ZNF423 and ZNF521: EBF1 Antagonists of Potential Relevance in B-Lymphoid Malignancies

PubMed Central

Mesuraca, Maria; Chiarella, Emanuela; Scicchitano, Stefania; Codispoti, Bruna; Giordano, Marco; Nappo, Giovanna; Bond, Heather M.; Morrone, Giovanni

2015-01-01

The development of the B-lymphoid cell lineage is tightly controlled by the concerted action of a network of transcriptional and epigenetic regulators. EBF1, a central component of this network, is essential for B-lymphoid specification and commitment as well as for the maintenance of the B-cell identity. Genetic alterations causing loss of function of these B-lymphopoiesis regulators have been implicated in the pathogenesis of B-lymphoid malignancies, with particular regard to B-cell acute lymphoblastic leukaemias (B-ALLs), where their presence is frequently detected. The activity of the B-cell regulatory network may also be disrupted by the aberrant expression of inhibitory molecules. In particular, two multi-zinc finger transcription cofactors named ZNF423 and ZNF521 have been characterised as potent inhibitors of EBF1 and are emerging as potentially relevant contributors to the development of B-cell leukaemias. Here we will briefly review the current knowledge of these factors and discuss the importance of their functional cross talk with EBF1 in the development of B-cell malignancies. PMID:26788497

Structural basis for catalytic activation by the human ZNF451 SUMO E3 ligase

DOE PAGES

Cappadocia, Laurent; Pichler, Andrea; Lima, Christopher D.

2015-11-02

E3 protein ligases enhance transfer of ubiquitin-like (Ubl) proteins from E2 conjugating enzymes to substrates by stabilizing the thioester-charged E2~Ubl in a closed configuration optimally aligned for nucleophilic attack. In this paper, we report biochemical and structural data that define the N-terminal domain of the Homo sapiens ZNF451 as the catalytic module for SUMO E3 ligase activity. The ZNF451 catalytic module contains tandem SUMO-interaction motifs (SIMs) bridged by a Pro-Leu-Arg-Pro (PLRP) motif. The first SIM and PLRP motif engage thioester-charged E2~SUMO while the next SIM binds a second molecule of SUMO bound to the back side of E2. We showmore » that ZNF451 is SUMO2 specific and that SUMO modification of ZNF451 may contribute to activity by providing a second molecule of SUMO that interacts with E2. Finally, our results are consistent with ZNF451 functioning as a bona fide SUMO E3 ligase.« less

Structural basis for catalytic activation by the human ZNF451 SUMO E3 ligase

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

Cappadocia, Laurent; Pichler, Andrea; Lima, Christopher D.

E3 protein ligases enhance transfer of ubiquitin-like (Ubl) proteins from E2 conjugating enzymes to substrates by stabilizing the thioester-charged E2~Ubl in a closed configuration optimally aligned for nucleophilic attack. In this paper, we report biochemical and structural data that define the N-terminal domain of the Homo sapiens ZNF451 as the catalytic module for SUMO E3 ligase activity. The ZNF451 catalytic module contains tandem SUMO-interaction motifs (SIMs) bridged by a Pro-Leu-Arg-Pro (PLRP) motif. The first SIM and PLRP motif engage thioester-charged E2~SUMO while the next SIM binds a second molecule of SUMO bound to the back side of E2. We showmore » that ZNF451 is SUMO2 specific and that SUMO modification of ZNF451 may contribute to activity by providing a second molecule of SUMO that interacts with E2. Finally, our results are consistent with ZNF451 functioning as a bona fide SUMO E3 ligase.« less

The schizophrenia risk gene ZNF804A: clinical associations, biological mechanisms and neuronal functions.

PubMed

Chang, H; Xiao, X; Li, M

2017-07-01

ZNF804A (zinc-finger protein 804A) has been recognized as a schizophrenia risk gene across multiple world populations. Its intronic single-nucleotide polymorphism (SNP) rs1344706 is among one of the strongest susceptibility variants that have achieved genome-wide significance in genome-wide association studies (GWAS) for schizophrenia and has been widely and intensively studied. To elucidate the biological mechanisms underlying the genetic risk conferred by rs1344706, we retrospectively analyzed the progresses in brain gene expression quantitative trait loci (eQTL) analyses, ZNF804A-induced pathway alterations in neural cells and changes in synaptic phenotypes associated with ZNF804A expression. Based on these data, we hypothesize a potential biological mechanism for a genetic risk allele of ZNF804A in schizophrenia pathogenesis. We also review the efforts being made to characterize the affected intermediate phenotypes using neuroimaging and neuropsychological approaches. We then discuss additional common and rare ZNF804A variants in schizophrenia susceptibility and the potential genetic heterogeneity of these genomic loci between Europeans and Asians. This review for we believe the first time systematically presents the evidence for ZNF804A, describing its discovery and likely roles in brain development and schizophrenia pathogenesis. We believe that this work has summarized this information with a systemic and broad assessment of recent findings.

Zinc finger protein 219-like (ZNF219L) and Sox9a regulate synuclein-γ2 (sncgb) expression in the developing notochord of zebrafish.

PubMed

Lien, Huang-Wei; Yang, Chung-Hsiang; Cheng, Chia-Hsiung; Liao, Yung-Feng; Han, Yu-San; Huang, Chang-Jen

2013-12-13

Zebrafish synuclein-γ2 (sncgb) has been reported to be expressed specifically in the notochord. However, the mechanism by which the sncgb gene promoter is regulated has not been described. In this paper, we demonstrate that Zinc finger protein 219-like (ZNF219L) and sox9a are involved in the regulation of sncgb gene expression. Furthermore, we observed that over-expression of both ZNF219L and Sox9a resulted in increased sncgb expression. In addition, ZNF219L is physically associated with Sox9a, and simultaneous morpholino knockdown of znf219L and sox9a caused a synergistic decrease of sncgb expression in the notochord. Taken together, our results reveal that coordination of ZNF219L with Sox9a is involved in the regulation of notochord-specific expression of sncgb. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Znf703, a novel target of Pax3 and Zic1, regulates hindbrain and neural crest development in Xenopus.

PubMed

Hong, Chang-Soo; Saint-Jeannet, Jean-Pierre

2017-12-01

The transcription factors Pax3 and Zic1 are critical to specify the neural plate border and to promote neural crest formation. In a microarray screen designed to identify genes regulated by Pax3 and Zic1 in Xenopus we isolated Znf703/Nlz1 a transcriptional repressor member of the NET (NocA/Nlz, Elbow, and TLP-1) protein family. At early neurula stage znf703 is expressed in the dorsal ectoderm, spanning the neural plate and neural plate border, with an anterior boundary of expression corresponding to rhombomeres 3 and 4 (r3/r4) in the prospective hindbrain. As a bonafide target of Pax3 and Zic1, znf703 is activated by neural plate border inducing signals, and its expression depends on Pax3 and Zic1 function in the embryo. Znf703 morpholino-mediated knockdown expanded several posterior hindbrain genes, while Znf703 overexpression completely obliterated the expression of these segmental genes, signifying that the transcriptional repressor activity of Znf703 is critical to pattern the hindbrain. Furthermore, snai2 and sox10 expression was severely impaired upon manipulation of Znf703 expression levels in the embryo suggesting that Znf703 participates in neural crest formation downstream of Pax3 and Zic1 in Xenopus. © 2017 Wiley Periodicals, Inc.

Probing the (110)-Oriented plane of rutile ZnF2: A DFT investigation

NASA Astrophysics Data System (ADS)

Tamijani, Ali Abbaspour; Ebrahimiaqda, Elham

2017-12-01

For many years, rutile-like crystals have given rise to pronounced enthusiasm amongst mineralogists. In this context, rutile-type ZnF2 has found numerous applications across a variety of disciplines, ranging from material sciences to optoelectronics. Surprisingly, very limited literature is concerned with the molecular adsorption on ZnF2 surfaces and related energetics. Additionally, surface probing with small particles is a well-entrenched technique to analyze the interfacial properties. In this regard, small organic species are valuable picks. In the present work, we have employed electronic structure calculations to simulate the adsorption of methane, chloroform, pyrrole, benzene, naphthalene, anthracene, tetracene and pentacene at the (110) plane of rutile ZnF2. Dispersion-corrected DFT method was chosen to predict the binding energies and structures of molecule-adsorbed surfaces. Interestingly, a linear proportionality relationship was found between the binding energies of aromatic adsorbates and their respective molecular lengths. By applying this relationship, we were able to predict the adsorption energy of pentacene on ZnF2 to within 2% of our DFT-based result.

MiR-525-3p Enhances the Migration and Invasion of Liver Cancer Cells by Downregulating ZNF395

PubMed Central

Pang, Fei; Zha, Ruopeng; Zhao, Yingjun; Wang, Qifeng; Chen, Di; Zhang, Zhenfeng; Chen, Taoyang; Yao, Ming; Gu, Jianren; He, Xianghuo

2014-01-01

Liver cancer is one of leading causes of cancer-related deaths. A deeper mechanistic understanding of liver cancer could lead to the development of more effective therapeutic strategies. In our previous work, we screened 646 miRNAs and identified 11 that regulate liver cancer cell migration. The current study shows that miR-525-3p is frequently up-regulated in liver cancer tissues, and enhanced expression of miR-525-3p can promote liver cancer cell migration and invasion. Zinc finger protein 395 (ZNF395) is the direct functional target gene for miR-525-3p, and it is frequently down-regulated in liver cancer tissues. High expression of ZNF395 can significantly inhibit while knockdown of ZNF395 expression can markedly enhance the migration and invasion of liver cancer cells, suggesting that ZNF395 suppresses metastasis in liver cancer. Down-regulation of ZNF395 can mediate miR-525-3p induced liver cancer cell migration and invasion. In conclusion, miR-525-3p promotes liver cancer cell migration and invasion by directly targeting ZNF395, and the fact that miR-525-3p and ZNF395 both play important roles in liver cancer progression makes them potential therapeutic targets. PMID:24599008

Expression of ZNF804A in human brain and alterations in schizophrenia, bipolar disorder, and major depressive disorder: a novel transcript fetally regulated by the psychosis risk variant rs1344706.

PubMed

Tao, Ran; Cousijn, Helena; Jaffe, Andrew E; Burnet, Philip W J; Edwards, Freya; Eastwood, Sharon L; Shin, Joo Heon; Lane, Tracy A; Walker, Mary A; Maher, Brady J; Weinberger, Daniel R; Harrison, Paul J; Hyde, Thomas M; Kleinman, Joel E

2014-10-01

The single-nucleotide polymorphism rs1344706 in the zinc finger protein 804A gene (ZNF804A) shows genome-wide association with schizophrenia and bipolar disorder. Little is known regarding the expression of ZNF804A and the functionality of rs1344706. To characterize ZNF804A expression in human brain and to investigate how it changes across the life span and how it is affected by rs1344706, schizophrenia, bipolar disorder, and major depressive disorder. Molecular and immunochemical methods were used to study ZNF804A messenger RNA (mRNA) and ZNF804A protein, respectively. ZNF804A transcripts were investigated using next-generation sequencing and polymerase chain reaction-based methods, and ZNF804A protein was investigated using Western blots and immunohistochemistry. Samples of dorsolateral prefrontal cortex and inferior parietal lobe tissue were interrogated from 697 participants between 14 weeks' gestational age and age 85 years, including patients with schizophrenia, bipolar disorder, or major depressive disorder. Quantitative measurements of ZNF804A mRNA and immunoreactivity, and the effect of diagnosis and rs1344706 genotype. ZNF804A was expressed across the life span, with highest expression prenatally. An abundant and developmentally regulated truncated ZNF804A transcript was identified, missing exons 1 and 2 (ZNF804AE3E4) and predicted to encode a protein lacking the zinc finger domain. rs1344706 influenced expression of ZNF804AE3E4 mRNA in fetal brain (P = .02). In contrast, full-length ZNF804A showed no association with genotype (P > .05). ZNF804AE3E4 mRNA expression was decreased in patients with schizophrenia (P = .006) and increased in those with major depressive disorder (P < .001), and there was a genotype-by-diagnosis interaction in bipolar disorder (P = .002). ZNF804A immunoreactivity was detected in fetal and adult human cerebral cortex. It was localized primarily to pyramidal neurons, with cytoplasmic as well as dendritic and

Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148.

PubMed

Fang, Jun; Jia, Jinping; Makowski, Matthew; Xu, Mai; Wang, Zhaoming; Zhang, Tongwu; Hoskins, Jason W; Choi, Jiyeon; Han, Younghun; Zhang, Mingfeng; Thomas, Janelle; Kovacs, Michael; Collins, Irene; Dzyadyk, Marta; Thompson, Abbey; O'Neill, Maura; Das, Sudipto; Lan, Qi; Koster, Roelof; Stolzenberg-Solomon, Rachael S; Kraft, Peter; Wolpin, Brian M; Jansen, Pascal W T C; Olson, Sara; McGlynn, Katherine A; Kanetsky, Peter A; Chatterjee, Nilanjan; Barrett, Jennifer H; Dunning, Alison M; Taylor, John C; Newton-Bishop, Julia A; Bishop, D Timothy; Andresson, Thorkell; Petersen, Gloria M; Amos, Christopher I; Iles, Mark M; Nathanson, Katherine L; Landi, Maria Teresa; Vermeulen, Michiel; Brown, Kevin M; Amundadottir, Laufey T

2017-05-02

Genome wide association studies (GWAS) have mapped multiple independent cancer susceptibility loci to chr5p15.33. Here, we show that fine-mapping of pancreatic and testicular cancer GWAS within one of these loci (Region 2 in CLPTM1L) focuses the signal to nine highly correlated SNPs. Of these, rs36115365-C associated with increased pancreatic and testicular but decreased lung cancer and melanoma risk, and exhibited preferred protein-binding and enhanced regulatory activity. Transcriptional gene silencing of this regulatory element repressed TERT expression in an allele-specific manner. Proteomic analysis identifies allele-preferred binding of Zinc finger protein 148 (ZNF148) to rs36115365-C, further supported by binding of purified recombinant ZNF148. Knockdown of ZNF148 results in reduced TERT expression, telomerase activity and telomere length. Our results indicate that the association with chr5p15.33-Region 2 may be explained by rs36115365, a variant influencing TERT expression via ZNF148 in a manner consistent with elevated TERT in carriers of the C allele.

Modulation of gene expression via overlapping binding sites exerted by ZNF143, Notch1 and THAP11

PubMed Central

Ngondo-Mbongo, Richard Patryk; Myslinski, Evelyne; Aster, Jon C.; Carbon, Philippe

2013-01-01

ZNF143 is a zinc-finger protein involved in the transcriptional regulation of both coding and non-coding genes from polymerase II and III promoters. Our study deciphers the genome-wide regulatory role of ZNF143 in relation with the two previously unrelated transcription factors Notch1/ICN1 and thanatos-associated protein 11 (THAP11) in several human and murine cells. We show that two distinct motifs, SBS1 and SBS2, are associated to ZNF143-binding events in promoters of >3000 genes. Without co-occupation, these sites are also bound by Notch1/ICN1 in T-lymphoblastic leukaemia cells as well as by THAP11, a factor involved in self-renewal of embryonic stem cells. We present evidence that ICN1 binding overlaps with ZNF143 binding events at the SBS1 and SBS2 motifs, whereas the overlap occurs only at SBS2 for THAP11. We demonstrate that the three factors modulate expression of common target genes through the mutually exclusive occupation of overlapping binding sites. The model we propose predicts that the binding competition between the three factors controls biological processes such as rapid cell growth of both neoplastic and stem cells. Overall, our study establishes a novel relationship between ZNF143, THAP11 and ICN1 and reveals important insights into ZNF143-mediated gene regulation. PMID:23408857

ZNF9 Activation of IRES-Mediated Translation of the Human ODC mRNA Is Decreased in Myotonic Dystrophy Type 2

PubMed Central

Sammons, Morgan A.; Antons, Amanda K.; Bendjennat, Mourad; Udd, Bjarne; Krahe, Ralf; Link, Andrew J.

2010-01-01

Myotonic dystrophy types 1 and 2 (DM1 and DM2) are forms of muscular dystrophy that share similar clinical and molecular manifestations, such as myotonia, muscle weakness, cardiac anomalies, cataracts, and the presence of defined RNA-containing foci in muscle nuclei. DM2 is caused by an expansion of the tetranucleotide CCTG repeat within the first intron of ZNF9, although the mechanism by which the expanded nucleotide repeat causes the debilitating symptoms of DM2 is unclear. Conflicting studies have led to two models for the mechanisms leading to the problems associated with DM2. First, a gain-of-function disease model hypothesizes that the repeat expansions in the transcribed RNA do not directly affect ZNF9 function. Instead repeat-containing RNAs are thought to sequester proteins in the nucleus, causing misregulation of normal cellular processes. In the alternative model, the repeat expansions impair ZNF9 function and lead to a decrease in the level of translation. Here we examine the normal in vivo function of ZNF9. We report that ZNF9 associates with actively translating ribosomes and functions as an activator of cap-independent translation of the human ODC mRNA. This activity is mediated by direct binding of ZNF9 to the internal ribosome entry site sequence (IRES) within the 5′UTR of ODC mRNA. ZNF9 can activate IRES-mediated translation of ODC within primary human myoblasts, and this activity is reduced in myoblasts derived from a DM2 patient. These data identify ZNF9 as a regulator of cap-independent translation and indicate that ZNF9 activity may contribute mechanistically to the myotonic dystrophy type 2 phenotype. PMID:20174632

Novel Variants in ZNF34 and Other Brain-Expressed Transcription Factors are Shared Among Early-Onset MDD Relatives

PubMed Central

Subaran, Ryan L.; Odgerel, Zagaa; Swaminathan, Rajeswari; Glatt, Charles E.; Weissman, Myrna M.

2018-01-01

There are no known genetic variants with large effects on susceptibility to major depressive disorder (MDD). Although one proposed study approach is to increase sensitivity by increasing sample sizes, another is to focus on families with multiple affected individuals to identify genes with rare or novel variants with strong effects. Choosing the family-based approach, we performed whole-exome analysis on affected individuals (n = 12) across five MDD families, each with at least five affected individuals, early onset, and prepubertal diagnoses. We identified 67 genes where novel deleterious variants were shared among affected relatives. Gene ontology analysis shows that of these 67 genes, 18 encode transcriptional regulators, eight of which are expressed in the human brain, including four KRAB-A box-containing Zn2+ finger repressors. One of these, ZNF34, has been reported as being associated with bipolar disorder and as differentially expressed in bipolar disorder patients compared to healthy controls. We found a novel variant—encoding a non-conservative P17R substitution in the conserved repressor domain of ZNF34 protein—segregating completely with MDD in all available individuals in the family in which it was discovered. Further analysis showed a common ZNF34 coding indel segregating with MDD in a separate family, possibly indicating the presence of an unobserved, linked, rare variant in that particular family. Our results indicate that genes encoding transcription factors expressed in the brain might be an important group of MDD candidate genes and that rare variants in ZNF34 might contribute to susceptibility to MDD and perhaps other affective disorders. PMID:26823146

The ZNF75 zinc finger gene subfamily: Isolation and mapping of the four members in humans and great apes

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

Villa, A.; Strina, D.; Frattini, A.

We have previously reported the characterization of the human ZNF75 gene located on Xq26, which has only limited homology (less than 65%) to other ZF genes in the databases. Here, we describe three human zinc finger genes with 86 to 95% homology to ZNF75 at the nucleotide level, which represent all the members of the human ZNF75 subfamily. One of these, ZNF75B, is a pseudogene mapped to chromosome 12q13. The other two, ZNF75A and ZNF75C, maintain on ORF in the sequenced region, and at least the latter is expressed in the U937 cell line. They were mapped to chromosomes 16more » and 11, respectively. All these genes are conserved in chimpanzees, gorillas, and orangutans. The ZNF75B homologue is a pseudogene in all three great apes, and in chimpanzee it is located on chromosome 10 (phylogenetic XII), at p13 (corresponding to the human 12q13). The chimpanzee homologue of ZNF75 is also located on the Xq26 chromosome, in the same region, as detected by in situ hybridization. As expected, nucleotide changes were clearly more abundant between human and organutan than between human and chimpanzee or gorilla homologues. Members of the same class were more similar to each other than to the other homologues within the same species. This suggests that the duplication and/or retrotranscription events occurred in a common ancestor long before great ape speciation. This, together with the existance of at least two genes in cows and horses, suggests a relatively high conservation of this gene family. 20 refs., 5 figs., 1 tab.« less

Long non-coding RNA ZNF674-1 acts as a cancer suppressor in nasopharyngeal carcinoma.

PubMed

Nie, Guo-Hui; Li, Zhao; Duan, Hong-Fang; Luo, Liang; Hu, Hong-Yi; Chen, Xiao-Fan; Zhang, Wei

2018-06-01

Nasopharyngeal carcinoma (NPC) is the most frequently occurring carcinoma of the head and neck. The complexity of NPC makes it difficult for it to be diagnosed and treated at an early stage. Certain long non-coding RNAs (lncRNAs) are closely associated with the carcinogenesis of NPC. In the present study, the expression of lncRNA ZNF674-1 in NPC tissues and an NPC cell line was analyzed and was revealed to be downregulated compared with normal tissues and cells. When the expression of lncRNA ZNF674-1 was reduced in NPC cells, the proliferation, migration and invasion of these cells was promoted, whereas the apoptosis of these cells was decreased. On the contrary, when overexpressed, the expression of lncRNA ZNF674-1 inhibited the proliferation, invasion and migration of cells, but promoted cell apoptosis. The results of the present study reveal that the lncRNA ZNF67-1 may restrain the carcinogenesis of NPC, and may also serve as a potential biomarker for the early diagnosis and treatment of NPC.

The hematopoietic tumor suppressor interferon regulatory factor 8 (IRF8) is upregulated by the antimetabolite cytarabine in leukemic cells involving the zinc finger protein ZNF224, acting as a cofactor of the Wilms' tumor gene 1 (WT1) protein.

PubMed

Montano, Giorgia; Ullmark, Tove; Jernmark-Nilsson, Helena; Sodaro, Gaetano; Drott, Kristina; Costanzo, Paola; Vidovic, Karina; Gullberg, Urban

2016-01-01

The transcription factor interferon regulatory factor-8 (IRF8) is highly expressed in myeloid progenitors, while most myeloid leukemias show low or absent expression. Loss of IRF8 in mice leads to a myeloproliferative disorder, indicating a tumor-suppressive role of IRF8. The Wilms tumor gene 1 (WT1) protein represses the IRF8-promoter. The zinc finger protein ZNF224 can act as a transcriptional co-factor of WT1 and potentiate the cytotoxic response to the cytostatic drug cytarabine. We hypothesized that cytarabine upregulates IRF8 and that transcriptional control of IRF8 involves WT1 and ZNF224. Treatment of leukemic K562 cells with cytarabine upregulated IRF8 protein and mRNA, which was correlated to increased expression of ZNF224. Knock down of ZNF224 with shRNA suppressed both basal and cytarabine-induced IRF8 expression. While ZNF224 alone did not affect IRF8 promoter activity, ZNF224 partially reversed the suppressive effect of WT1 on the IRF8 promoter, as judged by luciferase reporter experiments. Coprecipitation revealed nuclear binding of WT1 and ZNF224, and by chromatin immunoprecipitation (ChIP) experiments it was demonstrated that WT1 recruits ZNF224 to the IRF8 promoter. We conclude that cytarabine-induced upregulation of the IRF8 in leukemic cells involves increased levels of ZNF224, which can counteract the repressive activity of WT1 on the IRF8-promoter. Copyright © 2015 Elsevier Ltd. All rights reserved.

Common variants in ZNF365 are associated with both mammographic density and breast cancer risk.

PubMed

Lindström, Sara; Vachon, Celine M; Li, Jingmei; Varghese, Jajini; Thompson, Deborah; Warren, Ruth; Brown, Judith; Leyland, Jean; Audley, Tina; Wareham, Nicholas J; Loos, Ruth J F; Paterson, Andrew D; Rommens, Johanna; Waggott, Darryl; Martin, Lisa J; Scott, Christopher G; Pankratz, V Shane; Hankinson, Susan E; Hazra, Aditi; Hunter, David J; Hopper, John L; Southey, Melissa C; Chanock, Stephen J; Silva, Isabel dos Santos; Liu, JianJun; Eriksson, Louise; Couch, Fergus J; Stone, Jennifer; Apicella, Carmel; Czene, Kamila; Kraft, Peter; Hall, Per; Easton, Douglas F; Boyd, Norman F; Tamimi, Rulla M

2011-03-01

High-percent mammographic density adjusted for age and body mass index is one of the strongest risk factors for breast cancer. We conducted a meta analysis of five genome-wide association studies of percent mammographic density and report an association with rs10995190 in ZNF365 (combined P = 9.6 × 10(-10)). Common variants in ZNF365 have also recently been associated with susceptibility to breast cancer.

Association of the variants in the BUD13-ZNF259 genes and the risk of hyperlipidaemia.

PubMed

Aung, Lynn Htet Htet; Yin, Rui-Xing; Wu, Dong-Feng; Wang, Wei; Liu, Cheng-Wu; Pan, Shang-Ling

2014-07-01

The single nucleotide polymorphisms (SNPs) in the BUD13 homolog (BUD13) and zinc finger protein 259 (ZNF259) genes have been associated with one or more serum lipid traits in the European populations. However, little is known about such association in the Chinese populations. Our objectives were to determine the association of the BUD13/ZNF259 SNPs and their haplotypes with hypercholesterolaemia (HCH)/hypertriglyceridaemia (HTG) and to identify the possible gene-gene interactions among these SNPs. Genotyping of 6 SNPs was performed in 634 hyperlipidaemic and 547 normolipidaemic participants. The ZNF259 rs2075290, ZNF259 rs964184 and BUD13 rs10790162 SNPs were significantly associated with serum lipid levels in both HCH and non-HCH populations (P < 0.008-0.001). On single locus analysis, only BUD13 rs10790162 was associated with HCH (OR: 2.23, 95% CI: 1.05, 4.75, P = 0.015). The G-G-A-A-C-C haplotype, carrying rs964184-G-allele, was associated with increased risk of HCH (OR: 1.35, 95% CI: 1.10, 1.66, P = 0.005) and HTG (OR: 1.75, 95% CI: 1.39, 2.21, P = 0.000). The A-C-G-G-C-C and A-C-A-G-T-C haplotypes, carrying rs964184-C-allele, were associated with reduced risk of HCH (OR: 0.77, 95% CI: 0.61, 0.99, P = 0.039 and OR: 0.66, 95% CI: 0.47, 0.94, P = 0.021 respectively). On multifactor dimensionality reduction analyses, the two- to three-locus models showed a significant association with HCH and HTG (P < 0.01-0.001). The BUD13/ZNF259 SNPs, which were significant in the European populations, are also replicable in the Southern Chinese population. Moreover, inter-locus interactions may exist among these SNPs. However, further functional studies are required to clarify how these SNPs and genes actually affect the serum lipid levels. © 2014 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Variability in working memory performance explained by epistasis vs polygenic scores in the ZNF804A pathway.

PubMed

Nicodemus, Kristin K; Hargreaves, April; Morris, Derek; Anney, Richard; Gill, Michael; Corvin, Aiden; Donohoe, Gary

2014-07-01

independent test sets of narrow phenotype psychosis (schizophrenia and schizoaffective disorder), broad psychosis, and control participants (n = 89), the addition of 2 interaction terms containing 2 SNPs each increased the R2 for spatial working memory strategy in the independent psychosis test sets from 1.2% using the polygenic score only to 4.8% (P = .11 and .001, respectively) but did not explain additional variation in control participants. These data support a role for the ZNF804A pathway in IQ, memory, and social cognition in cases. Furthermore, we showed that epistasis increases the variation explained above the contribution of the polygenic score.

Genetic variations in the CLNK gene and ZNF518B gene are associated with gout in case-control sample sets.

PubMed

Jin, Tian-Bo; Ren, Yongchao; Shi, Xugang; Jiri, Mutu; He, Na; Feng, Tian; Yuan, Dongya; Kang, Longli

2015-07-01

A genome-wide association study of gout in European populations identified 12 genetic variants strongly associated with risk of gout, but it is unknown whether these variants are also associated with gout risk in Chinese populations. A total of 145 patients with gout and 310 healthy control patients were recruited for a case-control association study. Twelve SNPs of CLNK and ZNF518B gene were genotyped, and association analysis was performed. Odds ratios (ORs) with 95 % confidence intervals (CIs) were used to assess the association. Overall, we found four risk alleles for gout in patients: the allele "G" of rs2041215 and rs1686947 in the CLNK gene by dominant model (OR 1.66; 95 % CI 1.04-2.63; p = 0.031) (OR 2.19; 95 % CI 1.38-3.46; p = 0.001) and additive model (OR 1.39; 95 % CI 1.00-1.93; p = 0.049) (OR 1.67; 95 % CI 1.19-2.32; p = 0.003), respectively, and the allele "A" of rs10938799 and rs10016022 in ZNF518B gene by recessive model (OR 4.66; 95 % CI 1.44-15.09; p = 0.008) (OR 4.54; 95 % CI 1.23-16.76; p = 0.020). Further haplotype analysis showed that the TCATTCTGA haplotype of CLNK was more frequent among patients with gout (adjusted OR 0.48; 95 % CI 0.24-0.95; p = 0.036). Additionally, polymorphisms of rs2041215, rs10938799, and rs17467273 were also correlated with clinical pathological parameters. This study provides evidence for gout susceptibility genes, CLNK and ZNF518B, in a Chinese population, which may have potential as diagnostic and prognostic marker for gout patients.

Mutations in two large pedigrees highlight the role of ZNF711 in X-linked intellectual disability.

PubMed

van der Werf, Ilse M; Van Dijck, Anke; Reyniers, Edwin; Helsmoortel, Céline; Kumar, Ajay Anand; Kalscheuer, Vera M; de Brouwer, Arjan Pm; Kleefstra, Tjitske; van Bokhoven, Hans; Mortier, Geert; Janssens, Sandra; Vandeweyer, Geert; Kooy, R Frank

2017-03-20

Intellectual disability (ID) affects approximately 1-2% of the general population and is characterized by impaired cognitive abilities. ID is both clinically as well as genetically heterogeneous, up to 2000 genes are estimated to be involved in the emergence of the disease with various clinical presentations. For many genes, only a few patients have been reported and causality of some genes has been questioned upon the discovery of apparent loss-of-function mutations in healthy controls. Description of additional patients strengthens the evidence for the involvement of a gene in the disease and can clarify the clinical phenotype associated with mutations in a particular gene. Here, we present two large four-generation families with a total of 11 males affected with ID caused by mutations in ZNF711, thereby expanding the total number of families with ID and a ZNF711 mutation to four. Patients with mutations in ZNF711 all present with mild to moderate ID and poor speech accompanied by additional features in some patients, including autistic features and mild facial dysmorphisms, suggesting that ZNF711 mutations cause non-syndromic ID. Copyright © 2016 Elsevier B.V. All rights reserved.

ZNF208 polymorphisms associated with ischemic stroke in a southern Chinese Han population.

PubMed

Yu, Jianzhong; Zhou, Feng; Luo, Dong; Wang, Nianzhen; Zhang, Chong; Jin, Tianbo; Liang, Xiongfei; Yu, Dan

2017-01-01

Ischemic stroke is one of the most common diseases with a high burden of neurological deficits, disability and death. Zinc finger protein 208 (ZNF208) was found to be involved in coronary heart disease, although little information is available about its association with ischemic stroke. We performed the present case-control study to clarify the association between single-nucleotide polymorphisms (SNPs) within ZNF208 and the risk of ischemic stroke in a southern Chinese Han population. A total of 799 subjects (400 cases and 399 healthy controls) were enrolled in the present study. Five SNPs within ZNF208 gene were selected and genotyped using Sequenom MassARRY technology (Sequenom, Inc., San Diego, CA, USA). Data management and statistical analyses were conducted using Sequenom Typer, version 4.0, and a chi-squared test, as well as unconditional logistic regression. Statistical results showed that three variants were associated with the risk of ischemic stroke under allele models (rs2188971, rs2188972, rs8103163 and rs7248488). The variant rs2188972 was also associated with the risk of ischemic stroke in a recessive model after adjustment for age and sex. Haplotype analysis suggested that a significant difference existed between the A rs2188972 T rs2188971 A rs8103163 A rs7248488 haplotype and the risk of ischemic stroke, although this disappeared after adjustment for sex and age. The results obtained in the present study indicate a potential association between ZNF208 variants and the risk of ischemic risk in a southern Chinese Han population. Copyright © 2016 John Wiley & Sons, Ltd.

Interactome analysis reveals ZNF804A, a schizophrenia risk gene, as a novel component of protein translational machinery critical for embryonic neurodevelopment

PubMed Central

Zhou, Y; Dong, F; Lanz, T A; Reinhart, V; Li, M; Liu, L; Zou, J; Xi, H S; Mao, Y

2018-01-01

Recent genome-wide association studies identified over 100 genetic loci that significantly associate with schizophrenia (SZ). A top candidate gene, ZNF804A, was robustly replicated in different populations. However, its neural functions are largely unknown. Here we show in mouse that ZFP804A, the homolog of ZNF804A, is required for normal progenitor proliferation and neuronal migration. Using a yeast two-hybrid genome-wide screen, we identified novel interacting proteins of ZNF804A. Rather than transcriptional factors, genes involved in mRNA translation are highly represented in our interactome result. ZNF804A co-fractionates with translational machinery and modulates the translational efficiency as well as the mTOR pathway. The ribosomal protein RPSA interacts with ZNF804A and rescues the migration and translational defects caused by ZNF804A knockdown. RNA immunoprecipitation–RNAseq (RIP-Seq) identified transcripts bound to ZFP804A. Consistently, ZFP804A associates with many short transcripts involved in translational and mitochondrial regulation. Moreover, among the transcripts associated with ZFP804A, a SZ risk gene, neurogranin (NRGN), is one of ZFP804A targets. Interestingly, downregulation of ZFP804A decreases NRGN expression and overexpression of NRGN can ameliorate ZFP804A-mediated migration defect. To verify the downstream targets of ZNF804A, a Duolink in situ interaction assay confirmed genes from our RIP-Seq data as the ZNF804A targets. Thus, our work uncovered a novel mechanistic link of a SZ risk gene to neurodevelopment and translational control. The interactome-driven approach here is an effective way for translating genome-wide association findings into novel biological insights of human diseases. PMID:28924186

High-throughput cell-based screening reveals a role for ZNF131 as a repressor of ERalpha signaling

PubMed Central

Han, Xiao; Guo, Jinhai; Deng, Weiwei; Zhang, Chenying; Du, Peige; Shi, Taiping; Ma, Dalong

2008-01-01

Background Estrogen receptor α (ERα) is a transcription factor whose activity is affected by multiple regulatory cofactors. In an effort to identify the human genes involved in the regulation of ERα, we constructed a high-throughput, cell-based, functional screening platform by linking a response element (ERE) with a reporter gene. This allowed the cellular activity of ERα, in cells cotransfected with the candidate gene, to be quantified in the presence or absence of its cognate ligand E2. Results From a library of 570 human cDNA clones, we identified zinc finger protein 131 (ZNF131) as a repressor of ERα mediated transactivation. ZNF131 is a typical member of the BTB/POZ family of transcription factors, and shows both ubiquitous expression and a high degree of sequence conservation. The luciferase reporter gene assay revealed that ZNF131 inhibits ligand-dependent transactivation by ERα in a dose-dependent manner. Electrophoretic mobility shift assay clearly demonstrated that the interaction between ZNF131 and ERα interrupts or prevents ERα binding to the estrogen response element (ERE). In addition, ZNF131 was able to suppress the expression of pS2, an ERα target gene. Conclusion We suggest that the functional screening platform we constructed can be applied for high-throughput genomic screening candidate ERα-related genes. This in turn may provide new insights into the underlying molecular mechanisms of ERα regulation in mammalian cells. PMID:18847501

A CGG-repeat expansion mutation in ZNF713 causes FRA7A: association with autistic spectrum disorder in two families.

PubMed

Metsu, Sofie; Rainger, Jacqueline K; Debacker, Kim; Bernhard, Birgitta; Rooms, Liesbeth; Grafodatskaya, Daria; Weksberg, Rosanna; Fombonne, Eric; Taylor, Martin S; Scherer, Stephen W; Kooy, R Frank; FitzPatrick, David R

2014-11-01

We report de novo occurrence of the 7p11.2 folate-sensitive fragile site FRA7A in a male with an autistic spectrum disorder (ASD) due to a CGG-repeat expansion mutation (∼450 repeats) in a 5' intron of ZNF713. This expanded allele showed hypermethylation of the adjacent CpG island with reduced ZNF713 expression observed in a proband-derived lymphoblastoid cell line (LCL). His unaffected mother carried an unmethylated premutation (85 repeats). This CGG-repeat showed length polymorphism in control samples (five to 22 repeats). In a second unrelated family, three siblings with ASD and their unaffected father were found to carry FRA7A premutations, which were partially or mosaically methylated. In one of the affected siblings, mitotic instability of the premutation was observed. ZNF713 expression in LCLs in this family was increased in three of these four premutation carriers. A firm link cannot yet be established between ASD and the repeat expansion mutation but plausible pathogenic mechanisms are discussed. © 2014 WILEY PERIODICALS, INC.

The impact of α-Lipoic acid on cell viability and expression of nephrin and ZNF580 in normal human podocytes.

PubMed

Leppert, Ulrike; Gillespie, Allan; Orphal, Miriam; Böhme, Karen; Plum, Claudia; Nagorsen, Kaj; Berkholz, Janine; Kreutz, Reinhold; Eisenreich, Andreas

2017-09-05

Human podocytes (hPC) are essential for maintaining normal kidney function and dysfunction or loss of hPC play a pivotal role in the manifestation and progression of chronic kidney diseases including diabetic nephropathy. Previously, α-Lipoic acid (α-LA), a licensed drug for treatment of diabetic neuropathy, was shown to exhibit protective effects on diabetic nephropathy in vivo. However, the effect of α-LA on hPC under non-diabetic conditions is unknown. Therefore, we analyzed the impact of α-LA on cell viability and expression of nephrin and zinc finger protein 580 (ZNF580) in normal hPC in vitro. Protein analyses were done via Western blot techniques. Cell viability was determined using a functional assay. hPC viability was dynamically modulated via α-LA stimulation in a concentration-dependent manner. This was associated with reduced nephrin and ZNF580 expression and increased nephrin phosphorylation in normal hPC. Moreover, α-LA reduced nephrin and ZNF580 protein expression via 'kappa-light-chain-enhancer' of activated B-cells (NF-κB) inhibition. These data demonstrate that low α-LA had no negative influence on hPC viability, whereas, high α-LA concentrations induced cytotoxic effects on normal hPC and reduced nephrin and ZNF580 expression via NF-κB inhibition. These data provide first novel information about potential cytotoxic effects of α-LA on hPC under non-diabetic conditions. Copyright © 2017 Elsevier B.V. All rights reserved.

Common variants in ZNF365 are associated with both mammographic density and breast cancer risk

PubMed Central

Lindström, Sara; Vachon, Celine M.; Li, Jingmei; Varghese, Jajini; Thompson, Deborah; Warren, Ruth; Brown, Judith; Leyland, Jean; Audley, Tina; Wareham, Nicholas J.; Loos, Ruth J.F.; Paterson, Andrew D.; Waggott, Darryl; Martin, Lisa J.; Scott, Christopher G.; Pankratz, V. Shane; Hankinson, Susan E.; Hazra, Aditi; Hunter, David J.; Hopper, John L.; Southey, Melissa C.; Chanock, Stephen J.; Silva, Isabel dos Santos; Liu, JianJun; Eriksson, Louise; Couch, Fergus J.; Stone, Jennifer; Apicella, Carmel; Czene, Kamila; Kraft, Peter; Hall, Per; Easton, Douglas F.; Boyd, Norman F.; Tamimi, Rulla M.

2011-01-01

High percent mammographic density adjusted for age and body mass index (BMI) is one of the strongest risk factors for breast cancer. We conducted a meta-analysis of five genome-wide association studies of percent mammographic density and report an association with rs10995190 in ZNF365 (combined P=9×6·10−10). This finding might partly explain the underlying biology of the recently discovered association between common variants in ZNF365 and breast cancer risk. PMID:21278746

ZNF804A Variation May Affect Hippocampal-Prefrontal Resting-State Functional Connectivity in Schizophrenic and Healthy Individuals.

PubMed

Zhang, Yuyanan; Yan, Hao; Liao, Jinmin; Yu, Hao; Jiang, Sisi; Liu, Qi; Zhang, Dai; Yue, Weihua

2018-06-01

The ZNF804A variant rs1344706 has consistently been associated with schizophrenia and plays a role in hippocampal-prefrontal functional connectivity during working memory. Whether the effect exists in the resting state and in patients with schizophrenia remains unclear. In this study, we investigated the ZNF804A polymorphism at rs1344706 in 92 schizophrenic patients and 99 healthy controls of Han Chinese descent, and used resting-state functional magnetic resonance imaging to explore the functional connectivity in the participants. We found a significant main effect of genotype on the resting-state functional connectivity (RSFC) between the hippocampus and the dorsolateral prefrontal cortex (DLPFC) in both schizophrenic patients and healthy controls. The homozygous ZNF804A rs1344706 genotype (AA) conferred a high risk of schizophrenia, and also exhibited significantly decreased resting functional coupling between the left hippocampus and right DLPFC (F(2,165) = 13.43, P < 0.001). The RSFC strength was also correlated with cognitive performance and the severity of psychosis in schizophrenia. The current findings identified the neural impact of the ZNF804A rs1344706 on hippocampal-prefrontal RSFC associated with schizophrenia.

MicroRNA-1247 inhibits cell proliferation by directly targeting ZNF346 in childhood neuroblastoma.

PubMed

Wu, Tingting; Lin, Yun; Xie, Zhongguo

2018-05-24

Neuroblastoma (NB) represents the most common extracranial solid tumor in children. Accumulating evidence shows that microRNAs (miRs) play an important role in the carcinogenesis of NB. Here, we investigated the biological function of miR-1247 in NB in vitro. We found miR-1247 was downregulated in NB tissues and cells using quantitative PCR analysis. Gain- and loss-of-function studies demonstrated that miR-1247 significantly suppressed cell proliferation and induced cell cycle G0/G1 phase arrest and cell apoptosis of NB cells in vitro by using MTT, colony formation assay and Flow cytometry analysis. Luciferase assay suggested ZNF346 was the target of miR-1247 and its expression could be downregulated by miR-1247 overexpression using Western blotting. Furthermore, downregulation of ZNF346 by siRNA performed similar effects with overexpression of miR-1247 in NB cells. Our findings suggested miR-1247 directly targeted to repress ZNF346 expression, thus suppressing the progression of NB, which might be a novel therapeutic target against NB.

The genome-wide associated candidate gene ZNF804A and psychosis-proneness: Evidence of sex-modulated association

PubMed Central

de Castro-Catala, Marta; Mora-Solano, Aurea; Kwapil, Thomas R.; Cristóbal-Narváez, Paula; Sheinbaum, Tamara; Racioppi, Anna; Barrantes-Vidal, Neus

2017-01-01

Background The Zinc finger protein 804A (ZNF804A) is a promising candidate gene for schizophrenia and the broader psychosis phenotype that emerged from genome-wide association studies. It is related to neurodevelopment and associated to severe symptoms of schizophrenia and alterations in brain structure, as well as positive schizotypal personality traits in non-clinical samples. Moreover, a female-specific association has been observed between ZNF804A and schizophrenia. Aim The present study examined the association of two ZNF804A polymorphisms (rs1344706 and rs7597593) with the positive dimension of schizotypy and psychotic-like experiences in a sample of 808 non-clinical subjects. Additionally, we wanted to explore whether the sexual differences reported in schizophrenia are also present in psychosis-proneness. Results Our results showed an association between rs7597593 and both schizotypy and psychotic-like experiences. These associations were driven by females, such those carrying the C allele had higher scores in the positive dimension of both variables compared to TT allele homozygotes. Conclusion The findings of the present study support the inclusion of ZNF804 variability in studies of the vulnerability for the development of psychopathology in non-clinical samples and consideration of sex as a moderator of this association. PMID:28931092

Increased expression of zinc finger protein 267 in non-alcoholic fatty liver disease.

PubMed

Schnabl, Bernd; Czech, Barbara; Valletta, Daniela; Weiss, Thomas S; Kirovski, Georgi; Hellerbrand, Claus

2011-01-01

Hepatocellular lipid accumulation is a hallmark of non-alcoholicfatty liver disease (NAFLD), which encompasses a spectrum ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) and ultimately cirrhosis. Zinc finger protein 267 (ZNF267) belongs to the family of Kruppel-like transcription factors, which regulate diverse biological processes that include development, proliferation, and differentiation. We have previously demonstrated that ZNF267 expression is up-regulated in liver cirrhosis and is further increased in hepatocellular carcinoma (HCC). Here, we analyzed the expression of ZNF267 in tissue specimens of NAFLD patients and found a significant up-regulation compared to normal liver tissue. Noteworthy, ZNF267 mRNA was already significantly increased in steatotic liver tissue without inflammation. In line with this, incubation of primary human hepatocytes with palmitic acid induced a dose-dependent lipid accumulation and corresponding dose-dependent ZNF267 induction in vitro. Furthermore, hepatocellular lipid accumulation induced formation of reactive oxygen species (ROS), and also chemically induced ROS formation increased ZNF267 mRNA expression. In summary with previous findings, which revealed ZNF267 as pro-fibrogenic and pro-cancerogenic factor in chronic liver disease, the present study further suggests ZNF267 as promising therapeutic target particularly for NAFLD patients. In addition, it further indicates that hepatic steatosis per se has pathophysiological relevance and should not be considered as benign.

Increased expression of Zinc finger protein 267 in non-alcoholic fatty liver disease

PubMed Central

Schnabl, Bernd; Czech, Barbara; Valletta, Daniela; Weiss, Thomas S; Kirovski, Georgi; Hellerbrand, Claus

2011-01-01

Hepatocellular lipid accumulation is a hallmark of non-alcoholic fatty liver disease (NAFLD), which encompasses a spectrum ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) and ultimately cirrhosis. Zinc finger protein 267 (ZNF267) belongs to the family of Kruppel-like transcription factors, which regulate diverse biological processes that include development, proliferation, and differentiation. We have previously demonstrated that ZNF267 expression is up-regulated in liver cirrhosis and is further increased in hepatocellular carcinoma (HCC). Here, we analyzed the expression of ZNF267 in tissue specimens of NAFLD patients and found a significant up-regulation compared to normal liver tissue. Noteworthy, ZNF267 mRNA was already significantly increased in steatotic liver tissue without inflammation. In line with this, incubation of primary human hepatocytes with palmitic acid induced a dose-dependent lipid accumulation and corresponding dose-dependent ZNF267 induction in vitro. Furthermore, hepatocellular lipid accumulation induced formation of reactive oxygen species (ROS), and also chemically induced ROS formation increased ZNF267 mRNA expression. In summary with previous findings, which revealed ZNF267 as pro-fibrogenic and pro-cancerogenic factor in chronic liver disease, the present study further suggests ZNF267 as promising therapeutic target particularly for NAFLD patients. In addition, it further indicates that hepatic steatosis per se has pathophysiological relevance and should not be considered as benign. PMID:22076166

Circular RNA ZNF609 functions as a competitive endogenous RNA to regulate AKT3 expression by sponging miR-150-5p in Hirschsprung's disease.

PubMed

Peng, Lei; Chen, Guanglin; Zhu, Zhongxian; Shen, Ziyang; Du, Chunxia; Zang, Rujin; Su, Yang; Xie, Hua; Li, Hongxing; Xu, Xiaoqun; Xia, Yankai; Tang, Weibing

2017-01-03

Research over the past decade suggested critical roles for circular RNAs in the natural growth and disease progression. However, it remains poorly defined whether the circular RNAs participate in Hirschsprung disease (HSCR). Here, we reported that the cir-ZNF609 was down-regulated in HSCR compared with normal bowel tissues. Furthermore, suppression of cir-ZNF609 inhibited the proliferation and migration of cells. We screened out several putative cir-ZNF609 ceRNAs of which the AKT3 transcript was selected. Finally, RNA immunoprecipitation and luciferase reporter assays demonstrated that cir-ZNF609 may act as a sponge for miR-150-5p to modulate the expression of AKT3. In conclusion, these findings illustrated that cir-ZNF609 took part in the onset of HSCR through the crosstalk with AKT3 by competing for shared miR-150-5p.

Circ-ZNF609 Is a Circular RNA that Can Be Translated and Functions in Myogenesis.

PubMed

Legnini, Ivano; Di Timoteo, Gaia; Rossi, Francesca; Morlando, Mariangela; Briganti, Francesca; Sthandier, Olga; Fatica, Alessandro; Santini, Tiziana; Andronache, Adrian; Wade, Mark; Laneve, Pietro; Rajewsky, Nikolaus; Bozzoni, Irene

2017-04-06

Circular RNAs (circRNAs) constitute a family of transcripts with unique structures and still largely unknown functions. Their biogenesis, which proceeds via a back-splicing reaction, is fairly well characterized, whereas their role in the modulation of physiologically relevant processes is still unclear. Here we performed expression profiling of circRNAs during in vitro differentiation of murine and human myoblasts, and we identified conserved species regulated in myogenesis and altered in Duchenne muscular dystrophy. A high-content functional genomic screen allowed the study of their functional role in muscle differentiation. One of them, circ-ZNF609, resulted in specifically controlling myoblast proliferation. Circ-ZNF609 contains an open reading frame spanning from the start codon, in common with the linear transcript, and terminating at an in-frame STOP codon, created upon circularization. Circ-ZNF609 is associated with heavy polysomes, and it is translated into a protein in a splicing-dependent and cap-independent manner, providing an example of a protein-coding circRNA in eukaryotes. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

SLC2A9 and ZNF518B polymorphisms correlate with gout-related metabolic indices in Chinese Tibetan populations.

PubMed

Zhang, X Y; Geng, T T; Liu, L J; Yuan, D Y; Feng, T; Kang, L L; Jin, T B; Chen, C

2015-08-19

Current evidence suggests that heredity and metabolic syndrome contribute to gout progression. SLC2A9 and ZNF518B may play a role in gout progression in different populations, but no studies have focused on the Tibetan Chinese population. In this study, we determined whether variations in these 2 genes were correlated with gout-related indices in Chinese-Tibetan gout patients. We detected 6 single nucleotide polymorphisms in SLC2A9 and ZNF518B in 319 Chinese Tibetan gout patients. One-way analysis of variance was used to evaluate the polymorphisms' effects on gout based on mean serum levels of metabolism indicators. Polymorphisms in SLC2A9 and ZNF518B affected multiple risk factors related to gout development. Significant differences in serum triglyceride levels and high-density lipoprotein-cholesterol level were detected between different genotypic groups with SLC2A9 polymorphisms rs13129697 (P = 0.022), rs4447863 (P = 0.018), and rs1014290 (P = 0.045). Similarly in ZNF518B, rs3217 (P = 0.016) and rs10016022 (P = 0.046) were associated with high creatinine and glucose levels, respectively. This study is the first to investigate and identify positive correlations between SLC2A9 and ZNF518B gene polymorphisms and metabolic indices in Tibetan gout patients. We found significant evidence indicating that genetic polymorphisms affect gout-related factors in Chinese Tibetan populations.

The novel 19q13 KRAB zinc-finger tumour suppressor ZNF382 is frequently methylated in oesophageal squamous cell carcinoma and antagonises Wnt/β-catenin signalling.

PubMed

Zhang, Chong; Xiang, Tingxiu; Li, Shuman; Ye, Lin; Feng, Yixiao; Pei, Lijiao; Li, Lili; Wang, Xiangyu; Sun, Ran; Tao, Qian; Ren, Guosheng

2018-05-14

Zinc finger proteins (ZFPs) are the largest transcription factor family in mammals. About one-third of ZFPs are Krüppel-associated box domain (KRAB)-ZFPs and involved in the regulation of cell differentiation/proliferation/apoptosis and neoplastic transformation. We recently identified ZNF382 as a novel KRAB-ZFP epigenetically inactivated in multiple cancers due to frequent promoter CpG methylation. However, its epigenetic alterations, biological functions/mechanism and clinical significance in oesophageal squamous cell carcinoma (ESCC) are still unknown. Here, we demonstrate that ZNF382 expression was suppressed in ESCC due to aberrant promoter methylation, but highly expressed in normal oesophagus tissues. ZNF382 promoter methylation is correlated with ESCC differentiation levels. Restoration of ZNF382 expression in silenced ESCC cells suppressed tumour cell proliferation and metastasis through inducing cell apoptosis. Importantly, ZNF382 suppressed Wnt/β-catenin signalling and downstream target gene expression, likely through binding directly to FZD1 and DVL2 promoters. In summary, our findings demonstrate that ZNF382 functions as a bona fide tumour suppressor inhibiting ESCC pathogenesis through inhibiting the Wnt/β-catenin signalling pathway.

Silencing of cZNF292 circular RNA suppresses human glioma tube formation via the Wnt/β-catenin signaling pathway.

PubMed

Yang, Ping; Qiu, Zhijun; Jiang, Yuan; Dong, Lei; Yang, Wensheng; Gu, Chao; Li, Guang; Zhu, Yu

2016-09-27

CircRNA is a novel type of RNA molecule formed by a covalently closed loop which have no 5'-3' polarity and possess no polyA tail and relatively stable due to the cyclic structure. Therefore, they may serve as potential targets and diagnosis biomarkers for tumor therapy. cZNF292 is an important circular oncogenic RNA and plays a critical role in the progression of tube formation. This study is aimed at exploring the role of cZNF292 in human glioma tube formation and its potential mechanism of action. We found that cZNF292 silencing suppresses tube formation by inhibiting glioma cell proliferation and cell cycle progression. Cell cycle progression in human glioma U87MG and U251 cells was halted at S/G2/M phase via the Wnt/β-catenin signaling pathway and related genes such as PRR11, Cyclin A, p-CDK2, VEGFR-1/2, p-VEGFR-1/2 and EGFR. The results suggest that cZNF292 silencing plays an important role in the tube formation process and has potential for application as a therapeutic target and biomarker in glioma.

The multi-zinc finger protein ZNF217 contacts DNA through a two-finger domain.

PubMed

Nunez, Noelia; Clifton, Molly M K; Funnell, Alister P W; Artuz, Crisbel; Hallal, Samantha; Quinlan, Kate G R; Font, Josep; Vandevenne, Marylène; Setiyaputra, Surya; Pearson, Richard C M; Mackay, Joel P; Crossley, Merlin

2011-11-04

Classical C2H2 zinc finger proteins are among the most abundant transcription factors found in eukaryotes, and the mechanisms through which they recognize their target genes have been extensively investigated. In general, a tandem array of three fingers separated by characteristic TGERP links is required for sequence-specific DNA recognition. Nevertheless, a significant number of zinc finger proteins do not contain a hallmark three-finger array of this type, raising the question of whether and how they contact DNA. We have examined the multi-finger protein ZNF217, which contains eight classical zinc fingers. ZNF217 is implicated as an oncogene and in repressing the E-cadherin gene. We show that two of its zinc fingers, 6 and 7, can mediate contacts with DNA. We examine its putative recognition site in the E-cadherin promoter and demonstrate that this is a suboptimal site. NMR analysis and mutagenesis is used to define the DNA binding surface of ZNF217, and we examine the specificity of the DNA binding activity using fluorescence anisotropy titrations. Finally, sequence analysis reveals that a variety of multi-finger proteins also contain two-finger units, and our data support the idea that these may constitute a distinct subclass of DNA recognition motif.

The Multi-zinc Finger Protein ZNF217 Contacts DNA through a Two-finger Domain*

PubMed Central

Nunez, Noelia; Clifton, Molly M. K.; Funnell, Alister P. W.; Artuz, Crisbel; Hallal, Samantha; Quinlan, Kate G. R.; Font, Josep; Vandevenne, Marylène; Setiyaputra, Surya; Pearson, Richard C. M.; Mackay, Joel P.; Crossley, Merlin

2011-01-01

Classical C2H2 zinc finger proteins are among the most abundant transcription factors found in eukaryotes, and the mechanisms through which they recognize their target genes have been extensively investigated. In general, a tandem array of three fingers separated by characteristic TGERP links is required for sequence-specific DNA recognition. Nevertheless, a significant number of zinc finger proteins do not contain a hallmark three-finger array of this type, raising the question of whether and how they contact DNA. We have examined the multi-finger protein ZNF217, which contains eight classical zinc fingers. ZNF217 is implicated as an oncogene and in repressing the E-cadherin gene. We show that two of its zinc fingers, 6 and 7, can mediate contacts with DNA. We examine its putative recognition site in the E-cadherin promoter and demonstrate that this is a suboptimal site. NMR analysis and mutagenesis is used to define the DNA binding surface of ZNF217, and we examine the specificity of the DNA binding activity using fluorescence anisotropy titrations. Finally, sequence analysis reveals that a variety of multi-finger proteins also contain two-finger units, and our data support the idea that these may constitute a distinct subclass of DNA recognition motif. PMID:21908891

Hypoxia-inducible factors regulate pluripotency factor expression by ZNF217- and ALKBH5-mediated modulation of RNA methylation in breast cancer cells.

PubMed

Zhang, Chuanzhao; Zhi, Wanqing Iris; Lu, Haiquan; Samanta, Debangshu; Chen, Ivan; Gabrielson, Edward; Semenza, Gregg L

2016-10-04

Exposure of breast cancer cells to hypoxia increases the percentage of breast cancer stem cells (BCSCs), which are required for tumor initiation and metastasis, and this response is dependent on the activity of hypoxia-inducible factors (HIFs). We previously reported that exposure of breast cancer cells to hypoxia induces the ALKBH5-mediated demethylation of N6-methyladenosine (m6A) in NANOG mRNA leading to increased expression of NANOG, which is a pluripotency factor that promotes BCSC specification. Here we report that exposure of breast cancer cells to hypoxia also induces ZNF217-dependent inhibition of m6A methylation of mRNAs encoding NANOG and KLF4, which is another pluripotency factor that mediates BCSC specification. Although hypoxia induced the BCSC phenotype in all breast-cancer cell lines analyzed, it did so through variable induction of pluripotency factors and ALKBH5 or ZNF217. However, in every breast cancer line, the hypoxic induction of pluripotency factor and ALKBH5 or ZNF217 expression was HIF-dependent. Immunohistochemistry revealed that expression of HIF-1α and ALKBH5 was concordant in all human breast cancer biopsies analyzed. ALKBH5 knockdown in MDA-MB-231 breast cancer cells significantly decreased metastasis from breast to lungs in immunodeficient mice. Thus, HIFs stimulate pluripotency factor expression and BCSC specification by negative regulation of RNA methylation.

ZNF687 Mutations in Severe Paget Disease of Bone Associated with Giant Cell Tumor

PubMed Central

Divisato, Giuseppina; Formicola, Daniela; Esposito, Teresa; Merlotti, Daniela; Pazzaglia, Laura; Del Fattore, Andrea; Siris, Ethel; Orcel, Philippe; Brown, Jacques P.; Nuti, Ranuccio; Strazzullo, Pasquale; Benassi, Maria Serena; Cancela, M. Leonor; Michou, Laetitia; Rendina, Domenico; Gennari, Luigi; Gianfrancesco, Fernando

2016-01-01

Paget disease of bone (PDB) is a skeletal disorder characterized by focal abnormalities of bone remodeling, which result in enlarged and deformed bones in one or more regions of the skeleton. In some cases, the pagetic tissue undergoes neoplastic transformation, resulting in osteosarcoma and, less frequently, in giant cell tumor of bone (GCT). We performed whole-exome sequencing in a large family with 14 PDB-affected members, four of whom developed GCT at multiple pagetic skeletal sites, and we identified the c.2810C>G (p.Pro937Arg) missense mutation in the zinc finger protein 687 gene (ZNF687). The mutation precisely co-segregated with the clinical phenotype in all affected family members. The sequencing of seven unrelated individuals with GCT associated with PDB (GCT/PDB) identified the same mutation in all individuals, unravelling a founder effect. ZNF687 is highly expressed during osteoclastogenesis and osteoblastogenesis and is dramatically upregulated in the tumor tissue of individuals with GCT/PDB. Interestingly, our preliminary findings showed that ZNF687, indicated as a target gene of the NFkB transcription factor by ChIP-seq analysis, is also upregulated in the peripheral blood of PDB-affected individuals with (n = 5) or without (n = 6) mutations in SQSTM1, encouraging additional studies to investigate its potential role as a biomarker of PDB risk. PMID:26849110

Molecular mapping of four blast resistance genes using recombinant inbred lines of 93-11 and nipponbare

USDA-ARS?s Scientific Manuscript database

Molecular mapping of new blast resistance genes is important for developing resistant rice cultivars using marker-assisted selection. In this study, 259 recombinant inbred lines (RILs) were developed from a cross between Nipponbare and 93-11, and were used to construct a 1165.8-cM linkage map with 1...

Mutation spectrum of the FZD-4, TSPAN12 AND ZNF408 genes in Indian FEVR patients.

PubMed

Musada, Ganeswara Rao; Syed, Hameed; Jalali, Subhadra; Chakrabarti, Subhabrata; Kaur, Inderjeet

2016-06-17

Mutations in candidate genes that encode for a ligand (NDP) and receptor complex (FZD4, LRP5 and TSPAN12) in the Norrin β-catenin signaling pathway are involved in the pathogenesis of familial exudative vitreoretinopathy (FEVR, MIM # 133780). Recently, a transcription factor (ZNF408) has also been implicated in FEVR. We had earlier characterized the variations in NDP among FEVR patients from India. The present study aimed at understanding the involvement of the remaining genes (FZD4, TSPAN12 and ZNF408) in the same cohort. The DNA of 110 unrelated FEVR patients and 115 unaffected controls were screened for variations in the entire coding and untranslated regions of these 3 genes by resequencing. Segregation of the disease-associated variants was assessed in the family members of the probands. The effect of the observed missense changes were further analyzed by SIFT and PolyPhen-2 scores. The screening of FZD4, TSPAN12 and ZNF408 genes identified 11 different mutations in 15/110 FEVR probands. Of the 11 identified mutations, 6 mutations were novel. The detected missense mutations were mainly located in the domains which are functionally crucial for the formation of ligand-receptor complex and as they replaced evolutionarily highly conserved amino acids with a SIFT score < 0.005, they are predicted to be pathogenic. Additionally 2 novel and 16 reported single nucleotide polymorphisms (SNP) were also detected. Our genetic screening revealed varying mutation frequencies in the FZD4 (8.0 %), TSPAN12 (5.4 %) and ZNF408 (2.7 %) genes among the FEVR patients, indicating their potential role in the disease pathogenesis. The observed mutations segregated with the disease phenotype and exhibited variable expressivity. The mutations in FZD4 and TSPAN12 were involved in autosomal dominant and autosomal recessive families and further validates the involvement of these gene in FEVR development.

ZNF687 Mutations in Severe Paget Disease of Bone Associated with Giant Cell Tumor.

PubMed

Divisato, Giuseppina; Formicola, Daniela; Esposito, Teresa; Merlotti, Daniela; Pazzaglia, Laura; Del Fattore, Andrea; Siris, Ethel; Orcel, Philippe; Brown, Jacques P; Nuti, Ranuccio; Strazzullo, Pasquale; Benassi, Maria Serena; Cancela, M Leonor; Michou, Laetitia; Rendina, Domenico; Gennari, Luigi; Gianfrancesco, Fernando

2016-02-04

Paget disease of bone (PDB) is a skeletal disorder characterized by focal abnormalities of bone remodeling, which result in enlarged and deformed bones in one or more regions of the skeleton. In some cases, the pagetic tissue undergoes neoplastic transformation, resulting in osteosarcoma and, less frequently, in giant cell tumor of bone (GCT). We performed whole-exome sequencing in a large family with 14 PDB-affected members, four of whom developed GCT at multiple pagetic skeletal sites, and we identified the c.2810C>G (p.Pro937Arg) missense mutation in the zinc finger protein 687 gene (ZNF687). The mutation precisely co-segregated with the clinical phenotype in all affected family members. The sequencing of seven unrelated individuals with GCT associated with PDB (GCT/PDB) identified the same mutation in all individuals, unravelling a founder effect. ZNF687 is highly expressed during osteoclastogenesis and osteoblastogenesis and is dramatically upregulated in the tumor tissue of individuals with GCT/PDB. Interestingly, our preliminary findings showed that ZNF687, indicated as a target gene of the NFkB transcription factor by ChIP-seq analysis, is also upregulated in the peripheral blood of PDB-affected individuals with (n = 5) or without (n = 6) mutations in SQSTM1, encouraging additional studies to investigate its potential role as a biomarker of PDB risk. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Adaptive Change Inferred from Genomic Population Analysis of the ST93 Epidemic Clone of Community-Associated Methicillin-Resistant Staphylococcus aureus

PubMed Central

Stinear, Timothy P.; Holt, Kathryn E.; Chua, Kyra; Stepnell, Justin; Tuck, Kellie L.; Coombs, Geoffrey; Harrison, Paul Francis; Seemann, Torsten; Howden, Benjamin P.

2014-01-01

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has emerged as a major public health problem around the world. In Australia, ST93-IV[2B] is the dominant CA-MRSA clone and displays significantly greater virulence than other S. aureus. Here, we have examined the evolution of ST93 via genomic analysis of 12 MSSA and 44 MRSA ST93 isolates, collected from around Australia over a 17-year period. Comparative analysis revealed a core genome of 2.6 Mb, sharing greater than 99.7% nucleotide identity. The accessory genome was 0.45 Mb and comprised additional mobile DNA elements, harboring resistance to erythromycin, trimethoprim, and tetracycline. Phylogenetic inference revealed a molecular clock and suggested that a single clone of methicillin susceptible, Panton-Valentine leukocidin (PVL) positive, ST93 S. aureus likely spread from North Western Australia in the early 1970s, acquiring methicillin resistance at least twice in the mid 1990s. We also explored associations between genotype and important MRSA phenotypes including oxacillin MIC and production of exotoxins (α-hemolysin [Hla], δ-hemolysin [Hld], PSMα3, and PVL). High-level expression of Hla is a signature feature of ST93 and reduced expression in eight isolates was readily explained by mutations in the agr locus. However, subtle but significant decreases in Hld were also noted over time that coincided with decreasing oxacillin resistance and were independent of agr mutations. The evolution of ST93 S. aureus is thus associated with a reduction in both exotoxin expression and oxacillin MIC, suggesting MRSA ST93 isolates are under pressure for adaptive change. PMID:24482534

Hyperexpression of α-hemolysin explains enhanced virulence of sequence type 93 community-associated methicillin-resistant Staphylococcus aureus

PubMed Central

2014-01-01

Background The community-associated methicillin-resistant S. aureus (CA-MRSA) ST93 clone is becoming dominant in Australia and is clinically highly virulent. In addition, sepsis and skin infection models demonstrate that ST93 CA-MRSA is the most virulent global clone of S. aureus tested to date. While the determinants of virulence have been studied in other clones of CA-MRSA, the basis for hypervirulence in ST93 CA-MRSA has not been defined. Results Here, using a geographically and temporally dispersed collection of ST93 isolates we demonstrate that the ST93 population hyperexpresses key CA-MRSA exotoxins, in particular α-hemolysin, in comparison to other global clones. Gene deletion and complementation studies, and virulence comparisons in a murine skin infection model, showed unequivocally that increased expression of α-hemolysin is the key staphylococcal virulence determinant for this clone. Genome sequencing and comparative genomics of strains with divergent exotoxin profiles demonstrated that, like other S. aureus clones, the quorum sensing agr system is the master regulator of toxin expression and virulence in ST93 CA-MRSA. However, we also identified a previously uncharacterized AraC/XylS family regulator (AryK) that potentiates toxin expression and virulence in S. aureus. Conclusions These data demonstrate that hyperexpression of α-hemolysin mediates enhanced virulence in ST93 CA-MRSA, and additional control of exotoxin production, in particular α-hemolysin, mediated by regulatory systems other than agr have the potential to fine-tune virulence in CA-MRSA. PMID:24512075

A novel zinc finger protein 219-like (ZNF219L) is involved in the regulation of collagen type 2 alpha 1a (col2a1a) gene expression in zebrafish notochord.

PubMed

Lien, Huang-Wei; Yang, Chung-Hsiang; Cheng, Chia-Hsiung; Hung, Chin-Chun; Liao, Wei-Hao; Hwang, Pung-Pung; Han, Yu-San; Huang, Chang-Jen

2013-01-01

The notochord is required for body plan patterning in vertebrates, and defects in notochord development during embryogenesis can lead to diseases affecting the adult. It is therefore important to elucidate the gene regulatory mechanism underlying notochord formation. In this study, we cloned the zebrafish zinc finger 219-like (ZNF219L) based on mammalian ZNF219, which contains nine C2H2-type zinc finger domains. Through whole-mount in situ hybridization, we found that znf219L mRNA is mainly expressed in the zebrafish midbrain-hindbrain boundary, hindbrain, and notochord during development. The znf219L morpholino knockdown caused partial abnormal notochord phenotype and reduced expression of endogenous col2a1a in the notochord specifically. In addition, ZNF219L could recognize binding sites with GGGGG motifs and trigger augmented activity of the col2a1a promoter in a luciferase assay. Furthermore, in vitro binding experiments revealed that ZNF219L recognizes the GGGGG motifs in the promoter region of the zebrafish col2a1a gene through its sixth and ninth zinc finger domains. Taken together, our results reveal that ZNF219L is involved in regulating the expression of col2a1a in zebrafish notochord specifically.

A Novel Zinc Finger Protein 219-like (ZNF219L) is Involved in the Regulation of Collagen Type 2 Alpha 1a (col2a1a) Gene Expression in Zebrafish Notochord

PubMed Central

Lien, Huang-Wei; Yang, Chung-Hsiang; Cheng, Chia-Hsiung; Hung, Chin-Chun; Liao, Wei-Hao; Hwang, Pung-Pung; Han, Yu-San; Huang, Chang-Jen

2013-01-01

The notochord is required for body plan patterning in vertebrates, and defects in notochord development during embryogenesis can lead to diseases affecting the adult. It is therefore important to elucidate the gene regulatory mechanism underlying notochord formation. In this study, we cloned the zebrafish zinc finger 219-like (ZNF219L) based on mammalian ZNF219, which contains nine C2H2-type zinc finger domains. Through whole-mount in situ hybridization, we found that znf219L mRNA is mainly expressed in the zebrafish midbrain-hindbrain boundary, hindbrain, and notochord during development. The znf219L morpholino knockdown caused partial abnormal notochord phenotype and reduced expression of endogenous col2a1a in the notochord specifically. In addition, ZNF219L could recognize binding sites with GGGGG motifs and trigger augmented activity of the col2a1a promoter in a luciferase assay. Furthermore, in vitro binding experiments revealed that ZNF219L recognizes the GGGGG motifs in the promoter region of the zebrafish col2a1a gene through its sixth and ninth zinc finger domains. Taken together, our results reveal that ZNF219L is involved in regulating the expression of col2a1a in zebrafish notochord specifically. PMID:24155663

A novel long non-coding RNA linc-ZNF469-3 promotes lung metastasis through miR-574-5p-ZEB1 axis in triple negative breast cancer.

PubMed

Wang, Po-Shun; Chou, Cheng-Han; Lin, Cheng-Han; Yao, Yun-Chin; Cheng, Hui-Chuan; Li, Hao-Yi; Chuang, Yu-Chung; Yang, Chia-Ning; Ger, Luo-Ping; Chen, Yu-Chia; Lin, Forn-Chia; Shen, Tang-Long; Hsiao, Michael; Lu, Pei-Jung

2018-05-14

Triple-negative breast cancer (TNBC) patients usually lead to poor prognosis and survival because of metastasis. The major sites for TNBC metastasis include the lungs, brain, liver, and bone. Long non-coding RNAs (lncRNAs) are non-protein-coding transcripts longer than 200 nucleotides and have been reported as important regulators in BC metastasis. However, the underlying mechanisms for lncRNAs regulating TNBC metastasis are not fully understood. Here we found that linc-ZNF469-3 was highly expressed in lung-metastatic LM2-4175 TNBC cells and overexpression of linc-ZNF469-3 enhanced invasion ability and stemness properties in vitro and lung metastasis in vivo. Furthermore, we found linc-ZNF469-3 physically interacted with miR-574-5p and overexpression of miR-574-5p attenuated ZEB1 expression. Importantly, endogenous high expressions of linc-ZNF469-3 and ZEB1 were correlated with tumor recurrence in TNBC patients with lung metastasis. Taken together, our findings suggested that linc-ZNF469-3 promotes lung metastasis of TNBC through miR-574-5p-ZEB1 signaling axis and may be used as potential prognostic marker for TNBC patients.

Complete genome sequence of Flavobacterium psychrophilum strain CSF259-93 used to select rainbow trout for increased genetic resistance against bacterial cold water disease

USDA-ARS?s Scientific Manuscript database

The genome sequence of Flavobacterium psychrophilum strain CSF259-93, isolated from rainbow trout (Oncorhynchus mykiss), consists of a single circular genome of 2,900,735 bp and 2,701 predicted open reading frames (ORFs). Strain CSF259-93 has been used to select a line of rainbow trout with increase...

The E3 ubiquitin ligase and RNA-binding protein ZNF598 orchestrates ribosome quality control of premature polyadenylated mRNAs

PubMed Central

Garzia, Aitor; Jafarnejad, Seyed Mehdi; Meyer, Cindy; Chapat, Clément; Gogakos, Tasos; Morozov, Pavel; Amiri, Mehdi; Shapiro, Maayan; Molina, Henrik; Tuschl, Thomas; Sonenberg, Nahum

2017-01-01

Cryptic polyadenylation within coding sequences (CDS) triggers ribosome-associated quality control (RQC), followed by degradation of the aberrant mRNA and polypeptide, ribosome disassembly and recycling. Although ribosomal subunit dissociation and nascent peptide degradation are well-understood, the molecular sensors of aberrant mRNAs and their mechanism of action remain unknown. We studied the Zinc Finger Protein 598 (ZNF598) using PAR-CLIP and revealed that it cross-links to tRNAs, mRNAs and rRNAs, thereby placing the protein on translating ribosomes. Cross-linked reads originating from AAA-decoding tRNALys(UUU) were 10-fold enriched over its cellular abundance, and poly-lysine encoded by poly(AAA) induced RQC in a ZNF598-dependent manner. Encounter with translated polyA segments by ZNF598 triggered ubiquitination of several ribosomal proteins, requiring the E2 ubiquitin ligase UBE2D3 to initiate RQC. Considering that human CDS are devoid of >4 consecutive AAA codons, sensing of prematurely placed polyA tails by a specialized RNA-binding protein is a novel nucleic-acid-based surveillance mechanism of RQC. PMID:28685749

The E3 ubiquitin ligase and RNA-binding protein ZNF598 orchestrates ribosome quality control of premature polyadenylated mRNAs.

PubMed

Garzia, Aitor; Jafarnejad, Seyed Mehdi; Meyer, Cindy; Chapat, Clément; Gogakos, Tasos; Morozov, Pavel; Amiri, Mehdi; Shapiro, Maayan; Molina, Henrik; Tuschl, Thomas; Sonenberg, Nahum

2017-07-07

Cryptic polyadenylation within coding sequences (CDS) triggers ribosome-associated quality control (RQC), followed by degradation of the aberrant mRNA and polypeptide, ribosome disassembly and recycling. Although ribosomal subunit dissociation and nascent peptide degradation are well-understood, the molecular sensors of aberrant mRNAs and their mechanism of action remain unknown. We studied the Zinc Finger Protein 598 (ZNF598) using PAR-CLIP and revealed that it cross-links to tRNAs, mRNAs and rRNAs, thereby placing the protein on translating ribosomes. Cross-linked reads originating from AAA-decoding tRNA Lys (UUU) were 10-fold enriched over its cellular abundance, and poly-lysine encoded by poly(AAA) induced RQC in a ZNF598-dependent manner. Encounter with translated polyA segments by ZNF598 triggered ubiquitination of several ribosomal proteins, requiring the E2 ubiquitin ligase UBE2D3 to initiate RQC. Considering that human CDS are devoid of >4 consecutive AAA codons, sensing of prematurely placed polyA tails by a specialized RNA-binding protein is a novel nucleic-acid-based surveillance mechanism of RQC.

Circular RNA hsa_circRNA_103809 promotes lung cancer progression via facilitating ZNF121-dependent MYC expression by sequestering miR-4302.

PubMed

Liu, Wei; Ma, Weiming; Yuan, Yuan; Zhang, Youwei; Sun, Sanyuan

2018-06-12

Lung cancer characterized with malignant cell growth is the leading cause of cancer-related deaths. In recent years, several circular RNAs (circRNAs) have been reported to participate in lung cancer progression. However, the correlation between circular RNA (circRNA) and lung cancer still remains to be further investigated. In this study, we screened out a highly expressed circular RNA hsa_circRNA_103809 in lung cancer tissues. We showed hsa_circRNA_103809 could serve as a prognostic biomarker for patients with lung cancer. Furthermore, we found that hsa_circRNA_103809 knockdown significantly suppressed lung cancer cell proliferation and invasion in vitro and delayed tumor growth in vivo. In mechanism, we identified hsa_circRNA_103809 as a sponge of miR-4302 targeting ZNF121. By sequestering miR-4302, hsa_circRNA_103809 promoted the expression of ZNF121 which consequently enhanced MYC protein level in lung cancer cells. Through rescue assays, we demonstrated hsa_circRNA_103809 contributed to lung cancer cell proliferation and invasion via facilitating ZNF121-dependent MYC expression by sponging miR-4302. In conclusion, our findings illustrated a novel hsa_circRNA_103809/miR-4302/ZNF121/MYC regulatory signaling pathway in lung cancer progression. Copyright © 2018 Elsevier Inc. All rights reserved.

Zinc finger protein 598 inhibits cell survival by promoting UV-induced apoptosis.

PubMed

Yang, Qiaohong; Gupta, Romi

2018-01-19

UV is one of the major causes of DNA damage induced apoptosis. However, cancer cells adopt alternative mechanisms to evade UV-induced apoptosis. To identify factors that protect cancer cells from UV-induced apoptosis, we performed a genome wide short-hairpin RNA (shRNA) screen, which identified Zinc finger protein 598 (ZNF598) as a key regulator of UV-induced apoptosis. Here, we show that UV irradiation transcriptionally upregulates ZNF598 expression. Additionally, ZNF598 knockdown in cancer cells inhibited UV-induced apoptosis. In our study, we observe that ELK1 mRNA level as well as phosphorylated ELK1 levels was up regulated upon UV irradiation, which was necessary for UV irradiation induced upregulation of ZNF598. Cells expressing ELK1 shRNA were also resistant to UV-induced apoptosis, and phenocopy ZNF598 knockdown. Upon further investigation, we found that ZNF598 knockdown inhibits UV-induced apoptotic gene expression, which matches with decrease in percentage of annexin V positive cell. Similarly, ectopic expression of ZNF598 promoted apoptotic gene expression and also increased annexin V positive cells. Collectively, these results demonstrate that ZNF598 is a UV irradiation regulated gene and its loss results in resistance to UV-induced apoptosis.

Enhancing caries resistance with a short-pulsed CO2 9.3-μm laser: a laboratory study (Conference Presentation)

NASA Astrophysics Data System (ADS)

Rechmann, Peter; Rechmann, Beate M.; Groves, William H.; Le, Charles; Rapozo-Hilo, Marcia L.; Featherstone, John D. B.

2016-02-01

The objective of this laboratory study was to test whether irradiation with a new 9.3µm microsecond short-pulsed CO2-laser enhances enamel caries resistance with and without additional fluoride applications. 101 human enamel samples were divided into 7 groups. Each group was treated with different laser parameters (Carbon-dioxide laser, wavelength 9.3µm, 43Hz pulse-repetition rate, pulse duration between 3μs to 7μs (1.5mJ/pulse to 2.9mJ/pulse). Using a pH-cycling model and cross-sectional microhardness testing determined the mean relative mineral loss delta Z (∆Z) for each group. The pH-cycling was performed with or without additional fluoride. The CO2 9.3μm short-pulsed laser energy rendered enamel caries resistant with and without additional fluoride use.

A genome-wide RNAi screen identifies novel targets of neratinib resistance leading to identification of potential drug resistant genetic markers.

PubMed

Seyhan, Attila A; Varadarajan, Usha; Choe, Sung; Liu, Wei; Ryan, Terence E

2012-04-01

Neratinib (HKI-272) is a small molecule tyrosine kinase inhibitor of the ErbB receptor family currently in Phase III clinical trials. Despite its efficacy, the mechanism of potential cellular resistance to neratinib and genes involved with it remains unknown. We have used a pool-based lentiviral genome-wide functional RNAi screen combined with a lethal dose of neratinib to discover chemoresistant interactions with neratinib. Our screen has identified a collection of genes whose inhibition by RNAi led to neratinib resistance including genes involved in oncogenesis (e.g. RAB33A, RAB6A and BCL2L14), transcription factors (e.g. FOXP4, TFEC, ZNF), cellular ion transport (e.g. CLIC3, TRAPPC2P1, P2RX2), protein ubiquitination (e.g. UBL5), cell cycle (e.g. CCNF), and genes known to interact with breast cancer-associated genes (e.g. CCNF, FOXP4, TFEC, several ZNF factors, GNA13, IGFBP1, PMEPA1, SOX5, RAB33A, RAB6A, FXR1, DDO, TFEC, OLFM2). The identification of novel mediators of cellular resistance to neratinib could lead to the identification of new or neoadjuvant drug targets. Their use as patient or treatment selection biomarkers could make the application of anti-ErbB therapeutics more clinically effective.

Epigenetic Modification of TLRs in Leukocytes Is Associated with Increased Susceptibility to Salmonella enteritidis in Chickens

PubMed Central

Zhao, Guiping; Zheng, Maiqing; Li, Peng; Wang, Huihua; Zhu, Yun; Chen, Jilan; Wen, Jie

2012-01-01

Toll-like receptors (TLRs) signaling pathways are the first lines in defense against Salmonella enteritidis (S. enteritidis) infection but the molecular mechanism underlying susceptibility to S. enteritidis infection in chicken remains unclear. SPF chickens injected with S. enteritidis were partitioned into two groups, one consisted of those from Salmonella-susceptible chickens (died within 5 d after injection, n = 6), the other consisted of six Salmonella-resistant chickens that survived for 15 d after injection. The present study shows that the bacterial load in susceptible chickens was significantly higher than that in resistant chickens and TLR4, TLR2-1 and TLR21 expression was strongly diminished in the leukocytes of susceptible chickens compared with those of resistant chickens. The induction of expression of pro-inflammatory cytokine genes, IL-6 and IFN-β, was greatly enhanced in the resistant but not in susceptible chickens. Contrasting with the reduced expression of TLR genes, those of the zinc finger protein 493 (ZNF493) gene and Toll-interacting protein (TOLLIP) gene were enhanced in the susceptible chickens. Finally, the expression of TLR4 in peripheral blood mononuclear cells (PBMCs) infected in vitro with S. enteritidis increased significantly as a result of treatment with 5-Aza-2-deoxycytidine (5-Aza-dc) while either 5-Aza-dc or trichostatin A was effective in up-regulating the expression of TLR21 and TLR2-1. DNA methylation, in the predicted promoter region of TLR4 and TLR21 genes, and an exonic CpG island of the TLR2-1 gene was significantly higher in the susceptible chickens than in resistant chickens. Taken together, the results demonstrate that ZNF493-related epigenetic modification in leukocytes probably accounts for increased susceptibility to S. enteritidis in chickens by diminishing the expression and response of TLR4, TLR21 and TLR2-1. PMID:22438967

Recurrent patterns of DNA methylation in the ZNF154, CASP8, and VHL promoters across a wide spectrum of human solid epithelial tumors and cancer cell lines

PubMed Central

Sánchez-Vega, Francisco; Gotea, Valer; Petrykowska, Hanna M; Margolin, Gennady; Krivak, Thomas C; DeLoia, Julie A; Bell, Daphne W; Elnitski, Laura

2013-01-01

The study of aberrant DNA methylation in cancer holds the key to the discovery of novel biological markers for diagnostics and can help to delineate important mechanisms of disease. We have identified 12 loci that are differentially methylated in serous ovarian cancers and endometrioid ovarian and endometrial cancers with respect to normal control samples. The strongest signal showed hypermethylation in tumors at a CpG island within the ZNF154 promoter. We show that hypermethylation of this locus is recurrent across solid human epithelial tumor samples for 15 of 16 distinct cancer types from TCGA. Furthermore, ZNF154 hypermethylation is strikingly present across a diverse panel of ENCODE cell lines, but only in those derived from tumor cells. By extending our analysis from the Illumina 27K Infinium platform to the 450K platform, to sequencing of PCR amplicons from bisulfite treated DNA, we demonstrate that hypermethylation extends across the breadth of the ZNF154 CpG island. We have also identified recurrent hypomethylation in two genomic regions associated with CASP8 and VHL. These three genes exhibit significant negative correlation between methylation and gene expression across many cancer types, as well as patterns of DNaseI hypersensitivity and histone marks that reflect different chromatin accessibility in cancer vs. normal cell lines. Our findings emphasize hypermethylation of ZNF154 as a biological marker of relevance for tumor identification. Epigenetic modifications affecting the promoters of ZNF154, CASP8, and VHL are shared across a vast array of tumor types and may therefore be important for understanding the genomic landscape of cancer. PMID:24149212

Recurrent patterns of DNA methylation in the ZNF154, CASP8, and VHL promoters across a wide spectrum of human solid epithelial tumors and cancer cell lines.

PubMed

Sánchez-Vega, Francisco; Gotea, Valer; Petrykowska, Hanna M; Margolin, Gennady; Krivak, Thomas C; DeLoia, Julie A; Bell, Daphne W; Elnitski, Laura

2013-12-01

The study of aberrant DNA methylation in cancer holds the key to the discovery of novel biological markers for diagnostics and can help to delineate important mechanisms of disease. We have identified 12 loci that are differentially methylated in serous ovarian cancers and endometrioid ovarian and endometrial cancers with respect to normal control samples. The strongest signal showed hypermethylation in tumors at a CpG island within the ZNF154 promoter. We show that hypermethylation of this locus is recurrent across solid human epithelial tumor samples for 15 of 16 distinct cancer types from TCGA. Furthermore, ZNF154 hypermethylation is strikingly present across a diverse panel of ENCODE cell lines, but only in those derived from tumor cells. By extending our analysis from the Illumina 27K Infinium platform to the 450K platform, to sequencing of PCR amplicons from bisulfite treated DNA, we demonstrate that hypermethylation extends across the breadth of the ZNF154 CpG island. We have also identified recurrent hypomethylation in two genomic regions associated with CASP8 and VHL. These three genes exhibit significant negative correlation between methylation and gene expression across many cancer types, as well as patterns of DNaseI hypersensitivity and histone marks that reflect different chromatin accessibility in cancer vs. normal cell lines. Our findings emphasize hypermethylation of ZNF154 as a biological marker of relevance for tumor identification. Epigenetic modifications affecting the promoters of ZNF154, CASP8, and VHL are shared across a vast array of tumor types and may therefore be important for understanding the genomic landscape of cancer.

The brain finger protein gene (ZNF179), a member of the RING finger family, maps within the Smith-Magenis syndrome region at 17p11.2

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

Kimura, Toshiyuki; Arakawa, Yoshiki; Inazawa, Johji

1997-03-31

Smith-Magenis syndrome (SAIS) is caused by a microdeletion of 17p11.2 and comprises developmental and growth delay, facial abnormalities, unusual behavior and sleep problems. This phenotype may be due to haploinsufficiency of several contiguous genes. The human brain finger protein gene (ZNF179), a member of the RING finger protein family, has been isolated and mapped to l7p11.2. FISH analyses of metaphase or interphase chromosomes of 6 patients with SMS show that ZNF179 was deleted in one of the 2 homologs (17p11.2), indicating a possible association of the defect of this gene with the pathogenesis of SMS. Furthermore, using a prophase FISHmore » ordering system, we sublocalized ZNF179 proximally to LLGL which lies on the critical region for SMS. 27 refs., 2 figs.« less

Ampicillin-Resistant Non-β-Lactamase-Producing Haemophilus influenzae in Spain: Recent Emergence of Clonal Isolates with Increased Resistance to Cefotaxime and Cefixime▿

PubMed Central

García-Cobos, Silvia; Campos, José; Lázaro, Edurne; Román, Federico; Cercenado, Emilia; García-Rey, César; Pérez-Vázquez, María; Oteo, Jesús; de Abajo, Francisco

2007-01-01

The sequence of the ftsI gene encoding the transpeptidase domain of penicillin-binding protein 3 (PBP 3) was determined for 354 nonconsecutive Haemophilus influenzae isolates from Spain; 17.8% of them were ampicillin susceptible, 56% were β-lactamase nonproducing ampicillin resistant (BLNAR), 15.8% were β-lactamase producers and ampicillin resistant, and 10.4% displayed both resistance mechanisms. The ftsI gene sequences had 28 different mutation patterns and amino acid substitutions at 23 positions. Some 93.2% of the BLNAR strains had amino acid substitutions at the Lys-Thr-Gly (KTG) motif, the two most common being Asn526 to Lys (83.9%) and Arg517 to His (9.3%). Amino acid substitutions at positions 377, 385, and 389, which conferred cefotaxime and cefixime MICs 10 to 60 times higher than those of susceptible strains, were found for the first time in Europe. In 72 isolates for which the repressor acrR gene of the AcrAB efflux pump was sequenced, numerous amino acid substitutions were found. Eight isolates with ampicillin MICs of 0.25 to 2 μg/ml showed changes that predicted the early termination of the acrR reading frame. Pulsed-field gel electrophoresis analysis demonstrated that most BLNAR strains were genetically diverse, although clonal dissemination was detected in a group of isolates presenting with increased resistance to cefotaxime and cefixime. Background antibiotic use at the community level revealed a marked trend toward increased amoxicillin-clavulanic acid consumption. BLNAR H. influenzae strains have arisen by vertical and horizontal spread and have evolved to adapt rapidly to the increased selective pressures posed by the use of oral penicillins and cephalosporins. PMID:17470649

Co-self-assembly of cationic microparticles to deliver pEGFP-ZNF580 for promoting the transfection and migration of endothelial cells

PubMed Central

Feng, Yakai; Guo, Mengyang; Liu, Wen; Hao, Xuefang; Lu, Wei; Ren, Xiangkui; Shi, Changcan; Zhang, Wencheng

2017-01-01

The gene transfection efficiency of polyethylenimine (PEI) varies with its molecular weight. Usually, high molecular weight of PEI means high gene transfection, as well as high cytotoxicity in gene delivery in vivo. In order to enhance the transfection efficiency and reduce the cytotoxicity of PEI-based gene carriers, a novel cationic gene carrier was developed by co-self-assembly of cationic copolymers. First, a star-shaped copolymer poly(3(S)-methyl-morpholine-2,5-dione-co-lactide) (P(MMD-co-LA)) was synthesized using D-sorbitol as an initiator, and the cationic copolymer (P(MMD-co-LA)-g-PEI) was obtained after grafting low-molecular weight PEI. Then, by co-self-assembly of this cationic copolymer and a diblock copolymer methoxy-poly(ethylene glycol) (mPEG)-b-P(MMD-co-LA), microparticles (MPs) were formed. The core of MPs consisted of a biodegradable block of P(MMD-co-LA), and the shell was formed by mPEG and PEI blocks. Finally, after condensation of pEGFP-ZNF580 by these MPs, the plasmids were protected from enzymatic hydrolysis effectively. The result indicated that pEGFP-ZNF580-loaded MP complexes were suitable for cellular uptake and gene transfection. When the mass ratio of mPEG-b-P(MMD-co-LA) to P(MMD-co-LA)-g-PEI reached 3/1, the cytotoxicity of the complexes was very low at low concentration (20 μg mL−1). Additionally, pEGFP-ZNF580 could be transported into endothelial cells (ECs) effectively via the complexes of MPs/pEGFP-ZNF580. Wound-healing assay showed that the transfected ECs recovered in 24 h. Cationic MPs designed in the present study could be used as an applicable gene carrier for the endothelialization of artificial blood vessels. PMID:28053529

Effects of Polymorphisms in APOA4-APOA5-ZNF259-BUD13 Gene Cluster on Plasma Levels of Triglycerides and Risk of Coronary Heart Disease in a Chinese Han Population

PubMed Central

Su, Li; Zhang, Mingjun; Wang, Long; Jing, Jinjin; Zhou, Li

2015-01-01

Background/Aim Recent genome-wide association studies have identified several loci influencing lipid levels. The present study focused on the triglycerides (TG)-associated locus, the APOA4-APOA5-ZNF259-BUD13 gene cluster on chromosome 11, to explore the role of genetic variants in this gene cluster in the development of increasing TG levels and coronary heart disease (CHD). Methodology/Principal Findings Six single nucleotide polymorphisms (SNPs), rs4417316, rs651821, rs6589566, rs7396835, rs964184 and rs17119975, in the APOA4-APOA5-ZNF259-BUD13 gene cluster were selected and genotyped in 5374 healthy Chinese subjects. There were strong significant associations between the six SNPs and TG levels (P<1.0×10−8). Moreover, a weighted genotype score was found to be associated with TG levels (P = 3.28×10−13). The frequencies of three common haplotypes were observed to be significantly different between the high TG group and the low TG group (P<0.05). However, no significant effects were found for the SNPs regarding susceptibility to CHD in the Chinese case-control populations. Conclusions/Significance This study highlights the genotypes, genotype scores and haplotypes of the APOA4-APOA5-ZNF259-BUD13 gene cluster that were associated with TG levels in a Chinese population; however, the genetic variants in this gene cluster did not increase the risk of CHD in the Chinese population. PMID:26397108

Relationship of ZNF423 and CTSO with breast cancer risk in two randomised tamoxifen prevention trials.

PubMed

Brentnall, Adam R; Cuzick, Jack; Byers, Helen; Segal, Corrinne; Reuter, Caroline; Detre, Simone; Sestak, Ivana; Howell, Anthony; Powles, Trevor J; Newman, William G; Dowsett, Mitchell

2016-08-01

A case-control study from two randomised breast cancer prevention trials of tamoxifen and raloxifene (P-1 and P-2) identified single-nucleotide polymorphisms (SNPs) in or near genes ZNF423 and CTSO as factors which predict which women will derive most anti-cancer benefit from selective oestrogen receptor modulator (SERM) therapy. In this article, we further examine this question using blood samples from two randomised tamoxifen prevention trials: the International Breast Cancer Intervention Study I (IBIS-I) and the Royal Marsden trial (Marsden). A nested case-control study was designed with 2:1 matching in IBIS-I and 1:1 matching in Marsden. The OncoArray was used for genotyping and included two SNPs previously identified (rs8060157 in ZNF423 and rs10030044 near CTSO), and 102 further SNPs within the same regions. Overall, there were 369 cases and 662 controls, with 148 cases and 268 controls from the tamoxifen arms. Odds ratios were estimated by conditional logistic regression, with Wald 95 % confidence intervals. In the tamoxifen arms, the per-allele odds ratio for rs8060157 was 0.99 (95 %CI 0.73-1.34) and 1.00 (95 %CI 0.76-1.33) for rs10030044. In the placebo arm, the odds ratio was 1.10 (95 %CI 0.87-1.40) for rs8060157 and 1.01 (95 %CI 0.79-1.29) for rs10030044. There was no evidence to suggest that other SNPs in the surrounding regions of these SNPs might predict response to tamoxifen. Results from these two prevention trials do not support the earlier findings. rs8060157 in ZNF423 and rs10030044 near CTSO do not appear to predict response to tamoxifen.

Molecular Pap smear: HPV genotype and DNA methylation of ADCY8, CDH8, and ZNF582 as an integrated biomarker for high-grade cervical cytology.

PubMed

Shen-Gunther, Jane; Wang, Chiou-Miin; Poage, Graham M; Lin, Chun-Lin; Perez, Luis; Banks, Nancy A; Huang, Tim Hui-Ming

2016-01-01

The Pap smear has remained the foundation for cervical cancer screening for over 70 years. With advancements in molecular diagnostics, primary high-risk human papillomavirus (hrHPV) screening has recently become an accepted stand-alone or co-test with conventional cytology. However, both diagnostic tests have distinct limitations. The aim of this study was to determine the association between HPV genotypes and cellular epigenetic modifications in three grades of cervical cytology for screening biomarker discovery. This prospective, cross-sectional study used residual liquid-based cytology samples for HPV genotyping and epigenetic analysis. Extracted DNA was subjected to parallel polymerase chain reactions using three primer sets (MY09/11, FAP59/64, E6-E7 F/B) for HPV DNA amplification. HPV+ samples were genotyped by DNA sequencing. Promoter methylation of four candidate tumor suppressor genes (adenylate cyclase 8 (ADCY8), cadherin 8, type 2 (CDH8), MGMT, and zinc finger protein 582 (ZNF582)) out of 48 genes screened was quantified by bisulfite-pyrosequencing of genomic DNA. Independent validation of methylation profiles was performed by analyzing data from cervical cancer cell lines and clinical samples from The Cancer Genome Atlas (TCGA). Two hundred seventy-seven quality cytology samples were analyzed. HPV was detected in 31/100 (31 %) negative for intraepithelial lesion or malignancy (NILM), 95/100 (95 %) low-grade squamous intraepithelial lesion (LSIL), and 71/77 (92 %) high-grade squamous intraepithelial lesion (HSIL) samples. The proportion of IARC-defined carcinogenic HPV types in sequenced samples correlated with worsening grade: NILM 7/29 (24 %), LSIL 53/92 (58 %), and HSIL 65/70 (93 %). Promoter methylation of ADCY8, CDH8, and ZNF582 was measured in 170 samples: NILM (N = 33), LSIL (N = 70), and HSIL (N = 67) also correlated with worsening grade. Similar hypermethylation patterns were found in cancer cell lines and TCGA samples. The

Direct Downregulation of B-Cell Translocation Gene 3 by microRNA-93 Is Required for Desensitizing Esophageal Cancer to Radiotherapy.

PubMed

Cui, Hujun; Zhang, Shengqiang; Zhou, Hongbo; Guo, Ling

2017-08-01

Esophageal squamous carcinoma (ESC) is one of the most fatal malignancies worldwide with increasing occurrences yet poor outcome. MicroRNAs were reported to play roles in ESC. We aimed to understand how miRNAs affect the radiotherapy resistance of ESC. MicroRNA assays, real-time PCR, and Western blot were performed for expression analysis of miR-93 and BTG3. Luciferase activity assay was conducted with mutated B-cell translocation gene 3 (BTG3) 3'-UTR sequence in the 3' end of luciferase sequence with miR-93 inhibitor. ESC cells were treated with irradiation (IR) and clonogenic assay was utilized to detect the cell viability. Human ESC xenograft mouse model was established and subjected to target IR treatment followed by tumor size analysis. MiR-93 was decreased and BTG3 was increased in ESC cells, with negative correlation of their expression in ESC tissues. MiR-93 directly targeted BTG3 3'-UTR by luciferase activity assay. Either miR-93 inhibition or BTG3 overexpression decreased radiation resistance. Furthermore, miR-93 inhibition suppressed radiation resistance through BTG3. Direct downregulation of BTG3 by miR-93 is able to render ESC resistant to radiotherapy, and both BTG3 and miR-93 may potentially serve as clinical markers for ESC and contribute to the treatment of ESC.

Systematic Integration of Brain eQTL and GWAS Identifies ZNF323 as a Novel Schizophrenia Risk Gene and Suggests Recent Positive Selection Based on Compensatory Advantage on Pulmonary Function.

PubMed

Luo, Xiong-Jian; Mattheisen, Manuel; Li, Ming; Huang, Liang; Rietschel, Marcella; Børglum, Anders D; Als, Thomas D; van den Oord, Edwin J; Aberg, Karolina A; Mors, Ole; Mortensen, Preben Bo; Luo, Zhenwu; Degenhardt, Franziska; Cichon, Sven; Schulze, Thomas G; Nöthen, Markus M; Su, Bing; Zhao, Zhongming; Gan, Lin; Yao, Yong-Gang

2015-11-01

Genome-wide association studies have identified multiple risk variants and loci that show robust association with schizophrenia. Nevertheless, it remains unclear how these variants confer risk to schizophrenia. In addition, the driving force that maintains the schizophrenia risk variants in human gene pool is poorly understood. To investigate whether expression-associated genetic variants contribute to schizophrenia susceptibility, we systematically integrated brain expression quantitative trait loci and genome-wide association data of schizophrenia using Sherlock, a Bayesian statistical framework. Our analyses identified ZNF323 as a schizophrenia risk gene (P = 2.22×10(-6)). Subsequent analyses confirmed the association of the ZNF323 and its expression-associated single nucleotide polymorphism rs1150711 in independent samples (gene-expression: P = 1.40×10(-6); single-marker meta-analysis in the combined discovery and replication sample comprising 44123 individuals: P = 6.85×10(-10)). We found that the ZNF323 was significantly downregulated in hippocampus and frontal cortex of schizophrenia patients (P = .0038 and P = .0233, respectively). Evidence for pleiotropic effects was detected (association of rs1150711 with lung function and gene expression of ZNF323 in lung: P = 6.62×10(-5) and P = 9.00×10(-5), respectively) with the risk allele (T allele) for schizophrenia acting as protective allele for lung function. Subsequent population genetics analyses suggest that the risk allele (T) of rs1150711 might have undergone recent positive selection in human population. Our findings suggest that the ZNF323 is a schizophrenia susceptibility gene whose expression may influence schizophrenia risk. Our study also illustrates a possible mechanism for maintaining schizophrenia risk variants in the human gene pool. © The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please

Systematic Integration of Brain eQTL and GWAS Identifies ZNF323 as a Novel Schizophrenia Risk Gene and Suggests Recent Positive Selection Based on Compensatory Advantage on Pulmonary Function

PubMed Central

Luo, Xiong-Jian; Mattheisen, Manuel; Li, Ming; Huang, Liang; Rietschel, Marcella; Børglum, Anders D.; Als, Thomas D.; van den Oord, Edwin J.; Aberg, Karolina A.; Mors, Ole; Mortensen, Preben Bo; Luo, Zhenwu; Degenhardt, Franziska; Cichon, Sven; Schulze, Thomas G.; Nöthen, Markus M.; Su, Bing; Zhao, Zhongming; Gan, Lin; Yao, Yong-Gang

2015-01-01

Genome-wide association studies have identified multiple risk variants and loci that show robust association with schizophrenia. Nevertheless, it remains unclear how these variants confer risk to schizophrenia. In addition, the driving force that maintains the schizophrenia risk variants in human gene pool is poorly understood. To investigate whether expression-associated genetic variants contribute to schizophrenia susceptibility, we systematically integrated brain expression quantitative trait loci and genome-wide association data of schizophrenia using Sherlock, a Bayesian statistical framework. Our analyses identified ZNF323 as a schizophrenia risk gene (P = 2.22×10–6). Subsequent analyses confirmed the association of the ZNF323 and its expression-associated single nucleotide polymorphism rs1150711 in independent samples (gene-expression: P = 1.40×10–6; single-marker meta-analysis in the combined discovery and replication sample comprising 44123 individuals: P = 6.85×10−10). We found that the ZNF323 was significantly downregulated in hippocampus and frontal cortex of schizophrenia patients (P = .0038 and P = .0233, respectively). Evidence for pleiotropic effects was detected (association of rs1150711 with lung function and gene expression of ZNF323 in lung: P = 6.62×10–5 and P = 9.00×10–5, respectively) with the risk allele (T allele) for schizophrenia acting as protective allele for lung function. Subsequent population genetics analyses suggest that the risk allele (T) of rs1150711 might have undergone recent positive selection in human population. Our findings suggest that the ZNF323 is a schizophrenia susceptibility gene whose expression may influence schizophrenia risk. Our study also illustrates a possible mechanism for maintaining schizophrenia risk variants in the human gene pool. PMID:25759474

Antibiotic resistance increases with local temperature

NASA Astrophysics Data System (ADS)

MacFadden, Derek R.; McGough, Sarah F.; Fisman, David; Santillana, Mauricio; Brownstein, John S.

2018-06-01

Bacteria that cause infections in humans can develop or acquire resistance to antibiotics commonly used against them1,2. Antimicrobial resistance (in bacteria and other microbes) causes significant morbidity worldwide, and some estimates indicate the attributable mortality could reach up to 10 million by 20502-4. Antibiotic resistance in bacteria is believed to develop largely under the selective pressure of antibiotic use; however, other factors may contribute to population level increases in antibiotic resistance1,2. We explored the role of climate (temperature) and additional factors on the distribution of antibiotic resistance across the United States, and here we show that increasing local temperature as well as population density are associated with increasing antibiotic resistance (percent resistant) in common pathogens. We found that an increase in temperature of 10 °C across regions was associated with an increases in antibiotic resistance of 4.2%, 2.2%, and 2.7% for the common pathogens Escherichia coli, Klebsiella pneumoniae and Staphylococcus aureus. The associations between temperature and antibiotic resistance in this ecological study are consistent across most classes of antibiotics and pathogens and may be strengthening over time. These findings suggest that current forecasts of the burden of antibiotic resistance could be significant underestimates in the face of a growing population and climate change4.

The impact of CACNA1C gene, and its epistasis with ZNF804A, on white matter microstructure in health, schizophrenia and bipolar disorder1.

PubMed

Mallas, E; Carletti, F; Chaddock, C A; Shergill, S; Woolley, J; Picchioni, M M; McDonald, C; Toulopoulou, T; Kravariti, E; Kalidindi, S; Bramon, E; Murray, R; Barker, G J; Prata, D P

2017-04-01

Genome-wide studies have identified allele A (adenine) of single nucleotide polymorphism (SNP) rs1006737 of the calcium-channel CACNA1C gene as a risk factor for both schizophrenia (SZ) and bipolar disorder (BD) as well as allele A for rs1344706 in the ZNF804A gene. These illnesses have also been associated with white matter abnormalities, reflected by reductions in fractional anisotropy (FA), measured using diffusion tensor imaging (DTI). We assessed the impact of the CACNA1C psychosis risk variant on FA in SZ, BD and health. 230 individuals (with existing ZNF804A rs1344706 genotype data) were genotyped for CACNA1C rs1006737 and underwent DTI. FA data was analysed with tract-based spatial statistics and threshold-free cluster enhancement significance correction (P < 0.05) to detect effects of CACNA1C genotype on FA, and its potential interaction with ZNF804A genotype and with diagnosis, on FA. There was no significant main effect of the CACNA1C genotype on FA, nor diagnosis by genotype(s) interactions. Nevertheless, when inspecting SZ in particular, risk allele carriers had significantly lower FA than the protective genotype individuals, in portions of the left middle occipital and parahippocampal gyri, right cerebellum, left optic radiation and left inferior and superior temporal gyri. Our data suggests a minor involvement of CACNA1C rs1006737 in psychosis via conferring susceptibility to white matter microstructural abnormalities in SZ. Put in perspective, ZNF804A rs1344706, not only had a significant main effect, but its SZ-specific effects were two orders of magnitude more widespread than that of CACNA1C rs1006737. © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Theoretical study of local structure for Ni2+ ions at tetragonal sites in K2ZnF4:Ni2+ system.

PubMed

Wang, Su-Juan; Kuang, Xiao-Yu; Lu, Cheng

2008-12-15

A theoretical method for studying the local lattice structure of Ni2+ ions in (NiF6)(4-) coordination complex is presented. Using the ligand-field model, the formulas relating the microscopic spin Hamiltonian parameters with the crystal structure parameters are derived. Based on the theoretical formulas, the 45 x 45 complete energy matrices for d8 (d2) configuration ions in a tetragonal ligand-field are constructed. By diagonalizing the complete energy matrices, the local distortion structure parameters (R perpendicular and R || ) of Ni2+ ions in K2ZnF4:Ni2+ system have been investigated. The theoretical results are accorded well with the experimental values. Moreover, to understand the detailed physical and chemical properties of the fluoroperovskite crystals, the theoretical values of the g factor of K2ZnF4:Ni2+ system at 78 and 290 K are reported first.

Theoretical study of local structure for Ni 2+ ions at tetragonal sites in K 2ZnF 4:Ni 2+ system

NASA Astrophysics Data System (ADS)

Wang, Su-Juan; Kuang, Xiao-Yu; Lu, Cheng

2008-12-01

A theoretical method for studying the local lattice structure of Ni 2+ ions in (NiF 6) 4- coordination complex is presented. Using the ligand-field model, the formulas relating the microscopic spin Hamiltonian parameters with the crystal structure parameters are derived. Based on the theoretical formulas, the 45 × 45 complete energy matrices for d8 ( d2) configuration ions in a tetragonal ligand-field are constructed. By diagonalizing the complete energy matrices, the local distortion structure parameters ( R⊥ and R||) of Ni 2+ ions in K 2ZnF 4:Ni 2+ system have been investigated. The theoretical results are accorded well with the experimental values. Moreover, to understand the detailed physical and chemical properties of the fluoroperovskite crystals, the theoretical values of the g factor of K 2ZnF 4:Ni 2+ system at 78 and 290 K are reported first.

Inhaled corticosteroid treatment modulates ZNF432 gene variant's effect on bronchodilator response in asthmatics

PubMed Central

Wu, Ann C.; Himes, Blanca E.; Lasky-Su, Jessica; Litonjua, Augusto; Peters, Stephen P.; Lima, John; Kubo, Michiaki; Tamari, Mayumi; Nakamura, Yusuke; Qiu, Weiliang; Weiss, Scott T.; Tantisira, Kelan

2013-01-01

Background Single nucleotide polymorphisms (SNPs) influence a patient's response to inhaled corticosteroids and β2-agonists, and the effect of treatment with inhaled corticosteroids is synergistic with the effect of β2-agonists. We hypothesized that use of inhaled corticosteroids could influence the effect of SNPs associated with bronchodilator response. Objective To assess whether, among asthma subjects, the association of SNPs with bronchodilator response is different between those treated with inhaled corticosteroids vs. those on placebo. Methods A genome-wide association analysis was conducted using 581 white subjects from the Childhood Asthma Management Program (CAMP). Using data for 449,540 SNPs, we conducted a gene by environment analysis in PLINK with inhaled corticosteroid treatment as the environmental exposure and bronchodilator response as the outcome measure. We attempted to replicate the top 12 SNPs in the Leukotriene Modifier Or Corticosteroid or Corticosteroid-Salmeterol (LOCCS) Trial. Results The combined P-value for the CAMP and LOCCS populations was 4.81E-08 for rs3752120, which is located in the zinc finger protein gene ZNF432, and has unknown function. Conclusions Inhaled corticosteroids appear to modulate the association of bronchodilator response with variant(s) in the ZNF432 gene among adults and children with asthma. Clinical Implications Clinicians who treat asthma patients with inhaled corticosteroids should be aware that the patient's genetic makeup likely influences response as measured in lung function. Capsule Summary Our study suggests that inhaled corticosteroids could influence the effect of multiple SNPs associated with bronchodilator response across the genome. PMID:24280104

Increased platelet expression of glycoprotein IIIa following aspirin treatment in aspirin-resistant but not aspirin-sensitive subjects.

PubMed

Floyd, Christopher N; Goodman, Timothy; Becker, Silke; Chen, Nan; Mustafa, Agnesa; Schofield, Emma; Campbell, James; Ward, Malcolm; Sharma, Pankaj; Ferro, Albert

2014-08-01

Aspirin is widely used as an anti-platelet agent for cardiovascular prophylaxis. Despite aspirin treatment, many patients experience recurrent thrombotic events, and aspirin resistance may contribute to this. We examined the prevalence of aspirin resistance in a healthy population, and investigated whether the platelet proteome differed in aspirin-resistant subjects. Ninety-three healthy subjects received aspirin 300 mg daily for 28 days. Before and at the end of treatment, urine was taken to determine 11-dehydrothromboxane B2 , and blood was taken to measure arachidonic acid (AA)-induced aggregation of platelet-rich plasma and to interrogate the platelet proteome by mass spectrometric analysis with further confirmation of findings using Western blotting. In two of the 93 subjects, neither AA-induced aggregation nor urinary 11-dehydrothromboxane B2 was effectively suppressed by aspirin, despite measurable plasma salicylate concentrations, suggesting the presence of true aspirin resistance. Despite no detectable differences in the platelet proteome at baseline, following aspirin a marked increase was seen in platelet glycoprotein IIIa expression in the aspirin-resistant but not aspirin-sensitive subjects. An increase in platelet glycoprotein IIIa expression with aspirin resistance was confirmed in a separate cohort of 17 patients with stable coronary artery disease on long term aspirin treatment, four of whom exhibited aspirin resistance. In a healthy population, true aspirin resistance is uncommon but exists. Resistance is associated with an increase in platelet glycoprotein IIIa expression in response to aspirin. These data shed new light on the mechanism of aspirin resistance, and provide the potential to identify aspirin-resistant subjects using a novel biomarker. © 2014 The British Pharmacological Society.

Increased platelet expression of glycoprotein IIIa following aspirin treatment in aspirin-resistant but not aspirin-sensitive subjects

PubMed Central

Floyd, Christopher N; Goodman, Timothy; Becker, Silke; Chen, Nan; Mustafa, Agnesa; Schofield, Emma; Campbell, James; Ward, Malcolm; Sharma, Pankaj; Ferro, Albert

2014-01-01

Aims Aspirin is widely used as an anti-platelet agent for cardiovascular prophylaxis. Despite aspirin treatment, many patients experience recurrent thrombotic events, and aspirin resistance may contribute to this. We examined the prevalence of aspirin resistance in a healthy population, and investigated whether the platelet proteome differed in aspirin-resistant subjects. Methods Ninety-three healthy subjects received aspirin 300 mg daily for 28 days. Before and at the end of treatment, urine was taken to determine 11-dehydrothromboxane B2, and blood was taken to measure arachidonic acid (AA)-induced aggregation of platelet-rich plasma and to interrogate the platelet proteome by mass spectrometric analysis with further confirmation of findings using Western blotting. Results In two of the 93 subjects, neither AA-induced aggregation nor urinary 11-dehydrothromboxane B2 was effectively suppressed by aspirin, despite measurable plasma salicylate concentrations, suggesting the presence of true aspirin resistance. Despite no detectable differences in the platelet proteome at baseline, following aspirin a marked increase was seen in platelet glycoprotein IIIa expression in the aspirin-resistant but not aspirin-sensitive subjects. An increase in platelet glycoprotein IIIa expression with aspirin resistance was confirmed in a separate cohort of 17 patients with stable coronary artery disease on long term aspirin treatment, four of whom exhibited aspirin resistance. Conclusions In a healthy population, true aspirin resistance is uncommon but exists. Resistance is associated with an increase in platelet glycoprotein IIIa expression in response to aspirin. These data shed new light on the mechanism of aspirin resistance, and provide the potential to identify aspirin-resistant subjects using a novel biomarker. PMID:25099258

Common variants at the 19p13.1 and ZNF365 loci are associated with ER subtypes of breast cancer and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers

PubMed Central

Couch, Fergus J.; Gaudet, Mia M.; Antoniou, Antonis C.; Ramus, Susan J.; Kuchenbaecker, Karoline B.; Soucy, Penny; Beesley, Jonathan; Chen, Xiaoqing; Wang, Xianshu; Kirchhoff, Tomas; McGuffog, Lesley; Barrowdale, Daniel; Lee, Andrew; Healey, Sue; Sinilnikova, Olga M.; Andrulis, Irene L.; Ozcelik, Hilmi; Mulligan, Anna Marie; Thomassen, Mads; Gerdes, Anne-Marie; Jensen, Uffe Birk; Skytte, Anne-Bine; Kruse, Torben A.; Caligo, Maria A.; von Wachenfeldt, Anna; Barbany-Bustinza, Gisela; Loman, Niklas; Soller, Maria; Ehrencrona, Hans; Karlsson, Per; Nathanson, Katherine L.; Rebbeck, Timothy R.; Domchek, Susan M.; Jakubowska, Ania; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Złowocka, Elżbieta; Huzarski, Tomasz; Byrski, Tomasz; Gronwald, Jacek; Cybulski, Cezary; Górski, Bohdan; Osorio, Ana; Durán, Mercedes; Tejada, María Isabel; Benitez, Javier; Hamann, Ute; Hogervorst, Frans B.L.; van Os, Theo A.; van Leeuwen, Flora E.; Meijers-Heijboer, Hanne E.J.; Wijnen, Juul; Blok, Marinus J.; Kets, Marleen; Hooning, Maartje J.; Oldenburg, Rogier A.; Ausems, Margreet G.E.M.; Peock, Susan; Frost, Debra; Ellis, Steve D.; Platte, Radka; Fineberg, Elena; Evans, D. Gareth; Jacobs, Chris; Eeles, Rosalind A.; Adlard, Julian; Davidson, Rosemarie; Eccles, Diana M.; Cole, Trevor; Cook, Jackie; Paterson, Joan; Brewer, Carole; Douglas, Fiona; Hodgson, Shirley V.; Morrison, Patrick J.; Walker, Lisa; Porteous, Mary E.; Kennedy, M. John; Side, Lucy E.; Bove, Betsy; Godwin, Andrew K.; Stoppa-Lyonnet, Dominique; Fassy-Colcombet, Marion; Castera, Laurent; Cornelis, François; Mazoyer, Sylvie; Léoné, Mélanie; Boutry-Kryza, Nadia; Bressac-de Paillerets, Brigitte; Caron, Olivier; Pujol, Pascal; Coupier, Isabelle; Delnatte, Capucine; Akloul, Linda; Lynch, Henry T.; Snyder, Carrie L.; Buys, Saundra S.; Daly, Mary B.; Terry, MaryBeth; Chung, Wendy K.; John, Esther M.; Miron, Alexander; Southey, Melissa C.; Hopper, John L.; Goldgar, David E.; Singer, Christian F.; Rappaport, Christine; Tea, Muy-Kheng M.; Fink-Retter, Anneliese; Hansen, Thomas V. O.; Nielsen, Finn C.; Arason, Aðalgeir; Vijai, Joseph; Shah, Sohela; Sarrel, Kara; Robson, Mark E.; Piedmonte, Marion; Phillips, Kelly; Basil, Jack; Rubinstein, Wendy S.; Boggess, John; Wakeley, Katie; Ewart-Toland, Amanda; Montagna, Marco; Agata, Simona; Imyanitov, Evgeny N.; Isaacs, Claudine; Janavicius, Ramunas; Lazaro, Conxi; Blanco, Ignacio; Feliubadalo, Lidia; Brunet, Joan; Gayther, Simon A; Pharoah, Paul PD; Odunsi, Kunle O.; Karlan, Beth Y.; Walsh, Christine S.; Olah, Edith; Teo, Soo Hwang; Ganz, Patricia A.; Beattie, Mary S.; van Rensburg, Elizabeth J.; Dorfling, Cecelia M.; Diez, Orland; Kwong, Ava; Schmutzler, Rita K.; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Heidemann, Simone; Niederacher, Dieter; Preisler-Adams, Sabine; Gadzicki, Dorothea; Varon-Mateeva, Raymonda; Deissler, Helmut; Gehrig, Andrea; Sutter, Christian; Kast, Karin; Fiebig, Britta; Heinritz, Wolfram; Caldes, Trinidad; de la Hoya, Miguel; Muranen, Taru A.; Nevanlinna, Heli; Tischkowitz, Marc D.; Spurdle, Amanda B.; Neuhausen, Susan L.; Ding, Yuan Chun; Lindor, Noralane M.; Fredericksen, Zachary; Pankratz, V. Shane; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Barile, Monica; Bernard, Loris; Viel, Alessandra; Giannini, Giuseppe; Varesco, Liliana; Radice, Paolo; Greene, Mark H.; Mai, Phuong L.; Easton, Douglas F.; Chenevix-Trench, Georgia; Offit, Kenneth; Simard, Jacques

2012-01-01

Background Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Methods Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined. Results We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers (hazard ratio (HR)=1.17; 95%CI 1.07–1.27; p=7.42×10−4) and between rs16917302 at ZNF365 (HR=0.84; 95%CI 0.73–0.97; p=0.017) but not rs311499 at 20q13.3 (HR=1.11; 95%CI 0.94–1.31; p=0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR=1.16; 95%CI 1.05–1.29; p=3.8×10−4) and BRCA2 mutation carriers (HR=1.30; 95%CI 1.10–1.52; p=1.8×10−3). Conclusions 19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers. Impact These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers. PMID:22351618

Further evidence for the impact of a genome-wide-supported psychosis risk variant in ZNF804A on the Theory of Mind Network.

PubMed

Mohnke, Sebastian; Erk, Susanne; Schnell, Knut; Schütz, Claudia; Romanczuk-Seiferth, Nina; Grimm, Oliver; Haddad, Leila; Pöhland, Lydia; Garbusow, Maria; Schmitgen, Mike M; Kirsch, Peter; Esslinger, Christine; Rietschel, Marcella; Witt, Stephanie H; Nöthen, Markus M; Cichon, Sven; Mattheisen, Manuel; Mühleisen, Thomas; Jensen, Jimmy; Schott, Björn H; Maier, Wolfgang; Heinz, Andreas; Meyer-Lindenberg, Andreas; Walter, Henrik

2014-04-01

The single-nucleotide polymorphism (SNP) rs1344706 in ZNF804A is one of the best-supported risk variants for psychosis. We hypothesized that this SNP contributes to the development of schizophrenia by affecting the ability to understand other people's mental states. This skill, commonly referred to as Theory of Mind (ToM), has consistently been found to be impaired in schizophrenia. Using functional magnetic resonance imaging, we previously showed that in healthy individuals rs1344706 impacted on activity and connectivity of key areas of the ToM network, including the dorsomedial prefrontal cortex, temporo-parietal junction, and the posterior cingulate cortex, which show aberrant activity in schizophrenia patients, too. We aimed to replicate these results in an independent sample of 188 healthy German volunteers. In order to assess the reliability of brain activity elicited by the ToM task, 25 participants performed the task twice with an interval of 14 days showing excellent accordance in recruitment of key ToM areas. Confirming our previous results, we observed decreasing activity of the left temporo-parietal junction, dorsomedial prefrontal cortex, and the posterior cingulate cortex with increasing number of risk alleles during ToM. Complementing our replication sample with the discovery sample, analyzed in a previous report (total N=297), further revealed negative genotype effects in the left dorsomedial prefrontal cortex as well as in the temporal and parietal regions. In addition, as shown previously, rs1344706 risk allele dose positively predicted increased frontal-temporo-parietal connectivity. These findings confirm the effects of the psychosis risk variant in ZNF804A on the dysfunction of the ToM network.

Further Evidence for the Impact of a Genome-Wide-Supported Psychosis Risk Variant in ZNF804A on the Theory of Mind Network

PubMed Central

Mohnke, Sebastian; Erk, Susanne; Schnell, Knut; Schütz, Claudia; Romanczuk-Seiferth, Nina; Grimm, Oliver; Haddad, Leila; Pöhland, Lydia; Garbusow, Maria; Schmitgen, Mike M; Kirsch, Peter; Esslinger, Christine; Rietschel, Marcella; Witt, Stephanie H; Nöthen, Markus M; Cichon, Sven; Mattheisen, Manuel; Mühleisen, Thomas; Jensen, Jimmy; Schott, Björn H; Maier, Wolfgang; Heinz, Andreas; Meyer-Lindenberg, Andreas; Walter, Henrik

2014-01-01

The single-nucleotide polymorphism (SNP) rs1344706 in ZNF804A is one of the best-supported risk variants for psychosis. We hypothesized that this SNP contributes to the development of schizophrenia by affecting the ability to understand other people's mental states. This skill, commonly referred to as Theory of Mind (ToM), has consistently been found to be impaired in schizophrenia. Using functional magnetic resonance imaging, we previously showed that in healthy individuals rs1344706 impacted on activity and connectivity of key areas of the ToM network, including the dorsomedial prefrontal cortex, temporo-parietal junction, and the posterior cingulate cortex, which show aberrant activity in schizophrenia patients, too. We aimed to replicate these results in an independent sample of 188 healthy German volunteers. In order to assess the reliability of brain activity elicited by the ToM task, 25 participants performed the task twice with an interval of 14 days showing excellent accordance in recruitment of key ToM areas. Confirming our previous results, we observed decreasing activity of the left temporo-parietal junction, dorsomedial prefrontal cortex, and the posterior cingulate cortex with increasing number of risk alleles during ToM. Complementing our replication sample with the discovery sample, analyzed in a previous report (total N=297), further revealed negative genotype effects in the left dorsomedial prefrontal cortex as well as in the temporal and parietal regions. In addition, as shown previously, rs1344706 risk allele dose positively predicted increased frontal–temporo-parietal connectivity. These findings confirm the effects of the psychosis risk variant in ZNF804A on the dysfunction of the ToM network. PMID:24247043

Increased Resistance of Skin Flora to Antimicrobial Prophylaxis in Patients Undergoing Hip Revision Arthroplasty.

PubMed

Mühlhofer, Heinrich M L; Deiss, Lukas; Mayer-Kuckuk, Philipp; Pohlig, Florian; Harrasser, Norbert; Lenze, Ulrich; Gollwitzer, Hans; Suren, Christian; Prodinger, Peter; VON Eisenhart-Rothe, Rüdiger; Schauwecker, Johannes

2017-01-01

Prosthetic joint infection (PJI) remains a major complication after total joint replacement and is the primary indication for revision arthroplasty. Specifically, coagulase-negative Staphylococci (CNS) can cause low-grade infections. Despite the use of cephalosporin-based antimicrobial prophylaxis (AMP) and antiseptic treatment at the surgical site, evidence suggests that a significant number of cases of dermal CNS results in low-grade PJI. Thus, this study examined the bacterial colonization and resistance patterns at the surgical site. We hypothesized that the bacteria developed resistance to antibiotics that are frequently used in primary and revision total hip arthroplasty (THA) procedures. Ninety patients, including 63 primary and 27 revision THA patients, were enrolled in this study. For each patient, a single swab of the skin at the surgical site was subjected to clinical microbiology to assess bacterial colonization. Furthermore, resistance to a sentinel panel of antibiotics (benzylpenicillin, erythromycin, tetracycline, oxacillin, fusidic acid, clindamycin, gentamicin, levofloxacin/moxifloxacin, rifampicin, linezolid and vancomycin) was tested. In 96.7% of the patients, at least one bacterial strain was identified at the surgical site, with CNS strains comprising 93.1% of the total. The sentinel panel showed that 30.7% of the CNS strains exhibited maximal resistance to oxacillin, a commonly used cephalosporin. Additionally, oxacillin resistance increased 1.9-fold (p=0.042) between primary and revision THA. Notably, 8.1% of the CNS stains found on patients undergoing primary THA were resistant to gentamicin, an aminoglycoside, and this rate increased 4.7-fold (p=0.001) for patients undergoing revision THA. CNS strains have significant resistance to standard AMP, particularly in individuals undergoing revision THA. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Genetic investigation of 93 families with microphthalmia or posterior microphthalmos.

PubMed

Patel, N; Khan, A O; Alsahli, S; Abdel-Salam, G; Nowilaty, S R; Mansour, A M; Nabil, A; Al-Owain, M; Sogati, S; Salih, M A; Kamal, A M; Alsharif, H; Alsaif, H S; Alzahrani, S S; Abdulwahab, F; Ibrahim, N; Hashem, M; Faquih, T; Shah, Z A; Abouelhoda, M; Monies, D; Dasouki, M; Shaheen, R; Wakil, S M; Aldahmesh, M A; Alkuraya, F S

2018-06-01

Microphthalmia is a developmental eye defect that is highly variable in severity and in its potential for systemic association. Despite the discovery of many disease genes in microphthalmia, at least 50% of patients remain undiagnosed genetically. Here, we describe a cohort of 147 patients (93 families) from our highly consanguineous population with various forms of microphthalmia (including the distinct entity of posterior microphthalmos) that were investigated using a next-generation sequencing multi-gene panel (i-panel) as well as whole exome sequencing and molecular karyotyping. A potentially causal mutation was identified in the majority of the cohort with microphthalmia (61%) and posterior microphthalmos (82%). The identified mutations (55 point mutations, 15 of which are novel) spanned 24 known disease genes, some of which have not or only very rarely been linked to microphthalmia (PAX6, SLC18A2, DSC3 and CNKSR1). Our study has also identified interesting candidate variants in 2 genes that have not been linked to human diseases (MYO10 and ZNF219), which we present here as novel candidates for microphthalmia. In addition to revealing novel phenotypic aspects of microphthalmia, this study expands its allelic and locus heterogeneity and highlights the need for expanded testing of patients with this condition. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Association of rs1344706 in the ZNF804A gene with schizophrenia in a case/control sample from Indonesia.

PubMed

Schwab, Sibylle G; Kusumawardhani, Agung A A A; Dai, Nan; Qin, WenWen; Wildenauer, Mutiara D B; Agiananda, Feranindhya; Amir, Nurmiati; Antoni, Ronald; Arsianti, Tiana; Asmarahadi, Asmarahadi; Diatri, Hervita; Djatmiko, Prianto; Irmansyah, Irmansyah; Khalimah, Siti; Kusumadewi, Irmia; Kusumaningrum, Profitasari; Lukman, Petrin R; Mustar, Lukman; Nasrun, Martina W; Naswati, Safyuni; Prasetiyawan, Prasetiyawan; Semen, Gerald M; Siste, Kristiana; Tobing, Heriani; Widiasih, Natalia; Wiguna, Tjhin; Wulandari, Widayanti Dewi; Benyamin, Beben; Wildenauer, Dieter B

2013-06-01

Association of rs1344706 in the ZNF804A gene (2q32.1) with schizophrenia was first reported in a genome wide scan conducted in a sample of 479 cases and replicated in 6666 cases. Subsequently, evidence by replication was obtained in several samples with European- and Asian ancestral background. We report ascertainment, clinical characterization, quality control, and determination of ancestral background of a case control sample from Indonesia, comprising 1067 cases and 1111 ancestry matched controls. Genotyping was performed using a fluorescence-based allelic discrimination assay (TaqMan SNP genotyping assay) and a newly designed PCR-RFLP assay for confirmation of rs1344706 genotypes. We confirmed association of the T-allele of rs1344706 with schizophrenia in a newly ascertained sample from Indonesia with Southeast Asian ancestral background (P=0.019, OR=1.155, 95%, CI 1.025-1.301). In addition, we studied several SNPs in the vicinity of rs1344706, for which nominally significant results had been reported. None of the association P values of the additional SNPs exceeded that of rs1344706. We provide additional evidence for association of the ZNF804A gene with schizophrenia. We conclude that rs1344706 or a yet unknown polymorphism in linkage disequilibrium is also involved in conferring susceptibility to schizophrenia in samples with different (Asian) ancestral backgrounds. Copyright © 2013 Elsevier B.V. All rights reserved.

9 CFR 93.907-93.909 - [Reserved

Code of Federal Regulations, 2010 CFR

2010-01-01

... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false [Reserved] 93.907-93.909 Section 93.907-93.909 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF... FOR MEANS OF CONVEYANCE AND SHIPPING CONTAINERS Aquatic Animal Species General Provisions for Svc...

9 CFR 93.907-93.909 - [Reserved

Code of Federal Regulations, 2011 CFR

2011-01-01

... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false [Reserved] 93.907-93.909 Section 93.907-93.909 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF... FOR MEANS OF CONVEYANCE AND SHIPPING CONTAINERS Aquatic Animal Species General Provisions for Svc...

Emotions and stress increase respiratory resistance in asthma.

PubMed

Ritz, T; Steptoe, A; DeWilde, S; Costa, M

2000-01-01

Clinical reports suggest that various emotions and types of stress can precipitate asthmatic symptoms, but there is little experimental evidence to substantiate this claim. We studied the impact of different emotional states and stress on respiratory resistance in asthmatic and nonasthmatic individuals. Participants (24 asthmatic and 24 nonasthmatic patients) viewed short film sequences selected to induce anxiety, anger, depression, elation, happiness, contentment, or a neutral affective state and completed two stressful tasks, mental arithmetic to induce active coping efforts and viewing of medical slides to induce passive coping efforts. Oscillatory resistance, heart rate, blood pressure, baroreflex sensitivity, skin conductance level, respiration rate and volume, and self-reported affective state were measured throughout the session. Uniform increases in oscillatory resistance were found in all emotional states compared with the neutral state and during mental arithmetic in both groups. Asthmatic patients showed stronger reactions to the medical slides than healthy control subjects, with significant increases in oscillatory resistance, blood pressure, skin conductance level, and minute volume, as well as higher levels of self-reported depression, arousal, and shortness of breath. Changes in oscillatory resistance were inconsistently correlated with other physiological indices. Various emotional states and stress increase oscillatory resistance largely independently of concurrent increases in autonomic or ventilatory activity. The particular sensitivity of asthmatics to passive coping demand requires additional research.

Development of Castration Resistant Prostate Cancer can be Predicted by a DNA Hypermethylation Profile.

PubMed

Angulo, Javier C; Andrés, Guillermo; Ashour, Nadia; Sánchez-Chapado, Manuel; López, Jose I; Ropero, Santiago

2016-03-01

Detection of DNA hypermethylation has emerged as a novel molecular biomarker for prostate cancer diagnosis and evaluation of prognosis. We sought to define whether a hypermethylation profile of patients with prostate cancer on androgen deprivation would predict castrate resistant prostate cancer. Genome-wide methylation analysis was performed using a methylation cancer panel in 10 normal prostates and 45 tumor samples from patients placed on androgen deprivation who were followed until castrate resistant disease developed. Castrate resistant disease was defined according to EAU (European Association of Urology) guideline criteria. Two pathologists reviewed the Gleason score, Ki-67 index and neuroendocrine differentiation. Hierarchical clustering analysis was performed and relationships with outcome were investigated by Cox regression and log rank analysis. We found 61 genes that were significantly hypermethylated in greater than 20% of tumors analyzed. Three clusters of patients were characterized by a DNA methylation profile, including 1 at risk for earlier castrate resistant disease (log rank p = 0.019) and specific mortality (log rank p = 0.002). Hypermethylation of ETV1 (HR 3.75) and ZNF215 (HR 2.89) predicted disease progression despite androgen deprivation. Hypermethylation of IRAK3 (HR 13.72), ZNF215 (HR 4.81) and SEPT9 (HR 7.64) were independent markers of prognosis. Prostate specific antigen greater than 25 ng/ml, Gleason pattern 5, Ki-67 index greater than 12% and metastasis at diagnosis also predicted a negative response to androgen deprivation. Study limitations included the retrospective design and limited number of cases. Epigenetic silencing of the mentioned genes could be novel molecular markers for the prognosis of advanced prostate cancer. It might predict castrate resistance during hormone deprivation and, thus, disease specific mortality. Gene hypermethylation is associated with disease progression in patients who receive hormone therapy. It

Some methods of increasing the density of metal in order to increase him corrosion resistance

NASA Astrophysics Data System (ADS)

Chumanov, I. V.; Anikeev, A. N.; Sergeev, D. V.; Maltseva, A. N.

2017-11-01

Methods to increase the density of metal in order to increase its corrosion resistance in an aggressive environment are examined in the article. Two steel grades, differing in the content of alloying elements, increasing the resistance to corrosion are selected for the manufacture of experimental metallic materials. Two technologies are chosen as methods for increasing the density, and as a result, corrosion resistance, of the experimental materials obtained: the first is electroslag remelting with rotation of the consumable electrode, the second is centrifugal casting with modification. The microstructure of the metal becomes more homogeneous, the degree of metal refining from non-metallic inclusions increases, the rate of crystallization during metal smelting by the ESR method increases with rotation of the consumable electrode. When ingots are produced by the method of centrifugal casting, they are modified with dispersed WC and TiC particles, which increases the crystallization rate, increases the metal density, corrosion and mechanical properties. The evaluation of their corrosion resistance with the help of the autoclaved test complex “Cortest” is made after obtaining ingots by various technologies.

Soma size and Cav1.3 channel expression in vulnerable and resistant motoneuron populations of the SOD1G93A mouse model of ALS

PubMed Central

Shoenfeld, Liza; Westenbroek, Ruth E.; Fisher, Erika; Quinlan, Katharina A.; Tysseling, Vicki M.; Powers, Randall K.; Heckman, Charles J.; Binder, Marc D.

2014-01-01

Abstract Although the loss of motoneurons is an undisputed feature of amyotrophic lateral sclerosis (ALS) in man and in its animal models (SOD1 mutant mice), how the disease affects the size and excitability of motoneurons prior to their degeneration is not well understood. This study was designed to test the hypothesis that motoneurons in mutant SOD1G93A mice exhibit an enlargement of soma size (i.e., cross‐sectional area) and an increase in Cav1.3 channel expression at postnatal day 30, well before the manifestation of physiological symptoms that typically occur at p90 (Chiu et al. 1995). We made measurements of spinal and hypoglossal motoneurons vulnerable to degeneration, as well as motoneurons in the oculomotor nucleus that are resistant to degeneration. Overall, we found that the somata of motoneurons in male SOD1G93A mutants were larger than those in wild‐type transgenic males. When females were included in the two groups, significance was lost. Expression levels of the Cav1.3 channels were not differentiated by genotype, sex, or any interaction of the two. These results raise the intriguing possibility of an interaction between male sex steroid hormones and the SOD1 mutation in the etiopathogenesis of ALS. PMID:25107988

The B-subdomain of the Xenopus laevis XFIN KRAB-AB domain is responsible for its weaker transcriptional repressor activity compared to human ZNF10/Kox1.

PubMed

Born, Nadine; Thiesen, Hans-Jürgen; Lorenz, Peter

2014-01-01

The Krüppel-associated box (KRAB) domain interacts with the nuclear hub protein TRIM28 to initiate or mediate chromatin-dependent processes like transcriptional repression, imprinting or suppression of endogenous retroviruses. The prototype KRAB domain initially identified in ZNF10/KOX1 encompasses two subdomains A and B that are found in hundreds of zinc finger transcription factors studied in human and murine genomes. Here we demonstrate for the first time transcriptional repressor activity of an amphibian KRAB domain. After sequence correction, the updated KRAB-AB domain of zinc finger protein XFIN from the frog Xenopus laevis was found to confer transcriptional repression in reporter assays in Xenopus laevis A6 kidney cells as well as in human HeLa, but not in the minnow Pimephales promelas fish cell line EPC. Binding of the XFIN KRAB-AB domain to human TRIM28 was demonstrated in a classical co-immunoprecipitation approach and visualized in a single-cell compartmentalization assay. XFIN-AB displayed reduced potency in repression as well as lower strength of interaction with TRIM28 compared to ZNF10 KRAB-AB. KRAB-B subdomain swapping between the two KRAB domains indicated that it was mainly the KRAB-B subdomain of XFIN that was responsible for its lower capacity in repression and binding to human TRIM28. In EPC fish cells, ZNF10 and XFIN KRAB repressor activity could be partially restored to low levels by adding exogenous human TRIM28. In contrast to XFIN, we did not find any transcriptional repression activity for the KRAB-like domain of human PRDM9 in HeLa cells. PRDM9 is thought to harbor an evolutionary older domain related to KRAB whose homologs even occur in invertebrates. Our results support the notion that functional bona fide KRAB domains which confer transcriptional repression and interact with TRIM28 most likely co-evolved together with TRIM28 at the beginning of tetrapode evolution.

Increasing incidence of fluoroquinolone-resistant Mycobacterium tuberculosis in Mumbai, India.

PubMed

Agrawal, D; Udwadia, Z F; Rodriguez, C; Mehta, A

2009-01-01

Tertiary referral centre, private hospital, Mumbai, India. To analyse the incidence of fluoroquinolone (FQ) resistant Mycobacterium tuberculosis (TB) in our laboratory from 1995 to 2004. Retrospective review and analysis of the drug susceptibility test records of all M. tuberculosis culture-positive samples from our Microbiology Department from 1995 to 2004. FQ resistance has increased exponentially in our laboratory, from 3% in 1996 to 35% in 2004. The incidence of multidrug-resistant tuberculosis has also increased during the same period, from 33% in 1995 to 56% in 2004. The incidence of FQ-resistant M. tuberculosis is gradually increasing to alarming levels. This may be due to widespread use of this vital group of drugs in the treatment of community-acquired infections. We urge that these broad spectrum antibiotics be used judiciously, and ideally be reserved for treatment of resistant TB in TB-endemic areas.

14 CFR 93.93 - Description of area.

Code of Federal Regulations, 2012 CFR

2012-01-01

... Angeles International Airport § 93.93 Description of area. The Los Angeles Special Flight Rules Area is designated as that part of Area A of the Los Angeles Class B airspace area at 3,500 feet above mean sea level...

14 CFR 93.93 - Description of area.

Code of Federal Regulations, 2011 CFR

2011-01-01

... Angeles International Airport § 93.93 Description of area. The Los Angeles Special Flight Rules Area is designated as that part of Area A of the Los Angeles Class B airspace area at 3,500 feet above mean sea level...

14 CFR 93.93 - Description of area.

Code of Federal Regulations, 2010 CFR

2010-01-01

... Angeles International Airport § 93.93 Description of area. The Los Angeles Special Flight Rules Area is designated as that part of Area A of the Los Angeles Class B airspace area at 3,500 feet above mean sea level...

14 CFR 93.93 - Description of area.

Code of Federal Regulations, 2014 CFR

2014-01-01

... Angeles International Airport § 93.93 Description of area. The Los Angeles Special Flight Rules Area is designated as that part of Area A of the Los Angeles Class B airspace area at 3,500 feet above mean sea level...

14 CFR 93.93 - Description of area.

Code of Federal Regulations, 2013 CFR

2013-01-01

... Angeles International Airport § 93.93 Description of area. The Los Angeles Special Flight Rules Area is designated as that part of Area A of the Los Angeles Class B airspace area at 3,500 feet above mean sea level...

Sucralose Increases Antimicrobial Resistance and Stimulates Recovery of Escherichia coli Mutants.

PubMed

Qu, Yilin; Li, Rongyan; Jiang, Mingshan; Wang, Xiuhong

2017-07-01

Because of heavy use of antimicrobials, antimicrobial resistance in bacteria has become of great concern. The effect of some widely used food additives such as sucralose on bacteria in the gut and the environment has also drawn increasing attention. In this study, we investigated the interaction between antimicrobials and sucralose impacting antimicrobial resistance and mutation of Escherichia coli (E. coli). To examine antimicrobial resistance and mutation frequency, different subinhibitory concentrations of sucralose were added to cultures of E.coli BW25113 that were then treated with antimicrobials, oxolinic acid, or moxifloxacin. Then the E.coli were assayed for bacterial survival and recovery of mutants resistant to an unrelated antimicrobial, rifampicin. Pre-treatment of E.coli BW25113 with 1/2 minimal inhibitory concentration (MIC) of sucralose increased the survival rate in oxolinic acid or moxifloxacin. A 1/3 MIC of sucralose increased rifampicin-resistant mutation rate of E.coli BW25113 after 72 h, while rifampicin-resistant mutation rate was increased when co-treated with 1/8 MIC, 1/4 MIC, 1/3 MIC sucralose, and oxolinic acid after 24 h. Sucralose can increase the antimicrobial resistance and mutation frequency of E.coli to some antimicrobials.

Increased radiation resistance in lithium-counterdoped silicon solar cells

NASA Technical Reports Server (NTRS)

Weinberg, I.; Swartz, C. K.; Mehta, S.

1984-01-01

Lithium-counterdoped n(+)p silicon solar cells are found to exhibit significantly increased radiation resistance to 1-MeV electron irradiation when compared to boron-doped n(+)p silicon solar cells. In addition to improved radiation resistance, considerable damage recovery by annealing is observed in the counterdoped cells at T less than or equal to 100 C. Deep level transient spectroscopy measurements are used to identify the defect whose removal results in the low-temperature aneal. It is suggested that the increased radiation resistance of the counterdoped cells is primarily due to interaction of the lithium with interstitial oxygen.

Ethanologenic bacteria with increased resistance to furfural

DOEpatents

Miller, Elliot Norman; Jarboe, Laura R.; Yomano, Lorraine P.; York, Sean W.; Shanmugam, Keelnatham; Ingram, Lonnie O'Neal

2015-10-06

The invention relates to bacterium that have increased resistance to furfural and methods of preparation. The invention also relates to methods of producing ethanol using the bacterium and corresponding kits.

Scabies in the age of increasing drug resistance

PubMed Central

Khalil, Samar; Abbas, Ossama; Kibbi, Abdul Ghani; Kurban, Mazen

2017-01-01

Scabies is an infestation of the skin by the mite Sarcoptes scabiei. It manifests with pruritic erythematous papules and excoriations, in addition to the pathognomonic burrows. Multiple drugs can be used for treatment, but resistance to conventional therapy is increasing throughout the years. This paper will review the mechanisms of resistance proposed in the literature and some of the potential solutions to this problem. PMID:29190303

Scabies in the age of increasing drug resistance.

PubMed

Khalil, Samar; Abbas, Ossama; Kibbi, Abdul Ghani; Kurban, Mazen

2017-11-01

Scabies is an infestation of the skin by the mite Sarcoptes scabiei. It manifests with pruritic erythematous papules and excoriations, in addition to the pathognomonic burrows. Multiple drugs can be used for treatment, but resistance to conventional therapy is increasing throughout the years. This paper will review the mechanisms of resistance proposed in the literature and some of the potential solutions to this problem.

Identification of ANKRD11 and ZNF778 as candidate genes for autism and variable cognitive impairment in the novel 16q24.3 microdeletion syndrome

PubMed Central

Willemsen, Marjolein H; Fernandez, Bridget A; Bacino, Carlos A; Gerkes, Erica; de Brouwer, Arjan PM; Pfundt, Rolph; Sikkema-Raddatz, Birgit; Scherer, Stephen W; Marshall, Christian R; Potocki, Lorraine; van Bokhoven, Hans; Kleefstra, Tjitske

2010-01-01

The clinical use of array comparative genomic hybridization in the evaluation of patients with multiple congenital anomalies and/or mental retardation has recently led to the discovery of a number of novel microdeletion and microduplication syndromes. We present four male patients with overlapping molecularly defined de novo microdeletions of 16q24.3. The clinical features observed in these patients include facial dysmorphisms comprising prominent forehead, large ears, smooth philtrum, pointed chin and wide mouth, variable cognitive impairment, autism spectrum disorder, structural anomalies of the brain, seizures and neonatal thrombocytopenia. Although deletions vary in size, the common region of overlap is only 90 kb and comprises two known genes, Ankyrin Repeat Domain 11 (ANKRD11) (MIM 611192) and Zinc Finger 778 (ZNF778), and is located approximately 10 kb distally to Cadherin 15 (CDH15) (MIM 114019). This region is not found as a copy number variation in controls. We propose that these patients represent a novel and distinctive microdeletion syndrome, characterized by autism spectrum disorder, variable cognitive impairment, facial dysmorphisms and brain abnormalities. We suggest that haploinsufficiency of ANKRD11 and/or ZNF778 contribute to this phenotype and speculate that further investigation of non-deletion patients who have features suggestive of this 16q24.3 microdeletion syndrome might uncover other mutations in one or both of these genes. PMID:19920853

Biodiversity increases the resistance of ecosystem productivity to climate extremes

NASA Astrophysics Data System (ADS)

Isbell, Forest; Craven, Dylan; Connolly, John; Loreau, Michel; Schmid, Bernhard; Beierkuhnlein, Carl; Bezemer, T. Martijn; Bonin, Catherine; Bruelheide, Helge; de Luca, Enrica; Ebeling, Anne; Griffin, John N.; Guo, Qinfeng; Hautier, Yann; Hector, Andy; Jentsch, Anke; Kreyling, Jürgen; Lanta, Vojtěch; Manning, Pete; Meyer, Sebastian T.; Mori, Akira S.; Naeem, Shahid; Niklaus, Pascal A.; Polley, H. Wayne; Reich, Peter B.; Roscher, Christiane; Seabloom, Eric W.; Smith, Melinda D.; Thakur, Madhav P.; Tilman, David; Tracy, Benjamin F.; van der Putten, Wim H.; van Ruijven, Jasper; Weigelt, Alexandra; Weisser, Wolfgang W.; Wilsey, Brian; Eisenhauer, Nico

2015-10-01

It remains unclear whether biodiversity buffers ecosystems against climate extremes, which are becoming increasingly frequent worldwide. Early results suggested that the ecosystem productivity of diverse grassland plant communities was more resistant, changing less during drought, and more resilient, recovering more quickly after drought, than that of depauperate communities. However, subsequent experimental tests produced mixed results. Here we use data from 46 experiments that manipulated grassland plant diversity to test whether biodiversity provides resistance during and resilience after climate events. We show that biodiversity increased ecosystem resistance for a broad range of climate events, including wet or dry, moderate or extreme, and brief or prolonged events. Across all studies and climate events, the productivity of low-diversity communities with one or two species changed by approximately 50% during climate events, whereas that of high-diversity communities with 16-32 species was more resistant, changing by only approximately 25%. By a year after each climate event, ecosystem productivity had often fully recovered, or overshot, normal levels of productivity in both high- and low-diversity communities, leading to no detectable dependence of ecosystem resilience on biodiversity. Our results suggest that biodiversity mainly stabilizes ecosystem productivity, and productivity-dependent ecosystem services, by increasing resistance to climate events. Anthropogenic environmental changes that drive biodiversity loss thus seem likely to decrease ecosystem stability, and restoration of biodiversity to increase it, mainly by changing the resistance of ecosystem productivity to climate events.

Biodiversity increases the resistance of ecosystem productivity to climate extremes.

PubMed

Isbell, Forest; Craven, Dylan; Connolly, John; Loreau, Michel; Schmid, Bernhard; Beierkuhnlein, Carl; Bezemer, T Martijn; Bonin, Catherine; Bruelheide, Helge; de Luca, Enrica; Ebeling, Anne; Griffin, John N; Guo, Qinfeng; Hautier, Yann; Hector, Andy; Jentsch, Anke; Kreyling, Jürgen; Lanta, Vojtěch; Manning, Pete; Meyer, Sebastian T; Mori, Akira S; Naeem, Shahid; Niklaus, Pascal A; Polley, H Wayne; Reich, Peter B; Roscher, Christiane; Seabloom, Eric W; Smith, Melinda D; Thakur, Madhav P; Tilman, David; Tracy, Benjamin F; van der Putten, Wim H; van Ruijven, Jasper; Weigelt, Alexandra; Weisser, Wolfgang W; Wilsey, Brian; Eisenhauer, Nico

2015-10-22

It remains unclear whether biodiversity buffers ecosystems against climate extremes, which are becoming increasingly frequent worldwide. Early results suggested that the ecosystem productivity of diverse grassland plant communities was more resistant, changing less during drought, and more resilient, recovering more quickly after drought, than that of depauperate communities. However, subsequent experimental tests produced mixed results. Here we use data from 46 experiments that manipulated grassland plant diversity to test whether biodiversity provides resistance during and resilience after climate events. We show that biodiversity increased ecosystem resistance for a broad range of climate events, including wet or dry, moderate or extreme, and brief or prolonged events. Across all studies and climate events, the productivity of low-diversity communities with one or two species changed by approximately 50% during climate events, whereas that of high-diversity communities with 16-32 species was more resistant, changing by only approximately 25%. By a year after each climate event, ecosystem productivity had often fully recovered, or overshot, normal levels of productivity in both high- and low-diversity communities, leading to no detectable dependence of ecosystem resilience on biodiversity. Our results suggest that biodiversity mainly stabilizes ecosystem productivity, and productivity-dependent ecosystem services, by increasing resistance to climate events. Anthropogenic environmental changes that drive biodiversity loss thus seem likely to decrease ecosystem stability, and restoration of biodiversity to increase it, mainly by changing the resistance of ecosystem productivity to climate events.

Increasing drug resistance of Mycobacterium tuberculosis in Sinaloa, Mexico, 1997-2005.

PubMed

Zazueta-Beltran, Jorge; León-Sicairos, Nidia; Muro-Amador, Secundino; Flores-Gaxiola, Adrian; Velazquez-Roman, Jorge; Flores-Villaseñor, Hector; Canizalez-Roman, Adrian

2011-04-01

In 1997 the US Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) reported high proportions of drug-resistant Mycobacterium tuberculosis in three Mexican states: Sinaloa, Baja California, and Oaxaca. In 2006, we showed that resistance to anti-tuberculosis drugs remained frequent in Sinaloa. The objectives of this study were to describe drug-resistant tuberculosis (TB) trends and to investigate the probability that patients acquire resistance to first-line anti-TB drugs on recurrence after treatment in Sinaloa. Sputum specimens were collected from patients diagnosed with TB at all the health care institutions of Sinaloa during 1997-2005. Isolates were tested for susceptibility to first-line drugs. Among 671 isolates tested from 1997 to 2002, the overall resistance rate was 34.9% (95% confidence interval (CI) 31.2-38.4) with a 1.2% increase per year (Chi-square=4.258, p=0.03906). The prevalence of multi-drug resistance (MDR) was 17.9% (95% CI 14.9-20.7) with a 1.2% increase per year (Chi-square=8.352, p=0.00385). Of 50 patients registered twice between 1997 and 2005, 15 were fully susceptible at first registration, of whom six (40%) acquired drug resistance. Of 35 cases with any drug resistance at first registration, 21 (60%) came to acquire resistance to at least one other drug. The proportion of drug-resistant TB increased during 1997-2005 in Sinaloa. Major efforts are needed to prevent the further rise and spread of drug-resistant and MDR TB. Copyright © 2011 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Zinc Finger Protein 451 Is a Novel Smad Corepressor in Transforming Growth Factor-β Signaling*

PubMed Central

Feng, Yili; Wu, Hongxing; Xu, Yongxian; Zhang, Zhengmao; Liu, Ting; Lin, Xia; Feng, Xin-Hua

2014-01-01

ZNF451 is a transcriptional cofactor localized to promyelocytic leukemia bodies. Here, we present evidence demonstrating that ZNF451 physically interacts with Smad3/4 and functionally inhibits TGF-β signaling. Increased expression of ZNF451 attenuates TGF-β-induced growth inhibitory and gene transcriptional responses, whereas depletion of ZNF451 enhances TGF-β responses. Mechanistically, ZNF451 blocks the ability of Smad3/4 to recruit p300 in response to TGF-β, which causes reduction of histone H3K9 acetylation on the promoters of TGF-β target genes. Taken together, ZNF451 acts as a transcriptional corepressor for Smad3/4 and negatively regulates TGF-β signaling. PMID:24324267

Intermittent hypoxia increases insulin resistance in genetically obese mice.

PubMed

Polotsky, Vsevolod Y; Li, Jianguo; Punjabi, Naresh M; Rubin, Arnon E; Smith, Philip L; Schwartz, Alan R; O'Donnell, Christopher P

2003-10-01

Obstructive sleep apnoea, a syndrome that leads to recurrent intermittent hypoxia, is associated with insulin resistance in obese individuals, but the mechanisms underlying this association remain unknown. We utilized a mouse model to examine the effects of intermittent hypoxia on insulin resistance in lean C57BL/6J mice and leptin-deficient obese (C57BL/6J-Lepob) mice. In lean mice, exposure to intermittent hypoxia for 5 days (short term) resulted in a decrease in fasting blood glucose levels (from 173 +/- 11 mg dl-1 on day 0 to 138 +/- 10 mg dl-1 on day 5, P < 0.01), improvement in glucose tolerance without a change in serum insulin levels and an increase in serum leptin levels in comparison with control (2.6 +/- 0.3 vs. 1.7 +/- 0.2 ng ml-1, P < 0.05). Microarray mRNA analysis of adipose tissue revealed that leptin was the only upregulated gene affecting glucose uptake. In obese mice, short-term intermittent hypoxia led to a decrease in blood glucose levels accompanied by a 607 +/- 136 % (P < 0.01) increase in serum insulin levels. This increase in insulin secretion after 5 days of intermittent hypoxia was completely abolished by prior leptin infusion. Obese mice exposed to intermittent hypoxia for 12 weeks (long term) developed a time-dependent increase in fasting serum insulin levels (from 3.6 +/- 1.1 ng ml-1 at baseline to 9.8 +/- 1.8 ng ml-1 at week 12, P < 0.001) and worsening glucose tolerance, consistent with an increase in insulin resistance. We conclude that the increase in insulin resistance in response to intermittent hypoxia is dependent on the disruption of leptin pathways.

Intermittent Hypoxia Increases Insulin Resistance in Genetically Obese Mice

PubMed Central

Polotsky, Vsevolod Y; Li, Jianguo; Punjabi, Naresh M; Rubin, Arnon E; Smith, Philip L; Schwartz, Alan R; O'Donnell, Christopher P

2003-01-01

Obstructive sleep apnoea, a syndrome that leads to recurrent intermittent hypoxia, is associated with insulin resistance in obese individuals, but the mechanisms underlying this association remain unknown. We utilized a mouse model to examine the effects of intermittent hypoxia on insulin resistance in lean C57BL/6J mice and leptin-deficient obese (C57BL/6J−Lepob) mice. In lean mice, exposure to intermittent hypoxia for 5 days (short term) resulted in a decrease in fasting blood glucose levels (from 173 ± 11 mg dl−1 on day 0 to 138 ± 10 mg dl−1 on day 5, P < 0.01), improvement in glucose tolerance without a change in serum insulin levels and an increase in serum leptin levels in comparison with control (2.6 ± 0.3 vs. 1.7 ± 0.2 ng ml−1, P < 0.05). Microarray mRNA analysis of adipose tissue revealed that leptin was the only upregulated gene affecting glucose uptake. In obese mice, short-term intermittent hypoxia led to a decrease in blood glucose levels accompanied by a 607 ± 136 % (P < 0.01) increase in serum insulin levels. This increase in insulin secretion after 5 days of intermittent hypoxia was completely abolished by prior leptin infusion. Obese mice exposed to intermittent hypoxia for 12 weeks (long term) developed a time-dependent increase in fasting serum insulin levels (from 3.6 ± 1.1 ng ml−1 at baseline to 9.8 ± 1.8 ng ml−1 at week 12, P < 0.001) and worsening glucose tolerance, consistent with an increase in insulin resistance. We conclude that the increase in insulin resistance in response to intermittent hypoxia is dependent on the disruption of leptin pathways. PMID:12878760

Modified developer increases line resolution in photosensitive resist

NASA Technical Reports Server (NTRS)

1965-01-01

Standard developer solution is mixed with dipropyl carbonate. This reduces swelling in the photosensitive resist and permits application of relatively thick films with minimal pinhole formation and increased line resolution.

Increase in resistance to ceftriaxone and nonsusceptibility to ciprofloxacin and decrease in multidrug resistance among Salmonella strains, United States, 1996-2009.

PubMed

Medalla, Felicita; Hoekstra, Robert M; Whichard, Jean M; Barzilay, Ezra J; Chiller, Tom M; Joyce, Kevin; Rickert, Regan; Krueger, Amy; Stuart, Andrew; Griffin, Patricia M

2013-04-01

Salmonella is a major bacterial pathogen transmitted commonly through food. Increasing resistance to antimicrobial agents (e.g., ceftriaxone, ciprofloxacin) used to treat serious Salmonella infections threatens the utility of these agents. Infection with antimicrobial-resistant Salmonella has been associated with increased risk of severe infection, hospitalization, and death. We describe changes in antimicrobial resistance among nontyphoidal Salmonella in the United States from 1996 through 2009. The Centers for Disease Control and Prevention's National Antimicrobial Resistance Monitoring System conducts surveillance of resistance among Salmonella isolated from humans. From 1996 through 2009, public health laboratories submitted isolates for antimicrobial susceptibility testing. We used interpretive criteria from the Clinical and Laboratory Standards Institute and defined isolates with ciprofloxacin resistance or intermediate susceptibility as nonsusceptible to ciprofloxacin. Using logistic regression, we modeled annual data to assess changes in antimicrobial resistance. From 1996 through 2009, the percentage of nontyphoidal Salmonella isolates resistant to ceftriaxone increased from 0.2% to 3.4% (odds ratio [OR]=20, 95% confidence interval [CI] 6.3-64), and the percentage with nonsusceptibility to ciprofloxacin increased from 0.4% to 2.4% (OR=8.3, 95% CI 3.3-21). The percentage of isolates that were multidrug resistant (resistant to ≥3 antimicrobial classes) decreased from 17% to 9.6% (OR=0.6, 95% CI 0.5-0.7), which was driven mainly by a decline among serotype Typhimurium. However, multidrug resistance increased from 5.9% in 1996 to a peak of 31% in 2001 among serotype Newport and increased from 12% in 1996 to 26% in 2009 (OR=2.6, 95% CI 1.1-6.2) among serotype Heidelberg. We describe an increase in resistance to ceftriaxone and nonsusceptibility to ciprofloxacin and an overall decline in multidrug resistance. Trends varied by serotype. Because of evidence that

Does employee resistance during a robbery increase the risk of customer injury?

PubMed

Yau, Rebecca K; Casteel, Carri; Nocera, Maryalice; Bishop, Stephanie F; Peek-Asa, Corinne

2015-04-01

Retail business robberies can lead to employee and customer injury. Previous work demonstrates that employee resistance increases employee injury risk; limited research has investigated customer injuries. This study examines associations between employee resistance against perpetrators and the risk of customer injury. Retail and service robbery reports were obtained from a metropolitan police department. Generalized estimating equations estimated risk ratios and 95% confidence intervals (CIs). Customers were injured in 75 out of 697 robberies. Employees resisted the perpetrator in 32 out of 697 robberies. Customers had higher injury risk when employees resisted the perpetrator, compared with robberies where employees did not resist (adjusted risk ratio [95% CI], 2.6 [1.5 to 4.5]). Employee resistance against a perpetrator during a robbery increased customer injury risk. Businesses can train employees to not resist during a robbery, providing benefits for both customers and the business itself.

Identification and Characterization of Hypoxia-Regulated Endothelial Circular RNA.

PubMed

Boeckel, Jes-Niels; Jaé, Nicolas; Heumüller, Andreas W; Chen, Wei; Boon, Reinier A; Stellos, Konstantinos; Zeiher, Andreas M; John, David; Uchida, Shizuka; Dimmeler, Stefanie

2015-10-23

Circular RNAs (circRNAs) are noncoding RNAs generated by back splicing. Back splicing has been considered a rare event, but recent studies suggest that circRNAs are widely expressed. However, the expression, regulation, and function of circRNAs in vascular cells is still unknown. Here, we characterize the expression, regulation, and function of circRNAs in endothelial cells. Endothelial circRNAs were identified by computational analysis of ribo-minus RNA generated from human umbilical venous endothelial cells cultured under normoxic or hypoxic conditions. Selected circRNAs were biochemically characterized, and we found that the majority of them lacks polyadenylation, is resistant to RNase R digestion and localized to the cytoplasm. We further validated the hypoxia-induced circRNAs cZNF292, cAFF1, and cDENND4C, as well as the downregulated cTHSD1 by reverse transcription polymerase chain reaction in cultured endothelial cells. Cloning of cZNF292 validated the predicted back splicing of exon 4 to a new alternative exon 1A. Silencing of cZNF292 inhibited cZNF292 expression and reduced tube formation and spheroid sprouting of endothelial cells in vitro. The expression of pre-mRNA or mRNA of the host gene was not affected by silencing of cZNF292. No validated microRNA-binding sites for cZNF292 were detected in Argonaute high-throughput sequencing of RNA isolated by cross-linking and immunoprecipitation data sets, suggesting that cZNF292 does not act as a microRNA sponge. We show that the majority of the selected endothelial circRNAs fulfill all criteria of bona fide circRNAs. The circRNA cZNF292 exhibits proangiogenic activities in vitro. These data suggest that endothelial circRNAs are regulated by hypoxia and have biological functions. © 2015 American Heart Association, Inc.

Influence of irradiation by a novel CO2 9.3-μm short-pulsed laser on sealant bond strength.

PubMed

Rechmann, P; Sherathiya, K; Kinsel, R; Vaderhobli, R; Rechmann, B M T

2017-04-01

The objective of this in vitro study was to evaluate whether irradiation of enamel with a novel CO 2 9.3-μm short-pulsed laser using energies that enhance caries resistance influences the shear bond strength of composite resin sealants to the irradiated enamel. Seventy bovine and 240 human enamel samples were irradiated with a 9.3-μm carbon dioxide laser (Solea, Convergent Dental, Inc., Natick, MA) with four different laser energies known to enhance caries resistance or ablate enamel (pulse duration from 3 μs at 1.6 mJ/pulse to 43 μs at 14.9 mJ/pulse with fluences between 3.3 and 30.4 J/cm 2 , pulse repetition rate between 4.1 and 41.3 Hz, beam diameter of 0.25 mm and 1-mm spiral pattern, and focus distance of 4-15 mm). Irradiation was performed "freehand" or using a computerized, motor-driven stage. Enamel etching was achieved with 37% phosphoric acid (Scotchbond Universal etchant, 3M ESPE, St. Paul, MN). As bonding agent, Adper Single Bond Plus was used followed by placing Z250 Filtek Supreme flowable composite resin (both 3M ESPE). After 24 h water storage, a single-plane shear bond test was performed (UltraTester, Ultradent Products, Inc., South Jordan, UT). All laser-irradiated samples showed equal or higher bond strength than non-laser-treated controls. The highest shear bond strength values were observed with the 3-μs pulse duration/0.25-mm laser pattern (mean ± SD = 31.90 ± 2.50 MPa), representing a significant 27.4% bond strength increase over the controls (25.04 ± 2.80 MPa, P ≤ 0.0001). Two other caries-preventive irradiation (3 μs/1 mm and 7 μs/0.25 mm) and one ablative pattern (23 μs/0.25 mm) achieved significantly increased bond strength compared to the controls. Bovine enamel also showed in all test groups increased shear bond strength over the controls. Computerized motor-driven stage irradiation did not show superior bond strength values over the clinically more relevant freehand irradiation. Enamel

Calpastatin inhibits motor neuron death and increases survival of hSOD1(G93A) mice.

PubMed

Rao, Mala V; Campbell, Jabbar; Palaniappan, Arti; Kumar, Asok; Nixon, Ralph A

2016-04-01

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease with a poorly understood cause and no effective treatment. Given that calpains mediate neurodegeneration in other pathological states and are abnormally activated in ALS, we investigated the possible ameliorative effects of inhibiting calpain over-activation in hSOD1(G93A) transgenic (Tg) mice in vivo by neuron-specific over-expression of calpastatin (CAST), the highly selective endogenous inhibitor of calpains. Our data indicate that over-expression of CAST in hSOD1(G93A) mice, which lowered calpain activation to levels comparable to wild-type mice, inhibited the abnormal breakdown of cytoskeletal proteins (spectrin, MAP2 and neurofilaments), and ameliorated motor axon loss. Disease onset in hSOD1(G93A) /CAST mice compared to littermate hSOD1(G93A) mice is delayed, which accounts for their longer time of survival. We also find that neuronal over-expression of CAST in hSOD1(G93A) transgenic mice inhibited production of putative neurotoxic caspase-cleaved tau and activation of Cdk5, which have been implicated in neurodegeneration in ALS models, and also reduced the formation of SOD1 oligomers. Our data indicate that inhibition of calpain with CAST is neuroprotective in an ALS mouse model. CAST (encoding calpastatin) inhibits hyperactivated calpain to prevent motor neuron disease operating through a cascade of events as indicated in the schematic, with relevance to amyotrophic lateral sclerosis (ALS). We propose that over-expression of CAST in motor neurons of hSOD1(G93A) mice inhibits activation of CDK5, breakdown of cytoskeletal proteins (NFs, MAP2 and Tau) and regulatory molecules (Cam Kinase IV, Calcineurin A), and disease-causing proteins (TDP-43, α-Synuclein and Huntingtin) to prevent neuronal loss and delay neurological deficits. In our experiments, CAST could also inhibit cleavage of Bid, Bax, AIF to prevent mitochondrial, ER and lysosome-mediated cell death mechanisms. Similarly, CAST

Resistance Training Increases Skeletal Muscle Capillarization in Healthy Older Men.

PubMed

Verdijk, Lex B; Snijders, Tim; Holloway, Tanya M; VAN Kranenburg, Janneau; VAN Loon, Luc J C

2016-11-01

Skeletal muscle capillarization plays a key role in oxygen and nutrient delivery to muscle. The loss of muscle mass with aging and the concept of anabolic resistance have been, at least partly, attributed to changes in skeletal muscle capillary structure and function. We aimed to compare skeletal muscle capillarization between young and older men and evaluate whether resistance-type exercise training increases muscle capillarization in older men. Muscle biopsies were obtained from the vastus lateralis of healthy young (n = 14, 26 ± 2 yr) and older (n = 16, 72 ± 1 yr) adult men, with biopsies before and after 12 wk of resistance-type exercise training in the older subjects. Immunohistochemistry was used to assess skeletal muscle fiber size, capillary contacts (CC) per muscle fiber, and the capillary-to-fiber perimeter exchange (CFPE) index in type I and II muscle fibers. Type II muscle fibers were smaller in old versus young (4507 ± 268 vs 6084 ± 497 μm, respectively, P = 0.007). Type I and type II muscle fiber CC and CFPE index were smaller in old compared with young muscle (CC type I: 3.8 ± 0.2 vs 5.0 ± 0.3; CC type II: 3.2 ± 0.2 vs 4.2 ± 0.2, respectively; both P < 0.001). Resistance-type exercise training increased type II muscle fiber size only. In addition, CC and CFPE index increased in both the type I (26% ± 9% and 27% ± 8%) and type II muscle fibers (33% ± 7% and 24% ± 6%, respectively; all P ≤ 0.001) after 12 wk resistance training in older men. We conclude that resistance-type exercise training can effectively augment skeletal muscle fiber capillarization in older men. The greater capillary supply may be an important prerequisite to reverse anabolic resistance and support muscle hypertrophy during lifestyle interventions aiming to support healthy aging.

Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number.

PubMed

Price, Ric N; Uhlemann, Anne-Catrin; Brockman, Alan; McGready, Rose; Ashley, Elizabeth; Phaipun, Lucy; Patel, Rina; Laing, Kenneth; Looareesuwan, Sornchai; White, Nicholas J; Nosten, François; Krishna, Sanjeev

The borders of Thailand harbour the world's most multidrug resistant Plasmodium falciparum parasites. In 1984 mefloquine was introduced as treatment for uncomplicated falciparum malaria, but substantial resistance developed within 6 years. A combination of artesunate with mefloquine now cures more than 95% of acute infections. For both treatment regimens, the underlying mechanisms of resistance are not known. The relation between polymorphisms in the P falciparum multidrug resistant gene 1 (pfmdr1) and the in-vitro and in-vivo responses to mefloquine were assessed in 618 samples from patients with falciparum malaria studied prospectively over 12 years. pfmdr1 copy number was assessed by a robust real-time PCR assay. Single nucleotide polymorphisms of pfmdr1, P falciparum chloroquine resistance transporter gene (pfcrt) and P falciparum Ca2+ ATPase gene (pfATP6) were assessed by PCR-restriction fragment length polymorphism. Increased copy number of pfmdr1 was the most important determinant of in-vitro and in-vivo resistance to mefloquine, and also to reduced artesunate sensitivity in vitro. In a Cox regression model with control for known confounders, increased pfmdr1 copy number was associated with an attributable hazard ratio (AHR) for treatment failure of 6.3 (95% CI 2.9-13.8, p<0.001) after mefloquine monotherapy and 5.4 (2.0-14.6, p=0.001) after artesunate-mefloquine therapy. Single nucleotide polymorphisms in pfmdr1 were associated with increased mefloquine susceptibility in vitro, but not in vivo. Amplification in pfmdr1 is the main cause of resistance to mefloquine in falciparum malaria. Multidrug resistant P falciparum malaria is common in southeast Asia, but difficult to identify and treat. Genes that encode parasite transport proteins maybe involved in export of drugs and so cause resistance. In this study we show that increase in copy number of pfmdr1, a gene encoding a parasite transport protein, is the best overall predictor of treatment failure with

Zinc finger protein 267 is up-regulated in hepatocellular carcinoma and promotes tumor cell proliferation and migration.

PubMed

Schnabl, Bernd; Valletta, Daniela; Kirovski, Georgi; Hellerbrand, Claus

2011-12-01

Zinc finger protein 267 (ZNF267) belongs to the family of Kruppel-like transcription factors, which regulates diverse biological processes that include development, proliferation, and differentiation. We have previously demonstrated that ZNF267 mRNA is up-regulated in liver cirrhosis, which is the main risk factor for hepatocellular carcinoma (HCC). Here, we analyzed the expression of ZNF267 in human HCC cells and tissue specimens and found a significant up-regulation compared to primary human hepatocytes and corresponding non-tumorous liver tissue. Over-expression of the transcription factor Ets-1 further enhanced ZNF267 expression, and reporter gene assays revealed that mutation of the Ets-1 binding site to the ZNF267 promotor markedly inhibited ZNF267 promotor activity. Hypoxic conditions induced Ets-1 in HCC cells via HIF1alpha activation, and hypoxia induced ZNF267 expression while HIF1alpha inhibition significantly reduced both hypoxia-induced as well as basal ZNF267 expression in HCC cells. It is known that hypoxic conditions in tumorous tissues induce the formation of reactive oxygen species (ROS), and ROS have been identified as important factor in the regulation of Ets-1 expression in tumor cells. Here, we found that ROS induction induced and ROS scavenging reduced ZNF267 expression in HCC cells, respectively. Loss and gain of function analysis applying siRNA directed against ZNF267 or transient transfection revealed that ZNF267 promotes proliferation and migration of HCC cells in vitro. These findings indicate Ets-1 and HIF1alpha as critical regulators of basal and hypoxia- or ROS-induced ZNF267 expression in HCC, and further suggest that the pro-tumorigenic effect of these factors is at least in part mediated via increased ZNF267 expression in HCC. Since ZNF267 is already elevated in cirrhosis, ZNF267 appears as promising target for both prevention as well as treatment of HCC in patients with chronic liver disease. Copyright © 2011 Elsevier Inc. All

Zinc finger protein 267 is up-regulated in hepatocellular carcinoma and promotes tumor cell proliferation and migration

PubMed Central

Schnabl, Bernd; Valletta, Daniela; Kirovski, Georgi; Hellerbrand, Claus

2012-01-01

Zinc finger protein 267 (ZNF267) belongs to the family of Kruppel-like transcription factors, which regulates diverse biological processes that include development, proliferation, and differentiation. We have previously demonstrated that ZNF267 mRNA is up-regulated in liver cirrhosis, which is the main risk factor for hepatocellular carcinoma (HCC). Here, we analyzed the expression of ZNF267 in human HCC cells and tissue specimens and found a significant up-regulation compared to primary human hepatocytes and corresponding non-tumorous liver tissue. Over-expression of the transcription factor Ets-1 further enhanced ZNF267 expression, and reporter gene assays revealed that mutation of the Ets-1 binding site to the ZNF267 promotor markedly inhibited ZNF267 promotor activity. Hypoxic conditions induced Ets-1 in HCC cells via HIF1alpha activation, and hypoxia induced ZNF267 expression while HIF1alpha inhibition significantly reduced both hypoxia-induced as well as basal ZNF267 expression in HCC cells. It is known that hypoxic conditions in tumorous tissues induce the formation of reactive oxygen species (ROS), and ROS have been identified as important factor in the regulation of Ets-1 expression in tumor cells. Here, we found that ROS induction induced and ROS scavenging reduced ZNF267 expression in HCC cells, respectively. Loss and gain of function analysis applying siRNA directed against ZNF267 or transient transfection revealed that ZNF267 promotes proliferation and migration of HCC cells in vitro. These findings indicate Ets-1 and HIF1alpha as critical regulators of basal and hypoxia- or ROS-induced ZNF267 expression in HCC, and further suggest that the pro-tumorigenic effect of these factors is at least in part mediated via increased ZNF267 expression in HCC. Since ZNF267 is already elevated in cirrhosis, ZNF267 appears as promising target for both prevention as well as treatment of HCC in patients with chronic liver disease. PMID:21840307

Circulating adiponectin concentrations are increased by dietary resistant starch and correlate with serum 25-hydroxycholecalciferol concentrations and kidney function in Zucker diabetic fatty rats.

PubMed

Koh, Gar Yee; Derscheid, Rachel; Fuller, Kelly N Z; Valentine, Rudy J; Leow, Shu En; Reed, Leah; Wisecup, Emily; Schalinske, Kevin L; Rowling, Matthew J

2016-04-01

We previously reported that dietary resistant starch (RS) type 2 prevented proteinuria and promoted vitamin D balance in type 2 diabetic (T2D) rats. Here, our primary objective was to identify potential mechanisms that could explain our earlier observations. We hypothesized that RS could promote adiponectin secretion and regulate the renin-angiotensin system activity in the kidney. Lean Zucker rats (n = 5) were fed control diet; Zucker diabetic fatty rats (n = 5/group) were fed either an AIN-93G control diet (DC) or AIN-93G diet containing either 10% RS or 20% RS (HRS) for 6 weeks. Resistant starch had no impact on blood glucose concentrations and hemoglobin A1c percentage, yet circulating adiponectin was 77% higher in HRS-fed rats, compared to DC rats. Adiponectin concentrations strongly correlated with serum 25-hydroxycholecalciferol (r = 0.815; P < .001) and urinary creatinine concentrations (r = 0.818; P < .001) and inversely correlated with proteinuria (r = -0.583; P = .02). Serum angiotensin II concentrations were 44% lower, and expression of the angiotensin II receptor, type 1, was attenuated in RS-fed rats. Moreover, we observed a 14-fold increase in messenger RNA expression of nephrin, which is required for functioning of the renal filtration barrier, in HRS rats. The HRS, but not 10% RS diet, increased circulating 25-hydroxycholecalciferol concentrations and attenuated urinary loss of vitamin D metabolites in Zucker diabetic fatty rats. Taken together, we provide evidence that vitamin D balance in the presence of hyperglycemia is strongly associated with serum adiponectin levels and reduced renal renin-angiotensin system signaling. Copyright © 2016 Elsevier Inc. All rights reserved.

CROSS-RESISTANCE FOLLOWING ARTIFICIAL SELECTION FOR INCREASED DEFENSE AGAINST PARASITOIDS IN DROSOPHILA MELANOGASTER.

PubMed

Fellowes, M D E; Kraaijeveld, A R; Godfray, H C J

1999-06-01

An increase in resistance to one natural enemy may result in no correlated change, a positive correlated change, or a negative correlated change in the ability of the host or prey to resist other natural enemies. The type of specificity is important in understanding the evolutionary response to natural enemies and was studied here in a Drosophila-paxasitoid system. Drosophila melanogaster lines selected for increased larval resistance to the endoparasitoid wasps Asobara tabida or Leptopilina boulardi were exposed to attack by A. tabida, L. boulardi and Leptopilina heterotoma at 15°C, 20°C, and 25°C. In general, encapsulation ability increased with temperature, with the exception of the lines selected against L. boulardi, which showed the opposite trend. Lines selected against L. boulardi showed large increases in resistance against all three parasitoid species, and showed similar levels of defense against A. tabida to the lines selected against that parasitoid. In contrast, lines selected against A. tabida showed a large increase in resistance to A. tabida and generally to L. heterotoma, but displayed only a small change in their ability to survive attack by L. boulardi. Such asymmetries in correlated responses to selection for increased resistance to natural enemies may influence host-parasitoid community structure. © 1999 The Society for the Study of Evolution.

Dragon (RGMb) induces oxaliplatin resistance in colon cancer cells.

PubMed

Shi, Ying; Huang, Xiao-Xiao; Chen, Guo-Bin; Wang, Ying; Zhi, Qiang; Liu, Yuan-Sheng; Wu, Xiao-Ling; Wang, Li-Fen; Yang, Bing; Xiao, Chuan-Xing; Xing, Hui-Qin; Ren, Jian-Lin; Xia, Yin; Guleng, Bayasi

2016-07-26

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and a major cause of cancer mortality. Chemotherapy resistance remains a major challenge for treating advanced CRC. Therefore, the identification of targets that induce drug resistance is a priority for the development of novel agents to overcome resistance. Dragon (also known as RGMb) is a member of the repulsive guidance molecule (RGM) family. We previously showed that Dragon expression increases with CRC progression in human patients. In the present study, we found that Dragon inhibited apoptosis and increased viability of CMT93 and HCT116 cells in the presence of oxaliplatin. Dragon induced resistance of xenograft tumor to oxaliplatinin treatment in mice. Mechanistically, Dragon inhibited oxaliplatin-induced JNK and p38 MAPK activation, and caspase-3 and PARP cleavages. Our results indicate that Dragon may be a novel target that induces drug resistance in CRC.

Dragon (RGMb) induces oxaliplatin resistance in colon cancer cells

PubMed Central

Wang, Ying; Zhi, Qiang; Liu, Yuan-Sheng; Wu, Xiao-Ling; Wang, Li-Fen; Yang, Bing; Xiao, Chuan-Xing; Xing, Hui-Qin; Ren, Jian-Lin; Xia, Yin; Guleng, Bayasi

2016-01-01

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and a major cause of cancer mortality. Chemotherapy resistance remains a major challenge for treating advanced CRC. Therefore, the identification of targets that induce drug resistance is a priority for the development of novel agents to overcome resistance. Dragon (also known as RGMb) is a member of the repulsive guidance molecule (RGM) family. We previously showed that Dragon expression increases with CRC progression in human patients. In the present study, we found that Dragon inhibited apoptosis and increased viability of CMT93 and HCT116 cells in the presence of oxaliplatin. Dragon induced resistance of xenograft tumor to oxaliplatinin treatment in mice. Mechanistically, Dragon inhibited oxaliplatin-induced JNK and p38 MAPK activation, and caspase-3 and PARP cleavages. Our results indicate that Dragon may be a novel target that induces drug resistance in CRC. PMID:27384995

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

Oh, Yohan; Chung, Kwang Chul, E-mail: kchung@yonsei.ac.kr

Highlights: Black-Right-Pointing-Pointer ZNF131 directly interacts with ER{alpha}. Black-Right-Pointing-Pointer The binding affinity of ZNF131 to ER{alpha} increases upon E2 stimulation. Black-Right-Pointing-Pointer ZNF131 inhibits ER{alpha}-mediated trans-activation by suppressing its homo-dimerization. Black-Right-Pointing-Pointer ZNF131 inhibits ER{alpha}-dimerization and E2-induced breast cancer cell proliferation. Black-Right-Pointing-Pointer ZNF131 inhibits estrogen signaling by acting as an ER{alpha}-co-repressor. -- Abstract: Steroid hormone estrogen elicits various physiological functions, many of which are mediated through two structurally and functionally distinct estrogen receptors, ER{alpha} and ER{beta}. The functional role of zinc finger protein 131 (ZNF131) is poorly understood, but it is assumed to possess transcriptional regulation activity due to the presence of amore » DNA binding motif. A few recent reports, including ours, revealed that ZNF131 acts as a negative regulator of ER{alpha} and that SUMO modification potentiates the negative effect of ZNF131 on estrogen signaling. However, its molecular mechanism for ER{alpha} inhibition has not been elucidated in detail. Here, we demonstrate that ZNF131 directly interacts with ER{alpha}, which consequently inhibits ER{alpha}-mediated trans-activation by suppressing its homo-dimerization. Moreover, we show that the C-terminal region of ZNF131 containing the SUMOylation site is necessary for its inhibition of estrogen signaling. Taken together, these data suggest that ZNF131 inhibits estrogen signaling by acting as an ER{alpha}-co-repressor.« less

Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number

PubMed Central

Brockman, Alan; McGready, Rose; Ashley, Elizabeth; Phaipun, Lucy; Patel, Rina; Laing, Kenneth; Looareesuwan, Sornchai; White, Nicholas J; Nosten, François; Krishna, Sanjeev

2015-01-01

Summary Background The borders of Thailand harbour the world’s most multidrug resistant Plasmodium falciparum parasites. In 1984 mefloquine was introduced as treatment for uncomplicated falciparum malaria, but substantial resistance developed within 6 years. A combination of artesunate with mefloquine now cures more than 95% of acute infections. For both treatment regimens, the underlying mechanisms of resistance are not known. Methods The relation between polymorphisms in the P falciparum multidrug resistant gene 1 (pfmdr1) and the in-vitro and in-vivo responses to mefloquine were assessed in 618 samples from patients with falciparum malaria studied prospectively over 12 years. pfmdr1 copy number was assessed by a robust real-time PCR assay. Single nucleotide polymorphisms of pfmdr1, P falciparum chloroquine resistance transporter gene (pfcrt) and P falciparum Ca2+ ATPase gene (pfATP6) were assessed by PCR-restriction fragment length polymorphism. Findings Increased copy number of pfmdr1 was the most important determinant of in-vitro and in-vivo resistance to mefloquine, and also to reduced artesunate sensitivity in vitro. In a Cox regression model with control for known confounders, increased pfmdr1 copy number was associated with an attributable hazard ratio (AHR) for treatment failure of 6·3 (95% CI 2·9–13·8, p<0·001) after mefloquine monotherapy and 5·4 (2·0-14·6, p=0·001) after artesunate-mefloquine therapy. Single nucleotide polymorphisms in pfmdr1 were associated with increased mefloquine susceptibility in vitro, but not in vivo. Interpretation Amplification in pfmdr1 is the main cause of resistance to mefloquine in falciparum malaria. Relevance to practice Multidrug resistant P falciparum malaria is common in southeast Asia, but difficult to identify and treat. Genes that encode parasite transport proteins maybe involved in export of drugs and so cause resistance. In this study we show that increase in copy number of pfmdr1, a gene encoding a

Anomalous Hall Resistance in Bilayer Electron Systems

NASA Astrophysics Data System (ADS)

Ezawa, Z. F.; Suzuki, S.; Tsitsishvili, G.

2007-04-01

Interlayer phase coherence has revealed various novel features in bilayer quantum Hall (QH) systems. It is shown to make the QH resistance vanish instead of developing a Hall plateau in a bilayer counterflow geometry. It also induces another anomalous QH resistance discovered in a drag experiment. These theoretical results explain recent experimental data due to Kellogg et al. [PRL 93 (2004) 036801;PRL 88 (2002) 126804] and Tutuc et al.[PRL 93 (2004) 036802].

Resistance exercise increases intramuscular NF-κb signaling in untrained males.

PubMed

Townsend, Jeremy R; Stout, Jeffrey R; Jajtner, Adam R; Church, David D; Beyer, Kyle S; Oliveira, Leonardo P; La Monica, Michael B; Riffe, Joshua J; Muddle, Tyler W D; Baker, Kayla M; Fukuda, David H; Roberts, Michael D; Hoffman, Jay R

2016-12-01

The NF-κB signaling pathway regulates multiple cellular processes following exercise stress. This study aims to examine the effects of an acute lower-body resistance exercise protocol and subsequent recovery on intramuscular NF-κB signaling. Twenty-eight untrained males were assigned to either a control (CON; n = 11) or exercise group (EX; n = 17) and completed a lower-body resistance exercise protocol consisting of the back squat, leg press, and leg extension exercises. Skeletal muscle microbiopsies were obtained from the vastus lateralis pre-exercise (PRE), 1-hour (1H), 5-hours (5H), and 48-hours (48H) post-resistance exercise. Multiplex signaling assay kits (EMD Millipore, Billerica, MA, USA) were used to quantify the total protein (TNFR1, c-Myc) or phosphorylation status of proteins belonging to the NF-κB signaling pathway (IKKa/b, IkBα, NF-κB) using multiplex protein assay. Repeated measures ANOVA analysis was used to determine the effects of the exercise bout on intramuscular signaling at each time point. Additionally, change scores were analyzed by magnitude based inferences to determine a mechanistic interpretation. Repeated measures ANOVA indicated a trend for a two-way interaction between the EX and CON Group (p = 0.064) for c-Myc post resistance exercise. Magnitude based inference analysis suggest a "Very Likely" increase in total c-Myc from PRE-5H and a "Likely" increase in IkBα phosphorylation from PRE-5H post-resistance exercise. Results indicated that c-Myc transcription factor is elevated following acute intense resistance exercise in untrained males. Future studies should examine the role that post-resistance exercise NF-κβ signaling plays in c-Myc induction, ribosome biogenesis and skeletal muscle regeneration.

Interactions and phosphorylation of postsynaptic density 93 (PSD-93) by extracellular signal-regulated kinase (ERK).

PubMed

Guo, Ming-Lei; Xue, Bing; Jin, Dao-Zhong; Mao, Li-Min; Wang, John Q

2012-07-17

Postsynaptic density 93 (PSD-93) is a protein enriched at postsynaptic sites. As a key scaffolding protein, PSD-93 forms complexes with the clustering of various synaptic proteins to construct postsynaptic signaling networks and control synaptic transmission. Extracellular signal-regulated kinase (ERK) is a prototypic member of a serine/threonine protein kinase family known as mitogen-activated protein kinase (MAPK). This kinase, especially ERK2 isoform, noticeably resides in peripheral structures of neurons, such as dendritic spines and postsynaptic density areas, in addition to its distribution in the cytoplasm and nucleus, although little is known about specific substrates of ERK at synaptic sites. In this study, we found that synaptic PSD-93 is a direct target of ERK. This was demonstrated by direct protein-protein interactions between purified ERK2 and PSD-93 in vitro. The accurate ERK2-binding region seems to locate at an N-terminal region of PSD-93. In adult rat striatal neurons in vivo, native ERK from synaptosomal fractions also associated with PSD-93. In phosphorylation assays, active ERK2 phosphorylated PSD-93. An accurate phosphorylation site was identified at a serine site (S323). In striatal neurons, immunoprecipitated PSD-93 showed basal phosphorylation at an ERK-sensitive site. Our data provide evidence supporting PSD-93 as a new substrate of the synaptic species of ERK. ERK2 possesses the ability to interact with PSD-93 and phosphorylate PSD-93 at a specific site. Published by Elsevier B.V.

What is the impact of genome-wide supported risk variants for schizophrenia and bipolar disorder on brain structure and function? A systematic review.

PubMed

Gurung, R; Prata, D P

2015-01-01

The powerful genome-wide association studies (GWAS) revealed common mutations that increase susceptibility for schizophrenia (SZ) and bipolar disorder (BD), but the vast majority were not known to be functional or associated with these illnesses. To help fill this gap, their impact on human brain structure and function has been examined. We systematically discuss this output to facilitate its timely integration in the psychosis research field; and encourage reflection for future research. Irrespective of imaging modality, studies addressing the effect of SZ/BD GWAS risk genes (ANK3, CACNA1C, MHC, TCF4, NRGN, DGKH, PBRM1, NCAN and ZNF804A) were included. Most GWAS risk variations were reported to affect neuroimaging phenotypes implicated in SZ/BD: white-matter integrity (ANK3 and ZNF804A), volume (CACNA1C and ZNF804A) and density (ZNF804A); grey-matter (CACNA1C, NRGN, TCF4 and ZNF804A) and ventricular (TCF4) volume; cortical folding (NCAN) and thickness (ZNF804A); regional activation during executive tasks (ANK3, CACNA1C, DGKH, NRGN and ZNF804A) and functional connectivity during executive tasks (CACNA1C and ZNF804A), facial affect recognition (CACNA1C and ZNF804A) and theory-of-mind (ZNF804A); but inconsistencies and non-replications also exist. Further efforts such as standardizing reporting and exploring complementary designs, are warranted to test the reproducibility of these early findings.

Increased survival of experimentally evolved antimicrobial peptide-resistant Staphylococcus aureus in an animal host

PubMed Central

Dobson, Adam J; Purves, Joanne; Rolff, Jens

2014-01-01

Antimicrobial peptides (AMPs) have been proposed as new class of antimicrobial drugs, following the increasing prevalence of bacteria resistant to antibiotics. Synthetic AMPs are functional analogues of highly evolutionarily conserved immune effectors in animals and plants, produced in response to microbial infection. Therefore, the proposed therapeutic use of AMPs bears the risk of ‘arming the enemy’: bacteria that evolve resistance to AMPs may be cross-resistant to immune effectors (AMPs) in their hosts. We used a panel of populations of Staphylococcus aureus that were experimentally selected for resistance to a suite of individual AMPs and antibiotics to investigate the ‘arming the enemy’ hypothesis. We tested whether the selected strains showed higher survival in an insect model (Tenebrio molitor) and cross-resistance against other antimicrobials in vitro. A population selected for resistance to the antimicrobial peptide iseganan showed increased in vivo survival, but was not more virulent. We suggest that increased survival of AMP-resistant bacteria almost certainly poses problems to immune-compromised hosts. PMID:25469169

Interference-free determination of sub ng kg-1 levels of long-lived 93Zr in the presence of high concentrations (μg kg-1) of 93Mo and 93Nb using ICP-MS/MS.

PubMed

Petrov, Panayot; Russell, Ben; Douglas, David N; Goenaga-Infante, Heidi

2018-01-01

Long-lived high abundance radionuclides are of increasing interest with regard to decommissioning of nuclear sites and longer term nuclear waste storage and disposal. In many cases, no routine technique is available for their measurement in nuclear waste and low-level (ng kg -1 ) environmental samples. Recent advances in ICP-MS technology offer attractive features for the selective and sensitive determination of a wide range of long-lived radionuclides. In this work, inductively coupled plasma-tandem mass spectrometry (ICP-MS/MS)-based methodology, suitable for accurate routine determinations of 93 Zr at very low (ng kg -1 ) levels in the presence of high levels (μg kg -1 ) of the isobaric interferents 93 Nb and 93 Mo (often present in nuclear waste samples), is reported for the first time. Additionally, a novel and systematic strategy for method development based on the use of non-radioactive isotopes is proposed. It relies on gas-phase chemical reactions for different molecular ion formation to achieve isobaric interference removal. Using cell gas mixtures of NH 3 /He/H 2 or H 2 /O 2 , and suitable mass shifts, the signal from the 93 Nb and 93 Mo isobaric interferences on 93 Zr were suppressed by up to 5 orders of magnitude. The achieved limit of detection for 93 Zr was 1.3 × 10 -5  Bq g -1 (equivalent to 0.14 ng kg -1 ). The sample analysis time is 2 min, which represents a significant improvement in terms of sample throughput, compared to liquid scintillation counting methods. The method described here can be used for routine measurements of 93 Zr at environmentally relevant levels. It can also be combined with radiometric techniques for use towards the standardisation of 93 Zr measurements. Graphical abstract Interference-free determination of 93 Zr in the presence of high concentrations of isobaric 93 Mo and 93 Nb by ICP-MS/MS.

Increase of β-Lactam-Resistant Invasive Haemophilus influenzae in Sweden, 1997 to 2010

PubMed Central

Resman, Fredrik; Ristovski, Mikael; Forsgren, Arne; Kaijser, Bertil; Kronvall, Göran; Medstrand, Patrik; Melander, Eva; Odenholt, Inga

2012-01-01

The proportions of Haemophilus influenzae resistant to ampicillin and other β-lactam antibiotics have been low in Sweden compared to other countries in the Western world. However, a near-doubled proportion of nasopharyngeal Swedish H. influenzae isolates with resistance to β-lactams has been observed in the last decade. In the present study, the epidemiology and mechanisms of antimicrobial resistance of H. influenzae isolates from blood and cerebrospinal fluid in southern Sweden from 1997 to 2010 (n = 465) were studied. Antimicrobial susceptibility testing was performed using disk diffusion, and isolates with resistance to any tested β-lactam were further analyzed in detail. We identified a significantly increased (P = 0.03) proportion of β-lactam-resistant invasive H. influenzae during the study period, which was mainly attributed to a significant recent increase of β-lactamase-negative β-lactam-resistant isolates (P = 0.04). Furthermore, invasive β-lactamase-negative β-lactam-resistant H. influenzae isolates from 2007 and onwards were found in higher proportions than the corresponding proportions of nasopharyngeal isolates in a national survey. Multiple-locus sequence typing (MLST) of this group of isolates did not completely separate isolates with different resistance phenotypes. However, one cluster of β-lactamase-negative ampicillin-resistant (BLNAR) isolates was identified, and it included isolates from all geographical areas. A truncated variant of a β-lactamase gene with a promoter deletion, blaTEM-1-PΔ dominated among the β-lactamase-positive H. influenzae isolates. Our results show that the proportions of β-lactam-resistant invasive H. influenzae have increased in Sweden in the last decade. PMID:22687505

Zinc-finger protein 418 overexpression protects against cardiac hypertrophy and fibrosis

PubMed Central

Huang, Zirui; Zhu, Zhilin; Xu, Chunli; Teng, Lin; He, Ling; Gu, Chen; Yi, Cai

2017-01-01

Background This study aimed to investigated the effect and mechanism of zinc-finger protein 418 (ZNF418) on cardiac hypertrophy caused by aortic banding (AB), phenylephrine (PE) or angiotensin II (Ang II) in vivo and in vitro. Methods The expression of ZNF418 in hearts of patients with dilated cardiomyopathy (DCM) or hypertrophic cardiomyopathy (HCM) and AB-induced cardiac hypertrophy mice, as well as in Ang II- or PE-induced hypertrophic primary cardiomyocytes was detected by western blotting. Then, the expression of ZNF418 was up-regulated or down-regulated in AB-induced cardiac hypertrophy mice and Ang II -induced hypertrophic primary cardiomyocytes. The hypertrophic responses and fibrosis were evaluated by echocardiography and histological analysis. The mRNA levels of hypertrophy markers and fibrotic markers were detected by RT-qPCR. Furthermore, the phosphorylation and total levels of c-Jun were measured by western blotting. Results ZNF418 was markedly down-regulated in hearts of cardiac hypertrophy and hypertrophic primary cardiomyocytes. Down-regulated ZNF418 exacerbated the myocyte size and fibrosis, moreover increased the mRNA levels of ANP, BNP, β-MHC, MCIP1.4, collagen 1a, collagen III, MMP-2 and fibronection in hearts of AB-treated ZNF418 knockout mice or Ang II-treated cardiomyocytes with AdshZNF418. Conversely, these hypertrophic responses were reduced in the ZNF418 transgenic (TG) mice treated by AB and the AdZNF418-transfected primary cardiomyocytes treated by Ang II. Additionally, the deficiency of ZNF418 enhanced the phosphorylation level of c-jun, and overexpression of ZNF418 suppressed the phosphorylation level of c-jun in vivo and in vitro. Conclusion ZNF418 maybe attenuate hypertrophic responses by inhibiting the activity of c-jun/AP-1. PMID:29065170

Increased Resistance to Multiple Antimicrobials and Altered Resistance Gene Expression in CMY-2-Positive Salmonella enterica following a Simulated Patient Treatment with Ceftriaxone

PubMed Central

Hamilton, Russell D.; Hulsebus, Holly J.; Akbar, Samina

2012-01-01

Salmonellosis is one of the most common causes of food-borne disease in the United States. Increasing antimicrobial resistance and corresponding increases in virulence present serious challenges. Currently, empirical therapy for invasive Salmonella enterica infection includes either ceftriaxone or ciprofloxacin (E. L. Hohmann, Clin. Infect. Dis. 32:263–269, 2001). The blaCMY-2 gene confers resistance to ceftriaxone, the antimicrobial of choice for pediatric patients with invasive Salmonella enterica infections, making these infections especially dangerous (J. M. Whichard et al., Emerg. Infect. Dis. 11:1464–1466, 2005). We hypothesized that blaCMY-2-positive Salmonella enterica would exhibit increased MICs to multiple antimicrobial agents and increased resistance gene expression following exposure to ceftriaxone using a protocol that simulated a patient treatment in vitro. Seven Salmonella enterica strains survived a simulated patient treatment in vitro and, following treatment, exhibited a significantly increased ceftriaxone MIC. Not only would these isolates be less responsive to further ceftriaxone treatment, but because the blaCMY-2 genes are commonly located on large, multidrug-resistant plasmids, increased expression of the blaCMY-2 gene may be associated with increased expression of other drug resistance genes located on the plasmid (N. D. Hanson and C. C. Sanders, Curr. Pharm. Des. 5:881–894, 1999). The results of this study demonstrate that a simulated patient treatment with ceftriaxone can alter the expression of antimicrobial resistance genes, including blaCMY-2 and floR in S. enterica serovar Typhimurium and S. enterica serovar Newport. Additionally, we have shown increased MICs following a simulated patient treatment with ceftriaxone for tetracycline, amikacin, ceftriaxone, and cefepime, all of which have resistance genes commonly located on CMY-2 plasmids. The increases in resistance observed are significant and may have a negative impact on both

9 CFR 93.406 - Diagnostic tests.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Diagnostic tests. 93.406 Section 93... CONVEYANCE AND SHIPPING CONTAINERS Ruminants § 93.406 Diagnostic tests. (a) Tuberculosis and brucellosis tests of cattle. Except as provided in paragraph (d) of this section and in §§ 93.418, 93.427(d), and 93...

9 CFR 93.406 - Diagnostic tests.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Diagnostic tests. 93.406 Section 93... CONVEYANCE AND SHIPPING CONTAINERS Ruminants § 93.406 Diagnostic tests. (a) Tuberculosis and brucellosis tests of cattle. Except as provided in paragraph (d) of this section and in §§ 93.418, 93.427(d), and 93...

Coaxial Tubing Systems Increase Artificial Airway Resistance and Work of Breathing.

PubMed

Wenzel, Christin; Schumann, Stefan; Spaeth, Johannes

2017-09-01

Tubing systems are an essential component of the ventilation circuit, connecting the ventilator to the patient's airways. Coaxial tubing systems incorporate the inspiratory tube within the lumen of the expiratory one. We hypothesized that by design, these tubing systems increase resistance to air flow compared with conventional ones. We investigated the flow-dependent pressure gradient across coaxial, conventional disposable, and conventional reusable tubing systems from 3 different manufacturers. Additionally, the additional work of breathing and perception of resistance during breathing through the different devices were determined in 18 healthy volunteers. The pressure gradient across coaxial tubing systems was up to 6 times higher compared with conventional ones (1.90 ± 0.03 cm H 2 O vs 0.34 ± 0.01 cm H 2 O, P < .001) and was higher during expiration compared with inspiration ( P < .001). Additional work of breathing and perceived breathing resistance were highest in coaxial tubing systems, accordingly. Our findings suggest that the use of coaxial tubing systems should be carefully considered with respect to their increased resistance. Copyright © 2017 by Daedalus Enterprises.

Increasing socioeconomic inequality in childhood undernutrition in urban India: trends between 1992-93, 1998-99 and 2005-06.

PubMed

Kumar, Abhishek; Kumari, Divya; Singh, Aditya

2015-10-01

This article examines the trends and pattern in socioeconomic inequality in stunting, underweight and wasting among children aged <3 years in urban India over a 14-year period. We use three successive rounds of the National Family Health Survey data conducted during 1992-93, 1998-99 and 2005-06. The selected socioeconomic predictors are household wealth and mother's education level. We use principal component analysis to compute a separate wealth index for urban India for all three rounds of the survey. We have used descriptive statistics, concentration index and pooled logistic regression to analyse the data. The results show that between 1992-93 and 2005-06, the prevalence of childhood undernutrition has declined across household wealth quintiles and educational level of mothers. However, the pace of decline is much higher among the better-off socioeconomic groups than among the least-affluent groups. The result of pooled logistic regression analysis shows that the socioeconomic inequality in childhood undernutrition in urban India has increased over the study period. The salient findings of this study call for separate programmes targeting the children of lower socioeconomic groups in urban population of India. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine © The Author 2014; all rights reserved.

Neratinib resistance and cross-resistance to other HER2-targeted drugs due to increased activity of metabolism enzyme cytochrome P4503A4.

PubMed

Breslin, Susan; Lowry, Michelle C; O'Driscoll, Lorraine

2017-02-28

Neratinib is in Phase 3 clinical trials but, unfortunately, the development of resistance is inevitable. Here, we investigated the effects of acquired neratinib resistance on cellular phenotype and the potential mechanism of this resistance. Neratinib-resistant variants of HER2-positive breast cancer cells were developed and their cross-resistance investigated using cytotoxicity assays. Similarly, sensitivity of trastuzumab-resistant and lapatinib-resistant cells to neratinib was assessed. Cellular phenotype changes were evaluated using migration, invasion and anoikis assays. Immunoblotting for HER family members and drug efflux pumps, as well as enzyme activity assays were performed. Neratinib resistance conferred cross-resistance to trastuzumab, lapatinib and afatinib. Furthermore, the efficacy of neratinib was reduced in trastuzumab- and lapatinib-resistant cells. Neratinib-resistant cells were more aggressive than their drug-sensitive counterparts, with increased CYP3A4 activity identified as a novel mechanism of neratinib resistance. The potential of increased CYP3A4 activity as a biomarker and/or target to add value to neratinib warrants investigation.

HIV drug resistance in infants increases with changing prevention of mother-to-child transmission regimens.

PubMed

Poppe, Lisa K; Chunda-Liyoka, Catherine; Kwon, Eun H; Gondwe, Clement; West, John T; Kankasa, Chipepo; Ndongmo, Clement B; Wood, Charles

2017-08-24

The objectives of this study were to determine HIV drug resistance (HIVDR) prevalence in Zambian infants upon diagnosis, and to determine how changing prevention of mother-to-child transmission (PMTCT) drug regimens affect drug resistance. Dried blood spot (DBS) samples from infants in the Lusaka District of Zambia, obtained during routine diagnostic screening, were collected during four different years representing three different PMTCT drug treatment regimens. DNA extracted from dried blood spot samples was used to sequence a 1493 bp region of the reverse transcriptase gene. Sequences were analyzed via the Stanford HIVDRdatabase (http://hivdb.standford.edu) to screen for resistance mutations. HIVDR in infants increased from 21.5 in 2007/2009 to 40.2% in 2014. Nonnucleoside reverse transcriptase inhibitor resistance increased steadily over the sampling period, whereas nucleoside reverse transcriptase inhibitor resistance and dual class resistance both increased more than threefold in 2014. Analysis of drug resistance scores in each group revealed increasing strength of resistance over time. In 2014, children with reported PMTCT exposure, defined as infant prophylaxis and/or maternal treatment, showed a higher prevalence and strength of resistance compared to those with no reported exposure. HIVDR is on the rise in Zambia and presents a serious problem for the successful lifelong treatment of HIV-infected children. PMTCT affects both the prevalence and strength of resistance and further research is needed to determine how to mitigate its role leading to resistance.

Carboxylesterase-mediated insecticide resistance: Quantitative increase induces broader metabolic resistance than qualitative change.

PubMed

Cui, Feng; Li, Mei-Xia; Chang, Hai-Jing; Mao, Yun; Zhang, Han-Ying; Lu, Li-Xia; Yan, Shuai-Guo; Lang, Ming-Lin; Liu, Li; Qiao, Chuan-Ling

2015-06-01

Carboxylesterases are mainly involved in the mediation of metabolic resistance of many insects to organophosphate (OP) insecticides. Carboxylesterases underwent two divergent evolutionary events: (1) quantitative mechanism characterized by the overproduction of carboxylesterase protein; and (2) qualitative mechanism caused by changes in enzymatic properties because of mutation from glycine/alanine to aspartate at the 151 site (G/A151D) or from tryptophan to leucine at the 271 site (W271L), following the numbering of Drosophila melanogaster AChE. Qualitative mechanism has been observed in few species. However, whether this carboxylesterase mutation mechanism is prevalent in insects remains unclear. In this study, wild-type, G/A151D and W271L mutant carboxylesterases from Culex pipiens and Aphis gossypii were subjected to germline transformation and then transferred to D. melanogaster. These germlines were ubiquitously expressed as induced by tub-Gal4. In carboxylesterase activity assay, the introduced mutant carboxylesterase did not enhance the overall carboxylesterase activity of flies. This result indicated that G/A151D or W271L mutation disrupted the original activities of the enzyme. Less than 1.5-fold OP resistance was only observed in flies expressing A. gossypii mutant carboxylesterases compared with those expressing A. gossypii wild-type carboxylesterase. However, transgenic flies universally showed low resistance to OP insecticides compared with non-transgenic flies. The flies expressing A. gossypii W271L mutant esterase exhibited 1.5-fold resistance to deltamethrin, a pyrethroid insecticide compared with non-transgenic flies. The present transgenic Drosophila system potentially showed that a quantitative increase in carboxylesterases induced broader resistance of insects to insecticides than a qualitative change. Copyright © 2014 Elsevier Inc. All rights reserved.

Accumulation of phosphatidic acid increases vancomycin resistance in Escherichia coli.

PubMed

Sutterlin, Holly A; Zhang, Sisi; Silhavy, Thomas J

2014-09-01

In Gram-negative bacteria, lipopolysaccharide (LPS) contributes to the robust permeability barrier of the outer membrane, preventing entry of toxic molecules such as antibiotics. Mutations in lptD, the beta-barrel component of the LPS transport and assembly machinery, compromise LPS assembly and result in increased antibiotic sensitivity. Here, we report rare vancomycin-resistant suppressors that improve barrier function of a subset of lptD mutations. We find that all seven suppressors analyzed mapped to the essential gene cdsA, which is responsible for the conversion of phosphatidic acid to CDP-diacylglycerol in phospholipid biosynthesis. These cdsA mutations cause a partial loss of function and, as expected, accumulate phosphatidic acid. We show that this suppression is not confined to mutations that cause defects in outer membrane biogenesis but rather that these cdsA mutations confer a general increase in vancomycin resistance, even in a wild-type cell. We use genetics and quadrupole time of flight (Q-TOF) liquid chromatography-mass spectrometry (LC-MS) to show that accumulation of phosphatidic acid by means other than cdsA mutations also increases resistance to vancomycin. We suggest that increased levels of phosphatidic acid change the physical properties of the outer membrane to impede entry of vancomycin into the periplasm, hindering access to its target, an intermediate required for the synthesis of the peptidoglycan cell wall. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression.

PubMed

Darabi, Hatef; McCue, Karen; Beesley, Jonathan; Michailidou, Kyriaki; Nord, Silje; Kar, Siddhartha; Humphreys, Keith; Thompson, Deborah; Ghoussaini, Maya; Bolla, Manjeet K; Dennis, Joe; Wang, Qin; Canisius, Sander; Scott, Christopher G; Apicella, Carmel; Hopper, John L; Southey, Melissa C; Stone, Jennifer; Broeks, Annegien; Schmidt, Marjanka K; Scott, Rodney J; Lophatananon, Artitaya; Muir, Kenneth; Beckmann, Matthias W; Ekici, Arif B; Fasching, Peter A; Heusinger, Katharina; Dos-Santos-Silva, Isabel; Peto, Julian; Tomlinson, Ian; Sawyer, Elinor J; Burwinkel, Barbara; Marme, Frederik; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E; Flyger, Henrik; Benitez, Javier; González-Neira, Anna; Anton-Culver, Hoda; Neuhausen, Susan L; Arndt, Volker; Brenner, Hermann; Engel, Christoph; Meindl, Alfons; Schmutzler, Rita K; Arnold, Norbert; Brauch, Hiltrud; Hamann, Ute; Chang-Claude, Jenny; Khan, Sofia; Nevanlinna, Heli; Ito, Hidemi; Matsuo, Keitaro; Bogdanova, Natalia V; Dörk, Thilo; Lindblom, Annika; Margolin, Sara; Kosma, Veli-Matti; Mannermaa, Arto; Tseng, Chiu-Chen; Wu, Anna H; Floris, Giuseppe; Lambrechts, Diether; Rudolph, Anja; Peterlongo, Paolo; Radice, Paolo; Couch, Fergus J; Vachon, Celine; Giles, Graham G; McLean, Catriona; Milne, Roger L; Dugué, Pierre-Antoine; Haiman, Christopher A; Maskarinec, Gertraud; Woolcott, Christy; Henderson, Brian E; Goldberg, Mark S; Simard, Jacques; Teo, Soo H; Mariapun, Shivaani; Helland, Åslaug; Haakensen, Vilde; Zheng, Wei; Beeghly-Fadiel, Alicia; Tamimi, Rulla; Jukkola-Vuorinen, Arja; Winqvist, Robert; Andrulis, Irene L; Knight, Julia A; Devilee, Peter; Tollenaar, Robert A E M; Figueroa, Jonine; García-Closas, Montserrat; Czene, Kamila; Hooning, Maartje J; Tilanus-Linthorst, Madeleine; Li, Jingmei; Gao, Yu-Tang; Shu, Xiao-Ou; Cox, Angela; Cross, Simon S; Luben, Robert; Khaw, Kay-Tee; Choi, Ji-Yeob; Kang, Daehee; Hartman, Mikael; Lim, Wei Yen; Kabisch, Maria; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; McKay, James; Sangrajrang, Suleeporn; Toland, Amanda E; Yannoukakos, Drakoulis; Shen, Chen-Yang; Yu, Jyh-Cherng; Ziogas, Argyrios; Schoemaker, Minouk J; Swerdlow, Anthony; Borresen-Dale, Anne-Lise; Kristensen, Vessela; French, Juliet D; Edwards, Stacey L; Dunning, Alison M; Easton, Douglas F; Hall, Per; Chenevix-Trench, Georgia

2015-07-02

Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 [0.82-0.88]) and ER-negative (OR = 0.87 [0.82-0.91]) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:D) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 [0.91-0.95] and OR = 1.06 [1.03-1.09]) and ER-negative (OR = 0.95 [0.91-0.98] and OR = 1.08 [1.04-1.13]) disease. There was weaker evidence for iCHAV4, located 5' of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90-0.96]). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1-4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression

PubMed Central

Darabi, Hatef; McCue, Karen; Beesley, Jonathan; Michailidou, Kyriaki; Nord, Silje; Kar, Siddhartha; Humphreys, Keith; Thompson, Deborah; Ghoussaini, Maya; Bolla, Manjeet K.; Dennis, Joe; Wang, Qin; Canisius, Sander; Scott, Christopher G.; Apicella, Carmel; Hopper, John L.; Southey, Melissa C.; Stone, Jennifer; Broeks, Annegien; Schmidt, Marjanka K.; Scott, Rodney J.; Lophatananon, Artitaya; Muir, Kenneth; Beckmann, Matthias W.; Ekici, Arif B.; Fasching, Peter A.; Heusinger, Katharina; dos-Santos-Silva, Isabel; Peto, Julian; Tomlinson, Ian; Sawyer, Elinor J.; Burwinkel, Barbara; Marme, Frederik; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E.; Flyger, Henrik; Benitez, Javier; González-Neira, Anna; Anton-Culver, Hoda; Neuhausen, Susan L.; Arndt, Volker; Brenner, Hermann; Engel, Christoph; Meindl, Alfons; Schmutzler, Rita K.; Arnold, Norbert; Brauch, Hiltrud; Hamann, Ute; Chang-Claude, Jenny; Khan, Sofia; Nevanlinna, Heli; Ito, Hidemi; Matsuo, Keitaro; Bogdanova, Natalia V.; Dörk, Thilo; Lindblom, Annika; Margolin, Sara; Kosma, Veli-Matti; Mannermaa, Arto; Tseng, Chiu-chen; Wu, Anna H.; Floris, Giuseppe; Lambrechts, Diether; Rudolph, Anja; Peterlongo, Paolo; Radice, Paolo; Couch, Fergus J.; Vachon, Celine; Giles, Graham G.; McLean, Catriona; Milne, Roger L.; Dugué, Pierre-Antoine; Haiman, Christopher A.; Maskarinec, Gertraud; Woolcott, Christy; Henderson, Brian E.; Goldberg, Mark S.; Simard, Jacques; Teo, Soo H.; Mariapun, Shivaani; Helland, Åslaug; Haakensen, Vilde; Zheng, Wei; Beeghly-Fadiel, Alicia; Tamimi, Rulla; Jukkola-Vuorinen, Arja; Winqvist, Robert; Andrulis, Irene L.; Knight, Julia A.; Devilee, Peter; Tollenaar, Robert A.E.M.; Figueroa, Jonine; García-Closas, Montserrat; Czene, Kamila; Hooning, Maartje J.; Tilanus-Linthorst, Madeleine; Li, Jingmei; Gao, Yu-Tang; Shu, Xiao-Ou; Cox, Angela; Cross, Simon S.; Luben, Robert; Khaw, Kay-Tee; Choi, Ji-Yeob; Kang, Daehee; Hartman, Mikael; Lim, Wei Yen; Kabisch, Maria; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; McKay, James; Sangrajrang, Suleeporn; Toland, Amanda E.; Yannoukakos, Drakoulis; Shen, Chen-Yang; Yu, Jyh-Cherng; Ziogas, Argyrios; Schoemaker, Minouk J.; Swerdlow, Anthony; Borresen-Dale, Anne-Lise; Kristensen, Vessela; French, Juliet D.; Edwards, Stacey L.; Dunning, Alison M.; Easton, Douglas F.; Hall, Per; Chenevix-Trench, Georgia

2015-01-01

Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 [0.82–0.88]) and ER-negative (OR = 0.87 [0.82–0.91]) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:D) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 [0.91–0.95] and OR = 1.06 [1.03–1.09]) and ER-negative (OR = 0.95 [0.91–0.98] and OR = 1.08 [1.04–1.13]) disease. There was weaker evidence for iCHAV4, located 5′ of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90–0.96]). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1–4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer. PMID:26073781

Changing prevalence and resistance patterns in children with drug-resistant tuberculosis in Mumbai.

PubMed

Shah, Ira; Shah, Forum

2017-05-01

The prevalence of drug-resistant (DR) tuberculosis (TB) in children is increasing. Although, in India, multi-drug-resistant (MDR) TB rates have been relatively stable, the number of children with pre-extensively drug-resistant and extensively drug-resistant (XDR) TB is increasing. To determine whether the prevalence of DR TB in children in Mumbai is changing and to study the evolving patterns of resistance. A retrospective study was undertaken in 1311 paediatric patients referred between April 2007 and March 2013 to the Paediatric TB clinic at B. J. Wadia Hospital for Children, Mumbai. Children were defined as having DR TB on the basis of drug susceptibility testing (DST) of Mycobacterium tuberculosis grown on culture of body fluids (in the case of extra pulmonary TB) or from gastric lavage/bronchi-alveolar lavage/sputum in patients with pulmonary TB or from DST of the contacts. The prevalence of DR TB was calculated and the type of DR was evaluated yearly and in the pre-2010 and post-2010 eras. The overall prevalence of DR TB was 86 (6.6%) with an increase from 23 (5.6%) patients pre-2010 to 63 (7%) post-2010 (P = 0.40). Nine (10.4%) patients were diagnosed on the basis of contact with a parent with DR TB. Overall fluoroquinolone resistance increased from 9 (39.1%) pre-2010 to 59 (93.7%) post-2010 (P = 0.0001): moxifloxacin resistance increased from 2 (8.7%) to 29 (46%) (P = 0.0018) and ofloxacin resistance increased from 7 (30.4%) to 30 (47.6%) (P = 0.14). Ethionamide resistance also increased from 6 (26.1%) to 31 (49.2%) (P = 0.04), aminoglycoside resistance was one (4.3%) pre-2010 and 12 (19%) post-2010 (P = 0.17) and resistance remained virtually the same for both amikacin [0 pre-2010 and 6 (9.5%) after 2010] and kanamycin [one (4.3%) pre- and 6 (9.5%) post-2010]. Of the first-line drugs, resistance remained the same for isoniazid [23 (100%) to 61 (96.8%)], rifampicin [22 (95.7%) to 51 (80.9%),P = 0.17], pyrazinamide [15 (65.2%) to

Immobilisation increases yeast cells' resistance to dehydration-rehydration treatment.

PubMed

Borovikova, Diana; Rozenfelde, Linda; Pavlovska, Ilona; Rapoport, Alexander

2014-08-20

This study was performed with the goal of revealing if the dehydration procedure used in our new immobilisation method noticeably decreases the viability of yeast cells in immobilised preparations. Various yeasts were used in this research: Saccharomyces cerevisiae cells that were rather sensitive to dehydration and had been aerobically grown in an ethanol-containing medium, a recombinant strain of S. cerevisiae grown in aerobic conditions which were completely non-resistant to dehydration and an anaerobically grown bakers' yeast strain S. cerevisiae, as well as a fairly resistant Pichia pastoris strain. Experiments performed showed that immobilisation of all these strains essentially increased their resistance to a dehydration-rehydration treatment. The increase of cells' viability (compared with control cells dehydrated in similar conditions) was from 30 to 60%. It is concluded that a new immobilisation method, which includes a dehydration stage, does not lead to an essential loss of yeast cell viability. Correspondingly, there is no risk of losing the biotechnological activities of immobilised preparations. The possibility of producing dry, active yeast preparations is shown, for those strains that are very sensitive to dehydration and which can be used in biotechnology in an immobilised form. Finally, the immobilisation approach can be used for the development of efficient methods for the storage of recombinant yeast strains. Copyright © 2014 Elsevier B.V. All rights reserved.

Neratinib resistance and cross-resistance to other HER2-targeted drugs due to increased activity of metabolism enzyme cytochrome P4503A4

PubMed Central

Breslin, Susan; Lowry, Michelle C; O'Driscoll, Lorraine

2017-01-01

Background: Neratinib is in Phase 3 clinical trials but, unfortunately, the development of resistance is inevitable. Here, we investigated the effects of acquired neratinib resistance on cellular phenotype and the potential mechanism of this resistance. Methods: Neratinib-resistant variants of HER2-positive breast cancer cells were developed and their cross-resistance investigated using cytotoxicity assays. Similarly, sensitivity of trastuzumab-resistant and lapatinib-resistant cells to neratinib was assessed. Cellular phenotype changes were evaluated using migration, invasion and anoikis assays. Immunoblotting for HER family members and drug efflux pumps, as well as enzyme activity assays were performed. Results: Neratinib resistance conferred cross-resistance to trastuzumab, lapatinib and afatinib. Furthermore, the efficacy of neratinib was reduced in trastuzumab- and lapatinib-resistant cells. Neratinib-resistant cells were more aggressive than their drug-sensitive counterparts, with increased CYP3A4 activity identified as a novel mechanism of neratinib resistance. Conclusions: The potential of increased CYP3A4 activity as a biomarker and/or target to add value to neratinib warrants investigation. PMID:28152547

49 CFR 33.93 - Communications.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 49 Transportation 1 2012-10-01 2012-10-01 false Communications. 33.93 Section 33.93 Transportation Office of the Secretary of Transportation TRANSPORTATION PRIORITIES AND ALLOCATION SYSTEM Miscellaneous Provisions § 33.93 Communications. All communications concerning this part, including requests for copies of...

45 CFR 93.210 - Reporting.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 45 Public Welfare 1 2010-10-01 2010-10-01 false Reporting. 93.210 Section 93.210 Public Welfare... Employees § 93.210 Reporting. No reporting is required with respect to payments of reasonable compensation made to regularly employed officers or employees of a person. ...

9 CFR 93.800 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Definitions. 93.800 Section 93.800... CONVEYANCE AND SHIPPING CONTAINERS Elephants, Hippopotami, Rhinoceroses, and Tapirs § 93.800 Definitions. The... function involved. Person. Any individual, corporation, company, association, firm, partnership, society...

49 CFR 33.93 - Communications.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 49 Transportation 1 2013-10-01 2013-10-01 false Communications. 33.93 Section 33.93 Transportation Office of the Secretary of Transportation TRANSPORTATION PRIORITIES AND ALLOCATION SYSTEM Miscellaneous Provisions § 33.93 Communications. All communications concerning this part, including requests for copies of...

15 CFR 700.93 - Communications.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 15 Commerce and Foreign Trade 2 2014-01-01 2014-01-01 false Communications. 700.93 Section 700.93 Commerce and Foreign Trade Regulations Relating to Commerce and Foreign Trade (Continued) BUREAU OF... PRIORITIES AND ALLOCATIONS SYSTEM Miscellaneous Provisions § 700.93 Communications. All communications...

14 CFR 93.133 - Exceptions.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 2 2010-01-01 2010-01-01 false Exceptions. 93.133 Section 93.133 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR TRAFFIC AND GENERAL OPERATING RULES SPECIAL AIR TRAFFIC RULES High Density Traffic Airports § 93.133...

14 CFR 93.133 - Exceptions.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 2 2013-01-01 2013-01-01 false Exceptions. 93.133 Section 93.133 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR TRAFFIC AND GENERAL OPERATING RULES SPECIAL AIR TRAFFIC RULES High Density Traffic Airports § 93.133...

14 CFR 93.133 - Exceptions.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 2 2012-01-01 2012-01-01 false Exceptions. 93.133 Section 93.133 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR TRAFFIC AND GENERAL OPERATING RULES SPECIAL AIR TRAFFIC RULES High Density Traffic Airports § 93.133...

14 CFR 93.133 - Exceptions.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 2 2011-01-01 2011-01-01 false Exceptions. 93.133 Section 93.133 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR TRAFFIC AND GENERAL OPERATING RULES SPECIAL AIR TRAFFIC RULES High Density Traffic Airports § 93.133...

14 CFR 93.133 - Exceptions.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 2 2014-01-01 2014-01-01 false Exceptions. 93.133 Section 93.133 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR TRAFFIC AND GENERAL OPERATING RULES SPECIAL AIR TRAFFIC RULES High Density Traffic Airports § 93.133...

15 CFR 700.93 - Communications.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 15 Commerce and Foreign Trade 2 2010-01-01 2010-01-01 false Communications. 700.93 Section 700.93 Commerce and Foreign Trade Regulations Relating to Commerce and Foreign Trade (Continued) BUREAU OF... PRIORITIES AND ALLOCATIONS SYSTEM Miscellaneous Provisions § 700.93 Communications. All communications...

10 CFR 217.93 - Communications.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 10 Energy 3 2013-01-01 2013-01-01 false Communications. 217.93 Section 217.93 Energy DEPARTMENT OF ENERGY OIL ENERGY PRIORITIES AND ALLOCATIONS SYSTEM Miscellaneous Provisions § 217.93 Communications. All communications concerning this part, including requests for copies of the regulation and explanatory information...

14 CFR 93.303 - Definitions.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 2 2011-01-01 2011-01-01 false Definitions. 93.303 Section 93.303 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR TRAFFIC... Canyon National Park, AZ § 93.303 Definitions. For the purposes of this subpart: Allocation means...

14 CFR 93.303 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 2 2010-01-01 2010-01-01 false Definitions. 93.303 Section 93.303 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR TRAFFIC... Canyon National Park, AZ § 93.303 Definitions. For the purposes of this subpart: Allocation means...

9 CFR 381.93 - Decomposition.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 9 Animals and Animal Products 2 2011-01-01 2011-01-01 false Decomposition. 381.93 Section 381.93 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE AGENCY... § 381.93 Decomposition. Carcasses of poultry deleteriously affected by post mortem changes shall be...

9 CFR 381.93 - Decomposition.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 9 Animals and Animal Products 2 2014-01-01 2014-01-01 false Decomposition. 381.93 Section 381.93 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE AGENCY... § 381.93 Decomposition. Carcasses of poultry deleteriously affected by post mortem changes shall be...

9 CFR 381.93 - Decomposition.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 9 Animals and Animal Products 2 2012-01-01 2012-01-01 false Decomposition. 381.93 Section 381.93 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE AGENCY... § 381.93 Decomposition. Carcasses of poultry deleteriously affected by post mortem changes shall be...

9 CFR 381.93 - Decomposition.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 9 Animals and Animal Products 2 2013-01-01 2013-01-01 false Decomposition. 381.93 Section 381.93 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE AGENCY... § 381.93 Decomposition. Carcasses of poultry deleteriously affected by post mortem changes shall be...

14 CFR 93.51 - Applicability.

Code of Federal Regulations, 2011 CFR

2011-01-01

... AND GENERAL OPERATING RULES SPECIAL AIR TRAFFIC RULES Anchorage, Alaska, Terminal Area § 93.51... 14 Aeronautics and Space 2 2011-01-01 2011-01-01 false Applicability. 93.51 Section 93.51..., Terminal Area. [Doc. No. FAA-2002-13235, 68 FR 9795, Feb. 28, 2003] ...

14 CFR 93.51 - Applicability.

Code of Federal Regulations, 2014 CFR

2014-01-01

... AND GENERAL OPERATING RULES SPECIAL AIR TRAFFIC RULES Anchorage, Alaska, Terminal Area § 93.51... 14 Aeronautics and Space 2 2014-01-01 2014-01-01 false Applicability. 93.51 Section 93.51..., Terminal Area. [Doc. No. FAA-2002-13235, 68 FR 9795, Feb. 28, 2003] ...

14 CFR 93.51 - Applicability.

Code of Federal Regulations, 2010 CFR

2010-01-01

... AND GENERAL OPERATING RULES SPECIAL AIR TRAFFIC RULES Anchorage, Alaska, Terminal Area § 93.51... 14 Aeronautics and Space 2 2010-01-01 2010-01-01 false Applicability. 93.51 Section 93.51..., Terminal Area. [Doc. No. FAA-2002-13235, 68 FR 9795, Feb. 28, 2003] ...

14 CFR 93.51 - Applicability.

Code of Federal Regulations, 2012 CFR

2012-01-01

... AND GENERAL OPERATING RULES SPECIAL AIR TRAFFIC RULES Anchorage, Alaska, Terminal Area § 93.51... 14 Aeronautics and Space 2 2012-01-01 2012-01-01 false Applicability. 93.51 Section 93.51..., Terminal Area. [Doc. No. FAA-2002-13235, 68 FR 9795, Feb. 28, 2003] ...

14 CFR 93.51 - Applicability.

Code of Federal Regulations, 2013 CFR

2013-01-01

... AND GENERAL OPERATING RULES SPECIAL AIR TRAFFIC RULES Anchorage, Alaska, Terminal Area § 93.51... 14 Aeronautics and Space 2 2013-01-01 2013-01-01 false Applicability. 93.51 Section 93.51..., Terminal Area. [Doc. No. FAA-2002-13235, 68 FR 9795, Feb. 28, 2003] ...

Does on-water resisted rowing increase or maintain lower-body strength?

PubMed

Lawton, Trent W; Cronin, John B; McGuigan, Michael R

2013-07-01

Over the past 30 years, endurance volumes have increased by >20% among the rowing elite; therefore, informed decisions about the value of weight training over other possible activities in periodized training plans for rowing need to be made. The purpose of this study was to quantify the changes in lower-body strength development after two 14-week phases of intensive resisted on-water rowing, either incorporating weight training or rowing alone. Ten elite women performed 2 resisted rowing ("towing ropes," e.g., 8 × 3 minutes) plus 6 endurance (e.g., 16-28 km at 70-80% maximum heart rate) and 2 rate-regulated races (e.g., 8,000 m at 24 strokes per minute) on-water each week. After a 4-week washout phase, the 14-week phase was repeated with the addition of 2 weight-training sessions (e.g., 3-4 sets × 6-15 reps). Percent (±SD) and standardized differences in effects (effect size [ES] ± 90% confidence limit) for 5-repetition leg pressing and isometric pulling strength were calculated from data ratio scaled for body mass, log transformed and adjusted for pretest scores. Resisted rowing alone did not increase leg pressing (-1.0 ± 5.3%, p = 0.51) or isometric pulling (5.3 ± 13.4%, p = 0.28) strength. In contrast, after weight training, a moderately greater increase in leg pressing strength was observed (ES = 0.72 ± 0.49, p = 0.03), although differences in isometric pulling strength were unclear (ES = 0.56 ± 1.69, p = 0.52). In conclusion, intensive on-water training including resisted rowing maintained but did not increase lower-body strength. Elite rowers or coaches might consider the incorporation of high-intensity nonfatiguing weight training concurrent to endurance exercise if increases in lower-body strength without changes in body mass are desired.

Genetic variation associated with increased insecticide resistance in the malaria mosquito, Anopheles coluzzii.

PubMed

Main, Bradley J; Everitt, Amanda; Cornel, Anthony J; Hormozdiari, Fereydoun; Lanzaro, Gregory C

2018-04-04

Malaria mortality rates in sub-Saharan Africa have declined significantly in recent years as a result of increased insecticide-treated bed net (ITN) usage. A major challenge to further progress is the emergence and spread of insecticide resistance alleles in the Anopheles mosquito vectors, like An. coluzzii. A non-synonymous mutation in the para voltage-gated sodium channel gene reduces pyrethroid-binding affinity, resulting in knockdown resistance (kdr). Metabolic mechanisms of insecticide resistance involving detoxification genes like cytochrome P450 genes, carboxylesterases, and glutathione S-transferases are also important. As some gene activity is tissue-specific and/or environmentally induced, gene regulatory variation may be overlooked when comparing expression from whole mosquito bodies under standard rearing conditions. We detected complex insecticide resistance in a 2014 An. coluzzii colony from southern Mali using bottle bioassays. Additional bioassays involving recombinant genotypes from a cross with a relatively susceptible 1995 An. coluzzii colony from Mali confirmed the importance of kdr and associated increased permethrin resistance to the CYP9K1 locus on the X chromosome. Significant differential expression of CYP9K1 was not observed among these colonies in Malpighian tubules. However, the P450 gene CYP6Z1 was overexpressed in resistant individuals following sublethal permethrin exposure and the carboxylesterase gene COEAE5G was constitutively overexpressed. The significant P450-related insecticide resistance observed in the 2014 An. coluzzii colony indicates that ITNs treated with the P450 inhibitor piperonyl butoxide (PBO) would be more effective in this region. The known insecticide resistance gene CYP6Z1 was differentially expressed exclusively in the context of sublethal permethrin exposure, highlighting the importance of tissue-specificity and environmental conditions in gene expression studies. The increased activity of the carboxylesterase

14 CFR 93.153 - Communications.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 2 2012-01-01 2012-01-01 false Communications. 93.153 Section 93.153... § 93.153 Communications. (a) When the Ketchikan Flight Service Station is in operation, no person may... International Airport, unless that person has established two-way radio communications with the Ketchikan Flight...

14 CFR 93.153 - Communications.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 2 2014-01-01 2014-01-01 false Communications. 93.153 Section 93.153... § 93.153 Communications. (a) When the Ketchikan Flight Service Station is in operation, no person may... International Airport, unless that person has established two-way radio communications with the Ketchikan Flight...

29 CFR 9.3 - Coverage.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 29 Labor 1 2012-07-01 2012-07-01 false Coverage. 9.3 Section 9.3 Labor Office of the Secretary of Labor NONDISPLACEMENT OF QUALIFIED WORKERS UNDER SERVICE CONTRACTS (effective date pending) General § 9.3 Coverage. This part applies to all service contracts and their solicitations, except those...

14 CFR 93.153 - Communications.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 2 2010-01-01 2010-01-01 false Communications. 93.153 Section 93.153... § 93.153 Communications. (a) When the Ketchikan Flight Service Station is in operation, no person may... International Airport, unless that person has established two-way radio communications with the Ketchikan Flight...

32 CFR 9.3 - Jurisdiction.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 32 National Defense 1 2010-07-01 2010-07-01 false Jurisdiction. 9.3 Section 9.3 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE MILITARY COMMISSIONS PROCEDURES FOR TRIALS BY MILITARY COMMISSIONS OF CERTAIN NON-UNITED STATES CITIZENS IN THE WAR AGAINST TERRORISM § 9.3 Jurisdiction...

Radiation Induced Degradation of the White Thermal Control Paints Z-93 and Z-93P

NASA Technical Reports Server (NTRS)

Edwards, D. L.; Zwiener, J. M.; Wertz, G. E.; Vaughn, J. A.; Kamenetzky, R. R.; Finckenor, M. M.; Meshishnek, M. J.

1996-01-01

This paper details a comparison analysis of the zinc oxide pigmented white thermal control paints Z-93 and Z-93P. Both paints were simultaneously exposed to combined space environmental effects and analyzed using an in-vacuo reflectance technique. The dose applied to the paints was approximately equivalent to 5 years in a geosynchronous orbit. This comparison analysis showed that Z-93P is an acceptable substitute for Z-93. Irradiated samples of Z-93 and Z-93P were subjected to additional exposures of ultraviolet (UV) radiation and analyzed using the in-vacuo reflectance technique to investigate UV activated reflectance recovery. Both samples showed minimal UV activated reflectance recovery after an additional 190 equivalent sun hour (ESH) exposure. Reflectance response utilizing nitrogen as a repressurizing gas instead of air was also investigated. This investigation found the rates of reflectance recovery when repressurized with nitrogen are slower than when repressurized with air.

Increased Glycolytic ATP Synthesis Is Associated with Tafenoquine Resistance in Leishmania major▿

PubMed Central

Manzano, José Ignacio; Carvalho, Luis; Pérez-Victoria, José M.; Castanys, Santiago; Gamarro, Francisco

2011-01-01

Tafenoquine (TFQ), an 8-aminoquinoline used to treat and prevent Plasmodium infections, could represent an alternative therapy for leishmaniasis. Indeed, TFQ has shown significant leishmanicidal activity both in vitro and in vivo, where it targets Leishmania mitochondria and activates a final apoptosis-like process. In order not to jeopardize the life span of this potential antileishmania drug, it is important to determine the likelihood that Leishmania will develop resistance to TFQ and the mechanisms of resistance induced. To address this issue, a TFQ-resistant Leishmania major promastigote line (R4) was selected. This resistance, which is unstable in a drug-free medium (revertant line), was maintained in intramacrophage amastigote forms, and R4 promastigotes were found to be cross-resistant to other 8-aminoquinolines. A decreased TFQ uptake, which is probably associated with an alkalinization of the intracellular pH rather than drug efflux, was observed for both the R4 and revertant lines. TFQ induces a decrease in ATP synthesis in all Leishmania lines, although total ATP levels were maintained at higher values in R4 parasites. In contrast, ATP synthesis by glycolysis was significantly increased in R4 parasites, whereas mitochondrial ATP synthesis was similar to that in wild-type parasites. We therefore conclude that increased glycolytic ATP synthesis is the main mechanism underlying TFQ resistance in Leishmania. PMID:21199921

Increased glycolytic ATP synthesis is associated with tafenoquine resistance in Leishmania major.

PubMed

Manzano, José Ignacio; Carvalho, Luis; Pérez-Victoria, José M; Castanys, Santiago; Gamarro, Francisco

2011-03-01

Tafenoquine (TFQ), an 8-aminoquinoline used to treat and prevent Plasmodium infections, could represent an alternative therapy for leishmaniasis. Indeed, TFQ has shown significant leishmanicidal activity both in vitro and in vivo, where it targets Leishmania mitochondria and activates a final apoptosis-like process. In order not to jeopardize the life span of this potential antileishmania drug, it is important to determine the likelihood that Leishmania will develop resistance to TFQ and the mechanisms of resistance induced. To address this issue, a TFQ-resistant Leishmania major promastigote line (R4) was selected. This resistance, which is unstable in a drug-free medium (revertant line), was maintained in intramacrophage amastigote forms, and R4 promastigotes were found to be cross-resistant to other 8-aminoquinolines. A decreased TFQ uptake, which is probably associated with an alkalinization of the intracellular pH rather than drug efflux, was observed for both the R4 and revertant lines. TFQ induces a decrease in ATP synthesis in all Leishmania lines, although total ATP levels were maintained at higher values in R4 parasites. In contrast, ATP synthesis by glycolysis was significantly increased in R4 parasites, whereas mitochondrial ATP synthesis was similar to that in wild-type parasites. We therefore conclude that increased glycolytic ATP synthesis is the main mechanism underlying TFQ resistance in Leishmania.

42 CFR 93.216 - Notice.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 1 2010-10-01 2010-10-01 false Notice. 93.216 Section 93.216 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES HEALTH ASSESSMENTS AND HEALTH EFFECTS STUDIES OF... Definitions § 93.216 Notice. Notice means a written communication served in person, sent by mail or its...

29 CFR 93.105 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-07-01

... services in the private sector. (o) Recipient includes all contractors, subcontractors at any tier, and... 29 Labor 1 2010-07-01 2010-07-01 true Definitions. 93.105 Section 93.105 Labor Office of the Secretary of Labor NEW RESTRICTIONS ON LOBBYING General § 93.105 Definitions. For purposes of this part: (a...

29 CFR 9.3 - Coverage.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 29 Labor 1 2014-07-01 2013-07-01 true Coverage. 9.3 Section 9.3 Labor Office of the Secretary of Labor NONDISPLACEMENT OF QUALIFIED WORKERS UNDER SERVICE CONTRACTS General § 9.3 Coverage. This part applies to all service contracts and their solicitations, except those excluded by § 9.4 of this part...

29 CFR 9.3 - Coverage.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 29 Labor 1 2013-07-01 2013-07-01 false Coverage. 9.3 Section 9.3 Labor Office of the Secretary of Labor NONDISPLACEMENT OF QUALIFIED WORKERS UNDER SERVICE CONTRACTS General § 9.3 Coverage. This part applies to all service contracts and their solicitations, except those excluded by § 9.4 of this part...

42 CFR 93.512 - Discovery.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 1 2010-10-01 2010-10-01 false Discovery. 93.512 Section 93.512 Public Health... Process § 93.512 Discovery. (a) Request to provide documents. A party may only request another party to...) Responses to a discovery request. Within 30 days of receiving a request for the production of documents, a...

27 CFR 9.93 - Mendocino.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2012-04-01 2012-04-01 false Mendocino. 9.93 Section 9.93 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU, DEPARTMENT OF THE TREASURY LIQUORS AMERICAN VITICULTURAL AREAS Approved American Viticultural Areas § 9.93 Mendocino. (a) Name. The name of the viticultural area...

27 CFR 9.93 - Mendocino.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2011-04-01 2011-04-01 false Mendocino. 9.93 Section 9.93 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU, DEPARTMENT OF THE TREASURY LIQUORS AMERICAN VITICULTURAL AREAS Approved American Viticultural Areas § 9.93 Mendocino. (a) Name. The name of the viticultural area...

27 CFR 9.93 - Mendocino.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2010-04-01 2010-04-01 false Mendocino. 9.93 Section 9.93 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU, DEPARTMENT OF THE TREASURY LIQUORS AMERICAN VITICULTURAL AREAS Approved American Viticultural Areas § 9.93 Mendocino. (a) Name. The name of the viticultural area...

27 CFR 9.93 - Mendocino.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2014-04-01 2014-04-01 false Mendocino. 9.93 Section 9.93 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU, DEPARTMENT OF THE TREASURY ALCOHOL AMERICAN VITICULTURAL AREAS Approved American Viticultural Areas § 9.93 Mendocino. (a) Name. The name of the viticultural area...

27 CFR 9.93 - Mendocino.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2013-04-01 2013-04-01 false Mendocino. 9.93 Section 9.93 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU, DEPARTMENT OF THE TREASURY ALCOHOL AMERICAN VITICULTURAL AREAS Approved American Viticultural Areas § 9.93 Mendocino. (a) Name. The name of the viticultural area...

Biodiversity increases the resistance of ecosystem productivity to climate extremes

USDA-ARS?s Scientific Manuscript database

It remains unclear whether biodiversity buffers ecosystems against extreme climate events, which are becoming increasingly frequent worldwide. Although early results suggested that biodiversity might provide both resistance and resilience (sensu rapid recovery) of ecosystem productivity to drought, ...

Aging per se Increases the Susceptibility to Free Fatty Acid–Induced Insulin Resistance

PubMed Central

Huffman, Derek M.; Fishman, Sigal; Jerschow, Elina; Heo, Hye J.; Atzmon, Gil; Schechter, Clyde; Muzumdar, Radhika H.

2010-01-01

Elevations in systemic free fatty acids (FFA) contribute to insulin resistance. To determine the effects of an acute elevation in FFA on insulin action with aging, we infused saline or intralipid (IL) during a hyperinsulinemic–euglycemic clamp in three groups of rats: young ad libitum–fed (YAL), old ad libitum–fed (OAL), and old on lifelong calorie restriction (OCR). The OCR group was included to distinguish between aging per se and age-related changes in body fat distribution. IL induced marked insulin resistance in both YAL and OCR, but the onset of insulin resistance was approximately two to three times more rapid in OCR as compared with YAL. In response to IL infusion, plasminogen-activating inhibitor-1 (PAI-1) expression was increased in subcutaneous fat from OAL animals. In visceral fat, a marked increase in PAI-1 and interleukin-6 expression was observed in OAL and OCR rats, but not YAL, in response to IL treatment. Thus, aging per se increases the inflammatory response to excess nutrients and vulnerability to FFA-induced insulin resistance with aging. PMID:20504893

Overexpression of a citrus NDR1 ortholog increases disease resistance in Arabidopsis.

PubMed

Lu, Hua; Zhang, Chong; Albrecht, Ute; Shimizu, Rena; Wang, Guanfeng; Bowman, Kim D

2013-01-01

Emerging devastating diseases, such as Huanglongbing (HLB) and citrus canker, have caused tremendous losses to the citrus industry worldwide. Genetic engineering is a powerful approach that could allow us to increase citrus resistance against these diseases. The key to the success of this approach relies on a thorough understanding of defense mechanisms of citrus. Studies of Arabidopsis and other plants have provided a framework for us to better understand defense mechanisms of citrus. Salicylic acid (SA) is a key signaling molecule involved in basal defense and resistance (R) gene-mediated defense against broad-spectrum pathogens. The Arabidopsis gene NDR1 (NON-RACE-SPECIFIC DISEASE RESISTANCE 1) is a positive regulator of SA accumulation and is specifically required for signaling mediated by a subset of R genes upon recognition of their cognate pathogen effectors. Our bioinformatic analysis identified an ortholog of NDR1 from citrus, CsNDR1. Overexpression of CsNDR1 complemented susceptibility conferred by the Arabidopsis ndr1-1 mutant to Pseudomonas syringae strains and also led to enhanced resistance to an oomycete pathogen Hyaloperonospora arabidopsidis. Such heightened resistance is associated with increased SA production and expression of the defense marker gene PATHOGENESIS RELATED 1 (PR1). In addition, we found that expression of PR1 and accumulation of SA were induced to modest levels in citrus infected with Candidatus Liberibacter asiaticus, the bacterial pathogen associated with HLB disease. Thus, our data suggest that CsNDR1 is a functional ortholog of Arabidopsis NDR1. Since Ca. L. asiaticus infection only activates modest levels of defense responses in citrus, we propose that genetically increasing SA/NDR1-mediated pathways could potentially lead to enhanced resistance against HLB, citrus canker, and other destructive diseases challenging global citrus production.

Overexpression of a citrus NDR1 ortholog increases disease resistance in Arabidopsis

PubMed Central

Lu, Hua; Zhang, Chong; Albrecht, Ute; Shimizu, Rena; Wang, Guanfeng; Bowman, Kim D.

2013-01-01

Emerging devastating diseases, such as Huanglongbing (HLB) and citrus canker, have caused tremendous losses to the citrus industry worldwide. Genetic engineering is a powerful approach that could allow us to increase citrus resistance against these diseases. The key to the success of this approach relies on a thorough understanding of defense mechanisms of citrus. Studies of Arabidopsis and other plants have provided a framework for us to better understand defense mechanisms of citrus. Salicylic acid (SA) is a key signaling molecule involved in basal defense and resistance (R) gene-mediated defense against broad-spectrum pathogens. The Arabidopsis gene NDR1 (NON-RACE-SPECIFIC DISEASE RESISTANCE 1) is a positive regulator of SA accumulation and is specifically required for signaling mediated by a subset of R genes upon recognition of their cognate pathogen effectors. Our bioinformatic analysis identified an ortholog of NDR1 from citrus, CsNDR1. Overexpression of CsNDR1 complemented susceptibility conferred by the Arabidopsis ndr1-1 mutant to Pseudomonas syringae strains and also led to enhanced resistance to an oomycete pathogen Hyaloperonospora arabidopsidis. Such heightened resistance is associated with increased SA production and expression of the defense marker gene PATHOGENESIS RELATED 1 (PR1). In addition, we found that expression of PR1 and accumulation of SA were induced to modest levels in citrus infected with Candidatus Liberibacter asiaticus, the bacterial pathogen associated with HLB disease. Thus, our data suggest that CsNDR1 is a functional ortholog of Arabidopsis NDR1. Since Ca. L. asiaticus infection only activates modest levels of defense responses in citrus, we propose that genetically increasing SA/NDR1-mediated pathways could potentially lead to enhanced resistance against HLB, citrus canker, and other destructive diseases challenging global citrus production. PMID:23761797

Psychophysiological aspects of increasing resistance to space motion sickness.

PubMed

Berezhnov, E S; Vorobjev, O A; Lapaev, E V

1993-02-01

One of the actual and difficulty solved problems of the adaptation period to microgravitation is space motion sickness (MS) that has the negative influence on well-being and performance of crewmembers in the initial and highly crucial phase of the orbital flight. Among the prophylactic measures for decrease of the unfavourable influence of space MS the preflight training is of great importance, and its role in perspective undoubtedly will grow in connection with increase of the number of crewmembers. During the last years several authors received experimental materials evidenced that as a base of more effective increase of resistance to space MS there may be used adequate modelling of the main physiological effects of the adaptation period to microgravitation. In the most investigations the main attention is paid to modelling of "conflicting" vestibular-visual (VV) impacts. In other hand, in connection with the contradictory materials about the role of hemodynamic component in the development of space MS this effect of microgravitation conditions, as a rule, is not modelled in the methods of resistance enhancement to space MS. Hence in this work there was put a task to investigate the efficiency of application of different combination of VV-impacts and creation of redistribution of liquid medium of an organism in the cranial direction for increase of man resistance to space MS. For resolving this task there was used the specially developed stand, made in two modifications. This stand provided redistribution of liquid medium of an organism in the cranial direction by putting the investigated individual into the antiorthostatic position (AOP). During the rotation around the vertical axis individual was placed in such supine position on the turn table that labyrinth of the inner ear should be displaced by 8-10 centimeters from the axis of rotation to the head edge of the turn table. This increased the adequacy of vestibular apparatus irritation by gravitation and

Molecular identification of coagulase-negative staphylococci isolated from bovine mastitis and detection of β-lactam resistance.

PubMed

Srednik, Mariela Elizabeth; Grieben, Mario Andres; Bentancor, Adriana; Gentilini, Elida Raquel

2015-09-27

Bovine mastitis is a frequent cause of economic loss in dairy herds. Coagulase-negative staphylococci (CoNS) are increasing in importance as causeof bovine intramammary infection (IMI) throughout the world in recent years. CoNShave been isolated from milk samples collected from cows with clinical andsubclinical mastitis in several countries. Identification of mastitis pathogensis important when selection appropriate antimicrobial therapy. A total of 93 strains of Staphylococcusspp isolated from bovine clinical andsubclinical mastitis in Argentina during 2010-2013 were identified by Restriction Fragment Length Polymorphism (RFLP)-PCR using the gap gene. The isolates were tested by PCR for the presence of blaZ gene and mecA gene and were tested by disk diffusion for the susceptibilityto penicillin and cefoxitin. The most common CoNS species was S.chromogenes 46.2% (43/93), followed by S. devriesei 11.8% (11/93) and S. haemolyticus 9.7% (9/93). The blaZ gene was detected in 19 (20.4%) but only 16 (17.2%) isolates were resistant to penicillin; the mecA was detected in6 (6.5%) isolates but only 4 (4.3) were resistant to cefoxitin. The 6 mecA-positive isolates showed oxaxillinMICs ≤ 0.5 μg/ml. CoNSare important minor mastitis pathogens and can be the cause of substantial economic losses. Despite the low resistance to PEN in Argentina, the presenceof MR isolates found in this study emphasize the importance of identificationof CoNS when an IMI is present because of the potentially risk of lateraltransfer of resistance genes between staphylococcal species.

Increased prevalence of insulin resistance and nonalcoholic fatty liver disease in Asian-Indian men

PubMed Central

Petersen, Kitt Falk; Dufour, Sylvie; Feng, Jing; Befroy, Douglas; Dziura, James; Man, Chiara Dalla; Cobelli, Claudio; Shulman, Gerald I.

2006-01-01

Type 2 diabetes mellitus (T2DM) is strongly associated with obesity in most, but not all, ethnic groups, suggesting important ethnic differences in disease susceptibility. Although it is clear that insulin resistance plays a major role in the pathogenesis of T2DM and that insulin resistance is strongly associated with increases in hepatic (HTG) and/or intramyocellular lipid content, little is known about the prevalence of insulin resistance and potential differences in intracellular lipid distribution among healthy, young, lean individuals of different ethnic groups. To examine this question, 482 young, lean, healthy, sedentary, nonsmoking Eastern Asians (n = 49), Asian-Indians (n = 59), Blacks (n = 48), Caucasians (n = 292), and Hispanics (n = 34) underwent an oral glucose tolerance test to assess whole-body insulin sensitivity by an insulin sensitivity index. In addition, intramyocellular lipid and HTG contents were measured by using proton magnetic resonance spectroscopy. The prevalence of insulin resistance, defined as the lower quartile of insulin sensitivity index, was ≈2- to 3-fold higher in the Asian-Indians compared with all other ethnic groups, and this could entirely be attributed to a 3- to 4-fold increased prevalence of insulin resistance in Asian-Indian men. This increased prevalence of insulin resistance in the Asian-Indian men was associated with an ≈2-fold increase in HTG content and plasma IL-6 concentrations compared with Caucasian men. These data demonstrate important ethnic and gender differences in the pathogenesis of insulin resistance in Asian-Indian men and have important therapeutic implications for treatment of T2DM and for the development of steatosis-related liver disease in this ethnic group. PMID:17114290

Enhanced Locomotor Activity Is Required to Exert Dietary Restriction-Dependent Increase of Stress Resistance in Drosophila.

PubMed

Ghimire, Saurav; Kim, Man Su

2015-01-01

Dietary restriction (DR) is known to be one of the most effective interventions to increase stress resistance, yet the mechanisms remain elusive. One of the most obvious DR-induced changes in phenotype is an increase in locomotor activity. Although it is conceptually perceivable that nutritional scarcity should prompt enhanced foraging behavior to garner additional dietary resources, the significance of enhanced movement activity has not been associated with the DR-dependent increase of stress resistance. In this study, we confirmed that flies raised on DR exhibited enhanced locomotive activity and increased stress resistance. Excision of fly wings minimized the DR-induced increase in locomotive activity, which resulted in attenuation of the DR-dependent increase of stress resistance. The possibility that wing clipping counteracts the DR by coercing flies to have more intake was ruled out since it did not induce any weight gain. Rather it was found that elimination of reactive oxygen species (ROS) that is enhanced by DR-induced upregulation of expression of antioxidant genes was significantly reduced by wing clipping. Collectively, our data suggests that DR increased stress resistance by increasing the locomotor activity, which upregulated expression of protective genes including, but not limited to, ROS scavenger system.

A treatment plant receiving waste water from multiple bulk drug manufacturers is a reservoir for highly multi-drug resistant integron-bearing bacteria.

PubMed

Marathe, Nachiket P; Regina, Viduthalai R; Walujkar, Sandeep A; Charan, Shakti Singh; Moore, Edward R B; Larsson, D G Joakim; Shouche, Yogesh S

2013-01-01

The arenas and detailed mechanisms for transfer of antibiotic resistance genes between environmental bacteria and pathogens are largely unclear. Selection pressures from antibiotics in situations where environmental bacteria and human pathogens meet are expected to increase the risks for such gene transfer events. We hypothesize that waste-water treatment plants (WWTPs) serving antibiotic manufacturing industries may provide such spawning grounds, given the high bacterial densities present there together with exceptionally strong and persistent selection pressures from the antibiotic-contaminated waste. Previous analyses of effluent from an Indian industrial WWTP that processes waste from bulk drug production revealed the presence of a range of drugs, including broad spectrum antibiotics at extremely high concentrations (mg/L range). In this study, we have characterized the antibiotic resistance profiles of 93 bacterial strains sampled at different stages of the treatment process from the WWTP against 39 antibiotics belonging to 12 different classes. A large majority (86%) of the strains were resistant to 20 or more antibiotics. Although there were no classically-recognized human pathogens among the 93 isolated strains, opportunistic pathogens such as Ochrobactrum intermedium, Providencia rettgeri, vancomycin resistant Enterococci (VRE), Aerococcus sp. and Citrobacter freundii were found to be highly resistant. One of the O. intermedium strains (ER1) was resistant to 36 antibiotics, while P. rettgeri (OSR3) was resistant to 35 antibiotics. Class 1 and 2 integrons were detected in 74/93 (80%) strains each, and 88/93 (95%) strains harbored at least one type of integron. The qPCR analysis of community DNA also showed an unprecedented high prevalence of integrons, suggesting that the bacteria living under such high selective pressure have an appreciable potential for genetic exchange of resistance genes via mobile gene cassettes. The present study provides insight into

Advanced Wear-resistant Nanocomposites for Increased Energy Efficiency

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

Cook, B. A.; Harringa, J. L.; Russel, A. M.

This report summarizes the work performed by an Ames-led project team under a 4-year DOE-ITP sponsored project titled, 'Advanced Wear-resistant Nanocomposites for Increased Energy Efficiency.' The Report serves as the project deliverable for the CPS agreement number 15015. The purpose of this project was to develop and commercialize a family of lightweight, bulk composite materials that are highly resistant to degradation by erosive and abrasive wear. These materials, based on AlMgB{sub 14}, are projected to save over 30 TBtu of energy per year when fully implemented in industrial applications, with the associated environmental benefits of eliminating the burning of 1.5more » M tons/yr of coal and averting the release of 4.2 M tons/yr of CO{sub 2} into the air. This program targeted applications in the mining, drilling, machining, and dry erosion applications as key platforms for initial commercialization, which includes some of the most severe wear conditions in industry. Production-scale manufacturing of this technology has begun through a start-up company, NewTech Ceramics (NTC). This project included providing technical support to NTC in order to facilitate cost-effective mass production of the wear-resistant boride components. Resolution of issues related to processing scale-up, reduction in energy intensity during processing, and improving the quality and performance of the composites, without adding to the cost of processing were among the primary technical focus areas of this program. Compositional refinements were also investigated in order to achieve the maximum wear resistance. In addition, synthesis of large-scale, single-phase AlMgB{sub 14} powder was conducted for use as PVD sputtering targets for nanocoating applications.« less

Critical role of zinc finger protein 521 in the control of growth, clonogenicity and tumorigenic potential of medulloblastoma cells

PubMed Central

Iaccino, Enrico; Scicchitano, Stefania; Lupia, Michela; Chiarella, Emanuela; Mega, Tiziana; Bernaudo, Francesca; Pelaggi, Daniela; Mesuraca, Maria; Pazzaglia, Simonetta; Semenkow, Samantha; Bar, Eli E.; Kool, Marcel; Pfister, Stefan; Bond, Heather M.; Eberhart, Charles G.; Steinkühler, Christian; Morrone, Giovanni

2013-01-01

The stem cell-associated transcription co-factor ZNF521 has been implicated in the control of hematopoietic, osteo-adipogenic and neural progenitor cells. ZNF521 is highly expressed in cerebellum and in particular in the neonatal external granule layer that contains candidate medulloblastoma cells-of-origin, and in the majority of human medulloblastomas. Here we have explored its involvement in the control of human and murine medulloblastoma cells. The effect of ZNF521 on growth and tumorigenic potential of human medulloblastoma cell lines as well as primary Ptc1−/+ mouse medulloblastoma cells was investigated in a variety of in vitro and in vivo assays, by modulating its expression using lentiviral vectors carrying the ZNF521 cDNA, or shRNAs that silence its expression. Enforced overexpression of ZNF521 in DAOY medulloblastoma cells significantly increased their proliferation, growth as spheroids and ability to generate clones in single-cell cultures and semisolid media, and enhanced their migratory ability in wound-healing assays. Importantly, ZNF521-expressing cells displayed a greatly enhanced tumorigenic potential in nude mice. All these activities required the ZNF521 N-terminal motif that recruits the nucleosome remodeling and histone deacetylase complex, which might therefore represent an appealing therapeutic target. Conversely, silencing of ZNF521 in human UW228 medulloblastoma cells that display high baseline expression decreased their proliferation, clonogenicity, sphere formation and wound-healing ability. Similarly, Zfp521 silencing in mouse Ptc1−/+ medulloblastoma cells drastically reduced their growth and tumorigenic potential. Our data strongly support the notion that ZNF521, through the recruitment of the NuRD complex, contributes to the clonogenic growth, migration and tumorigenicity of medulloblastoma cells. PMID:23907569

Critical role of zinc finger protein 521 in the control of growth, clonogenicity and tumorigenic potential of medulloblastoma cells.

PubMed

Spina, Raffaella; Filocamo, Gessica; Iaccino, Enrico; Scicchitano, Stefania; Lupia, Michela; Chiarella, Emanuela; Mega, Tiziana; Bernaudo, Francesca; Pelaggi, Daniela; Mesuraca, Maria; Pazzaglia, Simonetta; Semenkow, Samantha; Bar, Eli E; Kool, Marcel; Pfister, Stefan; Bond, Heather M; Eberhart, Charles G; Steinkühler, Christian; Morrone, Giovanni

2013-08-01

The stem cell-associated transcription co-factor ZNF521 has been implicated in the control of hematopoietic, osteo-adipogenic and neural progenitor cells. ZNF521 is highly expressed in cerebellum and in particular in the neonatal external granule layer that contains candidate medulloblastoma cells-of-origin, and in the majority of human medulloblastomas. Here we have explored its involvement in the control of human and murine medulloblastoma cells. The effect of ZNF521 on growth and tumorigenic potential of human medulloblastoma cell lines as well as primary Ptc1-/+ mouse medulloblastoma cells was investigated in a variety of in vitro and in vivo assays, by modulating its expression using lentiviral vectors carrying the ZNF521 cDNA, or shRNAs that silence its expression. Enforced overexpression of ZNF521 in DAOY medulloblastoma cells significantly increased their proliferation, growth as spheroids and ability to generate clones in single-cell cultures and semisolid media, and enhanced their migratory ability in wound-healing assays. Importantly, ZNF521-expressing cells displayed a greatly enhanced tumorigenic potential in nude mice. All these activities required the ZNF521 N-terminal motif that recruits the nucleosome remodeling and histone deacetylase complex, which might therefore represent an appealing therapeutic target. Conversely, silencing of ZNF521 in human UW228 medulloblastoma cells that display high baseline expression decreased their proliferation, clonogenicity, sphere formation and wound-healing ability. Similarly, Zfp521 silencing in mouse Ptc1-/+ medulloblastoma cells drastically reduced their growth and tumorigenic potential. Our data strongly support the notion that ZNF521, through the recruitment of the NuRD complex, contributes to the clonogenic growth, migration and tumorigenicity of medulloblastoma cells.

Downregulation of LRRC8A protects human ovarian and alveolar carcinoma cells against Cisplatin-induced expression of p53, MDM2, p21Waf1/Cip1, and Caspase-9/-3 activation

PubMed Central

Sørensen, Belinda Halling; Nielsen, Dorthe; Thorsteinsdottir, Unnur Arna; Hoffmann, Else Kay

2016-01-01

The leucine-rich repeat containing 8A (LRRC8A) protein is an essential component of the volume-sensitive organic anion channel (VSOAC), and using pharmacological anion channel inhibitors (NS3728, DIDS) and LRRC8A siRNA we have investigated its role in development of Cisplatin resistance in human ovarian (A2780) and alveolar (A549) carcinoma cells. In Cisplatin-sensitive cells Cisplatin treatment increases p53-protein level as well as downstream signaling, e.g., expression of p21Waf1/Cip1, Bax, Noxa, MDM2, and activation of Caspase-9/-3. In contrast, Cisplatin-resistant cells do not enter apoptosis, i.e., their p53 and downstream signaling are reduced and caspase activity unaltered following Cisplatin exposure. Reduced LRRC8A expression and VSOAC activity are previously shown to correlate with Cisplatin resistance, and here we demonstrate that pharmacological inhibition and transient knockdown of LRRC8A reduce the protein level of p53, MDM2, and p21Waf1/Cip1 as well as Caspase-9/-3 activation in Cisplatin-sensitive cells. Cisplatin resistance is accompanied by reduction in total LRRC8A expression (A2780) or LRRC8A expression in the plasma membrane (A549). Activation of Caspase-3 dependent apoptosis by TNFα-exposure or hyperosmotic cell shrinkage is almost unaffected by pharmacological anion channel inhibition. Our data indicate 1) that expression/activity of LRRC8A is essential for Cisplatin-induced increase in p53 protein level and its downstream signaling, i.e., Caspase-9/-3 activation, expression of p21Waf1/Cip1 and MDM2; and 2) that downregulation of LRRC8A-dependent osmolyte transporters contributes to acquirement of Cisplatin resistance in ovarian and lung carcinoma cells. Activation of LRRC8A-containing channels is upstream to apoptotic volume decrease as hypertonic cell shrinkage induces apoptosis independent of the presence of LRRC8A. PMID:26984736

A chromosome 4 trisomy contributes to increased fluconazole resistance in a clinical isolate of Candida albicans

PubMed Central

Anderson, Matthew Z.; Saha, Amrita; Haseeb, Abid

2017-01-01

Candida albicans is an important opportunistic fungal pathogen capable of causing both mucosal and disseminated disease. Infections are often treated with fluconazole, a front-line antifungal drug that targets the biosynthesis of ergosterol, a major component of the fungal cell membrane. Resistance to fluconazole can arise through a variety of mechanisms, including gain-of-function mutations, loss of heterozygosity events and aneuploidy. The clinical isolate P60002 was found to be highly resistant to azole-class drugs, yet lacked mutations or chromosomal rearrangements known to be associated with azole resistance. Transcription profiling suggested that increased expression of two putative drug efflux pumps, CDR11 and QDR1, might confer azole resistance. However, ectopic expression of the P60002 alleles of these genes in a drug-susceptible strain did not increase fluconazole resistance. We next examined whether the presence of three copies of chromosome 4 (Chr4) or chromosome 6 (Chr6) contributed to azole resistance in P60002. We established that Chr4 trisomy contributes significantly to fluconazole resistance, whereas Chr6 trisomy has no discernible effect on resistance. In contrast, a Chr4 trisomy did not increase fluconazole resistance when present in the standard SC5314 strain background. These results establish a link between Chr4 trisomy and elevated fluconazole resistance, and demonstrate the impact of genetic background on drug resistance phenotypes in C. albicans. PMID:28640746

9 CFR 93.325 - Horses from Mexico.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Horses from Mexico. 93.325 Section 93... CONVEYANCE AND SHIPPING CONTAINERS Horses Mexico 18 § 93.325 Horses from Mexico. Horses offered for entry from Mexico shall be inspected as provided in §§ 93.306 and 93.323; shall be accompanied by a...

9 CFR 93.325 - Horses from Mexico.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Horses from Mexico. 93.325 Section 93... CONVEYANCE AND SHIPPING CONTAINERS Horses Mexico 18 § 93.325 Horses from Mexico. Horses offered for entry from Mexico shall be inspected as provided in §§ 93.306 and 93.323; shall be accompanied by a...

9 CFR 93.325 - Horses from Mexico.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Horses from Mexico. 93.325 Section 93... CONVEYANCE AND SHIPPING CONTAINERS Horses Mexico 18 § 93.325 Horses from Mexico. Horses offered for entry from Mexico shall be inspected as provided in §§ 93.306 and 93.323; shall be accompanied by a...

9 CFR 93.325 - Horses from Mexico.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Horses from Mexico. 93.325 Section 93... CONVEYANCE AND SHIPPING CONTAINERS Horses Mexico 18 § 93.325 Horses from Mexico. Horses offered for entry from Mexico shall be inspected as provided in §§ 93.306 and 93.323; shall be accompanied by a...

9 CFR 93.325 - Horses from Mexico.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Horses from Mexico. 93.325 Section 93... CONVEYANCE AND SHIPPING CONTAINERS Horses Mexico 18 § 93.325 Horses from Mexico. Horses offered for entry from Mexico shall be inspected as provided in §§ 93.306 and 93.323; shall be accompanied by a...

A new β chain hemoglobin variant with increased oxygen affinity: Hb Santa Giusta Sardegna [β93(F9)Cys→Trp; HBB c.282T>G].

PubMed

Fais, Antonella; Sollaino, Maria Carla; Barella, Susanna; Perseu, Lucia; Era, Benedetta; Corda, Marcella

2012-01-01

During a screening program for the identification of β-thalassemia (β-thal) carriers in Sardinia, Italy, we identified two subjects with increased hemoglobin (Hb) levels and an abnormal Hb variant. The same variant was detected in a family member. DNA sequencing revealed a TGT > TGG mutation at codon 93 of the β-globin gene. Structural analysis demonstrated that the cystine residue at position 93 of the β chain was substituted by tryptophan. Since this amino acid substitution had not yet been reported, we designated this variant Hb Santa Giusta Sardegna for the place of birth of the subjects. This amino acid substitution occurs at the tyrosine pocket of the β chain as well as at the α1β2/α2β1 contact of the quaternary structure of the molecule. The presence of this Hb in the hemolysate causes an increased oxygen affinity, a slightly reduced Bohr effect and a reduced heme-heme interaction (n(50), Hill's constant) in comparison with those of Hb A.

Caries inhibition with a CO2 9.3 μm laser: An in vitro study.

PubMed

Rechmann, Peter; Rechmann, Beate M T; Groves, William H; Le, Charles Q; Rapozo-Hilo, Marcia L; Kinsel, Richard; Featherstone, John D B

2016-07-01

The caries preventive effects of different laser wavelengths have been studied in the laboratory as well as in pilot clinical trials. The objective of this in vitro study was to evaluate whether irradiation with a new 9.3 μm microsecond short-pulsed CO2 -laser could enhance enamel caries resistance with and without additional fluoride applications. One hundred and one human tooth enamel samples were divided into seven groups. Each group was treated with different laser parameters (CO2 -laser, wavelength 9.3 μm, 43 Hz pulse-repetition rate, pulse duration between 3 µs at 1.5 mJ/pulse to 7 µs at 2.9 mJ/pulse). A laboratory pH-cycling model followed by cross-sectional microhardness testing determined the mean relative mineral loss delta Z (ΔZ) for each group to assess caries inhibition in tooth enamel by the CO2 9.3 µm short-pulsed laser irradiation. The pH-cycling was performed with or without additional fluoride. The non-laser control groups with additional fluoride had a relative mineral loss (ΔZ, vol% × µm) that ranged between 646 ± 215 and 773 ± 223 (mean ± SD). The laser irradiated and fluoride treated samples had a mean ΔZ ranging between 209 ± 133 and 403 ± 245 for an average 55% ± 9% reduction in mineral loss (ANOVA test, P < 0.0001). Increased mean mineral loss (ΔZ between 1166 ± 571 and 1339 ± 347) was found for the non-laser treated controls without additional fluoride. In contrast, the laser treated groups without additional fluoride showed a ΔZ between 470 ± 240 and 669 ± 209 (ANOVA test, P < 0.0001) representing an average 53% ± 11% reduction in mineral loss. Scanning electron microscopical assessment revealed that 3 µs pulses did not markedly change the enamel surface, while 7 µs pulses caused some enamel ablation. The CO2 9.3 µm short-pulsed laser energy renders enamel caries resistant with and without additional fluoride use. The observed enhanced

Desmopressin resistant nocturnal polyuria secondary to increased nocturnal osmotic excretion.

PubMed

Dehoorne, Jo L; Raes, Ann M; van Laecke, Erik; Hoebeke, Piet; Vande Walle, Johan G

2006-08-01

We investigated the role of increased solute excretion in children with desmopressin resistant nocturnal enuresis and nocturnal polyuria. A total of 42 children with monosymptomatic nocturnal enuresis and significant nocturnal polyuria with high nocturnal urinary osmolality (more than 850 mmol/l) were not responding to desmopressin. A 24-hour urinary concentration profile was obtained with measurement of urine volume, osmolality, osmotic excretion and creatinine. The control group consisted of 100 children without enuresis. Based on osmotic excretion patients were classified into 3 groups. Group 1 had 24-hour increased osmotic excretion, most likely secondary to a high renal osmotic load. This was probably diet related since 11 of these 12 patients were obese. Group 2 had increased osmotic excretion in the evening and night, probably due to a high renal osmotic load caused by the diet characteristics of the evening meal. Group 3 had deficient osmotic excretion during the day, secondary to extremely low fluid intake to compensate for small bladder capacity. Nocturnal polyuria with high urinary osmolality in our patients with desmopressin resistant monosymptomatic nocturnal enuresis is related to abnormal increased osmotic excretion. This may be explained by their fluid and diet habits, eg daytime fluid restriction, and high protein and salt intake.

7 CFR 3015.93 - Significant developments.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 15 2011-01-01 2011-01-01 false Significant developments. 3015.93 Section 3015.93... § 3015.93 Significant developments. Events may occur between the scheduled performance reporting dates... assistance needed to resolve the situation. (b) Favorable developments which enable meeting time schedules...

14 CFR 33.93 - Teardown inspection.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 1 2013-01-01 2013-01-01 false Teardown inspection. 33.93 Section 33.93 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT AIRWORTHINESS STANDARDS: AIRCRAFT ENGINES Block Tests; Turbine Aircraft Engines § 33.93 Teardown inspection. (a) After...

14 CFR 33.93 - Teardown inspection.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 1 2014-01-01 2014-01-01 false Teardown inspection. 33.93 Section 33.93 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT AIRWORTHINESS STANDARDS: AIRCRAFT ENGINES Block Tests; Turbine Aircraft Engines § 33.93 Teardown inspection. (a) After...

14 CFR 33.93 - Teardown inspection.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 1 2011-01-01 2011-01-01 false Teardown inspection. 33.93 Section 33.93 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT AIRWORTHINESS STANDARDS: AIRCRAFT ENGINES Block Tests; Turbine Aircraft Engines § 33.93 Teardown inspection. (a) After...

33 CFR 159.93 - Independent supporting.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 33 Navigation and Navigable Waters 2 2011-07-01 2011-07-01 false Independent supporting. 159.93 Section 159.93 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) POLLUTION MARINE SANITATION DEVICES Design, Construction, and Testing § 159.93 Independent supporting. The...

Methyl Ester Production via Heterogeneous Acid-Catalyzed Simultaneous Transesterification and Esterification Reactions

NASA Astrophysics Data System (ADS)

Indrayanah, S.; Erwin; Marsih, I. N.; Suprapto; Murwani, I. K.

2017-05-01

The heterogeneous acid catalysts (MgF2 and ZnF2) have been used to catalyze the simultaneous transesterification and esterification reactions of crude palm oil (CPO) with methanol. Catalysts were synthesized by sol-gel method (combination of fluorolysis and hydrolysis). The physicochemical, structural, textural, thermal stability of the prepared catalysts was investigated by N2 adsorption-desorption, XRD, FT-IR, SEM and TG/DTG. Both MgF2 and ZnF2 have rutile structures with a different phase. The surface area of ZnF2 is smaller than that of MgF2, but the pore size and volume of ZnF2 are larger than those of MgF2. However, these materials are thermally stable. The performance of the catalysts is determined from the yield of catalysts toward the formation of methyl ester determined based on the product of methyl ester obtained from the reaction. The catalytic activity of ZnF2 is higher than MgF2 amounted to 85.21% and 26.82% with the optimum condition. The high activity of ZnF2 could be attributed to its pore diameter and pore volume but was not correlated with its surface area. The yield of methyl ester decreased along with the increase in molar ratio of methanol/CPO from 85.21 to 80.99 for ZnF2, respectively.

MicroRNA-93 Promotes Epithelial–Mesenchymal Transition of Endometrial Carcinoma Cells

PubMed Central

Sun, Kai-Xuan; Xiu, Yin-Ling; Liu, Bo-Liang; Feng, Miao-Xiao; Sang, Xiu-Bo; Zhao, Yang

2016-01-01

MicroRNA-93, derived from a paralog (miR-106b-25) of the miR-17-92 cluster, is involved in the tumorigenesis and progression of many cancers such as breast, colorectal, hepatocellular, lung, ovarian, and pancreatic cancer. However, the role of miR-93 in endometrial carcinoma and the potential molecular mechanisms involved remain unknown. Our results showed that miR-93 was overexpressed in endometrial carcinoma tissues than normal endometrial tissues. The endometrial carcinoma cell lines HEC-1B and Ishikawa were transfected with miR-93-5P, after which cell migration and invasion ability and the expression of relevant molecules were detected. MiR-93 overexpression promoted cell migration and invasion, and downregulated E-cadherin expression while increasing N-cadherin expression. Dual-luciferase reporter assay showed that miR-93 may directly bind to the 3′ untranslated region of forkhead box A1 (FOXA1); furthermore, miR-93 overexpression downregulated FOXA1 expression while miR-93 inhibitor transfection upregulated FOXA1 expression at both mRNA and protein level. In addition, transfection with the most effective FOXA1 small interfering RNA promoted both endometrial cancer cell migration and invasion, and downregulated E-cadherin expression while upregulating N-cadherin expression. Therefore, we suggest that miR-93 may promote the process of epithelial–mesenchymal transition in endometrial carcinoma cells by targeting FOXA1. PMID:27829043

9 CFR 93.803 - Health certificate.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Health certificate. 93.803 Section 93.803 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE... CONVEYANCE AND SHIPPING CONTAINERS Elephants, Hippopotami, Rhinoceroses, and Tapirs § 93.803 Health...

9 CFR 93.803 - Health certificate.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Health certificate. 93.803 Section 93.803 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE... CONVEYANCE AND SHIPPING CONTAINERS Elephants, Hippopotami, Rhinoceroses, and Tapirs § 93.803 Health...

9 CFR 93.803 - Health certificate.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Health certificate. 93.803 Section 93.803 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE... CONVEYANCE AND SHIPPING CONTAINERS Elephants, Hippopotami, Rhinoceroses, and Tapirs § 93.803 Health...

9 CFR 93.803 - Health certificate.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Health certificate. 93.803 Section 93.803 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE... CONVEYANCE AND SHIPPING CONTAINERS Elephants, Hippopotami, Rhinoceroses, and Tapirs § 93.803 Health...

9 CFR 93.803 - Health certificate.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Health certificate. 93.803 Section 93.803 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE... CONVEYANCE AND SHIPPING CONTAINERS Elephants, Hippopotami, Rhinoceroses, and Tapirs § 93.803 Health...

42 CFR 93.103 - Research misconduct.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 42 Public Health 1 2012-10-01 2012-10-01 false Research misconduct. 93.103 Section 93.103 Public... EFFECTS STUDIES OF HAZARDOUS SUBSTANCES RELEASES AND FACILITIES PUBLIC HEALTH SERVICE POLICIES ON RESEARCH MISCONDUCT General § 93.103 Research misconduct. Research misconduct means fabrication, falsification, or...

42 CFR 93.103 - Research misconduct.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 42 Public Health 1 2011-10-01 2011-10-01 false Research misconduct. 93.103 Section 93.103 Public... EFFECTS STUDIES OF HAZARDOUS SUBSTANCES RELEASES AND FACILITIES PUBLIC HEALTH SERVICE POLICIES ON RESEARCH MISCONDUCT General § 93.103 Research misconduct. Research misconduct means fabrication, falsification, or...

42 CFR 93.103 - Research misconduct.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 42 Public Health 1 2014-10-01 2014-10-01 false Research misconduct. 93.103 Section 93.103 Public... EFFECTS STUDIES OF HAZARDOUS SUBSTANCES RELEASES AND FACILITIES PUBLIC HEALTH SERVICE POLICIES ON RESEARCH MISCONDUCT General § 93.103 Research misconduct. Research misconduct means fabrication, falsification, or...

42 CFR 93.103 - Research misconduct.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 1 2010-10-01 2010-10-01 false Research misconduct. 93.103 Section 93.103 Public... EFFECTS STUDIES OF HAZARDOUS SUBSTANCES RELEASES AND FACILITIES PUBLIC HEALTH SERVICE POLICIES ON RESEARCH MISCONDUCT General § 93.103 Research misconduct. Research misconduct means fabrication, falsification, or...

42 CFR 93.103 - Research misconduct.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 42 Public Health 1 2013-10-01 2013-10-01 false Research misconduct. 93.103 Section 93.103 Public... EFFECTS STUDIES OF HAZARDOUS SUBSTANCES RELEASES AND FACILITIES PUBLIC HEALTH SERVICE POLICIES ON RESEARCH MISCONDUCT General § 93.103 Research misconduct. Research misconduct means fabrication, falsification, or...

40 CFR 66.93 - Time limits.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 15 2010-07-01 2010-07-01 false Time limits. 66.93 Section 66.93 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) ASSESSMENT AND COLLECTION OF NONCOMPLIANCE PENALTIES BY EPA Supplemental Rules for Formal Adjudicatory Hearings § 66.93 Time...

40 CFR 66.93 - Time limits.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 16 2013-07-01 2013-07-01 false Time limits. 66.93 Section 66.93 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) ASSESSMENT AND COLLECTION OF NONCOMPLIANCE PENALTIES BY EPA Supplemental Rules for Formal Adjudicatory Hearings § 66.93 Time...

40 CFR 66.93 - Time limits.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 16 2014-07-01 2014-07-01 false Time limits. 66.93 Section 66.93 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) ASSESSMENT AND COLLECTION OF NONCOMPLIANCE PENALTIES BY EPA Supplemental Rules for Formal Adjudicatory Hearings § 66.93 Time...

40 CFR 66.93 - Time limits.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 15 2011-07-01 2011-07-01 false Time limits. 66.93 Section 66.93 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) ASSESSMENT AND COLLECTION OF NONCOMPLIANCE PENALTIES BY EPA Supplemental Rules for Formal Adjudicatory Hearings § 66.93 Time...

10 CFR 76.93 - Quality assurance.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 10 Energy 2 2013-01-01 2013-01-01 false Quality assurance. 76.93 Section 76.93 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) CERTIFICATION OF GASEOUS DIFFUSION PLANTS Safety § 76.93 Quality assurance. The Corporation shall establish, maintain, and execute a quality assurance program satisfying each of...

10 CFR 76.93 - Quality assurance.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 10 Energy 2 2012-01-01 2012-01-01 false Quality assurance. 76.93 Section 76.93 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) CERTIFICATION OF GASEOUS DIFFUSION PLANTS Safety § 76.93 Quality assurance. The Corporation shall establish, maintain, and execute a quality assurance program satisfying each of...

10 CFR 76.93 - Quality assurance.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 10 Energy 2 2014-01-01 2014-01-01 false Quality assurance. 76.93 Section 76.93 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) CERTIFICATION OF GASEOUS DIFFUSION PLANTS Safety § 76.93 Quality assurance. The Corporation shall establish, maintain, and execute a quality assurance program satisfying each of...

10 CFR 76.93 - Quality assurance.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 10 Energy 2 2011-01-01 2011-01-01 false Quality assurance. 76.93 Section 76.93 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) CERTIFICATION OF GASEOUS DIFFUSION PLANTS Safety § 76.93 Quality assurance. The Corporation shall establish, maintain, and execute a quality assurance program satisfying each of...

10 CFR 76.93 - Quality assurance.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 2 2010-01-01 2010-01-01 false Quality assurance. 76.93 Section 76.93 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) CERTIFICATION OF GASEOUS DIFFUSION PLANTS Safety § 76.93 Quality assurance. The Corporation shall establish, maintain, and execute a quality assurance program satisfying each of...

Intergranular metal phase increases thermal shock resistance of ceramic coating

NASA Technical Reports Server (NTRS)

Carpenter, H. W.

1966-01-01

Dispersed copper phase increases the thermal shock resistance of a plasma-arc-sprayed coating of zirconia used as a heat barrier on a metal substrate. A small amount of copper is deposited on the granules of the zirconia powder before arc-spraying the resultant powder composite onto the substrate.

PA-6 inhibits inward rectifier currents carried by V93I and D172N gain-of-function KIR2.1 channels, but increases channel protein expression.

PubMed

Ji, Yuan; Veldhuis, Marlieke G; Zandvoort, Jantien; Romunde, Fee L; Houtman, Marien J C; Duran, Karen; van Haaften, Gijs; Zangerl-Plessl, Eva-Maria; Takanari, Hiroki; Stary-Weinzinger, Anna; van der Heyden, Marcel A G

2017-07-15

The inward rectifier potassium current I K1 contributes to a stable resting membrane potential and phase 3 repolarization of the cardiac action potential. KCNJ2 gain-of-function mutations V93I and D172N associate with increased I K1 , short QT syndrome type 3 and congenital atrial fibrillation. Pentamidine-Analogue 6 (PA-6) is an efficient (IC 50  = 14 nM with inside-out patch clamp methodology) and specific I K1 inhibitor that interacts with the cytoplasmic pore region of the K IR 2.1 ion channel, encoded by KCNJ2. At 10 μM, PA-6 increases wild-type (WT) K IR 2.1 expression in HEK293T cells upon chronic treatment. We hypothesized that PA-6 will interact with and inhibit V93I and D172N K IR 2.1 channels, whereas impact on channel expression at the plasma membrane requires higher concentrations. Molecular modelling was performed with the human K IR 2.1 closed state homology model using FlexX. WT and mutant K IR 2.1 channels were expressed in HEK293 cells. Patch-clamp single cell electrophysiology measurements were performed in the whole cell and inside-out mode of the patch clamp method. K IR 2.1 expression level and localization were determined by western blot analysis and immunofluorescence microscopy, respectively. PA-6 docking in the V93I/D172N double mutant homology model of K IR 2.1 demonstrated that mutations and drug-binding site are >30 Å apart. PA-6 inhibited WT and V93I outward currents with similar potency (IC 50  = 35.5 and 43.6 nM at +50 mV for WT and V93I), whereas D172N currents were less sensitive (IC 50  = 128.9 nM at +50 mV) using inside-out patch-clamp electrophysiology. In whole cell mode, 1 μM of PA-6 inhibited outward I K1 at -50 mV by 28 ± 36%, 18 ± 20% and 10 ± 6%, for WT, V93I and D172N channels respectively. Western blot analysis demonstrated that PA-6 (5 μM, 24 h) increased K IR 2.1 expression levels of WT (6.3 ± 1.5 fold), and V93I (3.9 ± 0.9) and D172N (4.8 ± 2.0) mutants. Immunofluorescent

ANTIBIOTICS IN MANAGEMENT OF STAPHYLOCOCCAL ENDOCARDITIS—With Special Reference to Increasing Bacterial Resistance

PubMed Central

Levinson, David C.; Griffith, George C.; Pearson, Harold E.

1951-01-01

Eighteen patients with staphylococcal endocarditis were observed at the Los Angeles County Hospital over a 3-year period (1947-49, inclusive). Twelve died. Bacterial sensitivity studies were carried out in 15 of the cases, and there was resistance to penicillin in ten. Aureomycin was effective in two cases of Staphylococcus aureus endocarditis in which there was no response to penicillin therapy. In one case of Staphylococcus aureus endocarditis the organism was resistant to penicillin and developed increasing resistance to aureomycin. PMID:14812349

7 CFR 93.13 - Analytical methods.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 3 2011-01-01 2011-01-01 false Analytical methods. 93.13 Section 93.13 Agriculture... PROCESSED FRUITS AND VEGETABLES Peanuts, Tree Nuts, Corn and Other Oilseeds § 93.13 Analytical methods... manuals: (a) Approved Methods of the American Association of Cereal Chemists (AACC), American Association...

7 CFR 93.13 - Analytical methods.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 3 2014-01-01 2014-01-01 false Analytical methods. 93.13 Section 93.13 Agriculture... PROCESSED FRUITS AND VEGETABLES Peanuts, Tree Nuts, Corn and Other Oilseeds § 93.13 Analytical methods... manuals: (a) Approved Methods of the American Association of Cereal Chemists (AACC), American Association...

7 CFR 93.13 - Analytical methods.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 3 2013-01-01 2013-01-01 false Analytical methods. 93.13 Section 93.13 Agriculture... PROCESSED FRUITS AND VEGETABLES Peanuts, Tree Nuts, Corn and Other Oilseeds § 93.13 Analytical methods... manuals: (a) Approved Methods of the American Association of Cereal Chemists (AACC), American Association...

7 CFR 93.13 - Analytical methods.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 3 2010-01-01 2010-01-01 false Analytical methods. 93.13 Section 93.13 Agriculture... PROCESSED FRUITS AND VEGETABLES Peanuts, Tree Nuts, Corn and Other Oilseeds § 93.13 Analytical methods... manuals: (a) Approved Methods of the American Association of Cereal Chemists (AACC), American Association...

7 CFR 93.13 - Analytical methods.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 3 2012-01-01 2012-01-01 false Analytical methods. 93.13 Section 93.13 Agriculture... PROCESSED FRUITS AND VEGETABLES Peanuts, Tree Nuts, Corn and Other Oilseeds § 93.13 Analytical methods... manuals: (a) Approved Methods of the American Association of Cereal Chemists (AACC), American Association...

9 CFR 93.705 - Health certificate.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Health certificate. 93.705 Section 93.705 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE... CONVEYANCE AND SHIPPING CONTAINERS Miscellaneous Animals § 93.705 Health certificate. (a) No person may...

9 CFR 93.705 - Health certificate.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Health certificate. 93.705 Section 93.705 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE... CONVEYANCE AND SHIPPING CONTAINERS Miscellaneous Animals § 93.705 Health certificate. (a) No person may...

9 CFR 93.705 - Health certificate.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Health certificate. 93.705 Section 93.705 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE... CONVEYANCE AND SHIPPING CONTAINERS Miscellaneous Animals § 93.705 Health certificate. (a) No person may...

9 CFR 93.705 - Health certificate.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Health certificate. 93.705 Section 93.705 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE... CONVEYANCE AND SHIPPING CONTAINERS Miscellaneous Animals § 93.705 Health certificate. (a) No person may...

9 CFR 93.705 - Health certificate.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Health certificate. 93.705 Section 93.705 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE... CONVEYANCE AND SHIPPING CONTAINERS Miscellaneous Animals § 93.705 Health certificate. (a) No person may...

42 CFR 93.209 - Funding component.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 42 Public Health 1 2014-10-01 2014-10-01 false Funding component. 93.209 Section 93.209 Public... EFFECTS STUDIES OF HAZARDOUS SUBSTANCES RELEASES AND FACILITIES PUBLIC HEALTH SERVICE POLICIES ON RESEARCH MISCONDUCT Definitions § 93.209 Funding component. Funding component means any organizational unit of the PHS...

42 CFR 93.209 - Funding component.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 42 Public Health 1 2012-10-01 2012-10-01 false Funding component. 93.209 Section 93.209 Public... EFFECTS STUDIES OF HAZARDOUS SUBSTANCES RELEASES AND FACILITIES PUBLIC HEALTH SERVICE POLICIES ON RESEARCH MISCONDUCT Definitions § 93.209 Funding component. Funding component means any organizational unit of the PHS...

42 CFR 93.209 - Funding component.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 42 Public Health 1 2013-10-01 2013-10-01 false Funding component. 93.209 Section 93.209 Public... EFFECTS STUDIES OF HAZARDOUS SUBSTANCES RELEASES AND FACILITIES PUBLIC HEALTH SERVICE POLICIES ON RESEARCH MISCONDUCT Definitions § 93.209 Funding component. Funding component means any organizational unit of the PHS...

42 CFR 93.209 - Funding component.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 42 Public Health 1 2011-10-01 2011-10-01 false Funding component. 93.209 Section 93.209 Public... EFFECTS STUDIES OF HAZARDOUS SUBSTANCES RELEASES AND FACILITIES PUBLIC HEALTH SERVICE POLICIES ON RESEARCH MISCONDUCT Definitions § 93.209 Funding component. Funding component means any organizational unit of the PHS...

42 CFR 93.209 - Funding component.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 1 2010-10-01 2010-10-01 false Funding component. 93.209 Section 93.209 Public... EFFECTS STUDIES OF HAZARDOUS SUBSTANCES RELEASES AND FACILITIES PUBLIC HEALTH SERVICE POLICIES ON RESEARCH MISCONDUCT Definitions § 93.209 Funding component. Funding component means any organizational unit of the PHS...

9 CFR 93.510 - Quarantine requirements.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Quarantine requirements. 93.510 Section 93.510 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF... FOR MEANS OF CONVEYANCE AND SHIPPING CONTAINERS Swine § 93.510 Quarantine requirements. Swine shall be...

9 CFR 93.510 - Quarantine requirements.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Quarantine requirements. 93.510 Section 93.510 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF... FOR MEANS OF CONVEYANCE AND SHIPPING CONTAINERS Swine § 93.510 Quarantine requirements. Swine shall be...

25 CFR 700.93 - Relocation plan.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 25 Indians 2 2010-04-01 2010-04-01 false Relocation plan. 700.93 Section 700.93 Indians THE OFFICE OF NAVAJO AND HOPI INDIAN RELOCATION COMMISSION OPERATIONS AND RELOCATION PROCEDURES General Policies and Instructions Definitions § 700.93 Relocation plan. The relocation plan shall be the plan prepared...

12 CFR 560.93 - Lending limitations.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 12 Banks and Banking 5 2010-01-01 2010-01-01 false Lending limitations. 560.93 Section 560.93 Banks and Banking OFFICE OF THRIFT SUPERVISION, DEPARTMENT OF THE TREASURY LENDING AND INVESTMENT Lending and Investment Provisions Applicable to all Savings Associations § 560.93 Lending limitations. (a...

Mixed-Methods Resistance Training Increases Power and Strength of Young and Older Men.

ERIC Educational Resources Information Center

Newton, Robert U.; Hakkinen, Keijo; Hakkinen, Arja; McCormick, Matt; Volek, Jeff; Kraemer, William J.

2002-01-01

Examined the effects of a 10-week, mixed-methods resistance training program on young and older men. Although results confirmed some age-related reductions in muscle strength and power, the older men demonstrated similar capacity to the younger men for increases in muscle strength and power via an appropriate, periodized resistance training…

14 CFR 93.323 - Flight plans.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 2 2010-01-01 2010-01-01 false Flight plans. 93.323 Section 93.323... AND GENERAL OPERATING RULES SPECIAL AIR TRAFFIC RULES Special Flight Rules in the Vicinity of Grand Canyon National Park, AZ § 93.323 Flight plans. Each certificate holder conducting a commercial SFRA...

14 CFR 93.323 - Flight plans.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 2 2013-01-01 2013-01-01 false Flight plans. 93.323 Section 93.323... AND GENERAL OPERATING RULES SPECIAL AIR TRAFFIC RULES Special Flight Rules in the Vicinity of Grand Canyon National Park, AZ § 93.323 Flight plans. Each certificate holder conducting a commercial SFRA...

14 CFR 93.323 - Flight plans.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 2 2014-01-01 2014-01-01 false Flight plans. 93.323 Section 93.323... AND GENERAL OPERATING RULES SPECIAL AIR TRAFFIC RULES Special Flight Rules in the Vicinity of Grand Canyon National Park, AZ § 93.323 Flight plans. Each certificate holder conducting a commercial SFRA...

14 CFR 93.323 - Flight plans.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 2 2012-01-01 2012-01-01 false Flight plans. 93.323 Section 93.323... AND GENERAL OPERATING RULES SPECIAL AIR TRAFFIC RULES Special Flight Rules in the Vicinity of Grand Canyon National Park, AZ § 93.323 Flight plans. Each certificate holder conducting a commercial SFRA...

14 CFR 93.323 - Flight plans.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 2 2011-01-01 2011-01-01 false Flight plans. 93.323 Section 93.323... AND GENERAL OPERATING RULES SPECIAL AIR TRAFFIC RULES Special Flight Rules in the Vicinity of Grand Canyon National Park, AZ § 93.323 Flight plans. Each certificate holder conducting a commercial SFRA...

9 CFR 93.913 - Health certificate.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Health certificate. 93.913 Section 93.913 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE... § 93.913 Health certificate. (a) General. All live VHS-regulated fish that are imported from VHS...

9 CFR 93.913 - Health certificate.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Health certificate. 93.913 Section 93.913 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE... § 93.913 Health certificate. (a) General. All live VHS-regulated fish that are imported from VHS...

9 CFR 93.913 - Health certificate.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Health certificate. 93.913 Section 93.913 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE... § 93.913 Health certificate. (a) General. All live VHS-regulated fish that are imported from VHS...

9 CFR 93.913 - Health certificate.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Health certificate. 93.913 Section 93.913 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE... § 93.913 Health certificate. (a) General. All live VHS-regulated fish that are imported from VHS...

9 CFR 93.913 - Health certificate.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Health certificate. 93.913 Section 93.913 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE... § 93.913 Health certificate. (a) General. All live VHS-regulated fish that are imported from VHS...

42 CFR 93.224 - Research record.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 1 2010-10-01 2010-10-01 false Research record. 93.224 Section 93.224 Public... EFFECTS STUDIES OF HAZARDOUS SUBSTANCES RELEASES AND FACILITIES PUBLIC HEALTH SERVICE POLICIES ON RESEARCH MISCONDUCT Definitions § 93.224 Research record. Research record means the record of data or results that...

42 CFR 93.224 - Research record.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 42 Public Health 1 2011-10-01 2011-10-01 false Research record. 93.224 Section 93.224 Public... EFFECTS STUDIES OF HAZARDOUS SUBSTANCES RELEASES AND FACILITIES PUBLIC HEALTH SERVICE POLICIES ON RESEARCH MISCONDUCT Definitions § 93.224 Research record. Research record means the record of data or results that...

42 CFR 93.224 - Research record.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 42 Public Health 1 2013-10-01 2013-10-01 false Research record. 93.224 Section 93.224 Public... EFFECTS STUDIES OF HAZARDOUS SUBSTANCES RELEASES AND FACILITIES PUBLIC HEALTH SERVICE POLICIES ON RESEARCH MISCONDUCT Definitions § 93.224 Research record. Research record means the record of data or results that...

42 CFR 93.224 - Research record.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 42 Public Health 1 2012-10-01 2012-10-01 false Research record. 93.224 Section 93.224 Public... EFFECTS STUDIES OF HAZARDOUS SUBSTANCES RELEASES AND FACILITIES PUBLIC HEALTH SERVICE POLICIES ON RESEARCH MISCONDUCT Definitions § 93.224 Research record. Research record means the record of data or results that...

42 CFR 93.224 - Research record.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 42 Public Health 1 2014-10-01 2014-10-01 false Research record. 93.224 Section 93.224 Public... EFFECTS STUDIES OF HAZARDOUS SUBSTANCES RELEASES AND FACILITIES PUBLIC HEALTH SERVICE POLICIES ON RESEARCH MISCONDUCT Definitions § 93.224 Research record. Research record means the record of data or results that...

42 CFR 93.105 - Time limitations.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 1 2010-10-01 2010-10-01 false Time limitations. 93.105 Section 93.105 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES HEALTH ASSESSMENTS AND HEALTH... MISCONDUCT General § 93.105 Time limitations. (a) Six-year limitation. This part applies only to research...

42 CFR 93.105 - Time limitations.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 42 Public Health 1 2011-10-01 2011-10-01 false Time limitations. 93.105 Section 93.105 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES HEALTH ASSESSMENTS AND HEALTH... MISCONDUCT General § 93.105 Time limitations. (a) Six-year limitation. This part applies only to research...

29 CFR 102.93 - Alternative procedure.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 29 Labor 2 2010-07-01 2010-07-01 false Alternative procedure. 102.93 Section 102.93 Labor Regulations Relating to Labor NATIONAL LABOR RELATIONS BOARD RULES AND REGULATIONS, SERIES 8 Procedure To Hear and Determine Disputes Under Section 10(k) of the Act § 102.93 Alternative procedure. If, either...

21 CFR 640.93 - General requirements.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 7 2010-04-01 2010-04-01 false General requirements. 640.93 Section 640.93 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) BIOLOGICS ADDITIONAL STANDARDS FOR HUMAN BLOOD AND BLOOD PRODUCTS Plasma Protein Fraction (Human) § 640.93 General...

21 CFR 640.93 - General requirements.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 7 2012-04-01 2012-04-01 false General requirements. 640.93 Section 640.93 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) BIOLOGICS ADDITIONAL STANDARDS FOR HUMAN BLOOD AND BLOOD PRODUCTS Plasma Protein Fraction (Human) § 640.93 General...

21 CFR 640.93 - General requirements.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 7 2011-04-01 2010-04-01 true General requirements. 640.93 Section 640.93 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) BIOLOGICS ADDITIONAL STANDARDS FOR HUMAN BLOOD AND BLOOD PRODUCTS Plasma Protein Fraction (Human) § 640.93 General...

21 CFR 640.93 - General requirements.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 7 2013-04-01 2013-04-01 false General requirements. 640.93 Section 640.93 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) BIOLOGICS ADDITIONAL STANDARDS FOR HUMAN BLOOD AND BLOOD PRODUCTS Plasma Protein Fraction (Human) § 640.93 General...

21 CFR 640.93 - General requirements.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 7 2014-04-01 2014-04-01 false General requirements. 640.93 Section 640.93 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) BIOLOGICS ADDITIONAL STANDARDS FOR HUMAN BLOOD AND BLOOD PRODUCTS Plasma Protein Fraction (Human) § 640.93 General...

7 CFR 93.4 - Analytical methods.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 3 2013-01-01 2013-01-01 false Analytical methods. 93.4 Section 93.4 Agriculture... PROCESSED FRUITS AND VEGETABLES Citrus Juices and Certain Citrus Products § 93.4 Analytical methods. (a) The majority of analytical methods for citrus products are found in the Official Methods of Analysis of AOAC...

7 CFR 93.4 - Analytical methods.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 3 2014-01-01 2014-01-01 false Analytical methods. 93.4 Section 93.4 Agriculture... PROCESSED FRUITS AND VEGETABLES Citrus Juices and Certain Citrus Products § 93.4 Analytical methods. (a) The majority of analytical methods for citrus products are found in the Official Methods of Analysis of AOAC...

7 CFR 93.4 - Analytical methods.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 3 2010-01-01 2010-01-01 false Analytical methods. 93.4 Section 93.4 Agriculture... PROCESSED FRUITS AND VEGETABLES Citrus Juices and Certain Citrus Products § 93.4 Analytical methods. (a) The majority of analytical methods for citrus products are found in the Official Methods of Analysis of AOAC...

7 CFR 93.4 - Analytical methods.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 3 2011-01-01 2011-01-01 false Analytical methods. 93.4 Section 93.4 Agriculture... PROCESSED FRUITS AND VEGETABLES Citrus Juices and Certain Citrus Products § 93.4 Analytical methods. (a) The majority of analytical methods for citrus products are found in the Official Methods of Analysis of AOAC...

7 CFR 93.4 - Analytical methods.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 3 2012-01-01 2012-01-01 false Analytical methods. 93.4 Section 93.4 Agriculture... PROCESSED FRUITS AND VEGETABLES Citrus Juices and Certain Citrus Products § 93.4 Analytical methods. (a) The majority of analytical methods for citrus products are found in the Official Methods of Analysis of AOAC...

36 CFR 9.3 - Access permits.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 36 Parks, Forests, and Public Property 1 2014-07-01 2014-07-01 false Access permits. 9.3 Section 9.3 Parks, Forests, and Public Property NATIONAL PARK SERVICE, DEPARTMENT OF THE INTERIOR MINERALS MANAGEMENT Mining and Mining Claims § 9.3 Access permits. (a) All special use or other permits dealing with...

36 CFR 9.3 - Access permits.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 36 Parks, Forests, and Public Property 1 2012-07-01 2012-07-01 false Access permits. 9.3 Section 9.3 Parks, Forests, and Public Property NATIONAL PARK SERVICE, DEPARTMENT OF THE INTERIOR MINERALS MANAGEMENT Mining and Mining Claims § 9.3 Access permits. (a) All special use or other permits dealing with...

36 CFR 9.3 - Access permits.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 36 Parks, Forests, and Public Property 1 2013-07-01 2013-07-01 false Access permits. 9.3 Section 9.3 Parks, Forests, and Public Property NATIONAL PARK SERVICE, DEPARTMENT OF THE INTERIOR MINERALS MANAGEMENT Mining and Mining Claims § 9.3 Access permits. (a) All special use or other permits dealing with...

36 CFR 9.3 - Access permits.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 36 Parks, Forests, and Public Property 1 2010-07-01 2010-07-01 false Access permits. 9.3 Section 9.3 Parks, Forests, and Public Property NATIONAL PARK SERVICE, DEPARTMENT OF THE INTERIOR MINERALS MANAGEMENT Mining and Mining Claims § 9.3 Access permits. (a) All special use or other permits dealing with...

36 CFR 9.3 - Access permits.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 36 Parks, Forests, and Public Property 1 2011-07-01 2011-07-01 false Access permits. 9.3 Section 9.3 Parks, Forests, and Public Property NATIONAL PARK SERVICE, DEPARTMENT OF THE INTERIOR MINERALS MANAGEMENT Mining and Mining Claims § 9.3 Access permits. (a) All special use or other permits dealing with...

42 CFR 93.200 - Administrative action.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 42 Public Health 1 2011-10-01 2011-10-01 false Administrative action. 93.200 Section 93.200 Public... MISCONDUCT Definitions § 93.200 Administrative action. Administrative action means— (a) An HHS action in... related to that research or research training and to conserve public funds; or (b) An HHS action in...

42 CFR 93.510 - Filing motions.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 42 Public Health 1 2011-10-01 2011-10-01 false Filing motions. 93.510 Section 93.510 Public Health... MISCONDUCT Opportunity To Contest ORI Findings of Research Misconduct and HHS Administrative Actions Hearing Process § 93.510 Filing motions. (a) Parties must file all motions and requests for an order or ruling...

42 CFR 93.510 - Filing motions.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 1 2010-10-01 2010-10-01 false Filing motions. 93.510 Section 93.510 Public Health... MISCONDUCT Opportunity To Contest ORI Findings of Research Misconduct and HHS Administrative Actions Hearing Process § 93.510 Filing motions. (a) Parties must file all motions and requests for an order or ruling...

21 CFR 12.93 - Summary decisions.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 1 2010-04-01 2010-04-01 false Summary decisions. 12.93 Section 12.93 Food and... PUBLIC HEARING Hearing Procedures § 12.93 Summary decisions. (a) After the hearing commences, a participant may move, with or without supporting affidavits, for a summary decision on any issue in the...

Combining R gene and quantitative resistance increases effectiveness of cultivar resistance against Leptosphaeria maculans in Brassica napus in different environments

PubMed Central

Mitrousia, Georgia K.; Sidique, Siti Nordahliawate M.; Qi, Aiming; Fitt, Bruce D. L.

2018-01-01

Using cultivar resistance against pathogens is one of the most economical and environmentally friendly methods for control of crop diseases. However, cultivar resistance can be easily rendered ineffective due to changes in pathogen populations or environments. To test the hypothesis that combining R gene-mediated resistance and quantitative resistance (QR) in one cultivar can provide more effective resistance than use of either type of resistance on its own, effectiveness of resistance in eight oilseed rape (Brassica napus) cultivars with different R genes and/or QR against Leptosphaeria maculans (phoma stem canker) was investigated in 13 different environments/sites over three growing seasons (2010/2011, 2011/2012 and 2012/2013). Cultivar Drakkar with no R genes and no QR was used as susceptible control and for sampling L. maculans populations. Isolates of L. maculans were obtained from the 13 sites in 2010/2011 to assess frequencies of avirulent alleles of different effector genes (AvrLm1, AvrLm4 or AvrLm7) corresponding to the resistance genes (Rlm1, Rlm4 or Rlm7) used in the field experiments. Results of field experiments showed that cultivars DK Cabernet (Rlm1 + QR) and Adriana (Rlm4 + QR) had significantly less severe phoma stem canker than cultivars Capitol (Rlm1) and Bilbao (Rlm4), respectively. Results of controlled environment experiments confirmed the presence of Rlm genes and/or QR in these four cultivars. Analysis of L. maculans populations from different sites showed that the mean frequencies of AvrLm1 (10%) and AvrLm4 (41%) were less than that of AvrLm7 (100%), suggesting that Rlm1 and Rlm4 gene-mediated resistances were partially rendered ineffective while Rlm7 resistance was still effective. Cultivar Excel (Rlm7 + QR) had less severe canker than cultivar Roxet (Rlm7), but the difference between them was not significant due to influence of the effective resistance gene Rlm7. For the two cultivars with only QR, Es-Astrid (QR) had less severe stem

Numerical analysis of dense narrow backfills for increasing lateral passive resistance.

DOT National Transportation Integrated Search

2010-08-01

Previously, full-scale lateral load tests conducted on pile caps with different aspect ratios showed that placement : of a narrow, dense backfill zone against the cap could substantially increase the passive resistance. The objective : of this study ...

14 CFR 125.93 - Airplane limitations.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 3 2010-01-01 2010-01-01 false Airplane limitations. 125.93 Section 125.93...: AIRPLANES HAVING A SEATING CAPACITY OF 20 OR MORE PASSENGERS OR A MAXIMUM PAYLOAD CAPACITY OF 6,000 POUNDS OR MORE; AND RULES GOVERNING PERSONS ON BOARD SUCH AIRCRAFT Airplane Requirements § 125.93 Airplane...

14 CFR 125.93 - Airplane limitations.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 3 2012-01-01 2012-01-01 false Airplane limitations. 125.93 Section 125.93...: AIRPLANES HAVING A SEATING CAPACITY OF 20 OR MORE PASSENGERS OR A MAXIMUM PAYLOAD CAPACITY OF 6,000 POUNDS OR MORE; AND RULES GOVERNING PERSONS ON BOARD SUCH AIRCRAFT Airplane Requirements § 125.93 Airplane...

14 CFR 125.93 - Airplane limitations.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 3 2014-01-01 2014-01-01 false Airplane limitations. 125.93 Section 125.93...: AIRPLANES HAVING A SEATING CAPACITY OF 20 OR MORE PASSENGERS OR A MAXIMUM PAYLOAD CAPACITY OF 6,000 POUNDS OR MORE; AND RULES GOVERNING PERSONS ON BOARD SUCH AIRCRAFT Airplane Requirements § 125.93 Airplane...

14 CFR 125.93 - Airplane limitations.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 3 2011-01-01 2011-01-01 false Airplane limitations. 125.93 Section 125.93...: AIRPLANES HAVING A SEATING CAPACITY OF 20 OR MORE PASSENGERS OR A MAXIMUM PAYLOAD CAPACITY OF 6,000 POUNDS OR MORE; AND RULES GOVERNING PERSONS ON BOARD SUCH AIRCRAFT Airplane Requirements § 125.93 Airplane...

14 CFR 125.93 - Airplane limitations.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 3 2013-01-01 2013-01-01 false Airplane limitations. 125.93 Section 125.93...: AIRPLANES HAVING A SEATING CAPACITY OF 20 OR MORE PASSENGERS OR A MAXIMUM PAYLOAD CAPACITY OF 6,000 POUNDS OR MORE; AND RULES GOVERNING PERSONS ON BOARD SUCH AIRCRAFT Airplane Requirements § 125.93 Airplane...

14 CFR 93.175 - Applicability.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 2 2014-01-01 2014-01-01 false Applicability. 93.175 Section 93.175 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR TRAFFIC... VFR operations in the vicinity of Luke Air Force Base, AZ. ...

14 CFR 93.175 - Applicability.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 2 2013-01-01 2013-01-01 false Applicability. 93.175 Section 93.175 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR TRAFFIC... VFR operations in the vicinity of Luke Air Force Base, AZ. ...

14 CFR 93.175 - Applicability.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 2 2012-01-01 2012-01-01 false Applicability. 93.175 Section 93.175 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR TRAFFIC... VFR operations in the vicinity of Luke Air Force Base, AZ. ...

14 CFR 93.175 - Applicability.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 2 2011-01-01 2011-01-01 false Applicability. 93.175 Section 93.175 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR TRAFFIC... VFR operations in the vicinity of Luke Air Force Base, AZ. ...

14 CFR 93.175 - Applicability.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 2 2010-01-01 2010-01-01 false Applicability. 93.175 Section 93.175 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR TRAFFIC... VFR operations in the vicinity of Luke Air Force Base, AZ. ...

Decision and cost analysis of empirical antibiotic therapy of acute sinusitis in the era of increasing antimicrobial resistance: do we have an additional tool for antibiotic policy decisions?

PubMed

Babela, Robert; Jarcuska, Pavol; Uraz, Vladimir; Krčméry, Vladimír; Jadud, Branislav; Stevlik, Jan; Gould, Ian M

2017-11-01

No previous analyses have attempted to determine optimal therapy for upper respiratory tract infections on the basis of cost-minimization models and the prevalence of antimicrobial resistance among respiratory pathogens in Slovakia. This investigation compares macrolides and cephalosporines for empirical therapy and look at this new tool from the aspect of potential antibiotic policy decision-making process. We employed a decision tree model to determine the threshold level of macrolides and cephalosporines resistance among community respiratory pathogens that would make cephalosporines or macrolides cost-minimising. To obtain information on clinical outcomes and cost of URTIs, a systematic review of the literature was performed. The cost-minimization model of upper respiratory tract infections (URTIs) treatment was derived from the review of literature and published models. We found that the mean cost of empirical treatment with macrolides for an URTIs was €93.27 when the percentage of resistant Streptococcus pneumoniae in the community was 0%; at 5%, the mean cost was €96.45; at 10%, €99.63; at 20%, €105.99, and at 30%, €112.36. Our model demonstrated that when the percentage of macrolide resistant Streptococcus pneumoniae exceeds 13.8%, use of empirical cephalosporines rather than macrolides minimizes the treatment cost of URTIs. Empirical macrolide therapy is less expensive than cephalosporines therapy for URTIs unless macrolide resistance exceeds 13.8% in the community. Results have important antibiotic policy implications, since presented model can be use as an additional decision-making tool for new guidelines and reimbursement processes by local authorities in the era of continual increase in antibiotic resistance.

Increased corrosion resistance of the AZ80 magnesium alloy by rapid solidification.

PubMed

Aghion, E; Jan, L; Meshi, L; Goldman, J

2015-11-01

Magnesium (Mg) and Mg-alloys are being considered as implantable biometals. Despite their excellent biocompatibility and good mechanical properties, their rapid corrosion is a major impediment precluding their widespread acceptance as implantable biomaterials. Here, we investigate the potential for rapid solidification to increase the corrosion resistance of Mg alloys. To this end, the effect of rapid solidification on the environmental and stress corrosion behavior of the AZ80 Mg alloy vs. its conventionally cast counterpart was evaluated in simulated physiological electrolytes. The microstructural characteristics were examined by optical microscopy, SEM, TEM, and X-ray diffraction analysis. The corrosion behavior was evaluated by immersion, salt spraying, and potentiodynamic polarization. Stress corrosion resistance was assessed by Slow Strain Rate Testing. The results indicate that the corrosion resistance of rapidly solidified ribbons is significantly improved relative to the conventional cast alloy due to the increased Al content dissolved in the α-Mg matrix and the correspondingly reduced presence of the β-phase (Mg17 Al12 ). Unfortunately, extrusion consolidated solidified ribbons exhibited a substantial reduction in the environmental performance and stress corrosion resistance. This was mainly attributed to the detrimental effect of the extrusion process, which enriched the iron impurities and increased the internal stresses by imposing a higher dislocation density. In terms of immersion tests, the average corrosion rate of the rapidly solidified ribbons was <0.4 mm/year compared with ∼2 mm/year for the conventionally cast alloy and 26 mm/year for the rapidly solidified extruded ribbons. © 2014 Wiley Periodicals, Inc.

42 CFR 93.210 - Good faith.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 42 Public Health 1 2014-10-01 2014-10-01 false Good faith. 93.210 Section 93.210 Public Health... MISCONDUCT Definitions § 93.210 Good faith. Good faith as applied to a complainant or witness, means having a... allegation or cooperation with a research misconduct proceeding is not in good faith if made with knowing or...

42 CFR 93.210 - Good faith.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 42 Public Health 1 2013-10-01 2013-10-01 false Good faith. 93.210 Section 93.210 Public Health... MISCONDUCT Definitions § 93.210 Good faith. Good faith as applied to a complainant or witness, means having a... allegation or cooperation with a research misconduct proceeding is not in good faith if made with knowing or...

42 CFR 93.210 - Good faith.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 42 Public Health 1 2012-10-01 2012-10-01 false Good faith. 93.210 Section 93.210 Public Health... MISCONDUCT Definitions § 93.210 Good faith. Good faith as applied to a complainant or witness, means having a... allegation or cooperation with a research misconduct proceeding is not in good faith if made with knowing or...

27 CFR 6.93 - Combination packaging.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2010-04-01 2010-04-01 false Combination packaging. 6.93 Section 6.93 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU, DEPARTMENT OF THE TREASURY LIQUORS âTIED-HOUSEâ Exceptions § 6.93 Combination packaging. The act by an industry member of packaging and distributing...

27 CFR 6.93 - Combination packaging.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2011-04-01 2011-04-01 false Combination packaging. 6.93 Section 6.93 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU, DEPARTMENT OF THE TREASURY LIQUORS âTIED-HOUSEâ Exceptions § 6.93 Combination packaging. The act by an industry member of packaging and distributing...

46 CFR 64.93 - Pump controls.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 46 Shipping 2 2014-10-01 2014-10-01 false Pump controls. 64.93 Section 64.93 Shipping COAST GUARD... SYSTEMS Cargo Handling System § 64.93 Pump controls. (a) A pressure gauge must be installed— (1) On the pump discharge; (2) Near the pump controls; and (3) Visible to the operator. (b) A pump must have a...

46 CFR 64.93 - Pump controls.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 46 Shipping 2 2012-10-01 2012-10-01 false Pump controls. 64.93 Section 64.93 Shipping COAST GUARD... SYSTEMS Cargo Handling System § 64.93 Pump controls. (a) A pressure gauge must be installed— (1) On the pump discharge; (2) Near the pump controls; and (3) Visible to the operator. (b) A pump must have a...

46 CFR 64.93 - Pump controls.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 2 2010-10-01 2010-10-01 false Pump controls. 64.93 Section 64.93 Shipping COAST GUARD... SYSTEMS Cargo Handling System § 64.93 Pump controls. (a) A pressure gauge must be installed— (1) On the pump discharge; (2) Near the pump controls; and (3) Visible to the operator. (b) A pump must have a...

46 CFR 64.93 - Pump controls.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 46 Shipping 2 2013-10-01 2013-10-01 false Pump controls. 64.93 Section 64.93 Shipping COAST GUARD... SYSTEMS Cargo Handling System § 64.93 Pump controls. (a) A pressure gauge must be installed— (1) On the pump discharge; (2) Near the pump controls; and (3) Visible to the operator. (b) A pump must have a...

46 CFR 64.93 - Pump controls.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 46 Shipping 2 2011-10-01 2011-10-01 false Pump controls. 64.93 Section 64.93 Shipping COAST GUARD... SYSTEMS Cargo Handling System § 64.93 Pump controls. (a) A pressure gauge must be installed— (1) On the pump discharge; (2) Near the pump controls; and (3) Visible to the operator. (b) A pump must have a...

40 CFR 93.153 - Applicability.

Code of Federal Regulations, 2011 CFR

2011-07-01

... control activities and adopting approach, departure, and enroute procedures for aircraft operations above... 40 Protection of Environment 20 2011-07-01 2011-07-01 false Applicability. 93.153 Section 93.153 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) DETERMINING...

7 CFR 993.93 - Amendments.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 8 2010-01-01 2010-01-01 false Amendments. 993.93 Section 993.93 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE DRIED PRUNES PRODUCED IN CALIFORNIA...

7 CFR 993.93 - Amendments.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 8 2011-01-01 2011-01-01 false Amendments. 993.93 Section 993.93 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE DRIED PRUNES PRODUCED IN CALIFORNIA...

7 CFR 993.93 - Amendments.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 8 2012-01-01 2012-01-01 false Amendments. 993.93 Section 993.93 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE DRIED PRUNES PRODUCED IN CALIFORNIA...

7 CFR 993.93 - Amendments.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 8 2013-01-01 2013-01-01 false Amendments. 993.93 Section 993.93 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; FRUITS, VEGETABLES, NUTS), DEPARTMENT OF AGRICULTURE DRIED PRUNES PRODUCED IN CALIFORNIA...

7 CFR 993.93 - Amendments.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 8 2014-01-01 2014-01-01 false Amendments. 993.93 Section 993.93 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; FRUITS, VEGETABLES, NUTS), DEPARTMENT OF AGRICULTURE DRIED PRUNES PRODUCED IN CALIFORNIA...

40 CFR 408.93 - [Reserved

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 29 2011-07-01 2009-07-01 true [Reserved] 408.93 Section 408.93 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) EFFLUENT GUIDELINES AND STANDARDS CANNED AND PRESERVED SEAFOOD PROCESSING POINT SOURCE CATEGORY Non-Remote Alaskan Shrimp Processing...

40 CFR 408.93 - [Reserved

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 28 2010-07-01 2010-07-01 true [Reserved] 408.93 Section 408.93 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) EFFLUENT GUIDELINES AND STANDARDS CANNED AND PRESERVED SEAFOOD PROCESSING POINT SOURCE CATEGORY Non-Remote Alaskan Shrimp Processing...

Increased chalcone synthase (CHS) expression is associated with dicamba resistance in Kochia scoparia.

PubMed

Pettinga, Dean J; Ou, Junjun; Patterson, Eric L; Jugulam, Mithila; Westra, Philip; Gaines, Todd A

2017-10-30

Resistance to the synthetic auxin herbicide dicamba is increasingly problematic in Kochia scoparia. The resistance mechanism in an inbred dicamba-resistant K. scoparia line (9425R) was investigated using physiological and transcriptomics (RNA-Seq) approaches. No differences were found in dicamba absorption or metabolism between 9425R and a dicamba-susceptible line, but 9425R was found to have significantly reduced dicamba translocation. Known auxin-responsive genes ACC synthase (ACS) and indole-3-acetic acid amino synthetase (GH3) were transcriptionally induced following dicamba treatment in dicamba-susceptible K. scoparia but not in 9425R. Chalcone synthase (CHS), the gene regulating synthesis of the flavonols quertecin and kaemperfol, was found to have twofold higher transcription in 9425R both without and 12 h after dicamba treatment. Increased CHS transcription co-segregated with dicamba resistance in a forward genetics screen using an F 2 population. Prior work has shown that the flavonols quertecin and kaemperfol compete with auxin for intercellular movement and vascular loading via ATP-binding cassette subfamily B (ABCB) membrane transporters. The results of this study support a model in which constitutively increased CHS expression in the meristem produces more flavonols that would compete with dicamba for intercellular transport by ABCB transporters, resulting in reduced dicamba translocation. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

9 CFR 381.93 - Decomposition.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 9 Animals and Animal Products 2 2010-01-01 2010-01-01 false Decomposition. 381.93 Section 381.93 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE AGENCY... CERTIFICATION POULTRY PRODUCTS INSPECTION REGULATIONS Post Mortem Inspection; Disposition of Carcasses and Parts...

14 CFR 141.93 - Enrollment.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 3 2010-01-01 2010-01-01 false Enrollment. 141.93 Section 141.93 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) SCHOOLS AND... limitations and simulated emergency landing instructions; and (x) A description of and instructions regarding...

Mechanisms of Increased Resistance to Chlorhexidine and Cross-Resistance to Colistin following Exposure of Klebsiella pneumoniae Clinical Isolates to Chlorhexidine

PubMed Central

Bock, Lucy J.; Bonney, Laura C.

2016-01-01

ABSTRACT Klebsiella pneumoniae is an opportunistic pathogen that is often difficult to treat due to its multidrug resistance (MDR). We have previously shown that K. pneumoniae strains are able to “adapt” (become more resistant) to the widely used bisbiguanide antiseptic chlorhexidine. Here, we investigated the mechanisms responsible for and the phenotypic consequences of chlorhexidine adaptation, with particular reference to antibiotic cross-resistance. In five of six strains, adaptation to chlorhexidine also led to resistance to the last-resort antibiotic colistin. Here, we show that chlorhexidine adaptation is associated with mutations in the two-component regulator phoPQ and a putative Tet repressor gene (smvR) adjacent to the major facilitator superfamily (MFS) efflux pump gene, smvA. Upregulation of smvA (10- to 27-fold) was confirmed in smvR mutant strains, and this effect and the associated phenotype were suppressed when a wild-type copy of smvR was introduced on plasmid pACYC. Upregulation of phoPQ (5- to 15-fold) and phoPQ-regulated genes, pmrD (6- to 19-fold) and pmrK (18- to 64-fold), was confirmed in phoPQ mutant strains. In contrast, adaptation of K. pneumoniae to colistin did not result in increased chlorhexidine resistance despite the presence of mutations in phoQ and elevated phoPQ, pmrD, and pmrK transcript levels. Insertion of a plasmid containing phoPQ from chlorhexidine-adapted strains into wild-type K. pneumoniae resulted in elevated expression levels of phoPQ, pmrD, and pmrK and increased resistance to colistin, but not chlorhexidine. The potential risk of colistin resistance emerging in K. pneumoniae as a consequence of exposure to chlorhexidine has important clinical implications for infection prevention procedures. PMID:27799211

40 CFR 179.93 - Testimony.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 23 2010-07-01 2010-07-01 false Testimony. 179.93 Section 179.93 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) PESTICIDE PROGRAMS FORMAL EVIDENTIARY... the memory or demeanor of the witness is of importance. Written direct testimony shall be in the form...

14 CFR 93.303 - Definitions.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 2 2014-01-01 2014-01-01 false Definitions. 93.303 Section 93.303 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR TRAFFIC... of sightseeing flights as part of any travel arrangement package; or (7) Whether the flight in...

14 CFR 93.303 - Definitions.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 2 2013-01-01 2013-01-01 false Definitions. 93.303 Section 93.303 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR TRAFFIC... of sightseeing flights as part of any travel arrangement package; or (7) Whether the flight in...

14 CFR 93.303 - Definitions.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 2 2012-01-01 2012-01-01 false Definitions. 93.303 Section 93.303 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR TRAFFIC... of sightseeing flights as part of any travel arrangement package; or (7) Whether the flight in...

14 CFR 93.335 - Definitions.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 2 2014-01-01 2014-01-01 false Definitions. 93.335 Section 93.335 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR TRAFFIC... services. Fringe airports are the following airports located near the outer boundary of the Washington, DC...

14 CFR 93.335 - Definitions.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 2 2011-01-01 2011-01-01 false Definitions. 93.335 Section 93.335 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR TRAFFIC... services. Fringe airports are the following airports located near the outer boundary of the Washington, DC...

14 CFR 93.335 - Definitions.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 2 2012-01-01 2012-01-01 false Definitions. 93.335 Section 93.335 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR TRAFFIC... services. Fringe airports are the following airports located near the outer boundary of the Washington, DC...

14 CFR 93.335 - Definitions.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 2 2013-01-01 2013-01-01 false Definitions. 93.335 Section 93.335 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR TRAFFIC... services. Fringe airports are the following airports located near the outer boundary of the Washington, DC...

42 CFR 93.212 - Inquiry.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 42 Public Health 1 2011-10-01 2011-10-01 false Inquiry. 93.212 Section 93.212 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES HEALTH ASSESSMENTS AND HEALTH EFFECTS STUDIES OF HAZARDOUS SUBSTANCES RELEASES AND FACILITIES PUBLIC HEALTH SERVICE POLICIES ON RESEARCH MISCONDUCT...

42 CFR 93.204 - Contract.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 1 2010-10-01 2010-10-01 false Contract. 93.204 Section 93.204 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES HEALTH ASSESSMENTS AND HEALTH EFFECTS STUDIES OF HAZARDOUS SUBSTANCES RELEASES AND FACILITIES PUBLIC HEALTH SERVICE POLICIES ON RESEARCH...

42 CFR 93.204 - Contract.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 42 Public Health 1 2011-10-01 2011-10-01 false Contract. 93.204 Section 93.204 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES HEALTH ASSESSMENTS AND HEALTH EFFECTS STUDIES OF HAZARDOUS SUBSTANCES RELEASES AND FACILITIES PUBLIC HEALTH SERVICE POLICIES ON RESEARCH...

42 CFR 93.211 - Hearing.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 1 2010-10-01 2010-10-01 false Hearing. 93.211 Section 93.211 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES HEALTH ASSESSMENTS AND HEALTH EFFECTS STUDIES OF HAZARDOUS SUBSTANCES RELEASES AND FACILITIES PUBLIC HEALTH SERVICE POLICIES ON RESEARCH MISCONDUCT...

40 CFR 179.93 - Testimony.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 25 2013-07-01 2013-07-01 false Testimony. 179.93 Section 179.93 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) PESTICIDE PROGRAMS FORMAL EVIDENTIARY... the memory or demeanor of the witness is of importance. Written direct testimony shall be in the form...

40 CFR 179.93 - Testimony.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 25 2012-07-01 2012-07-01 false Testimony. 179.93 Section 179.93 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) PESTICIDE PROGRAMS FORMAL EVIDENTIARY... the memory or demeanor of the witness is of importance. Written direct testimony shall be in the form...

40 CFR 179.93 - Testimony.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 24 2014-07-01 2014-07-01 false Testimony. 179.93 Section 179.93 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) PESTICIDE PROGRAMS FORMAL EVIDENTIARY... the memory or demeanor of the witness is of importance. Written direct testimony shall be in the form...

40 CFR 179.93 - Testimony.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 24 2011-07-01 2011-07-01 false Testimony. 179.93 Section 179.93 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) PESTICIDE PROGRAMS FORMAL EVIDENTIARY... the memory or demeanor of the witness is of importance. Written direct testimony shall be in the form...

42 CFR 93.222 - Research.

Code of Federal Regulations, 2014 CFR

2014-10-01

..., demonstration or survey designed to develop or contribute to general knowledge (basic research) or specific... 42 Public Health 1 2014-10-01 2014-10-01 false Research. 93.222 Section 93.222 Public Health... STUDIES OF HAZARDOUS SUBSTANCES RELEASES AND FACILITIES PUBLIC HEALTH SERVICE POLICIES ON RESEARCH...

42 CFR 93.222 - Research.

Code of Federal Regulations, 2010 CFR

2010-10-01

..., demonstration or survey designed to develop or contribute to general knowledge (basic research) or specific... 42 Public Health 1 2010-10-01 2010-10-01 false Research. 93.222 Section 93.222 Public Health... STUDIES OF HAZARDOUS SUBSTANCES RELEASES AND FACILITIES PUBLIC HEALTH SERVICE POLICIES ON RESEARCH...

42 CFR 93.222 - Research.

Code of Federal Regulations, 2011 CFR

2011-10-01

..., demonstration or survey designed to develop or contribute to general knowledge (basic research) or specific... 42 Public Health 1 2011-10-01 2011-10-01 false Research. 93.222 Section 93.222 Public Health... STUDIES OF HAZARDOUS SUBSTANCES RELEASES AND FACILITIES PUBLIC HEALTH SERVICE POLICIES ON RESEARCH...

42 CFR 93.222 - Research.

Code of Federal Regulations, 2012 CFR

2012-10-01

..., demonstration or survey designed to develop or contribute to general knowledge (basic research) or specific... 42 Public Health 1 2012-10-01 2012-10-01 false Research. 93.222 Section 93.222 Public Health... STUDIES OF HAZARDOUS SUBSTANCES RELEASES AND FACILITIES PUBLIC HEALTH SERVICE POLICIES ON RESEARCH...

42 CFR 93.222 - Research.

Code of Federal Regulations, 2013 CFR

2013-10-01

..., demonstration or survey designed to develop or contribute to general knowledge (basic research) or specific... 42 Public Health 1 2013-10-01 2013-10-01 false Research. 93.222 Section 93.222 Public Health... STUDIES OF HAZARDOUS SUBSTANCES RELEASES AND FACILITIES PUBLIC HEALTH SERVICE POLICIES ON RESEARCH...

9 CFR 93.323 - Inspection.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Inspection. 93.323 Section 93.323 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE EXPORTATION AND IMPORTATION OF ANIMALS (INCLUDING POULTRY) AND ANIMAL PRODUCTS IMPORTATION OF CERTAIN ANIMALS...

9 CFR 93.323 - Inspection.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Inspection. 93.323 Section 93.323 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE EXPORTATION AND IMPORTATION OF ANIMALS (INCLUDING POULTRY) AND ANIMAL PRODUCTS IMPORTATION OF CERTAIN ANIMALS...

9 CFR 93.323 - Inspection.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Inspection. 93.323 Section 93.323 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE EXPORTATION AND IMPORTATION OF ANIMALS (INCLUDING POULTRY) AND ANIMAL PRODUCTS IMPORTATION OF CERTAIN ANIMALS...

9 CFR 93.323 - Inspection.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Inspection. 93.323 Section 93.323 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE EXPORTATION AND IMPORTATION OF ANIMALS (INCLUDING POULTRY) AND ANIMAL PRODUCTS IMPORTATION OF CERTAIN ANIMALS...

9 CFR 93.323 - Inspection.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Inspection. 93.323 Section 93.323 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE EXPORTATION AND IMPORTATION OF ANIMALS (INCLUDING POULTRY) AND ANIMAL PRODUCTS IMPORTATION OF CERTAIN ANIMALS...

The lncRNA RZE1 Controls Cryptococcal Morphological Transition

PubMed Central

Yang, Ence; Wang, Linqi; Cai, James J.; Lin, Xiaorong

2015-01-01

In the fungal pathogen Cryptococcus neoformans, the switch from yeast to hypha is an important morphological process preceding the meiotic events during sexual development. Morphotype is also known to be associated with cryptococcal virulence potential. Previous studies identified the regulator Znf2 as a key decision maker for hypha formation and as an anti-virulence factor. By a forward genetic screen, we discovered that a long non-coding RNA (lncRNA) RZE1 functions upstream of ZNF2 in regulating yeast-to-hypha transition. We demonstrate that RZE1 functions primarily in cis and less effectively in trans. Interestingly, RZE1’s function is restricted to its native nucleus. Accordingly, RZE1 does not appear to directly affect Znf2 translation or the subcellular localization of Znf2 protein. Transcriptome analysis indicates that the loss of RZE1 reduces the transcript level of ZNF2 and Znf2’s prominent downstream targets. In addition, microscopic examination using single molecule fluorescent in situ hybridization (smFISH) indicates that the loss of RZE1 increases the ratio of ZNF2 transcripts in the nucleus versus those in the cytoplasm. Taken together, this lncRNA controls Cryptococcus yeast-to-hypha transition through regulating the key morphogenesis regulator Znf2. This is the first functional characterization of a lncRNA in a human fungal pathogen. Given the potential large number of lncRNAs in the genomes of Cryptococcus and other fungal pathogens, the findings implicate lncRNAs as an additional layer of genetic regulation during fungal development that may well contribute to the complexity in these “simple” eukaryotes. PMID:26588844

A Treatment Plant Receiving Waste Water from Multiple Bulk Drug Manufacturers Is a Reservoir for Highly Multi-Drug Resistant Integron-Bearing Bacteria

PubMed Central

Walujkar, Sandeep A.; Charan, Shakti Singh; Moore, Edward R. B.; Larsson, D. G. Joakim; Shouche, Yogesh S.

2013-01-01

The arenas and detailed mechanisms for transfer of antibiotic resistance genes between environmental bacteria and pathogens are largely unclear. Selection pressures from antibiotics in situations where environmental bacteria and human pathogens meet are expected to increase the risks for such gene transfer events. We hypothesize that waste-water treatment plants (WWTPs) serving antibiotic manufacturing industries may provide such spawning grounds, given the high bacterial densities present there together with exceptionally strong and persistent selection pressures from the antibiotic-contaminated waste. Previous analyses of effluent from an Indian industrial WWTP that processes waste from bulk drug production revealed the presence of a range of drugs, including broad spectrum antibiotics at extremely high concentrations (mg/L range). In this study, we have characterized the antibiotic resistance profiles of 93 bacterial strains sampled at different stages of the treatment process from the WWTP against 39 antibiotics belonging to 12 different classes. A large majority (86%) of the strains were resistant to 20 or more antibiotics. Although there were no classically-recognized human pathogens among the 93 isolated strains, opportunistic pathogens such as Ochrobactrum intermedium, Providencia rettgeri, vancomycin resistant Enterococci (VRE), Aerococcus sp. and Citrobacter freundii were found to be highly resistant. One of the O. intermedium strains (ER1) was resistant to 36 antibiotics, while P. rettgeri (OSR3) was resistant to 35 antibiotics. Class 1 and 2 integrons were detected in 74/93 (80%) strains each, and 88/93 (95%) strains harbored at least one type of integron. The qPCR analysis of community DNA also showed an unprecedented high prevalence of integrons, suggesting that the bacteria living under such high selective pressure have an appreciable potential for genetic exchange of resistance genes via mobile gene cassettes. The present study provides insight into

Increased plasma FGF21 level as an early biomarker for insulin resistance and metabolic disturbance in obese insulin-resistant rats.

PubMed

Tanajak, Pongpan; Pongkan, Wanpitak; Chattipakorn, Siriporn C; Chattipakorn, Nipon

2018-05-01

Propose: To investigate the temporal relationship between plasma fibroblast growth factor 21 levels, insulin resistance, metabolic dysfunction and cardiac fibroblast growth factor 21 resistance in long-term high-fat diet-induced obese rats. In total, 36 male Wistar rats were fed with either a normal diet or high-fat diet for 12 weeks. Blood was collected from the tail tip, and plasma was used to determine metabolic profiles and fibroblast growth factor 21 levels. Rats were sacrificed at weeks 4, 8 and 12, and the hearts were rapidly removed for the determination of cardiac fibroblast growth factor 21 signalling pathways. Body weight and plasma fibroblast growth factor 21 levels were increased after 4 weeks of consumption of a high-fat diet. At weeks 8 and 12, high-fat diet rats had significantly increased body weight and plasma fibroblast growth factor 21 levels, together with increased plasma insulin, HOMA index, area under the curve of glucose, plasma total cholesterol, plasma low-density lipoprotein cholesterol, serum malondialdehyde and cardiac malondialdehyde levels. However, plasma high-density lipoprotein cholesterol levels and cardiac fibroblast growth factor 21 signalling proteins (p-FGFR1 Tyr 154 , p-ERK1/2 Thr 202 /Tyr 204 and p-Akt Ser 473 ) were decreased, compared with normal diet rats. These findings suggest that plasma fibroblast growth factor 21 levels could be an early predictive biomarker prior to the development of insulin resistance, metabolic disturbance and cardiac fibroblast growth factor 21 resistance.

14 CFR 93.313 - Communications.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 2 2011-01-01 2011-01-01 false Communications. 93.313 Section 93.313 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR TRAFFIC... directed by the U.S. Air Force Rescue Coordination Center, no person may operate an aircraft in the Special...

14 CFR 93.313 - Communications.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 2 2013-01-01 2013-01-01 false Communications. 93.313 Section 93.313 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR TRAFFIC... directed by the U.S. Air Force Rescue Coordination Center, no person may operate an aircraft in the Special...

14 CFR 93.313 - Communications.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 2 2010-01-01 2010-01-01 false Communications. 93.313 Section 93.313 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR TRAFFIC... directed by the U.S. Air Force Rescue Coordination Center, no person may operate an aircraft in the Special...

14 CFR 93.313 - Communications.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 2 2014-01-01 2014-01-01 false Communications. 93.313 Section 93.313 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR TRAFFIC... directed by the U.S. Air Force Rescue Coordination Center, no person may operate an aircraft in the Special...

14 CFR 93.313 - Communications.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 2 2012-01-01 2012-01-01 false Communications. 93.313 Section 93.313 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR TRAFFIC... directed by the U.S. Air Force Rescue Coordination Center, no person may operate an aircraft in the Special...

32 CFR 93.1 - References.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 32 National Defense 1 2013-07-01 2013-07-01 false References. 93.1 Section 93.1 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE PERSONNEL, MILITARY AND CIVILIAN ACCEPTANCE OF SERVICE OF PROCESS; RELEASE OF OFFICIAL INFORMATION IN LITIGATION; AND TESTIMONY BY NSA PERSONNEL AS...

32 CFR 93.4 - Policy.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 32 National Defense 1 2012-07-01 2012-07-01 false Policy. 93.4 Section 93.4 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE PERSONNEL, MILITARY AND CIVILIAN ACCEPTANCE OF SERVICE OF PROCESS; RELEASE OF OFFICIAL INFORMATION IN LITIGATION; AND TESTIMONY BY NSA PERSONNEL AS...

32 CFR 93.1 - References.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 32 National Defense 1 2012-07-01 2012-07-01 false References. 93.1 Section 93.1 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE PERSONNEL, MILITARY AND CIVILIAN ACCEPTANCE OF SERVICE OF PROCESS; RELEASE OF OFFICIAL INFORMATION IN LITIGATION; AND TESTIMONY BY NSA PERSONNEL AS...

32 CFR 93.4 - Policy.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 32 National Defense 1 2011-07-01 2011-07-01 false Policy. 93.4 Section 93.4 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE PERSONNEL, MILITARY AND CIVILIAN ACCEPTANCE OF SERVICE OF PROCESS; RELEASE OF OFFICIAL INFORMATION IN LITIGATION; AND TESTIMONY BY NSA PERSONNEL AS...

32 CFR 93.4 - Policy.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 32 National Defense 1 2014-07-01 2014-07-01 false Policy. 93.4 Section 93.4 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE PERSONNEL, MILITARY AND CIVILIAN ACCEPTANCE OF SERVICE OF PROCESS; RELEASE OF OFFICIAL INFORMATION IN LITIGATION; AND TESTIMONY BY NSA PERSONNEL AS...

32 CFR 93.4 - Policy.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 32 National Defense 1 2010-07-01 2010-07-01 false Policy. 93.4 Section 93.4 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE PERSONNEL, MILITARY AND CIVILIAN ACCEPTANCE OF SERVICE OF PROCESS; RELEASE OF OFFICIAL INFORMATION IN LITIGATION; AND TESTIMONY BY NSA PERSONNEL AS...

32 CFR 93.1 - References.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 32 National Defense 1 2014-07-01 2014-07-01 false References. 93.1 Section 93.1 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE PERSONNEL, MILITARY AND CIVILIAN ACCEPTANCE OF SERVICE OF PROCESS; RELEASE OF OFFICIAL INFORMATION IN LITIGATION; AND TESTIMONY BY NSA PERSONNEL AS...

32 CFR 93.1 - References.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 32 National Defense 1 2010-07-01 2010-07-01 false References. 93.1 Section 93.1 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE PERSONNEL, MILITARY AND CIVILIAN ACCEPTANCE OF SERVICE OF PROCESS; RELEASE OF OFFICIAL INFORMATION IN LITIGATION; AND TESTIMONY BY NSA PERSONNEL AS...

32 CFR 93.1 - References.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 32 National Defense 1 2011-07-01 2011-07-01 false References. 93.1 Section 93.1 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE PERSONNEL, MILITARY AND CIVILIAN ACCEPTANCE OF SERVICE OF PROCESS; RELEASE OF OFFICIAL INFORMATION IN LITIGATION; AND TESTIMONY BY NSA PERSONNEL AS...

32 CFR 93.4 - Policy.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 32 National Defense 1 2013-07-01 2013-07-01 false Policy. 93.4 Section 93.4 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE PERSONNEL, MILITARY AND CIVILIAN ACCEPTANCE OF SERVICE OF PROCESS; RELEASE OF OFFICIAL INFORMATION IN LITIGATION; AND TESTIMONY BY NSA PERSONNEL AS...

45 CFR 98.93 - Complaints.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 45 Public Welfare 1 2012-10-01 2012-10-01 false Complaints. 98.93 Section 98.93 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION CHILD CARE AND DEVELOPMENT FUND Monitoring... for Children and Families, 370 L'Enfant Promenade, SW., Washington, DC 20447. The complaint shall...

42 CFR 93.518 - Witnesses.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 1 2010-10-01 2010-10-01 false Witnesses. 93.518 Section 93.518 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES HEALTH ASSESSMENTS AND HEALTH EFFECTS... telephone, or by audio-visual communication as permitted by the ALJ. However, a respondent must always...

32 CFR 93.7 - Responsibilities.

Code of Federal Regulations, 2012 CFR

2012-07-01

... ACCEPTANCE OF SERVICE OF PROCESS; RELEASE OF OFFICIAL INFORMATION IN LITIGATION; AND TESTIMONY BY NSA... overseeing NSA compliance with § 93.1(a) and this part 93, and for consulting with DoJ when appropriate. In response to a litigation demand requesting official information or the testimony of NSA personnel as...

32 CFR 93.7 - Responsibilities.

Code of Federal Regulations, 2010 CFR

2010-07-01

... ACCEPTANCE OF SERVICE OF PROCESS; RELEASE OF OFFICIAL INFORMATION IN LITIGATION; AND TESTIMONY BY NSA... overseeing NSA compliance with § 93.1(a) and this part 93, and for consulting with DoJ when appropriate. In response to a litigation demand requesting official information or the testimony of NSA personnel as...

32 CFR 93.7 - Responsibilities.

Code of Federal Regulations, 2011 CFR

2011-07-01

... ACCEPTANCE OF SERVICE OF PROCESS; RELEASE OF OFFICIAL INFORMATION IN LITIGATION; AND TESTIMONY BY NSA... overseeing NSA compliance with § 93.1(a) and this part 93, and for consulting with DoJ when appropriate. In response to a litigation demand requesting official information or the testimony of NSA personnel as...

32 CFR 93.7 - Responsibilities.

Code of Federal Regulations, 2013 CFR

2013-07-01

... ACCEPTANCE OF SERVICE OF PROCESS; RELEASE OF OFFICIAL INFORMATION IN LITIGATION; AND TESTIMONY BY NSA... overseeing NSA compliance with § 93.1(a) and this part 93, and for consulting with DoJ when appropriate. In response to a litigation demand requesting official information or the testimony of NSA personnel as...

32 CFR 93.7 - Responsibilities.

Code of Federal Regulations, 2014 CFR

2014-07-01

... ACCEPTANCE OF SERVICE OF PROCESS; RELEASE OF OFFICIAL INFORMATION IN LITIGATION; AND TESTIMONY BY NSA... overseeing NSA compliance with § 93.1(a) and this part 93, and for consulting with DoJ when appropriate. In response to a litigation demand requesting official information or the testimony of NSA personnel as...

Dropout Report, 1992-93. Publication Number 93.17.

ERIC Educational Resources Information Center

Sanchez, Mario

The Office of Research and Evaluation of the Austin Independent School District TX annually collects dropout statistics for grades 7 through 12. This report contains various summaries and more detailed breakdowns for rates from 1985-86 to 1992-93. The class of 1993 had a 4-year dropout rate of 23.3%, the lowest rate in the last 5 years. Except for…

Inhibiting the osteocyte-specific protein sclerostin increases bone mass and fracture resistance in multiple myeloma

PubMed Central

Mohanty, Sindhu T.; Seckinger, Anja; Terry, Rachael L.; Pettitt, Jessica A.; Simic, Marija K.; Le, Lawrence M. T.; Kramer, Ina; Falank, Carolyne; Fairfield, Heather; Ghobrial, Irene M.; Baldock, Paul A.; Little, David G.; Kneissel, Michaela; Vanderkerken, Karin; Bassett, J. H. Duncan; Williams, Graham R.; Oyajobi, Babatunde O.; Hose, Dirk

2017-01-01

Multiple myeloma (MM) is a plasma cell cancer that develops in the skeleton causing profound bone destruction and fractures. The bone disease is mediated by increased osteoclastic bone resorption and suppressed bone formation. Bisphosphonates used for treatment inhibit bone resorption and prevent bone loss but fail to influence bone formation and do not replace lost bone, so patients continue to fracture. Stimulating bone formation to increase bone mass and fracture resistance is a priority; however, targeting tumor-derived modulators of bone formation has had limited success. Sclerostin is an osteocyte-specific Wnt antagonist that inhibits bone formation. We hypothesized that inhibiting sclerostin would prevent development of bone disease and increase resistance to fracture in MM. Sclerostin was expressed in osteocytes from bones from naive and myeloma-bearing mice. In contrast, sclerostin was not expressed by plasma cells from 630 patients with myeloma or 54 myeloma cell lines. Mice injected with 5TGM1-eGFP, 5T2MM, or MM1.S myeloma cells demonstrated significant bone loss, which was associated with a decrease in fracture resistance in the vertebrae. Treatment with anti-sclerostin antibody increased osteoblast numbers and bone formation rate but did not inhibit bone resorption or reduce tumor burden. Treatment with anti-sclerostin antibody prevented myeloma-induced bone loss, reduced osteolytic bone lesions, and increased fracture resistance. Treatment with anti-sclerostin antibody and zoledronic acid combined increased bone mass and fracture resistance when compared with treatment with zoledronic acid alone. This study defines a therapeutic strategy superior to the current standard of care that will reduce fractures for patients with MM. PMID:28515094

Exposure to dairy manure leads to greater antibiotic resistance and increased mass-specific respiration in soil microbial communities

PubMed Central

Avera, Bethany; Badgley, Brian; Barrett, John E.; Franklin, Josh; Knowlton, Katharine F.; Ray, Partha P.; Smitherman, Crystal

2017-01-01

Intensifying livestock production to meet the demands of a growing global population coincides with increases in both the administration of veterinary antibiotics and manure inputs to soils. These trends have the potential to increase antibiotic resistance in soil microbial communities. The effect of maintaining increased antibiotic resistance on soil microbial communities and the ecosystem processes they regulate is unknown. We compare soil microbial communities from paired reference and dairy manure-exposed sites across the USA. Given that manure exposure has been shown to elicit increased antibiotic resistance in soil microbial communities, we expect that manure-exposed sites will exhibit (i) compositionally different soil microbial communities, with shifts toward taxa known to exhibit resistance; (ii) greater abundance of antibiotic resistance genes; and (iii) corresponding maintenance of antibiotic resistance would lead to decreased microbial efficiency. We found that bacterial and fungal communities differed between reference and manure-exposed sites. Additionally, the β-lactam resistance gene ampC was 5.2-fold greater under manure exposure, potentially due to the use of cephalosporin antibiotics in dairy herds. Finally, ampC abundance was positively correlated with indicators of microbial stress, and microbial mass-specific respiration, which increased 2.1-fold under manure exposure. These findings demonstrate that the maintenance of antibiotic resistance associated with manure inputs alters soil microbial communities and ecosystem function. PMID:28356447

Exposure to dairy manure leads to greater antibiotic resistance and increased mass-specific respiration in soil microbial communities.

PubMed

Wepking, Carl; Avera, Bethany; Badgley, Brian; Barrett, John E; Franklin, Josh; Knowlton, Katharine F; Ray, Partha P; Smitherman, Crystal; Strickland, Michael S

2017-03-29

Intensifying livestock production to meet the demands of a growing global population coincides with increases in both the administration of veterinary antibiotics and manure inputs to soils. These trends have the potential to increase antibiotic resistance in soil microbial communities. The effect of maintaining increased antibiotic resistance on soil microbial communities and the ecosystem processes they regulate is unknown. We compare soil microbial communities from paired reference and dairy manure-exposed sites across the USA. Given that manure exposure has been shown to elicit increased antibiotic resistance in soil microbial communities, we expect that manure-exposed sites will exhibit (i) compositionally different soil microbial communities, with shifts toward taxa known to exhibit resistance; (ii) greater abundance of antibiotic resistance genes; and (iii) corresponding maintenance of antibiotic resistance would lead to decreased microbial efficiency. We found that bacterial and fungal communities differed between reference and manure-exposed sites. Additionally, the β-lactam resistance gene ampC was 5.2-fold greater under manure exposure, potentially due to the use of cephalosporin antibiotics in dairy herds. Finally, ampC abundance was positively correlated with indicators of microbial stress, and microbial mass-specific respiration, which increased 2.1-fold under manure exposure. These findings demonstrate that the maintenance of antibiotic resistance associated with manure inputs alters soil microbial communities and ecosystem function. © 2017 The Author(s).

Measurement of cross-sections for the 93Nb(p,n)93mMo and 93Nb(p,pn)92mNb reactions up to ∼20 MeV energy

NASA Astrophysics Data System (ADS)

Lawriniang, B.; Ghosh, R.; Badwar, S.; Vansola, V.; Santhi Sheela, Y.; Suryanarayana, S. V.; Naik, H.; Naik, Y. P.; Jyrwa, B.

2018-05-01

Excitation functions of the 93Nb(p,n)93mMo and 93Nb(p,pn)92mNb reactions were measured from threshold energies to ∼ 20MeV by employing stacked foil activation technique in combination with the off-line γ-ray spectroscopy at the BARC-TIFR Pelletron facility, Mumbai. For the 20 MeV proton beam, the energy degradation along the stack was calculated using the computer code SRIM 2013. The proton beam intensity was determined via the natCu(p,x)62Zn monitor reaction. The experimental data obtained were compared with the theoretical results from TALYS-1.8 as well as with the literature data available in EXFOR. It was found that for the 93Nb(p,n)92mMo reaction, the present data are in close agreement with some of the recent literature data and the theoretical values based on TALYS-1.8 but are lower than the other literature data. In the case of 93Nb(p,pn)93mNb reaction, present data agree very well with the literature data and the theoretical values.

40 CFR 600.011-93 - Reference materials.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Standard Test Method for Heat of Combustion of Liquid Hydrocarbon Fuels by Bomb Calorimeter 600.113-93, 600... Hydrocarbon Fuels by Bomb Calorimeter, IBR approved for §§ 600.113-93, 600.510-93, 600.113-08, and 600.510-08...

Molecular Surveillance of Antiviral Drug Resistance of Influenza A/H3N2 Virus in Singapore, 2009-2013

PubMed Central

Lee, Hong Kai; Tang, Julian Wei-Tze; Loh, Tze Ping; Hurt, Aeron C.; Oon, Lynette Lin-Ean; Koay, Evelyn Siew-Chuan

2015-01-01

Adamantanes and neuraminidase inhibitors (NAIs) are two classes of antiviral drugs available for the chemoprophylaxis and treatment of influenza infections. To determine the frequency of drug resistance in influenza A/H3N2 viruses in Singapore, large-scale sequencing of neuraminidase (NA) and matrix protein (MP) genes was performed directly without initial culture amplification. 241 laboratory-confirmed influenza A/H3N2 clinical samples, collected between May 2009 and November 2013 were included. In total, 229 NA (95%) and 241 MP (100%) complete sequences were obtained. Drug resistance mutations in the NA and MP genes were interpreted according to published studies. For the NAIs, a visual inspection of the aligned NA sequences revealed no known drug resistant genotypes (DRGs). For the adamantanes, the well-recognised S31N DRG was identified in all 241 MP genes. In addition, there was an increasing number of viruses carrying the combination of D93G+Y155F+D251V (since May 2013) or D93G (since March 2011) mutations in the NA gene. However, in-vitro NAI testing indicated that neither D93G+Y155F+D251V nor D93G alone conferred any changes in NAI susceptibility. Lastly, an I222T mutation in the NA gene that has previously been reported to cause oseltamivir-resistance in influenza A/H1N1/2009, B, and A/H5N1, was detected from a treatment-naïve patient. Further in-vitro NAI testing is required to confirm the effect of this mutation in A/H3N2 virus. PMID:25635767

32 CFR 93.6 - Fees.

Code of Federal Regulations, 2014 CFR

2014-07-01

... SERVICE OF PROCESS; RELEASE OF OFFICIAL INFORMATION IN LITIGATION; AND TESTIMONY BY NSA PERSONNEL AS WITNESSES § 93.6 Fees. Consistent with the guidelines in § 93.1(e), NSA may charge reasonable fees to... providing such information, and may include: (a) The costs of time expended by NSA employees to process and...

32 CFR 93.6 - Fees.

Code of Federal Regulations, 2011 CFR

2011-07-01

... SERVICE OF PROCESS; RELEASE OF OFFICIAL INFORMATION IN LITIGATION; AND TESTIMONY BY NSA PERSONNEL AS WITNESSES § 93.6 Fees. Consistent with the guidelines in § 93.1(e), NSA may charge reasonable fees to... providing such information, and may include: (a) The costs of time expended by NSA employees to process and...

32 CFR 93.6 - Fees.

Code of Federal Regulations, 2013 CFR

2013-07-01

... SERVICE OF PROCESS; RELEASE OF OFFICIAL INFORMATION IN LITIGATION; AND TESTIMONY BY NSA PERSONNEL AS WITNESSES § 93.6 Fees. Consistent with the guidelines in § 93.1(e), NSA may charge reasonable fees to... providing such information, and may include: (a) The costs of time expended by NSA employees to process and...

32 CFR 93.6 - Fees.

Code of Federal Regulations, 2010 CFR

2010-07-01

... SERVICE OF PROCESS; RELEASE OF OFFICIAL INFORMATION IN LITIGATION; AND TESTIMONY BY NSA PERSONNEL AS WITNESSES § 93.6 Fees. Consistent with the guidelines in § 93.1(e), NSA may charge reasonable fees to... providing such information, and may include: (a) The costs of time expended by NSA employees to process and...

32 CFR 93.6 - Fees.

Code of Federal Regulations, 2012 CFR

2012-07-01

... SERVICE OF PROCESS; RELEASE OF OFFICIAL INFORMATION IN LITIGATION; AND TESTIMONY BY NSA PERSONNEL AS WITNESSES § 93.6 Fees. Consistent with the guidelines in § 93.1(e), NSA may charge reasonable fees to... providing such information, and may include: (a) The costs of time expended by NSA employees to process and...

9 CFR 93.500 - Definitions.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Definitions. 93.500 Section 93.500 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE EXPORTATION AND IMPORTATION OF ANIMALS (INCLUDING POULTRY) AND ANIMAL PRODUCTS IMPORTATION OF CERTAIN ANIMALS, BIRDS, FISH, AND POULTRY, AND CERTAIN ANIMA...

9 CFR 93.500 - Definitions.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Definitions. 93.500 Section 93.500 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE EXPORTATION AND IMPORTATION OF ANIMALS (INCLUDING POULTRY) AND ANIMAL PRODUCTS IMPORTATION OF CERTAIN ANIMALS, BIRDS, FISH, AND POULTRY, AND CERTAIN ANIMA...

9 CFR 93.200 - Definitions.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Definitions. 93.200 Section 93.200 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE EXPORTATION AND IMPORTATION OF ANIMALS (INCLUDING POULTRY) AND ANIMAL PRODUCTS IMPORTATION OF CERTAIN ANIMALS, BIRDS, FISH, AND POULTRY, AND CERTAIN ANIMA...

9 CFR 93.500 - Definitions.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Definitions. 93.500 Section 93.500 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE EXPORTATION AND IMPORTATION OF ANIMALS (INCLUDING POULTRY) AND ANIMAL PRODUCTS IMPORTATION OF CERTAIN ANIMALS, BIRDS, FISH, AND POULTRY, AND CERTAIN ANIMA...

9 CFR 93.200 - Definitions.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Definitions. 93.200 Section 93.200 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE EXPORTATION AND IMPORTATION OF ANIMALS (INCLUDING POULTRY) AND ANIMAL PRODUCTS IMPORTATION OF CERTAIN ANIMALS, BIRDS, FISH, AND POULTRY, AND CERTAIN ANIMA...

9 CFR 93.200 - Definitions.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Definitions. 93.200 Section 93.200 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE EXPORTATION AND IMPORTATION OF ANIMALS (INCLUDING POULTRY) AND ANIMAL PRODUCTS IMPORTATION OF CERTAIN ANIMALS, BIRDS, FISH, AND POULTRY, AND CERTAIN ANIMA...

9 CFR 93.200 - Definitions.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Definitions. 93.200 Section 93.200 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE EXPORTATION AND IMPORTATION OF ANIMALS (INCLUDING POULTRY) AND ANIMAL PRODUCTS IMPORTATION OF CERTAIN ANIMALS, BIRDS, FISH, AND POULTRY, AND CERTAIN ANIMA...

10 CFR 9.3 - Definitions.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 10 Energy 1 2014-01-01 2014-01-01 false Definitions. 9.3 Section 9.3 Energy NUCLEAR REGULATORY... the Nuclear Regulatory Commission, established by the Energy Reorganization Act of 1974. NRC personnel... members or a quorum thereof sitting as a body, as provided by section 201 of the Energy Reorganization Act...

10 CFR 9.3 - Definitions.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 10 Energy 1 2013-01-01 2013-01-01 false Definitions. 9.3 Section 9.3 Energy NUCLEAR REGULATORY... the Nuclear Regulatory Commission, established by the Energy Reorganization Act of 1974. NRC personnel... members or a quorum thereof sitting as a body, as provided by section 201 of the Energy Reorganization Act...

10 CFR 9.3 - Definitions.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 10 Energy 1 2012-01-01 2012-01-01 false Definitions. 9.3 Section 9.3 Energy NUCLEAR REGULATORY... the Nuclear Regulatory Commission, established by the Energy Reorganization Act of 1974. NRC personnel... members or a quorum thereof sitting as a body, as provided by section 201 of the Energy Reorganization Act...

44 CFR 9.3 - Authority.

Code of Federal Regulations, 2014 CFR

2014-10-01

... GENERAL FLOODPLAIN MANAGEMENT AND PROTECTION OF WETLANDS § 9.3 Authority. The authority for these... Flood Insurance Act of 1968, as amended (Pub. L. 90-488); the Flood Disaster Protection Act of 1973, as amended (Pub. L. 93-234); and the National Environmental Policy Act of 1969 (NEPA) (Pub. L. 91-190...

44 CFR 9.3 - Authority.

Code of Federal Regulations, 2013 CFR

2013-10-01

... GENERAL FLOODPLAIN MANAGEMENT AND PROTECTION OF WETLANDS § 9.3 Authority. The authority for these... Flood Insurance Act of 1968, as amended (Pub. L. 90-488); the Flood Disaster Protection Act of 1973, as amended (Pub. L. 93-234); and the National Environmental Policy Act of 1969 (NEPA) (Pub. L. 91-190...

44 CFR 9.3 - Authority.

Code of Federal Regulations, 2010 CFR

2010-10-01

... GENERAL FLOODPLAIN MANAGEMENT AND PROTECTION OF WETLANDS § 9.3 Authority. The authority for these... Flood Insurance Act of 1968, as amended (Pub. L. 90-488); the Flood Disaster Protection Act of 1973, as amended (Pub. L. 93-234); and the National Environmental Policy Act of 1969 (NEPA) (Pub. L. 91-190...

44 CFR 9.3 - Authority.

Code of Federal Regulations, 2012 CFR

2012-10-01

... GENERAL FLOODPLAIN MANAGEMENT AND PROTECTION OF WETLANDS § 9.3 Authority. The authority for these... Flood Insurance Act of 1968, as amended (Pub. L. 90-488); the Flood Disaster Protection Act of 1973, as amended (Pub. L. 93-234); and the National Environmental Policy Act of 1969 (NEPA) (Pub. L. 91-190...

44 CFR 9.3 - Authority.

Code of Federal Regulations, 2011 CFR

2011-10-01

... GENERAL FLOODPLAIN MANAGEMENT AND PROTECTION OF WETLANDS § 9.3 Authority. The authority for these... Flood Insurance Act of 1968, as amended (Pub. L. 90-488); the Flood Disaster Protection Act of 1973, as amended (Pub. L. 93-234); and the National Environmental Policy Act of 1969 (NEPA) (Pub. L. 91-190...

10 CFR 9.3 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 1 2010-01-01 2010-01-01 false Definitions. 9.3 Section 9.3 Energy NUCLEAR REGULATORY... the Nuclear Regulatory Commission, established by the Energy Reorganization Act of 1974. NRC personnel... members or a quorum thereof sitting as a body, as provided by section 201 of the Energy Reorganization Act...

10 CFR 9.3 - Definitions.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 10 Energy 1 2011-01-01 2011-01-01 false Definitions. 9.3 Section 9.3 Energy NUCLEAR REGULATORY... the Nuclear Regulatory Commission, established by the Energy Reorganization Act of 1974. NRC personnel... members or a quorum thereof sitting as a body, as provided by section 201 of the Energy Reorganization Act...

Preparation and characterization of sorghum flour with increased resistant starch content

USDA-ARS?s Scientific Manuscript database

The primary objective of this research was to develop an effective process to increase the resistant starch content of sorghum flour. A secondary objective was to investigate the role of the sorghum proteins on starch digestibility. Samples of white sorghum flour (28.9% amylose content) with differe...

14 CFR 65.93 - Inspection authorization: Renewal.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 2 2011-01-01 2011-01-01 false Inspection authorization: Renewal. 65.93 Section 65.93 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIRMEN CERTIFICATION: AIRMEN OTHER THAN FLIGHT CREWMEMBERS Mechanics § 65.93 Inspection...

14 CFR 65.93 - Inspection authorization: Renewal.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 2 2010-01-01 2010-01-01 false Inspection authorization: Renewal. 65.93 Section 65.93 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIRMEN CERTIFICATION: AIRMEN OTHER THAN FLIGHT CREWMEMBERS Mechanics § 65.93 Inspection...

14 CFR 65.93 - Inspection authorization: Renewal.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 2 2013-01-01 2013-01-01 false Inspection authorization: Renewal. 65.93 Section 65.93 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIRMEN CERTIFICATION: AIRMEN OTHER THAN FLIGHT CREWMEMBERS Mechanics § 65.93 Inspection...

14 CFR 65.93 - Inspection authorization: Renewal.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 2 2012-01-01 2012-01-01 false Inspection authorization: Renewal. 65.93 Section 65.93 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIRMEN CERTIFICATION: AIRMEN OTHER THAN FLIGHT CREWMEMBERS Mechanics § 65.93 Inspection...

14 CFR 65.93 - Inspection authorization: Renewal.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 2 2014-01-01 2014-01-01 false Inspection authorization: Renewal. 65.93 Section 65.93 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIRMEN CERTIFICATION: AIRMEN OTHER THAN FLIGHT CREWMEMBERS Mechanics § 65.93 Inspection...

Sequence-Specific Targeting of Bacterial Resistance Genes Increases Antibiotic Efficacy

PubMed Central

Wong, Michael; Daly, Seth M.; Greenberg, David E.; Toprak, Erdal

2016-01-01

The lack of effective and well-tolerated therapies against antibiotic-resistant bacteria is a global public health problem leading to prolonged treatment and increased mortality. To improve the efficacy of existing antibiotic compounds, we introduce a new method for strategically inducing antibiotic hypersensitivity in pathogenic bacteria. Following the systematic verification that the AcrAB-TolC efflux system is one of the major determinants of the intrinsic antibiotic resistance levels in Escherichia coli, we have developed a short antisense oligomer designed to inhibit the expression of acrA and increase antibiotic susceptibility in E. coli. By employing this strategy, we can inhibit E. coli growth using 2- to 40-fold lower antibiotic doses, depending on the antibiotic compound utilized. The sensitizing effect of the antisense oligomer is highly specific to the targeted gene’s sequence, which is conserved in several bacterial genera, and the oligomer does not have any detectable toxicity against human cells. Finally, we demonstrate that antisense oligomers improve the efficacy of antibiotic combinations, allowing the combined use of even antagonistic antibiotic pairs that are typically not favored due to their reduced activities. PMID:27631336

Trophic compensation reinforces resistance: herbivory absorbs the increasing effects of multiple disturbances.

PubMed

Ghedini, Giulia; Russell, Bayden D; Connell, Sean D

2015-02-01

Disturbance often results in small changes in community structure, but the probability of transitioning to contrasting states increases when multiple disturbances combine. Nevertheless, we have limited insights into the mechanisms that stabilise communities, particularly how perturbations can be absorbed without restructuring (i.e. resistance). Here, we expand the concept of compensatory dynamics to include countervailing mechanisms that absorb disturbances through trophic interactions. By definition, 'compensation' occurs if a specific disturbance stimulates a proportional countervailing response that eliminates its otherwise unchecked effect. We show that the compounding effects of disturbances from local to global scales (i.e. local canopy-loss, eutrophication, ocean acidification) increasingly promote the expansion of weedy species, but that this response is countered by a proportional increase in grazing. Finally, we explore the relatively unrecognised role of compensatory effects, which are likely to maintain the resistance of communities to disturbance more deeply than current thinking allows. © 2015 John Wiley & Sons Ltd/CNRS.

45 CFR 93.105 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 45 Public Welfare 1 2010-10-01 2010-10-01 false Definitions. 93.105 Section 93.105 Public Welfare... Definitions. For purposes of this part: (a) Agency, as defined in 5 U.S.C. 552(f), includes Federal executive... Education Assistance Act (25 U.S.C. 450B). Alaskan Natives are included under the definitions of Indian...

7 CFR 3570.93 - Regional Commission grants.

Code of Federal Regulations, 2010 CFR

2010-01-01

... Appalachian Regional Commission (ARC) is authorized under the Appalachian Regional Development Act of 1965 to... 7 Agriculture 15 2010-01-01 2010-01-01 false Regional Commission grants. 3570.93 Section 3570.93... AGRICULTURE COMMUNITY PROGRAMS Community Facilities Grant Program § 3570.93 Regional Commission grants. (a...

9 CFR 93.409 - Articles accompanying ruminants.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Articles accompanying ruminants. 93.409 Section 93.409 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT...; REQUIREMENTS FOR MEANS OF CONVEYANCE AND SHIPPING CONTAINERS Ruminants § 93.409 Articles accompanying ruminants...

9 CFR 93.409 - Articles accompanying ruminants.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Articles accompanying ruminants. 93.409 Section 93.409 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT...; REQUIREMENTS FOR MEANS OF CONVEYANCE AND SHIPPING CONTAINERS Ruminants § 93.409 Articles accompanying ruminants...

9 CFR 93.409 - Articles accompanying ruminants.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Articles accompanying ruminants. 93.409 Section 93.409 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT...; REQUIREMENTS FOR MEANS OF CONVEYANCE AND SHIPPING CONTAINERS Ruminants § 93.409 Articles accompanying ruminants...

9 CFR 93.409 - Articles accompanying ruminants.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Articles accompanying ruminants. 93.409 Section 93.409 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT...; REQUIREMENTS FOR MEANS OF CONVEYANCE AND SHIPPING CONTAINERS Ruminants § 93.409 Articles accompanying ruminants...

9 CFR 93.409 - Articles accompanying ruminants.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Articles accompanying ruminants. 93.409 Section 93.409 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT...; REQUIREMENTS FOR MEANS OF CONVEYANCE AND SHIPPING CONTAINERS Ruminants § 93.409 Articles accompanying ruminants...

42 CFR 93.223 - Research misconduct proceeding.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 42 Public Health 1 2014-10-01 2014-10-01 false Research misconduct proceeding. 93.223 Section 93... POLICIES ON RESEARCH MISCONDUCT Definitions § 93.223 Research misconduct proceeding. Research misconduct proceeding means any actions related to alleged research misconduct taken under this part, including but not...

42 CFR 93.223 - Research misconduct proceeding.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 42 Public Health 1 2012-10-01 2012-10-01 false Research misconduct proceeding. 93.223 Section 93... POLICIES ON RESEARCH MISCONDUCT Definitions § 93.223 Research misconduct proceeding. Research misconduct proceeding means any actions related to alleged research misconduct taken under this part, including but not...

42 CFR 93.223 - Research misconduct proceeding.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 1 2010-10-01 2010-10-01 false Research misconduct proceeding. 93.223 Section 93... POLICIES ON RESEARCH MISCONDUCT Definitions § 93.223 Research misconduct proceeding. Research misconduct proceeding means any actions related to alleged research misconduct taken under this part, including but not...

42 CFR 93.223 - Research misconduct proceeding.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 42 Public Health 1 2013-10-01 2013-10-01 false Research misconduct proceeding. 93.223 Section 93... POLICIES ON RESEARCH MISCONDUCT Definitions § 93.223 Research misconduct proceeding. Research misconduct proceeding means any actions related to alleged research misconduct taken under this part, including but not...

32 CFR 842.93 - Delegations of authority.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 32 National Defense 6 2011-07-01 2011-07-01 false Delegations of authority. 842.93 Section 842.93 National Defense Department of Defense (Continued) DEPARTMENT OF THE AIR FORCE CLAIMS AND LITIGATION....93 Delegations of authority. (a) Settlement authority. (1) The following individuals have delegated...

42 CFR 93.223 - Research misconduct proceeding.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 42 Public Health 1 2011-10-01 2011-10-01 false Research misconduct proceeding. 93.223 Section 93... POLICIES ON RESEARCH MISCONDUCT Definitions § 93.223 Research misconduct proceeding. Research misconduct proceeding means any actions related to alleged research misconduct taken under this part, including but not...

14 CFR 93.130 - Suspension of allocations.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 2 2010-01-01 2010-01-01 false Suspension of allocations. 93.130 Section 93.130 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR TRAFFIC AND GENERAL OPERATING RULES SPECIAL AIR TRAFFIC RULES High Density Traffic Airports § 93...

14 CFR 93.130 - Suspension of allocations.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 2 2012-01-01 2012-01-01 false Suspension of allocations. 93.130 Section 93.130 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR TRAFFIC AND GENERAL OPERATING RULES SPECIAL AIR TRAFFIC RULES High Density Traffic Airports § 93...

14 CFR 93.130 - Suspension of allocations.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 2 2011-01-01 2011-01-01 false Suspension of allocations. 93.130 Section 93.130 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR TRAFFIC AND GENERAL OPERATING RULES SPECIAL AIR TRAFFIC RULES High Density Traffic Airports § 93...

14 CFR 93.130 - Suspension of allocations.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 2 2014-01-01 2014-01-01 false Suspension of allocations. 93.130 Section 93.130 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR TRAFFIC AND GENERAL OPERATING RULES SPECIAL AIR TRAFFIC RULES High Density Traffic Airports § 93...

14 CFR 93.130 - Suspension of allocations.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 2 2013-01-01 2013-01-01 false Suspension of allocations. 93.130 Section 93.130 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR TRAFFIC AND GENERAL OPERATING RULES SPECIAL AIR TRAFFIC RULES High Density Traffic Airports § 93...

38 CFR 18b.93 - Expeditious treatment.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 38 Pensions, Bonuses, and Veterans' Relief 2 2010-07-01 2010-07-01 false Expeditious treatment. 18b.93 Section 18b.93 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS... Judicial Standards of Practice § 18b.93 Expeditious treatment. Requests for expeditious treatment of...

Characterization of carbapenem-resistant Gram-negative bacteria from Tamil Nadu.

PubMed

Nachimuthu, Ramesh; Subramani, Ramkumar; Maray, Suresh; Gothandam, K M; Sivamangala, Karthikeyan; Manohar, Prasanth; Bozdogan, Bülent

2016-10-01

Carbapenem resistance is disseminating worldwide among Gram-negative bacteria. The aim of this study was to identify carbapenem-resistance level and to determine the mechanism of carbapenem resistance among clinical isolates from two centres in Tamil Nadu. In the present study, a total of 93 Gram-negative isolates, which is found to be resistant to carbapenem by disk diffusion test in two centres, were included. All isolates are identified at species level by 16S rRNA sequencing. Minimal inhibitory concentrations (MICs) of isolates for Meropenem were tested by agar dilution method. Presence of blaOXA, blaNDM, blaVIM, blaIMP and blaKPC genes was tested by PCR in all isolates. Amplicons were sequenced for confirmation of the genes. Among 93 isolates, 48 (%52) were Escherichia coli, 10 (%11) Klebsiella pneumoniae, nine (%10) Pseudomonas aeruginosa. Minimal inhibitory concentration results showed that of 93 suspected carbapenem-resistant isolates, 27 had meropenem MICs ≥ 2 μg/ml. The MIC range, MIC50 and MIC90 were < 0.06 to >128 μg/ml, 0.12 and 16 μg/ml, respectively. Fig. 1 . Among meropenem-resistant isolates, E. coli were the most common (9/48, 22%), followed by K. pneumoniae (7/9, 77%), P. aeruginosa (6/10, 60%), Acinetobacter baumannii (2/2, 100%), Enterobacter hormaechei (2/3, 67%) and one Providencia rettgeri (1/1, 100%). PCR results showed that 16 of 93 carried blaNDM, three oxa181, and one imp4. Among blaNDM carriers, nine were E. coli, four Klebsiella pneumoniae, two E. hormaechei and one P. rettgeri. Three K. pneumoniae were OXA-181 carriers. The only imp4 carrier was P. aeruginosa. A total of seven carbapenem-resistant isolates were negatives by PCR for the genes studied. All carbapenem-resistance gene-positive isolates had meropenem MICs >2 μg/ml. Our results confirm the dissemination of NDM and emergence of OXA-181 beta-lactamase among Gram-negative bacteria in South India. This study showed the emergence of NDM producer in clinical

Salicylic acid biosynthesis is enhanced and contributes to increased biotrophic pathogen resistance in Arabidopsis hybrids

PubMed Central

Yang, Li; Li, Bosheng; Zheng, Xiao-yu; Li, Jigang; Yang, Mei; Dong, Xinnian; He, Guangming; An, Chengcai; Deng, Xing Wang

2015-01-01

Heterosis, the phenotypic superiority of a hybrid over its parents, has been demonstrated for many traits in Arabidopsis thaliana, but its effect on defence remains largely unexplored. Here, we show that hybrids between some A. thaliana accessions show increased resistance to the biotrophic bacterial pathogen Pseudomonas syringae pv. tomato (Pst) DC3000. Comparisons of transcriptomes between these hybrids and their parents after inoculation reveal that several key salicylic acid (SA) biosynthesis genes are significantly upregulated in hybrids. Moreover, SA levels are higher in hybrids than in either parent. Increased resistance to Pst DC3000 is significantly compromised in hybrids of pad4 mutants in which the SA biosynthesis pathway is blocked. Finally, increased histone H3 acetylation of key SA biosynthesis genes correlates with their upregulation in infected hybrids. Our data demonstrate that enhanced activation of SA biosynthesis in A. thaliana hybrids may contribute to their increased resistance to a biotrophic bacterial pathogen. PMID:26065719

6 CFR 9.3 - Certification and disclosure.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 6 Domestic Security 1 2010-01-01 2010-01-01 false Certification and disclosure. 9.3 Section 9.3 Domestic Security DEPARTMENT OF HOMELAND SECURITY, OFFICE OF THE SECRETARY RESTRICTIONS UPON LOBBYING General § 9.3 Certification and disclosure. (a) Each person shall file a certification, and a disclosure...

9 CFR 93.307 - Articles accompanying horses.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Articles accompanying horses. 93.307 Section 93.307 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF... FOR MEANS OF CONVEYANCE AND SHIPPING CONTAINERS Horses § 93.307 Articles accompanying horses. No...

9 CFR 93.208 - Articles accompanying poultry.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Articles accompanying poultry. 93.208 Section 93.208 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF... FOR MEANS OF CONVEYANCE AND SHIPPING CONTAINERS Poultry § 93.208 Articles accompanying poultry. No...

9 CFR 93.307 - Articles accompanying horses.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Articles accompanying horses. 93.307 Section 93.307 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF... FOR MEANS OF CONVEYANCE AND SHIPPING CONTAINERS Horses § 93.307 Articles accompanying horses. No...

9 CFR 93.208 - Articles accompanying poultry.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Articles accompanying poultry. 93.208 Section 93.208 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF... FOR MEANS OF CONVEYANCE AND SHIPPING CONTAINERS Poultry § 93.208 Articles accompanying poultry. No...

9 CFR 93.307 - Articles accompanying horses.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Articles accompanying horses. 93.307 Section 93.307 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF... FOR MEANS OF CONVEYANCE AND SHIPPING CONTAINERS Horses § 93.307 Articles accompanying horses. No...

9 CFR 93.508 - Articles accompanying swine.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Articles accompanying swine. 93.508 Section 93.508 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF... FOR MEANS OF CONVEYANCE AND SHIPPING CONTAINERS Swine § 93.508 Articles accompanying swine. No litter...

9 CFR 93.508 - Articles accompanying swine.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Articles accompanying swine. 93.508 Section 93.508 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF... FOR MEANS OF CONVEYANCE AND SHIPPING CONTAINERS Swine § 93.508 Articles accompanying swine. No litter...

9 CFR 93.508 - Articles accompanying swine.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Articles accompanying swine. 93.508 Section 93.508 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF... FOR MEANS OF CONVEYANCE AND SHIPPING CONTAINERS Swine § 93.508 Articles accompanying swine. No litter...

9 CFR 93.208 - Articles accompanying poultry.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Articles accompanying poultry. 93.208 Section 93.208 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF... FOR MEANS OF CONVEYANCE AND SHIPPING CONTAINERS Poultry § 93.208 Articles accompanying poultry. No...

9 CFR 93.208 - Articles accompanying poultry.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Articles accompanying poultry. 93.208 Section 93.208 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF... FOR MEANS OF CONVEYANCE AND SHIPPING CONTAINERS Poultry § 93.208 Articles accompanying poultry. No...

9 CFR 93.508 - Articles accompanying swine.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Articles accompanying swine. 93.508 Section 93.508 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF... FOR MEANS OF CONVEYANCE AND SHIPPING CONTAINERS Swine § 93.508 Articles accompanying swine. No litter...

9 CFR 93.208 - Articles accompanying poultry.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Articles accompanying poultry. 93.208 Section 93.208 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF... FOR MEANS OF CONVEYANCE AND SHIPPING CONTAINERS Poultry § 93.208 Articles accompanying poultry. No...

9 CFR 93.307 - Articles accompanying horses.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Articles accompanying horses. 93.307 Section 93.307 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF... FOR MEANS OF CONVEYANCE AND SHIPPING CONTAINERS Horses § 93.307 Articles accompanying horses. No...