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The Death Gate Cycle Series Epub Filesl
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Mitsuko Rinkenberger
Dec 7, 2023, 4:48:30 AM12/7/23
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The primary drug-target interactions (aminoglycoside with the ribosome, quinolone with DNA gyrase, and β-lactam with penicillin-binding proteins) stimulate oxidation of NADH through the electron transport chain that is dependent on the TCA cycle. Hyperactivation of the electron transport chain stimulates superoxide formation. Superoxide damages iron-sulfur clusters, making ferrous iron available for oxidation by the Fenton reaction. The Fenton reaction leads to hydroxyl radical formation and the hydroxyl radicals damage DNA, proteins and lipids, which contributes to antibiotic-induced cell death. Quinolones, β-lactams and aminoglycosides also trigger radical formation and cell death through the Cpx and Arc two-component systems. It is also possible that redox-sensitive proteins such as those containing disulfide contribute in an as yet undetermined fashion to the common mechanism (dashed lines). (Modified with permission from ref 8)
The Death Gate Cycle Series Epub Filesl
Download https://shurll.com/2wIR5M
The road went in a series of long curves with a short rise at the end of each. The rising slopes to the left of the road and the falling slopes to tke right were thick with scrub holum; Hues of tall tree holum, spaced Just as if they had been planted, followed veins of ground water along the mountainsides. At the crest of a rise Shevek saw the clear gold of sunset above the dark and many-folded hills. There was no sign of mankind here except the road itself, going down into shadow. As he started down, the air grumbled a little and he felt a strangeness: no yHt, no tremor, but a displacement, a conviction that things were wrong. He completed the step he had been making, and the ground was there to meet his foot He went on; the road stayed lying down. He had been in no danger, but he had never in any danger known himself so close to death. Death was in him, under him; the earth itself was uncertain, unreliable. The enduring, the reliable, is a promise made by the human mind. Shevek felt the cold, clean air In his mouth and lungs. He listened. Remote, a mountain torrent thundered somewhere down in the shadows.
Hey guys there is a much better (epub) version available floating around as a torrent, ie it's on piratebay at time of writing. The copy here is terrible. There are a lot of weird and glaring errors all through it, several on every page. ie "watts". Do yourself a favour and grab the torrent version. This copy should be deleted but unfortunately it seems to have been already propagated across the internet. Of course if you like it maybe try and do the right thing and buy something directly from the author (if that even is possible).
Our microarray analysis following Sp1 knockdown revealed that reducing Sp1 promoter occupancy by siRNA knockdown altered the regulation of a number of genes involved the p53 signalling pathway. These data indicate that reduced promoter occupancy by Sp1, similar to that observed following acetylation of Sp1, can influence cell cycle/death decisions. We noted in our analysis of the array data that Bak was not altered sufficiently to reach the threshold for inclusion in the analysis. Our previous data [9] showed that at the transcriptional level, changes in Bak mRNA were modest, but consistent across several assays and we hypothesized that this was sufficient to unbalance the cell and drive apoptosis. Other genes, for example Bid, were identified as larger fold changes in this study and may synergise with alterations in Bak to yield an apoptosis-susceptible cell. Furthermore, these data demonstrate that p53 controlled pathways can be regulated by alteration of Sp1 promoter occupancy, indicating that a complex interaction occurs between these two transcription factors.
The colon epithelial cell exists bathed in high levels of butyrate. Cell turnover rates in the colon are high with movement from the stem cell to apoptosis from the flat musosa in 3-4 days. During this period the cell will proliferate, arrest, differentiate and die, relying on butyrate to drive the sequence of these events through a highly coordinated set of transcriptional responses. Low levels of butyrate, as may be the case in cancer-prone low-fibre consumers, would result in lower levels of Sp1 acetylation, resulting in less cell death and more proliferating cells in the colon as a consequence of reduced Bak and p21 expression. A second pro-carcinogenic pathway could be associated with the low-butyrate setting: the lower expression of pro-apoptotic protein, would result in a cell less likely to die in response to a fixed amount of cytotoxic damage. These pathways (impaired physiological cell turnover and reduced ability to respond to damage) could contribute to increased cancer risk. One limitation of this study is that it is undertaken in vitro with a cancer-derived cell line. Our ongoing studies are testing the hypothesis raised - that Sp1-HDAC interaction may be central to the cancer preventive actions of butyrate through engagement of specific target genes - in cross sectional studies involving human volunteers. Our work thus far highlights the key role acetylation plays in the regulation of colonocyte cell cycle. Furthermore there is a need for specific HDAC inhibitors for the treatment of cancers arising in this cell population.
Extensive inflammation in the liver is known to contribute to the pathogenesis of hepatitis C virus (HCV) infection. Apoptosis has, for a long time, been known to act as a mechanism of hepatocyte death, but our previous research also identified inflammasome-mediated pyroptosis in infected and uninfected bystander cells as an additional mechanism of HCV-induced cytopathicity. The purpose of this study was to investigate the mechanism of HCV-induced cell death and to determine the timing and relative contributions of apoptosis and pyroptosis during HCV infection. In a model employing a cell culture-adapted strain of JFH-1 HCV and Huh-7.5 hepatocyte-like cells, we found that pyroptosis occurred earlier than did apoptosis during infection. CRISPR knockout of NLRP3 resulted in decreased caspase-1 activation, but not complete elimination, indicating multiple sensors are likely involved in HCV-induced pyroptosis. Knockout of gasdermin-D resulted in increased activation of apoptosis-related caspase-3, suggesting potential crosstalk between the two cell death pathways. An unexpected decrease in activated caspase-1 levels was observed when caspase-3 was knocked out, implying that caspase-3 may have a role in the initiation of pyroptosis, at least in the context of HCV infection. Lower viral titres in culture fluids and increased ratios of intracellular to extracellular levels of infectious virus were observed in knockout versus wild-type Huh-7.5 cells, suggesting that HCV may induce programmed cell death in order to enhance virus release from infected cells. These results contribute to the understanding of HCV pathogenesis and add to the increasing volume of literature suggesting various programmed cell death pathways are not mutually exclusive.
eebf2c3492
The Death Gate Cycle Series Epub Filesl
Download https://shurll.com/2wIR5M
The road went in a series of long curves with a short rise at the end of each. The rising slopes to the left of the road and the falling slopes to tke right were thick with scrub holum; Hues of tall tree holum, spaced Just as if they had been planted, followed veins of ground water along the mountainsides. At the crest of a rise Shevek saw the clear gold of sunset above the dark and many-folded hills. There was no sign of mankind here except the road itself, going down into shadow. As he started down, the air grumbled a little and he felt a strangeness: no yHt, no tremor, but a displacement, a conviction that things were wrong. He completed the step he had been making, and the ground was there to meet his foot He went on; the road stayed lying down. He had been in no danger, but he had never in any danger known himself so close to death. Death was in him, under him; the earth itself was uncertain, unreliable. The enduring, the reliable, is a promise made by the human mind. Shevek felt the cold, clean air In his mouth and lungs. He listened. Remote, a mountain torrent thundered somewhere down in the shadows.
Hey guys there is a much better (epub) version available floating around as a torrent, ie it's on piratebay at time of writing. The copy here is terrible. There are a lot of weird and glaring errors all through it, several on every page. ie "watts". Do yourself a favour and grab the torrent version. This copy should be deleted but unfortunately it seems to have been already propagated across the internet. Of course if you like it maybe try and do the right thing and buy something directly from the author (if that even is possible).
Our microarray analysis following Sp1 knockdown revealed that reducing Sp1 promoter occupancy by siRNA knockdown altered the regulation of a number of genes involved the p53 signalling pathway. These data indicate that reduced promoter occupancy by Sp1, similar to that observed following acetylation of Sp1, can influence cell cycle/death decisions. We noted in our analysis of the array data that Bak was not altered sufficiently to reach the threshold for inclusion in the analysis. Our previous data [9] showed that at the transcriptional level, changes in Bak mRNA were modest, but consistent across several assays and we hypothesized that this was sufficient to unbalance the cell and drive apoptosis. Other genes, for example Bid, were identified as larger fold changes in this study and may synergise with alterations in Bak to yield an apoptosis-susceptible cell. Furthermore, these data demonstrate that p53 controlled pathways can be regulated by alteration of Sp1 promoter occupancy, indicating that a complex interaction occurs between these two transcription factors.
The colon epithelial cell exists bathed in high levels of butyrate. Cell turnover rates in the colon are high with movement from the stem cell to apoptosis from the flat musosa in 3-4 days. During this period the cell will proliferate, arrest, differentiate and die, relying on butyrate to drive the sequence of these events through a highly coordinated set of transcriptional responses. Low levels of butyrate, as may be the case in cancer-prone low-fibre consumers, would result in lower levels of Sp1 acetylation, resulting in less cell death and more proliferating cells in the colon as a consequence of reduced Bak and p21 expression. A second pro-carcinogenic pathway could be associated with the low-butyrate setting: the lower expression of pro-apoptotic protein, would result in a cell less likely to die in response to a fixed amount of cytotoxic damage. These pathways (impaired physiological cell turnover and reduced ability to respond to damage) could contribute to increased cancer risk. One limitation of this study is that it is undertaken in vitro with a cancer-derived cell line. Our ongoing studies are testing the hypothesis raised - that Sp1-HDAC interaction may be central to the cancer preventive actions of butyrate through engagement of specific target genes - in cross sectional studies involving human volunteers. Our work thus far highlights the key role acetylation plays in the regulation of colonocyte cell cycle. Furthermore there is a need for specific HDAC inhibitors for the treatment of cancers arising in this cell population.
Extensive inflammation in the liver is known to contribute to the pathogenesis of hepatitis C virus (HCV) infection. Apoptosis has, for a long time, been known to act as a mechanism of hepatocyte death, but our previous research also identified inflammasome-mediated pyroptosis in infected and uninfected bystander cells as an additional mechanism of HCV-induced cytopathicity. The purpose of this study was to investigate the mechanism of HCV-induced cell death and to determine the timing and relative contributions of apoptosis and pyroptosis during HCV infection. In a model employing a cell culture-adapted strain of JFH-1 HCV and Huh-7.5 hepatocyte-like cells, we found that pyroptosis occurred earlier than did apoptosis during infection. CRISPR knockout of NLRP3 resulted in decreased caspase-1 activation, but not complete elimination, indicating multiple sensors are likely involved in HCV-induced pyroptosis. Knockout of gasdermin-D resulted in increased activation of apoptosis-related caspase-3, suggesting potential crosstalk between the two cell death pathways. An unexpected decrease in activated caspase-1 levels was observed when caspase-3 was knocked out, implying that caspase-3 may have a role in the initiation of pyroptosis, at least in the context of HCV infection. Lower viral titres in culture fluids and increased ratios of intracellular to extracellular levels of infectious virus were observed in knockout versus wild-type Huh-7.5 cells, suggesting that HCV may induce programmed cell death in order to enhance virus release from infected cells. These results contribute to the understanding of HCV pathogenesis and add to the increasing volume of literature suggesting various programmed cell death pathways are not mutually exclusive.
eebf2c3492
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