Cylindrical equilibrium shapes of fluid membranes

Within the framework of the well-known curvature models, a fluid lipid bilayer membrane is regarded as a surface embedded in the three-dimensional Euclidean space whose equilibrium shapes are described in terms of its mean and Gaussian curvatures by the so-called membrane shape equation. In the present paper, all solutions to this equation determining cylindrical membrane shapes are found and presented, together with the expressions for the corresponding position vectors, in explicit analytic form. The necessary and sufficient conditions for such a surface to be closed are derived and several sufficient conditions for its directrix to be simple or self-intersecting are given.Comment: 17 pages, 4 figures. Published in J. Phys. A: Math. Theore

Section on Prospects for Dark Matter Detection of the White Paper on the Status and Future of Ground-Based TeV Gamma-Ray Astronomy

This is a report on the findings of the dark matter science working group for the white paper on the status and future of TeV gamma-ray astronomy. The white paper was commissioned by the American Physical Society, and the full white paper can be found on astro-ph (arXiv:0810.0444). This detailed section discusses the prospects for dark matter detection with future gamma-ray experiments, and the complementarity of gamma-ray measurements with other indirect, direct or accelerator-based searches. We conclude that any comprehensive search for dark matter should include gamma-ray observations, both to identify the dark matter particle (through the charac- teristics of the gamma-ray spectrum) and to measure the distribution of dark matter in galactic halos.Comment: Report from the Dark Matter Science Working group of the APS commissioned White paper on ground-based TeV gamma ray astronomy (19 pages, 9 figures

Research protocol: investigating the feasibility of a group self-management intervention for stroke (the GUSTO study)

Background: Life after stroke can be an ongoing struggle with over half of all survivors reporting unmet emotional and social needs. In the United Kingdom's (UK) national clinical guidelines for stroke, self-management is suggested as one approach which can support long-term needs. In the UK NHS, self-management interventions are delivered in various ways. Regardless of the delivery mechanism, a tailored approach and ways to integrate peer support are advocated. Group delivery offers a platform for peer support and has the potential to remain individualised. However, before the efficacy of a group self-management intervention can be tested, the feasibility must be explored. This research investigates the feasibility of a GroUp Self-management intervention for sTrOke (GUSTO). Methods: A randomised waitlist control design will be used to investigate the feasibility of a group self-management intervention adapted from an existing one-to-one intervention called Bridges. A mixed methods approach will be used. Qualitative work will capture participant experience, while quantitative work will allow preliminary comparison between the intervention and waitlist groups (between subjects) and pre-post intervention measures (within subjects). Interviews will be conducted with stroke survivors and focus groups with family and friends to assess acceptability of the intervention. Discussion: There is a growing interest in group-based self-management interventions for stroke as a method of supporting stroke survivors' ongoing unmet needs. This is an area with limited research to date. This study will inform design of a fully powered trial which would assess the efficacy of a group self-management intervention following stroke. Trial registration: ISRCTN19867168

A p53-independent role for the MDM2 antagonist Nutlin-3 in DNA damage response initiation.

BACKGROUND: The mammalian DNA-damage response (DDR) has evolved to protect genome stability and maximize cell survival following DNA-damage. One of the key regulators of the DDR is p53, itself tightly regulated by MDM2. Following double-strand DNA breaks (DSBs), mediators including ATM are recruited to the site of DNA-damage. Subsequent phosphorylation of p53 by ATM and ATM-induced CHK2 results in p53 stabilization, ultimately intensifying transcription of p53-responsive genes involved in DNA repair, cell-cycle checkpoint control and apoptosis. METHODS: In the current study, we investigated the stabilization and activation of p53 and associated DDR proteins in response to treatment of human colorectal cancer cells (HCT116p53+/+) with the MDM2 antagonist, Nutlin-3. RESULTS: Using immunoblotting, Nutlin-3 was observed to stabilize p53, and activate p53 target proteins. Unexpectedly, Nutlin-3 also mediated phosphorylation of p53 at key DNA-damage-specific serine residues (Ser15, 20 and 37). Furthermore, Nutlin-3 induced activation of CHK2 and ATM - proteins required for DNA-damage-dependent phosphorylation and activation of p53, and the phosphorylation of BRCA1 and H2AX - proteins known to be activated specifically in response to DNA damage. Indeed, using immunofluorescent labeling, Nutlin-3 was seen to induce formation of γH2AX foci, an early hallmark of the DDR. Moreover, Nutlin-3 induced phosphorylation of key DDR proteins, initiated cell cycle arrest and led to formation of γH2AX foci in cells lacking p53, whilst γH2AX foci were also noted in MDM2-deficient cells. CONCLUSION: To our knowledge, this is the first solid evidence showing a secondary role for Nutlin-3 as a DDR triggering agent, independent of p53 status, and unrelated to its role as an MDM2 antagonist

Squeezed between shells? On the origin of the Lupus I molecular cloud. - II. APEX CO and GASS HI observations

Accepted for publication in a future issue of Astronomy & Astrophysics. Reproduced with permission from Astronomy & Astrophysics. © 2018 ESO.Context. The Lupus I cloud is found between the Upper-Scorpius (USco) and the Upper-Centaurus-Lupus (UCL) sub-groups of the Scorpius-Centaurus OB-association, where the expanding USco H I shell appears to interact with a bubble currently driven by the winds of the remaining B-stars of UCL. Aims. We investigate if the Lupus I molecular could have formed in a colliding flow, and in particular, how the kinematics of the cloud might have been influenced by the larger scale gas dynamics. Methods. We performed APEX 13CO(2–1) and C 18O(2–1) line observations of three distinct parts of Lupus I that provide kinematic information on the cloud at high angular and spectral resolution. We compare those results to the atomic hydrogen data from the GASS H i survey and our dust emission results presented in the previous paper. Based on the velocity information, we present a geometric model for the interaction zone between the USco shell and the UCL wind bubble. Results. We present evidence that the molecular gas of Lupus I is tightly linked to the atomic material of the USco shell. The CO emission in Lupus I is found mainly at velocities between vLSR = 3–6 km s−1 which is in the same range as the H i velocities. Thus, the molecular cloud is co-moving with the expanding USco atomic H i shell. The gas in the cloud shows a complex kinematic structure with several line-of-sight components that overlay each other. The non-thermal velocity dispersion is in the transonic regime in all parts of the cloud and could be injected by external compression. Our observations and the derived geometric model agree with a scenario where Lupus I is located in the interaction zone between the USco shell and the UCL wind bubble. Conclusions. The kinematics observations are consistent with a scenario where the Lupus I cloud formed via shell instabilities. The particular location of Lupus I between USco and UCL suggests that counter-pressure from the UCL wind bubble and pre-existing density enhancements, perhaps left over from the gas stream that formed the stellar subgroups, may have played a role in its formation.Peer reviewedFinal Accepted Versio

Potential of the Julia programming language for high energy physics computing

Research in high energy physics (HEP) requires huge amounts of computing and storage, putting strong constraints on the code speed and resource usage. To meet these requirements, a compiled high-performance language is typically used; while for physicists, who focus on the application when developing the code, better research productivity pleads for a high-level programming language. A popular approach consists of combining Python, used for the high-level interface, and C++, used for the computing intensive part of the code. A more convenient and efficient approach would be to use a language that provides both high-level programming and high-performance. The Julia programming language, developed at MIT especially to allow the use of a single language in research activities, has followed this path. In this paper the applicability of using the Julia language for HEP research is explored, covering the different aspects that are important for HEP code development: runtime performance, handling of large projects, interface with legacy code, distributed computing, training, and ease of programming. The study shows that the HEP community would benefit from a large scale adoption of this programming language. The HEP-specific foundation libraries that would need to be consolidated are identifiedComment: 32 pages, 5 figures, 4 table

The degradation of p53 and its major E3 ligase Mdm2 is differentially dependent on the proteasomal ubiquitin receptor S5a.

p53 and its major E3 ligase Mdm2 are both ubiquitinated and targeted to the proteasome for degradation. Despite the importance of this in regulating the p53 pathway, little is known about the mechanisms of proteasomal recognition of ubiquitinated p53 and Mdm2. In this study, we show that knockdown of the proteasomal ubiquitin receptor S5a/PSMD4/Rpn10 inhibits p53 protein degradation and results in the accumulation of ubiquitinated p53. Overexpression of a dominant-negative deletion of S5a lacking its ubiquitin-interacting motifs (UIM)s, but which can be incorporated into the proteasome, also causes the stabilization of p53. Furthermore, small-interferring RNA (siRNA) rescue experiments confirm that the UIMs of S5a are required for the maintenance of low p53 levels. These observations indicate that S5a participates in the recognition of ubiquitinated p53 by the proteasome. In contrast, targeting S5a has no effect on the rate of degradation of Mdm2, indicating that proteasomal recognition of Mdm2 can be mediated by an S5a-independent pathway. S5a knockdown results in an increase in the transcriptional activity of p53. The selective stabilization of p53 and not Mdm2 provides a mechanism for p53 activation. Depletion of S5a causes a p53-dependent decrease in cell proliferation, demonstrating that p53 can have a dominant role in the response to targeting S5a. This study provides evidence for alternative pathways of proteasomal recognition of p53 and Mdm2. Differences in recognition by the proteasome could provide a means to modulate the relative stability of p53 and Mdm2 in response to cellular signals. In addition, they could be exploited for p53-activating therapies. This work shows that the degradation of proteins by the proteasome can be selectively dependent on S5a in human cells, and that this selectivity can extend to an E3 ubiquitin ligase and its substrate

MAGE-A cancer/testis antigens inhibit MDM2 ubiquitylation function and promote increased levels of MDM4

Melanoma antigen A (MAGE-A) proteins comprise a structurally and biochemically similar sub-family of Cancer/Testis antigens that are expressed in many cancer types and are thought to contribute actively to malignancy. MAGE-A proteins are established regulators of certain cancer-associated transcription factors, including p53, and are activators of several RING finger-dependent ubiquitin E3 ligases. Here, we show that MAGE-A2 associates with MDM2, a ubiquitin E3 ligase that mediates ubiquitylation of more than 20 substrates including mainly p53, MDM2 itself, and MDM4, a potent p53 inhibitor and MDM2 partner that is structurally related to MDM2. We find that MAGE-A2 interacts with MDM2 via the N-terminal p53-binding pocket and the RING finger domain of MDM2 that is required for homo/hetero-dimerization and for E2 ligase interaction. Consistent with these data, we show that MAGE-A2 is a potent inhibitor of the E3 ubiquitin ligase activity of MDM2, yet it does not have any significant effect on p53 turnover mediated by MDM2. Strikingly, however, increased MAGE-A2 expression leads to reduced ubiquitylation and increased levels of MDM4. Similarly, silencing of endogenous MAGE-A expression diminishes MDM4 levels in a manner that can be rescued by the proteasomal inhibitor, bortezomid, and permits increased MDM2/MDM4 association. These data suggest that MAGE-A proteins can: (i) uncouple the ubiquitin ligase and degradation functions of MDM2; (ii) act as potent inhibitors of E3 ligase function; and (iii) regulate the turnover of MDM4. We also find an association between the presence of MAGE-A and increased MDM4 levels in primary breast cancer, suggesting that MAGE-A-dependent control of MDM4 levels has relevance to cancer clinically