How Preussag became TUI : kissing too many toads can make you a toad

In the period 1997-2004, Preussag, a diversified German conglomerate of old economy businesses, changed itself into TUI, a company focused almost entirely on tourism and logistics. This paper analyzes how this strategy was executed and how it contributed to Preussag’s underperformance of the stock market. We collect 417 announcements of acquisitions, financial disclosures and other news and disentangle the impact of different parts of the company’s strategy. We find that only the divestitures created value, that the strategy to invest in tourism destroyed value, and that the acquisition premiums Preussag paid were mostly unjustified. Bad luck like the events of September 11, 2001 cannot account for the poor performance of the stock. Poor management resulted from poor governance, combining a state-owned bank as the largest shareholder, board interlocks, and insufficient managerial incentives. The case shows how divestiture programs increase the liquid resources available to management beyond free operating cash flows and casts doubt on the positive governance role of institutional blockholders

Renormalisation of heavy-light light ray operators

We calculate the renormalisation of different light ray operators with one light degree of freedom and a static heavy quark. Both $2\to2$- and $2\to3$-kernels are considered. A comparison with the light-light case suggests that the mixing with three-particle operators is solely governed by the light degrees of freedom. Additionally we show that conformal symmetry is already broken at the level of the one loop counterterms due to the additional UV-renormalisation of a cusp in the two contributing Wilson-lines. This general feature can be used to fix the $2\to2$-renormalisation kernels up to a constant. Some examples for applications of our results are given.Comment: 23 pages, 5 figures; v2: changed some wording, added a few references and one appendix concerning some subtleties related to gauge fixing and ghost terms; v3: clarified calculation in section 3.2., added an explicit calculation in section 5.2, corrected a few typos and one figure, added a few comments, results unchanged, except for typesetting matches version to appear in JHE

Absence of system xc⁻ on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis

Background: Multiple sclerosis (MS) is an autoimmune demyelinating disease that affects the central nervous system (CNS), leading to neurodegeneration and chronic disability. Accumulating evidence points to a key role for neuroinflammation, oxidative stress, and excitotoxicity in this degenerative process. System x(c)- or the cystine/glutamate antiporter could tie these pathological mechanisms together: its activity is enhanced by reactive oxygen species and inflammatory stimuli, and its enhancement might lead to the release of toxic amounts of glutamate, thereby triggering excitotoxicity and neurodegeneration. Methods: Semi-quantitative Western blotting served to study protein expression of xCT, the specific subunit of system x(c)-, as well as of regulators of xCT transcription, in the normal appearing white matter (NAWM) of MS patients and in the CNS and spleen of mice exposed to experimental autoimmune encephalomyelitis (EAE), an accepted mouse model of MS. We next compared the clinical course of the EAE disease, the extent of demyelination, the infiltration of immune cells and microglial activation in xCT-knockout (xCT(-/-)) mice and irradiated mice reconstituted in xCT(-/-) bone marrow (BM), to their proper wild type (xCT(+/+)) controls. Results: xCT protein expression levels were upregulated in the NAWM of MS patients and in the brain, spinal cord, and spleen of EAE mice. The pathways involved in this upregulation in NAWM of MS patients remain unresolved. Compared to xCT(+/+) mice, xCT(-/-) mice were equally susceptible to EAE, whereas mice transplanted with xCT(-/-) BM, and as such only exhibiting loss of xCT in their immune cells, were less susceptible to EAE. In none of the above-described conditions, demyelination, microglial activation, or infiltration of immune cells were affected. Conclusions: Our findings demonstrate enhancement of xCT protein expression in MS pathology and suggest that system x(c)- on immune cells invading the CNS participates to EAE. Since a total loss of system x(c)- had no net beneficial effects, these results have important implications for targeting system x(c)- for treatment of MS

Carba-Cyclophellitols are Neutral Retaining Glucosidase Inhibitors

The conformational analysis of glycosidases affords a route to their specific inhibition through transition-state mimicry. Inspired by the rapid reaction rates of cyclophellitol and cyclophellitol aziridineboth covalent retaining β-glucosidase inhibitorswe postulated that the corresponding carba “cyclopropyl” analogue would be a potent retaining β-glucosidase inhibitor for those enzymes reacting through the ⁴H₃ transition-state conformation. <i>Ab initio</i> metadynamics simulations of the conformational free energy landscape for the cyclopropyl inhibitors show a strong bias for the ⁴H₃ conformation, and carba-cyclophellitol, with an <i>N</i>-(4-azidobutyl)­carboxamide moiety, proved to be a potent inhibitor (<i>K</i>_i = 8.2 nM) of the <i>Thermotoga maritima</i> <i>Tm</i>GH1 β-glucosidase. 3-D structural analysis and comparison with unreacted epoxides show that this compound indeed binds in the ⁴H₃ conformation, suggesting that conformational strain induced through a cyclopropyl unit may add to the armory of tight-binding inhibitor designs

Light induced single molecule frequency shift

Alight induced frequency shift of the 0-0 line was measured in two-photon excitation spectra of single diphenyloctatetraene molecules doped in a crystal matrix. The shifts were proportional to the laser power with a slope of about 600 MHz/W when the laser beam of about 300 mW power was focused to a diameter of 2 mu m. Significantly, the observed line broadenings were an order of magnitude smaller than the shifts. The effect is ascribed mainly to a ''fast'' energy exchange between a local vibration and thermal phonons created by the third harmonic C-H band absorption in the matrix, and partially to an ac Stark shift

Design, Synthesis and Structural Analysis of Glucocerebrosidase Imaging Agents

Gaucher disease (GD) is a lysosomal storage disorder caused by inherited deficiencies in β-glucocerebrosidase (GBA). Current treatments require rapid disease diagnosis and a means of monitoring therapeutic efficacy, both of which may be supported by the use of GBA-targeting activity-based probes (ABPs). Here, we report the synthesis and structural analysis of a range of cyclophellitol epoxide and aziridine inhibitors and ABPs for GBA. We demonstrate their covalent mechanism-based mode of action and uncover binding of the new N- functionalised aziridines to the ligand binding cleft. These inhibitors became scaffolds for the development of ABPs; the O6-fluorescent tags of which bind in an allosteric site at the dimer interface. Considering GBA’s preference for O6- and N -functionalised reagents, we synthesised a bi-functional aziridine ABP which we hoped would offer a more powerful imaging agent. Whilst this ABP binds to two unique active site clefts of GBA, no further benefit in potency was achieved over our first generation ABPs. Nevertheless, such ABPs should serve useful in the study of GBA in relation to GD and inform the design of future probes

Impact of Treadmill Running and Sex on Hippocampal Neurogenesis in the Mouse Model of Amyotrophic Lateral Sclerosis

Hippocampal neurogenesis in the subgranular zone (SGZ) of dentate gyrus (DG) occurs throughout life and is regulated by pathological and physiological processes. The role of oxidative stress in hippocampal neurogenesis and its response to exercise or neurodegenerative diseases remains controversial. The present study was designed to investigate the impact of oxidative stress, treadmill exercise and sex on hippocampal neurogenesis in a murine model of heightened oxidative stress (G93A mice). G93A and wild type (WT) mice were randomized to a treadmill running (EX) or a sedentary (SED) group for 1 or 4 wk. Immunohistochemistry was used to detect bromodeoxyuridine (BrdU) labeled proliferating cells, surviving cells, and their phenotype, as well as for determination of oxidative stress (3-NT; 8-OHdG). BDNF and IGF1 mRNA expression was assessed by in situ hybridization. Results showed that: (1) G93A-SED mice had greater hippocampal neurogenesis, BDNF mRNA, and 3-NT, as compared to WT-SED mice. (2) Treadmill running promoted hippocampal neurogenesis and BDNF mRNA content and lowered DNA oxidative damage (8-OHdG) in WT mice. (3) Male G93A mice showed significantly higher cell proliferation but a lower level of survival vs. female G93A mice. We conclude that G93A mice show higher hippocampal neurogenesis, in association with higher BDNF expression, yet running did not further enhance these phenomena in G93A mice, probably due to a ‘ceiling effect’ of an already heightened basal levels of hippocampal neurogenesis and BDNF expression

Alcohol, tobacco and illicit drug use amongst same-sex attracted women: results from the Western Australian Lesbian and Bisexual Women's Health and Well-Being Survey

Background: The prevalence of alcohol, tobacco and illicit drug use has been reported to be higheramongst lesbian and bisexual women (LBW) than their heterosexual counterparts. However, few studieshave been conducted with this population in Australia and rates that have been reported vary considerably.Methods: A self-completed questionnaire exploring a range of health issues was administered to 917women aged 15-65 years (median 34 years) living in Western Australia, who identified as lesbian orbisexual, or reported having sex with another woman. Participants were recruited from a range of settings,including Perth Pride Festival events (67.0%, n = 615), online (13.2%, n = 121), at gay bars and nightclubs(12.9%, n = 118), and through community groups (6.9%, n = 63). Results were compared against availablestate and national surveillance data.Results: LBW reported consuming alcohol more frequently and in greater quantities than women in thegeneral population. A quarter of LBW (25.7%, n = 236) exceeded national alcohol guidelines by consumingmore than four standard drinks on a single occasion, once a week or more. However, only 6.8% (n = 62)described themselves as a heavy drinker, suggesting that exceeding national alcohol guidelines may be anormalised behaviour amongst LBW. Of the 876 women who provided data on tobacco use, 28.1% (n =246) were smokers, nearly double the rate in the female population as a whole. One third of the sample(33.6%, n = 308) reported use of an illicit drug in the previous six months. The illicit drugs most commonlyreported were cannabis (26.4%, n = 242), meth/amphetamine (18.6%, n = 171), and ecstasy (17.9%, n =164). Injecting drug use was reported by 3.5% (n = 32) of participants.Conclusion: LBW appear to use alcohol, tobacco and illicit drugs at higher rates than women generally,indicating that mainstream health promotion messages are not reaching this group or are not perceivedas relevant. There is an urgent need for public health practitioners working in the area of substance useto recognise that drug consumption and use patterns of LBW are likely to be different to the widerpopulation and that special considerations and strategies are required to address the unique and complexneeds of this population

A Cross-Study Transcriptional Analysis of Parkinson's Disease

The study of Parkinson's disease (PD), like other complex neurodegenerative disorders, is limited by access to brain tissue from patients with a confirmed diagnosis. Alternatively the study of peripheral tissues may offer some insight into the molecular basis of disease susceptibility and progression, but this approach still relies on brain tissue to benchmark relevant molecular changes against. Several studies have reported whole-genome expression profiling in post-mortem brain but reported concordance between these analyses is lacking. Here we apply a standardised pathway analysis to seven independent case-control studies, and demonstrate increased concordance between data sets. Moreover data convergence increased when the analysis was limited to the five substantia nigra (SN) data sets; this highlighted the down regulation of dopamine receptor signaling and insulin-like growth factor 1 (IGF1) signaling pathways. We also show that case-control comparisons of affected post mortem brain tissue are more likely to reflect terminal cytoarchitectural differences rather than primary pathogenic mechanisms. The implementation of a correction factor for dopaminergic neuronal loss predictably resulted in the loss of significance of the dopamine signaling pathway while axon guidance pathways increased in significance. Interestingly the IGF1 signaling pathway was also over-represented when data from non-SN areas, unaffected or only terminally affected in PD, were considered. Our findings suggest that there is greater concordance in PD whole-genome expression profiling when standardised pathway membership rather than ranked gene list is used for comparison

Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid: a pragmatic non-inferiority randomised controlled trial

Background: Bullous pemphigoid (BP) is a blistering skin disorder with increased mortality. We tested whether a strategy of starting treatment with doxycycline conveys acceptable short-term blister control whilst conferring long-term safety advantages over starting treatment with oral corticosteroids. Methods: Pragmatic multi-centre parallel-group randomised controlled trial of adults with BP (≥3 blisters ≥2 sites and linear basement membrane IgG/C3) plus economic evaluation. Participants were randomised to doxycycline (200 mg/day) or prednisolone (0·5 mg/kg/day). Localised adjuvant potent topical corticosteroids (<30 g/week) was permitted weeks 1-3. The non-inferiority primary effectiveness outcome was the proportion of participants with ≤3 blisters at 6 weeks. We assumed that doxycycline would be 25% less effective than corticosteroids with a 37% acceptable margin of noninferiority. The primary safety outcome was the proportion with severe, life-threatening or fatal treatment-related adverse events by 52 weeks. Analysis used a regression model adjusting for baseline disease severity, age and Karnofsky score, with missing data imputed. Results: 132 patients were randomised to doxycycline and 121 to prednisolone from 54 UK and 7 German dermatology centres. Mean age was 77·7 years and 68.4% had moderate to severe baseline disease. For those starting doxycycline, 83/112 (74·1%) had ≤3 blisters at 6 weeks compared with 92/101 (91·1%) for prednisolone, a difference of 18·6% favouring prednisolone (upper limit of 90% CI, 26·1%, within the predefined 37% margin). Related severe, life-threatening and fatal events at 52 weeks were 18·5% for those starting doxycycline and 36·6% for prednisolone (mITT analysis), an adjusted difference of 19·0% (95% CI, 7·9%, 30·1%, p=0·001). Conclusions: A strategy of starting BP patients on doxycycline is non-inferior to standard treatment with oral prednisolone for short-term blister control and significantly safer long-term