Coexistence of amplitude and frequency modulations in intracellular calcium dynamics

The complex dynamics of intracellular calcium regulates cellular responses to information encoded in extracellular signals. Here, we study the encoding of these external signals in the context of the Li-Rinzel model. We show that by control of biophysical parameters the information can be encoded in amplitude modulation, frequency modulation or mixed (AM and FM) modulation. We briefly discuss the possible implications of this new role of information encoding for astrocytes.Comment: 4 pages, 4 figure

Arguments against the proposal 2302 by John & al. to reject the name Gonyaulax catenella (Alexandrium catenella)

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The Association of a classical left bundle Branch Block Contraction Pattern by vendor-independent strain echocardiography and outcome after cardiac resynchronization therapy

Background: The association of a Classical left bundle branch block (LBBB) contraction pattern and better outcome after cardiac resynchronization therapy (CRT) has only been studied using vendor-specific software for echocardiographic speckle-tracked longitudinal strain analysis. The purpose of this study was to assess whether a Classical LBBB contraction pattern on longitudinal strain analysis using vendor-independent software is associated with clinical outcome in CRT recipients with LBBB. Methods: This was a retrospective cohort study including CRT recipients with LBBB, heart failure, and left ventricular (LV) ejection fraction ≤35%. Speckle-tracked echocardiographic longitudinal strain analysis was performed retrospectively on echocardiograms using vendor-independent software. The presence of a Classical LBBB contraction pattern was determined by consensus of two readers. The primary end point was a composite of time to death, heart transplantation or LV assist device implantation. Secondary outcome was ≥15% reduction in LV end-systolic volume. Intra- and inter-reader agreement of the longitudinal strain contraction pattern was assessed by calculating Cohen's κ. Results: Of 283 included patients, 113 (40%) were women, mean age was 66 ± 11 years, and 136 (48%) had ischemic heart disease. A Classical LBBB contraction pattern was present in 196 (69%). The unadjusted hazard ratio for reaching the primary end point was 1.93 (95% confidence interval, 1.36-2.76, p &lt; 0.001) when comparing patients without to patients with a Classical LBBB contraction pattern. Adjusted for ischemic heart disease and QRS duration &lt; 150 milliseconds the hazard ratio was 1.65 (95% confidence interval, 1.12-2.43, p = 0.01). Of the 123 (43%) patients with a follow-up echocardiogram, 64 of 85 (75%) of patients with a Classical LBBB contraction pattern compared to 13 of 38 (34%) without, had ≥15% reduction in LV end-systolic volume (p &lt; 0.001). Cohen's κ were 0.86 (95% confidence interval, 0.71-1.00) and 0.42 (95% confidence interval, 0.30-0.54) for intra- and inter-reader agreement, respectively. Conclusion: Using vendor-independent strain software, a Classical LBBB contraction pattern is associated with better outcome in CRT recipients with LBBB, but inter-reader agreement for the classification of contraction pattern is only moderate.</p

A systematic approach for evaluating the role of surface-exposed loops in trypsin-like serine proteases applied to the 170 loop in coagulation factor VIIa

Proteases play a major role in many vital physiological processes. Trypsin-like serine proteases (TLPs), in particular, are paramount in proteolytic cascade systems such as blood coagulation and complement activation. The structural topology of TLPs is highly conserved, with the trypsin fold comprising two β-barrels connected by a number of variable surface-exposed loops that provide a surprising capacity for functional diversity and substrate specificity. To expand our understanding of the roles these loops play in substrate and co-factor interactions, we employ a systematic methodology akin to the natural truncations and insertions observed through evolution of TLPs. The approach explores a larger deletion space than classical random or directed mutagenesis. Using FVIIa as a model system, deletions of 1–7 amino acids through the surface exposed 170 loop, a vital allosteric regulator, was introduced. All variants were extensively evaluated by established functional assays and computational loop modelling with Rosetta. The approach revealed detailed structural and functional insights recapitulation and expanding on the main findings in relation to 170 loop functions elucidated over several decades using more cumbersome crystallization and single deletion/mutation methodologies. The larger deletion space was key in capturing the most active variant, which unexpectedly had a six-amino acid truncation. This variant would have remained undiscovered if only 2–3 deletions were considered, supporting the usefulness of the methodology in general protease engineering approaches. Our findings shed further light on the complex role that surface-exposed loops play in TLP function and supports the important role of loop length in the regulation and fine-tunning of enzymatic function throughout evolution

Assessment of algorithms for mitosis detection in breast cancer histopathology images

The proliferative activity of breast tumors, which is routinely estimated by counting of mitotic figures in hematoxylin and eosin stained histology sections, is considered to be one of the most important prognostic markers. However, mitosis counting is laborious, subjective and may suffer from low inter-observer agreement. With the wider acceptance of whole slide images in pathology labs, automatic image analysis has been proposed as a potential solution for these issues. In this paper, the results from the Assessment of Mitosis Detection Algorithms 2013 (AMIDA13) challenge are described. The challenge was based on a data set consisting of 12 training and 11 testing subjects, with more than one thousand annotated mitotic figures by multiple observers. Short descriptions and results from the evaluation of eleven methods are presented. The top performing method has an error rate that is comparable to the inter-observer agreement among pathologists

Stable oxygen isotope variability in two contrasting glacier river catchments in Greenland

Analysis of stable oxygen isotope (δ18O) characteristics is a useful tool to investigate water provenance in glacier river systems. In order to attain knowledge on the diversity of δ18O variations in Greenlandic rivers, we examined two contrasting glacierised catchments disconnected from the Greenland Ice Sheet (GrIS). At the Mittivakkat Gletscher river, a small river draining a local temperate glacier in southeast Greenland, diurnal oscillations in δ18O occurred with a 3 h time lag to the diurnal oscillations in run-off. The mean annual δ18O was −14.68 ± 0.18 ‰ during the peak flow period. A hydrograph separation analysis revealed that the ice melt component constituted 82 ± 5 % of the total run-off and dominated the observed variations during peak flow in August 2004. The snowmelt component peaked between 10:00 and 13:00 local time, reflecting the long travel time and an inefficient distributed subglacial drainage network in the upper part of the glacier. At the Kuannersuit Glacier river on the island Qeqertarsuaq in west Greenland, the δ18O characteristics were examined after the major 1995–1998 glacier surge event. The mean annual δ18O was −19.47 ± 0.55 ‰. Despite large spatial variations in the δ18O values of glacier ice on the newly formed glacier tongue, there were no diurnal oscillations in the bulk meltwater emanating from the glacier in the post-surge years. This is likely a consequence of a tortuous subglacial drainage system consisting of linked cavities, which formed during the surge event. Overall, a comparison of the δ18O compositions from glacial river water in Greenland shows distinct differences between water draining local glaciers and ice caps (between −23.0 and −13.7 ‰) and the GrIS (between −29.9 and −23.2 ‰). This study demonstrates that water isotope analyses can be used to obtain important information on water sources and the subglacial drainage system structure that is highly desired for understanding glacier hydrology

The politicisation of evaluation: constructing and contesting EU policy performance

Although systematic policy evaluation has been conducted for decades and has been growing strongly within the European Union (EU) institutions and in the member states, it remains largely underexplored in political science literatures. Extant work in political science and public policy typically focuses on elements such as agenda setting, policy shaping, decision making, or implementation rather than evaluation. Although individual pieces of research on evaluation in the EU have started to emerge, most often regarding policy “effectiveness” (one criterion among many in evaluation), a more structured approach is currently missing. This special issue aims to address this gap in political science by focusing on four key focal points: evaluation institutions (including rules and cultures), evaluation actors and interests (including competencies, power, roles and tasks), evaluation design (including research methods and theories, and their impact on policy design and legislation), and finally, evaluation purpose and use (including the relationships between discourse and scientific evidence, political attitudes and strategic use). The special issue considers how each of these elements contributes to an evolving governance system in the EU, where evaluation is playing an increasingly important role in decision making

Abrupt climate changes for Iceland during the last millennium: evidence from high resolution sea ice reconstructions

International audienceA high resolution account of Icelandic sea ice over the last millennium has been constructed using a novel proxy based on the presence in sediments of a biomarker (IP25) produced by sea ice algae. Comparison with historical sea ice records demonstrates a strong correlation between documented sea ice occurrences and the IP25 proxy. An excellent agreement is also observed between the IP25 record and a diatom-based sea surface temperature reconstruction obtained from the same core and the Crowley and Lowery Northern Hemisphere temperature reconstruction. Using this approach, we provide new historical sea ice data for periods where records are scarce or absent and evidence for abrupt changes to sea ice and/or climate conditions around Iceland during the Little Ice Age

G_s protein peptidomimetics as allosteric modulators of the β₂-adrenergic receptor

A series of G(s) protein peptidomimetics were designed and synthesised based on the published X-ray crystal structure of the active state β(2)-adrenergic receptor (β(2)AR) in complex with the G(s) protein (PDB 3SN6). We hypothesised that such peptidomimetics may function as allosteric modulators that target the intracellular G(s) protein binding site of the β(2)AR. Peptidomimetics were designed to mimic the 15 residue C-terminal α-helix of the G(s) protein and were pre-organised in a helical conformation by (i, i + 4)-stapling using copper catalysed azide alkyne cycloaddition. Linear and stapled peptidomimetics were analysed by circular dichroism (CD) and characterised in a membrane-based cAMP accumulation assay and in a bimane fluorescence assay on purified β(2)AR. Several peptidomimetics inhibited agonist isoproterenol (ISO) induced cAMP formation by lowering the ISO maximal efficacy up to 61%. Moreover, some peptidomimetics were found to significantly decrease the potency of ISO up to 39-fold. In the bimane fluorescence assay none of the tested peptidomimetics could stabilise an active-like conformation of β(2)AR. Overall, the obtained pharmacological data suggest that some of the peptidomimetics may be able to compete with the native G(s) protein for the intracellular binding site to block ISO-induced cAMP formation, but are unable to stabilise an active-like receptor conformation