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PubMed2006

Effects of concentrated separator by-product (desugared molasses) on intake, site of digestion, microbial efficiency, and nitrogen balance in ruminants fed forage-based diets.

In Exp. 1, 4 ruminally and duodenally cannulated beef steers (444.0 +/- 9.8 kg) were used in a 4 x 4 Latin square with a 2 x 2 factorial treatment arrangement to evaluate the effects of forage type (alfalfa or corn stover) and concentrated separator byproduct (CSB) supplementation (0 or 10% of dietary DM) on intake, site of digestion, and microbial efficiency. In Exp. 2, 5 wethers (44 +/- 1.5 kg) were used in a 5 x 5 Latin square to evaluate the effects of CSB on intake, digestion, and N balance. Treatments were 0, 10, and 20% CSB (DM basis) mixed with forage; 10% CSB offered separately from the forage; and a urea control, in which urea was added to the forage at equal N compared with the 10% CSB treatment. In Exp. 1, intakes of OM and N (g/kg of BW) were greater (P < 0.01) for steers fed alfalfa compared with corn stover. Steers fed 10% CSB had greater (P < 0.08) OM and N intakes (g/kg of BW) compared with 0% CSB-fed steers. Total duodenal, microbial, and nonmicrobial flows of OM and N were greater (P < 0.01) for steers fed alfalfa compared with corn stover. Steers fed 10% CSB had increased (P = 0.02) duodenal microbial flow (N and OM) compared with 0% CSB-fed steers. Forage x CSB interactions (P < 0.01) existed for total tract N digestibility; alfalfa with or without CSB was similar (67.4 vs. 69.5), whereas corn stover with CSB was greater than corn stover without CSB (31.9 vs. -23.9%). True ruminal OM digestion was greater (P < 0.09) in steers fed alfalfa vs. corn stover (73.0 vs. 63.1%) and in steers fed 10 vs. 0% CSB (70.3 vs. 65.8%). Microbial efficiency was unaffected (P > 0.25) by forage type or CSB supplementation. In Exp. 2, forage and total intake increased (linear; P < 0.01) as CSB increased and were greater (P < 0.04) in 10% CSB mixed with forage compared with 10% CSB fed separately. Feeding 10% CSB separately resulted in similar DM and OM apparent total tract digestibility compared with 10% CSB fed mixed. Increasing CSB led to an increase (linear; P < 0.02) in DM, OM, apparent N digestion, and water intake. Nitrogen balance (g and percentage of N intake) increased (linear; P < 0.08) with CSB addition. Feeding 10% CSB separately resulted in greater (P < 0.01) N balance compared with 10% CSB fed mixed. Using urea resulted in similar (P = 0.30) N balance compared with 10% CSB fed mixed. Inclusion of CSB improves intake, digestion, and increases microbial N production in ruminants fed forage-based diets.

Animal Feed↗
PubMed2002

Functional crosstalk between hOgg1 and the helicase domain of Cockayne syndrome group B protein.

We have previously reported that the Cockayne syndrome group B gene product (CSB) contributes to base excision repair (BER) of 8-hydroxyguanine (8-OH-Gua) and the importance of motifs V and VI of the putative helicase domains of CSB in BER of 8-OH-Gua. To further elucidate the function of CSB in BER, we investigated its role in the pathway involving human 8-OH-Gua glycosylase/apurinic lyase (hOgg1). Depletion of CSB protein with anti-CSB antibody reduced the 8-OH-Gua incision rate of wild type cell extracts but not of CSB null and motif VI mutant cell extracts, suggesting a direct contribution of CSB to the catalytic process of 8-OH-Gua incision and the importance of its motif VI in this pathway. Introduction of recombinant purified CSB partially complemented the depletion of CSB as shown by the recovery of the incision activity. This complementation could not fully recover the deficiency of the incision activity in WCE from CS-B null and mutant cell lines, suggesting that some additional factor(s) are necessary for the full activity. Electrophoretic mobility shift assays (EMSAs) showed a defect in binding of CSB null and motif VI mutant cell extracts to 8-OH-Gua-containing oligonucleotides. We detected less hOgg1 transcript and protein in the cell extracts from CS-B null and mutant cells, suggesting hOgg1 may be the missing component. Pull-down of hOgg1 by histidine-tagged CSB and co-localization of those two proteins after gamma-radiation indicated their co-existence in vivo, particularly under cellular stress. However, we did not detect any functional and physical interaction between purified CSB and hOgg1 by incision, gel shift and yeast two-hybrid assays, suggesting that even though hOgg1 and CSB might be in a common protein complex, they may not interact directly. We conclude that CSB functions in the catalysis of 8-OH-Gua BER and in the maintenance of efficient hOgg1 expression, and that motif VI of the putative helicase domain of CSB is crucial in these functions.

Amino Acid Motifs↗
PubMed1983

CS-US contiguity and CS intensity in conditioning of the rabbit's nictitating membrane response to serial compound stimuli.

The present experiments examined acquisition of the rabbit's nictitating membrane response to serial compound stimuli. Each compound consisted of two distinctive conditioned stimuli (CSA and CSB) that were followed by a shock unconditioned stimulus (US). In Experiment 1, CSA was a highly salient 93-dB tone, and CSB was a moderately salient flashing light. The CSA-US interval was 800 msec, and the CSB-US interval was varied across 400, 600, and 800 msec. In Experiment 2, the flashing light served as CSA, and CSB was either a 73-, a 85-, or a 93-dB tone. The CSA-US interval remained 800 msec, and the CSB-US interval was fixed at 400 msec. The experiments revealed that the CSB-US interval and CSB intensity determined the rate of conditioned response (CR) acquisition to the compound. Yet, CR acquisition to CSB as measured on test trials showed impairments relative to the level of responding in single CS-control conditions. However, the impairment in CR acquisition to CSB was attenuated by increasing CSB-US contiguity, that is, by decreasing the CSB-US interval (Experiment 1) or by increasing CSB intensity (Experiment 2). In Experiment 1, the impairment in acquisition to the light CSB appeared to be primarily a consequence of the tone CSA's greater salience. However, in Experiment 2, impairments in CR acquisition to CSB appeared even when CSB had the combined advantages of CS-US contiguity and great salience relative to CSA. Thus, the results indicated a role for CSA's temporal primacy in determining CR acquisition to the components of a serial compound. The results are discussed in terms of selective-attention, generalization-decrement, and information hypotheses.

Acoustic Stimulation↗
PubMed2006

Effects of concentrated separator by-product (desugared molasses) on intake, ruminal fermentation, digestion, and microbial efficiency in beef steers fed grass hay.

Concentrated separator by-product (CSB) is produced when beet molasses goes through an industrial desugaring process. To investigate the nutritional value of CSB as a supplement for grass hay diets (12.5% CP; DM basis), 4 ruminally and duodenally cannulated beef steers (332 +/- 2.3 kg) were used in a 4 x 4 Latin square with a 2 x 2 factorial arrangement of treatments. Factors were intake level: ad libitum (AL) vs. restricted (RE; 1.25% of BW, DM basis) and dietary CSB addition (0 vs. 10%; DM basis). Experimental periods were 21 d in length, with the last 7 d used for collections. By design, intakes of both DM and OM (g/kg of BW) were greater (P < 0.01; 18.8 vs. 13.1 +/- 0.69 and 16.8 vs. 11.7 +/- 0.62, respectively) for animals consuming AL compared with RE diets. Main effect means for intake were not affected by CSB (P = 0.59). However, within AL-fed steers, CSB tended (P = 0.12) to improve DMI (6,018 vs. 6,585 +/- 185 g for 0 and 10% CSB, respectively). Feeding CSB resulted in similar total tract DM and OM digestion compared with controls (P = 0.50 and 0.87, respectively). There were no effects of CSB on apparent total tract NDF (P = 0.27) or ADF (P = 0.35) digestion; however, apparent N absorption increased (P = 0.10) with CSB addition. Total tract NDF, ADF, or N digestion coefficients were not different between AL- and RE-fed steers. Nitrogen intake (P = 0.02), total duodenal N flow (P = 0.02), and feed N escaping to the small intestine (P = 0.02) were increased with CSB addition. Microbial efficiency was unaffected by treatment (P = 0.17). Supplementation with CSB increased the rate of DM disappearance (P = 0.001; 4.9 vs. 6.9 +/- 0.33 %/h). Restricted intake increased the rate of in situ DM disappearance (P = 0.03; 6.4 vs. 5.3 +/- 0.33 %/h) compared with AL-fed steers. Ruminal DM fill was greater (P = 0.01) in AL compared with RE. Total VFA concentrations were greater (P = 0.04) for CSB compared with controls; however, ammonia concentrations were reduced (P = 0.03) with CSB addition. At different levels of dietary intake, supplementing medium-quality forage with 10% CSB increased N intake, small intestinal protein supply, and total ruminal VFA.

Animal Feed↗
PubMed2006

Ozone induces clear cellular and molecular responses in the mouse lung independently of the transcription-coupled repair status.

The oxidant ozone is a well-known air pollutant, inhalation of which is associated with respiratory tract inflammation and functional alterations of the lung. It is well established as an inducer of intracellular oxidative stress. We investigated whether Cockayne syndrome B, transcription-coupled, repair-deficient mice (Csb(-/-)), known to be sensitive to oxidative stressors, respond differently to ozone than repair-proficient controls (Csb(+/-)). Mice were exposed to 0.8 parts/million ozone for 8 h, and we examined a wide range of biological parameters in the lung at the gene expression, protein, and cellular level 4 h after the ozone exposure. Relevant biological responses to ozone for both repair-deficient Csb(-/-) and repair-proficient Csb(+/-) mice, as determined by biochemical analysis of bronchoalveolar lavage fluid (e.g., increases of polymorphonuclear neutrophils, alkaline phosphatase, macrophage-inflammatory protein-2, and tumor necrosis factor-alpha), pathological examinations, and gene expression (upregulation of oxidative-stress-related genes) analyses were observed. The bronchoalveolar lavage fluid showed significantly more tumor necrosis factor-alpha in repair-deficient Csb(-/-) mice than in repair-proficient Csb(+/-) mice after ozone exposure. In addition, a clear trend was observed toward fewer differentially expressed genes with a lower fold ratio in repair-deficient Csb(-/-) mice than in repair-proficient Csb(+/-) mice. However, repair-deficient Csb(-/-) mice do not respond significantly more sensitively to ozone compared with repair-proficient Csb(+/-) mice at the level of gene expression. We conclude that, under the conditions employed here, although small differences at the transcriptional level exist between repair-proficient Csb(+/-) mice and transcription-coupled repair defective Csb(-/-) mice, these do not have a significant effect on the ozone-induced lung injury.

Animals↗
PubMed1993

Effects of extrusion and expelling on the nutritional quality of conventional and Kunitz trypsin inhibitor-free soybeans.

Two chick growth experiments and a precision-fed cockerel digestibility assay were conducted to evaluate the effect of extrusion and expelling on the nutritive value of conventional (CSB) and Kunitz trypsin inhibitor-free (KFSB) soybeans. In the first experiment, performance of chicks fed CSB or KFSB autoclaved at 121 C was similar to that of chicks fed CSB or KFSB extruded at 138 C. The effect of extrusion temperature on protein quality of the soybeans was evaluated in the second experiment. Eleven corn-soybean diets were formulated to contain one of the following: CSB extruded at 104, 121, 138, or 154 C; KFSB extruded at 104, 121, or 138 C; CSB extruded at 121, 138, or 154 C followed by processing through an expeller; and commercial dehulled solvent-extracted soybean meal (SBM). All diets contained 20% crude protein and the same amount of soybean oil and were fed to chicks from 7 to 21 days of age. The CSB extruded at 104 or 121 C and KFSB extruded at 104 C yielded depressed growth and feed efficiency compared with SBM. Performance of chicks on the other treatments was similar to that of chicks fed SBM. Pancreas weight (as a percentage of BW) decreased as extrusion temperature increased, with the response being greater for CSB. Growth performance was greater and pancreas weights were lower for chicks fed KFSB extruded at 104 or 121 C compared with those of chicks fed CSB extruded at the same temperatures. Expelling improved weight gain and feed efficiency when CSB was extruded at 121 C. A 48-h digestibility assay with cecectomized cockerels indicated that digestibility of amino acids in CSB and KFSB increased as extrusion temperature increased and that digestibilities of amino acids in CSB extruded at 104 or 121 C were lower than those in KFSB extruded at the same temperatures. Results of this study indicated that extrusion of CSB at 138 to 154 C or extrusion of KFSB at 121 to 138 C yields protein quality similar to that of SBM.

Amino Acids↗
PubMed1999

The ATPase domain but not the acidic region of Cockayne syndrome group B gene product is essential for DNA repair.

Cockayne syndrome (CS) is a human genetic disorder characterized by UV sensitivity, developmental abnormalities, and premature aging. Two of the genes involved, CSA and CSB, are required for transcription-coupled repair (TCR), a subpathway of nucleotide excision repair that removes certain lesions rapidly and efficiently from the transcribed strand of active genes. CS proteins have also been implicated in the recovery of transcription after certain types of DNA damage such as those lesions induced by UV light. In this study, site-directed mutations have been introduced to the human CSB gene to investigate the functional significance of the conserved ATPase domain and of a highly acidic region of the protein. The CSB mutant alleles were tested for genetic complementation of UV-sensitive phenotypes in the human CS-B homologue of hamster UV61. In addition, the CSB mutant alleles were tested for their ability to complement the sensitivity of UV61 cells to the carcinogen 4-nitroquinoline-1-oxide (4-NQO), which introduces bulky DNA adducts repaired by global genome repair. Point mutation of a highly conserved glutamic acid residue in ATPase motif II abolished the ability of CSB protein to complement the UV-sensitive phenotypes of survival, RNA synthesis recovery, and gene-specific repair. These data indicate that the integrity of the ATPase domain is critical for CSB function in vivo. Likewise, the CSB ATPase point mutant failed to confer cellular resistance to 4-NQO, suggesting that ATP hydrolysis is required for CSB function in a TCR-independent pathway. On the contrary, a large deletion of the acidic region of CSB protein did not impair the genetic function in the processing of either UV- or 4-NQO-induced DNA damage. Thus the acidic region of CSB is likely to be dispensable for DNA repair, whereas the ATPase domain is essential for CSB function in both TCR-dependent and -independent pathways.

4-Nitroquinoline-1-oxide↗
PubMed2001

Disruption of the Cockayne syndrome B gene impairs spontaneous tumorigenesis in cancer-predisposed Ink4a/ARF knockout mice.

Cells isolated from individuals with Cockayne syndrome (CS) have a defect in transcription-coupled DNA repair, which rapidly corrects certain DNA lesions located on the transcribed strand of active genes. Despite this DNA repair defect, individuals with CS group A (CSA) or group B (CSB) do not exhibit an increased spontaneous or UV-induced cancer rate. In order to investigate the effect of CSB deficiency on spontaneous carcinogenesis, we crossed CSB(-/-) mice with cancer-prone mice lacking the p16(Ink4a)/p19(ARF) tumor suppressor locus. CSB(-/-) mice are sensitive to UV-induced skin cancer but show no increased rate of spontaneous cancer. CSB(-/-) Ink4a/ARF(-/-) mice developed 60% fewer tumors than Ink4a/ARF(-/-) animals and demonstrated a longer tumor-free latency time (260 versus 150 days). Moreover, CSB(-/-) Ink4a/ARF(-/-) mouse embryo fibroblasts (MEFs) exhibited a lower colony formation rate after low-density seeding, a lower rate of H-Ras-induced transformation, slower proliferation, and a lower mRNA synthesis rate than Ink4a/ARF(-/-) MEFs. CSB(-/-) Ink4a/ARF(-/-) MEFs were also more sensitive to UV-induced p53 induction and UV-induced apoptosis than were Ink4a/ARF(-/-) MEFs. In order to investigate whether the apparent antineoplastic effect of CSB gene disruption was caused by sensitization to genotoxin-induced (p53-mediated) apoptosis or by p53-independent sequelae, we also generated p53(-/-) and CSB(-/-) p53(-/-) MEFs. The CSB(-/-) p53(-/-) MEFs demonstrated lower colony formation efficiency, a lower proliferation rate, a lower mRNA synthesis rate, and a higher rate of UV-induced cell death than p53(-/-) MEFs. Collectively, these results indicate that the antineoplastic effect of CSB gene disruption is at least partially p53 independent; it may result from impaired transcription or from apoptosis secondary to environmental or endogenous DNA damage.

Age Factors↗
PubMed2006

siRNA-mediated silencing of Cockayne Cyndrome group B gene potentiates radiation-induced apoptosis and antiproliferative effect in HeLa cells.

BACKGROUND: Cockayne syndrome (CS) is a rare human genetic disorder characterized by increased UV sensitivity, developmental abnormalities and premature aging. Cells isolated from individuals with CS have a defect in transcription-coupled DNA repair. Despite the repair defect, there is no any increased risk of spontaneous or UV-induced cancer for CS individuals. The strategy of RNA interfering was used here to explore the potential radiosensitizing and anticancer activity of targeting CS group B (CSB) gene. METHODS: The vectors encoding CSB-specific siRNAs were constructed by inserting duplex siRNA encoding oligonucleotides into the plasmid P(silencer TM 3.1). The cell lines expressing the CSB-siRNA were generated from HeLa cells transfected with the above vectors. Colony-forming ability was used to assay cell survival. Cell cycle was analyzed by FACScan flow cytometry. The apoptosis was measured by detecting the accumulation of sub-G(1) population as well as by fluorescence staining assay. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to semi-quantify mRNA expression. Protein level was detected by Western blotting analysis. RESULTS: Two constructs encoding CSB-specific siRNA were generated, both of them resulted in remarkable suppression on CSB expression in HeLa cells, and led to an increased sensitivity to (gamma-ray and UV light. siRNA-mediated silencing of CSB decreased cell proliferation rate, increased spontaneous apoptosis as well as the occurrence of UV- or cisplatin-induced apoptosis by 2 to 3.5 fold. A significant S phase blockage and a remarkable reduction of G(1) population were induced in control HeLa cells at 18 hours after being exposed to 10 J/m(2) of UV light. The S phase blockage was also observed in UV-irradiated CSB-siRNA transfected HeLa cells, but the extent of increased S phase population was lower than that in the UV-irradiated control cells. No or a relative weak reduction on G(1) phase population was observed in UV-irradiated CSB-siRNA transfected HeLa cells. In addition, siRNA-mediated silencing of CSB promoted the elimination of G(2)/M phase cells after UV light radiation. CONCLUSIONS: siRNA-mediated silencing of CSB causes cells to proliferate more slowly, sensitize cells to genotoxicants, and modify UV radiation-induced cell cycle changes. siRNA-mediated inactivation of CSB could be an attractive strategy for ameliorating cancer therapy, which can be fulfilled via the combination of gene therapy and sensitization of radiotherapy or chemotherapy.

Apoptosis↗
PubMed1987

Isolation of a cDNA clone for murine catalase and analysis of an acatalasemic mutant.

We have investigated the genetic control of murine catalase expression by analyzing catalase transcription and translation products from the tissues of control (Csa) and acatalasemic (Csb) mouse strains. Csb animals possess nearly normal catalase enzyme activity levels in liver, while displaying approximately 20 and 1% of normal activity levels in kidney and red blood cells, respectively. Immunoblot analyses of catalase in these tissues have revealed reduced levels of immunologically reactive catalase protein in Csb kidney and red blood cells, paralleling the reduction of catalase enzyme activity in these tissues. In order to determine the molecular basis for Csb acatalasemia, we have isolated a cDNA clone for murine catalase and have used this probe to analyze Csa and Csb genomic DNA and catalase mRNA. These studies have revealed: 1) no restriction fragment length polymorphisms between Csa and Csb genomic DNAs; 2) no differences in the levels of Csa and Csb catalase mRNA within a single tissue; and 3) no differences in the sizes of Csa and Csb catalase mRNAs. These observations suggest that the genetic defect that produces the tissue-specific reduction of catalase expression in Csb mice is not due to a marked rearrangement of DNA within the Csb catalase structural gene. Furthermore, the Csb mutation does not act at the level of gene transcription or mRNA stability, but rather at the level of mRNA translation and/or catalase protein turnover.

Acatalasia↗
PubMed2002

Phenotypic consequences of mutations in the conserved motifs of the putative helicase domain of the human Cockayne syndrome group B gene.

Cockayne syndrome (CS) is a human genetic disorder characterized by several neurological and developmental abnormalities. Two genetic complementation groups, CS-A and CS-B, have been identified. The CSB protein belongs to helicase superfamily 2, and to the SWI/SNF family of proteins. The CSB protein is implicated in transcription-coupled repair (TCR), basal transcription and chromatin remodeling. In addition, CS cells undergo UV-induced apoptosis at much lower doses than normal cells. However, the molecular function of the CSB protein in these biological pathways has remained unclear. Evidence indicates that the integrity of the Walker A and B boxes (motifs I and II) are important for CSB function, but the functional significance of the helicase motifs Ia, III--IV has not been previously examined. In this study, single amino acid changes in highly conserved residues of helicase motifs Ia, III, V, VI and a second putative nucleotide-binding motif (NTB) of the CSB protein were generated by site-directed mutagenesis to analyze the genetic function of the CSB protein in survival, RNA synthesis recovery and apoptosis after UV treatment. The survival analysis of these CS-B mutant cell lines was also performed after treatment with the chemical carcinogen, 4-nitroquinoline-1-oxide (4-NQO). The lesions induced by UV light, cyclobutane pyrimidine dimers, are known to be repaired by TCR whereas the lesions induced by 4-NQO are repaired by global genome repair. The results of this study demonstrate that the point mutations in highly conserved residues of helicase motifs Ia, III, V and VI abolished the genetic function of the CSB protein in survival, RNA synthesis recovery and apoptosis after UV treatment. Similarly, the same mutants failed to complement the sensitivity toward 4-NQO. Thus, the integrity of these helicase motifs is important for the biological function of the CSB protein. On the contrary, a point mutation in a C-terminal, second, NTB motif of the CSB protein showed full complementation in the ability to repair damage induced by UV light or 4-NQO, suggesting that this motif is not important for the CSB repair function.

4-Nitroquinoline-1-oxide↗
PubMed2005

Cooperation of the Cockayne syndrome group B protein and poly(ADP-ribose) polymerase 1 in the response to oxidative stress.

Cockayne syndrome (CS) is a rare genetic disorder characterized as a segmental premature-aging syndrome. The CS group B (CSB) protein has previously been implicated in transcription-coupled repair, transcriptional elongation, and restoration of RNA synthesis after DNA damage. Recently, evidence for a role of CSB in base excision repair of oxidative DNA lesions has accumulated. In our search to understand the molecular function of CSB in this process, we identify a physical and functional interaction between CSB and poly(ADP-ribose) polymerase-1 (PARP-1). PARP-1 is a nuclear enzyme that protects the integrity of the genome by responding to oxidative DNA damage and facilitating DNA repair. PARP-1 binds to single-strand DNA breaks which activate the catalytic ability of PARP-1 to add polymers of ADP-ribose to various proteins. We find that CSB is present at sites of activated PARP-1 after oxidative stress, identify CSB as a new substrate of PARP-1, and demonstrate that poly(ADP-ribosyl)ation of CSB inhibits its DNA-dependent ATPase activity. Furthermore, we find that CSB-deficient cell lines are hypersensitive to inhibition of PARP. Our results implicate CSB in the PARP-1 poly(ADP-ribosyl)ation response after oxidative stress and thus suggest a novel role of CSB in the cellular response to oxidative damage.

Active Transport, Cell Nucleus↗