bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of HSV-1 strains circulating in Finland demonstrates the uncoupling of whole-genome relatedness and phenotypic outcomes of viral infection
Authors: Bowen Christopher D. , Paavilainen Henrik , Renner Daniel W. , Palomäki Jussi , Lehtinen Jenni , Vuorinen Tytti , Norberg Peter , Hukkanen Veijo , Szpara Moriah L.
Published: September 2018

A majority of adults in Finland are seropositive carriers of herpes simplex viruses (HSV). Infection occurs at epithelial or mucosal surfaces, after which virions enter innervating nerve endings, eventually establishing lifelong infection in neurons of the sensory or autonomic nervous system. Recent data have highlighted the genetic diversity of HSV-1 strains, and demonstrated apparent geographic patterns in strain similarity. Though multiple HSV-1 genomes have been sequenced from Europe to date, there is a lack of sequenced genomes from Nordic countries. Finland’s history includes at least two major waves of human migration, suggesting the potential for diverse viruses to persist in the population. Here we used HSV-1 clinical isolates from Finland to test the relationship between viral phylogeny, genetic variation, and phenotypic characteristics. We found that Finnish HSV-1 isolates separated into two distinct phylogenetic groups, potentially reflecting historical waves of human (and viral) migration into Finland. Each HSV-1 isolate harbored a distinct set of phenotypes in cell culture, including differences in virus production, extracellular virus release, and cell-type-specific fitness. Importantly, the phylogenetic clusters were not predictive of any detectable pattern in phenotypic differences, demonstrating that whole-genome relatedness is not a proxy for overall viral phenotype. Instead, we highlight specific gene-level differences that may contribute to observed phenotypic differences, and we note that strains from different phylogenetic groups contain the same genetic variations.

Importance

Herpes simplex viruses (HSV) infect a majority of adults. Recent data have highlighted the genetic diversity of HSV-1 strains, and demonstrated apparent genomic relatedness between strains from the same geographic region. We use HSV-1 clinical isolates from Finland to test the relationship between viral genomic and geographic relationships, differences in specific genes, and characteristics of viral infection. We found that viral isolates from Finland separated into two distinct groups of genomic and geographic relatedness, potentially reflecting historical patterns of human and viral migration into Finland. These Finland HSV-1 isolates had distinct infection characteristics in multiple cell types tested, which were specific to each isolate and did not group according to genomic and geographic relatedness. This demonstrates that HSV-1 strain differences in specific characteristics of infection are set by a combination of host cell type and specific viral gene-level differences.
Multiplex logic processing isothermal diagnostic assays for an evolving virus
Authors: Bhadra Sanchita , Saldaña Miguel A. , Han Hannah Grace , Hughes Grant L. , Ellington Andrew D.
Published: September 2018

We have developed a generalizable ‘smart molecular diagnostic’ capable of accurate point-of-care (POC) detection of variable nucleic acid targets. Our one-pot isothermal assay relies on multiplex execution of four loop-mediated isothermal amplification reactions, with primers that are degenerate and redundant, thereby increasing the breadth of targets while reducing the probability of amplification failure. An easy-to-read visual answer is computed directly by a multi-input Boolean OR gate signal transducer that uses degenerate strand exchange probes to assess any combination of amplicons. We demonstrate our platform by using the same assay to detect divergent Asian and African lineages of the evolving Zika virus (ZIKV), while maintaining selectivity against non-target viruses. Direct analysis of biological specimens proved possible, with 20 virions / µl being directly detected in human saliva within 90 minutes, and crudely macerated ZIKV-infected Aedes aegypti mosquitoes being identified with 100% specificity and sensitivity. The ease-of-use with minimal instrumentation, broad programmability, and built-in fail-safe reliability make our smart molecular diagnostic attractive for POC use.
Protein inference using PIA workflows and PSI standard file formats
Authors: Uszkoreit Julian , Perez-Riverol Yasset , Eggers Britta , Marcus Katrin , Eisenacher Martin
Published: September 2018

Proteomics using LC-MS/MS has become one of the main methods to analyze the proteins in biological samples in high-throughput. But the existing mass spectrometry instruments are still limited with respect to resolution and measurable mass ranges, which is one of the main reasons why shotgun proteomics is the major approach. Here, proteins are digested, which leads to the identification and quantification of peptides instead. While often neglected, the important step of protein inference needs to be conducted to infer from the identified peptides to the actual proteins in the original sample.

In this work, we highlight some of the previously published and newly added features of the tool PIA – Protein Inference Algorithms, which helps the user with the protein inference of measured samples. We also highlight the importance of the usage of PSI standard file formats, as PIA is the only current software supporting all available standards used for spectrum identification and protein inference. Additionally, we briefly describe the benefits of working with workflow environments for proteomics analyses and show the new features of the PIA nodes for the KNIME Analytics Platform. Finally, we benchmark PIA against a recently published dataset for isoform detection.

PIA is open source and available for download on GitHub (https://github.com/mpc-bioinformatics/pia) or directly via the community extensions inside the KNIME analytics platform.
Atypically larger variability of resource allocation accounts for visual working memory deficits in schizophrenia
Authors: Zhao Yi-Jie , Ma Tianye , Ran Xuemei , Zhang Li , Zhang Ru-Yuan , Ku Yixuan
Published: September 2018

Schizophrenia patients are known to have profound deficits in visual working memory (VWM), and almost all previous studies attribute the deficits to decreased memory capacity. This account, however, ignores the potential contributions of other VWM components (e.g., memory precision). Here, we measure the VWM performance of schizophrenia patients and healthy control subjects on two classical delay-estimation tasks. Moreover, we thoroughly evaluate several established computational models of VWM to compare the performance of the two groups. We find that the model assuming variable precision across items and trials is the best model to explain the performance of both groups. According to the variable-precision model, schizophrenia subjects exhibit abnormally larger variability of allocating memory resources rather than resources per se. These results invite a rethink of the widely accepted decreased-capacity theory and propose a new perspective on the diagnosis and rehabilitation of schizophrenia.
Snail shell colour evolution in urban heat islands detected via citizen science
Authors: Kerstes Niels A. G. , Breeschoten Thijmen , Kalkman Vincent , Schilthuizen Menno
Published: September 2018

The extreme environmental conditions that prevail in cities are known to cause selection pressures leading to adaptive changes in wild, city-dwelling, organisms (“urban evolution”). The urban heat island, elevated temperatures in the city centre due to a combination of generation, reflection, and trapping of heat, is one of the best recognised and most widespread urban environmental factors. Here, we used a citizen-science approach to study the effects of urban heat on genetically-determined shell colour in the land snailCepaea nemoralisin the Netherlands. We used smartphone applications to obtain colour data on almost 8,000 snails throughout the country. Our analysis shows that snails in urban centres are more likely to be yellow than pink, an effect predicted on the basis of thermal selection. Urban yellow snails are also more likely to carry dark bands at the underside of the shell; these bands might affect thermoregulation in yet underexplored ways.
Extinction times in diffusive public good population dynamics
Authors: Kimmel Gregory J. , Gerlee Philip , Altrock Philipp M.
Published: September 2018

The co-evolutionary dynamics of competing populations can be strongly affected by frequency-dependent selection and population structure in space. As co-evolving populations grow into a spatial domain, their initial spatial arrangement, as well as their growth rate differences determine the dynamics. Here, we are interested in the dynamics of producers and free-rider co-evolution in the context of an ecological public good that is produced by a sub-population but evokes growth benefits to all individuals. We consider the spatial growth dynamics in one, two and three dimensions by modeling producer cell, free-rider cell and public good densities in space, driven by birth, death and diffusion. Typically, one population goes extinct. We find that uncorrelated initial spatial structures do not influence the time to extinction in comparison to the well-mixed system. We derive a slow manifold solution in order to estimate the time to extinction of either free-riders or producers. For invading populations, i.e. for populations that are initially highly segregated, we observe a traveling wave, whose speed can be calculated to improve the extinction time estimate by a simple superposition of the two times. Our results show that local effects of spatial dynamics evolve independently of the dynamics of the mean populations. Our considerations provide quantitative predictions for the transient dynamics of cooperative traits under pressure of extinction, and a potential experiment to derive elusive details of the fitness function of an ecological public goods game through extinction time observations.

Author Summary

Ecological public goods (PG) relationships emerge in growing cellular populations, for example between bacteria and cancer cells. We study the eco-evolutionary dynamics of a PG in populations that grow in space. In our model, public good-producer cells and free-rider cells can grow according to their own birth and death rates. Co-evolution occurs due to public good-driven surplus in the intrinsic growth rates and a cost to producers. A net growth rate benefit to free-riders leads to the well-known tragedy of the commons in which producers go extinct. What is often omitted from discussions is the time scale on which this extinction can occur, especially in spatial populations. We derive analytical estimates of the time to extinction in different spatial settings, and identify spatial scenarios in which extinction takes long enough such that the tragedy of the commons never occurs within the lifetime of the populations. Using numerical simulations we analyze the deviations from analytical predictions. Our results have direct implications for inferring ecological public good game properties from in vitro and in vivo experimental observations.
A Hybridde novoAssembly of the Sea Pansy (Renilla muelleri) Genome
Authors: Jiang Justin , Quattrini Andrea M. , Francis Warren R. , Ryan Joseph F. , Rodríguez Estefanía , McFadden Catherine S.
Published: September 2018

Background

Over 3,000 species of octocorals (Cnidaria, Anthozoa) inhabit an expansive range of environments, from shallow tropical seas to the deep-ocean floor. They are important foundation species that create coral “forests” which provide unique niches and three-dimensional living space for other organisms. The octocoral genusRenillainhabits sandy, continental shelves in the subtropical and tropical Atlantic and eastern Pacific Oceans.Renillais especially interesting because it produces secondary metabolites for defense, exhibits bioluminescence, and produces a luciferase that is widely used in dual-reporter assays in molecular biology. Although several cnidarian genomes are currently available, the majority are from hexacorals. Here, we present ade novoassembly of theR. muellerigenome, making this the first complete draft genome from an octocoral.

Findings

We generated a hybridde novoassembly using the Maryland Super-Read Celera Assembler v.3.2.6 (MaSuRCA). The final assembly included 4,825 scaffolds and a haploid genome size of 172 Mb. A BUSCO assessment found 88% of metazoan orthologs present in the genome. An Augustusab initiogene prediction found 23,660 genes, of which 66% (15,635) had detectable similarity to annotated genes from the starlet sea anemone,Nematostella vectensis,or to the Uniprot database. Although theR. muellerigenome is smaller (172 Mb) than other publicly available, hexacoral genomes (256-448 Mb), theR. muellerigenome is similar to the hexacoral genomes in terms of the number of complete metazoan BUSCOs and predicted gene models.

Conclusions

TheR. muellerihybrid genome provides a novel resource for researchers to investigate the evolution of genes and gene families within Octocorallia and more widely across Anthozoa. It will be a key resource for future comparative genomics with other corals and for understanding the genomic basis of coral diversity.
Biophysical model of axonal stimulation in epiretinal visual prostheses
Authors: Beyeler Michael
Published: September 2018

Visual prostheses aim to restore vision to people blinded from degenerative photoreceptor diseases by electrically stimulating surviving neurons in the retina. However, a major challenge with epiretinal prostheses is that they may accidentally activate passing axon fibers, causing severe perceptual distortions. To investigate the effect of axonal stimulation on the retinal response, we developed a computational model of a small population of morphologically and biophysically detailed retinal ganglion cells, and simulated their response to epiretinal electrical stimulation. We found that activation thresholds of ganglion cell somas and axons varied systematically with both stimulus pulse duration and electrode-retina distance. These findings have important implications for the improvement of stimulus encoding methods for epiretinal prostheses.
Carbonic anhydrase network of genes trigger cytosolic pH enabling differentiation from quiescence
Authors: Yasin Jeshima Khan , Chaudhary Sakshi , Verma Nidhi , Vennila Sengottaiyan
Published: September 2018

Background

Carbonic anhydrase regulates various cellular processes. Intracellular pH flux impacted by carbonic anhydrase alters the enzyme’s allosteric active site which effects several downstream cellular processes. Earlier, we reported that, the catalytic activity of carbonic anhydrase is independent, but direction of catalysis is affected by cellular pH level. On the other hand carbonic anhydrase alters the cytosolic pH level to facilitate allosteric phosphorylation of proteins which further leads to cellular differentiation through a process being regulated by ncRNAs.

Results

This study illustrates various ways of cell differentiation/ organ development regulation via carbonic anhydrase interacting network of proteins involved in various cellular processes. It is involved in protein degradation process of other proteins like RPT, 26S proteasome, AT3G15120 and its variant producing ncRNA, etc. Carbonic anhydrase indirectly involved in signaling process along with MAPK in providing innate resistance against biotic and abiotic stresses. It is also indirectly linked to cell membrane transporters like H+-ATPase and V-ATPase B.

Conclusions

Though carbonic anhydrase is not directly linked with EMS1 as revealed by network analyses and protein-protein interaction there could be a suitable condition generated by the carbonic anhydrase for EMS1 to be active. Hence, we report that carbonic anhydrase, along with other pH regulating gene complexes plays a major role for making EMS1 functional.
When do shifts in trait dynamics precede population declines?
Authors: Baruah Gaurav , Clements Christopher F. , Guillaume Fréderic , Ozgul Arpat
Published: September 2018

Predicting population responses to environmental change is an on-going challenge in ecology. Studies investigating the links between fitness-related phenotypic traits and demography have shown that trait dynamic responses to environmental change can sometimes precede population dynamic responses, and thus, can be used as an early warning signal. However, it is still unknown under which ecological and evolutionary circumstances, shifts in fitness-related traits can precede population responses to environmental perturbation. Here, we take a trait-based demographic approach and investigate both trait and population dynamics in a density-regulated population in response to a gradual change in the environment. We explore the ecological and evolutionary constraints under which shifts in a fitness-related trait precedes a decline in population size. We show both analytically and with experimental data that under medium-to-slow rate of environmental change, shifts in trait value can precede population decline. We further show the positive influence of environmental predictability, average reproductive rate, plasticity, and genetic variation on shifts in trait dynamics preceding potential population declines. These results still hold under non-constant genetic variation and environmental stochasticity. Our study highlights ecological and evolutionary circumstances under which a fitness-related trait can be used as an early warning signal of an impending population decline.
Cdh2 coordinates Myosin-II dependent internalisation of the zebrafish neural plate
Authors: Araya Claudio , Häkkinen Hanna-Maria , Carcamo Luis , Cerda Mauricio , Savy Thierry , Rookyard Christopher , Peyriéras Nadine , Clarke Jonathan D
Published: September 2018

Tissue internalisation is a key morphogenetic mechanism by which embryonic tissues generate complex internal organs and a number of studies of epithelia have outlined a general view of tissue internalisation. Here we have used quantitative live imaging and mutant analysis to determine whether similar mechanisms are responsible for internalisation in a tissue that apparently does not have a typical epithelial organisation – the zebrafish neural plate. We found that although zebrafish embryos begin neurulation without a conventional epithelium, medially located neural plate cells adopt strategies typical of epithelia in order to constrict their dorsal surface membrane during cell internalisation. Furthermore, we show that Myosin-II activity is a significant driver of this transient cell remodeling which also depends on Cdh2 (N-cadherin). Abrogation of Cdh2 results in defective Myosin-II distribution, mislocalised internalisation events and defective neural plate morphogenesis. Our work suggests Cdh2 coordinates Myosin-II dependent internalisation of the zebrafish neural plate.
A Sparse Unreliable Distributed Code Underlies the Limits of Behavioral Discrimination
Authors: Sriram Balaji , Cruz-Martin Alberto , Li Lillian , Reinagel Pamela , Ghosh Anirvan
Published: September 2018

The cortical code that underlies perception must enable subjects to perceive the world at timescales relevant for behavior. We find that mice can integrate visual stimuli very quickly (<100 ms) to reach plateau performance in an orientation discrimination task. To define features of cortical activity that underlie performance at these timescales, we measured single unit responses in the mouse visual cortex at timescales relevant to this task. In contrast to high contrast stimuli of longer duration, which elicit reliable activity in individual neurons, stimuli at the threshold of perception elicit extremely sparse and unreliable responses in V1 such that the activity of individual neurons do not reliably report orientation. Integrating information across neurons, however, quickly improves performance. Using a linear decoding model, we estimate that integrating information over 50-100 neurons is sufficient to account for behavioral performance. Thus, at the limits of perception the visual system is able to integrate information across a relatively small number of highly unreliable single units to generate reliable behavior.
Genome-Wide Associations with Resistance to Bipolaris Leaf Spot (Bipolaris oryzae (Breda de Haan) Shoemaker) in a Northern Switchgrass Population (Panicum virgatum L.)
Authors: Songsomboon Kittikun , Crawford Ryan , Crawford Jamie , Hansen Julie , Cummings Jaime , Mattson Neil , Bergstrom Gary , Viands Donald
Published: September 2018

Switchgrass (Panicum virgatum L.), a northern native perennial grass, suffers from yield reduction from Bipolaris leaf spot caused by Bipolaris oryzae (Breda de Haan) Shoe-maker. This study aimed for determining the resistant populations via multiple phenotyping approaches and identifying potential resistance genes to the disease from genome-wide association studies in the switchgrass northern association panel. The disease resistance was evaluated from both natural (field evaluations in NY and PA) and artificial inoculations (detached leaf and leaf disk assays). There are ten out of the 66 populations showed the most resistant based on a combination of detached leaf, leaf disk, and mean from two locations. The GWAS from five subgroups from the association panel to different disease evaluation combinations yielded 27 significant SNPs on 12 chromosomes: 1K, 2K, 2N, 3K, 3N, 4N, 5K, 5N, 6N, 7K, 7N, and 9N accumulatively explaining phenotypic variance of BLUPs of detached leaf percent lesion via image analysis 26.52% at most and BLUPs of leaf disk percent lesion via image analysis 3.28% at least. Within linkage disequilibrium of 20 kb, these SNP markers linked with the potential resistance genes including genes encoding for NBS-LRR, PPR, cell wall related proteins, homeostatic proteins, anti-apoptotic proteins, and ABC transporters.
A Theory of Centriole Duplication Based on Self-Organized Spatial Pattern Formation
Authors: Takao Daisuke , Yamamoto Shohei , Kitagawa Daiju
Published: September 2018

In each cell cycle, centrioles are duplicated to produce a single copy of each pre-existing centriole. At the onset of centriole duplication, the master regulator Polo-like kinase 4 (Plk4) undergoes a dynamic change in its spatial pattern on the periphery of the pre-existing centriole, forming a single duplication site. However, the significance and mechanisms of this pattern transition remain largely unknown. Using super-resolution imaging, we found that centriolar Plk4 exhibits periodic discrete patterns resembling pearl necklaces, frequently with single prominent foci. We constructed mathematical models that simulated the pattern formation of Plk4 to gain insight into the discrete ring patterns. The simulations incorporating the self-organization properties of Plk4 successfully generated the experimentally observed patterns. We therefore propose that the self-patterning of Plk4 is crucial for the regulation of centriole duplication. These results, defining the mechanisms of self-organized regulation, provide a fundamental principle for understanding centriole duplication.
Change in sexual signaling traits outruns morphological divergence in a recent avian radiation across an ecological gradient
Authors: Friis Guillermo , Milá Borja
Published: September 2018

The relative roles of natural and sexual selection in promoting evolutionary lineage divergence remains controversial and difficult to assess in natural systems. Local adaptation through natural selection is known to play a central role in adaptive radiations, yet secondary sexual traits can vary widely among species in recent radiations, suggesting that sexual selection may also be important in the early stages of speciation. Here we compare rates of divergence in ecologically relevant traits (morphology) and sexually selected signaling traits (coloration) relative to neutral structure in genome-wide molecular markers, and examine patterns of variation in sexual dichromatism to understand the roles of natural and sexual selection in the diversification of the songbird genusJunco(Aves: Passerellidae). Juncos include divergent lineages in Central America and several dark-eyed junco (J. hyemalis) lineages that diversified recently as the group recolonized North America following the last glacial maximum (c.a. 18,000 years ago). We found an accelerated rate of divergence in sexually selected characters relative to ecologically relevant traits. Moreover, a synthetic index of sexual dichromatism comparable across lineages revealed a positive relationship between the degree of color divergence and the strength of sexual selection, especially when controlling for neutral genetic distance. We also found a positive correlation between dichromatism and latitude, which coincides with the latitudinal pattern of decreasing lineage age but also with a steep ecological gradient. Finally, we detected an association between outlier loci potentially under selection and both sexual dichromatism and latitude of breeding range. These results suggest that the joint effects of sexual and ecological selection have played a role in the junco radiation and can be important in the early stages of lineage formation.
Bacteria: A novel source for potent mosquito feeding – deterrents
Authors: Kajla Mayur K. , Barrett-Wilt Gregory A. , Paskewitz Susan M.
Published: September 2018

Antibiotic and insecticidal bioactivities of the extracellular secondary metabolites produced by entomopathogenic bacteria belonging to genus Xenorhabdus have been identified; however, their novel applications such as mosquito feeding-deterrence have not been reported. Here, we show that a mixture of compounds isolated fromXenorhabdus budapestensis in vitrocultures exhibits potent feeding-deterrent activity against three deadly mosquito vectors:Aedes aegypti, Anopheles gambiaeandCulex pipiens. We further demonstrate that the deterrent-active fraction isolated from replicate bacterial cultures is consistently highly enriched in two modified peptides identical to the previously described fabclavines, strongly suggesting that these are molecular species responsible for feeding-deterrence. The mosquito feeding-deterrent activity in the fabclavines-rich fraction is comparable to or better than that of N, N-diethyl-3-methylbenzamide (also known as Deet) or picaridin in side-by-side assays. Our unique discovery lays the groundwork for research into biologically derived, peptide-based low molecular weight compounds isolated from bacteria for exploitation as mosquito repellents and feeding-deterrents.
Novel deleterious nsSNPs withinMEFVgene that could be used as Diagnostic Markers to Predict Hereditary Familial Mediterranean Fever: Using bioinformatics analysis
Authors: Mustafa Mujahed I. , Abdelhameed Tebyan A , Abdelrhman Fatima A. , Osman Soada Ahmed , Hassan Mohamed A.
Published: September 2018

Background

Familial Mediterranean Fever (FMF) is the most common auto inflammatory disease (AID) affecting mainly the ethnic groups originating from Mediterranean basin, we aimed to identify the pathogenic SNPs in MEFV by computational analysis software.

Methods

We carried out in silico prediction of structural effect of each SNP using different bioinformatics tools to predict substitution influence on protein structure and function.

Result

23 novel mutations out of 857 nsSNPs that are found to be deleterious effect on the MEFV structure and function.

Conclusion

This is the first in silico analysis in MEFV gene to prioritize SNPs for further genetic mapping studies. After using multiple bioinformatics tools to compare and rely on the results predicted, we found 23 novel mutations that may cause FMF disease and it could be used as diagnostic markers for Mediterranean basin populations.
The origin and evolution of acetylcholine signaling through AchRs in metazoans
Authors: Faltine-Gonzalez Dylan Z. , Layden Michael J
Published: September 2018

Background

Acetylcholine is a cell signaling molecule that has been identified in plants, bacteria, and metazoans to play multiple roles in cells and as a neurotransmitter capable of exciting both neurons and muscle. While cell-cell communication activity has been reported in all phyla that have been investigated, its role as a neurotransmitter is less clear. Work within cnidarians implies that neurotransmitter activity emerged within or prior to the emergence of the cnidarian-bilaterian ancestor, but whether or not it is able to excite both muscles and neurons has not been addressed.

Results

To investigate the evolution of acetylcholine signaling we characterized the expression pattern of acetylcholine receptors (AchRs) and the neurotransmitter activity of acetylcholine in Nematostella vectensis. Expression patterns for 13 of the 21 known NvAchRs are consistent with acetylcholine acting as a cell signaling molecule and a neurotransmitter in neurons, muscles, or both. To dissect neurotransmitter activity we investigated the mechanism by which acetylcholine activates tentacular contractions in Nematostella. Tentacular contractions induced by application of acetylcholine are suppressed by inactivating voltage gated sodium channels with lidocaine indicating that acetylcholine specifically activates neurons in the tentacular contractile circuit.

Conclusion

Our results verify that acetylcholine’s neurotransmitter activity emerged prior to cnidarian-bilaterian divergence and that non-neuronal roles were likely retained in Nematostella. Additionally, we found no evidence to support a muscle activating role for acetylcholine indicating that its role in muscle excitability evolved during bilaterian evolution.
The oxysterol synthesizing enzyme CH25H contributes to the development of intestinal fibrosis
Authors: Raselli T. , Wyss A. , Gonzalez Alvarado M.N. , Weder B. , Mamie C. , Spalinger M.R. , van Haaften W. T. , Dijkstra G. , Sailer A.W. , Imenez Silva P.H. , Wagner C.A. , Tosevski V. , Leibl Sebastian , Scharl M. , Rogler G. , Hausmann M. , Misselwitz B.
Published: September 2018

Intestinal fibrosis and stenosis are common complications of Crohn’s disease (CD), frequently requiring surgery. Anti-inflammatory strategies can only partially prevent fibrosis; hence, anti-fibrotic therapies remain an unmet clinical need. Oxysterols are oxidized cholesterol derivatives, with important roles in various biological processes. The enzyme cholesterol 25-hydroxylase (CH25H) converts cholesterol to 25-hydroxycholesterol (25-HC), which modulates immune responses and oxidative stress. In human intestinal samples from CD patients we found a strong correlation of CH25H mRNA expression with the expression of fibrosis markers. We demonstrate reduced intestinal fibrosis in mice deficient for the CH25H enzyme using the sodium dextran sulfate (DSS)-induced chronic colitis model. Additionally, using a heterotopic transplantation model of intestinal fibrosis, we demonstrate reduced collagen deposition and lower concentrations of hydroxyproline in CH25H knockouts. In the heterotopic transplant model, CH25H was expressed in fibroblasts. Taken together, our findings indicate an involvement of oxysterol synthesis in the pathogenesis of intestinal fibrosis.
An Amyloid beta-derived Septapeptide has hMCP-1 Chemokine Activity
Authors: Van Alstyne Diane
Published: September 2018

Septapeptides (“septas”), previously identified as meningitis-specific antigens, defined by a rubella virus (RV) monoclonal antibody, were found in human Monocyte Chemoattractant Protein (hMCP-1) and on the surface of meningitis-causing bacteria, viruses and spirochetes. Some bacterial septas were tested for Ca+2 mobilization through receptor-associated heterotrimeric G-protein binding on THP-1 cells, progenitor cells of circulating peripheral macrophages. Certain of the free septas acted on their own as mild agonist of Ca+2 mobilization. Their signal transduction activity may be mediated through a single, or a single class, of receptor, but the data do not link this with the MCP-1 receptor on THP-1 cells. These data support the proposals that (1) the septas represent muteins of the MCP-1 active site for stem cell activation to macrophages and (2) infectious organisms may conserve and employ these sequences in order to facilitate their transport through the Blood Brain Barrier (BBB) to infect the Central Nervous System (CNS). Other MCP muteins have since been identified in the Alzheimer’s Disease (AD)-associated agents, amyloid beta (Abeta) and prions, as well as in viruses like HIV, known to establish chronic infections in the CNS. Rat glial progenitor cells in tissue culture were used to test for hMCP-1 activity in septas derived from amyloid beta. Nanomolar concentrations of the amyloid beta septa 13HHQKLVF19 were found to transform more than 60% of the progenitor cells into microglia in tissue culture. Taken together, these data support the hypothesis that amyloid beta may accumulate to increase the number of microglia available to combat chronic infection in the CNS. A new paradigm for neurodegenerative disease is presented.
Towards Zero-Latency Neurofeedback
Authors: Smetanin Nikolai , Lebedev Mikhail A. , Ossadtchi Alexei
Published: September 2018

Neurofeedback (NFB) is a real-time paradigm, where subjects monitor their own brain activity presented to them via one of the sensory modalities: visual, auditory or tactile. NFB has been proposed as an approach to treat neurological conditions and augment brain functions. In many applications, especially in the automatic learning scenario it is important to decrease NFB latency, so that appropriate brain mechanisms can be efficiently engaged. To this end, we propose a novel algorithm that significantly reduces feedback signal presentation in the electroencephalographic (EEG) NFB paradigm. The algorithm is based on the least squares optimization of the finite impulse response (FIR) filter weights and analytic signal reconstruction. In this approach, the trade-off between NFB latency and the accuracy of EEG envelope estimation can be achieved depending on the application needs. Moreover, the algorithm allows to implement predictive NFB by setting latency to negative values while maintaining acceptable envelope estimation accuracy. As such, our algorithm offers significant improvements in cases where subjects need to detect neural events as soon as possible and even in advance.
Muscle mechanics and energy expenditure of the triceps surae during rearfoot and forefoot running
Authors: Gruber Allison H. , Umberger Brian R. , Miller Ross H. , Hamill Joseph
Published: September 2018

Forefoot running is advocated to improve running economy because of increased elastic energy storage than rearfoot running. This claim has not been assessed with methods that predict the elastic energy contribution to positive work or estimate muscle metabolic cost. The purpose of this study was to compare the mechanical work and metabolic cost of the gastrocnemius and soleus between rearfoot and forefoot running. Seventeen rearfoot and seventeen forefoot runners ran over-ground with their habitual footfall pattern (3.33-3.68m•s−1) while collecting motion capture and ground reaction force data. Ankle and knee joint angles and ankle joint moments served as inputs into a musculoskeletal model that calculated the mechanical work and metabolic energy expenditure of each muscle using Hill-based muscle models with contractile (CE) and series elastic (SEE) elements. A mixed-factor ANOVA assessed the difference between footfall patterns and groups (α=0.05). Forefoot running resulted in greater SEE mechanical work in the gastrocnemius than rearfoot running but no differences were found in CE mechanical work or CE metabolic energy expenditure. Forefoot running resulted in greater soleus SEE and CE mechanical work and CE metabolic energy expenditure than rearfoot running. The metabolic cost associated with greater CE velocity, force production, and activation during forefoot running may outweigh any metabolic energy savings associated with greater SEE mechanical work. Therefore, there was no energetic benefit at the triceps surae for one footfall pattern or the other. The complex CE-SEE interactions must be considered when assessing muscle metabolic cost, not just the amount of SEE strain energy.
Time and space dimensions of gene dosage imbalance of aneuploidies revealed by single cell transcriptomes
Authors: Stamoulis Georgios , Garieri Marco , Makrythanasis Periklis , Letourneau Audrey , Guipponi Michel , Panousis Nikolaos , Sloan-Béna Frédérique , Falconnet Emilie , Ribaux Pascale , Borel Christelle , Santoni Federico , Antonarakis Stylianos E
Published: September 2018

The mechanisms underlying cellular and organismal phenotypes due to copy number alterations (CNA) are not fully understood. Aneuploidy is a major source of gene dosage imbalance due to CNA and viable human trisomies are model disorders of altered gene expression. To understand the cellular impact of gene dosage imbalance, we studied gene and allele specific expression (ASE) of 9668 single-cell fibroblasts in trisomies T21, T18, T13 and T8. To limit the bias of interindividual noise, all comparisons between euploid and trisomic single-cells were performed on an isogenic setting for all trisomies studied. Initially we examined 928 single cells with deep RNA-Seq. For T21 we used fibroblasts from one pair of monozygotic twins discordant for T21 and from mosaic T21. For T18, T13 and T8 we analyzed single cells from mosaic individuals. Single-cell analyses revealed inconsistencies concerning the overexpression of some genes observed in differential trisomic vs euploid bulk RNAseq while this imbalance was not detectable in trisomic vs. euploid single cells. Moreover, ASE profiling of all single cells uncovered a substantial monoallelic pattern of expression in the trisomic fraction of the genome. By classifying genes according to the level of mono and bi-allelic transcription, we have observed that, for genes with monoallelic and low-to-average expression, the altered gene dosage is mainly due to the higher fraction of cells simultaneously expressing these genes in the trisomic samples. These results were confirmed in a further experiment of 8740 single fibroblasts from the monozygotic twins discordant for T21 samples. We conclude that gene dosage imbalance is of bidimensional nature: over time (simultaneous expression of all alleles resulting in increased accumulation of RNA of copy altered genes in each single cell) as previously stated, and over space (increased fraction of cells simultaneously expressing copy altered genes). These results strongly suggest that each class of genes contributes to the phenotypic variability of trisomies according to its temporal and spatial behavior and propose an improved model to understand the effects of copy number alterations.
Vision using multiple distinct rod opsins in deep-sea fishes
Authors: Musilova Zuzana , Cortesi Fabio , Matschiner Michael , Davies Wayne I. L. , Stieb Sara M. , de Busserolles Fanny , Malmstrøm Martin , Tørresen Ole K. , Mountford Jessica K. , Hanel Reinhold , Jakobsen Kjetill S. , Carleton Karen L. , Jentoft Sissel , Marshall Justin , Salzburger Walter
Published: September 2018

Vertebrate vision is accomplished through a set of light-sensitive photopigments, which are located in the photoreceptors of the retina and consist of a visual opsin protein bound to a chromophore. In dim-light, vertebrates generally rely upon a single rod opsin (RH1) for obtaining visual information. By inspecting 101 fish genomes, we found that three deep-sea teleost lineages have independently expanded theirRH1gene repertoires. Amongst these, the silver spinyfin (Diretmus argenteusJohnson 1863) stands out as having the highest number of visual opsins known for animals to date (2 cone and 38 rod opsins). Spinyfins simultaneously express up to 14RH1sencoding for photopigments with different peak spectral sensitivities (λmax=448-513 nm) that cover the range of the residual daylight, as well as the bioluminescence spectrum present in the deep-sea. Our findings present novel molecular and functional evidence for the recurrent evolution of multiple rod opsin-based vision in vertebrates.

SHORT ABSTRACT

Contrary to the single rod opsin used by most vertebrates, some fishes use multiple rod opsins for vision in the dimly lit deep-sea.
Optimization of Energy State Transition Trajectory Supports the Development of Executive Function During Youth
Authors: Cui Zaixu , Stiso Jennifer , Baum Graham L. , Kim Jason Z. , Roalf David R. , Betzel Richard F. , Gu Shi , Lu Zhixin , Xia Cedric H. , Ciric Rastko , Moore Tyler M. , Shinohara Russell T. , Ruparel Kosha , Davatzikos Christos , Pasqualetti Fabio , Gur Raquel E. , Gur Ruben C. , Bassett Danielle S. , Satterthwaite Theodore D.
Published: September 2018

Executive function develops rapidly during adolescence, and failures of executive function are associated with both risk-taking behaviors and psychopathology. However, it remains relatively unknown how structural brain networks mature during this critical period to facilitate energetically demanding transitions to activate the frontoparietal system, which is critical for executive function. In a sample of 946 human youths (ages 8-23 yr) who completed diffusion imaging as part of the Philadelphia Neurodevelopment Cohort, we capitalized upon recent advances in network control theory in order to calculate the control energy necessary to activate the frontoparietal system given the existing structural network topology. We found that the control energy required to activate the frontoparietal system declined with development. Moreover, we found that this control energy pattern contains sufficient information to make accurate predictions about individuals’ brain maturity. Finally, the control energy costs of the cingulate cortex were negatively correlated with executive performance, and partially mediated the development of executive performance with age. These results could not be explained by changes in general network control properties or in network modularity. Taken together, our results reveal a mechanism by which structural networks develop during adolescence to facilitate the instantiation of activation states necessary for executive function.

SIGNIFICANCE STATEMENT

Executive function undergoes protracted development during youth, but it is unknown how structural brain networks mature to facilitate the activation of the frontoparietal cortex that is critical for executive processes. Here, we leverage recent advances in network control theory to establish that structural brain networks evolve in adolescence to lower the energetic cost of activating the frontoparietal system. Our results suggest a new mechanistic framework for understanding how brain network maturation supports cognition, with clear implications for disorders marked by executive dysfunction, such as ADHD and psychosis.
5-Hydroxymethylcytosines from Circulating Cell-free DNA as Diagnostic and Prognostic Markers for Hepatocellular Carcinoma
Authors: Cai Jiabin , Chen Lei , Zhang Zhou , Zhang Xinyu , Lu Xingyu , Liu Weiwei , Shi Guoming , Ge Yang , Gao Pingting , Yang Yuan , Ke Aiwu , Xiao Linlin , Dong Ruizhao , Zhu Yanjing , Yang Xuan , Wang Jiefei , Zhu Tongyu , Yang Deping , Huang Xiaowu , Sui Chengjun , Qiu Shuangjian , Shen Feng , Sun Huichuan , Zhou Weiping , Zhou Jian , Nie Ji , Zhang Xu , C-H.Chiu Brian , Lau Wan Yee , He Chuan , Wang Hongyang , Zhang Wei , Fan Jia
Published: September 2018

The lack of highly sensitive and specific diagnostic biomarkers is a major contributor to the poor outcomes of patients with hepatocellular carcinoma (HCC), the second-most common cause of cancer deaths worldwide. We sought to develop a clinically convenient and minimally-invasive approach that can be deployed at scale for the sensitive, specific, and highly reliable diagnosis of HCC, and to evaluate the potential prognostic value of this approach. The study cohort comprised of 2,728 subjects, including HCC patients (n = 1,208), controls (n = 965) (572 healthy individuals and 393 patients with benign lesions), as well as patients with chronic hepatitis B infection (CHB) (n =291), liver cirrhosis (LC) (n = 110), and cholangiocarcinoma (CCC) (n = 154), was recruited from three major liver cancer hospitals in Shanghai, China, from July 2016 to November 2017. Circulating cell-free DNA (cfDNA) were collected from plasma samples from these individuals before surgery or any radical treatment. Applying our 5hmC-Seal technique, the summarized 5-hydroxymethylcytosine (5hmC) profiles in cfDNA were obtained. Molecular annotation analysis suggested that the profiled 5hmC loci in cfDNA were enriched with liver tissue-derived regulatory markers (e.g., H3K4me1). We showed that a weighted diagnostic score (wd-score) based on 117 genes detected using the summarized 5hmC profiles in cfDNA accurately distinguished HCC patients from controls (AUC = 95.1%; 95% CI, 93.6-96.5%) in the validation set, markedly outperformed α-fetoprotein (AFP) with superior sensitivity. The wd-scores, which not only detected early BCLC stages (e.g., Stage 0: AUC = 96.2%; 95% CI,94.1-98.4%) and small tumors (e.g., < 2 cm: AUC = 95.7%; 95% CI: 93.6-97.7%), also showed high capacity for distinguishing HCC from non-cancer patients with CHB/LC (AUC = 80.2%; 95% CI, 75.8-84.6%). Moreover, the prognostic value of 5hmC markers in cfDNA was evaluated for HCC recurrence, showing that a weighted prognostic score (wp-score) based on 16 marker genes predicted the recurrence risk (HR = 6.67; 95% CI, 2.81-15.82, p < 0.0001) in 555 patients who have been followed up after surgery. In conclusion, we have developed and validated a robust 5hmC-based diagnostic model that can be applied routinely with clinically feasible amount of cfDNA (e.g., from ~2-5 mL of plasma). Applying this new approach in the clinic could significantly improve the clinical outcomes of HCC patients, for example by early detection of those patients with surgically resectable tumors or as a convenient disease surveillance tool for recurrence.
Topological exploration of artificial neuronal network dynamics
Authors: Bardin Jean-Baptiste , Spreemann Gard , Hess Kathryn
Published: September 2018

One of the paramount challenges in neuroscience is to understand the dynamics of individual neurons and how they give rise to network dynamics when interconnected. Historically, researchers have resorted to graph theory, statistics, and statistical mechanics to describe the spatiotemporal structure of such network dynamics. Our novel approach employs tools from algebraic topology to characterize the global properties of network structure and dynamics.

We propose a method based on persistent homology to automatically classify network dynamics using topological features of spaces built from various spike-train distances. We investigate the efficacy of our method by simulating activity in three small artificial neural networks with different sets of parameters, giving rise to dynamics that can be classified into four regimes. We then compute three measures of spike train similarity and use persistent homology to extract topological features that are fundamentally different from those used in traditional methods. Our results show that a machine learning classifier trained on these features can accurately predict the regime of the network it was trained on and also generalize to other networks that were not presented during training. Moreover, we demonstrate that using features extracted from multiple spike-train distances systematically improves the performance of our method.