Finance fragmented? Frankfurt and Paris as European financial centres after Brexit

Brexit creates an opportunity for alternative European financial centres. However, no comprehensive empirical analysis of the strategic positioning of actors within these financial centres has been conducted. In this article we outline findings from an extensive research project which we conducted in Frankfurt and Paris, two of the main ‘rivals’ to the City of London, in the aftermath of Brexit. We outline the core findings from this project and argue that the emerging competition between Frankfurt and Paris is shaped through four related axes: diversity, path dependency, territory and regulatory stability. Our analysis has implications for two bodies of literature within EU studies. First, inter-governmentalist and supra-nationalist approaches would benefit from interrogating more closely the contested sub-national politics of financial centres. Second, our analysis adds to a growing body of literature on European disintegration by interrogating the interaction of fragmentary and integrative dynamics in the sphere of European finance

A PWWP Domain-Containing Protein Targets the NuA3 Acetyltransferase Complex via Histone H3 Lysine 36 trimethylation to Coordinate Transcriptional Elongation at Coding Regions

Post-translational modifications of histones, such as acetylation and methylation, are differentially positioned in chromatin with respect to gene organization. For example, although histone H3 is often trimethylated on lysine 4 (H3K4me3) and acetylated on lysine 14 (H3K14ac) at active promoter regions, histone H3 lysine 36 trimethylation (H3K36me3) occurs throughout the open reading frames of transcriptionally active genes. The conserved yeast histone acetyltransferase complex, NuA3, specifically binds H3K4me3 through a plant homeodomain (PHD) finger in the Yng1 subunit, and subsequently catalyzes the acetylation of H3K14 through the histone acetyltransferase domain of Sas3, leading to transcription initiation at a subset of genes. We previously found that Ylr455w (Pdp3), an uncharacterized proline-tryptophan-tryptophan-proline (PWWP) domain-containing protein, copurifies with stable members of NuA3. Here, we employ mass-spectrometric analysis of affinity purified Pdp3, biophysical binding assays, and genetic analyses to classify NuA3 into two functionally distinct forms: NuA3a and NuA3b. Although NuA3a uses the PHD finger of Yng1 to interact with H3K4me3 at the 5′-end of open reading frames, NuA3b contains the unique member, Pdp3, which regulates an interaction between NuA3b and H3K36me3 at the transcribed regions of genes through its PWWP domain. We find that deletion of PDP3 decreases NuA3-directed transcription and results in growth defects when combined with transcription elongation mutants, suggesting NuA3b acts as a positive elongation factor. Finally, we determine that NuA3a, but not NuA3b, is synthetically lethal in combination with a deletion of the histone acetyltransferase GCN5, indicating NuA3b has a specialized role at coding regions that is independent of Gcn5 activity. Collectively, these studies define a new form of the NuA3 complex that associates with H3K36me3 to effect transcriptional elongation. MS data are available via ProteomeXchange with identifier PXD001156

Angiotensin II potentiates α-adrenergic vasoconstriction in the elderly

Abstract Aging is characterized by increased sympatho-excitation, expressed through both the α-adrenergic and RAAS (renin-angiotensin-aldosterone) pathways. Although the independent contribution of these two pathways to elevated vasoconstriction with age may be substantial, significant cross-talk exists that could produce potentiating effects. To examine this interaction, 14 subjects (n = 8 young, n = 6 old) underwent brachial artery catheterization for administration of AngII (angiotensin II; 0.8-25.6 ng/dl per min), NE [noradrenaline (norepinephrine); 2.5-80 ng/dl per min] and AngII with concomitant α-adrenergic antagonism [PHEN (phentolamine); 10 μg/dl per min]. Ultrasound Doppler was utilized to determine blood flow, and therefore vasoconstriction, in both infused and contralateral (control) limbs. Arterial blood pressure was measured directly, and sympathetic nervous system activity was assessed via microneurography and plasma NE analysis. AngII sensitivity was significantly greater in the old, indicated by both greater maximal vasoconstriction ( − 59 + − 4 % in old against − 48 + − 3 % in young) and a decreased EC 50 (half-maximal effective concentration) (1.4 + − 0.2 ng/dl per min in old against 2.6 + − 0.7 μg/dl per min in young), whereas the maximal NE-mediated vasoconstriction was similar between these groups ( − 58 + − 9 % in old and − 62 + − 5 % in young). AngII also increased venous NE in the old group, but was unchanged in the young group. In the presence of α-adrenergic blockade (PHEN), maximal AngII-mediated vasoconstriction in the old was restored to that of the young ( − 43 + − 8 % in old and − 39 + − 6 % in young). These findings indicate that, with healthy aging, the increased AngII-mediated vasoconstriction may be attributed, in part, to potentiation of the α-adrenergic pathway, and suggest that cross-talk between the RAAS and adrenergic systems may be an important consideration in therapeutic strategies targeting these two pathways

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Mid-IR ultrafast laser inscribed waveguides and devices

Ultrafast laser inscription (ULI) is a highly versatile technique for creating index modifications in glasses and crystalline materials. The process of ULI relies on ultrashort laser pulses focused inside of a material. The high intensity of the pulsed beam induces nonlinear absorption processes, which transfers the pulse energy to the material lattice. With careful experimental control of the laser parameters, a permanent change in the refractive can be obtained in the bulk material. The permanent refractive index change obtained by ULI can be used to create waveguides in active laser materials, such as Cr:ZnSe, Fe:ZnSe and Ho:YAG. Transition metal and rare-earth laser sources have been shown to operate over the 2 - 5 micron range. ULI can be used in conjunction with these materials to produce high power, guided-wave structures with reduced size, weight and power (SWaP) requirements. Power levels for Cr:ZnSe and Fe:ZnSe have been scaled to \u3e 5 W and \u3e 1 W respectively in ULI waveguide devices. Additionally, the first Ho:YAG ULI laser has been investigated, exhibiting output powers of ̃ 2 W. In addition to these advances, the theoretical limit for transition metal waveguide lasers was investigated. Transition metal lasers are highly sensitive to the operating temperature of the laser device. If the temperature increase induced in the sample is too high, phonon assisted transitions become dominant, thus decreasing the performance of the laser. Laser rate-equations and a thermal model for ULI waveguides were developed to establish a theoretical limit to ULI waveguide operation. Finally, several advancements were made with respect to creating ULI waveguides. An algorithm was developed for creating arbitrary ULI structures from computer generated models. The ability to create arbitrarily generated structures provides the ability to create complex structures using ULI, such as splitters, couplers, and photonic lanterns. Furthermore, a new helical inscription technique was devised for creating smooth index profiles and for creating Bragg structuring

Seeded, gain-switched chromium doped zinc selenide amplifier

Many scientific and military applications require pulsed laser sources with high peak power output which are tunable throughout the midwave infrared (mid-IR) spectral region. In this report we discuss the design, construction, and characterization of a gain-switched chromium-doped zinc selenide (Cr:ZnSe) amplifier pumped by a Q-switched holmium-doped yttrium aluminum garnate (Ho:YAG) laser and seeded by a free running continuous wave (CW) Cr:ZnSe laser. The amplifier pump laser was constructed using a 0.5% Ho-doped, Brewster-cut YAG rod. In CW operation, powers of up to 3.68 W and a slope efficiency of 45% were obtained. In pulsed operation at 1 kHz pulse repetition frequency (PRF), pulse energies of 2.6 mJ per pulse were obtained with temporal pulse widths less than 100 ns. The output wavelength of the pump was 2.1 μm with a spectral width less than 1 nm. The pulsed Ho:YAG laser was then used to gain-switch a Cr:ZnSe single-pass pulsed amplifier seeded with a CW Cr:ZnSe laser with a free-running wavelength of 2.4 μm and a spectral linewidth of 50 nm. The output of the gain-switched amplifier yields a pulsed beam at the seed wavelength demonstrating high gain. By design, this source will follow the lasing wavelength of the seed beam allowing for tunability over the entire emission wavelength of Cr:ZnSe with proper seed design. The end result of this work was a versatile, pulsed mid-IR source

Seeded, gain-switched chromium doped zinc selenide amplifier

Many scientific and military applications require pulsed laser sources with high peak power output which are tunable throughout the midwave infrared (mid-IR) spectral region. In this report we discuss the design, construction, and characterization of a gain-switched chromium-doped zinc selenide (Cr:ZnSe) amplifier pumped by a Q-switched holmium-doped yttrium aluminum garnate (Ho:YAG) laser and seeded by a free running continuous wave (CW) Cr:ZnSe laser. The amplifier pump laser was constructed using a 0.5% Ho-doped, Brewster-cut YAG rod. In CW operation, powers of up to 3.68 W and a slope efficiency of 45% were obtained. In pulsed operation at 1 kHz pulse repetition frequency (PRF), pulse energies of 2.6 mJ per pulse were obtained with temporal pulse widths less than 100 ns. The output wavelength of the pump was 2.1 μm with a spectral width less than 1 nm. The pulsed Ho:YAG laser was then used to gain-switch a Cr:ZnSe single-pass pulsed amplifier seeded with a CW Cr:ZnSe laser with a free-running wavelength of 2.4 μm and a spectral linewidth of 50 nm. The output of the gain-switched amplifier yields a pulsed beam at the seed wavelength demonstrating high gain. By design, this source will follow the lasing wavelength of the seed beam allowing for tunability over the entire emission wavelength of Cr:ZnSe with proper seed design. The end result of this work was a versatile, pulsed mid-IR source

Mid-IR Ultrafast Laser Inscribed Waveguides and Devices

Ultrafast laser inscription (ULI) is a highly versatile technique for creating index modifications in glasses and crystalline materials. The process of ULI relies on ultrashort laser pulses focused inside of a material. The high intensity of the pulsed beam induces nonlinear absorption processes, which transfers the pulse energy to the material lattice. With careful experimental control of the laser parameters, a permanent change in the refractive can be obtained in the bulk material. The permanent refractive index change obtained by ULI can be used to create waveguides in active laser materials, such as Cr:ZnSe, Fe:ZnSe and Ho:YAG. Transition metal and rare-earth laser sources have been shown to operate over the 2 - 5 micron range. ULI can be used in conjunction with these materials to produce high power, guided-wave structures with reduced size, weight and power (SWaP) requirements. Power levels for Cr:ZnSe and Fe:ZnSe have been scaled to \u3e 5 W and \u3e 1 W respectively in ULI waveguide devices. Additionally, the first Ho:YAG ULI laser has been investigated, exhibiting output powers of ̃ 2 W. In addition to these advances, the theoretical limit for transition metal waveguide lasers was investigated. Transition metal lasers are highly sensitive to the operating temperature of the laser device. If the temperature increase induced in the sample is too high, phonon assisted transitions become dominant, thus decreasing the performance of the laser. Laser rate-equations and a thermal model for ULI waveguides were developed to establish a theoretical limit to ULI waveguide operation. Finally, several advancements were made with respect to creating ULI waveguides. An algorithm was developed for creating arbitrary ULI structures from computer generated models. The ability to create arbitrarily generated structures provides the ability to create complex structures using ULI, such as splitters, couplers, and photonic lanterns. Furthermore, a new helical inscription technique was devised for creating smooth index profiles and for creating Bragg structuring