The BCL-2 family of proteins controls cell death primarily by direct binding interactions that regulate mitochondrial outer membrane permeabilization (MOMP) leading to the irreversible release of ...intermembrane space proteins, subsequent caspase activation and apoptosis. The affinities and relative abundance of the BCL-2 family proteins dictate the predominate interactions between anti-apoptotic and pro-apoptotic BCL-2 family proteins that regulate MOMP. We highlight the core mechanisms of BCL-2 family regulation of MOMP with an emphasis on how the interactions between the BCL-2 family proteins govern cell fate. We address the critical importance of both the concentration and affinities of BCL-2 family proteins and show how differences in either can greatly change the outcome. Further, we explain the importance of using full-length BCL-2 family proteins (versus truncated versions or peptides) to parse out the core mechanisms of MOMP regulation by the BCL-2 family. Finally, we discuss how post-translational modifications and differing intracellular localizations alter the mechanisms of apoptosis regulation by BCL-2 family proteins. Successful therapeutic intervention of MOMP regulation in human disease requires an understanding of the factors that mediate the major binding interactions between BCL-2 family proteins in cells.
The benefits and safety of the treatment of mild chronic hypertension (blood pressure, <160/100 mm Hg) during pregnancy are uncertain. Data are needed on whether a strategy of targeting a blood ...pressure of less than 140/90 mm Hg reduces the incidence of adverse pregnancy outcomes without compromising fetal growth.
In this open-label, multicenter, randomized trial, we assigned pregnant women with mild chronic hypertension and singleton fetuses at a gestational age of less than 23 weeks to receive antihypertensive medications recommended for use in pregnancy (active-treatment group) or to receive no such treatment unless severe hypertension (systolic pressure, ≥160 mm Hg; or diastolic pressure, ≥105 mm Hg) developed (control group). The primary outcome was a composite of preeclampsia with severe features, medically indicated preterm birth at less than 35 weeks' gestation, placental abruption, or fetal or neonatal death. The safety outcome was small-for-gestational-age birth weight below the 10th percentile for gestational age. Secondary outcomes included composites of serious neonatal or maternal complications, preeclampsia, and preterm birth.
A total of 2408 women were enrolled in the trial. The incidence of a primary-outcome event was lower in the active-treatment group than in the control group (30.2% vs. 37.0%), for an adjusted risk ratio of 0.82 (95% confidence interval CI, 0.74 to 0.92; P<0.001). The percentage of small-for-gestational-age birth weights below the 10th percentile was 11.2% in the active-treatment group and 10.4% in the control group (adjusted risk ratio, 1.04; 95% CI, 0.82 to 1.31; P = 0.76). The incidence of serious maternal complications was 2.1% and 2.8%, respectively (risk ratio, 0.75; 95% CI, 0.45 to 1.26), and the incidence of severe neonatal complications was 2.0% and 2.6% (risk ratio, 0.77; 95% CI, 0.45 to 1.30). The incidence of any preeclampsia in the two groups was 24.4% and 31.1%, respectively (risk ratio, 0.79; 95% CI, 0.69 to 0.89), and the incidence of preterm birth was 27.5% and 31.4% (risk ratio, 0.87; 95% CI, 0.77 to 0.99).
In pregnant women with mild chronic hypertension, a strategy of targeting a blood pressure of less than 140/90 mm Hg was associated with better pregnancy outcomes than a strategy of reserving treatment only for severe hypertension, with no increase in the risk of small-for-gestational-age birth weight. (Funded by the National Heart, Lung, and Blood Institute; CHAP ClinicalTrials.gov number, NCT02299414.).
Mechanisms of action of Bcl-2 family proteins Shamas-Din, Aisha; Kale, Justin; Leber, Brian ...
Cold Spring Harbor perspectives in biology,
2013-Apr-01, 2013-04-01, 20130401, Letnik:
5, Številka:
4
Journal Article
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The Bcl-2 family of proteins controls a critical step in commitment to apoptosis by regulating permeabilization of the mitochondrial outer membrane (MOM). The family is divided into three classes: ...multiregion proapoptotic proteins that directly permeabilize the MOM; BH3 proteins that directly or indirectly activate the pore-forming class members; and the antiapoptotic proteins that inhibit this process at several steps. Different experimental approaches have led to several models, each proposed to explain the interactions between Bcl-2 family proteins. The discovery that many of these interactions occur at or in membranes as well as in the cytoplasm, and are governed by the concentrations and relative binding affinities of the proteins, provides a new basis for rationalizing these models. Furthermore, these dynamic interactions cause conformational changes in the Bcl-2 proteins that modulate their apoptotic function, providing additional potential modes of regulation.
Converting low-frequency electrical signals into much higher-frequency optical signals has enabled modern communication networks to leverage the strengths of both microfabricated electrical circuits ...and optical bre transmission, enabling information networks to grow in size and complexity. A microwave-to-optical converter in a quantum information network could provide similar gains by linking quantum processors through low-loss optical bres and enabling a large-scale quantum network. However, no current technology can convert low-frequency microwave signals into high-frequency optical signals while preserving their fragile quantum state.
In this paper, we propose an instrumental variable approach to constructing confidence sets (CS's) for the true parameter in models defined by conditional moment inequalities/equalities. We show that ...by properly choosing instrument functions, one can transform conditional moment inequalities/equalities into unconditional ones without losing identification power. Based on the unconditional moment inequalities/equalities, we construct CS's by inverting Cramér—von Mises-type or Kolmogorov—Smirnov-type tests. Critical values are obtained using generalized moment selection (GMS) procedures. We show that the proposed CS's have correct uniform asymptotic coverage probabilities. New methods are required to establish these results because an infinite-dimensional nuisance parameter affects the asymptotic distributions. We show that the tests considered are consistent against all fixed alternatives and typically have power against n -1/2 -local alternatives to some, but not all, sequences of distributions in the null hypothesis. Monte Carlo simulations for five different models show that the methods perform well in finite samples.
Antibiotic tolerance, the capacity of genetically susceptible bacteria to survive the lethal effects of antibiotic treatment, plays a critical and underappreciated role in the disease burden of ...bacterial infections. Here, we take a pathogen-by-pathogen approach to illustrate the clinical significance of antibiotic tolerance and discuss how the physiology of specific pathogens in their infection environments impacts the mechanistic underpinnings of tolerance. We describe how these insights are leading to the development of species-specific therapeutic strategies for targeting antibiotic tolerance and highlight experimental platforms that are enabling us to better understand the complexities of drug-tolerant pathogens in in vivo settings.
Lack of efficacy of antibiotic treatment presents a critical challenge to clinical management of bacterial infections. This review discusses the significance of antibiotic tolerance as the culprit of this challenge and its underlying mechanism as the target for future therapeutic development.
This paper provides a set of results that can be used to establish the asymptotic size and/or similarity in a uniform sense of confidence sets and tests. The results are generic in that they can be ...applied to a broad range of problems. They are most useful in scenarios where the pointwise asymptotic distribution of a test statistic is a discontinuous function of a parameter.
The results are illustrated in several examples. These are: (i) the conditional likelihood ratio test of Moreira (2003) for linear instrumental variables models with instruments that may be weak, extended to the case of heteroskedastic errors; (ii) the grid bootstrap confidence interval of Hansen (1999) for the sum of the AR coefficients in a kth order autoregressive model with unknown innovation distribution, and (iii) the standard quasi-likelihood ratio test in a nonlinear regression model where identification is lost when the coefficient on the nonlinear regressor is zero. In addition, as a simple running example, we consider a two-sided equal-tailed CI for the AR coefficient in an AR(1) model, which is a simplified version of the CI in Andrews and Guggenberger (2014).
The topic of this paper is inference in models in which parameters are defined by moment inequalities and/or equalities. The parameters may or may not be identified. This paper introduces a new class ...of confidence sets and tests based on generalized moment selection (GMS). GMS procedures are shown to have correct asymptotic size in a uniform sense and are shown not to be asymptotically conservative. The power of GMS tests is compared to that of subsampling, m out of n bootstrap, and "plug-in asymptotic" (PA) tests. The latter three procedures are the only general procedures in the literature that have been shown to have correct asymptotic size (in a uniform sense) for the moment inequality/equality model. GMS tests are shown to have asymptotic power that dominates that of subsampling, m out of n bootstrap, and PA tests. Subsampling and m out of n bootstrap tests are shown to have asymptotic power that dominates that of PA tests.
Apoptosis is a highly regulated form of cell death that controls normal homeostasis as well as the antitumor activity of many chemotherapeutic agents. Commitment to death via the mitochondrial ...apoptotic pathway requires activation of the mitochondrial pore-forming proteins BAK or BAX. Activation can be effected by the activator BH3-only proteins BID or BIM, which have been considered to be functionally redundant in this role. Herein, we show that significant activation preferences exist between these proteins: BID preferentially activates BAK while BIM preferentially activates BAX. Furthermore, we find that cells lacking BAK are relatively resistant to agents that require BID activation for maximal induction of apoptosis, including topoisomerase inhibitors and TRAIL. Consequently, patients with tumors that harbor a loss of BAK1 exhibit an inferior response to topoisomerase inhibitor treatment in the clinic. Therefore, BID and BIM have nonoverlapping roles in the induction of apoptosis via BAK and BAX, affecting chemotherapy response.
•BID and BIM preferentially activate BAK and BAX, respectively•BID-dependent cell death correlates with BAK-dependent cell death•Patients with tumors lacking BAK respond poorly to topoisomerase inhibitors
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