Economics of Post Office Networks: Strategic Issues and the Impact on Mail Demand

The paper analyzes recent restructurings of post office networks. Based on these findings an on a time-series estimation of the impact of Swiss Post’s recent realignment of its network on overall mail demand we derive three generic strategies for the long term alignment of Post office networks.post office network, restructuring, mail demand

Retrograde transport of CDMPR depends on several machineries as analyzed by sulfatable nanobodies

Retrograde protein transport from the cell surface and endosomes to the TGN is essential for membrane homeostasis in general and for the recycling of mannose-6-phosphate receptors (MPRs) for sorting of lysosomal hydrolases in particular. We used a nanobody-based sulfation tool to more directly determine transport kinetics from the plasma membrane to the TGN for the cation-dependent MPR (CDMPR) with and without rapid or gradual inactivation of candidate machinery proteins. Although knockdown of retromer (Vps26), epsinR, or Rab9a reduced CDMPR arrival to the TGN, no effect was observed upon silencing of TIP47. Strikingly, when retrograde transport was analyzed by rapamycin-induced rapid depletion (knocksideways) or long-term depletion by knockdown of the clathrin adaptor AP-1 or of the GGA machinery, distinct phenotypes in sulfation kinetics were observed, suggesting a potential role of GGA adaptors in retrograde and anterograde transport. Our study illustrates the usefulness of derivatized, sulfation-competent nanobodies, reveals novel insights into CDMPR trafficking biology, and further outlines that the selection of machinery inactivation is critical for phenotype analysis

Rabaptin5 is recruited to endosomes by Rab4 and Rabex5 to regulate endosome maturation

Rab GTPases control membrane identity, fusion, and transport by interaction with effector proteins. Effectors that influence the activation/inactivation cycle of their own or other Rabs contribute to the timely conversion of Rab identities. Rab5 and its effector Rabaptin5 are generally considered the prime example for a positive feedback loop in which Rab5·GTP recruits Rabaptin5 complexed to Rabex5, the GDP/GTP exchange factor of Rab5, to early endosomes, thus maintaining the membrane's Rab5 identity. By deletion analysis, we found membrane recruitment of Rabaptin5 to require binding to Rab4 and Rabex5, but not Rab5. Deletion of either one of two Rab5 binding domains or silencing of Rab5 expression did not affect Rabaptin5 recruitment, but produced giant endosomes with early and late endosomal characteristics. The results contradict feedback activation of Rab5 and instead indicate that Rabaptin5 is recruited by Rabex5 recognizing ubiquitinated cargo and by Rab4 to activate Rab5 in a feed-forward manner

Quantity of HLA-C surface expression and licensing of KIR2DL+ natural killer cells

Natural killer (NK) cells require interaction of inhibitory surface receptors with human leukocyte antigen (HLA) ligands during development to acquire functional competence in a process termed "licensing.” The quantity of HLA required for this process is unknown. Two polymorphisms affecting HLA-C surface expression (rs9264942 and rs67384697) have recently been identified, and shown to influence progression of HIV infection. We typed a cohort of healthy donors for the two HLA-C-related polymorphisms, KIR2DL1 and KIR2DL3, and their respective HLA-C ligands and analyzed how HLA ligands influenced licensing status of killer cell immunoglobulin-like receptor (KIR)+ NK cells in terms of degranulation and cytokine production in response to HLA-deficient target cells. The presence of respective HLA class I ligands increased the function of KIR2DL1+ and KIR2DL3+ NK cells in a dose-dependent manner. In contrast, neither of the HLA-C-related polymorphisms nor the quantity of cell surface HLA-C had any significant effect on NK cell function. Interestingly, HLA-Cw7—an HLA-C allele with low surface expression—licensed KIR2DL3+ NK cells more strongly than any other KIR2DL3 ligand. The quantity of cell surface HLA-C does not appear to influence licensing of NK cells, and the HLA-C-related polymorphisms presumably influence HIV progression through factors unrelated to NK cell educatio

Ticagrelor induced systemic inflammatory response syndrome.

BACKGROUND Ticagrelor is a reversible and direct-acting oral antagonist of the adenosine diphosphate receptor P2Y12. Possible adenosine-mediated effects of ticagrelor on inflammation are complex and incompletely understood. To our knowledge, ticagrelor-induced systemic inflammatory response syndrome (SIRS) has not yet been described. CASE PRESENTATION We report the case of an 84 years old patient presenting with SIRS subsequent to initiation of ticagrelor after implantation of two drug eluting stents. A broad diagnostic work-up for alternative causes and therapeutic measures were unrevealing. Discontinuation of the agent was followed by rapid improvement in clinical and laboratory signs of SIRS. CONCLUSIONS After exclusion of other causes, ticagrelor needs to be considered as a possible causative agent for SIRS. Due to the widespread use of ticagrelor, clinicians should be aware of this possible adverse drug reaction

Head Coverings in the Courtroom: A Question of Respect for the Judge or of Judicial Tolerance?

The Human Rights Centre at Ghent University (the HRC) first initiated the present research while preparing an amicus curiae brief in the Lachiri v. Belgium case before the European Court of Human Rights (ECtHR). The applicant in Lachiri, who was a civil party in legal proceedings concerning the murder of her brother, was denied access to a Brussels courtroom after refusing to remove her Islamic headscarf . Ms. Lachiri’s admission was refused in reliance on Article 759 of the Belgian Judicial Code (Gerechtelijk Wetboek/ Code Judiciaire), which provides that “[t]he audience will attend the sessions with their heads uncovered, respectfully and silently; whatever the judge commands for the maintenance of order will be punctually and immediately executed.” In its third-party intervention, the HRC sought to supply the ECtHR with additional information concerning three points: the debate on the wearing of Islamic headscarves in Belgium, the history, object and purpose of Article 759 of the Belgian Judicial Code, and the scope of the State margin of appreciation in prohibiting religious items of clothing

Dynamical Mass Constraints on Low-Mass Pre-Main-Sequence Stellar Evolutionary Tracks: An Eclipsing Binary in Orion with a 1.0 Msun Primary and an 0.7 Msun Secondary

We report the discovery of a double-lined, spectroscopic, eclipsing binary in the Orion star-forming region. We analyze the system spectroscopically and photometrically to empirically determine precise, distance-independent masses, radii, effective temperatures, and luminosities for both components. The measured masses for the primary and secondary, accurate to ~1%, are 1.01 Msun and 0.73 Msun, respectively; thus the primary is a definitive pre-main-sequence solar analog, and the secondary is the lowest-mass star yet discovered among pre-main-sequence eclipsing binary systems. We use these fundamental measurements to test the predictions of pre-main-sequence stellar evolutionary tracks. None of the models we examined correctly predict the masses of the two components simultaneously, and we implicate differences between the theoretical and empirical effective temperature scales for this failing. All of the models predict the observed slope of the mass-radius relationship reasonably well, though the observations tend to favor models with low convection efficiencies. Indeed, considering our newly determined mass measurements together with other dynamical mass measurements of pre-main-sequence stars in the literature, as well as measurements of Li abundances in these stars, we show that the data strongly favor evolutionary models with inefficient convection in the stellar interior, even though such models cannot reproduce the properties of the present-day Sun.Comment: Accepted by Ap

Aplastic anemia and concomitant autoimmune diseases

The association of aplastic anemia (AA) with other autoimmune diseases (AID) has been described but so far not systematically evaluated. We assessed the incidence and the outcome of concomitant AID in a retrospective, single-center study of 243 patients with severe AA treated between 1974 and 2006 with either immunosuppression (186) or hematopoietic stem cell transplantation (57) and a median follow-up time of 9.3years (0-33). Clinically manifest AID were observed in 24 out of 243 (10 ± 3.7%) patients. Age at diagnosis of AA was significantly younger in patients without AID compared to patients with AID (median, 20 versus 52years; P < 0.001). In 12 patients where the diagnosis of AID was done before AA therapy, response to antithymocyte globulin was good for AA (ten out of 12) but not for AID (2 out of 12). In 13 patients in which AID occurred after first-line therapy, the median time to the AID was 7years (range 3months-27.5years