Hidden intrabasin extension: Evidence for dike-fault interaction from magnetic, gravity, and seismic reflection data in Surprise Valley, northeastern California

The relative contributions of tectonic and magmatic processes to continental rifting are highly variable. Magnetic, gravity, and seismic reflection data from Surprise Valley, California, in the northwest Basin and Range, reveal an intrabasin, fault-controlled, ~10-m-thick dike at a depth of ~150 m, providing an excellent example of the interplay between faulting and dike intrusion. The dike, likely a composite structure representing multiple successive intrusions, is inferred from modeling a positive magnetic anomaly that extends ~35 km and parallels the basin-bounding Surprise Valley normal fault on the west side of the valley. A two-dimensional high-resolution seismic reflection profile acquired across the magnetic high images a normal fault dipping 56°E with ~275 m of throw buried ~60 m below the surface. Densely spaced gravity measurements reveal a \u3c1 mGal gravity low consistent with the fault offset inferred from the seismic data. Collinearity of the magnetic high and gravity low for ~6 km implies normal fault control of the dike along that length. The unusually shallow angle of the dike suggests that motion along the fault (perhaps aided by reduced friction along the dike) and associated block rotation resulted in post-intrusion tilting of the dike. The source of the dike is likely related to a shallow brittle-ductile transition zone that was elevated following rapid slip on the Surprise Valley fault after 3 Ma. Prior to our work, the Surprise Valley fault was assumed to accommodate the vast majority of extension across the region. Our results indicate that subsurface features, although no longer active, are significant contributors to the processes, timing, and total amount of extension observed in continental rift environments

Selective Chemokine Receptor Usage by Central Nervous System Myeloid Cells in CCR2-Red Fluorescent Protein Knock-In Mice

Background: Monocyte subpopulations distinguished by differential expression of chemokine receptors CCR2 and CX3CR1 are difficult to track in vivo, partly due to lack of CCR2 reagents. Methodology/Principal Findings: We created CCR2-red fluorescent protein (RFP) knock-in mice and crossed them with CX3CR1-GFP mice to investigate monocyte subset trafficking. In mice with experimental autoimmune encephalomyelitis, CCR2 was critical for efficient intrathecal accumulation and localization of Ly6C hi /CCR2 hi monocytes. Surprisingly, neutrophils, not Ly6C lo monocytes, largely replaced Ly6C hi cells in the central nervous system of these mice. CCR2-RFP expression allowed the first unequivocal distinction between infiltrating monocytes/macrophages from resident microglia. Conclusion/Significance: These results refine the concept of monocyte subsets, provide mechanistic insight about monocyte entry into the central nervous system, and present a novel model for imaging and quantifying inflammatory myeloid populations

The diverse molecular profiles of lynch syndrome-associated colorectal cancers are (highly) dependent on underlying germline mismatch repair mutations

Lynch syndrome (LS) is a hereditary cancer syndrome that accounts for 3% of all new colorectal cancer (CRC) cases. Patients carry a germline pathogenic variant in one of the mismatch repair (MMR) genes (MLH1, MSH2, MSH6 or PMS2), which encode proteins involved in a post-replicative proofreading and editing mechanism. The clinical presentation of LS is highly heterogeneous, showing high variability in age at onset and penetrance of cancer, which may be partly attributable to the molecular profiles of carcinomas. This review discusses the frequency of alterations in the WNT/B-CATENIN, RAF/MEK/ERK and PI3K/PTEN/AKT pathways identified in all four LS subgroups and how these changes may relate to the 'three pathway model' of carcinogenesis, in which LS CRCs develop from MMR-proficient adenomas, MMR-deficient adenomas or directly from MMR-deficient crypts. Understanding the specific differences in carcinogenesis for each LS subgroup will aid in the further optimization of guidelines for diagnosis, surveillance and treatment.Molecular tumour pathology - and tumour geneticsMTG2 - Moleculaire genetica van gastrointestinale tumore

Genomic properties of variably methylated retrotransposons in mouse

Abstract: Background: Transposable elements (TEs) are enriched in cytosine methylation, preventing their mobility within the genome. We previously identified a genome-wide repertoire of candidate intracisternal A particle (IAP) TEs in mice that exhibit inter-individual variability in this methylation (VM-IAPs) with implications for genome function. Results: Here we validate these metastable epialleles and discover a novel class that exhibit tissue specificity (tsVM-IAPs) in addition to those with uniform methylation in all tissues (constitutive- or cVM-IAPs); both types have the potential to regulate genes in cis. Screening for variable methylation at other TEs shows that this phenomenon is largely limited to IAPs, which are amongst the youngest and most active endogenous retroviruses. We identify sequences enriched within cVM-IAPs, but determine that these are not sufficient to confer epigenetic variability. CTCF is enriched at VM-IAPs with binding inversely correlated with DNA methylation. We uncover dynamic physical interactions between cVM-IAPs with low methylation ranges and other genomic loci, suggesting that VM-IAPs have the potential for long-range regulation. Conclusion: Our findings indicate that a recently evolved interplay between genetic sequence, CTCF binding, and DNA methylation at young TEs can result in inter-individual variability in transcriptional outcomes with implications for phenotypic variation

Understanding context in knowledge translation: a concept analysis study protocol

AimTo conduct a concept analysis of clinical practice contexts (work environments) that facilitate or militate against the uptake of research evidence by healthcare professionals in clinical practice. This will involve developing a clear definition of context by describing its features, domains and defining characteristics.BackgroundThe context where clinical care is delivered influences that care. While research shows that context is important to knowledge translation (implementation), we lack conceptual clarity on what is context, which contextual factors probably modify the effect of knowledge translation interventions (and hence should be considered when designing interventions) and which contextual factors themselves could be targeted as part of a knowledge translation intervention (context modification).DesignConcept analysis.MethodsThe Walker and Avant concept analysis method, comprised of eight systematic steps, will be used: (1) concept selection; (2) determination of aims; (3) identification of uses of context; (4) determination of defining attributes of context; (5) identification/construction of a model case of context; (6) identification/construction of additional cases of context; (7) identification/construction of antecedents and consequences of context; and (8) definition of empirical referents of context. This study is funded by the Canadian Institutes of Health Research (January 2014).DiscussionThis study will result in a much needed framework of context for knowledge translation, which identifies specific elements that, if assessed and used to tailor knowledge translation activities, will result in increased research use by nurses and other healthcare professionals in clinical practice, ultimately leading to better patient care.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111196/1/jan12574.pd

Velocity structure of the Ligurian Sea (Mediterranean Sea) revealed by ambient noise tomography using ocean bottom seismometer data

The Liguro-Provencal-basin was formed as a back-arc basin of the retreating Calabrian-Apennines subduction zone during the Oligocene and Miocene. The resulting rotation of the Corsica-Sardinia block at roughly 32–24 Ma is associated with rifting, shaping the Ligurian Sea. It is highly debated though, whether oceanic or atypical oceanic crust was formed or if the crust is of continental nature, which was extremely thinned during opening of the basin. In order to investigate the velocity structure of the Ligurian Sea a network (LOBSTER) of 29 broadband Ocean Bottom Seismometer (OBS) was installed jointly by GEOMAR (Germany) and ISTerre (France). The LOBSTER array measured continuously for eight months between June 2017 and February 2018 and is part of the AlpArray seismic network. AlpArray is a European initiative to further reveal the geophysical and geological properties of the greater Alpine area. We contribute to the debate by surveying the type of crust and lithosphere flooring the Ligurian Sea. Because of additional noise sources in the ocean, causing instrument tilt or seafloor compliance, OBS data are rarely used for ambient noise studies. However, we extensively pre-process the data to improve the signal-to-noise ratio. Then, we calculate daily cross-correlation functions for the LOBSTER array and surrounding land stations. We use teleseismic events by correlating short time windows that include strong events. Those cross-correlations are dominated by earthquake signals and allow to derive surface wave group velocities for longer periods than using AN. Finally, phase velocity maps are obtained by inverting Green’s functions derived from cross-correlation of ambient noise (AN) and teleseismic events. In the course of this ongoing project we target to derive 3D velocity models of the adjacent Alpine belt region and its complex subduction geometry contributing to questions like the prolongation of the Alpine from beneath the Ligurian Sea

Extremely thinned continental crust underneath the Ligurian Basin?

The Ligurian Basin is situated at the transition from the western Alpine orogeny to the Apennine system, an area where a change in subduction polarity is observed. The back-arc basin was generated by the southeast trench retreat of the Apennines-Calabrian subduction zone. The opening took place from late Oligocene to Miocene. While the extension led to continental thinning and subsidence, oceanic spreading with unroofing of mantle material was proposed for the late opening period, 21-16 Ma. To shed light on the present day crustal and lithospheric architecture of the Ligurian Basin, active and passive seismic data have been recorded on ocean bottom seismometers of a long-term network consisting of 29 broad-band stations, installed from June 2017 to February 2018 in the framework of SPP2017 4D-MB, the German component of AlpArray. Two refraction seismic profiles were shot to serve two aspects: (1) Determine the orientation of the horizontal components of the long-term instruments and (2) estimate the velocity distribution of the upper lithosphere, to provide a velocity model for the passive seismic data analysis. Good quality data have been recorded, regional and teleseismic events as well as active shots could be detected by the network stations. The majority of the refraction seismic data show mantle phases at offsets up to 70 km and a very prominent wide-angle reflection originating at the crust mantle boundary. Its features share a number of characteristics (i.e. offset range, continuity) generally associated with continental settings rather than mimicking seafloor spreading lithosphere emplaced in back-arc basins. Based on traveltime tomography along the refraction lines, the crust-mantle boundary is determined at ~9.5 km depth below seafloor. The acoustic basement is difficult to map seismically. The transition to the crystalline basement is indicated at a depth of ~6.5 km below seafloor. The absolute seismic velocities can be interpreted as hyper-extended continental crust or serpentinised mantle. The thick sedimentary coverage allows for long lasting extension of the crust. The crustal portion interpreted from the seismic velocities thickens towards the north which is in good agreement with the anti-clockwise rotation of the Corsica-Sardinia block and an associated gradual opening of the Ligurian Basin

Phase I, Pharmacogenomic, Drug Interaction Study of Sorafenib and Bevacizumab in Combination with Paclitaxel in Patients with Advanced Refractory Solid Tumors

VEGF blockade does not uniformly result in clinical benefit. We evaluated safety, dose-limiting toxicities (DLT), recommended phase II dose (RP2D), antitumor efficacy, and exploratory biomarkers including pharmacogenomics and pharmacokinetics with sorafenib, bevacizumab, and paclitaxel in patients with refractory cancers. The study had a “3 + 3” design, using paclitaxel 80 mg/m2 every week for 3 weeks, in every 4 week cycles, bevacizumab 5 mg/kg every 2 weeks, and sorafenib 200 or 400 mg twice a day, 5 or 7 days/week (5/7, 7/7). The MTD cohort was expanded. Twenty-seven patients enrolled in 3 cohorts: sorafenib 200 mg twice a day 5/7, 200 mg twice a day 7/7, and 400 mg twice a day 5/7. DLTs were grade 3 neutropenia >7 days (cohort 1, 1), grade 3 hypertension (cohort 2, 1), grade 3 hand–foot skin reaction (HFSR; cohort 3, 2). MTD was sorafenib 200 mg twice a day 7/7. Six DLTs occurred in cohort 2 expansion: grade 3 HFSR (2), grade 2 HFSR with sorafenib delay >7 days (2), grade 4 cerebrovascular accident (1), grade 3 neutropenia >7 days (1). RP2D was sorafenib 200 mg twice a day 5/7. Most patients (62%) dose reduced sorafenib to 200 mg daily 5/7 after a median 3 (range, 2–17) cycles. Response rates were 48% overall (27) and 64% for ovarian cancers (14). VEGF-A-1154AA and -7TT recessive homozygous genotypes conferred worse overall survival versus alternative genotypes (7 vs. 22 months). Intermittent, low-dose sorafenib (200 mg twice a day 5/7) combined with bevacizumab and paclitaxel was tolerable and had high antitumor efficacy in patients with refractory cancer (NCT00572078)