Black Holes in Pseudobulges and Spheroidals: A Change in the Black Hole-Bulge Scaling Relations at Low Mass

We investigate the relationship between black hole mass and host galaxy properties for active galaxies with the lowest black hole masses currently known in galaxy nuclei. Hubble Space Telescope imaging confirms that the host galaxies have correspondingly low luminosity; they are ~1 mag below L*. In terms of morphology, ~60% of the members of the sample are disk-dominated, and all of these are consistent with containing a bulge or (more likely) pseudobulge, while the remainder are compact systems with no discernible disk component. In general the compact components of the galaxies do not obey the fundamental plane of giant elliptical galaxies and classical bulges, but rather are less centrally concentrated at a given luminosity, much like spheroidal galaxies. Our results strongly confirm that a classical bulge is not a requirement for a nuclear black hole. At the same time, the observed ratio of black hole to bulge mass is nearly an order of magnitude lower in this sample than that seen for classical bulges. While the M-sigma relation appears to continue to low mass, it seems that black hole-galaxy scaling relations do depend on galaxy structure.Comment: to appear in ApJ; 22 pages; 8 figures; original version available at http://www.astro.princeton.edu/~jgreene/paper.pd

Regulation of Tcf7l1 DNA Binding and Protein Stability as Principal Mechanisms of Wnt/β-Catenin Signaling

SummaryWnt/β-catenin signal transduction requires direct binding of β-catenin to Tcf/Lef proteins, an event that is classically associated with stimulating transcription by recruiting coactivators. This molecular cascade plays critical roles throughout embryonic development and normal postnatal life by affecting stem cell characteristics and tumor formation. Here, we show that this pathway utilizes a fundamentally different mechanism to regulate Tcf7l1 (formerly named Tcf3) activity. β-catenin inactivates Tcf7l1 without a switch to a coactivator complex by removing it from DNA, which leads to Tcf7l1 protein degradation. Mouse genetic experiments demonstrate that Tcf7l1 inactivation is the only required effect of the Tcf7l1-β-catenin interaction. Given the expression of Tcf7l1 in pluripotent embryonic and adult stem cells, as well as in poorly differentiated breast cancer, these findings provide mechanistic insights into the regulation of pluripotency and the role of Wnt/β-catenin in breast cancer

SUMO chain formation is required for response to replication arrest in S. pombe

SUMO is a ubiquitin-like protein that is post-translationally attached to one or more lysine residues on target proteins. Despite having only 18% sequence identity with ubiquitin, SUMO contains the conserved betabetaalphabetabetaalphabeta fold present in ubiquitin. However, SUMO differs from ubiquitin in having an extended N-terminus. In S. pombe the N-terminus of SUMO/Pmt3 is significantly longer than those of SUMO in S. cerevisiae, human and Drosophila. Here we investigate the role of this N-terminal region. We have used two dimensional gel electrophoresis to demonstrate that S. pombe SUMO/Pmt3 is phosphorylated, and that this occurs on serine residues at the extreme N-terminus of the protein. Mutation of these residues (in pmt3-1) results in a dramatic reduction in both the levels of high Mr SUMO-containing species and of total SUMO/Pmt3, indicating that phosphorylation of SUMO/Pmt3 is required for its stability. Despite the significant reduction in high Mr SUMO-containing species, pmt3-1 cells do not display an aberrant cell morphology or sensitivity to genotoxins or stress. Additionally, we demonstrate that two lysine residues in the N-terminus of S. pombe SUMO/Pmt3 (K14 and K30) can act as acceptor sites for SUMO chain formation in vitro. Inability to form SUMO chains results in aberrant cell and nuclear morphologies, including stretched and fragmented chromatin. SUMO chain mutants are sensitive to the DNA synthesis inhibitor, hydroxyurea (HU), but not to other genotoxins, such as UV, MMS or CPT. This implies a role for SUMO chains in the response to replication arrest in S. pomb

The relationship of self-efficacy to catastrophizing and depressive symptoms in community-dwelling older adults with chronic pain: A moderated mediation model

Self-efficacy has been consistently found to be a protective factor against psychological distress and disorders in the literature. However, little research is done on the moderating effect of self-efficacy on depressive symptoms in the context of chronic pain. This cross-sectional study aimed to examine if pain self-efficacy attenuated the direct relationship between pain intensity and depressive symptoms, as well as their indirect relationship through reducing the extent of catastrophizing when feeling pain (moderated mediation). 664 community-dwelling Chinese older adults aged 60–95 years who reported chronic pain for at least three months were recruited from social centers. They completed a battery of questionnaires on chronic pain, pain self-efficacy, catastrophizing, and depressive symptoms in individual face-to-face interviews. Controlling for age, gender, education, self-rated health, number of chronic diseases, pain disability, and pain self-efficacy, pain catastrophizing was found to partially mediate the connection between pain intensity and depressive symptoms. Furthermore, the relationship between pain intensity and depressive symptoms was moderated by pain self-efficacy. Self-efficacy was also found to moderate the relationship between pain intensity and catastrophizing and the moderated mediation effect was confirmed using bootstrap analysis. The results suggested that with increasing levels of self-efficacy, pain intensity’s direct effect on depressive symptoms and its indirect effect on depressive symptoms via catastrophizing were both reduced in a dose-dependent manner. Our findings suggest that pain self-efficacy is a significant protective factor that contributes to psychological resilience in chronic pain patients by attenuating the relationship of pain intensity to both catastrophizing and depressive symptoms

Patterns and Collective Behavior in Granular Media: Theoretical Concepts

Granular materials are ubiquitous in our daily lives. While they have been a subject of intensive engineering research for centuries, in the last decade granular matter attracted significant attention of physicists. Yet despite a major efforts by many groups, the theoretical description of granular systems remains largely a plethora of different, often contradicting concepts and approaches. Authors give an overview of various theoretical models emerged in the physics of granular matter, with the focus on the onset of collective behavior and pattern formation. Their aim is two-fold: to identify general principles common for granular systems and other complex non-equilibrium systems, and to elucidate important distinctions between collective behavior in granular and continuum pattern-forming systems.Comment: Submitted to Reviews of Modern Physics. Full text with figures (2Mb pdf) avaliable at http://mti.msd.anl.gov/AransonTsimringReview/aranson_tsimring.pdf Community responce is appreciated. Comments/suggestions send to [email protected]

Comparative Effectiveness of Biosimilar, Reference Product and Other Erythropoiesis-Stimulating Agents (ESAs) Still Covered by Patent in Chronic Kidney Disease and Cancer Patients: An Italian Population-Based Study

Background Since 2007 biosimilars of erythropoiesis-stimulating agents (ESAs) are available on the Italian market. Very limited post-marketing data exist on the comparative effectiveness of biosimilar and originator ESAs. Aim This population-based study was aimed to compare the effects of biosimilars, reference product and other ESAs still covered by patent on hemoglobinemia in chronic kidney disease (CKD) and cancer patients in a Local Health Unit (LHU) from Northern Italy. Methods A retrospective cohort study was conducted during the years 2009-2014 using data from Treviso LHU administrative database. Incident ESA users (no ESA dispensing within 6 months prior to treatment start, i.e. index date (ID)) with at least one hemoglobin measurement within one month prior to ID (baseline Hb value) and another measurement between 2nd and 3rd month after ID (follow-up Hb value) were identified. The strength of the consumption (as total number of defined daily dose (DDD) dispensed during the follow-up divided by days of follow-up) and the difference between follow-up and baseline Hb values [delta Hb (ΔHb)] were evaluated. Based on Hb changes, ESA users were classified as non-responders (ΔHb≤0 g/dl), responders (0Delta;Hb≤2 g/dl), and highly responders (ΔHb>2 g/ dl). A multivariate ordinal logistic regression model to identify predictors for responsiveness to treatment was performed. All analyses were stratified by indication for use and type of dispensed ESA at ID. Results Overall, 1,003 incident ESA users (reference product: 252, 25.1%; other ESAs covered by patent: 303, 30.2%; biosimilars: 448, 44.7%) with CKD or cancer were eligible for the study. No statistically significant difference in the amount of dose dispensed during the follow-up among biosimilars, reference product and other ESAs covered by patent was found in both CKD and cancer. After three months from treatment start, all ESAs increased Hb values on average by 2g/dl. No differences in ΔHb as well as in frequency of non-responders, responders and highly responders among different types of ESAs were observed in both indications of use. Overall, around 15-20% of ESA users were non-responders. Strength of treatment, but no type of dispensed ESAs was found to be predictor of responsiveness to treatment. Conclusions No difference on the effects on hemoglobinemia among users of either biosimilars or reference product or ESAs covered by patent was observed in a general population from Northern Italy, despite a comparable dispensed dose of the different ESAs during the first three months of treatment

Src Dependent Pancreatic Acinar Injury Can Be Initiated Independent of an Increase in Cytosolic Calcium

Several deleterious intra-acinar phenomena are simultaneously triggered on initiating acute pancreatitis. These culminate in acinar injury or inflammatory mediator generation in vitro and parenchymal damage in vivo. Supraphysiologic caerulein is one such initiator which simultaneously activates numerous signaling pathways including non-receptor tyrosine kinases such as of the Src family. It also causes a sustained increase in cytosolic calcium- a player thought to be crucial in regulating deleterious phenomena. We have shown Src to be involved in caerulein induced actin remodeling, and caerulein induced changes in the Golgi and post-Golgi trafficking to be involved in trypsinogen activation, which initiates acinar cell injury. However, it remains unclear whether an increase in cytosolic calcium is necessary to initiate acinar injury or if injury can be initiated at basal cytosolic calcium levels by an alternate pathway. To study the interplay between tyrosine kinase signaling and calcium, we treated mouse pancreatic acinar cells with the tyrosine phosphatase inhibitor pervanadate. We studied the effect of the clinically used Src inhibitor Dasatinib (BMS-354825) on pervanadate or caerulein induced changes in Src activation, trypsinogen activation, cell injury, upstream cytosolic calcium, actin and Golgi morphology. Pervanadate, like supraphysiologic caerulein, induced Src activation, redistribution of the F-actin from its normal location in the sub-apical area to the basolateral areas, and caused antegrade fragmentation of the Golgi. These changes, like those induced by supraphysiologic caerulein, were associated with trypsinogen activation and acinar injury, all of which were prevented by Dasatinib. Interestingly, however, pervanadate did not cause an increase in cytosolic calcium, and the caerulein induced increase in cytosolic calcium was not affected by Dasatinib. These findings suggest that intra-acinar deleterious phenomena may be initiated independent of an increase in cytosolic calcium. Other players resulting in acinar injury along with the Src family of tyrosine kinases remain to be explored. © 2013 Mishra et al