bluuebunny/crossref_metadata_2025 huggingface dataset:
Recapitulation of Unilateral Cleft Lip Nasal Deformity on Normal Nasal Structure: A Finite Element Model Analysis
Authors: Huang Hanyao , Luo Xiangyou , Cheng Xu , Zhang Zihao , Ma Guanqiu , Shi Bing , Li Jingtao
Published: October 2018

Cleft lip nasal deformity has been challenging to plastic surgeons. A better understanding of the biomechanical aspect of the cleft nose would contribute to a better correction. In this study, finite element model of a normal nose was constructed and loaded with forces to recapitulate the unilateral cleft lip nasal deformity. Tether at the alar base was simulated by a laterally directed force at the lateral crus, and tether at the columella base by a posteriorly directed force at the medial crus. The equivalent von-Mises stress and the total deformation consequent to different patterns of loading were captured. In accordance with clinical observations, unilaterally loaded forces caused deformation on both sides of the nose. A correlation between the patterns of loading and different cleft lip nasal deformities was documented in detail. When set at the same force magnitude, tether at the columella base led to more extensive changes in the nasal morphology and higher level of stress than at the alar base. Clear identification of major pathological tethers in the nasolabial region might lead to more accurate and stable correction of cleft lip nasal deformities.
Acute Lung Injury in Critically Ill Patients: Actin-Scavenger Gelsolin Signals Prolonged Respiratory Failure
Authors: Holm Freja Stæhr , Sivapalan Pradeesh , Seersholm Niels , Itenov Theis Skovsgaard , Christensen Per Hjort , Jensen Jens-Ulrik Stæhr
Published: October 2018

Background:

Gelsolin is an actin-scavenger controlling the tissue damage from actin in the blood. Gelsolin levels in circulation drops when tissue damage and corresponding actin release is pronounced due to catabolic conditions. The purpose of this study was to determine if low plasma gelsolin independently predicts a reduced chance of weaning from ventilator-demanding respiratory failure in critically ill patients within 28 days from admission.

Results:

This cohort study included 746 critically ill patients with ventilator-demanding respiratory failure from the randomized clinical trial, “Procalcitonin And Survival Study (PASS).” Primary end point was successful weaning from mechanical ventilation within 28 days. We used multivariable Cox regression adjusted for age, sepsis, PaO2/FiO2 ratio and other known and suspected predictors of persistent respiratory failure. Follow-up was complete.

For medical patients, baseline-gelsolin below the 25th percentile independently predicted a 40% lower chance of successful weaning within 28 days (HR 0.60, 95% CI 0.46–0.79, P = 0.0002); among surgical patients this end point was not predicted. Low gelsolin levels predicted chance of being “alive and out of intensive care at day 14” for both medical and surgical patients (HR 0.69, 95% CI 0.54–0.89, P = 0.004). Gelsolin levels did not predict 28 day mortality for surgical or medical patients.

Conclusions:

Low levels of serum gelsolin independently predict a decreased chance of successful weaning from ventilator within 28 days among medical intensive care patients. This finding has implications for identifying patients who need individualized intervention early in intensive care course to prevent unfavorable lung prognosis in acute respiratory failure.

Trial registration:

This is a substudy to the PASS, Clinicaltrials.gov ID: NCT00271752, first registered January 1, 2006.
Sphingosine-1-Phosphate Reduces Hemorrhagic Shock and Resuscitation-Induced Microvascular Leakage by Protecting Endothelial Mitochondrial Integrity
Authors: Alves Natascha G. , Trujillo Andrea N. , Breslin Jerome W. , Yuan Sarah Y.
Published: October 2018

Excessive microvascular permeability is a serious complication following hemorrhagic shock and resuscitation (HSR). S1P has been shown to ameliorate microvascular leakage in a model of combined alcohol intoxication and HSR. In the current study, we tested the hypothesis that S1P reduces HSR-induced microvascular leakage by preserving endothelial cell junctional structure and the endothelial glycocalyx through the protection of mitochondrial function. We used an established in vivo rat model of conscious HSR and assessed microvascular leakage, endothelial glycocalyx integrity, and mitochondrial function by intravital microscopy. Junctional integrity in the mesenteric microcirculation was assessed by confocal microscopy. Cultured rat intestinal microvascular endothelial cells monolayers were used to test the ability of S1P to protect against glycocalyx shedding and endothelial barrier dysfunction caused by direct disruption of mitochondrial integrity due to inhibition of mitochondrial complex III. The results show that in vivo, S1P protects against HSR-induced hyperpermeability, preserves the expression of adherens junctional proteins, and protects against glycocalyx degradation. S1P treatment during HSR also protects against mitochondrial membrane depolarization. S1P also protects against mitochondrial dysfunction-induced endothelial barrier dysfunction and glycocalyx degradation by acting through mitochondrial complex III. Taken together, our data indicate that S1P protects against HSR-induced mitochondrial dysfunction in endothelial cells, which in turn improves the structure of the endothelial glycocalyx after HSR and allows for better junctional integrity to the prevention of excess microvascular permeability.
Liver Transplantation Trends and Outcomes for Hereditary Hemorrhagic Telangiectasia in the United States
Authors: Iyer Vivek N. , Saberi Behnam , Heimbach Julie K. , Larson Joseph J. , Raghavaiah Suresh , Ditah Ivo , Swanson Karen , Kamath Patrick S. , Watt KD , Taner Timucin , Krowka Michael J. , Leise Michael D.
Published: October 2018

Background.

Liver arteriovenous malformations (AVM) in hereditary hemorrhagic telangiectasia (HHT) can necessitate liver transplantation. There is limited data on HHT patients undergoing liver transplantation (LT) in the United States.

Methods.

Two sources of data were used: (1) Scientific Registry of Transplant Recipients (SRTR) database (1998-2016) (2) Single center liver transplant database (Mayo Clinic Rochester, MN). The aims of this study were (1) to determine trends in LT for HHT-related liver involvement in the United States using the SRTR database; (2) to identify clinical characteristics, indications, and outcomes for LT in HHT.

Results.

Thirty-nine HHT patients were listed for LT in the SRTR database from 1998-2016 to 1998-2001 (n = 1); 2002-2005 (n = 4); 2006-2010 (n = 10), and 2011-2016 (n = 24). Twenty-four underwent LT at a median age of 47.5 years (interquartile range, 37.0-58.5 years). Median calculated MELD score at time of LT was 8.0 (interquartile range, 7.0-9.5), and 75% received an exception MELD score. Two status-1 patients died during transplant surgery. Nineteen (86%) patients were alive after a median post-LT follow-up of 48 months, whereas 2 patients were lost to follow-up. Five of the aforementioned HHT patients underwent LT at Mayo Clinic, 4 with high output cardiac failure, and 1 with biliary ischemia. All 5 were alive at the time of last follow-up with good graft function and resolution of heart failure.

Conclusions.

Outcomes after LT for HHT patients are excellent with 86% survival after a median follow-up of 48 months and resolution of heart failure. LT listing for HHT has increased in substantially in more recent eras.
Towards fungal computer
Authors: Adamatzky Andrew
Published: October 2018

We propose that fungi Basidiomycetes can be used as computing devices: information is represented by spikes of electrical activity, a computation is implemented in a mycelium network and an interface is realized via fruit bodies. In a series of scoping experiments, we demonstrate that electrical activity recorded on fruits might act as a reliable indicator of the fungi’s response to thermal and chemical stimulation. A stimulation of a fruit is reflected in changes of electrical activity of other fruits of a cluster, i.e. there is distant information transfer between fungal fruit bodies. In an automaton model of a fungal computer, we show how to implement computation with fungi and demonstrate that a structure of logical functions computed is determined by mycelium geometry.
From statistical inference to a differential learning rule for stochastic neural networks
Authors: Saglietti Luca , Gerace Federica , Ingrosso Alessandro , Baldassi Carlo , Zecchina Riccardo
Published: October 2018

Stochastic neural networks are a prototypical computational device able to build a probabilistic representation of an ensemble of external stimuli. Building on the relationship between inference and learning, we derive a synaptic plasticity rule that relies only on delayed activity correlations, and that shows a number of remarkable features. Our
delayed-correlations matching
(DCM) rule satisfies some basic requirements for biological feasibility: finite and noisy afferent signals, Dale’s principle and asymmetry of synaptic connections, locality of the weight update computations. Nevertheless, the DCM rule is capable of storing a large, extensive number of patterns as attractors in a stochastic recurrent neural network, under general scenarios without requiring any modification: it can deal with correlated patterns, a broad range of architectures (with or without hidden neuronal states), one-shot learning with the palimpsest property, all the while avoiding the proliferation of spurious attractors. When hidden units are present, our learning rule can be employed to construct Boltzmann machine-like generative models, exploiting the addition of hidden neurons in feature extraction and classification tasks.
Thermodynamic efficiency of contagions: a statistical mechanical analysis of the SIS epidemic model
Authors: Harding Nathan , Nigmatullin Ramil , Prokopenko Mikhail
Published: October 2018

We present a novel approach to the study of epidemics on networks as thermodynamic phenomena, quantifying the thermodynamic efficiency of contagions, considered as distributed computational processes. Modelling SIS dynamics on a contact network statistical-mechanically, we follow the maximum entropy (MaxEnt) principle to obtain steady-state distributions and derive, under certain assumptions, relevant thermodynamic quantities both analytically and numerically. In particular, we obtain closed-form solutions for some cases, while interpreting key epidemic variables, such as the reproductive ratioof a SIS model, in a statistical mechanical setting. On the other hand, we consider configuration and free entropy, as well as the Fisher information, in the epidemiological context. This allowed us to identify criticality and distinct phases of epidemic processes. For each of the considered thermodynamic quantities, we compare the analytical solutions informed by the MaxEnt principle with the numerical estimates for SIS epidemics simulated on Watts–Strogatz random graphs.
A thermodynamically consistent model of finite-state machines
Authors: Chu Dominique , Spinney Richard E.
Published: October 2018

Finite-state machines (FSMs) are a theoretically and practically important model of computation. We propose a general, thermodynamically consistent model of FSMs and characterize the resource requirements of these machines. We model FSMs as time-inhomogeneous Markov chains. The computation is driven by instantaneous manipulations of the energy levels of the states. We calculate the entropy production of the machine, its error probability, and the time required to complete one update step. We find that a sequence of generalized bit-setting operations is sufficient to implement any FSM.
Intrinsic limits of information transmission in biochemical signalling motifs
Authors: Suderman Ryan , Deeds Eric J.
Published: October 2018

All living things have evolved to sense changes in their environment in order to respond in adaptive ways. At the cellular level, these sensing systems generally involve receptor molecules at the cell surface, which detect changes outside the cell and relay those changes to the appropriate response elements downstream. With the advent of experimental technologies that can track signalling at the single-cell level, it has become clear that many signalling systems exhibit significant levels of ‘noise,’ manifesting as differential responses of otherwise identical cells to the same environment. This noise has a large impact on the capacity of cell signalling networks to transmit information from the environment. Application of information theory to experimental data has found that all systems studied to date encode less than 2.5 bits of information, with the majority transmitting significantly less than 1 bit. Given the growing interest in applying information theory to biological data, it is crucial to understand whether the low values observed to date represent some sort of intrinsic limit on information flow given the inherently stochastic nature of biochemical signalling events. In this work, we used a series of computational models to explore how much information a variety of common ‘signalling motifs’ can encode. We found that the majority of these motifs, which serve as the basic building blocks of cell signalling networks, can encode far more information (4–6 bits) than has ever been observed experimentally. In addition to providing a consistent framework for estimating information-theoretic quantities from experimental data, our findings suggest that the low levels of information flow observed so far in living system are not necessarily due to intrinsic limitations. Further experimental work will be needed to understand whether certain cell signalling systems actually can approach the intrinsic limits described here, and to understand the sources and purpose of the variation that reduces information flow in living cells.
Haematopoietic stem cells: entropic landscapes of differentiation
Authors: Wiesner K. , Teles J. , Hartnor M. , Peterson C.
Published: October 2018

The metaphor of a potential epigenetic differentiation landscape broadly suggests that during differentiation a stem cell approaches a stable equilibrium state from a higher free energy towards a stable equilibrium state which represents the final cell type. It has been conjectured that there is an analogy to the concept of entropy in statistical mechanics. In this context, in the undifferentiated state, the entropy would be large since fewer constraints exist on the gene expression programmes of the cell. As differentiation progresses, gene expression programmes become more and more constrained and thus the entropy would be expected to decrease. In order to assess these predictions, we compute the Shannon entropy for time-resolved single-cell gene expression data in two different experimental set-ups of haematopoietic differentiation. We find that the behaviour of this entropy measure is in contrast to these predictions. In particular, we find that the Shannon entropy is not a decreasing function of developmental pseudo-time but instead it increases towards the time point of commitment before decreasing again. This behaviour is consistent with an increase in gene expression disorder observed in populations sampled at the time point of commitment. Single cells in these populations exhibit different combinations of regulator activity that suggest the presence of multiple configurations of a potential differentiation network as a result of multiple entry points into the committed state.
Semantic information, autonomous agency and non-equilibrium statistical physics
Authors: Kolchinsky Artemy , Wolpert David H.
Published: October 2018

Shannon information theory provides various measures of so-called syntactic information, which reflect the amount of statistical correlation between systems. By contrast, the concept of ‘semantic information’ refers to those correlations which carry significance or ‘meaning’ for a given system. Semantic information plays an important role in many fields, including biology, cognitive science and philosophy, and there has been a long-standing interest in formulating a broadly applicable and formal theory of semantic information. In this paper, we introduce such a theory. We define semantic information as the syntactic information that a physical system has about its environment which is causally necessary for the system to maintain its own existence. ‘Causal necessity’ is defined in terms of counter-factual interventions which scramble correlations between the system and its environment, while ‘maintaining existence’ is defined in terms of the system's ability to keep itself in a low entropy state. We also use recent results in non-equilibrium statistical physics to analyse semantic information from a thermodynamic point of view. Our framework is grounded in the intrinsic dynamics of a system coupled to an environment, and is applicable to any physical system, living or otherwise. It leads to formal definitions of several concepts that have been intuitively understood to be related to semantic information, including ‘value of information’, ‘semantic content’ and ‘agency’.
Computation by natural systems
Authors: Chu Dominique , Prokopenko Mikhail , Ray J. Christian J.
Published: October 2018

Computation is a useful concept far beyond the disciplinary boundaries of computer science. Perhaps the most important class of natural computers can be found in biological systems that perform computation on multiple levels. From molecular and cellular information processing networks to ecologies, economies and brains, life computes. Despite ubiquitous agreement on this fact going back as far as von Neumann automata and McCulloch–Pitts neural nets, we so far lack principles to understand rigorously how computation is done in living, or active, matter. What is the ultimate nature of natural computation that has evolved, and how can we use these principles to engineer intelligent technologies and biological tissues?
Epigenome priming dictates transcription response and white matter fate upon perinatal inflammation
Authors: Schang Anne-Laure , van Steenwinckel Juliette , Lipecki Julia , Rich-Griffin Charlotte , Woolley-Allen Kate , Dyer Nigel , Charpentier Tifenn Le , Schäfer Patrick , Fleiss Bobbi , Ott Sascha , SabéRan-Djoneidi Délara , Mezger Valérie , Gressens Pierre
Published: October 2018

Inflammatory insults accompanying prematurity provokes diffuse white matter injury (DWMI) which is associated with increased risk of neurodevelopmental disorders: pre-term infants have a 10 to 18-fold increased risk of developing autism spectrum disorders, compared to term infants. DWMI is due to maturation arrest in oligodendrocyte precursor cells (OPCs). Using integrated genome-wide approaches in a validated mouse perinatal model of DWMI, induced by systemic- and neuro-inflammation based on repeated interleukin-1B administrations, we show that neuroinflammation induces limited epigenomic disturbances in OPCs. In contrast, we unravel marked transcriptomic alterations of genes of the immune/inflammatory pathways, which are expressed in unstressed OPCs and physiologically downregulated along OPC maturation. Consistently, we observe that transcription factors of the inflammatory pathways occupy DNA both in unstressed and inflamed OPCs. Thus, rather than altering genome-wide chromatin accessibility, neuroinflammation takes advantage of open chromatin regions and deeply counteracts the stage-dependent downregulation of these active transcriptional programs. Therefore, our study opens new avenues for the future development of targeted approaches to protect preterm brains.

Highlights

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Limited epigenomic impact of inflammation on OPC maturation blockade

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Major transcriptomic disturbances take advantage of a primed epigenetic landscape

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Proinflammatory genes are active in OPCs and downregulated upon maturation

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Neuroinflammation counteracts both this downregulation and maturation in OPCs
GRID – Genomics of Rare Immune Disorders: a highly sensitive and specific diagnostic gene panel for patients with primary immunodeficiencies
Authors: Simeoni Ilenia , Shamardina Olga , Deevi Sri VV , Thomas Moira , Megy Karyn , Staples Emily , Whitehorn Deborah , Duarte Daniel , Mapeta Rutendo , Ouwehand Willem H , Penkett Christopher J , Rayner-Matthews Paula , Stark Hannah , Stephens Jonathan C , Stirrups Kathleen E , Turro Ernest ,   NIHR BioResource, Thrasher Adrian , Kuijpers Taco W , Smith Kenneth GC , Savic Sinisa , Burns Siobhan O , Thaventhiran James E , Allen Hana Lango
Published: October 2018

Primary Immune disorders affect 15,000 new patients every year in Europe. Genetic tests are usually performed on a single or very limited number of genes leaving the majority of patients without a genetic diagnosis. We designed, optimised and validated a new clinical diagnostic platform called GRID, Genomics of Rare Immune Disorders, to screen in parallel 279 genes, including 2015 IUIS genes, known to be causative of Primary Immune disorders (PID). Validation to clinical standard using more than 58,000 variants in 176 PID patients shows an excellent sensitivity, specificity. The customised and automated bioinformatics pipeline prioritises and reports pertinent Single Nucleotide Variants (SNVs), INsertions and DELetions (INDELs) as well as Copy Number Variants (CNVs). An example of the clinical utility of the GRID panel, is represented by a patient initially diagnosed with X-linked agammaglobulinemia due to a missense variant in the BTK gene with severe inflammatory bowel disease. GRID results identified two additional compound heterozygous variants in IL17RC, potentially driving the altered phenotype.
Assessing the response of small RNA populations to allopolyploidy using resynthesized Brassica napus allotetraploids
Authors: Palacios Paulina Martinez , Jacquemot Marie-Pierre , Tapie Marion , Rousselet Agnès , Diop Mamoudou , Remoue Carine , Falque Matthieu , Lloyd Andrew , Jenczewski Eric , Lassalle Gilles , Chevre Anne-Marie , Lelandais Christine , Crespi Martin , Brabant Philippe , Joets Johann , Alix Karine
Published: October 2018

Allopolyploidy, combining interspecific hybridization with whole genome duplication, has had significant impact on plant evolution. Its evolutionary success is related to the rapid and profound genome reorganizations that allow neo-allopolyploids to form and adapt. Nevertheless, how neo-allopolyploid genomes adapt to regulate their expression remains poorly understood. The hypothesis of a major role for small non-coding RNAs (sRNAs) in mediating the transcriptional response of neo-allopolyploid genomes has progressively emerged. Generally, 21-nt sRNAs mediate post-transcriptional gene silencing (PTGS) by mRNA cleavage whereas 24-nt sRNAs repress transcription (transcriptional gene silencing, TGS) through epigenetic modifications. Here, we characterize the global response of sRNAs to allopolyploidy in Brassica, using three independently resynthesized B. napus allotetraploids surveyed at two different generations in comparison with their diploid progenitors. Our results suggest an immediate but transient response of specific sRNA populations to allopolyploidy. These sRNA populations mainly target non-coding components of the genome but also target the transcriptional regulation of genes involved in response to stresses and in metabolism; this suggests a broad role in adapting to allopolyploidy. We finally identify the early accumulation of both 21- and 24-nt sRNAs involved in regulating the same targets, supporting a PTGS-to-TGS shift at the first stages of the neo-allopolyploid formation. We propose that reorganization of sRNA production is an early response to allopolyploidy in order to control the transcriptional reactivation of various non-coding elements and stress-related genes, thus ensuring genome stability during the first steps of neo-allopolyploid formation.
Distinct neural mechanisms and temporal constraints govern a cascade of audiotactile interactions
Authors: Zumer Johanna M. , White Thomas P. , Noppeney Uta
Published: October 2018

Asynchrony is a critical cue informing the brain whether sensory signals are caused by a common source and should be integrated or segregated. It is unclear how the brain binds audiotactile signals into behavioural benefits depending on their asynchrony. Participants actively responded (psychophysics) or passively attended (electroencephalogrpahy) to noise bursts, ‘taps-to-the-face’, and their audiotactile (AT) combinations at seven audiotactile asynchronies: 0, ±20, ±70, and ±500ms. Observers were faster at detecting AT than unisensory stimuli, maximally for synchronous stimulation and declining within a ≤70ms temporal integration window. We observed AT interactions for (1) near-synchronous stimuli within a ≤20ms temporal integration window for evoked response potentials (ERPs) at 110ms and ∼400ms, (2) specifically ±70ms asynchronies, across the P200 ERP and theta-band inter-trial coherence (ITC) and power at ∼200ms, with a frontocentral topography, and (3) beta-band power across several asynchronies. Our results suggest that early AT interactions for ERP and theta-band ITC and power mediate behavioural response facilitation within a ≤70ms temporal integration window, but beta-band power reflects AT interactions that are less relevant for behaviour. This diversity of temporal profiles and constraints demonstrates how audiotactile integration unfolds in a cascade of interactions to generate behavioural benefits.
Molecularly distinct models of zebrafishMyc-induced B cell leukemia
Authors: Borga Chiara , Foster Clay A. , Iyer Sowmya , Garcia Sara P. , Langenau David M. , Frazer J. Kimble
Published: October 2018

Zebrafish models of T cell acute lymphoblastic leukemia (T-ALL) have been studied for over a decade, but curiously, robust zebrafish B cell ALL (B-ALL) models had not been described. Recently, our laboratories reported two seemingly closely-related models of zebrafish B-ALL. In these genetic lines, the primary difference is expression of either murine or human transgenic c-MYC, each controlled by the zebrafishrag2promoter. Here, we compare ALL gene expression in both models. Surprisingly, we find that B-ALL arise in different B cell lineages, withighm+vs.ighz+B-ALL driven by murineMycvs. humanMYC, respectively. Moreover, these B-ALL types exhibit signatures of distinct molecular pathways, further unexpected dissimilarity. Thus, despite sharing analogous genetic makeup, the ALL types in each model are markedly different, proving subtle genetic changes can profoundly impact model organism phenotypes. Investigating the mechanistic differences between mouse and human c-MYC in these contexts may reveal key functional aspects governing MYC-driven oncogenesis in human malignancies.
Assembly and seasonality of core phyllosphere microbiota on perennial biofuel crops
Authors: Grady Keara L , Sorensen Jackson W. , Stopnisek Nejc , Guittar John , Shade Ashley
Published: October 2018

Perennial grasses are promising feedstocks for biofuel production, and there is potential to leverage their native microbiomes to increase their productivity and resilience to environmental stress. Here, we characterize the 16S rRNA gene diversity and seasonal assembly of bacterial and archaeal microbiomes of two perennial cellulosic feedstocks, switchgrass (Panicum virgatum L.) and miscanthus (Miscanthus × giganteus). We sampled leaves and soil every three weeks from pre-emergence through senescence for two consecutive switchgrass growing seasons and one miscanthus season, and identified core leaf taxa based on abundance and occupancy. Virtually all leaf taxa are also detected in soil; source-sink modeling shows non-random, ecological filtering by the leaf, suggesting that soil is important reservoir of phyllosphere diversity. Core leaf taxa include early, mid, and late season groups that were consistent across years and crops. This consistency in leaf microbiome dynamics and core members is promising for microbiome manipulation or management to support biofuel crop production.
On Parameter Interpretability of Phenomenological-Based Semiphysical Models
Authors: Lema-Perez Laura , Muñoz-Tamayo Rafael , Garcia-Tirado Jose , Alvarez Hernan
Published: October 2018

Empirical and phenomenological based models are used to represent biological and physiological processes. Phenomenological models are derived from the knowledge of the mechanisms that underlie the behaviour of the system under study, while empirical models are derived from analysis of data to quantify relationships between variables of interest. For studying biological systems, the phenomenological modeling approach offers the great advantage of having a structure with variables and parameters with physical meaning that enhance the interpretability of the model and its further used for decision making. The interpretability property of models, however, remains a vague concept. In this study, we tackled the interpretability property for parameters of phenomenological-based models. To our knowledge, this property has not been deeply discussed, perhaps by the implicit assumption that interpretability is inherent to the phenomenological-based models. We propose a conceptual framework to address the parameter interpretability and its implications for parameter identifiability. We use as battle horse a simple but relevant model representing the enzymatic degradation ofβ–casein by aLactococcus lactisbacterium.
Conformational states control Lck switching between free and confined diffusion modes in T cells
Authors: Hilzenrat Geva , Pandžić Elvis , Yang Zhengmin , Nieves Daniel J. , Goyette Jesse , Rossy Jérémie , Gaus Katharina
Published: October 2018

T cell receptor (TCR) phosphorylation by Lck is an essential step in T cell activation. It is known the conformational states of Lck control enzymatic activity; however, the underlying principles of how Lck finds its substrate in the plasma membrane remain elusive. Here, single-particle tracking is paired with photoactivatable localization microscopy (sptPALM) to observe the diffusive modes of Lck in the plasma membrane. Individual Lck molecules switched between free and confined diffusion in resting and stimulated T cells. Conformational state, but not partitioning into membrane domains, caused Lck confinement as open conformation Lck was more confined than closed. Further confinement of kinase-dead versions of Lck suggests that Lck interacts with open active Lck to cause confinement, irrespectively of kinase activity. Our data supports a model that confined diffusion of open Lck results in high local phosphorylation rates and closed Lck diffuses freely to enable wide-range scanning of the plasma membrane.
A genome-wide analysis of adhesion inCaulobacter crescentusidentifies new regulatory and biosynthetic components for holdfast assembly
Authors: Hershey David M. , Fiebig Aretha , Crosson Sean
Published: October 2018

Due to their intimate physical interactions with the environment, surface polysaccharides are critical determinants of fitness for bacteria.Caulobacter crescentusproduces a specialized structure at one of its cell poles called the holdfast that enables attachment to surfaces. Previous studies have shown that the holdfast is a carbohydrate-based material and identified a number of genes required for holdfast development. However, incomplete information about its chemical structure, biosynthetic genes and regulatory principles has limited progress in understanding the mechanism of holdfast synthesis. We have leveraged the adhesive properties of the holdfast to perform a saturating screen for genes affecting attachment to cheesecloth over a multi-day time course. Using similarities in the temporal profiles of mutants in a transposon library, we defined discrete clusters of genes with related effects on cheesecloth colonization. Holdfast synthesis, flagellar motility, type IV pilus assembly and smooth lipopolysaccharide (SLPS) production represented key classes of adhesion determinants. Examining these clusters in detail allowed us to predict and experimentally define the functions of multiple uncharacterized genes in both the holdfast and SLPS pathways. In addition, we showed that the pilus and flagellum control holdfast synthesis separately by modulating the holdfast inhibitorhfiA.This study defines a set of genes contributing to adhesion that includes newly discovered genes required for holdfast biosynthesis and attachment. Our data provide evidence that the holdfast contains a complex polysaccharide with at least four monosaccharides in the repeating unit and underscore the central role of cell polarity in mediating attachment ofC. crescentusto surfaces.

Importance

Bacteria routinely encounter biotic and abiotic materials in their surrounding environments, and they often enlist specific behavioral programs to colonize these materials. Adhesion is an early step in colonizing a surface.Caulobacter crescentusproduces a structure called the holdfast, which allows this organism to attach to and colonize surfaces. To understand how the holdfast is produced, we performed a genome-wide search for genes that contribute to adhesion by selecting for mutants that could not attach to cheesecloth. We discovered complex interactions between genes that mediate surface contact and genes that contribute to holdfast development. Our genetic selection identified what likely represents a comprehensive set of genes required to generate a holdfast, laying the groundwork for a detailed characterization of the enzymes that build this specialized adhesin.
Local and landscape drivers of aquatic-to-terrestrial subsidies in riparian ecosystems: a worldwide meta-analysis
Authors: Lafage D. , Bergman E. , Eckstein R. L. , Österling M. , Sadler J.P. , Piccolo JJ
Published: October 2018

Cross-boundary fluxes of organisms and matter, termed “subsidies”, are now recognized to be reciprocal and of roughly equal importance for both aquatic and terrestrial systems, even if terrestrial input to aquatic ecosystems has received most attention. The magnitude of aquatic to terrestrial subsidies is well documented, but the drivers behind these subsidies and their utilization by terrestrial consumers are characteristically local scale studies, limiting the inferences that can be drawn for broader geographic scales. We therefore built and analyzed a database of stable isotope data extracted from 21 studies worldwide, to identify both landscape and local scale variables that may affect the diet of terrestrial predators in riparian ecosystems. Our meta-analysis revealed a greater magnitude of aquatic-to-terrestrial subsidies (> 50%) than previously reported, albeit with large geographic and inter-annual variations. We demonstrated a large effect of landscape-scale factors on aquatic-to-terrestrial subsidies, particularly anthropogenic land use and tree cover. Local human population was the only relevant factor at the local scale. We also found that studies on landscape-scale and anthropogenic land use effects on aquatic-to-terrestrial subsidies are currently strongly under-represented in the ecological literature. Such studies are needed to improve our understanding of how land use and environmental change might influence future patterns of biodiversity and ecosystem function.
Whole genome sequencing Mycobacterium tuberculosis directly from sputum identifies more genetic diversity than sequencing from culture
Authors: Nimmo Camus , Shaw Liam P. , Doyle Ronan , Williams Rachel , Brien Kayleen , Burgess Carrie , Breuer Judith , Balloux Francois , Pym Alexander S.
Published: October 2018

Background

Repeated culture reduces within-sample Mycobacterium tuberculosis genetic diversity due to selection of clones suited to growth in culture and/or random loss of lineages, but it is not known to what extent omitting the culture step altogether alters genetic diversity. We compared M. tuberculosis whole genome sequences generated from 33 paired clinical samples using two methods. In one method DNA was extracted directly from sputum then enriched with custom-designed SureSelect (Agilent) oligonucleotide baits and in the other it was extracted from mycobacterial growth indicator tube (MGIT) culture.

Results

DNA directly sequenced from sputum showed significantly more within-sample diversity than that from MGIT culture (median 5.0 vs 4.5 heterozygous alleles per sample, p=0.04). Resistance associated variants present as HAs occurred in four patients, and in two cases may provide a genotypic explanation for phenotypic resistance.

Conclusions

Culture-free M. tuberculosis whole genome sequencing detects more within-sample diversity than a leading culture-based method and may allow detection of mycobacteria that are not actively replicating.
Live cell imaging of meiosis in Arabidopsis thaliana - a landmark system
Authors: Prusicki Maria Ada , Keizer Emma Mathilde , van Rosmalen Rik Peter , Komaki Shinichiro , Seifert Felix , Müller Katja , Wijnker Erik , Fleck Christian , Schnittger Arp
Published: October 2018

Meiosis is essential for sexual reproduction and key to the generation of genetic diversity. To reveal the robustness of meiocyte differentiation and progression through meiosis, we have here established a live cell imaging setup to follow the dynamics of individual male meiocytes in Arabidopsis. Our method is based on the concomitant visualization of microtubules and a meiotic cohesion subunit that allowed following five cellular parameters: cell shape, nucleus position, nucleolus position, chromatin condensation and microtubule array. We find that the states of these parameters are not randomly associated and identify 11 states, referred to as landmarks, that occur much more frequently than closely related states, indicating that they are convergent points of meiotic progression. With this, the here-presented landmark system represents a novel method to analyze meiosis not only allowing a high-temporal dissection but also providing new criteria to evaluate mutants or environmental effects on meiosis.
Expectation and attention increase the integration of top-down and bottom-up signals in perception through different pathways
Authors: Gordon Noam , Tsuchiya Naotsugu , Koenig-Robert Roger , Hohwy Jakob
Published: October 2018

Perception results from the integration of incoming sensory information with pre-existing information available in the brain. In this EEG (electroencephalography) study we utilised the Hierarchical Frequency Tagging method to examine how such integration is modulated by expectation and attention. Using intermodulation (IM) components as a measure of non-linear signal integration, we show in three different experiments that both expectation and attention enhance integration between top-down and bottom-up signals. Based on multispectral phase coherence, we present two direct physiological measures to demonstrate the distinct yet related mechanisms of expectation and attention. Specifically, our results link expectation to the modulation of prediction signals and the integration of top-down and bottom-up information at lower levels of the visual hierarchy. Meanwhile, they link attention to the propagation of ascending signals and the integration of information at higher levels of the visual hierarchy. These results are consistent with the predictive coding account of perception.
A Mathematical Model Relating Pitocin Use During Labor with Offspring Autism Development in Terms of Oxytocin Receptor Desensitization in the Fetal Brain
Authors: Gottlieb Mark M.
Published: October 2018

This paper develops a mathematical model describing the potential buildup of high oxytocin concentrations in the maternal circulation during labor in terms of continuous Pitocin infusion rate, half-life and maternal weight. Oxytocin override of the degradation of oxytocin by placental oxytocinase is introduced to model the potential transfer of oxytocin from the maternal circulation across the placenta into the fetal circulation, and from there into the brain of the fetus. The desensitization unit D equal to 1.8E6 (pg-min)/ml is employed to establish a desensitization threshold, and by extension; a down-regulation threshold as a function of oxytocin override concentration and continuous Pitocin infusion time, that could be a factor in the subsequent development of autism among offspring. Epidemiological studies by Duke University (S.G. Gregory, 2013), Yale University (O. Weisman, 2015) and Harvard University (A.S. Oberg, 2016) are discussed regarding Pitocin use and offspring autism development for an explanation of the weak correlations they identified. The findings of the Harvard epidemiological study are re-interpreted regarding Pitocin use, and its conclusion questioned. Further evaluations of the findings of these three epidemiological studies are called for to incorporate medical information on quantity of Pitocin used, continuous Pitocin infusion rate, length of labor and maternal weight to determine if a correlation can be established with offspring autism development above an empirically determined desensitization threshold for Pitocin use. Suggestions for research are discussed, including an alternative to continuous Pitocin infusion, pulsatile infusion of Pitocin during labor induction, that may mitigate possible offspring autism development.

HIGHLIGHTS

Buildup of oxytocin (OT) in the maternal circulation mathematically modeled.

Relationship of OT half-life and OT concentration in maternal circulation identified.

OTR Desensitization related to Pitocin infusion time and OT override concentration.

Weak correlations for autism development in epidemiological studies explained.

Examination called for of medical records of Pitocin use in epidemiological studies.

OUTLINE OF PAPER

Introduction

Development and application of mathematical model – Sections 1 through 6, notably: Figures 1 through 4

Discussion of oxytocin receptor desensitization as it pertains to mathematical model – Sections 7 and 8

Influence of mathematical model on interpretation of epidemiological studies – Sections 9 and 10

Research considerations – Section 11, notably:Subsection 11.1 – Call for detailed epidemiological analysis of selected medical information indicated by mathematical model Subsection 11.2 – Review of pulsatile Pitocin infusion to mitigate possible offspring autism development indicated by mathematical model
RAxML-NG: A fast, scalable, and user-friendly tool for maximum likelihood phylogenetic inference
Authors: Kozlov Alexey M. , Darriba Diego , Flouri Tomáš , Morel Benoit , Stamatakis Alexandros
Published: October 2018

Motivation

Phylogenies are important for fundamental biological research, but also have numerous applications in biotechnology, agriculture, and medicine. Finding the optimal tree under the popular maximum like-lihood (ML) criterion is known to be NP-hard. Thus, highly optimized and scalable codes are needed to analyze constantly growing empirical datasets.

Results

We present RAxML-NG, a from scratch re-implementation of the established greedy tree search algorithm of RAxML/ExaML. RAxML- NG offers improved accuracy, flexibility, speed, scalability, and usability compared to RAxML/ExaML. On taxon-rich datasets, RAxML-NG typically finds higher-scoring trees than IQTree, an increasingly popular recent tool for ML-based phylogenetic inference (although IQ-Tree shows better stability). Finally, RAxML-NG introduces several new features, such as the detection of terraces in tree space and a the recently introduced transfer bootstrap support metric.

Availability

The code is available under GNU GPL athttps://github.com/amkozlov/raxml-ng.RAxML-NGweb service (maintained by Vital- IT) is available athttps://raxml-ng.vital-it.ch/.

Contact

alexey.kozlov@h-its.org
Vigour/tolerance trade-off in cultivated sunflower (Helianthus annuus) response to salinity stress is linked to leaf elemental composition
Authors: Temme Andries A. , Kerr Kelly L. , Donovan Lisa A.
Published: October 2018

Developing more stress-tolerant crops will require greater knowledge of the physiological basis of stress tolerance. Here we explore how biomass declines in response to salinity relate to leaf traits across twenty genotypes of cultivated sunflower (Helianthus annuus). Plant growth, leaf physiological traits, and leaf elemental composition were assessed after 21 days of salinity treatments (0, 50, 100, 150, or 200 mM NaCl) in a greenhouse study. There was a trade-off in performance such that vigorous genotypes, those with higher biomass at zero mM NaCl, had both a larger absolute decrease and proportional decrease in biomass due to increased salinity. More vigorous genotypes at control were less tolerant to salinity. Contrary to expectation, genotypes with a low increase in leaf Na and decrease in K:Na were not better at maintaining biomass with increasing salinity. Rather, genotypes with a greater reduction in leaf S and K content were better at maintaining biomass at increased salinity. While we found an overall trade-off between sunflower vigour and salt tolerance, some genotypes were more tolerant than expected. Further analysis of the traits and mechanisms underlying this trade-off may allow us to breed these into high vigour genotypes in order to increase their salt tolerance.
MITRE: predicting host status from microbiota time-series data
Authors: Bogart Elijah , Creswell Richard , Gerber Georg K.
Published: October 2018

Longitudinal studies are crucial for discovering casual relationships between the microbiome and human disease. We present Microbiome Interpretable Temporal Rule Engine (MITRE), the first machine learning method specifically designed for predicting host status from microbiome time-series data. Our method maintains interpretability by learning predictive rules over automatically inferred time-periods and phylogenetically related microbes. We validate MITRE’s performance on semi-synthetic data, and five real datasets measuring microbiome composition over time in infant and adult cohorts. Our results demonstrate that MITRE performs on par or outperforms “black box” machine learning approaches, providing a powerful new tool enabling discovery of biologically interpretable relationships between microbiome and human host.
Tactile enrichment drives emergence of functional columns and improves sensory coding in L2/3 of mouse S1
Authors: LeMessurier Amy M. , Feldman Daniel E.
Published: October 2018

Sensory maps in layer (L) 2/3 of rodent cortex lack precise functional column boundaries, and instead exhibit locally heterogeneous tuning superimposed on smooth global topography. Could this organization be a byproduct of impoverished experience in laboratory housing? We compared whisker map somatotopy in L2/3 and L4 excitatory cells of somatosensory (S1) cortex in normally housed vs. tactile-enriched mice, using GCaMP6s imaging. Normally housed mice had a dispersed, salt-and-pepper whisker map in L2/3, but L4 was more topographically precise. Enrichment (P21 to P46-71) sharpened whisker tuning and decreased, but did not abolish, local tuning heterogeneity. In L2/3, enrichment strengthened and sharpened whisker point representations, and created functional boundaries of tuning similarity and noise correlations at column edges. Thus, tactile experience drives emergence of functional columnar topography in S1, and reduces salt-and-pepper tuning heterogeneity. These changes predict improved single-trial population coding of whisker deflections within each column.