Yet another breakdown point notion: EFSBP - illustrated at scale-shape models

The breakdown point in its different variants is one of the central notions to quantify the global robustness of a procedure. We propose a simple supplementary variant which is useful in situations where we have no obvious or only partial equivariance: Extending the Donoho and Huber(1983) Finite Sample Breakdown Point, we propose the Expected Finite Sample Breakdown Point to produce less configuration-dependent values while still preserving the finite sample aspect of the former definition. We apply this notion for joint estimation of scale and shape (with only scale-equivariance available), exemplified for generalized Pareto, generalized extreme value, Weibull, and Gamma distributions. In these settings, we are interested in highly-robust, easy-to-compute initial estimators; to this end we study Pickands-type and Location-Dispersion-type estimators and compute their respective breakdown points.Comment: 21 pages, 4 figure

Infinitesimally Robust Estimation in General Smoothly Parametrized Models

We describe the shrinking neighborhood approach of Robust Statistics, which applies to general smoothly parametrized models, especially, exponential families. Equal generality is achieved by object oriented implementation of the optimally robust estimators. We evaluate the estimates on real datasets from literature by means of our R packages ROptEst and RobLox

YopJ-Induced Caspase-1 Activation in Yersinia-Infected Macrophages: Independent of Apoptosis, Linked to Necrosis, Dispensable for Innate Host Defense

Yersinia outer protein J (YopJ) is a type III secretion system (T3SS) effector of pathogenic Yersinia (Yersinia pestis, Yersinia enterocolitica and Yersinia pseudotuberculosis) that is secreted into host cells. YopJ inhibits survival response pathways in macrophages, causing cell death. Allelic variation of YopJ is responsible for differential cytotoxicity in Yersinia strains. YopJ isoforms in Y. enterocolitica O:8 (YopP) and Y. pestis KIM (YopJKIM) strains have high cytotoxic activity. In addition, YopJKIM-induced macrophage death is associated with caspase-1 activation and interleukin-1β (IL-1β secretion. Here, the mechanism of YopJKIM-induced cell death, caspase-1 activation, and IL-1β secretion in primary murine macrophages was examined. Caspase-3/7 activity was low and the caspase-3 substrate poly (ADP-ribose) polymerase (PARP) was not cleaved in Y. pestis KIM5-infected macrophages. In addition, cytotoxicity and IL-1β secretion were not reduced in the presence of a caspase-8 inhibitor, or in B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax)/Bcl-2 homologous antagonist/killer (Bak) knockout macrophages, showing that YopJKIM-mediated cell death and caspase-1 activation occur independent of mitochondrial-directed apoptosis. KIM5-infected macrophages released high mobility group protein B1 (HMGB1), a marker of necrosis, and microscopic analysis revealed that necrotic cells contained active caspase-1, indicating that caspase-1 activation is associated with necrosis. Inhibitor studies showed that receptor interacting protein 1 (RIP1) kinase and reactive oxygen species (ROS) were not required for cytotoxicity or IL-β release in KIM5-infected macrophages. IL-1β secretion was reduced in the presence of cathepsin B inhibitors, suggesting that activation of caspase-1 requires cathepsin B activity. Ectopically-expressed YopP caused higher cytotoxicity and secretion of IL-1β in Y. pseudotuberculosis-infected macrophages than YopJKIM. Wild-type and congenic caspase 1 knockout C57BL/6 mice were equally susceptible to lethal infection with Y. pseudotuberculosis ectopically expressing YopP. These data suggest that YopJ-induced caspase-1 activation in Yersinia-infected macrophages is a downstream consequence of necrotic cell death and is dispensable for innate host resistance to a strain with enhanced cytotoxicity

A Yersinia Effector with Enhanced Inhibitory Activity on the NF-κB Pathway Activates the NLRP3/ASC/Caspase-1 Inflammasome in Macrophages

A type III secretion system (T3SS) in pathogenic Yersinia species functions to translocate Yop effectors, which modulate cytokine production and regulate cell death in macrophages. Distinct pathways of T3SS-dependent cell death and caspase-1 activation occur in Yersinia-infected macrophages. One pathway of cell death and caspase-1 activation in macrophages requires the effector YopJ. YopJ is an acetyltransferase that inactivates MAPK kinases and IKKβ to cause TLR4-dependent apoptosis in naïve macrophages. A YopJ isoform in Y. pestis KIM (YopJKIM) has two amino acid substitutions, F177L and K206E, not present in YopJ proteins of Y. pseudotuberculosis and Y. pestis CO92. As compared to other YopJ isoforms, YopJKIM causes increased apoptosis, caspase-1 activation, and secretion of IL-1β in Yersinia-infected macrophages. The molecular basis for increased apoptosis and activation of caspase-1 by YopJKIM in Yersinia-infected macrophages was studied. Site directed mutagenesis showed that the F177L and K206E substitutions in YopJKIM were important for enhanced apoptosis, caspase-1 activation, and IL-1β secretion. As compared to YopJCO92, YopJKIM displayed an enhanced capacity to inhibit phosphorylation of IκB-α in macrophages and to bind IKKβ in vitro. YopJKIM also showed a moderately increased ability to inhibit phosphorylation of MAPKs. Increased caspase-1 cleavage and IL-1β secretion occurred in IKKβ-deficient macrophages infected with Y. pestis expressing YopJCO92, confirming that the NF-κB pathway can negatively regulate inflammasome activation. K+ efflux, NLRP3 and ASC were important for secretion of IL-1β in response to Y. pestis KIM infection as shown using macrophages lacking inflammasome components or by the addition of exogenous KCl. These data show that caspase-1 is activated in naïve macrophages in response to infection with a pathogen that inhibits IKKβ and MAPK kinases and induces TLR4-dependent apoptosis. This pro-inflammatory form of apoptosis may represent an early innate immune response to highly virulent pathogens such as Y. pestis KIM that have evolved an enhanced ability to inhibit host signaling pathways

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field

Preprocessing of gene expression data by optimally robust estimators

<p>Abstract</p> <p>Background</p> <p>The preprocessing of gene expression data obtained from several platforms routinely includes the aggregation of multiple raw signal intensities to one expression value. Examples are the computation of a single expression measure based on the perfect match (PM) and mismatch (MM) probes for the Affymetrix technology, the summarization of bead level values to bead summary values for the Illumina technology or the aggregation of replicated measurements in the case of other technologies including real-time quantitative polymerase chain reaction (RT-qPCR) platforms. The summarization of technical replicates is also performed in other "-omics" disciplines like proteomics or metabolomics.</p> <p>Preprocessing methods like MAS 5.0, Illumina's default summarization method, RMA, or VSN show that the use of robust estimators is widely accepted in gene expression analysis. However, the selection of robust methods seems to be mainly driven by their high breakdown point and not by efficiency.</p> <p>Results</p> <p>We describe how optimally robust radius-minimax (rmx) estimators, i.e. estimators that minimize an asymptotic maximum risk on shrinking neighborhoods about an ideal model, can be used for the aggregation of multiple raw signal intensities to one expression value for Affymetrix and Illumina data. With regard to the Affymetrix data, we have implemented an algorithm which is a variant of MAS 5.0.</p> <p>Using datasets from the literature and Monte-Carlo simulations we provide some reasoning for assuming approximate log-normal distributions of the raw signal intensities by means of the Kolmogorov distance, at least for the discussed datasets, and compare the results of our preprocessing algorithms with the results of Affymetrix's MAS 5.0 and Illumina's default method.</p> <p>The numerical results indicate that when using rmx estimators an accuracy improvement of about 10-20% is obtained compared to Affymetrix's MAS 5.0 and about 1-5% compared to Illumina's default method. The improvement is also visible in the analysis of technical replicates where the reproducibility of the values (in terms of Pearson and Spearman correlation) is increased for all Affymetrix and almost all Illumina examples considered. Our algorithms are implemented in the R package named <monospace>RobLoxBioC</monospace> which is publicly available via CRAN, The Comprehensive R Archive Network (<url>http://cran.r-project.org/web/packages/RobLoxBioC</url>/).</p> <p>Conclusions</p> <p>Optimally robust rmx estimators have a high breakdown point and are computationally feasible. They can lead to a considerable gain in efficiency for well-established bioinformatics procedures and thus, can increase the reproducibility and power of subsequent statistical analysis.</p

Older Patients' Aversion to Antidepressants: A Qualitative Study

BACKGROUND: Depression is common among older patients yet is often inadequately treated. Patient beliefs about antidepressants are known to affect treatment initiation and adherence, but are often not expressed in clinical settings. OBJECTIVE: To explore attitudes toward antidepressants in a sample of depressed, community-dwelling elders who were offered treatment. DESIGN: Cross-sectional, qualitative study utilizing semi-structured interviews. PARTICIPANTS: Primary care patients age 60 years and over with depression, from academic and community primary care practices of the University of Pennsylvania Health System and the Philadelphia Department of Veterans Affairs. Patients participated in either the Prevention of Suicide in Primary Care Elderly: Collaborative Trial or the Primary Care Research in Substance Abuse and Mental Health for the Elderly Trial. Sixty-eight patients were interviewed and responses from 42 participants with negative attitudes toward medication for depression were analyzed. MEASUREMENTS: Interviews were audiotaped, transcribed, and entered into a qualitative software program for coding and analysis. A multidisciplinary team of investigators coded the transcripts and identified key features of narratives expressing aversion to antidepressants. RESULTS: Four themes characterized resistance to antidepressants: (1) fear of dependence; (2) resistance to viewing depressive symptoms as a medical illness; (3) concern that antidepressants will prevent natural sadness; (4) prior negative experiences with medications for depression. CONCLUSIONS: Many elders resisted the use of antidepressants. Patients expressed concerns that seem to reflect their concept of depression as well as their specific concerns regarding antidepressants. These findings may enhance patient-provider communication about depression treatment in elders