MLLT1 YEATS domain mutations in clinically distinctive Favourable Histology Wilms tumours.

Wilms tumour is an embryonal tumour of childhood that closely resembles the developing kidney. Genomic changes responsible for the development of the majority of Wilms tumours remain largely unknown. Here we identify recurrent mutations within Wilms tumours that involve the highly conserved YEATS domain of MLLT1 (ENL), a gene known to be involved in transcriptional elongation during early development. The mutant MLLT1 protein shows altered binding to acetylated histone tails. Moreover, MLLT1-mutant tumours show an increase in MYC gene expression and HOX dysregulation. Patients with MLLT1-mutant tumours present at a younger age and have a high prevalence of precursor intralobar nephrogenic rests. These data support a model whereby activating MLLT1 mutations early in renal development result in the development of Wilms tumour

Influence of metals and metalloids on the composition and fluorescence quenching of the extracellular polymeric substances produced by the polymorphic fungus <i>Aureobasidium pullulans</i>

Aureobasidium pullulansis a ubiquitous and widely distributed fungus in the environment, and exhibits substantial tolerance against toxic metals. However, the interactions between metals and metalloids with the copious extracellular polymeric substances (EPS) produced byA. pullulansand possible relationships to tolerance are not well understood. In this study, it was found that mercury (Hg) and selenium (Se), as selenite, not only significantly inhibited growth ofA. pullulansbut also affected the composition of produced EPS. Lead (Pb) showed little influence on EPS yield or composition. The interactions of EPS fromA. pullulanswith the tested metals and metalloids depended on the specific element and their concentration. Fluorescence intensity measurements of the EPS showed that the presence of metal(loid)s stimulated the production of extracellular tryptophan-like and aromatic protein-like substances. Examination of fluorescence quenching and calculation of binding constants revealed that the fluorescence quenching process for Hg; arsenic (As), as arsenite; and Pb to EPS were mainly governed by static quenching which resulted in the formation of a stable non-fluorescent complexes between the EPS and metal(loid)s. Se showed no significant interaction with the EPS according to fluorescence quenching. These results provide further understanding of the interactions between metals and metalloids and EPS produced by fungi and their contribution to metal(loid) tolerance

Relationships Between Vestibular Measures as Potential Predictors for Spaceflight Sensorimotor Adaptation

Introduction: During space exploration missions astronauts are exposed to a series of novel sensorimotor environments, requiring sensorimotor adaptation. Until adaptation is complete, sensorimotor decrements occur, affecting critical tasks such as piloted landing or docking. Of particularly interest are locomotion tasks such as emergency vehicle egress or extra-vehicular activity. While nearly all astronauts eventually adapt sufficiently, it appears there are substantial individual differences in how quickly and effectively this adaptation occurs. These individual differences in capacity for sensorimotor adaptation are poorly understood. Broadly, we aim to identify measures that may serve as pre-flight predictors of and individual's adaptation capacity to spaceflight-induced sensorimotor changes. As a first step, since spaceflight is thought to involve a reinterpretation of graviceptor cues (e.g. otolith cues from the vestibular system) we investigate the relationships between various measures of vestibular function in humans. Methods: In a set of 15 ground-based control subjects, we quantified individual differences in vestibular function using three measures: 1) ocular vestibular evoked myogenic potential (oVEMP), 2) computerized dynamic posturography and 3) vestibular perceptual thresholds. oVEMP responses are elicited using a mechanical stimuli approach. Computerized dynamic posturography was used to quantify Sensory Organization Tests (SOTs), including SOT5M which involved performing pitching head movements while balancing on a sway-reference support surface with eyes closed. We implemented a vestibular perceptual threshold task using the tilt capabilities of the Tilt-Translation Sled (TTS) at JSC. On each trial, the subject was passively roll-tilted left ear down or right ear down in the dark and verbally provided a forced-choice response regarding which direction they felt tilted. The motion profile was a single-cycle sinusoid of angular acceleration with a duration of 5 seconds (frequency of 0.2 Hz), which was selected as it requires sensory integration of otolith and semicircular canal cues. Stimuli direction was randomized and magnitude was determined using an adaptive sampling procedure. One hundred trials were provided and each subject's responses were fit with a psychometric curve to estimate the subject's threshold. Results: Roll tilt perceptual thresholds at 0.2 Hz ranged from 0.5 degrees to 1.82 degrees across the 15 subjects (geometric mean of 1.04 degrees), consistent with previous studies. The inter-individual variability in thresholds may be able to help explain individual differences observed in sensorimotor adaptation to spaceflight. Analysis is ongoing for the oVEMPS and computerized dynamic posturography to identify relationships between the various vestibular measures. Discussion: Predicting individual differences in sensorimotor adaptation is critical both for the development of personalized countermeasures and mission planning. Here we aim to develop a basis of vestibular tests and parameters which may serve as predictors of individual differences in sensorimotor adaptability through studying the relationship between these measures

Biotransformation of lanthanum by Aspergillus niger

Lanthanum is an important rare earth element and has many applications in modern electronics and catalyst manufacturing. However, there exist several obstacles in the recovery and cycling of this element due to a low average grade in exploitable deposits and low recovery rates by energy-intensive extraction procedures. In this work, a novel method to transform and recover La has been proposed using the geoactive properties of Aspergillus niger. La-containing crystals were formed and collected after A. niger was grown on Czapek-Dox agar medium amended with LaCl 3. Energy-dispersive X-ray analysis (EDXA) showed the crystals contained C, O, and La; scanning electron microscopy revealed that the crystals were of a tabular structure with terraced surfaces. X-ray diffraction identified the mineral phase of the sample as La 2(C 2O 4) 3·10H 2O. Thermogravimetric analysis transformed the oxalate crystals into La 2O 3 with the kinetics of thermal decomposition corresponding well with theoretical calculations. Geochemical modelling further confirmed that the crystals were lanthanum decahydrate and identified optimal conditions for their precipitation. To quantify crystal production, biomass-free fungal culture supernatants were used to precipitate La. The results showed that the precipitated lanthanum decahydrate achieved optimal yields when the concentration of La was above 15 mM and that 100% La was removed from the system at 5 mM La. Our findings provide a new aspect in the biotransformation and biorecovery of rare earth elements from solution using biomass-free fungal culture systems. </p

Neural correlates of multi-day learning and savings in sensorimotor adaptation

Abstract In the present study we evaluated changes in neural activation that occur over the time course of multiple days of sensorimotor adaptation, and identified individual neural predictors of adaptation and savings magnitude. We collected functional MRI data while participants performed a manual adaptation task during four separate test sessions over a three-month period. This allowed us to examine changes in activation and associations with adaptation and savings at subsequent sessions. Participants exhibited reliable savings of adaptation across the four sessions. Brain activity associated with early adaptation increased across the sessions in a variety of frontal, parietal, cingulate, and temporal cortical areas, as well as various subcortical areas. We found that savings was positively associated with activation in several striatal, parietal, and cingulate cortical areas including the putamen, precuneus, angular gyrus, dorsal anterior cingulate cortex (dACC), and cingulate motor area. These findings suggest that participants may learn how to better engage cognitive processes across days, potentially reflecting improvements in action selection. We propose that such improvements may rely on action-value assignments, which previously have been linked to the dACC and striatum. As correct movements are assigned a higher value than incorrect movements, the former are more likely to be performed again

Metabolic synergies in the biotransformation of organic and metallic toxic compounds by a saprotrophic soil fungus

The saprotrophic fungus Penicillium griseofulvum was chosen as model organism to study responses to a mixture of hexachlorocyclohexane (HCH) isomers (α-HCH, β-HCH, γ-HCH, δ-HCH) and of potentially toxic metals (vanadium, lead) in solid and liquid media. The P. griseofulvum FBL 500 strain was isolated from polluted soil containing high concentrations of HCH isomers and potentially toxic elements (Pb, V). Experiments were performed in order to analyse the tolerance/resistance of this fungus to xenobiotics, and to shed further light on fungal potential in inorganic and organic biotransformations. The aim was to examine the ecological and bioremedial potential of this fungus verifying the presence of mechanisms that allow it to transform HCH isomers and metals under different, extreme, test conditions. To our knowledge, this work is the first to provide evidence on the biotransformation of HCH mixtures, in combination with toxic metals, by a saprotrophic non-white-rot fungus and on the metabolic synergies involved

Are there differences in all-cause and coronary heart disease mortality between immigrants in Sweden and in their country of birth? A follow-up study of total populations

BACKGROUND: Mortality from cardiovascular diseases is higher among immigrants than native Swedes. It is not clear whether the high mortality persists from the country of birth or is a result of migration. The purpose of the present study was to analyse whether all-cause and coronary heart disease mortality differ between immigrants in Sweden and in the country of birth. METHODS: Two cohorts including the total population from Swedish national registers and WHO were defined. All-cause and CHD mortality are presented as age-adjusted incidence rates and incidence density ratios (IDR) in eight immigrant groups in Sweden and in their country of birth. The data were analysed using Poisson regression. RESULTS: The all-cause mortality risk was lower among seven of eight male immigrant groups (IDR 0.39–0.97) and among six of eight female immigrant groups (IDR 0.42–0.81) than in their country of birth. The CHD mortality risk was significantly lower in male immigrants from Norway (IDR = 0.84), Finland (IDR = 0.91), Germany (IDR = 0.84) and Hungary (IDR = 0.59) and among female immigrants from Germany (IDR = 0.66) and Hungary (IDR = 0.54) than in their country of birth. In contrast, there was a significantly higher CHD mortality risk in male immigrants from Southern Europe (IDR = 1.23) than in their country of birth. CONCLUSION: The all-cause mortality risk was lower in the majority of immigrant groups in Sweden than in their country of birth. The differences in CHD mortality risks were more complex. For countries with high CHD mortality, such as Finland and Hungary, the risk was lower among immigrants in Sweden than in their country of birth. For low-risk countries in South Europe, the risk was higher in immigrants in Sweden than in South Europe

Structure-guided design and optimization of small molecules targeting the protein-protein interaction between the von hippel-lindau (VHL) E3 ubiquitin ligase and the hypoxia inducible factor (HIF) alpha subunit with in vitro nanomolar affinities

E3 ubiquitin ligases are attractive targets in the ubiquitin-proteasome system, however, the development of small-molecule ligands has been rewarded with limited success. The von Hippel-Lindau protein (pVHL) is the substrate recognition subunit of the VHL E3 ligase that targets HIF-1α for degradation. We recently reported inhibitors of the pVHL:HIF-1α interaction, however they exhibited moderate potency. Herein, we report the design and optimization, guided by X-ray crystal structures, of a ligand series with nanomolar binding affinities

A registry-based follow-up study, comparing the incidence of cardiovascular disease in native Danes and immigrants born in Turkey, Pakistan and the former Yugoslavia: do social inequalities play a role?

<p>Abstract</p> <p>Background</p> <p>This study compared the incidence of cardiovascular disease (CVD) and acute myocardial infarction (AMI) between native Danes and immigrants born in Turkey, Pakistan and the former Yugoslavia. Furthermore, we examined whether different indicators of socioeconomic status (SES), such as employment, income and housing conditions influenced potential differences.</p> <p>Methods</p> <p>In this registry-based follow-up study individuals were identified in a large database that included individuals from two major regions in Denmark, corresponding to about 60% of the Danish population. Incident cases of CVD and AMI included fatal and non-fatal events and were taken from registries. Using Cox regression models, we estimated incidence rates at 5-year follow-up.</p> <p>Results</p> <p>Immigrant men and women from Turkey and Pakistan had an increased incidence of CVD, compared with native Danish men. In the case of AMI, a similar pattern was observed; however, differences were more pronounced. Pakistanis and Turks with a shorter duration of residence had a lower incidence, compared with those of a longer residence. Generally, no notable differences were observed between former Yugoslavians and native Danes. In men, differences in CVD and AMI were reduced after adjustment for SES, in particular, among Turks regarding CVD. In women, effects were particularly reduced among Yugoslavians in the case of CVD and in Turks in the case of CVD and AMI after adjustment for SES.</p> <p>Conclusions</p> <p>In conclusion, country of birth-related differences in the incidence of CVD and AMI were observed. At least some of the differences that we uncovered were results of a socioeconomic effect. Duration of residence also played a certain role. Future studies should collect and test different indicators of SES in studies of CVD among immigrants.</p