Palaeogeological hiatus surface mapping: a tool to visualize vertical motion of the continents

Dynamic topography is a well-established consequence of global geodynamic models of mantle convection with horizontal dimensions of >1000 km and amplitudes up to 2 km. Such physical models guide the interpretation of geological records on equal dimensions. Continent-scale geological maps therefore serve as reference frames of choice to visualize erosion/non-deposition as a proxy for long-wavelength, low-amplitude vertical surface motion. At a resolution of systems or series, such maps display conformable and unconformable time boundaries traceable over hundreds to thousands of kilometres. Unconformable contact surfaces define the shape and size of time gap (hiatus) in millions of years based on the duration of time represented by the missing systems or series. Hiatus for a single system or series base datum diminishes laterally to locations (anchor points) where it is conformable at the mapped resolution; it is highly dependent upon scale. A comparison of hiatus area between two successive system or series boundaries yields changes in location, shape, size and duration, indicative of the transient nature of vertical surface motion. As a single-step technique, it serves as a quantitative proxy for palaeotopography that can be calibrated using other geological data. The tool magnifies the need for geological mapping at the temporal resolution of stages, matching process rates. The method has no resolving power within conformable regions (basins) but connects around them. When applied to marine seismic sections that relate to rock record, not to time, biostratigraphic and radiometric data from deep wells are needed before hiatus areas – that relate to time – can be mapped

Comparison of geodetic and geologic data from the Wasatch region, Utah, and implications for the spectral character of Earth deformation at periods of 10 to 10 million years

The Wasatch fault and adjacent fault zones provide an opportunity to compare present-day deformation rate estimates obtained from space geodesy with geologic displacement rates over at least four temporal windows, ranging from the last millennium up to 10 Myr. The three easternmost GPS sites of the Basin and Range Geodetic Network (BARGEN) at this latitude define a ∼130-km-wide region spanning three major normal faults extending east-west at a total rate of 2.7 ± 0.4 mm/yr, with an average regional strain rate estimated to be 21 ± 4 nstrain/yr, about twice the Basin and Range average. On the Wasatch fault, the vertical component of the geologic displacement rate is 1.7 ± 0.5 mm/yr since 6 ka, <0.6 mm/yr since 130 ka, and 0.5–0.7 mm/yr since 10 Ma. However, it appears likely that at the longest timescale, rates slowed over time, from 1.0 to 1.4 mm/yr between 10 and 6 Ma to 0.2 to 0.3 mm/yr since 6 Ma. The cumulative vertical displacement record across all three faults also shows time-variable strain release ranging from 2 to 4 mm/yr since 10 ka to <1 mm/yr averaged over the past 130 kyr. Conventional earthquake recurrence models (“Reid-type” behavior) would require an accordingly large variation in strain accumulation or loading rate on a 10-kyr timescale, for which there appears to be no obvious geophysical explanation. Alternatively, seismic strain release, given a wide range of plausible constitutive behaviors for frictional sliding, may be clustered on the 10-kyr timescale, resulting in the high Holocene rates, with comparatively low, uniform strain accumulation rates on the 100-kyr timescale (“Wallace-type” behavior). The latter alternative, combined with observations at the million-year timescale and the likelihood of a significant contribution of postseismic transients, implies maxima of spectral amplitude in the velocity field at periods of ∼10 Myr (variations in tectonic loading), ∼10 kyr (clustered strain release), and of 100 years (postseismic transients). If so, measurements of strain accumulation and strain release may be strongly timescale-dependent for any given fault system

Biochemical characterization and cellular imaging of a novel, membrane permeable fluorescent cAMP analog

&lt;p&gt;&lt;b&gt;Background&lt;/b&gt;&lt;/p&gt; &lt;p&gt;A novel fluorescent cAMP analog (8-[Pharos-575]- adenosine-3', 5'-cyclic monophosphate) was characterized with respect to its spectral properties, its ability to bind to and activate three main isoenzymes of the cAMP-dependent protein kinase (PKA-Iα, PKA-IIα, PKA-IIβ) in vitro, its stability towards phosphodiesterase and its ability to permeate into cultured eukaryotic cells using resonance energy transfer based indicators, and conventional fluorescence imaging.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Results&lt;/b&gt;&lt;/p&gt; &lt;p&gt;The Pharos fluorophore is characterized by a Stokes shift of 42 nm with an absorption maximum at 575 nm and the emission peaking at 617 nm. The quantum yield is 30%. Incubation of the compound to RIIα and RIIβ subunits increases the amplitude of excitation and absorption maxima significantly; no major change was observed with RIα. In vitro binding of the compound to RIα subunit and activation of the PKA-Iα holoenzyme was essentially equivalent to cAMP; RII subunits bound the fluorescent analog up to ten times less efficiently, resulting in about two times reduced apparent activation constants of the holoenzymes compared to cAMP. The cellular uptake of the fluorescent analog was investigated by cAMP indicators. It was estimated that about 7 μM of the fluorescent cAMP analog is available to the indicator after one hour of incubation and that about 600 μM of the compound had to be added to intact cells to half-maximally dissociate a PKA type IIα sensor.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Conclusion&lt;/b&gt;&lt;/p&gt; &lt;p&gt;The novel analog combines good membrane permeability- comparable to 8-Br-cAMP – with superior spectral properties of a modern, red-shifted fluorophore. GFP-tagged regulatory subunits of PKA and the analog co-localized. Furthermore, it is a potent, PDE-resistant activator of PKA-I and -II, suitable for in vitro applications and spatial distribution evaluations in living cells.&lt;/p&gt

Stability of proICA512/IA-2 and its targeting to insulin secretory granules require β4-sheet-mediated dimerization of its ectodomain in the endoplasmic reticulum

The type 1 diabetes autoantigen ICA512/IA-2/RPTPN is a receptor protein tyrosine phosphatase of the insulin secretory granules (SGs) which regulates the size of granule stores, possibly via cleavage/signaling of its cytosolic tail. The role of its extracellular region remains unknown. Structural studies indicated that β2- or β4-strands in the mature ectodomain (ME ICA512) form dimers in vitro. Here we show that ME ICA512 prompts proICA512 dimerization in the endoplasmic reticulum. Perturbation of ME ICA512 β2-strand N-glycosylation upon S508A replacement allows for proICA512 dimerization, O-glycosylation, targeting to granules, and conversion, which are instead precluded upon G553D replacement in the ME ICA512 β4-strand. S508A/G553D and N506A/G553D double mutants dimerize but remain in the endoplasmic reticulum. Removal of the N-terminal fragment (ICA512-NTF) preceding ME ICA512 allows an ICA512-ΔNTF G553D mutant to exit the endoplasmic reticulum, and ICA512-ΔNTF is constitutively delivered to the cell surface. The signal for SG sorting is located within the NTF RESP18 homology domain (RESP18-HD), whereas soluble NTF is retained in the endoplasmic reticulum. Hence, we propose that the ME ICA512 β2-strand fosters proICA512 dimerization until NTF prevents N506 glycosylation. Removal of this constraint allows for proICA512 β4-strand-induced dimerization, exit from the endoplasmic reticulum, O-glycosylation, and RESP18-HD-mediated targeting to granules.Instituto Multidisciplinario de Biología Celula

The Role of Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 in the p38/TNF-α Pathway of Systemic and Cutaneous Inflammation

Mitogen-activated protein kinase-activated protein kinase 2 (MK2) is a downstream molecule of p38, involved in the production of TNF-α, a key cytokine, and an established drug target for many inflammatory diseases. We investigated the role of MK2 in skin inflammation to determine its drug target potential. MK2 deficiency significantly decreased plasma TNF-α levels after systemic endotoxin application. Deficient mice showed decreased skin edema formation in chronic 2-O-tetradecanoylphorbol-13-acetate (TPA)-induced irritative dermatitis and in subacute 2,4-dinitrofluorobenzene (DNFB)-induced contact hypersensitivity. Surprisingly, MK2 deficiency did not inhibit edema formation in subacute 2,4-dinitrochlorobenzene (DNCB)-induced contact allergy and even increased TNF-α and IL-1β levels as well as granulocyte infiltration in diseased ears. Ear inflammation in this model, however, was inhibited by TNF-α neutralization as it was in the subacute DNFB model. MK2 deficiency also did not show anti-inflammatory effects in acute DNFB-induced contact hypersensitivity, whereas the p38 inhibitor, SB203580, ameliorated skin inflammation supporting a pathophysiological role of p38. When evaluating possible mechanisms, we found that TNF-α production in MK2-deficient spleen cells was strongly diminished after TLR stimulation but less affected after T-cell receptor stimulation. Our data suggest that MK2, in contrast to its downstream effector molecule, TNF-α, has a rather elusive role in T-cell-dependent cutaneous inflammation

Stability of proICA512/IA-2 and its targeting to insulin secretory granules require β4-sheet-mediated dimerization of its ectodomain in the endoplasmic reticulum

The type 1 diabetes autoantigen ICA512/IA-2/RPTPN is a receptor protein tyrosine phosphatase of the insulin secretory granules (SGs) which regulates the size of granule stores, possibly via cleavage/signaling of its cytosolic tail. The role of its extracellular region remains unknown. Structural studies indicated that β2- or β4-strands in the mature ectodomain (ME ICA512) form dimers in vitro. Here we show that ME ICA512 prompts proICA512 dimerization in the endoplasmic reticulum. Perturbation of ME ICA512 β2-strand N-glycosylation upon S508A replacement allows for proICA512 dimerization, O-glycosylation, targeting to granules, and conversion, which are instead precluded upon G553D replacement in the ME ICA512 β4-strand. S508A/G553D and N506A/G553D double mutants dimerize but remain in the endoplasmic reticulum. Removal of the N-terminal fragment (ICA512-NTF) preceding ME ICA512 allows an ICA512-ΔNTF G553D mutant to exit the endoplasmic reticulum, and ICA512-ΔNTF is constitutively delivered to the cell surface. The signal for SG sorting is located within the NTF RESP18 homology domain (RESP18-HD), whereas soluble NTF is retained in the endoplasmic reticulum. Hence, we propose that the ME ICA512 β2-strand fosters proICA512 dimerization until NTF prevents N506 glycosylation. Removal of this constraint allows for proICA512 β4-strand-induced dimerization, exit from the endoplasmic reticulum, O-glycosylation, and RESP18-HD-mediated targeting to granules.Instituto Multidisciplinario de Biología Celula

Putting prevention into practice: qualitative study of factors that inhibit and promote preventive care by general practitioners, with a focus on elderly patients

<p>Abstract</p> <p>Background</p> <p>General practitioners (GPs) have a key role in providing preventive care, particularly for elderly patients. However, various factors can inhibit or promote the implementation of preventive care. In the present study, we identified and examined factors that inhibit and promote preventive care by German GPs, particularly for elderly patients, and assessed changes in physicians' attitudes toward preventive care throughout their careers.</p> <p>Methods</p> <p>A qualitative, explorative design was used to identify inhibitors and promoters of preventive care in German general medical practice. A total of 32 GPs in Berlin and Hannover were surveyed. Questions about factors that promote or inhibit implementation of preventive care and changes in physicians' perceptions of promoting and inhibiting factors throughout their careers were identified. Episodic interviews, which encouraged the reporting of anecdotes regarding daily knowledge and experiences, were analyzed using ATLAS/ti. Socio-demographic data of GPs and structural information about their offices were collected using short questionnaires. The factors identified as inhibitory or promoting were classified as being related to patients, physicians, or the healthcare system. The changes in GP attitudes toward preventive care throughout their careers were classified as personal transitions or as social and health policy transitions.</p> <p>Results</p> <p>Most of the identified barriers to preventive care were related to patients, such as a lack of motivation for making lifestyle changes and a lack of willingness to pay for preventive interventions. In addition, the healthcare system seemed to inadequately promote preventive care, mainly due to poor reimbursement for preventive care and fragmentation of care. GPs own attitudes and health habits seemed to influence the implementation of preventive care. GPs recognized their own lack of awareness of effective preventive interventions, particularly for elderly patients. GPs were motivated by positive preventive experiences, but often lacked the necessary training to counsel and support their patients.</p> <p>Conclusions</p> <p>German GPs had positive attitudes towards prevention, but the implementation of preventive care was neither systematic nor continuous. Identification and elimination of barriers to preventive care is crucial. Further research is needed to identify effective practice-based approaches to overcome these barriers.</p

Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits

The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Throug