Effects of synaptic and myelin plasticity on learning in a network of Kuramoto phase oscillators.

Chaos. 2019 Aug;29(8):083122

Authors: Karimian M, Dibenedetto D, Moerel M, Burwick T, Westra RL, De Weerd P, Senden M

Abstract
Models of learning typically focus on synaptic plasticity. However, learning is the result of both synaptic and myelin plasticity. Specifically, synaptic changes often co-occur and interact with myelin changes, leading to complex dynamic interactions between these processes. Here, we investigate the implications of these interactions for the coupling behavior of a system of Kuramoto oscillators. To that end, we construct a fully connected, one-dimensional ring network of phase oscillators whose coupling strength (reflecting synaptic strength) as well as conduction velocity (reflecting myelination) are each regulated by a Hebbian learning rule. We evaluate the behavior of the system in terms of structural (pairwise connection strength and conduction velocity) and functional connectivity (local and global synchronization behavior). We find that adaptive myelination is able to both functionally decouple structurally connected oscillators as well as to functionally couple structurally disconnected oscillators. With regard to the latter, we find that for conditions in which a system limited to synaptic plasticity develops two distinct clusters both structurally and functionally, additional adaptive myelination allows for functional communication across these structural clusters. These results confirm that network states following learning may be different when myelin plasticity is considered in addition to synaptic plasticity, pointing toward the relevance of integrating both factors in computational models of learning.

PMID: 31472483 [PubMed - in process]

Network reconstruction and Significant Pathway Extraction Using Phosphoproteomic Data From Cancer Cells.

Proteomics. 2019 Aug 31;:e1800450

Authors: Marion B, Aurélien N, Ovidiu R, Coopman PJ, Larive RM, Gilles F

Abstract
Protein phosphorylation acts as an efficient switch controlling deregulated key signaling pathways in cancer. Computational biology aims to address the complexity of reconstructed networks but overrepresents well-known proteins and lacks information on less-studied proteins. We developed a bioinformatic tool to reconstruct and select relatively small networks that connect signaling proteins to their targets in specific contexts. It enabled us to propose and validate new signaling axes of the Syk kinase. To validate the potency of our tool, we applied it to two phosphoproteomic studies on oncogenic mutants of the well-known PIK3CA kinase and the unfamiliar SRMS kinase. By combining network reconstruction and signal propagation, we built comprehensive signaling networks from large-scale experimental data and extracted multiple molecular paths from these kinases to their targets. We retrieved specific paths from two distinct PIK3CA mutants, allowing us to explain their differential impact on the HER3 receptor kinase. In addition, to address the missing connectivities of the SRMS kinase to its targets in interaction pathway databases, we integrated phospho-tyrosine and phospho-serine/threonine proteomic data. The resulting SRMS-signaling network comprised casein kinase 2, thereby validating its currently suggested role downstream of SRMS. Our computational pipeline is publicly available, and contains a user-friendly graphical interface (http://doi.org/10.5281/zenodo.3333687). This article is protected by copyright. All rights reserved.

PMID: 31472481 [PubMed - as supplied by publisher]

Age-dependent Deformation of the Optic Nerve Head and Peripapillary Retina by Horizontal Duction.

Am J Ophthalmol. 2019 Aug 28;:

Authors: Le A, Chen J, Lesgart M, Gawargious BA, Suh SY, Demer JL

Abstract
PURPOSE: We studied effects of age and horizontal duction on deformation of the optic nerve (ON) head and peripapillary retina as reflected by displacement of vascular landmarks to explore the influence of adduction tethering.
DESIGN: Cross-sectional study.
METHODS: Setting: University.
STUDY POPULATION: Single eyes of 20 healthy young adults (average age 23.9±3.9 SD) years were compared to 20 older subjects (average age 61.4±9.3) years. Observational Procedure: The disc and peripapillary retina were imaged by scanning laser ophthalmoscopy in central gaze, and 35° abd- and adduction.
MAIN OUTCOME MEASURE: Deformations of the disc and adjacent PPR were measured by comparing positions of epipapillary and epiretinal blood vessels.
RESULTS: Vessels within the ONH of younger subjects shifted temporally during adduction and nasally during abduction. Displacement of the nasal hemi-disc in adduction was greater at 38.5±1.7μm (SEM) than the temporal half at 4.1±2.1μm (P<0.001). Peripapillary retina within one radius of the disc margin underwent 7.6±1.6μm average temporal displacement in adduction in young subjects. In abduction, the young temporal hemi-disc shifted 4.4±0.6μm nasally without significant displacement in the nasal half. Older subjects' ONH showed less temporal shift and less displacement in the PPR within one disc radius (P<0.0001) in adduction; the nasal hemi-disc shifted 24.5±1.3μm compared with 4.4±2.1μm in the temporal half. There were no significant deformations of the disc during abduction by older subjects.
CONCLUSION: Large horizontal duction, particularly adduction, deforms the disc and peripapillary vasculature. This deformation, which is larger in younger than older subjects, may be due to ON tethering in adduction.

PMID: 31472159 [PubMed - as supplied by publisher]

Analysis of Drosophila Nervous System Development Following an Early, Brief Exposure to Ethanol.

Dev Neurobiol. 2019 Aug 31;:

Authors: Scepanovic G, Stewart BA

Abstract
The effects of ethanol on neural function and development have been studied extensively, motivated in part by the addictive properties of alcohol and the neurodevelopmental deficits that arise in children with Fetal Alcohol Spectrum Disorder (FASD). Absent from this research area is a genetically tractable system to study the effects of early ethanol exposure on later neurodevelopmental and behavioural phenotypes. Here we used embryos of the fruit fly, Drosophila melanogaster, as a model system to investigate the neuronal defects that arise after an early exposure to ethanol. We found several disruptions of neural development and morphology following a brief ethanol exposure during embryogenesis and subsequent changes in larval behaviour. Altogether, this study establishes a new system to examine the effects of alcohol exposure in embryos and the potential to conduct large scale genetics screens to uncover novel factors that sensitize or protect neurons to the effects of alcohol.

PMID: 31472090 [PubMed - as supplied by publisher]

Parallel probability density approximation.

Behav Res Methods. 2019 Aug 30;:

Authors: Lin YS, Heathcote A, Holmes WR

Abstract
Probability density approximation (PDA) is a nonparametric method of calculating probability densities. When integrated into Bayesian estimation, it allows researchers to fit psychological processes for which analytic probability functions are unavailable, significantly expanding the scope of theories that can be quantitatively tested. PDA is, however, computationally intensive, requiring large numbers of Monte Carlo simulations in order to attain good precision. We introduce Parallel PDA (pPDA), a highly efficient implementation of this method utilizing the Armadillo C++ and CUDA C libraries to conduct millions of model simulations simultaneously in graphics processing units (GPUs). This approach provides a practical solution for rapidly approximating probability densities with high precision. In addition to demonstrating this method, we fit a piecewise linear ballistic accumulator model (Holmes, Trueblood, & Heathcote, 2016) to empirical data. Finally, we conducted simulation studies to investigate various issues associated with PDA and provide guidelines for pPDA applications to other complex cognitive models.

PMID: 31471826 [PubMed - as supplied by publisher]

High-resolution 13C metabolic flux analysis.

Nat Protoc. 2019 Aug 30;:

Authors: Long CP, Antoniewicz MR

Abstract
Precise quantification of metabolic pathway fluxes in biological systems is of major importance in guiding efforts in metabolic engineering, biotechnology, microbiology, human health, and cell culture. 13C metabolic flux analysis (13C-MFA) is the predominant technique used for determining intracellular fluxes. Here, we present a protocol for 13C-MFA that incorporates recent advances in parallel labeling experiments, isotopic labeling measurements, and statistical analysis, as well as best practices developed through decades of experience. Experimental design to ensure that fluxes are estimated with the highest precision is an integral part of the protocol. The protocol is based on growing microbes in two (or more) parallel cultures with 13C-labeled glucose tracers, followed by gas chromatography-mass spectrometry (GC-MS) measurements of isotopic labeling of protein-bound amino acids, glycogen-bound glucose, and RNA-bound ribose. Fluxes are then estimated using software for 13C-MFA, such as Metran, followed by comprehensive statistical analysis to determine the goodness of fit and calculate confidence intervals of fluxes. The presented protocol can be completed in 4 d and quantifies metabolic fluxes with a standard deviation of ≤2%, a substantial improvement over previous implementations. The presented protocol is exemplified using an Escherichia coli ΔtpiA case study with full supporting data, providing a hands-on opportunity to step through a complex troubleshooting scenario. Although applications to prokaryotic microbial systems are emphasized, this protocol can be easily adjusted for application to eukaryotic organisms.

PMID: 31471597 [PubMed - as supplied by publisher]

Publisher Correction: Gut microbiota-bile acid-interleukin-22 axis orchestrates polycystic ovary syndrome.

Nat Med. 2019 Aug 30;:

Authors: Qi X, Yun C, Sun L, Xia J, Wu Q, Wang Y, Wang L, Zhang Y, Liang X, Wang L, Gonzalez FJ, Patterson AD, Liu H, Mu L, Zhou Z, Zhao Y, Li R, Liu P, Zhong C, Pang Y, Jiang C, Qiao J

Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.

PMID: 31471570 [PubMed - as supplied by publisher]

A defined minimal medium for systems analyses of Staphylococcus aureus reveals strain-specific metabolic requirements.

Appl Environ Microbiol. 2019 Aug 30;:

Authors: Machado H, Weng LL, Dillon N, Seif Y, Holland M, Pekar JE, Monk JM, Nizet V, Palsson BO, Feist AM

Abstract
Staphylococcus aureus is a Gram-positive pathogenic bacterium that colonizes an estimated one-third of the human population and can cause a wide spectrum of disease, ranging from superficial skin infections to life-threatening sepsis. The adaptive mechanisms that contribute to the success of this pathogen remain obscure partially due to a lack of knowledge of its metabolic requirements. Systems biology approaches can be extremely useful in predicting and interpreting metabolic phenotypes; however, such approaches rely on a chemically defined minimal medium as a basis to investigate the requirements of the cell. In this work, a chemically defined minimal medium formulation, termed synthetic minimal medium (SMM), was investigated and validated to support growth of three S. aureus strains: LAC and TCH1516 (USA300 lineage), and D592 (USA100 lineage). The formulated SMM was used in an adaptive laboratory evolution (ALE) experiment to probe the various mutational trajectories of all three strains leading to optimized growth capabilities. The evolved strains were phenotypically characterized for their growth rate and antimicrobial susceptibility. Strains were also re-sequenced to examine the genetic basis for observed changes in phenotype and to design follow-up metabolite supplementation assays. Our results reveal evolutionary trajectories that arose from strain-specific metabolic requirements. SMM and the evolved strains can also serve as important tools to study antibiotic resistance phenotypes of S. aureus Importance As researchers try to understand and combat the development of antibiotic resistance in pathogens, there is a growing need to thoroughly understand the physiology and metabolism of the microbes. Staphylococcus aureus is a threatening pathogen with increased antibiotic resistance and well-studied virulence mechanisms. However, knowledge regarding the adaptive mechanisms used by this pathogen to survive environmental stresses remain unclear, mostly due to the lack of information about its metabolic requirements. Defining the minimal metabolic requirements for S. aureus growth is a first step towards unraveling the mechanisms by which it adapts to metabolic stresses. Here we present the development of a chemically defined minimal medium supporting growth of three S. aureus strains, and reveal key genetic mutations contributing to improved growth in minimal medium.

PMID: 31471305 [PubMed - as supplied by publisher]

Human metapneumovirus prevalence and patterns of subgroup persistence identified through surveillance of pediatric pneumonia hospital admissions in coastal Kenya, 2007-2016.

BMC Infect Dis. 2019 Aug 30;19(1):757

Authors: Oketch JW, Kamau E, Otieno GP, Otieno JR, Agoti CN, Nokes DJ

Abstract
BACKGROUND: Human metapneumovirus (HMPV) is an important respiratory pathogen that causes seasonal epidemics of acute respiratory illness and contributes significantly to childhood pneumonia. Current knowledge and understanding on its patterns of spread, prevalence and persistence in communities in low resource settings is limited.
METHODS: We present findings of a molecular-epidemiological analysis of nasal samples from children < 5 years of age admitted with syndromic pneumonia between 2007 and 2016 to Kilifi County Hospital, coastal Kenya. HMPV infection was detected using real-time RT-PCR and positives sequenced in the fusion (F) and attachment (G) genes followed by phylogenetic analysis. The association between disease severity and HMPV subgroup was assessed using Fisher's exact test.
RESULTS: Over 10 years, 274/6756 (4.1%) samples screened were HMPV positive. Annual prevalence fluctuated between years ranging 1.2 to 8.7% and lowest in the recent years (2014-2016). HMPV detections were most frequent between October of one year to April of the following year. Genotyping was successful for 205/274 (74.8%) positives revealing clades A2b (41.0%) and A2c (10.7%), and subgroups B1 (23.4%) and B2 (24.9%). The dominance patterns were: clade A2b between 2007 and 11, subgroup B1 between 2012 and 14, and clade A2c in more recent epidemics. Subgroup B2 viruses were present in all the years. Temporal phylogenetic clustering within the subgroups for both local and global sequence data was seen. Subgroups occurring in each epidemic season were comprised of multiple variants. Pneumonia severity did not vary by subgroup (p = 0.264). In both the F and G gene, the sequenced regions were found to be predominantly under purifying selection.
CONCLUSION: Subgroup patterns from this rural African setting temporally map with global strain distribution, suggesting a well-mixed global virus transmission pool of HMPV. Persistence in the local community is characterized by repeated introductions of HMPV variants from the global pool. The factors underlying the declining prevalence of HMPV in this population should be investigated.

PMID: 31470805 [PubMed - in process]

The Komodo dragon (Varanus komodoensis) genome and identification of innate immunity genes and clusters.

BMC Genomics. 2019 Aug 30;20(1):684

Authors: van Hoek ML, Prickett MD, Settlage RE, Kang L, Michalak P, Vliet KA, Bishop BM

Abstract
BACKGROUND: We report the sequencing, assembly and analysis of the genome of the Komodo dragon (Varanus komodoensis), the largest extant lizard, with a focus on antimicrobial host-defense peptides. The Komodo dragon diet includes carrion, and a complex milieu of bacteria, including potentially pathogenic strains, has been detected in the saliva of wild dragons. They appear to be unaffected, suggesting that dragons have robust defenses against infection. While little information is available regarding the molecular biology of reptile immunity, it is believed that innate immunity, which employs antimicrobial host-defense peptides including defensins and cathelicidins, plays a more prominent role in reptile immunity than it does in mammals. .
RESULTS: High molecular weight genomic DNA was extracted from Komodo dragon blood cells. Subsequent sequencing and assembly of the genome from the collected DNA yielded a genome size of 1.6 Gb with 45x coverage, and the identification of 17,213 predicted genes. Through further analyses of the genome, we identified genes and gene-clusters corresponding to antimicrobial host-defense peptide genes. Multiple β-defensin-related gene clusters were identified, as well as a cluster of potential Komodo dragon ovodefensin genes located in close proximity to a cluster of Komodo dragon β-defensin genes. In addition to these defensins, multiple cathelicidin-like genes were also identified in the genome. Overall, 66 β-defensin genes, six ovodefensin genes and three cathelicidin genes were identified in the Komodo dragon genome.
CONCLUSIONS: Genes with important roles in host-defense and innate immunity were identified in this newly sequenced Komodo dragon genome, suggesting that these organisms have a robust innate immune system. Specifically, multiple Komodo antimicrobial peptide genes were identified. Importantly, many of the antimicrobial peptide genes were found in gene clusters. We found that these innate immunity genes are conserved among reptiles, and the organization is similar to that seen in other avian and reptilian species. Having the genome of this important squamate will allow researchers to learn more about reptilian gene families and will be a valuable resource for researchers studying the evolution and biology of the endangered Komodo dragon.

PMID: 31470795 [PubMed - in process]

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A System for Analog Control of Cell Culture Dynamics to Reveal Capabilities of Signaling Networks.

iScience. 2019 Aug 08;19:586-596

Authors: Mokashi CS, Schipper DL, Qasaimeh MA, Lee REC

Abstract
Cellular microenvironments are dynamic. When exposed to extracellular cues, such as changing concentrations of inflammatory cytokines, cells activate signaling networks that mediate fate decisions. Exploring responses broadly to time-varying microenvironments is essential to understand the information transmission capabilities of signaling networks and how dynamic milieus influence cell fate decisions. Here, we present a gravity-driven cell culture and demonstrate that the system accurately produces user-defined concentration profiles for one or more dynamic stimuli. As proof of principle, we monitor nuclear factor-κB activation in single cells exposed to dynamic cytokine stimulation and reveal context-dependent sensitivity and uncharacterized single-cell response classes distinct from persistent stimulation. Using computational modeling, we find that cell-to-cell variability in feedback rates within the signaling network contributes to different response classes. Models are validated using inhibitors to predictably modulate response classes in live cells exposed to dynamic stimuli. These hidden capabilities, uncovered through dynamic stimulation, provide opportunities to discover and manipulate signaling mechanisms.

PMID: 31446223 [PubMed - as supplied by publisher]

Low ambient temperature reduces the time for fuel switching in the ruby-throated hummingbird (Archilochus colubris).

Comp Biochem Physiol A Mol Integr Physiol. 2019 Aug 22;:110559

Authors: Groom DJE, Bayram N, Shehata M, Herrera M LG, Welch KC

Abstract
Physiological adaptations that enhance flux through the sugar oxidation cascade permit hummingbirds to rapidly switch between burning lipids when fasted to burning ingested sugars when fed. Hummingbirds may be able to exert control over the timing and extent of use of ingested sugars by varying digestive rates when under pressure to accumulate energy stores or acquire energy in response to heightened energy demands. We hypothesized that hummingbirds would modulate the timing of a switch to reliance on ingested sugars differently when facing distinct energetic demands (cool versus warm ambient temperatures). The timing of the oxidation of a single nectar meal to fuel metabolism was assessed by open-flow respirometry, while the time to first excretion following the meal was used as a proxy for digestive throughput time. As predicted, birds showed a more rapid switch in respiratory exchange ratio (RER = rate of O2 consumption/CO2 production) and excreted earlier when held at cool temperatures compared to warm. In both cases, RER peaked barely above 1.0 indicating ingested sugar fueled ≈100% of resting metabolism. Our findings suggest that energetic demands modulate the rate of fuel switching through shifts of the sugar oxidation cascade. The speed of this shift may involve decreases in gut passage times which have previously been thought to be inflexible, or may be caused by changes in circulation as a result of low ambient temperature.

PMID: 31446070 [PubMed - as supplied by publisher]