The GAPS Experiment to Search for Dark Matter using Low-energy Antimatter

The GAPS experiment is designed to carry out a sensitive dark matter search by measuring low-energy cosmic ray antideuterons and antiprotons. GAPS will provide a new avenue to access a wide range of dark matter models and masses that is complementary to direct detection techniques, collider experiments and other indirect detection techniques. Well-motivated theories beyond the Standard Model contain viable dark matter candidates which could lead to a detectable signal of antideuterons resulting from the annihilation or decay of dark matter particles. The dark matter contribution to the antideuteron flux is believed to be especially large at low energies (E < 1 GeV), where the predicted flux from conventional astrophysical sources (i.e. from secondary interactions of cosmic rays) is very low. The GAPS low-energy antiproton search will provide stringent constraints on less than 10 GeV dark matter, will provide the best limits on primordial black hole evaporation on Galactic length scales, and will explore new discovery space in cosmic ray physics. Unlike other antimatter search experiments such as BESS and AMS that use magnetic spectrometers, GAPS detects antideuterons and antiprotons using an exotic atom technique. This technique, and its unique event topology, will give GAPS a nearly background-free detection capability that is critical in a rare-event search. GAPS is designed to carry out its science program using long-duration balloon flights in Antarctica. A prototype instrument was successfully flown from Taiki, Japan in 2012. GAPS has now been approved by NASA to proceed towards the full science instrument, with the possibility of a first long-duration balloon flight in late 2020. Here we motivate low-energy cosmic ray antimatter searches and discuss the current status of the GAPS experiment and the design of the payload.Comment: 8 pags, 3 figures, Proc. 35th International Cosmic Ray Conference (ICRC 2017), Busan, Kore

From planning the port/city to planning the port-city : exploring the economic interface in European port cities

In last three decades, planning agencies of most ports have institutionally evolved into a (semi-) independent port authority. The rationale behind this process is that port authorities are able to react more quickly to changing logistical and spatial preferences of maritime firms, hence increasing the competitiveness of ports. Although these dedicated port authorities have proven to be largely successful, new economic, social, and environmental challenges are quickly catching up on these port governance models, and particularly leads to (spatial) policy ‘conflicts’ between port and city. This chapter starts by assessing this conflict and argue that the conflict is partly a result of dominant—often also academic—spatial representations of the port city as two separate entities. To escape this divisive conception of contemporary port cities, this chapter presents a relational visualisation method that is able to analyse the economic interface between port and city. Based on our results, we reflect back on our proposition and argue that the core challenge today for researchers and policy makers is acknowledging the bias of port/city, being arguably a self-fulfilling prophecy. Hence, we turn the idea of (planning the) port/city conflicts into planning the port-city’s strengths and weaknesses

Truncated and Helix-Constrained Peptides with High Affinity and Specificity for the cFos Coiled-Coil of AP-1

Protein-based therapeutics feature large interacting surfaces. Protein folding endows structural stability to localised surface epitopes, imparting high affinity and target specificity upon interactions with binding partners. However, short synthetic peptides with sequences corresponding to such protein epitopes are unstructured in water and promiscuously bind to proteins with low affinity and specificity. Here we combine structural stability and target specificity of proteins, with low cost and rapid synthesis of small molecules, towards meeting the significant challenge of binding coiled coil proteins in transcriptional regulation. By iteratively truncating a Jun-based peptide from 37 to 22 residues, strategically incorporating i-->i+4 helix-inducing constraints, and positioning unnatural amino acids, we have produced short, water-stable, alpha-helical peptides that bind cFos. A three-dimensional NMR-derived structure for one peptide (24) confirmed a highly stable alpha-helix which was resistant to proteolytic degradation in serum. These short structured peptides are entropically pre-organized for binding with high affinity and specificity to cFos, a key component of the oncogenic transcriptional regulator Activator Protein-1 (AP-1). They competitively antagonized the cJun–cFos coiled-coil interaction. Truncating a Jun-based peptide from 37 to 22 residues decreased the binding enthalpy for cJun by ~9 kcal/mol, but this was compensated by increased conformational entropy (TDS ≤ 7.5 kcal/mol). This study demonstrates that rational design of short peptides constrained by alpha-helical cyclic pentapeptide modules is able to retain parental high helicity, as well as high affinity and specificity for cFos. These are important steps towards small antagonists of the cJun-cFos interaction that mediates gene transcription in cancer and inflammatory diseases

Empirically-Informed Modal Rationalism

In this chapter, it is suggested that our epistemic access to metaphysical modality generally involves rationalist, a priori elements. However, these a priori elements are much more subtle than ‘traditional’ modal rationalism assumes. In fact, some might even question the ‘apriority’ of these elements, but I should stress that I consider a priori and a posteriori elements especially in our modal inquiry to be so deeply intertwined that it is not easy to tell them apart. Supposed metaphysically necessary identity statements involving natural kind terms are a good example: the fact that empirical input is crucial in establishing their necessity has clouded the role and content of the a priori input, as I have previously argued (Tahko forthcoming). For instance, the supposed metaphysically necessary identity statement involving water and its microstructure can only be established with the help of a controversial a priori principle concerning the determination of chemical properties by microstructure. The Kripke-Putnam framework of modal epistemology fails precisely because it is unclear whether the required a priori element is present. My positive proposal builds on E. J. Lowe’s work. Lowe holds that our knowledge of metaphysical modality is based on our knowledge of essence. Lowe’s account strives to offer a uniform picture of modal epistemology: essence is the basis of all our modal knowledge. This is the basis of Lowe’s modal rationalism. I believe that Lowe’s proposal is on the right lines in the case of abstract objects, but I doubt that it can be successfully applied to the case of natural kinds. Accordingly, the case of natural kinds will be my main focus and I will suggest that modal rationalism, at least as it is traditionally understood, falls short of explaining modal knowledge concerning natural kinds. Yet, I think that Lowe has identified something of crucial importance for modal epistemology, namely the essentialist, a priori elements present in our modal inquiry. The upshot is that rather than moving all the way from modal rationalism to modal empiricism, a type of hybrid approach, ‘empirically-informed modal rationalism’, can be developed.Peer reviewe

Enhancing Specific Disruption of Intracellular Protein Complexes by Hydrocarbon Stapled Peptides Using Lipid Based Delivery

Linear peptides can mimic and disrupt protein-protein interactions involved in critical cell signaling pathways. Such peptides however are usually protease sensitive and unable to engage with intracellular targets due to lack of membrane permeability. Peptide stapling has been proposed to circumvent these limitations but recent data has suggested that this method does not universally solve the problem of cell entry and can lead to molecules with off target cell lytic properties. To address these issues a library of stapled peptides was synthesized and screened to identify compounds that bound Mdm2 and activated cellular p53. A lead peptide was identified that activated intracellular p53 with negligible nonspecific cytotoxicity, however it still bound serum avidly and only showed a marginal improvement in cellular potency. These hurdles were overcome by successfully identifying a pyridinium-based cationic lipid formulation, which significantly improved the activity of the stapled peptide in a p53 reporter cell line, principally through increased vesicular escape. These studies under score that stapled peptides, which are cell permeable and target specific, can be identified with rigorous experimental design and that these properties can be improved through use with lipid based formulations. This work should facilitate the clinical translation of stapled peptides

Study of B0(s)→K0Sh+h′− decays with first observation of B0s→K0SK±π∓ and B0s→K0Sπ+π−

A search for charmless three-body decays of B 0 and B0s mesons with a K0S meson in the final state is performed using the pp collision data, corresponding to an integrated luminosity of 1.0 fb−1, collected at a centre-of-mass energy of 7 TeV recorded by the LHCb experiment. Branching fractions of the B0(s)→K0Sh+h′− decay modes (h (′) = π, K), relative to the well measured B0→K0Sπ+π− decay, are obtained. First observation of the decay modes B0s→K0SK±π∓ and B0s→K0Sπ+π− and confirmation of the decay B0→K0SK±π∓ are reported. The following relative branching fraction measurements or limits are obtained B(B0→K0SK±π∓)B(B0→K0Sπ+π−)=0.128±0.017(stat.)±0.009(syst.), B(B0→K0SK+K−)B(B0→K0Sπ+π−)=0.385±0.031(stat.)±0.023(syst.), B(B0s→K0Sπ+π−)B(B0→K0Sπ+π−)=0.29±0.06(stat.)±0.03(syst.)±0.02(fs/fd), B(B0s→K0SK±π∓)B(B0→K0Sπ+π−)=1.48±0.12(stat.)±0.08(syst.)±0.12(fs/fd)B(B0s→K0SK+K−)B(B0→K0Sπ+π−)∈[0.004;0.068]at90%CL