Controls on the location of compressional deformation on the NW European margin

The distribution of Cenozoic compressional structures along the NW European margin has been compared with maps of the thickness of the crystalline crust derived from a compilation of seismic refraction interpretations and gravity modelling, and with the distribution of high-velocity lower crust and/or partially serpentinized upper mantle detected by seismic experiments. Only a subset of the mapped compressional structures coincide with areas susceptible to lithospheric weakening as a result of crustal hyperextension and partial serpentinization of the upper mantle. Notably, partially serpentinized upper mantle is well documented beneath the central part of the southern Rockall Basin, but compressional features are sparse in that area. Where compressional structures have formed but the upper mantle is not serpentinized, simple rheological modelling suggests an alternative weakening mechanism involving ductile lower crust and lithospheric decoupling. The presence of pre-existing weak zones (associated with the properties of the gouge and overpressure in fault zones) and local stress magnitude and orientation are important contributing factors

A patient-derived xenograft pre-clinical trial reveals treatment responses and a resistance mechanism to karonudib in metastatic melanoma

Karonudib (TH1579) is a novel compound that exerts anti-tumor activities and has recently entered phase I clinical testing. The aim of this study was to conduct a pre-clinical trial in patient-derived xenografts to identify the possible biomarkers of response or resistance that could guide inclusion of patients suffering from metastatic melanoma in phase II clinical trials. Patient-derived xenografts from 31 melanoma patients with metastatic disease were treated with karonudib or a vehicle for 18 days. Treatment responses were followed by measuring tumor sizes, and the models were categorized in the response groups. Tumors were harvested and processed for RNA sequencing and protein analysis. To investigate the effect of karonudib on T-cell-mediated anti-tumor activities, tumor-infiltrating T cells were injected in mice carrying autologous tumors and the mice treated with karonudib. We show that karonudib has heterogeneous anti-tumor effect on metastatic melanoma. Thus, based on the treatment responses, we could divide the 31 patient-derived xenografts in three treatment groups: progression group (32%), suppression group (42%), and regression group (26%). Furthermore, we show that karonudib has anti-tumor effect, irrespective of major melanoma driver mutations. Also, we identify high expression of ABCB1, which codes for p-gp pumps as a resistance biomarker. Finally, we show that karonudib treatment does not hamper T-cell-mediated anti-tumor responses. These findings can be used to guide future use of karonudib in clinical use with a potential approach as precision medicine

Structural insights into crista junction formation by the Mic60-Mic19 complex

Mitochondrial cristae membranes are the oxidative phosphorylation sites in cells. Crista junctions (CJs) form the highly curved neck regions of cristae and are thought to function as selective entry gates into the cristae space. Little is known about how CJs are generated and maintained. We show that the central coiled-coil (CC) domain of the mitochondrial contact site and cristae organizing system subunit Mic60 forms an elongated, bow tie–shaped tetrameric assembly. Mic19 promotes Mic60 tetramerization via a conserved interface between the Mic60 mitofilin and Mic19 CHCH (CC-helix-CC-helix) domains. Dimerization of mitofilin domains exposes a crescent-shaped membrane-binding site with convex curvature tailored to interact with the curved CJ neck. Our study suggests that the Mic60-Mic19 subcomplex traverses CJs as a molecular strut, thereby controlling CJ architecture and function

Search for the K(L) --> PI0 PI0 E+ E- Decay in the KTeV Experiment

The recent discovery of a large CP violating asymmetry in K(L) --> PI+ PI- E+ E- mode has prompted us to seach for the associated K(L) --> PI0 PI0 E+ E- decay mode in the KTeV-E799 experiment at Fermilab. In 2.7E+11 K(L) decays, one candidate event has been observed with an expected background of 0.3 event, resulting in an upper limit for the K(L) --> PI0 PI0 E+ E- branching ratio of 6.6E-09 at the 90% confidence level.Comment: To be published in Phys. Rev. Let

The standard model at low energies

The hadronic sector of the standard model at low energies is described by a non--decoupling effective field theory, chiral perturbation theory. An introduction is given to the construction of effective chiral Lagrangians, both in the purely mesonic sector and with inclusion of baryons. The connection between the relativistic formulation and the heavy baryon approach to chiral perturbation theory with baryons is reviewed.Comment: Lectures given at the 6th Indian-Summer School on Intermediate Energy Physics, Prague, Aug. 1993, Latex, 26 pages (with a4.sty), UWThPh-1993-3

Baseline values from the electrocardiograms of children and adolescents with ADHD

<p>Abstract</p> <p>Background</p> <p>An important issue in pediatric pharmacology is the determination of whether medications affect cardiac rhythm parameters, in particular the QT interval, which is a surrogate marker for the risk of adverse cardiac events and sudden death. To evaluate changes while on medication, it is useful to have a comparison of age appropriate values while off medication. The present meta-analysis provides baseline ECG values (i.e., off medication) from approximately 6000 children and adolescents with attention-deficit/hyperactivity disorder (ADHD).</p> <p>Methods</p> <p>Subjects were aged 6–18 years and participated in global trials within the atomoxetine registration program. Patients were administered a 12-lead ECG at study screening and cardiac rhythm parameters were recorded. Baseline QT intervals were corrected for heart rate using 3 different methods: Bazett's, Fridericia's, and a population data-derived formula.</p> <p>Results</p> <p>ECG data were obtained from 5289 North American and 641 non-North American children and adolescents. Means and percentiles are presented for each ECG measure and QTc interval based on pubertal status as defined by age and sex. Prior treatment history with stimulants and racial origin (Caucasian) were each associated with significantly longer mean QTc values.</p> <p>Conclusion</p> <p>Baseline ECG and QTc data from almost 6000 children and adolescents presenting with ADHD are provided to contribute to the knowledge base regarding mean values for pediatric cardiac parameters. Consistent with other studies of QT interval in children and adolescents, Bazett correction formula appears to overestimate the prevalence of prolonged QTc in the pediatric population.</p