Hematopoietic cell transplantation in Fanconi anemia: current evidence, challenges and recommendations.

PubMed

Ebens, Christen L; MacMillan, Margaret L; Wagner, John E

2017-01-01

Hematopoietic cell transplantation for Fanconi Anemia (FA) has improved dramatically over the past 40 years. With an enhanced understanding of the intrinsic DNA-repair defect and pathophysiology of hematopoietic failure and leukemogenesis, sequential changes to conditioning and graft engineering have significantly improved the expectation of survival after allogeneic hematopoietic cell transplantation (alloHCT) with incidence of graft failure decreased from 35% to <10% and acute graft-versus-host disease (GVHD) from >40% to <10%. Today, five-year overall survival exceeds 90% in younger FA patients with bone marrow failure but remains about 50% in those with hematologic malignancy. Areas covered: We review the evolution of alloHCT contributing to decreased rates of transplant related complications; highlight current challenges including poorer outcomes in cases of clonal hematologic disorders, alloHCT impact on endocrine function and intrinsic FA risk of epithelial malignancies; and describe investigational therapies for prevention and treatment of the hematologic manifestations of FA. Expert commentary: Current methods allow for excellent survival following alloHCT for FA associated BMF irrespective of donor hematopoietic cell source. Alternative curative approaches, such as gene therapy, are being explored to eliminate the risks of GVHD and minimize therapy-related adverse effects.

Evidence for complete epistasis of null mutations in murine Fanconi anemia genes Fanca and Fancg.

PubMed

van de Vrugt, Henri J; Koomen, Mireille; Bakker, Sietske; Berns, Mariska A D; Cheng, Ngan Ching; van der Valk, Martin A; de Vries, Yne; Rooimans, Martin A; Oostra, Anneke B; Hoatlin, Maureen E; Te Riele, Hein; Joenje, Hans; Arwert, Fré

2011-12-10

Fanconi anemia (FA) is a heritable disease characterized by bone marrow failure, congenital abnormalities, and cancer predisposition. The 15 identified FA genes operate in a molecular pathway to preserve genomic integrity. Within this pathway the FA core complex operates as an ubiquitin ligase that activates the complex of FANCD2 and FANCI to coordinate DNA repair. The FA core complex is formed by at least 12 proteins. However, only the FANCL subunit displays ubiquitin ligase activity. FANCA and FANCG are members of the FA core complex for which no other functions have been described than to participate in protein interactions. In this study we generated mice with combined null alleles for Fanca and Fancg to identify extended functions for these genes by characterizing the double mutant mice and cells. Double mutant a(-/-)/g(-/-) mice were born at near Mendelian frequencies without apparent developmental abnormalities. Histological analysis of a(-/-)/g(-/-) mice revealed a Leydig cell hyperplasia and frequent vacuolization of Sertoli cells in testes, while ovaries were depleted from developing follicles and displayed an interstitial cell hyperplasia. These gonadal aberrations were associated with a compromised fertility of a(-/-)/g(-/-) males and females. During the first year of life a(-/-)/g(-/-) did not develop malignancies or bone marrow failure. At the cellular level a(-/-)/g(-/-), Fanca(-/-), and Fancg(-/-) cells proved equally compromised in DNA crosslink and homology-directed repair. Overall the phenotype of a(-/-)/g(-/-) double knockout mice and cells appeared highly similar to the phenotype of Fanca or Fancg single knockouts. The lack of an augmented phenotype suggest that null mutations in Fanca or Fancg are fully epistatic, making additional important functions outside of the FA core complex highly unlikely. 2011 Elsevier B.V. All rights reserved.

Fanconi anemia founder mutation in Macedonian patients.

PubMed

Madjunkova, Svetlana; Kocheva, Svetlana A; Plaseska-Karanfilska, Dijana

2014-01-01

Fanconi anemia (FA) is a rare autosomal recessive disorder clinically characterized by developmental abnormalities, progressive bone marrow failure (BMF) and profound cancer predisposition. Approximately 65% of all affected individuals have mutation in the FANCA (Fanconi anemia complementation group A) gene. The mutation spectrum of the FANCA gene is highly heterogeneous. FA-A is usually associated with private FANCA mutations in individual families. We describe 3 unrelated patients with FA with a similar clinical presentation: BMF, renal anomalies and café-au-lait pigmentation without major skeletal abnormality. The molecular analysis of the FANCA gene using the FA MLPA kit P031-A2/P032 FANCA, showed homozygous deletion of exon 3 in all 3 patients. Molecular analysis of the flanking regions of exon 3 precisely defined unique deletion of 2,040 bp and duplication of C (1788_3828dupC). These are the first 3 patients homozygous for deletion of FANCA exon 3 described to date. Although not related, the patients originated from the same Gypsy-like ethnic population. We conclude that c.190-256_283 + 1680del2040 dupC mutation in the FANCA gene is a founder mutation in Macedonian FA patients of Gypsy-like ethnic origin. Our finding has very strong implications for these patients in formulating diagnostic and carrier-screening strategy for BMF and FA and to enable comprehensive genetic counseling. © 2013 S. Karger AG, Basel.

Rescue of replication failure by Fanconi anaemia proteins.

PubMed

Constantinou, Angelos

2012-02-01

Chromosomal aberrations are often associated with incomplete genome duplication, for instance at common fragile sites, or as a consequence of chemical alterations in the DNA template that block replication forks. Studies of the cancer-prone disease Fanconi anaemia (FA) have provided important insights into the resolution of replication problems. The repair of interstrand DNA crosslinks induced by chemotherapy drugs is coupled with DNA replication and controlled by FA proteins. We discuss here the recent discovery of new FA-associated proteins and the development of new tractable repair systems that have dramatically improved our understanding of crosslink repair. We focus also on how FA proteins protect against replication failure in the context of fragile sites and on the identification of reactive metabolites that account for the development of Fanconi anaemia symptoms.

Second allogeneic hematopoietic cell transplantation for Patients with Fanconi anemia and Bone Marrow Failure

PubMed Central

Ayas, Mouhab; Eapen, Mary; Le-Rademacher, Jennifer; Carreras, Jeanette; Abdel-Azim, Hisham; Alter, Blanche P.; Anderlini, Paolo; Battiwalla, Minoo; Bierings, Marc; Buchbinder, David K.; Bonfim, Carmem; Camitta, Bruce M.; Fasth, Anders L.; Gale, Robert Peter; Lee, Michelle A.; Lund, Troy C.; Myers, Kasiani C.; Olsson, Richard F.; Page, Kristin M.; Prestidge, Tim D.; Radhi, Mohamed; Shah, Ami J.; Schultz, Kirk R.; Wirk, Baldeep; Wagner, John E.; Deeg, H. Joachim

2015-01-01

Second allogeneic hematopoietic cell transplantation (HCT) is the only salvage option for those for develop graft failure after their first HCT. Data on outcomes after second HCT in Fanconi anemia (FA) are scarce. We report outcomes after second allogeneic HCT for FA (n=81). The indication for second HCT was graft failure after the first HCT. Transplants occurred between 1990 and 2012. The timing of second transplantation predicted subsequent graft failure and survival. Graft failure was high when the second transplant occurred less than 3 months from the first. The 3-month probability of graft failure was 69% when the interval between first and second transplant was less than 3 months compared to 23% when the interval was longer (p<0.001). Consequently, survival rates were substantially lower when the interval between first and second transplant was less than 3 months, 23% at 1-year compared to 58%, when the interval was longer (p=0.001). The corresponding 5-year probabilities of survival were 16% and 45%, respectively (p=0.006). Taken together, these data suggest that fewer than half of FA patients undergoing a second HCT for graft failure are long-term survivors. There is an urgent need to develop strategies to lower graft failure after first HCT. PMID:26116087

Identification of novel target genes involved in Indian Fanconi anemia patients using microarray.

PubMed

Shyamsunder, Pavithra; Ganesh, Kripa S; Vidyasekar, Prasanna; Mohan, Sheila; Verma, Rama Shanker

2013-12-01

Fanconi anemia (FA) is a genetic disorder characterized by progressive bone marrow failure and a predisposition to cancers. Mutations have been documented in 15 FA genes that participate in the FA-BRCA DNA repair pathway, a fundamental pathway in the development of the disease and the presentation of its characteristic symptoms. Certain symptoms such as oxygen sensitivity, hematological abnormalities and impaired immunity suggest that FA proteins could participate in or independently control other pathways as well. In this study, we identified 9 DNA repair genes that were down regulated in a genome wide analysis of 6 Indian Fanconi anemia patients. Functional clustering of a total of 233 dysregulated genes identified key biological processes that included regulation of transcription, DNA repair, cell cycle and chromosomal organization. Microarray data revealed the down regulation of ATXN3, ARID4A and ETS-1, which were validated by RTPCR in a subsequent sample set of 9 Indian FA patients. Here we report for the first time a gene expression profile of Fanconi anemia patients from the Indian population and a pool of genes that might aid in the acquisition and progression of the FA phenotype. © 2013 Elsevier B.V. All rights reserved.

Fanconi anemia.

PubMed

Soulier, Jean

2011-01-01

Fanconi anemia (FA) is the most frequent inherited cause of BM failure (BMF). Fifteen FANC genes have been identified to date, the most prevalent being FANCA, FANCC, FANCG, and FANCD2. In addition to classical presentations with progressive BMF during childhood and a positive chromosome breakage test in the blood, atypical clinical and/or biological situations can be seen in which a FA diagnosis has to be confirmed or eliminated. For this, a range of biological tools have been developed, including analysis of skin fibroblasts. FA patients experience a strong selective pressure in the BM that predisposes to clonal evolution and to the emergence in their teens or young adulthood of myelodysplasia syndrome (MDS) and/or acute myeloid leukemia (AML) with a specific pattern of somatic chromosomal lesions. The cellular mechanisms underlying (1) the hematopoietic defect which leads to progressive BMF and (2) somatic clonal evolutions in this background, are still largely elusive. Elucidation of these mechanisms at the molecular and cellular levels should be useful to understand the physiopathology of the disease and to adapt the follow-up and treatment of FA patients. This may also ultimately benefit older, non-FA patients with aplastic anemia, MDS/AML for whom FA represents a model genetic condition.

Repeated Induction of Inattentional Blindness in a Simulated Aviation Environment

NASA Technical Reports Server (NTRS)

Kennedy, Kellie D.; Stephens, Chad L.; Williams, Ralph A.; Schutte, Paul C.

2017-01-01

The study reported herein is a subset of a larger investigation on the role of automation in the context of the flight deck and used a fixed-based, human-in-the-loop simulator. This paper explored the relationship between automation and inattentional blindness (IB) occurrences in a repeated induction paradigm using two types of runway incursions. The critical stimuli for both runway incursions were directly relevant to primary task performance. Sixty non-pilot participants performed the final five minutes of a landing scenario twice in one of three automation conditions: full automation (FA), partial automation (PA), and no automation (NA). The first induction resulted in a 70 percent (42 of 60) detection failure rate with those in the PA condition significantly more likely to detect the incursion compared to the FA condition or the NA condition. The second induction yielded a 50 percent detection failure rate. Although detection improved (detection failure rates declined) in all conditions, those in the FA condition demonstrated the greatest improvement with doubled detection rates. The detection behavior in the first trial did not preclude a failed detection in the second induction. Group membership (IB vs. Detection) in the FA condition showed a greater improvement than those in the NA condition and rated the Mental Demand and Effort subscales of the NASA-TLX (NASA Task Load Index) significantly higher for Time 2 compared Time 1. Participants in the FA condition used the experience of IB exposure to improve task performance whereas those in the NA condition did not, indicating the availability and reallocation of attentional resources in the FA condition. These findings support the role of engagement in operational attention detriment and the consideration of attentional failure causation to determine appropriate mitigation strategies.

AluY-mediated germline deletion, duplication and somatic stem cell reversion in UBE2T defines a new subtype of Fanconi anemia.

PubMed

Virts, Elizabeth L; Jankowska, Anna; Mackay, Craig; Glaas, Marcel F; Wiek, Constanze; Kelich, Stephanie L; Lottmann, Nadine; Kennedy, Felicia M; Marchal, Christophe; Lehnert, Erik; Scharf, Rüdiger E; Dufour, Carlo; Lanciotti, Marina; Farruggia, Piero; Santoro, Alessandra; Savasan, Süreyya; Scheckenbach, Kathrin; Schipper, Jörg; Wagenmann, Martin; Lewis, Todd; Leffak, Michael; Farlow, Janice L; Foroud, Tatiana M; Honisch, Ellen; Niederacher, Dieter; Chakraborty, Sujata C; Vance, Gail H; Pruss, Dmitry; Timms, Kirsten M; Lanchbury, Jerry S; Alpi, Arno F; Hanenberg, Helmut

2015-09-15

Fanconi anemia (FA) is a rare inherited disorder clinically characterized by congenital malformations, progressive bone marrow failure and cancer susceptibility. At the cellular level, FA is associated with hypersensitivity to DNA-crosslinking genotoxins. Eight of 17 known FA genes assemble the FA E3 ligase complex, which catalyzes monoubiquitination of FANCD2 and is essential for replicative DNA crosslink repair. Here, we identify the first FA patient with biallelic germline mutations in the ubiquitin E2 conjugase UBE2T. Both mutations were aluY-mediated: a paternal deletion and maternal duplication of exons 2-6. These loss-of-function mutations in UBE2T induced a cellular phenotype similar to biallelic defects in early FA genes with the absence of FANCD2 monoubiquitination. The maternal duplication produced a mutant mRNA that could encode a functional protein but was degraded by nonsense-mediated mRNA decay. In the patient's hematopoietic stem cells, the maternal allele with the duplication of exons 2-6 spontaneously reverted to a wild-type allele by monoallelic recombination at the duplicated aluY repeat, thereby preventing bone marrow failure. Analysis of germline DNA of 814 normal individuals and 850 breast cancer patients for deletion or duplication of UBE2T exons 2-6 identified the deletion in only two controls, suggesting aluY-mediated recombinations within the UBE2T locus are rare and not associated with an increased breast cancer risk. Finally, a loss-of-function germline mutation in UBE2T was detected in a high-risk breast cancer patient with wild-type BRCA1/2. Cumulatively, we identified UBE2T as a bona fide FA gene (FANCT) that also may be a rare cancer susceptibility gene. © The Author 2015. Published by Oxford University Press.

A novel Fanconi anaemia subtype associated with a dominant-negative mutation in RAD51

PubMed Central

Ameziane, Najim; May, Patrick; Haitjema, Anneke; van de Vrugt, Henri J.; van Rossum-Fikkert, Sari E.; Ristic, Dejan; Williams, Gareth J.; Balk, Jesper; Rockx, Davy; Li, Hong; Rooimans, Martin A.; Oostra, Anneke B.; Velleuer, Eunike; Dietrich, Ralf; Bleijerveld, Onno B.; Maarten Altelaar, A. F.; Meijers-Heijboer, Hanne; Joenje, Hans; Glusman, Gustavo; Roach, Jared; Hood, Leroy; Galas, David; Wyman, Claire; Balling, Rudi; den Dunnen, Johan; de Winter, Johan P.; Kanaar, Roland; Gelinas, Richard; Dorsman, Josephine C.

2015-01-01

Fanconi anaemia (FA) is a hereditary disease featuring hypersensitivity to DNA cross-linker-induced chromosomal instability in association with developmental abnormalities, bone marrow failure and a strong predisposition to cancer. A total of 17 FA disease genes have been reported, all of which act in a recessive mode of inheritance. Here we report on a de novo g.41022153G>A; p.Ala293Thr (NM_002875) missense mutation in one allele of the homologous recombination DNA repair gene RAD51 in an FA-like patient. This heterozygous mutation causes a novel FA subtype, ‘FA-R', which appears to be the first subtype of FA caused by a dominant-negative mutation. The patient, who features microcephaly and mental retardation, has reached adulthood without the typical bone marrow failure and paediatric cancers. Together with the recent reports on RAD51-associated congenital mirror movement disorders, our results point to an important role for RAD51-mediated homologous recombination in neurodevelopment, in addition to DNA repair and cancer susceptibility. PMID:26681308

The concept and practice of Fanconi Anemia: from the clinical bedside to the laboratory bench

PubMed Central

2013-01-01

Fanconi Anemia (FA) is characterised with multiple gene mutations, multiple types of genetic abnormalities, multiple organ involvements and multiple types of cancer risks. It is a life threatening disease commonly at 5 years old children. Research on FA is one of the fastest areas in medical research field. The identification of 15 different FA genes and the elucidation of the FA molecular pathways have translated into the understanding of the pathogenic mechanism and practically provided the directions for therapies. Studies on FA rendered invaluable information for the studies on cancers because FA possesses the unique features in many different biological aspects. Studies revealed the genetic linking between FA and cancers that FA genes are in cancers and cancers genes are in FA. As a result, FA is named as a paradigmatic disease for the understanding of cancer and aging. In clinical practice, an early and accurate diagnosis of FA before the stage of bone marrow failure, cancer/leukemia is crucial for the adequate treatment, the prevention of serious medical complications and also for the properly management in the other caring areas including paediatric, hematology, immunology, endocrinology, reproductive/IVF, obstetrics and surgery. However, an early and accurate diagnosis for FA is often difficult because FA is genetically and phenotypically heterogeneous disease. Diagnosis in more or less cases can be delayed until bone marrow failure or cancer/leukemia occurs. As a result that delayed or misdiagnosis even wrong treatment received for patients with FA are not uncommon events clinically in some regions or countries due to the lack of recognition of FA from the clinicians and the limitation in testing resource in laboratory. In this review, the new concept, brief clinical characteristics, research advancing, diagnostic guidelines/differential diagnosis, laboratory testing issues and strategies on FA are discussed. PMID:26835301

Deletion of Fanca or Fancd2 dysregulates Treg in mice

PubMed Central

Du, Wei; Erden, Ozlem; Wilson, Andrew; Sipple, Jared M.; Schick, Jonathan; Mehta, Parinda; Myers, Kasiani C.; Steinbrecher, Kris A.; Davies, Stella M.

2014-01-01

Fanconi anemia (FA) is a genetic disorder associated with bone marrow (BM) failure and leukemia. Recent studies demonstrate variable immune defects in FA. However, the cause for FA immunodeficiency is unknown. Here we report that deletion of Fanca or Fancd2 dysregulates the suppressive activity of regulatory T cells (Tregs), shown functionally as exacerbation of graft-vs-host disease (GVHD) in mice. Recipient mice of Fanca−/− or Fancd2−/− BM chimeras exhibited severe acute GVHD after allogeneic BM transplantation (BMT). T cells from Fanca−/− or Fancd2−/− mice induced higher GVHD lethality than those from wild-type (WT) littermates. FA Tregs possessed lower proliferative suppression potential compared with WT Tregs, as demonstrated by in vitro proliferation assay and BMT. Analysis of CD25+Foxp3+ Tregs indicated that loss of Fanca or Fancd2 dysregulated Foxp3 target gene expression. Additionally, CD25+Foxp3+ Tregs of Fanca−/− or Fancd2−/− mice were less efficient in suppressing the production of GVHD-associated inflammatory cytokines. Consistently, aberrant NF-κB activity was observed in infiltrated T cells from FA GVHD mice. Conditional deletion of p65 in FA Tregs decreased GVHD mortality. Our study uncovers an essential role for FA proteins in maintaining Treg homeostasis, possibly explaining, at least in part, the immune deficiency reported in some FA patients. PMID:24501220

Phenotypic variability in patients with Fanconi anemia and biallelic FANCF mutations.

PubMed

Tryon, Rebecca; Zierhut, Heather; MacMillan, Margaret L; Wagner, John E

2017-01-01

Fanconi anemia is a heterogeneous genetic disorder that is characterized by progressive bone marrow failure, congenital anomalies, and markedly increased risk for malignancies. Mutations in the FANCF (FA-F) gene represent approximately 2% of affected patients. Currently, information on the phenotypic findings of patients with Fanconi anemia from biallelic mutations in FANCF is limited. Here, we report three patients who illustrate the clinical variability within the FA-F group. This analysis suggests a more severe phenotype for those with the common c.484_485delCT mutation. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

A never-ending story: the steadily growing family of the FA and FA-like genes

PubMed Central

Gueiderikh, Anna; Rosselli, Filippo; Neto, Januario B.C.

2017-01-01

Abstract Among the chromosome fragility-associated human syndromes that present cancer predisposition, Fanconi anemia (FA) is unique due to its large genetic heterogeneity. To date, mutations in 21 genes have been associated with an FA or an FA-like clinical and cellular phenotype, whose hallmarks are bone marrow failure, predisposition to acute myeloid leukemia and a cellular and chromosomal hypersensitivity to DNA crosslinking agents exposure. The goal of this review is to trace the history of the identification of FA genes, a history that started in the eighties and is not yet over, as indicated by the cloning of a twenty-first FA gene in 2016. PMID:28558075

Impaired immune function in children and adults with Fanconi anemia.

PubMed

Myers, Kasiani C; Sauter, Sharon; Zhang, Xue; Bleesing, Jacob J; Davies, Stella M; Wells, Susanne I; Mehta, Parinda A; Kumar, Ashish; Marmer, Daniel; Marsh, Rebecca; Brown, Darron; Butsch Kovacic, Melinda

2017-11-01

Fanconi anemia (FA) is a rare genetic disorder characterized by genome instability, bone marrow failure, and cancer predisposition. Previously, small studies have reported heterogeneous immune dysfunction in FA. We performed a detailed immunologic assessment in a large FA cohort who have not undergone bone marrow transplantation or developed malignancies. Comprehensive quantitative and functional immunologic assessment of 29 FA individuals was compared to healthy age-matched controls. Compared to non-FA persons of similar ages, FA individuals showed lower absolute total B cells (P < 0.001), lower memory B cells (P < 0.001), and decreased IgM (P < 0.001) but normal IgG. NK cells (P < 0.001) and NK cytotoxicity (P < 0.001) were decreased. CD4 + T cells were decreased (P = 0.022), while CD8 + T cell and absolute T-cell numbers were comparable. Cytotoxic T cells (P < 0.003), and antigen proliferation response to tetanus (P = 0.019) and candida (P = 0.019), were diminished in FA. Phytohemagglutinin responses and plasma cytokines were normal. Within FA subjects, adults and older children (≥10 years) exhibited higher CD8 + T cells than younger children (P = 0.004). Documented atypical infections were infrequent, although oral human papilloma virus (HPV) prevalence was higher (31% positive) in FA. Overall, these results demonstrate a high rate of significant humoral and cellular immune dysfunction. Continued longitudinal study of immune function is critical to understand evolution with age, bone marrow failure, and cancer development. © 2017 Wiley Periodicals, Inc.

Disrupted Signaling through the Fanconi Anemia Pathway Leads to Dysfunctional Hematopoietic Stem Cell Biology: Underlying Mechanisms and Potential Therapeutic Strategies

PubMed Central

Geiselhart, Anja; Lier, Amelie; Walter, Dagmar; Milsom, Michael D.

2012-01-01

Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome. FA patients suffer to varying degrees from a heterogeneous range of developmental defects and, in addition, have an increased likelihood of developing cancer. Almost all FA patients develop a severe, progressive bone marrow failure syndrome, which impacts upon the production of all hematopoietic lineages and, hence, is thought to be driven by a defect at the level of the hematopoietic stem cell (HSC). This hypothesis would also correlate with the very high incidence of MDS and AML that is observed in FA patients. In this paper, we discuss the evidence that supports the role of dysfunctional HSC biology in driving the etiology of the disease. Furthermore, we consider the different model systems currently available to study the biology of cells defective in the FA signaling pathway and how they are informative in terms of identifying the physiologic mediators of HSC depletion and dissecting their putative mechanism of action. Finally, we ask whether the insights gained using such disease models can be translated into potential novel therapeutic strategies for the treatment of the hematologic disorders in FA patients. PMID:22675615

[Molecular diagnosis and hematopoietic stem cell transplantation in 17 children with inherited bone marrow failure syndrome].

PubMed

Li, Qian; Li, Benshang; Luo, Changying; Wang, Jianmin; Luo, Chengjuan; Ding, Lixia; Chen, Jing

2015-11-01

To enrich our national database with data of rare diseases by analyzing molecular diagnosis and hematopoietic stem cell transplantation (HSCT) in children with inherited bone marrow failure syndromes (IBMFS). Next-generation sequencing (NGS)-based genetic diagnosis panel was applied for the clinical diagnosis and management of IBMFS. Retrospective analysis was performed on clinical and genetic data of 17 consecutive children who received HSCT over a long time interval (November. 2005-June 2015). Three patients were diagnosed only by clinical manifestation before 2012. After that NGS-based genetic diagnosis panel was used to identify IBMFS-related genes in 12/14.IBMFS patients (except two Diamond-Blackfan anemia (DBA) patients). Two Fanconi anemia (FA) patients were confirmed to be new variations through family-genotype-analysis and 3 families accepted prenatal diagnosis to avoid birth of affected fetuses. Seventeen IBMFS patients (10 FA,5 DBA and 2 dyskeratosis congenital (DKC)) were treated with HSCT from matched sibling donors (n=2), matched unrelated donors (n=8) or mismatched unrelated donors (n=7). The source of stem cells for transplantation included peripheral blood (n=12) and cord blood (n=5). With regard to the conditioning regimens, FA and DKC patients received fludarabine-based reduced intensity conditioning, while DBA patients received classical busulfan-based myeloablative conditioning. Median age at the time of HSCT was 36 months (7-156 months). The number of infused mononuclear cells and CD34⁺ cells was (10.6 ± 6.7) × 10⁸ and (5.9 ± 7.0) × 10⁶ per kilogram of recipient body weight, respectively. The median number of days to neutrophil recovery was 13 days after HSCT (range: 10-19 days). Platelet recovery was faster in the PBSCT group than in the CBT group ((16.3 ± 6.0) days vs. (30.0 ± 17.1) days,t=-2.487,P=0.026). During a median follow-up of 17 months (range: 2-114 months), except one FA patient who was transplanted with HLA-matched unrelated cord blood (CB) died from pneumonia and heart failure because of engraftment failure, other 16 children are alive after the successful HSCT. The failure-free survival rate of the patients three years after HSCT was 94%. NGS-based molecular diagnosis technology and effective HSCT have significantly facilitated the treatment of children with IBMFS in our country, and our national database about this rare disease is to be further exploited.

[Molecular basis of Fanconi's anemia].

PubMed

Digweed, M

1999-01-01

Fanconi anaemia (FA) is an autosomal recessive genetic disorder characterised clinically by progressive bone marrow failure, skeletal deformities and a predisposition to neoplasia. Patient cells manifest an extreme chromosomal instability and hypersensitivity to polyfunctional alkylating agents. It is assumed that the basic defect is related to the repair of DNA damage, in particular that of so-called DNA crosslinks. Currently there are eight complementation groups in FA (FA-A-FA-H) which indicates that at least eight independent genes can lead to FA. Three of these genes have been identified: FANCA, FANCC and FANCG. In this review, the molecular biology and genetics of FA are presented and possible functions of the FANC proteins are discussed.

Fanconi anemia and the cell cycle: new perspectives on aneuploidy

PubMed Central

2014-01-01

Fanconi anemia (FA) is a complex heterogenic disorder of genomic instability, bone marrow failure, cancer predisposition, and congenital malformations. The FA signaling network orchestrates the DNA damage recognition and repair in interphase as well as proper execution of mitosis. Loss of FA signaling causes chromosome instability by weakening the spindle assembly checkpoint, disrupting centrosome maintenance, disturbing resolution of ultrafine anaphase bridges, and dysregulating cytokinesis. Thus, the FA genes function as guardians of genome stability throughout the cell cycle. This review discusses recent advances in diagnosis and clinical management of Fanconi anemia and presents the new insights into the origins of genomic instability in FA. These new discoveries may facilitate the development of rational therapeutic strategies for FA and for FA-deficient malignancies in the general population. PMID:24765528

Gene Therapy in Fanconi Anemia: A Matter of Time, Safety and Gene Transfer Tool Efficiency.

PubMed

Verhoeyen, Els; Roman-Rodriguez, Francisco Jose; Cosset, Francois-Loic; Levy, Camille; Rio, Paula

2017-01-01

Fanconi anemia (FA) is a rare genetic syndrome characterized by progressive marrow failure. Gene therapy by infusion of FA-corrected autologous hematopoietic stem cells (HSCs) may offer a potential cure since it is a monogenetic disease with mutations in the FANC genes, coding for DNA repair enzymes [1]. However, the collection of hCD34+-cells in FA patients implies particular challenges because of the reduced numbers of progenitor cells present in their bone marrow (BM) [2] or mobilized peripheral blood [3-5]. In addition, the FA genetic defect fragilizes the HSCs [6]. These particular features might explain why the first clinical trials using murine leukemia virus derived retroviral vectors conducted for FA failed to show engraftment of corrected cells. The gene therapy field is now moving towards the use of lentiviral vectors (LVs) evidenced by recent succesful clinical trials for the treatment of patients suffering from adrenoleukodystrophy (ALD) [7], β-thalassemia [8], metachromatic leukodystrophy [9] and Wiskott-Aldrich syndrome [10]. LV trials for X-linked severe combined immunodificiency and Fanconi anemia (FA) defects were recently initiated [11, 12]. Fifteen years of preclinical studies using different FA mouse models and in vitro research allowed us to find the weak points in the in vitro culture and transduction conditions, which most probably led to the initial failure of FA HSC gene therapy. In this review, we will focus on the different obstacles, unique to FA gene therapy, and how they have been overcome through the development of optimized protocols for FA HSC culture and transduction and the engineering of new gene transfer tools for FA HSCs. These combined advances in the field hopefully will allow the correction of the FA hematological defect in the near future. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Ubiquitylation and the Fanconi Anemia Pathway

PubMed Central

Garner, Elizabeth; Smogorzewska, Agata

2012-01-01

The Fanconi anemia (FA) pathway maintains genome stability through co-ordination of DNA repair of interstrand crosslinks (ICLs). Disruption of the FA pathway yields hypersensitivity to interstrand crosslinking agents, bone marrow failure and cancer predisposition. Early steps in DNA damage dependent activation of the pathway are governed by monoubiquitylation of FANCD2 and FANCI by the intrinsic FA E3 ubiquitin ligase, FANCL. Downstream FA pathway components and associated factors such as FAN1 and SLX4 exhibit ubiquitin-binding motifs that are important for their DNA repair function, underscoring the importance of ubiquitylation in FA pathway mediated repair. Importantly, ubiquitylation provides the foundations for cross-talk between repair pathways, which in concert with the FA pathway, resolve interstrand crosslink damage and maintain genomic stability. PMID:21605559

Continuous in vivo infusion of interferon-gamma (IFN-γ) enhances engraftment of syngeneic wild-type cells in Fanca–/– and Fancg–/– mice

PubMed Central

Si, Yue; Ciccone, Samantha; Yang, Feng-Chun; Yuan, Jin; Zeng, Daisy; Chen, Shi; van de Vrugt, Henri J.; Critser, John; Arwert, Fre; Haneline, Laura S.; Clapp, D. Wade

2006-01-01

Fanconi anemia (FA) is a heterogeneous genetic disorder characterized by bone marrow (BM) failure and cancer susceptibility. Identification of the cDNAs of FA complementation types allows the potential of using gene transfer technology to introduce functional cDNAs as transgenes into autologous stem cells and provide a cure for the BM failure in FA patients. However, strategies to enhance the mobilization, transduction, and engraftment of exogenous stem cells are required to optimize efficacy prior to widespread clinical use. Hypersensitivity of Fancc–/– cells to interferon-gamma (IFN-γ), a nongenotoxic immune-regulatory cytokine, enhances engraftment of syngeneic wild-type (WT) cells in Fancc–/– mice. However, whether this phenotype is of broad relevance in other FA complementation groups is unresolved. Here we show that primitive and mature myeloid progenitors in Fanca–/– and Fancg–/– mice are hypersensitive to IFN-γ and that in vivo infusion of IFN-γ at clinically relevant concentrations was sufficient to allow consistent long-term engraftment of isogenic WT repopulating stem cells. Given that FANCA, FANCC, and FANCG complementation groups account for more than 90% of all FA patients, these data provide evidence that IFN-γ conditioning may be a useful nongenotoxic strategy for myelopreparation in FA patients. PMID:16946306

Continuous in vivo infusion of interferon-gamma (IFN-gamma) enhances engraftment of syngeneic wild-type cells in Fanca-/- and Fancg-/- mice.

PubMed

Si, Yue; Ciccone, Samantha; Yang, Feng-Chun; Yuan, Jin; Zeng, Daisy; Chen, Shi; van de Vrugt, Henri J; Critser, John; Arwert, Fre; Haneline, Laura S; Clapp, D Wade

2006-12-15

Fanconi anemia (FA) is a heterogeneous genetic disorder characterized by bone marrow (BM) failure and cancer susceptibility. Identification of the cDNAs of FA complementation types allows the potential of using gene transfer technology to introduce functional cDNAs as transgenes into autologous stem cells and provide a cure for the BM failure in FA patients. However, strategies to enhance the mobilization, transduction, and engraftment of exogenous stem cells are required to optimize efficacy prior to widespread clinical use. Hypersensitivity of Fancc-/- cells to interferon-gamma (IFN-gamma), a nongenotoxic immune-regulatory cytokine, enhances engraftment of syngeneic wild-type (WT) cells in Fancc-/- mice. However, whether this phenotype is of broad relevance in other FA complementation groups is unresolved. Here we show that primitive and mature myeloid progenitors in Fanca-/- and Fancg-/- mice are hypersensitive to IFN-gamma and that in vivo infusion of IFN-gamma at clinically relevant concentrations was sufficient to allow consistent long-term engraftment of isogenic WT repopulating stem cells. Given that FANCA, FANCC, and FANCG complementation groups account for more than 90% of all FA patients, these data provide evidence that IFN-gamma conditioning may be a useful nongenotoxic strategy for myelopreparation in FA patients.

White matter changes and word finding failures with increasing age.

PubMed

Stamatakis, Emmanuel A; Shafto, Meredith A; Williams, Guy; Tam, Phyllis; Tyler, Lorraine K

2011-01-07

Increasing life expectancy necessitates the better understanding of the neurophysiological underpinnings of age-related cognitive changes. The majority of research examining structural-cognitive relationships in aging focuses on the role of age-related changes to grey matter integrity. In the current study, we examined the relationship between age-related changes in white matter and language production. More specifically, we concentrated on word-finding failures, which increase with age. We used Diffusion tensor MRI (a technique used to image, in vivo, the diffusion of water molecules in brain tissue) to relate white matter integrity to measures of successful and unsuccessful picture naming. Diffusion tensor images were used to calculate Fractional Anisotropy (FA) images. FA is considered to be a measure of white matter organization/integrity. FA images were related to measures of successful picture naming and to word finding failures using voxel-based linear regression analyses. Successful naming rates correlated positively with white matter integrity across a broad range of regions implicated in language production. However, word finding failure rates correlated negatively with a more restricted region in the posterior aspect of superior longitudinal fasciculus. The use of DTI-MRI provides evidence for the relationship between age-related white matter changes in specific language regions and word finding failures in old age.

Incidence of Fanconi anaemia in phenotypically normal aplastic anaemia patients in West Bengal.

PubMed

Dutta, Atreyee; De, Rajib; Dolai, Tuphan Kanti; Pal, Pritha; Ghosh, Shanoli; Mitra, Pradip Kumar; Halder, Ajanta

2018-01-07

Fanconi anaemia (FA) is a rare inherited bone marrow failure and autosomal recessive blood disorder. FA patients have a higher risk of cancer, including acute myeloid leukaemia and squamous cell carcinoma. Maximum, but not all, affected individuals have one or more somatic abnormalities, including skin, skeletal, genitourinary, gastrointestinal, cardiac and neurological anomalies, etc. Positive stress cytogenetics has immense implications for the treatment and management of FA. The aim of our study was to find out the incidence of FA in the population of phenotypically normal aplastic anaemia (AA) patients in West Bengal. Ethical clearances were obtained from the corresponding institutional committees. A total of 117 AA cases was selected. Stress cytogenetics was performed from peripheral venous blood (PVB) samples of 63 AA patients (age ≤ 50 years) and 63 age- and sex-matched healthy individual (control) using Mitomycin C (MMC). Out of 63 AA patients, 6 (9.25%) cases showed positive stress cytogenetics suggestive of FA, which is statistically significant (p-value - 0.000532), analysed by chi-square test. A considerable percentage of patients showing sensitivity towards MMC, even if they are phenotypically normal and did not have any distinguishable features which are generally found in FA. This observation may indicate that stress cytogenetics analysis of phenotypically normal AA patients (≤50 years) is essential for the improvement of the treatment procedure.

Otologic manifestations of Fanconi anemia and other inherited bone marrow failure syndromes.

PubMed

Kalejaiye, Adedoyin; Giri, Neelam; Brewer, Carmen C; Zalewski, Christopher K; King, Kelly A; Adams, Charleen D; Rosenberg, Philip S; Kim, H Jeffrey; Alter, Blanche P

2016-12-01

The inherited bone marrow failure syndromes (IBMFSs) are diverse disorders with syndrome-specific features; their otologic and audiologic manifestations have not been well described. Our objective was to characterize these in patients with Fanconi anemia (FA), dyskeratosis congenita (DC), Diamond-Blackfan anemia (DBA), and Shwachman-Diamond syndrome (SDS), and to determine the association between physical findings and hearing loss. Patients with an IBMFS underwent comprehensive clinical and laboratory evaluations and testing for syndrome-specific gene mutations. Hearing loss was measured by pure tone audiometry and otologic abnormalities by otomicroscopy. Patients included 33 with FA, 37 with DC, 32 with DBA, and nine with SDS. Hearing loss was most frequent in patients with FA (45%) and DBA (14%). The most common type of hearing loss in FA was conductive (65%). Absent or hypoplastic radius, noted in 21% of the patients with FA, was associated with hearing loss in all cases. Otomicroscopy was abnormal in 66% of patients with FA. Characteristic ear abnormalities included small tympanic membrane (66%), malformed malleus (57%), aberrant tympanic bony island (48%), narrow external auditory canal (EAC) (32%), and abnormal course of chorda tympani (34%). Ear malformations were almost always associated with hearing loss. Hearing loss was rare in patients with DC and SDS. FA is the major IBMFS with associated hearing loss, which is most commonly conductive. Radial hypoplasia or aplasia and characteristic congenital ear malformations are associated with hearing loss in patients with FA. Recognition of these syndrome-specific abnormalities should lead to earlier management of hearing loss. © 2016 Wiley Periodicals, Inc.

Rapid lentiviral transduction preserves the engraftment potential of Fanca(-/-) hematopoietic stem cells.

PubMed

Müller, Lars U W; Milsom, Michael D; Kim, Mi-Ok; Schambach, Axel; Schuesler, Todd; Williams, David A

2008-06-01

Fanconi anemia (FA) is a rare recessive syndrome, characterized by congenital anomalies, bone marrow failure, and predisposition to cancer. Two earlier clinical trials utilizing gamma-retroviral vectors for the transduction of autologous FA hematopoietic stem cells (HSCs) required extensive in vitro manipulation and failed to achieve detectable long-term engraftment of transduced HSCs. As a strategy for minimizing ex vivo manipulation, we investigated the use of a "rapid" lentiviral transduction protocol in a murine Fanca(-/-) model. Importantly, while this and most murine models of FA fail to completely mimic the human hematopoietic phenotype, we observed a high incidence of HSC transplant engraftment failure and low donor chimerism after conventional transduction (CT) of Fanca(-/-) donor cells. In contrast, rapid transduction (RT) of Fanca(-/-) HSCs preserved engraftment to the level achieved in wild-type cells, resulting in long-term multilineage engraftment of gene-modified cells. We also demonstrate the correction of the characteristic hypersensitivity of FA cells against the cross-linking agent mitomycin C (MMC), and provide evidence for the advantage of using pharmacoselection as a means of further increasing gene-modified cells after RT. Collectively, these data support the use of rapid lentiviral transduction for gene therapy in FA.

TNF-α signaling in Fanconi anemia

PubMed Central

Du, Wei; Erden, Ozlem; Pang, Qishen

2013-01-01

Tumor necrosis factor-alpha (TNF-α is a major pro-inflammatory cytokine involved in systemic inflammation and the acute phase reaction. Dysregulation of TNF production has been implicated in a variety of human diseases including Fanconi anemia (FA). FA is a genomic instability syndrome characterized by progressive bone marrow failure and cancer susceptibility. The patients with FA are often found overproducing TNF-α, which may directly affect hematopoietic stem cell (HSC) function by impairing HSC survival, homing and proliferation, or indirectly change the bone marrow microenvironment critical for HSC homeostasis and function, therefore contribute to disease progression in FA. In this brief review, we discuss the link between TNF-α signaling and FA pathway with emphasis on the implication of inflammation in the pathophysiology and abnormal hematopoiesis in FA. PMID:23890415

TNF-α signaling in Fanconi anemia.

PubMed

Du, Wei; Erden, Ozlem; Pang, Qishen

2014-01-01

Tumor necrosis factor-alpha (TNF-α) is a major pro-inflammatory cytokine involved in systemic inflammation and the acute phase reaction. Dysregulation of TNF production has been implicated in a variety of human diseases including Fanconi anemia (FA). FA is a genomic instability syndrome characterized by progressive bone marrow failure and cancer susceptibility. The patients with FA are often found overproducing TNF-α, which may directly affect hematopoietic stem cell (HSC) function by impairing HSC survival, homing and proliferation, or indirectly change the bone marrow microenvironment critical for HSC homeostasis and function, therefore contributing to disease progression in FA. In this brief review, we discuss the link between TNF-α signaling and FA pathway with emphasis on the implication of inflammation in the pathophysiology and abnormal hematopoiesis in FA. © 2013.

The Fanconi anemia DNA damage repair pathway in the spotlight for germline predisposition to colorectal cancer.

PubMed

Esteban-Jurado, Clara; Franch-Expósito, Sebastià; Muñoz, Jenifer; Ocaña, Teresa; Carballal, Sabela; López-Cerón, Maria; Cuatrecasas, Miriam; Vila-Casadesús, Maria; Lozano, Juan José; Serra, Enric; Beltran, Sergi; Brea-Fernández, Alejandro; Ruiz-Ponte, Clara; Castells, Antoni; Bujanda, Luis; Garre, Pilar; Caldés, Trinidad; Cubiella, Joaquín; Balaguer, Francesc; Castellví-Bel, Sergi

2016-10-01

Colorectal cancer (CRC) is one of the most common neoplasms in the world. Fanconi anemia (FA) is a very rare genetic disease causing bone marrow failure, congenital growth abnormalities and cancer predisposition. The comprehensive FA DNA damage repair pathway requires the collaboration of 53 proteins and it is necessary to restore genome integrity by efficiently repairing damaged DNA. A link between FA genes in breast and ovarian cancer germline predisposition has been previously suggested. We selected 74 CRC patients from 40 unrelated Spanish families with strong CRC aggregation compatible with an autosomal dominant pattern of inheritance and without mutations in known hereditary CRC genes and performed germline DNA whole-exome sequencing with the aim of finding new candidate germline predisposition variants. After sequencing and data analysis, variant prioritization selected only those very rare alterations, producing a putative loss of function and located in genes with a role compatible with cancer. We detected an enrichment for variants in FA DNA damage repair pathway genes in our familial CRC cohort as 6 families carried heterozygous, rare, potentially pathogenic variants located in BRCA2/FANCD1, BRIP1/FANCJ, FANCC, FANCE and REV3L/POLZ. In conclusion, the FA DNA damage repair pathway may play an important role in the inherited predisposition to CRC.

Emerging functions of the Fanconi anemia pathway at a glance.

PubMed

Sumpter, Rhea; Levine, Beth

2017-08-15

Fanconi anemia (FA) is a rare disease, in which homozygous or compound heterozygous inactivating mutations in any of 21 genes lead to genomic instability, early-onset bone marrow failure and increased cancer risk. The FA pathway is essential for DNA damage response (DDR) to DNA interstrand crosslinks. However, proteins of the FA pathway have additional cytoprotective functions that may be independent of DDR. We have shown that many FA proteins participate in the selective autophagy pathway that is required for the destruction of unwanted intracellular constituents. In this Cell Science at a Glance and the accompanying poster, we briefly review the role of the FA pathway in DDR and recent findings that link proteins of the FA pathway to selective autophagy of viruses and mitochondria. Finally, we discuss how perturbations in FA protein-mediated selective autophagy may contribute to inflammatory as well as genotoxic stress. © 2017. Published by The Company of Biologists Ltd.

Loss of the homologous recombination gene rad51 leads to Fanconi anemia-like symptoms in zebrafish.

PubMed

Botthof, Jan Gregor; Bielczyk-Maczyńska, Ewa; Ferreira, Lauren; Cvejic, Ana

2017-05-30

RAD51 is an indispensable homologous recombination protein, necessary for strand invasion and crossing over. It has recently been designated as a Fanconi anemia (FA) gene, following the discovery of two patients carrying dominant-negative mutations. FA is a hereditary DNA-repair disorder characterized by various congenital abnormalities, progressive bone marrow failure, and cancer predisposition. In this report, we describe a viable vertebrate model of RAD51 loss. Zebrafish rad51 loss-of-function mutants developed key features of FA, including hypocellular kidney marrow, sensitivity to cross-linking agents, and decreased size. We show that some of these symptoms stem from both decreased proliferation and increased apoptosis of embryonic hematopoietic stem and progenitor cells. Comutation of p53 was able to rescue the hematopoietic defects seen in the single mutants, but led to tumor development. We further demonstrate that prolonged inflammatory stress can exacerbate the hematological impairment, leading to an additional decrease in kidney marrow cell numbers. These findings strengthen the assignment of RAD51 as a Fanconi gene and provide more evidence for the notion that aberrant p53 signaling during embryogenesis leads to the hematological defects seen later in life in FA. Further research on this zebrafish FA model will lead to a deeper understanding of the molecular basis of bone marrow failure in FA and the cellular role of RAD51.

SEM Analysis Techniques for LSI Microcircuits. Volume 1

DTIC Science & Technology

1980-08-01

CHIP, EBIC 70 1-40 COLUMN DECODE FAILURE, VOLTAGE CONTRAST 71 1-41 COLUMN DECODE FAILURE, VOLTAGE CONTRAST 72 1-42 OUTPUT FAILURE, VOLTAGE CONTRAST 73...317 5-22 DATA OUTPUT BUFFER, LIGHT PHOTO 318 5-23 DATA OUTPUT BUFFER, VOLTAGE CONTRAST 319 5-24 OVERALL CHIP FUNCTION, LIGHT PHOTO 320 5-25 ROW...34.. 91 75 87 80 99 93’ 76 71 0.4mA 1 IFA "0" 85 76 88 80 99 94 76 72 0.4mA 15 ’FA Ŕ" 58 42 60 58 64 66 52 48 0.4mA 13 IFE (A) 1101" 54 51 56 60 65 58 47

Common Variable Immunodeficiency Caused by FANC Mutations.

PubMed

Sekinaka, Yujin; Mitsuiki, Noriko; Imai, Kohsuke; Yabe, Miharu; Yabe, Hiromasa; Mitsui-Sekinaka, Kanako; Honma, Kenichi; Takagi, Masatoshi; Arai, Ayako; Yoshida, Kenichi; Okuno, Yusuke; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Miyano, Satoru; Muramatsu, Hideki; Kojima, Seiji; Hira, Asuka; Takata, Minoru; Ohara, Osamu; Ogawa, Seishi; Morio, Tomohiro; Nonoyama, Shigeaki

2017-07-01

Common variable immunodeficiency (CVID) is the most common adult-onset primary antibody deficiency disease due to various causative genes. Several genes, which are known to be the cause of different diseases, have recently been reported as the cause of CVID in patients by performing whole exome sequencing (WES) analysis. Here, we found FANC gene mutations as a cause of adult-onset CVID in two patients. B cells were absent and CD4 + T cells were skewed toward CD45RO + memory T cells. T-cell receptor excision circles (TRECs) and signal joint kappa-deleting recombination excision circles (sjKRECs) were undetectable in both patients. Both patients had no anemia, neutropenia, or thrombocytopenia. Using WES, we identified compound heterozygous mutations of FANCE in one patient and homozygous mutation of FANCA in another patient. The impaired function of FANC protein complex was confirmed by a monoubiquitination assay and by chromosome fragility test. We then performed several immunological evaluations including quantitative lymphocyte analysis and TRECs/sjKRECs analysis for 32 individuals with Fanconi anemia (FA). In total, 22 FA patients (68.8%) were found to have immunological abnormalities, suggesting that such immunological findings may be common in FA patients. These data indicate that FANC mutations are involved in impaired lymphogenesis probably by the accumulation of DNA replication stress, leading to CVID. It is important to diagnose FA because it drastically changes clinical management. We propose that FANC mutations can cause isolated immunodeficiency in addition to bone marrow failure and malignancy.

The Fanconi anemia ID2 complex: dueling saxes at the crossroads.

PubMed

Boisvert, Rebecca A; Howlett, Niall G

2014-01-01

Fanconi anemia (FA) is a rare recessive genetic disease characterized by congenital abnormalities, bone marrow failure and heightened cancer susceptibility in early adulthood. FA is caused by biallelic germ-line mutation of any one of 16 genes. While several functions for the FA proteins have been ascribed, the prevailing hypothesis is that the FA proteins function cooperatively in the FA-BRCA pathway to repair damaged DNA. A pivotal step in the activation of the FA-BRCA pathway is the monoubiquitination of the FANCD2 and FANCI proteins. Despite their importance for DNA repair, the domain structure, regulation, and function of FANCD2 and FANCI remain poorly understood. In this review, we provide an overview of our current understanding of FANCD2 and FANCI, with an emphasis on their posttranslational modification and common and unique functions.

The Fanconi anemia ID2 complex: Dueling saxes at the crossroads

PubMed Central

Boisvert, Rebecca A; Howlett, Niall G

2014-01-01

Fanconi anemia (FA) is a rare recessive genetic disease characterized by congenital abnormalities, bone marrow failure and heightened cancer susceptibility in early adulthood. FA is caused by biallelic germ-line mutation of any one of 16 genes. While several functions for the FA proteins have been ascribed, the prevailing hypothesis is that the FA proteins function cooperatively in the FA-BRCA pathway to repair damaged DNA. A pivotal step in the activation of the FA-BRCA pathway is the monoubiquitination of the FANCD2 and FANCI proteins. Despite their importance for DNA repair, the domain structure, regulation, and function of FANCD2 and FANCI remain poorly understood. In this review, we provide an overview of our current understanding of FANCD2 and FANCI, with an emphasis on their posttranslational modification and common and unique functions. PMID:25486561

Fanconi's Anemia Effect or Sickle Cell Anemia Effect: That is the Question.

PubMed

Unal, Sule; Chui, David H K; Gumruk, Fatma

2015-01-01

A 16-year-old boy who was diagnosed to have sickle cell anemia was referred to our center. The parental consanguinity, growth retardation and dysmorphic features prompted a search for possible Fanconi's Anemia (FA). The diepoxybutane (DEB) test was positive, confirming FA. The interaction of both diseases might account for his relatively mild phenotype in terms of both sickle cell anemia (or Hb S, HBB: c.20A > T) and FA. The high Hb F level that might be related to concomitant FA, may have caused a milder phenotype of sickle cell anemia, whereas nitric oxide (NO) depletion as a consequence of sickle cell anemia, may have caused a delay in the bone marrow failure of FA.

Fanconi anemia: a disorder defective in the DNA damage response.

PubMed

Kitao, Hiroyuki; Takata, Minoru

2011-04-01

Fanconi anemia (FA) is a cancer predisposition disorder characterized by progressive bone marrow failure, congenital developmental defects, chromosomal abnormalities, and cellular hypersensitivity to DNA interstrand crosslink (ICL) agents. So far mutations in 14 FANC genes were identified in FA or FA-like patients. These gene products constitute a common ubiquitin-phosphorylation network called the "FA pathway" and cooperate with other proteins involved in DNA repair and cell cycle control to repair ICL lesions and to maintain genome stability. In this review, we summarize recent exciting discoveries that have expanded our view of the molecular mechanisms operating in DNA repair and DNA damage signaling.

Retention of first aid and basic life support skills in undergraduate medical students.

PubMed

de Ruijter, Pim A; Biersteker, Heleen A; Biert, Jan; van Goor, Harry; Tan, Edward C

2014-01-01

Undergraduate medical students follow a compulsory first aid (FA) and basic life support (BLS) course. Retention of BLS seems poor and only little information is provided on the retention of FA skills. This study aims at evaluating 1- and 2-year retention of FA and BLS training in undergraduate medical students. One hundred and twenty students were randomly selected from first year (n=349) medical students who successfully followed a compulsory FA and BLS course. From these 120 students, 94 (78%) and 69 (58%) participated in retention tests of FA and BLS skills after 1 and 2 years, respectively. The assessment consisted of two FA stations and one BLS station. After 1 year, only 2% passed both FA and BLS stations and 68% failed both FA and BLS stations. After 2 years, 5% passed and 50% failed both FA and BLS stations. Despite the high failure rate at the stations, 90% adequately checked vital signs and started cardiopulmonary resuscitation appropriately. The long-term retention of FA and BLS skills after a compulsory course in the first year is poor. Adequate check of vital signs and commencing cardiopulmonary resuscitation retained longer.

Retention of first aid and basic life support skills in undergraduate medical students.

PubMed

de Ruijter, Pim A; Biersteker, Heleen A; Biert, Jan; van Goor, Harry; Tan, Edward C

2014-01-01

Background Undergraduate medical students follow a compulsory first aid (FA) and basic life support (BLS) course. Retention of BLS seems poor and only little information is provided on the retention of FA skills. This study aims at evaluating 1- and 2-year retention of FA and BLS training in undergraduate medical students. Methods One hundred and twenty students were randomly selected from first year (n=349) medical students who successfully followed a compulsory FA and BLS course. From these 120 students, 94 (78%) and 69 (58%) participated in retention tests of FA and BLS skills after 1 and 2 years, respectively. The assessment consisted of two FA stations and one BLS station. Results After 1 year, only 2% passed both FA and BLS stations and 68% failed both FA and BLS stations. After 2 years, 5% passed and 50% failed both FA and BLS stations. Despite the high failure rate at the stations, 90% adequately checked vital signs and started cardiopulmonary resuscitation appropriately. Conclusions The long-term retention of FA and BLS skills after a compulsory course in the first year is poor. Adequate check of vital signs and commencing cardiopulmonary resuscitation retained longer.

Fanconi anemia genes are highly expressed in primitive CD34+ hematopoietic cells

PubMed Central

Aubé, Michel; Lafrance, Matthieu; Brodeur, Isabelle; Delisle, Marie-Chantal; Carreau, Madeleine

2003-01-01

Background Fanconi anemia (FA) is a complex recessive genetic disease characterized by progressive bone marrow failure (BM) and a predisposition to cancer. We have previously shown using the Fancc mouse model that the progressive BM failure results from a hematopoietic stem cell defect suggesting that function of the FA genes may reside in primitive hematopoietic stem cells. Methods Since genes involved in stem cell differentiation and/or maintenance are usually regulated at the transcription level, we used a semiquantitative RT-PCR method to evaluate FA gene transcript levels in purified hematopoietic stem cells. Results We show that most FA genes are highly expressed in primitive CD34-positive and negative cells compared to lower levels in more differentiated cells. However, in CD34- stem cells the Fancc gene was found to be expressed at low levels while Fancg was undetectable in this population. Furthermore, Fancg expression is significantly decreased in Fancc -/- stem cells as compared to wild-type cells while the cancer susceptibility genes Brca1 and Fancd1/Brac2 are upregulated in Fancc-/- hematopoietic cells. Conclusions These results suggest that FA genes are regulated at the mRNA level, that increased Fancc expression in LTS-CD34+ cells correlates with a role at the CD34+ differentiation stage and that lack of Fancc affects the expression of other FA gene, more specifically Fancg and Fancd1/Brca2, through an unknown mechanism. PMID:12809565

Novel FANCI mutations in Fanconi anemia with VACTERL association.

PubMed

Savage, Sharon A; Ballew, Bari J; Giri, Neelam; Chandrasekharappa, Settara C; Ameziane, Najim; de Winter, Johan; Alter, Blanche P

2016-02-01

Fanconi anemia (FA) is an inherited bone marrow failure syndrome caused by mutations in DNA repair genes; some of these patients may have features of the VACTERL association. Autosomal recessive mutations in FANCI are a rare cause of FA. We identified FANCI mutations by next generation sequencing in three patients in our FA cohort among several whose mutated gene was unknown. Four of the six mutations are novel and all mutations are likely deleterious to protein function. There are now 16 reported cases of FA due to FANCI of whom 7 have at least 3 features of the VACTERL association (44%). This suggests that the VACTERL association in patients with FA may be seen in patients with FANCI mutations more often than previously recognized. © 2015 Wiley Periodicals, Inc.

Paternal or Maternal Uniparental Disomy of Chromosome 16 Resulting in Homozygosity of a Mutant Allele Causes Fanconi Anemia.

PubMed

Donovan, Frank X; Kimble, Danielle C; Kim, Yonghwan; Lach, Francis P; Harper, Ursula; Kamat, Aparna; Jones, MaryPat; Sanborn, Erica M; Tryon, Rebecca; Wagner, John E; MacMillan, Margaret L; Ostrander, Elaine A; Auerbach, Arleen D; Smogorzewska, Agata; Chandrasekharappa, Settara C

2016-05-01

Fanconi anemia (FA) is a rare inherited disorder caused by pathogenic variants in one of 19 FANC genes. FA patients display congenital abnormalities, and develop bone marrow failure, and cancer susceptibility. We identified homozygous mutations in four FA patients and, in each case, only one parent carried the obligate mutant allele. FANCA and FANCP/SLX4 genes, both located on chromosome 16, were the affected recessive FA genes in three and one family respectively. Genotyping with short tandem repeat markers and SNP arrays revealed uniparental disomy (UPD) of the entire mutation-carrying chromosome 16 in all four patients. One FANCA patient had paternal UPD, whereas FA in the other three patients resulted from maternal UPD. These are the first reported cases of UPD as a cause of FA. UPD indicates a reduced risk of having another child with FA in the family and has implications in prenatal diagnosis. © 2016 WILEY PERIODICALS, INC.

Modeling Fanconi Anemia pathogenesis and therapeutics using integration-free patient-derived iPSCs

PubMed Central

Montserrat, Nuria; Tarantino, Carolina; Gu, Ying; Yi, Fei; Xu, Xiuling; Zhang, Weiqi; Ruiz, Sergio; Plongthongkum, Nongluk; Zhang, Kun; Masuda, Shigeo; Nivet, Emmanuel; Tsunekawa, Yuji; Soligalla, Rupa Devi; Goebl, April; Aizawa, Emi; Kim, Na Young; Kim, Jessica; Dubova, Ilir; Li, Ying; Ren, Ruotong; Benner, Chris; del Sol, Antonio; Bueren, Juan; Trujillo, Juan Pablo; Surralles, Jordi; Cappelli, Enrico; Dufour, Carlo; Esteban, Concepcion Rodriguez; Belmonte, Juan Carlos Izpisua

2014-01-01

Fanconi Anemia (FA) is a recessive disorder characterized by genomic instability, congenital abnormalities, cancer predisposition and bone marrow failure. However, the pathogenesis of FA is not fully understood partly due to the limitations of current disease models. Here, we derive integration-free induced pluripotent stem cells (iPSCs) from an FA patient without genetic complementation and report in situ gene correction in FA-iPSCs as well as the generation of isogenic FANCA deficient human embryonic stem cell (ESC) lines. FA cellular phenotypes are recapitulated in iPSCs/ESCs and their adult stem/progenitor cell derivatives. By using isogenic pathogenic mutation-free controls as well as cellular and genomic tools, our model serves to facilitate the discovery of novel disease features. We validate our model as a drug-screening platform by identifying several compounds that improve hematopoietic differentiation of FA-iPSCs. These compounds are also able to rescue the hematopoietic phenotype of FA-patient bone marrow cells. PMID:24999918

Modelling Fanconi anemia pathogenesis and therapeutics using integration-free patient-derived iPSCs.

PubMed

Liu, Guang-Hui; Suzuki, Keiichiro; Li, Mo; Qu, Jing; Montserrat, Nuria; Tarantino, Carolina; Gu, Ying; Yi, Fei; Xu, Xiuling; Zhang, Weiqi; Ruiz, Sergio; Plongthongkum, Nongluk; Zhang, Kun; Masuda, Shigeo; Nivet, Emmanuel; Tsunekawa, Yuji; Soligalla, Rupa Devi; Goebl, April; Aizawa, Emi; Kim, Na Young; Kim, Jessica; Dubova, Ilir; Li, Ying; Ren, Ruotong; Benner, Chris; Del Sol, Antonio; Bueren, Juan; Trujillo, Juan Pablo; Surralles, Jordi; Cappelli, Enrico; Dufour, Carlo; Esteban, Concepcion Rodriguez; Belmonte, Juan Carlos Izpisua

2014-07-07

Fanconi anaemia (FA) is a recessive disorder characterized by genomic instability, congenital abnormalities, cancer predisposition and bone marrow (BM) failure. However, the pathogenesis of FA is not fully understood partly due to the limitations of current disease models. Here, we derive integration free-induced pluripotent stem cells (iPSCs) from an FA patient without genetic complementation and report in situ gene correction in FA-iPSCs as well as the generation of isogenic FANCA-deficient human embryonic stem cell (ESC) lines. FA cellular phenotypes are recapitulated in iPSCs/ESCs and their adult stem/progenitor cell derivatives. By using isogenic pathogenic mutation-free controls as well as cellular and genomic tools, our model serves to facilitate the discovery of novel disease features. We validate our model as a drug-screening platform by identifying several compounds that improve hematopoietic differentiation of FA-iPSCs. These compounds are also able to rescue the hematopoietic phenotype of FA patient BM cells.

Paternal or maternal uniparental disomy of chromosome 16 resulting in homozygosity of a mutant allele causes Fanconi anemia

PubMed Central

Donovan, Frank X.; Kimble, Danielle C.; Kim, Yonghwan; Lach, Francis P.; Harper, Ursula; Kamat, Aparna; Jones, MaryPat; Sanborn, Erica M.; Tryon, Rebecca; Wagner, John E.; MacMillan, Margaret L.; Ostrander, Elaine A.; Auerbach, Arleen D.; Smogorzewska, Agata; Chandrasekharappa, Settara C.

2016-01-01

Fanconi anemia (FA) is a rare inherited disorder caused by pathogenic variants in one of 19 FANC genes. FA patients display congenital abnormalities, and develop bone marrow failure, and cancer susceptibility. We identified homozygous mutations in four FA patients and, in each case, only one parent carried the obligate mutant allele. FANCA and FANCP/SLX4 genes, both located on chromosome 16, were the affected recessive FA genes in three and one family respectively. Genotyping with short tandem repeat markers and single nucleotide polymorphism (SNP) arrays revealed uniparental disomy (UPD) of the entire mutation-carrying chromosome 16 in all four patients. One FANCA patient had paternal UPD, whereas FA in the other three patients resulted from maternal UPD. These are the first reported cases of UPD as a cause of FA. UPD indicates a reduced risk of having another child with FA in the family and has implications in prenatal diagnosis. PMID:26841305

Fusidic acid for the treatment of bone and joint infections caused by meticillin-resistant Staphylococcus aureus.

PubMed

Wang, Jiun-Ling; Tang, Hung-Jen; Hsieh, Pang-Hsin; Chiu, Fang-Yao; Chen, Yen-Hsu; Chang, Ming-Chau; Huang, Ching-Tai; Liu, Chang-Pan; Lau, Yeu-Jun; Hwang, Kao-Pin; Ko, Wen-Chien; Wang, Chen-Ti; Liu, Cheng-Yi; Liu, Chien-Lin; Hsueh, Po-Ren

2012-08-01

There is a lack of surveillance data on resistance to fusidic acid (FA) in Asia, and no reviews of FA usage for the treatment of orthopaedic infections have been conducted since the year 2000. In this study, we present a systemic literature review of FA resistance in Asia and the clinical use of FA for the treatment of bone and joint infections (BJIs). The in vitro activity of FA against meticillin-resistant Staphylococcus aureus (MRSA) isolates remains good, with low (<10%) resistance rates in most Asian countries. FA in Asia appears to be a better oral anti-MRSA agent than trimethoprim/sulfamethoxazole and clindamycin. More than 80 cases of FA use for BJI have been reported since 2000 and the recurrence or failure rate is <10%. There is much evidence supporting the use of FA in combination with other antibiotics (e.g. rifampicin) as an oral treatment following intravenous glycopeptide treatment for BJIs. Copyright © 2012 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Complementation of hypersensitivity to DNA interstrand crosslinking agents demonstrates that XRCC2 is a Fanconi anaemia gene.

PubMed

Park, Jung-Young; Virts, Elizabeth L; Jankowska, Anna; Wiek, Constanze; Othman, Mohamed; Chakraborty, Sujata C; Vance, Gail H; Alkuraya, Fowzan S; Hanenberg, Helmut; Andreassen, Paul R

2016-10-01

Fanconi anaemia (FA) is a heterogeneous inherited disorder clinically characterised by progressive bone marrow failure, congenital anomalies and a predisposition to malignancies. Determine, based on correction of cellular phenotypes, whether XRCC2 is a FA gene. Cells (900677A) from a previously identified patient with biallelic mutation of XRCC2, among other mutations, were genetically complemented with wild-type XRCC2. Wild-type XRCC2 corrects each of three phenotypes characteristic of FA cells, all related to the repair of DNA interstrand crosslinks, including increased sensitivity to mitomycin C (MMC), chromosome breakage and G2-M accumulation in the cell cycle. Further, the p.R215X mutant of XRCC2, which is harboured by the patient, is unstable. This provides an explanation for the pathogenesis of this mutant, as does the fact that 900677A cells have reduced levels of other proteins in the XRCC2-RAD51B-C-D complex. Also, FANCD2 monoubiquitination and foci formation, but not assembly of RAD51 foci, are normal in 900677A cells. Thus, XRCC2 acts late in the FA-BRCA pathway as also suggested by hypersensitivity of 900677A cells to ionising radiation. These cells also share milder sensitivities towards olaparib and formaldehyde with certain other FA cells. XRCC2/FANCU is a FA gene, as is another RAD51 paralog gene, RAD51C/FANCO. Notably, similar to a subset of FA genes that act downstream of FANCD2, biallelic mutation of XRCC2/FANCU has not been associated with bone marrow failure. Taken together, our results yield important insights into phenotypes related to FA and its genetic origins. 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/

The nuclease hSNM1B/Apollo is linked to the Fanconi anemia pathway via its interaction with FANCP/SLX4.

PubMed

Salewsky, Bastian; Schmiester, Maren; Schindler, Detlev; Digweed, Martin; Demuth, Ilja

2012-11-15

The recessive genetic disorder Fanconi anemia (FA) is clinically characterized by congenital defects, bone marrow failure and an increased incidence of cancer. Cells derived from FA patients exhibit hypersensitivity to DNA interstrand crosslink (ICL)-inducing agents. We have earlier reported a similar cellular phenotype for human cells depleted of hSNM1B/Apollo (siRNA). In fact, hSNM1B/Apollo has a dual role in the DNA damage response and in generation and maintenance of telomeres, the latter function involving interaction with the shelterin protein TRF2. Here we find that ectopically expressed hSNM1B/Apollo co-immunoprecipitates with SLX4, a protein recently identified as a new FA protein, FANCP, and known to interact with several structure-specific nucleases. As shown by immunofluorescence analysis, FANCP/SLX4 depletion (siRNA) resulted in a significant reduction of hSNM1B/Apollo nuclear foci, supporting the functional relevance of this new protein interaction. Interestingly, as an additional consequence of FANCP/SLX4 depletion, we found a reduction of cellular TRF2, in line with its telomere-related function. Finally, analysis of human cells following double knockdown of hSNM1B/Apollo and FANCP/SLX4 indicated that they function epistatically. These findings further substantiate the role of hSNM1B/Apollo in a downstream step of the FA pathway during the repair of DNA ICLs.

BIK (NBK) is a mediator of the sensitivity of Fanconi anaemia group C lymphoblastoid cell lines to interstrand DNA cross-linking agents.

PubMed

Prieto-Remón, Inés; Sánchez-Carrera, Dámaso; López-Duarte, Mónica; Richard, Carlos; Pipaón, Carlos

2012-11-15

FA (Fanconi anaemia) is a rare hereditary disorder characterized by congenital malformations, progressive bone marrow failure and an extraordinary predisposition to develop cancer. At present, 15 genes have been related to this condition and mutations of them have also been found in different types of cancer. Bone marrow failure threatens the life of FA patients during the first decade of their life, but the mechanisms underlying this process are not completely understood. In the present study we investigate a possible imbalance between the expression of pro- and anti-apoptotic proteins as a cause for the hypersensitivity of FANCC (FA, complementation group C)-deficient cells to genotoxic stress. We found a BIK (Bcl-2 interacting killer) over-expression in lymphoblastoid cell lines derived from FA-C patients when compared with their phenotypically corrected counterparts. This overexpression has a transcriptional basis since the regulatory region of the gene shows higher activity in FANCC-deficient cells. We demonstrate the involvement of BIK in the sensitivity of FA-C lymphoblasts to interstrand DNA cross-linking agents as it is induced by these drugs and interference of its expression in these cells preserves their viability and reduces apoptosis. We investigate the mechanism of BIK overexpression in FANCC-deficient cells by analysing the activity of many different signalling pathways in these cells. Finally, we provide evidence of a previously undescribed indirect epigenetic regulation of BIK in FA-C lymphoblasts mediated by ΔNp73, an isoform of p73 lacking its transactivation domain that activates BIK through a proximal element in its promoter.

Functional analysis of the putative peroxidase domain of FANCA, the Fanconi anemia complementation group A protein.

PubMed

Ren, J; Youssoufian, H

2001-01-01

Fanconi anemia (FA) is an autosomal recessive disorder manifested by chromosomal breakage, birth defects, and susceptibility to bone marrow failure and cancer. At least seven complementation groups have been identified, and the genes defective in four groups have been cloned. The most common subtype is complementation group A. Although the normal functions of the gene products defective in FA cells are not completely understood, a clue to the function of the FA group A gene product (FANCA) was provided by the detection of limited homology in the amino terminal region to a class of heme peroxidases. We evaluated this hypothesis by mutagenesis and functional complementation studies. We substituted alanine residues for the most conserved FANCA residues in the putative peroxidase domain and tested their effects on known biochemical and cellular functions of FANCA. While the substitution mutants were comparable to wild-type FANCA with regard to their stability, subcellular localization, and interaction with FANCG, only the Trp(183)-to-Ala substitution (W183A) abolished the ability of FANCA to complement the sensitivity of FA group A cells to mitomycin C. By contrast, TUNEL assays for apoptosis after exposure to H2O2 showed no differences between parental FA group A cells, cells complemented with wild-type FANCA, and cells complemented with the W183A of FANCA. Moreover, semiquantitative RT-PCR analysis for the expression of the peroxide-sensitive heme oxygenase gene showed appropriate induction after H2O2 exposure. Thus, W183A appears to be essential for the in vivo activity of FANCA in a manner independent of its interaction with FANCG. Moreover, neither wild-type FANCA nor the W183A mutation appears to alter the peroxide-induced apoptosisor peroxide-sensing ability of FA group A cells. Copyright 2001 Academic Press.

Persistent response of Fanconi anemia haematopoietic stem and progenitor cells to oxidative stress.

PubMed

Li, Yibo; Amarachintha, Surya; Wilson, Andrew F; Li, Xue; Du, Wei

2017-06-18

Oxidative stress is considered as an important pathogenic factor in many human diseases including Fanconi anemia (FA), an inherited bone marrow failure syndrome with extremely high risk of leukemic transformation. Members of the FA protein family are involved in DNA damage and other cellular stress responses. Loss of FA proteins renders cells hypersensitive to oxidative stress and cancer transformation. However, how FA cells respond to oxidative DNA damage remains unclear. By using an in vivo stress-response mouse strain expressing the Gadd45β-luciferase transgene, we show here that haematopoietic stem and progenitor cells (HSPCs) from mice deficient for the FA gene Fanca or Fancc persistently responded to oxidative stress. Mechanistically, we demonstrated that accumulation of unrepaired DNA damage, particularly in oxidative damage-sensitive genes, was responsible for the long-lasting response in FA HSPCs. Furthermore, genetic correction of Fanca deficiency almost completely abolished the persistent oxidative stress-induced G 2 /M arrest and DNA damage response in vivo. Our study suggests that FA pathway is an integral part of a versatile cellular mechanism by which HSPCs respond to oxidative stress.

Persistent response of Fanconi anemia haematopoietic stem and progenitor cells to oxidative stress

PubMed Central

Wilson, Andrew F.; Li, Xue

2017-01-01

ABSTRACT Oxidative stress is considered as an important pathogenic factor in many human diseases including Fanconi anemia (FA), an inherited bone marrow failure syndrome with extremely high risk of leukemic transformation. Members of the FA protein family are involved in DNA damage and other cellular stress responses. Loss of FA proteins renders cells hypersensitive to oxidative stress and cancer transformation. However, how FA cells respond to oxidative DNA damage remains unclear. By using an in vivo stress-response mouse strain expressing the Gadd45β-luciferase transgene, we show here that haematopoietic stem and progenitor cells (HSPCs) from mice deficient for the FA gene Fanca or Fancc persistently responded to oxidative stress. Mechanistically, we demonstrated that accumulation of unrepaired DNA damage, particularly in oxidative damage-sensitive genes, was responsible for the long-lasting response in FA HSPCs. Furthermore, genetic correction of Fanca deficiency almost completely abolished the persistent oxidative stress-induced G2/M arrest and DNA damage response in vivo. Our study suggests that FA pathway is an integral part of a versatile cellular mechanism by which HSPCs respond to oxidative stress. PMID:28475398

Diagnosis of Fanconi Anemia: Mutation Analysis by Multiplex Ligation-Dependent Probe Amplification and PCR-Based Sanger Sequencing

PubMed Central

Gille, Johan J. P.; Floor, Karijn; Kerkhoven, Lianne; Ameziane, Najim; Joenje, Hans; de Winter, Johan P.

2012-01-01

Fanconi anemia (FA) is a rare inherited disease characterized by developmental defects, short stature, bone marrow failure, and a high risk of malignancies. FA is heterogeneous: 15 genetic subtypes have been distinguished so far. A clinical diagnosis of FA needs to be confirmed by testing cells for sensitivity to cross-linking agents in a chromosomal breakage test. As a second step, DNA testing can be employed to elucidate the genetic subtype of the patient and to identify the familial mutations. This knowledge allows preimplantation genetic diagnosis (PGD) and enables prenatal DNA testing in future pregnancies. Although simultaneous testing of all FA genes by next generation sequencing will be possible in the near future, this technique will not be available immediately for all laboratories. In addition, in populations with strong founder mutations, a limited test using Sanger sequencing and MLPA will be a cost-effective alternative. We describe a strategy and optimized conditions for the screening of FANCA, FANCB, FANCC, FANCE, FANCF, and FANCG and present the results obtained in a cohort of 54 patients referred to our diagnostic service since 2008. In addition, the follow up with respect to genetic counseling and carrier screening in the families is discussed. PMID:22778927

Overcoming reprogramming resistance of Fanconi anemia cells

PubMed Central

Müller, Lars U. W.; Milsom, Michael D.; Harris, Chad E.; Vyas, Rutesh; Brumme, Kristina M.; Parmar, Kalindi; Moreau, Lisa A.; Schambach, Axel; Park, In-Hyun; London, Wendy B.; Strait, Kelly; Schlaeger, Thorsten; DeVine, Alexander L.; Grassman, Elke; D'Andrea, Alan; Daley, George Q.

2012-01-01

Fanconi anemia (FA) is a recessive syndrome characterized by progressive fatal BM failure and chromosomal instability. FA cells have inactivating mutations in a signaling pathway that is critical for maintaining genomic integrity and protecting cells from the DNA damage caused by cross-linking agents. Transgenic expression of the implicated genes corrects the phenotype of hematopoietic cells, but previous attempts at gene therapy have failed largely because of inadequate numbers of hematopoietic stem cells available for gene correction. Induced pluripotent stem cells (iPSCs) constitute an alternate source of autologous cells that are amenable to ex vivo expansion, genetic correction, and molecular characterization. In the present study, we demonstrate that reprogramming leads to activation of the FA pathway, increased DNA double-strand breaks, and senescence. We also demonstrate that defects in the FA DNA-repair pathway decrease the reprogramming efficiency of murine and human primary cells. FA pathway complementation reduces senescence and restores the reprogramming efficiency of somatic FA cells to normal levels. Disease-specific iPSCs derived in this fashion maintain a normal karyotype and are capable of hematopoietic differentiation. These data define the role of the FA pathway in reprogramming and provide a strategy for future translational applications of patient-specific FA iPSCs. PMID:22371882

Chemosensitizing tumor cells by targeting the Fanconi anemia pathway with an adenovirus overexpressing dominant-negative FANCA.

PubMed

Ferrer, Miriam; de Winter, Johan P; Mastenbroek, D C Jeroen; Curiel, David T; Gerritsen, Winald R; Giaccone, Giuseppe; Kruyt, Frank A E

2004-08-01

Fanconi anemia (FA) is a rare genetic disorder characterized by bone-marrow failure and cellular hypersensitivity to crosslinking agents, including cisplatin. Here, we studied the use of the FA pathway as a possible target for cancer gene therapy with the aim to sensitize tumor cells for cisplatin by interfering with the FA pathway. As proof-of-principle, FA and non-FA lymphoblast-derived tumors were grown subcutaneously in scid mice and treated with two different concentrations of cisplatin. As predicted, the antitumor response was considerably improved in FA tumors. An adenoviral vector encoding a dominant-negative form of FANCA, FANCA600DN, was generated that interfered with endogenous FANCA-FANCG interaction resulting in the disruption of the FA pathway as illustrated by disturbed FANCD2 monoubiquitination. A panel of cell lines, including non-small-cell lung cancer cells, could be sensitized approximately two- to three-fold for cisplatin after Ad.CMV.FANCA600DN infection that may increase upon enhanced infection efficiency. In conclusion, targeting the FA pathway may provide a novel strategy for the sensitization of solid tumors for cisplatin and, in addition, provides a tool for examining the role of the FA pathway in determining chemoresistance in different tumor types.

75 FR 51657 - Airworthiness Directives; Pratt & Whitney Canada Corp. (P&WC) PW615F-A Turbofan Engines

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-23

... showed that the Fuel Filter Bypass Valve poppet in the Fuel Oil Heat Exchanger (FOHE) on that engine had... a dormant failure that could result in an unsafe condition. The PW615F-A engine Fuel Filter Bypass... that the Fuel Filter Bypass Valve poppet in the Fuel Oil Heat Exchanger (FOHE) on that engine had worn...

Comprehensive characterization of mesenchymal stromal cells from patients with Fanconi anaemia.

PubMed

Mantelli, Melissa; Avanzini, Maria Antonia; Rosti, Vittorio; Ingo, Daniela M; Conforti, Antonella; Novara, Francesca; Arrigo, Giulia; Boni, Marina; Zappatore, Rita; Lenta, Elisa; Moretta, Antonia; Acquafredda, Gloria; de Silvestri, Annalisa; Cirillo, Valentina; Cicchetti, Elisa; Algeri, Mattia; Strocchio, Luisa; Vinti, Luciana; Starc, Nadia; Biagini, Simone; Sirleto, Pietro; Bernasconi, Paolo; Zuffardi, Orsetta; Maserati, Emanuela; Maccario, Rita; Zecca, Marco; Locatelli, Franco; Bernardo, Maria Ester

2015-09-01

Fanconi anaemia (FA) is an inherited disorder characterized by pancytopenia, congenital malformations and a predisposition to develop malignancies. Alterations in the haematopoietic microenvironment of FA patients have been reported, but little is known regarding the components of their bone marrow (BM) stroma. We characterized mesenchymal stromal cells (MSCs) isolated from BM of 18 FA patients both before and after allogeneic haematopoietic stem cell transplantation (HSCT). Morphology, fibroblast colony-forming unit (CFU-F) ability, proliferative capacity, immunophenotype, differentiation potential, ability to support long-term haematopoiesis and immunomodulatory properties of FA-MSCs were analysed and compared with those of MSCs expanded from 15 age-matched healthy donors (HD-MSCs). FA-MSCs were genetically characterized through conventional karyotyping, diepoxybutane-test and array-comparative genomic hybridization. FA-MSCs generated before and after HSCT were compared. Morphology, immunophenotype, differentiation potential, ability in vitro to inhibit mitogen-induced T-cell proliferation and to support long-term haematopoiesis did not differ between FA-MSCs and HD-MSCs. CFU-F ability and proliferative capacity of FA-MSCs isolated after HSCT were significantly lower than those of HD-MSCs. FA-MSCs reached senescence significantly earlier than HD-MSCs and showed spontaneous chromosome fragility. Our findings indicate that FA-MSCs are defective in their ability to survive in vitro and display spontaneous chromosome breakages; whether these defects are involved in pathophysiology of BM failure syndromes deserves further investigation. © 2015 John Wiley & Sons Ltd.

FANCJ Helicase Operates in the Fanconi Anemia DNA Repair Pathway and the Response to Replicational Stress

PubMed Central

Wu, Yuliang; Brosh, Robert M.

2009-01-01

Fanconi anemia (FA) is an autosomal recessive disorder characterized by multiple congenital anomalies, progressive bone marrow failure, and high cancer risk. Cells from FA patients exhibit spontaneous chromosomal instability and hypersensitivity to DNA interstrand cross-linking (ICL) agents. Although the precise mechanistic details of the FA/BRCA pathway of ICL-repair are not well understood, progress has been made in the identification of the FA proteins that are required for the pathway. Among the 13 FA complementation groups from which all the FA genes have been cloned, only a few of the FA proteins are predicted to have direct roles in DNA metabolism. One of the more recently identified FA proteins, shown to be responsible for complementation of the FA complementation group J, is the BRCA1 Associated C-terminal Helicase (BACH1, designated FANCJ), originally identified as a protein associated with breast cancer. FANCJ has been proposed to function downstream of FANCD2 monoubiquitination, a critical event in the FA pathway. Evidence supports a role for FANCJ in a homologous recombination (HR) pathway of double strand break (DSB) repair. In this review, we will summarize the current knowledge in terms of FANCJ functions through its enzymatic activities and protein interactions. The molecular roles of FANCJ in DNA repair and the response to replicational stress will be discussed. PMID:19519404

The FA pathway counteracts oxidative stress through selective protection of antioxidant defense gene promoters.

PubMed

Du, Wei; Rani, Reena; Sipple, Jared; Schick, Jonathan; Myers, Kasiani C; Mehta, Parinda; Andreassen, Paul R; Davies, Stella M; Pang, Qishen

2012-05-03

Oxidative stress has been implicated in the pathogenesis of many human diseases including Fanconi anemia (FA), a genetic disorder associated with BM failure and cancer. Here we show that major antioxidant defense genes are down-regulated in FA patients, and that gene down-regulation is selectively associated with increased oxidative DNA damage in the promoters of the antioxidant defense genes. Assessment of promoter activity and DNA damage repair kinetics shows that increased initial damage, rather than a reduced repair rate, contributes to the augmented oxidative DNA damage. Mechanistically, FA proteins act in concert with the chromatin-remodeling factor BRG1 to protect the promoters of antioxidant defense genes from oxidative damage. Specifically, BRG1 binds to the promoters of the antioxidant defense genes at steady state. On challenge with oxidative stress, FA proteins are recruited to promoter DNA, which correlates with significant increase in the binding of BRG1 within promoter regions. In addition, oxidative stress-induced FANCD2 ubiquitination is required for the formation of a FA-BRG1-promoter complex. Taken together, these data identify a role for the FA pathway in cellular antioxidant defense.

Learning from a paradox: recent insights into Fanconi anaemia through studying mouse models.

PubMed

Bakker, Sietske T; de Winter, Johan P; te Riele, Hein

2013-01-01

Fanconi anaemia (FA) is a rare autosomal recessive or X-linked inherited disease characterised by an increased incidence of bone marrow failure (BMF), haematological malignancies and solid tumours. Cells from individuals with FA show a pronounced sensitivity to DNA interstrand crosslink (ICL)-inducing agents, which manifests as G2-M arrest, chromosomal aberrations and reduced cellular survival. To date, mutations in at least 15 different genes have been identified that cause FA; the products of all of these genes are thought to function together in the FA pathway, which is essential for ICL repair. Rapidly following the discovery of FA genes, mutant mice were generated to study the disease and the affected pathway. These mutant mice all show the characteristic cellular ICL-inducing agent sensitivity, but only partially recapitulate the developmental abnormalities, anaemia and cancer predisposition seen in individuals with FA. Therefore, the usefulness of modelling FA in mice has been questioned. In this Review, we argue that such scepticism is unjustified. We outline that haematopoietic defects and cancer predisposition are manifestations of FA gene defects in mice, albeit only in certain genetic backgrounds and under certain conditions. Most importantly, recent work has shown that developmental defects in FA mice also arise with concomitant inactivation of acetaldehyde metabolism, giving a strong clue about the nature of the endogenous lesion that must be repaired by the functional FA pathway. This body of work provides an excellent example of a paradox in FA research: that the dissimilarity, rather than the similarity, between mice and humans can provide insight into human disease. We expect that further study of mouse models of FA will help to uncover the mechanistic background of FA, ultimately leading to better treatment options for the disease.

FANCD2 monoubiquitination and activation by hexavalent chromium [Cr(VI)] exposure

PubMed Central

Vilcheck, Susan K.; Ceryak, Susan; O’Brien, Travis J.; Patierno, Steven R.

2007-01-01

Fanconi anemia (FA) is a rare autosomal recessive disorder characterized by congenital abnormalities, progressive bone marrow failure, and cancer susceptibility. FA cells are hypersensitive to DNA crosslinking agents. FA is a genetically heterogeneous disease with at least 11 complementation groups. The eight cloned FA proteins interact in a common pathway with established DNA-damage-response proteins, including BRCA1 and ATM. Six FA proteins (A, C, E, F, G, and L) regulate the monoubiquitination of FANCD2 after DNA damage by crosslinking agents, which targets FANCD2 to BRCA1 nuclear foci containing BRCA2 (FANCD1) and RAD51. Some forms of hexavalent chromium [Cr(VI)] are implicated as respiratory carcinogens and induce several types of DNA lesions, including DNA interstrand crosslinks. We have shown that FA-A fibroblasts are hypersensitive to both Cr(VI)-induced apoptosis and clonogenic lethality. Here we show that Cr(VI) treatment induced monoubiquitination of FANCD2 in normal human fibroblasts, providing the first molecular evidence of Cr(VI)-induced activation of the FA pathway. FA-A fibroblasts demonstrated no FANCD2 monoubiquitination, in keeping with the requirement of FA-A for this modification. We also found that Cr(VI) treatment induced significantly more S-phase-dependent DNA double strand breaks (DSBs), as measured by γ-H2AX expression, in FA-A fibroblasts compared to normal cells. However, and notably, DSBs were repaired equally in both normal and FA-A fibroblasts during recovery from Cr(VI) treatment. While previous research on FA has defined the genetic causes of this disease, it is critical in terms of individual risk assessment to address how cells from FA patients respond to genotoxic insult. PMID:16893675

Fanconi Anemia: A DNA repair disorder characterized by accelerated decline of the hematopoietic stem cell compartment and other features of aging.

PubMed

Brosh, Robert M; Bellani, Marina; Liu, Yie; Seidman, Michael M

2017-01-01

Fanconi Anemia (FA) is a rare autosomal genetic disorder characterized by progressive bone marrow failure (BMF), endocrine dysfunction, cancer, and other clinical features commonly associated with normal aging. The anemia stems directly from an accelerated decline of the hematopoietic stem cell compartment. Although FA is a complex heterogeneous disease linked to mutations in 19 currently identified genes, there has been much progress in understanding the molecular pathology involved. FA is broadly considered a DNA repair disorder and the FA gene products, together with other DNA repair factors, have been implicated in interstrand cross-link (ICL) repair. However, in addition to the defective DNA damage response, altered epigenetic regulation, and telomere defects, FA is also marked by elevated levels of inflammatory mediators in circulation, a hallmark of faster decline in not only other hereditary aging disorders but also normal aging. In this review, we offer a perspective of FA as a monogenic accelerated aging disorder, citing the latest evidence for its multi-factorial deficiencies underlying its unique clinical and cellular features. Published by Elsevier B.V.

Gap Junction Intercellular Communication in Bone Marrow Failure

DTIC Science & Technology

2012-10-01

enzyme systems, making individuals with these syndromes highly sensitive to DNA-damaging events. However, researchers suspect that modifier genes or...associated with a single gene defect. A major example of the progress in this area is Fanconi Anemia (FA), where mutations in up to 15 different...proteins have been associated to this disease, being FA-A the most frequent (1, 2). Single mutated genes in the DNA repair or ribosome biogenesis of HSC

Fanconi anemia protein, FANCG, is a phosphoprotein and is upregulated with FANCA after TNF-alpha treatment.

PubMed

Futaki, M; Watanabe, S; Kajigaya, S; Liu, J M

2001-02-23

Fanconi anemia (FA) is a genetic syndrome characterized by bone marrow failure, birth defects, and a predisposition to malignancy. At this time, six FA genes have been identified, and several gene products have been found to interact in a protein complex. FA cells appear to overexpress the proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha). We therefore examined the effects of TNF-alpha on the regulation of FA complementation group proteins, FANCG and FANCA. We found that treatment with TNF-alpha induced FANCG protein expression. FANCA was induced concurrently with FANCG, and the FANCA/FANCG complex was increased in the nucleus following TNF-alpha treatment. Inactivation of inhibitory kappa B kinase-2 modulated the expression of FANCG. We also found that both nuclear and cytoplasmic FANCG fractions were phosphorylated. These results show that FANCG is a phosphoprotein and suggest that the cellular accumulation of FA proteins is subject to regulation by TNF-alpha signaling.

Pluripotent cell models of fanconi anemia identify the early pathological defect in human hemoangiogenic progenitors.

PubMed

Suzuki, Naoya M; Niwa, Akira; Yabe, Miharu; Hira, Asuka; Okada, Chihiro; Amano, Naoki; Watanabe, Akira; Watanabe, Ken-Ichiro; Heike, Toshio; Takata, Minoru; Nakahata, Tatsutoshi; Saito, Megumu K

2015-04-01

Fanconi anemia (FA) is a disorder of genomic instability characterized by progressive bone marrow failure (BMF), developmental abnormalities, and an increased susceptibility to cancer. Although various consequences in hematopoietic stem/progenitor cells have been attributed to FA-BMF, the quest to identify the initial pathological event is still ongoing. To address this issue, we established induced pluripotent stem cells (iPSCs) from fibroblasts of six patients with FA and FANCA mutations. An improved reprogramming method yielded iPSC-like colonies from all patients, and iPSC clones were propagated from two patients. Quantitative evaluation of the differentiation ability demonstrated that the differentiation propensity toward the hematopoietic and endothelial lineages is already defective in early hemoangiogenic progenitors. The expression levels of critical transcription factors were significantly downregulated in these progenitors. These data indicate that the hematopoietic consequences in FA patients originate from the early hematopoietic stage and highlight the potential usefulness of iPSC technology for elucidating the pathogenesis of FA-BMF. ©AlphaMed Press.

Evaluation of wound healing activity of ferulic acid in diabetic rats.

PubMed

Ghaisas, Mahesh M; Kshirsagar, Shashank B; Sahane, Rajkumari S

2014-10-01

In diabetic patients, there is impairment in angiogenesis, neovascularisation and failure in matrix metalloproteineases (MMPs), keratinocyte and fibroblast functions, which affects wound healing mechanism. Hence, diabetic patients are more prone to infections and ulcers, which finally result in gangrene. Ferulic acid (FA) is a natural antioxidant found in fruits and vegetables, such as tomatoes, rice bran and sweet corn. In this study, wound healing activity of FA was evaluated in streptozotocin-induced diabetic rats using excision wound model. FA-treated wounds were found to epithelise faster as compared with diabetic wound control group. The hydroxyproline and hexosamine content increased significantly when compared with diabetic wound control. FA effectively inhibited the lipid peroxidation and elevated the catalase, superoxide dismutase, glutathione and nitric oxide levels along with the increase in the serum zinc and copper levels probably aiding the wound healing process. Hence, the results indicate that FA significantly promotes wound healing in diabetic rats. © 2012 The Authors. International Wound Journal © 2012 Medicalhelplines.com Inc and John Wiley & Sons Ltd.

Gene expression profiling reveals activation of the FA/BRCA pathway in advanced squamous cervical cancer with intrinsic resistance and therapy failure.

PubMed

Balacescu, Ovidiu; Balacescu, Loredana; Tudoran, Oana; Todor, Nicolae; Rus, Meda; Buiga, Rares; Susman, Sergiu; Fetica, Bogdan; Pop, Laura; Maja, Laura; Visan, Simona; Ordeanu, Claudia; Berindan-Neagoe, Ioana; Nagy, Viorica

2014-04-08

Advanced squamous cervical cancer, one of the most commonly diagnosed cancers in women, still remains a major problem in oncology due to treatment failure and distant metastasis. Antitumor therapy failure is due to both intrinsic and acquired resistance; intrinsic resistance is often decisive for treatment response. In this study, we investigated the specific pathways and molecules responsible for baseline therapy failure in locally advanced squamous cervical cancer. Twenty-one patients with locally advanced squamous cell carcinoma were enrolled in this study. Primary biopsies harvested prior to therapy were analyzed for whole human gene expression (Agilent) based on the patient's 6 months clinical response. Ingenuity Pathway Analysis was used to investigate the altered molecular function and canonical pathways between the responding and non-responding patients. The microarray results were validated by qRT-PCR and immunohistochemistry. An additional set of 24 formalin-fixed paraffin-embedded cervical cancer samples was used for independent validation of the proteins of interest. A 2859-gene signature was identified to distinguish between responder and non-responder patients. 'DNA Replication, Recombination and Repair' represented one of the most important mechanisms activated in non-responsive cervical tumors, and the 'Role of BRCA1 in DNA Damage Response' was predicted to be the most significantly altered canonical pathway involved in intrinsic resistance (p = 1.86E-04, ratio = 0.262). Immunohistological staining confirmed increased expression of BRCA1, BRIP1, FANCD2 and RAD51 in non-responsive compared with responsive advanced squamous cervical cancer, both in the initial set of 21 cervical cancer samples and the second set of 24 samples. Our findings suggest that FA/BRCA pathway plays an important role in treatment failure in advanced cervical cancer. The assessment of FANCD2, RAD51, BRCA1 and BRIP1 nuclear proteins could provide important information about the patients at risk for treatment failure.

248: Resuscitative Endovascular Balloon Occlusion of the Aorta Improves Survival in Lethal Hemorrhage

DTIC Science & Technology

2014-01-01

analyzed to evaluate for nonconvulsvie status epilepticus (NCSE) as defined in previous studies. Results: Out of the thirty patients that underwent...and oxygenation failure in 2,000 (38%) as indications for TI. In univariate analysis, shock status (OR 6.1 95%CI: 3.8-9.7, pɘ.0001) and...attempt, shock status remained associated with CAs (OR 6.2, 95%CI: 3.9-9.7, pɘ.0001) while oxygenation fa lure and resident providers were not (p=0.54

Workshop on Condition Based Maintenance Held in Atlantic Beach, North Carolina on November 15 - 17, 1993

DTIC Science & Technology

1993-11-17

pounds of Torque Over Three Minutes Continuous Operation IYMCO1A 14 DMAE Corporation C-130 Engine Gearbox January 19925 Stress Wave Analysis - I in’. I...FaUi.O The CBM needs associated with surface initiated failure mechanisms can be divided into I singular defects and low (h/a) operation. Singular defec-t...These include nicks, scratches, corrosion pits and dents caused by third’ body particles (hard or soft). These defects cause local stress risers

Short and long term behaviour of externally bonded fibre reinforced polymer laminates with bio-based resins for flexural strengthening of concrete beams

NASA Astrophysics Data System (ADS)

McSwiggan, Ciaran

The use of bio-based resins in composites for construction is emerging as a way to reduce of embodied energy produced by a structural system. In this study, two types of bio-based resins were explored: an epoxidized pine oil resin blend (EP) and a furfuryl alcohol resin (FA) derived from corn cobs and sugar cane. Nine large-scale reinforced concrete beams strengthened using externally bonded carbon and glass fibre reinforced bio-based polymer (CFRP and GFRP) sheets were tested. The EP resin resulted in a comparable bond strength to conventional epoxy (E) when used in wet layup, with a 7% higher strength for CFRP. The FA resin, on the other hand, resulted in a very weak bond, likely due to concrete alkalinity affecting curing. However, when FA resin was used to produce prefabricated cured CFRP plates which were then bonded to concrete using conventional epoxy paste, it showed an excellent bond strength. The beams achieved an increase in peak load ranging from 18-54% and a 9-46% increase in yielding load, depending on the number of FRP layers and type of fibres and resin. Additionally, 137 concrete prisms with a mid-span half-depth saw cut were used to test CFRP bond durability, and 195 CFRP coupons were used to examine tensile strength durability. Specimens were conditioned in a 3.5% saline solution at 23, 40 or 50°C, for up to 240 days. Reductions in bond strength did not exceed 15%. Bond failure of EP was adhesive with traces of cement paste on CFRP, whereas that of FA was cohesive with a thicker layer of concrete on CFRP, suggesting that the bond between FA and epoxy paste is excellent. EP tension coupons had similar strength and modulus to E resin, whereas FA coupons had a 9% lower strength and 14% higher modulus. After 240 days of exposure, maximum reductions in tensile strength were 8, 19 and 10% for EP, FA and E resins, respectively. Analysis of Variance (ANOVA) was also performed to assess the significance of the reductions observed. High degrees of variability in the test results may have skewed the results from this statistical analysis.

Voluntary running exercise prevents β-cell failure in susceptible islets of the Zucker diabetic fatty rat.

PubMed

Delghingaro-Augusto, Viviane; Décary, Simon; Peyot, Marie-Line; Latour, Martin G; Lamontagne, Julien; Paradis-Isler, Nicolas; Lacharité-Lemieux, Marianne; Akakpo, Huguette; Birot, Olivier; Nolan, Christopher J; Prentki, Marc; Bergeron, Raynald

2012-01-15

Physical activity improves glycemic control in type 2 diabetes (T2D), but its contribution to preserving β-cell function is uncertain. We evaluated the role of physical activity on β-cell secretory function and glycerolipid/fatty acid (GL/FA) cycling in male Zucker diabetic fatty (ZDF) rats. Six-week-old ZDF rats engaged in voluntary running for 6 wk (ZDF-A). Inactive Zucker lean and ZDF (ZDF-I) rats served as controls. ZDF-I rats displayed progressive hyperglycemia with β-cell failure evidenced by falling insulinemia and reduced insulin secretion to oral glucose. Isolated ZDF-I rat islets showed reduced glucose-stimulated insulin secretion expressed per islet and per islet protein. They were also characterized by loss of the glucose regulation of fatty acid oxidation and GL/FA cycling, reduced mRNA expression of key β-cell genes, and severe reduction of insulin stores. Physical activity prevented diabetes in ZDF rats through sustaining β-cell compensation to insulin resistance shown in vivo and in vitro. Surprisingly, ZDF-A islets had persistent defects in fatty acid oxidation, GL/FA cycling, and β-cell gene expression. ZDF-A islets, however, had preserved islet insulin mRNA and insulin stores compared with ZDF-I rats. Physical activity did not prevent hyperphagia, dyslipidemia, or obesity in ZDF rats. In conclusion, islets of ZDF rats have a susceptibility to failure that is possibly due to altered β-cell fatty acid metabolism. Depletion of pancreatic islet insulin stores is a major contributor to islet failure in this T2D model, preventable by physical activity.

FANCA and FANCG are the major Fanconi anemia genes in the Korean population.

PubMed

Park, J; Chung, N-G; Chae, H; Kim, M; Lee, S; Kim, Y; Lee, J-W; Cho, B; Jeong, D C; Park, I Y

2013-09-01

Fanconi anemia (FA) is a rare disorder characterized by physical abnormalities, bone marrow failure (BMF), increased risk of malignancies, and cellular hypersensitivity to DNA cross-linking agents. This study evaluated the genetic alterations in three major Fanconi genes (FANCA, FANCC, and FANCG) in 30 FA patients using multiplex ligation-dependent probe amplification and direct sequencing. Thirteen BMF patients were genetically classified as FA-A (n = 6, 46%) and FA-G (n = 7, 54%). Four common founder mutations were identified and included two FANCA mutations (c.2546delC and c.3720_3724delAAACA) and two FANCG mutations (c.307+1G>C and c.1066C>T), which had previously been commonly observed in a Japanese FA population. We also detected four novel deleterious mutations: c.2778+1G>C and c.3627-1G>A of FANCA, and c.1589_1591delATA and c.1761-1G>A of FANCG. This study shows that mutations in FANCA and FANCG are common in Korean FA patients and the existence of four common founder mutations in an East Asian FA population. Mutation screening workflow that includes these common mutations may be useful in the creation of an international database, and to better understand the ethnic characteristics of FA. © 2012 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Sonic Hedgehog, VACTERL, and Fanconi anemia: Pathogenetic connections and therapeutic implications.

PubMed

Lubinsky, Mark

2015-11-01

Three systems with VACTERL association findings- mutations of the Sonic Hedgehog (SHH) signaling pathway in mice, murine adriamycin teratogenicity, and human Fanconi anemia (FA) pathway mutations, may all involve a similar mechanism. SHH is up-regulated in irradiated cells, and DNA breaks common with radiation damage in the adriamycin and FA systems are plausible signals for such effects, which would affect development. Since FA related DNA breakage occurs throughout life, SHH disturbances may account for later FA related findings involving hematopoietic and malignancy issues. In support, androgen, a standard treatment for FA hematologic failure, down-regulates SHH, and common FA malignancies such as squamous cell carcinomas and acute myeloid leukemia have been linked to enhanced SHH function. This suggests that interventions lowering SHH levels may be useful therapeutically. Also supporting a connection between pre- and post- natal findings, the frequency and number of VACTERL anomalies with FA correlate with the severity and onset of hematopoietic and malignancy issues. In FA, radial anomalies are the most common of these defects, followed by renal findings, while vertebral and gastrointestinal anomalies are relatively uncommon, a pattern that differs from observations of the VACTERL association. Genes with more severe effects also show a greatly increased incidence of brain abnormalities, and a paucity of such findings with other FA genes suggests that brain development is relatively refractory to SHH related effects, accounting for the rarity of such findings with the association. © 2015 Wiley Periodicals, Inc.

IL-6, IL-8, MMP-2, MMP-9 are overexpressed in Fanconi anemia cells through a NF-κB/TNF-α dependent mechanism.

PubMed

Epanchintsev, Alexey; Shyamsunder, Pavithra; Verma, Rama S; Lyakhovich, Alex

2015-12-01

Fanconi anemia (FA) is a rare autosomal recessive genetic disorder associated with a bone-marrow failure, genome instability, hypersensitivity to DNA crosslinking agents and a predisposition to cancer. Mutations have been documented in 16 FA genes that participate in the FA-BRCA DNA repair pathway, a fundamental pathway in the development of the disease and the presentation of its symptoms. FA cells have been characterized by an overproduction of cytokines, MAPKs, and Interleukins. Through this study we have identified the overexpression of additional secretory factors such as IL-6, IL-8, MMP-2, and MMP-9 in FA cells and in cells depleted of FANCA or FANCC and proved that their expression is under the control of NF-κB/TNF-α signaling pathways. We also demonstrated that these overexpressed secretory factors were effective in promoting the proliferation, migration, and invasion of surrounding tumor cells a fundamental event in the process of epithelial mesenchymal transition (EMT) and that they also modulated the expression of EMT markers such as E-cadherin and SNAIL. Overall our data suggest that the upregulation of EMT promoting factors in FA may contribute to predisposing FA patients to cancer, thereby providing new insights into possible therapeutic interventions. © 2014 Wiley Periodicals, Inc.

Biallelic inactivation of REV7 is associated with Fanconi anemia.

PubMed

Bluteau, Dominique; Masliah-Planchon, Julien; Clairmont, Connor; Rousseau, Alix; Ceccaldi, Raphael; Dubois d'Enghien, Catherine; Bluteau, Olivier; Cuccuini, Wendy; Gachet, Stéphanie; Peffault de Latour, Régis; Leblanc, Thierry; Socié, Gérard; Baruchel, André; Stoppa-Lyonnet, Dominique; D'Andrea, Alan D; Soulier, Jean

2016-09-01

Fanconi anemia (FA) is a recessive genetic disease characterized by congenital abnormalities, chromosome instability, progressive bone marrow failure (BMF), and a strong predisposition to cancer. Twenty FA genes have been identified, and the FANC proteins they encode cooperate in a common pathway that regulates DNA crosslink repair and replication fork stability. We identified a child with severe BMF who harbored biallelic inactivating mutations of the translesion DNA synthesis (TLS) gene REV7 (also known as MAD2L2), which encodes the mutant REV7 protein REV7-V85E. Patient-derived cells demonstrated an extended FA phenotype, which included increased chromosome breaks and G2/M accumulation upon exposure to DNA crosslinking agents, γH2AX and 53BP1 foci accumulation, and enhanced p53/p21 activation relative to cells derived from healthy patients. Expression of WT REV7 restored normal cellular and functional phenotypes in the patient's cells, and CRISPR/Cas9 inactivation of REV7 in a non-FA human cell line produced an FA phenotype. Finally, silencing Rev7 in primary hematopoietic cells impaired progenitor function, suggesting that the DNA repair defect underlies the development of BMF in FA. Taken together, our genetic and functional analyses identified REV7 as a previously undescribed FA gene, which we term FANCV.

Biallelic inactivation of REV7 is associated with Fanconi anemia

PubMed Central

Masliah-Planchon, Julien; Clairmont, Connor; Rousseau, Alix; Ceccaldi, Raphael; Dubois d’Enghien, Catherine; Bluteau, Olivier; Cuccuini, Wendy; Gachet, Stéphanie; Peffault de Latour, Régis; Leblanc, Thierry; Socié, Gérard; Baruchel, André; Stoppa-Lyonnet, Dominique; D’Andrea, Alan D.

2016-01-01

Fanconi anemia (FA) is a recessive genetic disease characterized by congenital abnormalities, chromosome instability, progressive bone marrow failure (BMF), and a strong predisposition to cancer. Twenty FA genes have been identified, and the FANC proteins they encode cooperate in a common pathway that regulates DNA crosslink repair and replication fork stability. We identified a child with severe BMF who harbored biallelic inactivating mutations of the translesion DNA synthesis (TLS) gene REV7 (also known as MAD2L2), which encodes the mutant REV7 protein REV7-V85E. Patient-derived cells demonstrated an extended FA phenotype, which included increased chromosome breaks and G2/M accumulation upon exposure to DNA crosslinking agents, γH2AX and 53BP1 foci accumulation, and enhanced p53/p21 activation relative to cells derived from healthy patients. Expression of WT REV7 restored normal cellular and functional phenotypes in the patient’s cells, and CRISPR/Cas9 inactivation of REV7 in a non-FA human cell line produced an FA phenotype. Finally, silencing Rev7 in primary hematopoietic cells impaired progenitor function, suggesting that the DNA repair defect underlies the development of BMF in FA. Taken together, our genetic and functional analyses identified REV7 as a previously undescribed FA gene, which we term FANCV. PMID:27500492

Damaged mitochondria in Fanconi anemia - an isolated event or a general phenomenon?

PubMed

Pagano, Giovanni; Shyamsunder, Pavithra; Verma, Rama S; Lyakhovich, Alex

2014-01-01

Fanconi anemia (FA) is known as an inherited bone marrow failure syndrome associated with cancer predisposition and susceptibility to a number of DNA damaging stimuli, along with a number of clinical features such as upper limb malformations, increased diabetes incidence and typical anomalies in skin pigmentation. The proteins encoded by FA-defective genes (FANC proteins) display well-established roles in DNA damage and repair pathways. Moreover, some independent studies have revealed that mitochondrial dysfunction (MDF) is also involved in FA phenotype. Unconfined to FA, we have shown that other syndromes featuring DNA damage and repair (such as ataxia-telangiectasia, AT, and Werner syndrome, WS) display MDF-related phenotypes, along with oxidative stress (OS) that, altogether, may play major roles in these diseases. Experimental and clinical studies are warranted in the prospect of future therapies to be focused on compounds scavenging reactive oxygen species (ROS) as well as protecting mitochondrial functions.

Phenotypic correction of Fanconi anemia cells in the murine bone marrow after carrier cell mediated delivery of lentiviral vector.

PubMed

Chakkaramakkil Verghese, Santhosh; Goloviznina, Natalya A; Kurre, Peter

2016-11-19

Fanconi anemia (FA) is an autosomal-recessive disorder associated with hematopoietic failure and it is a candidate for hematopoietic stem cell (HSC)-directed gene therapy. However, the characteristically reduced HSC numbers found in FA patients, their ineffective mobilization from the marrow, and re-oxygenation damage during ex vivo manipulation have precluded clinical success using conventional in vitro approaches. We previously demonstrated that lentiviral vector (LV) particles reversibly attach to the cell surface where they gain protection from serum complement neutralization. We reasoned that cellular delivery of LV to the bone marrow niche could avoid detrimental losses during FA HSC mobilization and in vitro modification. Here, we demonstrate that a VSV-G pseudotyped lentivector, carrying the FANCC transgene, can be transmitted from carrier to bystander cells. In cell culture and transplantation models of FA, we further demonstrate that LV carrier cells migrate along SDF-1α gradients and transfer vector particles that stably integrate and phenotypically correct the characteristic DNA alkylator sensitivity in murine and human FA-deficient target bystander cells. Altogether, we demonstrate that cellular homing mechanisms can be harnessed for the functional phenotype correction in murine FA hematopoietic cells.

Transplant results in adults with Fanconi anaemia.

PubMed

Bierings, Marc; Bonfim, Carmem; Peffault De Latour, Regis; Aljurf, Mahmoud; Mehta, Parinda A; Knol, Cora; Boulad, Farid; Tbakhi, Abdelghani; Esquirol, Albert; McQuaker, Grant; Sucak, Gulsan A; Othman, Tarek B; Halkes, Constantijn J M; Carpenter, Ben; Niederwieser, Dietger; Zecca, Marco; Kröger, Nicolaus; Michallet, Mauricette; Risitano, Antonio M; Ehninger, Gerhard; Porcher, Raphael; Dufour, Carlo

2018-01-01

The outcomes of adult patients transplanted for Fanconi anaemia (FA) have not been well described. We retrospectively analysed 199 adult patients with FA transplanted between 1991 and 2014. Patients were a median of 16 years of age when diagnosed with FA, and underwent transplantation at a median age of 23 years. Time between diagnosis and transplant was shortest (median 2 years) in those patients who had a human leucocyte antigen identical sibling donor. Fifty four percent of patients had bone marrow (BM) failure at transplantation and 46% had clonal disease (34% myelodysplasia, 12% acute leukaemia). BM was the main stem cell source, the conditioning regimen included cyclophosphamide in 96% of cases and fludarabine in 64%. Engraftment occurred in 82% (95% confidence interval [CI] 76-87%), acute graft-versus-host disease (GvHD) grade II-IV in 22% (95% CI 16-28%) and the incidence of chronic GvHD at 96 months was 26% (95% CI 20-33). Non-relapse mortality at 96 months was 56% with an overall survival of 34%, which improved with more recent transplants. Median follow-up was 58 months. Patients transplanted after 2000 had improved survival (84% at 36 months), using BM from an identical sibling and fludarabine in the conditioning regimen. Factors associated with improved outcome in multivariate analysis were use of fludarabine and an identical sibling or matched non-sibling donor. Main causes of death were infection (37%), GvHD (24%) and organ failure (12%). The presence of clonal disease at transplant did not significant impact on survival. Secondary malignancies were reported in 15 of 131 evaluable patients. © 2017 John Wiley & Sons Ltd.

[Modifications in myocardial energy metabolism in diabetic patients

NASA Technical Reports Server (NTRS)

Grynberg, A.

2001-01-01

The capacity of cardiac myocyte to regulate ATP production to face any change in energy demand is a major determinant of cardiac function. Because FA is the main heart fuel (although the most expensive one in oxygen, and prompt to induce deleterious effects), this process is based on a balanced fatty acid (FA) metabolism. Several pathological situations are associated with an accumulation of FA or derivatives, or with an excessive b-oxidation. The diabetic cardiomyocyte is characterised by an over consumption of FA. The control of the FA/glucose balance clearly appears as a new strategy for cytoprotection, particularly in diabetes and requires a reduced FA contribution to ATP production. Cardiac myocytes can control FA mitochondrial entry, but display weak ability to control FA uptake, thus the fate of non beta-oxidized FA appear as a new impairment for the cell. Both the trigger and the regulation of cardiac contraction result from membrane activity, and the other major FA function in the myocardium is their role in membrane homeostasis, through the phospholipid synthesis and remodeling pathways. Sudden death, hypercatecholaminemia, diabetes and heart failure have been associated with an altered PUFA content in cardiac membranes. Experimental data suggest that the 2 metabolic pathways involved in membrane homeostasis may represent therapeutic targets for cytoprotection. The drugs that increase cardiac phospholipid turnover (trimetazidine, ranolazine,...) display anti-ischemic non hemodynamic effect. This effect is based on a redirection of FA utilization towards phospholipid synthesis, which decrease their availability for energy production. A nutritional approach gave also promising results. Besides its anti-arrhythmic effect, the dietary docosahexaenoic acid is able to reduce FA energy consumption and hence oxygen demand. The cardiac metabolic pathways involving FA should be considered as a whole, precariously balanced. The diabetic heart being characterised by a different metabolic "status" with similarities to that of myocardium in coronary disease. Diabetes and other chronic cardiac diseases share common FA metabolism disorders leading to an altered energy balance, a decrease in long chain polyunsaturated Fas, and altered FA profiles in cardiac membranes. These disturbances, however, do not represent independent therapeutic targets, and should be considered as a whole.

Increased red cell distribution width in Fanconi anemia: a novel marker of stress erythropoiesis.

PubMed

Sousa, Rosa; Gonçalves, Cristina; Guerra, Isabel Couto; Costa, Emília; Fernandes, Ana; do Bom Sucesso, Maria; Azevedo, Joana; Rodriguez, Alfredo; Rius, Rocio; Seabra, Carlos; Ferreira, Fátima; Ribeiro, Letícia; Ferrão, Anabela; Castedo, Sérgio; Cleto, Esmeralda; Coutinho, Jorge; Carvalho, Félix; Barbot, José; Porto, Beatriz

2016-07-25

Red cell distribution width (RDW), a classical parameter used in the differential diagnosis of anemia, has recently been recognized as a marker of chronic inflammation and high levels of oxidative stress (OS). Fanconi anemia (FA) is a genetic disorder associated to redox imbalance and dysfunctional response to OS. Clinically, it is characterized by progressive bone marrow failure, which remains the primary cause of morbidity and mortality. Macrocytosis and increased fetal hemoglobin, two indicators of bone marrow stress erythropoiesis, are generally the first hematological manifestations to appear in FA. However, the significance of RDW and its possible relation to stress erythropoiesis have never been explored in FA. In the present study we analyzed routine complete blood counts from 34 FA patients and evaluated RDW, correlating with the hematological parameters most consistently associated with the FA phenotype. We showed, for the first time, that RDW is significantly increased in FA. We also showed that increased RDW is correlated with thrombocytopenia, neutropenia and, most importantly, highly correlated with anemia. Analyzing sequential hemograms from 3 FA patients with different clinical outcomes, during 10 years follow-up, we confirmed a consistent association between increased RDW and decreased hemoglobin, which supports the postulated importance of RDW in the evaluation of hematological disease progression. This study shows, for the first time, that RDW is significantly increased in FA, and this increment is correlated with neutropenia, thrombocytopenia, and highly correlated with anemia. According to the present results, it is suggested that increased RDW can be a novel marker of stress erythropoiesis in FA.

Thinking of VACTERL-H? Rule out Fanconi Anemia according to PHENOS.

PubMed

Alter, Blanche P; Giri, Neelam

2016-06-01

VACTERL-H association includes three of eight features: vertebral anomalies, anal atresia, congenital heart disease, tracheo-esophageal fistula, esophageal atresia, renal, limb anomalies, and hydrocephalus. The VACTERL-H phenotype among cases with FA is considered to be about 5%; the frequency of FA among patients with VACTERL-H is unknown. We examined 54 patients with FA in the National Cancer Institute Inherited Bone Marrow Failure Syndrome Cohort for features of VACTERL-H, including imaging studies (radiology and ultrasound). Eighteen of the fifty-four patients had three or more VACTERL-H features. The presence of VACTERL-H association in 33% of those with FA is much higher than the previous estimate of 5% (P < 0.0001). We created the acronym PHENOS (Pigmentation, small Head, small Eyes, central Nervous system (not hydrocephalus), Otology, and Short stature) which includes all major phenotypic features of FA that are not in VACTERL-H; these findings were more frequent in the patients with FA who had VACTERL-H. Identification of any components of the VACTERL-H association should lead to imaging studies, and to consideration of the diagnosis of FA, particularly if the patient has radial ray and renal anomalies, as well as many features of PHENOS. There was no association of the presence or absence of VACTERL-H with development of cancer, stem cell transplant, or survival. Early diagnosis will lead to genetic counseling and early surveillance and management of complications of FA. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

The carboxyl terminus of FANCE recruits FANCD2 to the Fanconi Anemia (FA) E3 ligase complex to promote the FA DNA repair pathway.

PubMed

Polito, David; Cukras, Scott; Wang, Xiaozhe; Spence, Paige; Moreau, Lisa; D'Andrea, Alan D; Kee, Younghoon

2014-03-07

Fanconi anemia (FA) is a genome instability syndrome characterized by bone marrow failure and cellular hypersensitivity to DNA cross-linking agents. In response to DNA damage, the FA pathway is activated through the cooperation of 16 FA proteins. A central player in the pathway is a multisubunit E3 ubiquitin ligase complex or the FA core complex, which monoubiquitinates its substrates FANCD2 and FANCI. FANCE, a subunit of the FA core complex, plays an essential role by promoting the integrity of the complex and by directly recognizing FANCD2. To delineate its role in substrate ubiquitination from the core complex assembly, we analyzed a series of mutations within FANCE. We report that a phenylalanine located at the highly conserved extreme C terminus, referred to as Phe-522, is a critical residue for mediating the monoubiquitination of the FANCD2-FANCI complex. Using the FANCE mutant that specifically disrupts the FANCE-FANCD2 interaction as a tool, we found that the interaction-deficient mutant conferred cellular sensitivity in reconstituted FANCE-deficient cells to a similar degree as FANCE null cells, suggesting the significance of the FANCE-FANCD2 interaction in promoting cisplatin resistance. Intriguingly, ectopic expression of the FANCE C terminus fragment alone in FA normal cells disrupts DNA repair, consolidating the importance of the FANCE-FANCD2 interaction in the DNA cross-link repair.

The Carboxyl Terminus of FANCE Recruits FANCD2 to the Fanconi Anemia (FA) E3 Ligase Complex to Promote the FA DNA Repair Pathway*

PubMed Central

Polito, David; Cukras, Scott; Wang, Xiaozhe; Spence, Paige; Moreau, Lisa; D'Andrea, Alan D.; Kee, Younghoon

2014-01-01

Fanconi anemia (FA) is a genome instability syndrome characterized by bone marrow failure and cellular hypersensitivity to DNA cross-linking agents. In response to DNA damage, the FA pathway is activated through the cooperation of 16 FA proteins. A central player in the pathway is a multisubunit E3 ubiquitin ligase complex or the FA core complex, which monoubiquitinates its substrates FANCD2 and FANCI. FANCE, a subunit of the FA core complex, plays an essential role by promoting the integrity of the complex and by directly recognizing FANCD2. To delineate its role in substrate ubiquitination from the core complex assembly, we analyzed a series of mutations within FANCE. We report that a phenylalanine located at the highly conserved extreme C terminus, referred to as Phe-522, is a critical residue for mediating the monoubiquitination of the FANCD2-FANCI complex. Using the FANCE mutant that specifically disrupts the FANCE-FANCD2 interaction as a tool, we found that the interaction-deficient mutant conferred cellular sensitivity in reconstituted FANCE-deficient cells to a similar degree as FANCE null cells, suggesting the significance of the FANCE-FANCD2 interaction in promoting cisplatin resistance. Intriguingly, ectopic expression of the FANCE C terminus fragment alone in FA normal cells disrupts DNA repair, consolidating the importance of the FANCE-FANCD2 interaction in the DNA cross-link repair. PMID:24451376

The phenotype and clinical course of Japanese Fanconi Anaemia infants is influenced by patient, but not maternal ALDH2 genotype.

PubMed

Yabe, Miharu; Yabe, Hiromasa; Morimoto, Tsuyoshi; Fukumura, Akiko; Ohtsubo, Keisuke; Koike, Takashi; Yoshida, Kenichi; Ogawa, Seishi; Ito, Etsuro; Okuno, Yusuke; Muramatsu, Hideki; Kojima, Seiji; Matsuo, Keitaro; Hira, Asuka; Takata, Minoru

2016-11-01

Studies using Fanconi anaemia (FA) mutant mouse models suggested that the combination of a defective FA pathway and aldehyde dehydrogenase-2 (ALDH2) dysfunction could provoke bone marrow failure, leukaemia and developmental defects, and that both maternal and fetal aldehyde detoxification are crucial to protect the developing embryo from DNA damage. We studied the ALDH2 genotypes of 35 Japanese FA patients and their mothers. We found that a normal maternal ALDH2 allele was not essential for fetal development of ALDH2-deficient patients, and none of the post-natal clinical parameters were clearly affected by the maternal ALDH2 genotype in these patients. © 2016 John Wiley & Sons Ltd.

A cytoplasmic serine protein kinase binds and may regulate the Fanconi anemia protein FANCA.

PubMed

Yagasaki, H; Adachi, D; Oda, T; Garcia-Higuera, I; Tetteh, N; D'Andrea, A D; Futaki, M; Asano, S; Yamashita, T

2001-12-15

Fanconi anemia (FA) is an autosomal recessive disease with congenital anomalies, bone marrow failure, and susceptibility to leukemia. Patient cells show chromosome instability and hypersensitivity to DNA cross-linking agents. At least 8 complementation groups (A-G) have been identified and 6 FA genes (for subtypes A, C, D2, E, F, and G) have been cloned. Increasing evidence indicates that a protein complex assembly of multiple FA proteins, including FANCA and FANCG, plays a crucial role in the FA pathway. Previously, it was reported that FANCA was phosphorylated in lymphoblasts from normal controls, whereas the phosphorylation was defective in those derived from patients with FA of multiple complementation groups. The present study examined phosphorylation of FANCA ectopically expressed in FANCA(-) cells. Several patient-derived mutations abrogated in vivo phosphorylation of FANCA in this system, suggesting that FANCA phosphorylation is associated with its function. In vitro phosphorylation studies indicated that a physiologic protein kinase for FANCA (FANCA-PK) forms a complex with the substrate. Furthermore, at least a part of FANCA-PK as well as phosphorylated FANCA were included in the FANCA/FANCG complex. Thus, FANCA-PK appears to be another component of the FA protein complex and may regulate function of FANCA. FANCA-PK was characterized as a cytoplasmic serine kinase sensitive to wortmannin. Identification of the protein kinase is expected to elucidate regulatory mechanisms that control the FA pathway.

Cloning and characterization of murine fanconi anemia group A gene: Fanca protein is expressed in lymphoid tissues, testis, and ovary.

PubMed

van de Vrugt, H J; Cheng, N C; de Vries, Y; Rooimans, M A; de Groot, J; Scheper, R J; Zhi, Y; Hoatlin, M E; Joenje, H; Arwert, F

2000-04-01

Fanconi anemia (FA) is an autosomal recessive disorder in humans characterized by bone marrow failure, cancer predisposition, and cellular hypersensitivity to cross-linking agents such as mitomycin C and diepoxybutane. FA genes display a caretaker function essential for maintenance of genomic integrity. We have cloned the murine homolog of FANCA, the gene mutated in the major FA complementation group (FA-A). The full-length mouse Fanca cDNA consists of 4503 bp and encodes a protein with a predicted molecular weight of 161 kDa. The deduced Fanca mouse protein shares 81% amino acid sequence similarity and 66% identity with the human protein. The nuclear localization signal and partial leucine zipper consensus motifs found in the human FANCA protein were also present in the murine homolog. In spite of the species difference, the murine Fanca cDNA was capable of correcting the cross-linker sensitive phenotype of human FA-A cells, suggesting functional conservation. Based on Northern as well as Western blots, Fanca was mainly expressed in lymphoid tissues, testis, and ovary. This expression pattern correlates with some of the clinical symptoms observed in FA patients. The availability of the murine Fanca cDNA now allows the gene to be studied in experimental mouse models.

Determination of red blood cell fatty acid profiles: Rapid and high-confident analysis by chemical ionization-gas chromatography-tandem mass spectrometry.

PubMed

Schober, Yvonne; Wahl, Hans Günther; Renz, Harald; Nockher, Wolfgang Andreas

2017-01-01

Cellular fatty acid (FA) profiles have been acknowledged as biomarkers in various human diseases. Nevertheless, common FA analysis by gas chromatography mass spectrometry (GC-MS) requires long analysis time. Hence, there is a need for feasible methods for high throughput analysis in clinical studies. FA was extracted from red blood cells (RBC) and derivatized to fatty acid methyl esters (FAME). A method using gas chromatography tandem mass spectrometry (GC-MS/MS) with ammonia-induced chemical ionization (CI) was developed for the analysis of FA profiles in human RBC. We compared this method with classical single GC-MS using electron impact ionization (EI). The FA profiles of 703 RBC samples were determined by GC-MS/MS. In contrast to EI ammonia-induced CI resulted in adequate amounts of molecular ions for further fragmentation of FAME. Specific fragments for confident quantification and fragmentation were determined for 45 FA. The GC-MS/MS method has a total run time of 9min compared to typical analysis times of up to 60min in conventional GC-MS. Intra and inter assay variations were <10% for all FA analyzed. Analysis of RBC FA composition revealed an age-dependent increase of the omega-3 eicosapentaenoic and docosahexaenoic acid, and a decline of the omega-6 linoleic acid with a corresponding rise of the omega-3 index. The combination of ammonia-induced CI and tandem mass spectrometry after GC separation allows for high-throughput, robust and confident analysis of FA profiles in the clinical laboratory. Copyright © 2016. Published by Elsevier B.V.

Small Molecule Protection of Bone Marrow Hematopoietic Stem Cells

DTIC Science & Technology

2017-12-01

using isogenic (mutant/complemented) human cell line pairs from patients with Fanconi anemia (FA), a heritable human bone marrow failure (BMF) syndrome ...small molecules could be therapeutically useful in reducing the risk of BMF in diseases such as Fanconi anemia, and perhaps after radiation exposure...damage-repair, DNA damage response, Fanconi anemia and associated bone marrow failure syndromes and environmental and molecular toxicology will all be

Anti-Müllerian Hormone Deficiency in Females With Fanconi Anemia

PubMed Central

Sklavos, Martha M.; Giri, Neelam; Stratton, Pamela; Alter, Blanche P.

2014-01-01

Context: In females with Fanconi anemia (FA), infertility is often accompanied by diminished ovarian reserve and hypergonadotropic amenorrhea before the age of 30 years, suggesting primary ovarian insufficiency (POI). POI is typically diagnosed only after perimenopausal symptoms are observed. Objective: The objective of the study was to assess whether serum anti-Müllerian hormone (AMH) levels can serve as a cycle-independent marker for the diagnosis of POI in patients with FA. Design and Setting: This observational study used the National Cancer Institute's inherited bone marrow failure syndrome cohort at the National Institutes of Health Clinical Center. Participants: The study included 22 females with FA, 20 unaffected female relatives of patients with FA, and 21 unrelated healthy females under 41 years of age. Main Outcome Measure: Serum AMH, a marker of ovarian reserve, was measured in all participants. Results: Females with FA had very low AMH levels (median 0.05 ng/mL; range 0–2.32 ng/mL; P < .001) when compared with unaffected relatives (median 2.10 ng/mL; range 0.04–4.73 ng/mL) and unrelated healthy females (median 1.92 ng/mL; range 0.31–6.64 ng/mL). All patients with FA older than 25 years of age were diagnosed with POI and had undetectable AMH levels. Conclusions: AMH deficiency appears to be a shared trait across this heterogeneous FA cohort. Substantially reduced AMH levels in females with FA suggest a primary ovarian defect associated with reduced fertility. Measurement of AMH at the time of FA diagnosis and subsequent monitoring of AMH levels at regular intervals may be useful for the timely management of complications related to POI such as subfertility/infertility, osteoporosis, and menopausal symptoms. PMID:24438373

Incidence of Fanconi anemia in children with congenital thumb anomalies referred for diepoxybutane testing.

PubMed

Webb, Michelle L; Rosen, Heather; Taghinia, Amir; McCarty, Erika R; Cerrato, Felecia; Upton, Joseph; Labow, Brian I

2011-06-01

Fanconi anemia (FA) is a rare genetic disorder of DNA repair that with near uniformity leads to bone marrow failure and resulting morbidity and mortality. Approximately 50% of FA patients are born with anomalies of the thumb or thumb and radius, and it has been recommended that all patients born with thumb anomalies undergo testing. However, the risk of FA in this population is unknown. We determined the incidence of FA in children with congenital thumb anomalies referred for FA testing and characterized those who tested positive. We queried our database for patients who presented with congenital thumb anomalies and who underwent diepoxybutane (DEB) testing for FA between 1999 and 2008 at Children's Hospital Boston and the Dana-Farber Cancer Institute. During this time period, 543 congenital thumb anomaly patients (235 with thumb hypoplasia) presented to our institution. A total of 81 patients with thumb abnormalities underwent DEB testing. Six patients (7% of those tested; 1% of the total; 3% of thumb hypoplasia patients) had a positive DEB test consistent with the diagnosis of FA; all had other non-upper-extremity anomalies associated with FA. Of 6 FA patients, 5 had bilateral involvement; all had some degree of thumb hypoplasia (3 also had radial dysplasia). Mean age at testing was 2.6 years (SD 4.3). Most of the patients tested had multiple physical anomalies (n = 66). The anomaly distribution was: thumb hypoplasia and radial dysplasia (n = 29), thumb hypoplasia (n = 26), radial polydactyly (n = 12), radial polydactyly and radial dysplasia (n = 1), and proximally placed thumb and radial dysplasia (n = 1). Twelve patients had other thumb anomalies. Although the incidence of FA in patients with thumb anomalies may be low, patients with thumb hypoplasia and other physical findings associated with FA, specifically café au lait spots and short stature, appear to have an increased risk of FA. Because hand surgeons see these patients early in life, they have the opportunity to refer these patients for FA testing to initiate early education, family genetic counseling, and treatment if warranted. Prognostic IV. Copyright © 2011 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.

Fanconi anaemia in South Africa: Past, present and future.

PubMed

Feben, C; Wainstein, T; Kromberg, J; Essop, F; Krause, A

2018-04-25

Fanconi anaemia (FA) is an inherited genetic disorder characterised by somatic anomalies, bone marrow failure and an increased predisposition to solid tumours and haematological malignancies. South African (SA) black and Afrikaner individuals are at higher than average risk for this condition owing to genetic founder mutations in certain Fanconi-associated genes. This review explores the epidemiology, clinical presentation, diagnostic modalities and recommended care of affected patients, focusing on the founder population groups in SA. The early diagnosis of FA is important and provides improved opportunities for early intervention, but remains challenging.

The fanconi anemia proteins FANCA and FANCG stabilize each other and promote the nuclear accumulation of the Fanconi anemia complex.

PubMed

Garcia-Higuera, I; Kuang, Y; Denham, J; D'Andrea, A D

2000-11-01

Fanconi anemia (FA) is an autosomal recessive cancer susceptibility syndrome with 8 complementation groups. Four of the FA genes have been cloned, and at least 3 of the encoded proteins, FANCA, FANCC, and FANCG/XRCC9, interact in a multisubunit protein complex. The FANCG protein binds directly to the amino terminal nuclear localization sequence (NLS) of FANCA, suggesting that FANCG plays a role in regulating FANCA nuclear accumulation. In the current study the functional consequences of FANCG/FANCA binding were examined. Correction of an FA-G cell line with the FANCG complementary DNA (cDNA) resulted in FANCA/FANCG binding, prolongation of the cellular half-life of FANCA, and an increase in the nuclear accumulation of the FA protein complex. Similar results were obtained upon correction of an FA-A cell line, with a reciprocal increase in the half-life of FANCG. Patient-derived mutant forms of FANCA, containing an intact NLS sequence but point mutations in the carboxy-terminal leucine zipper region, bound FANCG in the cytoplasm. The mutant forms failed to translocate to the nucleus of transduced cells, thereby suggesting a model of coordinated binding and nuclear translocation. These results demonstrate that the FANCA/FANCG interaction is required to maintain the cellular levels of both proteins. Moreover, at least one function of FANCG and FANCA is to regulate the nuclear accumulation of the FA protein complex. Failure to accumulate the nuclear FA protein complex results in the characteristic spectrum of clinical and cellular abnormalities observed in FA.

Functional Analysis of Problem Behavior: A Systematic Approach for Identifying Idiosyncratic Variables

PubMed Central

Roscoe, Eileen M.; Schlichenmeyer, Kevin J.; Dube, William V.

2015-01-01

When inconclusive functional analysis (FA) outcomes occur, a number of modifications have been made to enhance the putative establishing operation or consequence associated with behavioral maintenance. However, a systematic method for identifying relevant events to test during modified FAs has not been evaluated. The purpose of this study was to develop and evaluate a technology for systematically identifying events to test in a modified FA after an initial FA led to inconclusive outcomes. Six individuals whose initial FA showed little or no responding or high levels only in the control condition participated. An indirect assessment (IA) questionnaire developed for identifying idiosyncratic variables was administered, and a descriptive analysis (DA) was conducted. Results from the IA only or a combination of the IA and DA were used to inform modified FA test and control conditions. Conclusive FA outcomes were obtained with five of the six participants during the modified FA phase. PMID:25930176

Deficiency of UBE2T, the E2 Ubiquitin Ligase Necessary for FANCD2 and FANCI Ubiquitination, Causes FA-T Subtype of Fanconi Anemia.

PubMed

Rickman, Kimberly A; Lach, Francis P; Abhyankar, Avinash; Donovan, Frank X; Sanborn, Erica M; Kennedy, Jennifer A; Sougnez, Carrie; Gabriel, Stacey B; Elemento, Olivier; Chandrasekharappa, Settara C; Schindler, Detlev; Auerbach, Arleen D; Smogorzewska, Agata

2015-07-07

Fanconi anemia (FA) is a rare bone marrow failure and cancer predisposition syndrome resulting from pathogenic mutations in genes encoding proteins participating in the repair of DNA interstrand crosslinks (ICLs). Mutations in 17 genes (FANCA-FANCS) have been identified in FA patients, defining 17 complementation groups. Here, we describe an individual presenting with typical FA features who is deficient for the ubiquitin-conjugating enzyme (E2), UBE2T. UBE2T is known to interact with FANCL, the E3 ubiquitin-ligase component of the multiprotein FA core complex, and is necessary for the monoubiquitination of FANCD2 and FANCI. Proband fibroblasts do not display FANCD2 and FANCI monoubiquitination, do not form FANCD2 foci following treatment with mitomycin C, and are hypersensitive to crosslinking agents. These cellular defects are complemented by expression of wild-type UBE2T, demonstrating that deficiency of the protein UBE2T can lead to Fanconi anemia. UBE2T gene gains an alias of FANCT. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Update of the human and mouse Fanconi anemia genes.

PubMed

Dong, Hongbin; Nebert, Daniel W; Bruford, Elspeth A; Thompson, David C; Joenje, Hans; Vasiliou, Vasilis

2015-11-24

Fanconi anemia (FA) is a recessively inherited disease manifesting developmental abnormalities, bone marrow failure, and increased risk of malignancies. Whereas FA has been studied for nearly 90 years, only in the last 20 years have increasing numbers of genes been implicated in the pathogenesis associated with this genetic disease. To date, 19 genes have been identified that encode Fanconi anemia complementation group proteins, all of which are named or aliased, using the root symbol "FANC." Fanconi anemia subtype (FANC) proteins function in a common DNA repair pathway called "the FA pathway," which is essential for maintaining genomic integrity. The various FANC mutant proteins contribute to distinct steps associated with FA pathogenesis. Herein, we provide a review update of the 19 human FANC and their mouse orthologs, an evolutionary perspective on the FANC genes, and the functional significance of the FA DNA repair pathway in association with clinical disorders. This is an example of a set of genes--known to exist in vertebrates, invertebrates, plants, and yeast--that are grouped together on the basis of shared biochemical and physiological functions, rather than evolutionary phylogeny, and have been named on this basis by the HUGO Gene Nomenclature Committee (HGNC).

Folic acid mitigated cardiac dysfunction by normalizing the levels of tissue inhibitor of metalloproteinase and homocysteine-metabolizing enzymes postmyocardial infarction in mice

PubMed Central

Qipshidze, Natia; Tyagi, Neetu; Sen, Utpal; Givvimani, Srikanth; Metreveli, Naira; Lominadze, David

2010-01-01

Myocardial infarction (MI) results in significant metabolic derangement, causing accumulation of metabolic by product, such as homocysteine (Hcy). Hcy is a nonprotein amino acid generated during nucleic acid methylation and demethylation of methionine. Folic acid (FA) decreases Hcy levels by remethylating the Hcy to methionine, by 5-methylene tetrahydrofolate reductase (5-MTHFR). Although clinical trials were inconclusive regarding the role of Hcy in MI, in animal models, the levels of 5-MTHFR were decreased, and FA mitigated the MI injury. We hypothesized that FA mitigated MI-induced injury, in part, by mitigating cardiac remodeling during chronic heart failure. Thus, MI was induced in 12-wk-old male C57BL/J mice by ligating the left anterior descending artery, and FA (0.03 g/l in drinking water) was administered for 4 wk after the surgery. Cardiac function was assessed by echocardiography and by a Millar pressure-volume catheter. The levels of Hcy-metabolizing enzymes, cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 5-MTHFR, were estimated by Western blot analyses. The results suggest that FA administered post-MI significantly improved cardiac ejection fraction and induced tissue inhibitor of metalloproteinase, CBS, CSE, and 5-MTHFR. We showed that FA supplementation resulted in significant improvement of myocardial function after MI. The study eluted the importance of homocysteine (Hcy) metabolism and FA supplementation in cardiovascular disease. PMID:20802128

Enhancing fatty acid utilization ameliorates mitochondrial fragmentation and cardiac dysfunction via rebalancing optic atrophy 1 processing in the failing heart.

PubMed

Guo, Yongzheng; Wang, Zhen; Qin, Xinghua; Xu, Jie; Hou, Zuoxu; Yang, Hongyan; Mao, Xuechao; Xing, Wenjuan; Li, Xiaoliang; Zhang, Xing; Gao, Feng

2018-06-01

Heart failure (HF) is characterized by reduced fatty acid (FA) utilization associated with mitochondrial dysfunction. Recent evidence has shown that enhancing FA utilization may provide cardioprotection against HF. Our aim was to investigate the effects and the underlying mechanisms of cardiac FA utilization on cardiac function in response to pressure overload. Transverse aortic constriction (TAC) was used in C57 mice to establish pressure overload-induced HF. TAC mice fed on a high fat diet (HFD) exhibited increased cardiac FA utilization and improved cardiac function and survival compared with those on control diet. Such cardioprotection could also be provided by cardiac-specific overexpression of CD36. Notably, both HFD and CD36 overexpression attenuated mitochondrial fragmentation and improved mitochondrial function in the failing heart. Pressure overload decreased ATP-dependent metalloprotease (YME1L) expression and induced the proteolytic cleavage of the dynamin-like guanosine triphosphatase OPA1 as a result of suppressed FA utilization. Enhancing FA utilization upregulated YME1L expression and subsequently rebalanced OPA1 processing, resulting in restoration of mitochondrial morphology in the failing heart. In addition, cardiac-specific overexpression of YME1L exerted similar cardioprotective effects against HF to those provided by HFD or CD36 overexpression. These findings demonstrate that enhancing FA utilization ameliorates mitochondrial fragmentation and cardiac dysfunction via rebalancing OPA1 processing in pressure overload-induced HF, suggesting a unique metabolic intervention approach to improving cardiac functions in HF.

FANCA and FANCC modulate TLR and p38 MAPK-dependent expression of IL-1β in macrophages.

PubMed

Garbati, Michael R; Hays, Laura E; Keeble, Winifred; Yates, Jane E; Rathbun, R Keaney; Bagby, Grover C

2013-10-31

Hematopoietic stem and progenitor cells with inactivated Fanconi anemia (FA) genes, FANCA and FANCC, are hypersensitive to inflammatory cytokines. One of these, tumor necrosis factor α (TNF-α), is also overproduced by FA mononuclear phagocytes in response to certain Toll-like receptor (TLR) agonists, creating an autoinhibitory loop that may contribute to the pathogenesis of progressive bone marrow (BM) failure and selection of TNF-α-resistant leukemic stem cell clones. In macrophages, the TNF-α overproduction phenotype depends on p38 mitogen-activated protein kinase (MAPK), an enzyme also known to induce expression of other inflammatory cytokines, including interleukin 1β (IL-1β). Reasoning that IL-1β might be involved in a like autoinhibitory loop, we determined that (1) TLR activation of FANCA- and FANCC-deficient macrophages induced overproduction of both TNF-α and IL-1β in a p38-dependent manner; (2) exposure of Fancc-deficient BM progenitors to IL-1β potently suppressed the expansion of multipotent progenitor cells in vitro; and (3) although TNF-α overexpression in FA cells is controlled posttranscriptionally by the p38 substrate MAPKAPK-2, p38-dependent overproduction of IL-1β is controlled transcriptionally. We suggest that multiple inflammatory cytokines overproduced by FANCA- and FANCC-deficient mononuclear phagocytes may contribute to the progressive BM failure that characterizes FA, and that to achieve suppression of this proinflammatory state, p38 is a more promising molecular therapeutic target than either IL-1β or TNF-α alone.

FANCA and FANCC modulate TLR and p38 MAPK–dependent expression of IL-1β in macrophages

PubMed Central

Garbati, Michael R.; Hays, Laura E.; Keeble, Winifred; Yates, Jane E.; Rathbun, R. Keaney

2013-01-01

Hematopoietic stem and progenitor cells with inactivated Fanconi anemia (FA) genes, FANCA and FANCC, are hypersensitive to inflammatory cytokines. One of these, tumor necrosis factor α (TNF-α), is also overproduced by FA mononuclear phagocytes in response to certain Toll-like receptor (TLR) agonists, creating an autoinhibitory loop that may contribute to the pathogenesis of progressive bone marrow (BM) failure and selection of TNF-α–resistant leukemic stem cell clones. In macrophages, the TNF-α overproduction phenotype depends on p38 mitogen-activated protein kinase (MAPK), an enzyme also known to induce expression of other inflammatory cytokines, including interleukin 1β (IL-1β). Reasoning that IL-1β might be involved in a like autoinhibitory loop, we determined that (1) TLR activation of FANCA- and FANCC-deficient macrophages induced overproduction of both TNF-α and IL-1β in a p38-dependent manner; (2) exposure of Fancc-deficient BM progenitors to IL-1β potently suppressed the expansion of multipotent progenitor cells in vitro; and (3) although TNF-α overexpression in FA cells is controlled posttranscriptionally by the p38 substrate MAPKAPK-2, p38-dependent overproduction of IL-1β is controlled transcriptionally. We suggest that multiple inflammatory cytokines overproduced by FANCA- and FANCC-deficient mononuclear phagocytes may contribute to the progressive BM failure that characterizes FA, and that to achieve suppression of this proinflammatory state, p38 is a more promising molecular therapeutic target than either IL-1β or TNF-α alone. PMID:24046015

The influence of cardiac rhythm type and frequency on the prognosis of severe heart failure patients initially qualified for heart transplantation.

PubMed

Sobieszczańska-Małek, Małgorzata; Zieliński, Tomasz; Rywik, Tomasz; Piotrowska, Małgorzata; Religa, Grzegorz; Przybyłowski, Piotr; Rózański, Jacek; Korewicki, Jerzy

2010-01-01

Atrial fibrillation (AF) is the most common arrhythmia among patients (pts) with heart failure and has significant influence on survival. to assess prognosis of pts with refractory heart failure (HF) qualified for heart transplantation (HTX). 872 pts (107 W and 765 M) were qualified for HTX between Dec 2003 and Oct 2007. Patient's death or super urgent heart transplantation were considered the end point in Kaplan-Meier survival curves. 680 pts were on sinus rhythm (SR) and 192(22.0%) had atrial fibrillation (AF). During follow-up (1-1464 days, mean 550 days) 155 pts (17.7%) died, 17.65% with SR and 18.23% with AF (ns). EF - mean 21,6 (SR) and 21,8 (FA), NYHA 3,1 (SR), NTproBNP- mean 3635, 4 (SR) and 4349,4 (FA), Arronson - mean 7,8 (SR) and 7,7 (FA). There were no significant differences between groups. We analyzed influence of heart rate (Kaplan-Maier method) on survival. The pts were divided according to HR: gr.I <70/min, gr II 71-89/min, gr III >90/min. The shortest survival rate was noticed in group III. There was no difference in survival between group I and II. The prognosis for patients qualified for heart transplant does not depend on the type of the dominant cardiac rhythm (atrial fibrillation or sinus rhythm). The prognosis is significantly better for those patients whose basic, resting heart rate does not exceed 90 bpm regardless of the rhythm type.

Stem Cell Genetic Therapy for Fanconi Anemia - A New Hope.

PubMed

Hanenberg, Helmut; Roellecke, Katharina; Wiek, Constanze

2017-01-01

Fanconi anemia (FA) is a rare inherited DNA disorder clinically characterized by congenital malformations, progressive bone marrow failure, and cancer susceptibility. Due to a strong survival advantage of spontaneously corrected 'normal' hematopoietic stem cells (HSCs) in a few patients, FA is considered a model disorder for genetic correction of autologous stem cells, where genetically corrected stem cells and their progeny have a strong in vivo selective advantage, ultimately leading to normal hematopoiesis. Despite these apparently ideal circumstances, three HSC gene therapy trials with gammaretroviral vectors (stage I) designed to cure the hematological manifestation of FA completely failed to provide long-term clinical benefits for patients, predominantly due to the combination of insufficient gene transfer technologies and incompletely understood FA HSC pathobiology. Currently, FA gene therapy is in stage II where, based on an improved understanding of the cellular defects in FA HSCs, consequently adapted transduction protocols are being used in two phase I/II trials for in vitro genetic correction of FANCA-deficient hematopoietic stem cells. These results are eagerly awaited. Independent from the outcome of these studies, technologies are already available that seem highly attractive for testing in FA. In stage III, this would ultimately include targeted in vivo correction of autologous HSCs by overexpression of nonintegrating lentiviral vectors with scaffold/matrix attachment region elements using specific envelopes as pseudotypes. Although currently still challenging, in a few years in vivo genome editing approaches will be readily available in stage IV, in which the delivery of the editing machinery/ complex is targeted to the autologous FA HSCs by the nonintegrating lentiviral vectors established in stage III. Even low levels of corrected stem cells will then quickly repopulate the entire hematopoiesis of the patient. We therefore are sanguine that in the future, genetic therapy can be used clinically for the correction of FA HSCs in the standard care of FA patients. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Metformin improves defective hematopoiesis and delays tumor formation in Fanconi anemia mice.

PubMed

Zhang, Qing-Shuo; Tang, Weiliang; Deater, Matthew; Phan, Ngoc; Marcogliese, Andrea N; Li, Hui; Al-Dhalimy, Muhsen; Major, Angela; Olson, Susan; Monnat, Raymond J; Grompe, Markus

2016-12-15

Fanconi anemia (FA) is an inherited bone marrow failure disorder associated with a high incidence of leukemia and solid tumors. Bone marrow transplantation is currently the only curative therapy for the hematopoietic complications of this disorder. However, long-term morbidity and mortality remain very high, and new therapeutics are badly needed. Here we show that the widely used diabetes drug metformin improves hematopoiesis and delays tumor formation in Fancd2 -/- mice. Metformin is the first compound reported to improve both of these FA phenotypes. Importantly, the beneficial effects are specific to FA mice and are not seen in the wild-type controls. In this preclinical model of FA, metformin outperformed the current standard of care, oxymetholone, by improving peripheral blood counts in Fancd2 -/- mice significantly faster. Metformin increased the size of the hematopoietic stem cell compartment and enhanced quiescence in hematopoietic stem and progenitor cells. In tumor-prone Fancd2 -/- Trp53 +/- mice, metformin delayed the onset of tumors and significantly extended the tumor-free survival time. In addition, we found that metformin and the structurally related compound aminoguanidine reduced DNA damage and ameliorated spontaneous chromosome breakage and radials in human FA patient-derived cells. Our results also indicate that aldehyde detoxification might be one of the mechanisms by which metformin reduces DNA damage in FA cells. © 2016 by The American Society of Hematology.

Fanconi Anemia complementation group C protein in metabolic disorders.

PubMed

Nepal, Manoj; Ma, Chi; Xie, Guoxiang; Jia, Wei; Fei, Peiwen

2018-06-21

Given importance of 22-Fanconi Anemia (FA) proteins together to act in a signaling pathway in preventing deleterious clinical symptoms, e.g. severe bone marrow failure, congenital defects, an early onset of aging and cancer, studies on each FA protein become increasingly attractive. However, an unbiased and systematic investigation of cellular effects resulting from each FA protein is missing. Here, we report roles of FA complementation C group protein (FANCC) in the protection from metabolic disorders. This study was prompted by the diabetes-prone feature displayed in FANCC knockout mice, which is not typically shown in patients with FA. We found that in cells expressing FANCC at different levels, there are representative alterations in metabolites associated with aging (glycine, citrulline, ornithine, L-asparagine, L-tyrosine, L-arginine, L-glutamine, L-leucine, L-isoleucine, L-valine, L-proline and L-alanine), Diabetes Mellitus (DM) (carbon monoxide, collagens, fatty acids, D-glucose, fumaric acid, 2-oxoglutaric acid, C3), inflammation (inosine, L-arginine, L-isoleucine, L-leucine, L-lysine, L-phenylalanine, hypoxanthine, L-methionine), and cancer ( L-methionine, sphingomyelin, acetyl-L-carnitine, L-aspartic acid, L-glutamic acid, niacinamide, phospho-rylethanolamine). We also found that FANCC can act in an FA-pathway-independent manner in tumor suppression. Collectively, featured-metabolic alterations are readouts of functional mechanisms underlying reduced tumorigenicity driven by FANCC, demonstrating close links among cancer, aging, inflammation and DM.

Diets containing salmon fillet delay development of high blood pressure and hyperfusion damage in kidneys in obese Zucker fa/fa rats.

PubMed

Vikøren, Linn A; Drotningsvik, Aslaug; Mwakimonga, Angela; Leh, Sabine; Mellgren, Gunnar; Gudbrandsen, Oddrun A

2018-04-01

Hypertension is the leading risk factor for cardiovascular and chronic renal diseases, affecting more than 1 billion people. Fish intake is inversely correlated with the prevalence of hypertension in several, but not all, studies, and intake of fish oil and fish proteins has shown promising potential to delay development of high blood pressure in rats. The effects of baked and raw salmon fillet intake on blood pressure and renal function were investigated in obese Zucker fa/fa rats, which spontaneously develop hypertension with proteinuria and renal failure. Rats were fed diets containing baked or raw salmon fillet in an amount corresponding to 25% of total protein from salmon and 75% of protein from casein, or casein as the sole protein source (control group) for 4 weeks. Results show lower blood pressure and lower urine concentrations of albumin and cystatin C (relative to creatinine) in salmon diet groups when compared to control group. Morphological examinations revealed less prominent hyperfusion damage in podocytes from rats fed diets containing baked or raw salmon when compared to control rats. In conclusion, diets containing baked or raw salmon fillet delayed the development of hypertension and protected against podocyte damage in obese Zucker fa/fa rats. Copyright © 2018 American Heart Association. Published by Elsevier Inc. All rights reserved.

Mild and Short-Term Caloric Restriction Prevents Obesity-Induced Cardiomyopathy in Young Zucker Rats without Changing in Metabolites and Fatty Acids Cardiac Profile

PubMed Central

Ruiz-Hurtado, Gema; García-Prieto, Concha F.; Pulido-Olmo, Helena; Velasco-Martín, Juan P.; Villa-Valverde, Palmira; Fernández-Valle, María E.; Boscá, Lisardo; Fernández-Velasco, María; Regadera, Javier; Somoza, Beatriz; Fernández-Alfonso, María S.

2017-01-01

Caloric restriction (CR) ameliorates cardiac dysfunction associated with obesity. However, most of the studies have been performed under severe CR (30–65% caloric intake decrease) for several months or even years in aged animals. Here, we investigated whether mild (20% food intake reduction) and short-term (2-weeks) CR prevented the obese cardiomyopathy phenotype and improved the metabolic profile of young (14 weeks of age) genetically obese Zucker fa/fa rats. Heart weight (HW) and HW/tibia length ratio was significantly lower in fa/fa rats after 2 weeks of CR than in counterparts fed ad libitum. Invasive pressure measurements showed that systolic blood pressure, maximal rate of positive left ventricle (LV) pressure, LV systolic pressure and LV end-diastolic pressure were all significantly higher in obese fa/fa rats than in lean counterparts, which were prevented by CR. Magnetic resonance imaging revealed that the increase in LV end-systolic volume, stroke volume and LV wall thickness observed in fa/fa rats was significantly lower in animals on CR diet. Histological analysis also revealed that CR blocked the significant increase in cardiomyocyte diameter in obese fa/fa rats. High resolution magic angle spinning magnetic resonance spectroscopy analysis of the LV revealed a global decrease in metabolites such as taurine, creatine and phosphocreatine, glutamate, glutamine and glutathione, in obese fa/fa rats, whereas lactate concentration was increased. By contrast, fatty acid concentrations in LV tissue were significantly elevated in obese fa/fa rats. CR failed to restore the LV metabolomic profile of obese fa/fa rats. In conclusion, mild and short-term CR prevented an obesity-induced cardiomyopathy phenotype in young obese fa/fa rats independently of the cardiac metabolic profile. PMID:28203206

Rapid evaluation and quality control of next generation sequencing data with FaQCs.

PubMed

Lo, Chien-Chi; Chain, Patrick S G

2014-11-19

Next generation sequencing (NGS) technologies that parallelize the sequencing process and produce thousands to millions, or even hundreds of millions of sequences in a single sequencing run, have revolutionized genomic and genetic research. Because of the vagaries of any platform's sequencing chemistry, the experimental processing, machine failure, and so on, the quality of sequencing reads is never perfect, and often declines as the read is extended. These errors invariably affect downstream analysis/application and should therefore be identified early on to mitigate any unforeseen effects. Here we present a novel FastQ Quality Control Software (FaQCs) that can rapidly process large volumes of data, and which improves upon previous solutions to monitor the quality and remove poor quality data from sequencing runs. Both the speed of processing and the memory footprint of storing all required information have been optimized via algorithmic and parallel processing solutions. The trimmed output compared side-by-side with the original data is part of the automated PDF output. We show how this tool can help data analysis by providing a few examples, including an increased percentage of reads recruited to references, improved single nucleotide polymorphism identification as well as de novo sequence assembly metrics. FaQCs combines several features of currently available applications into a single, user-friendly process, and includes additional unique capabilities such as filtering the PhiX control sequences, conversion of FASTQ formats, and multi-threading. The original data and trimmed summaries are reported within a variety of graphics and reports, providing a simple way to do data quality control and assurance.

Quantitative PCR analysis reveals a high incidence of large intragenic deletions in the FANCA gene in Spanish Fanconi anemia patients.

PubMed

Callén, E; Tischkowitz, M D; Creus, A; Marcos, R; Bueren, J A; Casado, J A; Mathew, C G; Surrallés, J

2004-01-01

Fanconi anaemia is an autosomal recessive disease characterized by chromosome fragility, multiple congenital abnormalities, progressive bone marrow failure and a high predisposition to develop malignancies. Most of the Fanconi anaemia patients belong to complementation group FA-A due to mutations in the FANCA gene. This gene contains 43 exons along a 4.3-kb coding sequence with a very heterogeneous mutational spectrum that makes the mutation screening of FANCA a difficult task. In addition, as the FANCA gene is rich in Alu sequences, it was reported that Alu-mediated recombination led to large intragenic deletions that cannot be detected in heterozygous state by conventional PCR, SSCP analysis, or DNA sequencing. To overcome this problem, a method based on quantitative fluorescent multiplex PCR was proposed to detect intragenic deletions in FANCA involving the most frequently deleted exons (exons 5, 11, 17, 21 and 31). Here we apply the proposed method to detect intragenic deletions in 25 Spanish FA-A patients previously assigned to complementation group FA-A by FANCA cDNA retroviral transduction. A total of eight heterozygous deletions involving from one to more than 26 exons were detected. Thus, one third of the patients carried a large intragenic deletion that would have not been detected by conventional methods. These results are in agreement with previously published data and indicate that large intragenic deletions are one of the most frequent mutations leading to Fanconi anaemia. Consequently, this technology should be applied in future studies on FANCA to improve the mutation detection rate. Copyright 2003 S. Karger AG, Basel

Failure Mechanisms for III-Nitride HEMT Devices

DTIC Science & Technology

2013-11-19

rf plasma-assisted molecular beam epitaxy on freestanding GaN substrates, J. Cryst. Growth 380, 14-17 (2013). ii) Conference presentations (Invited...1 eFinal Report – AOARD Grant FA-2386-11-1-4107 Failure Mechanisms for III-nitride HEMT devices 19 November 2013 Principal Investigators: Martha...aspects of III-nitride HEMT materials and devices. Energy-filtered imaging of unstressed and stressed Ni/Au-gated AlGaN/GaN HEMTs indicated that

Frequency of Fanconi anemia in Brazil and efficacy of screening for the FANCA 3788-3790del mutation.

PubMed

Magdalena, N; Pilonetto, D V; Bitencourt, M A; Pereira, N F; Ribeiro, R C; Jeng, M; Pasquini, R

2005-05-01

Fanconi anemia (FA) is an autosomal recessive genetic disease characterized by progressive bone marrow failure, susceptibility to cancer and multiple congenital anomalies. There is important clinical variability among patients and the knowledge of factors which might predict outcome would greatly help the decision making regarding the choices of treatment and the appropriate time to start it. Future studies of the possible correlation between specific mutations with specific clinical presentations will provide the answer to one of these factors. At our Center we standardized a rapid and precise screening test using a mismatch PCR assay for a specific mutation (3788-3790del in exon 38 of gene FANCA) in Brazilian FA patients. We present the results obtained after screening 80 non-consanguineous FA patients referred from all regions of Brazil with a clinical diagnosis of FA supported by cellular hypersensitivity to diepoxybutane. We were able to detect the 3788-3790del allele in 24 of the 80 (30%) FA patients studied. Thirteen of the 80 (16.25%) were homozygotes and 11 of the 80 (13.75%) were compound heterozygotes, thus confirming the high frequency of the FANCA 3788-3790del mutation in Brazilian FA patients. The identification of patients with specific mutations in the FA genes may lead to a better clinical description of this condition, also providing data for genotype-phenotype correlations, to a better understanding of the interaction of this specific mutation with other mutations in compound heterozygote patients, and ultimately to the right choices of treatment for each patient with improvement of the prognosis on future studies.

Fanconi anemia: causes and consequences of genetic instability.

PubMed

Kalb, R; Neveling, K; Nanda, I; Schindler, D; Hoehn, H

2006-01-01

Fanconi anemia (FA) is a rare recessive disease that reflects the cellular and phenotypic consequences of genetic instability: growth retardation, congenital malformations, bone marrow failure, high risk of neoplasia, and premature aging. At the cellular level, manifestations of genetic instability include chromosomal breakage, cell cycle disturbance, and increased somatic mutation rates. FA cells are exquisitely sensitive towards oxygen and alkylating drugs such as mitomycin C or diepoxybutane, pointing to a function of FA genes in the defense against reactive oxygen species and other DNA damaging agents. FA is caused by biallelic mutations in at least 12 different genes which appear to function in the maintenance of genomic stability. Eight of the FA proteins form a nuclear core complex with a catalytic function involving ubiquitination of the central FANCD2 protein. The posttranslational modification of FANCD2 promotes its accumulation in nuclear foci, together with known DNA maintenance proteins such as BRCA1, BRCA2, and the RAD51 recombinase. Biallelic mutations in BRCA2 cause a severe FA-like phenotype, as do biallelic mutations in FANCD2. In fact, only leaky or hypomorphic mutations in this central group of FA genes appear to be compatible with life birth and survival. The newly discovered FANCJ (= BRIP1) and FANCM (= Hef ) genes correspond to known DNA-maintenance genes (helicase resp. helicase-associated endonuclease for fork-structured DNA). These genes provide the most convincing evidence to date of a direct involvement of FA genes in DNA repair functions associated with the resolution of DNA crosslinks and stalled replication forks. Even though genetic instability caused by mutational inactivation of the FANC genes has detrimental effects for the majority of FA patients, around 20% of patients appear to benefit from genetic instability since genetic instability also increases the chance of somatic reversion of their constitutional mutations. Intragenic crossover, gene conversion, back mutation and compensating mutations in cis have all been observed in revertant, and, consequently, mosaic FA-patients, leading to improved bone marrow function. There probably is no other experiment of nature in our species in which causes and consequences of genetic instability, including the role of reactive oxygen species, can be better documented and explored than in FA.

Identification and quantification of fumonisin A1, A2, and A3 in corn by high-resolution liquid chromatography-orbitrap mass spectrometry.

PubMed

Tamura, Masayoshi; Mochizuki, Naoki; Nagatomi, Yasushi; Harayama, Koichi; Toriba, Akira; Hayakawa, Kazuichi

2015-02-16

Three compounds, hypothesized as fumonisin A1 (FA1), fumonisin A2 (FA2), and fumonisin A3 (FA3), were detected in a corn sample contaminated with mycotoxins by high-resolution liquid chromatography-Orbitrap mass spectrometry (LC-Orbitrap MS). One of them has been identified as FA1 synthesized by the acetylation of fumonisin B1 (FB1), and established a method for its quantification. Herein, we identified the two remaining compounds as FA2 and FA3, which were acetylated fumonisin B2 (FB2) and fumonisin B3 (FB3), respectively. Moreover, we examined a method for the simultaneous analysis of FA1, FA2, FA3, FB1, FB2, and FB3. The corn samples were prepared by extraction using a QuEChERS kit and purification using a multifunctional cartridge. The linearity, recovery, repeatability, limit of detection, and limit of quantification of the method were >0.99, 82.9%-104.6%, 3.7%-9.5%, 0.02-0.60 μg/kg, and 0.05-1.98 μg/kg, respectively. The simultaneous analysis of the six fumonisins revealed that FA1, FA2, and FA3 were present in all corn samples contaminated with FB1, FB2, and FB3. The results suggested that corn marketed for consumption can be considered as being contaminated with both the fumonisin B-series and with fumonisin A-series. This report presents the first identification and quantification of FA1, FA2, and FA3 in corn samples.

Quantification of the degree of reaction of fly ash

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

Ben Haha, M., E-mail: mohsen.ben-haha@empa.c; De Weerdt, K., E-mail: klaartje.de.weerdt@sintef.n; Lothenbach, B.

2010-11-15

The quantification of the fly ash (FA) in FA blended cements is an important parameter to understand the effect of the fly ash on the hydration of OPC and on the microstructural development. The FA reaction in two different blended OPC-FA systems was studied using a selective dissolution technique based on EDTA/NaOH, diluted NaOH solution, the portlandite content and by backscattered electron image analysis. The amount of FA determined by selective dissolution using EDTA/NaOH is found to be associated with a significant possible error as different assumptions lead to large differences in the estimate of FA reacted. In addition, atmore » longer hydration times, the reaction of the FA is underestimated by this method due to the presence of non-dissolved hydrates and MgO rich particles. The dissolution of FA in diluted NaOH solution agreed during the first days well with the dissolution as observed by image analysis. At 28 days and longer, the formation of hydrates in the diluted solutions leads to an underestimation. Image analysis appears to give consistent results and to be most reliable technique studied.« less

Monitoring of IgE-mediated food allergy in childhood.

PubMed

Thong, B Y H; Hourihane, J O' B

2004-06-01

The prevalence of IgE-mediated food allergy (FA) in childhood varies from 6% to 8% in the first year of life compared to 1% to 2% in adults. In contrast to adults, FA in childhood, often part of the "allergic march", resolves in more than 85% of children, especially those with hypersensitivity to cow's milk and egg. This paper explains the rationale for continuing care for childhood FA and describes how children should be monitored for resolution/persistence of FA. A clinical, multidisciplinary approach and management algorithm based on relevant, peer-reviewed original research articles and reviews using the keywords anaphylaxis, atopic eczema, children, milk allergy, double-blind placebo-controlled food challenge, egg allergy, epinephrine, failure to thrive, food allergy, food challenge, food hypersensitivity, immunoglobulin E, nutrition, natural history, paediatrics, peanut allergy, prevalence, psychosocial factors, quality of life, radioallergosorbent test, and tolerance from years 1966 to 2003 in MEDLINE. Additional studies were identified from article reference lists. A combination of outcome measures, a multidisciplinary approach involving a dietitian and allergy nurse specialist, and a management algorithm are useful tools in clinical management. Prospective studies of non-selected children, optimally from birth cohorts, are needed to evaluate the effects of such management programmes regarding FA in childhood.

Hematological consequences of a FANCG founder mutation in Black South African patients with Fanconi anemia.

PubMed

Feben, Candice; Kromberg, Jennifer; Wainwright, Rosalind; Stones, David; Poole, Janet; Haw, Tabitha; Krause, Amanda

2015-03-01

Fanconi anemia (FA) is a rare disorder of DNA repair, associated with various somatic abnormalities but characterized by hematological disease that manifests as bone marrow aplasia and malignancy. The mainstay of treatment, in developed nations, is hematopoietic stem cell transplantation (HSCT) with subsequent surveillance for solid organ and non-hematological malignancies. In South Africa, FA in the Black population is caused by a homozygous deletion mutation in the FANCG gene in more than 80% of cases. Many affected patients are not diagnosed until late in the disease course when severe cytopenia and bone marrow aplasia are already present. Most patients are not eligible for HSCT at this late stage of the disease, even when it is available in the state health care system. In this study, the hematological presentation and disease progression in 30 Black South African patients with FA, confirmed to have the FANCG founder mutation, were evaluated and compared to those described in other FA cohorts. Our results showed that patients, homozygous for the FANCG founder mutation, present with severe cytopenia but progress to bone marrow failure at similar ages to other individuals affected with FA of heterogeneous genotype. Further, the incidence of myelodysplastic syndrome is similar to that which has been previously described in other FA cohorts. Although severe cytopenia at presentation may be predicted by a higher number of somatic anomalies, the recognition of the physical FA phenotype in Black South African patients is challenging and may not be useful in expediting referral of suspected FA patients for tertiary level investigations and care. Given the late but severe hematological presentation of FA in Black South African patients, an investigative strategy is needed for earlier recognition of affected individuals to allow for possible HSCT and management of bone marrow disease. Copyright © 2014 Elsevier Inc. All rights reserved.

Evidence of Field-Evolved Resistance of Spodoptera frugiperda to Bt Corn Expressing Cry1F in Brazil That Is Still Sensitive to Modified Bt Toxins

PubMed Central

Monnerat, Rose; Martins, Erica; Macedo, Cristina; Queiroz, Paulo; Praça, Lilian; Soares, Carlos Marcelo; Moreira, Helio; Grisi, Isabella; Silva, Joseane; Soberon, Mario; Bravo, Alejandra

2015-01-01

Brazil ranked second only to the United States in hectares planted to genetically modified crops in 2013. Recently corn producers in the Cerrado region reported that the control of Spodoptera frugiperda with Bt corn expressing Cry1Fa has decreased, forcing them to use chemicals to reduce the damage caused by this insect pest. A colony of S. frugiperda was established from individuals collected in 2013 from Cry1Fa corn plants (SfBt) in Brazil and shown to have at least more than ten-fold higher resistance levels compared with a susceptible colony (Sflab). Laboratory assays on corn leaves showed that in contrast to SfLab population, the SfBt larvae were able to survive by feeding on Cry1Fa corn leaves. The SfBt population was maintained without selection for eight generations and shown to maintain high levels of resistance to Cry1Fa toxin. SfBt showed higher cross-resistance to Cry1Aa than to Cry1Ab or Cry1Ac toxins. As previously reported, Cry1A toxins competed the binding of Cry1Fa to brush border membrane vesicles (BBMV) from SfLab insects, explaining cross-resistance to Cry1A toxins. In contrast Cry2A toxins did not compete Cry1Fa binding to SfLab-BBMV and no cross-resistance to Cry2A was observed, although Cry2A toxins show low toxicity to S. frugiperda. Bioassays with Cry1AbMod and Cry1AcMod show that they are highly active against both the SfLab and the SfBt populations. The bioassay data reported here show that insects collected from Cry1Fa corn in the Cerrado region were resistant to Cry1Fa suggesting that resistance contributed to field failures of Cry1Fa corn to control S. frugiperda. PMID:25830928

Evidence of field-evolved resistance of Spodoptera frugiperda to Bt corn expressing Cry1F in Brazil that is still sensitive to modified Bt toxins.

PubMed

Monnerat, Rose; Martins, Erica; Macedo, Cristina; Queiroz, Paulo; Praça, Lilian; Soares, Carlos Marcelo; Moreira, Helio; Grisi, Isabella; Silva, Joseane; Soberon, Mario; Bravo, Alejandra

2015-01-01

Brazil ranked second only to the United States in hectares planted to genetically modified crops in 2013. Recently corn producers in the Cerrado region reported that the control of Spodoptera frugiperda with Bt corn expressing Cry1Fa has decreased, forcing them to use chemicals to reduce the damage caused by this insect pest. A colony of S. frugiperda was established from individuals collected in 2013 from Cry1Fa corn plants (SfBt) in Brazil and shown to have at least more than ten-fold higher resistance levels compared with a susceptible colony (Sflab). Laboratory assays on corn leaves showed that in contrast to SfLab population, the SfBt larvae were able to survive by feeding on Cry1Fa corn leaves. The SfBt population was maintained without selection for eight generations and shown to maintain high levels of resistance to Cry1Fa toxin. SfBt showed higher cross-resistance to Cry1Aa than to Cry1Ab or Cry1Ac toxins. As previously reported, Cry1A toxins competed the binding of Cry1Fa to brush border membrane vesicles (BBMV) from SfLab insects, explaining cross-resistance to Cry1A toxins. In contrast Cry2A toxins did not compete Cry1Fa binding to SfLab-BBMV and no cross-resistance to Cry2A was observed, although Cry2A toxins show low toxicity to S. frugiperda. Bioassays with Cry1AbMod and Cry1AcMod show that they are highly active against both the SfLab and the SfBt populations. The bioassay data reported here show that insects collected from Cry1Fa corn in the Cerrado region were resistant to Cry1Fa suggesting that resistance contributed to field failures of Cry1Fa corn to control S. frugiperda.

Upregulated ATM gene expression and activated DNA crosslink-induced damage response checkpoint in Fanconi anemia: implications for carcinogenesis.

PubMed

Yamamoto, Kazuhiko; Nihrane, Abdallah; Aglipay, Jason; Sironi, Juan; Arkin, Steven; Lipton, Jeffrey M; Ouchi, Toru; Liu, Johnson M

2008-01-01

Fanconi anemia (FA) predisposes to hematopoietic failure, birth defects, leukemia, and squamous cell carcinoma of the head and neck (HNSCC) and cervix. The FA/BRCA pathway includes 8 members of a core complex and 5 downstream gene products closely linked with BRCA1 or BRCA2. Precancerous lesions are believed to trigger the DNA damage response (DDR), and we focused on the DDR in FA and its putative role as a checkpoint barrier to cancer. In primary fibroblasts with mutations in the core complex FANCA protein, we discovered that basal expression and phosphorylation of ATM (ataxia telangiectasia mutated) and p53 induced by irradiation (IR) or mitomycin C (MMC) were upregulated. This heightened response appeared to be due to increased basal levels of ATM in cultured FANCA-mutant cells, highlighting the new observation that ATM can be regulated at the transcriptional level in addition to its well-established activation by autophosphorylation. Functional analysis of this response using gamma-H2AX foci as markers of DNA double-stranded breaks (DSBs) demonstrated abnormal persistence of only MMC- and not IR-induced foci. Thus, we describe a processing defect that leads to general DDR upregulation but specific persistence of DNA crosslinker-induced damage response foci. Underscoring the significance of these findings, we found resistance to DNA crosslinker-induced cell cycle arrest and apoptosis in a TP53-mutant, patient-derived HNSCC cell line, whereas a lymphoblastoid cell line derived from this same individual was not mutated at TP53 and retained DNA crosslinker sensitivity. Our results suggest that cancer in FA may arise from selection for cells that escape from a chronically activated DDR checkpoint.

Identification and Quantification of Fumonisin A1, A2, and A3 in Corn by High-Resolution Liquid Chromatography-Orbitrap Mass Spectrometry

PubMed Central

Tamura, Masayoshi; Mochizuki, Naoki; Nagatomi, Yasushi; Harayama, Koichi; Toriba, Akira; Hayakawa, Kazuichi

2015-01-01

Three compounds, hypothesized as fumonisin A1 (FA1), fumonisin A2 (FA2), and fumonisin A3 (FA3), were detected in a corn sample contaminated with mycotoxins by high-resolution liquid chromatography-Orbitrap mass spectrometry (LC-Orbitrap MS). One of them has been identified as FA1 synthesized by the acetylation of fumonisin B1 (FB1), and established a method for its quantification. Herein, we identified the two remaining compounds as FA2 and FA3, which were acetylated fumonisin B2 (FB2) and fumonisin B3 (FB3), respectively. Moreover, we examined a method for the simultaneous analysis of FA1, FA2, FA3, FB1, FB2, and FB3. The corn samples were prepared by extraction using a QuEChERS kit and purification using a multifunctional cartridge. The linearity, recovery, repeatability, limit of detection, and limit of quantification of the method were >0.99, 82.9%–104.6%, 3.7%–9.5%, 0.02–0.60 μg/kg, and 0.05–1.98 μg/kg, respectively. The simultaneous analysis of the six fumonisins revealed that FA1, FA2, and FA3 were present in all corn samples contaminated with FB1, FB2, and FB3. The results suggested that corn marketed for consumption can be considered as being contaminated with both the fumonisin B-series and with fumonisin A-series. This report presents the first identification and quantification of FA1, FA2, and FA3 in corn samples. PMID:25690692

Global and disease-associated genetic variation in the human Fanconi anemia gene family

PubMed Central

Rogers, Kai J.; Fu, Wenqing; Akey, Joshua M.; Monnat, Raymond J.

2014-01-01

Fanconi anemia (FA) is a human recessive genetic disease resulting from inactivating mutations in any of 16 FANC (Fanconi) genes. Individuals with FA are at high risk of developmental abnormalities, early bone marrow failure and leukemia. These are followed in the second and subsequent decades by a very high risk of carcinomas of the head and neck and anogenital region, and a small continuing risk of leukemia. In order to characterize base pair-level disease-associated (DA) and population genetic variation in FANC genes and the segregation of this variation in the human population, we identified 2948 unique FANC gene variants including 493 FA DA variants across 57 240 potential base pair variation sites in the 16 FANC genes. We then analyzed the segregation of this variation in the 7578 subjects included in the Exome Sequencing Project (ESP) and the 1000 Genomes Project (1KGP). There was a remarkably high frequency of FA DA variants in ESP/1KGP subjects: at least 1 FA DA variant was identified in 78.5% (5950 of 7578) individuals included in these two studies. Six widely used functional prediction algorithms correctly identified only a third of the known, DA FANC missense variants. We also identified FA DA variants that may be good candidates for different types of mutation-specific therapies. Our results demonstrate the power of direct DNA sequencing to detect, estimate the frequency of and follow the segregation of deleterious genetic variation in human populations. PMID:25104853

[FANCA gene mutation analysis in Fanconi anemia patients].

PubMed

Chen, Fei; Peng, Guang-Jie; Zhang, Kejian; Hu, Qun; Zhang, Liu-Qing; Liu, Ai-Guo

2005-10-01

To screen the FANCA gene mutation and explore the FANCA protein function in Fanconi anemia (FA) patients. FANCA protein expression and its interaction with FANCF were analyzed using Western blot and immunoprecipitation in 3 cases of FA-A. Genomic DNA was used for MLPA analysis followed by sequencing. FANCA protein was undetectable and FANCA and FANCF protein interaction was impaired in these 3 cases of FA-A. Each case of FA-A contained biallelic pathogenic mutations in FANCA gene. No functional FANCA protein was found in these 3 cases of FA-A, and intragenic deletion, frame shift and splice site mutation were the major pathogenic mutations found in FANCA gene.

Self-reported dietary intake of omega-3 fatty acids and association with bone and lower extremity function.

PubMed

Rousseau, James H; Kleppinger, Alison; Kenny, Anne M

2009-10-01

To assess the relationship between self-reported omega-3 fatty acid (O3FA) intake and bone mineral density (BMD) and lower extremity function in older adults. Cross-sectional analysis of baseline information from three separate ongoing studies of older adults, pooled for this analysis. Academic health center. Two hundred forty-seven men (n=118) and women (n=129) residing in the community or an assisted living facility. Self-reported dietary intake (O3FA, omega-6 fatty acids (O6FA), protein, and total calorie); BMD of the hip or heel; and lower extremity function including leg strength, chair rise time, walking speed, Timed Up and Go, and frailty. The mean reported intake of O3FA was 1.27 g/day. Correlation coefficients (r) between O3FA and T-scores from total femur (n=167) were 0.210 and 0.147 for combined femur and heel T scores. Similar correlations were found for leg strength (r=0.205) and chair rise time (r=-0.178), but the significance was lost when corrected for protein intake. Subjects with lower reported O3FA intake (<1.27 g/day) had lower BMD than those with higher reported O3FA intake. In a multiple regression analysis with femoral neck BMD as the dependent variable and reported intake of O3FA, O6FA, protein, and vitamin D as independent variables, reported O3FA intake was the only significant variable, accounting for 6% of the variance in BMD. Older adults had low reported intakes of O3FA. There was an association between greater reported O3FA intake and higher BMD. There was no independent association between reported O3FA intake and lower extremity function. Results from this preliminary report are promising and suggest further investigation.

Product Reliability Trends, Derating Considerations and Failure Mechanisms with Scaled CMOS

NASA Technical Reports Server (NTRS)

White, Mark; Vu, Duc; Nguyen, Duc; Ruiz, Ron; Chen, Yuan; Bernstein, Joseph B.

2006-01-01

As microelectronics is scaled into the deep sub-micron regime, space and aerospace users of advanced technology CMOS are reassessing how scaling effects impact long-term product reliability. The effects of electromigration (EM), time-dependent-dielectric-breakdown (TDDB) and hot carrier degradation (HCI and NBTI) wearout mechanisms on scaled technologies and product reliability are investigated, accelerated stress testing across several technology nodes is performed, and FA is conducted to confirm the failure mechanism(s).

In-Home Parent Training of Functional Analysis Skills

ERIC Educational Resources Information Center

Stokes, John V.; Luiselli, James K.

2008-01-01

We taught two sets of parents to conduct a functional analysis (FA) under simulated conditions in their homes. Relative to a baseline (pre-training) phase, the accuracy of FA implementation by parents improved when they were given verbal, written, and video performance feedback. When training concluded, parents were able to implement FA accurately…

Health Monitoring of Composite Overwrapped Pressure Vessels (COPVs) Using Meandering Winding Magnetometer ((MWM(Registered Trademark)) Eddy Current Sensors

NASA Technical Reports Server (NTRS)

Russell, Rick; Grundy, David; Jablonski, David; Martin, Christopher; Washabaugh, Andrew; Goldfine, Neil

2011-01-01

There are 3 mechanisms that affect the life of a COPV are: a) The age life of the overwrap; b) Cyclic fatigue of the metallic liner; c) Stress Rupture life. The first two mechanisms are understood through test and analysis. A COPV Stress Rupture is a sudden and catastrophic failure of the overwrap while holding at a stress level below the ultimate strength for an extended time. Currently there is no simple, deterministic method of determining the stress rupture life of a COPV, nor a screening technique to determine if a particular COPV is close to the time of a stress rupture failure. Conclusions: Demonstrated a correlation between MWM response and pressure or strain. Demonstrated the ability to monitor stress in COPV at different orientations and depths. FA41 provides best correlation with bottle pressure or stress.

Analysis of ATP-citrate lyase and malic enzyme mutants of Yarrowia lipolytica points out the importance of mannitol metabolism in fatty acid synthesis.

PubMed

Dulermo, Thierry; Lazar, Zbigniew; Dulermo, Rémi; Rakicka, Magdalena; Haddouche, Ramedane; Nicaud, Jean-Marc

2015-09-01

The role of the two key enzymes of fatty acid (FA) synthesis, ATP-citrate lyase (Acl) and malic enzyme (Mae), was analyzed in the oleaginous yeast Yarrowia lipolytica. In most oleaginous yeasts, Acl and Mae are proposed to provide, respectively, acetyl-CoA and NADPH for FA synthesis. Acl was mainly studied at the biochemical level but no strain depleted for this enzyme was analyzed in oleaginous microorganisms. On the other hand the role of Mae in FA synthesis in Y. lipolytica remains unclear since it was proposed to be a mitochondrial NAD(H)-dependent enzyme and not a cytosolic NADP(H)-dependent enzyme. In this study, we analyzed for the first time strains inactivated for corresponding genes. Inactivation of ACL1 decreases FA synthesis by 60 to 80%, confirming its essential role in FA synthesis in Y. lipolytica. Conversely, inactivation of MAE1 has no effects on FA synthesis, except in a FA overaccumulating strain where it improves FA synthesis by 35%. This result definitively excludes Mae as a major key enzyme for FA synthesis in Y. lipolytica. During the analysis of both mutants, we observed a negative correlation between FA and mannitol level. As mannitol and FA pathways may compete for carbon storage, we inactivated YlSDR, encoding a mannitol dehydrogenase converting fructose and NADPH into mannitol and NADP+. The FA content of the resulting mutant was improved by 60% during growth on fructose, demonstrating that mannitol metabolism may modulate FA synthesis in Y. lipolytica. Copyright © 2015. Published by Elsevier B.V.

An Analysis of Turnover Intentions: A Reexamination of Air Force Civil Engineering Company Grade Officers

DTIC Science & Technology

2012-03-01

edu 75 Appendix C Factor Analysis of Measurement Items Interrole conflict Factor Analysis (FA): Table: KMO and Bartlett’s Test Kaiser-Meyer...Extraction Method: Principal Component Analysis. Rotation Method: Varimax with Kaiser Normalization. 77 POS FA: Table: KMO and Bartlett’s...Tempo FA: Table: KMO and Bartlett’s Test Kaiser-Meyer-Olkin Measure of Sampling Adequacy. .733 Bartlett’s Test of Sphericity Approx. Chi-Square

FANCB is essential in the male germline and regulates H3K9 methylation on the sex chromosomes during meiosis

PubMed Central

Kato, Yasuko; Alavattam, Kris G.; Sin, Ho-Su; Meetei, Amom Ruhikanta; Pang, Qishen; Andreassen, Paul R.; Namekawa, Satoshi H.

2015-01-01

Fanconi anemia (FA) is a recessive X-linked and autosomal genetic disease associated with bone marrow failure and increased cancer, as well as severe germline defects such as hypogonadism and germ cell depletion. Although deficiencies in FA factors are commonly associated with germ cell defects, it remains unknown whether the FA pathway is involved in unique epigenetic events in germ cells. In this study, we generated Fancb mutant mice, the first mouse model of X-linked FA, and identified a novel function of the FA pathway in epigenetic regulation during mammalian gametogenesis. Fancb mutant mice were infertile and exhibited primordial germ cell (PGC) defects during embryogenesis. Further, Fancb mutation resulted in the reduction of undifferentiated spermatogonia in spermatogenesis, suggesting that FANCB regulates the maintenance of undifferentiated spermatogonia. Additionally, based on functional studies, we dissected the pathway in which FANCB functions during meiosis. The localization of FANCB on sex chromosomes is dependent on MDC1, a binding partner of H2AX phosphorylated at serine 139 (γH2AX), which initiates chromosome-wide silencing. Also, FANCB is required for FANCD2 localization during meiosis, suggesting that the role of FANCB in the activation of the FA pathway is common to both meiosis and somatic DNA damage responses. H3K9me2, a silent epigenetic mark, was decreased on sex chromosomes, whereas H3K9me3 was increased on sex chromosomes in Fancb mutant spermatocytes. Taken together, these results indicate that FANCB functions at critical stages of germ cell development and reveal a novel function of the FA pathway in the regulation of H3K9 methylation in the germline. PMID:26123487

[Fanconi anemia: cellular and molecular features].

PubMed

Macé, G; Briot, D; Guervilly, J-H; Rosselli, F

2007-02-01

Fanconi anemia (FA) is a recessive human cancer prone syndrome featuring bone marrow failure, developmental abnormalities and hypersensitivity to DNA crosslinking agents exposure. 11 among 12 FA gene have been isolated. The biochemical functions of the FANC proteins remain poorly understood. Anyhow, to cope with DNA crosslinks a cell needs a functional FANC pathway. Moreover, the FANC proteins appear to be involved in cell protection against oxidative damage and in the control of TNF-alpha activity. In this review, we describe the current understanding of the FANC pathway and we present how it may be integrated in the complex networks of proteins involved in maintaining the cellular homeostasis.

Teacher Learning of Technology Enhanced Formative Assessment

NASA Astrophysics Data System (ADS)

Feldman, Allan; Capobianco, Brenda M.

2008-02-01

This study examined the integration of technology enhanced formative assessment (FA) into teachers' practice. Participants were high school physics teachers interested in improving their use of a classroom response system (CRS) to promote FA. Data were collected using interviews, direct classroom observations, and collaborative discussions. The physics teachers engaged in collaborative action research (AR) to learn how to use FA and CRS to promote student and teacher learning. Data were analyzed using open coding, cross-case analysis, and content analysis. Results from data analysis allowed researchers to construct a model for knowledge skills necessary for the integration of technology enhanced FA into teachers' practice. The model is as a set of four technologies: hardware and software; methods for constructing FA items; pedagogical methods; and curriculum integration. The model is grounded in the idea that teachers must develop these respective technologies as they interact with the CRS (i.e., hardware and software, item construction) and their existing practice (i.e., pedagogical methods, curriculum). Implications are that for teachers to make FA an integral part of their practice using CRS, they must: 1) engage in the four technologies; 2) understand the nature of FA; and 3) collaborate with other interested teachers through AR.

Allogeneic hematopoietic cell transplantation for fanconi anemia in patients with pretransplantation cytogenetic abnormalities, myelodysplastic syndrome, or acute leukemia.

PubMed

Ayas, Mouhab; Saber, Wael; Davies, Stella M; Harris, Richard E; Hale, Gregory A; Socie, Gerard; LeRademacher, Jennifer; Thakar, Monica; Deeg, H Joachim J; Al-Seraihy, Amal; Battiwalla, Minoo; Camitta, Bruce M; Olsson, Richard; Bajwa, Rajinder S; Bonfim, Carmem M; Pasquini, Ricardo; Macmillan, Margaret L; George, Biju; Copelan, Edward A; Wirk, Baldeep; Al Jefri, Abdullah; Fasth, Anders L; Guinan, Eva C; Horn, Biljana N; Lewis, Victor A; Slavin, Shimon; Stepensky, Polina; Bierings, Marc; Gale, Robert Peter

2013-05-01

Allogeneic hematopoietic cell transplantation (HCT) can cure bone marrow failure in patients with Fanconi anemia (FA). Data on outcomes in patients with pretransplantation cytogenetic abnormalities, myelodysplastic syndrome (MDS), or acute leukemia have not been separately analyzed. We analyzed data on 113 patients with FA with cytogenetic abnormalities (n = 54), MDS (n = 45), or acute leukemia (n = 14) who were reported to the Center for International Blood and Marrow Transplant Research from 1985 to 2007. Neutrophil recovery occurred in 78% and 85% of patients at days 28 and 100, respectively. Day 100 cumulative incidences of acute graft-versus-host disease grades B to D and C to D were 26% (95% CI, 19% to 35%) and 12% (95% CI, 7% to 19%), respectively. Survival probabilities at 1, 3, and 5 years were 64% (95% CI, 55% to 73%), 58% (95% CI, 48% to 67%), and 55% (95% CI, 45% to 64%), respectively. In univariate analysis, younger age was associated with superior 5-year survival (≤ v > 14 years: 69% [95% CI, 57% to 80%] v 39% [95% CI, 26% to 53%], respectively; P = .001). In transplantations from HLA-matched related donors (n = 82), younger patients (≤ v > 14 years: 78% [95% CI, 64% to 90%] v 34% [95% CI, 20% to 50%], respectively; P < .001) and patients with cytogenetic abnormalities only versus MDS/acute leukemia (67% [95% CI, 52% to 81%] v 43% [95% CI, 27% to 59%], respectively; P = .03) had superior 5-year survival. Our analysis indicates that long-term survival for patients with FA with cytogenetic abnormalities, MDS, or acute leukemia is achievable. Younger patients and recipients of HLA-matched related donor transplantations who have cytogenetic abnormalities only have the best survival.

Allogeneic Hematopoietic Cell Transplantation for Fanconi Anemia in Patients With Pretransplantation Cytogenetic Abnormalities, Myelodysplastic Syndrome, or Acute Leukemia

PubMed Central

Ayas, Mouhab; Saber, Wael; Davies, Stella M.; Harris, Richard E.; Hale, Gregory A.; Socie, Gerard; LeRademacher, Jennifer; Thakar, Monica; Deeg, H. Joachim J.; Al-Seraihy, Amal; Battiwalla, Minoo; Camitta, Bruce M.; Olsson, Richard; Bajwa, Rajinder S.; Bonfim, Carmem M.; Pasquini, Ricardo; MacMillan, Margaret L.; George, Biju; Copelan, Edward A.; Wirk, Baldeep; Al Jefri, Abdullah; Fasth, Anders L.; Guinan, Eva C.; Horn, Biljana N.; Lewis, Victor A.; Slavin, Shimon; Stepensky, Polina; Bierings, Marc; Gale, Robert Peter

2013-01-01

Purpose Allogeneic hematopoietic cell transplantation (HCT) can cure bone marrow failure in patients with Fanconi anemia (FA). Data on outcomes in patients with pretransplantation cytogenetic abnormalities, myelodysplastic syndrome (MDS), or acute leukemia have not been separately analyzed. Patients and Methods We analyzed data on 113 patients with FA with cytogenetic abnormalities (n = 54), MDS (n = 45), or acute leukemia (n = 14) who were reported to the Center for International Blood and Marrow Transplant Research from 1985 to 2007. Results Neutrophil recovery occurred in 78% and 85% of patients at days 28 and 100, respectively. Day 100 cumulative incidences of acute graft-versus-host disease grades B to D and C to D were 26% (95% CI, 19% to 35%) and 12% (95% CI, 7% to 19%), respectively. Survival probabilities at 1, 3, and 5 years were 64% (95% CI, 55% to 73%), 58% (95% CI, 48% to 67%), and 55% (95% CI, 45% to 64%), respectively. In univariate analysis, younger age was associated with superior 5-year survival (≤ v > 14 years: 69% [95% CI, 57% to 80%] v 39% [95% CI, 26% to 53%], respectively; P = .001). In transplantations from HLA-matched related donors (n = 82), younger patients (≤ v > 14 years: 78% [95% CI, 64% to 90%] v 34% [95% CI, 20% to 50%], respectively; P < .001) and patients with cytogenetic abnormalities only versus MDS/acute leukemia (67% [95% CI, 52% to 81%] v 43% [95% CI, 27% to 59%], respectively; P = .03) had superior 5-year survival. Conclusion Our analysis indicates that long-term survival for patients with FA with cytogenetic abnormalities, MDS, or acute leukemia is achievable. Younger patients and recipients of HLA-matched related donor transplantations who have cytogenetic abnormalities only have the best survival. PMID:23547077

Rapid evaluation and quality control of next generation sequencing data with FaQCs

DOE PAGES

Lo, Chien -Chi; Chain, Patrick S. G.

2014-12-01

Background: Next generation sequencing (NGS) technologies that parallelize the sequencing process and produce thousands to millions, or even hundreds of millions of sequences in a single sequencing run, have revolutionized genomic and genetic research. Because of the vagaries of any platform's sequencing chemistry, the experimental processing, machine failure, and so on, the quality of sequencing reads is never perfect, and often declines as the read is extended. These errors invariably affect downstream analysis/application and should therefore be identified early on to mitigate any unforeseen effects. Results: Here we present a novel FastQ Quality Control Software (FaQCs) that can rapidly processmore » large volumes of data, and which improves upon previous solutions to monitor the quality and remove poor quality data from sequencing runs. Both the speed of processing and the memory footprint of storing all required information have been optimized via algorithmic and parallel processing solutions. The trimmed output compared side-by-side with the original data is part of the automated PDF output. We show how this tool can help data analysis by providing a few examples, including an increased percentage of reads recruited to references, improved single nucleotide polymorphism identification as well as de novo sequence assembly metrics. Conclusion: FaQCs combines several features of currently available applications into a single, user-friendly process, and includes additional unique capabilities such as filtering the PhiX control sequences, conversion of FASTQ formats, and multi-threading. The original data and trimmed summaries are reported within a variety of graphics and reports, providing a simple way to do data quality control and assurance.« less

Mycoplasma salivarium as a Dominant Coloniser of Fanconi Anaemia Associated Oral Carcinoma

PubMed Central

Henrich, Birgit; Rumming, Madis; Sczyrba, Alexander; Velleuer, Eunike; Dietrich, Ralf; Gerlach, Wolfgang; Gombert, Michael; Rahn, Sebastian; Stoye, Jens; Borkhardt, Arndt; Fischer, Ute

2014-01-01

Mycoplasma salivarium belongs to the class of the smallest self-replicating Tenericutes and is predominantly found in the oral cavity of humans. In general it is considered as a non-pathogenic commensal. However, some reports point to an association with human diseases. M. salivarium was found e.g. as causative agent of a submasseteric abscess, in necrotic dental pulp, in brain abscess and clogged biliary stent. Here we describe the detection of M. salivarium on the surface of a squamous cell carcinoma of the tongue of a patient with Fanconi anaemia (FA). FA is an inherited bone marrow failure syndrome based on defective DNA-repair that increases the risk of carcinomas especially oral squamous cell carcinoma. Employing high coverage, massive parallel Roche/454-next-generation-sequencing of 16S rRNA gene amplicons we analysed the oral microbiome of this FA patient in comparison to that of an FA patient with a benign leukoplakia and five healthy individuals. The microbiota of the FA patient with leukoplakia correlated well with that of the healthy controls. A dominance of Streptococcus, Veillonella and Neisseria species was typically observed. In contrast, the microbiome of the cancer bearing FA patient was dominated by Pseudomonas aeruginosa at the healthy sites, which changed to a predominance of 98% M. salivarium on the tumour surface. Quantification of the mycoplasma load in five healthy, two tumour- and two leukoplakia-FA patients by TaqMan-PCR confirmed the prevalence of M. salivarium at the tumour sites. These new findings suggest that this mycoplasma species with its reduced coding capacity found ideal breeding grounds at the tumour sites. Interestingly, the oral cavity of all FA patients and especially samples at the tumour sites were in addition positive for Candida albicans. It remains to be elucidated in further studies whether M. salivarium can be used as a predictive biomarker for tumour development in these patients. PMID:24642836

The Fanconi anemia/BRCA gene network in zebrafish: embryonic expression and comparative genomics.

PubMed

Titus, Tom A; Yan, Yi-Lin; Wilson, Catherine; Starks, Amber M; Frohnmayer, Jonathan D; Bremiller, Ruth A; Cañestro, Cristian; Rodriguez-Mari, Adriana; He, Xinjun; Postlethwait, John H

2009-07-31

Fanconi anemia (FA) is a genetic disease resulting in bone marrow failure, high cancer risks, and infertility, and developmental anomalies including microphthalmia, microcephaly, hypoplastic radius and thumb. Here we present cDNA sequences, genetic mapping, and genomic analyses for the four previously undescribed zebrafish FA genes (fanci, fancj, fancm, and fancn), and show that they reverted to single copy after the teleost genome duplication. We tested the hypothesis that FA genes are expressed during embryonic development in tissues that are disrupted in human patients by investigating fanc gene expression patterns. We found fanc gene maternal message, which can provide Fanc proteins to repair DNA damage encountered in rapid cleavage divisions. Zygotic expression was broad but especially strong in eyes, central nervous system and hematopoietic tissues. In the pectoral fin bud at hatching, fanc genes were expressed specifically in the apical ectodermal ridge, a signaling center for fin/limb development that may be relevant to the radius/thumb anomaly of FA patients. Hatching embryos expressed fanc genes strongly in the oral epithelium, a site of squamous cell carcinomas in FA patients. Larval and adult zebrafish expressed fanc genes in proliferative regions of the brain, which may be related to microcephaly in FA. Mature ovaries and testes expressed fanc genes in specific stages of oocyte and spermatocyte development, which may be related to DNA repair during homologous recombination in meiosis and to infertility in human patients. The intestine strongly expressed some fanc genes specifically in proliferative zones. Our results show that zebrafish has a complete complement of fanc genes in single copy and that these genes are expressed in zebrafish embryos and adults in proliferative tissues that are often affected in FA patients. These results support the notion that zebrafish offers an attractive experimental system to help unravel mechanisms relevant not only to FA, but also to breast cancer, given the involvement of fancj (brip1), fancn (palb2) and fancd1 (brca2) in both conditions.

The Fanconi anemia/BRCA gene network in zebrafish: Embryonic expression and comparative genomics

PubMed Central

Titus, Tom A.; Yan, Yi-Lin; Wilson, Catherine; Starks, Amber M.; Frohnmayer, Jonathan D.; Canestro, Cristian; Rodriguez-Mari, Adriana; He, Xinjun; Postlethwait, John H.

2008-01-01

Fanconi anemia (FA) is a genic disease resulting in bone marrow failure, high cancer risks, and infertility, and developmental anomalies including microphthalmia, microcephaly, hypoplastic radius and thumb. Here we present cDNA sequences, genetic mapping, and genomic analyses for the four previously undescribed zebrafish FA genes (fanci, fancj, fancm, and fancn, and show that they reverted to single copy after the teleost genome duplication. We tested the hypothesis that FA genes are expressed during embryonic development in tissues that are disrupted in human patients by investigating fanc gene expression patterns. We found fanc gene maternal message, which can provide Fanc proteins to repair DNA damage encountered in rapid cleavage divisions. Zygotic expression was broad but especially strong in eyes, central nervous system and hematopoietic tissues. In the pectoral fin bud at hatching, fanc genes were expressed specifically in the apical ectodermal ridge, a signaling center for fin/limb development that may be relevant to the radius/thumb anomaly of FA patients. Hatching embryos expressed fanc genes strongly in the oral epithelium, a site of squamous cell carcinomas in FA patients. Larval and adult zebrafish expressed fanc genes in proliferative regions of the brain, which may be related to microcephaly in FA. Mature ovaries and testes expressed fanc genes in specific stages of oocyte and spermatocyte development, which may be related to DNA repair during homologous recombination in meiosis and to infertility in human patients. The intestine strongly expressed some fanc genes specifically in proliferative zones. Our results show that zebrafish has a complete complement of fanc genes in single copy and that these genes are expressed in zebrafish embryos and adults in proliferative tissues that are often affected in FA patients. These results support the notion that zebrafish offers an attractive experimental system to help unravel mechanisms relevant not only to FA, but also to breast cancer, given the involvement of fancj (brip1), fancn (palb2) and fancd1 (brca2) in both conditions. PMID:19101574

Color Vision and the Railways: Part 3. Comparison of FaLant, OPTEC 900, and Railway LED Lantern Tests.

PubMed

Dain, Stephen J; Casolin, Armand; Long, Jennifer

2015-02-01

The Farnsworth Lantern (FaLant) and the OPTEC 900 are nominated in the Commission Internationale de l'Éclairage (CIE) Color Vision Standard 2. Neither test uses the railway signal color code of red, yellow, and green, and only the OPTEC 900 is commercially available. The Railway LED Lantern Test (RLLT) is based on railway signaling practices in New South Wales, Australia, and is nominated in the Australian railway medical standard. The objective of this study is to compare the performance of the three lantern tests. The RLLT, FaLant, and OPTEC 900 were administered to 46 color vision-normal and 37 color vision-deficient (CVD) subjects. The pattern of errors on the RLLT was different from that of the FaLant and OPTEC 900. This may be accounted for, at least in part, by the different colors and the use of blank presentations in the RLLT. The three lanterns showed agreement in failing 21 and passing 6 of the CVD subjects (72.9%). The lanterns gave different results for 10 CVD subjects (27.9%): n = 5 passed only the RLLT and n = 3 passed only the FaLant; n = 1 failed only the FaLant and n = 1 failed only the RLLT. The overall failure rate by CVD for each lantern was 67.6% (RLLT), 73.0% (FaLant), and 78.4% (OPTEC 900). Despite the different construction principles, the pass/fail levels of the RLLT, FaLant, and OPTEC 900 are comparable and consistent with the performance of other lanterns listed by the CIE for Color Vision Standard 2. The RLLT may be a little easier to pass and is based on the signal color code used and actual signaling practice. We propose that the RLLT is also an appropriate lantern for CIE Color Vision Standard 2.

Functional Assessment: Old Wine in New Bottles.

ERIC Educational Resources Information Center

Ervin, Ruth A.; Ehrhardt, Kristal E.; Poling, Alan

2001-01-01

Traces functional assessment (FA) in school settings to early contributions by B. F. Skinner. FA plays an important role in behavior analysis, and the value of this approach in dealing with behavior problems in many settings has long been evident. Although interest in FA in school settings has only recently become widespread, FA in education has a…

Spectrum of sequence variations in the FANCA gene: an International Fanconi Anemia Registry (IFAR) study.

PubMed

Levran, Orna; Diotti, Raffaella; Pujara, Kanan; Batish, Sat D; Hanenberg, Helmut; Auerbach, Arleen D

2005-02-01

Fanconi anemia (FA) is an autosomal recessive disorder that is defined by cellular hypersensitivity to DNA cross-linking agents, and is characterized clinically by developmental abnormalities, progressive bone-marrow failure, and predisposition to leukemia and solid tumors. There is extensive genetic heterogeneity, with at least 11 different FA complementation groups. FA-A is the most common group, accounting for approximately 65% of all affected individuals. The mutation spectrum of the FANCA gene, located on chromosome 16q24.3, is highly heterogeneous. Here we summarize all sequence variations (mutations and polymorphisms) in FANCA described in the literature and listed in the Fanconi Anemia Mutation Database as of March 2004, and report 61 novel FANCA mutations identified in FA patients registered in the International Fanconi Anemia Registry (IFAR). Thirty-eight novel SNPs, previously unreported in the literature or in dbSNP, were also identified. We studied the segregation of common FANCA SNPs in FA families to generate haplotypes. We found that FANCA SNP data are highly useful for carrier testing, prenatal diagnosis, and preimplantation genetic diagnosis, particularly when the disease-causing mutations are unknown. Twenty-two large genomic deletions were identified by detection of apparent homozygosity for rare SNPs. In addition, a conserved SNP haplotype block spanning at least 60 kb of the FANCA gene was identified in individuals from various ethnic groups. (c) 2005 Wiley-Liss, Inc.

Endocrinopathies, Bone Health, and Insulin Resistance in Patients with Fanconi Anemia after Hematopoietic Cell Transplantation

PubMed Central

Barnum, Jessie L.; Petryk, Anna; Zhang, Lei; DeFor, Todd E.; Baker, K. Scott; Steinberger, Julia; Nathan, Brandon; Wagner, John E.; MacMillan, Margaret L.

2017-01-01

A number of endocrinopathies have been described after hematopoietic cell transplantation (HCT), but data are limited in patients with Fanconi anemia (FA). We report several endocrine-based disorders in a cohort of 44 patients with FA after HCT compared with both 74 patients who received HCT for hematologic malignancies and with 275 healthy controls. Endocrinopathies assessed included hypothyroidism, hypogonadism, short stature, dyslipidemia, insulin resistance, abnormalities in body composition, and bone health. Most (86%) patients with FA had at least 1 endocrinopathy, with 11% having 3 or more. Hypothyroidism was seen in 57%, hypogonadism in 27%, short stature in 50%, and reduced total body and lumbar spine bone mineral density (BMD) (height adjusted Z-score < −1) in 57% and 21%, respectively. Vitamin D deficiency was seen in 71%. Short stature was associated with younger age at HCT and gonadal failure was associated with older age at HCT. Insulin resistance was associated with increased percent fat mass and increased android/gynoid ratio by dual energy X-ray absorptiometry. Hypothyroidism, short stature, and reduced total body BMD were more prevalent in patients with FA compared with patients with hematologic malignancies. We recommend an assessment before transplantation and close follow-up afterwards to ensure proper clinical management. Future studies should continue to explore the impact of HCT on endocrinopathies in FA patients. PMID:27180116

Spectrum of FANCA mutations in Italian Fanconi anemia patients: identification of six novel alleles and phenotypic characterization of the S858R variant.

PubMed

Savino, Maria; Borriello, Adriana; D'Apolito, Maria; Criscuolo, Maria; Del Vecchio, Maria; Bianco, Anna Monica; Di Perna, Michele; Calzone, Rita; Nobili, Bruno; Zatterale, Adriana; Zelante, Leopoldo; Joenje, Hans; Della Ragione, Fulvio; Savoia, Anna

2003-10-01

Fanconi anemia (FA) is an autosomal recessive disorder characterized by genomic instability, bone marrow failure, congenital malformations, and cancer predisposition. FA is a genetically heterogeneous disease with at least seven genes so far identified. The role of FA proteins is unknown although they interact in a common functional pathway. Here, we report six novel FANCA sequence changes and review all the mutations identified in Italy. Except for two missense substitutions, all are expected to cause a premature termination of the FANCA protein at various sites throughout the molecule. The premature terminations are due to nonsense and splice site mutations, as well as small insertions and deletions, and large genomic rearrangements. The expected truncated proteins were not detectable on Western blot analyses. The FANCA-S858R variant is instead expressed at lower level than that seen in normal cell lines and is associated with a non-ubiquinated FANCD2 protein, strongly suggesting that the amino acid substitution is a disease-causing mutation. The spectrum of FA mutations is widely in agreement with the heterogeneous ethnic origin of the Italian population. Copyright 2003 Wiley-Liss, Inc.

Global and disease-associated genetic variation in the human Fanconi anemia gene family.

PubMed

Rogers, Kai J; Fu, Wenqing; Akey, Joshua M; Monnat, Raymond J

2014-12-20

Fanconi anemia (FA) is a human recessive genetic disease resulting from inactivating mutations in any of 16 FANC (Fanconi) genes. Individuals with FA are at high risk of developmental abnormalities, early bone marrow failure and leukemia. These are followed in the second and subsequent decades by a very high risk of carcinomas of the head and neck and anogenital region, and a small continuing risk of leukemia. In order to characterize base pair-level disease-associated (DA) and population genetic variation in FANC genes and the segregation of this variation in the human population, we identified 2948 unique FANC gene variants including 493 FA DA variants across 57,240 potential base pair variation sites in the 16 FANC genes. We then analyzed the segregation of this variation in the 7578 subjects included in the Exome Sequencing Project (ESP) and the 1000 Genomes Project (1KGP). There was a remarkably high frequency of FA DA variants in ESP/1KGP subjects: at least 1 FA DA variant was identified in 78.5% (5950 of 7578) individuals included in these two studies. Six widely used functional prediction algorithms correctly identified only a third of the known, DA FANC missense variants. We also identified FA DA variants that may be good candidates for different types of mutation-specific therapies. Our results demonstrate the power of direct DNA sequencing to detect, estimate the frequency of and follow the segregation of deleterious genetic variation in human populations. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Fatty acid profiles of Vibrio parahaemolyticus and its changes with environment.

PubMed

Xu, Min; Wang, Jing; Mou, Haijin

2015-01-01

The fatty acid (FA) profiles of 15 strains representing four genera (Vibrio, Pseudomonas, Aeromonas, and Shewanella) and seven species were compared by capillary gas chromatography with flame ionization detection. FA fingerprints of Vibrio parahaemolyticus were established by similarity calculation and principle component analysis. This provided a simple measure for distinguishing V. parahaemolyticus from other bacteria. The similarity scores indicated by correlation coefficient and vector cosine were divided into three regions and suggested that the strains with scores higher than 0.980 probably belonged to V. parahaemolyticus. However, samples with low scores (<0.850) were classified under other genera. Furthermore, the alterations in FA profiles of V. parahaemolyticus in the presence of various environmental pressures were investigated. The production of saturated FA (SFA) increased gradually concomitant with a decreased proportion of unsaturated FA (UFA) with rising temperature. Similarly, the SFA tended to increase at the expense of UFA with prolonged culture time. In addition, V. parahaemolyticus changed its FA profiles to contain increased short-chained FA to resist an acidic environment, whereas alkaline conditions stimulated high production of long-chained FA. Analysis on FA profile is valuable for the physiological study of V. parahaemolyticus and its rapid identification. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The Use of Ammonium Formate as a Mobile-Phase Modifier for LC-MS/MS Analysis of Tryptic Digests

PubMed Central

Johnson, Darryl; Boyes, Barry; Orlando, Ron

2013-01-01

A major challenge facing current mass spectrometry (MS)-based proteomics research is the large concentration range displayed in biological systems, which far exceeds the dynamic range of commonly available mass spectrometers. One approach to overcome this limitation is to improve online reversed-phase liquid chromatography (RP-LC) separation methodologies. LC mobile-phase modifiers are used to improve peak shape and increase sample load tolerance. Trifluoroacetic acid (TFA) is a commonly used mobile-phase modifier, as it produces peptide separations that are far superior to other additives. However, TFA leads to signal suppression when incorporated with electrospray ionization (ESI), and thus, other modifiers, such as formic acid (FA), are used for LC-MS applications. FA exhibits significantly less signal suppression, but is not as effective of a modifier as TFA. An alternative mobile-phase modifier is the combination of FA and ammonium formate (AF), which has been shown to improve peptide separations. The ESI-MS compatibility of this modifier has not been investigated, particularly for proteomic applications. This work compares the separation metrics of mobile phases modified with FA and FA/AF and explores the use of FA/AF for the LC-MS analysis of tryptic digests. Standard tryptic-digest peptides were used for comparative analysis of peak capacity and sample load tolerance. The compatibility of FA/AF in proteomic applications was examined with the analysis of soluble proteins from canine prostate carcinoma tissue. Overall, the use of FA/AF improved online RP-LC separations and led to significant increases in peptide identifications with improved protein sequence coverage. PMID:24294112

The use of ammonium formate as a mobile-phase modifier for LC-MS/MS analysis of tryptic digests.

PubMed

Johnson, Darryl; Boyes, Barry; Orlando, Ron

2013-12-01

A major challenge facing current mass spectrometry (MS)-based proteomics research is the large concentration range displayed in biological systems, which far exceeds the dynamic range of commonly available mass spectrometers. One approach to overcome this limitation is to improve online reversed-phase liquid chromatography (RP-LC) separation methodologies. LC mobile-phase modifiers are used to improve peak shape and increase sample load tolerance. Trifluoroacetic acid (TFA) is a commonly used mobile-phase modifier, as it produces peptide separations that are far superior to other additives. However, TFA leads to signal suppression when incorporated with electrospray ionization (ESI), and thus, other modifiers, such as formic acid (FA), are used for LC-MS applications. FA exhibits significantly less signal suppression, but is not as effective of a modifier as TFA. An alternative mobile-phase modifier is the combination of FA and ammonium formate (AF), which has been shown to improve peptide separations. The ESI-MS compatibility of this modifier has not been investigated, particularly for proteomic applications. This work compares the separation metrics of mobile phases modified with FA and FA/AF and explores the use of FA/AF for the LC-MS analysis of tryptic digests. Standard tryptic-digest peptides were used for comparative analysis of peak capacity and sample load tolerance. The compatibility of FA/AF in proteomic applications was examined with the analysis of soluble proteins from canine prostate carcinoma tissue. Overall, the use of FA/AF improved online RP-LC separations and led to significant increases in peptide identifications with improved protein sequence coverage.

Factors Influencing the Decision-Making Process and Long-Term Interpersonal Outcomes for Parents Who Undergo Preimplantation Genetic Diagnosis for Fanconi Anemia: a Qualitative Investigation.

PubMed

Haude, K; McCarthy Veach, P; LeRoy, B; Zierhut, H

2017-06-01

Fanconi anemia (FA) is characterized by congenital malformations, progressive bone marrow failure, and predisposition to malignancy. Hematopoietic stem cell transplantation is used to treat FA, and best results are attained with sibling donors who are human leukocyte antigen (HLA) identical matches. Preimplantation genetic diagnosis (PGD) offers parents of an affected child the opportunity to have an unaffected child who is an HLA match. While some research has investigated parents' experiences during the PGD process, no published studies specifically address factors influencing their decision-making process and long-term interpersonal outcomes. The aims of this study are to: (1) examine parents' expectations and the influence of media, bioethics, and religion on their decision to undergo PGD; (2) examine parents' social support and emotional experiences during their PGD process; and (3) characterize long-term effects of PGD on relationship dynamics (partner, family, friends), others' attitudes, and parental regret. Nine parents participated in semi-structured interviews. Thematic analysis revealed their decision to use PGD was variously influenced by media, bioethics, and religion, in particular, affecting parents' initial confidence levels. Moreover, the PGD process was emotionally complex, with parents desiring varying amounts and types of support from different sources at different times. Parents reported others' attitudes towards them were similar or no different than before PGD. Parental regret regarding PGD was negligible. Results of this study will promote optimization of long-term care for FA families.

Assessment of workplace air concentrations of formaldehyde during and before working hours in medical facilities.

PubMed

Higashikubo, Ichiro; Miyauchi, Hiroyuki; Yoshida, Satoru; Tanaka, Shinsuke; Matsuoka, Mitsunori; Arito, Heihachiro; Araki, Akihiro; Shimizu, Hidesuke; Sakurai, Haruhiko

2017-04-07

Workplace air concentrations of formaldehyde (FA) in medical facilities where FA and FA-treated organs were stored and handled were measured before and during working hours and assessed by the official method specified by Work Environment Measurement Law. Sixty-percent of the total facilities examined were judged as inappropriately controlled work environment. The concentrations of FA before working hours by spot sampling were found to exceed 0.1 ppm in some facilities, and tended to increase with increasing volume of containers storing FA and FA-treated materials. Regression analysis revealed that logarithmic concentrations of FA during working hours by the Law-specified analytical method were highly correlated with those before working hours by spot sampling, suggesting the importance for appropriate storing methods of FA and FA-treated materials. The concentrations of FA during working hours are considered to be lowered by effective ventilation of FA-contaminated workplace air and appropriate storage of FA and FA-treated materials in plastic containers in the medical facilities. In particular, such improvement by a local exhaust ventilation system and tightly-sealed containment of FA-treated material were urgently needed for the dissecting room where FA-treated cadavers were prepared and handled for a gross anatomy course in a medical school.

Aptamer fluorescence anisotropy sensors for adenosine triphosphate by comprehensive screening tetramethylrhodamine labeled nucleotides.

PubMed

Zhao, Qiang; Lv, Qin; Wang, Hailin

2015-08-15

We previously reported a fluorescence anisotropy (FA) approach for small molecules using tetramethylrhodamine (TMR) labeled aptamer. It relies on target-binding induced change of intramolecular interaction between TMR and guanine (G) base. TMR-labeling sites are crucial for this approach. Only terminal ends and thymine (T) bases could be tested for TMR labeling in our previous work, possibly causing limitation in analysis of different targets with this FA strategy. Here, taking the analysis of adenosine triphosphate (ATP) as an example, we demonstrated a success of conjugating TMR on other bases of aptamer adenine (A) or cytosine (C) bases and an achievement of full mapping various labeling sites of aptamers. We successfully constructed aptamer fluorescence anisotropy (FA) sensors for adenosine triphosphate (ATP). We conjugated single TMR on adenine (A), cytosine (C), or thymine (T) bases or terminals of a 25-mer aptamer against ATP and tested FA responses of 14 TMR-labeled aptamer to ATP. The aptamers having TMR labeled on the 16th base C or 23rd base A were screened out and exhibited significant FA-decreasing or FA-increasing responses upon ATP, respectively. These two favorable TMR-labeled aptamers enabled direct FA sensing ATP with a detection limit of 1 µM and the analysis of ATP in diluted serum. The comprehensive screening various TMR labeling sites of aptamers facilitates the successful construction of FA sensors using TMR-labeled aptamers. It will expand application of TMR-G interaction based aptamer FA strategy to a variety of targets. Copyright © 2015 Elsevier B.V. All rights reserved.

Individual white matter fractional anisotropy analysis on patients with MRI negative partial epilepsy.

PubMed

Duning, Thomas; Kellinghaus, Christoph; Mohammadi, Siawoosh; Schiffbauer, Hagen; Keller, Simon; Ringelstein, E Bernd; Knecht, Stefan; Deppe, Michael

2010-02-01

Conventional structural MRI fails to identify a cerebral lesion in 25% of patients with cryptogenic partial epilepsy (CPE). Diffusion tensor imaging is an MRI technique sensitive to microstructural abnormalities of cerebral white matter (WM) by quantification of fractional anisotropy (FA). The objectives of the present study were to identify focal FA abnormalities in patients with CPE who were deemed MRI negative during routine presurgical evaluation. Diffusion tensor imaging at 3 T was performed in 12 patients with CPE and normal conventional MRI and in 67 age matched healthy volunteers. WM integrity was compared between groups on the basis of automated voxel-wise statistics of FA maps using an analysis of covariance. Volumetric measurements from high resolution T1-weighted images were also performed. Significant FA reductions in WM regions encompassing diffuse areas of the brain were observed when all patients as a group were compared with controls. On an individual basis, voxel based analyses revealed widespread symmetrical FA reduction in CPE patients. Furthermore, asymmetrical temporal lobe FA reduction was consistently ipsilateral to the electroclinical focus. No significant correlations were found between FA alterations and clinical data. There were no differences in brain volumes of CPE patients compared with controls. Despite normal conventional MRI, WM integrity abnormalities in CPE patients extend far beyond the epileptogenic zone. Given that unilateral temporal lobe FA abnormalities were consistently observed ipsilateral to the seizure focus, analysis of temporal FA may provide an informative in vivo investigation into the localisation of the epileptogenic zone in MRI negative patients.

Founder haplotype analysis of Fanconi anemia in the Korean population finds common ancestral haplotypes for a FANCG variant.

PubMed

Park, Joonhong; Kim, Myungshin; Jang, Woori; Chae, Hyojin; Kim, Yonggoo; Chung, Nack-Gyun; Lee, Jae-Wook; Cho, Bin; Jeong, Dae-Chul; Park, In Yang; Park, Mi Sun

2015-05-01

A common ancestral haplotype is strongly suggested in the Korean and Japanese patients with Fanconi anemia (FA), because common mutations have been frequently found: c.2546delC and c.3720_3724delAAACA of FANCA; c.307+1G>C, c.1066C>T, and c.1589_1591delATA of FANCG. Our aim in this study was to investigate the origin of these common mutations of FANCA and FANCG. We genotyped 13 FA patients consisting of five FA-A patients and eight FA-G patients from the Korean FA population. Microsatellite markers used for haplotype analysis included four CA repeat markers which are closely linked with FANCA and eight CA repeat markers which are contiguous with FANCG. As a result, Korean FA-A patients carrying c.2546delC or c.3720_3724delAAACA did not share the same haplotypes. However, three unique haplotypes carrying c.307+1G>C, c.1066C > T, or c.1589_1591delATA, that consisted of eight polymorphic loci covering a flanking region were strongly associated with Korean FA-G, consistent with founder haplotypes reported previously in the Japanese FA-G population. Our finding confirmed the common ancestral haplotypes on the origins of the East Asian FA-G patients, which will improve our understanding of the molecular population genetics of FA-G. To the best of our knowledge, this is the first report on the association between disease-linked mutations and common ancestral haplotypes in the Korean FA population. © 2015 John Wiley & Sons Ltd/University College London.

Three-dimensional fractal analysis of 99mTc-MAA SPECT images in chronic thromboembolic pulmonary hypertension for evaluation of response to balloon pulmonary angioplasty: association with pulmonary arterial pressure.

PubMed

Maruoka, Yasuhiro; Nagao, Michinobu; Baba, Shingo; Isoda, Takuro; Kitamura, Yoshiyuki; Yamazaki, Yuzo; Abe, Koichiro; Sasaki, Masayuki; Abe, Kohtaro; Honda, Hiroshi

2017-06-01

Balloon pulmonary angioplasty (BPA) is used for inoperable chronic thromboembolic pulmonary hypertension (CTEPH), but its effect cannot be evaluated noninvasively. We devised a noninvasive quantitative index of response to BPA using three-dimensional fractal analysis (3D-FA) of technetium-99m-macroaggregated albumin (Tc-MAA) single-photon emission computed tomography (SPECT). Forty CTEPH patients who underwent pulmonary perfusion scintigraphy and mean pulmonary arterial pressure (mPAP) measurement by right heart catheterization before and after BPA were studied. The total uptake volume (TUV) in bilateral lungs was determined from maximum intensity projection Tc-MAA SPECT images. Fractal dimension was assessed by 3D-FA. Parameters were compared before and after BPA, and between patients with post-BPA mPAP more than 30 mmHg and less than or equal to 30 mmHg. Receiver operating characteristic analysis was carried out. BPA significantly improved TUV (595±204-885±214 ml, P<0.001) and reduced the laterality of uptake (238±147-135±131 ml, P<0.001). Patients with poor therapeutic response (post-BPA mPAP≥30 mmHg, n=16) showed a significantly smaller TUV increase (P=0.044) and a significantly greater post-BPA fractal dimension (P<0.001) than the low-mPAP group. Fractal dimension correlated with mPAP values before and after BPA (P=0.013 and 0.001, respectively). A post-BPA fractal dimension threshold of 2.4 distinguished between BPA success and failure with 75% sensitivity, 79% specificity, 78% accuracy, and area under the curve of 0.85. 3D-FA using Tc-MAA SPECT pulmonary perfusion scintigraphy enables a noninvasive evaluation of the response of CTEPH patients to BPA.

Digestion of fatty acids in ruminants: a meta-analysis of flows and variation factors. 1. Total fatty acids.

PubMed

Schmidely, P; Glasser, F; Doreau, M; Sauvant, D

2008-05-01

A database built from 95 experiments with 303 treatments was used to quantify the ruminal biohydrogenation (BH) of fatty acids (FA), efficiency of microbial protein synthesis (EMPS), duodenal flow and intestinal absorption of total FA and of FA with 12 to 18 C units, in response to variations in dietary FA content, source or technological treatment of fat supplement. Flows of FA were expressed relative to dry matter intake (DMI) to compile data from bovine and ovine species. BH tended to increase curvilinearly with FA intake, whereas dietary FA did not affect EMPS. A linear relationship between FA intake and duodenal flow of total FA was obtained, with a coefficient of 0.75 ± 0.06 g duodenal FA/kg DMI for each g FA intake/kg DMI. Between experiments, positive balances of total FA (intake - duodenum) were related to low EMPS. Relationships between duodenal flows of FA with 12 to 18 C units and their respective intakes were linear, with a coefficient that increased with the number of C units. Duodenal flow of bacterial FA was linearly related to FA intake (coefficient 0.33 ± 0.13), whereas contribution of bacterial lipid to duodenal flow decreased as FA intake increased. For each FA with 12 to 16 C units, prediction of FA absorption from its respective duodenal flow was linear. For total FA and FA with 18 C units, apparent absorption levelled off at high duodenal flows. All these relationships were discussed according to current knowledge on microbial metabolism in the rumen and on the intestinal digestibility of FA in the intestine.

Cerebral diffusion tensor imaging and in vivo proton magnetic resonance spectroscopy in patients with fulminant hepatic failure.

PubMed

Saksena, Sona; Rai, Vijan; Saraswat, Vivek Anand; Rathore, Ramkishore Singh; Purwar, Ankur; Kumar, Manoj; Thomas, M Albert; Gupta, Rakesh Kumar

2008-07-01

Cerebral edema is a major complication in patients with fulminant hepatic failure (FHF). The aim of this study was to evaluate the metabolite alterations and cerebral edema in patients with FHF using in vivo proton magnetic resonance spectroscopy (MRS) and diffusion tensor imaging, and to look for its reversibility in survivors. Ten FHF patients along with 10 controls were studied. Five of the 10 patients who recovered had a repeat imaging after three weeks. N-acetylaspartate, choline (Cho), glutamine (Gln), glutamine/glutamate (Glx), and myoinositol ratios were calculated with respect to creatine (Cr). Mean diffusivity (MD) and fractional anisotropy (FA) were calculated in different brain regions. Patients exhibited significantly increased Gln/Cr and Glx/Cr, and reduced Cho/Cr ratios, compared to controls. In the follow-up study, all metabolite ratios were normalized except Glx/Cr. Significantly decreased Cho/Cr were observed in deceased patients compared to controls. In patients, significantly decreased MD and FA values were observed in most topographical locations of the brain compared to controls. MD and FA values showed insignificant increase in the follow-up study compared to their first study. We conclude that the Cho/Cr ratio appears to be an in vivo marker of prognosis in FHF. Decreased MD values suggest predominant cytotoxic edema may be present. Persistence of imaging and MRS abnormalities at three weeks' clinical recovery suggests that metabolic recovery may take longer than clinical recovery in FHF patients.

A modified version of fluctuating asymmetry, potential for the analysis of Aesculus hippocastanum L. compound leaves.

PubMed

Velickovic, Miroslava

2008-01-01

My research interest was to create a new, simple and tractable mathematical framework for analyzing fluctuating asymmetry (FA) in Aesculus hippocastanum L. palmately compound leaves (each compound leaf with 7 obviate, serrate leaflets). FA, being random differences in the development of both sides of a bilaterally symmetrical character, has been proposed as an indicator of environmental and genetic stress. In the present paper the well-established Palmer's procedure for FA has been modified to improve the suitability of the chosen index (FA1) to be used in compound leaf asymmetry analysis. The processing steps are described in detail, allowing us to apply these modifications for the other Palmer's indices of FA as well as for the compound leaves of other plant species.

Co-expression analysis identifies CRC and AP1 the regulator of Arabidopsis fatty acid biosynthesis.

PubMed

Han, Xinxin; Yin, Linlin; Xue, Hongwei

2012-07-01

Fatty acids (FAs) play crucial rules in signal transduction and plant development, however, the regulation of FA metabolism is still poorly understood. To study the relevant regulatory network, fifty-eight FA biosynthesis genes including de novo synthases, desaturases and elongases were selected as "guide genes" to construct the co-expression network. Calculation of the correlation between all Arabidopsis thaliana (L.) genes with each guide gene by Arabidopsis co-expression dating mining tools (ACT) identifies 797 candidate FA-correlated genes. Gene ontology (GO) analysis of these co-expressed genes showed they are tightly correlated to photosynthesis and carbohydrate metabolism, and function in many processes. Interestingly, 63 transcription factors (TFs) were identified as candidate FA biosynthesis regulators and 8 TF families are enriched. Two TF genes, CRC and AP1, both correlating with 8 FA guide genes, were further characterized. Analyses of the ap1 and crc mutant showed the altered total FA composition of mature seeds. The contents of palmitoleic acid, stearic acid, arachidic acid and eicosadienoic acid are decreased, whereas that of oleic acid is increased in ap1 and crc seeds, which is consistent with the qRT-PCR analysis revealing the suppressed expression of the corresponding guide genes. In addition, yeast one-hybrid analysis and electrophoretic mobility shift assay (EMSA) revealed that CRC can bind to the promoter regions of KCS7 and KCS15, indicating that CRC may directly regulate FA biosynthesis. © 2012 Institute of Botany, Chinese Academy of Sciences.

Starmerella camargoi f.a., sp. nov., Starmerella ilheusensis f.a., sp. nov., Starmerella litoralis f.a., sp. nov., Starmerella opuntiae f.a., sp. nov., Starmerella roubikii f.a., sp. nov. and Starmerella vitae f.a., sp. nov., isolated from flowers and bees, and transfer of related Candida species to the genus Starmerella as new combinations.

PubMed

Santos, Ana Raquel O; Leon, Marina P; Barros, Katharina O; Freitas, Larissa F D; Hughes, Alice F S; Morais, Paula B; Lachance, Marc-André; Rosa, Carlos A

2018-04-01

Six novel yeast species, Starmerella camargoi f.a., sp. nov., Starmerella ilheusensis f.a., sp. nov., Starmerella litoralis f.a., Starmerella opuntiae f.a., sp. nov., sp. nov., Starmerella roubikii f.a., sp. nov. and Starmerella vitae f.a, sp. nov. are proposed to accommodate 19 isolates recovered from ephemeral flowers or bees in Brazil, Costa Rica and Belize. Sequence analysis of the ITS-5.8S region (when available) and the D1/D2 domains of the large subunit of the rRNA gene showed that the six novel yeasts are phylogenetically related to several species of the Starmerella clade. The type strains are Starmerella camargoi f.a., sp. nov. UFMG-CM-Y595 T (=CBS 14130 T ; Mycobank number MB 822640), Starmerella ilheusensis f.a., sp. nov. UFMG-CM-Y596 T (=CBS CBS14131 T ; MB 822641), Starmerella litoralis f.a., sp. nov. UFMG-CM-Y603 T (=CBS14104 T ; MB 822642), Starmerella opuntiae f.a., sp. nov. UFMG-CM-Y286 T (=CBS 13466 T ; MB 822643), Starmerella roubikii f.a., sp. nov. UWOPS 01-191.1 (=CBS 15148; MB 822645) and Starmerella vitae f.a., sp. nov. UWOPS 00-107.2 (=CBS 15147 T ; MB 822646). In addition, 25 species currently assigned to the genus Candida are reassigned formally to the genus Starmerella.

A comprehensive tractography study of patients with bipolar disorder and their unaffected siblings.

PubMed

Sprooten, Emma; Barrett, Jennifer; McKay, D Reese; Knowles, Emma E; Mathias, Samuel R; Winkler, Anderson M; Brumbaugh, Margaret S; Landau, Stefanie; Cyr, Lindsay; Kochunov, Peter; Glahn, David C

2016-10-01

Diffusion tensor imaging studies show reductions in fractional anisotropy (FA) in individuals with bipolar disorder and their unaffected siblings. However, the use of various analysis methods is an important source of between-study heterogeneity. Using tract-based spatial statistics, we previously demonstrated widespread FA reductions in patients and unaffected relatives. To better interpret the neuroanatomical pattern of this previous finding and to assess the influence of methodological heterogeneity, we here applied tractography to the same sample. Diffusion-weighted images were acquired for 96 patients, 69 unaffected siblings and 56 controls. We applied TRACULA, an extension of a global probabilistic tractography algorithm, to automatically segment 18 major fiber tracts. Average FA within each tract and at each cross-section along each tract was compared between groups. Patients had reduced FA compared to healthy controls and their unaffected siblings in general, and in particular in the parietal part of the superior longitudinal fasciculus. In unaffected siblings, FA was nominally reduced compared to controls in the corpus callosum. Point-wise analyses indicated that similar effects were present along extended sections, but with variable effect sizes. Current symptom severity negatively correlated with FA in several fronto-limbic association tracts. The differential sensitivity of analysis techniques likely explains between-study heterogeneity in anatomical localization of FA reductions. The present tractography analysis confirms the presence of overall FA reductions in patients with bipolar disorder, which are most pronounced in the superior longitudinal fasciculus. Unaffected siblings may display similar, albeit more subtle and anatomically restricted FA reductions. Hum Brain Mapp 37:3474-3485, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Intestinal digestibility of long-chain fatty acids in lactating dairy cows: A meta-analysis and meta-regression.

PubMed

Boerman, J P; Firkins, J L; St-Pierre, N R; Lock, A L

2015-12-01

The objective of this analysis was to examine the intestinal digestibility of individual long-chain fatty acids (FA) in lactating dairy cows. Available data were collated from 15 publications containing 61 treatments, which reported total and individual FA duodenal flows and calculations of intestinal digestibility. All studies involved lactating dairy cows, and estimates of digestibility were based on measurements either between the duodenum and ileum (18 treatments) or between the duodenum and feces (43 treatments). Fatty acid digestibility was calculated for C16:0, C18:0, C18:1 (cis and trans isomers), C18:2, and C18:3. Digestibility of C18:0 was lower than for C18:1 and C18:3, with no difference in digestibility between saturated FA (C16:0 and C18:0). We weighted the studies by the reciprocal of the variance to generate best-fit equations to predict individual FA digestibility based on duodenal flow of FA and dietary independent variables. The flow of C18:0 negatively affected the digestibility of C18:0 and was also included in the best-fit equations for all other 18-carbon FA using duodenal flow characteristics. The type of fat supplemented had an effect on digestibility of individual FA, with whole seeds having reduced digestibility. Our meta-analysis results showed minimal differences in the digestibility of individual FA. However, C18:0 flow through the duodenum had a negative effect on the digestibility of several individual FA, with the largest negative effect on C18:0 digestibility. The mechanisms that reduce C18:0 absorption at high concentrations are unknown and warrant further investigation. Copyright © 2015 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Interactions between stepwise-eluted sub-fractions of fulvic acids and protons revealed by fluorescence titration combined with EEM-PARAFAC.

PubMed

Song, Fanhao; Wu, Fengchang; Guo, Fei; Wang, Hao; Feng, Weiying; Zhou, Min; Deng, Yanghui; Bai, Yingchen; Xing, Baoshan; Giesy, John P

2017-12-15

In aquatic environments, pH can control environmental behaviors of fulvic acid (FA) via regulating hydrolysis of functional groups. Sub-fractions of FA, eluted using pyrophosphate buffers with initial pHs of 3.0 (FA 3 ), 5.0 (FA 5 ), 7.0 (FA 7 ), 9.0 (FA 9 ) and 13.0 (FA 13 ), were used to explore interactions between the various, operationally defined, FA fractions and protons, by use of EEM-PARAFAC analysis. Splitting of peaks (FA 3 and FA 13 ), merging of peaks (FA 7 ), disappearance of peaks (FA 9 and FA 13 ), and red/blue-shifting of peaks were observed during fluorescence titration. Fulvic-like components were identified from FA 3 -FA 13 , and protein-like components were observed in fractions FA 9 and FA 13 . There primary compounds (carboxylic-like, phenolic-like, and protein-like chromophores) in PARAFAC components were distinguished based on acid-base properties. Dissociation constants (pK a ) for fulvic-like components with proton ranged from 2.43 to 4.13 in an acidic pH and from 9.95 to 11.27 at basic pH. These results might be due to protonation of di-carboxylate and phenolic functional groups. At basic pH, pK a values of protein-like components (9.77-10.13) were similar to those of amino acids. However, at acidic pH, pK a values of protein-like components, which ranged from 3.33 to 4.22, were 1-2units greater than those of amino acids. Results presented here, will benefit understanding of environmental behaviors of FA, as well as interactions of FA with environmental contaminants. Copyright © 2017 Elsevier B.V. All rights reserved.

Red blood cell oleic acid levels reflect olive oil intake while omega-3 levels reflect fish intake and the use of omega-3 acid ethyl esters: The Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-Heart Failure trial.

PubMed

Harris, William S; Masson, Serge; Barlera, Simona; Milani, Valentina; Pileggi, Silvana; Franzosi, Maria Grazia; Marchioli, Roberto; Tognoni, Gianni; Tavazzi, Luigi; Latini, Roberto

2016-09-01

The Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-Heart Failure (GISSI-HF) study reported benefits of n-3 fatty acid (FA) treatment on cardiovascular (CV) events, but the effects of treatment on a putative CV disease risk factor, the red blood cell (RBC) n-3 FA level (the omega-3 index), have not been examined in this context. We hypothesized that treatment with prescription omega-3 acid ethyl esters (O3AEE) would increase the omega-3 index to the proposed cardioprotective value of 8%. RBCs were collected from a subset of patients participating in the GISSI-HF study (n=461 out of 6975 randomized), at baseline and after 3 months of treatment with either an olive oil placebo or O3AEE (1 g/d). RBC FA levels were expressed as a percentage of total FA. Patients also reported their typical olive oil and fish intakes. RBC oleic acid levels were directly correlated with reported frequency of olive oil consumption, and the omega-3 index was correlated with reported fish intake (P for trends <0.001 for both). After treatment, the omega-3 index increased from 4.8±1.7% to 6.7±1.9% but was unchanged in the placebo group (4.7±1.7 to 4.8±1.5%) (P<.0001 for changes between groups). At 3 months, more patients reached the proposed target omega-3 index level of 8%-12% in the treated vs placebo group (22.6% vs. 1.3%, P<.0001), however, what omega-3 index levels were ultimately achieved after four years in this trial are unknown. Copyright © 2016 Elsevier Inc. All rights reserved.

Genomic instability in mice is greater in Fanconi anemia caused by deficiency of Fancd2 than Fancg.

PubMed

Reliene, Ramune; Yamamoto, Mitsuko L; Rao, P Nagesh; Schiestl, Robert H

2010-12-01

Fanconi anemia (FA) results from mutations in the FANC genes and is characterized by bone marrow failure, birth defects, and a high incidence of cancer. FANCG is a part of the FA core complex that is responsible for monoubiquitination of FANCD2 and FANCI. The precise role of the FA pathway is not well understood, although it may be involved in homologous recombination (HR), nonhomologous end joining, and translesion synthesis (TLS). Fancd2(-/-) mice have a more severe phenotype than Fancg(-/-), and other FA core complex-deficient mice, although both Fancg and Fancd2 belong to the same FA pathway. We hypothesized that Fancd2 deficiency results in a more severe phenotype because Fancd2 also has a FA pathway-independent function in the maintenance of genomic integrity. To test this hypothesis, we determined the level of DNA damage and genomic instability in Fancd2(-/-), Fancg(-/-), and wild-type controls. Fancd2(-/-) mice displayed a higher magnitude of chromosomal breakage and micronucleus formation than the wild-type or Fancg(-/-) mice. Also, DNA strand breaks were increased in Fancd2(-/-) but not in Fancg(-/-) mice. In addition, Fancd2(-/-) mice displayed an elevated frequency of DNA deletions, resulting from HR at the endogenous p(un) locus. In contrast, in Fancg(-/-) mice, the frequency of DNA deletions was decreased. Thus, Fancd2 but not Fancg deficiency results in elevated chromosomal/DNA breakage and permanent genome rearrangements. This provides evidence that Fancd2 plays an additional role in the maintenance of genomic stability than Fancg, which might explain the higher predisposition to cancer seen in the Fancd2(-/-) mice.

Rac1 Recruitment to the Archipelago Structure of the Focal Adhesion through the Fluid Membrane as Revealed by Single-Molecule Analysis

PubMed Central

Shibata, Akihiro C E; Chen, Limin H; Nagai, Rie; Ishidate, Fumiyoshi; Chadda, Rahul; Miwa, Yoshihiro; Naruse, Keiji; Shirai, Yuki M; Fujiwara, Takahiro K; Kusumi, Akihiro

2013-01-01

The focal adhesion (FA) is an integrin-based structure built in/on the plasma membrane (PM), linking the extracellular matrix to the actin stress-fibers, working as cell migration scaffolds. Previously, we proposed the archipelago architecture of the FA, in which FA largely consists of fluid membrane, dotted with small islands accumulating FA proteins: membrane molecules enter the inter-island channels in the FA zone rather freely, and the integrins in the FA-protein islands rapidly exchanges with those in the bulk membrane. Here, we examined how Rac1, a small G-protein regulating FA formation, and its activators αPIX and βPIX, are recruited to the FA zones. PIX molecules are recruited from the cytoplasm to the FA zones directly. In contrast, majorities of Rac1 molecules first arrive from the cytoplasm on the general inner PM surface, and then enter the FA zones via lateral diffusion on the PM, which is possible due to rapid Rac1 diffusion even within the FA zones, slowed only by a factor of two to four compared with that outside. The constitutively-active Rac1 mutant exhibited temporary and all-time immobilizations in the FA zone, suggesting that upon PIX-induced Rac1 activation at the FA-protein islands, Rac1 tends to be immobilized at the FA-protein islands. © 2013 Wiley Periodicals, Inc PMID:23341328

Low and high dietary folic acid levels perturb postnatal cerebellar morphology in growing rats.

PubMed

Partearroyo, Teresa; Pérez-Miguelsanz, Juliana; Peña-Melián, Ángel; Maestro-de-Las-Casas, Carmen; Úbeda, Natalia; Varela-Moreiras, Gregorio

2016-06-01

The brain is particularly sensitive to folate metabolic disturbances, because methyl groups are critical for brain functions. This study aimed to investigate the effects of different dietary levels of folic acid (FA) on postnatal cerebellar morphology, including the architecture and organisation of the various layers. A total of forty male OFA rats (a Sprague-Dawley strain), 5 weeks old, were classified into the following four dietary groups: FA deficient (0 mg/kg FA); FA supplemented (8 mg/kg FA); FA supra-supplemented (40 mg/kg FA); and control (2 mg/kg FA) (all n 10 per group). Rats were fed ad libitum for 30 d. The cerebellum was quickly removed and processed for histological and immunohistochemical analysis. Slides were immunostained for glial fibrillary acidic protein (to label Bergmann glia), calbindin (to label Purkinje cells) and NeuN (to label post-mitotic neurons). Microscopic analysis revealed two types of defect: partial disappearance of fissures and/or neuronal ectopia, primarily in supra-supplemented animals (incidence of 80 %, P≤0·01), but also in deficient and supplemented groups (incidence of 40 %, P≤0·05), compared with control animals. The primary fissure was predominantly affected, sometimes accompanied by defects in the secondary fissure. Our findings show that growing rats fed an FA-modified diet, including both deficient and supplemented diets, have an increased risk of disturbances in cerebellar corticogenesis. Defects caused by these diets may have functional consequences in later life. The present study is the first to demonstrate that cerebellar morphological defects can arise from deficient, as well as high, FA levels in the diet.

Dysfunction of protein kinase FA/GSK-3 alpha in lymphocytes of patients with schizophrenic disorder.

PubMed

Yang, S D; Yu, J S; Lee, T T; Yang, C C; Ni, M H; Yang, Y Y

1995-09-01

As compared to normal people, the lymphocytes of patients with schizophrenia were found to have an impairment of ATP.Mg-dependent protein phosphatase activation. More importantly, the impaired protein phosphatase activation in the lymphocytes of schizophrenic patients could be consistently and completely restored to normal by exogenous pure protein kinase FA/glycogen synthase kinase-3 alpha (kinase FA/GSK-3 alpha) (the activating factor of ATP.Mg-dependent protein phosphatase), indicating that the molecular mechanism for the impaired protein phosphatase activation in schizophrenic patients may be due to a functional loss of kinase FA/GSK-3 alpha. Immunoblotting and kinase activity analysis in an anti-kinase FA/GSK-3 alpha immunoprecipitate further demonstrate that both cellular activities and protein levels of kinase FA/GSK-3 alpha in the lymphocytes of schizophrenic patients were greatly impared as compared to normal controls. Statistical analysis revealed that the lymphocytes isolated from 37 normal people contain kinase FA/GSK-3 alpha activity in the high levels of 14.8 +/- 2.4 units/mg of cell protein, whereas the lymphocytes of 48 patients with schizophrenic disorder contain kinase FA/GSK-3 alpha activity in the low levels of 2.8 +/- 1.6 units/mg, indicating that the different levels of kinase FA/GSK-3 alpha activity between schizophrenic patients and normal people are statistically significant. Taken together, the results provide initial evidence that patients with schizophrenic disorder may have a common impairment in the protein levels and cellular activities of kinase FA/GSK-3 alpha, a multisubstrate protein kinase and a multisubstrate protein phosphatase activator in their lymphocytes.

Tetratricopeptide-motif-mediated interaction of FANCG with recombination proteins XRCC3 and BRCA2.

PubMed

Hussain, Shobbir; Wilson, James B; Blom, Eric; Thompson, Larry H; Sung, Patrick; Gordon, Susan M; Kupfer, Gary M; Joenje, Hans; Mathew, Christopher G; Jones, Nigel J

2006-05-10

Fanconi anaemia is an inherited chromosomal instability disorder characterised by cellular sensitivity to DNA interstrand crosslinkers, bone-marrow failure and a high risk of cancer. Eleven FA genes have been identified, one of which, FANCD1, is the breast cancer susceptibility gene BRCA2. At least eight FA proteins form a nuclear core complex required for monoubiquitination of FANCD2. The BRCA2/FANCD1 protein is connected to the FA pathway by interactions with the FANCG and FANCD2 proteins, both of which co-localise with the RAD51 recombinase, which is regulated by BRCA2. These connections raise the question of whether any of the FANC proteins of the core complex might also participate in other complexes involved in homologous recombination repair. We therefore tested known FA proteins for direct interaction with RAD51 and its paralogs XRCC2 and XRCC3. FANCG was found to interact with XRCC3, and this interaction was disrupted by the FA-G patient derived mutation L71P. FANCG was co-immunoprecipitated with both XRCC3 and BRCA2 from extracts of human and hamster cells. The FANCG-XRCC3 and FANCG-BRCA2 interactions did not require the presence of other FA proteins from the core complex, suggesting that FANCG also participates in a DNA repair complex that is downstream and independent of FANCD2 monoubiquitination. Additionally, XRCC3 and BRCA2 proteins co-precipitate in both human and hamster cells and this interaction requires FANCG. The FANCG protein contains multiple tetratricopeptide repeat motifs (TPRs), which function as scaffolds to mediate protein-protein interactions. Mutation of one or more of these motifs disrupted all of the known interactions of FANCG. We propose that FANCG, in addition to stabilising the FA core complex, may have a role in building multiprotein complexes that facilitate homologous recombination repair.

FANCA knockout in human embryonic stem cells causes a severe growth disadvantage.

PubMed

Vanuytsel, Kim; Cai, Qing; Nair, Nisha; Khurana, Satish; Shetty, Swati; Vermeesch, Joris R; Ordovas, Laura; Verfaillie, Catherine M

2014-09-01

Fanconi anemia (FA) is an autosomal recessive disorder characterized by progressive bone marrow failure (BMF) during childhood, aside from numerous congenital abnormalities. FA mouse models have been generated; however, they do not fully mimic the hematopoietic phenotype. As there is mounting evidence that the hematopoietic impairment starts already in utero, a human pluripotent stem cell model would constitute a more appropriate system to investigate the mechanisms underlying BMF in FA and its developmental basis. Using zinc finger nuclease (ZFN) technology, we have created a knockout of FANCA in human embryonic stem cells (hESC). We introduced a selection cassette into exon 2 thereby disrupting the FANCA coding sequence and found that whereas mono-allelically targeted cells retain an unaltered proliferation potential, disruption of the second allele causes a severe growth disadvantage. As a result, heterogeneous cultures arise due to the presence of cells still carrying an unaffected FANCA allele, quickly outgrowing the knockout cells. When pure cultures of FANCA knockout hESC are pursued either through selection or single cell cloning, this rapidly results in growth arrest and such cultures cannot be maintained. These data highlight the importance of a functional FA pathway at the pluripotent stem cell stage. Copyright © 2014. Published by Elsevier B.V.

Effects of hesperidin on formaldehyde-induced toxicity in pregnant rats

PubMed Central

Merzoug, Sameha; Toumi, Mohamed Lamine

2017-01-01

This experimental study aimed to investigate the protective effect of a bioflavonoid, hesperidin (HP), on formaldehyde (FA)-related pathophysiological and behavioral outcomes in pregnant rats and developmental aspects in their offspring. Female Wistar rats were subjected to perigestational exposure to FA (2 mg/kg/day per os) with a concomitant treatment with HP (50 mg/kg/day per os). Pregnant rats were weighed throughout gestation and tested in two behavioral paradigms (elevated plus-maze and open field) at gestational days (GD) 1, 10 and 19 to evaluate the anxiety-like behavior and locomotive alterations. Another subset of rats was decapitated at GD19 to determine the hematological profile along with cortisol, 17β-estradiol, and progesterone plasma levels. Reproductive and fetal measures and observations were also performed to check for developmental deformities. Significant body weight loss, hemato-immune decline, hormonal changes, anxiety and lethargy signs, locomotor disabilities, reproductive failure and fetal weight decrease were observed in FA-exposed rats. Treatment with HP alleviated the reproductive and fetal weight defects. Its behavioral benefits were only seen at GD1 and 10. This flavanone ameliorated some hematological parameters, decreased cortisol levels and increased 17β-estradiol rates. A potential preventive impact of HP was found against FA toxicity in pregnant rats. PMID:28507483

The identification of FANCD2 DNA binding domains reveals nuclear localization sequences.

PubMed

Niraj, Joshi; Caron, Marie-Christine; Drapeau, Karine; Bérubé, Stéphanie; Guitton-Sert, Laure; Coulombe, Yan; Couturier, Anthony M; Masson, Jean-Yves

2017-08-21

Fanconi anemia (FA) is a recessive genetic disorder characterized by congenital abnormalities, progressive bone-marrow failure, and cancer susceptibility. The FA pathway consists of at least 21 FANC genes (FANCA-FANCV), and the encoded protein products interact in a common cellular pathway to gain resistance against DNA interstrand crosslinks. After DNA damage, FANCD2 is monoubiquitinated and accumulates on chromatin. FANCD2 plays a central role in the FA pathway, using yet unidentified DNA binding regions. By using synthetic peptide mapping and DNA binding screen by electromobility shift assays, we found that FANCD2 bears two major DNA binding domains predominantly consisting of evolutionary conserved lysine residues. Furthermore, one domain at the N-terminus of FANCD2 bears also nuclear localization sequences for the protein. Mutations in the bifunctional DNA binding/NLS domain lead to a reduction in FANCD2 monoubiquitination and increase in mitomycin C sensitivity. Such phenotypes are not fully rescued by fusion with an heterologous NLS, which enable separation of DNA binding and nuclear import functions within this domain that are necessary for FANCD2 functions. Collectively, our results enlighten the importance of DNA binding and NLS residues in FANCD2 to activate an efficient FA pathway. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

In-situ coupling between kinase activities and protein dynamics within single focal adhesions

NASA Astrophysics Data System (ADS)

Wu, Yiqian; Zhang, Kaiwen; Seong, Jihye; Fan, Jason; Chien, Shu; Wang, Yingxiao; Lu, Shaoying

2016-07-01

The dynamic activation of oncogenic kinases and regulation of focal adhesions (FAs) are crucial molecular events modulating cell adhesion in cancer metastasis. However, it remains unclear how these events are temporally coordinated at single FA sites. Therefore, we targeted fluorescence resonance energy transfer (FRET)-based biosensors toward subcellular FAs to report local molecular events during cancer cell adhesion. Employing single FA tracking and cross-correlation analysis, we quantified the dynamic coupling characteristics between biochemical kinase activities and structural FA within single FAs. We show that kinase activations and FA assembly are strongly and sequentially correlated, with the concurrent FA assembly and Src activation leading focal adhesion kinase (FAK) activation by 42.6 ± 12.6 sec. Strikingly, the temporal coupling between kinase activation and individual FA assembly reflects the fate of FAs at later stages. The FAs with a tight coupling tend to grow and mature, while the less coupled FAs likely disassemble. During FA disassembly, however, kinase activations lead the disassembly, with FAK being activated earlier than Src. Therefore, by integrating subcellularly targeted FRET biosensors and computational analysis, our study reveals intricate interplays between Src and FAK in regulating the dynamic life of single FAs in cancer cells.

[Data mining analysis of professor Li Fa-zhi AIDS itchy skin medical record].

PubMed

Wang, Dan-Ni; Li, Zhen; Xu, Li-Ran; Guo, Hui-Jun

2013-08-01

Analysis of professor Li Fa-zhi in the treatment of AIDS drug laws of itchy skin, provide the corresponding drug reference basis for Chinese medicine treatment of AIDS, skin itching. By using the method of analyzing the complex network of Weishi county, Henan in 2007 October to 2011 July during an interview with professor Li Fa-zhi treatment of AIDS patients with skin pruritus, etiology and pathogenesis analysis, skin itching AIDS syndrome differentiation of old Chinese medicine treatment and medication rule. The use of multi-dimensional query analysis, core drug skin itching AIDS treatment in this study as a windbreak, cicada slough, bupleurum, Qufeng solution table drug, licorice detoxification efficacy of drugs, Radix Scutellariae, Kochia scoparia, clearing away heat and promoting diuresis medicine; core prescription for Jingfang San streak virus. Professor Li Fa-zhi treatment of AIDS in the skin itching Qufeng solution table dehumidification antipruritic treatment.

Functional Analysis and Treatment of Problem Behavior in Early Education Classrooms

ERIC Educational Resources Information Center

Greer, Brian D.; Neidert, Pamela L.; Dozier, Claudia L.; Payne, Steven W.; Zonneveld, Kimberley L. M.; Harper, Amy M.

2013-01-01

We conducted functional analyses (FA) with 4 typically developing preschool children during ongoing classroom activities and evaluated treatments that were based on FA results. Results of each child's FA suggested social-positive reinforcement functions, and differential reinforcement of alternative behavior plus time-out was effective in…

Functional analysis and treatment of problem behavior in early education classrooms.

PubMed

Greer, Brian D; Neidert, Pamela L; Dozier, Claudia L; Payne, Steven W; Zonneveld, Kimberley L M; Harper, Amy M

2013-01-01

We conducted functional analyses (FA) with 4 typically developing preschool children during ongoing classroom activities and evaluated treatments that were based on FA results. Results of each child's FA suggested social-positive reinforcement functions, and differential reinforcement of alternative behavior plus time-out was effective in decreasing problem behavior and increasing appropriate behavior. We discuss the utility of classroom-based FAs and potential compromises to experimental control. © Society for the Experimental Analysis of Behavior.

Safety assessment of historical masonry churches based on pre-assigned kinematic limit analysis, FE limit and pushover analyses

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

Milani, Gabriele, E-mail: milani@stru.polimi.it; Valente, Marco, E-mail: milani@stru.polimi.it

2014-10-06

This study presents some results of a comprehensive numerical analysis on three masonry churches damaged by the recent Emilia-Romagna (Italy) seismic events occurred in May 2012. The numerical study comprises: (a) pushover analyses conducted with a commercial code, standard nonlinear material models and two different horizontal load distributions; (b) FE kinematic limit analyses performed using a non-commercial software based on a preliminary homogenization of the masonry materials and a subsequent limit analysis with triangular elements and interfaces; (c) kinematic limit analyses conducted in agreement with the Italian code and based on the a-priori assumption of preassigned failure mechanisms, where themore » masonry material is considered unable to withstand tensile stresses. All models are capable of giving information on the active failure mechanism and the base shear at failure, which, if properly made non-dimensional with the weight of the structure, gives also an indication of the horizontal peak ground acceleration causing the collapse of the church. The results obtained from all three models indicate that the collapse is usually due to the activation of partial mechanisms (apse, façade, lateral walls, etc.). Moreover the horizontal peak ground acceleration associated to the collapse is largely lower than that required in that seismic zone by the Italian code for ordinary buildings. These outcomes highlight that structural upgrading interventions would be extremely beneficial for the considerable reduction of the seismic vulnerability of such kind of historical structures.« less

Benefits and concerns associated with biotechnology-derived foods: can additional research reduce children health risks?

PubMed

Cantani, A

2009-01-01

The development of techniques devised for the genetic manipulation of foods poses new risks for children with food allergy (FA). The introduction of foreign allergenic proteins from different foods into previously tolerated foods may trigger allergic reactions, often complicating with anaphylactic shock in a subset of allergic babies. Children with FA, even if subjected to preventative diets, always challenge the risk of developing allergic manifestations after unintentional intake of a non tolerated food in restaurant settings, with relatives or schoolmates, etc, where product labelling is necessarily lacking. The introduction of potentially allergenic proteins into foods generally considered safe for allergic children can be done deliberately, by either substantially altering the food ingredients, or by genetic manipulation which change the composition or transfer allergens, or unintentionally by qualitycontrol failures, due to contaminations in the production process, or to genetic mismanipulation. There is a controversy between multinationals often favored by governments and consumer association resistance, thus an equidistant analysis poses some unprecedented impediments. The importance of FA and the potential of transgenic plants to bring food allergens into the food supply should not be disregarded. The expression in soybeans of a Brazil nut protein resulted in a food allergen ex-pressed in widely used infant formulas, so paving the way to an often reported multinational debacle. Genetic engineering poses innovative ethical and social concerns, as well as serious challenges to the environment, human health, animal welfare, and the future of agriculture. In this paper will be emphasized practical concepts more crucial for pediatricians.

Cloning and expression analysis of FaPR-1 gene in strawberry

NASA Astrophysics Data System (ADS)

Mo, Fan; Luo, Ya; Ge, Cong; Mo, Qin; Ling, Yajie; Luo, Shu; Tang, Haoru

2018-04-01

The FaPR-1 gene was cloned by RT-PCR from `Benihoppe' strawberry and its bioinformatics analysis was conducted. The results showed that the open reading frame was 483 bp encoding encoding l60 amino acids which protein molecular weight and theoretical isoelectricity were 17854.17 and 8.72 respectively. Subcellular localization prediction shows that this gene is located extracellularly. By comparing strawberry FaPR-l and other plant Pathogenesis-related protein, homology and phylogenetic tree construction showed that the homology with grapes, peach is relatively close. In the treatments of ABA, sucrose and the mixture of the two, the expression of FaPR-1 in strawberry fruit were significantly increased.

FaSTR DNA: a new expert system for forensic DNA analysis.

PubMed

Power, Timothy; McCabe, Brendan; Harbison, Sally Ann

2008-06-01

The automation of DNA profile analysis of reference and crime samples continues to gain pace driven in part by a realisation by the criminal justice system of the positive impact DNA technology can have in aiding in the solution of crime and the apprehension of suspects. Expert systems to automate the profile analysis component of the process are beginning to be developed. In this paper, we report the validation of a new expert system FaSTR DNA, an expert system suitable for the analysis of DNA profiles from single source reference samples and from crime samples. We compare the performance of FaSTR DNA with that of other equivalent systems, GeneMapper ID v3.2 (Applied Biosystems, Foster City, CA) and FSS-i(3) v4 (The Forensic Science Service((R)) DNA expert System Suite FSS-i(3), Forensic Science Service, Birmingham, UK) with GeneScan Analysis v3.7/Genotyper v3.7 software (Applied Biosystems, Foster City, CA, USA) with manual review. We have shown that FaSTR DNA provides an alternative solution to automating DNA profile analysis and is appropriate for implementation into forensic laboratories. The FaSTR DNA system was demonstrated to be comparable in performance to that of GeneMapper ID v3.2 and superior to that of FSS-i(3) v4 for the analysis of DNA profiles from crime samples.

Relationship between diffusion tensor fractional anisotropy and long-term motor outcome in patients with hemiparesis after middle cerebral artery infarction.

PubMed

Koyama, Tetsuo; Marumoto, Kohei; Miyake, Hiroji; Domen, Kazuhisa

2014-10-01

Magnetic resonance diffusion tensor fractional anisotropy (DTI-FA) is often used to characterize neural damage after stroke. Here we assessed the relationship between DTI-FA and long-term motor outcome in patients after middle cerebral artery (MCA) infarction. Fractional anisotropy (FA) maps were generated from diffusion tensor brain images obtained from 16 patients 14-18 days postinfarction, and tract-based spatial statistics (TBSS) analysis was applied. Regions of interest were set within the right and left corticospinal tracts, and mean FA values were extracted from individual TBSS data. Hemiparesis motor outcome was evaluated according to Brunnstrom stage (BRS: 1-6, severe-normal) for separate shoulder/elbow/forearm, hand, and lower extremity functions, as well as the motor component score of the Functional Independence Measure (FIM-motor: 13-91, null-full) 5-7 months after onset. Ratios between FA values in the affected and unaffected hemispheres (rFA) were assessed by BRS and FIM-motor scores. rFA values were .636-.984 (median, .883) and BRS scores were 1-6 (median, 3) for shoulder/elbow/forearm, 2-6 (median, 3) for hand, and 3-6 (median, 5) for the lower extremities. FIM-motor scores were 51-90 (median, 75). Analysis revealed significant relationships between rFA and BRS data (correlation coefficient: .687 for shoulder/elbow/forearm, .579 for hand, and .623 for lower extremities) but no significance relationship between rFA and FIM-motor scores. The results suggest that DTI-FA is applicable for predicting the long-term outcome of extremity functions after MCA infarction. Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Implementation and Validation of Trial-Based Functional Analyses in Public Elementary School Settings

ERIC Educational Resources Information Center

Lloyd, Blair P.; Wehby, Joseph H.; Weaver, Emily S.; Goldman, Samantha E.; Harvey, Michelle N.; Sherlock, Daniel R.

2015-01-01

Although functional analysis (FA) remains the standard for identifying the function of problem behavior for students with developmental disabilities, traditional FA procedures are typically costly in terms of time, resources, and perceived risks. Preliminary research suggests that trial-based FA may be a less costly alternative. The purpose of…

Hydration studies of calcium sulfoaluminate cements blended with fly ash

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

García-Maté, M.; De la Torre, A.G.; León-Reina, L.

The main objective of this work is to study the hydration and properties of calcium sulfoaluminate cement pastes blended with fly ash (FA) and the corresponding mortars at different hydration ages. Laboratory X-ray powder diffraction, rheological studies, thermal analysis, porosimetry and compressive strength measurements were performed. The analysis of the diffraction data by Rietveld method allowed quantifying crystalline phases and overall amorphous contents. The studied parameters were: i) FA content, 0, 15 and 30 wt.%; and ii) water addition, water-to-CSA mass ratio (w/CSA = 0.50 and 0.65), and water-to-binder mass ratio (w/b = 0.50). Finally, compressive strengths after 6 monthsmore » of 0 and 15 wt.% FA [w/CSA = 0.50] mortars were similar: 73 ± 2 and 72 ± 3 MPa, respectively. This is justified by the filler effect of the FA as no strong evidences of reactivity of FA with CSA were observed. These results support the partial substitution of CSA cements with FA with the economic and environmental benefits.« less

Stopped-in-loop flow analysis of trace vanadium in water.

PubMed

Teshima, Norio; Ohno, Shinsuke; Sakai, Tadao

2007-01-01

The new concept of stopped-in-loop flow analysis (SIL-FA) is proposed, and an SIL-FA method for the catalytic determination of vanadium is demonstrated. In an SIL format, a sample solution merges with reagent(s), and the well-mixed solution is loaded into a loop. The solution in the loop is separated by a six-way switching valve from the main stream. While the reaction proceeds in the stationary loop, the SIL-FA system does not need to establish a baseline continuously. This leads to a reduction in reagent consumption and waste generation compared with traditional flow injection analysis.

Analysis of fatty acid methyl esters and oxidative stability of seed purpose watermelon (Citrullus lanatus) genotypes for edible oil.

PubMed

Mahla, H R; Rathore, S S; Venkatesan, K; Sharma, R

2018-04-01

World's vegetable oil demand is increasing day by day and oil seed supply is limited to a dozen oil seed crops on commercial scale. Efforts were made to explore the potential of water melon a traditionally grown native crop of Indian arid zone having oil content over 30% and seed yield potential of 500-600 kg per hectare under rainfed conditions. An analysis was carried out to explore the suitability of watermelon [ Citrullus lanatus (Thunb.)] oil for human consumption on the basis of fatty acid (FA) composition in selected genotypes. Total oil content ranged between 10.0 and 31.0%. Eleven FA were identified in seed oil. Linoleic, stearic, palmitic and oleic acid were found as major FA while myristic, heptadecanoic, arachidic, 9-hexadecenoic and 14-eicosenoic acid was present in traces. Linoleic acid single polyunsaturated FA contributor found in the range of 43.95% (WM-44) to 55.29% (WM-18). Saturated FA content ranged between 32.24 and 37.61%. Significant genetic variation was observed for mono-unsaturated FA. Metabolic capacity to inter-conversion of FA and nutritive value of watermelon oil was described on the basis of ratio of FA group. Total phenolics, antioxidant activity, peroxide value and oxidizability were also estimated along with oxidative stability of oil. Multivariate analysis showed that, oil content has positive correlation with linoleic acid. The Euclidean based UPGMA clustering revealed that genotypes WM-18 is most suitable for trait specific breeding program for high linoleic acid ( n -6), desaturation ratio and oleic desaturation ratio with higher oil content and lowest palmitic acid.

Genetic analysis of predicted fatty acid profiles of milk from Danish Holstein and Danish Jersey cattle populations.

PubMed

Hein, L; Sørensen, L P; Kargo, M; Buitenhuis, A J

2018-03-01

The objective of this study was to assess the genetic variability of the detailed fatty acid (FA) profiles of Danish Holstein (DH) and Danish Jersey (DJ) cattle populations. We estimated genetic parameters for 11 FA or groups of FA in milk samples from the Danish milk control system between May 2015 and October 2016. Concentrations of different FA and FA groups in milk samples were measured by mid-infrared spectroscopy. Data used for parameter estimation were from 132,732 first-parity DH cows and 21,966 first-parity DJ cows. We found the highest heritabilities for test day measurements in both populations for short-chain FA (DH = 0.16; DJ = 0.16) and C16:0 (DH = 0.14; DJ = 0.16). In DH, the highest heritabilities were also found for saturated FA and monounsaturated FA (both populations: 0.15). Genetic correlations between the fatty acid traits showed large differences between DH and DJ for especially short-chain FA with the other FA traits measured. Furthermore, genetic correlations of total fat with monounsaturated FA, polyunsaturated FA, short-chain FA, and C16:0 differed markedly between DH and DJ populations. In conclusion, we found genetic variation in the mid-infrared spectroscopy-predicted FA and FA groups of the DH and DJ cattle populations. This finding opens the possibility of using genetic selection to change the FA profiles of dairy cattle. The Authors. Published by FASS Inc. and Elsevier Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

Synthesis and characterization of covalent diphenylalanine nanotube-folic acid conjugates

NASA Astrophysics Data System (ADS)

Castillo, John J.; Rindzevicius, Tomas; Wu, Kaiyu; Schmidt, Michael S.; Janik, Katarzyna A.; Boisen, Anja; Svendsen, Winnie; Rozlosnik, Noemi; Castillo-León, Jaime

2014-07-01

Herein, we describe the synthesis and characterization of a covalent nanoscale assembly formed between diphenylalanine micro/nanotubes (PNT) and folic acid (FA). The conjugate was obtained via chemical functionalization through coupling of amine groups of PNTs and carboxylic groups of FA. The surface analysis of PNT-FA indicated the presence of FA aggregates on the surface of PNTs. The covalent interaction between FA and self-assembled PNTs was further investigated using fluorescence microscopy, Raman and surface-enhanced Raman scattering (SERS) spectroscopies. The SERS experiments were performed on a large area silver-capped (diameter of 62 nm) silicon nanopillars with an approximate height of 400 nm and a width of 200 nm. The results showed that the PNT-FA synthesis procedure preserves the molecular structure of FA. The PNT-FA conjugate presented in this study is a promising candidate for applications in the detection and diagnosis of cancer or tropical diseases such as leishmaniasis and as a carrier nanosystem delivering drugs to malignant tumors that overexpress folate receptors.

Insights into Fanconi Anaemia from the structure of human FANCE

PubMed Central

Nookala, Ravi K.; Hussain, Shobbir; Pellegrini, Luca

2007-01-01

Fanconi Anaemia (FA) is a cancer predisposition disorder characterized by spontaneous chromosome breakage and high cellular sensitivity to genotoxic agents. In response to DNA damage, a multi-subunit assembly of FA proteins, the FA core complex, monoubiquitinates the downstream FANCD2 protein. The FANCE protein plays an essential role in the FA process of DNA repair as the FANCD2-binding component of the FA core complex. Here we report a crystallographic and biological study of human FANCE. The first structure of a FA protein reveals the presence of a repeated helical motif that provides a template for the structural rationalization of other proteins defective in Fanconi Anaemia. The portion of FANCE defined by our crystallographic analysis is sufficient for interaction with FANCD2, yielding structural information into the mode of FANCD2 recruitment to the FA core complex. Disease-associated mutations disrupt the FANCE–FANCD2 interaction, providing structural insight into the molecular mechanisms of FA pathogenesis. PMID:17308347

Novel analytical method to measure formaldehyde release from heated hair straightening cosmetic products: Impact on risk assessment.

PubMed

Galli, Corrado Lodovico; Bettin, Federico; Metra, Pierre; Fidente, Paola; De Dominicis, Emiliano; Marinovich, Marina

2015-08-01

Hair straightening cosmetic products may contain formaldehyde (FA). In Europe, FA is permitted for use in personal care products at concentrations ⩽ 0.2g/100g. According to the Cosmetic Ingredient Review (CIR) Expert Panel products are safe when formalin (a 37% saturated solution of FA in water) concentration does not exceed 0.2g/100g (0.074 g/100g calculated as FA). The official method of reference does not discriminate between "free" FA and FA released into the air after heating FA donors. The method presented here captures and collects the FA released into the air from heated cosmetic products by derivatization with 2,4-dinitrophenylhydrazine and final analysis by UPLC/DAD instrument. Reliable data in terms of linearity, recovery, repeatability and sensitivity are obtained. On a total of 72 market cosmetic products analyzed, 42% showed FA concentrations very close to or above the threshold value (0.074 g/100g calculated as FA) suggested by the Cosmetic Ingredient Review committee, whereas 11 products, negative using the official method of reference, were close to or above the threshold value (0.074 g/100g calculated as FA). This may pose a health problem for occasional users and professional hair stylists. Copyright © 2015 Elsevier Inc. All rights reserved.

Architectural Kansei of ‘Wall’ in The Façade Design by Le Corbusier

NASA Astrophysics Data System (ADS)

Sendai, Shoichiro

The purpose of this paper is to discuss the modern architect Le Corbusier's architectural Kansei (sensibility) on wall in site environment through the analysis of his façade design, using Œuvres complètes (1910-1965, 8 vols., Les éditions d'architecture, Artemis, Zurich) and Le Corbusier Archives (1982-1984, 32 vols., Garland Publishing, Inc. and Fondation Le Corbusier, New York, London, Paris). At first, I arrange five façade types, according to the explanation by Le Corbusier ; ‘fenêtre en longueur (strip window)’, ‘pan de verre (glass wall)’, ‘brise-soleil (sun-breaker)’, ‘loggia’ and ‘claustra’. Through the analysis of the relationship between these types and the design process of each building, we find that Le Corbusier's façade design includes the affirmation and the negation of the ‘wall’ at the same time. In fact, the nature of façade modification during design process is divers: increase in transparency, decrease in transparency and spatialization of façade. That means, Le Corbusier studied the environmental condition by these façade types, and tried to realize the phenomenal openness. This trial bases on the function of architectural Kansei as correspondence between body and environment beyond the physical design.

Resistance to mitomycin C requires direct interaction between the Fanconi anemia proteins FANCA and FANCG in the nucleus through an arginine-rich domain.

PubMed

Kruyt, F A; Abou-Zahr, F; Mok, H; Youssoufian, H

1999-11-26

Fanconi anemia (FA) is a genetically heterogeneous disorder characterized by bone marrow failure, birth defects, and chromosomal instability. Because FA cells are sensitive to mitomycin C (MMC), FA gene products could be involved in cellular defense mechanisms. The FANCA and FANCG proteins deficient in FA groups A and G interact directly with each other. We have localized the mutual interaction domains of these proteins to amino acids 18-29 of FANCA and to two noncontiguous carboxyl-terminal domains of FANCG encompassing amino acids 400-475 and 585-622. Site-directed mutagenesis of FANCA residues 18-29 revealed a novel arginine-rich interaction domain (RRRAWAELLAG). By alanine mutagenesis, Arg(1), Arg(2), and Leu(8) but not Arg(3), Trp(5), and Glu(7) appeared to be critical for binding to FANCG. Similar immunolocalization for FANCA and FANCG suggested that these proteins interact in vivo. Moreover, targeting of FANCA to the nucleus or the cytoplasm with nuclear localization and nuclear export signals, respectively, showed concordance between the localization patterns of FANCA and FANCG. The complementation function of FANCA was abolished by mutations in its FANCG-binding domain. Conversely, stable expression of FANCA mutants encoding intact FANCG interaction domains induced hypersensitivity to MMC in HeLa cells. These results demonstrate that FANCA-FANCG complexes are required for cellular resistance to MMC. Because the FANCC protein deficient in FA group C works within the cytoplasm, we suggest that FANCC and the FANCA-FANCG complexes suppress MMC cytotoxicity within distinct cellular compartments.

[Data mining analysis of professor Li Fa-zhi AIDS herpes zoster medical record].

PubMed

Wang, Dan-Ni; Li, Zhen; Xu, Li-Ran; Guo, Hui-Jun

2013-08-01

Analysis of professor Li Fa-zhi in the treatment of AIDS drug laws of herpes zoster and postherpetic neuralgia, provide reference for the use of Chinese medicine treatment of AIDS, herpes zoster and postherpetic neuralgia. By using the method of analyzing the complex network of Weishi county, Henan in 2007 October to 2011 July during an interview with professor Li Fa-zhi treatment of AIDS of herpes zoster and postherpetic neuralgia patients, patients are input structured clinical information collection system, into the analysis of the data, carries on the research analysis theory of traditional Chinese medicine compatibility system algorithm and complex network analysis the use of complex networks. The use of multi-dimensional query analysis of AIDS drugs, the core of herpes zoster and postherpetic neuralgia treated in this study are Scutellariae Radix, Glucyrrhizae Radix, Carthame Flos, Plantaginis Semen, Trichosamthis Fructus, Angelicae Sinensis Radix, Gentianae Radix; core prescription for Longdan Xiegan decoction and Trichosanthes red liquorice decoction. Professor Li Fa-zhi treatment of AIDS, herpes zoster and postherpetic neuralgia by clearing heat and removing dampness and activating blood circulation to.

Architecture and DNA Recognition Elements of the Fanconi Anemia FANCM-FAAP24 Complex

PubMed Central

Coulthard, Rachel; Deans, Andrew J.; Swuec, Paolo; Bowles, Maureen; Costa, Alessandro; West, Stephen C.; McDonald, Neil Q.

2013-01-01

Summary Fanconi anemia (FA) is a disorder associated with a failure in DNA repair. FANCM (defective in FA complementation group M) and its partner FAAP24 target other FA proteins to sites of DNA damage. FANCM-FAAP24 is related to XPF/MUS81 endonucleases but lacks endonucleolytic activity. We report a structure of an FANCM C-terminal fragment (FANCMCTD) bound to FAAP24 and DNA. This S-shaped structure reveals the FANCM (HhH)2 domain is buried, whereas the FAAP24 (HhH)2 domain engages DNA. We identify a second DNA contact and a metal center within the FANCM pseudo-nuclease domain and demonstrate that mutations in either region impair double-stranded DNA binding in vitro and FANCM-FAAP24 function in vivo. We show the FANCM translocase domain lies in proximity to FANCMCTD by electron microscopy and that binding fork DNA structures stimulate its ATPase activity. This suggests a tracking model for FANCM-FAAP24 until an encounter with a stalled replication fork triggers ATPase-mediated fork remodeling. PMID:23932590

Regulation of Chromatin Assembly and Cell Transformation by Formaldehyde Exposure in Human Cells

PubMed Central

Chen, Danqi; Fang, Lei; Mei, Shenglin; Li, Hongjie; Xu, Xia; Des Marais, Thomas L.; Lu, Kun; Liu, X. Shirley

2017-01-01

Background: Formaldehyde (FA) is an environmental and occupational chemical carcinogen. Recent studies have shown that exogenous FA causes only a modest increase in DNA adduct formation compared with the amount of adducts formed by endogenous FA, raising the possibility that epigenetic mechanisms may contribute to FA-mediated carcinogenicity. Objectives: We investigated the effects of FA exposure on histone modifications and chromatin assembly. We also examined the role of defective chromatin assembly in FA-mediated transcription and cell transformation. Methods: Cellular fractionation and Western blot analysis were used to measure the levels of histone modifications in human bronchial epithelial BEAS-2B cells and human nasal RPMI2650 cells in the presence of FA. Chromatin immunoprecipitation (ChIP) and micrococcal nuclease (MNase) digest assays were performed to examine the changes in chromatin assembly and accessibility after FA exposure. RNA sequencing (RNA-seq) and real-time polymerase chain reaction (PCR) were used to examine transcriptional dysregulation. Finally, anchorage-independent cell growth ability was tested by soft agar assay following FA exposure. Results: Exposure to FA dramatically decreased the acetylation of the N-terminal tails of cytosolic histones. These modifications are important for histone nuclear import and subsequent chromatin assembly. Histone proteins were depleted in both the chromatin fraction and at most of the genomic loci tested following FA exposure, suggesting that FA compromises chromatin assembly. Moreover, FA increased chromatin accessibility and altered the expression of hundreds of cancer-related genes. Knockdown of the histone H3.3 gene (an H3 variant), which mimics inhibition of chromatin assembly, facilitated FA-mediated anchorage-independent cell growth. Conclusions: We propose that the inhibition of chromatin assembly represents a novel mechanism of cell transformation induced by the environmental and occupational chemical carcinogen FA. https://doi.org/10.1289/EHP1275 PMID:28937961

Function allocation for humans and automation in the context of team dynamics

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

Jeffrey C. Joe; John O'Hara; Jacques Hugo

Within Human Factors Engineering, a decision-making process called function allocation (FA) is used during the design life cycle of complex systems to distribute the system functions, often identified through a functional requirements analysis, to all human and automated machine agents (or teammates) involved in controlling the system. Most FA methods make allocation decisions primarily by comparing the capabilities of humans and automation, but then also by considering secondary factors such as cost, regulations, and the health and safety of workers. The primary analysis of the strengths and weaknesses of humans and machines, however, is almost always considered in terms ofmore » individual human or machine capabilities. Yet, FA is fundamentally about teamwork in that the goal of the FA decision-making process is to determine what are the optimal allocations of functions among agents. Given this framing of FA, and the increasing use of and sophistication of automation, there are two related social psychological issues that current FA methods need to address more thoroughly. First, many principles for effective human teamwork are not considered as central decision points or in the iterative hypothesis and testing phase in most FA methods, when it is clear that social factors have numerous positive and negative effects on individual and team capabilities. Second, social psychological factors affecting team performance and can be difficult to translate to automated agents, and most FA methods currently do not account for this effect. The implications for these issues are discussed.« less

75 FR 18774 - Airworthiness Directives; McCauley Propeller Systems Model 4HFR34C653/L106FA Propellers

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-13

... (ECI) of the propeller hub for cracks. That proposed AD resulted from reports of 3 hubs found cracked... NPRM results from reports of 7 additional hubs found cracked during propeller overhaul, totaling 10 cracked hubs. We are proposing this supplemental AD to prevent failure of the propeller hub, which could...

Biomarker of Long-Chain n-3 Fatty Acid Intake and Breast Cancer: Accumulative Evidence from an Updated Meta-Analysis of Epidemiological Studies.

PubMed

Yang, Bo; Ren, Xiao L; Wang, Zhi Y; Wang, Liang; Zhao, Feng; Guo, Xiao J; Li, Duo

2018-06-14

We aimed to summarize the up-to-date epidemiology evidence on biomarkers of long-chain (LC) n-3 fatty acid (FA) intake in relation to breast cancer (BC). Epidemiology studies determining FA levels in biospecimen (circulating blood or adipose tissue (AT)) were identified from PubMed, EMBASE, and Cochrane Library databases until March 2018. Multivariate-adjusted risk ratios (RRs) with 95% confidence intervals (CIs) were pooled using a random-effect model. Difference in biospecimen proportions of LC n-3 FA between BC cases and non-cases were analyzed as a standardized mean difference (SMD). Thirteen cohort and eleven case-control studies were eligible for the present meta-analysis. The estimated SMD was -0.14 (95% CI: -0.27, -0.11) for LC n-3 FA and -0.27 (95% CI: -0.42, -0.11) for LC n-3/n-6 FA ratio. When comparing the top tertiles with the bottom baseline levels, circulating LC n-3 FA was significantly associated with a lower risk of BC (RR: 0.84, 95% CI: 0.74, 0.96), but not AT (RR: 1.02, 95% CI: 0.70, 1.48). Significant inverse dose-response associations were observed for each 1% increment of circulating 20:5n-3 and 22:6n-3. This meta-analysis highlights that circulating LC n-3 FA as a biomarker of intake may be an independent predictive factor for BC, especially 20:5n-3 and 22:6n-3.

Achievement of lipid targets with the combination of rosuvastatin and fenofibric Acid in patients with type 2 diabetes mellitus.

PubMed

Rosenson, Robert S; Carlson, Dawn M; Kelly, Maureen T; Setze, Carolyn M; Hirshberg, Boaz; Stolzenbach, James C; Williams, Laura A

2011-02-01

The objective of this study was to assess the proportion of patients with type 2 diabetes mellitus (T2DM) attaining individual and combined targets of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), non-HDL-C, and apolipoprotein B (ApoB) after treatment with rosuvastatin (R) + fenofibric acid (FA) compared with corresponding-dose R monotherapy. This post hoc analysis evaluated data from the T2DM subset of patients with mixed dyslipidemia (LDL-C ≥130 mg/dL, HDL-C <40/50 mg/dL in men/women, and TG ≥150 mg/dL) from 2 randomized studies. Patients included in the analysis (N = 456) were treated with R (5, 10, or 20 mg), FA 135 mg, or R (5, 10, or 20 mg) + FA 135 mg for 12 weeks. Attainment of LDL-C <100 mg/dL, HDL-C >40/50 mg/dL in men/women, TG <150 mg/dL, non-HDL-C <130 mg/dL, ApoB <90 mg/dL, and the combined targets of these parameters was assessed. Treatment with R + FA resulted in a significantly higher proportion of patients achieving optimal levels of HDL-C (46.8% vs. 20.8%, P = 0.009 for R 10 mg + FA), TG (60.0% vs. 34.0%, P = 0.02 for R 10 mg + FA; 54.0% vs. 26.4%, P = 0.005 for R 20 mg + FA), non-HDL-C (55.1% vs. 36.4%, P = 0.04 for R 5 mg + FA), ApoB (58.0% vs. 36.4%, P = 0.02 for R 5 mg + FA); and the combined targets of LDL-C, HDL-C, and TG (28.3% vs. 8.3%, P = 0.02 for R 10 mg + FA) and all 5 parameters (26.1% vs. 8.3%, P = 0.03 for R 10 mg + FA) than corresponding-dose R monotherapies. A significantly greater proportion of T2DM patients achieved individual and combined lipid targets when treated with the combination of R + FA than corresponding-dose R monotherapies.

The Fanconi anemia protein FANCF forms a nuclear complex with FANCA, FANCC and FANCG.

PubMed

de Winter, J P; van der Weel, L; de Groot, J; Stone, S; Waisfisz, Q; Arwert, F; Scheper, R J; Kruyt, F A; Hoatlin, M E; Joenje, H

2000-11-01

Fanconi anemia (FA) is a chromosomal instability syndrome associated with a strong predisposition to cancer, particularly acute myeloid leukemia and squamous cell carcinoma. At the cellular level, FA is characterized by spontaneous chromosomal breakage and a unique hypersensitivity to DNA cross-linking agents. Complementation analysis has indicated that at least seven distinct genes are involved in the pathogenesis of FA. Despite the identification of four of these genes (FANCA, FANCC, FANCF and FANCG), the nature of the 'FA pathway' has remained enigmatic, as the FA proteins lack sequence homologies or motifs that could point to a molecular function. To further define this pathway, we studied the subcellular localizations and mutual interactions of the FA proteins, including the recently identified FANCF protein, in human lymphoblasts. FANCF was found predominantly in the nucleus, where it complexes with FANCA, FANCC and FANCG. These interactions were detected in wild-type and FA-D lymphoblasts, but not in lymphoblasts of other FA complementation groups. This implies that each of the FA proteins, except FANCD, is required for these complexes to form. Similarly, we show that the interaction between FANCA and FANCC is restricted to wild-type and FA-D cells. Furthermore, we document the subcellular localization of FANCA and the FANCA/FANCG complex in all FA complementation groups. Our results, along with published data, culminate in a model in which a multi-protein FA complex serves a nuclear function to maintain genomic integrity.

Fluctuating asymmetry in broiler chickens: a decision protocol for trait selection in seven measuring methods.

PubMed

Van Nuffel, A; Tuyttens, F A M; Van Dongen, S; Talloen, W; Van Poucke, E; Sonck, B; Lens, L

2007-12-01

Nonidentical development of bilateral traits due to disturbing genetic or developmental factors is called fluctuating asymmetry (FA) if such deviations are continuously distributed. Fluctuating asymmetry is believed to be a reliable indicator of the fitness and welfare of an animal. Despite an increasing body of research, the link between FA and animal performance or welfare is reported to be inconsistent, possibly, among other reasons, due to inaccurate measuring protocols or incorrect statistical analyses. This paper reviews problems of interpreting FA results in poultry and provides guidelines for the measurement and analysis of FA, applied to broilers. A wide range of morphological traits were measured by 7 different techniques (ranging from measurements on living broilers or intact carcasses to X-rays, bones, and digital images) and evaluated for their applicability to estimate FA. Following 4 selection criteria (significant FA, absence of directional asymmetry or antisymmetry, absence of between-trait correlation in signed FA values, and high signal-to-noise ratio), from 3 to 14 measurements per method were found suitable for estimating the degree of FA. The accuracy of FA estimates was positively related to the complexity and time investment of the measuring method. In addition, our study clearly shows the importance of securing adequate statistical power when designing FA studies. Repeatability analyses of FA estimates indicated the need for larger sample sizes, more repeated measurements, or both, than are commonly used in FA studies.

Developing Multidimensional Likert Scales Using Item Factor Analysis: The Case of Four-Point Items

ERIC Educational Resources Information Center

Asún, Rodrigo A.; Rdz-Navarro, Karina; Alvarado, Jesús M.

2016-01-01

This study compares the performance of two approaches in analysing four-point Likert rating scales with a factorial model: the classical factor analysis (FA) and the item factor analysis (IFA). For FA, maximum likelihood and weighted least squares estimations using Pearson correlation matrices among items are compared. For IFA, diagonally weighted…

Functional Analysis in Virtual Environments

ERIC Educational Resources Information Center

Vasquez, Eleazar, III; Marino, Matthew T.; Donehower, Claire; Koch, Aaron

2017-01-01

Functional analysis (FA) is an assessment procedure involving the systematic manipulation of an individual's environment to determine why a target behavior is occurring. An analog FA provides practitioners the opportunity to manipulate variables in a controlled environment and formulate a hypothesis for the function of a behavior. In previous…

Characterization and anticancer potential of ferulic acid-loaded chitosan nanoparticles against ME-180 human cervical cancer cell lines

NASA Astrophysics Data System (ADS)

Panwar, Richa; Sharma, Asvene K.; Kaloti, Mandeep; Dutt, Dharm; Pruthi, Vikas

2016-08-01

Ferulic acid (FA) is a widely distributed hydroxycinnamic acid found in various cereals and fruits exhibiting potent antioxidant and anticancer activities. However, due to low solubility and permeability, its availability to biological systems is limited. Non-toxic chitosan-tripolyphosphate pentasodium (CS-TPP) nanoparticles (NPs) are used to load sparingly soluble molecules and drugs, increasing their bioavailability. In the present work, we have encapsulated FA into the CS-TPP NPs to increase its potential as a therapeutic agent. Different concentrations of FA were tested to obtain optimum sized FA-loaded CS-TPP nanoparticles (FA/CS-TPP NPs) by ionic gelation method. Nanoparticles were characterized by scanning electron microscopy, Fourier transformation infrared spectroscopy (FTIR), thermogravimetric analyses and evaluated for their anticancer activity against ME-180 human cervical cancer cell lines. The FTIR spectra confirmed the encapsulation of FA and thermal analysis depicted its degradation profile. A concentration-dependent relationship between FA encapsulation efficiency and FA/CS-TPP NPs diameter was observed. Smooth and spherical FA-loaded cytocompatible nanoparticles with an average diameter of 125 nm were obtained at 40 µM FA conc. The cytotoxicity of 40 µM FA/CS-TPP NPs against ME-180 cervical cancer cell lines was found to be higher as compared to 40 µM native FA. Apoptotic morphological changes as cytoplasmic remnants and damaged wrinkled cells in ME-180 cells were visualized using scanning electron microscopic and fluorescent microscopic techniques. Data concluded that chitosan enveloped FA nanoparticles could be exploited as an excellent therapeutic drug against cancer cells proliferation.

Expression Profiling of Regulatory and Biosynthetic Genes in Contrastingly Anthocyanin Rich Strawberry (Fragaria × ananassa) Cultivars Reveals Key Genetic Determinants of Fruit Color.

PubMed

Hossain, Mohammad Rashed; Kim, Hoy-Taek; Shanmugam, Ashokraj; Nath, Ujjal Kumar; Goswami, Gayatri; Song, Jae-Young; Park, Jong-In; Nou, Ill-Sup

2018-02-26

Anthocyanins are the resultant end-point metabolites of phenylapropanoid/flavonoid (F/P) pathway which is regulated at transcriptional level via a series of structural genes. Identifying the key genes and their potential interactions can provide us with the clue for novel points of intervention for improvement of the trait in strawberry. We profiled the expressions of putative regulatory and biosynthetic genes of cultivated strawberry in three developmental and characteristically colored stages of fruits of contrastingly anthocyanin rich cultivars: Tokun, Maehyang and Soelhyang. Besides FaMYB10, a well-characterized positive regulator, FaMYB5 , FabHLH3 and FabHLH3-delta might also act as potential positive regulators, while FaMYB11 , FaMYB9 , FabHLH33 and FaWD44-1 as potential negative regulators of anthocyanin biosynthesis in these high-anthocyanin cultivars. Among the early BGs, Fa4CL7 , FaF3H , FaCHI1 , FaCHI3 , and FaCHS, and among the late BGs, FaDFR4-3 , FaLDOX , and FaUFGT2 showed significantly higher expression in ripe fruits of high anthocyanin cultivars Maehyang and Soelhyang. Multivariate analysis revealed the association of these genes with total anthocyanins. Increasingly higher expressions of the key genes along the pathway indicates the progressive intensification of pathway flux leading to final higher accumulation of anthocyanins. Identification of these key genetic determinants of anthocyanin regulation and biosynthesis in Korean cultivars will be helpful in designing crop improvement programs.

Analysis of the "endocannabinoidome" in peripheral tissues of obese Zucker rats.

PubMed

Iannotti, F A; Piscitelli, F; Martella, A; Mazzarella, E; Allarà, M; Palmieri, V; Parrella, C; Capasso, R; Di Marzo, V

2013-08-01

The endocannabinoid system (ECS) represents one of the major determinants of metabolic disorders. We investigated potential changes in the endogenous levels of anandamide (AEA), 2-arachidonoylglycerol (2-AG), N-oleoylethanolamine (OEA) and N-palmitoylethanolamine (PEA) in some peripheral organs and tissues of obese Zucker(fa/fa) and lean Zucker(fa/+) rats by qPCR, liquid chromatography mass spectrometry, western blot and enzymatic activity assays. At 10-12 weeks of age AEA levels were significantly lower in BAT, small intestine and heart and higher in soleus of Zucker(fa/fa) rats. In this tissue, also the expression of CB1 receptors was higher. By contrast in Zucker(fa/fa) rats, 2-AG levels were changed (and lower) solely in the small and large intestine. Finally, in Zucker(fa/fa), PEA levels were unchanged, whereas OEA was slightly lower in BAT, and higher in the large intestine. Interestingly, these differences were accompanied by differential alterations of the genes regulating ECS tone. In conclusion, the levels of endocannabinoids are altered during obesity in a way partly correlating with changes of the genes related to their metabolism and activity. Copyright © 2013 Elsevier Ltd. All rights reserved.

Phototropin 2 is involved in blue light-induced anthocyanin accumulation in Fragaria x ananassa fruits.

PubMed

Kadomura-Ishikawa, Yasuko; Miyawaki, Katsuyuki; Noji, Sumihare; Takahashi, Akira

2013-11-01

Anthocyanins are widespread, essential secondary metabolites in higher plants during color development in certain flowers and fruits. In strawberries, anthocyanins are also key contributors to fruit antioxidant capacity and nutritional value. However, the effects of different light qualities on anthocyanin accumulation in strawberry (Fragaria x ananassa, cv. Sachinoka) fruits remain elusive. In the present study, we showed the most efficient increase in anthocyanin content occurred by blue light irradiation. Light sensing at the molecular level was investigated by isolation of two phototropin (FaPHOT1 and FaPHOT2), two cryptochrome (FaCRY1 and FaCRY2), and two phytochrome (FaPHYA and FaPHYB) homologs. Expression analysis revealed only FaPHOT2 transcripts markedly increased depending on fruit developmental stage, and a corresponding increase in anthocyanin content was detected. FaPHOT2 knockdown resulted in decreased anthocyanin content; however, overexpression increased anthocyanin content. These findings suggested blue light induced anthocyanin accumulation, and FaPHOT2 may play a role in sensing blue light, and mediating anthocyanin biosynthesis in strawberry fruits. This is the first report to find a relationship between visible light sensing, and color development in strawberry fruits.

Disorganization of white matter architecture in major depressive disorder: a meta-analysis of diffusion tensor imaging with tract-based spatial statistics.

PubMed

Chen, Guangxiang; Hu, Xinyu; Li, Lei; Huang, Xiaoqi; Lui, Su; Kuang, Weihong; Ai, Hua; Bi, Feng; Gu, Zhongwei; Gong, Qiyong

2016-02-24

White matter (WM) abnormalities have long been suspected in major depressive disorder (MDD). Tract-based spatial statistics (TBSS) studies have detected abnormalities in fractional anisotropy (FA) in MDD, but the available evidence has been inconsistent. We performed a quantitative meta-analysis of TBSS studies contrasting MDD patients with healthy control subjects (HCS). A total of 17 studies with 18 datasets that included 641 MDD patients and 581 HCS were identified. Anisotropic effect size-signed differential mapping (AES-SDM) meta-analysis was performed to assess FA alterations in MDD patients compared to HCS. FA reductions were identified in the genu of the corpus callosum (CC) extending to the body of the CC and left anterior limb of the internal capsule (ALIC) in MDD patients relative to HCS. Descriptive analysis of quartiles, sensitivity analysis and subgroup analysis further confirmed these findings. Meta-regression analysis revealed that individuals with more severe MDD were significantly more likely to have FA reductions in the genu of the CC. This study provides a thorough profile of WM abnormalities in MDD and evidence that interhemispheric connections and frontal-striatal-thalamic pathways are the most convergent circuits affected in MDD.

Filaggrin loss-of-function mutations are associated with food allergy in childhood and adolescence.

PubMed

Venkataraman, Devasmitha; Soto-Ramírez, Nelís; Kurukulaaratchy, Ramesh J; Holloway, John W; Karmaus, Wilfried; Ewart, Susan L; Arshad, S Hasan; Erlewyn-Lajeunesse, Mich

2014-10-01

Filaggrin is an epidermal protein that has a role in skin barrier function. Filaggrin loss-of-function (FLG-LOF) mutations are a significant risk factor for eczema and atopy, but their association with food allergy (FA) is less clear. We explored the longitudinal relationship between 3 common FLG-LOF mutations and FA using the Isle of Wight birth cohort. FA diagnosis was based on recognized allergic reactions within 4 hours after exposure to known food allergens. Food allergen sensitization (FAS) was identified by using skin prick tests conducted between 1 and 18 years of age to a range of food allergens. Three FLG mutations were genotyped in 1150 (79%) of 1456 children. The temporal relationships between FA, FAS, and eczema in children with FLG mutations were explored by using path analysis with total, direct, and indirect effect models. There was a significant total effect of FLG-LOF mutations on the risk of FA in later childhood at the ages of 10 (odds ratio, 31.46; 95% CI, 2.86 to >100) and 18 (odds ratio, 4.25; 95% CI, 1.55-11.61) years. Path analysis showed that there was no direct effect of FLG-LOF mutations on FA at any age; however, an indirect effect was found on FA at all ages through eczema and FAS in the earlier years. FLG-LOF mutations are associated with FA in older children through eczema and FAS during early childhood. Our results highlight a biologically plausible pathway, which suggests that skin barrier function is important in the development and persistence of FA. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Association between Plasma Nonesterified Fatty Acids Species and Adipose Tissue Fatty Acid Composition

PubMed Central

Hellmuth, Christian; Demmelmair, Hans; Schmitt, Isabel; Peissner, Wolfgang; Blüher, Matthias; Koletzko, Berthold

2013-01-01

Fatty acid composition of adipose tissue (AT) is an established long-term biomarker for fatty acid (FA) intake and status, but AT samples are not easily available. Nonesterified FA composition in plasma (pNEFA) may be a good indicator of AT FA composition, because pNEFA are mainly generated by AT lipolysis. We investigated the correlation of 42 pNEFA and subcutaneous as well as visceral AT FA in 27 non-diabetic women with a median BMI of 36 kg/m2 (Q0.25: 25 kg/m2; Q0.75: 49 kg/m2). Close correlations of pNEFA and AT FA were found for odd-chain FA (15∶0 r = 0.838 and 0.862 for subcutaneous and visceral AT, respectively) and omega-3 FA (22∶6 r = 0.719/0.535), while no significant or low correlations were found for other FA including 18∶1 (r = 0.384/0.325) and 20∶4 (r = 0.386/0.266). Close correlations of pNEFA and AT FA were found for essential fatty acids, like 18∶2 (r = 0.541/0.610) and 20∶5 (r = 0.561/0.543). The lower correlation for some pNEFA species with AT FA indicates that the variation of most pNEFA is significantly affected by other FA sources and flux of FA to tissue, in addition to release from AT. A relevant influence of BMI on the level of correlation was shown for saturated FA. NEFA analysis in fasted plasma can serve as a virtual AT biopsy for some FA, and as a biomarker for intake of dairy products and sea fish. PMID:24098359

Association between plasma nonesterified fatty acids species and adipose tissue fatty acid composition.

PubMed

Hellmuth, Christian; Demmelmair, Hans; Schmitt, Isabel; Peissner, Wolfgang; Blüher, Matthias; Koletzko, Berthold

2013-01-01

Fatty acid composition of adipose tissue (AT) is an established long-term biomarker for fatty acid (FA) intake and status, but AT samples are not easily available. Nonesterified FA composition in plasma (pNEFA) may be a good indicator of AT FA composition, because pNEFA are mainly generated by AT lipolysis. We investigated the correlation of 42 pNEFA and subcutaneous as well as visceral AT FA in 27 non-diabetic women with a median BMI of 36 kg/m(2) (Q0.25: 25 kg/m(2); Q0.75: 49 kg/m(2)). Close correlations of pNEFA and AT FA were found for odd-chain FA (15∶0 r = 0.838 and 0.862 for subcutaneous and visceral AT, respectively) and omega-3 FA (22∶6 r = 0.719/0.535), while no significant or low correlations were found for other FA including 18∶1 (r = 0.384/0.325) and 20∶4 (r = 0.386/0.266). Close correlations of pNEFA and AT FA were found for essential fatty acids, like 18∶2 (r = 0.541/0.610) and 20∶5 (r = 0.561/0.543). The lower correlation for some pNEFA species with AT FA indicates that the variation of most pNEFA is significantly affected by other FA sources and flux of FA to tissue, in addition to release from AT. A relevant influence of BMI on the level of correlation was shown for saturated FA. NEFA analysis in fasted plasma can serve as a virtual AT biopsy for some FA, and as a biomarker for intake of dairy products and sea fish.

HPLC analysis of functionalized poly(amidoamine) dendrimers and the interaction between a folate-dendrimer conjugate and folate binding protein.

PubMed

Shi, Xiangyang; Bi, Xiangdong; Ganser, T Rose; Hong, Seungpyo; Myc, Lukasz A; Desai, Ankur; Holl, Mark M Banaszak; Baker, James R

2006-07-01

Poly(amidoamine) (PAMAM) dendrimers of different generations with carboxyl, acetyl, and hydroxyl terminal groups and a folic acid (FA)-dendrimer conjugate were separated and analyzed using reverse-phase high performance liquid chromatography (HPLC). Analysis of both the individual PAMAM derivatives and the separation of mixed generations can be achieved using a linear gradient 0-50% acetonitrile (ACN) (balance water) within 40 min. We also show that PAMAMs with defined acetylation and carboxylation degrees can be analyzed using HPLC. Furthermore, a generation 5 dendrimer-FA conjugate (G5.75Ac-FA4; Ac denotes acetyl) was analyzed and its specific binding with a bovine folic acid binding protein (FBP) was monitored. The HPLC and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) results indicate the formation of three complexes after the binding of G5.75Ac-FA4 with FBP. Dendrimers with FA moieties show much higher specific binding capability with FBP than those without FA moieties. Findings from this study indicate that HPLC is an effective technique not only for characterization and separation of functionalized PAMAM dendrimers and conjugates but also for investigation of the interaction between dendrimers and biomolecules.

New insights into the operative network of FaEO, an enone oxidoreductase from Fragaria x ananassa Duch.

PubMed

Collu, Gabriella; Farci, Domenica; Esposito, Francesca; Pintus, Francesca; Kirkpatrick, Joanna; Piano, Dario

2017-05-01

The 2-methylene-furan-3-one reductase or Fragaria x ananassa Enone Oxidoreductase (FaEO) catalyses the last reductive step in the biosynthesis of 4-hydroxy-2,5-dimethyl-3(2H)-furanone, a major component in the characteristic flavour of strawberries. In the present work, we describe the association between FaEO and the vacuolar membrane of strawberry fruits. Even if FaEO lacks epitopes for stable or transient membrane-interactions, it contains a calmodulin-binding region, suggesting that in vivo FaEO may be associated with the membrane via a peripheral protein complex with calmodulin. Moreover, we also found that FaEO occurs in dimeric form in vivo and, as frequently observed for calmodulin-regulated proteins, it may be expressed in different isoforms by alternative gene splicing. Further mass spectrometry analysis confirmed that the isolated FaEO consists in the already known isoform and that it is the most characteristic during ripening. Finally, a characterization by absorption spectroscopy showed that FaEO has specific flavoprotein features. The relevance of these findings and their possible physiological implications are discussed.

Structural integrity assessment and stress measurement of chasnupp-1 fuel assembly skeleton: under tensile loading condition

NASA Astrophysics Data System (ADS)

Waseem; Siddiqui, Ashfaq Ahmad; Murtaza, Ghulam; Maqbool, Abu Baker

2017-12-01

Fuel assembly (FA) structure without fuel rods is called FA skeleton which is a long and flexible structure. This study has been made in an attempt to find the structural integrity of the Chashma Nuclear power plant-1 FA skeleton at room temperature. The finite element (FE) analysis has been performed using ANSYS, in order to determine the elongation of the FA skeleton as well as the location of max. stress and stresses developed in axial direction under tensile load of 9800 N or 2 g being the FA handling or lifting load [Y. Zhang et al., Fuel Assembly Design Report, SNERDI, China, 1994]. The FE model of grids, guide thimbles with dash-pots and flow holes has been developed using Shell 181. It has been observed that FA skeleton elongation values obtained through FE analysis and experiment are comparable and show linear behaviors. Moreover, the values of stresses obtained at different locations of the guide thimbles are also comparable with the stress values of the experiment determined at the same locations through strain gauges. Therefore, validation of the FE methodology is confirmed. The values of stresses are less than the design limit of the materials used for the grid and the guide thimble. Therefore, the structural integrity criterion of CHASNUPP-1 FA skeleton is fulfilled safely.

Disease-specific hematopoietic stem cell transplantation in children with inherited bone marrow failure syndromes.

PubMed

Li, Qian; Luo, Changying; Luo, Chengjuan; Wang, Jianmin; Li, Benshang; Ding, Lixia; Chen, Jing

2017-08-01

Hematopoietic stem cell transplantation (HSCT) using an optimized conditioning regimen is essential for the long-term survival of patients with inherited bone marrow failure syndromes (IBMFS). We report HSCT in 24 children with Fanconi anemia (FA, n = 12), Diamond-Blackfan anemia (DBA, n = 7), and dyskeratosis congenita (DC, n = 5) from a single HSCT center. The graft source was peripheral blood stem cells (n = 19) or cord blood stem cells (n = 5). FA and DC patients received reduced-intensity conditioning, while DBA patients had myeloablative conditioning. The median numbers of infused mononuclear cells and CD34+ cells were 14.20 × 10 8 /kg and 4.3 × 10 6 /kg, respectively. The median time for neutrophil and platelet recovery was 12 and 18 days, respectively. Complete donor engraftment was achieved in 23 of 24 patients. There was one primary graft failure. During a median follow-up of 27.5 months (range, 2-130 months), the overall survival in all patients was 95.8%. The incidence of grade II-III acute graft versus host disease (GvHD) and chronic GvHD was 29.2% and 16.7%, respectively. We conclude that HSCT can be a curative option for patients with IBMFS. Modification of the conditioning regimen based on the type of disease may lead to encouraging long-term outcomes.

Surface-coated fly ash reinforced biodegradable poly(vinyl alcohol) composite films: part 2-analysis and characterization

NASA Astrophysics Data System (ADS)

Nath, D. C. D.; Bandyopadhyay, S.; Campbell, J.; Yu, A.; Blackburn, D.; White, C.

2010-12-01

Composite films of poly(vinyl alcohol) (PVA) reinforced with 5, 10, 15, 20 and 25 wt.% surface-coated fly ash by surfactant, sodium lauryl sulphate (SLS-FA) along with 1 wt.% cross-linking agent, glutaraldehyde (GLA) were prepared by aqueous casting method. The tensile strengths of the composite films were increased proportionally with the addition of SLS-FA. The maximum 75% higher strength of the composite with 20 wt.% was achieved compared to that of neat PVA. The modulus of the composites was also increased proportionally with SLS-FA and the maximum 218% reached in composite with 20 wt.%, but the strain at break was decreased with addition of SLS-FA. Changes in FTIR spectra reflect the chemical and/or physical bonding in the ternary PVA, SLS-FA and GLA component systems. In the study of surface morphology, the connectivity was visualized in SEM images along with interstitial voids. The films with SLS-FA show 53% smoother surface calculated with AFM compared to unmodified FA composite films.

Investigation of FANCA mutations in Greek patients.

PubMed

Selenti, Nikoletta; Sofocleous, Christalena; Kattamis, Antonis; Kolialexi, Aggeliki; Kitsiou, Sophia; Fryssira, Elena; Polychronopoulou, Sophia; Kanavakis, Emmanouel; Mavrou, Ariadni

2013-08-01

Fanconi anemia (FA) is a rare genetic disease characterized by considerable heterogeneity. Fifteen subtypes are currently recognised and deletions of the Fanconi anemia complementation group A (FANCA) gene account for more than 65% of FA cases. We report on the results from a cohort of 166 patients referred to the Department of Medical Genetics of Athens University for genetic investigation after the clinical suspicion of FA. For clastogen-induced chromosome damage, cultures were set up with the addition of mitomycin C (MMC) and diepoxybutane (DEB), respectively. Following a positive cytogenetic result, molecular analysis was performed to allow identification of causative mutations in the FANCA gene. A total of 13/166 patients were diagnosed with FA and 8/13 belonged to the FA-A subtype. A novel point mutation was identified in exon 26 of FANCA gene. In our study 62% of FA patients were classified in the FA-A subtype and a point mutation in exon 26 was noted for the first time.

Microwave-assisted Derivatization of Fatty Acids for Its Measurement in Milk Using High-Performance Liquid Chromatography.

PubMed

Shrestha, Rojeet; Miura, Yusuke; Hirano, Ken-Ichi; Chen, Zhen; Okabe, Hiroaki; Chiba, Hitoshi; Hui, Shu-Ping

2018-01-01

Fatty acid (FA) profiling of milk has important applications in human health and nutrition. Conventional methods for the saponification and derivatization of FA are time-consuming and laborious. We aimed to develop a simple, rapid, and economical method for the determination of FA in milk. We applied a beneficial approach of microwave-assisted saponification (MAS) of milk fats and microwave-assisted derivatization (MAD) of FA to its hydrazides, integrated with HPLC-based analysis. The optimal conditions for MAS and MAD were determined. Microwave irradiation significantly reduced the sample preparation time from 80 min in the conventional method to less than 3 min. We used three internal standards for the measurement of short-, medium- and long-chain FA. The proposed method showed satisfactory analytical sensitivity, recovery and reproducibility. There was a significant correlation in the milk FA concentrations between the proposed and conventional methods. Being quick, economic, and convenient, the proposed method for the milk FA measurement can be substitute for the convention method.

White Matter Injuries in Mild Traumatic Brain Injury and Posttraumatic Migraines: Diffusion Entropy Analysis.

PubMed

Delic, Joseph; Alhilali, Lea M; Hughes, Marion A; Gumus, Serter; Fakhran, Saeed

2016-06-01

Purpose To determine the performance of Shannon entropy (SE) as a diagnostic tool in patients with mild traumatic brain injury (mTBI) with posttraumatic migraines (PTMs) and those without PTMs on the basis of analysis of fractional anisotropy (FA) maps. Materials and Methods The institutional review board approved this retrospective study, with waiver of informed consent. FA maps were obtained and neurocognitive testing was performed in 74 patients with mTBI (57 with PTM, 17 without PTM). FA maps were obtained in 22 healthy control subjects and in 20 control patients with migraine headaches. Mean FA and SE were extracted from total brain FA histograms and were compared between patients with mTBI and control subjects and between patients with and those without PTM. Mean FA and SE were correlated with clinical variables and were used to determine the areas under the receiver operating characteristic curve (AUCs) and likelihood ratios for mTBI and development of PTM. Results Patients with mTBI had significantly lower SE (P < .001) and trended toward lower mean FA (P = .07) compared with control subjects. SE inversely correlated with time to recovery (TTR) (r = -0.272, P = .02). Patients with mTBI with PTM had significantly lower SE (P < .001) but not mean FA (P = .15) than did other patients with mTBI. SE provided better discrimination between patients with mTBI and control subjects than mean FA (AUC = 0.92; P = .01), as well as better discrimination between patients with mTBI with PTM and those without PTM (AUC = 0.85; P < .001). SE of less than 0.751 resulted in a 16.1 increased likelihood of having experienced mTBI and a 3.2 increased likelihood of developing PTM. Conclusion SE more accurately reveals mTBI than mean FA, more accurately reveals those patients with mTBI who develop PTM, and inversely correlates with TTR. (©) RSNA, 2016.

The multiple synaesthete E.S.: neuroanatomical basis of interval-taste and tone-colour synaesthesia.

PubMed

Hänggi, Jürgen; Beeli, Gian; Oechslin, Mathias S; Jäncke, Lutz

2008-11-01

Synaesthesia is the involuntary physical experience of a crossmodal linkage such as when hearing a tone evokes the additional sensation of seeing a colour. We previously described a professional musician with absolute pitch perception who experiences both different tastes in response to hearing different tone intervals (e.g., major third and sweet) and the more common tone-colour synaesthesia in which each particular tone is linked to a specific colour (e.g., C and red). One of the current theories of synaesthesia proposes that local crossactivation or disinhibition of feedback occurs because of increased connectivity between relevant brain areas. Based on diffusion tensor and T1-weighted magnetic resonance imaging we performed fractional anisotropy (FA) analysis, probabilistic fibre tractography, and voxel-based morphometry in the synaesthete E.S. compared with 17 professional musicians and 20 normal control subjects using voxel-wise z-score transformations. We report increased FA and volumetric white (WM) and grey matter (GM) peculiarities in E.S.'s auditory and gustatory areas, hence explaining the interval-taste synaesthesia. Probabilistic fibre tractography revealed hyperconnectivity in bilateral perisylvian-insular regions in the synaesthete E.S. Differences in FA and volumetric WM and GM alterations in visual areas might represent the neuroarchitectural foundation of the tone-colour synaesthesia. Still unknown are the causes of the structural alterations, although an X-chromosomal linked dominant trait has been suggested. Whether hyperconnectivity occurs due to a failure in neural pruning or even synaptic sprouting remains to be shown. Our findings might have implications for the understanding of multimodal integration and may encourage similar research into dysfunctional perceptual phenomenon such as hallucinations in schizophrenics or in Charles Bonnet syndrome.

Homozygous loss of function BRCA1 variant causing a Fanconi-anemia-like phenotype, a clinical report and review of previous patients.

PubMed

Freire, Bruna L; Homma, Thais K; Funari, Mariana F A; Lerario, Antônio M; Leal, Aline M; Velloso, Elvira D R P; Malaquias, Alexsandra C; Jorge, Alexander A L

2018-03-01

Fanconi Anemia (FA) is a rare and heterogeneous genetic syndrome. It is associated with short stature, bone marrow failure, high predisposition to cancer, microcephaly and congenital malformation. Many genes have been associated with FA. Previously, two adult patients with biallelic pathogenic variant in Breast Cancer 1 gene (BRCA1) had been identified in Fanconi Anemia-like condition. The proband was a 2.5 year-old girl with severe short stature, microcephaly, neurodevelopmental delay, congenital heart disease and dysmorphic features. Her parents were third degree cousins. Routine screening tests for short stature was normal. We conducted whole exome sequencing (WES) of the proband and used an analysis pipeline to identify rare nonsynonymous genetic variants that cause short stature. We identified a homozygous loss-of-function BRCA1 mutation (c.2709T > A; p. Cys903*), which promotes the loss of critical domains of the protein. Cytogenetic study with DEB showed an increased chromosomal breakage. We screened heterozygous parents of the index case for cancer and we detected, in her mother, a metastatic adenocarcinoma in an axillar lymph node with probable primary site in the breast. It is possible to consolidate the FA-like phenotype associated with biallelic loss-of-function BRCA1, characterized by microcephaly, short stature, developmental delay, dysmorphic face features and cancer predisposition. In our case, the WES allowed to establish the genetic cause of short stature in the context of a chromosome instability syndrome. An identification of BRCA1 mutations in our patient allowed precise genetic counseling and also triggered cancer screening for the patient and her family members. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Heterochronicity of white matter development and aging explains regional patient control differences in schizophrenia.

PubMed

Kochunov, Peter; Ganjgahi, Habib; Winkler, Anderson; Kelly, Sinead; Shukla, Dinesh K; Du, Xiaoming; Jahanshad, Neda; Rowland, Laura; Sampath, Hemalatha; Patel, Binish; O'Donnell, Patricio; Xie, Zhiyong; Paciga, Sara A; Schubert, Christian R; Chen, Jian; Zhang, Guohao; Thompson, Paul M; Nichols, Thomas E; Hong, L Elliot

2016-12-01

Altered brain connectivity is implicated in the development and clinical burden of schizophrenia. Relative to matched controls, schizophrenia patients show (1) a global and regional reduction in the integrity of the brain's white matter (WM), assessed using diffusion tensor imaging (DTI) fractional anisotropy (FA), and (2) accelerated age-related decline in FA values. In the largest mega-analysis to date, we tested if differences in the trajectories of WM tract development influenced patient-control differences in FA. We also assessed if specific tracts showed exacerbated decline with aging. Three cohorts of schizophrenia patients (total n = 177) and controls (total n = 249; age = 18-61 years) were ascertained with three 3T Siemens MRI scanners. Whole-brain and regional FA values were extracted using ENIGMA-DTI protocols. Statistics were evaluated using mega- and meta-analyses to detect effects of diagnosis and age-by-diagnosis interactions. In mega-analysis of whole-brain averaged FA, schizophrenia patients had lower FA (P = 10 -11 ) and faster age-related decline in FA (P = 0.02) compared with controls. Tract-specific heterochronicity measures, that is, abnormal rates of adolescent maturation and aging explained approximately 50% of the regional variance effects of diagnosis and age-by-diagnosis interaction in patients. Interactive, three-dimensional visualization of the results is available at www.enigma-viewer.org. WM tracts that mature later in life appeared more sensitive to the pathophysiology of schizophrenia and were more susceptible to faster age-related decline in FA values. Hum Brain Mapp 37:4673-4688, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Methanoculleus sediminis sp. nov., a methanogen from sediments near a submarine mud volcano.

PubMed

Chen, Sheng-Chung; Chen, Mei-Fei; Lai, Mei-Chin; Weng, Chieh-Yin; Wu, Sue-Yao; Lin, Saulwood; Yang, Tsanyao F; Chen, Po-Chun

2015-07-01

A mesophilic, hydrogenotrophic methanogen, strain S3Fa(T), was isolated from sediments collected by Ocean Researcher I cruise ORI-934 in 2010 near the submarine mud volcano MV4 located at the upper slope of south-west Taiwan. The methanogenic substrates utilized by strain S3Fa(T) were formate and H2/CO2 but not acetate, secondary alcohols, methylamines, methanol or ethanol. Cells of strain S3Fa(T) were non-motile, irregular cocci, 0.5-1.0 μm in diameter. The surface-layer protein showed an Mr of 128,000.The optimum growth conditions were 37 °C, pH 7.1 and 0.17 M NaCl. The DNA G+C content of the genome of strain S3Fa(T) was 62.3 mol%. Phylogenetic analysis revealed that strain S3Fa(T) was most closely related to Methanoculleus marisnigri JR1(T) (99.3% 16S rRNA gene sequence similarity). Genome relatedness between strain S3Fa(T) and Methanoculleus marisnigri JR1(T) was computed using both genome-to-genome distance analysis (GGDA) and average nucleotide identity (ANI) with values of 46.3-55.5% and 93.08%, respectively. Based on morphological, phenotypic, phylogenetic and genomic relatedness data, it is evident that strain S3Fa(T) represents a novel species of the genus Methanoculleus, for which the name Methanoculleus sediminis sp. nov. is proposed. The type strain is S3Fa(T) ( = BCRC AR10044(T) = DSM 29354(T)).

Effects of intravenous gadolinium administration and flip angle on the assessment of liver fat signal fraction with opposed-phase and in-phase imaging.

PubMed

Yokoo, Takeshi; Collins, Julie M; Hanna, Robert F; Bydder, Mark; Middleton, Michael S; Sirlin, Claude B

2008-07-01

To assess the effects of intravenous gadolinium (Gd) and flip angle (FA) on liver fat quantification by opposed-phase (OP) and in-phase (IP) imaging. Our Institutional Review Board (IRB) approved this Health Insurance Portability and Accountability Act (HIPAA)-compliant, retrospective, clinical study. We identified 79 patients in whom abdominal OP and IP gradient-echoes were obtained at 1.5T before and after Gd administration. All 79 patients were imaged at high FA (> or =70 degrees ); 57 were also imaged at low FA (< or =20 degrees ). Fat signal fraction (FSF) was calculated from pre- and post-Gd liver images for each subject and FA using the formula, FSF = (S(IP) - S(OP))/2S(IP), where S(IP) and S(OP) are the OP and IP signal intensities, respectively. The dataset pairs (pre-Gd vs. post-Gd; high-FA vs. low-FA) were compared using linear regression analysis. Before Gd, FSF was significantly greater at high FA than at low FA, with regression parameters (slope/intercept) of 1.27*/0.02*, where * indicates P value <0.01. After Gd, FSF was similar at high and low FA (0.99/-0.00). Gd administration caused an FA-dependent reduction in FSF, larger at high FA (0.68*/-0.03*) than at low FA (0.94, -0.01*). FSF by OP-IP imaging is highly dependent on FA before Gd, but this dependency is eliminated after administration of Gd. Gd appears to minimize the effect of T1-weighting and may improve the accuracy of liver fat quantification. (c) 2008 Wiley-Liss, Inc.

Adverse effects of metallic artifacts on voxel-wise analysis and tract-based spatial statistics in diffusion tensor imaging.

PubMed

Goto, Masami; Abe, Osamu; Hata, Junichi; Fukunaga, Issei; Shimoji, Keigo; Kunimatsu, Akira; Gomi, Tsutomu

2017-02-01

Background Diffusion tensor imaging (DTI) is a magnetic resonance imaging (MRI) technique that reflects the Brownian motion of water molecules constrained within brain tissue. Fractional anisotropy (FA) is one of the most commonly measured DTI parameters, and can be applied to quantitative analysis of white matter as tract-based spatial statistics (TBSS) and voxel-wise analysis. Purpose To show an association between metallic implants and the results of statistical analysis (voxel-wise group comparison and TBSS) for fractional anisotropy (FA) mapping, in DTI of healthy adults. Material and Methods Sixteen healthy volunteers were scanned with 3-Tesla MRI. A magnetic keeper type of dental implant was used as the metallic implant. DTI was acquired three times in each participant: (i) without a magnetic keeper (FAnon1); (ii) with a magnetic keeper (FAimp); and (iii) without a magnetic keeper (FAnon2) as reproducibility of FAnon1. Group comparisons with paired t-test were performed as FAnon1 vs. FAnon2, and as FAnon1 vs. FAimp. Results Regions of significantly reduced and increased local FA values were revealed by voxel-wise group comparison analysis (a P value of less than 0.05, corrected with family-wise error), but not by TBSS. Conclusion Metallic implants existing outside the field of view produce artifacts that affect the statistical analysis (voxel-wise group comparisons) for FA mapping. When statistical analysis for FA mapping is conducted by researchers, it is important to pay attention to any dental implants present in the mouths of the participants.

Monitoring fractional anisotropy in developing rabbit brain using MR diffusion tensor imaging at 3T

NASA Astrophysics Data System (ADS)

Jao, Jo-Chi; Yang, Yu-Ting; Hsiao, Chia-Chi; Chen, Po-Chou

2016-03-01

The aim of this study was to investigate the factional anisotropy (FA) in various regions of developing rabbit brain using magnetic resonance diffusion tensor imaging (MR DTI) at 3 T. A whole-body clinical MR imaging (MRI) scanner with a 15-channel high resolution knee coil was used. An echo-planar-imaging (EPI)-DTI pulse sequence was performed. Five 5 week-old New Zealand white (NZW) rabbits underwent MRI once per week for 24 weeks. After scanning, FA maps were obtained. ROIs (regions of interests) in the frontal lobe, parietal & temporal lobe, and occipital lobe were measured. FA changes with time were evaluated with a linear regression analysis. The results show that the FA values in all lobes of the brain increased linearly with age. The ranking of FA values was FA(frontal lobe) < FA(parietal & temporal lobe) > FA(occipital lobe). There was significant difference (p < 0.05) among these lobes. FA values are associated with the nerve development and brain functions. The FA change rate could be a biomarker to monitor the brain development. Understanding the FA values of various lobes during development could provide helpful information to diagnosis the abnormal syndrome earlier and have a better treatment and prognosis. This study established a brain MR-DTI protocol for rabbits to investigate the brain anatomy during development using clinical MRI. This technique can be further applied to the pre-clinical diagnosis, treatment, prognosis and follow-up of brain lesions.

A cost minimization analysis of early correction of anterior crossbite-a randomized controlled trial.

PubMed

Wiedel, Anna-Paulina; Norlund, Anders; Petrén, Sofia; Bondemark, Lars

2016-04-01

Economic evaluations provide an important basis for allocation of resources and health services planning. The aim of this study was to evaluate and compare the costs of correcting anterior crossbite with functional shift, using fixed or removable appliances (FA or RA) and to relate the costs to the effects, using cost-minimization analysis. Sixty-two patients with anterior crossbite and functional shift were randomized in blocks of 10. Thirty-one patients were randomized to be treated with brackets and arch wire (FA) and 31 with an acrylic plate (RA). Duration of treatment and number and estimated length of appointments and cancellations were registered. Direct costs (premises, staff salaries, material, and laboratory costs) and indirect costs (the accompanying parents' loss of income while absent from work) were calculated and evaluated with reference to successful outcome alone, to successful and unsuccessful outcomes and to re-treatment when required. Societal costs were defined as the sum of direct and indirect costs. Treatment with FA or RA. There were no significant differences between FA and RA with respect to direct costs for treatment time, but both indirect costs and direct costs for material were significantly lower for FA. The total societal costs were lower for FA than for RA. Costs depend on local factors and should not be directly extrapolated to other locations. The analysis disclosed significant economic benefits for FA over RA. Even when only successful outcomes were assessed, treatment with RA was more expensive. This trial was not registered. The protocol was not published before trial commencement. © The Author 2015. Published by Oxford University Press on behalf of the European Orthodontic Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Schizophrenia symptomatic associations with diffusion tensor imaging measured fractional anisotropy of brain: a meta-analysis.

PubMed

Yang, Xu; Cao, Ding; Liang, Xiumei; Zhao, Jiannong

2017-07-01

Several studies have examined the relationships between diffusion tensor imaging (DTI)-measured fractional anisotropy (FA) and the symptoms of schizophrenia, but results vary across the studies. The aim of this study was to carry out a meta-analysis of correlation coefficients reported by relevant studies to evaluate the correlative relationships between FA of various parts of the brain and schizophrenia symptomatic assessments. Literature was searched in several electronic databases, and study selection was based on précised eligibility criteria. Correlation coefficients between FA of a part of the brain and schizophrenia symptom were first converted into Fisher's z-scores for meta-analyses, and then overall effect sizes were back transformed to correlation coefficients. Thirty-three studies (1121 schizophrenia patients; age 32.66 years [95% confidence interval (CI) 30.19, 35.13]; 65.95 % [57.63, 74.28] males) were included in this meta-analysis. Age was inversely associated with brain FA (z-scores [95% CI] -0.23 [-0.14, -0.32]; p ˂ 0.00001). Brain FA of various areas was inversely associated with negative symptoms of schizophrenia (z-score -0.30 [-0.23, -0.36]; p ˂ 0.00001) but was positively associated with positive symptoms of schizophrenia (z-score 0.16 [0.04, 0.27]; p = 0.007) and general psychopathology of schizophrenia (z-score 0.26 [0.15, 0.37]; p = 0.00001). Although, DTI-measured brain FA is found to be inversely associated with negative symptoms and positively associated with positive symptoms and general psychopathology of schizophrenia, the effect sizes of these correlations are low and may not be clinically significant. Moreover, brain FA was also negatively associated with age of patients.

A cost minimization analysis of early correction of anterior crossbite—a randomized controlled trial

PubMed Central

Norlund, Anders; Petrén, Sofia; Bondemark, Lars

2016-01-01

Summary Objective: Economic evaluations provide an important basis for allocation of resources and health services planning. The aim of this study was to evaluate and compare the costs of correcting anterior crossbite with functional shift, using fixed or removable appliances (FA or RA) and to relate the costs to the effects, using cost-minimization analysis. Design, Setting, and Participants: Sixty-two patients with anterior crossbite and functional shift were randomized in blocks of 10. Thirty-one patients were randomized to be treated with brackets and arch wire (FA) and 31 with an acrylic plate (RA). Duration of treatment and number and estimated length of appointments and cancellations were registered. Direct costs (premises, staff salaries, material, and laboratory costs) and indirect costs (the accompanying parents’ loss of income while absent from work) were calculated and evaluated with reference to successful outcome alone, to successful and unsuccessful outcomes and to re-treatment when required. Societal costs were defined as the sum of direct and indirect costs. Interventions: Treatment with FA or RA. Results: There were no significant differences between FA and RA with respect to direct costs for treatment time, but both indirect costs and direct costs for material were significantly lower for FA. The total societal costs were lower for FA than for RA. Limitations: Costs depend on local factors and should not be directly extrapolated to other locations. Conclusion: The analysis disclosed significant economic benefits for FA over RA. Even when only successful outcomes were assessed, treatment with RA was more expensive. Trial registration: This trial was not registered. Protocol: The protocol was not published before trial commencement. PMID:25940585

Small Molecule Protection of Bone Marrow Hematopoietic Stem Cells

DTIC Science & Technology

2016-10-01

early phase clinical trials of metformin in Fanconi anemia patients. – What was the impact on other disciplines? The fields of DNA damage...patent applications, study questionnaires, and surveys , etc. Reminder: Pages shall be consecutively numbered throughout the report. DO NOT RENUMBER...crosslinks, which impede replication and transcription.2,3 The primary cause of early morbidity and mortality for FA patients is bone marrow failure.4

Relationship between symptom dimensions and white matter alterations in obsessive-compulsive disorder.

PubMed

Yagi, Michiyo; Hirano, Yoshiyuki; Nakazato, Michiko; Nemoto, Kiyotaka; Ishikawa, Kazuhiro; Sutoh, Chihiro; Miyata, Haruko; Matsumoto, Junko; Matsumoto, Koji; Masuda, Yoshitada; Obata, Takayuki; Iyo, Masaomi; Shimizu, Eiji; Nakagawa, Akiko

2017-06-01

To investigate the relationship between the severities of symptom dimensions in obsessive-compulsive disorder (OCD) and white matter alterations. We applied tract-based spatial statistics for diffusion tensor imaging (DTI) acquired by 3T magnetic resonance imaging. First, we compared fractional anisotropy (FA) between 20 OCD patients and 30 healthy controls (HC). Then, applying whole brain analysis, we searched the brain regions showing correlations between the severities of symptom dimensions assessed by Obsessive-Compulsive Inventory-Revised and FA in all participants. Finally, we calculated the correlations between the six symptom dimensions and multiple DTI measures [FA, axial diffusivity (AD), radial diffusivity (RD), mean diffusivity (MD)] in a region-of-interest (ROI) analysis and explored the differences between OCD patients and HC. There were no between-group differences in FA or brain region correlations between the severities of symptom dimensions and FA in any of the participants. ROI analysis revealed negative correlations between checking severity and left inferior frontal gyrus white matter and left middle temporal gyrus white matter and a positive correlation between ordering severity and right precuneus in FA in OCD compared with HC. We also found negative correlations between ordering severity and right precuneus in RD, between obsessing severities and right supramarginal gyrus in AD and MD, and between hoarding severity and right insular gyrus in AD. Our study supported the hypothesis that the severities of respective symptom dimensions are associated with different patterns of white matter alterations.

Fatty acid composition in native bees: Associations with thermal and feeding ecology.

PubMed

Giri, Susma; Rule, Daniel C; Dillon, Michael E

2018-04-01

Fatty acid (FA) composition of lipids plays a crucial role in the functioning of lipid-containing structures in organisms and may be affected by the temperature an organism experiences, as well as its diet. We compared FA composition among four bee genera: Andrena, Bombus, Megachile, and Osmia which differ in their thermal ecology and diet. Fatty acid methyl esters (FAME) were prepared by direct transesterification with KOH and analyzed using gas-liquid chromatography with a flame ionization detector. Sixteen total FAs ranging in chain length from eight to 22 carbon atoms were identified. Linear discriminant analysis separated the bees based on their FA composition. Andrena was characterized by relatively high concentrations of polyunsaturated FAs, Bombus by high monounsaturated FAs and Megachilids (Megachile and Osmia) by relatively high amounts of saturated FAs. These differences in FA composition may in part be explained by variation in the diets of these bees. Because tongue (proboscis) length may be used as a proxy for the types of flowers bees may visit for nectar and pollen, we compared FA composition among Bombus that differed in proboscis length (but have similar thermal ecology). A clear separation in FA composition within Bombus with varying proboscis lengths was found using linear discriminant analysis. Further, comparing the relationship between each genus by cluster analysis revealed aggregations by genus that were not completely separated, suggesting potential overlap in dietary acquisition of FAs. Copyright © 2018 Elsevier Inc. All rights reserved.

White matter disease correlates with lexical retrieval deficits in primary progressive aphasia.

PubMed

Powers, John P; McMillan, Corey T; Brun, Caroline C; Yushkevich, Paul A; Zhang, Hui; Gee, James C; Grossman, Murray

2013-01-01

To relate fractional anisotropy (FA) changes associated with the semantic and logopenic variants of primary progressive aphasia (PPA) to measures of lexical retrieval. We collected neuropsychological testing, volumetric magnetic resonance imaging, and diffusion-weighted imaging on semantic variant PPA (svPPA) (n = 11) and logopenic variant PPA (lvPPA) (n = 13) patients diagnosed using published criteria. We also acquired neuroimaging data on a group of demographically comparable healthy seniors (n = 34). FA was calculated and analyzed using a white matter (WM) tract-specific analysis approach. This approach utilizes anatomically guided data reduction to increase sensitivity and localizes results within canonically defined tracts. We used non-parametric, cluster-based statistical analysis to relate language performance to FA and determine regions of reduced FA in patients. We found widespread FA reductions in WM for both variants of PPA. FA was related to both confrontation naming and category naming fluency performance in left uncinate fasciculus and corpus callosum in svPPA and left superior and inferior longitudinal fasciculi in lvPPA. SvPPA and lvPPA are associated with distinct disruptions of a large-scale network implicated in lexical retrieval, and the WM disease in each phenotype may contribute to language impairments including lexical retrieval.

Assessing FAÇADE Visibility in 3d City Models for City Marketing

NASA Astrophysics Data System (ADS)

Albrecht, F.; Moser, J.; Hijazi, I.

2013-08-01

In city marketing, different applications require the evaluation of the visual impression of displays in the urban environment on people that visit the city. Therefore, this research focuses on the way how visual displays on façades for movie performances are perceived during a cultural event triggered by city marketing. We describe the different visibility analysis methods that are applicable to the analysis of façades. The methods advanced from the domains of Geographic Information Science, architecture and computer graphics. A detailed scenario is described in order to perform a requirements analysis for identifying the requirements to visibility information. This visibility information needs to describe the visual perception of displays on façades adequately. The requirements are compared to the visibility information that can be provided by the visibility methods. A discussion of the comparison summarizes the advantages and disadvantages of existing visibility analysis methods for describing the visibility of façades. The results show that part of the researched approaches is able to support the requirements to visibility information. But they also show that for a complete support of the entire analysis workflow, there remain unsolved workflow integration issues.

HPLC-MRM relative quantification analysis of fatty acids based on a novel derivatization strategy.

PubMed

Cai, Tie; Ting, Hu; Xin-Xiang, Zhang; Jiang, Zhou; Jin-Lan, Zhang

2014-12-07

Fatty acids (FAs) are associated with a series of diseases including tumors, diabetes, and heart diseases. As potential biomarkers, FAs have attracted increasing attention from both biological researchers and the pharmaceutical industry. However, poor ionization efficiency, extreme diversity, strict dependence on internal standards and complicated multiple reaction monitoring (MRM) optimization protocols have challenged efforts to quantify FAs. In this work, a novel derivatization strategy based on 2,4-bis(diethylamino)-6-hydrazino-1,3,5-triazine was developed to enable quantification of FAs. The sensitivity of FA detection was significantly enhanced as a result of the derivatization procedure. FA quantities as low as 10 fg could be detected by high-performance liquid chromatography coupled with triple-quadrupole mass spectrometry. General MRM conditions were developed for any FA, which facilitated the quantification and extended the application of the method. The FA quantification strategy based on HPLC-MRM was carried out using deuterated derivatization reagents. "Heavy" derivatization reagents were used as internal standards (ISs) to minimize matrix effects. Prior to statistical analysis, amounts of each FA species were normalized by their corresponding IS, which guaranteed the accuracy and reliability of the method. FA changes in plasma induced by ageing were studied using this strategy. Several FA species were identified as potential ageing biomarkers. The sensitivity, accuracy, reliability, and full coverage of the method ensure that this strategy has strong potential for both biomarker discovery and lipidomic research.

Flow cytometric analysis of lymphocyte proliferative responses to food allergens in dogs with food allergy.

PubMed

Fujimura, Masato; Masuda, Kenichi; Hayashiya, Makio; Okayama, Taro

2011-10-01

Two different allergy tests, antigen-specific immunoglobulin E quantification (IgE test) and flow cytometric analysis of antigen-specific proliferation of peripheral lymphocytes (lymphocyte proliferation test), were performed to examine differences in allergic reactions to food allergens in dogs with food allergy (FA). Thirteen dogs were diagnosed as FA based on clinical findings and elimination diet trials. Seven dogs clinically diagnosed with canine atopic dermatitis (CAD) were used as a disease control group, and 5 healthy dogs were used as a negative control group. In the FA group, 19 and 33 allergen reactions were identified using the serum IgE test and the lymphocyte proliferation test, respectively. Likewise, in the CAD group, 12 and 6 allergen reactions and in the healthy dogs 3 and 0 allergen reactions were identified by each test, respectively. A significant difference was found between FA and healthy dogs in terms of positive allergen detection by the lymphocyte proliferation test, suggesting that the test can be useful to differentiate FA from healthy dogs but not from CAD. Both tests were repeated in 6 of the dogs with FA after a 1.5- to 5-month elimination diet trial. The IgE concentrations in 9 of 11 of the positive reactions decreased by 20-80%, whereas all the positive reactions in the lymphocyte proliferation test decreased to nearly zero (P<0.05), suggesting that lymphocytes against food allergens may be involved in the pathogenesis of canine FA.

Functional analysis-based interventions for challenging behaviour in dementia.

PubMed

Moniz Cook, Esme D; Swift, Katie; James, Ian; Malouf, Reem; De Vugt, Marjolein; Verhey, Frans

2012-02-15

Functional analysis (FA) for the management of challenging behaviour is a promising behavioural intervention that involves exploring the meaning or purpose of an individual's behaviour. It extends the 'ABC' approach of behavioural analysis, to overcome the restriction of having to derive a single explanatory hypothesis for the person's behaviour. It is seen as a first line alternative to traditional pharmacological management for agitation and aggression. FA typically requires the therapist to develop and evaluate hypotheses-driven strategies that aid family and staff caregivers to reduce or resolve a person's distress and its associated behavioural manifestations. To assess the effects of functional analysis-based interventions for people with dementia (and their caregivers) living in their own home or in other settings. We searched ALOIS: the Cochrane Dementia and Cognitive Improvement Group's Specialized Register on 3 March 2011 using the terms: FA, behaviour (intervention, management, modification), BPSD, psychosocial and Dementia. Randomised controlled trials (RCTs) with reported behavioural outcomes that could be associated with functional analysis for the management of challenging behaviour in dementia. Four reviewers selected trials for inclusion. Two reviewers worked independently to extract data and assess trial quality, including bias. Meta-analyses for reported incidence, frequency, severity of care recipient challenging behaviour and mood (primary outcomes) and caregiver reaction, burden and mood were performed. Details of adverse effects were noted. Eighteen trials are included in the review. The majority were in family care settings. For fourteen studies, FA was just one aspect of a broad multi-component programme of care. Assessing the effect of FA was compromised by ill-defined protocols for the duration of component parts of these programmes (i.e. frequency of the intervention or actual time spent). Therefore, establishing the real effect of the FA component was not possible.Overall, positive effects were noted at post-intervention for the frequency of reported challenging behaviour (but not for incidence or severity) and for caregiver reaction (but not burden or depression). These effects were not seen at follow-up. The delivery of FA has been incorporated within wide ranging multi-component programmes and study designs have varied according to setting - i.e. family care, care homes and hospital, with surprisingly few studies located in care homes. Our findings suggest potential beneficial effects of multi-component interventions, which utilise FA. Whilst functional analysis for challenging behaviour in dementia care shows promise, it is too early to draw conclusions about its efficacy.

Can turned inward patella predict an excess of femoral anteversion during gait in spastic diplegic children?

PubMed

Simon, Anne-Laure; Presedo, Ana; Ilharreborde, Brice; Mallet, Cindy; Mazda, Keyvan; Penneçot, Georges-François

2014-06-01

Determining patellar orientation in the transverse plane during observational gait analysis is a fundamental aspect of physical examinations. Many physicians consider that an abnormal position of the patella in the transverse planes is only explained by a rotational abnormality of the proximal femur. A total of 188 spastic diplegic children with cerebral palsy were reviewed (376 lower limbs). The physical examination included observation of patellar orientation at midstride and measuring femoral anteversion (FA). All patients also underwent 3-dimensional (3D) computerized gait analysis of pelvic and hip rotation kinematics. Observational gait analysis and videotapes found 103 children (206 lower limbs) with inturned patella at midstance. Kinematic data from 3D gait analysis showed that the visual impression of turned inward patella was erroneous in 48 limbs. Of the remaining 158 lower limbs, 117 (74%) exhibited excessive FA and 41 (26%) did not. Of the 117 with excessive FA, kinematics showed only 66 (56%) with excessive internal hip rotation (with or without excessive internal pelvic rotation). Of the 41 lower limbs without excessive FA, 25 were explained by excessive internal pelvic rotation and 16 were explained by excessive internal hip rotation (isolated spasticity and/or contracture of internal rotator muscles). Turned inward patella was caused by isolated excessive internal pelvic rotation in 48%, excessive internal hip rotation in 35% (including 44 cases with excessive FA and 12 cases with isolated spasticity and/or contracture of internal hip rotators), and excessive internal hip rotation combined with excessive internal pelvic rotation in 17%. Excessive FA was not the only cause of turned inward patella gait and could not explain this gait anomaly by itself. Excessive internal pelvic rotation was the most frequent cause of turned inward patella gait. Level IV.

Fanconi anemia mesenchymal stromal cells-derived glycerophospholipids skew hematopoietic stem cell differentiation through Toll-like receptor signaling

PubMed Central

Amarachintha, Surya; Sertorio, Mathieu; Wilson, Andrew; Li, Xiaoli; Pang, Qishen

2015-01-01

Fanconi anemia (FA) patients develop bone marrow (BM) failure or leukemia. One standard care for these devastating complications is hematopoietic stem cell transplantation. We identified a group of mesenchymal stromal cells (MSCs)-derived metabolites, glycerophospholipids and their endogenous inhibitor, 5-(Tetradecyloxy)-2-furoic acid (TOFA), as regulators of donor hematopoietic stem and progenitor cells (HSPCs). We provided two pieces of evidence that TOFA could improve hematopoiesis-supporting function of FA MSCs: (1) limiting-dilution CAFC assay revealed that TOFA significantly increased cobblestone colonies in Fanca−/− or Fancd2−/− co-cultures compared to untreated co-cultures. (2) Competitive repopulating assay using output cells collected from co-cultures showed that TOFA greatly alleviated the abnormal expansion of the donor myeloid (CD45.2+Gr1+Mac1+) compartment in both peripheral blood and BM of recipient mice transplanted with cells from Fanca−/− or Fancd2−/− co-cultures. Further, mechanistic studies identified Tlr4 signaling as the responsible pathway mediating the effect of glycerophospholipids. Thus, targeting Glycerophospholipid biosynthesis in FA MSCs could be a therapeutic strategy to improve hematopoiesis and stem cell transplantation. PMID:26212365

Fanconi Anemia Mesenchymal Stromal Cells-Derived Glycerophospholipids Skew Hematopoietic Stem Cell Differentiation Through Toll-Like Receptor Signaling.

PubMed

Amarachintha, Surya; Sertorio, Mathieu; Wilson, Andrew; Li, Xiaoli; Pang, Qishen

2015-11-01

Fanconi anemia (FA) patients develop bone marrow (BM) failure or leukemia. One standard care for these devastating complications is hematopoietic stem cell transplantation. We identified a group of mesenchymal stromal cells (MSCs)-derived metabolites, glycerophospholipids, and their endogenous inhibitor, 5-(tetradecyloxy)-2-furoic acid (TOFA), as regulators of donor hematopoietic stem and progenitor cells. We provided two pieces of evidence that TOFA could improve hematopoiesis-supporting function of FA MSCs: (a) limiting-dilution cobblestone area-forming cell assay revealed that TOFA significantly increased cobblestone colonies in Fanca-/- or Fancd2-/- cocultures compared to untreated cocultures. (b) Competitive repopulating assay using output cells collected from cocultures showed that TOFA greatly alleviated the abnormal expansion of the donor myeloid (CD45.2+Gr1+Mac1+) compartment in both peripheral blood and BM of recipient mice transplanted with cells from Fanca-/- or Fancd2-/- cocultures. Furthermore, mechanistic studies identified Tlr4 signaling as the responsible pathway mediating the effect of glycerophospholipids. Thus, targeting glycerophospholipid biosynthesis in FA MSCs could be a therapeutic strategy to improve hematopoiesis and stem cell transplantation. © 2015 AlphaMed Press.

Supplementation with Folic Acid, but Not Creatine, Increases Plasma Betaine, Decreases Plasma Dimethylglycine, and Prevents a Decrease in Plasma Choline in Arsenic-Exposed Bangladeshi Adults.

PubMed

Hall, Megan N; Howe, Caitlin G; Liu, Xinhua; Caudill, Marie A; Malysheva, Olga; Ilievski, Vesna; Lomax-Luu, Angela M; Parvez, Faruque; Siddique, Abu B; Shahriar, Hasan; Uddin, Mohammad N; Islam, Tariqul; Graziano, Joseph H; Gamble, Mary V

2016-05-01

Folic acid (FA) supplementation facilitates urinary excretion of arsenic, a human carcinogen. A better understanding of interactions between one-carbon metabolism intermediates may improve the ability to design nutrition interventions that further facilitate arsenic excretion. The objective was to determine if FA and/or creatine supplementation increase choline and betaine and decrease dimethylglycine (DMG). We conducted a secondary analysis of the Folic Acid and Creatine Trial, a randomized trial in arsenic-exposed Bangladeshi adults (n = 605, aged 24-55 y, 50.3% male) who received arsenic-removal water filters. We examined treatment effects of FA and/or creatine supplementation on plasma choline, betaine, and DMG concentrations, measured by LC-tandem mass spectrometry at baseline and at week 12. Group comparisons were between 1) 400 and 800 μg FA/d (FA400 and FA800, respectively) compared with placebo, 2) creatine (3 g/d) compared with placebo, and 3) creatine plus FA400 compared with FA400. Choline decreased in the placebo group (-6.6%; 95% CI: -10.2%, -2.9%) but did not change in the FA groups (FA400: 2.5%; 95% CI: -0.9%, 6.1%; FA800: 1.4%; 95% CI: -2.5%, 5.5%; P < 0.05). Betaine did not change in the placebo group (-3.5%; 95% CI: -9.3%, 2.6%) but increased in the FA groups (FA400: 14.1%; 95% CI: 9.4%, 19.0%; FA800: 13.0%; 95% CI: 7.2%, 19.1%; P < 0.01). The decrease in DMG was greater in the FA groups (FA400: -26.7%; 95% CI: -30.9%, -22.2%; FA800: -27.8%; 95% CI: -31.8%, -23.4%) than in the placebo group (-12.3%; 95% CI: -18.1%, -6.2%; P < 0.01). The percentage change in choline, betaine, and DMG did not differ between creatine treatment arms and their respective reference groups. Supplementation for 12 wk with FA, but not creatine, increases plasma betaine, decreases plasma DMG, and prevents a decrease in plasma choline in arsenic-exposed Bangladeshi adults. This trial was registered at clinicaltrials.gov as NCT01050556. © 2016 American Society for Nutrition.

Supplementation with Folic Acid, but Not Creatine, Increases Plasma Betaine, Decreases Plasma Dimethylglycine, and Prevents a Decrease in Plasma Choline in Arsenic-Exposed Bangladeshi Adults123

PubMed Central

Hall, Megan N; Liu, Xinhua; Caudill, Marie A; Malysheva, Olga; Ilievski, Vesna; Lomax-Luu, Angela M; Parvez, Faruque; Siddique, Abu B; Shahriar, Hasan; Uddin, Mohammad N; Islam, Tariqul; Graziano, Joseph H; Gamble, Mary V

2016-01-01

Background: Folic acid (FA) supplementation facilitates urinary excretion of arsenic, a human carcinogen. A better understanding of interactions between one-carbon metabolism intermediates may improve the ability to design nutrition interventions that further facilitate arsenic excretion. Objective: The objective was to determine if FA and/or creatine supplementation increase choline and betaine and decrease dimethylglycine (DMG). Methods: We conducted a secondary analysis of the Folic Acid and Creatine Trial, a randomized trial in arsenic-exposed Bangladeshi adults (n = 605, aged 24–55 y, 50.3% male) who received arsenic-removal water filters. We examined treatment effects of FA and/or creatine supplementation on plasma choline, betaine, and DMG concentrations, measured by LC–tandem mass spectrometry at baseline and at week 12. Group comparisons were between 1) 400 and 800 μg FA/d (FA400 and FA800, respectively) compared with placebo, 2) creatine (3 g/d) compared with placebo, and 3) creatine plus FA400 compared with FA400. Results: Choline decreased in the placebo group (−6.6%; 95% CI: −10.2%, −2.9%) but did not change in the FA groups (FA400: 2.5%; 95% CI: −0.9%, 6.1%; FA800: 1.4%; 95% CI: −2.5%, 5.5%; P < 0.05). Betaine did not change in the placebo group (−3.5%; 95% CI: −9.3%, 2.6%) but increased in the FA groups (FA400: 14.1%; 95% CI: 9.4%, 19.0%; FA800: 13.0%; 95% CI: 7.2%, 19.1%; P < 0.01). The decrease in DMG was greater in the FA groups (FA400: −26.7%; 95% CI: −30.9%, −22.2%; FA800: −27.8%; 95% CI: −31.8%, −23.4%) than in the placebo group (−12.3%; 95% CI: −18.1%, −6.2%; P < 0.01). The percentage change in choline, betaine, and DMG did not differ between creatine treatment arms and their respective reference groups. Conclusion: Supplementation for 12 wk with FA, but not creatine, increases plasma betaine, decreases plasma DMG, and prevents a decrease in plasma choline in arsenic-exposed Bangladeshi adults. This trial was registered at clinicaltrials.gov as NCT01050556. PMID:27052531

Fatty acid patterns of dog erythrocyte membranes after feeding of a fish-oil based DHA-rich supplement with a base diet low in n-3 fatty acids versus a diet containing added n-3 fatty acids.

PubMed

Stoeckel, Katja; Nielsen, Leif Højvang; Fuhrmann, Herbert; Bachmann, Lisa

2011-10-24

In dogs, increasing the tissue n-3 fatty acid (FA) content is associated with potential benefit in some medical conditions, e.g. atopic dermatitis, cancer or heart disease. Therefore effectively and conveniently increasing tissue n-3 FA levels in dogs is of interest. Incorporation of dietary n-3 FA into cell membranes may be studied by FA analysis of erythrocyte membranes (EM), because of the correlation of its FA composition with the FA composition of other cells. Aim of the study was to determine whether an n-3 FA additive added to a control diet is as effective in increasing EM n-3 FA content as feeding an n-3 FA enriched diet. Furthermore the time course of the incorporation of dietary n-3 FA into canine EM was investigated. Thirty dogs were randomly divided into three dietary groups with ten dogs per group. CONT got a dry dog food diet which did not contain EPA or DHA. FO got a dry dog food diet with a high EPA and DHA content. ADD got the CONT diet combined with an n-3 FA additive rich in DHA and EPA. After a feeding period of 12 weeks the additive was discontinued in ADD and these dogs were fed CONT diet for another four weeks to observe washout effects. Erythrocyte lipids were extracted from venous blood samples and their FA composition was determined by gas chromatography. The Mann-Whitney-U-test was used to detect significant differences between the different groups and time points. After one week the proportions of n-3 FA, DHA and EPA were already significantly increased in ADD and FO, apparently reaching a plateau within eight weeks. In our study DHA and not EPA was preferably incorporated into the EM. After discontinuing the administration of the additive in ADD, the n-3 FA values declined slowly without reaching baseline levels within four weeks. In dogs, an increase of dietary n-3 FA content leads to a rapid inclusion of n-3 FA into EM, regardless of whether the n-3 FA are offered as an enriched diet or as a normal diet supplemented with an n-3 FA additive.

Fatty acid patterns of dog erythrocyte membranes after feeding of a fish-oil based DHA-rich supplement with a base diet low in n-3 fatty acids versus a diet containing added n-3 fatty acids

PubMed Central

2011-01-01

Background In dogs, increasing the tissue n-3 fatty acid (FA) content is associated with potential benefit in some medical conditions, e.g. atopic dermatitis, cancer or heart disease. Therefore effectively and conveniently increasing tissue n-3 FA levels in dogs is of interest. Incorporation of dietary n-3 FA into cell membranes may be studied by FA analysis of erythrocyte membranes (EM), because of the correlation of its FA composition with the FA composition of other cells. Aim of the study was to determine whether an n-3 FA additive added to a control diet is as effective in increasing EM n-3 FA content as feeding an n-3 FA enriched diet. Furthermore the time course of the incorporation of dietary n-3 FA into canine EM was investigated. Methods Thirty dogs were randomly divided into three dietary groups with ten dogs per group. CONT got a dry dog food diet which did not contain EPA or DHA. FO got a dry dog food diet with a high EPA and DHA content. ADD got the CONT diet combined with an n-3 FA additive rich in DHA and EPA. After a feeding period of 12 weeks the additive was discontinued in ADD and these dogs were fed CONT diet for another four weeks to observe washout effects. Erythrocyte lipids were extracted from venous blood samples and their FA composition was determined by gas chromatography. The Mann-Whitney-U-test was used to detect significant differences between the different groups and time points. Results After one week the proportions of n-3 FA, DHA and EPA were already significantly increased in ADD and FO, apparently reaching a plateau within eight weeks. In our study DHA and not EPA was preferably incorporated into the EM. After discontinuing the administration of the additive in ADD, the n-3 FA values declined slowly without reaching baseline levels within four weeks. Conclusions In dogs, an increase of dietary n-3 FA content leads to a rapid inclusion of n-3 FA into EM, regardless of whether the n-3 FA are offered as an enriched diet or as a normal diet supplemented with an n-3 FA additive. PMID:22024384

Regulation of L-ascorbic acid content in strawberry fruits

PubMed Central

Cruz-Rus, Eduardo; Amaya, Iraida; Sánchez-Sevilla, José F.; Botella, Miguel A.; Valpuesta, Victoriano

2011-01-01

Plants have several L-ascorbic acid (AsA) biosynthetic pathways, but the contribution of each one to the synthesis of AsA varyies between different species, organs, and developmental stages. Strawberry (Fragaria×ananassa) fruits are rich in AsA. The pathway that uses D-galacturonate as the initial substrate is functional in ripe fruits, but the contribution of other pathways to AsA biosynthesis has not been studied. The transcription of genes encoding biosynthetic enzymes such as D-galacturonate reductase (FaGalUR) and myo-inositol oxygenase (FaMIOX), and the AsA recycling enzyme monodehydroascorbate reductase (FaMDHAR) were positively correlated with the increase in AsA during fruit ripening. Fruit storage for 72 h in a cold room reduced the AsA content by 30%. Under an ozone atmosphere, this reduction was 15%. Ozone treatment increased the expression of the FaGalUR, FaMIOX, and L-galactose-1-phosphate phosphatase (FaGIPP) genes, and transcription of the L-galactono-1,4-lactone dehydrogenase (FaGLDH) and FAMDHAR genes was higher in the ozone-stored than in the air-stored fruits. Analysis of AsA content in a segregating population from two strawberry cultivars showed high variability, which did not correlate with the transcription of any of the genes studied. Study of GalUR protein in diverse cultivars of strawberry and different Fragaria species showed that a correlation between GalUR and AsA content was apparent in most cases, but it was not general. Three alleles were identified in strawberry, but any sequence effect on the AsA variability was eliminated by analysis of the allele-specific expression. Taken together, these results indicate that FaGalUR shares the control of AsA levels with other enzymes and regulatory elements in strawberry fruit. PMID:21561953

Building integrated semi-transparent photovoltaics: energy and daylighting performance

NASA Astrophysics Data System (ADS)

Kapsis, Konstantinos; Athienitis, Andreas K.

2011-08-01

This paper focuses on modeling and evaluation of semi-transparent photovoltaic technologies integrated into a coolingdominated office building façade by employing the concept of three-section façade. An energy simulation model is developed, using building simulation software, to investigate the effect of semi-transparent photovoltaic transmittance on the energy performance of an office in a typical office building in Montreal. The analysis is performed for five major façade orientations and two façade configurations. Using semi-transparent photovoltaic integrated into the office façade, electricity savings of up to 53.1% can be achieved compared to a typical office equipped with double glazing with Argon filling and a low emissivity coating, and lighting controlled based on occupancy and daylight levels.e.c

p38 MAPK inhibition suppresses the TLR-hypersensitive phenotype in FANCC- and FANCA-deficient mononuclear phagocytes

PubMed Central

Anur, Praveen; Yates, Jane; Garbati, Michael R.; Vanderwerf, Scott; Keeble, Winifred; Rathbun, Keaney; Hays, Laura E.; Tyner, Jeffrey W.; Svahn, Johanna; Cappelli, Enrico; Dufour, Carlo

2012-01-01

Fanconi anemia, complementation group C (FANCC)–deficient hematopoietic stem and progenitor cells are hypersensitive to a variety of inhibitory cytokines, one of which, TNFα, can induce BM failure and clonal evolution in Fancc-deficient mice. FANCC-deficient macrophages are also hypersensitive to TLR activation and produce TNFα in an unrestrained fashion. Reasoning that suppression of inhibitory cytokine production might enhance hematopoiesis, we screened small molecules using TLR agonist–stimulated FANCC- and Fanconi anemia, complementation group A (FANCA)–deficient macrophages containing an NF-κB/AP-1–responsive reporter gene (SEAP). Of the 75 small molecules screened, the p38 MAPK inhibitor BIRB 796 and dasatinib potently suppressed TLR8-dependent expression of the reporter gene. Fanconi anemia (FA) macrophages were hypersensitive to the TLR7/8 activator R848, overproducing SEAP and TNFα in response to all doses of the agonist. Low doses (50nM) of both agents inhibited p38 MAPK–dependent activation of MAPKAPK2 (MK2) and suppressed MK2-dependent TNFα production without substantially influencing TNFα gene transcription. Overproduction of TNFα by primary FA cells was likewise suppressed by these agents and involved inhibition of MK2 activation. Because MK2 is also known to influence production and/or sensitivity to 2 other suppressive factors (MIP-1α and IFNγ) to which FA hematopoietic progenitor cells are uniquely vulnerable, targeting of p38 MAPK in FA hematopoietic cells is a rational objective for preclinical evaluation. PMID:22234699

p38 MAPK inhibition suppresses the TLR-hypersensitive phenotype in FANCC- and FANCA-deficient mononuclear phagocytes.

PubMed

Anur, Praveen; Yates, Jane; Garbati, Michael R; Vanderwerf, Scott; Keeble, Winifred; Rathbun, Keaney; Hays, Laura E; Tyner, Jeffrey W; Svahn, Johanna; Cappelli, Enrico; Dufour, Carlo; Bagby, Grover C

2012-03-01

Fanconi anemia, complementation group C (FANCC)-deficient hematopoietic stem and progenitor cells are hypersensitive to a variety of inhibitory cytokines, one of which, TNFα, can induce BM failure and clonal evolution in Fancc-deficient mice. FANCC-deficient macrophages are also hypersensitive to TLR activation and produce TNFα in an unrestrained fashion. Reasoning that suppression of inhibitory cytokine production might enhance hematopoiesis, we screened small molecules using TLR agonist-stimulated FANCC- and Fanconi anemia, complementation group A (FANCA)-deficient macrophages containing an NF-κB/AP-1-responsive reporter gene (SEAP). Of the 75 small molecules screened, the p38 MAPK inhibitor BIRB 796 and dasatinib potently suppressed TLR8-dependent expression of the reporter gene. Fanconi anemia (FA) macrophages were hypersensitive to the TLR7/8 activator R848, overproducing SEAP and TNFα in response to all doses of the agonist. Low doses (50nM) of both agents inhibited p38 MAPK-dependent activation of MAPKAPK2 (MK2) and suppressed MK2-dependent TNFα production without substantially influencing TNFα gene transcription. Overproduction of TNFα by primary FA cells was likewise suppressed by these agents and involved inhibition of MK2 activation. Because MK2 is also known to influence production and/or sensitivity to 2 other suppressive factors (MIP-1α and IFNγ) to which FA hematopoietic progenitor cells are uniquely vulnerable, targeting of p38 MAPK in FA hematopoietic cells is a rational objective for preclinical evaluation.

Human Fanconi anemia monoubiquitination pathway promotes homologous DNA repair

PubMed Central

Nakanishi, Koji; Yang, Yun-Gui; Pierce, Andrew J.; Taniguchi, Toshiyasu; Digweed, Martin; D'Andrea, Alan D.; Wang, Zhao-Qi; Jasin, Maria

2005-01-01

Fanconi anemia (FA) is a recessive disorder characterized by congenital abnormalities, progressive bone-marrow failure, and cancer susceptibility. Cells from FA patients are hypersensitive to agents that produce DNA crosslinks and, after treatment with these agents, have pronounced chromosome breakage and other cytogenetic abnormalities. Eight FANC genes have been cloned, and the encoded proteins interact in a common cellular pathway. DNA-damaging agents activate the monoubiquitination of FANCD2, resulting in its targeting to nuclear foci that also contain BRCA1 and BRCA2/FANCD1, proteins involved in homology-directed DNA repair. Given the interaction of the FANC proteins with BRCA1 and BRCA2, we tested whether cells from FA patients (groups A, G, and D2) and mouse Fanca–/– cells with a targeted mutation are impaired for this repair pathway. We find that both the upstream (FANCA and FANCG) and downstream (FANCD2) FA pathway components promote homology-directed repair of chromosomal double-strand breaks (DSBs). The FANCD2 monoubiquitination site is critical for normal levels of repair, whereas the ATM phosphorylation site is not. The defect in these cells, however, is mild, differentiating them from BRCA1 and BRCA2 mutant cells. Surprisingly, we provide evidence that these proteins, like BRCA1 but unlike BRCA2, promote a second DSB repair pathway involving homology, i.e., single-strand annealing. These results suggest an early role for the FANC proteins in homologous DSB repair pathway choice. PMID:15650050

Human Fanconi anemia monoubiquitination pathway promotes homologous DNA repair.

PubMed

Nakanishi, Koji; Yang, Yun-Gui; Pierce, Andrew J; Taniguchi, Toshiyasu; Digweed, Martin; D'Andrea, Alan D; Wang, Zhao-Qi; Jasin, Maria

2005-01-25

Fanconi anemia (FA) is a recessive disorder characterized by congenital abnormalities, progressive bone-marrow failure, and cancer susceptibility. Cells from FA patients are hypersensitive to agents that produce DNA crosslinks and, after treatment with these agents, have pronounced chromosome breakage and other cytogenetic abnormalities. Eight FANC genes have been cloned, and the encoded proteins interact in a common cellular pathway. DNA-damaging agents activate the monoubiquitination of FANCD2, resulting in its targeting to nuclear foci that also contain BRCA1 and BRCA2/FANCD1, proteins involved in homology-directed DNA repair. Given the interaction of the FANC proteins with BRCA1 and BRCA2, we tested whether cells from FA patients (groups A, G, and D2) and mouse Fanca-/- cells with a targeted mutation are impaired for this repair pathway. We find that both the upstream (FANCA and FANCG) and downstream (FANCD2) FA pathway components promote homology-directed repair of chromosomal double-strand breaks (DSBs). The FANCD2 monoubiquitination site is critical for normal levels of repair, whereas the ATM phosphorylation site is not. The defect in these cells, however, is mild, differentiating them from BRCA1 and BRCA2 mutant cells. Surprisingly, we provide evidence that these proteins, like BRCA1 but unlike BRCA2, promote a second DSB repair pathway involving homology, i.e., single-strand annealing. These results suggest an early role for the FANC proteins in homologous DSB repair pathway choice.

Patterns of adaptation to children's food allergies.

PubMed

Fedele, D A; McQuaid, E L; Faino, A; Strand, M; Cohen, S; Robinson, J; Atkins, D; Hourihane, J O'B; Klinnert, M D

2016-04-01

Families with food allergy (FA) are at risk of reduced quality of life and elevated anxiety. A moderate level of anxiety may be beneficial to sustain vigilance for food avoidance; however, excessive anxiety may increase risk for burden and maladjustment. The current study presents a framework for understanding the patterns of adaptation to FA across families and to identify typologies of families that would benefit from intervention. Participants included 57 children, 6-12 years old with documented FA, and their mothers. Families were assessed using the Food Allergy Management and Adaptation Scale. Families also completed measures of quality of life, anxiety, FA management, and psychosocial impairment. A hierarchical cluster analysis revealed that 56 of the 57 families of food-allergic children were categorized into four groups that differed on their adequacy of family FA management, levels of anxiety, and balanced psychosocial functioning: balanced responders (n = 23; 41%), high responders (n = 25; 45%), and low responders (n = 3; 5%). The fourth group, anxious high responders (n = 5; 9%), was characterized by extremely high maternal FA anxiety scores and low scores for balanced integration of FA management and psychosocial functioning. Families in clusters differed across illness and psychosocial outcome variables. Families with FA were characterized by patterns of FA management, anxiety, and ability to integrate FA demands into daily life. Identified adaptation patterns correspond with clinical impressions and provide a framework for identifying families in need of intervention. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Fluorescence analysis of humic and fulvic acids from two Brazilian oxisols as affected by biosolid amendment.

PubMed

Bertoncini, E I; D'Orazio, V; Senesi, N; Mattiazzo, M E

2005-03-01

Conventional monodimensional fluorescence spectroscopy in the emission, excitation, and synchronous-scan modes and total luminescence spectroscopy have proven to be sensitive techniques for characterization and differentiation of humic acid (HA) and fulvic acid (FA) fractions isolated from an aerobically and anaerobically digested and limed biosolid, two layers of a sandy and a clayey Brazilian oxisol, and the corresponding biosolid-amended soils. The spectral patterns and the relative fluorescence intensities suggest greater molecular heterogeneity, less aromatic polycondensation, and less humification of biosolid HA and FA compared with soil HA and FA. However, the differences are smaller for the FA fractions than for the HA fractions. Fluorescence properties of soil HA and FA differ slightly as a function of soil type and soil layer. Biosolid application causes a shift to shorter wavelengths of the main fluorescence peaks and marked variation of the relative fluorescence intensities of HA and FA isolated from amended soils. These results suggest that molecular components of relatively small molecular size, with a low level of aromatic polycondensation, and low degree of humification present in biosolid HA and FA are partially and variously incorporated into amended soil HA and FA. In general, these modifications seem to be smaller in HA and FA from the clayey soil layers than in those from the sandy soil layers, possibly because of protective effects exerted by clay minerals of native soil HA and FA against disturbances caused by biosolid application.

A leu-rich repeat receptor-like protein kinase, FaRIPK1, interacts with the ABA receptor, FaABAR, to regulate fruit ripening in strawberry.

PubMed

Hou, Bing-Zhu; Xu, Cheng; Shen, Yuan-Yue

2018-03-24

Strawberry (Fragaria×ananassa) is a model plant for studying non-climacteric fruit ripening regulated by abscisic acid (ABA); however, its exact molecular mechanisms are yet not fully understood. In this study, a predicted leu-rich repeat (LRR) receptor-like kinase in strawberry, red-initial protein kinase 1 (FaRIPK1), was screened and, using a yeast two-hybrid assay, was shown to interact with a putative ABA receptor, FaABAR. This association was confirmed by bimolecular fluorescence complementation and co-immunoprecipitation assays, and shown to occur in the nucleus. Expression analysis by real-time PCR showed that FaRIPK1 is expressed in roots, stems, leaves, flowers, and fruit, with a particularly high expression in white fruit at the onset of coloration. Down-regulation of FaRIPK1 expression in strawberry fruit, using Tobacco rattle virus-induced gene silencing, inhibited ripening, as evidenced by suppression of ripening-related physiological changes and reduced expression of several genes involved in softening, sugar content, pigmentation, and ABA biosynthesis and signaling. The yeast-expressed LRR and STK (serine/threonine protein kinase) domains of FaRIPK1 bound ABA and showed kinase activity, respectively. A fruit disc-incubation test revealed that FaRIPK1 expression was induced by ABA and ethylene. The synergistic action of FaRIPK1 with FaABAR in regulation of strawberry fruit ripening is discussed.

Comparing the performance of FA, DFA and DMA using different synthetic long-range correlated time series

PubMed Central

Shao, Ying-Hui; Gu, Gao-Feng; Jiang, Zhi-Qiang; Zhou, Wei-Xing; Sornette, Didier

2012-01-01

Notwithstanding the significant efforts to develop estimators of long-range correlations (LRC) and to compare their performance, no clear consensus exists on what is the best method and under which conditions. In addition, synthetic tests suggest that the performance of LRC estimators varies when using different generators of LRC time series. Here, we compare the performances of four estimators [Fluctuation Analysis (FA), Detrended Fluctuation Analysis (DFA), Backward Detrending Moving Average (BDMA), and Centred Detrending Moving Average (CDMA)]. We use three different generators [Fractional Gaussian Noises, and two ways of generating Fractional Brownian Motions]. We find that CDMA has the best performance and DFA is only slightly worse in some situations, while FA performs the worst. In addition, CDMA and DFA are less sensitive to the scaling range than FA. Hence, CDMA and DFA remain “The Methods of Choice” in determining the Hurst index of time series. PMID:23150785

Surface-coated fly ash used as filler in biodegradable poly(vinyl alcohol) composite films: Part 1—The modification process

NASA Astrophysics Data System (ADS)

Nath, D. C. D.; Bandyopadhyay, S.; Gupta, S.; Yu, A.; Blackburn, D.; White, C.

2010-02-01

The surfaces of fly ash (FA) particles were modified by surfactant, sodium lauryl sulphate (SLS) and used in fabrication of composite films with polyvinyl alcohol (PVA). Both unmodified fly ash (FA) and modified fly ash (SLS-FA) samples were examined using a range of analytical tools including X-ray fluorescence spectroscopy (XRF), scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared (FTIR) and X-ray photoelectron spectroscopy (XPS). The distribution patterns of SLS-FA particles were shifted to the higher regions compared to FA by adding 1.2-4.2 μm in the ranges between 2 and 25 μm, whereas the modification process reduced the size of the particles over 25 μm due to grinding during the activation process. The increased 1.2-4.2 μm in average can be considered the thickness of the surfactant on the SLS-FA surface. On the oxides based chemical analysis by XRF, the compositions were almost unchanged. SEM and TEM were visualised the irregular sizes morphology mostly spherical of the particles, although it is impossible to capture the images of exactly same particles in modified and unmodified forms. The composite films reinforced with SLS-FA showed 33% higher strength than those of FA filled films. The enhancement of tensile strength attributed from the level of physical bonding between SLS-FA and PVA surfaces.

Microarray mRNA expression analysis of Fanconi anemia fibroblasts.

PubMed

Galetzka, D; Weis, E; Rittner, G; Schindler, D; Haaf, T

2008-01-01

Fanconi anemia (FA) cells are generally hypersensitive to DNA cross-linking agents, implying that mutations in the different FANC genes cause a similar DNA repair defect(s). By using a customized cDNA microarray chip for DNA repair- and cell cycle-associated genes, we identified three genes, cathepsin B (CTSB), glutaredoxin (GLRX), and polo-like kinase 2 (PLK2), that were misregulated in untreated primary fibroblasts from three unrelated FA-D2 patients, compared to six controls. Quantitative real-time RT PCR was used to validate these results and to study possible molecular links between FA-D2 and other FA subtypes. GLRX was misregulated to opposite directions in a variety of different FA subtypes. Increased CTSB and decreased PLK2 expression was found in all or almost all of the analyzed complementation groups and, therefore, may be related to the defective FA pathway. Transcriptional upregulation of the CTSB proteinase appears to be a secondary phenomenon due to proliferation differences between FA and normal fibroblast cultures. In contrast, PLK2 is known to play a pivotal role in processes that are linked to FA defects and may contribute in multiple ways to the FA phenotype: PLK2 is a target gene for TP53, is likely to function as a tumor suppressor gene in hematologic neoplasia, and Plk2(-/-) mice are small because of defective embryonal development. (c) 2008 S. Karger AG, Basel.

Quantification of Forecasting and Change-Point Detection Methods for Predictive Maintenance

DTIC Science & Technology

2015-08-19

industries to manage the service life of equipment, and also to detect precursors to the failure of components found in nuclear power plants, wind turbines ...detection methods for predictive maintenance 5a. CONTRACT NUMBER FA2386-14-1-4096 5b. GRANT NUMBER Grant 14IOA015 AOARD-144096 5c. PROGRAM ELEMENT...sensitive to changes related to abnormality. 15. SUBJECT TERMS predictive maintenance , predictive maintenance , forecasting 16

Use of a Tier 3 Evidence-Based Intervention with Progress Monitoring, Formative Assessment, and Student Goal-Setting: An Evaluation of the Immediate and Long-Term Effects on Student Reading Achievement

ERIC Educational Resources Information Center

McMasters, Angela B.

2011-01-01

Early identification and intervention for students at risk for reading failure is essential to establish the foundational skills necessary for students to become skilled readers. The focus on evidence-based practices and data-driven decision making leads educators to consider additional instructional approaches, such as formative assessment (FA)…

Multiple constitutional aetiological factors in bone marrow failure syndrome (BMFS) patients from north India.

PubMed

Varma, Neelam; Varma, Subhash; Marwaha, Ram Kumar; Malhotra, Pankaj; Bansal, Deepak; Malik, Kiran; Kaur, Sukhdeep; Garewal, Gurjeevan

2006-07-01

A large number of patients diagnosed with bone marrow failure syndromes (BMFS), comprising aplastic anaemia (AA) and myelodysplastic syndromes (MDS), remain aetiologically uncharacterized worldover, especially in resource constrained set up. We carried out this study to identify a few constitutional causes in BMFS patients attending a tertiary care hospital in north India. Peripheral blood lymphocyte cultures were performed (with and without clastogens) in a cohort of 135 consecutive BMFS patients, in order to detect Fanconi anaemia (FA), Down's syndrome (+21), trisomy 8 (+8) and monosomy 7 (-7). Constitutional factors were detected in 17 (12.6%) patients. FA defect was observed in 24.07 percent (13/54), 16.66 percent (1/6) and 2.85 percent (1/35) paediatric aplastic anaemia, paediatric MDS and adult MDS patients respectively. Down's syndrome was detected in 5.00 percent (2/40) adult aplastic anaemia patients. None of the patients revealed trisomy 8 or monosomy 7. Presence of an underlying factor determines appropriate management, prognostication, family screening and genetic counselling of BMFS patients. Special tests required to confirm or exclude constitutional aetiological factors are not available to majority of the patients in our country. Diepoxybutane (DEB) test yielded better results than mitomycin C (MMC) test in our experience.

Recycled asphalt pavement - fly ash geopolymers as a sustainable pavement base material: Strength and toxic leaching investigations.

PubMed

Hoy, Menglim; Horpibulsuk, Suksun; Rachan, Runglawan; Chinkulkijniwat, Avirut; Arulrajah, Arul

2016-12-15

In this research, a low-carbon stabilization method was studied using Recycled Asphalt Pavement (RAP) and Fly Ash (FA) geopolymers as a sustainable pavement material. The liquid alkaline activator (L) is a mixture of sodium silicate (Na 2 SiO 3 ) and sodium hydroxide (NaOH), and high calcium FA is used as a precursor to synthesize the FA-RAP geopolymers. Unconfined Compressive Strength (UCS) of RAP-FA blend and RAP-FA geopolymer are investigated and compared with the requirement of the national road authorities of Thailand. The leachability of the heavy metals is measured by Toxicity Characteristic Leaching Procedure (TCLP) and compared with international standards. The Scanning Electron Microscopy (SEM) analysis of RAP-FA blend indicates the Calcium Aluminate (Silicate) Hydrate (C-A-S-H) formation, which is due to a reaction between the high calcium in RAP and high silica and alumina in FA. The low geopolymerization products (N-A-S-H) of RAP-FA geopolymer at NaOH/Na 2 SiO 3 =100:0 are detected at the early 7days of curing, hence its UCS is lower than that of RAP-FA blend. The 28-day UCS of RAP-FA geopolymers at various NaOH/Na 2 SiO 3 ratios are significantly higher than that of the RAP-FA blend, which can be attributed to the development of geopolymerization reactions. With the input of Na 2 SiO 3 , the highly soluble silica from Na 2 SiO 3 reacted with leached silica and alumina from FA and RAP and with free calcium from FA and RAP; hence the coexistence of N-A-S-H gel and C-A-S-H products. Therefore, the 7-day UCS values of RAP-FA geopolymers increase with decreasing NaOH/Na 2 SiO 3 ratio. TCLP results demonstrated that there is no environmental risk for both RAP-FA blends and RAP-FA geopolymers in road construction. The geopolymer binder reduces the leaching of heavy metal in RAP-FA mixture. The outcomes from this research will promote the move toward increased applications of recycled materials in a sustainable manner in road construction. Copyright © 2016 Elsevier B.V. All rights reserved.

Nitrogen-doped carbon quantum dots as a fluorescence probe combined with magnetic solid-phase extraction purification for analysis of folic acid in human serum.

PubMed

Wang, Meng; Jiao, Yang; Cheng, Chunsheng; Hua, Jianhao; Yang, Yaling

2017-12-01

A novel and sensitive method based on nitrogen-doped carbon quantum dots as a fluorescence probe coupled with magnetic solid-phase extraction (MSPE) purification for analysis of folic acid (FA) in human serum samples has been established for the first time. In the developed system, magnetic nanoparticles coated with hexanoic acid (Fe 3 O 4 @C 6 ) were synthesized by a one-step chemical co-precipitation method with good magnetic properties and dispersibility for sample purification, and it is better to be separated from the sample. High fluorescence nitrogen-doped carbon quantum dots (N-CQDs), simply prepared using a one-step hydrothermal method with nitrilotriacetic acid, could be selectively quenched by FA. Based on this phenomenon, a fluorescence assay was proposed for specific determination of FA. Various operational experiment parameters have been studied and optimized in detail. Under the optimum experimental conditions, the detection limit of the proposed method for FA was evaluated to be 0.5 nM (S/N = 3), while the relative standard deviation (RSD) was 1.2% (n = 6). Finally, the proposed method was applied for determination of trace levels of FA from human serum samples and quantitative recoveries were achieved within the range of 95.7-103.5%. All of the results showed that the proposed method had significant application in further research. Graphical abstract Schematic of synthesis of N-CQDs and schematic of suggested mode for analysis of folic acid (FA).

Droplet digital PCR analysis of NOTCH1 gene mutations in chronic lymphocytic leukemia.

PubMed

Minervini, Angela; Francesco Minervini, Crescenzio; Anelli, Luisa; Zagaria, Antonella; Casieri, Paola; Coccaro, Nicoletta; Cumbo, Cosimo; Tota, Giuseppina; Impera, Luciana; Orsini, Paola; Brunetti, Claudia; Giordano, Annamaria; Specchia, Giorgina; Albano, Francesco

2016-12-27

In chronic lymphocytic leukemia (CLL), NOTCH1 gene mutations (NOTCH1mut) have been associated with adverse prognostic features but the independence of these as a prognostic factor is still controversial. In our study we validated a c.7541-7542delCT NOTCH1 mutation assay based on droplet digital PCR (ddPCR); we also analyzed the NOTCH1mut allelic burden, expressed as fractional abundance (FA), in 88 CLL patients at diagnosis to assess its prognostic role and made a longitudinal ddPCR analysis in 10 cases harboring NOTCH1mut to verify the FA variation over time. Our data revealed that with the ddPCR approach the incidence of NOTCH1mut in CLL was much higher (53.4%) than expected. However, longitudinal ddPCR analysis of CLL cases showed a statistically significant reduction of the NOTCH1mut FA detected at diagnosis after treatment (median FA 11.67 % vs 0.09 %, respectively, p = 0.01); the same difference, in terms of NOTCH1mut FA, was observed in the relapsed cases compared to the NOTCH1mut allelic fraction observed in patients in complete or partial remission (median FA 4.75% vs 0.43%, respectively, p = 0.007). Our study demonstrated a much higher incidence of NOTCH1mut in CLL than has previously been reported, and showed that the NOTCH1mut allelic burden evaluation by ddPCR might identify patients in need of a closer clinical follow-up during the "watch and wait" interval and after standard chemotherapy.

Omega-3 fatty acids improve appetite in cancer anorexia, but tumor resecting restores it.

PubMed

Goncalves, Carolina G; Ramos, Eduardo J B; Romanova, Irina V; Suzuki, Susumu; Chen, Chung; Meguid, Michael M

2006-02-01

Tumor growth leads to cancer anorexia that is ameliorated using omega-3 fatty acids (omega-3FA). We hypothesize that omega-3FA modulates up-regulation of hypothalamic orexigenic neuropeptide Y (NPY) and down-regulation of anorexigenic alpha melanocyte-stimulating hormone (alpha-MSH) and serotonin 1B receptors (5-HT(1B)-receptors) in tumor-bearing rats. Twenty-eight tumor-bearing rats were fed either chow (TB-Control) or omega-3FA (TB-omega-3FA). When anorexia developed in TB-Control rats, they and a cohort of TB-omega-pi-3 rats were killed. The rest had their tumor resected (R-Control and R-omega-3FA), and when anorexic TB-Controls normalized their food intake, brains were removed for hypothalamic immunocytochemical study of NPY, alpha-MSH, and 5-HT(1B)-receptor antibodies concentrations. Comparison among slides were assessed by image analysis and analyzed by ANOVA and t test. At anorexia, hypothalamic NPY in arcuate nucleus (ARC) increased by 38% in TB-omega3FA versus TB-Control, whereas alpha-MSH decreased 64% in ARC and 29% in paraventricular nucleus (PVN). Omega-3FA diet in anorexia (TB-omega-3FA vs R-omega-3FA) produced similar qualitative changes of NPY (22% increase) and alpha-MSH (31% decrease) in ARC, with concomitant decrease of 37% in 5-HT(1B)-receptors in PVN, confirming the influence of omega-3FA on the hypothalamic food intake modulators. However, after tumor resection (TB-Control vs R-Control) a 97% increase in NPY and a 62% decrease in alpha-MSH occurred that was significantly greater than in rats fed omega-3FA diet. Tumor resection and omega-3FA modifies hypothalamic food intake activity, up-regulating NPY and down-regulating alpha-MSH and 5-HT(1B)-receptors. Tumor resection in anorexic rats on chow diet restored hypothalamic NPY, alpha-MSH, and food intake quantitatively more than in rats fed omega3FA diet.

FaStore - a space-saving solution for raw sequencing data.

PubMed

Roguski, Lukasz; Ochoa, Idoia; Hernaez, Mikel; Deorowicz, Sebastian

2018-03-29

The affordability of DNA sequencing has led to the generation of unprecedented volumes of raw sequencing data. These data must be stored, processed, and transmitted, which poses significant challenges. To facilitate this effort, we introduce FaStore, a specialized compressor for FASTQ files. FaStore does not use any reference sequences for compression, and permits the user to choose from several lossy modes to improve the overall compression ratio, depending on the specific needs. FaStore in the lossless mode achieves a significant improvement in compression ratio with respect to previously proposed algorithms. We perform an analysis on the effect that the different lossy modes have on variant calling, the most widely used application for clinical decision making, especially important in the era of precision medicine. We show that lossy compression can offer significant compression gains, while preserving the essential genomic information and without affecting the variant calling performance. FaStore can be downloaded from https://github.com/refresh-bio/FaStore. sebastian.deorowicz@polsl.pl. Supplementary data are available at Bioinformatics online.

Validation of the facial dysfunction domain of the Penn Acoustic Neuroma Quality-of-Life (PANQOL) Scale.

PubMed

Lodder, Wouter L; Adan, Guleed H; Chean, Chung S; Lesser, Tristram H; Leong, Samuel C

2017-06-01

The objective of this study is to evaluate the strength of content validity within the facial dysfunction domain of the Penn Acoustic Neuroma Quality-of-Life (PANQOL) Scale and to compare how it correlates with a facial dysfunction-specific QOL instrument (Facial Clinimetric Evaluation, FaCE). The study design is online questionnaire survey. Members of the British Acoustic Neuroma Association received both PANQOL questionnaires and the FaCE scale. 158 respondents with self-identified facial paralysis or dysfunction had completed PANQOL and FaCE data sets for analysis. The mean composite PANQOL score was 53.5 (range 19.2-93.5), whilst the mean total FaCE score was 50.9 (range 10-95). The total scores of the PANQOL and FaCE correlated moderate (r = 0.48). Strong correlation (r = 0.63) was observed between the PANQOL's facial dysfunction domain and the FaCE total score. Of all the FaCE domains, social function was strongly correlated with the PANQOL facial dysfunction domain (r = 0.66), whilst there was very weak-to-moderate correlation (range 0.01-0.43) to the other FaCE domains. The current study has demonstrated a strong correlation between the facial dysfunction domains of PANQOL with a facial paralysis-specific QOL instrument.

Effect of an Automated Training Presentation on Pre-Service Behavior Analysts' Implementation of Trial-Based Functional Analysis

ERIC Educational Resources Information Center

Lambert, Joseph M.; Lloyd, Blair P.; Staubitz, Johanna L.; Weaver, Emily S.; Jennings, Chelsea M.

2014-01-01

The trial-based functional analysis (FA) is a useful alternative to the traditional FA in contexts in which it is challenging to establish environmental control for extended periods of time. Previous researchers have demonstrated that others can be trained to conduct trial-based FAs with high procedural fidelity by providing a didactic…

Maximizing the Information and Validity of a Linear Composite in the Factor Analysis Model for Continuous Item Responses

ERIC Educational Resources Information Center

Ferrando, Pere J.

2008-01-01

This paper develops results and procedures for obtaining linear composites of factor scores that maximize: (a) test information, and (b) validity with respect to external variables in the multiple factor analysis (FA) model. I treat FA as a multidimensional item response theory model, and use Ackerman's multidimensional information approach based…

Partial Activation of SA- and JA-Defensive Pathways in Strawberry upon Colletotrichum acutatum Interaction.

PubMed

Amil-Ruiz, Francisco; Garrido-Gala, José; Gadea, José; Blanco-Portales, Rosario; Muñoz-Mérida, Antonio; Trelles, Oswaldo; de Los Santos, Berta; Arroyo, Francisco T; Aguado-Puig, Ana; Romero, Fernando; Mercado, José-Ángel; Pliego-Alfaro, Fernando; Muñoz-Blanco, Juan; Caballero, José L

2016-01-01

Understanding the nature of pathogen host interaction may help improve strawberry (Fragaria × ananassa) cultivars. Plant resistance to pathogenic agents usually operates through a complex network of defense mechanisms mediated by a diverse array of signaling molecules. In strawberry, resistance to a variety of pathogens has been reported to be mostly polygenic and quantitatively inherited, making it difficult to associate molecular markers with disease resistance genes. Colletotrichum acutatum spp. is a major strawberry pathogen, and completely resistant cultivars have not been reported. Moreover, strawberry defense network components and mechanisms remain largely unknown and poorly understood. Assessment of the strawberry response to C. acutatum included a global transcript analysis, and acidic hormones SA and JA measurements were analyzed after challenge with the pathogen. Induction of transcripts corresponding to the SA and JA signaling pathways and key genes controlling major steps within these defense pathways was detected. Accordingly, SA and JA accumulated in strawberry after infection. Contrastingly, induction of several important SA, JA, and oxidative stress-responsive defense genes, including FaPR1-1, FaLOX2, FaJAR1, FaPDF1, and FaGST1, was not detected, which suggests that specific branches in these defense pathways (those leading to FaPR1-2, FaPR2-1, FaPR2-2, FaAOS, FaPR5, and FaPR10) were activated. Our results reveal that specific aspects in SA and JA dependent signaling pathways are activated in strawberry upon interaction with C. acutatum. Certain described defense-associated transcripts related to these two known signaling pathways do not increase in abundance following infection. This finding suggests new insight into a specific putative molecular strategy for defense against this pathogen.

Reference values of whole-blood fatty acids by age and sex from European children aged 3-8 years.

PubMed

Wolters, M; Schlenz, H; Foraita, R; Galli, C; Risé, P; Moreno, L A; Molnár, D; Russo, P; Veidebaum, T; Tornaritis, M; Vyncke, K; Eiben, G; Iacoviello, L; Ahrens, W

2014-09-01

To establish reference values for fatty acids (FA) especially for n-3 and n-6 long-chain polyunsaturated FAs (LC PUFA) in whole-blood samples from apparently healthy 3-8-year-old European children. The whole-blood FA composition was analysed and the age- and sex-specific distribution of FA was determined. Blood samples for FA analysis were taken from 2661 children of the IDEFICS (identification and prevention of dietary- and lifestyle-induced health effects in children and infants) study cohort. Children with obesity (n=454) and other diseases that are known to alter the FA composition (n=450) were excluded leaving 1653 participants in the reference population. The FA composition of whole blood was analysed from blood drops by a rapid, validated gas chromatographic method. Pearson correlation coefficients showed an age-dependent increase of C18:2n-6 and a decrease of C18:1n-9 in a subsample of normal weight boys and girls. Other significant correlations with age were weak and only seen either in boys or in girls, whereas most of the FA did not show any age dependence. For age-dependent n-3 and n-6 PUFA as well as for other FA that are correlated with age (16:0, C18:0 and C18:1n-9) percentiles analysed with the general additive model for location scale and shape are presented. A higher median in boys than in girls was observed for C20:3n-6, C20:4n-6 and C22:4n-6. Given the reported associations between FA status and health-related outcome, the provision of FA reference ranges may be useful for the interpretation of the FA status of children in epidemiological and clinical studies.

Partial Activation of SA- and JA-Defensive Pathways in Strawberry upon Colletotrichum acutatum Interaction

PubMed Central

Amil-Ruiz, Francisco; Garrido-Gala, José; Gadea, José; Blanco-Portales, Rosario; Muñoz-Mérida, Antonio; Trelles, Oswaldo; de los Santos, Berta; Arroyo, Francisco T.; Aguado-Puig, Ana; Romero, Fernando; Mercado, José-Ángel; Pliego-Alfaro, Fernando; Muñoz-Blanco, Juan; Caballero, José L.

2016-01-01

Understanding the nature of pathogen host interaction may help improve strawberry (Fragaria × ananassa) cultivars. Plant resistance to pathogenic agents usually operates through a complex network of defense mechanisms mediated by a diverse array of signaling molecules. In strawberry, resistance to a variety of pathogens has been reported to be mostly polygenic and quantitatively inherited, making it difficult to associate molecular markers with disease resistance genes. Colletotrichum acutatum spp. is a major strawberry pathogen, and completely resistant cultivars have not been reported. Moreover, strawberry defense network components and mechanisms remain largely unknown and poorly understood. Assessment of the strawberry response to C. acutatum included a global transcript analysis, and acidic hormones SA and JA measurements were analyzed after challenge with the pathogen. Induction of transcripts corresponding to the SA and JA signaling pathways and key genes controlling major steps within these defense pathways was detected. Accordingly, SA and JA accumulated in strawberry after infection. Contrastingly, induction of several important SA, JA, and oxidative stress-responsive defense genes, including FaPR1-1, FaLOX2, FaJAR1, FaPDF1, and FaGST1, was not detected, which suggests that specific branches in these defense pathways (those leading to FaPR1-2, FaPR2-1, FaPR2-2, FaAOS, FaPR5, and FaPR10) were activated. Our results reveal that specific aspects in SA and JA dependent signaling pathways are activated in strawberry upon interaction with C. acutatum. Certain described defense-associated transcripts related to these two known signaling pathways do not increase in abundance following infection. This finding suggests new insight into a specific putative molecular strategy for defense against this pathogen. PMID:27471515

Diffusion tensor eigenvector directional color imaging patterns in the evaluation of cerebral white matter tracts altered by tumor.

PubMed

Field, Aaron S; Alexander, Andrew L; Wu, Yu-Chien; Hasan, Khader M; Witwer, Brian; Badie, Behnam

2004-10-01

To categorize the varied appearances of tumor-altered white matter (WM) tracts on diffusion tensor eigenvector directional color maps. Diffusion tensor imaging (DTI) was obtained preoperatively in 13 patients with brain tumors ranging from benign to high-grade malignant, including primary and metastatic lesions, and maps of apparent diffusion coefficient (ADC), fractional anisotropy (FA), and major eigenvector direction were generated. Regions of interest (ROIs) were drawn within identifiable WM tracts affected by tumor, avoiding grossly cystic and necrotic regions, known fiber crossings, and gray matter. Patterns of WM tract alteration were categorized on the basis of qualitative analysis of directional color maps and correlation analysis of ADC and FA. Four basic patterns of WM alteration were identified: 1) normal or nearly normal FA and ADC, with abnormal tract location or tensor directions attributable to bulk mass displacement, 2) moderately decreased FA and increased ADC with normal tract locations and tensor directions, 3) moderately decreased FA and increased ADC with abnormal tensor directions, and 4) near isotropy. FA and ADC were inversely correlated for Patterns 1-3 but did not discriminate edema from infiltrating tumor. However, in the absence of mass displacement, infiltrating tumor was found to produce tensor directional changes that were not observed with vasogenic edema, suggesting the possibility of discrimination on the basis of directional statistics. Tumor alteration of WM tracts tends to produce one of four patterns on FA and directional color maps. Clinical application of these patterns must await further study. Copyright 2004 Wiley-Liss, Inc.

Association of protein kinase FA/GSK-3alpha (a proline-directed kinase and a regulator of protooncogenes) with human cervical carcinoma dedifferentiation/progression.

PubMed

Yang, S D; Yu, J S; Lee, T T; Ni, M H; Yang, C C; Ho, Y S; Tsen, T Z

1995-10-01

Computer analysis of protein phosphorylation-sites sequence revealed that most transcriptional factors and viral oncoproteins are prime targets for regulation of proline-directed protein phosphorylation, suggesting an association of proline-directed protein kinase (PDPK) family with neoplastic transformation and tumorigenesis. In this report, an immunoprecipitate activity assay of protein kinase FA/glycogen synthase kinase-3alpha (kinase FA/GSK-3alpha) (a particular member of PDPK family) has been optimized for human cervical tissue and used to demonstrate for the first time significantly increased (P < 0.001) activity in poorly differentiated cervical carcinoma (82.8 +/- 6.6 U/mg of protein), moderately differentiated carcinoma (36.2 +/- 3.4 U/mg of protein), and well-differentiated carcinoma (18.3 +/- 2.4 U/mg of protein) from 36 human cervical carcinoma samples when compared to 12 normal controls (4.9 +/- 0.6 U/mg of protein). Immunoblotting analysis further revealed that increased activity of kinase FA/GSK-3alpha in cervical carcinoma is due to overexpression of protein synthesis of the kinase. Taken together, the results provide initial evidence that overexpression of protein synthesis and cellular activity of kinase FA/GSK-3alpha may be involved in human cervical carcinoma dedifferentiation/progression, supporting an association of proline-directed protein kinase with neoplastic transformation and tumorigenesis. Since protein kinase FA/GSK-3alpha may function as a possible regulator of transcription factors/proto-oncogenes, the results further suggest that kinase FA/GSK-3alpha may play a potential role in human cervical carcinogenesis, especially in its dedifferentiation and progression.

[Effect of exercise load on apparent diffusion coefficient and fractional anisotropy of normal lumbar intervertebral discs in diffusion tensor imaging].

PubMed

Zhong, Xiu; Qiu, Shijun

2015-06-01

To investigate the effect of exercise load on apparent diffusion coefficient (ADC) and fractional anisotropy (FA) of normal lumbar intervertebral discs in magnetic resonance (MR) diffusion tensor imaging (DTI). Thirty healthy volunteers (24 males and 6 females, aged 19 to 25 years) underwent examinations with MR T2WI and DTI of the lumbar intervertebral discs before and after exercise load. Pfirrmann grading was evaluated with T2WI, and the B0 map, ADC map and FA map were reconstructed based on the DTI data to investigate the changes in ADC and FA after exercise. Of the 30 volunteers (150 intervertebral discs) receiving the examination, 27 with discs of Pfirrminn grade II were included for analysis. In these 27 volunteers, the average ADC and FA before exercise were (1.99 ± 0.18)×10⁻³ mm²/s and 0.155∓0.059, respectively. After exercise, ADC was lowered significantly to (1.93 ± 0.17)×10⁻³ mm²/s (P<0.05) and FA increased slightly to 0.1623 ± 0.017 (P>0.05). DTI allows quantitatively analysis of the changes in water molecular diffusion and anisotropy of the lumbar intervertebral discs after exercise load, which can cause a decreased ADC and a increased FA value, and the change of ADC is more sensitive to exercise load.

Analysis of the Three-Dimensional Vector FAÇADE Model Created from Photogrammetric Data

NASA Astrophysics Data System (ADS)

Kamnev, I. S.; Seredovich, V. A.

2017-12-01

The results of the accuracy assessment analysis for creation of a three-dimensional vector model of building façade are described. In the framework of the analysis, analytical comparison of three-dimensional vector façade models created by photogrammetric and terrestrial laser scanning data has been done. The three-dimensional model built from TLS point clouds was taken as the reference one. In the course of the experiment, the three-dimensional model to be analyzed was superimposed on the reference one, the coordinates were measured and deviations between the same model points were determined. The accuracy estimation of the three-dimensional model obtained by using non-metric digital camera images was carried out. Identified façade surface areas with the maximum deviations were revealed.

The potassium channel FaTPK1 plays a critical role in fruit quality formation in strawberry (Fragaria × ananassa).

PubMed

Wang, Shufang; Song, Miaoyu; Guo, Jiaxuan; Huang, Yun; Zhang, Fangfang; Xu, Cheng; Xiao, Yinghui; Zhang, Lusheng

2018-03-01

Potassium (K + ), an abundant cation in plant cells, is important in fruit development and plant resistance. However, how cellular K + is directed by potassium channels in fruit development and quality formation of strawberry (Fragaria × ananassa) is not yet fully clear. Here, a two-pore K + (TPK) channel gene in strawberry, FaTPK1, was cloned using reverse transcription-PCR. A green fluorescent protein subcellular localization analysis showed that FaTPK1 localized in the vacuole membrane. A transcription analysis indicated that the mRNA expression level of FaTPK1 increased rapidly and was maintained at a high level in ripened fruit, which was coupled with the fruit's red colour development, suggesting that FaTPK1 is related to fruit quality formation. The down- and up-regulation of the FaTPK1 mRNA expression levels using RNA interference and overexpression, respectively, inhibited and promoted fruit ripening, respectively, as demonstrated by consistent changes in firmness and the contents of soluble sugars, anthocyanin and abscisic acid, as well as the transcript levels of ripening-regulated genes PG1 (polygalacturonase), GAL6 (beta-galactosidase), XYL2 (D-xylulose reductase), SUT1 (sucrose transporter), CHS (chalcone synthase) and CHI (chalcone flavanone isomerase). Additionally, the regulatory changes influenced fruit resistance to Botrytis cinerea. An isothermal calorimetry analysis showed that the Escherichia coli-expressed FaTPK1 recombinant protein could bind K + with a binding constant of 2.1 × 10 -3  m -1 and a dissociation constant of 476 μm. Thus, the strawberry TPK1 is a ubiquitously expressed, tonoplast-localized two-pore potassium channel that plays important roles in fruit ripening and quality formation. © 2017 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.

Biomedical applications of SPION@APTES@PEG-folic acid@carboxylated quercetin nanodrug on various cancer cells

NASA Astrophysics Data System (ADS)

Akal, Z. Ü.; Alpsoy, L.; Baykal, A.

2016-08-01

In this study, carboxylated quercetin (CQ) was conjugated to superparamagnetic iron oxide nanoparticles (SPIONs) which were modified by (3-aminopropyl) triethoxysilane (APTES), Folic acid (FA) and carboxylated Polyethylene glycol (PEG); (SPION@APTES@FA-PEG@CQ), nanodrug has been synthesized via polyol and accompanying by various chemical synthesis routes. The characterization of the final product was done via X-ray powder diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), Thermal gravimetric analysis (TGA), Transmission electron spectroscopy (TEM) and Vibrating sample magnetometer (VSM). Its cytotoxic and apoptotic activities on over expressed folic acid receptor (FR +) (MCF-7, HeLa) and none expressed folic acid receptor (FR-) (A549) cancer cell lines were determined by using MTT assay, Real-Time Cell Analysis, TUNEL assay, Annexin assay and RT-PCR analysis for Caspase3/7 respectively. SPION@APTES@FA-PEG@CQ nanodrug showed higher cytotoxicity against HeLa and MCF-7 cell lines as compared with A549 cell line. Moreover, SPION@APTES@FA-PEG@CQ nanodrug also caused higher apoptotic and necrotic effects in 100 μg/mL HeLa and MCF-7 cells than A549 cells. The findings showed that SPION@APTES@FA-PEG@CQ nanodrug has cytotoxic, apoptotic and necrotic effects on HeLa and MCF-7 which are FR over expressed cell lines and can be potentially used for the delivery of quercetin to cervical and breast cancer cells.

Antioxidant effects of Genkwa flos flavonoids on Freund׳s adjuvant-induced rheumatoid arthritis in rats.

PubMed

Zhang, Chun-Feng; Zhang, Su-Li; He, Xin; Yang, Xiao-Lin; Wu, Hai-Tao; Lin, Bao-Qin; Jiang, Cui-Ping; Wang, Jun; Yu, Chun-Hao; Yang, Zhong-Lin; Wang, Chong-Zhi; Li, Ping; Yuan, Chun-Su

2014-05-14

Genkwa flos (Daphne genkwa Sieb. et Zucc.), a Chinese herbal medicine, has been traditionally used for over two thousand years in China for inflammation related symptoms, including joint pain. To evaluate the antioxidative effects of flavonoid aglycones (FA) isolated from Genkwa flos on adjuvant arthritis in rats and to identify the relationship between antioxidant potential and whole blood viscosity (WBV). FA compounds were identified using LC-MS and the content was assayed by HPLC. Arthritis was induced by an intradermal injection of Freund׳s complete adjuvant in the footpad. The effects of FA on paw volumes, secondary arthritis scores, histopathology of joints, and body and organ weights were measured. The antioxidant effects of FA and WBV were determined. LC-MS analysis showed that the FA contained four major compounds: luteolin, apigenin, hydroxygenkwanin and genkwanin. FA significantly decreased paw edema, arthritis scores, and weight loss. These observations were consistent with the reduction of oxidative stress and the improvement of the WBV. FA significantly decreased arthritis in a rat model through antioxidant and hemorheological modulatory mechanisms. The Genkwa flos flavonoids may have clinical potential for the treatment of rheumatoid arthritis. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Relationships among the serum omega fatty acid levels, serum C-reactive protein levels and arterial stiffness/wave reflection in Japanese men.

PubMed

Tomiyama, Hirofumi; Matsumoto, Chisa; Odaira, Mari; Yamada, Jiko; Yoshida, Masanobu; Shiina, Kazuki; Nagata, Mikio; Yamashina, Akira

2011-08-01

We examined the relationship among the serum omega-3 and omega-6 fatty acid (O3FA and O6FA) levels, serum C-reactive protein (CRP) levels, and arterial stiffness/wave reflection (AS/WR) in healthy Japanese men. In 2206 Japanese healthy men, parameters related to the AS/WR (i.e., brachial-ankle pulse wave velocity and radial arterial pulse wave analysis) were measured. No significant inverse relationships were observed between the serum O3FA levels and the AS/WR-related parameters. Adjusted values of the AS/WR-related parameters and serum CRP levels were higher in the subjects with serum O6FA levels in the highest tertile than in those with serum O6FA levels in the lowest tertile. In healthy Japanese men with known high dietary intakes of O3FAs, the serum O3FA levels may not reflect the pathophysiological abnormalities related to AS/WR. Increased serum O6FA levels appeared to be independently associated with the unfavorable conditions related to AS/WR and inflammation. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Characterization of interaction between amino acids and fulvic-like organic matter by fluorescence spectroscopy combining thermodynamic calculation.

PubMed

Lin, Tao; Hou, Bingwei; Wang, Jian; Xu, Yaqun; Chen, Wei

2017-03-01

Dissolved organic matter (DOM), as a very fine colloidal suspension, could inevitably affect the transformation process of dissolved organic nitrogen (DON) in drinking water treatment. Tryptophan and tyrosine were used as representatives of DON to investigate the interactions between amino acids and fulvic-like components of fluorescent DOM using titration experiments. The fluorescence intensity decreased significantly with the increasing fulvic acid (FA) concentration, suggesting that FA could greatly quench the intrinsic fluorescence of amino acids such as tryptophan and tyrosine. The absolute spectrum peaks of amino acids (AA) were changed in the presence of FA, possibly being resulted from non-covalent interactions between amino acids and FA. The specific hydrogen bonding and van der Waals forces played dominant roles in the interactions according to the results of theoretical analysis and thermodynamic calculation. The distance between donor and acceptor was 1.25 and 1.14 nm for the FA-tyrosine and FA-tryptophan system, indicating the energy transfer from tyrosine or tryptophan to FA. The association constant (K) decreased with the increase of temperature and pH value, while the change of ionic strength had no obvious influence on K value.

Exploring JLA supernova data with improved flux-averaging technique

NASA Astrophysics Data System (ADS)

Wang, Shuang; Wen, Sixiang; Li, Miao

2017-03-01

In this work, we explore the cosmological consequences of the ``Joint Light-curve Analysis'' (JLA) supernova (SN) data by using an improved flux-averaging (FA) technique, in which only the type Ia supernovae (SNe Ia) at high redshift are flux-averaged. Adopting the criterion of figure of Merit (FoM) and considering six dark energy (DE) parameterizations, we search the best FA recipe that gives the tightest DE constraints in the (zcut, Δ z) plane, where zcut and Δ z are redshift cut-off and redshift interval of FA, respectively. Then, based on the best FA recipe obtained, we discuss the impacts of varying zcut and varying Δ z, revisit the evolution of SN color luminosity parameter β, and study the effects of adopting different FA recipe on parameter estimation. We find that: (1) The best FA recipe is (zcut = 0.6, Δ z=0.06), which is insensitive to a specific DE parameterization. (2) Flux-averaging JLA samples at zcut >= 0.4 will yield tighter DE constraints than the case without using FA. (3) Using FA can significantly reduce the redshift-evolution of β. (4) The best FA recipe favors a larger fractional matter density Ωm. In summary, we present an alternative method of dealing with JLA data, which can reduce the systematic uncertainties of SNe Ia and give the tighter DE constraints at the same time. Our method will be useful in the use of SNe Ia data for precision cosmology.

Doxorubicin-conjugated D-glucosamine- and folate- bi-functionalised InP/ZnS quantum dots for cancer cells imaging and therapy.

PubMed

Ranjbar-Navazi, Zahra; Eskandani, Morteza; Johari-Ahar, Mohammad; Nemati, Ali; Akbari, Hamid; Davaran, Soudabeh; Omidi, Yadollah

2018-03-01

Nanoscaled quantum dots (QDs), with unique optical properties have been used for the development of theranostics. Here, InP/ZnS QDs were synthesised and functionalised with folate (QD-FA), D-glucosamine (QD-GA) or both (QD-FA-GA). The bi-functionalised QDs were further conjugated with doxorubicin (QD-FA-GA-DOX). Optimum Indium to fatty acid (In:MA) ratio was 1:3.5. Transmission electron microscopy (TEM) micrographs revealed spherical morphology for the QDs (11 nm). Energy-dispersive spectroscopy (EDS) spectrum confirmed the chemical composition of the QDs. MTT analysis in the OVCAR-3 cells treated with bare QDs, QD-FA, QD-GA, QD-FA-GA and QD-FA-GA-DOX (0.2 mg/mL of QDs) after 24 h indicated low toxicity for the bare QDs and functionalised QDs (about 80-90% cell viability). QD-FA-GA-DOX nanoparticles elicited toxicity in the cells. Cellular uptake of the engineered QDs were investigated in both folate receptor (FR)-positive OVCAR-3 cells and FR-negative A549 cells using fluorescence microscopy and FACS flow cytometry. The FA-functionalised QDs showed significantly higher uptake in the FR-positive OVCAR-3 cells, nonetheless the GA-functionalised QDs resulted in an indiscriminate uptake in both cell lines. In conclusion, our findings indicated that DOX-conjugated FA-armed QDs can be used as theranostics for simultaneous imaging and therapy of cancer.

Eigenstructure Assignment for Fault Tolerant Flight Control Design

NASA Technical Reports Server (NTRS)

Sobel, Kenneth; Joshi, Suresh (Technical Monitor)

2002-01-01

In recent years, fault tolerant flight control systems have gained an increased interest for high performance military aircraft as well as civil aircraft. Fault tolerant control systems can be described as either active or passive. An active fault tolerant control system has to either reconfigure or adapt the controller in response to a failure. One approach is to reconfigure the controller based upon detection and identification of the failure. Another approach is to use direct adaptive control to adjust the controller without explicitly identifying the failure. In contrast, a passive fault tolerant control system uses a fixed controller which achieves acceptable performance for a presumed set of failures. We have obtained a passive fault tolerant flight control law for the F/A-18 aircraft which achieves acceptable handling qualities for a class of control surface failures. The class of failures includes the symmetric failure of any one control surface being stuck at its trim value. A comparison was made of an eigenstructure assignment gain designed for the unfailed aircraft with a fault tolerant multiobjective optimization gain. We have shown that time responses for the unfailed aircraft using the eigenstructure assignment gain and the fault tolerant gain are identical. Furthermore, the fault tolerant gain achieves MIL-F-8785C specifications for all failure conditions.

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

Lo, Chien -Chi; Chain, Patrick S. G.

Background: Next generation sequencing (NGS) technologies that parallelize the sequencing process and produce thousands to millions, or even hundreds of millions of sequences in a single sequencing run, have revolutionized genomic and genetic research. Because of the vagaries of any platform's sequencing chemistry, the experimental processing, machine failure, and so on, the quality of sequencing reads is never perfect, and often declines as the read is extended. These errors invariably affect downstream analysis/application and should therefore be identified early on to mitigate any unforeseen effects. Results: Here we present a novel FastQ Quality Control Software (FaQCs) that can rapidly processmore » large volumes of data, and which improves upon previous solutions to monitor the quality and remove poor quality data from sequencing runs. Both the speed of processing and the memory footprint of storing all required information have been optimized via algorithmic and parallel processing solutions. The trimmed output compared side-by-side with the original data is part of the automated PDF output. We show how this tool can help data analysis by providing a few examples, including an increased percentage of reads recruited to references, improved single nucleotide polymorphism identification as well as de novo sequence assembly metrics. Conclusion: FaQCs combines several features of currently available applications into a single, user-friendly process, and includes additional unique capabilities such as filtering the PhiX control sequences, conversion of FASTQ formats, and multi-threading. The original data and trimmed summaries are reported within a variety of graphics and reports, providing a simple way to do data quality control and assurance.« less

Comparisons of synthesized and individual reinforcement contingencies during functional analysis.

PubMed

Fisher, Wayne W; Greer, Brian D; Romani, Patrick W; Zangrillo, Amanda N; Owen, Todd M

2016-09-01

Researchers typically modify individual functional analysis (FA) conditions after results are inconclusive (Hanley, Iwata, & McCord, 2003). Hanley, Jin, Vanselow, and Hanratty (2014) introduced a marked departure from this practice, using an interview-informed synthesized contingency analysis (IISCA). In the test condition, they delivered multiple contingencies simultaneously (e.g., attention and escape) after each occurrence of problem behavior; in the control condition, they delivered those same reinforcers noncontingently and continuously. In the current investigation, we compared the results of the IISCA with a more traditional FA in which we evaluated each putative reinforcer individually. Four of 5 participants displayed destructive behavior that was sensitive to the individual contingencies evaluated in the traditional FA. By contrast, none of the participants showed a response pattern consistent with the assumption of the IISCA. We discuss the implications of these findings on the development of accurate and efficient functional analyses. © 2016 Society for the Experimental Analysis of Behavior.

Increased Expression of Fatty-Acid and Calcium Metabolism Genes in Failing Human Heart

PubMed Central

Rodríguez-Penas, Diego; Feijóo-Bandín, Sandra; Noguera-Moreno, Teresa; Calaza, Manuel; Álvarez-Barredo, María; Mosquera-Leal, Ana; Parrington, John; Brugada, Josep; Portolés, Manuel; Rivera, Miguel; González-Juanatey, José Ramón; Lago, Francisca

2012-01-01

Background Heart failure (HF) involves alterations in metabolism, but little is known about cardiomyopathy-(CM)-specific or diabetes-independent alterations in gene expression of proteins involved in fatty-acid (FA) uptake and oxidation or in calcium-(Ca2+)-handling in the human heart. Methods RT-qPCR was used to quantify mRNA expression and immunoblotting to confirm protein expression in left-ventricular myocardium from patients with HF (n = 36) without diabetes mellitus of ischaemic (ICM, n = 16) or dilated (DCM, n = 20) cardiomyopathy aetiology, and non-diseased donors (CTL, n = 6). Results Significant increases in mRNA of genes regulating FA uptake (CD36) and intracellular transport (Heart-FA-Binding Protein (HFABP)) were observed in HF patients vs CTL. Significance was maintained in DCM and confirmed at protein level, but not in ICM. mRNA was higher in DCM than ICM for peroxisome-proliferator-activated-receptor-alpha (PPARA), PPAR-gamma coactivator-1-alpha (PGC1A) and CD36, and confirmed at the protein level for PPARA and CD36. Transcript and protein expression of Ca2+-handling genes (Two-Pore-Channel 1 (TPCN1), Two-Pore-Channel 2 (TPCN2), and Inositol 1,4,5-triphosphate Receptor type-1 (IP3R1)) increased in HF patients relative to CTL. Increases remained significant for TPCN2 in all groups but for TPCN1 only in DCM. There were correlations between FA metabolism and Ca2+-handling genes expression. In ICM there were six correlations, all distinct from those found in CTL. In DCM there were also six (all also different from those found in CTL): three were common to and three distinct from ICM. Conclusion DCM-specific increases were found in expression of several genes that regulate FA metabolism, which might help in the design of aetiology-specific metabolic therapies in HF. Ca2+-handling genes TPCN1 and TPCN2 also showed increased expression in HF, while HF- and CM-specific positive correlations were found among several FA and Ca2+-handling genes. PMID:22701570

Folate conjugated Mn{sub 3}O{sub 4}@SiO{sub 2} nanoparticles for targeted magnetic resonance imaging in vivo

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

Yang, Xinyi; Zhou, Zhiguo, E-mail: zgzhou@shnu.edu.cn; Wang, Li

2014-09-15

Graphical abstract: The Mn{sub 3}O{sub 4}@SiO{sub 2}(PEG)–FA has been used as a T{sub 1}-MRI probe for in vivo. - Highlights: • The PEG and FA modified Mn{sub 3}O{sub 4}@SiO{sub 2} nanoparticles (Mn{sub 3}O{sub 4}@SiO{sub 2}–FA) were prepared. • Mn{sub 3}O{sub 4}@SiO{sub 2}–FA exhibited the good colloidal stability in the simulated biological medium. • Mn{sub 3}O{sub 4}@SiO{sub 2}–FA showed the targeting ability to HeLa cells overexpressed the FA receptor. • The T{sub 1}-weighted magnetic resonance (MR) imaging demonstrated the targeting ability of Mn{sub 3}O{sub 4}@SiO{sub 2}–FA in vivo tumor. - Abstract: The monodisperse silica-coated manganese oxide nanoparticles (Mn{sub 3}O{sub 4}@SiO{sub 2}more » NPs) were synthesized via the high temperature pyrolysis approach and were aminated through silanization. The amine-functionalized Mn{sub 3}O{sub 4} NPs enabled the covalent conjugation of hydrophilic methoxypoly(ethylene glycol) (PEG) and the targeting ligand of folate (FA) onto their surface. The formed PEG and FA modified Mn{sub 3}O{sub 4} NPs (Mn{sub 3}O{sub 4}@SiO{sub 2}(PEG)–FA) exhibited the good colloidal stability in the simulated biological medium and the targeting ability to HeLa cells overexpressed the FA receptor. The T{sub 1}-weighted magnetic resonance (MR) imaging and inductively coupled plasma atomic emission spectroscopy (ICP-AES) analysis of Mn{sub 3}O{sub 4}@SiO{sub 2}(PEG)–FA NPs further demonstrated their targeting ability in tumor.« less

Initial Technology Assessment for the Environmental Sentinel Biomonitor (ESB) System

DTIC Science & Technology

2006-08-01

McFarlane-Abdulla E, Andersson M, Barile FA, et al. 1996. MEIC evaluation of acute systemic toxicity Part II. In vitro results from 68 toxicity assays used...to test the first 30 reference chemicals and a comparative cytotoxicity analysis. A TLA 24:273-311. Clemedson C, Andersson M, Aoki Y, Barile FA, et al...Clemedson C, McFarlane-Abdulla E, Andersson M, Barile FA, et al. 1996. MEIC evaluation of acute systemic toxicity Part I. Methodology of 68 in vitro

Comparing the Fit of Item Response Theory and Factor Analysis Models

ERIC Educational Resources Information Center

Maydeu-Olivares, Alberto; Cai, Li; Hernandez, Adolfo

2011-01-01

Linear factor analysis (FA) models can be reliably tested using test statistics based on residual covariances. We show that the same statistics can be used to reliably test the fit of item response theory (IRT) models for ordinal data (under some conditions). Hence, the fit of an FA model and of an IRT model to the same data set can now be…

Pearl Harbor: Failure of Intelligence?

DTIC Science & Technology

1997-04-01

N.E.I.), “NISHI.” The above will be repeated five times and included at beginning and end. Relay to Rio de Janeiro , Buenos Aires, Mexico City, and San...limits of their equipment. ( e ) To effect a state of readiness throughout the Army and Navy establishments designed to meet all possible attacks. (f...a timely manner to the national command authorities, the War and Navy Departments, and Admiral Husband E . Kimmel and Lieutenant General Walter C

Regulation of Fanconi anemia protein FANCD2 monoubiquitination by miR-302

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

Suresh, Bharathi; College of Medicine, Hanyang University, Seoul; Kumar, A. Madhan

2015-10-16

Fanconi anemia (FA) is a recessively inherited multigene disease characterized by congenital defects, progressive bone marrow failure, and heightened cancer susceptibility. Monoubiquitination of the FA pathway member FANCD2 contributes to the repair of replication stalling DNA lesions. However, cellular regulation of FANCD2 monoubiquitination remains poorly understood. In the present study, we identified the miR-302 cluster as a potential regulator of FANCD2 by bioinformatics analysis. MicroRNAs (miRNAs) are the major posttranscriptional regulators of a wide variety of biological processes, and have been implicated in a number of diseases. Expression of the exogenous miR-302 cluster (without miR-367) reduced FANCD2 monoubiquitination and nuclearmore » foci formation. Furthermore, miR-302 cells showed extensive chromosomal breakage upon MMC treatment when compared to mock control cells. Taken together, our results suggest that overexpression of miR-302 plays a critical role in the regulation of FANCD2 monoubiquitination, resulting in characteristic defects in DNA repair within cells. - Highlights: • miR-302 binds to the 3′UTR promoter of the FANCD2 gene to regulate gene expression. • miR-302 cluster down-regulates FANCD2 protein expression. • miR-302 cluster reduces FANCD2 monoubiquitination and nuclear foci formation. • miR-302 exhibits the characteristic defects in DNA repair in cells.« less

A design space exploration for control of Critical Quality Attributes of mAb.

PubMed

Bhatia, Hemlata; Read, Erik; Agarabi, Cyrus; Brorson, Kurt; Lute, Scott; Yoon, Seongkyu

2016-10-15

A unique "design space (DSp) exploration strategy," defined as a function of four key scenarios, was successfully integrated and validated to enhance the DSp building exercise, by increasing the accuracy of analyses and interpretation of processed data. The four key scenarios, defining the strategy, were based on cumulative analyses of individual models developed for the Critical Quality Attributes (23 Glycan Profiles) considered for the study. The analyses of the CQA estimates and model performances were interpreted as (1) Inside Specification/Significant Model (2) Inside Specification/Non-significant Model (3) Outside Specification/Significant Model (4) Outside Specification/Non-significant Model. Each scenario was defined and illustrated through individual models of CQA aligning the description. The R(2), Q(2), Model Validity and Model Reproducibility estimates of G2, G2FaGbGN, G0 and G2FaG2, respectively, signified the four scenarios stated above. Through further optimizations, including the estimation of Edge of Failure and Set Point Analysis, wider and accurate DSps were created for each scenario, establishing critical functional relationship between Critical Process Parameters (CPPs) and Critical Quality Attributes (CQAs). A DSp provides the optimal region for systematic evaluation, mechanistic understanding and refining of a QbD approach. DSp exploration strategy will aid the critical process of consistently and reproducibly achieving predefined quality of a product throughout its lifecycle. Copyright © 2016 Elsevier B.V. All rights reserved.

Determining the fatty acid composition in plasma and tissues as fatty acid methyl esters using gas chromatography – a comparison of different derivatization and extraction procedures.

PubMed

Ostermann, Annika I; Müller, Maike; Willenberg, Ina; Schebb, Nils Helge

2014-12-01

Analysis of the fatty acid (FA) composition in biological samples is commonly carried out using gas liquid chromatography (GC) after transesterification to volatile FA methyl esters (FAME). We compared the efficacy of six frequently used protocols for derivatization of different lipid classes as well as for plasma and tissue samples. Transesterification with trimethylsulfonium hydroxide (TMSH) led to insufficient derivatization efficacies for polyunsaturated FAs (PUFA, <50%). Derivatization in presence of potassium hydroxide (KOH) failed at derivatizing free FAs (FFAs). Boron trifluoride (BF3) 7% in hexane/MeOH (1:1) was insufficient for the transesterification of cholesterol ester (CE) as well as triacylglycerols (TGs). In contrast, methanolic hydrochloric acid (HCl) as well as a combination of BF3 with methanolic sodium hydroxide (NaOH+BF3) were suitable for the derivatization of FFAs, polar lipids, TGs, and CEs (derivatization rate >80% for all tested lipids). Regarding plasma samples, all methods led to an overall similar relative FA pattern. However, significant differences were observed, for example, for the relative amount of EPA+DHA (n3-index). Absolute FA plasma concentrations differed considerably among the methods, with low yields for KOH and BF3. We also demonstrate that lipid extraction with tert-butyl methyl ether/methanol (MTBE/MeOH) is as efficient as the classical method according to Bligh and Dyer, making it possible to replace (environmentally) toxic chloroform.We conclude that HCl-catalyzed derivatization in combination with MeOH/MTBE extraction is the most appropriate among the methods tested for the analysis of FA concentrations and FA pattern in small biological samples. A detailed protocol for the analysis of plasma and tissues is included in this article.

Structural integrity of the contralesional hemisphere predicts cognitive impairment in ischemic stroke at three months.

PubMed

Dacosta-Aguayo, Rosalia; Graña, Manuel; Fernández-Andújar, Marina; López-Cancio, Elena; Cáceres, Cynthia; Bargalló, Núria; Barrios, Maite; Clemente, Immaculada; Monserrat, Pere Toran; Sas, Maite Alzamora; Dávalos, Antoni; Auer, Tibor; Mataró, Maria

2014-01-01

After stroke, white matter integrity can be affected both locally and distally to the primary lesion location. It has been shown that tract disruption in mirror's regions of the contralateral hemisphere is associated with degree of functional impairment. Fourteen patients suffering right hemispheric focal stroke (S) and eighteen healthy controls (HC) underwent Diffusion Weighted Imaging (DWI) and neuropsychological assessment. The stroke patient group was divided into poor (SP; n = 8) and good (SG; n = 6) cognitive recovery groups according to their cognitive improvement from the acute phase (72 hours after stroke) to the subacute phase (3 months post-stroke). Whole-brain DWI data analysis was performed by computing Diffusion Tensor Imaging (DTI) followed by Tract Based Spatial Statistics (TBSS). Assessment of effects was obtained computing the correlation of the projections on TBSS skeleton of Fractional Anisotropy (FA) and Radial Diffusivity (RD) with cognitive test results. Significant decrease of FA was found only in right brain anatomical areas for the S group when compared to the HC group. Analyzed separately, stroke patients with poor cognitive recovery showed additional significant FA decrease in several left hemisphere regions; whereas SG patients showed significant decrease only in the left genu of corpus callosum when compared to the HC. For the SG group, whole brain analysis revealed significant correlation between the performance in the Semantic Fluency test and the FA in the right hemisphere as well as between the performance in the Grooved Pegboard Test (GPT) and the Trail Making Test-part A and the FA in the left hemisphere. For the SP group, correlation analysis revealed significant correlation between the performance in the GPT and the FA in the right hemisphere.

Structural Integrity of the Contralesional Hemisphere Predicts Cognitive Impairment in Ischemic Stroke at Three Months

PubMed Central

Dacosta-Aguayo, Rosalia; Graña, Manuel; Fernández-Andújar, Marina; López-Cancio, Elena; Cáceres, Cynthia; Bargalló, Núria; Barrios, Maite; Clemente, Immaculada; Monserrat, Pere Toran; Sas, Maite Alzamora; Dávalos, Antoni

2014-01-01

After stroke, white matter integrity can be affected both locally and distally to the primary lesion location. It has been shown that tract disruption in mirror’s regions of the contralateral hemisphere is associated with degree of functional impairment. Fourteen patients suffering right hemispheric focal stroke (S) and eighteen healthy controls (HC) underwent Diffusion Weighted Imaging (DWI) and neuropsychological assessment. The stroke patient group was divided into poor (SP; n = 8) and good (SG; n = 6) cognitive recovery groups according to their cognitive improvement from the acute phase (72 hours after stroke) to the subacute phase (3 months post-stroke). Whole-brain DWI data analysis was performed by computing Diffusion Tensor Imaging (DTI) followed by Tract Based Spatial Statistics (TBSS). Assessment of effects was obtained computing the correlation of the projections on TBSS skeleton of Fractional Anisotropy (FA) and Radial Diffusivity (RD) with cognitive test results. Significant decrease of FA was found only in right brain anatomical areas for the S group when compared to the HC group. Analyzed separately, stroke patients with poor cognitive recovery showed additional significant FA decrease in several left hemisphere regions; whereas SG patients showed significant decrease only in the left genu of corpus callosum when compared to the HC. For the SG group, whole brain analysis revealed significant correlation between the performance in the Semantic Fluency test and the FA in the right hemisphere as well as between the performance in the Grooved Pegboard Test (GPT) and theTrail Making Test-part A and the FA in the left hemisphere. For the SP group, correlation analysis revealed significant correlation between the performance in the GPT and the FA in the right hemisphere. PMID:24475078

Knowing your face: A componential analysis of self-perceived facial attractiveness.

PubMed

Yoder, Marcel S; Ault, Lara K; Mathews, Maureen A

2017-01-01

Facial attractiveness (FA) is a highly agreed upon and socially important characteristic, but contemporary research has not fully investigated individuals' enhancement of their FA. We used the social relations model (SRM) to analyze data from 187 participants. In face-to-face groups of four, participants rated their own and others' FA. We assessed the degree of FA enhancement using unconfounded measures of both self-insight and social comparison. Results indicated African Americans and men enhanced more than Caucasians and women. Race effects were mediated by psychological adjustment, while gender effects were related to meta-perceptions. Men tended to view themselves through a "frog prince" lens, such that they accurately predicted others' lesser views of them but persisted in overly positive self-perceptions of FA. Findings suggest further consideration of SRM measures, meta-perceptions, and a focus on sample diversity in the study of self-enhancement.

Development and verification of real-time controllers for the F/A-18 vertical fin buffet load alleviation

NASA Astrophysics Data System (ADS)

Chen, Yong; Viresh, Wickramasinghe; Zimcik, David

2006-03-01

Twin-tail fighter aircraft such as the F/A-18 may experience intense buffet loads at high angles of attack flight conditions and the broadband buffet loads primarily excite the first bending and torsional modes of the vertical fin that results in severe vibration and dynamic stresses on the vertical fin structures. To reduce the premature fatigue failure of the structure and to increase mission availability, a novel hybrid actuation system was developed to actively alleviate the buffet response of a full-scale F/A-18 vertical fin. A hydraulic rudder actuator was used to control the bending mode of the fin by engaging the rudder inertial force. Multiple Macro Fiber Composites actuators were surface mounted to provide induced strain actuation authority to control the torsional mode. Experimental system identification approach was selected to obtain a state-space model of the system using open-loop test data. An LQG controller was developed to minimize the dynamic response of the vertical fin at critical locations. Extensive simulations were conducted to evaluate the control authority of the actuators and the performance of the controller under various buffet load cases and levels. Closed-loop tests were performed on a full-scale F/A-18 empennage and the results validated the effectiveness of the real-time controller as well as the development methodology. In addition, the ground vibration test demonstrated that the hybrid actuation system is a feasible solution to alleviate the vertical tail buffet loads in high performance fighter aircraft.

Genotypic and environmental effects on coffee (Coffea arabica L.) bean fatty acid profile: impact on variety and origin chemometric determination.

PubMed

Villarreal, Diana; Laffargue, Andreina; Posada, Huver; Bertrand, Benoit; Lashermes, Philippe; Dussert, Stephane

2009-12-09

In a previous study, the effectiveness of chlorogenic acids, fatty acids (FA), and elements was compared for the discrimination of Arabica varieties and growing terroirs. Since FA provided the best results, the aim of the present work was to validate their discrimination ability using an extended experimental design, including twice the number of location x variety combinations and 2 years of study. It also aimed at understanding how the environment influences FA composition through correlation analysis using different climatic parameters. Percentages of correct classification of known samples remained very high, independent of the classification criterion. However, cross-validation tests across years indicated that prediction of unknown locations was less efficient than that of unknown genotypes. Environmental temperature during the development of coffee beans had a dramatic influence on their FA composition. Analysis of climate patterns over years enabled us to understand the efficient location discrimination within a single year but only moderate efficiency across years.

Reduced white matter integrity and facial emotion perception in never-medicated patients with first-episode schizophrenia: A diffusion tensor imaging study.

PubMed

Zhao, Xiaoxin; Sui, Yuxiu; Yao, Jingjing; Lv, Yiding; Zhang, Xinyue; Jin, Zhuma; Chen, Lijun; Zhang, Xiangrong

2017-07-03

Facial emotion perception is impaired in schizophrenia. Although the pathology of schizophrenia is thought to involve abnormality in white matter (WM), few studies have examined the correlation between facial emotion perception and WM abnormalities in never-medicated patients with first-episode schizophrenia. The present study tested associations between facial emotion perception and WM integrity in order to investigate the neural basis of impaired facial emotion perception in schizophrenia. Sixty-three schizophrenic patients and thirty control subjects underwent facial emotion categorization (FEC). The FEC data was inserted into a logistic function model with subsequent analysis by independent-samples T test and the shift point and slope as outcome measurements. Severity of symptoms was measured using a five-factor model of the Positive and Negative Syndrome Scale (PANSS). Voxelwise group comparison of WM fractional anisotropy (FA) was operated using tract-based spatial statistics (TBSS). The correlation between impaired facial emotion perception and FA reduction was examined in patients using simple regression analysis within brain areas that showed a significant FA reduction in patients compared with controls. The same correlation analysis was also performed for control subjects in the whole brain. The patients with schizophrenia reported a higher shift point and a steeper slope than control subjects in FEC. The patients showed a significant FA reduction in left deep WM in the parietal, temporal and occipital lobes, a small portion of the corpus callosum (CC), and the corona radiata. In voxelwise correlation analysis, we found that facial emotion perception significantly correlated with reduced FA in various WM regions, including left forceps major (FM), inferior longitudinal fasciculus (ILF), inferior fronto-occipital fasciculus (IFOF), Left splenium of CC, and left ILF. The correlation analyses in healthy controls revealed no significant correlation of FA with FEC task. These results showed disrupted WM integrity in these regions constitutes a potential neural basis for the facial emotion perception impairments in schizophrenia. Copyright © 2017 Elsevier Inc. All rights reserved.

The influence of local mechanisms on large scale seismic vulnerability estimation of masonry building aggregates

NASA Astrophysics Data System (ADS)

Formisano, Antonio; Chieffo, Nicola; Milo, Bartolomeo; Fabbrocino, Francesco

2016-12-01

The current paper deals with the seismic vulnerability evaluation of masonry constructions grouped in aggregates through an "ad hoc" quick vulnerability form based on new assessment parameters considering local collapse mechanisms. First, a parametric kinematic analysis on masonry walls with different height (h) / thickness (t) ratios has been developed with the purpose of identifying the collapse load multiplier for activation of the main four first-order failure mechanisms. Subsequently, a form initially conceived for building aggregates suffering second-mode collapse mechanisms, has been expanded on the basis of the achieved results. Tre proposed quick vulnerability technique has been applied to one case study within the territory of Arsita (Teramo, Italy) and, finally, it has been also validated by the comparison of results with those deriving from application of the well-known FaMIVE procedure.

Dynamic molecular imaging of cardiac innervation using a dual headpinhole SPECT system

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

Hu, Jicun; Boutchko, Rostyslav; Sitek, Arkadiusz

2008-03-29

Typically 123I-MIBG is used for the study of innervation andfunction of the sympathetic nervous system in heart failure. The protocolinvolves two studies: first a planar or SPECT scan is performed tomeasure initial uptake of the tracer, followed some 3-4 hours later byanother study measuring the wash-out of the tracer from the heart. A fastwash-out is indicative of a compromised heart. In this work, a dual headpinhole SPECT system was used for imaging the distribution and kineticsof 123I-MIBG in the myocardium of spontaneous hypertensive rats (SHR) andnormotensive Wistar Kyoto (WKY) rats. The system geometry was calibratedbased on a nonlinear point projectionmore » fitting method using a three-pointsource phantom. The angle variation effect of the parameters was modeledwith a sinusoidal function. A dynamic acquisition was performed byinjecting 123I-MIBG into rats immediately after starting the dataacquisition. The detectors rotated continuously performing a 360o dataacquisition every 90 seconds. We applied the factor analysis (FA)methodand region of interest (ROI) sampling method to obtain time activitycurves (TACs)in the blood pool and myocardium and then appliedtwo-compartment modeling to estimate the kinetic parameters. Since theinitial injection bolus is too fast for obtaining a consistenttomographic data set in the first few minutes of the study, we appliedthe FA method directly to projections during the first rotation. Then thetime active curves for blood and myocardial tissue were obtained from ROIsampling. The method was applied to determine if there were differencesin the kinetics between SHR and WKY rats and requires less time byreplacing the delayed scan at 3-4 hours after injection with a dynamicacquisition over 90 to 120 minutes. The results of a faster washout and asmaller distribution volume of 123IMIBG near the end of life in the SHRmodel of hypertrophic cardiomyopthy may be indicative of a failing heartin late stages of heart failure.« less

A feasibility study of municipal solid waste incineration fly ash utilisation in Estonia.

PubMed

Berber, Hakan; Frey, Ruedi; Voronova, Viktoria; Koroljova, Arina

2017-09-01

The purpose of this paper is to discuss the alternative environmental management options for the utilisation of municipal solid waste (MSW) incineration fly ash (FA), which is generated at Iru Power Plant where MSW is incinerated in Estonia. To determine sustainable and economically feasible environmental management options for MSW incineration FA in Estonia, CO 2 sequestration with a further carbonation process was examined. A partial Cost & Benefit Analysis has been conducted to compare the carbonation process to the current situation. Two carbonation options were developed. Option 1 is to use carbonated FA in any other processes based on the waste-to-product principle. Option 2 is to send carbonated FA to the non-hazardous landfill in Tallinn, Estonia. Important parameters, such as Net Present Value (NPV), Internal Rate of Return (IRR), Benefit-Cost Ratio (BCR) and Break Even Point (BEP), have been calculated for carbonation options and the current case. In addition, a sensitivity analysis has been conducted to examine its robustness. The results showed that the best option is carbonation Option 1 with NPV of 9,209,662 EUR, IRR of 43%, BCR of 2.63 and BEP between 2018 and 2019. Both Options 1 and 2 constitute more sustainable and environmentally friendly management options compared to the current situation. It can be concluded that this preliminary feasibility study showed that running a carbonation plant may be profitable and sustainable for Estonia. Currently, there is no treatment technology for MSW incineration FA in Estonia and FA is sent to a neighbouring country for further utilisation. This is the first study to demonstrate FA management options with economic and environmental benefits.

Three-Dimensional Reconstruction and Solar Energy Potential Estimation of Buildings

NASA Astrophysics Data System (ADS)

Chen, Y.; Li, M.; Cheng, L.; Xu, H.; Li, S.; Liu, X.

2017-12-01

In the context of the construction of low-carbon cities, green cities and eco-cities, the ability of the airborne and mobile LiDAR should be explored in urban renewable energy research. As the main landscape in urban environment, buildings have large regular envelopes could receive a huge amount of solar radiation. In this study, a relatively complete calculation scheme about building roof and façade solar utilization potential is proposed, using building three-dimensional geometric feature information. For measuring the city-level building solar irradiance, the precise three-dimensional building roof and façade models should be first reconstructed from the airborne and mobile LiDAR, respectively. In order to obtaining the precise geometric structure of building facades from the mobile LiDAR data, a new method for structure detection and the three-dimensional reconstruction of building façades from mobile LiDAR data is proposed. The method consists of three steps: the preprocessing of façade points, the detection of façade structure, the restoration and reconstruction of building façade. As a result, the reconstruction method can effectively deal with missing areas caused by occlusion, viewpoint limitation, and uneven point density, as well as realizing the highly complete 3D reconstruction of a building façade. Furthermore, the window areas can be excluded for more accurate estimation of solar utilization potential. After then, the solar energy utilization potential of global building roofs and facades is estimate by using the solar irradiance model, which combine the analysis of the building shade and sky diffuse, based on the analysis of the geometrical structure of buildings.

Fatty Acid Proportions in Plasma Cholesterol Esters and Phospholipids Are Positively Correlated in Various Swedish Populations.

PubMed

Marklund, Matti; Pingel, Ronnie; Rosqvist, Fredrik; Lindroos, Anna Karin; Eriksson, Jan W; Vessby, Bengt; Oscarsson, Jan; Lind, Lars; Risérus, Ulf

2017-11-01

Background: Fatty acid (FA) proportions in cholesterol esters (CEs) and plasma phospholipids are widely used as dietary biomarkers. Information on how proportions in these fractions correlate could have implications for interpretation and use of FA biomarkers in observational and interventional studies. Objective: We investigated correlations between FA proportions in CEs and phospholipids in free-living individuals and assessed how diet-induced alterations of FA proportions correlate between fractions. Methods: Spearman's rank correlation coefficients ( r s ) between FA proportions (percentage of total FAs) in circulating CEs and phospholipids were calculated separately in 8 individual study populations including Swedish females and males ( N = 2052; age range: 11-84 y), and pooled by inverse-variance weighted meta-analysis. In addition, study populations were stratified by age, sex, body mass index (BMI; in kg/m 2 ), and diabetes status, and strata-specific r s were pooled by meta-analysis. In 2 randomized trials ( N = 79) in which dietary saturated FAs were isocalorically replaced with unsaturated FAs, treatment-wise calculations of r s were conducted between FA changes in CEs and phospholipids. Results: Overall, FA proportions in CEs and phospholipids correlated well and especially strongly for polyunsaturated FAs (PUFAs), with pooled r s (95% CIs) ranging from 0.74 (0.72, 0.76) for α-linolenic acid to 0.92 (0.91, 0.93) for eicosapentaenoic acid. Weak correlations (pooled r s < 0.4) were observed only for palmitic acid and stearic acid, with pooled r s (95% CIs): 0.29 (0.24, 0.33) and 0.30 (0.25, 0.34), respectively. Overall, correlations were not affected by age, sex, BMI, or diabetes status. Strong correlations ( r s ≥ 0.6) between diet-induced FA changes in CEs and phospholipids were observed for most PUFAs. Conclusions: Proportions of most FAs in CEs and phospholipids ranked individuals similarly, suggesting that FA proportions in these fractions can be used interchangeably in populations of diverse age, sex, body composition, and diabetes status. Caution is advised, however, when comparing results from studies assessing palmitic acid or stearic acid in different lipid fractions. © 2017 American Society for Nutrition.

Investigation of the protective effects of proanthocyanidin and vitamin E against the toxic effect caused by formaldehyde on the liver tissue.

PubMed

Bakar, Elvan; Ulucam, Enis; Cerkezkayabekir, Aysegul

2015-12-01

We aimed to investigate of protective role of proanthocyanidin (PA) and vitamin E (vit E) against to toxic effect of formaldehyde (FA). Twenty-eight Wistar albino rats were divided into four groups: control group, rats treated with FA intraperitoneal (i.p.) (10 mg/kg), FA + vit E intragastric (i.g.) (30 mg/kg), and FA + PA i.g. (100 mg/kg). We assayed superoxide dismutase (SOD), glutathione peroxidase (Gpx), myeloperoxidase (MPO) activity and levels of malondialdehyde (MDA) and total sialic acid (TSA) in liver. Liver tissue was taken in order to morphological analysis and hepatocytes apoptosis using terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay immunostaining. SOD decreased in FA and increased in FA + vit E and FA + PA (p < 0.05). Gpx didn't change in FA and increased in FA + PA (p < 0.05). No significant variation between the groups was found in MPO activity. MDA increased only in FA and decreased in FA + vit E and FA+PA (p < 0.05). TSA didn't alter in FA and FA + vit E but decreased in FA + PA (p < 0.05). Degeneration in hepatocytes and endothelial cells, cytoplasm losses, vacuolization, picnotic nuclei, and mononuclear cell infiltration were identified in FA. Degeneration in chromatin material, membrane damage in mitochondria and losses in mitochondrial cristae in hepatocytes were observed in FA. We found that partially recovery in liver as a result of FA + vit E and FA + PA. We have concluded that long term use should be investigated for complete explanation of PA's protective effects on FA toxicity. © 2014 Wiley Periodicals, Inc.

A combined behavioral and morphological study on the effects of fetal asphyxia on the nigrostriatal dopaminergic system in adult rats.

PubMed

Strackx, E; Van den Hove, D L A; Steinbusch, H P; Steinbusch, H W M; Vles, J S H; Blanco, C E; Gavilanes, A W D

2008-06-01

Fetal asphyxic insults in the brain are known to be associated with developmental neurological problems like neuromotor disorders. However, little is known about the long-term consequences of fetal asphyxia (FA). For that reason, the present study investigated the long-term effects of FA on motor behavior and dopaminergic circuitry. FA was induced at embryonic day 17 by 75-minute clamping of the uterine circulation. SHAM animals underwent the same procedure except for the clamping. This was followed by full-term vaginal delivery of animals in all groups (FA, SHAM and untreated controls). At 6 months, basal and amphetamine-induced locomotor activity was measured during open field testing. Brain sections were stained for tyrosine hydroxylase (TH) and glial fibrillary acidic protein (GFAP). TH-positive cells and GFAP-positive cells in substantia nigra pars compacta (SN(C)) and striatum were counted using design-based stereology. Moreover, TH-immunoreactivity in the striatum was assessed by grey value measurements. Behavioral analysis demonstrated that SHAM and FA showed less basal and amphetamine-induced activity than controls. Histochemically, FA decreased the number of TH-positive neurons in the SN(C) and lowered TH-positive in the striatum. Furthermore, more GFAP-positive cells were found in the SN(C) and striatum in FA than in either control and SHAM groups. Additionally, FA animals showed ventriculomegaly associated with smaller white matter as well as grey matter volumes. The data show that FA was associated with deficits in both dopamine-related motor behavior and biochemistry. These alterations were associated with nigrostriatal astrogliosis. The present study demonstrates the sensitivity of the dopaminergic system towards FA.

A genome-wide association study of red-blood cell fatty acids and ratios incorporating dietary covariates: Framingham Heart Study Offspring Cohort.

PubMed

Kalsbeek, Anya; Veenstra, Jenna; Westra, Jason; Disselkoen, Craig; Koch, Kristin; McKenzie, Katelyn A; O'Bott, Jacob; Vander Woude, Jason; Fischer, Karen; Shearer, Greg C; Harris, William S; Tintle, Nathan L

2018-01-01

Recent analyses have suggested a strong heritable component to circulating fatty acid (FA) levels; however, only a limited number of genes have been identified which associate with FA levels. In order to expand upon a previous genome wide association study done on participants in the Framingham Heart Study Offspring Cohort and FA levels, we used data from 2,400 of these individuals for whom red blood cell FA profiles, dietary information and genotypes are available, and then conducted a genome-wide evaluation of potential genetic variants associated with 22 FAs and 15 FA ratios, after adjusting for relevant dietary covariates. Our analysis found nine previously identified loci associated with FA levels (FADS, ELOVL2, PCOLCE2, LPCAT3, AGPAT4, NTAN1/PDXDC1, PKD2L1, HBS1L/MYB and RAB3GAP1/MCM6), while identifying four novel loci. The latter include an association between variants in CALN1 (Chromosome 7) and eicosapentaenoic acid (EPA), DHRS4L2 (Chromosome 14) and a FA ratio measuring delta-9-desaturase activity, as well as two loci associated with less well understood proteins. Thus, the inclusion of dietary covariates had a modest impact, helping to uncover four additional loci. While genome-wide association studies continue to uncover additional genes associated with circulating FA levels, much of the heritable risk is yet to be explained, suggesting the potential role of rare genetic variation, epistasis and gene-environment interactions on FA levels as well. Further studies are needed to continue to understand the complex genetic picture of FA metabolism and synthesis.

Providing theoretical data for detection of four formamidic acid isomers in astrophysical media

NASA Astrophysics Data System (ADS)

Vichietti, R. M.; da Silva, A. B. F.; Haiduke, R. L. A.

2018-03-01

We present a theoretical study, so that molecular data (geometrical parameters, vibrational frequencies, infrared intensities, electronic energies, enthalpies, and Gibbs energies) of four formamidic acid (FA) isomers (labeled here as FA1, FA2, FA3, and FA4) and formamide (HCONH2) are obtained from CCSD/cc-pVTZ, CCSD/aug-cc-pVTZ, CCSD/cc-pVQZ, and CCSD(T)/cc-pVTZ calculations. Furthermore, on the basis of insufficient or even lacking theoretical and experimental results in the literature, we employed the aforementioned theory levels to determine benchmark values of dipole moments and rotational constants for these four FA isomers in order to contribute for their detection in astrophysical environments. Besides, we provide for the first time data about forward and reverse rate constants (200-4000 K) and Arrhenius' parameters for each interconversion reaction between pairs of FA isomers as well as for the tautomeric process involving FA4 and formamide, which were calculated from a Complete Basis Set (CBS) extrapolation equation obtained at CCSD/cc-pVTZ optimized geometries. Our kinetic analysis indicated a faster interconversion between the FA structures in comparison with the FA4 ↔ HCONH2 process, suggesting that these isomers could co-exist in astrophysical media. Finally, we estimated that these isomers may be detected with relative abundances, [FAx]/[HCONH2] (x = 1, 2, 3, and 4), between ∼0.01 and ∼0.1% in astrophysical sources at chemical equilibrium conditions and temperatures around 1000 K. However, these ratios can become as high as ∼1, ∼3, and ∼5%, respectively, in hotter regions with temperatures around 2000, 3000, and 4000 K (expected, for example, in massive star-forming regions).

Infant feeding practices and reported food allergies at 6 years of age.

PubMed

Luccioli, Stefano; Zhang, Yuanting; Verrill, Linda; Ramos-Valle, Moraima; Kwegyir-Afful, Ernest

2014-09-01

The goal of this study was to identify the frequency of physician-diagnosed food allergies among 6-year-old US children and study the impact of exclusive breastfeeding and complementary food introduction on this frequency. Data were analyzed from children who participated in the Infant Feeding Practices Study II Year 6 Follow-Up Study (Y6FU). Children with probable food allergy (pFA) were defined as children with report of physician-diagnosed food allergy at age 6 years. Subgroups of pFA included children who were not diagnosed before 1 year of age (new pFA) and those with atopic risk factors (high risk). Prevalence of total pFA in the Y6FU was 6.34%. The majority of these children had new pFA and high-risk factors. Higher maternal education, higher family income, family history of food allergy, and reported eczema before 1 year of age were significantly associated with higher odds of total or new pFA. Exclusive breastfeeding duration and timing of complementary food introduction were not significantly associated with total pFA. However, exclusive breastfeeding of ≥4 months compared with no breastfeeding was marginally associated with lower odds of new pFA (adjusted odds ratio: 0.51; P = .07); this effect was not observed with high-risk children. Analysis of infant and maternal variables in the Y6FU cohort of US children revealed that socioeconomic and atopic factors were the main predictors of pFA at age 6 years. Exclusive breastfeeding of ≥4 months may have a preventive effect on development of pFA after 1 year of age in non high-risk children. Copyright © 2014 by the American Academy of Pediatrics.

A genome-wide association study of red-blood cell fatty acids and ratios incorporating dietary covariates: Framingham Heart Study Offspring Cohort

PubMed Central

Veenstra, Jenna; Westra, Jason; Disselkoen, Craig; Koch, Kristin; McKenzie, Katelyn A.; O’Bott, Jacob; Vander Woude, Jason; Fischer, Karen; Shearer, Greg C.; Harris, William S.; Tintle, Nathan L.

2018-01-01

Recent analyses have suggested a strong heritable component to circulating fatty acid (FA) levels; however, only a limited number of genes have been identified which associate with FA levels. In order to expand upon a previous genome wide association study done on participants in the Framingham Heart Study Offspring Cohort and FA levels, we used data from 2,400 of these individuals for whom red blood cell FA profiles, dietary information and genotypes are available, and then conducted a genome-wide evaluation of potential genetic variants associated with 22 FAs and 15 FA ratios, after adjusting for relevant dietary covariates. Our analysis found nine previously identified loci associated with FA levels (FADS, ELOVL2, PCOLCE2, LPCAT3, AGPAT4, NTAN1/PDXDC1, PKD2L1, HBS1L/MYB and RAB3GAP1/MCM6), while identifying four novel loci. The latter include an association between variants in CALN1 (Chromosome 7) and eicosapentaenoic acid (EPA), DHRS4L2 (Chromosome 14) and a FA ratio measuring delta-9-desaturase activity, as well as two loci associated with less well understood proteins. Thus, the inclusion of dietary covariates had a modest impact, helping to uncover four additional loci. While genome-wide association studies continue to uncover additional genes associated with circulating FA levels, much of the heritable risk is yet to be explained, suggesting the potential role of rare genetic variation, epistasis and gene-environment interactions on FA levels as well. Further studies are needed to continue to understand the complex genetic picture of FA metabolism and synthesis. PMID:29652918

Patterns of white matter damage are non-random and associated with cognitive function in secondary progressive multiple sclerosis.

PubMed

Meijer, K A; Cercignani, M; Muhlert, N; Sethi, V; Chard, D; Geurts, J J G; Ciccarelli, O

2016-01-01

In multiple sclerosis (MS), white matter damage is thought to contribute to cognitive dysfunction, which is especially prominent in secondary progressive MS (SPMS). While studies in healthy subjects have revealed patterns of correlated fractional anisotropy (FA) across white matter tracts, little is known about the underlying patterns of white matter damage in MS. In the present study, we aimed to map the SPMS-related covariance patterns of microstructural white matter changes, and investigated whether or not these patterns were associated with cognitive dysfunction. Diffusion MRI was acquired from 30 SPMS patients and 32 healthy controls (HC). A tensor model was fitted and FA maps were processed using tract-based spatial statistics (TBSS) in order to obtain a skeletonised map for each subject. The skeletonised FA maps of patients only were decomposed into 18 spatially independent components (ICs) using independent component analysis. Comprehensive cognitive assessment was conducted to evaluate five cognitive domains. Correlations between cognitive performance and (1) severity of FA abnormalities of the extracted ICs (i.e. z-scores relative to FA values of HC) and (2) IC load (i.e. FA covariance of a particular IC) were examined. SPMS patients showed lower FA values of all examined patterns of correlated FA (i.e. spatially independent components) than HC (p < 0.01). Tracts visually assigned to the supratentorial commissural class were most severely damaged (z = - 3.54; p < 0.001). Reduced FA was significantly correlated with reduced IC load (i.e. FA covariance) (r = 0.441; p < 0.05). Lower mean FA and component load of the supratentorial projection tracts and limbic association tracts classes were associated with worse cognitive function, including executive function, working memory and verbal memory. Despite the presence of white matter damage, it was possible to reveal patterns of FA covariance across SPMS patients. This could indicate that white matter tracts belonging to the same cluster, and thus with similar characteristics, tend to follow similar trends during neurodegeneration. Furthermore, these underlying FA patterns might help to explain cognitive dysfunction in SPMS.

[Construction of FANCA mutant protein from Fanconi anemia patient and analysis of its function].

PubMed

Chen, Fei; Zhang, Ke-Jian; Zuo, Xue-Lan; Zeng, Xian-Chang

2007-11-01

To study FANCA protein expression in Fanconi anemia patient's (FA) cells and explore its function. FANCA protein expression was analyzed in 3 lymphoblast cell lines derived from 3 cases of type A FA (FA-A) patients using Western blot. Nucleus and cytoplasm localization of FANCA protein was analyzed in one case of FA-A which contained a truncated FANCA (exon 5 deletion). The FANCA mutant was constructed from the same patient and its interaction with FANCG was evaluated by mammalian two-hybrid (M2H) assay. FANCA protein was not detected in the 3 FA-A patients by rabbit anti-human MoAb, but a truncated FANCA protein was detected in 1 of them by mouse anti-human MoAb. The truncated FANCA could not transport from cytoplasm into nucleus. The disease-associated FANCA mutant was defective in binding to FANCG in M2H system. FANCA proteins are defective in the 3 FA-A patients. Disfunction of disease-associated FANCA mutant proved to be the pathogenic mutations in FANCA gene. Exon 5 of FANCA gene was involved in the interaction between FANCA and FANCG.

Fatty Acids Regulate Germline Sex Determination through ACS-4-Dependent Myristoylation.

PubMed

Tang, Hongyun; Han, Min

2017-04-20

Fat metabolism has been linked to fertility and reproductive adaptation in animals and humans, and environmental sex determination potentially plays a role in the process. To investigate the impact of fatty acids (FA) on sex determination and reproductive development, we examined and observed an impact of FA synthesis and mobilization by lipolysis in somatic tissues on oocyte fate in Caenorhabditis elegans. The subsequent genetic analysis identified ACS-4, an acyl-CoA synthetase and its FA-CoA product, as key germline factors that mediate the role of FA in promoting oocyte fate through protein myristoylation. Further tests indicated that ACS-4-dependent protein myristoylation perceives and translates the FA level into regulatory cues that modulate the activities of MPK-1/MAPK and key factors in the germline sex-determination pathway. These findings, including a similar role of ACS-4 in a male/female species, uncover a likely conserved mechanism by which FA, an environmental factor, regulates sex determination and reproductive development. Copyright © 2017 Elsevier Inc. All rights reserved.

Adaptive firefly algorithm: parameter analysis and its application.

PubMed

Cheung, Ngaam J; Ding, Xue-Ming; Shen, Hong-Bin

2014-01-01

As a nature-inspired search algorithm, firefly algorithm (FA) has several control parameters, which may have great effects on its performance. In this study, we investigate the parameter selection and adaptation strategies in a modified firefly algorithm - adaptive firefly algorithm (AdaFa). There are three strategies in AdaFa including (1) a distance-based light absorption coefficient; (2) a gray coefficient enhancing fireflies to share difference information from attractive ones efficiently; and (3) five different dynamic strategies for the randomization parameter. Promising selections of parameters in the strategies are analyzed to guarantee the efficient performance of AdaFa. AdaFa is validated over widely used benchmark functions, and the numerical experiments and statistical tests yield useful conclusions on the strategies and the parameter selections affecting the performance of AdaFa. When applied to the real-world problem - protein tertiary structure prediction, the results demonstrated improved variants can rebuild the tertiary structure with the average root mean square deviation less than 0.4Å and 1.5Å from the native constrains with noise free and 10% Gaussian white noise.

Adaptive Firefly Algorithm: Parameter Analysis and its Application

PubMed Central

Shen, Hong-Bin

2014-01-01

As a nature-inspired search algorithm, firefly algorithm (FA) has several control parameters, which may have great effects on its performance. In this study, we investigate the parameter selection and adaptation strategies in a modified firefly algorithm — adaptive firefly algorithm (AdaFa). There are three strategies in AdaFa including (1) a distance-based light absorption coefficient; (2) a gray coefficient enhancing fireflies to share difference information from attractive ones efficiently; and (3) five different dynamic strategies for the randomization parameter. Promising selections of parameters in the strategies are analyzed to guarantee the efficient performance of AdaFa. AdaFa is validated over widely used benchmark functions, and the numerical experiments and statistical tests yield useful conclusions on the strategies and the parameter selections affecting the performance of AdaFa. When applied to the real-world problem — protein tertiary structure prediction, the results demonstrated improved variants can rebuild the tertiary structure with the average root mean square deviation less than 0.4Å and 1.5Å from the native constrains with noise free and 10% Gaussian white noise. PMID:25397812

Effects of antiglucocorticoid RU 486 on development of obesity in obese fa/fa Zucker rats.

PubMed

Langley, S C; York, D A

1990-09-01

The effects of RU 486 (mitepristone), an antagonist of type II glucocorticoid receptors (GR), on the development of obesity in young 5-wk-old obese fa/fa rats has been investigated. After 15 days of treatment, body composition of obese RU 486-treated rats was similar to that of lean-vehicle rats. Analysis of body composition changes showed that RU 486 effectively reversed the obesity. It stopped fat deposition in obese rats but increased protein deposition to the level of lean-vehicle rats. RU 486 prevented the development of hyperphagia and reduced gross energetic efficiency in the obese rats but had little effect on lean rats. Brown adipose tissue mitochondrial GDP binding was increased in obese rats but was reduced in lean rats by RU 486 treatment. RU 486 also reduced the elevated activity of hippocampal glycerophosphate dehydrogenase, a glucocorticoid-responsive enzyme, of obese rats to the level of lean rats. The evidence suggests that abnormal activity of glucocorticoid GR receptors or abnormal cellular responsiveness to corticosterone receptor complexes may be important in the development of obesity in the fa/fa rat.

CRISPR/Cas9-Mediated Correction of the FANCD1 Gene in Primary Patient Cells.

PubMed

Skvarova Kramarzova, Karolina; Osborn, Mark J; Webber, Beau R; DeFeo, Anthony P; McElroy, Amber N; Kim, Chong Jai; Tolar, Jakub

2017-06-14

Fanconi anemia (FA) is an inherited condition characterized by impaired DNA repair, physical anomalies, bone marrow failure, and increased incidence of malignancy. Gene editing holds great potential to precisely correct the underlying genetic cause such that gene expression remains under the endogenous control mechanisms. This has been accomplished to date only in transformed cells or their reprogrammed induced pluripotent stem cell counterparts; however, it has not yet been reported in primary patient cells. Here we show the ability to correct a mutation in Fanconi anemia D1 ( FANCD1 ) primary patient fibroblasts. The clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system was employed to target and correct a FANCD1 gene deletion. Homologous recombination using an oligonucleotide donor was achieved and a pure population of modified cells was obtained by using inhibitors of poly adenosine diphosphate-ribose polymerase (poly ADP-ribose polymerase). FANCD1 function was restored and we did not observe any promiscuous cutting of the CRISPR/Cas9 at off target sites. This consideration is crucial in the context of the pre-malignant FA phenotype. Altogether we show the ability to correct a patient mutation in primary FANCD1 cells in a precise manner. These proof of principle studies support expanded application of gene editing for FA.

Overexpression of protein kinase FA/GSK-3 alpha (a proline-directed protein kinase) correlates with human hepatoma dedifferentiation/progression.

PubMed

Yang, S D; Yu, J S; Yang, C C; Lee, S C; Lee, T T; Ni, M H; Kuan, C Y; Chen, H C

1996-05-01

Computer analysis of protein phosphorylation sites sequence revealed that transcriptional factors and viral oncoproteins are prime targets for regulation of proline-directed protein phosphorylation, suggesting an association of the proline-directed protein kinase (PDPK) family with neoplastic transformation and tumorigenesis. In this report, an immunoprecipitate activity assay of protein kinase FA/glycogen synthase kinase-3 alpha (kinase F(A)/GSK-3 alpha) (a member of PDPK family) has been optimized for human hepatoma and used to demonstrate for the first time significantly increased (P < 0.01) activity in poorly differentiated SK-Hep-1 hepatoma (24.2 +/- 2.8 units/mg) and moderately differentiated Mahlavu hepatoma (14.5 +/- 2.2 units/mg) when compared to well differentiated Hep 3B hepatoma (8.0 +/- 2.4 units/mg). Immunoblotting analysis revealed that increased activity of kinase FA/GSK-3 alpha is due to overexpression of the protein. Elevated kinase FA/GSK-3 alpha expression in human hepatoma biopsies relative to normal liver tissue was found to be even more profound. This kinase appeared to be fivefold overexpressed in well differentiated hepatoma and 13-fold overexpressed in poorly differentiated hepatoma when compared to normal liver tissue. Taken together, the results provide initial evidence that overexpression of kinase FA/GSK-3 alpha is involved in human hepatoma dedifferentiation/progression. Since kinase FA/GSK-3 alpha is a PDPK, the results further support a potential role of this kinase in human liver tumorigenesis, especially in its dedifferentiation/progression.

Systems-level computational modeling demonstrates fuel selection switching in high capacity running and low capacity running rats

PubMed Central

Qi, Nathan R.

2018-01-01

High capacity and low capacity running rats, HCR and LCR respectively, have been bred to represent two extremes of running endurance and have recently demonstrated disparities in fuel usage during transient aerobic exercise. HCR rats can maintain fatty acid (FA) utilization throughout the course of transient aerobic exercise whereas LCR rats rely predominantly on glucose utilization. We hypothesized that the difference between HCR and LCR fuel utilization could be explained by a difference in mitochondrial density. To test this hypothesis and to investigate mechanisms of fuel selection, we used a constraint-based kinetic analysis of whole-body metabolism to analyze transient exercise data from these rats. Our model analysis used a thermodynamically constrained kinetic framework that accounts for glycolysis, the TCA cycle, and mitochondrial FA transport and oxidation. The model can effectively match the observed relative rates of oxidation of glucose versus FA, as a function of ATP demand. In searching for the minimal differences required to explain metabolic function in HCR versus LCR rats, it was determined that the whole-body metabolic phenotype of LCR, compared to the HCR, could be explained by a ~50% reduction in total mitochondrial activity with an additional 5-fold reduction in mitochondrial FA transport activity. Finally, we postulate that over sustained periods of exercise that LCR can partly overcome the initial deficit in FA catabolic activity by upregulating FA transport and/or oxidation processes. PMID:29474500

GS-Nitroxide (JP4-039)-Mediated Radioprotection of Human Fanconi Anemia Cell Lines

PubMed Central

Bernard, Mark E.; Kim, Hyun; Berhane, Hebist; Epperly, Michael W.; Franicola, Darcy; Zhang, Xichen; Houghton, Frank; Shields, Donna; Wang, Hong; Bakkenist, Christopher J.; Frantz, Marie-Celine; Forbeck, Erin M.; Goff, Julie P.; Wipf, Peter; Greenberger, Joel S.

2011-01-01

Fanconi anemia (FA) is an inherited disorder characterized by defective DNA repair and cellular sensitivity to DNA crosslinking agents. Clinically, FA is associated with high risk for marrow failure, leukemia and head and neck squamous cell carcinoma (HNSCC). Radiosensitivity in FA patients compromises the use of total-body irradiation for hematopoietic stem cell transplantation and radiation therapy for HNSCC. A radioprotector for the surrounding tissue would therefore be very valuable during radiotherapy for HNSCC. Clonogenic radiation survival curves were determined for pre- or postirradiation treatment with the parent nitroxide Tempol or JP4-039 in cells of four FA patient-derived cell lines and two transgene-corrected subclonal lines. FancG–/– (PD326) and FancD2–/– (PD20F) patient lines were more sensitive to the DNA crosslinking agent mitomycin C (MMC) than their transgene-restored subclonal cell lines (both P < 0.0001). FancD2–/– cells were more radiosensitive than the transgene restored subclonal cell line (ñ = 2.0 ± 0.7 and 4.7 ± 2.2, respectively, P = 0.03). In contrast, FancG–/– cells were radioresistant relative to the transgene-restored subclonal cell line (ñ = 9.4 ± 1.5 and 2.2 ± 05, respectively, P = 0.001). DNA strand breaks measured by the comet assay correlated with radiosensitivity. Cell lines from a Fanc-C and Fanc-A patients showed radiosensitivity similar to that of Fanc-D2–/– cells. A fluorophore-tagged JP4-039 (BODIPY-FL) analog targeted the mitochondria of the cell lines. Preirradiation or postirradiation treatment with JP4-039 at a lower concentration than Tempol significantly increased the radioresistance and stabilized the antioxidant stores of all cell lines. Tempol increased the toxicity of MMC in FancD2–/– cells. These data provide support for the potential clinical use of JP4-039 for normal tissue radioprotection during chemoradiotherapy in FA patients. PMID:21939290

GS-nitroxide (JP4-039)-mediated radioprotection of human Fanconi anemia cell lines.

PubMed

Bernard, Mark E; Kim, Hyun; Berhane, Hebist; Epperly, Michael W; Franicola, Darcy; Zhang, Xichen; Houghton, Frank; Shields, Donna; Wang, Hong; Bakkenist, Christopher J; Frantz, Marie-Celine; Forbeck, Erin M; Goff, Julie P; Wipf, Peter; Greenberger, Joel S

2011-11-01

Fanconi anemia (FA) is an inherited disorder characterized by defective DNA repair and cellular sensitivity to DNA crosslinking agents. Clinically, FA is associated with high risk for marrow failure, leukemia and head and neck squamous cell carcinoma (HNSCC). Radiosensitivity in FA patients compromises the use of total-body irradiation for hematopoietic stem cell transplantation and radiation therapy for HNSCC. A radioprotector for the surrounding tissue would therefore be very valuable during radiotherapy for HNSCC. Clonogenic radiation survival curves were determined for pre- or postirradiation treatment with the parent nitroxide Tempol or JP4-039 in cells of four FA patient-derived cell lines and two transgene-corrected subclonal lines. FancG(-/-) (PD326) and FancD2(-/-) (PD20F) patient lines were more sensitive to the DNA crosslinking agent mitomycin C (MMC) than their transgene-restored subclonal cell lines (both P < 0.0001). FancD2(-/-) cells were more radiosensitive than the transgene restored subclonal cell line (ñ = 2.0 ± 0.7 and 4.7 ± 2.2, respectively, P = 0.03). In contrast, FancG(-/-) cells were radioresistant relative to the transgene-restored subclonal cell line (ñ = 9.4 ± 1.5 and 2.2 ± 05, respectively, P = 0.001). DNA strand breaks measured by the comet assay correlated with radiosensitivity. Cell lines from a Fanc-C and Fanc-A patients showed radiosensitivity similar to that of Fanc-D2(-/-) cells. A fluorophore-tagged JP4-039 (BODIPY-FL) analog targeted the mitochondria of the cell lines. Preirradiation or postirradiation treatment with JP4-039 at a lower concentration than Tempol significantly increased the radioresistance and stabilized the antioxidant stores of all cell lines. Tempol increased the toxicity of MMC in FancD2(-/-) cells. These data provide support for the potential clinical use of JP4-039 for normal tissue radioprotection during chemoradiotherapy in FA patients.

Analysis of correlation between white matter changes and functional responses in thalamic stroke: a DTI & EEG study.

PubMed

Duru, Adil Deniz; Duru, Dilek Göksel; Yumerhodzha, Sami; Bebek, Nerses

2016-06-01

Diffusion tensor imaging (DTI) allows in vivo structural brain mapping and detection of microstructural disruption of white matter (WM). One of the commonly used parameters for grading the anisotropic diffusivity in WM is fractional anisotropy (FA). FA value helps to quantify the directionality of the local tract bundle. Therefore, FA images are being used in voxelwise statistical analyses (VSA). The present study used Tract-Based Spatial Statistics (TBSS) of FA images across subjects, and computes the mean skeleton map to detect voxelwise knowledge of the tracts yielding to groupwise comparison. The skeleton image illustrates WM structure and shows any changes caused by brain damage. The microstructure of WM in thalamic stroke is investigated, and the VSA results of healthy control and thalamic stroke patients are reported. It has been shown that several skeleton regions were affected subject to the presence of thalamic stroke (FWE, p < 0.05). Furthermore the correlation of quantitative EEG (qEEG) scores and neurophysiological tests with the FA skeleton for the entire test group is also investigated. We compared measurements that are related to the same fibers across subjects, and discussed implications for VSA of WM in thalamic stroke cases, for the relationship between behavioral tests and FA skeletons, and for the correlation between the FA maps and qEEG scores.Results obtained through the regression analyses did not exceed the corrected statistical threshold values for multiple comparisons (uncorrected, p < 0.05). However, in the regression analysis of FA values and the theta band activity of EEG, cingulum bundle and corpus callosum were found to be related. These areas are parts of the Default Mode Network (DMN) where DMN is known to be involved in resting state EEG theta activity. The relation between the EEG alpha band power values and FA values of the skeleton was found to support the cortico-thalamocortical cycles for both subject groups. Further, the neurophysiological tests including Benton Face Recognition (BFR), Digit Span test (DST), Warrington Topographic Memory test (WTMT), California Verbal Learning test (CVLT) has been regressed with the FA skeleton maps for both subject groups. Our results corresponding to DST task were found to be similar with previously reported findings for working memory and episodic memory tasks. For the WTMT, FA values of the cingulum (right) that plays a role in memory process was found to be related with the behavioral responses. Splenium of corpus callosum was found to be correlated for both subject groups for the BFR.

Isolation, purification and analysis of dissolved organic carbon from Gohagoda uncontrolled open dumpsite leachate, Sri Lanka.

PubMed

Vithanage, Meththika; Wijesekara, Hasintha; Mayakaduwa, S S

2017-07-01

Extract and analysis of the Dissolved Organic Carbon (DOC) fractions were analyzed from the leachate of an uncontrolled dumpsite at Gohagoda, Sri Lanka. DOC fractions, humic acid (HA), fulvic acid (FA) and the hydrophilic (Hyd) fractions were isolated and purified with the resin techniques. Spectroscopic techniques and elemental analysis were performed to characterize DOCs. Maximum TOC and DOC values recorded were 56,955 and 28,493 mg/L, respectively. Based on the total amount of DOC fractionation, Hyd dominated accounting for ∼60%, and HA and FA constituted ∼22% and ∼17%, respectively, exhibiting the mature phase of the dumpsite. The elemental analysis of DOCs revealed carbon variation following HA > FA > Hyd, while hydrogen and nitrogen were similar in each fraction. The N/C ratio for HA was recorded as 0.18, following a similar trend in old dumpsite leachate elsewhere. The O/C ratios for HA and FA were recorded higher as much as 1.0 and 9.3, respectively, indicating high degree of carbon mineralization in the leachates. High content of carboxylic, phenolic and lactone groups in all DOCs was observed disclosing their potential for toxic substances transportation. The results strongly suggest the risk associated with DOCs in dumpsite leachate to the aquatic and terrestrial environment.

Yamadazyma kitorensis f.a., sp. nov. and Zygoascus biomembranicola f.a., sp. nov., novel yeasts from the stone chamber interior of the Kitora tumulus, and five novel combinations in Yamadazyma and Zygoascus for species of Candida.

PubMed

Nagatsuka, Yuka; Ninomiya, Shinya; Kiyuna, Tomohiko; Kigawa, Rika; Sano, Chie; Sugiyama, Junta

2016-04-01

Analysis of D1/D2 large-subunit (LSU) rRNA gene sequences predicted that 17 yeast isolates, mainly from viscous gels (biofilms) taken from the stone chamber interior of the Kitora tumulus in Nara, Japan, were placed in the Yamadazyma and Zygoascus clades. Polyphasic characterization, including morphological, physiological and chemotaxonomic characteristics, multigene sequence divergence and DNA-DNA hybridization, strongly suggested the assignment of one novel species to each of the clades; these are Yamadazyma kitorensis f.a., sp. nov., with the type strain JCM 31005T (ex-type CBS 14158T=isolate K8617-6-8T), and Zygoascus biomembranicola f.a., sp. nov., with the type strain JCM 31007T (ex-type CBS 14157T=isolate K61208-2-11T). Furthermore, the transfer of five known species of the genus Candida as novel combinations to the genera Yamadazyma and Zygoascus is proposed; these are Yamadazyma olivae f.a., comb. nov. (type strain CBS 11171T=ATCC MYA-4568T), Yamadazyma tumulicola f.a., comb. nov. (type strain JCM 15403T=ex-type CBS 10917T=isolate T6517-9-5T), Yamadazyma takamatsuzukensis f.a., comb. nov. (type strain JCM 15410T=CBS 10916T = isolate T4922-1-1T), Zygoascus polysorbophila f.a., comb. nov. (type strain NRRL Y-27161T=CBS 7317T) and Zygoascus bituminiphila f.a., comb. nov. (type strain CBS 8813T=MUCL 41424T).

Exploring JLA supernova data with improved flux-averaging technique

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

Wang, Shuang; Wen, Sixiang; Li, Miao, E-mail: wangshuang@mail.sysu.edu.cn, E-mail: wensx@mail2.sysu.edu.cn, E-mail: limiao9@mail.sysu.edu.cn

2017-03-01

In this work, we explore the cosmological consequences of the ''Joint Light-curve Analysis'' (JLA) supernova (SN) data by using an improved flux-averaging (FA) technique, in which only the type Ia supernovae (SNe Ia) at high redshift are flux-averaged. Adopting the criterion of figure of Merit (FoM) and considering six dark energy (DE) parameterizations, we search the best FA recipe that gives the tightest DE constraints in the ( z {sub cut}, Δ z ) plane, where z {sub cut} and Δ z are redshift cut-off and redshift interval of FA, respectively. Then, based on the best FA recipe obtained, wemore » discuss the impacts of varying z {sub cut} and varying Δ z , revisit the evolution of SN color luminosity parameter β, and study the effects of adopting different FA recipe on parameter estimation. We find that: (1) The best FA recipe is ( z {sub cut} = 0.6, Δ z =0.06), which is insensitive to a specific DE parameterization. (2) Flux-averaging JLA samples at z {sub cut} ≥ 0.4 will yield tighter DE constraints than the case without using FA. (3) Using FA can significantly reduce the redshift-evolution of β. (4) The best FA recipe favors a larger fractional matter density Ω {sub m} . In summary, we present an alternative method of dealing with JLA data, which can reduce the systematic uncertainties of SNe Ia and give the tighter DE constraints at the same time. Our method will be useful in the use of SNe Ia data for precision cosmology.« less

Aeroservoelastic Modeling and Validation of a Thrust-Vectoring F/A-18 Aircraft

NASA Technical Reports Server (NTRS)

Brenner, Martin J.

1996-01-01

An F/A-18 aircraft was modified to perform flight research at high angles of attack (AOA) using thrust vectoring and advanced control law concepts for agility and performance enhancement and to provide a testbed for the computational fluid dynamics community. Aeroservoelastic (ASE) characteristics had changed considerably from the baseline F/A-18 aircraft because of structural and flight control system amendments, so analyses and flight tests were performed to verify structural stability at high AOA. Detailed actuator models that consider the physical, electrical, and mechanical elements of actuation and its installation on the airframe were employed in the analysis to accurately model the coupled dynamics of the airframe, actuators, and control surfaces. This report describes the ASE modeling procedure, ground test validation, flight test clearance, and test data analysis for the reconfigured F/A-18 aircraft. Multivariable ASE stability margins are calculated from flight data and compared to analytical margins. Because this thrust-vectoring configuration uses exhaust vanes to vector the thrust, the modeling issues are nearly identical for modem multi-axis nozzle configurations. This report correlates analysis results with flight test data and makes observations concerning the application of the linear predictions to thrust-vectoring and high-AOA flight.

Long-Term Dynamic Monitoring of the Historical Masonry FAÇADE: the Case of Palazzo Ducale in Venice, Italy

NASA Astrophysics Data System (ADS)

Noh, J.; Russo, S.

2017-08-01

Long-term dynamic monitoring of the masonry façade of Palazzo Ducale known as Doge's palace in Venice, Italy was performed from September 2010 to October 2012. This article demonstrates the results of preliminary analysis on the data set of the first 12-month long monitoring campaign for out-of-plumb dynamic responses of the medieval façade of the monument. The aim of the analysis of the dynamic signals is to validate the data set and investigate dynamic characteristics of the vibration signature of the historical masonry wall in the long-term. Palazzo Ducale is a heavily visited heritage due to its high cultural importance and architectural value. Nevertheless, little is known about the dynamic behaviour of the double-leaf masonry façade. In this study, the dynamic properties of the structure are presented by dynamic identification carried out with the effect of the ambient vibration measured at four different locations on the façade and portico level. The trend and intensity of the vibration at each measurement locations are identified over the year. In addition, the issue on eliminating the noise blended in the signals for reliable analysis are also discussed.

Novel Variations of FANCA Gene Provokes Fanconi Anemia: Molecular Diagnosis in a Special Chinese Family.

PubMed

Li, Niu; Song, Aiyun; Ding, Lixia; Zhu, Hua; Li, Guoqiang; Miao, Yan; Wang, Jian; Li, Benshang; Chen, Jing

2018-07-01

Fanconi anemia (FA) is a rare autosomal recessive or X-linked disorder with highly variable clinical manifestations and an incidence of ∼1 to 5 in 1 million births. To date, 15 bona fide FA genes have been reported to be responsible for the known FA complementation groups and the FANCA gene accounts for almost 60%. In the present study, we report a special Chinese family, which has 2 children with classic FA characteristics. Via 2-step analysis of the whole-exome sequencing data and verification using multiplex ligation-dependent probe amplification test, one child was found to have a novel compound heterozygous mutation of a splicing variant (c.1471-1G>A) and a large intragenic deletion (exons 23-30 del) of the FANCA gene. The other child had the same splicing variant and another novel large deletion (exons 1-18 del) in the FANCA gene. Clone sequencing showed the c.1471-1G>A variant generate an altered transcript with 1 cryptic splice site in intron 15, resulting in a premature termination codon (p.Val490HisfsX6). This study not only shows the complexity of FA molecular diagnosis via comprehensively studying the FA pathogenic genes and the mutational spectrum, but also has significant reference value for the future molecular diagnosis of FA.

Uncertainty analysis of the nonideal competitive adsorption-donnan model: effects of dissolved organic matter variability on predicted metal speciation in soil solution.

PubMed

Groenenberg, Jan E; Koopmans, Gerwin F; Comans, Rob N J

2010-02-15

Ion binding models such as the nonideal competitive adsorption-Donnan model (NICA-Donnan) and model VI successfully describe laboratory data of proton and metal binding to purified humic substances (HS). In this study model performance was tested in more complex natural systems. The speciation predicted with the NICA-Donnan model and the associated uncertainty were compared with independent measurements in soil solution extracts, including the free metal ion activity and fulvic (FA) and humic acid (HA) fractions of dissolved organic matter (DOM). Potentially important sources of uncertainty are the DOM composition and the variation in binding properties of HS. HS fractions of DOM in soil solution extracts varied between 14 and 63% and consisted mainly of FA. Moreover, binding parameters optimized for individual FA samples show substantial variation. Monte Carlo simulations show that uncertainties in predicted metal speciation, for metals with a high affinity for FA (Cu, Pb), are largely due to the natural variation in binding properties (i.e., the affinity) of FA. Predictions for metals with a lower affinity (Cd) are more prone to uncertainties in the fraction FA in DOM and the maximum site density (i.e., the capacity) of the FA. Based on these findings, suggestions are provided to reduce uncertainties in model predictions.

High-Content Microscopy Analysis of Subcellular Structures: Assay Development and Application to Focal Adhesion Quantification.

PubMed

Kroll, Torsten; Schmidt, David; Schwanitz, Georg; Ahmad, Mubashir; Hamann, Jana; Schlosser, Corinne; Lin, Yu-Chieh; Böhm, Konrad J; Tuckermann, Jan; Ploubidou, Aspasia

2016-07-01

High-content analysis (HCA) converts raw light microscopy images to quantitative data through the automated extraction, multiparametric analysis, and classification of the relevant information content. Combined with automated high-throughput image acquisition, HCA applied to the screening of chemicals or RNAi-reagents is termed high-content screening (HCS). Its power in quantifying cell phenotypes makes HCA applicable also to routine microscopy. However, developing effective HCA and bioinformatic analysis pipelines for acquisition of biologically meaningful data in HCS is challenging. Here, the step-by-step development of an HCA assay protocol and an HCS bioinformatics analysis pipeline are described. The protocol's power is demonstrated by application to focal adhesion (FA) detection, quantitative analysis of multiple FA features, and functional annotation of signaling pathways regulating FA size, using primary data of a published RNAi screen. The assay and the underlying strategy are aimed at researchers performing microscopy-based quantitative analysis of subcellular features, on a small scale or in large HCS experiments. © 2016 by John Wiley & Sons, Inc. Copyright © 2016 John Wiley & Sons, Inc.

Development and application of nanoparticles synthesized with folic acid-conjugated soy protein

USDA-ARS?s Scientific Manuscript database

In this study, soy protein isolate (SPI) was conjugated with folic acid (FA) to prepare nanoparticles for target-specific drug delivery. Successful conjugation was evidenced by UV spectrophotometry and primary amino group analysis. An increase in count rate by at least 142% was observed in FA-conjug...

False-Positive Tangible Outcomes of Functional Analyses

ERIC Educational Resources Information Center

Rooker, Griffin W.; Iwata, Brian A.; Harper, Jill M.; Fahmie, Tara A.; Camp, Erin M.

2011-01-01

Functional analysis (FA) methodology is the most precise method for identifying variables that maintain problem behavior. Occasionally, however, results of an FA may be influenced by idiosyncratic sensitivity to aspects of the assessment conditions. For example, data from several studies suggest that inclusion of a tangible condition during an FA…

Homozygosity mapping of Fanconi anemia

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

Gschwend, M.; Botstein, D.; Kruglyak, L.

1994-09-01

Fanconi anemia (FA) is a rare, recessive, genetically heterogeneous disease characterized by progressive insufficiency of the bone marrow and increased cellular sensitivity to DNA crosslinking agents. Complementation tests among different FA cells have indicated the presence of at least 4 FA-causing genes. One of the genes, FACC, was identified by functional complementation but appears unlikely to account for many phenotypically indistinguishable FA caes. We have begun a linkage study of FA using {open_quotes}homozygosity mapping{close_quotes}, a method that involves genotyping with DNA markers on affected individuals whose parents are related. Because FA is a rare recessive disease, it is most likelymore » that probands are homozygous by descent at the disease locus and, therefore, at nearby DNA markers. Although the probability that any given marker will be homozygous in an inbred individual is high, given markers with moderate heterozygosities, the chance that two unrelated inbred individuals will be homozygous at the same marker is considerably lower. By locating overlapping regions of homozygosity between different families we hope to identify genes that cause FA. Sixteen consanguineous non-FACC FA families from the International Fanconi Anemia Registry at Rockefeller University are under study. An efficient algorithm for data analysis was developed and incorporated into software that can quickly compute exact multipoint lod scores using all markers on an entire chromosome. At the time of this writing, 171 of 229 microsatellite markers spaced at 20 cM intervals across the genome have been analyzed.« less

Fatty acid composition and desaturase gene expression in flax (Linum usitatissimum L.).

PubMed

Thambugala, Dinushika; Cloutier, Sylvie

2014-11-01

Little is known about the relationship between expression levels of fatty acid desaturase genes during seed development and fatty acid (FA) composition in flax. In the present study, we looked at promoter structural variations of six FA desaturase genes and their relative expression throughout seed development. Computational analysis of the nucleotide sequences of the sad1, sad2, fad2a, fad2b, fad3a and fad3b promoters showed several basic transcriptional elements including CAAT and TATA boxes, and several putative target-binding sites for transcription factors, which have been reported to be involved in the regulation of lipid metabolism. Using semi-quantitative reverse transcriptase PCR, the expression patterns throughout seed development of the six FA desaturase genes were measured in six flax genotypes that differed for FA composition but that carried the same desaturase isoforms. FA composition data were determined by phenotyping the field grown genotypes over four years in two environments. All six genes displayed a bell-shaped pattern of expression peaking at 20 or 24 days after anthesis. Sad2 was the most highly expressed. The expression of all six desaturase genes did not differ significantly between genotypes (P = 0.1400), hence there were no correlations between FA desaturase gene expression and variations in FA composition in relatively low, intermediate and high linolenic acid genotypes expressing identical isoforms for all six desaturases. These results provide further clues towards understanding the genetic factors responsible for FA composition in flax.

Source apportionment of trace metals in surface waters of a polluted stream using multivariate statistical analyses.

PubMed

Pekey, Hakan; Karakaş, Duran; Bakoğlu, Mithat

2004-11-01

Surface water samples were collected from ten previously selected sites of the polluted Dil Deresi stream, during two field surveys, December 2001 and April 2002. All samples were analyzed using ICP-AES, and the concentrations of trace metals (Al, As, Ba, Cd, Co, Cr, Cu, Fe, Pb, Sn and Zn) were determined. The results were compared with national and international water quality guidelines, as well as literature values reported for similar rivers. Factor analysis (FA) and a factor analysis-multiple regression (FA-MR) model were used for source apportionment and estimation of contributions from identified sources to the concentration of each parameter. By a varimax rotated factor analysis, four source types were identified as the paint industry; sewage, crustal and road traffic runoff for trace metals, explaining about 83% of the total variance. FA-MR results showed that predicted concentrations were calculated with uncertainties lower than 15%.

Factor analytical study of the short version of the World Health Organization Quality of Life Instrument.

PubMed

Ohaeri, Jude U; Olusina, Adewunmi K; Al-Abassi, Abdul-Hamid M

2004-01-01

The domains of the 26-item World Health Organization Quality of Life Instrument (WHOQOL-Bref) contain heterogeneous items and do not encompass the logical constructs of subjective quality of life (QOL). We compared the WHO 4-domain and 6-domain models of the WHOQOL-Bref with the 8-domain model that we obtained from factor analysis (FA). Data from 118 recently recovered Nigerian psychotic patients were used in confirmatory factor analysis (CFA) to assess goodness of fit and clarity of concept. Our FA model had superior goodness of fit for CFA and provided clarity of concept. Analysis of the WHOQOL-Bref should consider the domains from FA and include 'overall QOL' as an item and dependent variable. Subjective QOL is an aggregate of the following constructs: satisfaction with life circumstances; fulfillment of needs, and opportunity for experience in the milieu.

Multi-site genetic analysis of diffusion images and voxelwise heritability analysis: A pilot project of the ENIGMA–DTI working group

PubMed Central

Jahanshad, Neda; Kochunov, Peter; Sprooten, Emma; Mandl, René C.; Nichols, Thomas E.; Almassy, Laura; Blangero, John; Brouwer, Rachel M.; Curran, Joanne E.; de Zubicaray, Greig I.; Duggirala, Ravi; Fox, Peter T.; Hong, L. Elliot; Landman, Bennett A.; Martin, Nicholas G.; McMahon, Katie L.; Medland, Sarah E.; Mitchell, Braxton D.; Olvera, Rene L.; Peterson, Charles P.; Starr, John M.; Sussmann, Jessika E.; Toga, Arthur W.; Wardlaw, Joanna M.; Wright, Margaret J.; Hulshoff Pol, Hilleke E.; Bastin, Mark E.; McIntosh, Andrew M.; Deary, Ian J.; Thompson, Paul M.; Glahn, David C.

2013-01-01

The ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) Consortium was set up to analyze brain measures and genotypes from multiple sites across the world to improve the power to detect genetic variants that influence the brain. Diffusion tensor imaging (DTI) yields quantitative measures sensitive to brain development and degeneration, and some common genetic variants may be associated with white matter integrity or connectivity. DTI measures, such as the fractional anisotropy (FA) of water diffusion, may be useful for identifying genetic variants that influence brain microstructure. However, genome-wide association studies (GWAS) require large populations to obtain sufficient power to detect and replicate significant effects, motivating a multi-site consortium effort. As part of an ENIGMA–DTI working group, we analyzed high-resolution FA images from multiple imaging sites across North America, Australia, and Europe, to address the challenge of harmonizing imaging data collected at multiple sites. Four hundred images of healthy adults aged 18–85 from four sites were used to create a template and corresponding skeletonized FA image as a common reference space. Using twin and pedigree samples of different ethnicities, we used our common template to evaluate the heritability of tract-derived FA measures. We show that our template is reliable for integrating multiple datasets by combining results through meta-analysis and unifying the data through exploratory mega-analyses. Our results may help prioritize regions of the FA map that are consistently influenced by additive genetic factors for future genetic discovery studies. Protocols and templates are publicly available at (http://enigma.loni.ucla.edu/ongoing/dti-working-group/). PMID:23629049

Identification of a novel large intragenic deletion in a family with Fanconi anemia: first molecular report from India and review of literature.

PubMed

Shukla, Pallavi; Rao, Anita; Ghosh, Kanjaksha; Vundinti, Babu Rao

2013-04-15

We report here an Indian case with Fanconi anemia (FA) presented with fever, pallor, short stature, hyperpigmentation and upper limb anomaly. Chromosome breakage analysis together with FANCD2 Western blot monoubiquitination assay confirmed the diagnosis as FA. Multiplex ligation-dependent probe amplification (MLPA) revealed a novel homozygous large intragenic deletion (exons 8-27 del) in the FANCA gene in the proband. His sib and parents were also analyzed and found to be heterozygous for the same mutation. We also reviewed the literature of FANCA large intragenic deletions found in FA patients from different countries and the mechanism involved in the formation of these deletions. To the best of our knowledge, this is the first molecular report from India on FA. The finding expands the mutation spectrum of the FANCA gene. Identification of the mutation confirms the diagnosis of FA at DNA level and helps in providing proper genetic counseling to the family. Copyright © 2013 Elsevier B.V. All rights reserved.

Studies on performance evaluation of a green plasticizer made by enzymatic esterification of furfuryl alcohol and castor oil fatty acid.

PubMed

Mukherjee, Sohini; Ghosh, Mahua

2017-02-10

The esterification of furfuryl alcohol (FA) and castor oil fatty acid (COFA) at 3:1 molar ratio, by immobilized Candida antarctica Lipase B (NS 435 from Novozyme) in a solvent free system gave a maximum yield of 88.64% (%w/w) at 5h. Performance of the FA-COFA ester plasticized Ethyl Cellulose (EC) films were evaluated by surface morphologies, XRD analysis, mechanical properties,thermal properties, water vapor permeability and migration stability test. It was an effective plasticizer with better mechanical properties and thermal stability at the increasing concentration of FA-COFA ester (15-25%) containing EC film, than the traditional plasticizer, i.e; dibutyl phthalate (DBP) in producing good quality films. Chemical structure and the intermolecular interactions between FA-COFA ester and ethyl cellulose chains were the causative agents of these outstanding performances. Therefore, this FA-COFA ester, with significant plasticizing property, at a certain concentration, can be a substitute of DBP. Copyright © 2016 Elsevier Ltd. All rights reserved.

Analysis of features of hydrodynamics and heat transfer in the fuel assembly of prospective sodium reactor with a high rate of reproduction in the uranium-plutonium fuel cycle

NASA Astrophysics Data System (ADS)

Lubina, A. S.; Subbotin, A. S.; Sedov, A. A.; Frolov, A. A.

2016-12-01

The fast sodium reactor fuel assembly (FA) with U-Pu-Zr metallic fuel is described. In comparison with a "classical" fast reactor, this FA contains thin fuel rods and a wider fuel rod grid. Studies of the fluid dynamics and the heat transfer were carried out for such a new FA design. The verification of the ANSYS CFX code was provided for determination of the velocity, pressure, and temperature fields in the different channels. The calculations in the cells and in the FA were carried out using the model of shear stress transport (SST) selected at the stage of verification. The results of the hydrodynamics and heat transfer calculations have been analyzed.

Host-guest inclusion system of ferulic acid with p-Sulfonatocalix[n]arenes: Preparation, characterization and antioxidant activity

NASA Astrophysics Data System (ADS)

Chao, Jianbin; Wang, Huijuan; Song, Kailun; Wang, Yongzhao; Zuo, Ying; Zhang, Liwei; Zhang, Bingtai

2017-02-01

The inclusion complexes of ferulic acid (FA) with p-Sulfonatocalix[n]arenes (SCXn, n = 4, 6, 8) were prepared and characterized both in the solid state and in solution using fluorescence spectroscopy, 1H nuclear magnetic resonance (1H NMR), attenuated total reflectance-fourier transform infrared spectroscopy (ATR-FTIR), atomic force microscopy (AFM) and differential scanning calorimetry (DSC). The results show that FA is able to form inclusion complexes with SCXn in a molar ratio of 1:1, causing a significant decrease in the fluorescence intensity of FA. The association constant of the inclusion complexes was calculated from the fluorescence titration data. 1H NMR spectroscopy analysis demonstrates that the aromatic ring and methoxy group of FA are partially covered by SCXn.

Detection of fatty product falsifications using a portable near infrared spectrometer

NASA Astrophysics Data System (ADS)

Kalinin, A. V.; Krasheninnikov, V. N.

2017-01-01

Spreading sales of counterfeited fatty-oil foods leads to a development of portable and operational analyzer of typical fatty acids (FA) which may be a near infrared (NIR) spectrometer. In this work the calibration models for prediction of named FA were built with the spectra of FT-NIR spectrometer for different absorption bands of the FA. The best parameters were obtained for the wavelength sub-band 1.0-1.8 μ, which includes the 2nd and 3rd overtones of C-H stretching vibrations (near 1.7 and 1.2 μ) and the combination band (1.42 μ). Applicability of the portable spectrometer based on linear NIR array photosensor for the quality analysis of spread, butter and fish oil by the typical FA has been tested.

Characterization of fumonisin A-series by high-resolution liquid chromatography-orbitrap mass spectrometry.

PubMed

Tamura, Masayoshi; Mochizuki, Naoki; Nagatomi, Yasushi; Toriba, Akira; Hayakawa, Kazuichi

2014-08-21

Fumonisin A-series (FAs) in a reference material of corn sample that was naturally contaminated with fumonisins was characterized using high-resolution liquid chromatography-Orbitrap mass spectrometry (LC-Orbitap MS). Peaks for fumonisin B1 (FB1), fumonisin B2 (FB2), and fumonisin B3 (FB3), in addition to three peaks corresponding to unknown compounds I, II, and III, were detected in the chromatogram for the corn sample. Fragment ion analysis for FB1, FB2, and FB3 showed that while the ions formed at m/z values of 200-800 were similar to those formed by the cleavage of the tricarballylic acids and the hydroxyl groups, the fragmentation patterns at m/z values of 50-200 varied depending on the hydroxyl group locations in the compounds. Fragment ion analysis of compounds I-III revealed structural similarities to FBs, only differing by an additional C2H2O in the unknown compounds. Using these results and by comparing the product ion mass spectra of compound I with fumonisin A1 (FA1) synthesized from FB1 standards, compounds I-III were hypothesized to be N-acetyl analogs of FBs: fumonisins A1 (FA1), A2 (FA2), and A3 (FA3). The method for determining concentrations was validated with FA1, FB1, FB2, and FB3 standards and applied to analyze the reference material. The FB1, FB2, and FB3 analytical levels were within acceptance limits and the amount of FA1 in the material was ~15% of FB1 amount at 4.2 mg/kg.

A smart pH-responsive nano-carrier as a drug delivery system for the targeted delivery of ursolic acid: suppresses cancer growth and metastasis by modulating P53/MMP-9/PTEN/CD44 mediated multiple signaling pathways.

PubMed

Jiang, Kai; Chi, Ting; Li, Tao; Zheng, Guirong; Fan, Lulu; Liu, Yajun; Chen, Xiufen; Chen, Sijia; Jia, Lee; Shao, Jingwei

2017-07-13

Ursolic acid (UA) has been recently used as a promising anti-tumor and cancer metastatic chemo-preventive agent due to its low toxicity and liver-protecting property. However, the low bioavailability and nonspecific tumor targeting restrict its further clinical application. To address the problem, a silica-based mesoporous nanosphere (MSN) controlled-release drug delivery system (denoted UA@M-CS-FA) was designed and successfully synthesized, and was functionalized with folic acid (FA) and pH-sensitive chitosan (CS) for the targeted delivery of UA to folate receptor (FR) positive tumor cells. UA@M-CS-FA were spherical with mean diameter below 150 nm, and showed about -20 mV potential. Meanwhile, UA@M-CS-FA exhibited a pH-sensitive release manner and high cellular uptake in FR over-expressing HeLa cancer cells. Also, in vitro cellular assays suggested that UA@M-CS-FA inhibited cancer cell growth, invasion and migration. Mechanistically, UA@M-CS-FA induced cancer cell apoptosis and inhibited migration via cell cycle arrest in the G0/G1 stage, regulating the PARP/Bcl-2/MMP-9/CD44/PTEN/P53. Importantly, in vivo experiments further confirmed that UA@M-CS-FA significantly suppressed the tumor progression and lung metastasis in tumor-bearing nude mice. Immunohistochemical analysis revealed that UA@M-CS-FA treatment regulated CD44, a biomarker of cancer metastasis. Overall, our data demonstrated that a CS and FA modified MSN controlled-release drug delivery system could help broaden the usage of UA and reflect the great application potential of the UA as an anticancer or cancer metastatic chemopreventive agent.

Reproducibility, interrater agreement, and age-related changes of fractional anisotropy measures at 3T in healthy subjects: effect of the applied b-value.

PubMed

Bisdas, S; Bohning, D E; Besenski, N; Nicholas, J S; Rumboldt, Z

2008-06-01

There is no reproducibility study of fractional anisotropy (FA) measurements at 3T using regions of interest (ROIs). Our purpose was to establish the extent and statistical significance of the interrater variability, the variability observed with 2 different b-values, and in 2 separate scanning sessions. Twelve healthy volunteers underwent MR imaging twice. MR imaging was performed on a 3T unit, and FA maps were analyzed independently by 2 observers using ROIs positioned in the corpus callosum, internal capsules, corticospinal tracts, and right thalamus. Changes in FA values (x10(3)) measured with 2 b-values (700 and 1000 s/mm(2)), age-related differences, interobserver agreement, and measurement reproducibility were assessed. In the right internal capsule genu (FA = 702/728; b = 1000/700 s/mm(2)) and the left anterior limb of the internal capsule (AIC; FA = 617/745; b = 1000/700 s/mm(2)), the FA values were significantly different between the 2 b-values (P = .02 and .05, respectively). Significant age-related differences in FA were observed in the genu of the corpus callosum and in the left AIC. Interrater measurements showed fair-to-moderate agreement for most anatomic structures. The lowest significant change for a single subject regarding any FA values between the 2 sessions was in the corpus callosum (4%), whereas the highest one was in the corticospinal tracts (27%). The Bland-Altman plot analysis showed that the 1000-s/mm(2) b-value gave satisfactorily reproducible measurements equally good or better than the 700-s/mm(2) b-value. The reproducibility of FA estimates using ROIs was satisfactory. Measurements with a b-value at 1000 s/mm(2) showed superior reproducibility in most anatomic locations.

Folic acid supplementation and preterm birth: results from observational studies.

PubMed

Mantovani, Elena; Filippini, Francesca; Bortolus, Renata; Franchi, Massimo

2014-01-01

Folic acid (FA) supplementation is recommended worldwide in the periconceptional period for the prevention of neural tube defects. Due to its involvement in a number of cellular processes, its role in other pregnancy outcomes such as miscarriage, recurrent miscarriage, low birth weight, preterm birth (PTB), preeclampsia, abruptio placentae, and stillbirth has been investigated. PTB is a leading cause of perinatal mortality and morbidity; therefore its association with FA supplementation is of major interest. The analysis of a small number of randomized clinical trials (RCTs) has not found a beneficial role of FA in reducing the rate of PTBs. The aim of this review was to examine the results from recent observational studies about the effect of FA supplementation on PTB. We carried out a search on Medline and by manual search of the observational studies from 2009 onwards that analyzed the rate of PTB in patients who received supplementation with FA before and/or throughout pregnancy. The results from recent observational studies suggest a slight reduction of PTBs that is not consistent with the results from RCTs. Further research is needed to better understand the role of FA supplementation before and during pregnancy in PTB.

[Validity and reliability of Korean version of the Family Management Measure (Korean FaMM) for families with children having chronic illness].

PubMed

Kim, Dong Hee; Im, Yeo Jin

2013-02-01

To develop and test the validity and reliability of the Korean version of the Family Management Measure (Korean FaMM) to assess applicability for families with children having chronic illnesses. The Korean FaMM was articulated through forward-backward translation methods. Internal consistency reliability, construct and criterion validity were calculated using PASW WIN (19.0) and AMOS (20.0). Survey data were collected from 341 mothers of children suffering from chronic disease enrolled in a university hospital in Seoul, South Korea. The Korean version of FaMM showed reliable internal consistency with Cronbach's alpha for the total scale of .69-.91. Factor loadings of the 53 items on the six sub-scales ranged from 0.28-0.84. The model of six subscales for the Korean FaMM was validated by expiratory and confirmatory factor analysis (χ²<.001, RMR<.05, GFI, AGFI, NFI, NNFI>.08). Criterion validity compared to the Parental Stress Index (PSI) showed significant correlation. The findings of this study demonstrate that the Korean FaMM showed satisfactory construct and criterion validity and reliability. It is useful to measure Korean family's management style with their children who have a chronic illness.

Diffusion tensor imaging with quantitative evaluation and fiber tractography of lumbar nerve roots in sciatica.

PubMed

Shi, Yin; Zong, Min; Xu, Xiaoquan; Zou, Yuefen; Feng, Yang; Liu, Wei; Wang, Chuanbing; Wang, Dehang

2015-04-01

To quantitatively evaluate nerve roots by measuring fractional anisotropy (FA) values in healthy volunteers and sciatica patients, visualize nerve roots by tractography, and compare the diagnostic efficacy between conventional magnetic resonance imaging (MRI) and DTI. Seventy-five sciatica patients and thirty-six healthy volunteers underwent MR imaging using DTI. FA values for L5-S1 lumbar nerve roots were calculated at three levels from DTI images. Tractography was performed on L3-S1 nerve roots. ROC analysis was performed for FA values. The lumbar nerve roots were visualized and FA values were calculated in all subjects. FA values decreased in compressed nerve roots and declined from proximal to distal along the compressed nerve tracts. Mean FA values were more sensitive and specific than MR imaging for differentiating compressed nerve roots, especially in the far lateral zone at distal nerves. DTI can quantitatively evaluate compressed nerve roots, and DTT enables visualization of abnormal nerve tracts, providing vivid anatomic information and localization of probable nerve compression. DTI has great potential utility for evaluating lumbar nerve compression in sciatica. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Implications of obesity for tendon structure, ultrastructure and biochemistry: a study on Zucker rats.

PubMed

Biancalana, Adriano; Velloso, Lício Augusto; Taboga, Sebastião Roberto; Gomes, Laurecir

2012-02-01

The extracellular matrix consists of collagen, proteoglycans and non-collagen proteins. The incidence of obesity and associated diseases is currently increasing in developed countries. Obesity is considered to be a disease of modern times, and genes predisposing to the disease have been identified in humans and animals. The objective of the present study was to compare the morphological and biochemical aspects of the deep digital flexor tendon of lean (Fa/Fa or Fa/fa) and genetically obese (fa/fa) Zucker rats. Ultrastructural analysis showed the presence of lipid droplets in both groups, whereas disorganized collagen fibril bundles were observed in obese animals. Lean animals presented a larger amount of non-collagen proteins and glycosaminoglycans than obese rats. We propose that the overweight and lesser physical activity in obese animals may have provoked the alterations in the composition and organization of extracellular matrix components but a genetic mechanism cannot be excluded. These alterations might be related to organizational and structural modifications in the collagen bundles that influence the mechanical properties of tendons and the progression to a pathological state. Copyright © 2011 Elsevier Ltd. All rights reserved.

Conversion of fusaric acid to fusarinol by Aspergillus niger: A detoxification reaction

USDA-ARS?s Scientific Manuscript database

The fungus Fusarium oxysporum causes wilt diseases of plants and produces a potent phytotoxin fusaric acid (FA) which is also toxic to many microorganisms. An Aspergillus strain with high tolerance to FA was isolated from soil. HPLC analysis of culture filtrates from A. niger grown with the addition...

Training Teachers to Conduct Trial-Based Functional Analyses

ERIC Educational Resources Information Center

Kunnavatana, S. Shanun; Bloom, Sarah E.; Samaha, Andrew L.; Dayton, Elizabeth

2013-01-01

The trial-based functional analysis (FA) is a promising approach to identification of behavioral function and is especially suited for use in educational settings. Not all studies on trial-based FA have included teachers as therapists, and those studies that have, included minimal information on teacher training. The purpose of this study was to…

Loss-of-Function FANCL Mutations Associate with Severe Fanconi Anemia Overlapping the VACTERL Association.

PubMed

Vetro, Annalisa; Iascone, Maria; Limongelli, Ivan; Ameziane, Najim; Gana, Simone; Della Mina, Erika; Giussani, Ursula; Ciccone, Roberto; Forlino, Antonella; Pezzoli, Laura; Rooimans, Martin A; van Essen, Antoni J; Messa, Jole; Rizzuti, Tommaso; Bianchi, Paolo; Dorsman, Josephine; de Winter, Johan P; Lalatta, Faustina; Zuffardi, Orsetta

2015-05-01

The diagnosis of VACTERL syndrome can be elusive, especially in the prenatal life, due to the presence of malformations that overlap those present in other genetic conditions, including the Fanconi anemia (FA). We report on three VACTERL cases within two families, where the two who arrived to be born died shortly after birth due to severe organs' malformations. The suspicion of VACTERL association was based on prenatal ultrasound assessment and postnatal features. Subsequent chromosome breakage analysis suggested the diagnosis of FA. Finally, by next-generation sequencing based on the analysis of the exome in one family and of a panel of Fanconi genes in the second one, we identified novel FANCL truncating mutations in both families. We used ectopic expression of wild-type FANCL to functionally correct the cellular FA phenotype for both mutations. Our study emphasizes that the diagnosis of FA should be considered when VACTERL association is suspected. Furthermore, we show that loss-of-function mutations in FANCL result in a severe clinical phenotype characterized by early postnatal death. © 2015 WILEY PERIODICALS, INC.

Approximation of traveling wave solutions in wall-bounded flows using resolvent modes

NASA Astrophysics Data System (ADS)

McKeon, Beverley; Graham, Michael; Moarref, Rashad; Park, Jae Sung; Sharma, Ati; Willis, Ashley

2014-11-01

Significant recent attention has been devoted to computing and understanding exact traveling wave solutions of the Navier-Stokes equations. These solutions can be interpreted as the state-space skeleton of turbulence and are attractive benchmarks for studying low-order models of wall turbulence. Here, we project such solutions onto the velocity response (or resolvent) modes supplied by the gain-based resolvent analysis outlined by McKeon & Sharma (JFM, 2010). We demonstrate that in both pipe (Pringle et al., Phil. Trans. R. Soc. A, 2009) and channel (Waleffe, JFM, 2001) flows, the solutions can be well-described by a small number of resolvent modes. Analysis of the nonlinear forcing modes sustaining these solutions reveals the importance of small amplitude forcing, consistent with the large amplifications admitted by the resolvent operator. We investigate the use of resolvent modes as computationally cheap ``seeds'' for the identification of further traveling wave solutions. The support of AFOSR under Grants FA9550-09-1-0701, FA9550-12-1-0469, FA9550-11-1-0094 and FA9550-14-1-0042 (program managers Rengasamy Ponnappan, Doug Smith and Gregg Abate) is gratefully acknowledged.

Diffusion tensor imaging reveals changes in the adult rat brain following long-term and passive moderate acoustic exposure.

PubMed

Abdoli, Sherwin; Ho, Leon C; Zhang, Jevin W; Dong, Celia M; Lau, Condon; Wu, Ed X

2016-12-01

This study investigated neuroanatomical changes following long-term acoustic exposure at moderate sound pressure level (SPL) under passive conditions, without coupled behavioral training. The authors utilized diffusion tensor imaging (DTI) to detect morphological changes in white matter. DTIs from adult rats (n = 8) exposed to continuous acoustic exposure at moderate SPL for 2 months were compared with DTIs from rats (n = 8) reared under standard acoustic conditions. Two distinct forms of DTI analysis were applied in a sequential manner. First, DTI images were analyzed using voxel-based statistics which revealed greater fractional anisotropy (FA) of the pyramidal tract and decreased FA of the tectospinal tract and trigeminothalamic tract of the exposed rats. Region of interest analysis confirmed (p < 0.05) that FA had increased in the pyramidal tract but did not show a statistically significant difference in the FA of the tectospinal or trigeminothalamic tract. The results of the authors show that long-term and passive acoustic exposure at moderate SPL increases the organization of white matter in the pyramidal tract.

Activation of PPARδ signaling improves skeletal muscle oxidative metabolism and endurance function in an animal model of ischemic left ventricular dysfunction

PubMed Central

Zizola, Cynthia; Kennel, Peter J.; Akashi, Hirokazu; Ji, Ruiping; Castillero, Estibaliz; George, Isaac; Homma, Shunichi

2015-01-01

Exercise intolerance in heart failure has been linked to impaired skeletal muscle oxidative capacity. Oxidative metabolism and exercise capacity are regulated by PPARδ signaling. We hypothesized that PPARδ stimulation reverts skeletal muscle oxidative dysfunction. Myocardial infarction (MI) was induced in C57BL/6 mice and the development of ventricular dysfunction was monitored over 8 wk. Mice were randomized to the PPARδ agonist GW501516 (5 mg/kg body wt per day for 4 wk) or placebo 8 wk post-MI. Muscle function was assessed through running tests and grip strength measurements. In muscle, we analyzed muscle fiber cross-sectional area and fiber types, metabolic gene expression, fatty acid (FA) oxidation and ATP content. Signaling pathways were studied in C2C12 myotubes. FA oxidation and ATP levels decreased in muscle from MI mice compared with sham- operated mice. GW501516 administration increased oleic acid oxidation levels in skeletal muscle of the treated MI group compared with placebo treatment. This was accompanied by transcriptional changes including increased CPT1 expression. Further, the PPARδ-agonist improved running endurance compared with placebo. Cell culture experiments revealed protective effects of GW501516 against the cytokine-induced decrease of FA oxidation and changes in metabolic gene expression. Skeletal muscle dysfunction in HF is associated with impaired PPARδ signaling and treatment with the PPARδ agonist GW501516 corrects oxidative capacity and FA metabolism and improves exercise capacity in mice with LV dysfunction. Pharmacological activation of PPARδ signaling could be an attractive therapeutic intervention to counteract the progressive skeletal muscle dysfunction in HF. PMID:25713305

Activation of PPARδ signaling improves skeletal muscle oxidative metabolism and endurance function in an animal model of ischemic left ventricular dysfunction.

PubMed

Zizola, Cynthia; Kennel, Peter J; Akashi, Hirokazu; Ji, Ruiping; Castillero, Estibaliz; George, Isaac; Homma, Shunichi; Schulze, P Christian

2015-05-01

Exercise intolerance in heart failure has been linked to impaired skeletal muscle oxidative capacity. Oxidative metabolism and exercise capacity are regulated by PPARδ signaling. We hypothesized that PPARδ stimulation reverts skeletal muscle oxidative dysfunction. Myocardial infarction (MI) was induced in C57BL/6 mice and the development of ventricular dysfunction was monitored over 8 wk. Mice were randomized to the PPARδ agonist GW501516 (5 mg/kg body wt per day for 4 wk) or placebo 8 wk post-MI. Muscle function was assessed through running tests and grip strength measurements. In muscle, we analyzed muscle fiber cross-sectional area and fiber types, metabolic gene expression, fatty acid (FA) oxidation and ATP content. Signaling pathways were studied in C2C12 myotubes. FA oxidation and ATP levels decreased in muscle from MI mice compared with sham- operated mice. GW501516 administration increased oleic acid oxidation levels in skeletal muscle of the treated MI group compared with placebo treatment. This was accompanied by transcriptional changes including increased CPT1 expression. Further, the PPARδ-agonist improved running endurance compared with placebo. Cell culture experiments revealed protective effects of GW501516 against the cytokine-induced decrease of FA oxidation and changes in metabolic gene expression. Skeletal muscle dysfunction in HF is associated with impaired PPARδ signaling and treatment with the PPARδ agonist GW501516 corrects oxidative capacity and FA metabolism and improves exercise capacity in mice with LV dysfunction. Pharmacological activation of PPARδ signaling could be an attractive therapeutic intervention to counteract the progressive skeletal muscle dysfunction in HF. Copyright © 2015 the American Physiological Society.

Multiple TPR motifs characterize the Fanconi anemia FANCG protein.

PubMed

Blom, Eric; van de Vrugt, Henri J; de Vries, Yne; de Winter, Johan P; Arwert, Fré; Joenje, Hans

2004-01-05

The genome protection pathway that is defective in patients with Fanconi anemia (FA) is controlled by at least eight genes, including BRCA2. A key step in the pathway involves the monoubiquitylation of FANCD2, which critically depends on a multi-subunit nuclear 'core complex' of at least six FANC proteins (FANCA, -C, -E, -F, -G, and -L). Except for FANCL, which has WD40 repeats and a RING finger domain, no significant domain structure has so far been recognized in any of the core complex proteins. By using a homology search strategy comparing the human FANCG protein sequence with its ortholog sequences in Oryzias latipes (Japanese rice fish) and Danio rerio (zebrafish) we identified at least seven tetratricopeptide repeat motifs (TPRs) covering a major part of this protein. TPRs are degenerate 34-amino acid repeat motifs which function as scaffolds mediating protein-protein interactions, often found in multiprotein complexes. In four out of five TPR motifs tested (TPR1, -2, -5, and -6), targeted missense mutagenesis disrupting the motifs at the critical position 8 of each TPR caused complete or partial loss of FANCG function. Loss of function was evident from failure of the mutant proteins to complement the cellular FA phenotype in FA-G lymphoblasts, which was correlated with loss of binding to FANCA. Although the TPR4 mutant fully complemented the cells, it showed a reduced interaction with FANCA, suggesting that this TPR may also be of functional importance. The recognition of FANCG as a typical TPR protein predicts this protein to play a key role in the assembly and/or stabilization of the nuclear FA protein core complex.

Extensive analysis of milk fatty acids in two fat-tailed sheep breeds during lactation.

PubMed

Payandeh, S; Kafilzadeh, F; Juárez, M; de la Fuente, M A; Ghadimi, D; Marín, A L Martínez

2016-12-01

The profile of fatty acids (FA) in the milk fat of two Iranian fat-tailed sheep breeds, Sanjabi and Mehraban, was compared during lactation. Eight ewes of each breed, balanced in parity and carrying one foetus, were selected before parturition. Ewes were kept separated in individual pens during the experimental period, under the same management practices and fed the same diet, in order to eliminate any confounding effects on milk FA profile. Milk was sampled at biweekly intervals up to 10 weeks of lactation, starting 2 weeks after parturition. More than 100 FA were determined in milk fat by means of gas chromatography. The milk fat of Sanjabi ewes contained more cis-9 18:1, that of Mehraban ewes was richer in 10:0, 12:0 and 14:0, and no differences were found for 16:0 and 18:0. No breed differences were found for most branched-chain FA. Mehraban ewes showed a higher presence of vaccenic and rumenic acids in their milk fat. The milk fat of Sanjabi ewes had a lower atherogenicity index and n-6/n-3 FA ratio. The contents of several FA showed time-dependent changes, so breed differences were more apparent or disappeared as lactation progressed. The milk fat of Sanjabi ewes showed a better FA profile from the human health point of view.

Plant growth inhibitors isolated from sugarcane (Saccharum officinarum) straw.

PubMed

Sampietro, Diego Alejandro; Vattuone, Marta Amelia; Isla, María Ines

2006-07-01

Several compounds related with plant defense and pharmacological activities have been isolated from sugarcane. Straw phytotoxins and their possible mechanisms of growth inhibition are largely unknown. A bioassay-guided fractionation of the phytotoxic constituents leachated from a sugarcane straw led to the isolation of trans-ferulic (trans-FA), cis-ferulic (cis-FA), vanillic (VA) and syringic (SA) acids. The straw leachates and their identified constituents significantly inhibited root growth of lettuce and four weeds. VA was more phytotoxic to root elongation than FA and SA. The identified phenolic compounds significantly increased leakage of root cell constituents, inhibited dehydrogenase activity and reduced chlorophyll content in lettuce. VA and FA inhibited mitotic index while SA increased cell division. Additive (VA-FA and FA-SA) and synergistic (VA-SA) interactions on root growth were observed at the response level of EC(25). Although the isolated compounds differed in their relative phytotoxic activities, the observed physiological responses suggest that they have a common mode of action. HPLC analysis indicated that sugarcane straw can potentially release 1.43 (ratio 2:1, trans:cis), 1.14 and 0.14mmolkg(-1) (straw dry weight) of FA, VA and SA, respectively. As phenolic acids are often found spatially concentrated in the top soil layers under plant straws, further studies are needed to establish the impact of these compounds in natural settings.

Personal safety issues related to the use of pesticides in agricultural production in the Al-Batinah region of Northern Oman.

PubMed

Al Zadjali, Said; Morse, Stephen; Chenoweth, Jonathan; Deadman, Mike

2015-01-01

The level of uptake and use of personal protective equipment (PPE) by farm workers in Oman is low; the conditions under which pesticides are stored are frequently below acceptable international standards. Research was undertaken to explore the drivers working against safe storage of agrochemicals and effective personal protection usage by pesticide application personnel. Results from a survey of over 200 respondents, representing workers in, and owners of, farms either within or outside a local farmer's association (FA), suggest that FA membership raises standards of behaviour both in terms of safe pesticide storage and use of PPE. Age of respondents had no apparent effect on the likelihood of PPE (gloves and masks) use. PPE use was, however, highest among respondents with more advanced educational backgrounds. Positive responses for glove and mask use, when applying pesticides, were higher for owners and workers in FA farms compared to non-FA farms. Lowest reported use of PPE was among workers in non-FA farms. Analysis of responses appears to indicate that behaviour patterns of workers in FA farms mirror that of the farm owners. This was not the case in non-FA farms. The results suggest that conformity to social norms, in this case acceptable work-environment behaviour, is a powerful driver behind raised usage levels of PPE in farms in Oman. Copyright © 2014 Elsevier B.V. All rights reserved.

Cleavable DNA-protein hybrid molecular beacon: A novel efficient signal translator for sensitive fluorescence anisotropy bioassay.

PubMed

Hu, Pan; Yang, Bin

2016-01-15

Due to its unique features such as high sensitivity, homogeneous format, and independence on fluorescent intensity, fluorescence anisotropy (FA) assay has become a hotspot of study in oligonucleotide-based bioassays. However, until now most FA probes require carefully customized structure designs, and thus are neither generalizable for different sensing systems nor effective to obtain sufficient signal response. To address this issue, a cleavable DNA-protein hybrid molecular beacon was successfully engineered for signal amplified FA bioassay, via combining the unique stable structure of molecular beacon and the large molecular mass of streptavidin. Compared with single DNA strand probe or conventional molecular beacon, the DNA-protein hybrid molecular beacon exhibited a much higher FA value, which was potential to obtain high signal-background ratio in sensing process. As proof-of-principle, this novel DNA-protein hybrid molecular beacon was further applied for FA bioassay using DNAzyme-Pb(2+) as a model sensing system. This FA assay approach could selectively detect as low as 0.5nM Pb(2+) in buffer solution, and also be successful for real samples analysis with good recovery values. Compatible with most of oligonucleotide probes' designs and enzyme-based signal amplification strategies, the molecular beacon can serve as a novel signal translator to expand the application prospect of FA technology in various bioassays. Copyright © 2015 Elsevier B.V. All rights reserved.

The cleaner, the greener? Product sustainability assessment of the biomimetic façade paint Lotusan® in comparison to the conventional façade paint Jumbosil®

PubMed Central

Antony, Florian; Grießhammer, Rainer; Speck, Thomas

2016-01-01

Background: The debate on the question whether biomimetics has a specific potential to contribute to sustainability is discussed among scientists, business leaders, politicians and those responsible for project funding. The objective of this paper is to contribute to this controversial debate by presenting the sustainability assessment of one of the most well-known and most successful biomimetic products: the façade paint Lotusan®. Results: As a first step it has been examined and verified that the façade paint Lotusan® is correctly defined as a biomimetic product. Secondly, Lotusan® has been assessed and compared to a conventional façade paint within the course of a detailed product sustainability assessment (PROSA). For purposes of comparison, the façade paint Jumbosil® was chosen as reference for a conventional paint available on the market. The benefit analysis showed that both paints fulfil equally well the requirements of functional utility. With respect to the symbolic utility, Lotusan® has a particular added aesthetic value by the preservation of the optical quality over the life cycle. Within the social analysis no substantial differences between the two paints could be found regarding the handling and disposal of the final products. Regarding the life-cycle cost, Lotusan® is the more expensive product. However, the higher investment cost for a Lotusan®-based façade painting are more than compensated by the longer life time, resulting in both reduced overall material demand and lower labour cost. In terms of the life-cycle impact assessment, it can be ascertained that substantial differences between the paints arise from the respective service life, which are presented in terms of four scenario analyses. Conclusion: In summary, the biomimetic façade paint Lotusan® has been identified as a cost-effective and at the same time resource-saving product. Based on the underlying data and assumptions it could be demonstrated that Lotusan®-based façade paintings have a comparatively low overall impact on the environment. Summarizing our results, it can be emphasized that Lotusan® is the more favourable product compared to Jumbosil® according to sustainability aspects. PMID:28144557

Capecitabine Plus Oxaliplatin Compared With Fluorouracil/Folinic Acid As Adjuvant Therapy for Stage III Colon Cancer: Final Results of the NO16968 Randomized Controlled Phase III Trial.

PubMed

Schmoll, Hans-Joachim; Tabernero, Josep; Maroun, Jean; de Braud, Filippo; Price, Timothy; Van Cutsem, Eric; Hill, Mark; Hoersch, Silke; Rittweger, Karen; Haller, Daniel G

2015-11-10

To report the final efficacy findings and biomarker analysis from the NO16968 trial comparing bolus fluorouracil/folinic acid (FU/FA) with capecitabine plus oxaliplatin (XELOX) in resected stage III colon cancer. After curative resection, patients were randomly assigned to receive XELOX, as oxaliplatin 130 mg/m(2) on day 1 and capecitabine 1,000 mg/m(2) twice daily on days 1 to 14 every 3 weeks, or bolus FU/FA, as the Mayo Clinic or Roswell Park regimens, for 6 months. The primary end point was disease-free survival (DFS). Secondary end points included overall survival (OS). The intention-to-treat population comprised 1,886 patients (XELOX, n = 944; FU/FA, n = 942). Seven-year DFS rates were 63% and 56% in the XELOX and FU/FA groups, respectively (hazard ratio [HR], 0.80; 95% CI, 0.69 to 0.93; P = .004). Seven-year OS rates were 73% and 67% in the XELOX and FU/FA groups, respectively (HR, 0.83; 95% CI, 0.70 to 0.99; P = .04). A total of 68% and 77% of patients who experienced relapse or a new colorectal cancer in the XELOX and FU/FA groups, respectively, received drug treatment for metastatic disease. Four hundred ninety-eight patients consented to the biomarker analysis: 242 in the XELOX group and 256 in the FU/FA group. Low tumor expression of dihydropyrimidine dehydrogenase may be predictive for XELOX efficacy; in the XELOX group, for high versus low dihydropyrimidine dehydrogenase expression levels, DFS HR was 2.45 (95% CI, 1.55 to 3.86; P < .001), and OS HR was 2.75 (95% CI, 1.65 to 4.59; P < .001). In the FU/FA group, no statistically significant associations were observed between any tumor biomarker and outcomes. XELOX improved OS compared with bolus FU/FA in patients with resected stage III colon cancer after a median follow-up of almost 7 years. XELOX should be considered a standard adjuvant treatment option in patients with stage III disease. Tumoral dihydropyrimidine dehydrogenase expression is a promising predictive, and potentially, highly clinically relevant, biomarker for XELOX efficacy requiring further prospective evaluation. © 2015 by American Society of Clinical Oncology.

The cleaner, the greener? Product sustainability assessment of the biomimetic façade paint Lotusan® in comparison to the conventional façade paint Jumbosil®.

PubMed

Antony, Florian; Grießhammer, Rainer; Speck, Thomas; Speck, Olga

2016-01-01

Background: The debate on the question whether biomimetics has a specific potential to contribute to sustainability is discussed among scientists, business leaders, politicians and those responsible for project funding. The objective of this paper is to contribute to this controversial debate by presenting the sustainability assessment of one of the most well-known and most successful biomimetic products: the façade paint Lotusan ® . Results: As a first step it has been examined and verified that the façade paint Lotusan ® is correctly defined as a biomimetic product. Secondly, Lotusan ® has been assessed and compared to a conventional façade paint within the course of a detailed product sustainability assessment (PROSA). For purposes of comparison, the façade paint Jumbosil ® was chosen as reference for a conventional paint available on the market. The benefit analysis showed that both paints fulfil equally well the requirements of functional utility. With respect to the symbolic utility, Lotusan ® has a particular added aesthetic value by the preservation of the optical quality over the life cycle. Within the social analysis no substantial differences between the two paints could be found regarding the handling and disposal of the final products. Regarding the life-cycle cost, Lotusan ® is the more expensive product. However, the higher investment cost for a Lotusan ® -based façade painting are more than compensated by the longer life time, resulting in both reduced overall material demand and lower labour cost. In terms of the life-cycle impact assessment, it can be ascertained that substantial differences between the paints arise from the respective service life, which are presented in terms of four scenario analyses. Conclusion: In summary, the biomimetic façade paint Lotusan ® has been identified as a cost-effective and at the same time resource-saving product. Based on the underlying data and assumptions it could be demonstrated that Lotusan ® -based façade paintings have a comparatively low overall impact on the environment. Summarizing our results, it can be emphasized that Lotusan ® is the more favourable product compared to Jumbosil ® according to sustainability aspects.

Fatty acid composition of porcine cumulus oocyte complexes (COC) during maturation: effect of the lipid modulators trans-10, cis-12 conjugated linoleic acid (t10,c12 CLA) and forskolin.

PubMed

Prates, E G; Alves, S P; Marques, C C; Baptista, M C; Horta, A E M; Bessa, R J B; Pereira, R M

2013-05-01

The effect of maturation and of two lipid modulators supplementation along in vitro maturation (IVM) on fatty acid (FA) and dimethylacetal (DMA) composition of porcine cumulus oocyte complexes (COC) were studied. Abattoir-derived immature COC were analyzed for FA and DMA or submitted to IVM as follows: control group; t10,c12 CLA group, t10,c12 CLA supplementation for 44 h; Forskolin group, forskolin supplementation during the initial 2 h; t10,c12 CLA + forskolin group, t10,c12 CLA for 44 h and forskolin for just 2h. Each experimental group had five replicates. FA analysis of oocytes, cumulus cells (CC), follicular fluid, and culture media were performed by gas-liquid chromatography. Oocytes and their CC had different FA composition. Oocytes were richer in saturated FA (SFA) preferentially maintaining their FA profile during maturation. Mature CC had the highest polyunsaturated FA (PUFA) content. Five individual and total SFA, and monounsaturated FA (MUFA), notably oleic acid (c9-18:1), percentages were lower (P ≤ 0.023) in mature than in immature CC. t10,c12 CLA was accumulated by COC from t10,c12 CLA and t10,c12 CLA + forskolin groups, mostly in CC where MUFA and an eicosatrienoic isomer decreased (P ≤ 0.043). Nevertheless, PUFA or FA and DMA total content were not affected. Arachidonic acid was reduced in t10,c12 CLA + forskolin CC and hexadecanal-DMA-16:0 in t10,c12 CLA CC. Forskolin alone increased (P ≤ 0.043) c9-18:1 in oocytes. In conclusion, maturation process clearly changed porcine COC FA and DMA profiles, mostly of CC, also more susceptible to modifications induced by t10,c12 CLA. This possibility of manipulating COC lipid composition during IVM could be used to improve oocyte quality/cryopreservation efficiency.

The role of omega-3 fatty acids in acute pancreatitis: a meta-analysis of randomized controlled trials.

PubMed

Lei, Qiu Cheng; Wang, Xin Ying; Xia, Xian Feng; Zheng, Hua Zhen; Bi, Jing Cheng; Tian, Feng; Li, Ning

2015-03-31

To determine whether treatment with omega-3 fatty acids (ω-3 FA) provides benefits to patients with acute pancreatitis (AP). The Cochrane Library, PubMed, Embase, Web of Science, and Chinese Biomedical Literature Database were searched. Data analysis was performed using Revman 5.2 software. A total of eight randomized controlled trials (RCTs) were included. Overall, ω-3 FA treatment resulted in a significantly reduced risk of mortality (RR 0.35; 95% CI 0.16 to 0.75, p < 0.05), infectious complications (RR 0.54; 95% CI 0.34 to 0.85, p < 0.05) and length of hospital stay (MD -6.50; 95% CI -9.54 to -3.46, p < 0.05), but not length of ICU stay (MD -1.98; 95% CI -6.92 to 2.96, p > 0.05). In subgroup analysis, only patients who received ω-3 FA parenterally had some statistically significant benefits in terms of mortality (risk ratio (RR) 0.37; 95% confidence interval (CI) 0.16 to 0.86, p < 0.05), infectious complications (RR 0.5; 95% CI 0.28 to 0.9, p < 0.05) and length of hospital stay (mean difference (MD) -8.13; 95% CI -10.39 to -5.87, p < 0.001). The administration of ω-3 FA may be beneficial for decreasing mortality, infectious complications, and length of hospital stay in AP, especially when used parenterally. Large and rigorously designed RCTs are required to elucidate the efficacy of parenteral or enteral ω-3 FA treatment in AP.

The King is Dead: Regaining the Throne -- The Current State of the Field Artillery, Core Competency Atrophy, and the Way Ahead

DTIC Science & Technology

2011-03-17

with a built -in glass ceiling is not likely to retain or attract the best and the brightest. If it hasn’t happened already, FA accessions will begin...officer. This would also facilitate removing the glass ceiling currently atop the field 19 artillery with only six tactical command opportunities. This...missions excluding conventional warfare strategic failure can result. 71 In summer 2006 in southern Lebanon , the Israeli army suffered a significant

Current Launch Vehicle Practice and Data Base Assessment. Volume 1. Executive Summary and Report Body

DTIC Science & Technology

1989-06-01

resulted in an increase of the intermediate seal purge pressure, revised redlines, and a design change from a lift-off seal to a labyrinth seal design. This...engine 0003 caused fa&i!ure of the primary lox seal and an uncontained engine fire. The redline cut was set by a HPOTP overspeed. This failure...occurred as a result of undetected internal HEX damage caused during arc welding which resulted in an engine fire. HEX coil leakage resulted in an

Limbic and corpus callosum aberrations in adolescents with bipolar disorder: a tract-based spatial statistics analysis.

PubMed

Barnea-Goraly, Naama; Chang, Kiki D; Karchemskiy, Asya; Howe, Meghan E; Reiss, Allan L

2009-08-01

Bipolar disorder (BD) is a common and debilitating condition, often beginning in adolescence. Converging evidence from genetic and neuroimaging studies indicates that white matter abnormalities may be involved in BD. In this study, we investigated white matter structure in adolescents with familial bipolar disorder using diffusion tensor imaging (DTI) and a whole brain analysis. We analyzed DTI images using tract-based spatial statistics (TBSS), a whole-brain voxel-by-voxel analysis, to investigate white matter structure in 21 adolescents with BD, who also were offspring of at least one parent with BD, and 18 age- and IQ-matched control subjects. Fractional anisotropy (FA; a measure of diffusion anisotropy), trace values (average diffusivity), and apparent diffusion coefficient (ADC; a measure of overall diffusivity) were used as variables in this analysis. In a post hoc analysis, we correlated between FA values, behavioral measures, and medication exposure. Adolescents with BD had lower FA values than control subjects in the fornix, the left mid-posterior cingulate gyrus, throughout the corpus callosum, in fibers extending from the fornix to the thalamus, and in parietal and occipital corona radiata bilaterally. There were no significant between-group differences in trace or ADC values and no significant correlation between behavioral measures, medication exposure, and FA values. Significant white matter tract alterations in adolescents with BD were observed in regions involved in emotional, behavioral, and cognitive regulation. These results suggest that alterations in white matter are present early in the course of disease in familial BD.

The DCDC2/intron 2 deletion and white matter disorganization: focus on developmental dyslexia.

PubMed

Marino, Cecilia; Scifo, Paola; Della Rosa, Pasquale A; Mascheretti, Sara; Facoetti, Andrea; Lorusso, Maria L; Giorda, Roberto; Consonni, Monica; Falini, Andrea; Molteni, Massimo; Gruen, Jeffrey R; Perani, Daniela

2014-08-01

The DCDC2 gene is involved in neuronal migration. Heterotopias have been found within the white matter of DCDC2-knockdown rats. A deletion in DCDC2/intron 2 (DCDC2d), which encompasses a regulatory region named 'regulatory element associated with dyslexia 1' (READ1), increases the risk for dyslexia. We hypothesized that DCDC2d can be associated to alterations of the white matter structure in general and in dyslexic brains. Based on a full-factorial analysis of covariance (ANCOVA) model, we investigated voxel-based diffusion tensor imaging (VB-DTI) data of four groups of subjects: dyslexia with/without DCDC2d, and normal readers with/without DCDC2d. We also tested DCDC2d effects upon correlation patterns between fractional anisotropy (FA) and reading scores. We found that FA was reduced in the left arcuate fasciculus and splenium of the corpus callosum in subjects with versus without DCDC2d, irrespective of dyslexia. Subjects with dyslexia and DCDC2d showed reduced FA, mainly in the left hemisphere and in the corpus callosum; their counterpart without DCDC2d showed similar FA alterations. Noteworthy, a conjunction analysis in impaired readers revealed common regions with lower FA mainly in the left hemisphere. When we compared subjects with dyslexia with versus without DCDC2d, we found lower FA in the inferior longitudinal fasciculus and genu of the corpus callosum, bilaterally. Normal readers with versus without DCDC2d had FA increases and decreases in both the right and left hemisphere. The major contribution of our study was to provide evidence relating genes, brain and behaviour. Overall, our findings support the hypothesis that DCDC2d is associated with altered FA. In normal readers, DCDC2-related anatomical patterns may mark some developmental cognitive vulnerability to learning disabilities. In subjects with dyslexia, DCDC2d accounted for both common - mainly located in the left hemisphere - and unique - a more severe and extended pattern - alterations of white matter fibre tracts. Copyright © 2014 Elsevier Ltd. All rights reserved.

Insights into the effects of polygalacturonase FaPG1 gene silencing on pectin matrix disassembly, enhanced tissue integrity, and firmness in ripe strawberry fruits

PubMed Central

Posé, Sara; Paniagua, Candelas; Cifuentes, Manuel; Blanco-Portales, Rosario; Quesada, Miguel A.; Mercado, José A.

2013-01-01

Antisense-mediated down-regulation of the fruit-specific polygalacturonase (PG) gene FaPG1 in strawberries (Fragaria×ananassa Duch.) has been previously demonstrated to reduce fruit softening and to extend post-harvest shelf life, despite the low PG activity detected in this fruit. The improved fruit traits were suggested to be attributable to a reduced cell wall disassembly due to FaPG1 silencing. This research provides empirical evidence that supports this assumption at the biochemical, cellular, and tissue levels. Cell wall modifications of two independent transgenic antisense lines that demonstrated a >90% reduction in FaPG1 transcript levels were analysed. Sequential extraction of cell wall fractions from control and ripe fruits exhibited a 42% decrease in pectin solubilization in transgenic fruits. A detailed chromatographic analysis of the gel filtration pectin profiles of the different cell wall fractions revealed a diminished depolymerization of the more tightly bound pectins in transgenic fruits, which were solubilized with both a chelating agent and sodium carbonate. The cell wall extracts from antisense FaPG1 fruits also displayed less severe in vitro swelling. A histological analysis revealed more extended cell–cell adhesion areas and an enhanced tissue integrity in transgenic ripe fruits. An immunohistological analysis of fruit sections using the JIM5 antibody against low methyl-esterified pectins demonstrated a higher labelling in transgenic fruit sections, whereas minor differences were observed with JIM7, an antibody that recognizes highly methyl-esterified pectins. These results support that the increased firmness of transgenic antisense FaPG1 strawberry fruits is predominantly due to a decrease in pectin solubilization and depolymerization that correlates with more tightly attached cell wall-bound pectins. This limited disassembly in the transgenic lines indicates that these pectin fractions could play a key role in tissue integrity maintenance that results in firmer ripe fruit. PMID:23873994

White matter alterations in temporal lobe epilepsy

NASA Astrophysics Data System (ADS)

Diniz, P. B.; Salmon, C. E.; Velasco, T. R.; Sakamoto, A. C.; Leite, J. P.; Santos, A. C.

2011-03-01

In This study, we used Fractional anisotropy (FA), mean diffusivity (D), parallel diffusivity (D//) and perpendicular diffusivity (D), to localize the regions where occur axonal lesion and demyelization. TBSS was applied to analyze the FA data. After, the regions with alteration were studied with D, D// and D maps. Patients exhibited widespread degradation of FA. With D, D// and D maps analysis we found alterations in corpus callosum, corticospinal tract, fornix, internal capsule, corona radiate, Sagittal stratum, cingulum, fronto-occipital fasciculus and uncinate fasciculus. Our results are consistent with the hypothesis that exist demyelization and axonal damage in patients with TLE.

Independent component analysis of DTI data reveals white matter covariances in Alzheimer's disease

NASA Astrophysics Data System (ADS)

Ouyang, Xin; Sun, Xiaoyu; Guo, Ting; Sun, Qiaoyue; Chen, Kewei; Yao, Li; Wu, Xia; Guo, Xiaojuan

2014-03-01

Alzheimer's disease (AD) is a progressive neurodegenerative disease with the clinical symptom of the continuous deterioration of cognitive and memory functions. Multiple diffusion tensor imaging (DTI) indices such as fractional anisotropy (FA) and mean diffusivity (MD) can successfully explain the white matter damages in AD patients. However, most studies focused on the univariate measures (voxel-based analysis) to examine the differences between AD patients and normal controls (NCs). In this investigation, we applied a multivariate independent component analysis (ICA) to investigate the white matter covariances based on FA measurement from DTI data in 35 AD patients and 45 NCs from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. We found that six independent components (ICs) showed significant FA reductions in white matter covariances in AD compared with NC, including the genu and splenium of corpus callosum (IC-1 and IC-2), middle temporal gyral of temporal lobe (IC-3), sub-gyral of frontal lobe (IC-4 and IC-5) and sub-gyral of parietal lobe (IC-6). Our findings revealed covariant white matter loss in AD patients and suggest that the unsupervised data-driven ICA method is effective to explore the changes of FA in AD. This study assists us in understanding the mechanism of white matter covariant reductions in the development of AD.

Tracing carbon flow in an arctic marine food web using fatty acid-stable isotope analysis.

PubMed

Budge, S M; Wooller, M J; Springer, A M; Iverson, S J; McRoy, C P; Divoky, G J

2008-08-01

Global warming and the loss of sea ice threaten to alter patterns of productivity in arctic marine ecosystems because of a likely decline in primary productivity by sea ice algae. Estimates of the contribution of ice algae to total primary production range widely, from just 3 to >50%, and the importance of ice algae to higher trophic levels remains unknown. To help answer this question, we investigated a novel approach to food web studies by combining the two established methods of stable isotope analysis and fatty acid (FA) analysis--we determined the C isotopic composition of individual diatom FA and traced these biomarkers in consumers. Samples were collected near Barrow, Alaska and included ice algae, pelagic phytoplankton, zooplankton, fish, seabirds, pinnipeds and cetaceans. Ice algae and pelagic phytoplankton had distinctive overall FA signatures and clear differences in delta(13)C for two specific diatom FA biomarkers: 16:4n-1 (-24.0+/-2.4 and -30.7+/-0.8 per thousand, respectively) and 20:5n-3 (-18.3+/-2.0 and -26.9+/-0.7 per thousand, respectively). Nearly all delta(13)C values of these two FA in consumers fell between the two stable isotopic end members. A mass balance equation indicated that FA material derived from ice algae, compared to pelagic diatoms, averaged 71% (44-107%) in consumers based on delta(13)C values of 16:4n-1, but only 24% (0-61%) based on 20:5n-3. Our estimates derived from 16:4n-1, which is produced only by diatoms, probably best represented the contribution of ice algae relative to pelagic diatoms. However, many types of algae produce 20:5n-3, so the lower value derived from it likely represented a more realistic estimate of the proportion of ice algae material relative to all other types of phytoplankton. These preliminary results demonstrate the potential value of compound-specific isotope analysis of marine lipids to trace C flow through marine food webs and provide a foundation for future work.

Production responses of Holstein dairy cows when fed supplemental fat containing saturated free fatty acids: a meta-analysis

PubMed Central

Hu, Wenping; Boerman, Jacquelyn P.; Aldrich, James M.

2017-01-01

Objective A meta-analysis was conducted to evaluate the effects of supplemental fat containing saturated free fatty acids (FA) on milk performance of Holstein dairy cows. Methods A database was developed from 21 studies published between 1991 and 2016 that included 502 dairy cows and a total of 29 to 30 comparisons between dietary treatment and control without fat supplementation. Only saturated free FA (>80% of total FA) was considered as the supplemental fat. Concentration of the supplemental fat was not higher than 3.5% of diet dry matter (DM). Dairy cows were offered total mixed ration, and fed individually. Statistical analysis was conducted using random- or mixed-effects models with Metafor package in R. Results Sub-group analysis showed that there were no differences in studies between randomized block design and Latin square/crossover design for dry matter intake (DMI) and milk production responses to the supplemental fat (all response variables, p≥0.344). The supplemental fat across all studies improved milk yield, milk fat concentration and yield, and milk protein yield by 1.684 kg/d (p<0.001), 0.095 percent unit (p = 0.003), 0.072 kg/d (p<0.001), and 0.036 kg/d (p<0.001), respectively, but tended to decrease milk protein concentration (mean difference = −0.022 percent unit; p = 0.063) while DMI (mean difference = 0.061 kg/d; p = 0.768) remained unchanged. The assessment of heterogeneity suggested that no substantial heterogeneity occurred among all studies for DMI and milk production responses to the supplemental fat (all response variables, I2≤24.1%; p≥0.166). Conclusion The effects of saturated free FA were quantitatively evaluated. Higher milk production and yields of milk fat and protein, with DMI remaining unchanged, indicated that saturated free FA, supplemented at ≤3.5% dietary DM from commercially available fat sources, likely improved the efficiency of milk production. Nevertheless, more studies are needed to assess the variation of production responses to different saturated free FA, either C16:0 or C18:0 alone, or in combination with potentially optimal ratio, when supplemented in dairy cow diets. PMID:28183166

Molecular and genealogical evidence for a founder effect in Fanconi anemia families of the Afrikaner population of South Africa.

PubMed

Tipping, A J; Pearson, T; Morgan, N V; Gibson, R A; Kuyt, L P; Havenga, C; Gluckman, E; Joenje, H; de Ravel, T; Jansen, S; Mathew, C G

2001-05-08

Fanconi anemia (FA) is a rare, genetically heterogeneous autosomal recessive disorder associated with progressive aplastic anemia, congenital abnormalities, and cancer. FA has a very high incidence in the Afrikaner population of South Africa, possibly due to a founder effect. Previously we observed allelic association between polymorphic markers flanking the FA group A gene (FANCA) and disease chromosomes in Afrikaners. We genotyped 26 FA families with microsatellite and single nucleotide polymorphic markers and detected five FANCA haplotypes. Mutation scanning of the FANCA gene revealed association of these haplotypes with four different mutations. The most common was an intragenic deletion of exons 12-31, accounting for 60% of FA chromosomes in 46 unrelated Afrikaner FA patients, while two other mutations accounted for an additional 20%. Screening for these mutations in the European populations ancestral to the Afrikaners detected one patient from the Western Ruhr region of Germany who was heterozygous for the major deletion. The mutation was associated with the same unique FANCA haplotype as in Afrikaner patients. Genealogical investigation of 12 Afrikaner families with FA revealed that all were descended from a French Huguenot couple who arrived at the Cape on June 5, 1688, whereas mutation analysis showed that the carriers of the major mutation were descendants of this same couple. The molecular and genealogical evidence is consistent with transmission of the major mutation to Western Germany and the Cape near the end of the 17th century, confirming the existence of a founder effect for FA in South Africa.

Molecular and genealogical evidence for a founder effect in Fanconi anemia families of the Afrikaner population of South Africa

PubMed Central

Tipping, A. J.; Pearson, T.; Morgan, N. V.; Gibson, R. A.; Kuyt, L. P.; Havenga, C.; Gluckman, E.; Joenje, H.; de Ravel, T.; Jansen, S.; Mathew, C. G.

2001-01-01

Fanconi anemia (FA) is a rare, genetically heterogeneous autosomal recessive disorder associated with progressive aplastic anemia, congenital abnormalities, and cancer. FA has a very high incidence in the Afrikaner population of South Africa, possibly due to a founder effect. Previously we observed allelic association between polymorphic markers flanking the FA group A gene (FANCA) and disease chromosomes in Afrikaners. We genotyped 26 FA families with microsatellite and single nucleotide polymorphic markers and detected five FANCA haplotypes. Mutation scanning of the FANCA gene revealed association of these haplotypes with four different mutations. The most common was an intragenic deletion of exons 12–31, accounting for 60% of FA chromosomes in 46 unrelated Afrikaner FA patients, while two other mutations accounted for an additional 20%. Screening for these mutations in the European populations ancestral to the Afrikaners detected one patient from the Western Ruhr region of Germany who was heterozygous for the major deletion. The mutation was associated with the same unique FANCA haplotype as in Afrikaner patients. Genealogical investigation of 12 Afrikaner families with FA revealed that all were descended from a French Huguenot couple who arrived at the Cape on June 5, 1688, whereas mutation analysis showed that the carriers of the major mutation were descendants of this same couple. The molecular and genealogical evidence is consistent with transmission of the major mutation to Western Germany and the Cape near the end of the 17th century, confirming the existence of a founder effect for FA in South Africa. PMID:11344308

Relationship between diffusion tensor fractional anisotropy and motor outcome in patients with hemiparesis after corona radiata infarct.

PubMed

Koyama, Tetsuo; Marumoto, Kohei; Miyake, Hiroji; Domen, Kazuhisa

2013-11-01

This study examined the relationship between fractional anisotropy (FA) values of magnetic resonance-diffusion tensor imaging (DTI) and motor outcome (1 month after onset) in 15 patients with hemiparesis after ischemic stroke of corona radiata lesions. DTI data were obtained on days 14-18. FA values within the cerebral peduncle were analyzed using a computer-automated method. Motor outcome of hemiparesis was evaluated according to Brunnstrom stage (BRS; 6-point scale: severe to normal) for separate shoulder/elbow/forearm, wrist/hand, and lower extremity functions. The ratio of FA values in the affected hemisphere to those in the unaffected hemisphere (rFA) was assessed in relation to the BRS data (Spearman rank correlation test, P<.05). rFA values ranged from .715 to 1.002 (median=.924). BRS ranged from 1 to 6 (median=4) for shoulder/elbow/forearm, from 1 to 6 (median=5) for wrist/hand, and from 2 to 6 (median=4) for the lower extremities. Analysis revealed statistically significant relationships between rFA and upper extremity functions (correlation coefficient=.679 for shoulder/elbow/forearm and .706 for wrist/hand). Although slightly less evident, the relationship between rFA and lower extremity function was also statistically significant (correlation coefficient=.641). FA values within the cerebral peduncle are moderately associated with the outcome of both upper and lower extremity functions, suggesting that DTI may be applicable for outcome prediction in stroke patients with corona radiata infarct. Copyright © 2013 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Possible radioprotective effect of folic acid supplementation on low dose ionizing radiation-induced genomic instability in vitro.

PubMed

Padula, Gisel; Ponzinibbio, María Virginia; Seoane, Analia I

2016-08-01

Ionizing radiation (IR) induces DNA damage through production of single and double-strand breaks and reactive oxygen species (ROS). Folic acid (FA) prevents radiation-induced DNA damage by modification of DNA synthesis and/or repair and as a radical scavenger. We hypothesized that in vitro supplementation with FA will decrease the sensitivity of cells to genetic damage induced by low dose of ionizing radiation. Annexin V, comet and micronucleus assays were performed in cultured CHO cells. After 7 days of pre-treatment with 0, 100, 200 or 300 nM FA, cultures were exposed to radiation (100 mSv). Two un-irradiated controls were executed (0 and 100 nM FA). Data were statistically analyzed with X2-test and linear regression analysis (P 0.05). We observed a significantly decreased frequency of apoptotic cells with the increasing FA concentration (P <0.05). The same trend was observed when analyzing DNA damage and chromosomal instability (P <0.05 for 300 nM). Only micronuclei frequencies showed significant differences for linear regression analysis (R2=94.04; P <0.01). Our results have demonstrated the radioprotective effect of folic acid supplementation on low dose ionizing radiation-induced genomic instability in vitro; folate status should be taken into account when studying the effect of low dose radiation in environmental or occupational exposure.

Use of LiDAR for calculating solar irradiance on roofs and façades of buildings at city scale: Methodology, validation, and analysis

NASA Astrophysics Data System (ADS)

Cheng, Liang; Xu, Hao; Li, Shuyi; Chen, Yanming; Zhang, Fangli; Li, Manchun

2018-04-01

As the rate of urbanization continues to accelerate, the utilization of solar energy in buildings plays an increasingly important role in sustainable urban development. For this purpose, we propose a LiDAR-based joint approach for calculating the solar irradiance incident on roofs and façades of buildings at city scale, which includes a methodology for calculating solar irradiance, the validation of the proposed method, and analysis of its application. The calculation of surface irradiance on buildings may then inform photovoltaic power generation simulations, architectural design, and urban energy planning. Application analyses of the proposed method in the experiment area found that: (1) Global and direct irradiations vary significantly by hour, day, month and season, both following the same trends; however, diffuse irradiance essentially remains unchanged over time. (2) Roof irradiation, but not façade irradiation, displays distinct time-dependent patterns. (3) Global and direct irradiations on roofs are highly correlated with roof aspect and slope, with high global and direct irradiations observed on roofs of aspect 100-250° and slopes of 0-60°, whereas diffuse irradiation on roofs is only affected by roof slope. (4) The façade of a building receives higher levels of global and direct irradiations if facing southeast, south, and southwest; however, diffuse irradiation remains constant regardless of façade orientation.

Tract-based spatial statistics analysis of white matter changes in children with anisometropic amblyopia.

PubMed

Li, Qian; Zhai, Liying; Jiang, Qinying; Qin, Wen; Li, Qingji; Yin, Xiaohui; Guo, Mingxia

2015-06-15

Amblyopia is a neurological disorder of vision that follows abnormal binocular interaction or visual deprivation during early life. Previous studies have reported multiple functional or structural cortical alterations. Although white matter was also studied, it still cannot be clarified clearly which fasciculus was affected by amblyopia. In the present study, tract-based spatial statistics analysis was applied to diffusion tensor imaging (DTI) to investigate potential diffusion changes of neural tracts in anisometropic amblyopia. Fractional anisotropy (FA) value was calculated and compared between 20 amblyopic children and 18 healthy age-matched controls. In contrast to the controls, significant decreases in FA values were found in right optic radiation (OR), left inferior longitudinal fasciculus/inferior fronto-occipital fasciculus (ILF/IFO) and right superior longitudinal fasciculus (SLF) in the amblyopia. Furthermore, FA values of these identified tracts showed positive correlation with visual acuity. It can be inferred that abnormal visual input not only hinders OR from well developed, but also impairs fasciculi associated with dorsal and ventral visual pathways, which may be responsible for the amblyopic deficiency in object discrimination and stereopsis. Increased FA was detected in right posterior part of corpus callosum (CC) with a medium effect size, which may be due to compensation effect. DTI with subsequent measurement of FA is a useful tool for investigating neuronal tract involvement in amblyopia. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Plasma and white adipose tissue lipid composition in marmots.

PubMed

Florant, G L; Nuttle, L C; Mullinex, D E; Rintoul, D A

1990-05-01

White adipose tissue biopsies and plasma samples were obtained from hibernating yellow-bellied marmots (Marmota flaviventris) maintained in the laboratory. In addition, biopsies and plasma samples were obtained from normothermic animals in the field and laboratory. Measurement of plasma free fatty acid (FA) levels indicated that winter laboratory animals exhibited increased lipolysis. Additionally, analysis of white adipose tissue triacylglycerol revealed that the FA composition of the storage fat in animals maintained on the standard laboratory diet is remarkably simple and uniform between different adipose depots in the same animal. Three FAs (palmitic, oleic, and linoleic acids) made up greater than 95% of the total. Triene (alpha-linolenate) was found in newly captured animals, but the percentage of this FA decreased rapidly when the animals were maintained on the standard laboratory diet. Throughout the hibernation season (October to April), white adipose tissue-saturated FA percentage decreased, monoene percentage remained constant, and diene percentage increased. Analysis of plasma FA composition suggested that these animals tended to metabolize saturated FAs from stored lipid during hibernation and that dienes were mobilized briefly after the last arousal from hibernation in spring. From these observations, we hypothesize that marmots preferentially metabolize saturated fats during the hibernation period and that essential FAs of the omega 6 series tend to be metabolized more slowly than other FAs. These characteristics suggest that marmots are a valuable animal model in which to study lipid metabolism.

High calcium fly ash geopolymer stabilized lateritic soil and granulated blast furnace slag blends as a pavement base material.

PubMed

Phummiphan, Itthikorn; Horpibulsuk, Suksun; Rachan, Runglawan; Arulrajah, Arul; Shen, Shui-Long; Chindaprasirt, Prinya

2018-01-05

Granulated Blast Furnace Slag (GBFS) was used as a replacement material in marginal lateritic soil (LS) while class C Fly Ash (FA) was used as a precursor for the geopolymerization process to develop a low-carbon pavement base material at ambient temperature. Unconfined Compression Strength (UCS) tests were performed to investigate the strength development of geopolymer stabilized LS/GBFS blends. Scanning Electron Microscopy and X-ray Diffraction analysis were undertaken to examine the role of the various influencing factors on UCS development. The influencing factors studied included GBFS content, Na 2 SiO 3 :NaOH ratio (NS:NH) and curing time. The 7-day soaked UCS of FA geopolymer stabilized LS/GBFS blends at various NS:NH ratios tested was found to satisfy the specifications of the Thailand national road authorities. The GBFS replacement was found to be insignificant for the improvement of the UCS of FA geopolymer stabilized LS/GBFS blends at low NS:NH ratio of 50:50. Microstructural analysis indicated the coexistence of Calcium Silicate Hydrate (CSH) and Sodium Alumino Silicate Hydrate products in FA geopolymer stabilized LS/GBFS blends. This research enables GBFS, which is traditionally considered as a waste material, to be used as a replacement and partially reactive material in FA geopolymer pavement applications. Copyright © 2017 Elsevier B.V. All rights reserved.

Using Fatty-Acid Profile Analysis as an Ecologic Indicator in the Management of Tourist Impacts on Marine Wildlife: A Case of Stingray-Feeding in the Caribbean

NASA Astrophysics Data System (ADS)

Semeniuk, Christina A. D.; Speers-Roesch, Ben; Rothley, Kristina D.

2007-10-01

Feeding marine wildlife as a tourism experience has become a popular means by which to attract both people and wildlife, although management efforts are still in their infancy. “Stingray City Sandbar” in the Cayman Islands, where visitors can hand feed free-ranging Southern Stingrays ( Dasyatis americana), is a world-famous attraction currently undergoing visitor and wildlife management. One plan is to decrease the amount of nonnatural food provided by tourists with the intention of decreasing stingray habituation to the artificial food source and promoting stingray health. However, the effectiveness of this action is uncertain given that neither the extent of squid composition in the stingray diet nor the degree of nutrient similarity between the fed and natural diets is unknown. We used fatty acid (FA) profile analysis to address these questions by assessing the serum nonesterified FA composition of fed and unfed stingrays around the island and compared them with FA profiles of (1) the provisioned food source (squid) and (2) other warm- and cold-water elasmobranchs (sharks and rays). Our results indicated that fed stingrays were distinct. The FA profiles of the fed stingray population were expressly different from those of the unfed populations and showed a remarkable similarity to the FA composition of squid, suggesting that squid is the main food source. The tropical fed stingrays also exhibited essential FA ratios, specific to both species and habitat, comparable with those of elasmobranchs and squid from cold-water environs, implying that the provisioned food does not provide a similar nutritional lipid composition to that eaten in the wild. Our results suggest that FA profiles are a valuable indicator for the management and monitoring of fed Southern Stingrays because they can be used to assess differences in diet composition and provide an index of nutritional similarity. Our findings are currently being used by Caymanian stakeholders in designing practical management actions for their wildlife attraction.

Decreased cerebral α4β2* nicotinic acetylcholine receptor availability in patients with mild cognitive impairment and Alzheimer's disease assessed with positron emission tomography.

PubMed

Kendziorra, Kai; Wolf, Henrike; Meyer, Philipp Mael; Barthel, Henryk; Hesse, Swen; Becker, Georg Alexander; Luthardt, Julia; Schildan, Andreas; Patt, Marianne; Sorger, Dietlind; Seese, Anita; Gertz, Herman-Josef; Sabri, Osama

2011-03-01

Postmortem studies indicate a loss of nicotinic acetylcholine receptor (nAChRs) in Alzheimer's disease (AD). In order to establish whether these changes in the cholinergic system occur at an early stage of AD, we carried out positron emission tomography (PET) with a specific radioligand for the α4β2* nicotinic acetylcholine receptor (α4β2* nAChR) in patients with mild to moderate AD and in patients with amnestic mild cognitive impairment (MCI), who have a high risk to progress to AD. Nine patients with moderate AD, eight patients with MCI and seven age-matched healthy controls underwent 2-[(18)F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[(18)F]FA-85380) PET. After coregistration with individual magnetic resonance imaging the binding potential (BP(ND)) of 2-[(18)F]FA-85380 was calculated using either the corpus callosum or the cerebellum as reference regions. PET data were analysed by region of interest analysis and by voxel-based analysis. Both patients with AD and MCI showed a significant reduction in 2-[(18)F]FA-85380 BP(ND) in typical AD-affected brain regions. Thereby, the corpus callosum was identified as the most suitable reference region. The 2-[(18)F]FA-85380 BP(ND) correlated with the severity of cognitive impairment. Only MCI patients that converted to AD in the later course (n = 5) had a reduction in 2-[(18)F]FA-85380 BP(ND). 2-[(18)F]FA-85380 PET appears to be a sensitive and feasible tool for the detection of a reduction in α4β2* nAChRs which seems to be an early event in AD. In addition, 2-[(18)F]FA-85380 PET might give prognostic information about a conversion from MCI to AD.

Experience of diffusion tensor imaging and 1H spectroscopy for outcome prediction in severe traumatic brain injury: Preliminary results.

PubMed

Tollard, Eléonore; Galanaud, Damien; Perlbarg, Vincent; Sanchez-Pena, Paola; Le Fur, Yann; Abdennour, Lamine; Cozzone, Patrick; Lehericy, Stéphane; Chiras, Jacques; Puybasset, Louis

2009-04-01

The objective of the study is to test whether multimodal magnetic resonance imaging can provide a reliable outcome prediction of the clinical status, focusing on consciousness at 1 year after severe traumatic brain injury (TBI). Single center prospective cohort with consecutive inclusions. Critical Care Neurosurgical Unit of a university hospital. Forty-three TBI patients not responding to simple orders after sedation cessation and 15 healthy controls. A multimodal magnetic resonance imaging combining morphologic sequences, diffusion tensor imaging (DTI), and H proton magnetic resonance spectroscopy (MRS) was performed 24 +/- 11 days after severe TBI. The ability of DTI and MRS to predict 1-year outcome was assessed by linear discriminant analysis (LDA). Robustness of the classification was tested using a bootstrap procedure. Fractional anisotropy (FA) was computed as the mean of values at discrete brain sites in the infratentorial and supratentorial regions. The N-acetyl aspartate/creatine (NAA/Cr) ratio was measured in the thalamus, lenticular nucleus, insular cortex, occipital periventricular white matter, and pons. After 1 year, 19 (44%) patients had unfavorable outcomes (death, persistent vegetative state, or minimally conscious state) and 24 (56%) favorable outcomes (normal consciousness with or without functional impairments). Analysis of variance was performed to compare FA and NAA/Cr in the two outcome groups and controls. FA and MRS findings showed highly significant differences between the outcome groups, with significant variables by LDA being supratentorial FA, NAA/Cr (pons), NAA/Cr (thalamus), NAA/Cr (insula), and infratentorial FA. LDA of combined FA and MRS data clearly separated the unfavorable outcome, favorable outcome, and control groups, with no overlap. Unfavorable outcome was predicted with up to 86% sensitivity and 97% specificity; these values were better than those obtained with DTI or MRS alone. FA and NAA/Cr hold potential as quantitative outcome-prediction tools at the subacute phase of TBI.

Identification of differentially expressed genes associated with the enhancement of X-ray susceptibility by RITA in a hypopharyngeal squamous cell carcinoma cell line (FaDu).

PubMed

Luan, Jinwei; Li, Xianglan; Guo, Rutao; Liu, Shanshan; Luo, Hongyu; You, Qingshan

2016-06-01

Next generation sequencing and bio-informatic analyses were conducted to investigate the mechanism of reactivation of p53 and induction of tumor cell apoptosis (RITA)-enhancing X-ray susceptibility in FaDu cells. The cDNA was isolated from FaDu cells treated with 0 X-ray, 8 Gy X-ray, or 8 Gy X-ray + RITA. Then, cDNA libraries were created and sequenced using next generation sequencing, and each assay was repeated twice. Subsequently, differentially expressed genes (DEGs) were identified using Cuffdiff in Cufflinks and their functions were predicted by pathway enrichment analyses. Genes that were constantly up- or down-regulated in 8 Gy X-ray-treated FaDu cells and 8 Gy X-ray + RITA-treated FaDu cells were obtained as RITA genes. Afterward, the protein-protein interaction (PPI) relationships were obtained from the STRING database and a PPI network was constructed using Cytoscape. Furthermore, ClueGO was used for pathway enrichment analysis of genes in the PPI network. Total 2,040 and 297 DEGs were identified in FaDu cells treated with 8 Gy X-ray or 8 Gy X-ray + RITA, respectively. PARP3 and NEIL1 were enriched in base excision repair, and CDK1 was enriched in p53 signaling pathway. RFC2 and EZH2 were identified as RITA genes. In the PPI network, many interaction relationships were identified (e.g., RFC2-CDK1, EZH2-CDK1 and PARP3-EZH2). ClueGO analysis showed that RFC2 and EZH2 were related to cell cycle. RFC2, EZH2, CDK1, PARP3 and NEIL1 may be associated, and together enhance the susceptibility of FaDu cells treated with RITA to the deleterious effects of X-ray.

A minimal threshold of FANCJ helicase activity is required for its response to replication stress or double-strand break repair.

PubMed

Bharti, Sanjay Kumar; Sommers, Joshua A; Awate, Sanket; Bellani, Marina A; Khan, Irfan; Bradley, Lynda; King, Graeme A; Seol, Yeonee; Vidhyasagar, Venkatasubramanian; Wu, Yuliang; Abe, Takuye; Kobayashi, Koji; Shin-Ya, Kazuo; Kitao, Hiroyuki; Wold, Marc S; Branzei, Dana; Neuman, Keir C; Brosh, Robert M

2018-05-21

Fanconi Anemia (FA) is characterized by bone marrow failure, congenital abnormalities, and cancer. Of over 20 FA-linked genes, FANCJ uniquely encodes a DNA helicase and mutations are also associated with breast and ovarian cancer. fancj-/- cells are sensitive to DNA interstrand cross-linking (ICL) and replication fork stalling drugs. We delineated the molecular defects of two FA patient-derived FANCJ helicase domain mutations. FANCJ-R707C was compromised in dimerization and helicase processivity, whereas DNA unwinding by FANCJ-H396D was barely detectable. DNA binding and ATP hydrolysis was defective for both FANCJ-R707C and FANCJ-H396D, the latter showing greater reduction. Expression of FANCJ-R707C or FANCJ-H396D in fancj-/- cells failed to rescue cisplatin or mitomycin sensitivity. Live-cell imaging demonstrated a significantly compromised recruitment of FANCJ-R707C to laser-induced DNA damage. However, FANCJ-R707C expressed in fancj-/- cells conferred resistance to the DNA polymerase inhibitor aphidicolin, G-quadruplex ligand telomestatin, or DNA strand-breaker bleomycin, whereas FANCJ-H396D failed. Thus, a minimal threshold of FANCJ catalytic activity is required to overcome replication stress induced by aphidicolin or telomestatin, or to repair bleomycin-induced DNA breakage. These findings have implications for therapeutic strategies relying on DNA cross-link sensitivity or heightened replication stress characteristic of cancer cells.

Analysis of features of hydrodynamics and heat transfer in the fuel assembly of prospective sodium reactor with a high rate of reproduction in the uranium-plutonium fuel cycle

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

Lubina, A. S., E-mail: lubina-as@nrcki.ru; Subbotin, A. S.; Sedov, A. A.

2016-12-15

The fast sodium reactor fuel assembly (FA) with U–Pu–Zr metallic fuel is described. In comparison with a “classical” fast reactor, this FA contains thin fuel rods and a wider fuel rod grid. Studies of the fluid dynamics and the heat transfer were carried out for such a new FA design. The verification of the ANSYS CFX code was provided for determination of the velocity, pressure, and temperature fields in the different channels. The calculations in the cells and in the FA were carried out using the model of shear stress transport (SST) selected at the stage of verification. The resultsmore » of the hydrodynamics and heat transfer calculations have been analyzed.« less

Analysis of transporter responsible for the secretion of fusaric acid from the plant pathogen Fusarium oxysporum f. sp. vasinfectum

USDA-ARS?s Scientific Manuscript database

Fusaric acid (FA), a phytotoxic polyketide produced by Fusarium oxysporum f. sp. vasinfectum (Fov), has been suggested to be associated with disease symptoms on cotton. In response to a potential threat on cotton production by the introduction of high FA producing strains from Australia, new sources...

Using Additional Analyses to Clarify the Functions of Problem Behavior: An Analysis of Two Cases

ERIC Educational Resources Information Center

Payne, Steven W.; Dozier, Claudia L.; Neidert, Pamela L.; Jowett, Erica S.; Newquist, Matthew H.

2014-01-01

Functional analyses (FA) have proven useful for identifying contingencies that influence problem behavior. Research has shown that some problem behavior may only occur in specific contexts or be influenced by multiple or idiosyncratic variables. When these contexts or sources of influence are not assessed in an FA, further assessment may be…

Teacher-Conducted Trial-Based Functional Analyses as the Basis for Intervention

ERIC Educational Resources Information Center

Bloom, Sarah E.; Lambert, Joseph M.; Dayton, Elizabeth; Samaha, Andrew L.

2013-01-01

Previous studies have focused on whether a trial-based functional analysis (FA) yields the same outcomes as more traditional FAs, and whether interventions based on trial-based FAs can reduce socially maintained problem behavior. We included a full range of behavior functions and taught 3 teachers to conduct a trial-based FA with 3 boys with…

Sex differences in white matter abnormalities after mild traumatic brain injury: localization and correlation with outcome.

PubMed

Fakhran, Saeed; Yaeger, Karl; Collins, Michael; Alhilali, Lea

2014-09-01

To evaluate sex differences in diffusion-tensor imaging (DTI) white matter abnormalities after mild traumatic brain injury (mTBI) using tract-based spatial statistics (TBSS) and to compare associated clinical outcomes. The institutional review board approved this study, with waiver of informed consent. DTI in 69 patients with mTBI (47 male and 22 female patients) and 21 control subjects (10 male and 11 female subjects) with normal conventional magnetic resonance (MR) images were retrospectively reviewed. Fractional anisotropy (FA) maps were generated as a measure of white matter integrity. Patients with mTBI underwent serial neurocognitive testing with Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT). Correlation between sex, white matter FA values, ImPACT scores, and time to symptom resolution (TSR) were analyzed with multivariate analysis and TBSS. No significant difference in age was seen between males and females (control subjects, P = .3; patients with mTBI, P = .34). No significant difference was seen in initial ImPACT symptom scores (P = .33) between male and female patients with mTBI. Male patients with mTBI had significantly decreased FA values in the uncinate fasciculus (UF) bilaterally (mean FA, 0.425; 95% confidence interval: 0.375, 0.476) compared with female patients with mTBI and control subjects (P < .05), with a significantly longer TSR (P = .04). Multivariate analysis showed sex and UF FA values independently correlated with TSR longer than 3 months (adjusted odds ratios, 2.27 and 2.38; P = .04 and P < .001, respectively), but initial symptom severity did not (adjusted odds ratio, 1.15; P = .35). Relative sparing of the UF is seen in female compared with male patients after mTBI, with sex and UF FA values as stronger predictors of TSR than initial symptom severity.

Characterization of Fumonisin A-Series by High-Resolution Liquid Chromatography-Orbitrap Mass Spectrometry

PubMed Central

Tamura, Masayoshi; Mochizuki, Naoki; Nagatomi, Yasushi; Toriba, Akira; Hayakawa, Kazuichi

2014-01-01

Fumonisin A-series (FAs) in a reference material of corn sample that was naturally contaminated with fumonisins was characterized using high-resolution liquid chromatography-Orbitrap mass spectrometry (LC-Orbitap MS). Peaks for fumonisin B1 (FB1), fumonisin B2 (FB2), and fumonisin B3 (FB3), in addition to three peaks corresponding to unknown compounds I, II, and III, were detected in the chromatogram for the corn sample. Fragment ion analysis for FB1, FB2, and FB3 showed that while the ions formed at m/z values of 200–800 were similar to those formed by the cleavage of the tricarballylic acids and the hydroxyl groups, the fragmentation patterns at m/z values of 50–200 varied depending on the hydroxyl group locations in the compounds. Fragment ion analysis of compounds I–III revealed structural similarities to FBs, only differing by an additional C2H2O in the unknown compounds. Using these results and by comparing the product ion mass spectra of compound I with fumonisin A1 (FA1) synthesized from FB1 standards, compounds I–III were hypothesized to be N-acetyl analogs of FBs: fumonisins A1 (FA1), A2 (FA2), and A3 (FA3). The method for determining concentrations was validated with FA1, FB1, FB2, and FB3 standards and applied to analyze the reference material. The FB1, FB2, and FB3 analytical levels were within acceptance limits and the amount of FA1 in the material was ~15% of FB1 amount at 4.2 mg/kg. PMID:25153258

Genetic Study of White Matter Integrity in UK Biobank (N=8448) and the Overlap With Stroke, Depression, and Dementia.

PubMed

Rutten-Jacobs, Loes C A; Tozer, Daniel J; Duering, Marco; Malik, Rainer; Dichgans, Martin; Markus, Hugh S; Traylor, Matthew

2018-06-01

Structural integrity of the white matter is a marker of cerebral small vessel disease, which is the major cause of vascular dementia and a quarter of all strokes. Genetic studies provide a way to obtain novel insights in the disease mechanism underlying cerebral small vessel disease. The aim was to identify common variants associated with microstructural integrity of the white matter and to elucidate the relationships of white matter structural integrity with stroke, major depressive disorder, and Alzheimer disease. This genome-wide association analysis included 8448 individuals from UK Biobank-a population-based cohort study that recruited individuals from across the United Kingdom between 2006 and 2010, aged 40 to 69 years. Microstructural integrity was measured as fractional anisotropy- (FA) and mean diffusivity (MD)-derived parameters on diffusion tensor images. White matter hyperintensity volumes (WMHV) were assessed on T2-weighted fluid-attenuated inversion recovery images. We identified 1 novel locus at genome-wide significance ( VCAN [versican]: rs13164785; P =3.7×10 -18 for MD and rs67827860; P =1.3×10 -14 for FA). LD score regression showed a significant genome-wide correlation between FA, MD, and WMHV (FA-WMHV rG 0.39 [SE, 0.15]; MD-WMHV rG 0.56 [SE, 0.19]). In polygenic risk score analysis, FA, MD, and WMHV were significantly associated with lacunar stroke, MD with major depressive disorder, and WMHV with Alzheimer disease. Genetic variants within the VCAN gene may play a role in the mechanisms underlying microstructural integrity of the white matter in the brain measured as FA and MD. Mechanisms underlying white matter alterations are shared with cerebrovascular disease, and inherited differences in white matter microstructure impact on Alzheimer disease and major depressive disorder. © 2018 The Authors.

White matter organization in cervical spinal cord relates differently to age and control of grip force in healthy subjects.

PubMed

Lindberg, Påvel G; Feydy, Antoine; Maier, Marc A

2010-03-17

Diffusion tensor imaging (DTI) can be used to elucidate relations between CNS structure and function. We hypothesized that the degree of spinal white matter organization relates to the accuracy of control of grip force. Healthy subjects of different age were studied using DTI and visuomotor tracking of precision grip force. The latter is a prime component of manual dexterity. A regional analysis of spinal white matter [fractional anisotropy (FA)] across multiple cervical levels (C2-C3, C4-C5, and C6-C7) and in different regions of interest (left and right lateral or medial spinal cord) was performed. FA was highest at the C2-C3 level, higher on the right than the left side, and higher in the lateral than in the medial spinal cord (p < 0.001). FA of whole cervical spinal cord (C2-C7) was lower in subjects with high tracking error (r = -0.56, p = 0.004) and decreased with age (r = -0.63, p = 0.001). A multiple regression analysis revealed an independent contribution of each predictor (semipartial correlations: age, r = -0.55, p < 0.001; tracking error, r = -0.49, p = 0.003). The closest relation between FA and tracking error was found at the C6-C7 level in the lateral spinal cord, in which the corticospinal tract innervates spinal circuitry controlling hand and digit muscles. FA of the medial spinal cord correlated consistently with age across all cervical levels, whereas FA of the lateral spinal cord did not. The results suggest (1) a functionally relevant specialization of lateral spinal cord white matter and (2) an increased sensitivity to age-related decline in medial spinal cord white matter in healthy subjects.

Fatty acid profiling of tropical marine macroalgae: an analysis from chemotaxonomic and nutritional perspectives.

PubMed

Kumari, Puja; Bijo, A J; Mantri, Vaibhav A; Reddy, C R K; Jha, Bhavanath

2013-02-01

The lipid and fatty acid (FA) compositions for 100 marine macroalgae were determined and discussed from the context of chemotaxonomic and nutritional perspectives. In general, the lipid contents in macroalgae were low (2.3-20 mg/g fr. wt.) but with substantially high amounts of nutritionally important polyunsaturated fatty acids (PUFAs) such as LA, ALA, STA, AA, EPA and DHA, that ranged from 10% to 70% of TFAs. More than 90% of the species showed nutritionally beneficial n6/n3 ratio (0.1:1-3.6:1) (p≤0.001). A closer look at the FA data revealed characteristic chemotaxonomic features with C18 PUFAs (LA, ALA and STA) being higher in Chlorophyta, C20 PUFAs (AA and EPA) in Rhodophyta while Phaeophyta depicted evenly distribution of C18 and C20 PUFAs. The ability of macroalgae to produce long-chain PUFAs could be attributed to the coupling of chloroplastic FA desaturase enzyme system from a photosynthetic endosymbiont to the FA desaturase/elongase enzyme system of a non-photosynthetic eukaryotic protist host. Further, the principal component analysis segregated the three macroalgal groups with a marked distinction of different genera, families and orders, Hierarchical cluster analyses substantiated the phylogenetic relationships of all orders investigated except for those red algal taxa belonging to Gigartinales, Ceramiales, Halymeniales and Rhodymeniales for which increased sampling effort is required to infer a conclusion. Also, the groups deduced from FA compositions were congruent with the clades inferred from nuclear and plastid genome sequences. This study further indicates that FA signatures could be employed as a valid chemotaxonomic tool to differentiate macroalgae at higher taxonomic levels such as family and orders. Copyright © 2012 Elsevier Ltd. All rights reserved.

An enhanced functional ability questionnaire (faVIQ) to measure the impact of rehabilitation services on the visually impaired

PubMed Central

Wolffsohn, James Stuart; Jackson, Jonathan; Hunt, Olivia Anne; Cottriall, Charles; Lindsay, Jennifer; Gilmour, Richard; Sinclair, Anne; Harper, Robert

2014-01-01

AIM To develop a short, enhanced functional ability Quality of Vision (faVIQ) instrument based on previous questionnaires employing comprehensive modern statistical techniques to ensure the use of an appropriate response scale, items and scoring of the visual related difficulties experienced by patients with visual impairment. METHODS Items in current quality-of-life questionnaires for the visually impaired were refined by a multi-professional group and visually impaired focus groups. The resulting 76 items were completed by 293 visually impaired patients with stable vision on two occasions separated by a month. The faVIQ scores of 75 patients with no ocular pathology were compared to 75 age and gender matched patients with visual impairment. RESULTS Rasch analysis reduced the faVIQ items to 27. Correlation to standard visual metrics was moderate (r=0.32-0.46) and to the NEI-VFQ was 0.48. The faVIQ was able to clearly discriminate between age and gender matched populations with no ocular pathology and visual impairment with an index of 0.983 and 95% sensitivity and 95% specificity using a cut off of 29. CONCLUSION The faVIQ allows sensitive assessment of quality-of-life in the visually impaired and should support studies which evaluate the effectiveness of low vision rehabilitation services. PMID:24634868

An enhanced functional ability questionnaire (faVIQ) to measure the impact of rehabilitation services on the visually impaired.

PubMed

Wolffsohn, James Stuart; Jackson, Jonathan; Hunt, Olivia Anne; Cottriall, Charles; Lindsay, Jennifer; Gilmour, Richard; Sinclair, Anne; Harper, Robert

2014-01-01

To develop a short, enhanced functional ability Quality of Vision (faVIQ) instrument based on previous questionnaires employing comprehensive modern statistical techniques to ensure the use of an appropriate response scale, items and scoring of the visual related difficulties experienced by patients with visual impairment. Items in current quality-of-life questionnaires for the visually impaired were refined by a multi-professional group and visually impaired focus groups. The resulting 76 items were completed by 293 visually impaired patients with stable vision on two occasions separated by a month. The faVIQ scores of 75 patients with no ocular pathology were compared to 75 age and gender matched patients with visual impairment. Rasch analysis reduced the faVIQ items to 27. Correlation to standard visual metrics was moderate (r=0.32-0.46) and to the NEI-VFQ was 0.48. The faVIQ was able to clearly discriminate between age and gender matched populations with no ocular pathology and visual impairment with an index of 0.983 and 95% sensitivity and 95% specificity using a cut off of 29. The faVIQ allows sensitive assessment of quality-of-life in the visually impaired and should support studies which evaluate the effectiveness of low vision rehabilitation services.

Effect of fly ash on properties of crushed brick and reclaimed asphalt in pavement base/subbase applications.

PubMed

Mohammadinia, Alireza; Arulrajah, Arul; Horpibulsuk, Suksun; Chinkulkijniwat, Avirut

2017-01-05

Fly Ash (FA), an abundant by-product with no carbon footprint, is a potential stabilizer for enhancing the physical and geotechnical properties of pavement aggregates. In this research, FA was used in different ratios to stabilize crushed brick (CB) and reclaimed asphalt pavement (RAP) for pavement base/subbase applications. The FA stabilization of CB and RAP was targeted to improve the strength and durability of these recycled materials for pavement base/subbase applications. The Unconfined Compressive Strength (UCS) and resilient modulus (M R ) development of the stabilized CB and RAP aggregates was studied under room temperature and at an elevated temperatures of 40°C, and results compared with unbound CB and RAP. Analysis of atomic silica content showed that when the amount of silica and alumina crystalline was increased, the soil structure matrix deteriorated, resulting in strength reduction. The results of UCS and M R testing of FA stabilized CB and RAP aggregates indicated that FA was a viable binder for the stabilization of recycled CB and RAP. CB and RAP stabilized with 15% FA showed the highest UCS results at both room temperature and at 40°C. Higher temperature curing was also found to result in higher strengths. Copyright © 2016 Elsevier B.V. All rights reserved.

Identification of the geographical origins of sea cucumber (Apostichopus japonicus) in northern China by using stable isotope ratios and fatty acid profiles.

PubMed

Zhang, Xufeng; Liu, Yu; Li, Ying; Zhao, Xinda

2017-03-01

Geographic traceability is an important issue for food quality and safety control of seafood. In this study,δ 13 C and δ 15 N values, as well as fatty acid (FA) content of 133 samples of A. japonicus from seven sampling points in northern China Sea were determined to evaluate their applicability in the origin traceability of A. japonicus. Principal component analysis (PCA) and discriminant analysis (DA) were applied to different data sets in order to evaluate their performance in terms of classification or predictive ability. δ 13 C and δ 15 N values could effectively discriminate between different origins of A. japonicus. Significant differences in the FA compositions showed the effectiveness of FA composition as a tool for distinguishing between different origins of A. japonicus. The two technologies, combined with multivariate statistical analysis, can be promising methods to discriminate A. japonicus from different geographical areas. Copyright © 2016. Published by Elsevier Ltd.

Tunable ferroelectric polarization and its interplay with spin-orbit coupling in tin iodide perovskites

NASA Astrophysics Data System (ADS)

Stroppa, Alessandro; di Sante, Domenico; Barone, Paolo; Bokdam, Menno; Kresse, Georg; Franchini, Cesare; Whangbo, Myung-Hwan; Picozzi, Silvia

2014-12-01

Ferroelectricity is a potentially crucial issue in halide perovskites, breakthrough materials in photovoltaic research. Using density functional theory simulations and symmetry analysis, we show that the lead-free perovskite iodide (FA)SnI3, containing the planar formamidinium cation FA, (NH2CHNH2)+, is ferroelectric. In fact, the perpendicular arrangement of FA planes, leading to a ‘weak’ polarization, is energetically more stable than parallel arrangements of FA planes, being either antiferroelectric or ‘strong’ ferroelectric. Moreover, we show that the ‘weak’ and ‘strong’ ferroelectric states with the polar axis along different crystallographic directions are energetically competing. Therefore, at least at low temperatures, an electric field could stabilize different states with the polarization rotated by π/4, resulting in a highly tunable ferroelectricity appealing for multistate logic. Intriguingly, the relatively strong spin-orbit coupling in noncentrosymmetric (FA)SnI3 gives rise to a co-existence of Rashba and Dresselhaus effects and to a spin texture that can be induced, tuned and switched by an electric field controlling the ferroelectric state.

Solidification/stabilization of chromite ore processing residue using alkali-activated composite cementitious materials.

PubMed

Huang, Xiao; Zhuang, RanLiang; Muhammad, Faheem; Yu, Lin; Shiau, YanChyuan; Li, Dongwei

2017-02-01

Chromite Ore Processing Residue (COPR) produced in chromium salt production process causes a great health and environmental risk with Cr(VI) leaching. The solidification/stabilization (S/S) of COPR using alkali-activated blast furnace slag (BFS) and fly ash (FA) based cementitious material was investigated in this study. The optimum percentage of BFS and FA for preparing the alkali-activated BFS-FA binder had been studied. COPR was used to replace the amount of BFS-FA or ordinary Portland cement (OPC) for the preparation of the cementitious materials, respectively. The immobilization effect of the alkali-activated BFS-FA binder on COPR was much better than that of OPC based cementitious material. The potential for reusing the final treatment product as a readily available construction material was evaluated. X-ray diffraction (XRD), Fourier transform infrared spectrometry (FTIR) and scanning electron microscope with energy dispersive spectrometer (SEM-EDS) analysis indicated that COPR had been effectively immobilized. The solidification mechanism is the combined effect of reduction, ion exchange, precipitation, adsorption and physical fixation in the alkali-activated composite cementitious material. Copyright © 2016 Elsevier Ltd. All rights reserved.

β-hydroxy-β-methylbutyrate free acid supplementation may improve recovery and muscle adaptations after resistance training: a systematic review.

PubMed

Silva, Vagner R; Belozo, Felipe L; Micheletti, Thayana O; Conrado, Marcelo; Stout, Jeffrey R; Pimentel, Gustavo D; Gonzalez, Adam M

2017-09-01

β-Hydroxy-β-methylbutyrate free acid (HMB-FA) has been suggested to accelerate the regenerative capacity of skeletal muscle after high-intensity exercise and attenuate markers of skeletal muscle damage. Herein a systematic review on the use of HMB-FA supplementation as an ergogenic aid to improve measures of muscle recovery, performance, and hypertrophy after resistance training was conducted. This review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. We included randomized, double-blinded, placebo-controlled trials investigating the effects of HMB-FA supplementation in conjunction with resistance exercise in humans. The search was conducted using Medline and Google Scholar databases for the terms beta-hydroxy-beta-methylbutyrate, HMB free acid, exercise, resistance exercise, strength training, and HMB supplementation. Only research articles published from 1996 to 2016 in English language were considered for the analysis. Nine studies met the criteria for inclusion in the analyses. Most studies included resistance-trained men, and the primary intervention strategy involved administration of 3g of HMB-FA per day. In conjunction with resistance training, HMB-FA supplementation may attenuate markers of muscle damage, augment acute immune and endocrine responses, and enhance training-induced muscle mass and strength. HMB-FA supplementation may also improve markers of aerobic fitness when combined with high-intensity interval training. Nevertheless, more studies are needed to determine the overall efficacy of HMB-FA supplementation as an ergogenic aid. Copyright © 2017 Elsevier Inc. All rights reserved.

[Diffusion tensor imaging findings in first-episode and chronic schizophrenics].

PubMed

Wei, Qin-Ling; Kang, Zhuang; Wu, Xiao-Li; Zhang, Jin-Bei; Li, Lei-Jun; Zheng, Liang-Rong; Guo, Xiao-Feng; Zhao, Jing-Ping

2011-08-23

To investigate the integrity of white matters in first-episode and chronic schizophrenics. For this study, 39 first-episode and 38 chronic schizophrenics, 69 healthy controls (age, gender and years of received education no significantly different from those of the patients) underwent diffusion weighted images with a single-shot echo planar imaging (EPI) sequence aligned to the straight axial plane. The fractional anisotropy (FA) images of three groups underwent one-way ANOVA with the methods of voxel-based morphometric (VBM) analysis. (1) There were three brain regions where the FA values of white matter were different among three groups: right caudate nucleus (MNI: 20, 12, 14; cluster = 432 voxels; FA value: 0.36 ± 0.18 vs 0.35 ± 0.24 vs 0.38 ± 0.17), left insula (MNI: -32, 18, 2; cluster = 204 voxels; FA value: 0.35 ± 0.31 vs 0.33 ± 0.24 vs 0.36 ± 0.21) and right anterior cingulate (MNI: 16, 36, 12; cluster = 132 voxels; FA value: 0.35 ± 0.29 vs 0.34 ± 0.31 vs 0.37 ± 0.25). (2) The mean FA values of the three brain regions of two patients groups decreased versus those of healthy controls (P < 0.05). (3) The mean FA values of left insular region in chronic patients decreased versus those of the first-episode patients (P < 0.05). The reduced integrity of white matter may play an etiological role in schizophrenia and the changes are probably progressive.

Apoptosis selectively induced in BEL-7402 cells by folic acid-modified magnetic nanoparticles combined with 100 Hz magnetic field

PubMed Central

Wen, Jian; Jiang, Shulian; Chen, Zhiqiang; Zhao, Wei; Yi, Yongxiang; Yang, Ruili; Chen, Baoan

2014-01-01

Objective To explore the effect of folic acid-modified magnetic nanoparticles (FA-MNPs) combined with a 100 Hz extremely low-frequency electromagnetic field (ELF-EMF) on the apoptosis of liver cancer BEL-7402 cells. Materials and methods MNPs (20 nm) were prepared by coprecipitation, and then folic acid was coated onto MNPs to prepare FA-MNPs. BEL-7402 cells and HL7702 cells were selected as liver cancer cells and normal liver cells, respectively. The ELF-EMF was generated from a solenoid coil. Cellular uptake of NPs was determined by inductively coupled plasma atomic emission spectroscopy. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to evaluate cell inhibition. Apoptosis was analyzed by flow cytometry. Statistical analyses were performed using two-way analysis of variance. Results FA-MNPs combined with a 100 Hz magnetic field significantly inhibited cell proliferation and induced higher apoptosis compared to either the ELF-EMF alone or FA-MNPs alone. FA-MNPs showed a better apoptosis effect and higher iron uptake in BEL-7402 cells compared to in HL7702 cells. On the basis of the ELF-EMF, higher doses of FA-MNPs brought higher apoptosis and higher iron uptake in either BEL-7402 cells or HL7702 cells. Conclusion These results suggest that FA-MNPs may induce apoptosis in a cellular iron uptake-dependent manner when combined with an ELF-EMF in BEL-7402 cells. PMID:24790442

Colloidal diatomite, radionickel, and humic substance interaction: a combined batch, XPS, and EXAFS investigation.

PubMed

Sheng, Guodong; Shen, Runpu; Dong, Huaping; Li, Yimin

2013-06-01

This work determined the influence of humic acid (HA) and fulvic acid (FA) on the interaction mechanism and microstructure of Ni(II) onto diatomite by using batch experiments, X-ray photoelectron spectroscopy (XPS), and extended X-ray absorption fine structure (EXAFS) methods. Macroscopic and spectroscopic experiments have been combined to see the evolution of the interaction mechanism and microstructure of Ni(II) in the presence of HA/FA as compared with that in the absence of HA/FA. The results indicated that the interaction of Ni(II) with diatomite presents the expected solution pH edge at 7.0, which is modified by addition of HA/FA. In the presence of HA/FA, the interaction of Ni(II) with diatomite increased below solution pH 7.0, while Ni(II) interaction decreased above solution pH 7.0. XPS analysis suggested that the enrichment of Ni(II) onto diatomite may be due to the formation of (≡SO)2Ni. EXAFS results showed that binary surface complexes and ternary surface complexes of Ni(II) can be simultaneously formed in the presence of HA/FA, whereas only binary surface complexes of Ni(II) are formed in the absence of HA/FA, which contribute to the enhanced Ni(II) uptake at low pH values. The results observed in this work are important for the evaluation of Ni(II) and related radionuclide physicochemical behavior in the natural soil and water environment.

The effect of sex and handedness on white matter anisotropy: a diffusion tensor magnetic resonance imaging study.

PubMed

Powell, J L; Parkes, L; Kemp, G J; Sluming, V; Barrick, T R; García-Fiñana, M

2012-04-05

Diffusion tensor magnetic resonance imaging provides a way of assessing the asymmetry of white matter (WM) connectivity, the degree of anisotropic diffusion within a given voxel being a marker of coherently bundled myelinated fibers. Voxel-based statistical analysis was performed on fractional anisotropy (FA) images of 42 right- and 40 left-handers, to assess differences in underlying WM anisotropy and FA asymmetry across the whole brain. Right-handers show greater anisotropy than left-handers in the uncinate fasciculus (UF) within the limbic lobe, and WM underlying prefrontal cortex, medial and inferior frontal gyri. Significantly greater leftward FA asymmetry in cerebellum posterior lobe is seen in left- than right-handers, and males show significantly greater rightward (right-greater-than-left) FA asymmetry in regions of middle occipital lobe, medial temporal gyrus, and a region of the superior longitudinal fasciculus underlying the supramarginal gyrus. Leftward (left-greater-than-right) anisotropy is found in regions of the arcuate fasciculus (AF), UF, and WM underlying pars triangularis in both handedness groups, with right-handers alone showing additional leftward FA asymmetry along the length of the superior temporal gyrus. Overall results indicate that although both handedness groups show anisotropy in similar WM regions, greater anisotropy is observed in right-handers compared with left-handers. The largest differences in FA asymmetry are found between males and females, suggesting a greater effect of sex than handedness on FA asymmetry. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

Current Knowledge and Priorities for Future Research in Late Effects after Hematopoietic Cell Transplantation for Inherited Bone Marrow Failure Syndromes: Consensus Statement from the Second Pediatric Blood and Marrow Transplant Consortium International Conference on Late Effects after Pediatric Hematopoietic Cell Transplantation

PubMed Central

Dietz, Andrew C.; Mehta, Parinda A.; Vlachos, Adrianna; Savage, Sharon A.; Bresters, Dorine; Tolar, Jakub; Boulad, Farid; Dalle, Jean Hugues; Bonfim, Carmem; de la Fuente, Josu; Duncan, Christine N.; Baker, K. Scott; Pulsipher, Michael A.; Lipton, Jeffrey M.; Wagner, John E.; Alter, Blanche P.

2017-01-01

Fanconi anemia (FA), dyskeratosis congenita (DC), and Diamond Blackfan anemia (DBA) are 3 of the most common inherited bone marrow failure syndromes (IBMFS), in which the hematologic manifestations can be cured with hematopoietic cell transplantation (HCT). Later in life, these patients face a variety of medical conditions, which may be a manifestation of underlying disease or due to pre-HCT therapy, the HCT, or a combination of all these elements. Very limited long-term follow-up data exist in these populations, with FA the only IBMFS that has specific published data. During the international consensus conference sponsored by the Pediatric Blood and Marrow Transplant Consortium entitled “Late Effects Screening and Recommendations following Allogeneic Hematopoietic Cell Transplant (HCT) for Immune Deficiency and Nonmalignant Hematologic Disease” held in Minneapolis, Minnesota in May of 2016, a half-day session was focused specifically on the unmet needs for these patients with IBMFS. A multidisciplinary group of experts discussed what is currently known, outlined an agenda for future research, and laid out long-term follow-up guidelines based on a combination of evidence in the literature as well as expert opinion. This article addresses the state of science in that area as well as consensus regarding the agenda for future research, with specific screening guidelines to follow in the next article from this group. PMID:28115275

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

Kajimoto, Masaki; Ledee, Dolena R.; Xu, Chun

Background: Extracorporeal membrane oxygenation (ECMO) provides a rescue for children with severe cardiac failure. We previously showed that triiodothyronine (T3) improves cardiac function by modulating pyruvate oxidation during weaning. This study was focused on fatty acid (FA) metabolism modulated by T3 for weaning from ECMO after cardiac injury. Methods: Nineteen immature piglets (9.1-15.3 kg) were separated into 3 groups with ECMO (6.5 hours) and wean: normal circulation (Group-C);transient coronary occlusion (10 minutes) followed by ECMO (Group-IR); and IR with T3 supplementation (Group-IR-T3). 13-Carbon labeled lactate, medium-chain and long-chain FAs were infused as oxidative substrates. Substrate fractional contribution to the citricmore » acid cycle (FC) was analyzed by 13-Carbon nuclear magnetic resonance. Results: ECMO depressed circulating T3 levels to 40% baseline at 4 hours and were restored in Group-IR-T3. Group-IR decreased cardiac power, which was not fully restorable and 2 pigs were lost because of weaning failure. Group-IR also depressed FC-lactate, while the excellent contractile function and energy efficiency in Group-IR-T3 occurred along with a marked FC-lactate increase and [ATP]/[ADP] without either decreasing FC-FAs or elevating myocardial oxygen consumption over Group-C or -IR. Conclusions: T3 releases inhibition of lactate oxidation following ischemia-reperfusion injury without impairing FA oxidation. These findings indicate that T3 depression during ECMO is maladaptive, and that restoring levels improves metabolic flux and enhances contractile function during weaning.« less

Augmentation of the therapeutic efficacy of WEE1 kinase inhibitor AZD1775 by inhibiting the YAP-E2F1-DNA damage response pathway axis.

PubMed

Oku, Yusuke; Nishiya, Naoyuki; Tazawa, Takaaki; Kobayashi, Takaya; Umezawa, Nanami; Sugawara, Yasuyo; Uehara, Yoshimasa

2018-06-01

The main reasons for failure of cancer chemotherapy are intrinsic and acquired drug resistance. The Hippo pathway effector Yes-associated protein (YAP) is associated with resistance to both cytotoxic and molecular targeted drugs. Several lines of evidence indicate that YAP activates transcriptional programmes to promote cell cycle progression and DNA damage responses. Therefore, we hypothesised that YAP is involved in the sensitivity of cancer cells to small-molecule agents targeting cell cycle-related proteins. Here, we report that the inactivation of YAP sensitises the OVCAR-8 ovarian cancer cell line to AZD1775, a small-molecule WEE1 kinase inhibitor. The accumulation of DNA damage and mitotic failures induced by AZD1775-based therapy were further enhanced by YAP depletion. YAP depletion reduced the expression of the Fanconi anaemia (FA) pathway components required for DNA repair and their transcriptional regulator E2F1. These results suggest that YAP activates the DNA damage response pathway, exemplified by the FA pathway and E2F1. Furthermore, we aimed to apply this finding to combination chemotherapy against ovarian cancers. The regimen containing dasatinib, which inhibits the nuclear localisation of YAP, improved the response to AZD1775-based therapy in the OVCAR-8 ovarian cancer cell line. We propose that dasatinib acts as a chemosensitiser for a subset of molecular targeted drugs, including AZD1775, by targeting YAP.

Analysis of aldehydes in beer by gas-diffusion microextraction: characterization by high-performance liquid chromatography-diode-array detection-atmospheric pressure chemical ionization-mass spectrometry.

PubMed

Gonçalves, Luís Moreira; Magalhães, Paulo Jorge; Valente, Inês Maria; Pacheco, João Grosso; Dostálek, Pavel; Sýkora, David; Rodrigues, José António; Barros, Aquiles Araújo

2010-06-11

In this work, a recently developed extraction technique for sample preparation aiming the analysis of volatile and semi-volatile compounds named gas-diffusion microextraction (GDME) is applied in the chromatographic analysis of aldehydes in beer. Aldehydes-namely acetaldehyde (AA), methylpropanal (MA) and furfural (FA)-were simultaneously extracted and derivatized with 2,4-dinitrophenylhydrazine (DNPH), then the derivatives were separated and analyzed by high-performance liquid chromatography with spectrophotometric detection (HPLC-UV). The identity of the eluted compounds was confirmed by high-performance liquid chromatography-atmospheric pressure chemical ionization-mass-spectrometry detection in the negative ion mode (HPLC-APCI-MS). The developed methodology showed good repeatability (ca. 5%) and linearity as well as good limits of detection (AA-12.3, FA-1.5 and MA 5.4microgL(-1)) and quantification (AA-41, FA-4.9 and MA 18microgL(-1)); it also appears to be competitive in terms of speed and cost of analysis. Copyright 2010 Elsevier B.V. All rights reserved.

Linkage analysis of the Fanconi anemia gene FACC with chromosome 9q markers

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

Auerbach, A.D.; Shin, H.T.; Kaporis, A.G.

1994-09-01

Fanconi anemia (FA) is a genetically heterogeneous syndrome, with at least four different complementation groups as determined by cell fusion studies. The gene for complementation group C, FACC, has been cloned and mapped to chromosome 9q22.3 by in situ hybridization, while linkage analysis has supported the placement of another gene on chromosome 20q. We have analyzed five microsatellite markers and one RFLP on chromosome 9q in a panel of FA families from the International Fanconi Anemia Registry (IFAR) in order to place FACC on the genetic map. Polymorphisms were typed in 308 individuals from 51 families. FACC is tightly linkedmore » to both D9S151 [{Theta}{sub max}=0.025, Z{sub max}=7.75] and to D9S196 [{Theta}{sub max}=0.041, Z{sub max}=7.89]; multipoint analysis is in progress. We are currently screening a YAC clone that contains the entire FACC gene for additional microsatellite markers suitable for haplotype analysis of FA families.« less

Hydroxyapatite, fluor-hydroxyapatite and fluorapatite produced via the sol-gel method: bonding to titanium and scanning electron microscopy.

PubMed

Tredwin, Christopher J; Georgiou, George; Kim, Hae-Won; Knowles, Jonathan C

2013-05-01

Hydroxyapatite (HA), fluor-hydroxyapatite (FHA) with varying levels of fluoride ion substitution and fluorapatite (FA) production has been characterised and optimised by the sol-gel method and the dissolution and biological properties of these materials were investigated. It was the objective of this study to investigate the potential bond strength and interaction of these materials with titanium. HA, FHA and FA were synthesised by a sol-gel method. Calcium nitrate and triethyl phosphite were used as precursors under an ethanol-water based solution. Different amounts of ammonium fluoride (NH4F) were incorporated for the preparation of the FHA and FA sol-gels. Using a spin coating technique the sol-gels were coated onto commercially pure titanium disks and crystallised at various temperatures. Using scanning electron microscopy (SEM) and elemental analysis, the surface characteristics, coating thickness and interaction of the Ti substrate and coating were investigated. The bond strengths of the coating to the Ti were investigated using an Instron Universal Load Testing Machine. Statistical analysis was performed with a two-way analysis of variance and post hoc testing with a Bonferroni correction. (1) Coating speed inversely influenced the coating thickness. (2) Increasing fluoride ion substitution and heating temperature significantly increased bond strength and (3) increasing fluoride ion substitution increased the coating thickness. FHA and FA synthesised using the sol-gel technique may offer a superior alternative to coating titanium implants with HA and plasma spraying. HA, FHA and FA materials synthesised by the sol-gel method may also have a use as bone grafting materials. Copyright © 2013 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

Free ammonia pre-treatment of secondary sludge significantly increases anaerobic methane production.

PubMed

Wei, Wei; Zhou, Xu; Wang, Dongbo; Sun, Jing; Wang, Qilin

2017-07-01

Energy recovery in the form of methane from sludge/wastewater is restricted by the poor and slow biodegradability of secondary sludge. An innovative pre-treatment technology using free ammonia (FA, i.e. NH 3 ) was proposed in this study to increase anaerobic methane production. The solubilisation of secondary sludge was significantly increased after FA pre-treatment at up to 680 mg NH 3 -N/L for 1 day, under which the solubilisation (i.e. 0.4 mg SCOD/mg VS; SCOD: soluble chemical oxygen demand; VS: volatile solids) was >10 times higher than that without FA pre-treatment (i.e. 0.03 mg SCOD/mg VS). Biochemical methane potential assays showed that FA pre-treatment at above 250 mg NH 3 -N/L is effective in improving anaerobic methane production. The highest improvement in biochemical methane potential (B 0 ) and hydrolysis rate (k) was achieved at FA concentrations of 420-680 mg NH 3 -N/L, and was determined as approximately 22% (from 160 to 195 L CH 4 /kg VS added) and 140% (from 0.22 to 0.53 d -1 ) compared to the secondary sludge without pre-treatment. More analysis revealed that the FA induced improvement in B 0 and k could be attributed to the rapidly biodegradable substances rather than the slowly biodegradable substances. Economic and environmental analyses showed that the FA-based technology is economically favourable and environmentally friendly. Since this FA technology aims to use the wastewater treatment plants (WWTPs) waste (i.e. anaerobic digestion liquor) to enhance methane production from the WWTPs, it will set an example for the paradigm shift of the WWTPs from 'linear economy' to 'circular economy'. Copyright © 2017 Elsevier Ltd. All rights reserved.

Δ(9)-THC modulation of fatty acid 2-hydroxylase (FA2H) gene expression: possible involvement of induced levels of PPARα in MDA-MB-231 breast cancer cells.

PubMed

Takeda, Shuso; Ikeda, Eriko; Su, Shengzhong; Harada, Mari; Okazaki, Hiroyuki; Yoshioka, Yasushi; Nishimura, Hajime; Ishii, Hiroyuki; Kakizoe, Kazuhiro; Taniguchi, Aya; Tokuyasu, Miki; Himeno, Taichi; Watanabe, Kazuhito; Omiecinski, Curtis J; Aramaki, Hironori

2014-12-04

We recently reported that Δ(9)-tetrahydrocannabinol (Δ(9)-THC), a major cannabinoid component in Cannabis Sativa (marijuana), significantly stimulated the expression of fatty acid 2-hydroxylase (FA2H) in human breast cancer MDA-MB-231 cells. Peroxisome proliferator-activated receptor α (PPARα) was previously implicated in this induction. However, the mechanisms mediating this induction have not been elucidated in detail. We performed a DNA microarray analysis of Δ(9)-THC-treated samples and showed the selective up-regulation of the PPARα isoform coupled with the induction of FA2H over the other isoforms (β and γ). Δ(9)-THC itself had no binding/activation potential to/on PPARα, and palmitic acid (PA), a PPARα ligand, exhibited no stimulatory effects on FA2H in MDA-MB-231 cells; thus, we hypothesized that the levels of PPARα induced were involved in the Δ(9)-THC-mediated increase in FA2H. In support of this hypothesis, we herein demonstrated that; (i) Δ(9)-THC activated the basal transcriptional activity of PPARα in a concentration-dependent manner, (ii) the concomitant up-regulation of PPARα/FA2H was caused by Δ(9)-THC, (iii) PA could activate PPARα after the PPARα expression plasmid was introduced, and (iv) the Δ(9)-THC-induced up-regulation of FA2H was further stimulated by the co-treatment with L-663,536 (a known PPARα inducer). Taken together, these results support the concept that the induced levels of PPARα may be involved in the Δ(9)-THC up-regulation of FA2H in MDA-MB-231 cells. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Comparative Analysis of the Wako β-Glucan Test and the Fungitell® Assay for the Diagnosis of Candidemia and Pneumocystis jirovecii Pneumonia.

PubMed

Friedrich, Ricarda; Rappold, Elfriede; Bogdan, Christian; Held, Jürgen

2018-06-13

Background (1→3)-β-D-glucan (BDG) is a biomarker for invasive fungal disease. Until now, all BDG-data in the western hemisphere were obtained using the Fungitell® assay (FA). How it compares to the Wako β-Glucan Test (GT), that was recently launched in Europe, is largely unknown. Methods We conducted a case-control study to compare both assays in serum samples of 120 candidemia and 63 Pneumocystis jirovecii pneumonia (PCP) patients. 200 patients with bacteremia or negative blood cultures served as candidemia control group. Results In patients with candidemia the median BDG values of the FA and the GT were 351 and 8.4 pg/ml, respectively. With both assays, the BDG levels in candidemia were significantly higher than those measured in the control group (p<0.001). The sensitivity, specificity, positive and negative predictive values for the diagnosis of candidemia were 86.7%, 85.0%, 6.0% and 99.8% for the FA and 42.5%, 98.0%, 19.0% and 99.4% for the GT, respectively.In PCP patients the median BDG values of the FA and the GT were 963 and 57.7 pg/ml, respectively. The sensitivity for PCP diagnosis was 100% for the FA and 88.9% for the GT. In practical terms, the GT proved to be robust and applicable for testing single samples, whereas for economic reasons the FA required the samples to be tested in batch. Conclusions The sensitivity of the FA is superior to that of the GT. However, the GT is a valuable alternative to the FA especially in patients with suspected PCP and in laboratories with low sample throughput. Copyright © 2018 American Society for Microbiology.

Effects of blend of canola oil and palm oil on nutrient intake and digestibility, growth performance, rumen fermentation and fatty acids in goats.

PubMed

Adeyemi, Kazeem Dauda; Sazili, Awis Qurni; Ebrahimi, Mahdi; Samsudin, Anjas Asmara; Alimon, Abd Rasak; Karim, Roselina; Karsani, Saiful Anuar; Sabow, Azad Behnan

2016-09-01

The study examined the effects of blend of 80% canola oil and 20% palm oil (BCPO) on nutrient intake and digestibility, growth performance, rumen fermentation and fatty acids (FA) in goats. Twenty-four Boer bucks were randomly assigned to diets containing 0, 4 and 8% BCPO on a dry matter basis, fed for 100 days and slaughtered. Diet did not affect feed efficiency, growth performance, intake and digestibility of all nutrients except ether extract. Intakes and digestibilities of ether extract, unsaturated fatty acids (FA) and total FA were higher (P < 0.05) while digestibility of C18:0 was lower (P < 0.05) in oil-fed goats than the control goats. Total volatile FA, acetate, butyrate, acetate/propionate ratio and methane decreased (P < 0.05) with increasing BCPO but propionate, NH3 -N and rumen pH did not differ between diets. Ruminal concentration of C18:0, n-3 FA and total FA increased (P < 0.05) while C12:0, C14:0, C15:0 and n-6 FA decreased with increasing BCPO. Analysis of the FA composition of Triceps brachii muscle showed that concentrations of C16:0, C14:0 and C18:2n-6 were lower (P < 0.05) while C18:1n-9, C18:3n-3 and C20:5n-3 were higher in oil-fed goats compared with control goats. Dietary BCPO altered muscle lipids without having detrimental effects on nutrient intake and digestibility and growth performance in goats. © 2015 Japanese Society of Animal Science.

Biotransformation of ferulic acid to protocatechuic acid by Corynebacterium glutamicum ATCC 21420 engineered to express vanillate O-demethylase.

PubMed

Okai, Naoko; Masuda, Takaya; Takeshima, Yasunobu; Tanaka, Kosei; Yoshida, Ken-Ichi; Miyamoto, Masanori; Ogino, Chiaki; Kondo, Akihiko

2017-12-01

Ferulic acid (4-hydroxy-3-methoxycinnamic acid, FA) is a lignin-derived phenolic compound abundant in plant biomass. The utilization of FA and its conversion to valuable compounds is desired. Protocatechuic acid (3,4-dihydroxybenzoic acid, PCA) is a precursor of polymers and plastics and a constituent of food. A microbial conversion system to produce PCA from FA was developed in this study using a PCA-producing strain of Corynebacterium glutamicum F (ATCC 21420). C. glutamicum strain F grown at 30 °C for 48 h utilized 2 mM each of FA and vanillic acid (4-hydroxy-3-methoxybenzoic acid, VA) to produce PCA, which was secreted into the medium. FA may be catabolized by C. glutamicum through proposed (I) non-β-oxidative, CoA-dependent or (II) β-oxidative, CoA-dependent phenylpropanoid pathways. The conversion of VA to PCA is the last step in each pathway. Therefore, the vanillate O-demethylase gene (vanAB) from Corynebacterium efficiens NBRC 100395 was expressed in C. glutamicum F (designated strain FVan) cultured at 30 °C in AF medium containing FA. Strain C. glutamicum FVan converted 4.57 ± 0.07 mM of FA into 2.87 ± 0.01 mM PCA after 48 h with yields of 62.8% (mol/mol), and 6.91 mM (1064 mg/L) of PCA was produced from 16.0 mM of FA after 12 h of fed-batch biotransformation. Genomic analysis of C. glutamicum ATCC 21420 revealed that the PCA-utilization genes (pca cluster) were conserved in strain ATCC 21420 and that mutations were present in the PCA importer gene pcaK.

Somatic mosaicism of an intragenic FANCB duplication in both fibroblast and peripheral blood cells observed in a Fanconi anemia patient leads to milder phenotype.

PubMed

Asur, Rajalakshmi S; Kimble, Danielle C; Lach, Francis P; Jung, Moonjung; Donovan, Frank X; Kamat, Aparna; Noonan, Raymond J; Thomas, James W; Park, Morgan; Chines, Peter; Vlachos, Adrianna; Auerbach, Arleen D; Smogorzewska, Agata; Chandrasekharappa, Settara C

2018-01-01

Fanconi anemia (FA) is a rare disorder characterized by congenital malformations, progressive bone marrow failure, and predisposition to cancer. Patients harboring X-linked FANCB pathogenic variants usually present with severe congenital malformations resembling VACTERL syndrome with hydrocephalus. We employed the diepoxybutane (DEB) test for FA diagnosis, arrayCGH for detection of duplication, targeted capture and next-gen sequencing for defining the duplication breakpoint, PacBio sequencing of full-length FANCB aberrant transcript, FANCD2 ubiquitination and foci formation assays for the evaluation of FANCB protein function by viral transduction of FANCB-null cells with lentiviral FANCB WT and mutant expression constructs, and droplet digital PCR for quantitation of the duplication in the genomic DNA and cDNA. We describe here an FA-B patient with a mild phenotype. The DEB diagnostic test for FA revealed somatic mosaicism. We identified a 9154 bp intragenic duplication in FANCB, covering the first coding exon 3 and the flanking regions. A four bp homology (GTAG) present at both ends of the breakpoint is consistent with microhomology-mediated duplication mechanism. The duplicated allele gives rise to an aberrant transcript containing exon 3 duplication, predicted to introduce a stop codon in FANCB protein (p.A319*). Duplication levels in the peripheral blood DNA declined from 93% to 7.9% in the span of eleven years. Moreover, the patient fibroblasts have shown 8% of wild-type (WT) allele and his carrier mother showed higher than expected levels of WT allele (79% vs. 50%) in peripheral blood, suggesting that the duplication was highly unstable. Unlike sequence point variants, intragenic duplications are difficult to precisely define, accurately quantify, and may be very unstable, challenging the proper diagnosis. The reversion of genomic duplication to the WT allele results in somatic mosaicism and may explain the relatively milder phenotype displayed by the FA-B patient described here. © 2017 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.

[Fanconi anemia: genes and function(s) revisited].

PubMed

Papadopoulo, Dora; Moustacchi, Ethel

2005-01-01

Fanconi anemia (FA), a rare inherited disorder, exhibits a complex phenotype including progressive bone marrow failure, congenital malformations and increased risk of cancers, mainly acute myeloid leukaemia. At the cellular level, FA is characterized by hypersensitivity to DNA cross-linking agents and by high frequencies of induced chromosomal aberrations, a property used for diagnosis. FA results from mutations in one of the eleven FANC (FANCA to FANCJ) genes. Nine of them have been identified. In addition, FANCD1 gene has been shown to be identical to BRCA2, one of the two breast cancer susceptibility genes. Seven of the FANC proteins form a complex, which exists in four different forms depending of its subcellular localisation. Four FANC proteins (D1(BRCA2), D2, I and J) are not associated to the complex. The presence of the nuclear form of the FA core complex is necessary for the mono-ubiquitinylation of FANCD2 protein, a modification required for its re-localization to nuclear foci, likely to be sites of DNA repair. A clue towards understanding the molecular function of the FANC genes comes from the recently identified connection of FANC to the BRCA1, ATM, NBS1 and ATR genes. Two of the FANC proteins (A and D2) directly interact with BRCA1, which in turn interacts with the MRE11/RAD50/NBS1 complex, which is one of the key components in the mechanisms involved in the cellular response to DNA double strand breaks (DSB). Moreover, ATM, a protein kinase that plays a central role in the network of DSB signalling, phosphorylates in vitro and in vivo FANCD2 in response to ionising radiations. Moreover, the NBS1 protein and the monoubiquitinated form of FANCD2 seem to act together in response to DNA crosslinking agents. Taken together with the previously reported impaired DSB and DNA interstrand crosslinks repair in FA cells, the connection of FANC genes to the ATM, ATR, NBS1 and BRCA1 links the FANC genes function to the finely orchestrated network involved in the sensing, signalling and repair of DNA replication-blocking lesions.

The Effects of Conducting a Functional Analysis on Problem Behavior in Other Settings

ERIC Educational Resources Information Center

Call, Nathan A.; Findley, Addie J.; Reavis, Andrea R.

2012-01-01

It has been suggested that reinforcing problem behavior during functional analyses (FAs) may be unethical (e.g., Carr, 1977), the implication being that doing so may result in an increase in problem behavior outside of FA sessions. The current study assessed whether conducting a FA resulted in increases in problem behavior outside of the FA…

Low-fat beef patties with augmented omega-3 fatty acid and CLA levels and influence of grape seed extract.

PubMed

Gómez, Inmaculada; Beriain, María J; Sarriés, María V; Insausti, Kizkitza; Mendizabal, José A

2014-11-01

The effects of raising the omega-3 fatty acid (FA), conjugated linoleic acid (CLA), or omega-3 FA plus CLA levels on beef by means of dietary supplementation and of adding grape seed extract (250 mg/kg meat product) in beef patties stored at 2 ± 1 °C in aerobic packaging under simulated retail display conditions for 6 d was evaluated by measuring the thiobarbituric acid reactive substances (TBARS), pH, and instrumental color measurement values and by means of sensory analysis. The pH, instrumental color measurements, and sensory attribute values for patties made from beef with augmented omega-3 FA and/or CLA contents were similar to the values for the control patties made from beef from animals fed a conventional diet. Adding GSE lowered oxidation levels on day 6 (P < 0.001) and did not affect the instrumental color or sensory analysis results during the display period. This suggests that omega-3 FA and CLA-augmented beef could be used to make low-fat beef patties having characteristics similar to those of conventional beef patties while being more in keeping with currently recommended nutritional guidelines. © 2014 Institute of Food Technologists®

Mobility-based correction for accurate determination of binding constants by capillary electrophoresis-frontal analysis.

PubMed

Qian, Cheng; Kovalchik, Kevin A; MacLennan, Matthew S; Huang, Xiaohua; Chen, David D Y

2017-06-01

Capillary electrophoresis frontal analysis (CE-FA) can be used to determine binding affinity of molecular interactions. However, its current data processing method mandate specific requirement on the mobilities of the binding pair in order to obtain accurate binding constants. This work shows that significant errors are resulted when the mobilities of the interacting species do not meet these requirements. Therefore, the applicability of CE-FA in many real word applications becomes questionable. An electrophoretic mobility-based correction method is developed in this work based on the flux of each species. A simulation program and a pair of model compounds are used to verify the new equations and evaluate the effectiveness of this method. Ibuprofen and hydroxypropyl-β-cyclodextrinare used to demonstrate the differences in the obtained binding constant by CE-FA when different calculation methods are used, and the results are compared with those obtained by affinity capillary electrophoresis (ACE). The results suggest that CE-FA, with the mobility-based correction method, can be a generally applicable method for a much wider range of applications. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

False-positive tangible outcomes of functional analyses.

PubMed

Rooker, Griffin W; Iwata, Brian A; Harper, Jill M; Fahmie, Tara A; Camp, Erin M

2011-01-01

Functional analysis (FA) methodology is the most precise method for identifying variables that maintain problem behavior. Occasionally, however, results of an FA may be influenced by idiosyncratic sensitivity to aspects of the assessment conditions. For example, data from several studies suggest that inclusion of a tangible condition during an FA may be prone to a false-positive outcome, although the extent to which tangible reinforcement routinely produces such outcomes is unknown. We examined susceptibility to tangible reinforcement by determining whether a new response was acquired more readily when exposed to a tangible contingency relative to others commonly used in an FA (Study 1), and whether problem behavior known not to have a social function nevertheless emerged when exposed to tangible reinforcement (Study 2). Results indicated that inclusion of items in the tangible condition should be done with care and that selection should be based on those items typically found in the individual's environment.

Assessment of the psychometric properties of the Family Management Measure.

PubMed

Knafl, Kathleen; Deatrick, Janet A; Gallo, Agatha; Dixon, Jane; Grey, Margaret; Knafl, George; O'Malley, Jean

2011-06-01

This paper reports development of the Family Management Measure (FaMM) of parental perceptions of family management of chronic conditions. By telephone interview, 579 parents of children age 3 to 19 with a chronic condition (349 partnered mothers, 165 partners, 65 single mothers) completed the FaMM and measures of child functional status and behavioral problems and family functioning. Analyses addressed reliability, factor structure, and construct validity. Exploratory factor analysis yielded six scales: Child's Daily Life, Condition Management Ability, Condition Management Effort, Family Life Difficulty, Parental Mutuality, and View of Condition Impact. Internal consistency reliability ranged from .72 to .91, and test-retest reliability from .71 to .94. Construct validity was supported by significant correlations in hypothesized directions between FaMM scales and established measures. Results support FaMM's; reliability and validity, indicating it performs in a theoretically meaningful way and taps distinct aspects of family response to childhood chronic conditions.

Fluocinolone acetonide partially restores the mineralization of LPS-stimulated dental pulp cells through inhibition of NF-κB pathway and activation of AP-1 pathway

PubMed Central

Liu, Zhongning; Jiang, Ting; Wang, Xinzhi; Wang, Yixiang

2013-01-01

BACKGROUND AND PURPOSE Fluocinolone acetonide (FA) is commonly used as a steroidal anti-inflammatory drug. We recently found that in dental pulp cells (DPCs) FA has osteo-/odonto-inductive as well as anti-inflammatory effects. However, the mechanism by which FA induces these effects in DPCs is poorly understood. EXPERIMENTAL APPROACH The effect of FA on the mineralization of DPCs during inflammatory conditions and the underlying mechanism were investigated by real-time PCR, Western blot, EMSA, histochemical staining, immunostaining and pathway blockade assays. KEY RESULTS FA significantly inhibited the inflammatory response in LPS-treated DPCs not only by down-regulating the expression of pro–inflammation-related genes, but also by up-regulating the expression of the anti-inflammatory gene PPAR-γ and mineralization-related genes. Moreover, histochemical staining and immunostaining showed that FA could partially restore the expressions of alkaline phosphatase, osteocalcin and dentin sialophosphoprotein (DSPP) and mineralization in LPS-stimulated DPCs. Real-time PCR and Western blot analysis revealed that FA up-regulated DSPP and runt-related transcription factor 2 expression by inhibiting the expression of phosphorylated-NF-κB P65 and activating activator protein-1 (AP-1) (p-c-Jun and Fra-1). These results were further confirmed through EMSA, by detection of NF-κB DNA-binding activity and pathway blockade assays using a NF-κB pathway inhibitor, AP-1 pathway inhibitor and glucocorticoid receptor antagonist. CONCLUSIONS AND IMPLICATIONS Inflammation induced by LPS suppresses the mineralization process in DPCs. FA partially restored this osteo-/odonto-genesis process in LPS-treated DPCs and had an anti-inflammatory effect through inhibition of the NF-κB pathway and activation of the AP-1 pathway. Hence, FA is a potential new treatment for inflammation-associated bone/teeth diseases. PMID:24024985

Targeting property and toxicity of a novel ultrasound contrast agent microbubble carrying the targeting and drug-loaded complex FA-CNTs-PTX on MCF7 cells.

PubMed

Zhang, Jie; Zhang, Yu; Liu, Junxi; Li, Guozhong; Wen, Zhaohui; Zhao, Yue; Zhang, Xiangyu; Liu, Fenghua

2017-10-01

The application of ultrasound contrast agents not only is confined to the enhancement of ultrasound imaging but also has started to be used as a drug system for diagnosis and treatment. In this paper, Span60 and PEG1500 were used as membrane materials, and a new targeting and drug-loading multifunctional ultrasound contrast agent microbubble enveloping the FA-CNTs-PTX complex was successfully prepared by acoustic cavitation. With the breast cancer cell line MCF7 as the research target, the effects of the microbubble with FA-CNTs-PTX on the proliferation and toxicity of MCF7 cells were studied using a CCK-8 and AO/EB double-staining method. The influences of the microbubbles with FA-CNTs-PTX on the cellular morphology and apoptosis period of the MCF7 cells were detected using an inverted fluorescence microscope. The apoptosis of MCF7 cells induced by the microbubbles with FA-CNTs-PTX was investigated with flow cytometry and an annexin and PI double staining fluorescence quantitative analysis. The results indicated that the ultrasound contrast agent microbubble with FA-CNTs-PTX remarkably inhibited the proliferation of MCF7 cells, which was mainly controlled by the drug loading rate and the nanometer size of the microbubbles. Moreover, the proliferative inhibition rate of the microbubbles with FA-CNTs-PTX was related to the cell apoptosis period of MCF7 cells. Its inhibition degree on the proliferation of MCF7 cells was higher than that of the hepatoma HepG2 cells. The apoptosis rate of MCF7 cells induced by the microbubbles with FA-CNTs-PTX was higher than that of normal human umbilical vein endothelial cells (HUVECs), and the microbubbles with FA-CNTs-PTX could target the MCF7 cells. Copyright © 2017 Elsevier B.V. All rights reserved.

Diffusion tensor imaging of nigral degeneration in Parkinson's disease: A region-of-interest and voxel-based study at 3 T and systematic review with meta-analysis☆

PubMed Central

Schwarz, Stefan T.; Abaei, Maryam; Gontu, Vamsi; Morgan, Paul S.; Bajaj, Nin; Auer, Dorothee P.

2013-01-01

There is increasing interest in developing a reliable, affordable and accessible disease biomarker of Parkinson's disease (PD) to facilitate disease modifying PD-trials. Imaging biomarkers using magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) can describe parameters such as fractional anisotropy (FA), mean diffusivity (MD) or apparent diffusion coefficient (ADC). These parameters, when measured in the substantia nigra (SN), have not only shown promising but also varying and controversial results. To clarify the potential diagnostic value of nigral DTI in PD and its dependency on selection of region-of-interest, we undertook a high resolution DTI study at 3 T. 59 subjects (32 PD patients, 27 age and sex matched healthy controls) were analysed using manual outlining of SN and substructures, and voxel-based analysis (VBA). We also performed a systematic literature review and meta-analysis to estimate the effect size (DES) of disease related nigral DTI changes. We found a regional increase in nigral mean diffusivity in PD (mean ± SD, PD 0.80 ± 0.10 vs. controls 0.73 ± 0.06 · 10− 3 mm2/s, p = 0.002), but no difference using a voxel based approach. No significant disease effect was seen using meta-analysis of nigral MD changes (10 studies, DES = + 0.26, p = 0.17, I2 = 30%). None of the nigral regional or voxel based analyses of this study showed altered fractional anisotropy. Meta-analysis of 11 studies on nigral FA changes revealed a significant PD induced FA decrease. There was, however, a very large variation in results (I2 = 86%) comparing all studies. After exclusion of five studies with unusual high values of nigral FA in the control group, an acceptable heterogeneity was reached, but there was non-significant disease effect (DES = − 0.5, p = 0.22, I2 = 28%). The small PD related nigral MD changes in conjunction with the negative findings on VBA and meta-analysis limit the usefulness of nigral MD measures as biomarker of Parkinson's disease. The negative results of nigral FA measurements at regional, sub-regional and voxel level in conjunction with the results of the meta-analysis of nigral FA changes question the stability and validity of this measure as a PD biomarker. PMID:24273730

Values of molecular markers in the differential diagnosis of thyroid abnormalities.

PubMed

Tennakoon, T M P B; Rushdhi, M; Ranasinghe, A D C U; Dassanayake, R S

2017-06-01

Thyroid cancer (TC), follicular adenoma (FA) and Hashimoto's thyroiditis (HT) are three of the most frequently reported abnormalities that affect the thyroid gland. A frequent co-occurrence along with similar histopathological features is observed between TC and FA as well as between TC and HT. The conventional diagnostic methods such as histochemical analysis present complications in differential diagnosis when these abnormalities occur simultaneously. Hence, the authors recognize novel methods based on screening genetic defects of thyroid abnormalities as viable diagnostic and prognostic methods that could complement the conventional methods. We have extensively reviewed the existing literature on TC, FA and HT and also on three genes, namely braf, nras and ret/ptc, that could be used to differentially diagnose the three abnormalities. Emphasis was also given to the screening methods available to detect the said molecular markers. It can be conferred from the analysis of the available data that the utilization of braf, nras and ret/ptc as markers for the therapeutic evaluation of FA and HT is debatable. However, molecular screening for braf, nras and ret/ptc mutations proves to be a conclusive method that could be employed to differentially diagnose TC from HT and FA in the instance of a suspected co-occurrence. Thyroid cancer patients can be highly benefited from the screening for the said genetic markers, especially the braf gene due to its diagnostic value as well as due to the availability of personalized medicine targeted specifically for braf mutants.

Change-point analysis data of neonatal diffusion tensor MRI in preterm and term-born infants.

PubMed

Wu, Dan; Chang, Linda; Akazawa, Kentaro; Oishi, Kumiko; Skranes, Jon; Ernst, Thomas; Oishi, Kenichi

2017-06-01

The data presented in this article are related to the research article entitled "Mapping the Critical Gestational Age at Birth that Alters Brain Development in Preterm-born Infants using Multi-Modal MRI" (Wu et al., 2017) [1]. Brain immaturity at birth poses critical neurological risks in the preterm-born infants. We used a novel change-point model to analyze the critical gestational age at birth (GAB) that could affect postnatal development, based on diffusion tensor MRI (DTI) acquired from 43 preterm and 43 term-born infants in 126 brain regions. In the corresponding research article, we presented change-point analysis of fractional anisotropy (FA) and mean diffusivities (MD) measurements in these infants. In this article, we offered the relative changes of axonal and radial diffusivities (AD and RD) in relation to the change of FA and FA-based change-points, and we also provided the AD- and RD-based change-point results.

Analysis of Tangential Slot Blowing on F/A-18 Isolated Forebody

NASA Technical Reports Server (NTRS)

Gee, Ken; Rizk, Yehia M.; Schiff, Lewis B.

1995-01-01

The generation of significant side forces and yawing moments on an F/A-18 fuselage through tangential slot blowing is analyzed using computational fluid dynamics. The effects of freestream Mach number, jet exit conditions, jet length, and jet location are studied. The effects of over- and underblowing on force and moment production are analyzed. Non-time-accurate solutions are obtained to determine the steady-state side forces, yawing moments, and surface pressure distributions generated by tangential slot blowing. Time-accurate solutions are obtained to study the force onset time lag of tangential slot blowing. Comparison with available experimental data from full-scale wind-tunnel and subscale wind-tunnel tests are made. This computational analysis complements the experimental results and provides a detailed understanding of the effects of tangential slot blowing on the flowfield about the isolated F/A-18 forebody. Additionally, it extends the slot-blowing database to transonic maneuvering Mach numbers.

Fatty acid profile of new promising unconventional plant oils for cosmetic use.

PubMed

Bialek, A; Bialek, M; Jelinska, M; Tokarz, A

2016-08-01

Oils have been used on the cosmetic application since antiquity. With the growing interest in cosmetic formulation of strictly natural origin there has been also an increased interest in the use of alternative oils obtained from nuts, herbs, fruit and vegetable seeds. Due to lack of good scientific reports on the cosmetic plant oils available in Poland, the aim of our research was to characterize fatty acids (FA) profile and oxidative quality of selected unconventional plant oils, which are used as cosmetics or potential cosmetic ingredients. Oils were purchased from cosmetic health shops in Warsaw (Poland); FA profile was analysed by gas chromatography with flame-ionization detection. Peroxide index (PI), content of hydroperoxides (PV) and free fatty acids (AV) were also determined. Oxidative quality and FA composition of examined oils varied widely among analyzed oils. Cluster analysis revealed three clusters. Clusters S1 and S3 include only one oil (Perilla and sea buckthorn, respectively). Perilla oil is characterized by relatively small content of both saturated FA (8.5%) and monounsaturated FA (14.2%) and much higher amount of polyunsaturated FA (73.5%) whereas in sea buckthorn these proportions are opposite (saturated FA and monounsaturated FA - 33.5% and 51.0% respectively, and the lowest amount of polyunsaturated FA - 5.2%). In cluster S2 two sub-clusters were distinguished and the content of linoleic (p = 0.0015), α-linolenic (p = 0.0092) and oleic (p = 0.0015) acid caused this distinction. PI ranged from 8.9 in sea buckthorn oil to 135 in Perilla oil. Perilla oil and raspberry seed oil were also characterized by the highest PV (225 ± 14.9 mEq O/kg oil and 232 ± 13.8 mEq O/kg oil, respectively), whereas the lowest PV was determined for walnut oil (0.82 ± 0.18 mEq O/kg oil) and carrot seed oil (0.87 ± 0.21 mEq O/kg oil) oils. FA composition of cosmetic oils in combination with data concerning their oxidative quality, is very important for determining their safe and effective use. It is very important to standardize and test the FA content in commercially available oils of cosmetic use. © 2015 Society of Cosmetic Scientists and the Société Française de Cosmétologie.

Folic acid supplements during pregnancy and child psychomotor development after the first year of life.

PubMed

Valera-Gran, Desirée; García de la Hera, Manuela; Navarrete-Muñoz, Eva María; Fernandez-Somoano, Ana; Tardón, Adonina; Julvez, Jordi; Forns, Joan; Lertxundi, Nerea; Ibarluzea, Jesús María; Murcia, Mario; Rebagliato, Marisa; Vioque, Jesús

2014-11-01

Folate intake during pregnancy has been associated with improved neuropsychological development in children, although the effects of high dosages of folic acid (FA) supplements are unclear. To examine the association between the use of high dosages of FA supplements during pregnancy and child neuropsychological development after the first year of life. The multicenter prospective mother-child cohort Infancia y Medio Ambiente (INMA) Project recruited pregnant women from 4 areas of Spain (Asturias, Sabadell, Gipuzkoa, and Valencia) between November 2003 and January 2008. Pregnant women completed an interviewer-administered questionnaire on the usual dietary folate intake and FA supplements at 10 to 13 weeks and 28 to 32 weeks of gestation. The main analyses were based on a sample of 2213 children with complete information on neuropsychological development and FA supplement intake during pregnancy. Multiple linear and logistic regression analyses were used to explore the effects of FA supplements on child neuropsychological development. Neuropsychological development was assessed using the Bayley Scales of Infant Development. We calculated mental scale and psychomotor scale scores. One SD below the mean established a delay in neurodevelopment (score <85). A high proportion of women (57.3%) did not reach the recommended dosages of FA supplements (400 μg/d), but 25.2% women took more than 1000 μg/d of FA supplements (3.5% consuming >5000 μg/d). In multivariate analysis, we observed that children whose mothers used FA supplement dosages higher than 5000 μg/d during pregnancy had a statistically significantly lower mean psychomotor scale score (difference, -4.35 points; 95% CI, -8.34 to -0.36) than children whose mothers used a recommended dosage of FA supplements (400-1000 μg/d). An increased risk of delayed psychomotor development (psychomotor scale score <85) was also evident among children whose mothers took FA supplement dosages higher than 5000 μg/d, although the association was not statistically significant (odds ratio = 1.59; 95% CI, 0.82-3.08). To our knowledge, this is the first time a detrimental effect of high dosages of FA supplements during pregnancy on psychomotor development after the first year of life has been shown. Further research from longitudinal studies is warranted to confirm these results.

Diabetes-associated microbiota in fa/fa rats is modified by Roux-en-Y gastric bypass.

PubMed

Arora, Tulika; Seyfried, Florian; Docherty, Neil G; Tremaroli, Valentina; le Roux, Carel W; Perkins, Rosie; Bäckhed, Fredrik

2017-09-01

Roux-en-Y gastric bypass (RYGB) and duodenal jejunal bypass (DJB), two different forms of bariatric surgery, are associated with improved glucose tolerance, but it is not clear whether the gut microbiota contributes to this effect. Here we used fa/fa rats as a model of impaired glucose tolerance to investigate whether (i) the microbiota varies between fa/fa and nondiabetic fa/+ rats; (ii) the microbiota of fa/fa rats is affected by RYGB and/or DJB; and (iii) surgically induced microbiota alterations contribute to glucose metabolism. We observed a profound expansion of Firmicutes (specifically, Lactobacillus animalis and Lactobacillus reuteri) in the small intestine of diabetic fa/fa compared with nondiabetic fa/+ rats. RYGB-, but not DJB-, treated fa/fa rats exhibited greater microbiota diversity in the ileum and lower L. animalis and L. reuteri abundance compared with sham-operated fa/fa rats in all intestinal segments, and their microbiota composition resembled that of unoperated fa/+ rats. To investigate the functional role of RYGB-associated microbiota alterations, we transferred microbiota from sham- and RYGB-treated fa/fa rats to germ-free mice. The metabolic phenotype of RYGB-treated rats was not transferred by the transplant of ileal microbiota. In contrast, postprandial peak glucose levels were lower in mice that received cecal microbiota from RYGB- versus sham-operated rats. Thus, diabetes-associated microbiota alterations in fa/fa rats can be modified by RYGB, and modifications in the cecal microbiota may partially contribute to improved glucose tolerance after RYGB.

Positive Association of Fibroadenomatoid Change with HER2-Negative Invasive Breast Cancer: A Co-Occurrence Study

PubMed Central

Kovatich, Albert J.; Hooke, Jeffrey A.; Liu, Jianfang; Kvecher, Leonid; Fantacone-Campbell, J. Leigh; Mitchell, Edith P.; Rui, Hallgeir; Shriver, Craig D.; Hu, Hai

2015-01-01

Background Risk assessment of a benign breast disease/lesion (BBD) for invasive breast cancer (IBC) is typically done through a longitudinal study. For an infrequently-reported BBD, the shortage of occurrence data alone is a limiting factor to conducting such a study. Here we present an approach based on co-occurrence analysis, to help address this issue. We focus on fibroadenomatoid change (FAC), an under-studied BBD, as our preliminary analysis has suggested its previously unknown significant co-occurrence with IBC. Methods A cohort of 1667 female patients enrolled in the Clinical Breast Care Project was identified. A single experienced breast pathologist reviewed all pathology slides for each case and recorded all observed lesions, including FAC. Fibroadenoma (FA) was studied for comparison since FAC had been speculated to be an immature FA. FA and Fibrocystic Changes (FCC) were used for method validation since they have been comprehensively studied. Six common IBC and BBD risk/protective factors were also studied. Co-occurrence analyses were performed using logistic regression models. Results Common risk/protective factors were associated with FA, FCC, and IBC in ways consistent with the literature in general, and they were associated with FAC, FA, and FCC in distinct patterns. Age was associated with FAC in a bell-shape curve so that middle-aged women were more likely to have FAC. We report for the first time that FAC is positively associated with IBC with odds ratio (OR) depending on BMI (OR = 6.78, 95%CI = 3.43-13.42 at BMI<25 kg/m2; OR = 2.13, 95%CI = 1.20-3.80 at BMI>25 kg/m2). This association is only significant with HER2-negative IBC subtypes. Conclusions We conclude that FAC is a candidate risk factor for HER2-negative IBCs, and it is a distinct disease from FA. Co-occurrence analysis can be used for initial assessment of the risk for IBC from a BBD, which is vital to the study of infrequently-reported BBDs. PMID:26098961

Is the onset of obesity in suckling fa/fa rats linked to a potentially larger milk intake?

PubMed

Buchberger, P; Schmidt, I

1996-08-01

We wanted to find out whether fatty (fa/fa) sucklings show abnormal intake when given access to an abundant milk reservoir. To do this, we gravimetrically determined the milk ingested by small groups (4-5 pups) of 5- to 15-day-old lean (+/fa) and fatty littermates allowed to suckle for 30 min after their mother had not been nursing for periods of between 1 and 7 h. The pups were grouped randomly and their phenotypes retrospectively identified. Within both genotypes, the intakes of simultaneously tested pups were significantly higher in pups deprived for longer periods. Deprived and undeprived fa/fa pups ingested, however, slightly but significantly less milk than +/fa littermates did in the same nursing bout. In the first 2 wk of life, when fa/fa pups deposit nearly twice as much body fat as their +/fa littermates do, fa/fa pups will thus suckle less rather than more milk. This extends previous findings showing that the onset of fa/fa obesity is independent of larger intakes and thus questions that fa impairs a receptor primarily controlling food intake.

Theranostic pH-sensitive nanoparticles for highly efficient targeted delivery of doxorubicin for breast tumor treatment.

PubMed

Pan, Changqie; Liu, Yuqing; Zhou, Minyu; Wang, Wensheng; Shi, Min; Xing, Malcolm; Liao, Wangjun

2018-01-01

A multifunctional theranostic nanoplatform integrated with environmental responses has been developed rapidly over the past few years as a novel treatment strategy for several solid tumors. We synthesized pH-sensitive poly(β-thiopropionate) nanoparticles with a supermagnetic core and folic acid (FA) conjugation (FA-doxorubicin-iron oxide nanoparticles [FA-DOX@ IONPs]) to deliver an antineoplastic drug, DOX, for the treatment of folate receptor (FR)-overexpressed breast cancer. In addition to an imaging function, the nanoparticles can release their payloads in response to an environment of pH 5, such as the acidic environment found in tumors. After chemical ( 1 H nuclear magnetic resonance) and physical (morphology and super-magnetic) characterization, FA-DOX@IONPs were shown to demonstrate pH-dependent drug release profiles. Western blotting analysis revealed the expression of FRs in three breast cancer cell lines, MCF-7, BT549, and MD-MBA-231. The cell counting kit-8 assay and transmission electron microscopy showed that FA-DOX@IONPs had the strongest cytotoxicity against breast cancer cells, compared with free DOX and non-FR targeted nanoparticles (DOX@IONPs), and caused cellular apoptosis. The FA-DOX@IONP-mediated cellular uptake and intracellular internalization were clarified by fluorescence microscopy. FA-DOX@IONPs plus magnetic field treatment suppressed in vivo tumor growth in mice to a greater extent than either treatment alone; furthermore, the nanoparticles exerted no toxicity against healthy organs. Magnetic resonance imaging was successfully applied to monitor the nanoparticle accumulation. Our results suggest that theranostic pH-sensitive nanoparticles with dual targeting could enhance the available therapies for cancer.

A COMPREHENSIVE EXAMINATION OF WHITE MATTER TRACTS AND CONNECTOMETRY IN MAJOR DEPRESSIVE DISORDER

PubMed Central

Delaparte, Lauren; Yeh, Fang‐Cheng; DeLorenzo, Christine; McGrath, Patrick J.; Weissman, Myrna M.; Adams, Phillip; Fava, Maurizio; Deckersbach, Thilo; McInnis, Melvin G.; Carmody, Thomas J.; Cooper, Crystal M.; Kurian, Benji T.; Lu, Hanzhang; Toups, Marisa S.; Trivedi, Madhukar H.; Parsey, Ramin V.

2015-01-01

Background Major depressive disorder (MDD) is a debilitating disorder characterized by widespread brain abnormalities. The literature is mixed as to whether or not white matter abnormalities are associated with MDD. This study sought to examine fractional anisotropy (FA) in white matter tracts in individuals with MDD using diffusion tensor imaging (DTI). Methods 139 participants with MDD and 39 healthy controls (HC) in a multisite study were included. DTI scans were acquired in 64 directions and FA was determined in the brain using four methods: region of interest (ROI), tract‐based spatial statistics (TBSS), and diffusion tractography. Diffusion connectometry was used to identify white matter pathways associated with MDD. Results There were no significant differences when comparing FA in MDD and HC groups using any method. In the MDD group, there was a significant relationship between depression severity and FA in the right medial orbitofrontal cortex, and between age of onset of MDD and FA in the right caudal anterior cingulate cortex using the ROI method. There was a significant relationship between age of onset and connectivity in the thalamocortical radiation, inferior longitudinal fasciculus, and cerebellar tracts using diffusion connectometry. Conclusions The lack of group differences in FA and connectometry analysis may result from the clinically heterogenous nature of MDD. However, the relationship between FA and depression severity may suggest a state biomarker of depression that should be investigated as a potential indicator of response. Age of onset may also be a significant clinical feature to pursue when studying white matter tracts. PMID:26477532

Cyanidin-3-glucoside and its phenolic acid metabolites attenuate visible light-induced retinal degeneration in vivo via activation of Nrf2/HO-1 pathway and NF-κB suppression.

PubMed

Wang, Yong; Huo, Yazhen; Zhao, Liang; Lu, Feng; Wang, Ou; Yang, Xue; Ji, Baoping; Zhou, Feng

2016-07-01

Cyanidin-3-glucoside (C3G) is a major anthocyanin in berries and a potential nutritional supplement for preventing retinal degeneration. However, the protective mechanism of C3G and its metabolites, protocatechuic acid (PCA) and ferulic acid (FA), remain unclear. The molecular mechanisms of C3G and its metabolites against retinal photooxidative damage in vivo are investigated. Pigmented rabbits were orally administered C3G, PCA, and FA (0.11 mmol/kg/day) for 3 weeks. Electroretinography, histological analysis, and TUNEL assay showed that C3G and its metabolites attenuated retinal cell apoptosis. The expression of oxidative stress markers were upregulated after light exposure but attenuated by C3G and FA, which may be attributed to the elevated secretion and expression of heme oxygenase (HO-1) and nuclear factor erythroid-2 related factor 2 (Nrf2). C3G, PCA, and FA attenuated the secretion or expression of inflammation-related genes; FA suppressed nuclear factor kappa B (NF-κB) activation. The treatments attenuated the light-induced changes on certain apoptotic proteins and angiogenesis-related cytokines. C3G and FA reduced light-induced retinal oxidative stress by activating the Nrf2/HO-1 antioxidant pathway. FA attenuated the light-induced retinal inflammation by suppressing NF-κB activation. C3G and its metabolites attenuated the photooxidation-induced apoptosis and angiogenesis in the retina. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Student Buy-In Toward Formative Assessments: The Influence of Student Factors and Importance for Course Success †

PubMed Central

Brazeal, Kathleen R.; Couch, Brian A.

2017-01-01

Formative assessment (FA) techniques, such as pre-class assignments, in-class activities, and post-class homework, have been shown to improve student learning. While many students find these techniques beneficial, some students may not understand how they support learning or may resist their implementation. Improving our understanding of FA buy-in has important implications, since buy-in can potentially affect whether students fully engage with and learn from FAs. We investigated FAs in 12 undergraduate biology courses to understand which student characteristics influenced buy-in toward FAs and whether FA buy-in predicted course success. We administered a mid-semester survey that probed student perceptions toward several different FA types, including activities occurring before, during, and after class. The survey included closed-ended questions aligned with a theoretical framework outlining key FA objectives. We used factor analysis to calculate an overall buy-in score for each student and general linear models to determine whether certain characteristics were associated with buy-in and whether buy-in predicted exam scores and course grades. We found that unfixed student qualities, such as perceptions, behaviors, and beliefs, consistently predicted FA buy-in, while fixed characteristics, including demographics, previous experiences, and incoming performance metrics, had more limited effects. Importantly, we found that higher buy-in toward most FA types predicted higher exam scores and course grades, even when controlling for demographic characteristics and previous academic performance. We further discuss steps that instructors can take to maximize student buy-in toward FAs. PMID:28512523

The nanostructural characterization of strawberry pectins in pectate lyase or polygalacturonase silenced fruits elucidates their role in softening.

PubMed

Posé, Sara; Kirby, Andrew R; Paniagua, Candelas; Waldron, Keith W; Morris, Victor J; Quesada, Miguel A; Mercado, José A

2015-11-05

To ascertain the role of pectin disassembly in fruit softening, chelated- (CSP) and sodium carbonate-soluble (SSP) pectins from plants with a pectate lyase, FaplC, or a polygalacturonase, FaPG1, downregulated by antisense transformation were characterized at the nanostructural level. Fruits from transgenic plants were firmer than the control, although FaPG1 suppression had a greater effect on firmness. Size exclusion chromatography showed that the average molecular masses of both transgenic pectins were higher than that of the control. Atomic force microscopy analysis of pectins confirmed the higher degree of polymerization as result of pectinase silencing. The mean length values for CSP chains increased from 84 nm in the control to 95.5 and 101 nm, in antisense FaplC and antisense FaPG1 samples, respectively. Similarly, SSP polyuronides were longer in transgenic fruits (61, 67.5 and 71 nm, in the control, antisense FaplC and antisense FaPG1 samples, respectively). Transgenic pectins showed a more complex structure, with a higher percentage of branched chains than the control, especially in the case of FaPG1 silenced fruits. Supramolecular pectin aggregates, supposedly formed by homogalacturonan and rhamnogalacturonan I, were more frequently observed in antisense FaPG1 samples. The larger modifications in the nanostructure of pectins in FaPG1 silenced fruits when compared with antisense pectate lyase plants correlate with the higher impact of polygalacturonase silencing on reducing strawberry fruit softening. Copyright © 2015 Elsevier Ltd. All rights reserved.

Childhood trauma- and cannabis-associated microstructural white matter changes in patients with psychotic disorder: a longitudinal family-based diffusion imaging study.

PubMed

Domen, Patrick; Michielse, Stijn; Peeters, Sanne; Viechtbauer, Wolfgang; van Os, Jim; Marcelis, Machteld

2018-05-29

Decreased white matter (WM) integrity in patients with psychotic disorder has been a consistent finding in diffusion tensor imaging (DTI) studies. However, the contribution of environmental risk factors to these WM alterations is rarely investigated. The current study examines whether individuals with (increased risk for) psychotic disorder will show increased WM integrity change over time with increasing levels of childhood trauma and cannabis exposure. DTI scans were obtained from 85 patients with a psychotic disorder, 93 non-psychotic siblings and 80 healthy controls, of which 60% were rescanned 3 years later. In a whole-brain voxel-based analysis, associations between change in fractional anisotropy (ΔFA) and environmental exposures as well as interactions between group and environmental exposure in the model of FA and ΔFA were investigated. Analyses were adjusted for a priori hypothesized confounding variables: age, sex, and level of education. At baseline, no significant associations were found between FA and both environmental risk factors. At follow-up as well as over a 3-year interval, significant interactions between group and, respectively, cannabis exposure and childhood trauma exposure in the model of FA and ΔFA were found. Patients showed more FA decrease over time compared with both controls and siblings when exposed to higher levels of cannabis or childhood trauma. Higher levels of cannabis or childhood trauma may compromise connectivity over the course of the illness in patients, but not in individuals at low or higher than average genetic risk for psychotic disorder, suggesting interactions between the environment and illness-related factors.

Diabetes-associated microbiota in fa/fa rats is modified by Roux-en-Y gastric bypass

PubMed Central

Arora, Tulika; Seyfried, Florian; Docherty, Neil G; Tremaroli, Valentina; le Roux, Carel W; Perkins, Rosie; Bäckhed, Fredrik

2017-01-01

Roux-en-Y gastric bypass (RYGB) and duodenal jejunal bypass (DJB), two different forms of bariatric surgery, are associated with improved glucose tolerance, but it is not clear whether the gut microbiota contributes to this effect. Here we used fa/fa rats as a model of impaired glucose tolerance to investigate whether (i) the microbiota varies between fa/fa and nondiabetic fa/+ rats; (ii) the microbiota of fa/fa rats is affected by RYGB and/or DJB; and (iii) surgically induced microbiota alterations contribute to glucose metabolism. We observed a profound expansion of Firmicutes (specifically, Lactobacillus animalis and Lactobacillus reuteri) in the small intestine of diabetic fa/fa compared with nondiabetic fa/+ rats. RYGB-, but not DJB-, treated fa/fa rats exhibited greater microbiota diversity in the ileum and lower L. animalis and L. reuteri abundance compared with sham-operated fa/fa rats in all intestinal segments, and their microbiota composition resembled that of unoperated fa/+ rats. To investigate the functional role of RYGB-associated microbiota alterations, we transferred microbiota from sham- and RYGB-treated fa/fa rats to germ-free mice. The metabolic phenotype of RYGB-treated rats was not transferred by the transplant of ileal microbiota. In contrast, postprandial peak glucose levels were lower in mice that received cecal microbiota from RYGB- versus sham-operated rats. Thus, diabetes-associated microbiota alterations in fa/fa rats can be modified by RYGB, and modifications in the cecal microbiota may partially contribute to improved glucose tolerance after RYGB. PMID:28524868

Fatty acid composition indicates two types of metabolic syndrome independent of clinical and laboratory parameters.

PubMed

Žák, A; Burda, M; Vecka, M; Zeman, M; Tvrzická, E; Staňková, B

2014-01-01

Dietary composition and metabolism of fatty acids (FA) influence insulin resistance, atherogenic dyslipidemia and other components of the metabolic syndrome (MS). It is known that patients with MS exhibit a heterogeneous phenotype; however, the relationships of individual FA to MS components have not yet been consistently studied. We examined the plasma phosphatidylcholine FA composition of 166 individuals (68F/98M) with MS and of 188 (87F/101M) controls. Cluster analysis of FA divided the groups into two clusters. In cluster 1, there were 65.7 % of MS patients and 37.8 % of controls, cluster 2 contained 34.3 % of patients and 62.2 % of controls (P<0.001). Those with MS within cluster 1 (MS1) differed from individuals with MS in cluster 2 (MS2) by concentrations of glucose (P<0.05), NEFA (P<0.001), HOMA-IR (P<0.05), and levels of conjugated dienes in LDL (P<0.05). The FA composition in MS1 group differed from MS2 by higher contents of palmitoleic (+30 %), gamma-linolenic (+22 %), dihomo-gamma-linolenic (+9 %) acids and by a lower content of linoleic acid (-25 %) (all P<0.01). These FA patterns are supposed to be connected with the progression and/or impaired biochemical measures of MS (lipolysis, oxidative stress, dysglycidemia, and insulin resistance).

The solid-state characterization of fusidic acid.

PubMed

Gilchrist, Samuel E; Letchford, Kevin; Burt, Helen M

2012-01-17

The aim of this work was to characterize the solid-state properties of fusidic acid (FA). Solid forms of FA were prepared by solvent-mediated polymorphic transformation of commercial FA (Form III) in acetonitrile (ACN), and methanol:H(2)O (50:50), or generated by solvent recrystallization from dichloromethane (DCM). Polymorphs were characterized using, X-ray diffraction (XRD), differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), polarizing hot stage microscopy (HSM), and intrinsic dissolution rate (IDR). Slurrying commercial FA (Form III) in methanol:H(2)O (50:50), yielded a metastable form (Form IV). This metastable form converts to Form I or back to Form III in ACN and H(2)O, respectively, and Form II upon recrystallization from DCM. IDR of Form IV was 0.092 mg/min/cm(2), and was statistically different (p<0.05) from the IDR of Forms I, II, and III, with IDR of 0.053, 0.043, and 0.045mg/min/cm(2), respectively. The amorphous FA had an IDR of 0.125 mg/min/cm(2), and was significantly higher (p<0.05) than any other solid form. There were no statistical differences in the IDR of Form I, II, or III. This work provides evidence for the existence of two previously unreported polymorphic forms of FA (Forms II and IV) and an amorphate. Copyright © 2011 Elsevier B.V. All rights reserved.

[A semimicroquality evaluation method on Panax notoginseng and its application in analysis of continuous cropping obstacles research samples].

PubMed

Cao, Yi; Wang, Chao-Qun; Xu, Feng; Jia, Xiu-Hong; Liu, Guang-Xue; Yang, Sheng-Chao; Long, Guang-Qiang; Chen, Zhong-Jian; Wei, Fu-Zhou; Yang, Shao-Zhou; Fukuda, Kozo; Wang, Xuan; Cai, Shao-Qing

2016-10-01

Panax notoginseng is a commonly used traditional Chinese medicine with blood activating effect while has continuous cropping obstacle problem in planting process. In present study, a semimicroextraction method with water-saturated n-butanol on 0.1 g notoginseng sample was established with good repeatability (RSD<2.5%) and 9.6%-20.6% higher extraction efficiency of seven saponins than the conventional method. A total of 16 characteristic peaks were identified by LC-MS-IT-TOF, including eight 20(S)-protopanaxatriol (PPT) type saponins and eight 20(S)-protopanaxadiol (PPD) type saponins. The established method was utilized to evaluate the quality of notoginseng samples cultivated by manual intervened methods to overcome continuous cropping obstacles.As a result, HPLC fingerprint similarity, content of Fa and ratio of notoginsenoside K and notoginsenoside Fa (N-K/Fa) were found out to be as valuatable markers of the quality of samples in continuous cropping obstacle research, of which N-K/Fa could also be applied to the analysis of notoginseng samples with different growth years.Notoginseng samples with continuous cropping obstacle had HPLC fingerprint similarity lower than 0.87, in consistent with normal sample, and had significant lower content of notoginsenoside Fa and significant higher N-K/Fa (2.35-4.74) than normal group (0.45-1.33). All samples in the first group with manual intervention showed high similarity with normal group (>0.87), similar content of common peaks and N-K/Fa (0.42-2.06). The content of notoginsenoside K in the second group with manual intervention was higher than normal group. All samples except two displayed similarity higher than 0.87 and possessed content of 16 saponins close to normal group. The result showed that notoginseng samples with continuous cropping obstacle had lower quality than normal sample. And manual intervened methods could improve their quality in different levels.The method established in this study was simple, fast and accurate, and the markers may provide new guides for quality control in continuous cropping obstacle research of notoginseng. Copyright© by the Chinese Pharmaceutical Association.

Maternal Continuing Folic Acid Supplementation after the First Trimester of Pregnancy Increased the Risk of Large-for-Gestational-Age Birth: A Population-Based Birth Cohort Study

PubMed Central

Wang, Sufang; Ge, Xing; Zhu, Beibei; Xuan, Yujie; Huang, Kun; Rutayisire, Erigene; Mao, Leijing; Huang, Sanhuan; Yan, Shuangqin; Tao, Fangbiao

2016-01-01

Supplementation with folic acid (FA) was proven to prevent neural tube defects (NTDs) and was recommended worldwide before and during early pregnancy. However, much less is known regarding the role of FA after the 12th gestational week (GW). This study aimed to investigate the related effects of continued FA supplementation after the first trimester of pregnancy on fetal growth. The study subjects came from the Ma’anshan-Anhui Birth Cohort Study (MABC) that recruited 3474 pregnant women from the city of Ma’anshan in Anhui Province in China during the period of May 2013 to September 2014. The information on use of vitamin and mineral supplements was recorded in different periods (the first/second/third trimester of pregnancy). Small-for-gestational-age (SGA) births were live-born infants that were <10th percentile of birth weight, and large-for-gestational-age (LGA) births were live-born infants that were ≥90th percentile of birth weight according to nomograms based on gender and gestational age from the latest standards. We used multivariable logistic regression to evaluate the effects of FA supplement consumption in the second/third trimester of pregnancy on the risk of LGA and SGA. In addition, propensity score analysis was also performed to examine the effects. In this prospective birth cohort study conducted in Chinese women who had taken FA in the first trimester of pregnancy, we found that continued FA supplementation with 400 micrograms/day in the second and third trimesters of pregnancy significantly increased the risk of LGA (RR = 1.98 (1.29, 3.04)). This relation was strong or monotonic after adjusting for maternal age, newborn’s gender, maternal pre-pregnancy BMI, maternal education level, smoking, alcohol consumption and calcium supplementation. We did not observe that continuing FA supplementation after the first trimester of pregnancy remarkably decreased the risk of SGA. The propensity score analysis showed similar results. To confirm these findings, additional investigations or trials with a large sample and the tracking of folate status throughout pregnancy are recommended. PMID:27537908

Assessment of the structural brain network reveals altered connectivity in children with unilateral cerebral palsy due to periventricular white matter lesions.

PubMed

Pannek, Kerstin; Boyd, Roslyn N; Fiori, Simona; Guzzetta, Andrea; Rose, Stephen E

2014-01-01

Cerebral palsy (CP) is a term to describe the spectrum of disorders of impaired motor and sensory function caused by a brain lesion occurring early during development. Diffusion MRI and tractography have been shown to be useful in the study of white matter (WM) microstructure in tracts likely to be impacted by the static brain lesion. The purpose of this study was to identify WM pathways with altered connectivity in children with unilateral CP caused by periventricular white matter lesions using a whole-brain connectivity approach. Data of 50 children with unilateral CP caused by periventricular white matter lesions (5-17 years; manual ability classification system [MACS] I = 25/II = 25) and 17 children with typical development (CTD; 7-16 years) were analysed. Structural and High Angular Resolution Diffusion weighted Images (HARDI; 64 directions, b = 3000 s/mm(2)) were acquired at 3 T. Connectomes were calculated using whole-brain probabilistic tractography in combination with structural parcellation of the cortex and subcortical structures. Connections with altered fractional anisotropy (FA) in children with unilateral CP compared to CTD were identified using network-based statistics (NBS). The relationship between FA and performance of the impaired hand in bimanual tasks (Assisting Hand Assessment-AHA) was assessed in connections that showed significant differences in FA compared to CTD. FA was reduced in children with unilateral CP compared to CTD. Seven pathways, including the corticospinal, thalamocortical, and fronto-parietal association pathways were identified simultaneously in children with left and right unilateral CP. There was a positive relationship between performance of the impaired hand in bimanual tasks and FA within the cortico-spinal and thalamo-cortical pathways (r(2) = 0.16-0.44; p < 0.05). This study shows that network-based analysis of structural connectivity can identify alterations in FA in unilateral CP, and that these alterations in FA are related to clinical function. Application of this connectome-based analysis to investigate alterations in connectivity following treatment may elucidate the neurological correlates of improved functioning due to intervention.

A canonical discriminant analysis to study the association between milk fatty acids of ruminal origin and milk fat depression in dairy cows.

PubMed

Conte, G; Dimauro, C; Serra, A; Macciotta, N P P; Mele, M

2018-04-04

Although milk fat depression (MFD) has been observed and described since the beginning of the last century, all the molecular and biochemical mechanisms involved are still not completely understood. Some fatty acids (FA) originating during rumen biohydrogenation have been proposed as causative elements of MFD. However, contradictory results were obtained when studying the effect of single FA on MFD. An alternative could be the simultaneous evaluation of the effect of many FA using a multivariate approach. The aim of this study was to evaluate the relationship between individual milk FA of ruminal origin and MFD using canonical discriminant analysis, a multivariate technique able to distinguish 2 or more groups on the basis of a pool of variables. In a commercial dairy herd, a diet containing 26% starch on a DM basis induced an unintentional MFD syndrome in 14 cows out of 40. Milk yielded by these 14 animals showed a fat content lower than 50% of the ordinary value, whereas milk production and protein content were normal. The remaining 26 cows secreted typical milk fat content and therefore were considered the control group, even though they ate the same diet. The stepwise discriminant analysis selected 14 milk FA of ruminal origin most able to distinguish the 2 groups. This restricted pool of FA was used, as variables, in a run of the canonical discriminant analysis that was able to significantly discriminate between the 2 groups. Out of the 14 FA, 5 conjugated linoleic acid isomers (C18:2 trans-10,trans-12, C18:2 trans-8,trans-10, C18:2 trans-11,cis-13, C18:2 cis-9,cis-11, C18:2 cis-10,cis-12) and C15:0 iso were more related to the control group, whereas C18:2 trans-10,cis-12, C16:1 trans-6-7, C16:1 trans-9, C18:1 trans-6-8, C18:1 trans-9, C18:1 trans-10, C18:1 cis-11, and C18:3n-3 were positively associated with the MFD group, allowing a complete discrimination. On the basis of these results, we can conclude that (1) the shift of ruminal biohydrogenation from C18:1 trans-11 to C18:1 trans-10 seemed to be strongly associated with MFD; (2) at the same time, other C18:1 trans isomers showed a similar association; (3) on the contrary, conjugated linoleic acid isomers other than C18:2 trans-10,cis-12 seemed to be associated with a normal fat secretion. Results confirmed that MFD is the consequence of a combined effect of the outflow of many ruminal FA, which collectively affect mammary fat synthesis. Because the animals of the 2 groups were fed the same diet, these results suggested that factors other than diet are involved in the MFD syndrome. Feeding behavior (i.e., ability to select dietary ingredients in a total mixed ration), rumen environment and the composition of ruminal bacteria are additional factors able to modify the products of rumen biohydrogenation. Results of the present work confirmed that the multivariate approach can be a useful tool to evaluate a metabolic pathway that involves several parameters, providing interesting suggestions about the role of some FA involved in MFD. However, results about the MFD syndrome obtained in the present research require a deep molecular investigation to be confirmed. Copyright © 2018 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Evaluation of the National Research Council (2001) dairy model and derivation of new prediction equations. 1. Digestibility of fiber, fat, protein, and nonfiber carbohydrate.

PubMed

White, R R; Roman-Garcia, Y; Firkins, J L; VandeHaar, M J; Armentano, L E; Weiss, W P; McGill, T; Garnett, R; Hanigan, M D

2017-05-01

Evaluation of ration balancing systems such as the National Research Council (NRC) Nutrient Requirements series is important for improving predictions of animal nutrient requirements and advancing feeding strategies. This work used a literature data set (n = 550) to evaluate predictions of total-tract digested neutral detergent fiber (NDF), fatty acid (FA), crude protein (CP), and nonfiber carbohydrate (NFC) estimated by the NRC (2001) dairy model. Mean biases suggested that the NRC (2001) lactating cow model overestimated true FA and CP digestibility by 26 and 7%, respectively, and under-predicted NDF digestibility by 16%. All NRC (2001) estimates had notable mean and slope biases and large root mean squared prediction error (RMSPE), and concordance (CCC) ranged from poor to good. Predicting NDF digestibility with independent equations for legumes, corn silage, other forages, and nonforage feeds improved CCC (0.85 vs. 0.76) compared with the re-derived NRC (2001) equation form (NRC equation with parameter estimates re-derived against this data set). Separate FA digestion coefficients were derived for different fat supplements (animal fats, oils, and other fat types) and for the basal diet. This equation returned improved (from 0.76 to 0.94) CCC compared with the re-derived NRC (2001) equation form. Unique CP digestibility equations were derived for forages, animal protein feeds, plant protein feeds, and other feeds, which improved CCC compared with the re-derived NRC (2001) equation form (0.74 to 0.85). New NFC digestibility coefficients were derived for grain-specific starch digestibilities, with residual organic matter assumed to be 98% digestible. A Monte Carlo cross-validation was performed to evaluate repeatability of model fit. In this procedure, data were randomly subsetted 500 times into derivation (60%) and evaluation (40%) data sets, and equations were derived using the derivation data and then evaluated against the independent evaluation data. Models derived with random study effects demonstrated poor repeatability of fit in independent evaluation. Similar equations derived without random study effects showed improved fit against independent data and little evidence of biased parameter estimates associated with failure to include study effects. The equations derived in this analysis provide interesting insight into how NDF, starch, FA, and CP digestibilities are affected by intake, feed type, and diet composition. The Authors. Published by the Federation of Animal Science Societies and Elsevier Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

Rapid Quantitation of Ascorbic and Folic Acids in SRM 3280 Multivitamin/Multielement Tablets using Flow-Injection Tandem Mass Spectrometry

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

Bhandari, Deepak; Kertesz, Vilmos; Van Berkel, Gary J

RATIONALE: Ascorbic acid (AA) and folic acid (FA) are water-soluble vitamins and are usually fortified in food and dietary supplements. For the safety of human health, proper intake of these vitamins is recommended. Improvement in the analysis time required for the quantitative determination of these vitamins in food and nutritional formulations is desired. METHODS: A simple and fast (~5 min) in-tube sample preparation was performed, independently for FA and AA, by mixing extraction solvent with a powdered sample aliquot followed by agitation, centrifugation, and filtration to recover an extract for analysis. Quantitative detection was achieved by flow-injection (1 L injectionmore » volume) electrospray ionization tandem mass spectrometry (ESI-MS/MS) in negative ion mode using the method of standard addition. RESULTS: Method of standard addition was employed for the quantitative estimation of each vitamin in a sample extract. At least 2 spiked and 1 non-spiked sample extract were injected in triplicate for each quantitative analysis. Given an injection-to-injection interval of approximately 2 min, about 18 min was required to complete the quantitative estimation of each vitamin. The concentration values obtained for the respective vitamins in the standard reference material (SRM) 3280 using this approach were within the statistical range of the certified values provided in the NIST Certificate of Analysis. The estimated limit of detections of FA and AA were 13 and 5.9 ng/g, respectively. CONCLUSIONS: Flow-injection ESI-MS/MS was successfully applied for the rapid quantitation of FA and AA in SRM 3280 multivitamin/multielement tablets.« less

Motor function outcomes of pediatric patients with hemiplegic cerebral palsy after rehabilitation treatment: a diffusion tensor imaging study

PubMed Central

Kim, Jin Hyun; Kwon, Yong Min; Son, Su Min

2015-01-01

Previous diffusion tensor imaging (DTI) studies regarding pediatric patients with motor dysfunction have confirmed the correlation between DTI parameters of the injured corticospinal tract and the severity of motor dysfunction. There is also evidence that DTI parameters can help predict the prognosis of motor function of patients with cerebral palsy. But few studies are reported on the DTI parameters that can reflect the motor function outcomes of pediatric patients with hemiplegic cerebral palsy after rehabilitation treatment. In the present study, 36 pediatric patients with hemiplegic cerebral palsy were included. Before and after rehabilitation treatment, DTI was used to measure the fiber number (FN), fractional anisotropy (FA) and apparent diffusion coefficient (ADC) of bilateral corticospinal tracts. Functional Level of Hemiplegia scale (FxL) was used to assess the therapeutic effect of rehabilitative therapy on clinical hemiplegia. Correlation analysis was performed to assess the statistical interrelationship between the change amount of DTI parameters and FxL. DTI findings obtained at the initial and follow-up evaluations demonstrated that more affected corticospinal tract yielded significantly decreased FN and FA values and significantly increased ADC value compared to the less affected corticospinal tract. Correlation analysis results showed that the change amount of FxL was positively correlated to FN and FA values, and the correlation to FN was stronger than the correlation to FA. The results suggest that FN and FA values can be used to evaluate the motor function outcomes of pediatric patients with hemiplegic cerebral palsy after rehabilitation treatment and FN is of more significance for evaluation. PMID:26170825

Factor analysis for delineation of organ structures, creation of in- and output functions, and standardization of multicenter kinetic modeling

NASA Astrophysics Data System (ADS)

Schiepers, Christiaan; Hoh, Carl K.; Dahlbom, Magnus; Wu, Hsiao-Ming; Phelps, Michael E.

1999-05-01

PET imaging can quantify metabolic processes in-vivo; this requires the measurement of an input function which is invasive and labor intensive. A non-invasive, semi-automated, image based method of input function generation would be efficient, patient friendly, and allow quantitative PET to be applied routinely. A fully automated procedure would be ideal for studies across institutions. Factor analysis (FA) was applied as processing tool for definition of temporally changing structures in the field of view. FA has been proposed earlier, but the perceived mathematical difficulty has prevented widespread use. FA was utilized to delineate structures and extract blood and tissue time-activity-curves (TACs). These TACs were used as input and output functions for tracer kinetic modeling, the results of which were compared with those from an input function obtained with serial blood sampling. Dynamic image data of myocardial perfusion studies with N-13 ammonia, O-15 water, or Rb-82, cancer studies with F-18 FDG, and skeletal studies with F-18 fluoride were evaluated. Correlation coefficients of kinetic parameters obtained with factor and plasma input functions were high. Linear regression usually furnished a slope near unity. Processing time was 7 min/patient on an UltraSPARC. Conclusion: FA can non-invasively generate input functions from image data eliminating the need for blood sampling. Output (tissue) functions can be simultaneously generated. The method is simple, requires no sophisticated operator interaction and has little inter-operator variability. FA is well suited for studies across institutions and standardized evaluations.

A novel free ammonia based pretreatment technology to enhance anaerobic methane production from primary sludge.

PubMed

Wei, Wei; Zhou, Xu; Xie, Guo-Jun; Duan, Haoran; Wang, Qilin

2017-10-01

This study proposed a novel free ammonia (FA, i.e., NH 3 ) pretreatment technology to enhance anaerobic methane production from primary sludge for the first time. The solubilization of primary sludge was substantially enhanced following 24 h FA pretreatment (250-680 mg NH 3 -N/L), by which the release of soluble chemical oxygen demand (SCOD) (i.e., 0.4 mg SCOD/mg VS added; VS: volatile solids) was approximately 10 times as much as that without pretreatment (i.e., 0.03 mg SCOD/mg VS added). Then, biochemical methane potential (BMP) tests demonstrated that FA pretreatment of 250-680 mg NH 3 -N/L was capable of enhancing anaerobic methane production while the digestion time was more than 7 days. Model based analysis indicated that the improved anaerobic methane production was due to an increased biochemical methane potential (B 0 ) of 8-17% (i.e., from 331 to 357-387 L CH 4 /kg VS added), with the highest B 0 achieved at 420 mg NH 3 -N/L pretreatment. However, FA pretreatment of 250-680 mg NH 3 -N/L decreased hydrolysis rate (k) by 24-38% compared with control (i.e., from 0.29 d -1 to 0.18-0.22 d -1 ), which explained the lower methane production over the first 7 days' digestion period. Economic analysis and environmental evaluation demonstrated that FA pretreatment technology was environmentally friendly and economically favorable. Biotechnol. Bioeng. 2017;114: 2245-2252. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Novel signature fatty acid profile of the giant manta ray suggests reliance on an uncharacterised mesopelagic food source low in polyunsaturated fatty acids

PubMed Central

Guerrero, Michel; Marshall, Andrea D.; Richardson, Anthony J.; Bennett, Mike B.; Couturier, Lydie I. E.

2018-01-01

Traditionally, large planktivorous elasmobranchs have been thought to predominantly feed on surface zooplankton during daytime hours. However, the recent application of molecular methods to examine long-term assimilated diets, has revealed that these species likely gain the majority from deeper or demersal sources. Signature fatty acid analysis (FA) of muscle tissue was used to examine the assimilated diet of the giant manta ray Mobula birostris, and then compared with surface zooplankton that was collected during feeding and non-feeding events at two aggregation sites off mainland Ecuador. The FA profiles of M. birostris and surface zooplankton were markedly different apart from similar proportions of arachidonic acid, which suggests daytime surface zooplankton may comprise a small amount of dietary intake for M. birostris. The FA profile of M. birostris muscle was found to be depleted in polyunsaturated fatty acids, and instead comprised high proportions of 18:1ω9 isomers. While 18:1ω9 isomers are not explicitly considered dietary FAs, they are commonly found in high proportions in deep-sea organisms, including elasmobranch species. Overall, the FA profile of M. birostris suggests a diet that is mesopelagic in origin, but many mesopelagic zooplankton species also vertically migrate, staying deep during the day and moving to shallower waters at night. Here, signature FA analysis is unable to resolve the depth at which these putative dietary items were consumed and how availability of this prey may drive distribution and movements of this large filter-feeder. PMID:29329295

Novel signature fatty acid profile of the giant manta ray suggests reliance on an uncharacterised mesopelagic food source low in polyunsaturated fatty acids.

PubMed

Burgess, Katherine B; Guerrero, Michel; Marshall, Andrea D; Richardson, Anthony J; Bennett, Mike B; Couturier, Lydie I E

2018-01-01

Traditionally, large planktivorous elasmobranchs have been thought to predominantly feed on surface zooplankton during daytime hours. However, the recent application of molecular methods to examine long-term assimilated diets, has revealed that these species likely gain the majority from deeper or demersal sources. Signature fatty acid analysis (FA) of muscle tissue was used to examine the assimilated diet of the giant manta ray Mobula birostris, and then compared with surface zooplankton that was collected during feeding and non-feeding events at two aggregation sites off mainland Ecuador. The FA profiles of M. birostris and surface zooplankton were markedly different apart from similar proportions of arachidonic acid, which suggests daytime surface zooplankton may comprise a small amount of dietary intake for M. birostris. The FA profile of M. birostris muscle was found to be depleted in polyunsaturated fatty acids, and instead comprised high proportions of 18:1ω9 isomers. While 18:1ω9 isomers are not explicitly considered dietary FAs, they are commonly found in high proportions in deep-sea organisms, including elasmobranch species. Overall, the FA profile of M. birostris suggests a diet that is mesopelagic in origin, but many mesopelagic zooplankton species also vertically migrate, staying deep during the day and moving to shallower waters at night. Here, signature FA analysis is unable to resolve the depth at which these putative dietary items were consumed and how availability of this prey may drive distribution and movements of this large filter-feeder.

Quantification of diffusion tensor imaging in normal white matter maturation of early childhood using an automated processing pipeline.

PubMed

Loh, K B; Ramli, N; Tan, L K; Roziah, M; Rahmat, K; Ariffin, H

2012-07-01

The degree and status of white matter myelination can be sensitively monitored using diffusion tensor imaging (DTI). This study looks at the measurement of fractional anistropy (FA) and mean diffusivity (MD) using an automated ROI with an existing DTI atlas. Anatomical MRI and structural DTI were performed cross-sectionally on 26 normal children (newborn to 48 months old), using 1.5-T MRI. The automated processing pipeline was implemented to convert diffusion-weighted images into the NIfTI format. DTI-TK software was used to register the processed images to the ICBM DTI-81 atlas, while AFNI software was used for automated atlas-based volumes of interest (VOIs) and statistical value extraction. DTI exhibited consistent grey-white matter contrast. Triphasic temporal variation of the FA and MD values was noted, with FA increasing and MD decreasing rapidly early in the first 12 months. The second phase lasted 12-24 months during which the rate of FA and MD changes was reduced. After 24 months, the FA and MD values plateaued. DTI is a superior technique to conventional MR imaging in depicting WM maturation. The use of the automated processing pipeline provides a reliable environment for quantitative analysis of high-throughput DTI data. Diffusion tensor imaging outperforms conventional MRI in depicting white matter maturation. • DTI will become an important clinical tool for diagnosing paediatric neurological diseases. • DTI appears especially helpful for developmental abnormalities, tumours and white matter disease. • An automated processing pipeline assists quantitative analysis of high throughput DTI data.

Folic Acid Modulates Matrix Metalloproteinase-2 Expression, Alleviates Neuropathic Pain, and Improves Functional Recovery in Spinal Cord-Injured Rats

PubMed Central

Miranpuri, Gurwattan S.; Meethal, Sivan Vadakkadath; Sampene, Emmanuel; Chopra, Abhishek; Buttar, Seah; Nacht, Carrie; Moreno, Neydis; Patel, Kush; Liu, Lisa; Singh, Anupama; Singh, Chandra K.; Hariharan, Nithya; Iskandar, Bermans; Resnick, Daniel K.

2017-01-01

Background The molecular underpinnings of spinal cord injury (SCI) associated with neuropathic pain (NP) are unknown. Recent studies have demonstrated that matrix metalloproteinases (MMPs) such as MMP2 play a critical role in inducing NP following SCI. Promoter methylation of MMPs is known to suppress their transcription and reduce NP. In this context, it has been shown in rodents that folic acid (FA), an FDA approved dietary supplement and key methyl donor in the central nervous system (CNS), increases axonal regeneration and repair of injured CNS in part via methylation. Purpose Based on above observations, in this study, we test whether FA could decrease MMP2 expression and thereby decrease SCI-induced NP. Methods Sprague-Dawley male rats weighing 250–270 g received contusion spinal cord injuries (cSCIs) with a custom spinal cord impactor device that drops a 10 g weight from a height of 12.5 mm. The injured rats received either i.p. injections of FA (80 µg/kg) or water (control) 3 days prior and 17 days post-cSCI (mid phase) or for 3 days pre-cSCI and 14 days post-cSCI ending on the 42nd day of cSCI (late phase). The functional neurological deficits due to cSCI were then assessed by Basso, Beattie, and Bresnahan (BBB) scores either on post-impaction days 0 through 18 post-cSCI (mid phase) or on days 0, 2, 7, 14, 21, 28, 35, and 42 (late phase). Baseline measurements were taken the day before starting treatments. Thermal hyperalgesia (TH) testing for pain was performed on 4 days pre-cSCI (baseline data) and on days 18, 21, 28, 35, and 42 post-cSCI. Following TH testing, animals were euthanized and spinal cords harvested for MMP-2 expression analysis. Result The FA-treated groups showed higher BBB scores during mid phase (day 18) and in late phase (day 42) of injury compared to controls, suggesting enhanced functional recovery. There is a transient decline in TH in animals from the FA-treated group compared to controls when tested on days 18, 21, 28, and 35, indicative of a decrease in NP. However, when tested 25 days after stopping FA administration on day 42 of cSCI, no significant difference in TH was observed between FA-treated and control animals. Western blot analysis of the injured spinal cord from FA-treated animals showed significant decline in MMP2 expression compared to spinal cord samples from water-treated controls. Conclusion Together, these data suggest that FA could alleviate NP and improve functional recovery post-SCI, possibly by reducing the expression of MMP2. Further studies will open up a novel and easy natural therapy, ideal for clinical translation with minimal side effects, for managing SCI-induced NP. Such studies might also throw light on a possible epigenetic mechanism in FA-induced recovery after SCI. PMID:28588362

The Convergent Validity of the Questions about Behavioral Function Scale and Functional Analysis for Problem Behavior Displayed by Individuals with Autism Spectrum Disorder

ERIC Educational Resources Information Center

Watkins, Nicholas; Rapp, John T.

2013-01-01

Only a few studies have compared the convergent validity of the Questions About Behavioral Function (QABF) scale to the results of functional analyses (FA). In the current study, six participants who emitted problem behaviors participated in either a brief, or a no-interaction-series FA, while each participant's parent completed the QABF. The…

An Evaluation Technique for an F/A-18 Aircraft Loads Model Using F/A-18 Systems Research Aircraft Flight Data

NASA Technical Reports Server (NTRS)

Olney, Candida D.; Hillebrandt, Heather; Reichenbach, Eric Y.

2000-01-01

A limited evaluation of the F/A-18 baseline loads model was performed on the Systems Research Aircraft at NASA Dryden Flight Research Center (Edwards, California). Boeing developed the F/A-18 loads model using a linear aeroelastic analysis in conjunction with a flight simulator to determine loads at discrete locations on the aircraft. This experiment was designed so that analysis of doublets could be used to establish aircraft aerodynamic and loads response at 20 flight conditions. Instrumentation on the right outboard leading edge flap, left aileron, and left stabilator measured the hinge moment so that comparisons could be made between in-flight-measured hinge moments and loads model-predicted values at these locations. Comparisons showed that the difference between the loads model-predicted and in-flight-measured hinge moments was up to 130 percent of the flight limit load. A stepwise regression technique was used to determine new loads derivatives. These derivatives were placed in the loads model, which reduced the error to within 10 percent of the flight limit load. This paper discusses the flight test methodology, a process for determining loads coefficients, and the direct comparisons of predicted and measured hinge moments and loads coefficients.

Comparative Studies on the Characteristic Fatty Acid Profiles of Four Different Chinese Medicinal Sargassum Seaweeds by GC-MS and Chemometrics.

PubMed

Chen, Zhen; Xu, Yibing; Liu, Tao; Zhang, Lining; Liu, Hongbing; Guan, Huashi

2016-03-29

Sargassum seaweeds produce abundant biomass in China and have long been used as herbal medicine and food. Their characteristic fatty acid (FA) profiles and related potential function in promoting cardiovascular health (CVH) have not been systematically investigated. In this study, FA profiles of four medicinal Sargassum were characterized using GC-MS. Principal component analysis was used to discriminate the four medicinal Sargassum, and orthogonal projection to latent structures discriminant analysis was carried out between the two official species HAI ZAO and between the two folk medicine species HAI QIAN. In all of the algae investigated, the major SFA and MUFA were palmitic and stearic acid, respectively, while the major PUFAs were linoleic, arachidonic, and eicosapentaenoic acid. S. fusiforme and S. horneri had higher concentrations of PUFAs. With respect to CVH, all of the studied species, particularly S. fusiforme, exhibited satisfactory levels such as PUFA/SFA ratio and n-6/n-3 ratio. Each species possesses a unique FA profile and is discriminated clearly. Potential key FA markers (between the two Chinese official species, and between the two folk species) are assessed. The study provides characteristic fatty acid profiles of four Chinese medicinal Sargassum and their related potential function in promoting CVH.

Comparative Studies on the Characteristic Fatty Acid Profiles of Four Different Chinese Medicinal Sargassum Seaweeds by GC-MS and Chemometrics

PubMed Central

Chen, Zhen; Xu, Yibing; Liu, Tao; Zhang, Lining; Liu, Hongbing; Guan, Huashi

2016-01-01

Sargassum seaweeds produce abundant biomass in China and have long been used as herbal medicine and food. Their characteristic fatty acid (FA) profiles and related potential function in promoting cardiovascular health (CVH) have not been systematically investigated. In this study, FA profiles of four medicinal Sargassum were characterized using GC-MS. Principal component analysis was used to discriminate the four medicinal Sargassum, and orthogonal projection to latent structures discriminant analysis was carried out between the two official species HAI ZAO and between the two folk medicine species HAI QIAN. In all of the algae investigated, the major SFA and MUFA were palmitic and stearic acid, respectively, while the major PUFAs were linoleic, arachidonic, and eicosapentaenoic acid. S. fusiforme and S. horneri had higher concentrations of PUFAs. With respect to CVH, all of the studied species, particularly S. fusiforme, exhibited satisfactory levels such as PUFA/SFA ratio and n-6/n-3 ratio. Each species possesses a unique FA profile and is discriminated clearly. Potential key FA markers (between the two Chinese official species, and between the two folk species) are assessed. The study provides characteristic fatty acid profiles of four Chinese medicinal Sargassum and their related potential function in promoting CVH. PMID:27043581

An alternative to FASTSIM for tangential solution of the wheel-rail contact

NASA Astrophysics Data System (ADS)

Sichani, Matin Sh.; Enblom, Roger; Berg, Mats

2016-06-01

In most rail vehicle dynamics simulation packages, tangential solution of the wheel-rail contact is gained by means of Kalker's FASTSIM algorithm. While 5-25% error is expected for creep force estimation, the errors of shear stress distribution, needed for wheel-rail damage analysis, may rise above 30% due to the parabolic traction bound. Therefore, a novel algorithm named FaStrip is proposed as an alternative to FASTSIM. It is based on the strip theory which extends the two-dimensional rolling contact solution to three-dimensional contacts. To form FaStrip, the original strip theory is amended to obtain accurate estimations for any contact ellipse size and it is combined by a numerical algorithm to handle spin. The comparison between the two algorithms shows that using FaStrip improves the accuracy of the estimated shear stress distribution and the creep force estimation in all studied cases. In combined lateral creepage and spin cases, for instance, the error in force estimation reduces from 18% to less than 2%. The estimation of the slip velocities in the slip zone, needed for wear analysis, is also studied. Since FaStrip is as fast as FASTSIM, it can be an alternative for tangential solution of the wheel-rail contact in simulation packages.

Fanconi anemia protein, FANCA, associates with BRG1, a component of the human SWI/SNF complex.

PubMed

Otsuki, T; Furukawa, Y; Ikeda, K; Endo, H; Yamashita, T; Shinohara, A; Iwamatsu, A; Ozawa, K; Liu, J M

2001-11-01

Fanconi anemia (FA) is a genetic disorder that predisposes to hematopoietic failure, birth defects and cancer. We identified an interaction between the FA protein, FANCA and brm-related gene 1 (BRG1) product. BRG1 is a subunit of the SWI/SNF complex, which remodels chromatin structure through a DNA-dependent ATPase activity. FANCA was demonstrated to associate with the endogenous SWI/SNF complex. We also found a significant increase in the molecular chaperone, glucose-regulated protein 94 (GRP94) among BRG1-associated factors isolated from a FANCA-mutant cell line, which was not seen in either a normal control cell line or the mutant line complemented by wild-type FANCA. Despite this specific difference, FANCA did not appear to be absolutely required for in vitro chromatin remodeling. Finally, we demonstrated co-localization in the nucleus between transfected FANCA and BRG1. The physiological action of FANCA on the SWI/SNF complex remains to be clarified, but our work suggests that FANCA may recruit the SWI/SNF complex to target genes, thereby enabling coupled nuclear functions such as transcription and DNA repair.

Oral manifestations of Fanconi's anaemia: a case report.

PubMed

Saleh, A; Stephen, L X G

2008-02-01

Fanconi's anaemia (FA) is a rare, inherited autosomal recessive genetic disease characterized by progressive bone marrow failure, congenital abnormalities, and high predisposition to malignancies. The incidence of the disease is unusually high in the Afrikaner population of South Africa with calculated heterozygote prevalence being approximately 1 in 77. This report describes the oral clinical and radiological findings in a 16 year old male with FA. Medical and dental history was noted, the oral mucosa was examined and the teeth were screened for fillings and caries. Periodontal examination consisted of: measurement of probing depths, recession, mobility of teeth, furcation involvement, plaque index and gingival index. An orthopantomograph was taken. There was a generalized black hyper-pigmentation on the buccal mucosa, tongue and palate. The patient had generalized gingival recession and most of the periodontal pockets were deeper than 5mm. Several teeth were mobile and the orthopantomograph showed loss of alveolar bone in the furcation areas of most posterior teeth. A diagnosis of severe generalized periodontitis associated with systemic disease was made. Patients with Fanconi's anaemia are susceptible to severe dental and periodontal diseases.

Sustainability of an in situ aided phytostabilisation on highly contaminated soils using fly ashes: Effects on the vertical distribution of physicochemical parameters and trace elements.

PubMed

Bidar, Géraldine; Waterlot, Christophe; Verdin, Anthony; Proix, Nicolas; Courcot, Dominique; Détriché, Sébastien; Fourrier, Hervé; Richard, Antoine; Douay, Francis

2016-04-15

Aided phytostabilisation using trees and fly ashes is a promising technique which has shown its effectiveness in the management of highly metal-contaminated soils. However, this success is generally established based on topsoil physicochemical analysis and short-term experiments. This paper focuses on the long-term effects of the afforestation and two fly ashes (silico-aluminous and sulfo-calcic called FA1 and FA2, respectively) by assessing the integrity of fly ashes 10 years after their incorporation into the soil as well as the vertical distribution of the physicochemical parameters and trace elements (TEs) in the amended soils (F1 and F2) in comparison with a non-amended soil (R). Ten years after the soil treatment, the particle size distribution analysis between fly ashes and their corresponding masses (fly ash + soil particles) showed a loss or an agglomeration of finer particles. This evolution matches with the appearance of gypsum (CaSO4 2H2O) in FA2m instead of anhydrite (CaSO4), which is the major compound of FA2. This finding corresponds well with the dissolution and the lixiviation of Ca, S and P included in FA2 along the F2 soil profile, generating an accumulation of these elements at 30 cm depth. However, no variation of TE contamination was found between 0 and 25 cm depth in F2 soil except for Cd. Conversely, Cd, Pb, Zn and Hg enrichment was observed at 25 cm depth in the F1 soil, whereas no enrichment was observed for As. The fly ashes studied, and notably FA2, were able to reduce Cd, Pb and Zn availability in soil and this capacity persists over the time despite their structural and chemical changes. Copyright © 2016 Elsevier Ltd. All rights reserved.

Complementation of a Fanconi anemia group A cell line by UbA{sup 52}

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

Moses, R.E.; Heina, J.A.; Jakobs, P.M.

1994-09-01

Cells from patients with Fanconi anemia (FA) display chromosomal instability and increased sensitivity to mitomycin C (MMC) and diepoxybutane (DEB) relative to normal cells. Several genes act in this pathway of DNA damage processing based upon four known complementation groups in FA. We have made a cDNA expression library in a vector with a G418 selectable marker to identify FA genes other than the FA-C group. Approximately 1 x 10{sup 6} independent cDNA clones were isolated with an average cDNA size of 1.5 kb. Five cell lines resistant to MMC and DEB were isolated from 6 x 10{sup 6} G418-resistantmore » transfectants from 65 individual transfections of the FA-A fibroblast line GM6914. The isolated cell lines also showed normal chromosome stability. The same cDNA (600 bp) was recovered from three independent cell lines by PCR using flanking sequence primers. The gene has sequence identity with a known gene, the ubiquitin fusion gene, UbA{sub 52}. Interestingly, each of the cDNAs were inserted in antisense orientation relative to the cytomegalovirus (CMV) promoter as determined by sequencing and PCR using UbA{sub 52}-specific internal primers. Southern blot analysis indicated the cell lines had distinct chromosomal insertion sites. Mutation analysis by chemical cleavage showed no reading frame mutations, indicating that UbA{sub 52} is not the FA-A gene. Re-transfection with the UbA{sub 52} gene in antisense gave complementation for MMC, DEB and chromosome stability to varying degrees. Re-transfection of the antisense construct with the CMV promotor removed or with a sense construct did not alter the MMC sensitivity. We conclude that the antisense UbA{sub 52} gene has a non-specific effect, perhaps acting by altering the cell cycle or susceptibility to apoptosis.« less

Improved scatter correction with factor analysis for planar and SPECT imaging

NASA Astrophysics Data System (ADS)

Knoll, Peter; Rahmim, Arman; Gültekin, Selma; Šámal, Martin; Ljungberg, Michael; Mirzaei, Siroos; Segars, Paul; Szczupak, Boguslaw

2017-09-01

Quantitative nuclear medicine imaging is an increasingly important frontier. In order to achieve quantitative imaging, various interactions of photons with matter have to be modeled and compensated. Although correction for photon attenuation has been addressed by including x-ray CT scans (accurate), correction for Compton scatter remains an open issue. The inclusion of scattered photons within the energy window used for planar or SPECT data acquisition decreases the contrast of the image. While a number of methods for scatter correction have been proposed in the past, in this work, we propose and assess a novel, user-independent framework applying factor analysis (FA). Extensive Monte Carlo simulations for planar and tomographic imaging were performed using the SIMIND software. Furthermore, planar acquisition of two Petri dishes filled with 99mTc solutions and a Jaszczak phantom study (Data Spectrum Corporation, Durham, NC, USA) using a dual head gamma camera were performed. In order to use FA for scatter correction, we subdivided the applied energy window into a number of sub-windows, serving as input data. FA results in two factor images (photo-peak, scatter) and two corresponding factor curves (energy spectra). Planar and tomographic Jaszczak phantom gamma camera measurements were recorded. The tomographic data (simulations and measurements) were processed for each angular position resulting in a photo-peak and a scatter data set. The reconstructed transaxial slices of the Jaszczak phantom were quantified using an ImageJ plugin. The data obtained by FA showed good agreement with the energy spectra, photo-peak, and scatter images obtained in all Monte Carlo simulated data sets. For comparison, the standard dual-energy window (DEW) approach was additionally applied for scatter correction. FA in comparison with the DEW method results in significant improvements in image accuracy for both planar and tomographic data sets. FA can be used as a user-independent approach for scatter correction in nuclear medicine.

Multimodal voxel-based meta-analysis of white matter abnormalities in obsessive-compulsive disorder.

PubMed

Radua, Joaquim; Grau, Mar; van den Heuvel, Odile A; Thiebaut de Schotten, Michel; Stein, Dan J; Canales-Rodríguez, Erick J; Catani, Marco; Mataix-Cols, David

2014-06-01

White matter (WM) abnormalities have long been suspected in obsessive-compulsive disorder (OCD) but the available evidence has been inconsistent. We conducted the first multimodal meta-analysis of WM volume (WMV) and fractional anisotropy (FA) studies in OCD. All voxel-wise studies comparing WMV or FA between patients with OCD and healthy controls in the PubMed, ScienceDirect, Google Scholar, Web of Knowledge and Scopus databases were retrieved. Manual searches were also conducted and authors were contacted soliciting additional data. Thirty-four data sets were identified, of which 22 met inclusion criteria (five of them unpublished; comprising 537 adult and pediatric patients with OCD and 575 matched healthy controls). Whenever possible, raw statistical parametric maps were also obtained from the authors. Peak and raw WMV and FA data were combined using novel multimodal meta-analytic methods implemented in effect-size signed differential mapping. Patients with OCD showed widespread WM abnormalities, but findings were particularly robust in the anterior midline tracts (crossing between anterior parts of cingulum bundle and body of corpus callosum), which showed both increased WMV and decreased FA, possibly suggesting an increase of fiber crossing in these regions. This finding was also observed when the analysis was limited to adult participants, and especially pronounced in samples with a higher proportion of medicated patients. Therefore, patients with OCD may have widespread WM abnormalities, particularly evident in anterior midline tracts, although these changes might be, at least in part, attributable to the effects of therapeutic drugs.

Oral manifestations compatible with chronic graft-versus-host disease in patients with Fanconi anemia.

PubMed

Grein Cavalcanti, Laura; Fuentes Araújo, Renata L; Bonfim, Carmem; Torres-Pereira, Cassius C

2015-02-01

Fanconi anemia (FA) is a genetic disease that is characterized by several congenital abnormalities and progressive bone marrow failure and is associated with an increased susceptibility to malignant disorders. Currently, the only potential cure for hematological disorders is hematopoietic stem cell transplantation (HSCT). However, 1 of the most common complications after HSCT is the development of oral chronic graft-versus-host disease (cGVHD), which is also a risk factor for the development of cancer, particularly oral squamous cell carcinoma. Therefore, the purpose of this study was to describe the prevalence and characteristics of oral manifestations compatible with cGVHD in patients diagnosed with FA according to the National Institutes of Health (NIH) consensus criteria. A total of 96 patients (51 females, 45 males; median age, 16 years) with FA, who were in medical follow-up after HSCT at the outpatient clinic of the bone marrow transplantation unit (Hospital de Clínicas from the Universidade Federal do Paraná) underwent an oral evaluation between January 2013 and December 2013. Post-HSCT periods varied from 1 to 261 months and were divided into 3 periods: immediate post-HSCT period; intermediate post-HSC period, and late post-HSCT period. Among the evaluated patients, 40 of 96 (42%) presented with oral manifestations of cGVHD, with 29 of 40 (73%) of these patients in the late post-HSCT period. NIH scale scores varied from 0 to 10, and lichenoid and hyperkeratotic lesions were the abnormalities most frequently observed (100%). Overall, a high prevalence of oral manifestations was observed for cGVHD patients with FA. These data highlight the importance of monitoring oral manifestations compatible with cGVHD to identify and treat individuals with a higher risk of developing oral cancer. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Structural analysis of binding functionality of folic acid-PEG dendrimers against folate receptor.

PubMed

Sampogna-Mireles, Diana; Araya-Durán, Ingrid D; Márquez-Miranda, Valeria; Valencia-Gallegos, Jesús A; González-Nilo, Fernando D

2017-03-01

Dendrimers functionalized with folic acid (FA) are drug delivery systems that can selectively target cancer cells with folate receptors (FR-α) overexpression. Incorporation of polyethylene glycol (PEG) can enhance dendrimers solubility and pharmacokinetics, but ligand-receptor binding must not be affected. In this work we characterized, at atomic level, the binding functionality of conventional site-specific dendrimers conjugated with FA with PEG 750 or PEG 3350 as a linker. After Molecular Dynamics simulation, we observed that both PEG's did not interfere over ligand-receptor binding functionality. Although binding kinetics could be notably affected, the folate fragment from both dendrimers remained exposed to the solvent before approaching selectively to FR-α. PEG 3350 provided better solubility and protection from enzymatic degradation to the dendrimer than PEG 750. Also, FA-PEG3350 dendrimer showed a slightly better interaction with FR-α than FA-PEG750 dendrimer. Therefore, theoretical evidence supports that both dendrimers are suitable as drug delivery systems for cancer therapies. Copyright © 2017 Elsevier Inc. All rights reserved.

Ferulic acid destabilizes preformed {beta}-amyloid fibrils in vitro

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

Ono, Kenjiro; Hirohata, Mie; Yamada, Masahito

2005-10-21

Inhibition of the formation of {beta}-amyloid fibrils (fA{beta}), as well as the destabilization of preformed fA{beta} in the CNS, would be attractive therapeutic targets for the treatment of Alzheimer's disease (AD). We reported previously that curcumin (Cur) inhibits fA{beta} formation from A{beta} and destabilizes preformed fA{beta} in vitro. Using fluorescence spectroscopic analysis with thioflavin T and electron microscopic studies, we examined the effects of ferulic acid (FA) on the formation, extension, and destabilization of fA{beta} at pH 7.5 at 37 deg C in vitro. We next compared the anti-amyloidogenic activities of FA with Cur, rifampicin, and tetracycline. Ferulic acid dose-dependentlymore » inhibited fA{beta} formation from amyloid {beta}-peptide, as well as their extension. Moreover, it destabilized preformed fA{beta}s. The overall activity of the molecules examined was in the order of: Cur > FA > rifampicin = tetracycline. FA could be a key molecule for the development of therapeutics for AD.« less

Triiodothyronine activates lactate oxidation without impairing fatty acid oxidation and improves weaning from extracorporeal membrane oxygenation.

PubMed

Kajimoto, Masaki; Ledee, Dolena R; Xu, Chun; Kajimoto, Hidemi; Isern, Nancy G; Portman, Michael A

2014-01-01

Extracorporeal membrane oxygenation (ECMO) provides a rescue for children with severe cardiac failure. It has previously been shown that triiodothyronine (T3) improves cardiac function by modulating pyruvate oxidation during weaning. This study focused on fatty acid (FA) metabolism modulated by T3 for weaning from ECMO after cardiac injury. METHODS AND RESULTS: Nineteen immature piglets (9.1-15.3 kg) were separated into 3 groups with ECMO (6.5 h) and wean: normal circulation (Group-C); transient coronary occlusion (10 min) for ischemia-reperfusion (IR) followed by ECMO (Group-IR); and IR with T3 supplementation (Group-IR-T3). 13-Carbon ((13)C)-labeled lactate, medium-chain and long-chain FAs, was infused as oxidative substrates. Substrate fractional contribution (FC) to the citric acid cycle was analyzed by(13)C-nuclear magnetic resonance. ECMO depressed circulating T3 levels to 40% of the baseline at 4 h and were restored in Group-IR-T3. Group-IR decreased cardiac power, which was not fully restorable and 2 pigs were lost because of weaning failure. Group-IR also depressed FC-lactate, while the excellent contractile function and energy efficiency in Group-IR-T3 occurred along with a marked FC-lactate increase and [adenosine triphosphate]/[adenosine diphosphate] without either decreasing FC-FAs or elevating myocardial oxygen consumption over Group-C or -IR. T3 releases inhibition of lactate oxidation following IR injury without impairing FA oxidation. These findings indicate that T3 depression during ECMO is maladaptive, and that restoring levels improves metabolic flux and enhances contractile function during weaning.

Current Knowledge and Priorities for Future Research in Late Effects after Hematopoietic Cell Transplantation for Inherited Bone Marrow Failure Syndromes: Consensus Statement from the Second Pediatric Blood and Marrow Transplant Consortium International Conference on Late Effects after Pediatric Hematopoietic Cell Transplantation.

PubMed

Dietz, Andrew C; Mehta, Parinda A; Vlachos, Adrianna; Savage, Sharon A; Bresters, Dorine; Tolar, Jakub; Boulad, Farid; Dalle, Jean Hugues; Bonfim, Carmem; de la Fuente, Josu; Duncan, Christine N; Baker, K Scott; Pulsipher, Michael A; Lipton, Jeffrey M; Wagner, John E; Alter, Blanche P

2017-05-01

Fanconi anemia (FA), dyskeratosis congenita (DC), and Diamond Blackfan anemia (DBA) are 3 of the most common inherited bone marrow failure syndromes (IBMFS), in which the hematologic manifestations can be cured with hematopoietic cell transplantation (HCT). Later in life, these patients face a variety of medical conditions, which may be a manifestation of underlying disease or due to pre-HCT therapy, the HCT, or a combination of all these elements. Very limited long-term follow-up data exist in these populations, with FA the only IBMFS that has specific published data. During the international consensus conference sponsored by the Pediatric Blood and Marrow Transplant Consortium entitled "Late Effects Screening and Recommendations following Allogeneic Hematopoietic Cell Transplant (HCT) for Immune Deficiency and Nonmalignant Hematologic Disease" held in Minneapolis, Minnesota in May of 2016, a half-day session was focused specifically on the unmet needs for these patients with IBMFS. A multidisciplinary group of experts discussed what is currently known, outlined an agenda for future research, and laid out long-term follow-up guidelines based on a combination of evidence in the literature as well as expert opinion. This article addresses the state of science in that area as well as consensus regarding the agenda for future research, with specific screening guidelines to follow in the next article from this group. Copyright © 2017 The American Society for Blood and Marrow Transplantation. All rights reserved.

White Bass (Morone chrysops) Preferentially Retain n-3 PUFA in Ova When Fed Prepared Diets with Varying FA Content.

PubMed

Fuller, S Adam; Rawles, Steven D; McEntire, Matthew E; Bader, Troy J; Riche, Marty; Beck, Benjamin H; Webster, Carl D

2017-10-01

We evaluated the fatty acid (FA) composition of broodstock white bass ova fed one of six commercial diets with increasing polyunsaturated FA content (n-6/n-3 ratio; 0.36, 0.39, 0.46, 0.83, 1.07, 1.12) eight weeks prior to sampling. Fatty acid profiles of ova from brooders fed each of the six diets were significantly altered according to canonical discriminant analysis. Ova FA profiles resulting from the 0.39 diet separated those from the 0.36 diet based on lower 18:2n-6 (LNA) and higher 20:1n-9 concentrations from the 0.36 diet. Ova profiles were further separated based on lower concentrations of 22:5n-3 (DPA) from the 0.46 diet, lower concentrations of 20:5n-3 (EPA) in the 1.12 and 0.83 diets, and lower concentrations of 22:6n-3 (DHA) in all other diets relative to the 0.46 diet. Changes in ova FA profile at four and eight weeks were consistent with dietary intake with an approximate 2% increase in any given FA class with increasing time on individual diet. There was no correlation between dietary ARA concentrations (0.7-1.1 mol%), or dietary EPA/ARA ratios (7-15), and the concentrations (1.4-1.7 mol%) or ratios (3.3-4.4) found in the ova by diet. Our results suggest that white bass females have the ability to preferentially incorporate n-3 PUFA, particularly DHA, suggesting mobilization of this FA from other tissues for ova deposition or preferential dietary incorporation of PUFA into ova. These results will add to the limited FA information available in white bass and enable nutritionists to formulate broodstock diets that maximize reproductive potential in this species.

Decreased FOXP3 mRNA expression in children with atopic asthma and IgE-mediated food allergy.

PubMed

Krogulska, Aneta; Polakowska, Ewa; Wąsowska-Królikowska, Krystyna; Małachowska, Beata; Młynarski, Wojciech; Borowiec, Maciej

2015-11-01

The role of T regulatory lymphocytes has been investigated in various allergic diseases. However, the precise relation between the phenotype and severity of allergic diseases and the changes in FOXP3 mRNA expression are not fully understood. To compare the expression of FOXP3 mRNA in children with asthma with and without concomitant food allergy (FA) with healthy children and children with only FA. The study included 82 children: 15 with atopic asthma and IgE-dependent FA, 27 with atopic asthma without FA, 20 with IgE-dependent FA without asthma, and 20 healthy children without atopy. Reverse transcription was performed using a commercially available High Capacity cDNA Archive Kit (Applied Biosystems, Carlsbad, California). Analysis was carried out with a 7900HT real-time polymerase chain reaction system (Applied Biosystems). The average level of the FOXP3 gene expression in children with allergy was significantly lower compared with healthy children (2.2 ± 1.3 vs 4.2 ± 4.2; P = .014). The lowest mean level of FOXP3 mRNA expression (1.9 ± 1.6) was recorded in children with asthma and FA, and the highest level (4.2 ± 4.2) was recorded in healthy children without atopy (P = .036). A milder course of asthma or the degree of allergic reaction after a food challenge was associated with higher FOXP3 mRNA expression. Significantly lower levels of FOXP3 gene expression, observed more commonly in children with asthma and IgE-dependent FA than in healthy controls, were associated with a more severe clinical course. Therefore, FOXP3 expression could serve as an indicator of severe asthma with concomitant atopic conditions such as IgE-dependent FA. Copyright © 2015 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Functionalized rare earth-doped nanoparticles for breast cancer nanodiagnostic using fluorescence and CT imaging.

PubMed

Jain, Akhil; Fournier, Pierrick G J; Mendoza-Lavaniegos, Vladimir; Sengar, Prakhar; Guerra-Olvera, Fernando M; Iñiguez, Enrique; Kretzschmar, Thomas G; Hirata, Gustavo A; Juárez, Patricia

2018-03-22

Breast cancer is the second leading cause of cancer death among women and represents 14% of death in women around the world. The standard diagnosis method for breast tumor is mammography, which is often related with false-negative results leading to therapeutic delays and contributing indirectly to the development of metastasis. Therefore, the development of new tools that can detect breast cancer is an urgent need to reduce mortality in women. Here, we have developed Gd 2 O 3 :Eu 3+ nanoparticles functionalized with folic acid (FA), for breast cancer detection. Gd 2 O 3 :Eu 3+ nanoparticles were synthesized by sucrose assisted combustion synthesis and functionalized with FA using EDC-NHS coupling. The FA-conjugated Gd 2 O 3 :Eu 3+ nanoparticles exhibit strong red emission at 613 nm with a quantum yield of ~ 35%. In vitro cytotoxicity studies demonstrated that the nanoparticles had a negligible cytotoxic effect on normal 293T and T-47D breast cancer cells. Cellular uptake analysis showed significantly higher internalization of FA-conjugated RE nanoparticles into T-47D cells (Folr hi ) compared to MDA-MB-231 breast cancer cells (Folr lo ). In vivo confocal and CT imaging studies indicated that FA-conjugated Gd 2 O 3 :Eu 3+ nanoparticles accumulated more efficiently in T-47D tumor xenograft compared to the MDA-MB-231 tumor. Moreover, we found that FA-conjugated Gd 2 O 3 :Eu 3+ nanoparticles were well tolerated at high doses (300 mg/kg) in CD1 mice after an intravenous injection. Thus, FA-conjugated Gd 2 O 3 :Eu 3+ nanoparticles have great potential to detect breast cancer. Our findings provide significant evidence that could permit the future clinical application of FA-conjugated Gd 2 O 3 :Eu 3+ nanoparticles alone or in combination with the current detection methods to increase its sensitivity and precision.

High doses of folic acid in the periconceptional period and risk of low weight for gestational age at birth in a population based cohort study.

PubMed

Navarrete-Muñoz, Eva María; Valera-Gran, Desirée; Garcia-de-la-Hera, Manuela; Gonzalez-Palacios, Sandra; Riaño, Isolina; Murcia, Mario; Lertxundi, Aitana; Guxens, Mònica; Tardón, Adonina; Amiano, Pilar; Vrijheid, Martine; Rebagliato, Marisa; Vioque, Jesus

2017-11-27

We investigated the association between maternal use of folic acid (FA) during pregnancy and child anthropometric measures at birth. We included 2302 mother-child pairs from a population-based birth cohort in Spain (INMA Project). FA dosages at first and third trimester of pregnancy were assessed using a specific battery questionnaire and were categorized in non-user, < 1000, 1000-4999, and ≥ 5000 µg/day. Anthropometric measures at birth (weight in grams, length and head circumference in centimetres) were obtained from medical records. Small for gestational age according to weight (SGA-w), length (SGA-l) and head circumference (SGA-hc) were defined using the 10th percentile based on Spanish standardized growth reference charts. Multiple linear and logistic regression analyses were used to explore the association between FA dosages in different stages of pregnancy and child anthropometric measures at birth. In the multiple linear regression analysis, we found a tendency for a negative association between the use of high dosages of FA (≥ 5000 µg/day) in the periconceptional period of pregnancy and weight at birth compared to mothers who were non-users of FA (β = - 73.83; 95% CI - 151.71, 4.06). In the multiple logistic regression, a greater risk of SGA-w was also evident among children whose mothers took FA dosages of 1000-4999 (OR = 2.21; 95% CI 1.17, 4.19) and of ≥ 5000 µg/day (OR = 2.32; 95% CI 1.06, 5.08) compared to mothers non-users of FA in the periconceptional period of pregnancy. Our findings suggest that a high dosage of FA (≥ 1000 µg/day) may be associated with an increased risk of SGA-w at birth.

Development of an MgO-based binder for stabilizing fine sediments and storing CO2.

PubMed

Hwang, Kyung-Yup; Ahn, Jun-Young; Kim, Cheolyong; Seo, Jeong-Yun; Hwang, Inseong

2015-12-01

An MgO-based binder was developed that could stabilize fine dredged sediments for reuse and store CO2. Initially, a binder consisting of fly ash (FA) and blast furnace slag (BFS) was developed by using alkaline activators such as KOH, NaOH, and lime. The FA0.4-BFS0.6 binder (mixed at a FA-to-BFS weight ratio of 4:6) showed the highest compressive strength of 10.7 MPa among FA/BFS binders when 5 M KOH was used. When lime (L) was tested as an alkaline activator, the strength was comparable with those obtained when KOH or NaOH was used. The L0.1-(FA0.4BFS0.6)0.9 binder (10 % lime mixed with the FA/BFS binder) showed the highest strength of 11.0 MPa. Finally, by amending this L0.1-(FA0.4BFS0.6)0.9 binder with MgO, a novel MgO-based binder (MgO0.5-(L0.1-(FA0.4BFS0.6)0.9) 0.5) was developed, which demonstrated the 28th day strength of 11.9 MPa. The MgO-based binder was successfully applied to stabilize a fine sediment to yield a compressive strength of 4.78 MPa in 365 days, which was higher than that obtained by the Portland cement (PC) system (3.22 MPa). Carbon dioxide sequestration was evidenced by three observations: (1) the decrease in pH of the treated sediment from 12.2 to 11.0; (2) the progress of the carbonation front inward the treated sediment; and (3) the presence of magnesium carbonates. The thermogravimetric analysis (TGA) results showed that 67.2 kg of CO2 per ton of the treated sediment could be stored under the atmospheric condition during 1 year.

Analysis of radiological parameters associated with decreased fractional anisotropy values on diffusion tensor imaging in patients with lumbar spinal stenosis.

PubMed

Wang, Xiandi; Wang, Hongli; Sun, Chi; Zhou, Shuyi; Meng, Tao; Lv, Feizhou; Ma, Xiaosheng; Xia, Xinlei; Jiang, Jianyuan

2018-04-26

Previous studies have indicated that decreased fractional anisotropy (FA) values on diffusion tensor imaging (DTI) are well correlated with the symptoms of nerve root compression. The aim of our study is to determine primary radiological parameters associated with decreased FA values in patients with lumbar spinal stenosis involving single L5 nerve root. Patients confirmed with single L5 nerve root compression by transforaminal nerve root blocks were included in this study. FA values of L5 nerve roots on both symptomatic and asymptomatic side were obtained. Conventional radiological parameters, such as disc height, degenerative scoliosis, dural sac cross-sectional area (DSCSA), foraminal height (FH), hypertrophic facet joint degeneration (HFJD), sagittal rotation (SR), sedimentation sign, sagittal translation and traction spur were measured. Correlation and regression analyses were performed between the radiological parameters and FA values of the symptomatic L5 nerve roots. A predictive regression equation was established. Twenty-one patients were included in this study. FA values were significantly lower at the symptomatic side comparing to the asymptomatic side (0.263 ± 0.069 vs. 0.334 ± 0.080, P = 0.038). DSCSA, FH, HFJD, and SR were significantly correlated with the decreased FA values, with r = 0.518, 0.443, 0.472 and - 0.910, respectively (P < 0.05). DSCSA and SR were found to be the primary radiological parameters related to the decreased FA values, and the regression equation is FA = - 0.012 × SR + 0.002 × DSCSA. DSCSA and SR were primary contributors to decreased FA values in LSS patients involving single L5 nerve root, indicating that central canal decompression and segmental stability should be the first considerations in preoperative planning of these patients. These slides can be retrieved under Electronic Supplementary Material.

Fusaric Acid Induces DNA Damage and Post-Translational Modifications of p53 in Human Hepatocellular Carcinoma (HepG2 ) Cells.

PubMed

Ghazi, Terisha; Nagiah, Savania; Tiloke, Charlette; Sheik Abdul, Naeem; Chuturgoon, Anil A

2017-11-01

Fusaric acid (FA), a common fungal contaminant of maize, is known to mediate toxicity in plants and animals; however, its mechanism of action is unclear. p53 is a tumor suppressor protein that is activated in response to cellular stress. The function of p53 is regulated by post-translational modifications-ubiquitination, phosphorylation, and acetylation. This study investigated a possible mechanism of FA induced toxicity in the human hepatocellular carcinoma (HepG 2 ) cell line. The effect of FA on DNA integrity and post-translational modifications of p53 were investigated. Methods included: (a) culture and treatment of HepG 2 cells with FA (IC 50 : 580.32 μM, 24 h); (b) comet assay (DNA damage); (c) Western blots (protein expression of p53, MDM2, p-Ser-15-p53, a-K382-p53, a-CBP (K1535)/p300 (K1499), HDAC1 and p-Ser-47-Sirt1); and (d) Hoechst 33342 assay (apoptosis analysis). FA caused DNA damage in HepG 2 cells relative to the control (P < 0.0001). FA decreased the protein expression of p53 (0.24-fold, P = 0.0004) and increased the expression of p-Ser-15-p53 (12.74-fold, P = 0.0126) and a-K382-p53 (2.24-fold, P = 0.0096). This occurred despite the significant decrease in the histone acetyltransferase, a-CBP (K1535)/p300 (K1499) (0.42-fold, P = 0.0023) and increase in the histone deacetylase, p-Ser-47-Sirt1 (1.22-fold, P = 0.0020). The expression of MDM2, a negative regulator of p53, was elevated in the FA treatment compared to the control (1.83-fold, P < 0.0001). FA also inhibited cell proliferation and induced apoptosis in HepG 2 cells as evidenced by the Hoechst assay. Together, these results indicate that FA is genotoxic and post-translationally modified p53 leading to HepG 2 cell death. J. Cell. Biochem. 118: 3866-3874, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

SU-F-T-118: Characterization of Change in Fractional Anisotropy After Radiation Therapy: Does Nearby Disruption Predict for White Matter Damage?

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

Pettersson, N; Karunamuni, R; Connor, M

Purpose: We investigated predictors of fractional anisotropy (FA) change in the corticospinal white matter tract (CST) following radiation therapy (RT). Methods: Diffusion tensor imaging (DTI) is a non-invasive modality which models water diffusion properties. FA quantifies the extent of directional bias—a decrease indicates disrupted white matter integrity. Fifteen patients with high-grade glioma underwent DTI scans before, and ten months after RT to 59.4–60 Gy. The CST was segmented using an automated atlas-based algorithm on all DTI images. Treatment planning CT and DTI images were aligned using non-linear registration allowing for baseline FA, follow-up FA, and absorbed dose to be determinedmore » in each voxel. Relative FA change was dichotomized into a binary outcome using 25% decrease as cutoff. Three metrics were assessed as predictors: voxel dose, distance from the voxel to the center of the CST (Rc), and the number of neighboring voxels (Nadj from 0 to 26) with ≥25% decrease in FA. Logistic regression and the area under the receiver-operating characteristics curve (AUC) analysis were performed for each patient. Results: Median age of the cohort was 59 years (range: 40–85). The average number of voxels in the CST amongst all patients was 1181 (±172, SD). In logistic regression, the probability of FA change was highly associated with Nadj in all 15 patients with corresponding AUCs between 0.81 and 0.97. With all three metrics included in the logistic regression models, Nadj was highly significant (p<0.001) in all patients, voxel dose significant (p<0.05) in 3/15 patients, and Rc significant in 12/15 patients (p<0.05). Conclusion: The number of neighboring voxels with change in FA was the dominant predictor of FA change at any given voxel. This suggests that the microenvironment of surrounding white matter disruption after radiation therapy may drive local effects along a white matter tract. Pettersson and Cervino are funded by a Varian Medical Systems grant.« less

On a class of Newton-like methods for solving nonlinear equations

NASA Astrophysics Data System (ADS)

Argyros, Ioannis K.

2009-06-01

We provide a semilocal convergence analysis for a certain class of Newton-like methods considered also in [I.K. Argyros, A unifying local-semilocal convergence analysis and applications for two-point Newton-like methods in Banach space, J. Math. Anal. Appl. 298 (2004) 374-397; I.K. Argyros, Computational theory of iterative methods, in: C.K. Chui, L. Wuytack (Eds.), Series: Studies in Computational Mathematics, vol. 15, Elsevier Publ. Co, New York, USA, 2007; J.E. Dennis, Toward a unified convergence theory for Newton-like methods, in: L.B. Rall (Ed.), Nonlinear Functional Analysis and Applications, Academic Press, New York, 1971], in order to approximate a locally unique solution of an equation in a Banach space. Using a combination of Lipschitz and center-Lipschitz conditions, instead of only Lipschitz conditions [F.A. Potra, Sharp error bounds for a class of Newton-like methods, Libertas Math. 5 (1985) 71-84], we provide an analysis with the following advantages over the work in [F.A. Potra, Sharp error bounds for a class of Newton-like methods, Libertas Math. 5 (1985) 71-84] which improved the works in [W.E. Bosarge, P.L. Falb, A multipoint method of third order, J. Optimiz. Theory Appl. 4 (1969) 156-166; W.E. Bosarge, P.L. Falb, Infinite dimensional multipoint methods and the solution of two point boundary value problems, Numer. Math. 14 (1970) 264-286; J.E. Dennis, On the Kantorovich hypothesis for Newton's method, SIAM J. Numer. Anal. 6 (3) (1969) 493-507; J.E. Dennis, Toward a unified convergence theory for Newton-like methods, in: L.B. Rall (Ed.), Nonlinear Functional Analysis and Applications, Academic Press, New York, 1971; H.J. Kornstaedt, Ein allgemeiner Konvergenzstaz fü r verschä rfte Newton-Verfahrem, in: ISNM, vol. 28, Birkhaü ser Verlag, Basel and Stuttgart, 1975, pp. 53-69; P. Laasonen, Ein überquadratisch konvergenter iterativer algorithmus, Ann. Acad. Sci. Fenn. Ser I 450 (1969) 1-10; F.A. Potra, On a modified secant method, L'analyse numérique et la theorie de l'approximation 8 (2) (1979) 203-214; F.A. Potra, An application of the induction method of V. Pták to the study of Regula Falsi, Aplikace Matematiky 26 (1981) 111-120; F.A. Potra, On the convergence of a class of Newton-like methods, in: Iterative Solution of Nonlinear Systems of Equations, in: Lecture Notes in Mathematics, vol. 953, Springer-Verlag, New York, 1982; F.A. Potra, V. Pták, Nondiscrete induction and double step secant method, Math. Scand. 46 (1980) 236-250; F.A. Potra, V. Pták, On a class of modified Newton processes, Numer. Funct. Anal. Optim. 2 (1) (1980) 107-120; F.A. Potra, Sharp error bounds for a class of Newton-like methods, Libertas Math. 5 (1985) 71-84; J.W. Schmidt, Untere Fehlerschranken für Regula-Falsi Verfahren, Period. Math. Hungar. 9 (3) (1978) 241-247; J.W. Schmidt, H. Schwetlick, Ableitungsfreie Verfhren mit höherer Konvergenzgeschwindifkeit, Computing 3 (1968) 215-226; J.F. Traub, Iterative Methods for the Solution of Equations, Prentice Hall, Englewood Cliffs, New Jersey, 1964; M.A. Wolfe, Extended iterative methods for the solution of operator equations, Numer. Math. 31 (1978) 153-174]: larger convergence domain and weaker sufficient convergence conditions. Numerical examples further validating the results are also provided.

Solubility of iron from combustion source particles in acidic media linked to iron speciation.

PubMed

Fu, Hongbo; Lin, Jun; Shang, Guangfeng; Dong, Wenbo; Grassian, Vichi H; Carmichael, Gregory R; Li, Yan; Chen, Jianmin

2012-10-16

In this study, iron solubility from six combustion source particles was investigated in acidic media. For comparison, a Chinese loess (CL) dust was also included. The solubility experiments confirmed that iron solubility was highly variable and dependent on particle sources. Under dark and light conditions, the combustion source particles dissolved faster and to a greater extent relative to CL. Oil fly ash (FA) yielded the highest soluble iron as compared to the other samples. Total iron solubility fractions measured in the dark after 12 h ranged between 2.9 and 74.1% of the initial iron content for the combustion-derived particles (Oil FA > biomass burning particles (BP) > coal FA). Ferrous iron represented the dominant soluble form of Fe in the suspensions of straw BP and corn BP, while total dissolved Fe presented mainly as ferric iron in the cases of oil FA, coal FA, and CL. Mössbauer measurements and TEM analysis revealed that Fe in oil FA was commonly presented as nanosized Fe(3)O(4) aggregates and Fe/S-rich particles. Highly labile source of Fe in corn BP could be originated from amorphous Fe form mixed internally with K-rich particles. However, Fe in coal FA was dominated by the more insoluble forms of both Fe-bearing aluminosilicate glass and Fe oxides. The data presented herein showed that iron speciation varies by source and is an important factor controlling iron solubility from these anthropogenic emissions in acidic solutions, suggesting that the variability of iron solubility from combustion-derived particles is related to the inherent character and origin of the aerosols themselves. Such information can be useful in improving our understanding on iron solubility from combustion aerosols when they undergo acidic processing during atmospheric transport.