Segmentation of glioblastomas in early post-operative multi-modal MRI with deep neural networks

Extent of resection after surgery is one of the main prognostic factors for patients diagnosed with glioblastoma. To achieve this, accurate segmentation and classification of residual tumor from post-operative MR images is essential. The current standard method for estimating it is subject to high inter- and intra-rater variability, and an automated method for segmentation of residual tumor in early post-operative MRI could lead to a more accurate estimation of extent of resection. In this study, two state-of-the-art neural network architectures for pre-operative segmentation were trained for the task. The models were extensively validated on a multicenter dataset with nearly 1000 patients, from 12 hospitals in Europe and the United States. The best performance achieved was a 61\% Dice score, and the best classification performance was about 80\% balanced accuracy, with a demonstrated ability to generalize across hospitals. In addition, the segmentation performance of the best models was on par with human expert raters. The predicted segmentations can be used to accurately classify the patients into those with residual tumor, and those with gross total resection.Comment: 13 pages, 4 figures, 4 table

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

An Analysis of the Sequence Variability of Meningococcal fHbp, NadA and NHBA over a 50-Year Period in the Netherlands

<div><p>Studies of meningococcal evolution and genetic population structure, including the long-term stability of non-random associations between variants of surface proteins, are essential for vaccine development. We analyzed the sequence variability of factor H-binding protein (fHbp), Neisserial Heparin-Binding Antigen (NHBA) and <i>Neisseria</i> adhesin A (NadA), three major antigens in the multicomponent meningococcal serogroup B vaccine 4CMenB. A panel of invasive isolates collected in the Netherlands over a period of 50 years was used. To our knowledge, this strain collection covers the longest time period of any collection available worldwide. Long-term persistence of several antigen sub/variants and of non-overlapping antigen sub/variant combinations was observed. Our data suggest that certain antigen sub/variants including those used in 4CMenB are conserved over time and promoted by selection.</p></div

Distribution of antigens from 1960 to 2008-2009.

<p><b>A) fHbp variants and sub/variants.</b> Out of the 45 sub/variants in frame identified from 1960 to 2008-2009, fHbp-1.14 (16%), 2.16 (13%), 1.1 (8%), 1.4 (8%), and 2.24 (8%) were the most frequent and persisting. fHbp-2.24 was predominant in 1960, 2.16 in 1970, 1.4 in 1980, 1.14 in 1990, 2000 and 2008-2009, together with 1.1. <b>B) NHBA peptides.</b> Out of the 43 peptides identified from 1960 to 2008-2009, NHBA- 2 (24%) and 20 (22%) were the most frequent and persisting. NHBA-2 was predominant in 1960, 1990, 2000 and 2008-2009, NHBA-20 in 1970 and 1980 (this latter case, together with NHBA-29). <b>C) NadA presence, variants and sub/variants. </b><i>nadA</i> gene was absent or presented frame-shift mutations or insertion sequences in 115 out of 165 isolates. Out of the 11 sub/variants identified from 1960 to 2008-2009 in the 50 isolates with the gene, NadA-3.8 (40%) and NadA-1.1 (28%) were the most frequent and persisting. NadA-3.8 was present from 1960 to 1990, NadA-1.1 from 1980 to 2008-2009.</p

The evolution of cc41/44 over 50 years.

<p>The structure of cc41/44 was analysed with phyloviz based on the goeBURST algorithm <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0065043#pone.0065043-Francisco1" target="_blank">[62]</a>. Each number correspond to a different ST, the sizes of circles are proportional to the number of isolates. <b>A) fHbp variants.</b> In 1960-1970, when the ST-44 sub-complex was predominant, fHbp-2 and fHbp-3 were most represented. After 1980, when the ST-41 sub-complex was prevalent, fHbp-1 became the most frequent. Of note, independently from its prevalence, fHbp-1 was the only variant that was present in both sub-complexes at all time periods. <b>B) NHBA</b>. NHBA-2, the most frequent in cc41/44 (82%), was equally shared by the two sub-complexes from 1960 to 2008-2009.</p

Associations between different loci.

<p>The Cramer’s V coefficient was used to measure association statistics with clonal complexes. The values indicated a strong association between antigen alleles and clonal complexes. The Standardized Index of Association <i>I_A^S</i> was used to test the stability of associations between different loci. The antigen pairs showed relatively high <i>I_A^S</i> values, indicative of strong, stable associations between the different loci over time. Moreover, the combinations showed a non-overlapping structure (measured by f* metrics) that suggested the immune selection maintaining antigenic combinations.</p>§<p>The three statistical parameters V, <i>I_A^S</i> and <i>f*</i> are based on the frequency of the alleles and vary between 0 (random distribution) and 1 (perfect association or non overlapping distribution in the case of <i>f*</i>).</p

Longevity of the most frequent combinations of two and three antigen sub/variants.

<p>Out of the 9 most frequent combinations observed, several persisted for at least twenty years. fHbp-1.1:NadA-1.1 and fHbp-2.16:NHBA-20 were very stable, persisting for thirty and forty years, respectively. Combinations generated by fHbp-2.16, NHBA-20 and NadA-3.8 were indicated by the symbol (*). Combinations generated by fHbp-1.1, NHBA-3 and NadA-1.1 were indicated by the symbol (§).</p

Persistence of the fHbp, NHBA and NadA sub/variants included in 4CMenB.

<p>fHbp-1.1 and NadA-3.8 persisted for thirty years, NHBA-2 for fifty years.</p

Distribution of the three fHbp variants Over Time.

<p>fHbp-2 predominated in 1960-1980 and was subsequently substituted by fHbp-1. The presence of fHbp-3 in 2008-2009 was mainly related with the emergence of the cc213.</p