IRE1 phosphatase PP2Ce regulates adaptive ER stress response in the postpartum mammary gland.

We recently reported that the PPM1l gene encodes an endoplasmic reticulum (ER) membrane targeted protein phosphatase (named PP2Ce) with highly specific activity towards Inositol-requiring protein-1 (IRE1) and regulates the functional outcome of ER stress. In the present report, we found that the PP2Ce protein is highly expressed in lactating epithelium of the mammary gland. Loss of PP2Ce in vivo impairs physiological unfolded protein response (UPR) and induces stress kinase activation, resulting in loss of milk production and induction of epithelial apoptosis in the lactating mammary gland. This study provides the first in vivo evidence that PP2Ce is an essential regulator of normal lactation, possibly involving IRE1 signaling and ER stress regulation in mammary epithelium

BRCA1 Forms a Functional Complex with γ-H2AX as a Late Response to Genotoxic Stress

Following genotoxic stress, the histone H2AX becomes phosphorylated at serine 139 by the ATM/ATR family of kinases. The tumor suppressor BRCA1, also phosphorylated by ATM/ATR kinases, is one of several proteins that colocalize with phospho-H2AX (γ-H2AX) at sites of active DNA repair. Both the precise mechanism and the purpose of BRCA1 recruitment to sites of DNA damage are unknown. Here we show that BRCA1 and γ-H2AX form an acid-stable biochemical complex on chromatin after DNA damage. Maximal association of BRCA1 with γ-H2AX correlates with reduced global γ-H2AX levels on chromatin late in the repair process. Since BRCA1 is known to have E3 ubiquitin ligase activity in vitro, we examined H2AX for evidence of ubiquitination. We found that H2AX is ubiquitinated at lysines 119 and 119 in vivo and that blockage of 26S proteasome function stabilizes γ-H2AX levels within cells. When BRCA1 levels were reduced, ubiquitination of H2AX was also reduced, and the cells retained higher levels of phosphorylated H2AX. These results indicate that BRCA1 is recruited into stable complexes with γ-H2AX and that the complex is involved in attenuation of the γ-H2AX repair signal after DNA damage

Halo globular clusters observed with AAOmega: dark matter content, metallicity and tidal heating

Globular clusters have proven to be essential to our understanding of many important astrophysical phenomena. Here we analyse spectroscopic observations of ten Halo globular clusters to determine their dark matter content, their tidal heating by the Galactic disc and halo, describe their metallicities and the likelihood that Newtonian dynamics explain their kinematics. We analyse a large number of members in all clusters, allowing us to address all these issues together, and we have included NGC 288 and M30 to overlap with previous studies. We find that any flattening of the velocity dispersion profiles in the outer regions of our clusters can be explained by tidal heating. We also find that all our GCs have M/L_V < 5, therefore, we infer the observed dynamics do not require dark matter, or a modification of gravity. We suggest that the lack of tidal heating signatures in distant clusters indicates the Halo is not triaxial. The isothermal rotations of each cluster are measured, with M4 and NGC 288 exhibiting rotation at a level of 0.9 +/- 0.1 km/s and 0.25 +/- 0.15 km/s, respectively. We also indirectly measure the tidal radius of NGC 6752, determining a more realistic figure for this cluster than current literature values. Lastly, an unresolved and intriguing puzzle is uncovered with regard to the cooling of the outer regions of all ten clusters.Comment: 12 pages, 8 figures, 1 table. Accepted for publication in MNRAS

Testing Newtonian Gravity with AAOmega: Mass-to-Light Profiles of Four Globular Clusters

Testing Newtonian gravity in the weak-acceleration regime is vital to our understanding of the nature of the gravitational interaction. It has recently been claimed that the velocity dispersion profiles of several globular clusters flatten out at large radii, reminiscent of galaxy rotation curves, even though globular clusters are thought to contain little or no dark matter. We investigate this claim, using AAOmega observations of four globular clusters, namely M22, M30, M53 and M68. M30, one such cluster that has had this claim made for its velocity dispersion, was included for comparison with previous studies. We find no statistically significant flattening of the velocity dispersion at large radii for any of our target clusters and therefore we infer the observed dynamics do not require that globular clusters are dark matter dominated, or a modification of gravity. Furthermore, by applying a simple dynamical model we determine the radial mass-to-light profiles for each cluster. The isothermal rotations of each cluster are also measured, with M22 exhibiting clear rotation, M68 possible rotation and M30 and M53 lacking any rotation, within the uncertainties.Comment: 7 pages, 4 figures and two tables. Accepted by MNRA

Type I Interferon Production Enhances Susceptibility to Listeria monocytogenes Infection

Numerous bacterial products such as lipopolysaccharide potently induce type I interferons (IFNs); however, the contribution of this innate response to host defense against bacterial infection remains unclear. Although mice deficient in either IFN regulatory factor (IRF)3 or the type I IFN receptor (IFNAR)1 are highly susceptible to viral infection, we show that these mice exhibit a profound resistance to infection caused by the Gram-positive intracellular bacterium Listeria monocytogenes compared with wild-type controls. Furthermore, this enhanced bacterial clearance is accompanied by a block in L. monocytogenes–induced splenic apoptosis in IRF3- and IFNAR1-deficient mice. Thus, our results highlight the disparate roles of type I IFNs during bacterial versus viral infections and stress the importance of proper IFN modulation in host defense

Testing Newtonian Gravity with AAOmega: Mass-To-Light Profiles and Metallicity Calibrations From 47 Tuc and M55

Globular clusters are an important test bed for Newtonian gravity in the weak-acceleration regime, which is vital to our understanding of the nature of the gravitational interaction. Recent claims have been made that the velocity dispersion profiles of globular clusters flatten out at large radii, despite an apparent paucity of dark matter in such objects, indicating the need for a modification of gravitational theories. We continue our investigation of this claim, with the largest spectral samples ever obtained of 47 Tucanae and M55. Furthermore, this large sample allows for an accurate metallicity calibration based on the equivalent widths of the calcium triplet lines and K band magnitude of the Tip of the Red Giant Branch. Assuming an isothermal distribution, the rotations of each cluster are also measured with both clusters exhibiting clear rotation signatures. The global velocity dispersions of NGC 121 and Kron 3, two globular clusters in the Small Magellanic Cloud, are also calculated. By applying a simple dynamical model to the velocity dispersion profiles of 47 Tuc and M55, we calculate their mass-to-light profiles, total masses and central velocity dispersions. We find no statistically significant flattening of the velocity dispersion at large radii for M55, and a marked increase in the profile of 47 Tuc for radii greater than approximately half the tidal radius. We interpret this increase as an evaporation signature, indicating that 47 Tuc is undergoing, or has undergone, core-collapse, but find no requirement for dark matter or a modification of gravitational theories in either cluster.Comment: 11 pages, 12 figures, 4 tables. Accepted by MNRA

Toll-like Receptors Induce a Phagocytic Gene Program through p38

Toll-like receptor (TLR) signaling and phagocytosis are hallmarks of macrophage-mediated innate immune responses to bacterial infection. However, the relationship between these two processes is not well established. Our data indicate that TLR ligands specifically promote bacterial phagocytosis, in both murine and human cells, through induction of a phagocytic gene program. Importantly, TLR-induced phagocytosis of bacteria was found to be reliant on myeloid differentiation factor 88–dependent signaling through interleukin-1 receptor–associated kinase-4 and p38 leading to the up-regulation of scavenger receptors. Interestingly, individual TLRs promote phagocytosis to varying degrees with TLR9 being the strongest and TLR3 being the weakest inducer of this process. We also demonstrate that TLR ligands not only amplify the percentage of phagocytes uptaking Escherichia coli, but also increase the number of bacteria phagocytosed by individual macrophages. Taken together, our data describe an evolutionarily conserved mechanism by which TLRs can specifically promote phagocytic clearance of bacteria during infection

Physiotherapy and occupational therapy vs no therapy in mild to moderate Parkinson disease: a randomized clinical trial

IMPORTANCE It is unclear whether physiotherapy and occupational therapy are clinically effective and cost-effective in Parkinson disease (PD). OBJECTIVE To perform a large pragmatic randomized clinical trial to evaluate the clinical effectiveness of individualized physiotherapy and occupational therapy in PD. DESIGN, SETTING, AND PARTICIPANTS The PD REHAB Trial was a multicenter, open-label, parallel group, controlled efficacy trial. A total of 762 patients with mild to moderate PD were recruited from 38 sites across the United Kingdom. Recruitment took place between October 2009 and June 2012, with 15 months of follow-up. INTERVENTIONS Participants with limitations in activities of daily living (ADL) were randomized to physiotherapy and occupational therapy or no therapy. MAIN OUTCOMES AND MEASURES The primary outcome was the Nottingham Extended Activities of Daily Living (NEADL) Scale score at 3 months after randomization. Secondary outcomes were health-related quality of life (assessed by Parkinson Disease Questionnaire–39 and EuroQol-5D); adverse events; and caregiver quality of life. Outcomes were assessed before trial entry and then 3, 9, and 15 months after randomization. RESULTS Of the 762 patients included in the study (mean [SD] age, 70 [9.1] years), 381 received physiotherapy and occupational therapy and 381 received no therapy. At 3 months, there was no difference between groups in NEADL total score (difference, 0.5 points; 95%CI, −0.7 to 1.7; P = .41) or Parkinson Disease Questionnaire–39 summary index (0.007 points; 95%CI, −1.5 to 1.5; P = .99). The EuroQol-5D quotient was of borderline significance in favor of therapy (−0.03; 95%CI, −0.07 to −0.002; P = .04). The median therapist contact time was 4 visits of 58 minutes over 8 weeks. Repeated-measures analysis showed no difference in NEADL total score, but Parkinson Disease Questionnaire–39 summary index (diverging 1.6 points per annum; 95%CI, 0.47 to 2.62; P = .005) and EuroQol-5D score (0.02; 95%CI, 0.00007 to 0.03; P = .04) showed small differences in favor of therapy. There was no difference in adverse events. CONCLUSIONS AND RELEVANCE Physiotherapy and occupational therapy were not associated with immediate or medium-term clinically meaningful improvements in ADL or quality of life in mild to moderate PD. This evidence does not support the use of low-dose, patient-centered, goal-directed physiotherapy and occupational therapy in patients in the early stages of PD. Future research should explore the development and testing of more structured and intensive physical and occupational therapy programs in patients with all stages of PD