Chronic infections are difficult to treat with antibiotics but are caused primarily by drug-sensitive pathogens. Dormant persister cells that are tolerant to killing by antibiotics are responsible ...for this apparent paradox. Persisters are phenotypic variants of normal cells and pathways leading to dormancy are redundant, making it challenging to develop anti-persister compounds. Biofilms shield persisters from the immune system, suggesting that an antibiotic for treating a chronic infection should be able to eradicate the infection on its own. We reasoned that a compound capable of corrupting a target in dormant cells will kill persisters. The acyldepsipeptide antibiotic (ADEP4) has been shown to activate the ClpP protease, resulting in death of growing cells. Here we show that ADEP4-activated ClpP becomes a fairly nonspecific protease and kills persisters by degrading over 400 proteins, forcing cells to self-digest. Null mutants of clpP arise with high probability, but combining ADEP4 with rifampicin produced complete eradication of Staphylococcus aureus biofilms in vitro and in a mouse model of a chronic infection. Our findings indicate a general principle for killing dormant cells-activation and corruption of a target, rather than conventional inhibition. Eradication of a biofilm in an animal model by activating a protease suggests a realistic path towards developing therapies to treat chronic infections.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Climate actions can advance sustainable development
The Paris Climate Agreement under the United Nations Framework Convention on Climate Change (UNFCCC) explicitly links the world's long-term climate ...and near-term sustainable development and poverty eradication agendas. Urgent action is needed, but there are many paths toward the agreement's long-term, end-of-century, 1.5° to 2°C climate target. We propose that reducing short-lived climate pollutants (SLCPs) enough to slow projected global warming by 0.5°C over the next 25 years be adopted as a near-term goal, with many potential benefits toward achieving Sustainable Development Goals (SDGs). As countries' climate commitments are formally adopted under the agreement and they prepare for its 2018 stocktaking, there is a need for them to pledge and report progress toward reductions not just in CO
2
but in the full range of greenhouse gases (GHGs) and black carbon (BC) (plus co-emissions) in order to track progress toward long-term goals.
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BFBNIB, NMLJ, NUK, ODKLJ, PNG, SAZU, UL, UM, UPUK
Modulation of mRNA binding to the 40 S ribosomal subunit during translation initiation controls not only global rates of protein synthesis but also regulates the pattern of protein expression by ...allowing for selective inclusion, or exclusion, of mRNAs encoding particular proteins from polysomes. The mRNA binding step is modulated by signaling through a protein kinase known as the mechanistic target of rapamycin complex 1 (mTORC1). mTORC1 directly phosphorylates the translational repressors eIF4E binding proteins (4E-BP) 1 and 2, releasing them from the mRNA cap binding protein eIF4E, thereby promoting assembly of the eIF4E·eIF4G complex. mTORC1 also phosphorylates the 70-kDa ribosomal protein S6 kinase 1 (p70S6K1), which subsequently phosphorylates eIF4B, and programmed cell death 4 (PDCD4), which sequesters eIF4A from the eIF4E·eIF4G complex, resulting in repressed translation of mRNAs with highly structured 5′-untranslated regions. In the present study, we compared the role of the 4E-BPs in the regulation of global rates of protein synthesis to that of eIF4B and PDCD4. We found that maintenance of eIF4E interaction with eIF4G was not by itself sufficient to sustain global rates of protein synthesis in the absence of mTORC1 signaling to p70S6K1; phosphorylation of both eIF4B and PDCD4 was additionally required. We also found that the interaction of eIF4E with eIF4G was maintained in the liver of fasted rats as well as in serum-deprived mouse embryo fibroblasts lacking both 4E-BP1 and 4E-BP2, suggesting that the interaction of eIF4G with eIF4E is controlled primarily through the 4E-BPs.
Background: mTORC1 directly phosphorylates p70S6K1 and the 4E-BPs.
Results: Although necessary, eIF4E·eIF4G complex formation was insufficient for sustaining global rates of protein synthesis.
Conclusion: p70S6K1-mediated phosphorylation of eIF4B and PDCD4 also was required to optimally stimulate protein synthesis.
Significance: Both eIF4E·eIF4G complex formation and activation of p70S6K1 individually stimulate global rates of protein synthesis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The protein kinase mTOR (mechanistic target of rapamycin) in complex 1 (mTORC1) promotes cell growth and proliferation in response to anabolic stimuli, including growth factors and nutrients. Growth ...factors activate mTORC1 by stimulating the kinase Akt, which phosphorylates and inhibits the tuberous sclerosis complex TSC; which is composed of TSC1, TSC2, and TBC1D7 (Tre2-Bub2-Cdc16 domain family member 7), thereby stimulating the mTORC1 activator Rheb (Ras homolog enriched in brain). We identified the mechanism through which REDD1 (regulated in DNA damage and development 1) represses the mTORC1 signaling pathway. We found that REDD1 promoted the protein phosphatase 2A (PP2A)-dependent dephosphorylation of Akt on Thr(308) but not on Ser(473). Consistent with previous studies showing that phosphorylation of Akt on Thr(308), but not on Ser(473), is necessary for phosphorylation of TSC2, we observed a REDD1-dependent reduction in the phosphorylation of TSC2 and subsequently in the activation state of Rheb. REDD1 and PP2A coimmunoprecipitated with Akt from wild-type but not REDD1 knockout mouse embryonic fibroblasts, suggesting that REDD1 may act as a targeting protein for the catalytic subunit of PP2A. Furthermore, binding to both Akt and PP2A was essential for REDD1 to repress signaling to mTORC1. Overall, the results demonstrate that REDD1 acts not only as a repressor of mTORC1 but also as a constant modulator of the phosphorylation of Akt in response to growth factors and nutrients.
Autonomous robotic surgery has the potential to provide efficacy, safety, and consistency independent of individual surgeon's skill and experience. Autonomous anastomosis is a challenging soft-tissue ...surgery task because it requires intricate imaging, tissue tracking, and surgical planning techniques, as well as a precise execution via highly adaptable control strategies often in unstructured and deformable environments. In the laparoscopic setting, such surgeries are even more challenging because of the need for high maneuverability and repeatability under motion and vision constraints. Here we describe an enhanced autonomous strategy for laparoscopic soft tissue surgery and demonstrate robotic laparoscopic small bowel anastomosis in phantom and in vivo intestinal tissues. This enhanced autonomous strategy allows the operator to select among autonomously generated surgical plans and the robot executes a wide range of tasks independently. We then use our enhanced autonomous strategy to perform in vivo autonomous robotic laparoscopic surgery for intestinal anastomosis on porcine models over a 1-week survival period. We compared the anastomosis quality criteria-including needle placement corrections, suture spacing, suture bite size, completion time, lumen patency, and leak pressure-of the developed autonomous system, manual laparoscopic surgery, and robot-assisted surgery (RAS). Data from a phantom model indicate that our system outperforms expert surgeons' manual technique and RAS technique in terms of consistency and accuracy. This was also replicated in the in vivo model. These results demonstrate that surgical robots exhibiting high levels of autonomy have the potential to improve consistency, patient outcomes, and access to a standard surgical technique.
The protein kinase target of rapamycin (mTOR) in complex 1 (mTORC1) is activated by amino acids and in turn upregulates anabolic processes. Under nutrient-deficient conditions, e.g., amino acid ...insufficiency, mTORC1 activity is suppressed and autophagy is activated. Intralysosomal amino acids generated by autophagy reactivate mTORC1. However, sustained mTORC1 activation during periods of nutrient insufficiency would likely be detrimental to cellular homeostasis. Thus, mechanisms must exist to prevent amino acids released by autophagy from reactivating the kinase.
The objective of the present study was to test whether mTORC1 activity is inhibited during prolonged leucine deprivation through ATF4-dependent upregulation of the mTORC1 suppressors regulated in development and DNA damage response 1 (REDD1) and Sestrin2.
Mice (8 wk old; C57Bl/6 × 129SvEV) were food deprived (FD) overnight and one-half were refed the next morning. Mouse embryo fibroblasts (MEFs) deficient in ATF4, REDD1, and/or Sestrin2 were deprived of leucine for 0–16 h. mTORC1 activity and ATF4, REDD1, and Sestrin2 expression were assessed in liver and cell lysates.
Refeeding FD mice resulted in activation of mTORC1 in association with suppressed expression of both REDD1 and Sestrin2 in the liver. In cells in culture, mTORC1 exhibited a triphasic response to leucine deprivation, with an initial suppression followed by a transient reactivation from 2 to 4 h and a subsequent resuppression after 8 h. Resuppression occurred concomitantly with upregulated expression of ATF4, REDD1, and Sestrin2. However, in cells lacking ATF4, neither REDD1 nor Sestrin2 expression was upregulated by leucine deprivation, and resuppression of mTORC1 was absent. Moreover, in cells lacking either REDD1 or Sestrin2, mTORC1 resuppression was attenuated, and in cells lacking both proteins resuppression was further blunted.
The results suggest that leucine deprivation upregulates expression of both REDD1 and Sestrin2 in an ATF4-dependent manner, and that upregulated expression of both proteins is involved in resuppression of mTORC1 during prolonged leucine deprivation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Background Multiparametric magnetic resonance imaging (mp-MRI) is increasingly used in prostate cancer (CaP). Understanding the limitations of tumor detection, particularly in multifocal ...disease, is important in its clinical application. Objective To determine predictors of CaP detection by mp-MRI as confirmed by whole-mount histopathology. Design, setting, and participants A retrospective study was performed of 122 consecutive men who underwent mp-MRI before radical prostatectomy at a single referral academic center. A genitourinary radiologist and pathologist collectively determined concordance. Outcome measurements and statistical analysis The odds of tumor detection were calculated for clinical, MRI, and histopathologic variables using a multivariate logistic regression model. Results and limitations The 122 patients had 283 unique histologically confirmed CaP tumor foci. Gleason score was 6 in 21 (17%), 7 in 88 (72%), and ≥8 in 13 (11%) patients. Of the 122 cases, 44 (36%) had solitary and 78 (64%) had multifocal tumors. Overall mp-MRI sensitivity for tumor detection was 47% (132/283), with increased sensitivity for larger (102/141 72% >1.0 cm), higher-grade (96/134 72% Gleason ≥7) tumors, and index tumors (98/122 80%). Index tumor status, size, and prostate weight were significant predictors of detection in a multivariate analysis, and multifocality did not adversely impact detection of index tumors. A prostatectomy population was necessary by design, which may limit the ability to generalize these results. Conclusions Sensitivity for tumor detection increased with tumor size and grade. Index tumor status and tumor size were the strongest predictors of tumor detection, regardless of tumor focality. Some 80% of index tumors were detected, but nonindex tumor detection, even of high-grade lesions, was poor. These findings have important implications for focal therapy. Patient summary We evaluated the ability of magnetic resonance imaging (MRI) to detect cancer in patients undergoing prostatectomy. We found that tumor size and grade were important predictors of tumor detection, and although cancer is often multifocal, MRI is often able to detect the worst focus of cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The purpose of this study was to determine how violation of gender-based expectancies might influence straight men’s attitudes toward men who differ by sexual orientation (i.e., straight or gay). ...This study was specifically designed to avoid methodological issues that may have been present in similar research. Hypotheses were informed by Expectancy-Violation Theory (EVT) and the Black Sheep Effect (BSE), which together suggest that an effeminate straight man should be evaluated by other straight men more negatively than an effeminate gay man because the former target negatively violated expectations. Additionally, EVT suggests that a masculine gay man should be evaluated more positively than a masculine straight man because the former positively violates expectations, while the BSE instead suggests the latter should be evaluated more positively than the former due to ingroup bias. Self-identified straight men evaluated a male target whose sexual orientation and gender conformity were manipulated through a photo and vignette. A moderated mediation analysis was performed to determine if perceived expectancy violation mediated the relationship between sexual orientation and evaluations for both effeminate and masculine men. Straight effeminate targets were evaluated more negatively than gay effeminate targets; however, straight masculine targets were evaluated more favorably than gay masculine targets, a finding more consistent with the BSE. In addition, perceived expectancy violation did not mediate the relationship between sexual orientation and evaluations regardless of gender expression. More research should be conducted to identify the mechanisms through which evaluations of straight and gay targets differ based on gender expression.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Recent research indicates that cadmium (Cd) induces oxidative damage in cells; however, the mechanism of the oxidative stress induced by this metal is unclear. We investigated the effects of Cd on ...the individual complexes of the electron transfer chain (ETC) and on the stimulation of reactive oxygen species (ROS) production in mitochondria. The activity of complexes II (succinate:ubiquinone oxidoreductase) and III (ubiquinol:cytochrome
c oxidoreductase) of mitochondrial ETC from liver, brain, and heart showed greater inhibition by Cd than the other complexes. Cd stimulated ROS production in the mitochondria of all three tissues mentioned above. The effect of various electron donors (NADH, succinate, and 2,3-dimethoxy-5-methyl-6-decyl-1,4-benzoquinol) on ROS production was tested separately in the presence and in the absence of Cd. ESR showed that complex III might be the only site of ROS production induced by Cd. The results of kinetic studies and electron turnover experiments suggest that Cd may bind between semiubiquinone and cytochrome
b
566 of the Q
0 site of cytochrome
b of complex III, resulting in accumulation of semiubiquinones at the Q
0 site. The semiubiquinones, being unstable, are prone to transfer one electron to molecular oxygen to form superoxide, providing a possible mechanism for Cd-induced generation of ROS in mitochondria.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
10.
Initial performance of the COSINE-100 experiment Adhikari, G.; Adhikari, P.; de Souza, E. Barbosa ...
The European physical journal. C, Particles and fields,
02/2018, Volume:
78, Issue:
2
Journal Article
Peer reviewed
Open access
COSINE is a dark matter search experiment based on an array of low background NaI(Tl) crystals located at the Yangyang underground laboratory. The assembly of COSINE-100 was completed in the summer ...of 2016 and the detector is currently collecting physics quality data aimed at reproducing the DAMA/LIBRA experiment that reported an annual modulation signal. Stable operation has been achieved and will continue for at least 2 years. Here, we describe the design of COSINE-100, including the shielding arrangement, the configuration of the NaI(Tl) crystal detection elements, the veto systems, and the associated operational systems, and we show the current performance of the experiment.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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