Our current understanding of epidermal growth factor receptor (EGFR) autoinhibition is based on X-ray structural data of monomer and dimer receptor fragments and does not explain how mutations ...achieve ligand-independent phosphorylation. Using a repertoire of imaging technologies and simulations we reveal an extracellular head-to-head interaction through which ligand-free receptor polymer chains of various lengths assemble. The architecture of the head-to-head interaction prevents kinase-mediated dimerisation. The latter, afforded by mutation or intracellular treatments, splits the autoinhibited head-to-head polymers to form stalk-to-stalk flexible non-extended dimers structurally coupled across the plasma membrane to active asymmetric tyrosine kinase dimers, and extended dimers coupled to inactive symmetric kinase dimers. Contrary to the previously proposed main autoinhibitory function of the inactive symmetric kinase dimer, our data suggest that only dysregulated species bear populations of symmetric and asymmetric kinase dimers that coexist in equilibrium at the plasma membrane under the modulation of the C-terminal domain.
Differences in Vertebrate MicroRNA Expression Ason, Brandon; Darnell, Diana K.; Wittbrodt, Beate ...
Proceedings of the National Academy of Sciences - PNAS,
09/2006, Volume:
103, Issue:
39
Journal Article
Peer reviewed
Open access
MicroRNAs (miRNAs) attenuate gene expression by means of translational inhibition and mRNA degradation. They are abundant, highly conserved, and predicted to regulate a large number of transcripts. ...Several hundred miRNA classes are known, and many are associated with cell proliferation and differentiation. Many exhibit tissue-specific expression, which aids in evaluating their functions, and it has been assumed that their high level of sequence conservation implies a high level of expression conservation. A limited amount of data supports this, although discrepancies do exist. By comparing the expression of ≈100 miRNAs in medaka and chicken with existing data for zebrafish and mouse, we conclude that the timing and location of miRNA expression is not strictly conserved. In some instances, differences in expression are associated with changes in miRNA copy number, genomic context, or both between species. Variation in miRNA expression is more pronounced the greater the differences in physiology, and it is enticing to speculate that changes in miRNA expression may play a role in shaping the physiological differences produced during animal development.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Liquid metals (LMs) are emerging as unique fluids for a variety of applications, but their nanoscale solvation properties remain largely understudied. In this work, a combination of atomic force ...microscopy (AFM) and molecular dynamics (MD) simulations are used to investigate the structure of the interface between the bulk room temperature liquid metal (RTLM) and the LM oxide in nanodroplet systems of gallium, EGaIn (75.5% gallium, 24.5% indium), and Galinstan (68.5% gallium, 21.5% indium, 10% tin). Field's metal (51% indium, 32.5% bismuth, 16.5% tin) is also investigated, which melts at ≈62 °C, as a contrast to the other systems. AFM measurements reveal distinct sub‐oxide nanostructured layering in all three RTLM systems, and Field's metal above the melting point, to differing degrees. EGaIn and Galinstan show multiple penetration events between 20 and 30 nm, with smaller, less complex events in Ga. MD simulations suggest that this layering is a result of the near‐surface ordering of LM atoms beneath the oxide layer. Importantly, the atoms in this region do not behave as solids but are more ordered than in a pure disordered liquid system. The surface nanostructure elucidated here significantly expands the understanding of LM systems and their behavior at interfaces.
Atomic force microscopy and molecular dynamics simulations reveal distinct sub‐oxide nanostructured layering in room‐temperature liquid metals.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract
We augment the heliospheric network of galactic cosmic ray (GCR) monitors using 2012–2017 penetrating radiation measurements from the New Horizons (NH) Pluto Energetic Particle Spectrometer ...Science Investigation (PEPSSI), obtaining intensities of ≳75 MeV particles. The new, predominantly GCR observations provide critical links between the Sun and Voyager 2 and Voyager 1 (V2 and V1), in the heliosheath and local interstellar medium (LISM), respectively. We provide NH, Advanced Composition Explorer (ACE), V2, and V1 GCR observations, using them to track solar cycle variations and short-term Forbush decreases from the Sun to the LISM, and to examine the interaction that results in the surprising, previously reported V1 LISM anisotropy episodes. To investigate these episodes and the hitherto unexplained lagging of associated in situ shock features at V1, propagating disturbances seen at ACE, NH, and V2 were compared to V1. We conclude that the region where LISM magnetic field lines drape around the heliopause is likely critical for communicating solar disturbance signals upstream of the heliosheath to V1. We propose that the anisotropy-causing physical process that suppresses intensities at ∼90° pitch angles relies on GCRs escaping from a single compression in the draping region, not on GCRs trapped between two compressions. We also show that NH suprathermal and energetic particle data from PEPSSI are consistent with the interpretation that traveling shocks and corotating interaction region (CIR) remnants can be distinguished by the existence or lack of Forbush decreases, respectively, because turbulent magnetic fields at local shocks inhibit GCR transport while older CIR structures reaching the outer heliosphere do not.
The effect of inducers of systemic acquired resistance, dichloroisonicotinic acid (DCINA) and acibenzolar‐S‐methyl (BION), on compatible interactions between Bremia lactucae and lettuce were examined ...using a detached cotyledon infection assay. Treatment with both activators caused a reduction in sporulation on susceptible cultivars Cobham Green challenged with isolate CL9W and Diana inoculated with isolate Tv, with DCINA being more effective than BION on an equimolar basis. Unexpectedly, treatment with both compounds suppressed the resistance conferred by the Dm7 gene in cv. Diana challenged by isolate CL9W (A7). The frequency of sporulation was greatly increased by DCINA in the incompatible interaction. The suppression of defence was associated with a delay in the onset of the Dm7‐based hypersensitive reaction as indicated by the extended viability of penetrated epidermal cells, and reductions in both the accumulation of the phytoalexin lettucenin A and the deposition of autofluorescent phenolics such as syringaldehyde on plant and oomycete cell walls. The analysis of DCINA homologues indicated that 2‐chloroisonicotinic acid was as effective as the dichloro‐derivative in suppressing resistance in cv. Diana, whereas the absence of the carboxyl group rendered 2,6‐dichloropyridine inactive. Infection of cotyledons by Botrytis cinerea was also found to be enhanced by DCINA treatment. Based on our results, we discuss the possibility that DCINA reduces Dm7 transcription through an epigenetic mechanism, as is supported by bioinformatic analyses of the resistance gene, and that it suppresses jasmonate‐dependent resistance to B. cinerea.
The striking suppression of R gene‐mediated defence by the SAR inducer was linked to a delay in the Dm7‐based HR, and reductions in both the accumulation of the phytoalexin lettucenin A and the deposition of autofluorescent phenolics.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background: Histone deacetylase blockade can promote heat shock protein 90 (HSP90) acetylation, abrogating androgen receptor signaling. A phase II trial of the histone deacetylase inhibitor (HDACi) ...romidepsin was conducted in patients with progressing, metastatic, castration-resistant prostate cancer (CRPC). Patients and methods: A dose of 13 mg/m2 was administered i.v. over 4 h on days 1, 8 and 15 every 28 days. The primary end point was rate of disease control defined as no evidence of radiological progression at 6 months. A sample size of 16 assessable patients in stage 1 and nine assessable patients in stage 2 was selected; progression to stage 2 required one or more patients with disease control in stage 1 (Ho = 0.10, Ha = 0.30; α and β = 0.10). Results: Thirty-five patients were enrolled. Two patients achieved a confirmed radiological partial response (RECIST) lasting ≥6 months, along with a confirmed prostate-specific antigen decline of ≥50%. Eleven patients experienced toxicity necessitating early discontinuation. The commonest adverse events were nausea (30 patients; 85.7%), fatigue (28 patients; 80.0%), vomiting (23 patients; 65.7%) and anorexia (20 patients; 57.1%). There was no significant cardiac toxicity. Conclusions: At the dose and schedule selected, romidepsin demonstrated minimal antitumor activity in chemonaive patients with CRPC. Further studies of improved HDACi, alone and in combination with other therapies, should nevertheless be investigated.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Usability of FDA-Approved Medication Guides Wolf, Michael S.; King, Jennifer; Wilson, Elizabeth A. H. ...
Journal of general internal medicine,
12/2012, Volume:
27, Issue:
12
Journal Article
Peer reviewed
Open access
BACKGROUND
Medication guides are required documents to be distributed to patients in order to convey serious risks associated with certain prescribed medicines. Little is known about the ...effectiveness of this information to adequately inform patients on safe use.
OBJECTIVE
To examine the readability, suitability, and comprehensibility of medication guides, particularly for those with limited literacy.
DESIGN
Assessments of suitability and readability of 185 medication guides, and a sub-study examining change in suitability and readability from 2006 to 2010 among 32 of the medication guides (Study 1); ‘open book’ comprehension assessment of medication guides (Study 2).
SETTING
Two general internal medicine clinics in Chicago, IL.
PATIENTS
Four hundred and forty-nine adults seeking primary care services, ages 18–85.
MEASUREMENTS
For Study 1, the Suitability Assessment of Materials (SAM) and Lexile score for readability. For Study 2, a tailored comprehension assessment of content found in three representative medication guides.
RESULTS
The 185 analyzed medication guides were on average 1923 words (SD = 1022), with a mean reading level of 10–11th grade. Only one medication guide was deemed suitable in SAM analyses. None provided summaries or reviews, or framed the context first, while very few were rated as having made the purpose evident (8 %), or limited the scope of content (22 %). For Study 2, participants’ comprehension of medication guides was poor (M = 52.7 % correct responses, SD = 22.6). In multivariable analysis, low and marginal literacy were independently associated with poorer understanding (β = –14.3, 95 % CI –18.0 – –10.6, p < 0.001; low: β = –23.7, 95 % CI –28.3 – –19.0, p < 0.001).
CONCLUSION
Current medication guides are of little value to patients, as they are too complex and difficult to understand especially for individuals with limited literacy. Explicit guidance is offered for improving these print materials.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background: The purpose of this study was to evaluate the association of circulating tumour cell (CTC) counts, before and after commencing treatment, with overall survival (OS) in patients with ...castration-resistant prostate cancer (CRPC).
Experimental design: A 7.5ml of blood was collected before and after treatment in 119 patients with CRPC. CTCs were enumerated using the CellSearch®System.
Results: Higher CTC counts associated with baseline characteristics portending aggressive disease. Multivariate analyses indicated that a CTC ≥5 was an independent prognostic factor at all time points evaluated. Patients with baseline CTC ≥5 had shorter OS than those with <5 median OS 19.5 versus >30 months, hazard ratio (HR) 3.25, P = 0.012; patients with CTC >50 had a poorer OS than those with CTCs 5–50 (median OS 6.3 versus 21.1 months, HR 4.1, P < 0.001). Patients whose CTC counts reduced from ≥5 at baseline to <5 following treatment had a better OS compared with those who did not. CTC counts showed a similar, but earlier and independent, ability to time to disease progression to predict OS.
Conclusion: CTC counts predict OS and provide independent prognostic information to time to disease progression; CTC dynamics following therapy need to be evaluated as an intermediate end point of outcome in randomised phase III trials.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Extrastriate visual area V5/MT in primates is defined both structurally by myeloarchitecture and functionally by distinct responses to visual motion. Myelination is directly identifiable from ...postmortem histology but also indirectly by image contrast with structural magnetic resonance imaging (sMRI). First, we compared the identification of V5/MT using both sMRI and histology in Rhesus macaques. A section-by-section comparison of histological slices with in vivo and postmortem sMRI for the same block of cortical tissue showed precise correspondence in localizing heavy myelination for V5/MT and neighboring MST. Thus, sMRI in macaques accurately locates histologically defined myelin within areas known to be motion selective. Second, we investigated the functionally homologous human motion complex (hMT+) using high-resolution in vivo imaging. Humans showed considerable intersubject variability in hMT+ location, when defined with myelin-weighted sMRI signals to reveal structure. When comparing sMRI markers to functional MRI in response to moving stimuli, a region of high myelin signal was generally located within the hMT+ complex. However, there were considerable differences in the alignment of structural and functional markers between individuals. Our results suggest that variation in area identification for hMT+ based on structural and functional markers reflects individual differences in human regional brain architecture.
The AAO/UKST SuperCOSMOS Hα survey Parker, Quentin A.; Phillipps, S.; Pierce, M. J. ...
Monthly Notices of the Royal Astronomical Society,
09/2005, Volume:
362, Issue:
2
Journal Article
Peer reviewed
Open access
The UK Schmidt Telescope (UKST) of the Anglo-Australian Observatory completed a narrow-band Hα plus N ii 6548, 6584-Å survey of the Southern Galactic Plane and Magellanic Clouds in late 2003. The ...survey, which was the last UKST wide-field photographic survey and the only one undertaken in a narrow-band, is now an online digital data product of the Wide-Field Astronomy Unit of the Royal Observatory Edinburgh (ROE). The survey utilized a high specification, monolithic Hα interference bandpass filter of exceptional quality. In conjunction with the fine-grained Tech-Pan film as a detector it has produced a survey with a powerful combination of area coverage (4000 square degrees), resolution (∼1 arcsec) and sensitivity (≤5 Rayleighs), reaching a depth for continuum point sources of R≃ 20.5. The main survey consists of 233 individual fields on a grid of centres separated by 4° at declinations below +2° and covers a swathe approximately 20° wide about the Southern Galactic Plane. The original survey films were scanned by the SuperCOSMOS measuring machine at the Royal Observatory, Edinburgh, to provide the online digital atlas called the SuperCOSMOS Hα Survey (SHS). We present the background of the survey, the key survey characteristics, details and examples of the data product, calibration process, comparison with other surveys and a brief description of its potential for scientific exploitation.
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BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
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