The mitochondrial caseinolytic protease P (ClpP) plays a central role in mitochondrial protein quality control by degrading misfolded proteins. Using genetic and chemical approaches, we showed that ...hyperactivation of the protease selectively kills cancer cells, independently of p53 status, by selective degradation of its respiratory chain protein substrates and disrupts mitochondrial structure and function, while it does not affect non-malignant cells. We identified imipridones as potent activators of ClpP. Through biochemical studies and crystallography, we show that imipridones bind ClpP non-covalently and induce proteolysis by diverse structural changes. Imipridones are presently in clinical trials. Our findings suggest a general concept of inducing cancer cell lethality through activation of mitochondrial proteolysis.
•Activation of the mitochondrial ClpP induces p53-independent cancer cell lethality•Imipridones are allosteric agonists of ClpP, being tested in human clinical trials•ClpP activation increases proteolysis of mitochondrial proteins•ClpP-mediated mitochondrial proteolysis impairs mitochondrial respiratory function
Ishizawa et al. report that hyperactivating the mitochondrial caseinolytic protease P (ClpP) degrades respiratory chain proteins, disrupts mitochondrial function, and selectively kills cancer cells, regardless of p53 status. They identify imipridones as hyperactivators of ClpP and show their anti-tumor activity.
We used clustered regularly interspaced short palindromic repeats/Cas9-mediated genomic modification to investigate B-cell receptor (BCR) signaling in cell lines of diffuse large B-cell lymphoma ...(DLBCL). Three manipulations that altered BCR genes without affecting surface BCR levels showed that BCR signaling differs between the germinal center B-cell (GCB) subtype, which is insensitive to Bruton tyrosine kinase inhibition by ibrutinib, and the activated B-cell (ABC) subtype. Replacing antigen-binding BCR regions had no effect on BCR signaling in GCB-DLBCL lines, reflecting this subtype's exclusive use of tonic BCR signaling. Conversely, Y188F mutation in the immunoreceptor tyrosine-based activation motif of CD79A inhibited tonic BCR signaling in GCB-DLBCL lines but did not affect their calcium flux after BCR cross-linking or the proliferation of otherwise-unmodified ABC-DLBCL lines. CD79A-GFP fusion showed BCR clustering or diffuse distribution, respectively, in lines of ABC and GCB subtypes. Tonic BCR signaling acts principally to activate AKT, and forced activation of AKT rescued GCB-DLBCL lines from knockout (KO) of the BCR or 2 mediators of tonic BCR signaling, SYK and CD19. The magnitude and importance of tonic BCR signaling to proliferation and size of GCB-DLBCL lines, shown by the effect of BCR KO, was highly variable; in contrast, pan-AKT KO was uniformly toxic. This discrepancy was explained by finding that BCR KO–induced changes in AKT activity (measured by gene expression, CXCR4 level, and a fluorescent reporter) correlated with changes in proliferation and with baseline BCR surface density. PTEN protein expression and BCR surface density may influence clinical response to therapeutic inhibition of tonic BCR signaling in DLBCL.
•The GCB subtype of DLBCL relies exclusively on tonic BCR signaling via CD79A Y188.•PTEN protein expression and BCR surface density determine the contribution of tonic BCR signaling to AKT activity in GCB-DLBCL.
Established metrics reward academic faculty for clinical productivity. Few data have analyzed a bonus model to measure and reward academic productivity. This study's objective was to describe ...development and use of a departmental academic bonus system for incenting faculty scholarly and educational productivity.
This cross-sectional study analyzed a departmental bonus system among emergency medicine academic faculty at Oregon Health & Science University, including growth from 2005 to 2015. All faculty members with a primary appointment were eligible for participation. Each activity was awarded points based on a predetermined education or scholarly point scale. Faculty members accumulated points based on their activity (numerator), and the cumulative points of all faculty were the denominator. Variables were individual faculty member (deidentified), academic year, bonus system points, bonus amounts awarded, and measures of academic productivity. Data were analyzed using descriptive statistics, including measures of variance.
The total annual financial bonus pool ranged from $211,622 to $274,706. The median annual per faculty academic bonus remained fairly constant over time ($3,980 in 2005-2006 vs. $4,293 in 2014-2015), with most change at the upper quartile of academic bonus (max bonus $16,920 in 2005-2006 vs. $39,207 in 2014-2015). Bonuses rose linearly among faculty in the bottom three quartiles of academic productivity, but increased exponentially in the 75th to 100th percentile.
Faculty academic productivity can be measured and financially rewarded according to an objective academic bonus system. The "academic point" used to measure productivity functions as an "academic relative value unit."
•Three types of fiber were added to enhance the compressive strength and frost resistance.•The coupling effect of freeze-thaw cycling and axial compressive loading was studied.•S fiber has a ...complicated impact on the structural compactness and frost resistance of FGPC under pressure.
The poor frost resistance of low-calcium geopolymer concrete is an urgent problem that needs to be solved before its application in practice. In this study, polypropylene (PP) fiber, polyvinyl alcohol (PVA) fiber and steel (S) fiber were added to enhance the frost resistance of blended slag and Class F fly ash-based geopolymer concrete (SFGPC). More importantly, to evaluate the frost resistance of fiber-reinforced SFGPC under axial compressive loading, a coupling experiment with 20 MPa of compressive stress and 125 freeze-cycles was conducted. It was found that the addition of fibers did not inhibit the initiation of microcracks but could suppress their propagation. The water penetration depth and mercury intrusion porosimetry (MIP) test results verified that the applied compressive loading further compacts the concrete, which significantly improves the frost resistance. In comparison, the S fiber-reinforced SFGPC exhibited an inconsistent frost resistance with and without compressive stress due to the extremely high elastic modulus of the S fiber. Overall, 0.3% vol PVA fiber had the best effect on improving both the mechanical properties and the frost resistance of SFGPC.
•96 samples were tested to investigate the bond behavior of reinforcing bars in UHPC.•The minimum development lengths for different concrete cover were recommended.•A theoretical bond strength model ...using fiber–matrix discrete concept was proposed.•The proposed model was in good agreement with 343 test data collected from literature.
The study provided an experimental and theoretical investigation on the bond behavior of reinforcing bars in ultra-high performance concrete (UHPC) via a series of pullout tests. Test parameters included depth of concrete cover, bar embedment length and bar diameter. Failure mode, crack pattern and load-slip response were recorded and discussed under different test parameters. Test results indicated that inadequate concrete cover depth led to splitting failure while short embedment length resulted in concrete cone failure, corresponding to lower bond strengths. The bond strength increased up to 229.8% and the pullout energy increased 401.4% as the concrete cover depth increased from 0.5d to 2d. The development lengths were recommended to be 6d and 8d corresponding to the concrete cover depth of 2d, 1.5d, respectively. A theoretical bond strength model using fiber–matrix discrete concept was proposed and validated by comparing the calculated values with the test results and 343 test data collected from literature. The average ratios of the calculated results to the test results and collected data were 0.996 and 1.039, with a standard deviation of 0.255 and 0.252. The proposed model established the connection between the meso-scale bond property of fibers and matrix and the macro-scale bond strength of steel bars and UHPC, offering an alternative perspective in understanding the bond performance of steel bars in UHPC.
Summary Background Colorectal cancer is the third most common cancer worldwide and has a high mortality rate. We tested the hypothesis that only one flexible sigmoidoscopy screening between 55 and 64 ...years of age can substantially reduce colorectal cancer incidence and mortality. Methods This randomised controlled trial was undertaken in 14 UK centres. 170 432 eligible men and women, who had indicated on a previous questionnaire that they would accept an invitation for screening, were randomly allocated to the intervention group (offered flexible sigmoidoscopy screening) or the control group (not contacted). Randomisation by sequential number generation was done centrally in blocks of 12, with stratification by trial centre, general practice, and household type. The primary outcomes were the incidence of colorectal cancer, including prevalent cases detected at screening, and mortality from colorectal cancer. Analyses were intention to treat and per protocol. The trial is registered, number ISRCTN28352761. Findings 113 195 people were assigned to the control group and 57 237 to the intervention group, of whom 112 939 and 57 099, respectively, were included in the final analyses. 40 674 (71%) people underwent flexible sigmoidoscopy. During screening and median follow-up of 11·2 years (IQR 10·7–11·9), 2524 participants were diagnosed with colorectal cancer (1818 in control group vs 706 in intervention group) and 20 543 died (13 768 vs 6775; 727 certified from colorectal cancer 538 vs 189). In intention-to-treat analyses, colorectal cancer incidence in the intervention group was reduced by 23% (hazard ratio 0·77, 95% CI 0·70–0·84) and mortality by 31% (0·69, 0·59–0·82). In per-protocol analyses, adjusting for self-selection bias in the intervention group, incidence of colorectal cancer in people attending screening was reduced by 33% (0·67, 0·60–0·76) and mortality by 43% (0·57, 0·45–0·72). Incidence of distal colorectal cancer (rectum and sigmoid colon) was reduced by 50% (0·50, 0·42–0·59; secondary outcome). The numbers needed to be screened to prevent one colorectal cancer diagnosis or death, by the end of the study period, were 191 (95% CI 145–277) and 489 (343–852), respectively. Interpretation Flexible sigmoidoscopy is a safe and practical test and, when offered only once between ages 55 and 64 years, confers a substantial and longlasting benefit. Funding Medical Research Council, National Health Service R&D, Cancer Research UK, KeyMed.
We prove a bubble tree convergence theorem for a sequence of closed Hamiltonian stationary Lagrangian surfaces with bounded areas and Willmore energies in a complete Kähler surface. We also prove two ...strong compactness theorems on the space of Hamiltonian stationary Lagrangian tori in
C
2
and
C
P
2
respectively.
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