865 research outputs found
Contribution of an alveolar cell of origin to the high-grade malignant phenotype of pregnancy-associated breast cancer.
Pregnancy-associated breast cancers (PABCs) are tumors diagnosed during pregnancy or up to 5 years following parturition, and are usually high-grade, connective tissue-rich, and estrogen receptor (ER)/progesterone receptor-negative. Little is known about the cellular origin of PABCs or the mechanisms by which PABCs are initiated. Using the RCAS retrovirus to deliver the ErbB2 oncogene into the mammary epithelium of our previously reported MMTV-tva transgenic mice, we detected high-grade, poorly differentiated, stroma-rich and ER-negative tumors during pregnancy and lactation. These high-grade and stroma-rich tumors were less frequent in involuted mice or in age-matched nulliparous mice. More importantly, by generating a WAP-tva transgenic line for expression of ErbB2 selectively in WAP(+) mammary alveolar cells, we found that tumors had similar morphological phenotypes (high grade, poorly differentiated, stroma-rich and ER-negative), irrespective of the time since pregnancy and even in the absence of pregnancy. These data suggest that PABCs arise preferentially from an alveolar cell population that expands during pregnancy and lactation. This somatic mouse model may also be useful for preclinical testing of new prophylactic and therapeutic strategies against PABC
Evaluation of an early detection tool for social-emotional and behavioral problems in toddlers: The Brief Infant Toddler Social and Emotional Assessment - A cluster randomized trial
<p>Abstract</p> <p>Background</p> <p>The prevalence of social-emotional and behavioral problems is estimated to be 8 to 9% among preschool children. Effective early detection tools are needed to promote the provision of adequate care at an early stage. The Brief Infant-Toddler Social and Emotional Assessment (BITSEA) was developed for this purpose. This study evaluates the effectiveness of the BITSEA to enhance social-emotional and behavioral health of preschool children.</p> <p>Methods and Design</p> <p>A cluster randomized controlled trial is set up in youth health care centers in the larger Rotterdam area in the Netherlands, to evaluate the BITSEA. The 31 youth health care centers are randomly allocated to either the control group or the intervention group. The intervention group uses the scores on the BITSEA and cut-off points to evaluate a child's social-emotional and behavioral health and to decide whether or not the child should be referred. The control group provides care as usual, which involves administering a questionnaire that structures the conversation between child health professionals and parents. At a one year follow-up measurement the social-emotional and behavioral health of all children included in the study population will be evaluated.</p> <p>Discussion</p> <p>It is hypothesized that better results will be found, in terms of social-emotional and behavioral health in the intervention group, compared to the control group, due to more adequate early detection, referral and more appropriate and timely care.</p> <p>Trial registration</p> <p>Current Controlled Trials <a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2035">NTR2035</a></p
Extraordinarily high biomass benthic community on Southern Ocean seamounts
We describe a previously unknown assemblage of seamount-associated megabenthos that has by far the highest peak biomass reported in the deep-sea outside of vent communities. The assemblage was found at depths of 2–2.5 km on rocky geomorphic features off the southeast coast of Australia, in an area near the Sub-Antarctic Zone characterised by high rates of surface productivity and carbon export to the deep-ocean. These conditions, and the taxa in the assemblage, are widely distributed around the Southern mid-latitudes, suggesting the high-biomass assemblage is also likely to be widespread. The role of this assemblage in regional ecosystem and carbon dynamics and its sensitivities to anthropogenic impacts are unknown. The discovery highlights the lack of information on deep-sea biota worldwide and the potential for unanticipated
impacts of deep-sea exploitation
Bayesian modeling of recombination events in bacterial populations
Background: We consider the discovery of recombinant segments jointly with their origins within multilocus DNA sequences from bacteria representing heterogeneous populations of fairly closely related species. The currently available methods for recombination detection capable of probabilistic characterization of uncertainty have a limited applicability in practice as the number of
strains in a data set increases.
Results: We introduce a Bayesian spatial structural model representing the continuum of origins over sites within the observed sequences, including a probabilistic characterization of uncertainty related to the origin of any particular site. To enable a statistically accurate and practically feasible approach to the analysis of large-scale data sets representing a single genus, we have developed a novel software tool (BRAT, Bayesian Recombination Tracker) implementing the model and the
corresponding learning algorithm, which is capable of identifying the posterior optimal structure and to estimate the marginal posterior probabilities of putative origins over the sites.
Conclusion: A multitude of challenging simulation scenarios and an analysis of real data from seven
housekeeping genes of 120 strains of genus Burkholderia are used to illustrate the possibilities
offered by our approach. The software is freely available for download at URL http://web.abo.fi/fak/
mnf//mate/jc/software/brat.html
Investigating human audio-visual object perception with a combination of hypothesis-generating and hypothesis-testing fMRI analysis tools
Primate multisensory object perception involves distributed brain regions. To investigate the network character of these regions of the human brain, we applied data-driven group spatial independent component analysis (ICA) to a functional magnetic resonance imaging (fMRI) data set acquired during a passive audio-visual (AV) experiment with common object stimuli. We labeled three group-level independent component (IC) maps as auditory (A), visual (V), and AV, based on their spatial layouts and activation time courses. The overlap between these IC maps served as definition of a distributed network of multisensory candidate regions including superior temporal, ventral occipito-temporal, posterior parietal and prefrontal regions. During an independent second fMRI experiment, we explicitly tested their involvement in AV integration. Activations in nine out of these twelve regions met the max-criterion (A < AV > V) for multisensory integration. Comparison of this approach with a general linear model-based region-of-interest definition revealed its complementary value for multisensory neuroimaging. In conclusion, we estimated functional networks of uni- and multisensory functional connectivity from one dataset and validated their functional roles in an independent dataset. These findings demonstrate the particular value of ICA for multisensory neuroimaging research and using independent datasets to test hypotheses generated from a data-driven analysis
Substrate stabilisation and small structures in coral restoration: State of knowledge, and considerations for management and implementation.
Coral reef ecosystems are under increasing pressure from local and regional stressors and a changing climate. Current management focuses on reducing stressors to allow for natural recovery, but in many areas where coral reefs are damaged, natural recovery can be restricted, delayed or interrupted because of unstable, unconsolidated coral fragments, or rubble. Rubble fields are a natural component of coral reefs, but repeated or high-magnitude disturbances can prevent natural cementation and consolidation processes, so that coral recruits fail to survive. A suite of interventions have been used to target this issue globally, such as using mesh to stabilise rubble, removing the rubble to reveal hard substrate and deploying rocks or other hard substrates over the rubble to facilitate recruit survival. Small, modular structures can be used at multiple scales, with or without attached coral fragments, to create structural complexity and settlement surfaces. However, these can introduce foreign materials to the reef, and a limited understanding of natural recovery processes exists for the potential of this type of active intervention to successfully restore local coral reef structure. This review synthesises available knowledge about the ecological role of coral rubble, natural coral recolonisation and recovery rates and the potential benefits and risks associated with active interventions in this rapidly evolving field. Fundamental knowledge gaps include baseline levels of rubble, the structural complexity of reef habitats in space and time, natural rubble consolidation processes and the risks associated with each intervention method. Any restoration intervention needs to be underpinned by risk assessment, and the decision to repair rubble fields must arise from an understanding of when and where unconsolidated substrate and lack of structure impair natural reef recovery and ecological function. Monitoring is necessary to ascertain the success or failure of the intervention and impacts of potential risks, but there is a strong need to specify desired outcomes, the spatial and temporal context and indicators to be measured. With a focus on the Great Barrier Reef, we synthesise the techniques, successes and failures associated with rubble stabilisation and the use of small structures, review monitoring methods and indicators, and provide recommendations to ensure that we learn from past projects
Evolutionary distances in the twilight zone -- a rational kernel approach
Phylogenetic tree reconstruction is traditionally based on multiple sequence
alignments (MSAs) and heavily depends on the validity of this information
bottleneck. With increasing sequence divergence, the quality of MSAs decays
quickly. Alignment-free methods, on the other hand, are based on abstract
string comparisons and avoid potential alignment problems. However, in general
they are not biologically motivated and ignore our knowledge about the
evolution of sequences. Thus, it is still a major open question how to define
an evolutionary distance metric between divergent sequences that makes use of
indel information and known substitution models without the need for a multiple
alignment. Here we propose a new evolutionary distance metric to close this
gap. It uses finite-state transducers to create a biologically motivated
similarity score which models substitutions and indels, and does not depend on
a multiple sequence alignment. The sequence similarity score is defined in
analogy to pairwise alignments and additionally has the positive semi-definite
property. We describe its derivation and show in simulation studies and
real-world examples that it is more accurate in reconstructing phylogenies than
competing methods. The result is a new and accurate way of determining
evolutionary distances in and beyond the twilight zone of sequence alignments
that is suitable for large datasets.Comment: to appear in PLoS ON
Reliability and Validity of the Dutch Version of the Brief Infant-Toddler Social and Emotional Assessment (BITSEA)
Background: The Brief Infant-Toddler Social and Emotional Assessment (BITSEA) is a relatively new and short (42-item) questionnaire that measures psychosocial problems in toddlers and consists of a Problem and a Competence scale. In this study the reliability and validity of the Dutch version of the BITSEA were examined for the whole group and for gender and ethnicity subgroups. Methods: Parents of 7140 two-year-old children were invited in the study, of which 3170 (44.4%) parents completed the BITSEA. For evaluation of the score distribution, the presence of floor/ceiling effects was determined. The internal consistency (Cronbach's alpha) was evaluated and in subsamples the test-retest, parent-childcare provider interrater reliability and concurrent validity with regard to the Child Behavioral Checklist (CBCL). Discriminative validity was evaluated by comparing scores of parents that worry and parents that do not worry about their child's development. Results: The BITSEA showed no floor or ceiling effects. Psychometric properties of the BITSEA Problem and Competence scale were respectively: Cronbach's alphas were 0.76 and 0.63. Test-retest correlations were 0.75 and 0.61. Interrater reliability correlations were 0.30 and 0.17. Concurrent validity was as hypothesised. The BITSEA was able to discriminate between parents that worry about their child and parents that do not worry. The psychometric properties of the BITSEA were comparable across gender and ethnic background. Conclusion: The results in this large-scale study of a diverse sample support the reliability and validity of the BITSEA Problem scale. The BITSEA Competence scale needs further study. The performance of the BITSEA appears to be similar in subgroups by gender and ethnic background
W2S: Microscopy Data with Joint Denoising and Super-Resolution for Widefield to SIM Mapping
In fluorescence microscopy live-cell imaging, there is a critical trade-off
between the signal-to-noise ratio and spatial resolution on one side, and the
integrity of the biological sample on the other side. To obtain clean
high-resolution (HR) images, one can either use microscopy techniques, such as
structured-illumination microscopy (SIM), or apply denoising and
super-resolution (SR) algorithms. However, the former option requires multiple
shots that can damage the samples, and although efficient deep learning based
algorithms exist for the latter option, no benchmark exists to evaluate these
algorithms on the joint denoising and SR (JDSR) tasks. To study JDSR on
microscopy data, we propose such a novel JDSR dataset, Widefield2SIM (W2S),
acquired using a conventional fluorescence widefield and SIM imaging. W2S
includes 144,000 real fluorescence microscopy images, resulting in a total of
360 sets of images. A set is comprised of noisy low-resolution (LR) widefield
images with different noise levels, a noise-free LR image, and a corresponding
high-quality HR SIM image. W2S allows us to benchmark the combinations of 6
denoising methods and 6 SR methods. We show that state-of-the-art SR networks
perform very poorly on noisy inputs. Our evaluation also reveals that applying
the best denoiser in terms of reconstruction error followed by the best SR
method does not necessarily yield the best final result. Both quantitative and
qualitative results show that SR networks are sensitive to noise and the
sequential application of denoising and SR algorithms is sub-optimal. Lastly,
we demonstrate that SR networks retrained end-to-end for JDSR outperform any
combination of state-of-the-art deep denoising and SR networksComment: ECCVW 2020. Project page: \<https://github.com/ivrl/w2s
Peptide exchange on MHC-I by TAPBPR is driven by a negative allostery release cycle.
Chaperones TAPBPR and tapasin associate with class I major histocompatibility complexes (MHC-I) to promote optimization (editing) of peptide cargo. Here, we use solution NMR to investigate the mechanism of peptide exchange. We identify TAPBPR-induced conformational changes on conserved MHC-I molecular surfaces, consistent with our independently determined X-ray structure of the complex. Dynamics present in the empty MHC-I are stabilized by TAPBPR and become progressively dampened with increasing peptide occupancy. Incoming peptides are recognized according to the global stability of the final pMHC-I product and anneal in a native-like conformation to be edited by TAPBPR. Our results demonstrate an inverse relationship between MHC-I peptide occupancy and TAPBPR binding affinity, wherein the lifetime and structural features of transiently bound peptides control the regulation of a conformational switch located near the TAPBPR binding site, which triggers TAPBPR release. These results suggest a similar mechanism for the function of tapasin in the peptide-loading complex
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