3D deep convolutional neural network-based ventilated lung segmentation using multi-nuclear hyperpolarized gas MRI

Hyperpolarized gas MRI enables visualization of regional lung ventilation with high spatial resolution. Segmentation of the ventilated lung is required to calculate clinically relevant biomarkers. Recent research in deep learning (DL) has shown promising results for numerous segmentation problems. In this work, we evaluate a 3D V-Net to segment ventilated lung regions on hyperpolarized gas MRI scans. The dataset consists of 743 helium-3 (3He) or xenon-129 (129Xe) volumetric scans and corresponding expert segmentations from 326 healthy subjects and patients with a wide range of pathologies. We evaluated segmentation performance for several DL experimental methods via overlap, distance and error metrics and compared them to conventional segmentation methods, namely, spatial fuzzy c-means (SFCM) and K-means clustering. We observed that training on combined 3He and 129Xe MRI scans outperformed other DL methods, achieving a mean ± SD Dice of 0.958 ± 0.022, average boundary Hausdorff distance of 2.22 ± 2.16 mm, Hausdorff 95th percentile of 8.53 ± 12.98 mm and relative error of 0.087 ± 0.049. Moreover, no difference in performance was observed between 129Xe and 3He scans in the testing set. Combined training on 129Xe and 3He yielded statistically significant improvements over the conventional methods (p < 0.0001). The DL approach evaluated provides accurate, robust and rapid segmentations of ventilated lung regions and successfully excludes non-lung regions such as the airways and noise artifacts and is expected to eliminate the need for, or significantly reduce, subsequent time-consuming manual editing

The HLA class II allele DRB1*1501 is over-represented in patients with idiopathic pulmonary fibrosis

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and medically refractory lung disease with a grim prognosis. Although the etiology of IPF remains perplexing, abnormal adaptive immune responses are evident in many afflicted patients. We hypothesized that perturbations of human leukocyte antigen (HLA) allele frequencies, which are often seen among patients with immunologic diseases, may also be present in IPF patients. Methods/Principal Findings: HLA alleles were determined in subpopulations of IPF and normal subjects using molecular typing methods. HLA-DRB1*15 was over-represented in a discovery cohort of 79 Caucasian IPF subjects who had lung transplantations at the University of Pittsburgh (36.7%) compared to normal reference populations. These findings were prospectively replicated in a validation cohort of 196 additional IPF subjects from four other U.S. medical centers that included both ambulatory patients and lung transplantation recipients. High-resolution typing was used to further define specific HLA-DRB1*15 alleles. DRB1*1501 prevalence in IPF subjects was similar among the 143 ambulatory patients and 132 transplant recipients (31.5% and 34.8%, respectively, p = 0.55). The aggregate prevalence of DRB1*1501 in IPF patients was significantly greater than among 285 healthy controls (33.1% vs. 20.0%, respectively, OR 2.0; 95%CI 1.3-2.9, p = 0.0004). IPF patients with DRB1*1501 (n = 91) tended to have decreased diffusing capacities for carbon monoxide (DLCO) compared to the 184 disease subjects who lacked this allele (37.8±1.7% vs. 42.8±1.4%, p = 0.036). Conclusions/Significance: DRB1*1501 is more prevalent among IPF patients than normal subjects, and may be associated with greater impairment of gas exchange. These data are novel evidence that immunogenetic processes can play a role in the susceptibility to and/or manifestations of IPF. Findings here of a disease association at the HLA-DR locus have broad pathogenic implications, illustrate a specific chromosomal area for incremental, targeted genomic study, and may identify a distinct clinical phenotype among patients with this enigmatic, morbid lung disease

Anchored enrichment dataset for true flies (order Diptera) reveals insights into the phylogeny of flower flies (family Syrphidae)

Background: Anchored hybrid enrichment is a form of next-generation sequencing that uses oligonucleotide probes to target conserved regions of the genome flanked by less conserved regions in order to acquire data useful for phylogenetic inference from a broad range of taxa. Once a probe kit is developed, anchored hybrid enrichment is superior to traditional PCR-based Sanger sequencing in terms of both the amount of genomic data that can be recovered and effective cost. Due to their incredibly diverse nature, importance as pollinators, and historical instability with regard to subfamilial and tribal classification, Syrphidae (flower flies or hoverflies) are an ideal candidate for anchored hybrid enrichment-based phylogenetics, especially since recent molecular phylogenies of the syrphids using only a few markers have resulted in highly unresolved topologies. Over 6200 syrphids are currently known and uncovering their phylogeny will help us to understand how these species have diversified, providing insight into an array of ecological processes, from the development of adult mimicry, the origin of adult migration, to pollination patterns and the evolution of larval resource utilization. Results: We present the first use of anchored hybrid enrichment in insect phylogenetics on a dataset containing 30 flower fly species from across all four subfamilies and 11 tribes out of 15. To produce a phylogenetic hypothesis, 559 loci were sampled to produce a final dataset containing 217,702 sites. We recovered a well resolved topology with bootstrap support values that were almost universally >95 %. The subfamily Eristalinae is recovered as paraphyletic, with the strongest support for this hypothesis to date. The ant predators in the Microdontinae are sister to all other syrphids. Syrphinae and Pipizinae are monophyletic and sister to each other. Larval predation on soft-bodied hemipterans evolved only once in this family. Conclusions: Anchored hybrid enrichment was successful in producing a robustly supported phylogenetic hypothesis for the syrphids. Subfamilial reconstruction is concordant with recent phylogenetic hypotheses, but with much higher support values. With the newly designed probe kit this analysis could be rapidly expanded with further sampling, opening the door to more comprehensive analyses targeting problem areas in syrphid phylogenetics and ecology.Peer reviewe

Extensive Copy-Number Variation of Young Genes across Stickleback Populations

MM received funding from the Max Planck innovation funds for this project. PGDF was supported by a Marie Curie European Reintegration Grant (proposal nr 270891). CE was supported by German Science Foundation grants (DFG, EI 841/4-1 and EI 841/6-1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

A new multicompartmental reaction-diffusion modeling method links transient membrane attachment of E. coli MinE to E-ring formation

Many important cellular processes are regulated by reaction-diffusion (RD) of molecules that takes place both in the cytoplasm and on the membrane. To model and analyze such multicompartmental processes, we developed a lattice-based Monte Carlo method, Spatiocyte that supports RD in volume and surface compartments at single molecule resolution. Stochasticity in RD and the excluded volume effect brought by intracellular molecular crowding, both of which can significantly affect RD and thus, cellular processes, are also supported. We verified the method by comparing simulation results of diffusion, irreversible and reversible reactions with the predicted analytical and best available numerical solutions. Moreover, to directly compare the localization patterns of molecules in fluorescence microscopy images with simulation, we devised a visualization method that mimics the microphotography process by showing the trajectory of simulated molecules averaged according to the camera exposure time. In the rod-shaped bacterium _Escherichia coli_, the division site is suppressed at the cell poles by periodic pole-to-pole oscillations of the Min proteins (MinC, MinD and MinE) arising from carefully orchestrated RD in both cytoplasm and membrane compartments. Using Spatiocyte we could model and reproduce the _in vivo_ MinDE localization dynamics by accounting for the established properties of MinE. Our results suggest that the MinE ring, which is essential in preventing polar septation, is largely composed of MinE that is transiently attached to the membrane independently after recruited by MinD. Overall, Spatiocyte allows simulation and visualization of complex spatial and reaction-diffusion mediated cellular processes in volumes and surfaces. As we showed, it can potentially provide mechanistic insights otherwise difficult to obtain experimentally

Porphyromonas gingivalis–dendritic cell interactions: consequences for coronary artery disease

An estimated 80 million US adults have one or more types of cardiovascular diseases. Atherosclerosis is the single most important contributor to cardiovascular diseases; however, only 50% of atherosclerosis patients have currently identified risk factors. Chronic periodontitis, a common inflammatory disease, is linked to an increased cardiovascular risk. Dendritic cells (DCs) are potent antigen presenting cells that infiltrate arterial walls and may destabilize atherosclerotic plaques in cardiovascular disease. While the source of these DCs in atherosclerotic plaques is presently unclear, we propose that dermal DCs from peripheral inflamed sites such as CP tissues are a potential source. This review will examine the role of the opportunistic oral pathogen Porphyromonas gingivalis in invading DCs and stimulating their mobilization and misdirection through the bloodstream. Based on our published observations, combined with some new data, as well as a focused review of the literature we will propose a model for how P. gingivalis may exploit DCs to gain access to systemic circulation and contribute to coronary artery disease. Our published evidence supports a significant role for P. gingivalis in subverting normal DC function, promoting a semimature, highly migratory, and immunosuppressive DC phenotype that contributes to the inflammatory development of atherosclerosis and, eventually, plaque rupture

Spatial memory in the grey mouse lemur (Microcebus murinus)

Wild animals face the challenge of locating feeding sites distributed across broad spatial and temporal scales. Spatial memory allows animals to find a goal, such as a productive feeding patch, even when there are no goal-specific sensory cues available. Because there is little experimental information on learning and memory capabilities in free-ranging primates, the aim of this study was to test whether grey mouse lemurs (Microcebus murinus), as short-term dietary specialists, rely on spatial memory in relocating productive feeding sites. In addition, we asked what kind of spatial representation might underlie their orientation in their natural environment. Using an experimental approach, we set eight radio-collared grey mouse lemurs a memory task by confronting them with two different spatial patterns of baited and non-baited artificial feeding stations under exclusion of sensory cues. Positional data were recorded by focal animal observations within a grid system of small foot trails. A change in the baiting pattern revealed that grey mouse lemurs primarily used spatial cues to relocate baited feeding stations and that they were able to rapidly learn a new spatial arrangement. Spatially concentrated, non-random movements revealed preliminary evidence for a route-based restriction in mouse lemur space; during a subsequent release experiment, however, we found high travel efficiency in directed movements. We therefore propose that mouse lemur spatial memory is based on some kind of mental representation that is more detailed than a route-based network map

Total synthesis of Escherichia coli with a recoded genome

Nature uses 64 codons to encode the synthesis of proteins from the genome, and chooses 1 sense codon—out of up to 6 synonyms—to encode each amino acid. Synonymous codon choice has diverse and important roles, and many synonymous substitutions are detrimental. Here we demonstrate that the number of codons used to encode the canonical amino acids can be reduced, through the genome-wide substitution of target codons by defined synonyms. We create a variant of Escherichia coli with a four-megabase synthetic genome through a high-fidelity convergent total synthesis. Our synthetic genome implements a defined recoding and refactoring scheme—with simple corrections at just seven positions—to replace every known occurrence of two sense codons and a stop codon in the genome. Thus, we recode 18,214 codons to create an organism with a 61-codon genome; this organism uses 59 codons to encode the 20 amino acids, and enables the deletion of a previously essential transfer RNA

Action ability modulates time‑to‑collision judgments

Time-to-collision (TTC) underestimation has been interpreted as an adaptive response that allows observers to have more time to engage in a defensive behaviour. This bias seems, therefore, strongly linked to action preparation. There is evidence that the observer’s physical fitness modulates the underestimation effect so that people who need more time to react (i.e. those with less physical fitness) show a stronger underestimation effect. Here we investigated whether this bias is influenced by the momentary action capability of the observers. In the first experiment, participants estimated the time-to-collision of threatening or non-threatening stimuli while being mildly immobilized (with a chin rest) or while standing freely. Having reduced the possibility of movement led participants to show more underestimation of the approaching stimuli. However, this effect was not stronger for threatening relative to non-threatening stimuli. The effect of the action capability found in the first experiment could be interpreted as an expansion of peripersonal space (PPS). In the second experiment, we thus investigated the generality of this effect using an established paradigm to measure the size of peripersonal space. Participants bisected lines from different distances while in the chin rest or standing freely. The results replicated the classic left-to-right gradient in lateral spatial attention with increasing viewing distance, but no effect of immobilization was found. The manipulation of the momentary action capability of the observers influenced the participants’ performance in the TTC task but not in the line bisection task. These results are discussed in relation to the different functions of PPS