Short-term MRI measurements as predictors of EDSS progression in relapsing-remitting multiple sclerosis: grey matter atrophy but not lesions are predictive in a real-life setting
Background Magnetic resonance imaging (MRI) is the best biomarker of inflammatory disease activity in relapsing remitting Multiple Sclerosis (RRMS) so far but the association with disability is weak. Appearance of new MRI-lesions is used to evaluate response to immunotherapies in individual patients as well as being the most common primary outcome in phase-2 trials. Measurements of brain atrophy show promising outcomes in natural cohort studies and some phase-2 trials. From a theoretical perspective they might represent irreversible neurodegeneration and be more closely associated with disability. However, these atrophy measurements are not yet established as prognostic factors in real-life clinical routine. High field MRI has improved image quality and resolution and new methods to measure atrophy dynamics have become available. Objective To investigate the predictive value of MRI classification criteria in to high/low atrophy and inflammation groups, and to explore predictive capacity of two consecutive routine MRI scans for disability progression in RRMS in a real-life prospective cohort. Methods 82 RRMS-patients (40 untreated, 42 treated with immunotherapies, mean age 40 years, median Expanded Disability Status Scale (EDSS) of 2, underwent two clinically indicated MRI scans (3 Tesla) within 5–14 months, and EDSS assessment after a mean of 3.0 (1.5–4.2) years. We investigated the predictive value of predefined classifications in low/high inflammatory and atrophy groups for EDSS progression (≥1.5 if baseline EDSS = 0, ≥1.0 if baseline EDSS <5, ≥0.5 for other) by chi-square tests and by analysis of variance (ANOVA). The classifications were based on current scientific or clinical recommendation (e.g., treatment response criteria). Brain atrophy was assessed with three different methods (SIENA, SIENAX, and FreeSurfer). Post-hoc analyses aimed to explore clinical data and dynamics of MRI outcomes as predictors in multivariate linear and logit models. Results Progression was observed in 24% of patients and was independent from treatment status. None of the predefined classifications were predictive for progression. Explorative post-hoc analyses found lower baseline EDSS and higher grey matter atrophy (FreeSurfer) as best predictors (R2 = 0.29) for EDSS progression and the accuracy was overall good (Area under the curve = 0.81). Conclusion Beside EDSS at baseline, short-term grey matter atrophy is predictive for EDSS progression in treated and untreated RRMS. The development of atrophy measurements for individual risk counselling and evaluation of treatment response seems possible, but needs further validation in larger cohorts. MRI-atrophy estimates from the FreeSurfer toolbox seem to be more reliable than older methods.
von Gumberz et al. (2016) Short-term MRI measurements as predictors of EDSS progression in relapsing-remitting multiple sclerosis: grey matter atrophy but not lesions are predictive in a real-life setting. PeerJ 4:e2442 https://doi.org/10.7717/peerj.2442
Environment and host species shape the skin microbiome of captive neotropical bats
Background A wide range of microorganisms inhabit animal skin. This microbial community (microbiome) plays an important role in host defense against pathogens and disease. Bats (Chiroptera: Mammalia) are an ecologically and evolutionarily diversified group with a relatively unexplored skin microbiome. The bat skin microbiome could play a role in disease resistance, for example, to white nose syndrome (WNS), an infection which has been devastating North American bat populations. However, fundamental knowledge of the bat skin microbiome is needed before understanding its role in health and disease resistance. Captive neotropical frugivorous bats Artibeus jamaicensis and Carollia perspicillataprovide a simple controlled system in which to characterize the factors shaping the bat microbiome. Here, we aimed to determine the relative importance of habitat and host species on the bat skin microbiome. Methods We performed high-throughput 16S rRNA gene sequencing of the skin microbiome of two different bat species living in captivity in two different habitats. In the first habitat, A. jamaicensis and C. perspicillata lived together, while the second habitat contained only A. jamaicensis. Results We found that both habitat and host species shape the composition and diversity of the skin microbiome, with habitat having the strongest influence. Cohabitating A. jamaicensis and C. perspicillata shared more similar skin microbiomes than members of the same species (A. jamaicensis) across two habitats. Discussion These results suggest that in captivity, the skin microbial community is homogenised by the shared environments and individual proximities of bats living together in the same habitat, at the expense of the innate host species factors. The predominant influence of habitat suggests that environmental microorganisms or pathogens might colonize bat skin. We also propose that bat populations could differ in pathogen susceptibility depending on their immediate environment and habitat.
Lemieux-Labonté et al. (2016) Environment and host species shape the skin microbiome of captive neotropical bats. PeerJ 4:e2430 https://doi.org/10.7717/peerj.2430
In situ visualization of bacterial populations in coral tissues: pitfalls and solutions
In situ visualization of microbial communities within their natural habitats provides a powerful approach to explore complex interactions between microorganisms and their macroscopic hosts. Specifically, the application of fluorescence in situ hybridization (FISH) to simultaneously identify and visualize diverse microbial taxa associated with coral hosts, including symbiotic algae (Symbiodinium), Bacteria, Archaea, Fungi and protists, could help untangle the structure and function of these diverse taxa within the coral holobiont. However, the application of FISH approaches to coral samples is constrained by non-specific binding of targeted rRNA probes to cellular structures within the coral animal tissues (including nematocysts, spirocysts, granular gland cells within the gastrodermis and cnidoglandular bands of mesenterial filaments). This issue, combined with high auto-fluorescence of both host tissues and endosymbiotic dinoflagellates (Symbiodinium), make FISH approaches for analyses of coral tissues challenging. Here we outline the major pitfalls associated with applying FISH to coral samples and describe approaches to overcome these challenges.
Wada et al. (2016) In situ visualization of bacterial populations in coral tissues: pitfalls and solutions. PeerJ 4:e2424 https://doi.org/10.7717/peerj.2424
Parameter estimation in tree graph metabolic networks
We study the glycosylation processes that convert initially toxic substrates to nutritionally valuable metabolites in the flavonoid biosynthesis pathway of tomato (Solanum lycopersicum) seedlings. To estimate the reaction rates we use ordinary differential equations (ODEs) to model the enzyme kinetics. A popular choice is to use a system of linear ODEs with constant kinetic rates or to use Michaelis–Menten kinetics. In reality, the catalytic rates, which are affected among other factors by kinetic constants and enzyme concentrations, are changing in time and with the approaches just mentioned, this phenomenon cannot be described. Another problem is that, in general these kinetic coefficients are not always identifiable. A third problem is that, it is not precisely known which enzymes are catalyzing the observed glycosylation processes. With several hundred potential gene candidates, experimental validation using purified target proteins is expensive and time consuming. We aim at reducing this task via mathematical modeling to allow for the pre-selection of most potential gene candidates. In this article we discuss a fast and relatively simple approach to estimate time varying kinetic rates, with three favorable properties: firstly, it allows for identifiable estimation of time dependent parameters in networks with a tree-like structure. Secondly, it is relatively fast compared to usually applied methods that estimate the model derivatives together with the network parameters. Thirdly, by combining the metabolite concentration data with a corresponding microarray data, it can help in detecting the genes related to the enzymatic processes. By comparing the estimated time dynamics of the catalytic rates with time series gene expression data we may assess potential candidate genes behind enzymatic reactions. As an example, we show how to apply this method to select prominent glycosyltransferase genes in tomato seedlings.
Astola et al. (2016) Parameter estimation in tree graph metabolic networks. PeerJ 4:e2417 https://doi.org/10.7717/peerj.2417
Contributions to the functional morphology of caudate skulls: kinetic and akinetic forms
A strongly ossified and rigid skull roof, which prevents parietal kinesis, has been reported for the adults of all amphibian clades. Our μ-CT investigations revealed that the Buresch’s newt (Triturus ivanbureschi) possess a peculiar cranial construction. In addition to the typical amphibian pleurokinetic articulation between skull roof and palatoquadrate associated structures, we found flexible connections between nasals and frontals (prokinesis), vomer and parasphenoid (palatokinesis), and between frontals and parietals (mesokinesis). This is the first description of mesokinesis in urodelans. The construction of the skull in the Buresch’s newts also indicates the presence of an articulation between parietals and the exocipitals, discussed as a possible kind of metakinesis. The specific combination of pleuro-, pro-, meso-, palato-, and metakinetic skull articulations indicate to a new kind of kinetic systems unknown for urodelans to this date. We discuss the possible neotenic origin of the skull kinesis and pose the hypothesis that the kinesis in T. ivanbureschi increases the efficiency of fast jaw closure. For that, we compared the construction of the skull in T. ivanbureschi to the akinetic skull of the Common fire salamander Salamandra salamandra. We hypothesize that the design of the skull in the purely terrestrial living salamander shows a similar degree of intracranial mobility. However, this mobility is permitted by elasticity of some bones and not by true articulation between them. We comment on the possible relation between the skull construction and the form of prey shaking mechanism that the species apply to immobilize their victims.
Natchev et al. (2016) Contributions to the functional morphology of caudate skulls: kinetic and akinetic forms. PeerJ 4:e2392 https://doi.org/10.7717/peerj.2392
Are sites with multiple single nucleotide variants in cancer genomes a consequence of drivers, hypermutable sites or sequencing errors?
Across independent cancer genomes it has been observed that some sites have been recurrently hit by single nucleotide variants (SNVs). Such recurrently hit sites might be either (i) drivers of cancer that are postively selected during oncogenesis, (ii) due to mutation rate variation, or (iii) due to sequencing and assembly errors. We have investigated the cause of recurrently hit sites in a dataset of >3 million SNVs from 507 complete cancer genome sequences. We find evidence that many sites have been hit significantly more often than one would expect by chance, even taking into account the effect of the adjacent nucleotides on the rate of mutation. We find that the density of these recurrently hit sites is higher in non-coding than coding DNA and hence conclude that most of them are unlikely to be drivers. We also find that most of them are found in parts of the genome that are not uniquely mappable and hence are likely to be due to mapping errors. In support of the error hypothesis, we find that recurently hit sites are not randomly distributed across sequences from different laboratories. We fit a model to the data in which the rate of mutation is constant across sites but the rate of error varies. This model suggests that ∼4% of all SNVs are errors in this dataset, but that the rate of error varies by thousands-of-fold between sites.
Smith et al. (2016) Are sites with multiple single nucleotide variants in cancer genomes a consequence of drivers, hypermutable sites or sequencing errors?. PeerJ 4:e2391 https://doi.org/10.7717/peerj.2391
A ‘post-honeymoon’ measles epidemic in Burundi: mathematical model-based analysis and implications for vaccination timing
Using a mathematical model with realistic demography, we analyze a large outbreak of measles in Muyinga sector in rural Burundi in 1988–1989. We generate simulated epidemic curves and age × time epidemic surfaces, which we qualitatively and quantitatively compare with the data. Our findings suggest that supplementary immunization activities (SIAs) should be used in places where routine vaccination cannot keep up with the increasing numbers of susceptible individuals resulting from population growth or from logistical problems such as cold chain maintenance. We use the model to characterize the relationship between SIA frequency and SIA age range necessary to suppress measles outbreaks. If SIAs are less frequent, they must expand their target age range.
Corey et al. (2016) A ‘post-honeymoon’ measles epidemic in Burundi: mathematical model-based analysis and implications for vaccination timing. PeerJ 4:e2476 https://doi.org/10.7717/peerj.2476
Integrated analysis of ischemic stroke datasets revealed sex and age difference in anti-stroke targets
Ischemic stroke is a common neurological disorder and the burden in the world is growing. This study aims to explore the effect of sex and age difference on ischemic stroke using integrated microarray datasets. The results showed a dramatic difference in whole gene expression profiles and influenced pathways between males and females, and also in the old and young individuals. Furthermore, compared with old males, old female patients showed more serious biological function damage. However, females showed less affected pathways than males in young subjects. Functional interaction networks showed these differential expression genes were mostly related to immune and inflammation-related functions. In addition, we found ARG1 and MMP9 were up-regulated in total and all subgroups. Importantly, IL1A, ILAB, IL6 and TNF and other anti-stroke target genes were up-regulated in males. However, these anti-stroke target genes showed low expression in females. This study found huge sex and age differences in ischemic stroke especially the opposite expression of anti-stroke target genes. Future studies are needed to uncover these pathological mechanisms, and to take appropriate pre-prevention, treatment and rehabilitation measures.
Li et al. (2016) Integrated analysis of ischemic stroke datasets revealed sex and age difference in anti-stroke targets. PeerJ 4:e2470 https://doi.org/10.7717/peerj.2470
Bcl-2 homologue Debcl enhances α-synuclein-induced phenotypes in Drosophila
Background Parkinson disease (PD) is a debilitating movement disorder that afflicts 1–2% of the population over 50 years of age. The common hallmark for both sporadic and familial forms of PD is mitochondrial dysfunction. Mammals have at least twenty proapoptotic and antiapoptotic Bcl-2 family members, in contrast, only two Bcl-2 family genes have been identified in Drosophila melanogaster, the proapoptotic mitochondrial localized Debcl and the antiapoptotic Buffy. The expression of the human transgene α-synuclein, a gene that is strongly associated with inherited forms of PD, in dopaminergic neurons (DA) of Drosophila, results in loss of neurons and locomotor dysfunction to model PD in flies. The altered expression of Debcl in the DA neurons and neuron-rich eye and along with the expression of α-synuclein offers an opportunity to highlight the role of Debcl in mitochondrial-dependent neuronal degeneration and death. Results The directed overexpression of Debcl using the Ddc-Gal4 transgene in the DA of Drosophila resulted in flies with severely decreased survival and a premature age-dependent loss in climbing ability. The inhibition of Debcl resulted in enhanced survival and improved climbing ability whereas the overexpression of Debcl in the α-synuclein-induced Drosophila model of PD resulted in more severe phenotypes. In addition, the co-expression of Debcl along with Buffy partially counteracts the Debcl-induced phenotypes, to improve the lifespan and the associated loss of locomotor ability observed. In complementary experiments, the overexpression of Debcl along with the expression of α-synuclein in the eye, enhanced the eye ablation that results from the overexpression of Debcl. The co-expression of Buffy along with Debcl overexpression results in the rescue of the moderate developmental eye defects. The co-expression of Buffy along with inhibition of Debcl partially restores the eye to a roughened eye phenotype. Discussion The overexpression of Debcl in DA neurons produces flies with shortened lifespan and impaired locomotor ability, phenotypes that are strongly associated with models of PD in Drosophila. The co-expression of Debcl along with α-synuclein enhanced the PD-like phenotypes. The co-expression of Debcl along with Buffy suppresses these phenotypes. Complementary experiments in the Drosophila eye show similar trends during development. Taken all together these results suggest a role for Debcl in neurodegenerative disorders.
M’Angale et al. (2016) Bcl-2 homologue Debcl enhances α-synuclein-induced phenotypes in Drosophila. PeerJ 4:e2461 https://doi.org/10.7717/peerj.2461
Progesterone influences cytoplasmic maturation in porcine oocytes developing in vitro
Progesterone (P4), an ovarian steroid hormone, is an important regulator of female reproduction. In this study, we explored the influence of progesterone on porcine oocyte nuclear maturation and cytoplasmic maturation and development in vitro. We found that the presence of P4 during oocyte maturation did not inhibit polar body extrusions but significantly increased glutathione and decreased reactive oxygen species (ROS) levels relative to that in control groups. The incidence of parthenogenetically activated oocytes that could develop to the blastocyst stage was higher (p < 0.05) when oocytes were exposed to P4 as compared to that in the controls. Cell numbers were increased in the P4-treated groups. Further, the P4-specific inhibitor mifepristone (RU486) prevented porcine oocyte maturation, as represented by the reduced incidence (p < 0.05) of oocyte first polar body extrusions. RU486 affected maturation promoting factor (MPF) activity and maternal mRNA polyadenylation status. In general, these data show that P4 influences the cytoplasmic maturation of porcine oocytes, at least partially, by decreasing their polyadenylation, thereby altering maternal gene expression.
Yuan et al. (2016) Progesterone influences cytoplasmic maturation in porcine oocytes developing in vitro. PeerJ 4:e2454 https://doi.org/10.7717/peerj.2454