yApoptosis: yeast apoptosis database

In the past few years, programmed cell death (PCD) has become a popular research area due to its fundamental aspects and its links to human diseases. Yeast has been used as a model for studying PCD, since the discovery of morphological markers of apoptotic cell death in yeast in 1997. Increasing knowledge in identification of components and molecular pathways created a need for organization of information. To meet the demands from the research community, we have developed a curated yeast apoptosis database, yApoptosis. The database structurally collects an extensively curated set of apoptosis, PCD and related genes, their genomic information, supporting literature and relevant external links. A web interface including necessary functions is provided to access and download the data. In addition, we included several networks where the apoptosis genes or proteins are involved, and present them graphically and interactively to facilitate rapid visualization. We also promote continuous inputs and curation by experts. yApoptosis is a highly specific resource for sharing information online, which supports researches and studies in the field of yeast apoptosis and cell death

Different expression levels of human mutant ubiquitin B+1 (UBB+1) can modify chronological lifespan or stress resistance of saccharomyces cerevisiae

The ubiquitin-proteasome system (UPS) is the main pathway responsible for the degradation of misfolded proteins, and its dysregulation has been implicated in several neurodegenerative diseases, including Alzheimer’s disease (AD). UBB+1, a mutant variant of ubiquitin B, was found to accumulate in neurons of AD patients and it has been linked to UPS dysfunction and neuronal death. Using the yeast Saccharomyces cerevisiae as a model system, we constitutively expressed UBB+1to evaluate its effects on proteasome function and cell death, particularly under conditions of chronological aging. We showed that the expression of UBB+1caused inhibition of the three proteasomal proteolytic activities (caspase-like (β1), trypsin-like (β2) and chymotrypsin-like (β5) activities) in yeast. Interestingly, this inhibition did not alter cell viability of growing cells. Moreover, we showed that cells expressing UBB+1at lower level displayed an increased capacity to degrade induced misfolded proteins. When we evaluated cells during chronological aging, UBB+1expression at lower level, prevented cells to accumulate reactive oxygen species (ROS) and avert apoptosis, dramatically increasing yeast life span. Since proteasome inhibition by UBB+1has previously been shown to induce chaperone expression and thus protect against stress, we evaluated our UBB+1model under heat shock and oxidative stress. Higher expression of UBB+1caused thermotolerance in yeast due to induction of chaperones, which occurred to a lesser extent at lower expression level of UBB+1(where we observed the phenotype of extended life span). Altering UPS capacity by differential expression of UBB+1protects cells against several stresses during chronological aging. This system can be valuable to study the effects of UBB+1on misfolded proteins involved in neurodegeneration and aging

The Janthinobacterium sp. HH01 genome encodes a homologue of the V. cholerae CqsA and L. pneumophila LqsA autoinducer synthases

Janthinobacteria commonly form biofilms on eukaryotic hosts and are known to synthesize antibacterial and antifungal compounds. Janthinobacterium sp. HH01 was recently isolated from an aquatic environment and its genome sequence was established. The genome consists of a single chromosome and reveals a size of 7.10 Mb, being the largest janthinobacterial genome so far known. Approximately 80% of the 5,980 coding sequences (CDSs) present in the HH01 genome could be assigned putative functions. The genome encodes a wealth of secretory functions and several large clusters for polyketide biosynthesis. HH01 also encodes a remarkable number of proteins involved in resistance to drugs or heavy metals. Interestingly, the genome of HH01 apparently lacks the N-acylhomoserine lactone (AHL)-dependent signaling system and the AI-2-dependent quorum sensing regulatory circuit. Instead it encodes a homologue of the Legionella- and Vibrio-like autoinducer (lqsA/cqsA) synthase gene which we designated jqsA. The jqsA gene is linked to a cognate sensor kinase (jqsS) which is flanked by the response regulator jqsR. Here we show that a jqsA deletion has strong impact on the violacein biosynthesis in Janthinobacterium sp. HH01 and that a jqsA deletion mutant can be functionally complemented with the V. cholerae cqsA and the L. pneumophila lqsA genes

Different Expression Levels of Human Mutant Ubiquitin B+1 (UBB+1) Can Modify Chronological Lifespan or Stress Resistance of Saccharomyces cerevisiae

The ubiquitin-proteasome system (UPS) is the main pathway responsible for the degradation of misfolded proteins, and its dysregulation has been implicated in several neurodegenerative diseases, including Alzheimer’s disease (AD). UBB+1, a mutant variant of ubiquitin B, was found to accumulate in neurons of AD patients and it has been linked to UPS dysfunction and neuronal death. Using the yeast Saccharomyces cerevisiae as a model system, we constitutively expressed UBB+1 to evaluate its effects on proteasome function and cell death, particularly under conditions of chronological aging. We showed that the expression of UBB+1 caused inhibition of the three proteasomal proteolytic activities (caspase-like (β1), trypsin-like (β2) and chymotrypsin-like (β5) activities) in yeast. Interestingly, this inhibition did not alter cell viability of growing cells. Moreover, we showed that cells expressing UBB+1 at lower level displayed an increased capacity to degrade induced misfolded proteins. When we evaluated cells during chronological aging, UBB+1 expression at lower level, prevented cells to accumulate reactive oxygen species (ROS) and avert apoptosis, dramatically increasing yeast life span. Since proteasome inhibition by UBB+1 has previously been shown to induce chaperone expression and thus protect against stress, we evaluated our UBB+1 model under heat shock and oxidative stress. Higher expression of UBB+1 caused thermotolerance in yeast due to induction of chaperones, which occurred to a lesser extent at lower expression level of UBB+1 (where we observed the phenotype of extended life span). Altering UPS capacity by differential expression of UBB+1 protects cells against several stresses during chronological aging. This system can be valuable to study the effects of UBB+1 on misfolded proteins involved in neurodegeneration and aging

The Run Control and Monitoring System of the CMS Experiment

The CMS experiment at the LHC at CERN will start taking data in 2008. To configure, control and monitor the experiment during data-taking the Run Control and Monitoring System (RCMS) was developed. This paper describes the architecture and the technology used to implement the RCMS, as well as the deployment and commissioning strategy of this important component of the online software for the CMS experiment

Lactoferrin modulates gut microbiota and Toll-like receptors (TLRs) in mice with dysbiosis induced by antibiotics

Background: Antibiotic administration can result in gut microbiota and immune system alterations that impact health. Bovine lactoferrin is a milk protein with anticancer, anti-inflammatory, antimicrobial and immune modulatory activities. The aim was to study the ability of native and iron-saturated lactoferrin to reverse the effects of clindamycin on gut microbiota and intestinal Toll-like receptor (TLR) expression in a murine model. Methods: Male C57BL/6 mice were treated with vehicle, clindamycin (Clin), native bovine lactoferrin (nLf), nLf + clindamycin (nLf_Clin), iron-saturated bovine lactoferrin (sLf) and sLf + clindamycin (sLf_Clin). Fecal samples of each group were collected, and bacterial DNA was extracted. Sequencing of 16s rRNA V4 hypervariable gene regions was conducted to assess the microbial composition. mRNA expression levels of TLRs (1-9) were determined in mouse colon by qPCR. Pearson\u27s correlation test was carried out between bacteria showing differences in abundance among samples and TLR2, TLR8 and TLR9. Results: Beta-diversity analysis showed that the microbial community of the vehicle was different from the communities of Clin, nLf_Clin and sLf_Clin. At the family level, Bacteroidaceae, Prevotellaceae and Rikenellaceae decreased in the Clin group, and treatment with nLf or sLf reverted these effects. Clin reduced the expression of TLR2, TLR8 and TLR9 and sLf reverted the decrease in the expression of these receptors. Finally, TLR8 was positively correlated with Rikenellaceae abundance. Conclusion: In a situation of intestinal dysbiosis induced by clindamycin, lactoferrin restores the normal levels of some anti-inflammatory bacteria and TLRs and, therefore, could be a good ingredient to be added to functional foods

Presentation_1_Different Expression Levels of Human Mutant Ubiquitin B+1 (UBB+1) Can Modify Chronological Lifespan or Stress Resistance of Saccharomyces cerevisiae.PDF

<p>The ubiquitin-proteasome system (UPS) is the main pathway responsible for the degradation of misfolded proteins, and its dysregulation has been implicated in several neurodegenerative diseases, including Alzheimer’s disease (AD). UBB⁺¹, a mutant variant of ubiquitin B, was found to accumulate in neurons of AD patients and it has been linked to UPS dysfunction and neuronal death. Using the yeast Saccharomyces cerevisiae as a model system, we constitutively expressed UBB⁺¹ to evaluate its effects on proteasome function and cell death, particularly under conditions of chronological aging. We showed that the expression of UBB⁺¹ caused inhibition of the three proteasomal proteolytic activities (caspase-like (β1), trypsin-like (β2) and chymotrypsin-like (β5) activities) in yeast. Interestingly, this inhibition did not alter cell viability of growing cells. Moreover, we showed that cells expressing UBB⁺¹ at lower level displayed an increased capacity to degrade induced misfolded proteins. When we evaluated cells during chronological aging, UBB⁺¹ expression at lower level, prevented cells to accumulate reactive oxygen species (ROS) and avert apoptosis, dramatically increasing yeast life span. Since proteasome inhibition by UBB⁺¹ has previously been shown to induce chaperone expression and thus protect against stress, we evaluated our UBB⁺¹ model under heat shock and oxidative stress. Higher expression of UBB⁺¹ caused thermotolerance in yeast due to induction of chaperones, which occurred to a lesser extent at lower expression level of UBB⁺¹ (where we observed the phenotype of extended life span). Altering UPS capacity by differential expression of UBB⁺¹ protects cells against several stresses during chronological aging. This system can be valuable to study the effects of UBB⁺¹ on misfolded proteins involved in neurodegeneration and aging.</p

Lowered rilpivirine exposure during the third trimester of pregnancy in human immunodeficiency virus type 1-infected women

Background: The use of antiretroviral therapy during pregnancy is important for control of maternal human immunodeficiency virus (HIV) disease and the prevention of perinatal HIV transmission. Physiological changes during pregnancy can reduce antiret-roviral exposure. We studied the pharmacokinetics of rilpivirine 25 mg once daily in HIV-1-infected women during late pregnancy. Methods: We conducted a nonrandomized, open-label, multicenter, phase 4 study. HIV-infected pregnant women receiving rilpivirine 25 mg once daily were included. Intensive 24-hour pharmacokinetic sampling was performed in the third trimester and at least 2 weeks postpartum. Pharmacokinetic parameters were calculated by noncompartmental analysis. Results: Sixteen subjects were included. Geometric mean ratios of third trimester vs postpartum were 0.55 (90% confidence interval [CI], 46-.66) for the 24-hour area under the concentration-time curve (AUC0-24h); 0.65 (90% CI, 55-.76) for the maximum concentration; and 0.51 (90% CI, 41-.63) for the minimum observed concentration (Cmin). Four of 16 (25%) subjects had Cmin below the target concentration (0.04 mg/L) in the third trimester of pregnancy. No subtherapeutic levels were observed postpartum. No detectable viral loads were observed in this study. All newborns tested negative for HIV. No birth defects were reported. The median (range, n = 5) rilpivirine cord-to-maternal plasma concentration ratio was 0.50 (range, 35-.81). Conclusions. Rilpivirine exposure is substantially lowered during late pregnancy. Despite lower exposure, virologic suppression was maintained and no perinatal transmission was observed. Overall, these results suggest that rilpivirine 25 mg once daily may be an alternative treatment option for HIV-1-infected pregnant women who are virologically suppressed, in settings where therapeutic drug monitoring and/or close viral load monitoring are feasible to detect suboptimal antiretroviral therapy.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Raltegravir in HIV-1-infected pregnant women: Pharmacokinetics, safety, and efficacy

Background. The use of raltegravir in human immunodeficiency virus (HIV)-infected pregnant women is important in the prevention of mother-to-child HIV transmission, especially in circumstances when a rapid decline of HIV RNA load is warranted or when preferred antiretroviral agents cannot be used. Physiological changes during pregnancy can reduce antiretroviral drug exposure. We studied the effect of pregnancy on the pharmacokinetics of raltegravir and its safety and efficacy in HIV-infected pregnant women. Methods. An open-label, multicenter, phase 4 study in HIV-infected pregnant women receiving raltegravir 400 mg twice daily was performed (Pharmacokinetics of Newly Developed Antiretroviral Agents in HIV-Infected Pregnant Women Network). Steady-state pharmacokinetic profiles were obtained in the third trimester and postpartum along with cord and maternal delivery concentrations. Safety and virologic efficacy were evaluated. Results. Twenty-two patients were included, of which 68% started raltegravir during pregnancy. Approaching delivery, 86% of the patients had an undetectable viral load (<50 copies/mL). None of the children were HIV-infected. Exposure to raltegravir was highly variable. Overall area under the plasma concentration-time curve (AUC) and plasma concentration at 12 hours after intake (C12h) plasma concentrations in the third trimester were on average 29% and 36% lower, respectively, compared with postpartum: Geometric mean ratios (90% confidence interval) were 0.71 (.53-.96) for AUC0-12h and 0.64 (.34-1.22) for C12h. The median ratio of raltegravir cord to maternal blood was 1.21 (interquartile range, 1.02-2.17; n = 9). Conclusions. Raltegravir was well tolerated during pregnancy. The pharmacokinetics of raltegravir showed extensive variability. The observed mean decrease in exposure to raltegravir during third trimester compared to postpartum is not considered to be of clinical importance. Raltegravir can be used in standard dosages in HIV-infected pregnant women.SCOPUS: ar.jinfo:eu-repo/semantics/publishe