based support for prioritizing dysregulated genes in VL-blood or skin as potential therapeutic targets. We examined the VL-blood transcriptome in context with our (previously published) VL-skin transcriptional profile to address a major gap in knowledge regarding the systemic changes underlying skin-specific manifestation of vitiligo. Several transcriptional "hot spots" observed in both environments offer prioritized targets for identifying disease risk genes. Finally, within the transcriptional framework of VL, we identify five novel molecules (STAT1, PRKCD, PTPN6, MYC and FGFR2) that lend themselves to being targeted by drugs for future potential VL-therapy.

Inheritance of proportionate dwarfism in Angus cattle.

PubMed

Latter, M R; Latter, B D H; Wilkins, J F; Windsor, P A

2006-04-01

To determine the mode of inheritance of congenital proportionate dwarfism in Angus and Angus crossbred cattle, initially detected in two commercial beef herds in northern New South Wales. Matings of normal carrier sires to unrelated cows of diverse breeds, and of one carrier sire to his unaffected daughters. An unrelated Piedmontese bull was also mated to unaffected daughters of the carrier sires. Two carrier Angus bulls and nine unaffected daughters, all of whom were completely indistinguishable from normal animals, were purchased for controlled breeding studies under known nutritional and disease conditions. Affected and carrier individuals were examined for the presence of obvious chromosomal abnormalities. Angus dwarfism has been successfully reproduced under controlled experimental conditions over successive years using unrelated dams and is undoubtedly heritable. The high frequency of occurrence of affected individuals (23/61 = 0.38 +/- .06) among the progeny of matings of the Angus sires to unrelated females of diverse breeding is not compatible with recessive inheritance, because of the negligible frequency of proportionate dwarfism in the breeds of the dams. Both paternal and maternal transmission of the defect was demonstrated, so that imprinting in the strict sense of a gene that is only expressed when received from the male parent appears not to be involved. Tested individuals showed no evidence of gross chromosomal abnormality. Dominant autosomal inheritance with incomplete penetrance was indicated by the lack of expression of the defective gene in the two Angus sires and in three unaffected daughters who produced dwarf calves from matings to the Piedmontese bull. The mode of inheritance is that of a single autosomal dominant gene with a penetrance coefficient of 0.75 +/- 0.12, estimated from the observed incidence of 23/61 affected offspring of the two carrier Angus bulls mated to unrelated dams. Simple genetic models involving either (i) an unstable mutant which changes at high frequency to the expressed dominant dwarfing allele during gametogenesis, or (ii) a dominant allele with penetrance determined by an unlinked modifying locus, are shown to be compatible with the experimental data. Both models indicate that penetrance of the dwarfing gene may possibly be higher in matings involving carrier daughters of the two Angus bulls.

An sRNA and Cold Shock Protein Homolog-Based Feedforward Loop Post-transcriptionally Controls Cell Cycle Master Regulator CtrA

PubMed Central

Robledo, Marta; Schlüter, Jan-Philip; Loehr, Lars O.; Linne, Uwe; Albaum, Stefan P.; Jiménez-Zurdo, José I.; Becker, Anke

2018-01-01

Adjustment of cell cycle progression is crucial for bacterial survival and adaptation under adverse conditions. However, the understanding of modulation of cell cycle control in response to environmental changes is rather incomplete. In α-proteobacteria, the broadly conserved cell cycle master regulator CtrA underlies multiple levels of control, including coupling of cell cycle and cell differentiation. CtrA levels are known to be tightly controlled through diverse transcriptional and post-translational mechanisms. Here, small RNA (sRNA)-mediated post-transcriptional regulation is uncovered as an additional level of CtrA fine-tuning. Computational predictions as well as transcriptome and proteome studies consistently suggested targeting of ctrA and the putative cold shock chaperone cspA5 mRNAs by the trans-encoded sRNA (trans-sRNA) GspR (formerly SmelC775) in several Sinorhizobium species. GspR strongly accumulated in the stationary growth phase, especially in minimal medium (MM) cultures. Lack of the gspR locus confers a fitness disadvantage in competition with the wild type, while its overproduction hampers cell growth, suggesting that this riboregulator interferes with cell cycle progression. An eGFP-based reporter in vivo assay, involving wild-type and mutant sRNA and mRNA pairs, experimentally confirmed GspR-dependent post-transcriptional down-regulation of ctrA and cspA5 expression, which most likely occurs through base-pairing to the respective mRNA. The energetically favored secondary structure of GspR is predicted to comprise three stem-loop domains, with stem-loop 1 and stem-loop 3 targeting ctrA and cspA5 mRNA, respectively. Moreover, this work reports evidence for post-transcriptional control of ctrA by CspA5. Thus, this regulation and GspR-mediated post-transcriptional repression of ctrA and cspA5 expression constitute a coherent feed-forward loop, which may enhance the negative effect of GspR on CtrA levels. This novel regulatory circuit involving the riboregulator GspR, CtrA, and a cold shock chaperone may contribute to fine-tuning of ctrA expression. PMID:29740411

An sRNA and Cold Shock Protein Homolog-Based Feedforward Loop Post-transcriptionally Controls Cell Cycle Master Regulator CtrA.

PubMed

Robledo, Marta; Schlüter, Jan-Philip; Loehr, Lars O; Linne, Uwe; Albaum, Stefan P; Jiménez-Zurdo, José I; Becker, Anke

2018-01-01

Adjustment of cell cycle progression is crucial for bacterial survival and adaptation under adverse conditions. However, the understanding of modulation of cell cycle control in response to environmental changes is rather incomplete. In α-proteobacteria, the broadly conserved cell cycle master regulator CtrA underlies multiple levels of control, including coupling of cell cycle and cell differentiation. CtrA levels are known to be tightly controlled through diverse transcriptional and post-translational mechanisms. Here, small RNA (sRNA)-mediated post-transcriptional regulation is uncovered as an additional level of CtrA fine-tuning. Computational predictions as well as transcriptome and proteome studies consistently suggested targeting of ctrA and the putative cold shock chaperone cspA5 mRNAs by the trans- encoded sRNA ( trans- sRNA) GspR (formerly SmelC775) in several Sinorhizobium species. GspR strongly accumulated in the stationary growth phase, especially in minimal medium (MM) cultures. Lack of the gspR locus confers a fitness disadvantage in competition with the wild type, while its overproduction hampers cell growth, suggesting that this riboregulator interferes with cell cycle progression. An eGFP-based reporter in vivo assay, involving wild-type and mutant sRNA and mRNA pairs, experimentally confirmed GspR-dependent post-transcriptional down-regulation of ctrA and cspA5 expression, which most likely occurs through base-pairing to the respective mRNA. The energetically favored secondary structure of GspR is predicted to comprise three stem-loop domains, with stem-loop 1 and stem-loop 3 targeting ctrA and cspA5 mRNA, respectively. Moreover, this work reports evidence for post-transcriptional control of ctrA by CspA5. Thus, this regulation and GspR-mediated post-transcriptional repression of ctrA and cspA5 expression constitute a coherent feed-forward loop, which may enhance the negative effect of GspR on CtrA levels. This novel regulatory circuit involving the riboregulator GspR, CtrA, and a cold shock chaperone may contribute to fine-tuning of ctrA expression.

MONALISA for stochastic simulations of Petri net models of biochemical systems.

PubMed

Balazki, Pavel; Lindauer, Klaus; Einloft, Jens; Ackermann, Jörg; Koch, Ina

2015-07-10

The concept of Petri nets (PN) is widely used in systems biology and allows modeling of complex biochemical systems like metabolic systems, signal transduction pathways, and gene expression networks. In particular, PN allows the topological analysis based on structural properties, which is important and useful when quantitative (kinetic) data are incomplete or unknown. Knowing the kinetic parameters, the simulation of time evolution of such models can help to study the dynamic behavior of the underlying system. If the number of involved entities (molecules) is low, a stochastic simulation should be preferred against the classical deterministic approach of solving ordinary differential equations. The Stochastic Simulation Algorithm (SSA) is a common method for such simulations. The combination of the qualitative and semi-quantitative PN modeling and stochastic analysis techniques provides a valuable approach in the field of systems biology. Here, we describe the implementation of stochastic analysis in a PN environment. We extended MONALISA - an open-source software for creation, visualization and analysis of PN - by several stochastic simulation methods. The simulation module offers four simulation modes, among them the stochastic mode with constant firing rates and Gillespie's algorithm as exact and approximate versions. The simulator is operated by a user-friendly graphical interface and accepts input data such as concentrations and reaction rate constants that are common parameters in the biological context. The key features of the simulation module are visualization of simulation, interactive plotting, export of results into a text file, mathematical expressions for describing simulation parameters, and up to 500 parallel simulations of the same parameter sets. To illustrate the method we discuss a model for insulin receptor recycling as case study. We present a software that combines the modeling power of Petri nets with stochastic simulation of dynamic processes in a user-friendly environment supported by an intuitive graphical interface. The program offers a valuable alternative to modeling, using ordinary differential equations, especially when simulating single-cell experiments with low molecule counts. The ability to use mathematical expressions provides an additional flexibility in describing the simulation parameters. The open-source distribution allows further extensions by third-party developers. The software is cross-platform and is licensed under the Artistic License 2.0.

Treatment of Intravenous Leiomyomatosis with Cardiac Extension following Incomplete Resection.

PubMed

Doyle, Mathew P; Li, Annette; Villanueva, Claudia I; Peeceeyen, Sheen C S; Cooper, Michael G; Hanel, Kevin C; Fermanis, Gary G; Robertson, Greg

2015-01-01

Aim. Intravenous leiomyomatosis (IVL) with cardiac extension (CE) is a rare variant of benign uterine leiomyoma. Incomplete resection has a recurrence rate of over 30%. Different hormonal treatments have been described following incomplete resection; however no standard therapy currently exists. We review the literature for medical treatments options following incomplete resection of IVL with CE. Methods. Electronic databases were searched for all studies reporting IVL with CE. These studies were then searched for reports of patients with inoperable or incomplete resection and any further medical treatments. Our database was searched for patients with medical therapy following incomplete resection of IVL with CE and their results were included. Results. All studies were either case reports or case series. Five literature reviews confirm that surgery is the only treatment to achieve cure. The uses of progesterone, estrogen modulation, gonadotropin-releasing hormone antagonism, and aromatase inhibition have been described following incomplete resection. Currently no studies have reviewed the outcomes of these treatments. Conclusions. Complete surgical resection is the only means of cure for IVL with CE, while multiple hormonal therapies have been used with varying results following incomplete resection. Aromatase inhibitors are the only reported treatment to prevent tumor progression or recurrence in patients with incompletely resected IVL with CE.

Treatment of Intravenous Leiomyomatosis with Cardiac Extension following Incomplete Resection

PubMed Central

Doyle, Mathew P.; Li, Annette; Villanueva, Claudia I.; Peeceeyen, Sheen C. S.; Cooper, Michael G.; Hanel, Kevin C.; Fermanis, Gary G.; Robertson, Greg

2015-01-01

Aim. Intravenous leiomyomatosis (IVL) with cardiac extension (CE) is a rare variant of benign uterine leiomyoma. Incomplete resection has a recurrence rate of over 30%. Different hormonal treatments have been described following incomplete resection; however no standard therapy currently exists. We review the literature for medical treatments options following incomplete resection of IVL with CE. Methods. Electronic databases were searched for all studies reporting IVL with CE. These studies were then searched for reports of patients with inoperable or incomplete resection and any further medical treatments. Our database was searched for patients with medical therapy following incomplete resection of IVL with CE and their results were included. Results. All studies were either case reports or case series. Five literature reviews confirm that surgery is the only treatment to achieve cure. The uses of progesterone, estrogen modulation, gonadotropin-releasing hormone antagonism, and aromatase inhibition have been described following incomplete resection. Currently no studies have reviewed the outcomes of these treatments. Conclusions. Complete surgical resection is the only means of cure for IVL with CE, while multiple hormonal therapies have been used with varying results following incomplete resection. Aromatase inhibitors are the only reported treatment to prevent tumor progression or recurrence in patients with incompletely resected IVL with CE. PMID:26783463

Ablation of Neurons Expressing Melanin-Concentrating Hormone (MCH) in Adult Mice Improves Glucose Tolerance Independent of MCH Signaling

PubMed Central

Whiddon, Benjamin B.; Palmiter, Richard D.

2013-01-01

Melanin-concentrating hormone (MCH)-expressing neurons have been ascribed many roles based on tudies of MCH-deficient mice. However, MCH neurons express other neurotransmitters, including GABA, nesfatin, and cocaine–amphetamine-regulated transcript. The importance of these other signaling molecules made by MCH neurons remains incompletely characterized. To determine the roles of MCH neurons in vivo, we targeted expression of the human diphtheria toxin receptor (DTR) to the gene for MCH (Pmch). Within 2 weeks of diphtheria toxin injection, heterozygous PmchDTR/+ mice lost 98% of their MCH neurons. These mice became lean but ate normally and were hyperactive, especially during a fast. They also responded abnormally to psychostimulants. For these phenotypes, ablation of MCH neurons recapitulated knock-out of MCH, so MCH appears to be the critical neuromodulator released by these neurons. In contrast, MCH-neuron-ablated mice showed improved glucose tolerance when compared with MCH-deficient mutant mice and wild-type mice. We conclude that MCH neurons regulate glucose tolerance through signaling molecules other than MCH. PMID:23365238

Cardiogenic Genes Expressed in Cardiac Fibroblasts Contribute to Heart Development and Repair

PubMed Central

Furtado, Milena B.; Costa, Mauro W.; Pranoto, Edward Adi; Salimova, Ekaterina; Pinto, Alex; Lam, Nicholas T.; Park, Anthony; Snider, Paige; Chandran, Anjana; Harvey, Richard P.; Boyd, Richard; Conway, Simon J.; Pearson, James; Kaye, David M.; Rosenthal, Nadia A.

2014-01-01

Rationale Cardiac fibroblasts are critical to proper heart function through multiple interactions with the myocardial compartment but appreciation of their contribution has suffered from incomplete characterization and lack of cell-specific markers. Objective To generate an unbiased comparative gene expression profile of the cardiac fibroblast pool, identify and characterize the role of key genes in cardiac fibroblast function, and determine their contribution to myocardial development and regeneration. Methods and Results High-throughput cell surface and intracellular profiling of cardiac and tail fibroblasts identified canonical MSC and a surprising number of cardiogenic genes, some expressed at higher levels than in whole heart. Whilst genetically marked fibroblasts contributed heterogeneously to interstitial but not cardiomyocyte compartments in infarcted hearts, fibroblast-restricted depletion of one highly expressed cardiogenic marker, Tbx20, caused marked myocardial dysmorphology and perturbations in scar formation upon myocardial infarction. Conclusions The surprising transcriptional identity of cardiac fibroblasts, the adoption of cardiogenic gene programs and direct contribution to cardiac development and repair provokes alternative interpretations for studies on more specialized cardiac progenitors, offering a novel perspective for reinterpreting cardiac regenerative therapies. PMID:24650916

Cocaine-induced adaptation of dopamine D2S, but not D2L autoreceptors

PubMed Central

Radl, Daniela; Borrelli, Emiliana; Williams, John T; Neve, Kim A

2017-01-01

The dopamine D2 receptor has two splice variants, D2S (Short) and D2L (Long). In dopamine neurons, both variants can act as autoreceptors to regulate neuronal excitability and dopamine release, but the roles of each variant are incompletely characterized. In a previous study we used viral receptor expression in D2 receptor knockout mice to show distinct effects of calcium signaling on D2S and D2L autoreceptor function (Gantz et al., 2015). However, the cocaine-induced plasticity of D2 receptor desensitization observed in wild type mice was not recapitulated with this method of receptor expression. Here we use mice with genetic knockouts of either the D2S or D2L variant to investigate cocaine-induced plasticity in D2 receptor signaling. Following a single in vivo cocaine exposure, the desensitization of D2 receptors from neurons expressing only the D2S variant was reduced. This did not occur in D2L-expressing neurons, indicating differential drug-induced plasticity between the variants. PMID:29154756

Cocaine-induced adaptation of dopamine D2S, but not D2L autoreceptors.

PubMed

Robinson, Brooks G; Condon, Alec F; Radl, Daniela; Borrelli, Emiliana; Williams, John T; Neve, Kim A

2017-11-20

The dopamine D2 receptor has two splice variants, D2S (Short) and D2L (Long). In dopamine neurons, both variants can act as autoreceptors to regulate neuronal excitability and dopamine release, but the roles of each variant are incompletely characterized. In a previous study we used viral receptor expression in D2 receptor knockout mice to show distinct effects of calcium signaling on D2S and D2L autoreceptor function (Gantz et al., 2015). However, the cocaine-induced plasticity of D2 receptor desensitization observed in wild type mice was not recapitulated with this method of receptor expression. Here we use mice with genetic knockouts of either the D2S or D2L variant to investigate cocaine-induced plasticity in D2 receptor signaling. Following a single in vivo cocaine exposure, the desensitization of D2 receptors from neurons expressing only the D2S variant was reduced. This did not occur in D2L-expressing neurons, indicating differential drug-induced plasticity between the variants.

The non-coding RNA landscape of human hematopoiesis and leukemia.

PubMed

Schwarzer, Adrian; Emmrich, Stephan; Schmidt, Franziska; Beck, Dominik; Ng, Michelle; Reimer, Christina; Adams, Felix Ferdinand; Grasedieck, Sarah; Witte, Damian; Käbler, Sebastian; Wong, Jason W H; Shah, Anushi; Huang, Yizhou; Jammal, Razan; Maroz, Aliaksandra; Jongen-Lavrencic, Mojca; Schambach, Axel; Kuchenbauer, Florian; Pimanda, John E; Reinhardt, Dirk; Heckl, Dirk; Klusmann, Jan-Henning

2017-08-09

Non-coding RNAs have emerged as crucial regulators of gene expression and cell fate decisions. However, their expression patterns and regulatory functions during normal and malignant human hematopoiesis are incompletely understood. Here we present a comprehensive resource defining the non-coding RNA landscape of the human hematopoietic system. Based on highly specific non-coding RNA expression portraits per blood cell population, we identify unique fingerprint non-coding RNAs-such as LINC00173 in granulocytes-and assign these to critical regulatory circuits involved in blood homeostasis. Following the incorporation of acute myeloid leukemia samples into the landscape, we further uncover prognostically relevant non-coding RNA stem cell signatures shared between acute myeloid leukemia blasts and healthy hematopoietic stem cells. Our findings highlight the importance of the non-coding transcriptome in the formation and maintenance of the human blood hierarchy.While micro-RNAs are known regulators of haematopoiesis and leukemogenesis, the role of long non-coding RNAs is less clear. Here the authors provide a non-coding RNA expression landscape of the human hematopoietic system, highlighting their role in the formation and maintenance of the human blood hierarchy.

Ablation of neurons expressing melanin-concentrating hormone (MCH) in adult mice improves glucose tolerance independent of MCH signaling.

PubMed

Whiddon, Benjamin B; Palmiter, Richard D

2013-01-30

Melanin-concentrating hormone (MCH)-expressing neurons have been ascribed many roles based on studies of MCH-deficient mice. However, MCH neurons express other neurotransmitters, including GABA, nesfatin, and cocaine-amphetamine-regulated transcript. The importance of these other signaling molecules made by MCH neurons remains incompletely characterized. To determine the roles of MCH neurons in vivo, we targeted expression of the human diphtheria toxin receptor (DTR) to the gene for MCH (Pmch). Within 2 weeks of diphtheria toxin injection, heterozygous Pmch(DTR/+) mice lost 98% of their MCH neurons. These mice became lean but ate normally and were hyperactive, especially during a fast. They also responded abnormally to psychostimulants. For these phenotypes, ablation of MCH neurons recapitulated knock-out of MCH, so MCH appears to be the critical neuromodulator released by these neurons. In contrast, MCH-neuron-ablated mice showed improved glucose tolerance when compared with MCH-deficient mutant mice and wild-type mice. We conclude that MCH neurons regulate glucose tolerance through signaling molecules other than MCH.

Gene expression profiling at early organogenesis reveals both common and diverse mechanisms in foregut patterning

PubMed Central

Fagman, Henrik; Amendola, Elena; Parrillo, Luca; Zoppoli, Pietro; Marotta, Pina; Scarfò, Marzia; De Luca, Pasquale; de Carvalho, Denise Pires; Ceccarelli, Michele; De Felice, Mario; Di Lauro, Roberto

2011-01-01

The thyroid and lungs originate as neighboring bud shaped outgrowths from the midline of the embryonic foregut. When and how organ specific programs regulate development into structures of distinct shapes, positions and functions is incompletely understood. To characterize, at least in part, the genetic basis of these events, we have employed laser capture microdissection and microarray analysis to define gene expression in the mouse thyroid and lung primordia at E10.5. By comparing the transcriptome of each bud to that of the whole embryo as well as to each other, we broadly describe the genes that are preferentially expressed in each developing organ as well as those with an enriched expression common to both. The results thus obtained provide a valuable resource for further analysis of genes previously unrecognized to participate in thyroid and lung morphogenesis and to discover organ specific as well as common developmental mechanisms. As an initial step in this direction we describe a regulatory pathway involving the anti-apoptotic gene Bcl2 that controls cell survival in early thyroid development. PMID:21924257

β-Aminoisobutyric Acid Induces Browning of White Fat and Hepatic β-oxidation and is Inversely Correlated with Cardiometabolic Risk Factors

PubMed Central

Roberts, Lee D.; Boström, Pontus; O’Sullivan, John F.; Schinzel, Robert T.; Lewis, Gregory D.; Dejam, Andre; Lee, Youn-Kyoung; Palma, Melinda J.; Calhoun, Sondra; Georgiadi, Anastasia; Chen, Ming-Huei; Ramachandran, Vasan S.; Larson, Martin G.; Bouchard, Claude; Rankinen, Tuomo; Souza, Amanda L.; Clish, Clary B.; Wang, Thomas J.; Estall, Jennifer L.; Soukas, Alexander A.; Cowan, Chad A.; Spiegelman, Bruce M.; Gerszten, Robert E.

2014-01-01

Summary The transcriptional co-activator peroxisome proliferator-activated receptor-gamma co-activator-1 α (PGC-1α) regulates metabolic genes in skeletal muscle, and contributes substantially to the response of muscle to exercise. Muscle specific PGC-1α transgenic expression and exercise both increase the expression of thermogenic genes within white adipose. How the PGC-1α mediated response to exercise in muscle conveys signals to other tissues remains incompletely defined. We employed a metabolic profiling approach to examine metabolites secreted from myocytes with forced expression of PGC-1α, and identified β-aminoisobutyric acid (BAIBA) as a novel small molecule myokine. BAIBA increases the expression of brown adipocyte-specific genes in white adipose tissue and fatty acid β-oxidation in hepatocytes both in vitro and in vivo through a PPARα mediated mechanism, induces a brown adipose-like phenotype in human pluripotent stem cells, and improves glucose homeostasis in mice. In humans, plasma BAIBA concentrations are increased with exercise and inversely associated with metabolic risk factors. BAIBA may thus contribute to exercise-induced protection from metabolic diseases. PMID:24411942

Pervasive transcription read-through promotes aberrant expression of oncogenes and RNA chimeras in renal carcinoma

PubMed Central

Grosso, Ana R; Leite, Ana P; Carvalho, Sílvia; Matos, Mafalda R; Martins, Filipa B; Vítor, Alexandra C; Desterro, Joana MP; Carmo-Fonseca, Maria; de Almeida, Sérgio F

2015-01-01

Aberrant expression of cancer genes and non-canonical RNA species is a hallmark of cancer. However, the mechanisms driving such atypical gene expression programs are incompletely understood. Here, our transcriptional profiling of a cohort of 50 primary clear cell renal cell carcinoma (ccRCC) samples from The Cancer Genome Atlas (TCGA) reveals that transcription read-through beyond the termination site is a source of transcriptome diversity in cancer cells. Amongst the genes most frequently mutated in ccRCC, we identified SETD2 inactivation as a potent enhancer of transcription read-through. We further show that invasion of neighbouring genes and generation of RNA chimeras are functional outcomes of transcription read-through. We identified the BCL2 oncogene as one of such invaded genes and detected a novel chimera, the CTSC-RAB38, in 20% of ccRCC samples. Collectively, our data highlight a novel link between transcription read-through and aberrant expression of oncogenes and chimeric transcripts that is prevalent in cancer. DOI: http://dx.doi.org/10.7554/eLife.09214.001 PMID:26575290

Baicalin protects against thrombin induced cell injury in SH-SY5Y cells

PubMed Central

Ju, Xiao-Ning; Mu, Wei-Na; Liu, Yuan-Tao; Wang, Mei-Hong; Kong, Feng; Sun, Chao; Zhou, Qing-Bo

2015-01-01

Baicalin, an extract from the dried root of Scutellaria baicalensis Georgi, was shown to be neuroprotective. However, the precise mechanisms are incompletely known. In this study, we determined the effect of baicalin on thrombin induced cell injury in SH-SY5Y cells, and explored the possible mechanisms. SH-SY5Y cells was treated with thrombin alone or pre-treated with baicalin (5, 10, 20 μM) for 2 h followed by thrombin treatment. Cells without thrombin and baicalin treatment were used as controls. Cell viability was detected by MTT assay. Cell apoptosis was analyzed by flow cytometry. Real-time PCR was performed to determine the mRNA expression of protease-activated receptor-1 (PAR-1). Western blotting was conducted to determine the protein expression of PAR-1, Caspase-3 and NF-κB. Baicalin reduced cell death following thrombin treatment in a dose-dependent manner, with concomitant inhibition of NF-κB activation and suppression of PAR-1 expression. In addition, baicalin reduced Caspase-3 expression. The above findings indicated that baicalin prevents against cell injury after thrombin stimulation possibly through inhibition of PAR-1 expression and NF-κB activation. PMID:26823714

Ribonuclease 7, an antimicrobial peptide upregulated during infection, contributes to microbial defense of the human urinary tract.

PubMed

Spencer, John David; Schwaderer, Andrew L; Wang, Huanyu; Bartz, Julianne; Kline, Jennifer; Eichler, Tad; DeSouza, Kristin R; Sims-Lucas, Sunder; Baker, Peter; Hains, David S

2013-04-01

The mechanisms that maintain sterility in the urinary tract are incompletely understood; however, recent studies stress the importance of antimicrobial peptides in protecting the urinary tract from infection. Ribonuclease 7 (RNase 7), a potent antimicrobial peptide contributing to urinary tract sterility, is expressed by intercalated cells in the renal collecting tubules and is present in the urine at levels sufficient to kill bacteria at baseline. Here, we characterize the expression and function of RNase 7 in the human urinary tract during infection. Both quantitative real-time PCR and enzyme-linked immunosorbant assays demonstrated increases in RNASE7 expression in the kidney along with kidney and urinary RNase 7 peptide concentrations with infection. While immunostaining localized RNase 7 production to the intercalated cells of the collecting tubule during sterility, its expression during pyelonephritis was found to increase throughout the nephron but not in glomeruli or the interstitium. Recombinant RNase 7 exhibited antimicrobial activity against uropathogens at low micromolar concentrations by disrupting the microbial membrane as determined by atomic force microscopy. Thus, RNase 7 expression is increased in the urinary tract with infection and has antibacterial activity against uropathogens at micromolar concentrations.

Ribonuclease 7, an antimicrobial peptide up-regulated during infection, contributes to microbial defense of the human urinary tract

PubMed Central

Spencer, John David; Schwaderer, Andrew L.; Wang, Huanyu; Bartz, Julianne; Kline, Jennifer; Eichler, Tad; DeSouza, Kristin R.; Sims-Lucas, Sunder; Baker, Peter; Hains, David S.

2012-01-01

The mechanisms that maintain sterility in the urinary tract are incompletely understood; however, recent studies stress the importance of antimicrobial peptides in protecting the urinary tract from infection. Ribonuclease 7 (RNase 7), a potent antimicrobial peptide contributing to urinary tract sterility, is expressed by intercalated cells in the renal collecting tubules and is present in the urine at levels sufficient to kill bacteria at baseline. Here, we characterize the expression and function of RNase 7 in the human urinary tract during infection. Both quantitative real-time PCR and ELISA assays demonstrated increases in RNASE7 expression in the kidney along with kidney and urinary RNase 7 peptide concentrations with infection. While immunostaining localized RNase 7 production to the intercalated cells of the collecting tubule during sterility, its expression during pyelonephritis was found to increase throughout the nephron but not in glomeruli or the interstitium. Recombinant RNase 7 exhibited antimicrobial activity against uropathogens at low micromolar concentrations by disrupting the microbial membrane as determined by atomic force microscopy. Thus, RNase 7 expression is increased in the urinary tract with infection, and has antibacterial activity against uropathogens at micromolar concentrations. PMID:23302724

Classification and data acquisition with incomplete data

NASA Astrophysics Data System (ADS)

Williams, David P.

In remote-sensing applications, incomplete data can result when only a subset of sensors (e.g., radar, infrared, acoustic) are deployed at certain regions. The limitations of single sensor systems have spurred interest in employing multiple sensor modalities simultaneously. For example, in land mine detection tasks, different sensor modalities are better-suited to capture different aspects of the underlying physics of the mines. Synthetic aperture radar sensors may be better at detecting surface mines, while infrared sensors may be better at detecting buried mines. By employing multiple sensor modalities to address the detection task, the strengths of the disparate sensors can be exploited in a synergistic manner to improve performance beyond that which would be achievable with either single sensor alone. When multi-sensor approaches are employed, however, incomplete data can be manifested. If each sensor is located on a separate platform ( e.g., aircraft), each sensor may interrogate---and hence collect data over---only partially overlapping areas of land. As a result, some data points may be characterized by data (i.e., features) from only a subset of the possible sensors employed in the task. Equivalently, this scenario implies that some data points will be missing features. Increasing focus in the future on using---and fusing data from---multiple sensors will make such incomplete-data problems commonplace. In many applications involving incomplete data, it is possible to acquire the missing data at a cost. In multi-sensor remote-sensing applications, data is acquired by deploying sensors to data points. Acquiring data is usually an expensive, time-consuming task, a fact that necessitates an intelligent data acquisition process. Incomplete data is not limited to remote-sensing applications, but rather, can arise in virtually any data set. In this dissertation, we address the general problem of classification when faced with incomplete data. We also address the closely related problem of active data acquisition, which develops a strategy to acquire missing features and labels that will most benefit the classification task. We first address the general problem of classification with incomplete data, maintaining the view that all data (i.e., information) is valuable. We employ a logistic regression framework within which we formulate a supervised classification algorithm for incomplete data. This principled, yet flexible, framework permits several interesting extensions that allow all available data to be utilized. One extension incorporates labeling error, which permits the usage of potentially imperfectly labeled data in learning a classifier. A second major extension converts the proposed algorithm to a semi-supervised approach by utilizing unlabeled data via graph-based regularization. Finally, the classification algorithm is extended to the case in which (image) data---from which features are extracted---are available from multiple resolutions. Taken together, this family of incomplete-data classification algorithms exploits all available data in a principled manner by avoiding explicit imputation. Instead, missing data is integrated out analytically with the aid of an estimated conditional density function (conditioned on the observed features). This feat is accomplished by invoking only mild assumptions. We also address the problem of active data acquisition by determining which missing data should be acquired to most improve performance. Specifically, we examine this data acquisition task when the data to be acquired can be either labels or features. The proposed approach is based on a criterion that accounts for the expected benefit of the acquisition. This approach, which is applicable for any general missing data problem, exploits the incomplete-data classification framework introduced in the first part of this dissertation. This data acquisition approach allows for the acquisition of both labels and features. Moreover, several types of feature acquisition are permitted, including the acquisition of individual or multiple features for individual or multiple data points, which may be either labeled or unlabeled. Furthermore, if different types of data acquisition are feasible for a given application, the algorithm will automatically determine the most beneficial type of data to acquire. Experimental results on both benchmark machine learning data sets and real (i.e., measured) remote-sensing data demonstrate the advantages of the proposed incomplete-data classification and active data acquisition algorithms.

Robustness of raw quantum tomography

NASA Astrophysics Data System (ADS)

Asorey, M.; Facchi, P.; Florio, G.; Man'ko, V. I.; Marmo, G.; Pascazio, S.; Sudarshan, E. C. G.

2011-01-01

We scrutinize the effects of non-ideal data acquisition on the tomograms of quantum states. The presence of a weight function, schematizing the effects of a finite window or equivalently noise, only affects the state reconstruction procedure by a normalization constant. The results are extended to a discrete mesh and show that quantum tomography is robust under incomplete and approximate knowledge of tomograms.

75 FR 51678 - Hazardous Waste Management System; Identification and Listing of Hazardous Waste; Final Exclusion

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-23

... present a disproportionate risk to children. The basis for this belief is that the Agency used the DRAS...: ``Under civil and criminal penalty of law for the making or submission of false or fraudulent statements... determined by EPA in its sole discretion to be false, inaccurate or incomplete, and upon conveyance of this...

Spanish Gender Agreement under Complete and Incomplete Acquisition: Early and Late Bilinguals' Linguistic Behavior within the Noun Phrase

ERIC Educational Resources Information Center

Alarcon, Irma V.

2011-01-01

The present study explores knowledge of Spanish grammatical gender in both comprehension and production by heritage language speakers and second language (L2) learners, with native Spanish speakers as a baseline. Most L2 research has tended to interpret morphosyntactic variability in interlanguage production, such as errors in gender agreement, as…

S100A4 is a biomarker and regulator of glioma stem cells that is critical for mesenchymal transition in glioblastoma

USDA-ARS?s Scientific Manuscript database

Glioma stem cells (GSCs) and epithelial-mesenchymal transition (EMT) are strongly associated with therapy resistance and tumor recurrence, but the underlying mechanisms are incompletely understood. Here we show that S100A4 is a novel biomarker of GSCs. S100A4+ cells in gliomas are enriched with canc...

Castration Resistance in Prostate Cancer Is Mediated by the Kinase NEK6. | Office of Cancer Genomics

Cancer.gov

In prostate cancer, the development of castration resistance is pivotal in progression to aggressive disease. However, understanding of the pathways involved remains incomplete. In this study, we performed a high-throughput genetic screen to identify kinases that enable tumor formation by androgen-dependent prostate epithelial (LHSR-AR) cells under androgen-deprived conditions.

Rotation to a Partially Specified Target Matrix in Exploratory Factor Analysis: How Many Targets?

ERIC Educational Resources Information Center

Myers, Nicholas D.; Ahn, Soyeon; Jin, Ying

2013-01-01

The purpose of this study was to explore the influence of the number of targets specified on the quality of exploratory factor analysis solutions with a complex underlying structure and incomplete substantive measurement theory. Three Monte Carlo studies were performed based on the ratio of the number of observed variables to the number of…

Spectroscopic studies of triethoxysilane sol-gel and coating process.

PubMed

Li, Ying-Sing; Ba, Abdul

2008-10-01

Silica sol-gels have been prepared under different conditions using triethoxysilane (TES) as precursor. The prepared sol-gels have been used to coat aluminum for corrosion protection. Vibrational assignments have been made for most vibration bands of TES, TES sol-gel, TES sol-gel-coated aluminum and xerogel. It has been noticed that air moisture may have helped the hydrolysis of the thin coating films. Xerogels have been obtained from the sol-gel under different temperature conditions and the resulting samples have been characterized by using infrared and Raman spectroscopic methods. IR data indicate that the sol-gel process is incomplete under the ambient conditions although an aqueous condition can have slightly improved the process. Two nonequivalent silicon atoms have been identified from the collected 29Si NMR spectra for the sol-gel, supporting the result derived from the IR data. The frequency of Si-H bending vibration has been found to be more sensitive to the skeletal structure than that of the Si-H stretching vibration. A higher temperature condition could favor the progression of hydrolysis and condensation. A temperature higher than 300 degrees C would cause sample decomposition without seriously damaging the silica network. From infrared intensity measurements and thermo-gravimetric analyses, the fractions of incomplete hydrolysis and condensation species have been estimated to be 4% and 3%, respectively. Electrochemical data have shown that the sol-gel coating significantly improves the corrosion protection properties of aluminum.

THY-1 Receptor Expression Differentiates Cardiosphere-Derived Cells with Divergent Cardiogenic Differentiation Potential

PubMed Central

Gago-Lopez, Nuria; Awaji, Obinna; Zhang, Yiqiang; Ko, Christopher; Nsair, Ali; Liem, David; Stempien-Otero, April; MacLellan, W. Robb

2014-01-01

Summary Despite over a decade of intense research, the identity and differentiation potential of human adult cardiac progenitor cells (aCPC) remains controversial. Cardiospheres have been proposed as a means to expand aCPCs in vitro, but the identity of the progenitor cell within these 3D structures is unknown. We show that clones derived from cardiospheres could be subdivided based on expression of thymocyte differentiation antigen 1 (THY-1/CD90) into two distinct populations that exhibit divergent cardiac differentiation potential. One population, which is CD90+, expressed markers consistent with a mesenchymal/myofibroblast cell. The second clone type was CD90− and could form mature, functional myocytes with sarcomeres albeit at a very low rate. These two populations of cardiogenic clones displayed distinct cell surface markers and unique transcriptomes. Our study suggests that a rare aCPC exists in cardiospheres along with a mesenchymal/myofibroblast cell, which demonstrates incomplete cardiac myocyte differentiation. PMID:24936447

Alteration of the RANKL/RANK/OPG System in Periprosthetic Osteolysis with Septic Loosening.

PubMed

Wang, Long; Dai, Zixun; Xie, Jie; Liao, Hao; Lv, Cheng; Hu, Yihe

2016-02-01

The pathogenesis of periprosthetic osteolysis with septic loosening remains incompletely understood. The purpose of this study was to investigate whether expression of the RANKL/RANK/OPG system is altered in septic interface membranes (SIMs). Seventeen cases with a SIM, 26 cases with an aseptic interface membrane (AIM), and 12 cases with a normal synovium (NS) were assessed. Scanning and transmission electron microscopy (SEM and TEM, respectively) were used to observe the microscopic morphology of three tissue conditions. Differences in RANKL, RANK, and OPG expression at the mRNA level were assessed by real-time quantitative PCR, and differences at the protein level were assessed by immunohistochemical staining and Western blotting. SEM showed wear debris widely distributed on the AIM surface, and TEM showed Bacillus activity in the SIM. RANKL expression and the RANKL/OPG ratio were significantly increased in SIMs. Imbalance in the RANKL/RANK/OPG system is related to periprosthetic osteolysis with septic loosening but is not the only possible pathogenic mechanism.

Insights into GATA-1 Mediated Gene Activation versus Repression via Genome-wide Chromatin Occupancy Analysis

PubMed Central

Yu, Ming; Riva, Laura; Xie, Huafeng; Schindler, Yocheved; Moran, Tyler B.; Cheng, Yong; Yu, Duonan; Hardison, Ross; Weiss, Mitchell J; Orkin, Stuart H.; Bernstein, Bradley E.; Fraenkel, Ernest; Cantor, Alan B.

2009-01-01

Summary The transcription factor GATA-1 is required for terminal erythroid maturation and functions as an activator or repressor depending on gene context. Yet its in vivo site selectivity and ability to distinguish between activated versus repressed genes remain incompletely understood. In this study, we performed GATA-1 ChIP-seq in erythroid cells and compared it to GATA-1 induced gene expression changes. Bound and differentially expressed genes contain a greater number of GATA binding motifs, a higher frequency of palindromic GATA sites, and closer occupancy to the transcriptional start site versus non-differentially expressed genes. Moreover, we show that the transcription factor Zbtb7a occupies GATA-1 bound regions of some direct GATA-1 target genes, that the presence of SCL/TAL1 helps distinguish transcriptional activation versus repression, and that Polycomb Repressive Complex 2 (PRC2) is involved in epigenetic silencing of a subset of GATA-1 repressed genes. These data provide insights into GATA-1 mediated gene regulation in vivo. PMID:19941827

Evolution of Alternative Adaptive Immune Systems in Vertebrates.

PubMed

Boehm, Thomas; Hirano, Masayuki; Holland, Stephen J; Das, Sabyasachi; Schorpp, Michael; Cooper, Max D

2018-04-26

Adaptive immunity in jawless fishes is based on antigen recognition by three types of variable lymphocyte receptors (VLRs) composed of variable leucine-rich repeats, which are differentially expressed by two T-like lymphocyte lineages and one B-like lymphocyte lineage. The T-like cells express either VLRAs or VLRCs of yet undefined antigen specificity, whereas the VLRB antibodies secreted by B-like cells bind proteinaceous and carbohydrate antigens. The incomplete VLR germline genes are assembled into functional units by a gene conversion-like mechanism that employs flanking variable leucine-rich repeat sequences as templates in association with lineage-specific expression of cytidine deaminases. B-like cells develop in the hematopoietic typhlosole and kidneys, whereas T-like cells develop in the thymoid, a thymus-equivalent region at the gill fold tips. Thus, the dichotomy between T-like and B-like cells and the presence of dedicated lymphopoietic tissues emerge as ancestral vertebrate features, whereas the somatic diversification of structurally distinct antigen receptor genes evolved independently in jawless and jawed vertebrates.

Silencing alpha-fetoprotein inhibits VEGF and MMP-2/9 production in human hepatocellular carcinoma cell.

PubMed

Meng, Wenbo; Li, Xun; Bai, Zhongtian; Li, Yan; Yuan, Jinqiu; Liu, Tao; Yan, Jun; Zhou, Wence; Zhu, Kexiang; Zhang, Hui; Li, Yumin

2014-01-01

Alpha-fetoprotein not only serves as a diagnostic marker for liver cancer, but also posses a variety of biological functions. However, the role of Alpha-fetoprotein on tumor angiogenesis and cell invasion remains incompletely understood. In this study, we aimed to evaluate if Alpha-fetoprotein can regulate the major angiogenic factors and matrix metalloproteinases in human liver cancer cells. Alpha-fetoprotein silencing was achieved by Stealth RNAi. Expression of Alpha-fetoprotein was examined by a full-automatic electrochemistry luminescence immunity analyzer. Expression of VEGF, VEGFR-2, MMP-9, and MMP-2 was examined by Western blot and immunocytochemistry. Apoptosis was detected by TUNEL assay. Angiogenesis was detected by in vitro angiogenesis assay kit. Silencing of Alpha-fetoprotein led to an increased apoptosis, which was associated with a decreased expression of vascular endothelial growth factor, vascular endothelial growth factor receptor 2, matrix metalloproteinases-2/9. These results suggest that Alpha-fetoprotein may play a regulatory role on angiogenesis and cell invasion during liver cancer development.

A High-Dimensional Atlas of Human T Cell Diversity Reveals Tissue-Specific Trafficking and Cytokine Signatures.

PubMed

Wong, Michael Thomas; Ong, David Eng Hui; Lim, Frances Sheau Huei; Teng, Karen Wei Weng; McGovern, Naomi; Narayanan, Sriram; Ho, Wen Qi; Cerny, Daniela; Tan, Henry Kun Kiaang; Anicete, Rosslyn; Tan, Bien Keem; Lim, Tony Kiat Hon; Chan, Chung Yip; Cheow, Peng Chung; Lee, Ser Yee; Takano, Angela; Tan, Eng-Huat; Tam, John Kit Chung; Tan, Ern Yu; Chan, Jerry Kok Yen; Fink, Katja; Bertoletti, Antonio; Ginhoux, Florent; Curotto de Lafaille, Maria Alicia; Newell, Evan William

2016-08-16

Depending on the tissue microenvironment, T cells can differentiate into highly diverse subsets expressing unique trafficking receptors and cytokines. Studies of human lymphocytes have primarily focused on a limited number of parameters in blood, representing an incomplete view of the human immune system. Here, we have utilized mass cytometry to simultaneously analyze T cell trafficking and functional markers across eight different human tissues, including blood, lymphoid, and non-lymphoid tissues. These data have revealed that combinatorial expression of trafficking receptors and cytokines better defines tissue specificity. Notably, we identified numerous T helper cell subsets with overlapping cytokine expression, but only specific cytokine combinations are secreted regardless of tissue type. This indicates that T cell lineages defined in mouse models cannot be clearly distinguished in humans. Overall, our data uncover a plethora of tissue immune signatures and provide a systemic map of how T cell phenotypes are altered throughout the human body. Copyright © 2016 Elsevier Inc. All rights reserved.

A Study of Incomplete Abortion Following Medical Method of Abortion (MMA).

PubMed

Pawde, Anuya A; Ambadkar, Arun; Chauhan, Anahita R

2016-08-01

Medical method of abortion (MMA) is a safe, efficient, and affordable method of abortion. However, incomplete abortion is a known side effect. To study incomplete abortion due to medication abortion and compare to spontaneous incomplete abortion and to study referral practices and prescriptions in cases of incomplete abortion following MMA. Prospective observational study of 100 women with first trimester incomplete abortion, divided into two groups (spontaneous or following MMA), was administered a questionnaire which included information regarding onset of bleeding, treatment received, use of medications for abortion, its prescription, and administration. Comparison of two groups was done using Fisher exact test (SPSS 21.0 software). Thirty percent of incomplete abortions were seen following MMA; possible reasons being self-administration or prescription by unregistered practitioners, lack of examination, incorrect dosage and drugs, and lack of follow-up. Complications such as collapse, blood requirement, and fever were significantly higher in these patients compared to spontaneous abortion group. The side effects of incomplete abortions following MMA can be avoided by the following standard guidelines. Self medication, over- the-counter use, and prescription by unregistered doctors should be discouraged and reported, and need of follow-up should be emphasized.

COEXISTENCE OF CONSTIPATION AND INCONTINENCE IN CHILDREN AND ADULTS

PubMed Central

Nurko, S; Scott, SM

2011-01-01

The coexistence of constipation and fecal incontinence has long been recognized in pediatric and geriatric populations, but is grossly underappreciated in the rest of the adult population. In children, functional fecal incontinence is usually associated with constipation, stool retention and incomplete evacuation, and is frequently allied to urinary incontinence. Pathophysiology of the incontinence is incompletely understood, although both in children and adults, it is thought to be secondary to overflow, while in adults it may also be related to pelvic floor dysfunction and denervation. Incontinence has an important impact on quality of life and daily functioning, and in children may be associated with behavior problems. The treatment of underlying constipation usually results in improvement in incontinence. This review broadly addresses the epidemiology and pathophysiology of coexistent constipation and incontinence in both children and adults, and also reviews clinical presentation and treatment response in pediatrics. PMID:21382577

On fairness, full cooperation, and quantum game with incomplete information

NASA Astrophysics Data System (ADS)

Lei, Zhen-Zhou; Liu, Bo-Yang; Yi, Ying; Dai, Hong-Yi; Zhang, Ming

2018-03-01

Quantum entanglement has emerged as a new resource to enhance cooperation and remove dilemmas. This paper aims to explore conditions under which full cooperation is achievable even when the information of payoff is incomplete. Based on the quantum version of the extended classical cash in a hat game, we demonstrate that quantum entanglement may be used for achieving full cooperation or avoiding moral hazards with the reasonable profit distribution policies even when the profit is uncertain to a certain degree. This research further suggests that the fairness of profit distribution should play an important role in promoting full cooperation. It is hopeful that quantum entanglement and fairness will promote full cooperation among distant people from various interest groups when quantum networks and quantum entanglement are accessible to the public. Project supported by the National Natural Science Foundation of China (Grant Nos. 61673389, 61273202, and 61134008.

Estimate of true incomplete exchanges using fluorescence in situ hybridization with telomere probes

NASA Technical Reports Server (NTRS)

Wu, H.; George, K.; Yang, T. C.

1998-01-01

PURPOSE: To study the frequency of true incomplete exchanges in radiation-induced chromosome aberrations. MATERIALS AND METHODS: Human lymphocytes were exposed to 2 Gy and 5 Gy of gamma-rays. Chromosome aberrations were studied using the fluorescence in situ hybridization (FISH) technique with whole chromosome-specific probes, together with human telomere probes. Chromosomes 2 and 4 were chosen in the present study. RESULTS: The percentage of incomplete exchanges was 27% when telomere signals were not considered. After excluding false incomplete exchanges identified by the telomere signals, the percentage of incomplete exchanges decreased to 11%. Since telomere signals appear on about 82% of the telomeres, the percentage of true incomplete exchanges should be even lower and was estimated to be 3%. This percentage was similar for chromosomes 2 and 4 and for doses of both 2 Gy and 5 Gy. CONCLUSIONS: The percentage of true incomplete exchanges is significantly lower in gamma-irradiated human lymphocytes than the frequencies reported in the literature.

Genome-wide analysis, expression profile of heat shock factor gene family (CaHsfs) and characterisation of CaHsfA2 in pepper (Capsicum annuum L.).

PubMed

Guo, Meng; Lu, Jin-Ping; Zhai, Yu-Fei; Chai, Wei-Guo; Gong, Zhen-Hui; Lu, Ming-Hui

2015-06-19

Heat shock factors (Hsfs) play crucial roles in plant developmental and defence processes. The production and quality of pepper (Capsicum annuum L.), an economically important vegetable crop, are severely reduced by adverse environmental stress conditions, such as heat, salt and osmotic stress. Although the pepper genome has been fully sequenced, the characterization of the Hsf gene family under abiotic stress conditions remains incomplete. A total of 25 CaHsf members were identified in the pepper genome by bioinformatics analysis and PCR assays. They were grouped into three classes, CaHsfA, B and C, based on highly conserved Hsf domains, were distributed over 11 of 12 chromosomes, with none found on chromosome 11, and all of them, except CaHsfA5, formed a protein-protein interaction network. According to the RNA-seq data of pepper cultivar CM334, most CaHsf members were expressed in at least one tissue among root, stem, leaf, pericarp and placenta. Quantitative real-time PCR assays showed that all of the CaHsfs responded to heat stress (40 °C for 2 h), except CaHsfC1 in thermotolerant line R9 leaves, and that the expression patterns were different from those in thermosensitive line B6. Many CaHsfs were also regulated by salt and osmotic stresses, as well as exogenous Ca(2+), putrescine, abscisic acid and methyl jasmonate. Additionally, CaHsfA2 was located in the nucleus and had transcriptional activity, consistent with the typical features of Hsfs. Time-course expression profiling of CaHsfA2 in response to heat stress revealed differences in its expression level and pattern between the pepper thermosensitive line B6 and thermotolerant line R9. Twenty-five Hsf genes were identified in the pepper genome and most of them responded to heat, salt, osmotic stress, and exogenous substances, which provided potential clues for further analyses of CaHsfs functions in various kinds of abiotic stresses and of corresponding signal transduction pathways in pepper.

Modeling invasive breast cancer: growth factors propel progression of HER2-positive premalignant lesions

PubMed Central

Pradeep, C-R; Zeisel, A; Köstler, WJ; Lauriola, M; Jacob-Hirsch, J; Haibe-Kains, B; Amariglio, N; Ben-Chetrit, N; Emde, A; Solomonov, I; Neufeld, G; Piccart, M; Sagi, I; Sotiriou, C; Rechavi, G; Domany, E; Desmedt, C; Yarden, Y

2013-01-01

The HER2/neu oncogene encodes a receptor-like tyrosine kinase whose overexpression in breast cancer predicts poor prognosis and resistance to conventional therapies. However, the mechanisms underlying aggressiveness of HER2 (human epidermal growth factor receptor 2)-overexpressing tumors remain incompletely understood. Because it assists epidermal growth factor (EGF) and neuregulin receptors, we overexpressed HER2 in MCF10A mammary cells and applied growth factors. HER2-overexpressing cells grown in extracellular matrix formed filled spheroids, which protruded outgrowths upon growth factor stimulation. Our transcriptome analyses imply a two-hit model for invasive growth: HER2-induced proliferation and evasion from anoikis generate filled structures, which are morphologically and transcriptionally analogous to preinvasive patients’ lesions. In the second hit, EGF escalates signaling and transcriptional responses leading to invasive growth. Consistent with clinical relevance, a gene expression signature based on the HER2/EGF-activated transcriptional program can predict poorer prognosis of a subgroup of HER2-overexpressing patients. In conclusion, the integration of a three-dimensional cellular model and clinical data attributes progression of HER2-overexpressing lesions to EGF-like growth factors acting in the context of the tumor's microenvironment. PMID:22139081

CRISPR-mediated targeting of HER2 inhibits cell proliferation through a dominant negative mutation.

PubMed

Wang, Huajing; Sun, William

2017-01-28

With the discovery of the CRISPR/Cas9 technology, genome editing could be performed in a rapid, precise and effective manner. Its potential applications in functional interrogation of cancer-causing genes and cancer therapy have been extensively explored. In this study, we demonstrated the use of the CRISPR/Cas9 system to directly target the oncogene HER2. Directing Cas9 to exons of the HER2 gene inhibited cell growth in breast cancer cell lines that harbor amplification of the HER2 locus. The inhibitory effect was potentiated with the addition of PARP inhibitors. Unexpectedly, CRISPR-induced mutations did not significantly affect the level of HER2 protein expression. Instead, CRISPR targeting appeared to exert its effect through a dominant negative mutation. This HER2 mutant interfered with the MAPK/ERK axis of HER2 downstream signaling. Our work provides a novel mechanism underlying the anti-cancer effects of HER2-targeting by CRISPR/Cas9, which is distinct from the clinical drug Herceptin. In addition, it opens up the possibility that incomplete CRISPR targeting of certain oncogenes could still have therapeutic value by generation of dominant negative mutants. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Physiological Regulation of Isocitrate Dehydrogenase and the Role of 2-Oxoglutarate in Prochlorococcus sp. Strain PCC 9511

PubMed Central

Diez, Jesús; Gómez-Baena, Guadalupe; Rangel-Zúñiga, Oriol Alberto; García-Fernández, José Manuel

2014-01-01

The enzyme isocitrate dehydrogenase (ICDH; EC 1.1.1.42) catalyzes the oxidative decarboxylation of isocitrate, to produce 2-oxoglutarate. The incompleteness of the tricarboxylic acids cycle in marine cyanobacteria confers a special importance to isocitrate dehydrogenase in the C/N balance, since 2-oxoglutarate can only be metabolized through the glutamine synthetase/glutamate synthase pathway. The physiological regulation of isocitrate dehydrogenase was studied in cultures of Prochlorococcus sp. strain PCC 9511, by measuring enzyme activity and concentration using the NADPH production assay and Western blotting, respectively. The enzyme activity showed little changes under nitrogen or phosphorus starvation, or upon addition of the inhibitors DCMU, DBMIB and MSX. Azaserine, an inhibitor of glutamate synthase, induced clear increases in the isocitrate dehydrogenase activity and icd gene expression after 24 h, and also in the 2-oxoglutarate concentration. Iron starvation had the most significant effect, inducing a complete loss of isocitrate dehydrogenase activity, possibly mediated by a process of oxidative inactivation, while its concentration was unaffected. Our results suggest that isocitrate dehydrogenase responds to changes in the intracellular concentration of 2-oxoglutarate and to the redox status of the cells in Prochlorococcus. PMID:25061751

Lawyers' delights and geneticists' nightmares: at forty, the double helix shows some wrinkles.

PubMed

Sgaramella, V

1993-12-15

The National Institutes of Health (NIH) request to patent the base sequences of incomplete and uncharacterized fragments of DNA copied on messenger RNAs (cDNAs) extracted from human tissues, the refusal by the patent office, and the appeal placed by NIH, have incited a violent controversy, fueled by rational, as well as emotional elements. In a compromising mode between liberalism and protectionism, I propose that legal protection be considered only for those RNA/DNA sequences, either natural or artificial, which can generate practical applications per se, and not through their expression products. Another controversy is developing around a popular tool for genomic research: the fidelity of yeast artificial chromosome (YAC) libraries being distributed worldwide for physical mapping is being questioned. Some of these libraries have been shown to be affected by surprisingly high levels of co-cloning, in addition to more common gene reshuffling instances. Also in this case, scientific as well as non-scientific components have to be considered. Possible remedies for the underlying problems may be found in the proper use of kinetic, enzymatic and microbiological variables in the production of YACs. Here too, a sharper distinction between the secular and scientific gratifications of research could help.

[In vitro differentiation of synovial-derived mesenchymal stem cells infected by adenovirus vector mediated by bone morphogenetic protein 2/7 genes into fibrocartilage cells in rabbits].

PubMed

Fu, Peiliang; Zhang, Lei; Wu, Haishan; Cong, Ruijun; Chen, Song; Ding, Zheru; Hu, Kaimen

2013-03-01

To investigate the feasibility of rabbit synovial-derived mesenchymal stem cells (SMSCs) differentiating into fibrocartilage cells by the recombinant adenovirus vector mediated by bone morphogenetic protein 2/7 (BMP-2/7) genes in vitro. SMSCs were isolated and purified from 3-month-old New Zealand white rabbits [male or female, weighing (2.1 +/- 0.3) kg]; the morphology was observed; the cells were identified with immunocytological fluorescent staining, flow cytometry, and cell cycles. The adipogenic, osteogenic, and chondrogenic differentiations were detected. The recombinant plasmid of pAdTrack-BMP-2-internal ribosome entry site (IRES)-BMP-7 was constructed and then was used to infect SMSCs. The cell DNA content and the oncogenicity were tested to determine the safety. Then infected SMSCs were cultured in incomplete chondrogenic medium in vitro. Chondrogenic differentiation of infected SMSCs was detected by RT-PCR, immunofluorescent staining, and toluidine blue staining. SMSCs expressed surface markers of stem cells, and had multi-directional potential. The transfection efficiency of SMSCs infected by recombinant plasmid of pAdTrack-BMP-2-IRES-BMP-7 was about 70%. The safety results showed that infected SMSCs had normal double time, normal chromosome number, and normal DNA content and had no oncogenicity. At 21 days after cultured in incomplete chondrocyte medium, RT-PCR results showed SMSCs had increased expressions of collegan type I and collegan type II, particularly collegan type II; the expressions of RhoA and Sox-9 increased obviously. Immunofluorescent staining and toluidine blue staining showed differentiation of SMSCs into fibrocartilage cells. It is safe to use pAdTrack-BMP-2-IRES-BMP-7 for infecting SMSCs. SMSCs infected by pAdTrack-BMP-2-IRES-BMP-7 can differentiate into fibrocartilage cells spontaneously in vitro.

Haploinsufficiency of the ammonia transporter Rhcg predisposes to chronic acidosis: Rhcg is critical for apical and basolateral ammonia transport in the mouse collecting duct.

PubMed

Bourgeois, Soline; Bounoure, Lisa; Christensen, Erik I; Ramakrishnan, Suresh K; Houillier, Pascal; Devuyst, Olivier; Wagner, Carsten A

2013-02-22

Ammonia secretion by the collecting duct (CD) is critical for acid-base homeostasis and, when defective, causes distal renal tubular acidosis (dRTA). The Rhesus protein RhCG mediates NH(3) transport as evident from cell-free and cellular models as well as from Rhcg-null mice. Here, we investigated in a Rhcg mouse model the metabolic effects of Rhcg haploinsufficiency, the role of Rhcg in basolateral NH(3) transport, and the mechanisms of adaptation to the lack of Rhcg. Both Rhcg(+/+) and Rhcg(+/-) mice were able to handle an acute acid load, whereas Rhcg(-/-) mice developed severe metabolic acidosis with reduced ammonuria and high mortality. However, chronic acid loading revealed that Rhcg(+/-) mice did not fully recover, showing lower blood HCO(3)(-) concentration and more alkaline urine. Microperfusion studies demonstrated that transepithelial NH(3) permeability was reduced by 80 and 40%, respectively, in CDs from Rhcg(-/-) and Rhcg(+/-) mice compared with controls. Basolateral membrane permeability to NH(3) was reduced in CDs from Rhcg(-/-) mice consistent with basolateral Rhcg localization. Rhcg(-/-) responded to acid loading with normal expression of enzymes and transporters involved in proximal tubular ammoniagenesis but reduced abundance of the NKCC2 transporter responsible for medullary accumulation of ammonium. Consequently, tissue ammonium content was decreased. These data demonstrate a role for apical and basolateral Rhcg in transepithelial NH(3) transport and uncover an incomplete dRTA phenotype in Rhcg(+/-) mice. Haploinsufficiency or reduced expression of RhCG may underlie human forms of (in)complete dRTA.

Complete Dosage Compensation and Sex-Biased Gene Expression in the Moth Manduca sexta

PubMed Central

Smith, Gilbert; Chen, Yun-Ru; Blissard, Gary W.; Briscoe, Adriana D.

2014-01-01

Sex chromosome dosage compensation balances homogametic sex chromosome expression with autosomal expression in the heterogametic sex, leading to sex chromosome expression parity between the sexes. If compensation is incomplete, this can lead to expression imbalance and sex-biased gene expression. Recent work has uncovered an intriguing and variable pattern of dosage compensation across species that includes a lack of complete dosage compensation in ZW species compared with XY species. This has led to the hypothesis that ZW species do not require complete compensation or that complete compensation would negatively affect their fitness. To date, only one study, a study of the moth Bombyx mori, has discovered evidence for complete dosage compensation in a ZW species. We examined another moth species, Manduca sexta, using high-throughput sequencing to survey gene expression in the head tissue of males and females. We found dosage compensation to be complete in M. sexta with average expression between the Z chromosome in males and females being equal. When genes expressed at very low levels are removed by filtering, we found that average autosome expression was highly similar to average Z expression, suggesting that the majority of genes in M. sexta are completely dosage compensated. Further, this compensation was accompanied by sex-specific gene expression associated with important sexually dimorphic traits. We suggest that complete dosage compensation in ZW species might be more common than previously appreciated and linked to additional selective processes, such as sexual selection. More ZW and lepidopteran species should now be examined in a phylogenetic framework, to understand the evolution of dosage compensation. PMID:24558255

Influence of incomplete fusion on complete fusion at energies above the Coulomb barrier

NASA Astrophysics Data System (ADS)

Shuaib, Mohd; Sharma, Vijay R.; Yadav, Abhishek; Sharma, Manoj Kumar; Singh, Pushpendra P.; Singh, Devendra P.; Kumar, R.; Singh, R. P.; Muralithar, S.; Singh, B. P.; Prasad, R.

2017-10-01

In the present work, excitation functions of several reaction residues in the system 19F+169Tm, populated via the complete and incomplete fusion processes, have been measured using off-line γ-ray spectroscopy. The analysis of excitation functions has been done within the framework of statistical model code pace4. The excitation functions of residues populated via xn and pxn channels are found to be in good agreement with those estimated by the theoretical model code, which confirms the production of these residues solely via complete fusion process. However, a significant enhancement has been observed in the cross-sections of residues involving α-emitting channels as compared to the theoretical predictions. The observed enhancement in the cross-sections has been attributed to the incomplete fusion processes. In order to have a better insight into the onset and strength of incomplete fusion, the incomplete fusion strength function has been deduced. At present, there is no theoretical model available which can satisfactorily explain the incomplete fusion reaction data at energies ≈4-6 MeV/nucleon. In the present work, the influence of incomplete fusion on complete fusion in the 19F+169Tm system has also been studied. The measured cross-section data may be important for the development of reactor technology as well. It has been found that the incomplete fusion strength function strongly depends on the α-Q value of the projectile, which is found to be in good agreement with the existing literature data. The analysis strongly supports the projectile-dependent mass-asymmetry systematics. In order to study the influence of Coulomb effect ({Z}{{P}}{Z}{{T}}) on incomplete fusion, the deduced strength function for the present work is compared with the nearby projectile-target combinations. The incomplete fusion strength function is found to increase linearly with {Z}{{P}}{Z}{{T}}, indicating a strong influence of Coulomb effect in the incomplete fusion reactions.

D Topological Indoor Building Modeling Integrated with Open Street Map

NASA Astrophysics Data System (ADS)

Jamali, A.; Rahman, A. Abdul; Boguslawski, P.

2016-09-01

Considering various fields of applications for building surveying and various demands, geometry representation of a building is the most crucial aspect of a building survey. The interiors of the buildings need to be described along with the relative locations of the rooms, corridors, doors and exits in many kinds of emergency response, such as fire, bombs, smoke, and pollution. Topological representation is a challenging task within the Geography Information Science (GIS) environment, as the data structures required to express these relationships are particularly difficult to develop. Even within the Computer Aided Design (CAD) community, the structures for expressing the relationships between adjacent building parts are complex and often incomplete. In this paper, an integration of 3D topological indoor building modeling in Dual Half Edge (DHE) data structure and outdoor navigation network from Open Street Map (OSM) is presented.

Dynamic methylation and expression of Oct4 in early neural stem cells.

PubMed

Lee, Shih-Han; Jeyapalan, Jennie N; Appleby, Vanessa; Mohamed Noor, Dzul Azri; Sottile, Virginie; Scotting, Paul J

2010-09-01

Neural stem cells are a multipotent population of tissue-specific stem cells with a broad but limited differentiation potential. However, recent studies have shown that over-expression of the pluripotency gene, Oct4, alone is sufficient to initiate a process by which these can form 'induced pluripotent stem cells' (iPS cells) with the same broad potential as embryonic stem cells. This led us to examine the expression of Oct4 in endogenous neural stem cells, as data regarding its expression in neural stem cells in vivo are contradictory and incomplete. In this study we have therefore analysed the expression of Oct4 and other genes associated with pluripotency throughout development of the mouse CNS and in neural stem cells grown in vitro. We find that Oct4 is still expressed in the CNS by E8.5, but that this expression declines rapidly until it is undetectable by E15.5. This decline is coincident with the gradual methylation of the Oct4 promoter and proximal enhancer. Immunostaining suggests that the Oct4 protein is predominantly cytoplasmic in location. We also found that neural stem cells from all ages expressed the pluripotency associated genes, Sox2, c-Myc, Klf4 and Nanog. These data provide an explanation for the varying behaviour of cells from the early neuroepithelium at different stages of development. The expression of these genes also provides an indication of why Oct4 alone is sufficient to induce iPS formation in neural stem cells at later stages.

SRY protein is expressed in ovotestis and streak gonads from human sex-reversal.

PubMed

Salas-Cortés, L; Jaubert, F; Nihoul-Feketé, C; Brauner, R; Rosemblatt, M; Fellous, M

2000-01-01

In mammals, a master gene located on the Y chromosome, the testis-determining gene SRY, controls sex determination. SRY protein is expressed in the genital ridge before testis determination, and in the testis it is expressed in Sertoli and germ cells. Completely sex-reversed patients are classified as either 46,XX males or 46,XY females. SRY mutations have been described in only 15% of patients with 46,XY complete or partial gonadal dysgenesis. However, although incomplete or partial sex-reversal affects 46,XX true hermaphrodites, 46,XY gonadal dysgenesis, and 46,XX/46,XY mosaicism, only 15% of the 46,XX true hermaphrodites analyzed have the SRY gene. Here, we demonstrate that the SRY protein is expressed in the tubules of streak gonads and rete testis, indicating that the SRY protein is normally expressed early during testis determination. Based on these results, we propose that some factors downstream from SRY may be mutated in these 46,XY sex-reversal patients. We have also analyzed SRY protein expression in the ovotestis from 46,XX true hermaphrodites and 46,XX/46,XY mosaicism, demonstrating SRY protein expression in both testicular and ovarian portions in these patients. This suggests that the SRY protein does not inhibit ovary development. These results confirm that other factors are needed for complete testis development, in particular, those downstream of the SRY protein. Copyright 2001 S. Karger AG, Basel

Circulating promyelocytes and low levels of CD16 expression on polymorphonuclear leukocytes accompany early-onset periodontitis.

PubMed Central

Nemoto, E; Nakamura, M; Shoji, S; Horiuchi, H

1997-01-01

Early-onset periodontitis (EOP) is characterized by rapidly progressive alveolar bone loss, chemotactic defects of neutrophils, and significant familial aggregation. We found immature myeloid lineage cells, defined as promyelocytes, in the peripheral blood in patients with EOP. A hematological examination of peripheral blood cells showed normal reference values regarding cell proportions. Flow cytometry revealed significantly lower expression of CD16, a glycosylphosphatidylinositol (GPI)-anchored protein, on peripheral neutrophils in patients compared with those in age- and sex-matched healthy controls, whereas the levels of CD11a and CD11b expression were similar. The chemotactic response of neutrophils was lower toward not only formyl-methionyl-leucyl-phenylalanine but also complement fragment C5a than that of healthy controls. The expression of another GPI-anchored protein, CD14, was equally expressed by controls and patients. Therefore, the low level of CD16 expression was not due to the incomplete synthesis of the GPI anchor. GPI anchors of CD16 on neutrophils from controls and patients were both partially resistant to phosphatidylinositol-specific phospholipase C. The presence of promyelocytes in peripheral blood, low expression of CD16, and low chemotactic response of neutrophils suggest that patients with EOP have an abnormal maturation system in myeloid lineage cells in the bone marrow, which may be associated with the onset and course of EOP. PMID:9284170

Modeling Expert Opinion: Likelihoods under Incomplete Probabilistic Specification

DTIC Science & Technology

1992-12-09

regarding points per game for participants in the 1991 NBA championship basketball series. 2 1. Introduction Expert opinion is often sought with regard to...for the participants in the 1991 NBA championship basketball series. We present a synthesis of this opinion. The key features of our approach are...applied to opinion collected regarding points per game for participants in the 1991 NBA championship basketball series.

New Directions in the Digital Signal Processing of Image Data.

DTIC Science & Technology

1987-05-01

and identify by block number) FIELD GROUP SUB-GROUP Object detection and idLntification 12 01 restoration of photon noise limited imagery 15 04 image...from incomplete information, restoration of blurred images in additive and multiplicative noise , motion analysis with fast hierarchical algorithms...different resolutions. As is well known, the solution to the matched filter problem under additive white noise conditions is the correlation receiver

Effects of unconventional breakup modes on incomplete fusion of weakly bound nuclei

NASA Astrophysics Data System (ADS)

Diaz-Torres, Alexis; Quraishi, Daanish

2018-02-01

The incomplete fusion dynamics of 6Li+209Bi collisions at energies above the Coulomb barrier is investigated. The classical dynamical model implemented in the platypus code is used to understand and quantify the impact of both 6Li resonance states and transfer-triggered breakup modes (involving short-lived projectile-like nuclei such as 8Be and 5Li) on the formation of incomplete fusion products. Model calculations explain the experimental incomplete-fusion excitation function fairly well, indicating that (i) delayed direct breakup of 6Li reduces the incomplete fusion cross sections and (ii) the neutron-stripping channel practically determines those cross sections.

Guidance for Avoiding Incomplete Premanufacture Notices or Bona Fides in the New Chemicals Program

EPA Pesticide Factsheets

This page contains documents to help you avoid having an incomplete Premanufacture notice or Bona Fide . The documents go over the chemical identity requirements and common errors that result in incompletes.

Safety assessment for In-service Pressure Bending Pipe Containing Incomplete Penetration Defects

NASA Astrophysics Data System (ADS)

Wang, M.; Tang, P.; Xia, J. F.; Ling, Z. W.; Cai, G. Y.

2017-12-01

Incomplete penetration defect is a common defect in the welded joint of pressure pipes. While the safety classification of pressure pipe containing incomplete penetration defects, according to periodical inspection regulations in present, is more conservative. For reducing the repair of incomplete penetration defect, a scientific and applicable safety assessment method for pressure pipe is needed. In this paper, the stress analysis model of the pipe system was established for the in-service pressure bending pipe containing incomplete penetration defects. The local finite element model was set up to analyze the stress distribution of defect location and the stress linearization. And then, the applicability of two assessment methods, simplified assessment and U factor assessment method, to the assessment of incomplete penetration defects located at pressure bending pipe were analyzed. The results can provide some technical supports for the safety assessment of complex pipelines in the future.

Estimate of the frequency of true incomplete exchanges in human lymphocytes exposed to 1 GeV/u Fe ions in vitro

NASA Technical Reports Server (NTRS)

Wu, H.; George, K.; Yang, T. C.

1999-01-01

PURPOSE: To study the frequency of true incomplete exchanges induced by high-LET radiation. MATERIALS AND METHODS: Human lymphocytes were exposed to 1 GeV/u Fe ions (LET = 140 keV/microm). Chromosome aberrations were analysed by a fluorescence in situ hybridization using a combination of whole-chromosome-specific probes and human telomere probes. Chromosomes 1, 3 and 4 were investigated. RESULTS: The percentage of incomplete exchanges was between 23 and 29% if telomere signals were not considered. The percentage decreased to approximately 10% after ruling out false incomplete exchanges containing telomere signals. The final estimation of true incomplete exchanges was <10%. CONCLUSION: Within a degree of uncertainty, the percentage of true incomplete exchanges in 1 GeV/u Fe ion-irradiated human lymphocytes was similar to that induced by gamma rays.

Superconductivity achieved at over liquid nitrogen temperature by (mixed rare earths)-Ba-Cu oxides

NASA Astrophysics Data System (ADS)

Kishio, Kohji; Kuwahara, Kazuyuki; Kitazawa, Koichi; Fueki, Kazuo; Nakamura, Osamu

1987-05-01

Superconducting oxides were fabricated by reaction of powders of BaCO3, CuO and mixed rare earth (RE) carbonates at compositions expressed as (RE)1Ba2Cu3O(9-y). Two types of incompletely separated raw materials of mixed rare earths, namely, heavy rare earths (HRE) and medium rare earths (MRE), were examined. The zero-resistivity critical temperatures were observed at 92.5 K for the (HRE)-Ba-Cu-O and 85.0 K for the (MRE)-Ba-Cu-O systems, respectively, both of which were well above the boiling point of liquid nitrogen.

Barriers to Specialty Care and Specialty Referral Completion in the Community Health Center Setting

PubMed Central

Zuckerman, Katharine E.; Perrin, James M.; Hobrecker, Karin; Donelan, Karen

2013-01-01

Objective To assess the frequency of barriers to specialty care and to assess which barriers are associated with an incomplete specialty referral (not attending a specialty visit when referred by a primary care provider) among children seen in community health centers. Study design Two months after their child’s specialty referral, 341 parents completed telephone surveys assessing whether a specialty visit was completed and whether they experienced any of 10 barriers to care. Family/community barriers included difficulty leaving work, obtaining childcare, obtaining transportation, and inadequate insurance. Health care system barriers included getting appointments quickly, understanding doctors and nurses, communicating with doctors’ offices, locating offices, accessing interpreters, and inconvenient office hours. We calculated barrier frequency and total barriers experienced. Using logistic regression, we assessed which barriers were associated with incomplete referral, and whether experiencing ≥4 barriers was associated with incomplete referral. Results A total of 22.9% of families experienced incomplete referral. 42.0% of families encountered 1 or more barriers. The most frequent barriers were difficulty leaving work, obtaining childcare, and obtaining transportation. On multivariate analysis, difficulty getting appointments quickly, difficulty finding doctors’ offices, and inconvenient office hours were associated with incomplete referral. Families experiencing ≥4 barriers were more likely than those experiencing ≤3 barriers to have incomplete referral. Conclusion Barriers to specialty care were common and associated with incomplete referral. Families experiencing many barriers had greater risk of incomplete referral. Improving family/community factors may increase satisfaction with specialty care; however, improving health system factors may be the best way to reduce incomplete referrals. PMID:22929162

Acylcarnitines: potential implications for skeletal muscle insulin resistance.

PubMed

Aguer, Céline; McCoin, Colin S; Knotts, Trina A; Thrush, A Brianne; Ono-Moore, Kikumi; McPherson, Ruth; Dent, Robert; Hwang, Daniel H; Adams, Sean H; Harper, Mary-Ellen

2015-01-01

Insulin resistance may be linked to incomplete fatty acid β-oxidation and the subsequent increase in acylcarnitine species in different tissues including skeletal muscle. It is not known if acylcarnitines participate in muscle insulin resistance or simply reflect dysregulated metabolism. The aims of this study were to determine whether acylcarnitines can elicit muscle insulin resistance and to better understand the link between incomplete muscle fatty acid β-oxidation, oxidative stress, inflammation, and insulin-resistance development. Differentiated C2C12, primary mouse, and human myotubes were treated with acylcarnitines (C4:0, C14:0, C16:0) or with palmitate with or without carnitine acyltransferase inhibition by mildronate. Treatment with C4:0, C14:0, and C16:0 acylcarnitines resulted in 20-30% decrease in insulin response at the level of Akt phosphorylation and/or glucose uptake. Mildronate reversed palmitate-induced insulin resistance concomitant with an ∼25% decrease in short-chain acylcarnitine and acetylcarnitine secretion. Although proinflammatory cytokines were not affected under these conditions, oxidative stress was increased by 2-3 times by short- or long-chain acylcarnitines. Acylcarnitine-induced oxidative stress and insulin resistance were reversed by treatment with antioxidants. Results are consistent with the conclusion that incomplete muscle fatty acid β-oxidation causes acylcarnitine accumulation and associated oxidative stress, raising the possibility that these metabolites play a role in muscle insulin resistance. © FASEB.

Relaxation of bending stresses and the reversibility of residual stresses in amorphous soft magnetic alloys

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

Kekalo, I. B.; Mogil’nikov, P. S., E-mail: pavel-mog@mail.ru

2015-06-15

The reversibility of residual bending stresses is revealed in ribbon samples of cobalt- and iron-based amorphous alloys Co{sub 69}Fe{sub 3.7}Cr{sub 3.8}Si{sub 12.5}B{sub 11} and Fe{sub 57}Co{sub 31}Si{sub 2.9}B{sub 9.1}: the ribbons that are free of applied stresses and bent under the action of residual stresses become completely or incompletely straight upon annealing at the initial temperatures. The influence of annealing on the relaxation of bending stresses is studied. Preliminary annealing is found to sharply decrease the relaxation rate of bending stresses, and the initial stage of fast relaxation of these stresses is absent. Complete straightening of preliminarily annealed ribbons ismore » shown to occur at significantly higher temperatures than that of the initial ribbons. Incomplete straightening of the ribbons is explained by the fact that bending stresses relaxation at high annealing temperatures proceeds due to both reversible anelastic deformation and viscous flow, which is a fully irreversible process. Incomplete reversibility is also caused by irreversible processes, such as the release of excess free volume and clustering (detected by small-angle X-ray scattering). The revealed differences in the relaxation processes that occur in the cobalt- and iron-based amorphous alloys are discussed in terms of different atomic diffusion mobilities in these alloys.« less

Identification student’s misconception of heat and temperature using three-tier diagnostic test

NASA Astrophysics Data System (ADS)

Suliyanah; Putri, H. N. P. A.; Rohmawati, L.

2018-03-01

The objective of this research is to develop a Three-Tier Diagnostic Test (TTDT) to identify the student's misconception of heat and temperature. Stages of development include: analysis, planning, design, development, evaluation and revise. The results of this study show that (1) the quality of the three-tier type diagnostic test instrument developed has been expressed well with the following details: (a) Internal validity of 88.19% belonging to the valid category. (b) External validity of empirical construct validity test using Pearson Product Moment obtained 0.43 is classified and result of empirical construct validity test obtained false positives 6.1% and false negatives 5.9% then the instrument was valid. (c) Test reliability by using Cronbach’s Alpha of 0.98 which means acceptable. (d) The 80% difficulty level test is quite difficult. (2) Student misconceptions on the temperature of heat and displacement materials based on the II test the highest (84%), the lowest (21%), and the non-misconceptions (7%). (3) The highest cause of misconception among students is associative thinking (22%) and the lowest is caused by incomplete or incomplete reasoning (11%). Three-Tier Diagnostic Test (TTDT) could identify the student's misconception of heat and temperature.

Correlation between compliance and brace treatment in juvenile and adolescent idiopathic scoliosis: SOSORT 2014 award winner

PubMed Central

2014-01-01

Background Over the last years, evidence has accumulated in support of bracing as an effective treatment option in patients with idiopathic scoliosis. Yet, little information is available on the impact of compliance on the outcome of conservative treatment in scoliotic subjects. The aim of the present study was to prospectively evaluate the association between compliance to brace treatment and the progression of scoliotic curve in patients with idiopathic adolescent (AIS) or juvenile scoliosis (JIS). Methods Among 1.424 patients treated for idiopathic scoliosis, 645 were eligible for inclusion criteria. Three outcomes were distinguished in agreement with the SRS criteria: curve correction, curve stabilization and curve progression. Brace wearing was assessed by one orthopaedic surgeon (LA) and scored on a standardized form. Compliance to treatment was categorized as complete (brace worn as prescribed), incomplete A (brace removed for 1 month), incomplete B (brace removed for 2 months), incomplete C (brace removed during school hours), and incomplete D (brace worn overnight only). Chi square test, T test or ANOVA and ANOVA for repeated measures tests were used as statistical tests. Results The results from our study showed that at follow-up the compliance was: Complete 61.1%; Incomplete A 5.2%; Incomplete B 10.7%; Incomplete C 14.2%; Incomplete D 8.8%. Curve correction was accomplished in 301/319 of Complete, 19/27 Incomplete A, 25/56 Incomplete B, 52/74 Incomplete C, 27/46 Incomplete D. Cobb mean value was 29.8 ± 7.5 SD at beginning and 17.1 ± 10.9 SD at follow-up. Both Cobb and Perdriolle degree amelioration was significantly higher in patients with complete compliance over all other groups, both in juvenile, both in adolescent scoliosis. In the intention-to-treat analysis, the rate of surgical treatment was 2.1% among patients with definite outcome and 12.1% among those with drop-out. Treatment compliance showed significant interactions with time. Conclusion Curve progression and referral to surgery are lower in patients with high brace compliance. Bracing discontinuation up to 1 month does not impact on the treatment outcome. Conversely, wearing the brace only overnight is associated with a high rate of curve progression. PMID:24995038

Genes that act downstream of sensory neurons to influence longevity, dauer formation, and pathogen responses in Caenorhabditis elegans.

PubMed

Gaglia, Marta M; Jeong, Dae-Eun; Ryu, Eun-A; Lee, Dongyeop; Kenyon, Cynthia; Lee, Seung-Jae

2012-01-01

The sensory systems of multicellular organisms are designed to provide information about the environment and thus elicit appropriate changes in physiology and behavior. In the nematode Caenorhabditis elegans, sensory neurons affect the decision to arrest during development in a diapause state, the dauer larva, and modulate the lifespan of the animals in adulthood. However, the mechanisms underlying these effects are incompletely understood. Using whole-genome microarray analysis, we identified transcripts whose levels are altered by mutations in the intraflagellar transport protein daf-10, which result in impaired development and function of many sensory neurons in C. elegans. In agreement with existing genetic data, the expression of genes regulated by the transcription factor DAF-16/FOXO was affected by daf-10 mutations. In addition, we found altered expression of transcriptional targets of the DAF-12/nuclear hormone receptor in the daf-10 mutants and showed that this pathway influences specifically the dauer formation phenotype of these animals. Unexpectedly, pathogen-responsive genes were repressed in daf-10 mutant animals, and these sensory mutants exhibited altered susceptibility to and behavioral avoidance of bacterial pathogens. Moreover, we found that a solute transporter gene mct-1/2, which was induced by daf-10 mutations, was necessary and sufficient for longevity. Thus, sensory input seems to influence an extensive transcriptional network that modulates basic biological processes in C. elegans. This situation is reminiscent of the complex regulation of physiology by the mammalian hypothalamus, which also receives innervations from sensory systems, most notably the visual and olfactory systems.

Deletion of Gab2 in mice protects against hepatic steatosis and steatohepatitis: a novel therapeutic target for fatty liver disease.

PubMed

Chen, Shuai; Kang, Yujia; Sun, Yan; Zhong, Yanhong; Li, Yanli; Deng, Lijuan; Tao, Jin; Li, Yang; Tian, Yingpu; Zhao, Yinan; Cheng, Jianghong; Liu, Wenjie; Feng, Gen-Sheng; Lu, Zhongxian

2016-12-01

Fatty liver disease is a serious health problem worldwide and is the most common cause for chronic liver disease and metabolic disorders. The major challenge in the prevention and intervention of this disease is the incomplete understanding of the underlying mechanism and thus lack of potent therapeutic targets due to multifaceted and interdependent disease factors. In this study, we investigated the role of a signaling adaptor protein, GRB2-associated-binding protein 2 (Gab2), in fatty liver using an animal disease model. Gab2 expression in hepatocytes responded to various disease factor stimulations, and Gab2 knockout mice exhibited resistance to fat-induced obesity, fat- or alcohol-stimulated hepatic steatosis, as well as methionine and choline deficiency-induced steatohepatitis. Concordantly, the forced expression or knockdown of Gab2 enhanced or diminished oleic acid (OA)- or ethanol-induced lipid production in hepatocytes in vitro, respectively. During lipid accumulation in hepatocytes, both fat and alcohol induced the recruitment of PI3K or Socs3 by Gab2 and the activation of their downstream signaling proteins AKT, ERK, and Stat3. Therefore, Gab2 may be a disease-associated protein that is induced by pathogenic factors to amplify and coordinate multifactor-induced signals to govern disease development in the liver. Our research provides a novel potential target for the prevention and intervention of fatty liver disease. © The Author (2016). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS.

Light and electron microscopic analyses of Vasa expression in adult germ cells of the fish medaka.

PubMed

Yuan, Yongming; Li, Mingyou; Hong, Yunhan

2014-07-15

Germ cells of diverse animal species have a unique membrane-less organelle called germ plasm (GP). GP is usually associated with mitochondria and contains RNA binding proteins and mRNAs of germ genes such as vasa. GP has been described as the mitochondrial cloud (MC), intermitochondrial cement (IC) and chromatoid body (CB). The mechanism underlying varying GP structures has remained incompletely understood. Here we report the analysis of GP through light and electron microscopy by using Vasa as a marker in adult male germ cells of the fish medaka (Oryzias latipes). Immunofluorescence light microscopy revealed germ cell-specific Vasa expression. Vasa is the most abundant in mitotic germ cells (oogonia and spermatogonia) and reduced in meiotic germ cells. Vasa in round spermatids exist as a spherical structure reminiscent of CB. Nanogold immunoelectron microscopy revealed subcellular Vasa redistribution in male germ cells. Vasa in spermatogonia concentrates in small areas of the cytoplasm and is surrounded by mitochondria, which is reminiscent of MC. Vasa is intermixed with mitochondria to form IC in primary spermatocytes, appears as the free cement (FC) via separation from mitochondria in secondary spermatocyte and becomes condensed in CB at the caudal pole of round spermatids. During spermatid morphogenesis, Vasa redistributes and forms a second CB that is a ring-like structure surrounding the dense fiber of the flagellum in the midpiece. These structures resemble those described for GP in various species. Thus, Vasa identifies GP and adopts varying structures via dynamic reorganization at different stages of germ cell development. Copyright © 2014 Elsevier B.V. All rights reserved.

Analytical approximations for effective relative permeability in the capillary limit

NASA Astrophysics Data System (ADS)

Rabinovich, Avinoam; Li, Boxiao; Durlofsky, Louis J.

2016-10-01

We present an analytical method for calculating two-phase effective relative permeability, krjeff, where j designates phase (here CO2 and water), under steady state and capillary-limit assumptions. These effective relative permeabilities may be applied in experimental settings and for upscaling in the context of numerical flow simulations, e.g., for CO2 storage. An exact solution for effective absolute permeability, keff, in two-dimensional log-normally distributed isotropic permeability (k) fields is the geometric mean. We show that this does not hold for krjeff since log normality is not maintained in the capillary-limit phase permeability field (Kj=k·krj) when capillary pressure, and thus the saturation field, is varied. Nevertheless, the geometric mean is still shown to be suitable for approximating krjeff when the variance of ln⁡k is low. For high-variance cases, we apply a correction to the geometric average gas effective relative permeability using a Winsorized mean, which neglects large and small Kj values symmetrically. The analytical method is extended to anisotropically correlated log-normal permeability fields using power law averaging. In these cases, the Winsorized mean treatment is applied to the gas curves for cases described by negative power law exponents (flow across incomplete layers). The accuracy of our analytical expressions for krjeff is demonstrated through extensive numerical tests, using low-variance and high-variance permeability realizations with a range of correlation structures. We also present integral expressions for geometric-mean and power law average krjeff for the systems considered, which enable derivation of closed-form series solutions for krjeff without generating permeability realizations.

Acute intermittent hypoxia and rehabilitative training following cervical spinal injury alters neuronal hypoxia- and plasticity-associated protein expression.

PubMed

Hassan, Atiq; Arnold, Breanna M; Caine, Sally; Toosi, Behzad M; Verge, Valerie M K; Muir, Gillian D

2018-01-01

One of the most promising approaches to improve recovery after spinal cord injury (SCI) is the augmentation of spontaneously occurring plasticity in uninjured neural pathways. Acute intermittent hypoxia (AIH, brief exposures to reduced O2 levels alternating with normal O2 levels) initiates plasticity in respiratory systems and has been shown to improve recovery in respiratory and non-respiratory spinal systems after SCI in experimental animals and humans. Although the mechanism by which AIH elicits its effects after SCI are not well understood, AIH is known to alter protein expression in spinal neurons in uninjured animals. Here, we examine hypoxia- and plasticity-related protein expression using immunofluorescence in spinal neurons in SCI rats that were treated with AIH combined with motor training, a protocol which has been demonstrated to improve recovery of forelimb function in this lesion model. Specifically, we assessed protein expression in spinal neurons from animals with incomplete cervical SCI which were exposed to AIH treatment + motor training either for 1 or 7 days. AIH treatment consisted of 10 episodes of AIH: (5 min 11% O2: 5 min 21% O2) for 7 days beginning at 4 weeks post-SCI. Both 1 or 7 days of AIH treatment + motor training resulted in significantly increased expression of the transcription factor hypoxia-inducible factor-1α (HIF-1α) relative to normoxia-treated controls, in neurons both proximal (cervical) and remote (lumbar) to the SCI. All other markers examined were significantly elevated in the 7 day AIH + motor training group only, at both cervical and lumbar levels. These markers included vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), and phosphorylated and nonphosphorylated forms of the BDNF receptor tropomyosin-related kinase B (TrkB). In summary, AIH induces plasticity at the cellular level after SCI by altering the expression of major plasticity- and hypoxia-related proteins at spinal regions proximal and remote to the SCI. These changes occur under the same AIH protocol which resulted in recovery of limb function in this animal model. Thus AIH, which induces plasticity in spinal circuitry, could also be an effective therapy to restore motor function after nervous system injury.

Semantics-based plausible reasoning to extend the knowledge coverage of medical knowledge bases for improved clinical decision support.

PubMed

Mohammadhassanzadeh, Hossein; Van Woensel, William; Abidi, Samina Raza; Abidi, Syed Sibte Raza

2017-01-01

Capturing complete medical knowledge is challenging-often due to incomplete patient Electronic Health Records (EHR), but also because of valuable, tacit medical knowledge hidden away in physicians' experiences. To extend the coverage of incomplete medical knowledge-based systems beyond their deductive closure, and thus enhance their decision-support capabilities, we argue that innovative, multi-strategy reasoning approaches should be applied. In particular, plausible reasoning mechanisms apply patterns from human thought processes, such as generalization, similarity and interpolation, based on attributional, hierarchical, and relational knowledge. Plausible reasoning mechanisms include inductive reasoning , which generalizes the commonalities among the data to induce new rules, and analogical reasoning , which is guided by data similarities to infer new facts. By further leveraging rich, biomedical Semantic Web ontologies to represent medical knowledge, both known and tentative, we increase the accuracy and expressivity of plausible reasoning, and cope with issues such as data heterogeneity, inconsistency and interoperability. In this paper, we present a Semantic Web-based, multi-strategy reasoning approach, which integrates deductive and plausible reasoning and exploits Semantic Web technology to solve complex clinical decision support queries. We evaluated our system using a real-world medical dataset of patients with hepatitis, from which we randomly removed different percentages of data (5%, 10%, 15%, and 20%) to reflect scenarios with increasing amounts of incomplete medical knowledge. To increase the reliability of the results, we generated 5 independent datasets for each percentage of missing values, which resulted in 20 experimental datasets (in addition to the original dataset). The results show that plausibly inferred knowledge extends the coverage of the knowledge base by, on average, 2%, 7%, 12%, and 16% for datasets with, respectively, 5%, 10%, 15%, and 20% of missing values. This expansion in the KB coverage allowed solving complex disease diagnostic queries that were previously unresolvable, without losing the correctness of the answers. However, compared to deductive reasoning, data-intensive plausible reasoning mechanisms yield a significant performance overhead. We observed that plausible reasoning approaches, by generating tentative inferences and leveraging domain knowledge of experts, allow us to extend the coverage of medical knowledge bases, resulting in improved clinical decision support. Second, by leveraging OWL ontological knowledge, we are able to increase the expressivity and accuracy of plausible reasoning methods. Third, our approach is applicable to clinical decision support systems for a range of chronic diseases.

State of reporting of primary biomedical research: a scoping review protocol

PubMed Central

Mbuagbaw, Lawrence; Samaan, Zainab; Jin, Yanling; Nwosu, Ikunna; Levine, Mitchell A H; Adachi, Jonathan D; Thabane, Lehana

2017-01-01

Introduction Incomplete or inconsistent reporting remains a major concern in the biomedical literature. Incomplete or inconsistent reporting may yield the published findings unreliable, irreproducible or sometimes misleading. In this study based on evidence from systematic reviews and surveys that have evaluated the reporting issues in primary biomedical studies, we aim to conduct a scoping review with focuses on (1) the state-of-the-art extent of adherence to the emerging reporting guidelines in primary biomedical research, (2) the inconsistency between protocols or registrations and full reports and (3) the disagreement between abstracts and full-text articles. Methods and analyses We will use a comprehensive search strategy to retrieve all available and eligible systematic reviews and surveys in the literature. We will search the following electronic databases: Web of Science, Excerpta Medica Database (EMBASE), MEDLINE and Cumulative Index to Nursing and Allied Health Literature (CINAHL). Our outcomes are levels of adherence to reporting guidelines, levels of consistency between protocols or registrations and full reports and the agreement between abstracts and full reports, all of which will be expressed as percentages, quality scores or categorised rating (such as high, medium and low). No pooled analyses will be performed quantitatively given the heterogeneity of the included systematic reviews and surveys. Likewise, factors associated with improved completeness and consistency of reporting will be summarised qualitatively. The quality of the included systematic reviews will be evaluated using AMSTAR (a measurement tool to assess systematic reviews). Ethics and dissemination All findings will be published in peer-reviewed journals and relevant conferences. These results may advance our understanding of the extent of incomplete and inconsistent reporting, factors related to improved completeness and consistency of reporting and potential recommendations for various stakeholders in the biomedical community. PMID:28360252

Physical therapists' perceptions about patients with incomplete post-traumatic paraplegia adherence to recommended home exercises: a qualitative study.

PubMed

Serpanou, Ismini; Sakellari, Evanthia; Psychogiou, Maria; Zyga, Sofia; Sapountzi-Krepia, Despina

2018-06-08

The overall purpose of physical therapy for patients with spinal cord injury is to improve health-related quality of life. However, poor adherence is a problem in physical therapy and may have negative impact on outcomes. To explore the physical therapists' perspectives about patients with incomplete post-traumatic paraplegia adherence to recommended home exercises. A qualitative content analysis was conducted. Data were collected in a convenience sample using semi-structured interviews. Thirteen registered physical therapists in Athens area participated in the study. Five categories emerged from the data: (1) reasons to recommend home exercise by the physical therapist; (2) obstacles to recommend home exercise by the physical therapist; (3) methods addressing these obstacles; (4) the family's role in the adherence to recommended home exercise; and (5) the impact of financial crisis in adherence to recommended home exercise. All participants found the recommended home exercises essential to rehabilitation and health maintenance, and they value their benefits. They also expressed the obstacles that need to be faced during rehabilitation process in order to promote adherence. Physical therapists should take into account the different obstacles that may prevent patients with incomplete post-traumatic paraplegia adherence to recommended home exercises. These involve the patients and their families, while, financial crisis has also an impact in adherence. In order to overcome these obstacles and increase adherence, communication with patient and family while taking into account the individual's needs, capacities, and resources are essential. Copyright © 2018 Associação Brasileira de Pesquisa e Pós-Graduação em Fisioterapia. Publicado por Elsevier Editora Ltda. All rights reserved.

Factors Affecting Formation of Incomplete Vi Antibody in Mice

PubMed Central

Gaines, Sidney; Currie, Julius A.; Tully, Joseph G.

1965-01-01

Gaines, Sidney (Walter Reed Army Institute of Research, Washington, D.C.), Julius A. Currie, and Joseph G. Tully. Factors affecting formation of incomplete Vi antibody in mice. J. Bacteriol. 90:635–642. 1965.—Single immunizing doses of purified Vi antigen elicited complete and incomplete Vi antibodies in BALB/c mice, but only incomplete antibody in Cinnamon mice. Three of six other mouse strains tested responded like BALB/c mice; the remaining three, like Cinnamon mice. Varying the quantity of antigen injected or the route of administration failed to stimulate the production of detectable complete Vi antibody in Cinnamon mice. Such antibody was evoked in these animals by multiple injections of Vi antigen or by inoculating them with Vi-containing bacilli or Vi-coated erythrocytes. The early protection afforded by serum from Vi-immunized BALB/c mice coincided with the appearance of incomplete Vi antibody, 1 day prior to the advent of complete antibody. Persistence of incomplete as well as complete antibody in the serum of immunized mice was demonstrated for at least 56 days after injection of 10 μg of Vi antigen. Incomplete Vi antibody was shown to have blocking ability, in vitro bactericidal activity, and the capability of protecting mice against intracerebral as well as intraperitoneal challenge with virulent typhoid bacilli. Production of incomplete and complete Vi antibodies was adversely affected by immunization with partially depolymerized Vi antigens. PMID:16562060

Incomplete sex chromosome dosage compensation in the Indian meal moth, Plodia interpunctella, based on de novo transcriptome assembly.

PubMed

Harrison, Peter W; Mank, Judith E; Wedell, Nina

2012-01-01

Males and females experience differences in gene dose for loci in the nonrecombining region of heteromorphic sex chromosomes. If not compensated, this leads to expression imbalances, with the homogametic sex on average exhibiting greater expression due to the doubled gene dose. Many organisms with heteromorphic sex chromosomes display global dosage compensation mechanisms, which equalize gene expression levels between the sexes. However, birds and Schistosoma have been previously shown to lack chromosome-wide dosage compensation mechanisms, and the status in other female heterogametic taxa including Lepidoptera remains unresolved. To further our understanding of dosage compensation in female heterogametic taxa and to resolve its status in the lepidopterans, we assessed the Indian meal moth, Plodia interpunctella. As P. interpunctella lacks a complete reference genome, we conducted de novo transcriptome assembly combined with orthologous genomic location prediction from the related silkworm genome, Bombyx mori, to compare Z-linked and autosomal gene expression levels for each sex. We demonstrate that P. interpunctella lacks complete Z chromosome dosage compensation, female Z-linked genes having just over half the expression level of males and autosomal genes. This finding suggests that the Lepidoptera and possibly all female heterogametic taxa lack global dosage compensation, although more species will need to be sampled to confirm this assertion.

Incomplete Sex Chromosome Dosage Compensation in the Indian Meal Moth, Plodia interpunctella, Based on De Novo Transcriptome Assembly

PubMed Central

Harrison, Peter W.; Mank, Judith E.; Wedell, Nina

2012-01-01

Males and females experience differences in gene dose for loci in the nonrecombining region of heteromorphic sex chromosomes. If not compensated, this leads to expression imbalances, with the homogametic sex on average exhibiting greater expression due to the doubled gene dose. Many organisms with heteromorphic sex chromosomes display global dosage compensation mechanisms, which equalize gene expression levels between the sexes. However, birds and Schistosoma have been previously shown to lack chromosome-wide dosage compensation mechanisms, and the status in other female heterogametic taxa including Lepidoptera remains unresolved. To further our understanding of dosage compensation in female heterogametic taxa and to resolve its status in the lepidopterans, we assessed the Indian meal moth, Plodia interpunctella. As P. interpunctella lacks a complete reference genome, we conducted de novo transcriptome assembly combined with orthologous genomic location prediction from the related silkworm genome, Bombyx mori, to compare Z-linked and autosomal gene expression levels for each sex. We demonstrate that P. interpunctella lacks complete Z chromosome dosage compensation, female Z-linked genes having just over half the expression level of males and autosomal genes. This finding suggests that the Lepidoptera and possibly all female heterogametic taxa lack global dosage compensation, although more species will need to be sampled to confirm this assertion. PMID:23034217

The missions and means framework as an ontology

NASA Astrophysics Data System (ADS)

Deitz, Paul H.; Bray, Britt E.; Michaelis, James R.

2016-05-01

The analysis of warfare frequently suffers from an absence of logical structure for a] specifying explicitly the military mission and b] quantitatively evaluating the mission utility of alternative products and services. In 2003, the Missions and Means Framework (MMF) was developed to redress these shortcomings. The MMF supports multiple combatants, levels of war and, in fact, is a formal embodiment of the Military Decision-Making Process (MDMP). A major effect of incomplete analytic discipline in military systems analyses is that they frequently fall into the category of ill-posed problems in which they are under-specified, under-determined, or under-constrained. Critical context is often missing. This is frequently the result of incomplete materiel requirements analyses which have unclear linkages to higher levels of warfare, system-of-systems linkages, tactics, techniques and procedures, and the effect of opposition forces. In many instances the capabilities of materiel are assumed to be immutable. This is a result of not assessing how platform components morph over time due to damage, logistics, or repair. Though ill-posed issues can be found many places in military analysis, probably the greatest challenge comes in the disciplines of C4ISR supported by ontologies in which formal naming and definition of the types, properties, and interrelationships of the entities are fundamental to characterizing mission success. Though the MMF was not conceived as an ontology, over the past decade some workers, particularly in the field of communication, have labelled the MMF as such. This connection will be described and discussed.

Test Equality between Three Treatments under an Incomplete Block Crossover Design.

PubMed

Lui, Kung-Jong

2015-01-01

Under a random effects linear additive risk model, we compare two experimental treatments with a placebo in continuous data under an incomplete block crossover trial. We develop three test procedures for simultaneously testing equality between two experimental treatments and a placebo, as well as interval estimators for the mean difference between treatments. We apply Monte Carlo simulations to evaluate the performance of these test procedures and interval estimators in a variety of situations. We note that the bivariate test procedure accounting for the dependence structure based on the F-test is preferable to the other two procedures when there is only one of the two experimental treatments has a non-zero effect vs. the placebo. We note further that when the effects of the two experimental treatments vs. a placebo are in the same relative directions and are approximately of equal magnitude, the summary test procedure based on a simple average of two weighted-least-squares (WLS) estimators can outperform the other two procedures with respect to power. When one of the two experimental treatments has a relatively large effect vs. the placebo, the univariate test procedure with using Bonferroni's equality can be still of use. Finally, we use the data about the forced expiratory volume in 1 s (FEV1) readings taken from a double-blind crossover trial comparing two different doses of formoterol with a placebo to illustrate the use of test procedures and interval estimators proposed here.

The expression of podoplanin protein is a diagnostic marker to distinguish the early infiltration of esophageal squamous cell carcinoma.

PubMed

Chen, Guangyong; Xu, Rui; Yue, Bing; Mei, Xue; Li, Peng; Zhou, Xiaoge; Huang, Shoufang; Gong, Liping; Zhang, Shutian

2017-03-21

The esophageal squamous cell carcinoma (ESCC) is usually develped from low-grade intraepithelial neoplasia (LGIEN) and high-grade intraepithelial neoplasia (HGIEN) to infiltrative squamous cell carcinoma. Till now, it remains hard to screen for infiltration at earlier stages, especially the differentiation between HGEIN and early infiltrative carcinoma. The purpose of this study is to determine a role of podoplanin in differentiating between HGEIN and early infiltrative squamous cell carcinoma. Totally 133 patients pathologically diagnosed with early ESCC and/or precancerous lesions were enrolled.The EnVision two-step IHC staining technique was applied using the monoclonal mouse anti-human Podoplanin antibody (clone number: D2-40). The expressions of PDPN protein on the basal layer of squamous epithelium lesions could be divided into three different patterns: complete type, incomplete (non-continuous) type, or missing type. A diagnosis of HGEIN can be made if the basal layer showed non-continuous or complete expression of PDPN and a diagnosis of early infiltration can be made if the expression of PDPN is completely missing. Our study confirmed that PDPN was a potential biomarker to identify the presence of early infiltrative squamous cell carcinoma.

The expression of podoplanin protein is a diagnostic marker to distinguish the early infiltration of esophageal squamous cell carcinoma

PubMed Central

Chen, Guangyong; Xu, Rui; Yue, Bing; Mei, Xue; Li, Peng; Zhou, Xiaoge; Huang, Shoufang; Gong, Liping; Zhang, Shutian

2017-01-01

The esophageal squamous cell carcinoma (ESCC) is usually develped from low-grade intraepithelial neoplasia (LGIEN) and high-grade intraepithelial neoplasia (HGIEN) to infiltrative squamous cell carcinoma. Till now, it remains hard to screen for infiltration at earlier stages, especially the differentiation between HGEIN and early infiltrative carcinoma. The purpose of this study is to determine a role of podoplanin in differentiating between HGEIN and early infiltrative squamous cell carcinoma. Totally 133 patients pathologically diagnosed with early ESCC and/or precancerous lesions were enrolled.The EnVision two-step IHC staining technique was applied using the monoclonal mouse anti-human Podoplanin antibody (clone number: D2-40). The expressions of PDPN protein on the basal layer of squamous epithelium lesions could be divided into three different patterns: complete type, incomplete (non-continuous) type, or missing type. A diagnosis of HGEIN can be made if the basal layer showed non-continuous or complete expression of PDPN and a diagnosis of early infiltration can be made if the expression of PDPN is completely missing. Our study confirmed that PDPN was a potential biomarker to identify the presence of early infiltrative squamous cell carcinoma. PMID:28086225

Eph/Ephrin signalling maintains eye field segregation from adjacent neural plate territories during forebrain morphogenesis

PubMed Central

Cavodeassi, Florencia; Ivanovitch, Kenzo; Wilson, Stephen W.

2013-01-01

During forebrain morphogenesis, there is extensive reorganisation of the cells destined to form the eyes, telencephalon and diencephalon. Little is known about the molecular mechanisms that regulate region-specific behaviours and that maintain the coherence of cell populations undergoing specific morphogenetic processes. In this study, we show that the activity of the Eph/Ephrin signalling pathway maintains segregation between the prospective eyes and adjacent regions of the anterior neural plate during the early stages of forebrain morphogenesis in zebrafish. Several Ephrins and Ephs are expressed in complementary domains in the prospective forebrain and combinatorial abrogation of their activity results in incomplete segregation of the eyes and telencephalon and in defective evagination of the optic vesicles. Conversely, expression of exogenous Ephs or Ephrins in regions of the prospective forebrain where they are not usually expressed changes the adhesion properties of the cells, resulting in segregation to the wrong domain without changing their regional fate. The failure of eye morphogenesis in rx3 mutants is accompanied by a loss of complementary expression of Ephs and Ephrins, suggesting that this pathway is activated downstream of the regional fate specification machinery to establish boundaries between domains undergoing different programmes of morphogenesis. PMID:24026122

A threshold level of NFATc1 activity facilitates thymocyte differentiation and opposes notch-driven leukaemia development

PubMed Central

Klein-Hessling, Stefan; Rudolf, Ronald; Muhammad, Khalid; Knobeloch, Klaus-Peter; Maqbool, Muhammad Ahmad; Cauchy, Pierre; Andrau, Jean-Christophe; Avots, Andris; Talora, Claudio; Ellenrieder, Volker; Screpanti, Isabella; Serfling, Edgar; Patra, Amiya Kumar

2016-01-01

NFATc1 plays a critical role in double-negative thymocyte survival and differentiation. However, the signals that regulate Nfatc1 expression are incompletely characterized. Here we show a developmental stage-specific differential expression pattern of Nfatc1 driven by the distal (P1) or proximal (P2) promoters in thymocytes. Whereas, preTCR-negative thymocytes exhibit only P2 promoter-derived Nfatc1β expression, preTCR-positive thymocytes express both Nfatc1β and P1 promoter-derived Nfatc1α transcripts. Inducing NFATc1α activity from P1 promoter in preTCR-negative thymocytes, in addition to the NFATc1β from P2 promoter impairs thymocyte development resulting in severe T-cell lymphopenia. In addition, we show that NFATc1 activity suppresses the B-lineage potential of immature thymocytes, and consolidates their differentiation to T cells. Further, in the pTCR-positive DN3 cells, a threshold level of NFATc1 activity is vital in facilitating T-cell differentiation and to prevent Notch3-induced T-acute lymphoblastic leukaemia. Altogether, our results show NFATc1 activity is crucial in determining the T-cell fate of thymocytes. PMID:27312418

TIP60 represses telomerase expression by inhibiting Sp1 binding to the TERT promoter

PubMed Central

Pandey, Amit Kumar; Xiuzhen, Magdalene Claire; Lee, Kwok Kin; Hora, Shainan; Zhang, Yanzhou; Kwok, Hui Si; Deng, Lih Wen; Tenen, Daniel G.; Kappei, Dennis

2017-01-01

HIV1-TAT interactive protein (TIP60) is a haploinsufficient tumor suppressor. However, the potential mechanisms endowing its tumor suppressor ability remain incompletely understood. It plays a vital role in virus-induced cancers where TIP60 down-regulates the expression of human papillomavirus (HPV) oncoprotein E6 which in turn destabilizes TIP60. This intrigued us to identify the role of TIP60, in the context of a viral infection, where it is targeted by oncoproteins. Through an array of molecular biology techniques such as Chromatin immunoprecipitation, expression analysis and mass spectrometry, we establish the hitherto unknown role of TIP60 in repressing the expression of the catalytic subunit of the human telomerase complex, TERT, a key driver for immortalization. TIP60 acetylates Sp1 at K639, thus inhibiting Sp1 binding to the TERT promoter. We identified that TIP60-mediated growth suppression of HPV-induced cervical cancer is mediated in part due to TERT repression through Sp1 acetylation. In summary, our study has identified a novel substrate for TIP60 catalytic activity and a unique repressive mechanism acting at the TERT promoter in virus-induced malignancies. PMID:29045464

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

Michelsen, H. A.; Schulz, C.; Smallwood, G. J.

The understanding of soot formation in combustion processes and the optimization of practical combustion systems require in situ measurement techniques that can provide important characteristics, such as particle concentrations and sizes, under a variety of conditions. Of equal importance are techniques suitable for characterizing soot particles produced from incomplete combustion and emitted into the environment. Also, the production of engineered nanoparticles, such as carbon blacks, may benefit from techniques that allow for online monitoring of these processes.

17 CFR 240.6a-4 - Notice of registration under Section 6(g) of the Act, amendment to such notice, and supplemental...

Code of Federal Regulations, 2013 CFR

2013-04-01

... chapter), which shall set forth the nature and effective date of the action taken and shall provide any...), within: (i) Ten days after any action is taken that renders inaccurate, or that causes to be incomplete, any information filed on the Execution Page of Form 1-N (§ 249.10 of this chapter), or amendment...

17 CFR 240.6a-4 - Notice of registration under Section 6(g) of the Act, amendment to such notice, and supplemental...

Code of Federal Regulations, 2014 CFR

2014-04-01

... chapter), which shall set forth the nature and effective date of the action taken and shall provide any...), within: (i) Ten days after any action is taken that renders inaccurate, or that causes to be incomplete, any information filed on the Execution Page of Form 1-N (§ 249.10 of this chapter), or amendment...

Semi-Markov Approach to the Shipping Safety Modelling

NASA Astrophysics Data System (ADS)

Guze, Sambor; Smolarek, Leszek

2012-02-01

In the paper the navigational safety model of a ship on the open area has been studied under conditions of incomplete information. Moreover the structure of semi-Markov processes is used to analyse the stochastic ship safety according to the subjective acceptance of risk by the navigator. In addition, the navigator’s behaviour can be analysed by using the numerical simulation to estimate the probability of collision in the safety model.

Informativeness of Wind Data in Linear Madden-Julian Oscillation Prediction

DTIC Science & Technology

2016-08-15

Linear inverse models (LIMs) are used to explore predictability and information content of the Madden–Julian Oscillation (MJO). Hindcast skill for...mostly at the largest scales, adds 1–2 days of skill. Keywords: linear inverse modeling; Madden–Julian Oscillation; sub-seasonal prediction 1...tion that may reflect on the MJO’s incompletely under- stood dynamics. Cavanaugh et al. (2014, hereafter C14) explored the skill of linear inverse

Statistical physics of crime: A review

NASA Astrophysics Data System (ADS)

D'Orsogna, Maria R.; Perc, Matjaž

2015-03-01

Containing the spread of crime in urban societies remains a major challenge. Empirical evidence suggests that, if left unchecked, crimes may be recurrent and proliferate. On the other hand, eradicating a culture of crime may be difficult, especially under extreme social circumstances that impair the creation of a shared sense of social responsibility. Although our understanding of the mechanisms that drive the emergence and diffusion of crime is still incomplete, recent

Mode Reduction and Upscaling of Reactive Transport Under Incomplete Mixing

NASA Astrophysics Data System (ADS)

Lester, D. R.; Bandopadhyay, A.; Dentz, M.; Le Borgne, T.

2016-12-01

Upscaling of chemical reactions in partially-mixed fluid environments is a challenging problem due to the detailed interactions between inherently nonlinear reaction kinetics and complex spatio-temporal concentration distributions under incomplete mixing. We address this challenge via the development of an order reduction method for the advection-diffusion-reaction equation (ADRE) via projection of the reaction kinetics onto a small number N of leading eigenmodes of the advection-diffusion operator (the so-called "strange eigenmodes" of the flow) as an N-by-N nonlinear system, whilst mixing dynamics only are projected onto the remaining modes. For simple kinetics and moderate Péclet and Damkhöler numbers, this approach yields analytic solutions for the concentration mean, evolving spatio-temporal distribution and PDF in terms of the well-mixed reaction kinetics and mixing dynamics. For more complex kinetics or large Péclet or Damkhöler numbers only a small number of modes are required to accurately quantify the mixing and reaction dynamics in terms of the concentration field and PDF, facilitating greatly simplified approximation and analysis of reactive transport. Approximate solutions of this low-order nonlinear system provide quantiative predictions of the evolving concentration PDF. We demonstrate application of this method to a simple random flow and various mass-action reaction kinetics.

Reinterpreting the importance of oxygen-based biodegradation in chloroethene-contaminated groundwater

USGS Publications Warehouse

Bradley, Paul M.

2011-01-01

Chlororespiration is common in shallow aquifer systems under conditions nominally identified as anoxic. Consequently, chlororespiration is a key component of remediation at many chloroethene-contaminated sites. In some instances, limited accumulation of reductive dechlorination daughter products is interpreted as evidence that natural attenuation is not adequate for site remediation. This conclusion is justified when evidence for parent compound (tetrachloroethene, PCE, or trichloroethene, TCE) degradation is lacking. For many chloroethene-contaminated shallow aquifer systems, however, nonconservative losses of the parent compounds are clear but the mass balance between parent compound attenuation and accumulation of reductive dechlorination daughter products is incomplete. Incomplete mass balance indicates a failure to account for important contaminant attenuation mechanisms and is consistent with contaminant degradation to nondiagnostic mineralization products like CO2. While anoxic mineralization of chloroethene compounds has been proposed previously, recent results suggest that oxygen-based mineralization of chloroethenes also can be significant at dissolved oxygen concentrations below the currently accepted field standard for nominally anoxic conditions. Thus, reassessment of the role and potential importance of low concentrations of oxygen in chloroethene biodegradation are needed, because mischaracterization of operant biodegradation processes can lead to expensive and ineffective remedial actions. A modified interpretive framework is provided for assessing the potential for chloroethene biodegradation under different redox conditions and the probable role of oxygen in chloroethene biodegradation.

The long non-coding RNA ROCR contributes to SOX9 expression and chondrogenic differentiation of human mesenchymal stem cells

PubMed Central

Hyatt, Sam; Cheung, Kat; Skelton, Andrew J.; Xu, Yaobo; Clark, Ian M.

2017-01-01

Long non-coding RNAs (lncRNAs) are expressed in a highly tissue-specific manner and function in various aspects of cell biology, often as key regulators of gene expression. In this study, we established a role for lncRNAs in chondrocyte differentiation. Using RNA sequencing we identified a human articular chondrocyte repertoire of lncRNAs from normal hip cartilage donated by neck of femur fracture patients. Of particular interest are lncRNAs upstream of the master chondrocyte transcription factor SOX9 locus. SOX9 is an HMG-box transcription factor that plays an essential role in chondrocyte development by directing the expression of chondrocyte-specific genes. Two of these lncRNAs are upregulated during chondrogenic differentiation of mesenchymal stem cells (MSCs). Depletion of one of these lncRNAs, LOC102723505, which we termed ROCR (regulator of chondrogenesis RNA), by RNA interference disrupted MSC chondrogenesis, concomitant with reduced cartilage-specific gene expression and incomplete matrix component production, indicating an important role in chondrocyte biology. Specifically, SOX9 induction was significantly ablated in the absence of ROCR, and overexpression of SOX9 rescued the differentiation of MSCs into chondrocytes. Our work sheds further light on chondrocyte-specific SOX9 expression and highlights a novel method of chondrocyte gene regulation involving a lncRNA. PMID:29084806

Altered imprinted gene expression and methylation patterns in mid-gestation aborted cloned porcine fetuses and placentas.

PubMed

Zhang, Xiaoyang; Wang, Dongxu; Han, Yang; Duan, Feifei; Lv, Qinyan; Li, Zhanjun

2014-11-01

To determine the expression patterns of imprinted genes and their methylation status in aborted cloned porcine fetuses and placentas. RNA and DNA were prepared from fetuses and placentas that were produced by SCNT and controls from artificial insemination. The expression of 18 imprinted genes was determined by quantitative real-time PCR (q-PCR). Bisulfite sequencing PCR (BSP) was conducted to determine the methylation status of PRE-1 short interspersed repetitive element (SINE), satellite DNA and H19 differentially methylated region 3 (DMR3). The weight, imprinted gene expression and genome-wide DNA methylation patterns were compared between the mid-gestation aborted and normal control samples. The results showed hypermethylation of PRE-1 and satellite sequences, the aberrant expression of imprinted genes, and the hypomethylation of H19 DMR3 occurred in mid-gestation aborted fetuses and placentas. Cloned pigs generated by somatic cell nuclear transfer (SCNT) showed a greater ratio of early abortion during mid-gestation than did normal controls because of the incomplete epigenetic reprogramming of the donor cells. Altered expression of imprinted genes and the hypermethylation profile of the repetitive regions (PRE-1 and satellite DNA) may be associated with defective development and early abortion of cloned pigs, emphasizing the importance of epigenetics during pregnancy and implications thereof for patient-specific embryonic stem cells for human therapeutic cloning and improvement of human assisted reproduction.

The Inheritance of Apomixis in Poa pratensis Confirms a Five Locus Model with Differences in Gene Expressivity and PenetranceW⃞

PubMed Central

Matzk, Fritz; Prodanovic, Sanja; Bäumlein, Helmut; Schubert, Ingo

2005-01-01

The genetic control of apomixis was studied in numerous segregating progenies originated from intercrossing and selfing of obligate sexual and facultative apomictic parents in Poa pratensis by means of the flow cytometric seed screen. The data support a novel model with five major genes required to control asexual seed formation: the Apospory initiator (Ait) gene, the Apospory preventer (Apv) gene, a Megaspore development (Mdv) gene, the Parthenogenesis initiator (Pit) gene, and the Parthenogenesis preventer (Ppv) gene. Differences in expressivity and interactions of these genes are responsible for the wide variation of the mode of reproduction. Apospory and parthenogenesis as well as the initiator and preventer genes of these components segregate independently. The genotypes with the highest expressivity of apospory and parthenogenesis were assigned as Ait-/apvapv/Pit-/ppvppv, those with intermediate expressivity as Ait-/Apv-/Pit-/Ppv-, and those with low expressivity as aitait/apvapv/pitpit/ppvppv. Among the self progenies of obligate sexual individuals, plants with a low capacity for apospory and/or parthenogenesis occurred, indicating that the sexual parents were heterozygous for the preventer genes and homozygous for the recessive initiator alleles (aitait/Apv-/pitpit/Ppv-). The dominant allele Ait exhibits incomplete penetrance. The degree of expressivity of apospory and parthenogenesis was constant among several harvest years of F1 plants. PMID:15608334

β₂ adrenergic receptor activation suppresses bone morphogenetic protein (BMP)-induced alkaline phosphatase expression in osteoblast-like MC3T3E1 cells.

PubMed

Yamada, Takayuki; Ezura, Yoichi; Hayata, Tadayoshi; Moriya, Shuichi; Shirakawa, Jumpei; Notomi, Takuya; Arayal, Smriti; Kawasaki, Makiri; Izu, Yayoi; Harada, Kiyoshi; Noda, Masaki

2015-06-01

β adrenergic stimulation suppresses bone formation in vivo while its actions in osteoblastic differentiation are still incompletely understood. We therefore examined the effects of β2 adrenergic stimulation on osteoblast-like MC3T3-E1 cells focusing on BMP-induced alkaline phosphatase expression. Morphologically, isoproterenol treatment suppresses BMP-induced increase in the numbers of alkaline phosphatase-positive small foci in the cultures of MC3T3-E1 cells. Biochemically, isoproterenol treatment suppresses BMP-induced enzymatic activity of alkaline phosphatase in a dose-dependent manner. Isoproterenol suppression of alkaline phosphatase activity is observed even when the cells are treated with high concentrations of BMP. With respect to cell density, isoproterenol treatment tends to suppress BMP-induced increase in alkaline phosphatase expression more in osteoblasts cultured at higher cell density. In terms of treatment protocol, continuous isoproterenol treatment is compared to cyclic treatment. Continuous isoproterenol treatment is more suppressive against BMP-induced increase in alkaline phosphatase expression than cyclic regimen. At molecular level, isoproterenol treatment suppresses BMP-induced enhancement of alkaline phosphatase mRNA expression. Regarding the mode of isoproterenol action, isoproterenol suppresses BMP-induced BRE-luciferase activity. These data indicate that isoproterenol regulates BMP-induced alkaline phosphatase expression in osteoblast-like MC3T3E1 cells. © 2014 Wiley Periodicals, Inc.

Prognostic stratification improvement by integrating ID1/ID3/IGJ gene expression signature and immunophenotypic profile in adult patients with B-ALL.

PubMed

Cruz-Rodriguez, Nataly; Combita, Alba L; Enciso, Leonardo J; Raney, Lauren F; Pinzon, Paula L; Lozano, Olga C; Campos, Alba M; Peñaloza, Niyireth; Solano, Julio; Herrera, Maria V; Zabaleta, Jovanny; Quijano, Sandra

2017-02-28

Survival of adults with B-Acute Lymphoblastic Leukemia requires accurate risk stratification of patients in order to provide the appropriate therapy. Contemporary techniques, using clinical and cytogenetic variables are incomplete for prognosis prediction. To improve the classification of adult patients diagnosed with B-ALL into prognosis groups, two strategies were examined and combined: the expression of the ID1/ID3/IGJ gene signature by RT-PCR and the immunophenotypic profile of 19 markers proposed in the EuroFlow protocol by Flow Cytometry in bone marrow samples. Both techniques were correlated to stratify patients into prognostic groups. An inverse relationship between survival and expression of the three-genes signature was observed and an immunophenotypic profile associated with clinical outcome was identified. Markers CD10 and CD20 were correlated with simultaneous overexpression of ID1, ID3 and IGJ. Patients with simultaneous expression of the poor prognosis gene signature and overexpression of CD10 or CD20, had worse Event Free Survival and Overall Survival than patients who had either the poor prognosis gene expression signature or only CD20 or CD10 overexpressed. By utilizing the combined evaluation of these two immunophenotypic markers along with the poor prognosis gene expression signature, the risk stratification can be significantly strengthened. Further studies including a large number of patients are needed to confirm these findings.

Sensitivity of low-energy incomplete fusion to various entrance-channel parameters

NASA Astrophysics Data System (ADS)

Kumar, Harish; Tali, Suhail A.; Afzal Ansari, M.; Singh, D.; Ali, Rahbar; Kumar, Kamal; Sathik, N. P. M.; Ali, Asif; Parashari, Siddharth; Dubey, R.; Bala, Indu; Kumar, R.; Singh, R. P.; Muralithar, S.

2018-03-01

The disentangling of incomplete fusion dependence on various entrance channel parameters has been made from the forward recoil range distribution measurement for the 12C+175Lu system at ≈ 88 MeV energy. It gives the direct measure of full and/or partial linear momentum transfer from the projectile to the target nucleus. The comparison of observed recoil ranges with theoretical ranges calculated using the code SRIM infers the production of evaporation residues via complete and/or incomplete fusion process. Present results show that incomplete fusion process contributes significantly in the production of α xn and 2α xn emission channels. The deduced incomplete fusion probability (F_{ICF}) is compared with that obtained for systems available in the literature. An interesting behavior of F_{ICF} with ZP ZT is observed in the reinvestigation of incomplete fusion dependency with the Coulomb factor (ZPZT), contrary to the recent observations. The present results based on (ZPZT) are found in good agreement with recent observations of our group. A larger F_{ICF} value for 12C induced reactions is found than that for 13C, although both have the same ZPZT. A nonsystematic behavior of the incomplete fusion process with the target deformation parameter (β2) is observed, which is further correlated with a new parameter (ZP ZT . β2). The projectile α -Q-value is found to explain more clearly the discrepancy observed in incomplete fusion dependency with parameters ( ZPZT) and (ZP ZT . β2). It may be pointed out that any single entrance channel parameter (mass-asymmetry or (ZPZT) or β2 or projectile α-Q-value) may not be able to explain completely the incomplete fusion process.

Evaluation of transcatheter arterial embolization therapy on hepatocellular carcinomas using contrast-enhanced harmonic power Doppler sonography: comparison with CT, power Doppler sonography, and dynamic MRI.

PubMed

Shima, Toshihide; Mizuno, Masayuki; Otsuji, Hideaki; Mizuno, Chiemi; Obata, Hirozumi; Park, Hyohun; Nakajo, Shinobu; Okanoue, Takeshi

2005-09-01

The aim of this study was to assess and compare the sensitivity of power Doppler sonography, contrast-enhanced sonography, plain computed tomography (CT), and dynamic magnetic resonance imaging (MRI) for detecting hepatocellular carcinoma (HCC) nodules incompletely treated with transcatheter arterial embolization (TAE). A total of 63 unresectable HCC nodules were examined in this study. The HCCs were treated with TAE. All patients underwent plain CT, power Doppler sonography, contrast-enhanced harmonic power Doppler sonography, and dynamic MRI 1 week after TAE. The sensitivity of each modality to incompletely treated HCC nodules was compared. Detection of the residual viable HCC on angiography or tumor biopsy was regarded as the gold standard for the diagnosis of incomplete treatment. Twenty-four nodules (38%) were diagnosed as incompletely treated. The sensitivities of plain CT, power Doppler sonography, contrast-enhanced harmonic power Doppler sonography, and dynamic MRI to these incompletely treated nodules were 42% (10/24), 46% (11/24), 88% (21/24), and 79% (19/24), respectively. Eighty percent (19 nodules) of the 24 incompletely treated nodules were located within a depth of less than 8 cm. The sensitivities of plain CT, power Doppler sonography, contrast-enhanced harmonic power Doppler sonography, and dynamic MRI to these superficial incompletely treated nodules were 37% (7/19), 53% (10/19), 100% (19/19), and 74% (14/19), respectively. In contrast, the sensitivities of each modality to deeply located nodules were 60% (3/5), 20% (1/5), 40% (2/5), and 100% (5/5), respectively. Plain CT and power Doppler sonography had a low sensitivity to HCC nodules incompletely treated with TAE. Except for those that were deeply located, contrast-enhanced harmonic sonography showed the highest sensitivity in detecting incompletely treated HCC nodules.

High expression of A-type lamin in the leading front is required for Drosophila thorax closure.

PubMed

Kosakamoto, Hina; Fujisawa, Yuya; Obata, Fumiaki; Miura, Masayuki

2018-05-05

Tissue closure involves the coordinated unidirectional movement of a group of cells without loss of cell-cell contact. However, the molecular mechanisms controlling the tissue closure are not fully understood. Here, we demonstrate that Lamin C, the sole A-type lamin in Drosophila, contributes to the process of thorax closure in pupa. High expression of Lamin C was observed at the leading front of the migrating wing imaginal discs. Live imaging analysis revealed that knockdown of Lamin C in the thorax region affected the coordinated movement of the leading front, resulting in incomplete tissue fusion required for formation of the adult thorax. The closure defect due to knockdown of Lamin C correlated with insufficient accumulation of F-actin at the front. Our study indicates a link between A-type lamin and the cell migration behavior during tissue closure. Copyright © 2018 Elsevier Inc. All rights reserved.

Identification of genes regulated during mechanical load-induced cardiac hypertrophy

NASA Technical Reports Server (NTRS)

Johnatty, S. E.; Dyck, J. R.; Michael, L. H.; Olson, E. N.; Abdellatif, M.; Schneider, M. (Principal Investigator)

2000-01-01

Cardiac hypertrophy is associated with both adaptive and adverse changes in gene expression. To identify genes regulated by pressure overload, we performed suppressive subtractive hybridization between cDNA from the hearts of aortic-banded (7-day) and sham-operated mice. In parallel, we performed a subtraction between an adult and a neonatal heart, for the purpose of comparing different forms of cardiac hypertrophy. Sequencing more than 100 clones led to the identification of an array of functionally known (70%) and unknown genes (30%) that are upregulated during cardiac growth. At least nine of those genes were preferentially expressed in both the neonatal and pressure over-load hearts alike. Using Northern blot analysis to investigate whether some of the identified genes were upregulated in the load-independent calcineurin-induced cardiac hypertrophy mouse model, revealed its incomplete similarity with the former models of cardiac growth. Copyright 2000 Academic Press.

Regulation of anoikis by Deleted in Breast Cancer-1 (DBC1) through NF-κB

PubMed Central

Park, Sun Hee; Riley, Philip; Frisch, Steven M

2013-01-01

Anoikis-resistance of tumor cells is critical for anchorage-independent growth and metastasis. The inflammatory-response transcription factor NF-κB contributes to anoikis-resistance and tumor progression through mechanisms that are understood incompletely. Deleted in Breast Cancer-1 protein (KIAA1967) is over-expressed in several tumor types, and correlates with a poorer prognosis in some cases. We report here that DBC1 suppressed anoikis in normal epithelial and breast cancer cell lines. DBC1 interacted with IKK-β, stimulating its kinase activity, promoting NF-κB transcriptional activity through the phosphorylation of relA serine-536 and enhancing the expression of the NF-κB target genes, c-FLIP and bcl-xl. Our results indicate that DBC1 is an important co-factor for the control of the IKK-β-NF-κB signaling pathway that regulates anoikis. PMID:23588592

Necklace: combining reference and assembled transcriptomes for more comprehensive RNA-Seq analysis.

PubMed

Davidson, Nadia M; Oshlack, Alicia

2018-05-01

RNA sequencing (RNA-seq) analyses can benefit from performing a genome-guided and de novo assembly, in particular for species where the reference genome or the annotation is incomplete. However, tools for integrating an assembled transcriptome with reference annotation are lacking. Necklace is a software pipeline that runs genome-guided and de novo assembly and combines the resulting transcriptomes with reference genome annotations. Necklace constructs a compact but comprehensive superTranscriptome out of the assembled and reference data. Reads are subsequently aligned and counted in preparation for differential expression testing. Necklace allows a comprehensive transcriptome to be built from a combination of assembled and annotated transcripts, which results in a more comprehensive transcriptome for the majority of organisms. In addition RNA-seq data are mapped back to this newly created superTranscript reference to enable differential expression testing with standard methods.

49 CFR 630.6 - Late and incomplete reports.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 49 Transportation 7 2013-10-01 2013-10-01 false Late and incomplete reports. 630.6 Section 630.6 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL TRANSIT ADMINISTRATION, DEPARTMENT OF TRANSPORTATION NATIONAL TRANSIT DATABASE § 630.6 Late and incomplete reports. (a) Late reports...

49 CFR 630.6 - Late and incomplete reports.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 49 Transportation 7 2010-10-01 2010-10-01 false Late and incomplete reports. 630.6 Section 630.6 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL TRANSIT ADMINISTRATION, DEPARTMENT OF TRANSPORTATION NATIONAL TRANSIT DATABASE § 630.6 Late and incomplete reports. (a) Late reports...

49 CFR 630.6 - Late and incomplete reports.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 49 Transportation 7 2011-10-01 2011-10-01 false Late and incomplete reports. 630.6 Section 630.6 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL TRANSIT ADMINISTRATION, DEPARTMENT OF TRANSPORTATION NATIONAL TRANSIT DATABASE § 630.6 Late and incomplete reports. (a) Late reports...

49 CFR 630.6 - Late and incomplete reports.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 49 Transportation 7 2014-10-01 2014-10-01 false Late and incomplete reports. 630.6 Section 630.6 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL TRANSIT ADMINISTRATION, DEPARTMENT OF TRANSPORTATION NATIONAL TRANSIT DATABASE § 630.6 Late and incomplete reports. (a) Late reports...

49 CFR 630.6 - Late and incomplete reports.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 49 Transportation 7 2012-10-01 2012-10-01 false Late and incomplete reports. 630.6 Section 630.6 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL TRANSIT ADMINISTRATION, DEPARTMENT OF TRANSPORTATION NATIONAL TRANSIT DATABASE § 630.6 Late and incomplete reports. (a) Late reports...

Assessment of stem cell differentiation based on genome-wide expression profiles.

PubMed

Godoy, Patricio; Schmidt-Heck, Wolfgang; Hellwig, Birte; Nell, Patrick; Feuerborn, David; Rahnenführer, Jörg; Kattler, Kathrin; Walter, Jörn; Blüthgen, Nils; Hengstler, Jan G

2018-07-05

In recent years, protocols have been established to differentiate stem and precursor cells into more mature cell types. However, progress in this field has been hampered by difficulties to assess the differentiation status of stem cell-derived cells in an unbiased manner. Here, we present an analysis pipeline based on published data and methods to quantify the degree of differentiation and to identify transcriptional control factors explaining differences from the intended target cells or tissues. The pipeline requires RNA-Seq or gene array data of the stem cell starting population, derived 'mature' cells and primary target cells or tissue. It consists of a principal component analysis to represent global expression changes and to identify possible problems of the dataset that require special attention, such as: batch effects; clustering techniques to identify gene groups with similar features; over-representation analysis to characterize biological motifs and transcriptional control factors of the identified gene clusters; and metagenes as well as gene regulatory networks for quantitative cell-type assessment and identification of influential transcription factors. Possibilities and limitations of the analysis pipeline are illustrated using the example of human embryonic stem cell and human induced pluripotent cells to generate 'hepatocyte-like cells'. The pipeline quantifies the degree of incomplete differentiation as well as remaining stemness and identifies unwanted features, such as colon- and fibroblast-associated gene clusters that are absent in real hepatocytes but typically induced by currently available differentiation protocols. Finally, transcription factors responsible for incomplete and unwanted differentiation are identified. The proposed method is widely applicable and allows an unbiased and quantitative assessment of stem cell-derived cells.This article is part of the theme issue 'Designer human tissue: coming to a lab near you'. © 2018 The Author(s).

Base-CP proteasome can serve as a platform for stepwise lid formation

PubMed Central

Yu, Zanlin; Livnat-Levanon, Nurit; Kleifeld, Oded; Mansour, Wissam; Nakasone, Mark A.; Castaneda, Carlos A.; Dixon, Emma K.; Fushman, David; Reis, Noa; Pick, Elah; Glickman, Michael H.

2015-01-01

26S proteasome, a major regulatory protease in eukaryotes, consists of a 20S proteolytic core particle (CP) capped by a 19S regulatory particle (RP). The 19S RP is divisible into base and lid sub-complexes. Even within the lid, subunits have been demarcated into two modules: module 1 (Rpn5, Rpn6, Rpn8, Rpn9 and Rpn11), which interacts with both CP and base sub-complexes and module 2 (Rpn3, Rpn7, Rpn12 and Rpn15) that is attached mainly to module 1. We now show that suppression of RPN11 expression halted lid assembly yet enabled the base and 20S CP to pre-assemble and form a base-CP. A key role for Regulatory particle non-ATPase 11 (Rpn11) in bridging lid module 1 and module 2 subunits together is inferred from observing defective proteasomes in rpn11–m1, a mutant expressing a truncated form of Rpn11 and displaying mitochondrial phenotypes. An incomplete lid made up of five module 1 subunits attached to base-CP was identified in proteasomes isolated from this mutant. Re-introducing the C-terminal portion of Rpn11 enabled recruitment of missing module 2 subunits. In vitro, module 1 was reconstituted stepwise, initiated by Rpn11–Rpn8 heterodimerization. Upon recruitment of Rpn6, the module 1 intermediate was competent to lock into base-CP and reconstitute an incomplete 26S proteasome. Thus, base-CP can serve as a platform for gradual incorporation of lid, along a proteasome assembly pathway. Identification of proteasome intermediates and reconstitution of minimal functional units should clarify aspects of the inner workings of this machine and how multiple catalytic processes are synchronized within the 26S proteasome holoenzymes. PMID:26182356

Structure and Interactions of the Human Programmed Cell Death 1 Receptor*

PubMed Central

Cheng, Xiaoxiao; Veverka, Vaclav; Radhakrishnan, Anand; Waters, Lorna C.; Muskett, Frederick W.; Morgan, Sara H.; Huo, Jiandong; Yu, Chao; Evans, Edward J.; Leslie, Alasdair J.; Griffiths, Meryn; Stubberfield, Colin; Griffin, Robert; Henry, Alistair J.; Jansson, Andreas; Ladbury, John E.; Ikemizu, Shinji; Carr, Mark D.; Davis, Simon J.

2013-01-01

PD-1, a receptor expressed by T cells, B cells, and monocytes, is a potent regulator of immune responses and a promising therapeutic target. The structure and interactions of human PD-1 are, however, incompletely characterized. We present the solution nuclear magnetic resonance (NMR)-based structure of the human PD-1 extracellular region and detailed analyses of its interactions with its ligands, PD-L1 and PD-L2. PD-1 has typical immunoglobulin superfamily topology but differs at the edge of the GFCC′ sheet, which is flexible and completely lacks a C″ strand. Changes in PD-1 backbone NMR signals induced by ligand binding suggest that, whereas binding is centered on the GFCC′ sheet, PD-1 is engaged by its two ligands differently and in ways incompletely explained by crystal structures of mouse PD-1·ligand complexes. The affinities of these interactions and that of PD-L1 with the costimulatory protein B7-1, measured using surface plasmon resonance, are significantly weaker than expected. The 3–4-fold greater affinity of PD-L2 versus PD-L1 for human PD-1 is principally due to the 3-fold smaller dissociation rate for PD-L2 binding. Isothermal titration calorimetry revealed that the PD-1/PD-L1 interaction is entropically driven, whereas PD-1/PD-L2 binding has a large enthalpic component. Mathematical simulations based on the biophysical data and quantitative expression data suggest an unexpectedly limited contribution of PD-L2 to PD-1 ligation during interactions of activated T cells with antigen-presenting cells. These findings provide a rigorous structural and biophysical framework for interpreting the important functions of PD-1 and reveal that potent inhibitory signaling can be initiated by weakly interacting receptors. PMID:23417675

Modeling Cyber Conflicts Using an Extended Petri Net Formalism

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

Zakrzewska, Anita N; Ferragut, Erik M

2011-01-01

When threatened by automated attacks, critical systems that require human-controlled responses have difficulty making optimal responses and adapting protections in real- time and may therefore be overwhelmed. Consequently, experts have called for the development of automatic real-time reaction capabilities. However, a technical gap exists in the modeling and analysis of cyber conflicts to automatically understand the repercussions of responses. There is a need for modeling cyber assets that accounts for concurrent behavior, incomplete information, and payoff functions. Furthermore, we address this need by extending the Petri net formalism to allow real-time cyber conflicts to be modeled in a way thatmore » is expressive and concise. This formalism includes transitions controlled by players as well as firing rates attached to transitions. This allows us to model both player actions and factors that are beyond the control of players in real-time. We show that our formalism is able to represent situational aware- ness, concurrent actions, incomplete information and objective functions. These factors make it well-suited to modeling cyber conflicts in a way that allows for useful analysis. MITRE has compiled the Common Attack Pattern Enumera- tion and Classification (CAPEC), an extensive list of cyber attacks at various levels of abstraction. CAPEC includes factors such as attack prerequisites, possible countermeasures, and attack goals. These elements are vital to understanding cyber attacks and to generating the corresponding real-time responses. We demonstrate that the formalism can be used to extract precise models of cyber attacks from CAPEC. Several case studies show that our Petri net formalism is more expressive than other models, such as attack graphs, for modeling cyber conflicts and that it is amenable to exploring cyber strategies.« less

Toll-like Receptor 4-mediated Endoplasmic Reticulum Stress in Intestinal Crypts Induces Necrotizing Enterocolitis*

PubMed Central

Afrazi, Amin; Branca, Maria F.; Sodhi, Chhinder P.; Good, Misty; Yamaguchi, Yukihiro; Egan, Charlotte E.; Lu, Peng; Jia, Hongpeng; Shaffiey, Shahab; Lin, Joyce; Ma, Congrong; Vincent, Garrett; Prindle, Thomas; Weyandt, Samantha; Neal, Matthew D.; Ozolek, John A.; Wiersch, John; Tschurtschenthaler, Markus; Shiota, Chiyo; Gittes, George K.; Billiar, Timothy R.; Mollen, Kevin; Kaser, Arthur; Blumberg, Richard; Hackam, David J.

2014-01-01

The cellular cues that regulate the apoptosis of intestinal stem cells (ISCs) remain incompletely understood, yet may play a role in diseases characterized by ISC loss including necrotizing enterocolitis (NEC). Toll-like receptor-4 (TLR4) was recently found to be expressed on ISCs, where its activation leads to ISC apoptosis through mechanisms that remain incompletely explained. We now hypothesize that TLR4 induces endoplasmic reticulum (ER) stress within ISCs, leading to their apoptosis in NEC pathogenesis, and that high ER stress within the premature intestine predisposes to NEC development. Using transgenic mice and cultured enteroids, we now demonstrate that TLR4 induces ER stress within Lgr5 (leucine-rich repeat-containing G-protein-coupled receptor 5)-positive ISCs, resulting in crypt apoptosis. TLR4 signaling within crypts was required, because crypt ER stress and apoptosis occurred in TLR4ΔIEC-OVER mice expressing TLR4 only within intestinal crypts and epithelium, but not TLR4ΔIEC mice lacking intestinal TLR4. TLR4-mediated ER stress and apoptosis of ISCs required PERK (protein kinase-related PKR-like ER kinase), CHOP (C/EBP homologous protein), and MyD88 (myeloid differentiation primary response gene 88), but not ATF6 (activating transcription factor 6) or XBP1 (X-box-binding protein 1). Human and mouse NEC showed high crypt ER stress and apoptosis, whereas genetic inhibition of PERK or CHOP attenuated ER stress, crypt apoptosis, and NEC severity. Strikingly, using intragastric delivery into fetal mouse intestine, prevention of ER stress reduced TLR4-mediated ISC apoptosis and mucosal disruption. These findings identify a novel link between TLR4-induced ER stress and ISC apoptosis in NEC pathogenesis and suggest that increased ER stress within the premature bowel predisposes to NEC development. PMID:24519940

Toll-like receptor 4-mediated endoplasmic reticulum stress in intestinal crypts induces necrotizing enterocolitis.

PubMed

Afrazi, Amin; Branca, Maria F; Sodhi, Chhinder P; Good, Misty; Yamaguchi, Yukihiro; Egan, Charlotte E; Lu, Peng; Jia, Hongpeng; Shaffiey, Shahab; Lin, Joyce; Ma, Congrong; Vincent, Garrett; Prindle, Thomas; Weyandt, Samantha; Neal, Matthew D; Ozolek, John A; Wiersch, John; Tschurtschenthaler, Markus; Shiota, Chiyo; Gittes, George K; Billiar, Timothy R; Mollen, Kevin; Kaser, Arthur; Blumberg, Richard; Hackam, David J

2014-04-04

The cellular cues that regulate the apoptosis of intestinal stem cells (ISCs) remain incompletely understood, yet may play a role in diseases characterized by ISC loss including necrotizing enterocolitis (NEC). Toll-like receptor-4 (TLR4) was recently found to be expressed on ISCs, where its activation leads to ISC apoptosis through mechanisms that remain incompletely explained. We now hypothesize that TLR4 induces endoplasmic reticulum (ER) stress within ISCs, leading to their apoptosis in NEC pathogenesis, and that high ER stress within the premature intestine predisposes to NEC development. Using transgenic mice and cultured enteroids, we now demonstrate that TLR4 induces ER stress within Lgr5 (leucine-rich repeat-containing G-protein-coupled receptor 5)-positive ISCs, resulting in crypt apoptosis. TLR4 signaling within crypts was required, because crypt ER stress and apoptosis occurred in TLR4(ΔIEC-OVER) mice expressing TLR4 only within intestinal crypts and epithelium, but not TLR4(ΔIEC) mice lacking intestinal TLR4. TLR4-mediated ER stress and apoptosis of ISCs required PERK (protein kinase-related PKR-like ER kinase), CHOP (C/EBP homologous protein), and MyD88 (myeloid differentiation primary response gene 88), but not ATF6 (activating transcription factor 6) or XBP1 (X-box-binding protein 1). Human and mouse NEC showed high crypt ER stress and apoptosis, whereas genetic inhibition of PERK or CHOP attenuated ER stress, crypt apoptosis, and NEC severity. Strikingly, using intragastric delivery into fetal mouse intestine, prevention of ER stress reduced TLR4-mediated ISC apoptosis and mucosal disruption. These findings identify a novel link between TLR4-induced ER stress and ISC apoptosis in NEC pathogenesis and suggest that increased ER stress within the premature bowel predisposes to NEC development.

[Clinical research of Bordetella pertussis infection in infants with prolonged cough].

PubMed

Mi, Rong; Fu, Jin; Wang, Xiao-ying; Kang, Li-min; Li, Li; Xu, Fang-sheng; Cui, Xiao-dai

2013-06-11

To explore the prevalence of Bordetella pertussis (B. pertussis) infection in unvaccinated or incomplete vaccinated infants with cough for a prolonged duration. The serum samples and nasopharyngeal secretions were collected from 176 patients with cough for a prolonged duration ( ≥ 2 weeks) from 2011 to 2012 at Children's Hospital Affiliated to Capital Institute of Pediatrics. Multiplex PCR of nasopharyngeal secretion was employed to identify B.pertussis. And enzyme-linked immunosorbent assay(ELISA) was used to detect antibody to pertussis toxin(PT-IgG). Total bacterial DNA was enacted from nasopharyngeal secretion and two-target IS481/PT of B.pertussis was detected by PCR. The sera and nasopharyngeal secretions were also collected from household contacts with cough for a prolonged duration. Their clinical characteristic and epidemiological profiles were collected and analyzed. B.Pertussis infection was demonstrated in 51 cases (29.0%). The patients ages were from 23 days to 4 years. Among them, 46 cases (90.2%) were aged under 12 months and 5 cases (9.8%) over 12 months. And 40 cases were unvaccinated (31 cases <3 months old, 4 cases 3-12 months old, 5 cases >5 years old) and 11 cases incompletely vaccinated. There were 31 males and 20 females. More patients were found in spring and summer than those in autumn and winter. Nine infant cases had 12 household contacts. Among 12 household contacts, 3 were PCR positive and 12 PT-IgG positive. Pertussis was remarkably critical in infants. Serious complications included failure to thrive, pneumonia, respiratory failure and seizures. B.pertussis infection is an important cause in unvaccinated or incomplete vaccinated infants with prolonged cough. Peak seasons of pertussis are spring and summer. Undiagnosed adolescents and adults with pertussis may be a significant source for transmission of B.pertussis to other susceptible children. Infants aged under 1 year are at risk for severe pertussis and life-threatening complications. As a rapid and sensitive method of detecting B.pertussis, PCR may be used in early phase.

Influence of medium components on the expression of recombinant lipoproteins in Escherichia coli.

PubMed

Tseng, Chi-Ling; Leng, Chih-Hsiang

2012-02-01

Bacterial lipoproteins are crucial antigens for protective immunity against bacterial pathogens. Expression of exogenous lipoproteins in Escherichia coli at high levels is thought to be an extremely difficult endeavor because it frequently results in incomplete or absent lipid modification. Previously, we identified a fusion sequence (D1) from a Neisseria meningitidis lipoprotein that induced a non-lipidated protein, E3 (the domain III of the dengue virus envelope protein), to become lipidated. However, without optimizing the growth conditions, some of the D1-fusion proteins were not lipidated. Here, we report the influence of medium components on the expression of recombinant lipoproteins in E. coli. For high-level expression of mature lipoproteins in the C43 (DE3) strain, M9 medium was better than M63 and the rich medium. Furthermore, we analyzed the influence of other media factors (including nitrogen and carbon sources, phosphate, ferrous ions, calcium, magnesium, and pH) on the levels of lipoprotein expression. The results showed that excess nitrogen sources and phosphate in M9 medium could increase the amount of immature lipoproteins, and glucose was a better carbon source than glycerol for expressing mature lipoproteins. We also found that lipoproteins tended to be completely processed in the alkaline environment, even in the nutrient-rich medium. Additional constructs expressing different immunogens or lipid signal peptides as targets were also utilized, demonstrating that these targets could be expressed as completely mature lipoproteins in the M9 medium but not in the rich medium. Our results provide the useful information for expressing mature exogenous lipoproteins in E. coli.

Dynamic methylation and expression of Oct4 in early neural stem cells

PubMed Central

Lee, Shih-Han; Jeyapalan, Jennie N; Appleby, Vanessa; Mohamed Noor, Dzul Azri; Sottile, Virginie; Scotting, Paul J

2010-01-01

Neural stem cells are a multipotent population of tissue-specific stem cells with a broad but limited differentiation potential. However, recent studies have shown that over-expression of the pluripotency gene, Oct4, alone is sufficient to initiate a process by which these can form ‘induced pluripotent stem cells’ (iPS cells) with the same broad potential as embryonic stem cells. This led us to examine the expression of Oct4 in endogenous neural stem cells, as data regarding its expression in neural stem cells in vivo are contradictory and incomplete. In this study we have therefore analysed the expression of Oct4 and other genes associated with pluripotency throughout development of the mouse CNS and in neural stem cells grown in vitro. We find that Oct4 is still expressed in the CNS by E8.5, but that this expression declines rapidly until it is undetectable by E15.5. This decline is coincident with the gradual methylation of the Oct4 promoter and proximal enhancer. Immunostaining suggests that the Oct4 protein is predominantly cytoplasmic in location. We also found that neural stem cells from all ages expressed the pluripotency associated genes, Sox2, c-Myc, Klf4 and Nanog. These data provide an explanation for the varying behaviour of cells from the early neuroepithelium at different stages of development. The expression of these genes also provides an indication of why Oct4 alone is sufficient to induce iPS formation in neural stem cells at later stages. PMID:20646110

43 CFR 46.125 - Incomplete or unavailable information.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 43 Public Lands: Interior 1 2011-10-01 2011-10-01 false Incomplete or unavailable information. 46... THE NATIONAL ENVIRONMENTAL POLICY ACT OF 1969 Protection and Enhancement of Environmental Quality § 46.125 Incomplete or unavailable information. In circumstances where the provisions of 40 CFR 1502.22...

43 CFR 46.125 - Incomplete or unavailable information.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 43 Public Lands: Interior 1 2013-10-01 2013-10-01 false Incomplete or unavailable information. 46... THE NATIONAL ENVIRONMENTAL POLICY ACT OF 1969 Protection and Enhancement of Environmental Quality § 46.125 Incomplete or unavailable information. In circumstances where the provisions of 40 CFR 1502.22...

49 CFR 568.4 - Requirements for incomplete vehicle manufacturers.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 49 Transportation 6 2013-10-01 2013-10-01 false Requirements for incomplete vehicle manufacturers. 568.4 Section 568.4 Transportation Other Regulations Relating to Transportation (Continued) NATIONAL HIGHWAY TRAFFIC SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION VEHICLES MANUFACTURED IN TWO OR MORE STAGES-ALL INCOMPLETE, INTERMEDIATE AND...

Short- and long-term results following standing fracture repair in 34 horses.

PubMed

Payne, R J; Compston, P C

2012-11-01

Standing fracture repair in the horse is a recently described surgical procedure and currently there are few follow-up data. This case series contains 2 novel aspects in the standing horse: repair of incomplete sagittal fractures of the proximal phalanx and medial condylar repair from a lateral aspect. To describe outcome in a case series of horses that had lower limb fractures repaired under standing sedation at Rossdales Equine Hospital. Case records for all horses that had a fracture surgically repaired, by one surgeon at Rossdales Equine Hospital, under standing sedation and local anaesthesia up until June 2011, were retrieved. Hospital records, owner/trainer telephone questionnaire and the Racing Post website were used to evaluate follow-up. Thirty-four horses satisfied the inclusion criteria. Fracture sites included the proximal phalanx (incomplete sagittal fracture, n = 14); the third metacarpal bone (lateral condyle, n = 12, and medial condyle, n = 7); and the third metatarsal bone (lateral condyle, n = 1). One horse required euthanasia due to caecal rupture 10 days post operatively. Twenty horses (66.7% of those with available follow-up) have returned to racing. Where available, mean time from operation to return to racing was 226 days (range 143-433 days). Standing fracture repair produced similar results to fracture repair under general anaesthesia in terms of both the number of horses that returned to racing and the time between surgery and race. Repair of lower limb fracture in the horse under standing sedation is a procedure that has the potential for tangible benefits, including avoidance of the inherent risks of general anaesthesia. The preliminary findings in this series of horses are encouraging and informative when discussing options available prior to fracture repair. © 2012 EVJ Ltd.

Differentiation of human SH-SY5Y neuroblastoma cells by all-trans retinoic acid activates the interleukin-18 system.

PubMed

Sallmon, Hannes; Hoene, Victoria; Weber, Sven C; Dame, Christof

2010-02-01

The clinical prognosis of children with high-stage neuroblastoma is still poor. Therapeutic approaches include surgery and cellular differentiation by retinoic acid, but also experimental interleukin-based immune modulation. However, the molecular mechanisms of all-trans retinoic acid (ATRA)-induced differentiation of neuroblastoma cells are incompletely understood. Herein, we examined the effect of ATRA on the activity of the interleukin-18 (IL-18) system in human SH-SY5Y neuroblastoma cells. It is shown that SH-SY5Y cells express IL-18 receptor (IL-18R) and the secreted antagonist IL-18-binding protein (IL-18BP), but no IL-18. SH-SY5Y cells are highly sensitive to ATRA treatment and react by cellular differentiation from a neuroblastic toward a more neuronal phenotype. This was associated with induction of IL-18 and reduction of IL-18BP expression, while IL-18R expression remained stable. Thereby, we identified the IL-18 system as a novel target of ATRA in neuroblastoma cells that might contribute to the therapeutic properties of retinoids in treatment of neuroblastoma.

Oncogenic Kras initiates leukemia in hematopoietic stem cells.

PubMed

Sabnis, Amit J; Cheung, Laurene S; Dail, Monique; Kang, Hio Chung; Santaguida, Marianne; Hermiston, Michelle L; Passegué, Emmanuelle; Shannon, Kevin; Braun, Benjamin S

2009-03-17

How oncogenes modulate the self-renewal properties of cancer-initiating cells is incompletely understood. Activating KRAS and NRAS mutations are among the most common oncogenic lesions detected in human cancer, and occur in myeloproliferative disorders (MPDs) and leukemias. We investigated the effects of expressing oncogenic Kras(G12D) from its endogenous locus on the proliferation and tumor-initiating properties of murine hematopoietic stem and progenitor cells. MPD could be initiated by Kras(G12D) expression in a highly restricted population enriched for hematopoietic stem cells (HSCs), but not in common myeloid progenitors. Kras(G12D) HSCs demonstrated a marked in vivo competitive advantage over wild-type cells. Kras(G12D) expression also increased the fraction of proliferating HSCs and reduced the overall size of this compartment. Transplanted Kras(G12D) HSCs efficiently initiated acute T-lineage leukemia/lymphoma, which was associated with secondary Notch1 mutations in thymocytes. We conclude that MPD-initiating activity is restricted to the HSC compartment in Kras(G12D) mice, and that distinct self-renewing populations with cooperating mutations emerge during cancer progression.

CD34 cells from patients with trisomy 8 myelodysplastic syndrome (MDS) express early apoptotic markers but avoid programmed cell death by up-regulation of antiapoptotic proteins

PubMed Central

Pfannes, Loretta; Chen, Gubin; Shah, Simant; Solomou, Elena E.; Barrett, John; Young, Neal S.

2007-01-01

CD34 cells from patients with trisomy 8 myelodysplastic syndrome (MDS) are distinguished from other MDS cells and from normal hematopoietic cells by their pronounced expression of apoptotic markers. Paradoxically, trisomy 8 clones can persist in patients with bone marrow failure and expand following immunosuppression. We previously demonstrated up-regulation of c-myc and CD1 by microarray analysis. Here, we confirmed these findings by real-time polymerase chain reaction (PCR), demonstrated up-regulation of survivin, c-myc, and CD1 protein expression, and documented comparable colony formation by annexin+ trisomy 8− CD34+ and annexin− CD34 cells. There were low levels of DNA degradation in annexin+ trisomy 8 CD34 cells, which were comparable with annexin− CD34 cells. Trisomy 8 cells were resistant to apoptosis induced by gamma irradiation. Knock-down of survivin by siRNA resulted in preferential loss of trisomy 8 cells. These results suggest that trisomy 8 cells undergo incomplete apoptosis and are nonetheless capable of colony formation and growth. PMID:17090657

Altered Innate Defenses in the Neonatal Gastrointestinal Tract in Response to Colonization by Neuropathogenic Escherichia coli

PubMed Central

Birchenough, George M. H.; Johansson, Malin E. V.; Stabler, Richard A.; Dalgakiran, Fatma; Hansson, Gunnar C.; Wren, Brendan W.; Luzio, J. Paul

2013-01-01

Two-day-old (P2), but not 9-day-old (P9), rat pups are susceptible to systemic infection following gastrointestinal colonization by Escherichia coli K1. Age dependency reflects the capacity of colonizing K1 to translocate from gastrointestinal (GI) tract to blood. A complex GI microbiota developed by P2, showed little variation over P2 to P9, and did not prevent stable K1 colonization. Substantial developmental expression was observed over P2 to P9, including upregulation of genes encoding components of the small intestinal (α-defensins Defa24 and Defa-rs1) and colonic (trefoil factor Tff2) mucus barrier. K1 colonization modulated expression of these peptides: developmental expression of Tff2 was dysregulated in P2 tissues and was accompanied by a decrease in mucin Muc2. Conversely, α-defensin genes were upregulated in P9 tissues. We propose that incomplete development of the mucus barrier during early neonatal life and the capacity of colonizing K1 to interfere with mucus barrier maturation provide opportunities for neuropathogen translocation into the bloodstream. PMID:23798529

Porcine parvovirus capsid protein expressed in Escherichia coli self-assembles into virus-like particles with high immunogenicity in mice and guinea pigs.

PubMed

Ji, Pengchao; Liu, Yunchao; Chen, Yumei; Wang, Aiping; Jiang, Dawei; Zhao, Baolei; Wang, Jvcai; Chai, Shujun; Zhou, Enmin; Zhang, Gaiping

2017-03-01

Porcine parvovirus (PPV) is a causative agent of reproductive failure in pregnant sows. Classical inactivated vaccine is extensively used to control PPV infection, but problems concerning safety, such as incomplete inactivation may occur. In this study, a novel subunit vaccine against PPV based on virus-like particles (VLPs) formed from the complete PPV VP2 protein expressed in a prokaryotic system with co-expressed chaperones is reported. The VLPs have a similar size, shape, and hemagglutination property to the PPV. Immunization with these VLPs stimulated the neutralization antibody and hemagglutination inhibition (HI) antibody responses in mice and guinea pigs. The lymphocyte proliferation response and cytokine secretion was also induced in immunized guinea pigs comparable to those immunized with PPV inactivated vaccine. In addition, immunization with VLPs also significantly reduced the PPV content in the spleen of guinea pigs 14 days after the challenge with intact virus. These studies suggest that PPV VLPs created as described here could be a potential candidate for vaccine development. Copyright © 2017 Elsevier B.V. All rights reserved.

Multi-spectral fluorescent reporter influenza viruses (Color-flu) as powerful tools for in vivo studies

PubMed Central

Fukuyama, Satoshi; Katsura, Hiroaki; Zhao, Dongming; Ozawa, Makoto; Ando, Tomomi; Shoemaker, Jason E.; Ishikawa, Izumi; Yamada, Shinya; Neumann, Gabriele; Watanabe, Shinji; Kitano, Hiroaki; Kawaoka, Yoshihiro

2015-01-01

Seasonal influenza A viruses cause annual epidemics of respiratory disease; highly pathogenic avian H5N1 and the recently emerged H7N9 viruses cause severe infections in humans, often with fatal outcomes. Although numerous studies have addressed the pathogenicity of influenza viruses, influenza pathogenesis remains incompletely understood. Here we generate influenza viruses expressing fluorescent proteins of different colours (‘Color-flu’ viruses) to facilitate the study of viral infection in in vivo models. On adaptation to mice, stable expression of the fluorescent proteins in infected animals allows their detection by different types of microscopy and by flow cytometry. We use this system to analyse the progression of viral spread in mouse lungs, for live imaging of virus-infected cells, and for differential gene expression studies in virus antigen-positive and virus antigen-negative live cells in the lungs of Color-flu-infected mice. Collectively, Color-flu viruses are powerful tools to analyse virus infections at the cellular level in vivo to better understand influenza pathogenesis. PMID:25807527

Dynamical properties of a family of collisionless models of elliptical galaxies

NASA Astrophysics Data System (ADS)

Bertin, G.; Trenti, M.

2004-04-01

N-body simulations of collisionless collapse have offered important clues to the construction of realistic stellar dynamical models of elliptical galaxies. Such simulations confirm and quantify the qualitative expectation that rapid collapse of a self-gravitating collisionless system, initially cool and significantly far from equilibrium, leads to incomplete relaxation, that is to a quasi-equilibrium configuration characterized by isotropic, quasi-Maxwellian distribution of stellar orbits in the inner regions and by radially biased anisotropic pressure in the outer parts. In earlier studies, as illustrated in a number of papers several years ago, the attention was largely focused on the successful comparison between the models (constructed under the qualitative clues offered by the N-body simulations mentioned above) and the observations. In this paper we revisit the problem of incomplete violent relaxation, by making a direct comparison between the detailed properties of a family of distribution functions and those of the products of collisionless collapse found in N-body simulations.

Vented spikes improve delivery from intravenous bags with no air headspace.

PubMed

Galush, William J; Horst, Travis A

2015-07-01

Flexible plastic bags are the container of choice for most intravenous (i.v.) infusions. Under certain circumstances, however, the air-liquid interface present in these i.v. bags can lead to physical instability of protein biopharmaceuticals, resulting in product aggregation. In principle, the air headspace present in the bags can be removed to increase drug stability, but experiments described here show that this can result in incomplete draining of solution from the bag using gravity delivery, or generation of negative pressure in the bag when an infusion pump is used. It is expected that these issues could lead to incomplete delivery of medication to patients or pump-related problems, respectively. However, here it is shown that contrary to the standard pharmacy practice of using nonvented spikes with i.v. bags, the use of vented spikes with i.v. bags that lack air headspace allows complete delivery of the dose solution without impacting the physical stability of a protein-based drug. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Generalized Cross Entropy Method for estimating joint distribution from incomplete information

NASA Astrophysics Data System (ADS)

Xu, Hai-Yan; Kuo, Shyh-Hao; Li, Guoqi; Legara, Erika Fille T.; Zhao, Daxuan; Monterola, Christopher P.

2016-07-01

Obtaining a full joint distribution from individual marginal distributions with incomplete information is a non-trivial task that continues to challenge researchers from various domains including economics, demography, and statistics. In this work, we develop a new methodology referred to as ;Generalized Cross Entropy Method; (GCEM) that is aimed at addressing the issue. The objective function is proposed to be a weighted sum of divergences between joint distributions and various references. We show that the solution of the GCEM is unique and global optimal. Furthermore, we illustrate the applicability and validity of the method by utilizing it to recover the joint distribution of a household profile of a given administrative region. In particular, we estimate the joint distribution of the household size, household dwelling type, and household home ownership in Singapore. Results show a high-accuracy estimation of the full joint distribution of the household profile under study. Finally, the impact of constraints and weight on the estimation of joint distribution is explored.

The Treatment of the Incompletely Descended Testis

PubMed Central

Wilson, D. S. Poole

1939-01-01

(1) Under three years of age the diagnosis of the incompletely descended testis is uncertain. (2) The policy of awaiting spontaneous descent may be pursued until 10 years of age but, unless the testis lies in the superior scrotal position, this policy should not be persisted in thereafter. (3) Hormonal therapy may be employed before operative treatment as a means of determining testes which will descend spontaneously. It should only be used in the prepuberty period. (4) Operative treatment may be safely carried out at any age after 3 years and should be completed before puberty. The optimum period is between 8 and 11 years. The Bevan operation may be successful when the testis is very mobile but the most consistent results are obtained by the septal transposition or Keetley-Torek operations. ImagesFig. 1Fig. 2Fig. 3Fig. 4Fig. 5Fig. 8Fig. 9Fig. 10Fig. 13Fig. 14Fig. 15Fig. 16Fig. 18Fig. 19Fig. 20Fig. 21Fig. 22 PMID:19991991

Experimental analysis for fabrication of high-aspect-ratio piezoelectric ceramic structure by micro-powder injection molding process

NASA Astrophysics Data System (ADS)

Han, Jun Sae; Gal, Chang Woo; Park, Jae Man; Kim, Jong Hyun; Park, Seong Jin

2018-04-01

Aspect ratio effects in the micro-powder injection molding process were experimentally analyzed for fabrication of high-aspect-ratio piezoelectric ceramic structure. The mechanisms of critical defects have been studied according to individual manufacturing steps. In the molding process, incomplete filling phenomenon determines the critical aspect ratios of a micro pattern. According to mold temperature, an incomplete filling phenomenon has been analyzed with respect to different pattern sizes and aspect ratio. In demolding and drying process, the capillary behavior of sacrificial polymeric mold insert determines the critical aspect ratio of a micro pattern. With respect to pattern dimensions, slumping behavior has been analyzed. Based on our current systems, micro PZT feature has stability when it has lower aspect ratio than 5. Under optimized processing conditions, 20 μm and 40 μm ceramic rod array feature which has 5 of aspect ratio were successfully fabricated by the developed process. Further modification points to fabricate the smaller and higher feature were specifically addressed.

IRF4 haploinsufficiency in a family with Whipple’s disease

PubMed Central

Guérin, Antoine; Kerner, Gaspard; Marr, Nico; Markle, Janet G; Fenollar, Florence; Wong, Natalie; Boughorbel, Sabri; Avery, Danielle T; Ma, Cindy S; Bougarn, Salim; Bouaziz, Matthieu; Béziat, Vivien; Della Mina, Erika; Oleaga-Quintas, Carmen; Lazarov, Tomi; Worley, Lisa; Nguyen, Tina; Patin, Etienne; Deswarte, Caroline; Martinez-Barricarte, Rubén; Boucherit, Soraya; Ayral, Xavier; Edouard, Sophie; Boisson-Dupuis, Stéphanie; Rattina, Vimel; Bigio, Benedetta; Vogt, Guillaume; Geissmann, Frédéric; Quintana-Murci, Lluis; Chaussabel, Damien; Tangye, Stuart G; Raoult, Didier; Abel, Laurent; Bustamante, Jacinta

2018-01-01

Most humans are exposed to Tropheryma whipplei (Tw). Whipple’s disease (WD) strikes only a small minority of individuals infected with Tw (<0.01%), whereas asymptomatic chronic carriage is more common (<25%). We studied a multiplex kindred, containing four WD patients and five healthy Tw chronic carriers. We hypothesized that WD displays autosomal dominant (AD) inheritance, with age-dependent incomplete penetrance. We identified a single very rare non-synonymous mutation in the four patients: the private R98W variant of IRF4, a transcription factor involved in immunity. The five Tw carriers were younger, and also heterozygous for R98W. We found that R98W was loss-of-function, modified the transcriptome of heterozygous leukocytes following Tw stimulation, and was not dominant-negative. We also found that only six of the other 153 known non-synonymous IRF4 variants were loss-of-function. Finally, we found that IRF4 had evolved under purifying selection. AD IRF4 deficiency can underlie WD by haploinsufficiency, with age-dependent incomplete penetrance. PMID:29537367

An empirical investigation of incompleteness in a large clinical sample of obsessive compulsive disorder.

PubMed

Sibrava, Nicholas J; Boisseau, Christina L; Eisen, Jane L; Mancebo, Maria C; Rasmussen, Steven A

2016-08-01

Obsessive Compulsive Disorder (OCD) is a disorder with heterogeneous clinical presentations. To advance our understanding of this heterogeneity we investigated the prevalence and clinical features associated with incompleteness (INC), a putative underlying core feature of OCD. We predicted INC would be prominent in individuals with OCD and associated with greater severity and impairment. We examined the impact of INC in 307 adults with primary OCD. Participants with clinically significant INC (22.8% of the sample) had significantly greater OCD severity, greater rates of comorbidity, poorer ratings of functioning, lower quality of life, and higher rates of unemployment and disability. Participants with clinically significant INC were also more likely to be diagnosed with OCPD and to endorse symmetry/exactness obsessions and ordering/arranging compulsions than those who reported low INC. Our findings provide evidence that INC is associated with greater severity, comorbidity, and impairment, highlighting the need for improved assessment and treatment of INC in OCD. Copyright © 2016 Elsevier Ltd. All rights reserved.

An Empirical Investigation of Incompleteness in a Large Clinical Sample of Obsessive Compulsive Disorder

PubMed Central

Sibrava, Nicholas J.; Boisseau, Christina L.; Eisen, Jane L.; Mancebo, Maria C.; Rasmussen, Steven A.

2016-01-01

Obsessive Compulsive Disorder (OCD) is a disorder with heterogeneous clinical presentations. To advance our understanding of this heterogeneity we investigated the prevalence and clinical features associated with incompleteness (INC), a putative underlying core feature of OCD. We predicted INC would be prominent in individuals with OCD and associated with greater severity and impairment. We examined the impact of INC in 307 adults with primary OCD. Participants with clinically significant INC (22.8% of the sample) had significantly greater OCD severity, greater rates of comorbidity, poorer ratings of functioning, lower quality of life, and higher rates of unemployment and disability. Participants with clinically significant INC were also more likely to be diagnosed with OCPD and to endorse symmetry/exactness obsessions and ordering/arranging compulsions than those who reported low INC. Our findings provide evidence that INC is associated with greater severity, comorbidity, and impairment, highlighting the need for improved assessment and treatment of INC in OCD. PMID:27268401

Invariant protection of high-voltage electric motors of technological complexes at industrial enterprises at partial single-phase ground faults

NASA Astrophysics Data System (ADS)

Abramovich, B. N.; Sychev, Yu A.; Pelenev, D. N.

2018-03-01

Development results of invariant protection of high-voltage motors at incomplete single-phase ground faults are observed in the article. It is established that current protections have low action selectivity because of an inadmissible decrease in entrance signals during the shirt circuit occurrence in the place of transient resistance. The structural functional scheme and an algorithm of protective actions where correction of automatic zero sequence currents signals of the protected accessions implemented according to the level of incompleteness of ground faults are developed. It is revealed that automatic correction of zero sequence currents allows one to provide the invariance of sensitivity factor for protection under the variation conditions of a transient resistance in the place of damage. Application of invariant protection allows one to minimize damages in 6-10 kV electrical installations of industrial enterprises for a cause of infringement of consumers’ power supply and their system breakdown due to timely localization of emergency of ground faults modes.

47 CFR 73.4015 - Applications for AM and FM construction permits, incomplete or defective.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 47 Telecommunication 4 2010-10-01 2010-10-01 false Applications for AM and FM construction permits, incomplete or defective. 73.4015 Section 73.4015 Telecommunication FEDERAL COMMUNICATIONS COMMISSION....4015 Applications for AM and FM construction permits, incomplete or defective. See Public Notice, FCC...

47 CFR 73.4015 - Applications for AM and FM construction permits, incomplete or defective.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 47 Telecommunication 4 2011-10-01 2011-10-01 false Applications for AM and FM construction permits, incomplete or defective. 73.4015 Section 73.4015 Telecommunication FEDERAL COMMUNICATIONS COMMISSION....4015 Applications for AM and FM construction permits, incomplete or defective. See Public Notice, FCC...

19 CFR 146.35 - Temporary deposit in a zone; incomplete documentation.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 19 Customs Duties 2 2010-04-01 2010-04-01 false Temporary deposit in a zone; incomplete... SECURITY; DEPARTMENT OF THE TREASURY (CONTINUED) FOREIGN TRADE ZONES Admission of Merchandise to a Zone § 146.35 Temporary deposit in a zone; incomplete documentation. (a) General. Temporary deposit of...

Estimating inbreeding rates in natural populations: addressing the problem of incomplete pedigrees

Treesearch

Mark P. Miller; Susan M. Haig; Jonathan D. Ballou; Ashley Steel

2017-01-01

Understanding and estimating inbreeding is essential for managing threatened and endangered wildlife populations. However, determination of inbreeding rates in natural populations is confounded by incomplete parentage information. We present an approach for quantifying inbreeding rates for populations with incomplete parentage information. The approach exploits...

19 CFR 146.35 - Temporary deposit in a zone; incomplete documentation.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 19 Customs Duties 2 2013-04-01 2013-04-01 false Temporary deposit in a zone; incomplete... SECURITY; DEPARTMENT OF THE TREASURY (CONTINUED) FOREIGN TRADE ZONES Admission of Merchandise to a Zone § 146.35 Temporary deposit in a zone; incomplete documentation. (a) General. Temporary deposit of...

19 CFR 146.35 - Temporary deposit in a zone; incomplete documentation.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 19 Customs Duties 2 2012-04-01 2012-04-01 false Temporary deposit in a zone; incomplete... SECURITY; DEPARTMENT OF THE TREASURY (CONTINUED) FOREIGN TRADE ZONES Admission of Merchandise to a Zone § 146.35 Temporary deposit in a zone; incomplete documentation. (a) General. Temporary deposit of...

19 CFR 146.35 - Temporary deposit in a zone; incomplete documentation.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 19 Customs Duties 2 2014-04-01 2014-04-01 false Temporary deposit in a zone; incomplete... SECURITY; DEPARTMENT OF THE TREASURY (CONTINUED) FOREIGN TRADE ZONES Admission of Merchandise to a Zone § 146.35 Temporary deposit in a zone; incomplete documentation. (a) General. Temporary deposit of...

19 CFR 146.35 - Temporary deposit in a zone; incomplete documentation.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 19 Customs Duties 2 2011-04-01 2011-04-01 false Temporary deposit in a zone; incomplete... SECURITY; DEPARTMENT OF THE TREASURY (CONTINUED) FOREIGN TRADE ZONES Admission of Merchandise to a Zone § 146.35 Temporary deposit in a zone; incomplete documentation. (a) General. Temporary deposit of...

40 CFR 86.085-20 - Incomplete vehicles, classification.

Code of Federal Regulations, 2010 CFR

2010-07-01

..., classification. (a) An incomplete truck less than 8,500 pounds gross vehicle weight rating shall be classified by... 40 Protection of Environment 18 2010-07-01 2010-07-01 false Incomplete vehicles, classification... PROGRAMS (CONTINUED) CONTROL OF EMISSIONS FROM NEW AND IN-USE HIGHWAY VEHICLES AND ENGINES General...

An incomplete assembly with thresholding algorithm for systems of reaction-diffusion equations in three space dimensions IAT for reaction-diffusion systems

NASA Astrophysics Data System (ADS)

Moore, Peter K.

2003-07-01

Solving systems of reaction-diffusion equations in three space dimensions can be prohibitively expensive both in terms of storage and CPU time. Herein, I present a new incomplete assembly procedure that is designed to reduce storage requirements. Incomplete assembly is analogous to incomplete factorization in that only a fixed number of nonzero entries are stored per row and a drop tolerance is used to discard small values. The algorithm is incorporated in a finite element method-of-lines code and tested on a set of reaction-diffusion systems. The effect of incomplete assembly on CPU time and storage and on the performance of the temporal integrator DASPK, algebraic solver GMRES and preconditioner ILUT is studied.

Mapping and genomic targeting of the major leaf shape gene (L) in Upland cotton (Gossypium hirsutum L.).

PubMed

Andres, Ryan J; Bowman, Daryl T; Kaur, Baljinder; Kuraparthy, Vasu

2014-01-01

A major leaf shape locus (L) was mapped with molecular markers and genomically targeted to a small region in the D-genome of cotton. By using expression analysis and candidate gene mapping, two LMI1 -like genes are identified as possible candidates for leaf shape trait in cotton. Leaf shape in cotton is an important trait that influences yield, flowering rates, disease resistance, lint trash, and the efficacy of foliar chemical application. The leaves of okra leaf cotton display a significantly enhanced lobing pattern, as well as ectopic outgrowths along the lobe margins when compared with normal leaf cotton. These phenotypes are the hallmark characteristics of mutations in various known modifiers of leaf shape that culminate in the mis/over-expression of Class I KNOX genes. To better understand the molecular and genetic processes underlying leaf shape in cotton, a normal leaf accession (PI607650) was crossed to an okra leaf breeding line (NC05AZ21). An F2 population of 236 individuals confirmed the incompletely dominant single gene nature of the okra leaf shape trait in Gossypium hirsutum L. Molecular mapping with simple sequence repeat markers localized the leaf shape gene to 5.4 cM interval in the distal region of the short arm of chromosome 15. Orthologous mapping of the closely linked markers with the sequenced diploid D-genome (Gossypium raimondii) tentatively resolved the leaf shape locus to a small genomic region. RT-PCR-based expression analysis and candidate gene mapping indicated that the okra leaf shape gene (L (o) ) in cotton might be an upstream regulator of Class I KNOX genes. The linked molecular markers and delineated genomic region in the sequenced diploid D-genome will assist in the future high-resolution mapping and map-based cloning of the leaf shape gene in cotton.

Characterization of the genome and transcriptome of the blue tit Cyanistes caeruleus: polymorphisms, sex-biased expression and selection signals.

PubMed

Mueller, Jakob C; Kuhl, Heiner; Timmermann, Bernd; Kempenaers, Bart

2016-03-01

Decoding genomic sequences and determining their variation within populations has potential to reveal adaptive processes and unravel the genetic basis of ecologically relevant trait variation within a species. The blue tit Cyanistes caeruleus--a long-time ecological model species--has been used to investigate fitness consequences of variation in mating and reproductive behaviour. However, very little is known about the underlying genetic changes due to natural and sexual selection in the genome of this songbird. As a step to bridge this gap, we assembled the first draft genome of a single blue tit, mapped the transcriptome of five females and five males to this reference, identified genomewide variants and performed sex-differential expression analysis in the gonads, brain and other tissues. In the gonads, we found a high number of sex-biased genes, and of those, a similar proportion were sex-limited (genes only expressed in one sex) in males and females. However, in the brain, the proportion of female-limited genes within the female-biased gene category (82%) was substantially higher than the proportion of male-limited genes within the male-biased category (6%). This suggests a predominant on-off switching mechanism for the female-limited genes. In addition, most male-biased genes were located on the Z-chromosome, indicating incomplete dosage compensation for the male-biased genes. We called more than 500,000 SNPs from the RNA-seq data. Heterozygote detection in the single reference individual was highly congruent between DNA-seq and RNA-seq calling. Using information from these polymorphisms, we identified potential selection signals in the genome. We list candidate genes which can be used for further sequencing and detailed selection studies, including genes potentially related to meiotic drive evolution. A public genome browser of the blue tit with the described information is available at http://public-genomes-ngs.molgen.mpg.de. © 2015 John Wiley & Sons Ltd.

Pharmacological inhibition of DNA methylation attenuates pressure overload-induced cardiac hypertrophy in rats.

PubMed

Stenzig, Justus; Schneeberger, Yvonne; Löser, Alexandra; Peters, Barbara S; Schaefer, Andreas; Zhao, Rong-Rong; Ng, Shi Ling; Höppner, Grit; Geertz, Birgit; Hirt, Marc N; Tan, Wilson; Wong, Eleanor; Reichenspurner, Hermann; Foo, Roger S-Y; Eschenhagen, Thomas

2018-07-01

Heart failure is associated with altered gene expression and DNA methylation. De novo DNA methylation is associated with gene silencing, but its role in cardiac pathology remains incompletely understood. We hypothesized that inhibition of DNA methyltransferases (DNMT) might prevent the deregulation of gene expression and the deterioration of cardiac function under pressure overload (PO). To test this hypothesis, we evaluated a DNMT inhibitor in PO in rats and analysed DNA methylation in cardiomyocytes. Young male Wistar rats were subjected to PO by transverse aortic constriction (TAC) or to sham surgery. Rats from both groups received solvent or 12.5 mg/kg body weight of the non-nucleosidic DNMT inhibitor RG108, initiated on the day of the intervention. After 4 weeks, we analysed cardiac function by MRI, fibrosis with Sirius Red staining, gene expression by RNA sequencing and qPCR, and DNA methylation by reduced representation bisulphite sequencing (RRBS). RG108 attenuated the ~70% increase in heart weight/body weight ratio of TAC over sham to 47% over sham, partially rescued reduced contractility, diminished the fibrotic response and the downregulation of a set of genes including Atp2a2 (SERCA2a) and Adrb1 (beta1-adrenoceptor). RG108 was associated with significantly lower global DNA methylation in cardiomyocytes by ~2%. The differentially methylated pathways were "cardiac hypertrophy", "cell death" and "xenobiotic metabolism signalling". Among these, "cardiac hypertrophy" was associated with significant methylation differences in the group comparison sham vs. TAC, but not significant between sham+RG108 and TAC+RG108 treatment, suggesting that RG108 partially prevented differential methylation. However, when comparing TAC and TAC+RG108, the pathway cardiac hypertrophy was not significantly differentially methylated. DNMT inhibitor treatment is associated with attenuation of cardiac hypertrophy and moderate changes in cardiomyocyte DNA methylation. The potential mechanistic link between these two effects and the role of non-myocytes need further clarification. Copyright © 2018 Elsevier Ltd. All rights reserved.

Genetic and functional analyses demonstrate a role for abnormal glycinergic signaling in autism.

PubMed

Pilorge, M; Fassier, C; Le Corronc, H; Potey, A; Bai, J; De Gois, S; Delaby, E; Assouline, B; Guinchat, V; Devillard, F; Delorme, R; Nygren, G; Råstam, M; Meier, J C; Otani, S; Cheval, H; James, V M; Topf, M; Dear, T N; Gillberg, C; Leboyer, M; Giros, B; Gautron, S; Hazan, J; Harvey, R J; Legendre, P; Betancur, C

2016-07-01

Autism spectrum disorder (ASD) is a common neurodevelopmental condition characterized by marked genetic heterogeneity. Recent studies of rare structural and sequence variants have identified hundreds of loci involved in ASD, but our knowledge of the overall genetic architecture and the underlying pathophysiological mechanisms remains incomplete. Glycine receptors (GlyRs) are ligand-gated chloride channels that mediate inhibitory neurotransmission in the adult nervous system but exert an excitatory action in immature neurons. GlyRs containing the α2 subunit are highly expressed in the embryonic brain, where they promote cortical interneuron migration and the generation of excitatory projection neurons. We previously identified a rare microdeletion of the X-linked gene GLRA2, encoding the GlyR α2 subunit, in a boy with autism. The microdeletion removes the terminal exons of the gene (GLRA2(Δex8-9)). Here, we sequenced 400 males with ASD and identified one de novo missense mutation, p.R153Q, absent from controls. In vitro functional analysis demonstrated that the GLRA2(Δex8)(-)(9) protein failed to localize to the cell membrane, while the R153Q mutation impaired surface expression and markedly reduced sensitivity to glycine. Very recently, an additional de novo missense mutation (p.N136S) was reported in a boy with ASD, and we show that this mutation also reduced cell-surface expression and glycine sensitivity. Targeted glra2 knockdown in zebrafish induced severe axon-branching defects, rescued by injection of wild type but not GLRA2(Δex8-9) or R153Q transcripts, providing further evidence for their loss-of-function effect. Glra2 knockout mice exhibited deficits in object recognition memory and impaired long-term potentiation in the prefrontal cortex. Taken together, these results implicate GLRA2 in non-syndromic ASD, unveil a novel role for GLRA2 in synaptic plasticity and learning and memory, and link altered glycinergic signaling to social and cognitive impairments.