In and out of Madagascar : dispersal to peripheral islands, insular speciation and diversification of Indian Ocean daisy trees (Psiadia, Asteraceae)

This study was supported by the European Union’s HOTSPOTS Training Network (MEST-2005-020561)Madagascar is surrounded by archipelagos varying widely in origin, age and structure. Although small and geologically young, these archipelagos have accumulated disproportionate numbers of unique lineages in comparison to Madagascar, highlighting the role of waif-dispersal and rapid in situ diversification processes in generating endemic biodiversity. We reconstruct the evolutionary and biogeographical history of the genus Psiadia (Asteraceae), a plant genus with near equal numbers of species in Madagascar and surrounding islands. Analyzing patterns and processes of diversification, we explain species accumulation on peripheral islands and aim to offer new insights on the origin and potential causes for diversification in the Madagascar and Indian Ocean Islands biodiversity hotspot. Our results provide support for an African origin of the group, with strong support for non-monophyly. Colonization of the Mascarenes took place by two evolutionary distinct lineages from Madagascar, via two independent dispersal events, each unique for their spatial and temporal properties. Significant shifts in diversification rate followed regional expansion, resulting in co-occurring and phenotypically convergent species on high-elevation volcanic slopes. Like other endemic island lineages, Psiadia have been highly successful in dispersing to and radiating on isolated oceanic islands, typified by high habitat diversity and dynamic ecosystems fuelled by continued geological activity. Results stress the important biogeographical role for Rodrigues in serving as an outlying stepping stone from which regional colonization took place. We discuss how isolated volcanic islands contribute to regional diversity by generating substantial numbers of endemic species on short temporal scales. Factors pertaining to the mode and tempo of archipelago formation and its geographical isolation strongly govern evolutionary pathways available for species diversification, and the potential for successful diversification of dispersed lineages, therefore, appears highly dependent on the timing of arrival, as habitat and resource properties change dramatically over the course of oceanic island evolution.Publisher PDFPeer reviewe

Use of a ‘molecular tug’ to overcome limitations in the production of ‘difficult to express’ recombinant proteins

In recent years there has been an increased drive towards the production of recombinant proteins in large amounts using rapid cell culture processes. Mammalian expression systems such as Chinese Hamster Ovary (CHO) cells have remained the preferred choice for large-scale recombinant protein production (Walsh, 2014). However, in mammalian cells certain recombinant targets can prove to be ‘difficult to express’ and require extensive upstream process optimisation which can have a negative impact on industrial processes. This study has investigated the molecular mechanisms that are responsible for poor recombinant protein production. Model proteins from the Tissue Inhibitors of Metalloproteinase (TIMP) family, TIMP-2, TIMP-3 and TIMP-4, were subject to detailed study to characterise the molecular mechanisms that limit production of recombinant proteins with high sequence homology (Hussain et al., 2017). TIMP-2, -3 and -4, share significant sequence/structural homology (Douglas et al., 1997, Garcia et al., 2012), but show differences when produced in a transient CHO expression system (Hussain et al., 2017) . A systematic screen of the protein expression pathway showed all three TIMPs were detectable at the mRNA and protein level within the cell but only TIMP-2 was secreted in significant amounts into the culture medium. Analysis of the intracellular protein suggested the post-translational processing of poorly expressed TIMPs was limiting. A protein engineering approach was employed to overcome challenges in the production of these ‘difficult to express’ TIMP proteins. This approach involved the attachment of a furin-cleavable pro-sequence from a secretory growth factor to recombinant targets. The pro-sequence was predicted to act as a ‘molecular tug’ to aid transit through the protein expression pathway and/or promote correct post-translational processing. Initially, the furin-cleavable pro-sequence was added to TIMP-3 (non-secreted), which resulted in secretion of TIMP-3, however incomplete processing of the pro-sequence was observed. The protein engineering approach was optimised further and applied in combination with cell engineering (furin overexpression) to TIMP-4 (poorly secreted), which was also successfully detected in significantly higher amounts in the culture medium (Hussain et al., 2017). Together, the described protein engineering approach presents a novel strategy to increase the production of ‘difficult-to-express’ recombinant targets. References: Douglas, D. A., Shi, Y. E. & Sang, Q. X. A. 1997. Computational sequence analysis of the tissue inhibitor of metalloproteinase family. Journal of Protein Chemistry, 16, 237-255. Garcia, M. P. S., Suarez-Penaranda, J. M., Gayoso-Diz, P., Barros-Angueira, F., Gandara-Rey, J. M. & Garcia-Garcia, A. 2012. Tissue inhibitor of metalloproteinases in oral squamous cell carcinomas - A therapeutic target? Cancer Letters, 323, 11-19. Hussain, H., Fisher, D. I., Abbott, W. M., Roth, R. G. & Dickson, A. J. 2017. Use of a protein engineering strategy to overcome limitations in the production of Difficult to Express recombinant proteins. Biotechnology and Bioengineering, 114, 2348-2359. Walsh, G. 2014. Biopharmaceutical benchmarks 2014. Nature Biotechnology, 32, 992-1000

A 2000 year varve-based climate record from the central Brooks Range, Alaska

Varved minerogenic sediments from glacial-fed Blue Lake, northern Alaska, are used to investigate late Holocene climate variability. Varve-thickness measurements track summer temperature recorded at Atigun Pass, located 41 km east at a similar elevation (r2 = 0.31, P = 0.08). Results indicate that climate in the Brooks Range from 10 to 730 AD (varve year) was warm with precipitation inferred to be higher than during the twentieth century. The varve-temperature relationship for this period was likely compromised and not used in our temperature reconstruction because the glacier was greatly reduced, or absent, exposing sub-glacial sediments to erosion from enhanced precipitation. Varve-inferred summer temperatures and precipitation decreased after 730 AD, averaging 0.4°C above the last millennial average (LMA = 4.2°C) from 730 to 850 AD, and 0.1°C above the LMA from 850 to 980 AD. Cooling culminated between 980 and 1030 AD with temperatures 0.7°C below the LMA. Varve-inferred summer temperatures increased between 1030 and 1620 AD to the LMA, though the period between 1260 and 1350 AD was 0.2°C below the LMA. Although there is no equivalent to the European Medieval Warm Period in the Blue Lake record, two warm intervals occurred from 1350 to 1450 AD and 1500 to 1620 AD (0.4 and 0.3°C above the LMA, respectively). During the Little Ice Age (LIA; 1620 to 1880 AD), inferred summer temperature averaged 0.2°C below the LMA. After 1880 AD, inferred summer temperature increased to 0.8°C above the LMA, glaciers retreated, but aridity persisted based on a number of regional paleoclimate records. Despite warming and glacial retreat, varve thicknesses have not achieved pre-730 AD levels. This reflects limited sediment availability and transport due to a less extensive retreat compared to the first millennium, and continued relative aridity. Overall, the Blue Lake record is similar to varve records from the eastern Canadian Arctic that document a cool LIA and twentieth century warming. However, the occurrence and timing of events, such as the LIA and Medieval Warm Period, varies considerably among records, suggesting heterogeneous climatic patterns across the North American Arctic

Molecular Design Parameters of Anthraquinone Dyes for Guest-Host Liquid-Crystal Applications : Experimental and Computational Studies of Spectroscopy, Structure and Stability

A set of five anthraquinone dyes with bis(4-propylphenyl) substituent groups, connected via sulfide or amine linkages at the 1,5-positions or directly at the 2,6-positions, have been studied in solution by UV-vis spectroscopy and electrochemistry, allied with density functional theory calculations of structures, electronic transitions, and redox potentials. The visible transitions and redox potentials are shown to vary with the HOMO and LUMO energies, with the variation in both color and redox stability between the dyes being attributable principally to variations in the HOMOs located mainly on the substituents and outer anthraquinone rings. The calculated molecular structures and visible transition dipole moments are shown to vary subtly with substituent, giving variations in the molecular aspect ratios, minimum moment of inertia axes, and transition dipole moment vector orientations that can rationalize the alignment trends reported in the literature for such anthraquinone dyes in liquid crystal hosts, showing why 1,5-disulfide and 2,6-diphenyl substituents give better designs than 1,5-diamine substituents. The computational approaches reported here are shown to give good matches with experimental trends, indicating that they may be used more generally to aid the rational molecular design of dyes for applications as guests in liquid crystal hosts

Considerations in the determination of orientational order parameters from X-ray scattering experiments

An assessment of the data processing and analysis methods used to obtain the second- and fourth-rank orientational order parameters of liquid crystals from X-ray scattering experiments has been carried out, using experimental data from four extensively studied alkyl-cyanobiphenyls and calculated data generated from two general types of theoretical orientational distribution function. The application of a background subtraction and two different baseline correction methods to the scattering profiles is assessed, along with three different methods to analyse the processed data. The choice of baseline correction method is shown to have a significant effect: an offset to zero overestimates the order parameters from the experimental and calculated data sets, particularly for lower order parameters arising from broad distributions, whereas an offset to a value estimated from regions of low scattering intensity provides experimental values close to those reported from other experimental techniques. By contrast, the three different analysis methods are shown generally to result in relatively small absolute differences between the order parameters. We outline a straightforward general approach to experimental X-ray scattering data processing and analysis for uniaxial phases that results in order parameters that match well with those reported using other experimental techniques

Estimating number of cases and spread of coronavirus disease (COVID-19) using critical care admissions, United Kingdom, February to March 2020.

An exponential growth model was fitted to critical care admissions from two surveillance databases to determine likely coronavirus disease (COVID-19) case numbers, critical care admissions and epidemic growth in the United Kingdom before the national lockdown. We estimate, on 23 March, a median of 114,000 (95% credible interval (CrI): 78,000-173,000) new cases and 258 (95% CrI: 220-319) new critical care reports, with 527,000 (95% CrI: 362,000-797,000) cumulative cases since 16 February

MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia.

A novel potassium channel gene has been cloned, characterized, and associated with cardiac arrhythmia. The gene encodes MinK-related peptide 1 (MiRP1), a small integral membrane subunit that assembles with HERG, a pore-forming protein, to alter its function. Unlike channels formed only with HERG, mixed complexes resemble native cardiac IKr channels in their gating, unitary conductance, regulation by potassium, and distinctive biphasic inhibition by the class III antiarrhythmic E-4031. Three missense mutations associated with long QT syndrome and ventricular fibrillation are identified in the gene for MiRP1. Mutants form channels that open slowly and close rapidly, thereby diminishing potassium currents. One variant, associated with clarithromycin-induced arrhythmia, increases channel blockade by the antibiotic. A mechanism for acquired arrhythmia is revealed: genetically based reduction in potassium currents that remains clinically silent until combined with additional stressors

Constraints on Axion Models from K+→π+aK^+\to\pi^+ a

We explore a new class of axion models in which some, but not all, of the left-handed quarks have a Peccei-Quinn symmetry. These models are potentially afflicted by flavour changing neutral currents. We derive the bounds on the Peccei-Quinn symmetry-breaking scale from bounds on the $K^+\to \pi^+ a$ branching ratio, showing that in some cases they are even stronger than the astrophysical ones, but still not strong enough to kill off the models.Comment: 15pp RevTeX, 1 eps fig, uses graphics style. Expanded discussion on massive scalars and pseudoscalars, typos. To appear in Physical Review

Gambling in Great Britain:a response to Rogers

A recent issue of Practice: Social Work in Action featured a paper by Rogers that examined whether the issue of problem gambling was a suitable case for social work. Rogers’ overview was (in various places) out of date, highly selective, contradictory, presented unsupported claims and somewhat misleading. Rogers’ paper is to be commended for putting the issue of problem gambling on the social work agenda. However, social workers need up-to-date information and contextually situated information if they are to make informed decisions in helping problem gamblers

Metastability in Two Dimensions and the Effective Potential

We study analytically and numerically the decay of a metastable phase in (2+1)-dimensional classical scalar field theory coupled to a heat bath, which is equivalent to two-dimensional Euclidean quantum field theory at zero temperature. By a numerical simulation we obtain the nucleation barrier as a function of the parameters of the potential, and compare it to the theoretical prediction from the bounce (critical bubble) calculation. We find the nucleation barrier to be accurately predicted by theory using the bounce configuration obtained from the tree-level (``classical'') effective action. Within the range of parameters probed, we found that using the bounce derived from the one-loop effective action requires an unnaturally large prefactor to match the lattice results. Deviations from the tree-level prediction are seen in the regime where loop corrections would be expected to become important.Comment: 13pp, LaTex with Postscript figs, CLNS 93/1202, DART-HEP-93/0