Feleucin-BO1: A Novel Antimicrobial Non-Apeptide Amide from the Skin Secretion of the Toad, Bombina orientalis, and Design of a Potent Broad-Spectrum Synthetic Analogue, Feleucin-K3

Feleucins-BV1 and -BV2 are recently-described prototypes of a novel antimicrobial nonapeptide (AMP) family identified in the skin secretion of the bombinid toad, Bombina variegata. They are encoded on different precursors that also encode a novel bombinin. Here we describe the identification of feleucin-BO1 (FLGLLGSLLamide) which is co-encoded with a different novel bombinin, named feleucin precursor-associated bombinin (FPA-bombinin-BO), from the skin secretion of Bombina orientalis. Synthetic feleucin-BO1 displayed activity against a reference Gram-positive bacterium. Staphylococcus aureus (MIC 34 μM) but was inactive (> 250 μM) against the Gram-negative bacterium, Escherichia coli, and the yeast, Candida albicans. This pattern of activity was similar to that of the prototypes. Design and synthesis of a cationicity-enhanced analogue, feleucin-K3 (F-K3), in which the amino acid residues at positions 3 (G), 6 (G) and 7 (S) of feleucin-BO1 were substituted with Lys (K) residues, resulted in a peptide with significantly-enhanced potency and spectrum of activity. The MICs of F-K3 against the reference microorganisms were 7 μM (S. aureus), 14 μM (E. coli) and 7 μM (C. albicans). These data indicate that the skin secretions of amphibians can continue to provide novel peptide templates for the rational design of analogues with possible therapeutic utility.

Using mesh-geometry relationships to transfer analysis models between CAE tools

Integrating analysis and design models is a complex task due to differences between the models and the architectures of the toolsets used to create them. This complexity is increased with the use of many different tools for specific tasks using an analysis process. In this work various design and analysis models are linked throughout the design lifecycle, allowing them to be moved between packages in a way not currently available. Three technologies named Cellular Modeling, Virtual Topology and Equivalencing are combined to demonstrate how different finite element meshes generated on abstract analysis geometries can be linked to their original geometry. Cellular models allow interfaces between adjacent cells to be extracted and exploited to transfer analysis attributes such as mesh associativity or boundary conditions between equivalent model representations. Virtual Topology descriptions used for geometry clean-up operations are explicitly stored so they can be reused by downstream applications. Establishing the equivalence relationships between models enables analysts to utilize multiple packages for specialist tasks without worrying about compatibility issues or substantial rework.

Microbial community of the deep-sea brine Lake Kryos seawater-brine interface is active below the chaotropicity limit of life as revealed by recovery of mRNA

Within the complex of deep, hypersaline anoxic lakes (DHALs) of the Mediterranean Ridge, we identified a new, unexplored DHAL and named it ‘Lake Kryos’ after a nearby depression. This lake is filled with magnesium chloride (MgCl2)-rich, athalassohaline brine (salinity > 470 practical salinity units), presumably formed by the dissolution of Messinian bischofite. Compared with the DHAL Discovery, it contains elevated concentrations of kosmotropic sodium and sulfate ions, which are capable of reducing the net chaotropicily of MgCl2-rich solutions. The brine of Lake Kryos may therefore be biologically permissive at MgCl2 concentrations previously considered incompatible with life. We characterized the microbiology of the seawater–Kryos brine interface and managed to recover mRNA from the 2.27–3.03 MMgCl2 layer (equivalent to 0.747–0.631 water activity), thereby expanding the established chaotropicity window-for-life. The primary bacterial taxa present there were Kebrit Deep Bacteria 1 candidate division and DHAL-specific group of organisms, distantly related toDesulfohalobium. Two euryarchaeal candidate divisions, Mediterranean Sea Brine Lakes group 1 and halophilic cluster 1, accounted for > 85% of the rRNA-containing archaeal clones derived from the 2.27–3.03 M MgCl2 layer, but were minority community-members in the overlying interface-layers. These findings shed light on the plausibility of life in highly chaotropic environments, geochemical windows for microbial extremophiles, and have implications for habitability elsewhere in the Solar System.

'"These schemes will win for themselves the confidence of the people": Irish independence, poor law reform and hospital provision'

This article examines hospital provision in Ireland during the early twentieth century. It examines attempts by the newly independent Irish Free State to reform and de-stigmatise medical relief in former workhouse infirmaries. Such reforms were designed to move away from nineteenth century welfare regimes which were underpinned by principles of deterrence. The reform initiated in independent Ireland - the first attempted break-up of the New Poor Law in Great Britain or Ireland - was partly successful. Many of the newly named County and District Hospitals provided solely for medical cases and managed to dissociate such health care provision from the relief of poverty. However, some hospitals continued to act as multifunctional institutions and provided for various categories including the sick, the aged and infirm, 'unmarried mothers' and 'harmless lunatics'. Such institutions often remained associated with the relief of poverty. This article also examines patient fee-payment and outlines how fresh terms of entitlement and means-testing were established. Such developments were even more pronounced in voluntary hospitals where the majority of patients made a financial contribution to their treatment. The article argues that the ability to pay at times determined the type of provision, either voluntary or rate-aided, available to the sick. However, it concludes that the clinical condition of patients often determined whether they entered a more prestigious voluntary hospital or the former workhouse. Although this article concentrates on two Irish case studies, County Kerry and Cork City; it is conceptualised within wider developments with particular reference to the British context.

Cationicity-Enhanced Analogues of the Antimicrobial Peptides, AcrAP1 and AcrAP2, from the Venom of the Scorpion, Androctonus crassicauda, Display Potent Growth Modulation Effects on Human Cancer Cell Lines

The non disulphide-bridged peptides (NDBPs) of scorpion venoms are attracting increased interest due to their structural heterogeneity and broad spectrum of biological activities. Here, two novel peptides, named AcrAP1 and AcrAP2, have been identified in the lyophilised venom of the Arabian scorpion, Androctonus crassicauda, through “shotgun” molecular cloning of their biosynthetic precursor-encoding cDNAs. The respective mature peptides, predicted from these cloned cDNAs, were subsequently isolated from the same venom sample using reverse phase HPLC and their identities were confirmed by use of mass spectrometric techniques. Both were found to belong to a family of highly-conserved scorpion venom antimicrobial peptides - a finding confirmed through the biological investigation of synthetic replicates. Analogues of both peptides designed for enhanced cationicity, displayed enhanced potency and spectra of antimicrobial activity but, unlike the native peptides, these also displayed potent growth modulation effects on a range of human cancer cell lines. Thus natural peptide templates from venom peptidomes can provide the basis for rational analogue design to improve both biological potency and spectrum of action. The diversity of such templates from such natural sources undoubtedly provides the pharmaceutical industry with unique lead compounds for drug discovery.

Enabling ultra high precision on hard steels using surface defect machining

This paper is an extension to an idea coined during the 13th EUSPEN Conference (P6.23) named "surface defect machining" (SDM). The objective of this work was to demonstrate how a conventional CNC turret lathe can be used to obtain ultra high precision machined surface finish on hard steels without recourse to a sophisticated ultra precision machine tool. An AISI 4340 hard steel (69 HRC) workpiece was machined using a CBN cutting tool with and without SDM. Post-machining measurements by a Form Talysurf and a Scanning Electron Microscope (FEI Quanta 3D) revealed that SDM culminates to several key advantages (i) provides better quality of the machined surface integrity and offers (ii) lowering feed rate to 5μm/rev to obtain a machined surface roughness of 30 nm (optical quality).

Distal volcanic ash layers in the Lateglacial Interstadial (GI-1): problems of stratigraphic discrimination

A new Icelandic ash layer has been detected in mid-Interstadial sediments in a number of Scottish Lateglacial sequences and has been named the Penifiler Tephra. It is rhyolitic in composition and possesses a chemistry, which is similar to the Borrobol Tephra of early Lateglacial Interstadial age, which also occurs in a number of these same sequences. Where the Borrobol Tephra has been identified in these sequences it consistently exhibits a diffuse distribution accompanied in some cases by stratigraphic bimodality. A number of sedimentological and taphonomic factors are considered in order to account for this distribution. One possibility is that these distributions are produced by taphonomic factors. Another possibility is that the Borrobol Tephra may not be the product of a single Icelandic eruption, but of two events closely spaced in time. In at least two of the sequences investigated in this study, basaltic shards were found in association with the Penifiler and Borrobol tephras, suggesting either a basaltic phase associated with these eruptions, or coincident eruptions from a separate basaltic volcanic centre. The discovery of the new Penifiler Tephra makes a contribution to the regional tephrostratigraphic framework, and provides an additional isochron for assessing the synchroneity of palaeoenvironmental changes during the Interstadial. The true stratigraphic nature and age of the Borrobol Tephra, however, remains unresolved and, therefore, its use as an isochron is more problematic. The possible occurrence of basaltic populations may strengthen correlations with basaltic tephras recently detected in the NGRIP ice-core.

Three new distal tephras in sediments spanning the Last Glacial-Interglacial Transition in Scotland

Three new microtephras are reported from a number of lake sites from the Inner Hebrides and Scottish mainland. One occurs stratigrapically in the middle of Greenland Interstadial 1 (GI-1) and has been named the Penifiler Tephra. It is rhyolitic and possesses a geochemical signature that is very similar to that of the Borrobol Tephra, which also occurs in three of the sequences reported here, but which lies close to the lower boundary of GI-1. The second occurs stratigraphically in the early Holocene below the Saksunarvatn Ash and is named the Ashik Tephra. This tephra is geochemically bimodal, with a rhyolitic component comparable to the An Druim Tephra that occurs later in the Holocene, and a basaltic component which is similar to the Saksunarvatn Ash. A third tephra occurs stratigraphically above the Saksunarvatn Ash and is provisionally named the Breakish Tephra. The consistent inter-site correlation demonstrated for these new tephras at several sites enhances the regional tephrostratigraphic framework, and increases the potential for correlating palaeoenvironmental events during GI-1 and the early Holocene. However, the occurrence of multiple tephras with similar geochemistry in close stratigraphic and temporal proximity has implications for the rigour with which tephrostratigraphic investigations must be performed.

Identification and Functional Analysis of a Novel Tryptophyllin Peptide from the Skin of the Red-eye Leaf Frog, Agalychnis callidryas

Amphibian skin has proved repeatedly to be a largely untapped source of bioactive peptides and this is especially true of members of the Phyllomedusinae subfamily of frogs native to South and Central America. Tryptophyllins are a group of peptides mainly found in the skin of members of this genus. In this study, a novel tryptophyllin (TPH) type 3 peptide, named AcT-3, has been isolated and structurally-characterised from the skin secretion and lyophilised skin extract of the red-eye leaf frog, Agalychnis callidryas. The peptide was identified in and purified from the skin secretion by reverse-phase HPLC. MALDI-TOF mass spectrometry and MS/MS fragmentation sequencing established its primary structure as: pGlu-Gly-Lys-Pro-Tyr-Trp-Pro-Pro-Pro-Phe-Leu-Pro-Glu, with a non-protonated molecular mass of 1538.19Da. The mature peptide possessed the canonical N-terminal pGlu residue that arises from post-translational modification of a Gln residue. The deduced open-reading frame consisted of 63 amino acid residues encoding a highly-conserved signal peptide of approximately 22 amino acid residues, an intervening acidic spacer peptide domain, a single AcT-3 encoding domain and a C terminal processing site. A synthetic replicate of AcT-3 was found to antagonise the effect of BK on rat tail artery smooth muscle and to contract the intestinal smooth muscle preparations. It was also found that AcT-3 could dose-dependently inhibit the proliferation of human prostate cancer cell lines after 72h incubation.

Energy-Aware Rate and Description Allocation Optimized Video Streaming for Mobile D2D Communications

The proliferation problem of video streaming applications and mobile devices has prompted wireless network operators to put more efforts into improving quality of experience (QoE) while saving resources that are needed for high transmission rate and large size of video streaming. To deal with this problem, we propose an energy-aware rate and description allocation optimization method for video streaming in cellular network assisted device-to-device (D2D) communications. In particular, we allocate the optimal bit rate to each layer of video segments and packetize the segments into multiple descriptions with embedded forward error correction (FEC) for realtime streaming without retransmission. Simultaneously, the optimal number of descriptions is allocated to each D2D helper for transmission. The two allocation processes are done according to the access rate of segments, channel state information (CSI) of D2D requester, and remaining energy of helpers, to gain the highest optimization performance. Simulation results demonstrate that our proposed method (named OPT) significantly enhances the performance of video streaming in terms of high QoE and energy saving.

The NOTCH signaling pathway in normal and malignant blood cell production

The NOTCH pathway is an evolutionarily conserved signalling network, which is fundamental in regulating developmental processes in invertebrates and vertebrates (Gazave et al. in BMC Evol Biol 9:249, 2009). It regulates self-renewal (Butler et al. in Cell Stem Cell 6:251–264, 2010), differentiation (Auderset et al. in Curr Top Microbiol Immunol 360:115–134, 2012), proliferation (VanDussen et al. in Development 139:488–497, 2012) and apoptosis (Cao et al. in APMIS 120:441–450, 2012) of diverse cell types at various stages of their development. NOTCH signalling governs cell-cell interactions and the outcome of such responses is highly context specific. This makes it impossible to generalize about NOTCH functions as it stimulates survival and differentiation of certain cell types, whereas inhibiting these processes in others (Meier-Stiegen et al. in PLoS One 5:e11481, 2010). NOTCH was first identified in 1914 in Drosophila and was named after the indentations (notches) present in the wings of the mutant flies (Bigas et al. in Int J Dev Biol 54:1175–1188, 2010). Homologs of NOTCH in vertebrates were initially identified in Xenopus (Coffman et al. in Science 249:1438–1441, 1990) and in humans NOTCH was first identified in T-Acute Lymphoblastic Leukaemia (T-ALL) (Ellisen et al. in Cell 66:649–61, 1991). NOTCH signalling is integral in neurogenesis (Mead and Yutzey in Dev Dyn 241:376–389, 2012), myogenesis (Schuster-Gossler et al. in Proc Natl Acad Sci U S A 104:537–542, 2007), haematopoiesis (Bigas et al. in Int J Dev Biol 54:1175–1188, 2010), oogenesis (Xu and Gridley in Genet Res Int 2012:648207, 2012), differentiation of intestinal cells (Okamoto et al. in Am J Physiol Gastrointest Liver Physiol 296:G23–35, 2009) and pancreatic cells (Apelqvist et al. in Nature 400:877–881, 1999). The current review will focus on NOTCH signalling in normal and malignant blood cell production or haematopoiesis.

Operation X: Soviet Russia and the Spanish Civil War

This article offers a critical reassessment of the Soviet role in the Spanish Civil War, based on recent scholarship and declassified official documents. The author interrogates the broad historiographical consensus that reduces Soviet intervention in Spain to a sinister and nefarious force. Stalin's ignominious reputation vis-à-vis the Loyalist side is present in nearly all Western scholarship on the war, whether specialized studies by Nationalist sympathizers or Republicans in exile, or general treatments of European history written in England or America. It would be difficult to locate even a brief overview of the Civil War published outside of Russia that does not in some fashion demonize the Soviet dictator and the Soviet military assistance, code-named ‘Operation X’. The author argues that the basic error in the wide-ranging literature of this topic has always been to approach Stalin's position in Spain as one based on strength rather than weakness. If framed within the context of failure, Stalin's long-standing reputation as the villain of the Civil War may appear in a strikingly different light, and Soviets’ overall contribution to the Loyalist struggle therefore deserving a nuanced revision. The author also explores the multiple strands of the Soviet-Spanish relationship, which included not only military aid but also diplomatic, cultural and humanitarian facets.

Transform both sides model: A parametric approach

A parametric regression model for right-censored data with a log-linear median regression function and a transformation in both response and regression parts, named parametric Transform-Both-Sides (TBS) model, is presented. The TBS model has a parameter that handles data asymmetry while allowing various different distributions for the error, as long as they are unimodal symmetric distributions centered at zero. The discussion is focused on the estimation procedure with five important error distributions (normal, double-exponential, Student's t, Cauchy and logistic) and presents properties, associated functions (that is, survival and hazard functions) and estimation methods based on maximum likelihood and on the Bayesian paradigm. These procedures are implemented in TBSSurvival, an open-source fully documented R package. The use of the package is illustrated and the performance of the model is analyzed using both simulated and real data sets.

Ethnic Segregation, Moral Panics and Social Class: A Comparative Study of the Experiences and Perspectives of Working Class and Middle Class Children in Belfast

This paper begins by describing the moral panics that have tended to emerge sporadically in Northern Ireland over the last few years with regard to young people’s involvement in sectarian violence in Belfast. Within this, while these young people have been cast in the traditional role of folk devils, the paper will show how younger children also tend to be explicitly identified and named in an ambiguous way through such moral panics; playing a deviant role as participators, and sometimes instigators, of sectarian violence but also carrying the symbolic responsibility of representing Belfast’s future. It will be shown that it is because of this ambiguous position that it is adults rather than the children themselves that tend to be held responsible for their actions; either as rioters using the children as political pawns or as parents guilty of neglect. With this as a starting point the paper then explores the perspectives and experiences of two groups of 10-11 year old children living in Belfast and the impact of these moral panics on them. One group of children, living in affluent middle class areas were found to be appropriating and re-working these broader moral panics into more general discourses of derision that tended to pathologize working class children and communities more generally. For the other group of children, living in economically deprived areas with high levels of sectarian tensions and violence, their experiences of such violence and their participation in it are discussed. It will be shown that for these children, the broader moral panics that exist tend to have the effect of reinforcing the processes that tend to segregate and exclude them.

Conceptual Design and Workspace Analysis of an Exechon-inspired Parallel Kinematic Machine

Inspired by the commercial application of the Exechon machine, this paper proposed a novel parallel kinematic machine (PKM) named Exe-Variant. By exchanging the sequence of kinematic pairs in each limb of the Exechon machine, the Exe-Variant PKM claims an arrangement of 2UPR/1SPR topology and consists of two identical UPR limbs and one SPR limb. The inverse kinematics of the 2UPR/1SPR parallel mechanism was firstly analyzed based on which a conceptual design of the Exe-Variant was carried out. Then an algorithm of reachable workspace searching for the Exe-Variant and the Exchon was proposed. Finally, the workspaces of two example systems of the Exechon and the Exe-Variant with approximate dimensions were numerically simulated and compared. The comparison shows that the Exe-Variant possesses a competitive workspace with the Exechon machine, indicating it can be used as a promising reconfigurable module in a hybrid 5-DOF machine tool system.