Primary radiation damage in bone evolves via collagen destruction by photoelectrons and secondary emission self-absorption

X-rays are invaluable for imaging and sterilization of bones, yet the resulting ionization and primary radiation damage mechanisms are poorly understood. Here we monitor in-situ collagen backbone degradation in dry bones using second-harmonic-generation and X-ray diffraction. Collagen breaks down by cascades of photon-electron excitations, enhanced by the presence of mineral nanoparticles. We observe protein disintegration with increasing exposure, detected as residual strain relaxation in pre-stressed apatite nanocrystals. Damage rapidly grows from the onset of irradiation, suggesting that there is no minimal ‘safe’ dose that bone collagen can sustain. Ionization of calcium and phosphorous in the nanocrystals yields fluorescence and high energy electrons giving rise to structural damage that spreads beyond regions directly illuminated by the incident radiation. Our findings highlight photoelectrons as major agents of damage to bone collagen with implications to all situations where bones are irradiated by hard X-rays and in particular for small-beam mineralized collagen fiber investigations

Bicyclic imidazolium inhibitors of Gli transcription factor activity

Gli transcription factors within the Hedgehog (Hh) signaling pathway direct key events in mammalian development and promote a number of human cancers. Current therapies for Gli‐driven tumors target Smoothened (SMO), a G protein‐coupled receptor‐like protein that functions upstream in the Hh pathway. Although these drugs can have remarkable clinical efficacy, mutations in SMO and downstream Hh pathway components frequently lead to chemoresistance. In principle, therapies that act at the level of Gli proteins, through direct or indirect mechanisms, would be more efficacious. We therefore conducted a screen of 325,120 compounds for their ability to block the constitutive Gli activity induced by loss of Suppressor of Fused (SUFU), a scaffolding protein that directly inhibits Gli function. Our studies reveal a family of bicyclic imidazolium derivatives that can inhibit Gli‐dependent transcription without affecting the ciliary trafficking or proteolytic processing of these transcription factors. We anticipate that these chemical antagonists will be valuable tools for investigating the mechanisms of Gli regulation and developing new strategies for targeting Gli‐driven cancers

Híbridos e variedades de milho submetidos à inoculação de sementes com Herbaspirillum seropedicae.

Resumo: A fixação biológica de nitrogênio proporcionada por bactérias diazotróficas pode representar alternativa para a produção de milho em sistemas agrícolas mais sustentáveis ou de baixa utilização de insumos. Objetivando-se avaliar o crescimento, teor e acúmulo de nitrogênio em genótipos de milho, em função da inoculação das sementes com Herbaspirillum seropedicae, foi conduzido experimento em casa de vegetação avaliando-se 35 genótipos de milho híbridos simples, duplo, triplo e variedades. Para inoculação das sementes foi utilizado inoculante turfoso contendo a estirpe bacteriana de H. seropedicae (ZAE 94). Entre os genótipos comerciais de milho estudados, apenas nove híbridos apresentam ganhos de crescimento ou acúmulo de N com a inoculação das sementes com a estirpe Herbaspirillum seropedicae (ZAE 94). Há distinção de resposta entre cultivares de milho em termos de produção de biomassa e incremento de teor de N na parte aérea das plantas. Abstract: The biological nitrogen fixation provided by diazotrophic bacteria may represent an alternative to maize production in more sustainable agricultural systems or low use of technology. In order to evaluate the growth, content and accumulation of nitrogen in corn genotypes, depending on seed inoculation with Herbaspirillum seropedicae experiment was conducted in greenhouse evaluating 35 corn genotypes hybrid single, double, triple and varieties. For seed inoculation was used peat inoculant containing the bacterial strain of H. seropedicae (ZAE 94). Among the commercial corn genotypes studied, only nine hybrids show increase of growth or accumulation of N with the seed inoculation with Herbaspirillum seropedicae (ZAE 94). There is a distinction in response between maize cultivars in terms of biomass production and increase of N content in the shoots

Snow-driven uncertainty in CryoSat-2-derived Antarctic sea ice thickness – insights from McMurdo Sound

Knowledge of the snow depth distribution on Antarctic sea ice is poor but is critical to obtaining sea ice thickness from satellite altimetry measurements of the freeboard. We examine the usefulness of various snow products to provide snow depth information over Antarctic fast ice in McMurdo Sound with a focus on a novel approach using a high-resolution numerical snow accumulation model (SnowModel). We compare this model to results from ECMWF ERA-Interim precipitation, EOS Aqua AMSR-E passive microwave snow depths and in situ measurements at the end of the sea ice growth season in 2011. The fast ice was segmented into three areas by fastening date and the onset of snow accumulation was calibrated to these dates. SnowModel captures the spatial snow distribution gradient in McMurdo Sound and falls within 2&thinsp;cm snow water equivalent (s.w.e) of in situ measurements across the entire study area. However, it exhibits deviations of 5&thinsp;cm&thinsp;s.w.e. from these measurements in the east where the effect of local topographic features has caused an overestimate of snow depth in the model. AMSR-E provides s.w.e. values half that of SnowModel for the majority of the sea ice growth season. The coarser-resolution ERA-Interim produces a very high mean s.w.e. value 20&thinsp;cm higher than the in situ measurements. These various snow datasets and in situ information are used to infer sea ice thickness in combination with CryoSat-2 (CS-2) freeboard data. CS-2 is capable of capturing the seasonal trend of sea ice freeboard growth but thickness results are highly dependent on what interface the retracked CS-2 height is assumed to represent. Because of this ambiguity we vary the proportion of ice and snow that represents the freeboard – a mathematical alteration of the radar penetration into the snow cover – and assess this uncertainty in McMurdo Sound. The ranges in sea ice thickness uncertainty within these bounds, as means of the entire growth season, are 1.08, 4.94 and 1.03&thinsp;m for SnowModel, ERA-Interim and AMSR-E respectively. Using an interpolated in situ snow dataset we find the best agreement between CS-2-derived and in situ thickness when this interface is assumed to be 0.07&thinsp;m below the snow surface.</p

Derivation of Del180 from sediment core log data\u27 Implications for millennial-scale climate change in the Labrador Sea

Sediment core logs from six sediment cores in the Labrador Sea show millennial-scale climate variability during the last glacial by recording all Heinrich events and several major Dansgaard-Oeschger cycles. The same millennial-scale climate change is documented for surface water δ18O records of Neogloboquadrina pachyderma (left coiled); hence the surface water δ18O record can be derived from sediment core logging by means of multiple linear regression, providing a paleoclimate proxy record at very high temporal resolution (70 years). For the Labrador Sea, sediment core logs contain important information about deepwater current velocities and also reflect the variable input of ice-rafted debris from different sources as inferred from grain-size analysis, the relation of density and P wave velocity, and magnetic susceptibility. For the last glacial, faster deepwater currents, which correspond to highs in sediment physical properties, occurred during iceberg discharge and lasted from several centuries to a few millennia. Those enhanced currents might have contributed to increased production of intermediate waters during times of reduced production of North Atlantic Deep Water. Hudson Strait might have acted as a major supplier of detrital carbonate only during lowered sea level (greater ice extent). During coldest atmospheric temperatures over Greenland, deepwater currents increased during iceberg discharge in the Labrador Sea, then surface water freshened shortly thereafter, while the abrupt atmospheric temperature rise happened after a larger time lag of ≥ 1 kyr. The correlation implies a strong link and common forcing for atmosphere, sea surface, and deep water during the last glacial at millennial timescales but decoupling at orbital timescales

Clinical disease course and survival outcomes following disease recurrence in adenoid cystic carcinoma with and without NOTCH signaling pathway activation.

BACKGROUND: Adenoid cystic carcinoma (ACC) is a rare salivary cancer. The highest rates of disease recurrence are in patients with NOTCH pathway activation, reported in up to 20%. Novel drugs targeting NOTCH signaling are under investigation in the recurrent/metastatic (R/M) setting. To understand their clinical utility, there is an urgent need to better characterize the disease course and outcomes following current standard of care treatment. METHODS: 120 patients with R/M ACC underwent clinical review at a single UK Cancer Centre. Patients were retrospectively assessed for tumor NOTCH pathway activation using next generation sequencing (NGS) targeting NOTCH1/2/3 genes and/or NOTCH1 intra-cellular domain (NICD1) immunohistochemistry. Demographic and treatment data were extracted from the clinical notes. Kaplan-Meier survival analysis was performed using log rank test. RESULTS: NOTCH pathway activation was identified in 13/120 patients (11 %). In 12/101 patients analyzed by NGS, NOTCH1/3 activating somatic mutations were identified, and a further patient was identified with NICD1 diffuse nuclear staining in whom NGS testing was not possible. Patients with NOTCH pathway activation had shorter median RFS (1.1 vs 3.4 years, p = 0.2032) and significantly reduced median OS from diagnosis (4.0 vs 16.3 years, p < 0.0001). There was significantly reduced median OS from time of disease recurrence/metastasis (1.9 vs 9.6 years, p < 0.0001). CONCLUSION: This study clearly demonstrates a reduction in OS from time of first confirmed disease recurrence/metastasis for patients with NOTCH pathway activated ACC. This provides support for developing new drugs for this sub-group of patients, for whom clinical outcomes are significantly worse and effective treatments are lacking

Snow accumulation and compaction derived from GPR data near Ross Island, Antarctica

We present an improved method for estimating accumulation and compaction rates of dry snow in Antarctica with ground penetrating radar (GPR). Using an estimate of the emitted waveform from direct measurements, we apply deterministic deconvolution via the Fourier domain to GPR data with a nominal frequency of 500 MHz. This reveals unambiguous reflection horizons which can be observed in repeat measurements made one year apart. At two measurement sites near Scott Base, Antarctica, we extrapolate point measurements of average accumulation from snow pits and firn cores to a larger area by identifying a dateable dust layer horizon in the radargrams. Over an 800 m × 800 m area on the McMurdo Ice Shelf (77°45´ S, 167°17´ E) the average accumulation is found to be 269 ± 9 kg m−2 a−1. The accumulation over an area of 400 m × 400 m on Ross Island (77°40´ S, 167°11´ E, 350 m a.s.l.) is found to be higher (404 ± 22 kg m−2 a−1) and shows increased variability related to undulating terrain. Compaction of snow between 2 m and 13 m depth is estimated at both sites by tracking several internal reflection horizons along the radar profiles and calculating the average change in separation of horizon pairs from one year to the next. The derived compaction rates range from 7 cm m−1 at a depth of 2 m, down to no measurable compaction at 13 m depth, and are similar to published values from point measurements

Primary radiation damage in bone evolves via collagen destruction by photoelectrons and secondary emission self absorption

X rays are invaluable for imaging and sterilization of bones, yet the resulting ionization and primary radiation damage mechanisms are poorly understood. Here we monitor in situ collagen backbone degradation in dry bones using second harmonic generation and X ray diffraction. Collagen breaks down by cascades of photon electron excitations, enhanced by the presence of mineral nanoparticles. We observe protein disintegration with increasing exposure, detected as residual strain relaxation in pre stressed apatite nanocrystals. Damage rapidly grows from the onset of irradiation, suggesting that there is no minimal safe dose that bone collagen can sustain. Ionization of calcium and phosphorous in the nanocrystals yields fluorescence and high energy electrons giving rise to structural damage that spreads beyond regions directly illuminated by the incident radiation. Our findings highlight photoelectrons as major agents of damage to bone collagen with implications to all situations where bones are irradiated by hard X rays and in particular for small beam mineralized collagen fiber investigation