Phosphorylation at serines 104 and 106 by Erk1/2 MAPK is important for estrogen receptor-α activity

Phosphorylation of estrogen receptor-α (ERα) at specific residues in transcription activation function 1 (AF-1) can stimulate ERα activity in a ligand-independent manner. This has led to the proposal that AF-1 phosphorylation and the consequent increase in ERα activity could contribute to resistance to endocrine therapies in breast cancer patients. Previous studies have shown that serine 118 (S118) in AF-1 is phosphorylated by extracellular signal-regulated kinases 1 and 2 (Erk1/2) mitogen-activated protein kinase (MAPK) in a ligand-independent manner. Here, we show that serines 104 (S104) and 106 (S106) are also phosphorylated by MAPK in vitro and upon stimulation of MAPK activity in vivo. Phosphorylation of S104 and S106 can be inhibited by the MAP-erk kinase (MEK)1/2 inhibitor U0126 and by expression of kinase-dead Raf1. Further, we show that, although S118 is important for the stimulation of ERα activity by the selective ER modulator 4-hydroxytamoxifen (OHT), S104 and S106 are also required for the agonist activity of OHT. Acidic amino acid substitution of S104 or S106 stimulates ERα activity to a greater extent than the equivalent substitution at S118, suggesting that phosphorylation at S104 and S106 is important for ERα activity. Collectively, these data indicate that the MAPK stimulation of ERα activity involves the phosphorylation not only of S118 but also of S104 and S106, and that MAPK-mediated hyperphosphorylation of ERα at these sites may contribute to resistance to tamoxifen in breast cancer

System and Methods for Deploying Payloads

Embodiments of the present invention include systems for launching primary or secondary payloads or actuating other launch vehicle or payload or instrumentation devices. The system includes an adapter assembly and at least one sequencer mounted to the adapter assembly. The sequencer includes: controller boards, each of the controller boards having a controller for controlling deployment of the payloads and data files; output ports coupled to the controller boards and configured to transmit signals from the controller boards to dispensers therethrough, deployment mechanisms containing the payloads, the adapter assembly having channels for accommodating the dispensers; and a detector coupled to the controller boards and adapted to detect an external signal and, in response to the external signal, to send an initiation signal to the controller boards. The system also includes at least one power supply coupled to the sequencer and adapted to provide an electrical power to the sequencer

A retrospective comparative outcome analysis following systemic therapy in Mycosis fungoides and Sezary syndrome

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134845/1/ajh24564_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134845/2/ajh24564.pd

Real-time observation of the dry oxidation of the Si(100) surface with ambient pressure x-ray photoelectron spectroscopy

We have applied ambient-pressure x-ray photoelectron spectroscopy with Si 2p chemical shifts to study the real-time dry oxidation of Si(100), using pressures in the range of 0.01-1 Torr and temperatures of 300-530 ??C, and examining the oxide thickness range from 0 to ???25 A. The oxidation rate is initially very high (with rates of up to ???225 Ah) and then, after a certain initial thickness of the oxide in the range of 6-22 A is formed, decreases to a slow state (with rates of ???1.5-4.0 Ah). Neither the rapid nor the slow regime is explained by the standard Deal-Grove model for Si oxidation.open171

The implementation research institute: Training mental health implementation researchers in the United States

Abstract Background The Implementation Research Institute (IRI) provides two years of training in mental health implementation science for 10 new fellows each year. The IRI is supported by a National Institute of Mental Health (NIMH) R25 grant and the Department of Veterans Affairs (VA). Fellows attend two annual week-long trainings at Washington University in St. Louis. Training is provided through a rigorous curriculum, local and national mentoring, a ‘learning site visit’ to a federally funded implementation research project, pilot research, and grant writing. Methods This paper describes the rationale, components, outcomes to date, and participant experiences with IRI. Results IRI outcomes include 31 newly trained implementation researchers, their new grant proposals, contributions to other national dissemination and implementation research training, and publications in implementation science authored by the Core Faculty and fellows. Former fellows have obtained independent research funding in implementation science and are beginning to serve as mentors for more junior investigators. Conclusions Based on the number of implementation research grant proposals and papers produced by fellows to date, the IRI is proving successful in preparing new researchers who can inform the process of making evidence-based mental healthcare more available through real-world settings of care and who are advancing the field of implementation science

Effect of increasing fruit and vegetable intake by dietary intervention on nutritional biomarkers and attitudes to dietary change : a randomised trial

This work was funded by The Scottish Government Rural and Environmental Science and Analytical Sciences Division (RESAS) and supported by the Rank Prize Funds.Peer reviewedPublisher PD

In situ observation of wet oxidation kinetics on Si(100) via ambient pressure x-ray photoemission spectroscopy

e initial stages of wet thermal oxidation of Si (100) - (2??1) have been investigated by in situ ambient pressure x-ray photoemission spectroscopy, including chemical-state resolution via Si 2p core-level spectra. Real-time growth rates of silicon dioxide have been monitored at 100 mTorr of water vapor. This pressure is considerably higher than in any prior study using x-ray photoemission spectroscopy. Substrate temperatures have been varied between 250 and 500 ??C. Above a temperature of ???400 ??C, two distinct regimes, a rapid and a quasisaturated one, are identified, and growth rates show a strong temperature dependence which cannot be explained by the conventional Deal-Grove model.open7

Missing Clinical Information in NHS hospital outpatient clinics: prevalence, causes and effects on patient care

In Britain over 39,000 reports were received by the National Patient Safety Agency relating to failures in documentation in 2007 and the UK Health Services Journal estimated in 2008 that over a million hospital outpatient visits each year might take place without the full record available. Despite these high numbers, the impact of missing clinical information has not been investigated for hospital outpatients in the UK.Studies in primary care in the USA have found 13.6% of patient consultations have missing clinical information, with this adversely affecting care in about half of cases, and in Australia 1.8% of medical errors were found to be due to the unavailability of clinical information.Our objectives were to assess the frequency, nature and potential impact on patient care of missing clinical information in NHS hospital outpatients and to assess the principal causes. This is the first study to present such figures for the UK and the first to look at how clinicians respond, including the associated impact on patient care

Spatiotemporal structure of intracranial electric fields induced by transcranial electric stimulation in humans and nonhuman primates

Transcranial electric stimulation (TES) is an emerging technique, developed to non-invasively modulate brain function. However, the spatiotemporal distribution of the intracranial electric fields induced by TES remains poorly understood. In particular, it is unclear how much current actually reaches the brain, and how it distributes across the brain. Lack of this basic information precludes a firm mechanistic understanding of TES effects. In this study we directly measure the spatial and temporal characteristics of the electric field generated by TES using stereotactic EEG (s-EEG) electrode arrays implanted in cebus monkeys and surgical epilepsy patients. We found a small frequency dependent decrease (10%) in magnitudes of TES induced potentials and negligible phase shifts over space. Electric field strengths were strongest in superficial brain regions with maximum values of about 0.5 mV/mm. Our results provide crucial information of the underlying biophysics in TES applications in humans and the optimization and design of TES stimulation protocols. In addition, our findings have broad implications concerning electric field propagation in non-invasive recording techniques such as EEG/MEG

Geographic variation in phenotypic divergence between two hybridizing field cricket species

Patterns of morphological divergence across species' ranges can provide insight into local adaptation and speciation. In this study, we compared phenotypic divergence among 4,221 crickets from 337 populations of two closely related species of field cricket, Gryllus firmus and G. pennsylvanicus, and their hybrids. We found that these species differ across their geographic range in key morphological traits, such as body size and ovipositor length, and we directly compared phenotype with genotype for a subset of crickets to demonstrate nuclear genetic introgression, phenotypic intermediacy of hybrids, and essentially unidirectional mitochondrial introgression. We discuss how these morphological traits relate to life history differences between the two species. Our comparisons across geographic areas support prior research suggesting that cryptic variation within G. firmus may represent different species. Our study highlights how variable morphology can be across wide-ranging species and the importance of studying reproductive barriers in more than one or two transects of a hybrid zone