bluuebunny/crossref_metadata_2025 huggingface dataset:
Dopamine Optimizes Venous Return During Cardiopulmonary Bypass and Reduces the Need for Postoperative Blood Transfusion
Authors: Moscarelli Marco , Condello Ignazio , Fattouch Khalil , Punjabi Prakash , Ajello Valentina , Solimando Carlo , Fiore Flavio , Angelini Gianni , Speziale Giuseppe
Published: December 2018

Venodilation occurs shortly after the institution of cardiopulmonary bypass (CPB), necessitating fluid or vasoconstrictor administration to maintain adequate oxygen delivery. The vasoconstrictor effects of dopamine are not well studied in this context. Therefore, we conducted a single-center, double-blind case–control study to determine the role and utility of dopamine as a vasoconstrictor during CPB. The study included 60 adults who were scheduled for isolated elective/urgent coronary artery bypass grafting. Patients in group A (n = 30) received a dopamine bolus (2 mg) 20 min after cross-clamping, whereas patients in group B (n = 30) did not receive any intervention at a specific time point. Both groups received standard care as needed (fluid replacement or norepinephrine bolus). Venous return was measured directly in the reservoir and indirectly by Doppler measurement at the level of the inferior vena cava with transesophageal echocardiography. Both open and closed circuits were used for CPB. A single dopamine bolus (2 mg) increased volume in the venous reservoir in group A. Group A patients also received significantly fewer units of red blood cells in the intensive care unit (ICU) than did patients in group B. There were no significant between-group differences in postoperative bleeding, mechanical ventilation, or length of stay in the ICU. These findings suggest that use of a dopamine bolus can increase venous return and reduce the need for fluid replacement during and after CPB in patients undergoing coronary artery bypass grafting.
Risk Factors Associated With Upper Aerodigestive Tract or Coliform Bacterial Overgrowth of the Small Intestine in Symptomatic Patients
Authors: Bohm Matthew , Shin Andrea , Teagarden Sean , Xu Huiping , Gupta Anita , Siwiec Robert , Nelson David , Wo John M.
Published: December 2018

Introduction:

The clinical relevance of bacterial types identified in small bowel aspirate cultures during diagnostic evaluation of small intestinal bacterial overgrowth (SIBO) is unclear.

Aim:

The main purpose of this study was to assess associations between risk factors for upper aerodigestive tract (UAT) or coliform SIBO and SIBO diagnosis by culture.

Materials and Methods:

Small bowel aspirates were cultured in patients with suspected SIBO, defined as ≥104 colony-forming units/mL coliform or ≥105 colony-forming units/mL UAT bacteria. History was reviewed for risk factors and potential SIBO complications. Symptoms, quality of life, psychological traits, and laboratory values were assessed. We compared groups by 2-sample t test, Wilcoxon rank sum test, and the Fisher exact test. Overall associations of primary and secondary endpoints with type of bacterial overgrowth were assessed by analysis of variance F-test, Kruskal-Wallis test, and the Fisher exact tests. Associations of risk factors with type of overgrowth were explored using multinomial logistic regression.

Results:

Among 76 patients, 37 had SIBO (68% coliform, 33% UAT) and 39 did not. Conditions (P=0.02) and surgery (P<0.01) associated with decreased gastric acid were associated with SIBO. In multinomial logistic regression, conditions of decreased acid was associated with UAT SIBO [odds ratio (OR), 5.8; 95% confidence interval, 1.4-33.3]. Surgery causing decreased acid was associated with UAT [OR, 9.5 (1.4-106)] and coliform SIBO [OR, 8.4 (1.6-86.4)]. Three patients with discontinuous small bowel had coliform SIBO [OR, 17.4 (1.2-2515)]. There were no differences in complications, overall symptoms, quality of life, or psychological traits.

Conclusions:

Conditions or surgeries associated with decreased gastric acid are associated with SIBO diagnosis by culture.
Risk and Protective Factors Related to Early Adverse Life Events in Irritable Bowel Syndrome
Authors: Ju Tiffany , Naliboff Bruce D. , Shih Wendy , Presson Angela P. , Liu Cathy , Gupta Arpana , Mayer Emeran A. , Chang Lin
Published: December 2018

Background:

Irritable bowel syndrome (IBS) is a stress-sensitive disorder of brain-gut interactions associated with a higher prevalence of early adverse life events (EALs). However, it is incompletely understood how trauma severity or disclosure influence the risk of developing IBS or symptom severity.

Aims:

To determine whether (1) IBS patients report a greater number of EALs compared with healthy controls; (2) trauma severity and first age of EAL increase the odds of IBS; (3) confiding in others reduces the odds of IBS; (4) the number, trauma severity, and first age of EAL are associated with symptom severity; (5) sex differences exist.

Methods:

In total, 197 IBS patients (72% women, mean age=30.28 y) and 165 healthy controls (59% women, mean age=30.77 y) completed the Childhood Traumatic Events Scale, measuring severity of EALs and degree of confiding in others. Regression analyses were used to predict IBS status from EALs and association between gastrointestinal symptoms and EALs.

Results:

A greater number of EALs [odds ratio (OR)=1.36, 95% confidence interval (CI), 1.14-1.62; P<0.001] and higher perceived trauma severity (OR=1.13, 95% CI, 1.08-1.19; P<0.001) were associated with increased odds of IBS. Confiding in others decreased the odds of having IBS (OR=0.83, 95% CI, 0.72-0.96; P=0.012). The first age of EAL was not predictive of IBS. No sex differences were found.

Conclusions:

Assessing the traumatic severity of EALs and amount of confiding in others is important as they can affect the risk of having IBS. Our findings emphasize early intervention to improve health outcomes in individuals with EALs.
Quantitative Hepatitis B Surface Antigen Predicts Hepatitis B Transmission in Infants Born to e Antigen–positive Mothers
Authors: Peng Songxu , Wan Zhihua , Liu Tingting , Wang Yanni , Chen Hongyan , Li Xiu , Du Yukai
Published: December 2018

Goals:

This study aimed to explore whether quantitative surface antigen [hepatitis B surface antigen (HBsAg)] can be used as a surrogate marker of hepatitis B virus (HBV) DNA to predict hepatitis B transmission before the first hepatitis vaccine dose in infants born to hepatitis B e antigen (HBeAg)-positive pregnant women.

Background:

Currently, HBV transmission persistently occurs worldwide, especially in infants born to e antigen (HBeAg)-positive highly viremic mothers. However, due to high cost, the extensive use of viral load testing to identify these high-risk mothers is limited.

Materials and Methods:

In total of 275 HBeAg-positive pregnant women paired with 280 infants were enrolled in this study. Quantitative HBsAg and HBV DNA levels were measured in the third trimester. Spearman rank correlation was used to assess the correlation between HBsAg levels and viral load, and multivariate logistic regression to identify factors related to HBV transmission in infants.

Results:

Among 280 infants included, 15 (5.4%) infants were infected with HBV. In this study, we observed that quantitative HBsAg was positively correlated with maternal viral load (r=0.70, P<0.001) and highly predicted HBV transmission in infants born to HBeAg-positive mothers with area under the curve of 0.76 (95% confidence interval, 0.71-0.81). The optimum threshold HBsAg levels above 4.6 log10 IU/mL to predict HBV transmission in infants had a sensitivity of 80.0%, specificity of 67.9%.

Conclusions:

Quantitative HBsAg could be used as a surrogate marker of HBV DNA levels to predict hepatitis B transmission occurring before the injection of first-dose vaccine in infants born to e antigen–positive mothers.
Concerning suppression and facilitation of motion perception in humans
Authors: Schallmo Michael-Paul , Murray Scott
Published: December 2018

Here we consider some topics from a commentary by Tzvetanov (2018) on our article entitled Suppression and facilitation of human neural responses (Schallmo et al., 2018). The author raises two main points of criticism, which we will summarize thus: 1) psychophysical response bias is not adequately modeled, and 2) other computational models may be better suited to describe the psychophysical motion discrimination data. Both of these points are reasonable in principle, but we disagree with the author in a few areas. We provide some discussion of both issues in order to further elevate the scientific dialogue.
Structures of the Human Spliceosomes Before and After Release of the Ligated Exon
Authors: Zhang Xiaofeng , Zhan Xiechao , Yan Chuangye , Zhang Wenyu , Liu Dongliang , Lei Jianlin , Shi Yigong
Published: December 2018

Pre-mRNA splicing is executed by the spliceosome, which has eight major functional states each with distinct composition. Five of these eight human spliceosomal complexes, all preceding exon ligation, have been structurally characterized. In this study, we report the cryo-electron microscopy structures of the human post-catalytic spliceosome (P complex) and intron lariat spliceosome (ILS) at average resolutions of 3.0 and 2.9 Å, respectively. In the P complex, the ligated exon remains anchored to loop I of U5 small nuclear RNA, and the 3'-splice site is recognized by the junction between the 5'-splice site and the branch point sequence. The ATPase/helicase Prp22, along with the ligated exon and eight other proteins, are dissociated in the P-to-ILS transition. Intriguingly, the ILS complex exists in two distinct conformations, one with the ATPase/helicase Prp43 and one without. Comparison of these three late-stage human spliceosomes reveals mechanistic insights into exon release and spliceosome disassembly.
Percolation models of pathogen spillover
Authors: Washburne Alex , Crowley Daniel E , Manlove Kezia , Becker Daniel J , Plowright Raina K
Published: December 2018

A series of logical events must occur for a pathogen to spill over from animals to people. The pathogen must be present in an animal reservoir, it must be shed from the reservoir into the environment or be transferred from the reservoir to a vector, it must persist in the environment or vector until contact with a human or amplifier host, and it must successfully enter, colonize, and reproduce within the human. These events each represent a barrier the pathogen must cross to successfully infect a human. Percolation models of pathogens completing the series of barriers or logical events can connect models of spillover risk with standard tools for statistical inference. Here, we develop percolation-based models of spillover risk and a theoretical framework for managing spillover as an inextricably multilevel process. Through analysis and simulation, we show that estimated associations between level-specific covariates and spillover events will err towards associations from dominant pathway to spillover, a potential problem if there are alternative pathways to spillover with different associations with covariates. Furthermore, estimated associations between covariates and spillover will better reflect associations between covariates and success probabilities of bottleneck events with the highest pathogen attrition rates in the data observed. If one agrees with a percolation model for spillover, then GLMs should not be used to estimate relative importance of various levels. We recommend always using nonlinear models for predicting spillover risk with quantitative covariates and discuss why switching regression models may be well suited for avoiding some obvious pitfalls in predicting spillover from alternative pathways or wildlife reservoirs. Finally, we demonstrate how percolation models formalize an intuitive management paradigm for mitigating risk in the inherently multilevel process of pathogen spillover.
Violating the normality assumption may be the lesser of two evils
Authors: Knief Ulrich , Forstmeier Wolfgang
Published: December 2018

When data are not normally distributed (e.g. skewed, zero-inflated, binomial, or count data) researchers are often uncertain whether it may be legitimate to use tests that assume Gaussian errors (e.g. regression, t-test, ANOVA, Gaussian mixed models), or whether one has to either model a more specific error structure or use randomization techniques.

Here we use Monte Carlo simulations to explore the pros and cons of fitting Gaussian models to non-normal data in terms of risk of type I error, power and utility for parameter estimation.

We find that Gaussian models are remarkably robust to non-normality over a wide range of conditions, meaning that P-values remain fairly reliable except for data with influential outliers judged at strict alpha levels. Gaussian models also perform well in terms of power and they can be useful for parameter estimation but usually not for extrapolation. Transformation of data before analysis is often advisable and visual inspection for outliers and heteroscedasticity is important for assessment. In strong contrast, some non-Gaussian models and randomization techniques bear a range of risks that are often insufficiently known. High rates of false-positive conclusions can arise for instance when overdispersion in count data is not controlled appropriately or when randomization procedures ignore existing non-independencies in the data.

Overall, we argue that violating the normality assumption bears risks that are limited and manageable, while several more sophisticated approaches are relatively error prone and difficult to check during peer review. Hence, as long as scientists and reviewers are not fully aware of the risks, science might benefit from preferentially trusting Gaussian mixed models in which random effects account for non-independencies in the data in a transparent way.

Tweetable abstract

Gaussian models are remarkably robust to even dramatic violations of the normality assumption.
A Modeling Framework for Exploring Sampling and Observation Process Biases in Genome and Phenome-wide Association Studies using Electronic Health Records
Authors: Beesley Lauren J. , Fritsche Lars G. , Mukherjee Bhramar
Published: December 2018

Large-scale agnostic association analyses based on existing observational health care databases such as electronic health records have been a topic of increasing interest in the scientific community. However, particular challenges of non-probability sampling and phenotype misclassification associated with the use of these data sources are often ignored in standard analyses. In general, the extent of the bias that may be introduced by ignoring these factors is unknown. In this paper, we develop a statistical framework for characterizing the degree of bias expected in association studies based on electronic health records when disease status misclassification and the sampling mechanism are ignored. Through a sensitivity analysis type approach, this framework can be used to obtain plausible values for parameters of interest given results obtained from standard naive analysis methods under varying degree of misclassification and sampling biases. We develop an online tool for performing this sensitivity analysis in some special cases that occur frequently. Simulations demonstrate promising properties of the proposed way of characterizing biases. We apply our approach to study bias in genetic association studies using data from the Michigan Genomics Initiative, a longitudinal biorepository effort within Michigan Medicine.
Getting personal: how vaccination exemptions shape herd immunity
Authors: Nedell Emma R , Garnier Romain , Omer Saad B , Bansal Shweta
Published: December 2018

Background: State-mandated school entry immunization requirements in the United States play an important role in achieving high vaccine coverage and preventing outbreaks of vaccine-preventable diseases. Most states allow non-medical exemptions that let children remain unvaccinated on the basis of personal beliefs. However, the ease of obtaining such exemptions varies, resulting in a patchwork of state vaccination exemption laws, contributing to heterogeneity in vaccine coverage across the country. In this study, we evaluate epidemiological effects and spatial variations in non-medical exemption rates in the context of vaccine policies.
Methods and Findings: We first analyzed the correlation between non-medical exemption rates and vaccine coverage for three significant childhood vaccinations and found that higher rates of non-medical exemptions were associated with lower vaccination rates of school-aged children in all cases. We then identified a subset of states where exemption policy has recently changed and found that the effects on statewide non-medical exemption rates varied widely. Focusing further on Vermont and California, we illustrated how the decrease in non-medical exemptions due to policy change was concurrent to an increase in medical exemptions (in CA) or religious exemptions (in VT). Finally, a spatial clustering analysis was performed for Connecticut, Illinois, and California, identifying clusters of high non-medical exemption rates in these states before and after a policy change occurred. The clustering analyses show that policy changes affect spatial distribution of non-medical exemptions within a state.
Conclusions: Our work suggests that vaccination policies have significant impacts on patterns of herd immunity. Our findings can be used to develop evidence-based vaccine legislation.
Plant breeders should be determining economic weights for a selection index instead of using independent culling for choosing parents in breeding programs with genomic selection
Authors: Batista Lorena G. , Gaynor R. Chris , Margarido Gabriel R. A. , Byrne Tim , Amer Peter , Gorjanc Gregor , Hickey John M.
Published: December 2018

In the context of genomic selection, we evaluated and compared recurrent selection breeding programs using either index selection or independent culling for selection of parents. We simulated a clonally propagated crop breeding program for 20 cycles of selection using either independent culling or an economic selection index with two unfavourably correlated traits under selection. Cycle time from crossing to selection of parents was kept the same for both strategies. Our results demonstrate that accurate knowledge of the economic importance of traits is essential even when performing independent culling. This is because independent culling achieved its optimum genetic gain when the culling threshold for each trait varied accordingly to the economic importance of the traits. When gains from independent culling were maximised, the efficiency of converting genetic diversity into genetic gain of both selection methods were equivalent. When the same proportion selected of 10% for each trait was used instead of optimal culling levels, index selection was 10%, 128% and 310% more efficient than independent culling when T2 had a relative economic importance of 1.0, 2.5 and 5.0, respectively. Given the complexity of estimating optimal culling levels and the fact that the gains achieved with independent culling are, at most, equivalent to index selection, the use of an economic selection index is recommended for multi-trait genomic selection.
An advanced strategy for comprehensive profiling of ADP-ribosylation sites using mass spectrometry-based proteomics
Authors: Hendriks Ivo A. , Larsen Sara C. , Nielsen Michael L.
Published: December 2018

ADP-ribosylation is a widespread post-translational modification (PTM) with crucial functions in many cellular processes. Here, we describe an in-depth ADP-ribosylome using our Af1521-based proteomics methodology for comprehensive profiling of ADP-ribosylation sites, by systematically assessing complementary proteolytic digestions and precursor fragmentation through application of electron-transfer higher-energy collisional dissociation (EThcD) and electron transfer dissociation (ETD), respectively. While ETD spectra yielded higher identification scores, EThcD generally proved superior to ETD in identification and localization of ADP-ribosylation sites regardless of protease employed. Notwithstanding, the propensities of complementary proteases and fragmentation methods expanded the detectable repertoire of ADP-ribosylation to an unprecedented depth. This system-wide profiling of the ADP-ribosylome in HeLa cells subjected to DNA damage uncovered >11,000 unique ADP-ribosylated peptides mapping to >7,000 ADP-ribosylation sites, in total modifying over one-third of the human nuclear proteome and highlighting the vast scope of this PTM. High-resolution MS/MS spectra enabled identification of dozens of proteins concomitantly modified by ADP-ribosylation and phosphorylation, revealing a considerable degree of crosstalk on histones. ADP-ribosylation was confidently localized to various amino acid residue types, including less abundantly modified residues, with hundreds of ADP-ribosylation sites pinpointed on histidine, arginine, and tyrosine residues. Functional enrichment analysis suggested modification of these specific residue types is directed in a spatial manner, with tyrosine ADP-ribosylation linked to the ribosome, arginine ADP-ribosylation linked to the endoplasmic reticulum, and histidine ADP-ribosylation linked to the mitochondrion.
In situestimation of genetic variation of functional and ecological traits inQuercus petraeaandQ.robur
Authors: Alexandre Hermine , Truffaut Laura , Ducousso Alexis , Louvet Jean-Marc , Nepveu Gérard , Torres-Ruiz José M. , Lagane Frédéric , Firmat Cyril , Musch Brigitte , Delzon Sylvain , Kremer Antoine
Published: December 2018

Background

Predicting the evolutionary potential of natural tree populations requires the estimation of heritability and genetic correlations among traits on which selection acts, as differences in evolutionary success between species may rely on differences for these genetic parameters.In situestimates are expected to be more accurate than measures done under controlled conditions which do not reflect the natural environmental variance.

Aims

The aim of the current study was to estimate three genetic parameters (i.e. heritability, evolvability and genetic correlations) in a natural mixed oak stand composed ofQuercus petraeaandQuercus roburabout 100 years old, for 58 traits of ecological and functional relevance (growth, reproduction, phenology, physiology, resilience, structure, morphology and defence).

Methods

First we estimated genetic parameters directlyin situusing realized genomic relatedness of adult trees and parentage relationships over two generations to estimate the traits additive variance. Secondly, we benefited from existingex situexperiments (progeny tests and conservation collection) installed with the same populations, thus allowing comparisons ofin situheritability estimates with more traditional methods.

Results

Heritability and evolvability estimates obtained with different methods varied substantially and showed large confidence intervals, however we found thatin situwere less precise thanex situesti-mates, and assessments over two generations (with deeper relatedness) improved estimates of heritability while large sampling sizes are needed for accurate estimations. At the biological level, heritability values varied moderately across different ecological and functional categories of traits, and genetic correlations among traits were conserved over the two species.

Conclusion

We identified limits for using realized genomic relatedness in natural stands to estimate the genetic variance, given the overall low variance of genetic relatedness and the rather low sampling sizes of currently used long term genetic plots in forestry. These limits can be overcome if larger sample sizes are considered, or if the approach is extended over the next generation.
Blurred molecular epidemiological lines between the two dominant methicillin-resistant Staphylococcus aureus clones
Authors: Dupper Amy C. , Sullivan Mitchell J. , Chacko Kieran I. , Mishkin Aaron , Ciferri Brianne , Kumaresh Ajay , Caban Ana Berbel , Oussenko Irina , Beckford Colleen , Zeitouni Nathalie E. , Sebra Robert , Hamula Camille , Smith Melissa , Kasarskis Andrew , Patel Gopi , McBride Russell B. , van Bakel Harm , Altman Deena R.
Published: December 2018

Background

Methicillin-resistant Staphylococcus aureus (MRSA) causes life-threatening infections in both community and hospital settings and is a leading cause of healthcare-associated infections (HAIs). We sought to describe the molecular epidemiological landscape of patients with MRSA bloodstream infections (BSIs) at an urban medical center by evaluating the clinical characteristics associated with the two dominant endemic clones.

Methods

Comprehensive clinical data extraction from the electronic health records of 227 hospitalized patients ≥18 years old with MRSA BSI over a 33-month period in New York City were collected. The descriptive epidemiology and mortality associated with the two dominant clones was compared using logistic regression.

Results

Molecular analysis revealed that 91% of all single-patient MRSA BSIs were due to two equally represented genotypes, clonal complex (CC) 5 (N=117) and CC8 (N=110). MRSA BSIs were associated with a 90-day mortality of 27%. CC8 caused disease more frequently in younger age groups (56 ± 17 vs 67 ± 17 years old; p<0.001) and in non-White race (OR=3.45 95% CI [1.51-7.87]; p=0.003), with few other major distinguishing features. Morbidity and mortality also did not differ significantly between the two clones. CC8 caused BSIs more frequently in the setting of peripheral intravenous catheters (OR=5.96; 95% CI [1.51-23.50]; p=0.01).

Conclusion

The clinical features distinguishing dominant MRSA clones continue to converge. The association of CC8 with peripheral intravenous catheter infections underscores the importance of classical community clones causing hospital-onset infections. Ongoing monitoring and analysis of the dynamic epidemiology of this endemic pathogen is crucial to inform management to prevent disease.
Plasmacytoid dendritic cells are functionally exhausted while non-haematopoietic sources of type I interferon dominate human autoimmunity
Authors: Psarras Antonios , Alase Adewonuola , Antanaviciute Agne , Carr Ian M. , Md Yusof Md Yuzaiful , Wittmann Miriam , Emery Paul , Tsokos George C. , Vital Edward M.
Published: December 2018

Autoimmune connective tissue diseases arise in a stepwise fashion from asymptomatic preclinical autoimmunity. Type I interferons (IFNs) have a crucial role in the progression to established autoimmune diseases such as systemic lupus erythematosus (SLE). However, their cellular source and regulation in disease initiation are unclear. The current paradigm suggests that plasmacytoid dendritic cells (pDCs) are activated in SLE contributing to excessive IFN production. Here, we show that in preclinical autoimmunity, established SLE, and primary Sjögren’s Syndrome, pDCs are not effector cells, but rather have lost their capacity for TLR-mediated IFN-α and TNF production and fail to induce T cell activation, independently of disease activity and blood IFN signature. In addition, pDCs present a transcriptional signature of cellular stress and senescence accompanied by increased telomere erosion. Instead, we demonstrate a marked enrichment of IFN signature in non-lesional skin in preclinical autoimmunity. In these individuals and SLE patients, type I IFNs were abundantly produced by keratinocytes in the absence of infiltrating leucocytes. These findings revise our understanding of the role of IFN in the initiation of human autoimmunity, with non-haematopoietic tissues perpetuating IFN responses, which in turn predict clinical disease. These data indicate potential therapeutic targets outside the conventional immune system for treatment and prevention.
Seed masting causes fluctuations in optimum litter size and lag load in a seed predator
Authors: McAdam Andrew , Boutin Stan , Dantzer Ben , Lane Jeff
Published: December 2018

The episodic production of large seed crops by some perennial plants, is referred to as masting and is known to increase seed escape by alternately starving and swamping seed predators. These pulses of resources, however, might also act as an agent of selection on the life histories of seed predators, which could indirectly enhance seed escape by inducing an evolutionary load on seed predator populations. Lag loads in seed predators could result from mast-induced shifts in optimum phenotypes that exceed the capacity of seed predators to adaptively track optimum phenotypes through phenotypic plasticity. Alternatively, masting could generate mismatches in selection across generations, where adaptation to the parental environment leads to maladaptation in the offspring environment. Here we measured natural selection on female North American red squirrels (Tamiasciurus hudsonicus) across 28 years and five white spruce (Picea glauca) masting events. Red squirrel litter sizes were similar to optimum litter sizes during non-mast years, but were well below optimum litter sizes during resource-rich mast years. Mast events, therefore caused selection for larger litters (B = 0.25) and a lag load (L = 0.25) on red squirrels during mast years. Furthermore, we found that the annual fitness of spruce trees was negatively related to the local density of squirrels during mast years, indicating that the observed lag load on squirrels enhanced the number of spruce cones escaping squirrel predation. Although, the frequency of mast events and the demography of red squirrels were such that offspring and parents often experienced opposite environments with respect to the mast, we found no effect of environmental mismatches across generations on either offspring survival or population growth. Instead, squirrels plastically increased litter sizes in anticipation of mast events, which partially, although not completely, reduced the lag load resulting from this change in food availability. Variable selection on litter size caused by white spruce mast events, therefore, induced a lag load on the population of red squirrels that was not affected by whether individual squirrels were born during mast (matching) or non-mast (mismatching) conditions.
A simple egg marking method for polygynous fishes
Authors: Solomon-Lane Tessa K , Grober Matthew S
Published: December 2018

Fitness is the ultimate measure of organismal function; however, technical challenges can limit researchers' ability to quantify fitness. We developed a simple and inexpensive method of marking eggs inside of the ovary of a nesting fish, the bluebanded goby (Lythrypnus dalli), in order to quantify female reproductive success. Multiple females in a harem of L. dalli can lay eggs inside of the male's nest within a short period of time, making the timing of egg laying or developmental stage of the eggs insufficient to identify which female laid which clutch of eggs. After injecting small volumes of food coloring into the ovaries, each female's eggs can be identified throughout development by the color of the yolk. We make preliminary observations about the efficacy of different colors (red, yellow, green, blue) for use in L. dalli, including effects on female survival, social behavior, and the enzyme immunoassays used to quantify hormones. While rigorous validations should be conducted for each species and experimental context, this method of marking eggs has the potential to be broadly useful for directly estimating fitness in species with external fertilization, thus facilitating research in reproductive biology, behavioral ecology, and evolution.
The domain architecture of JBP1 suggests synergy between J-base DNA binding and thymidine hydroxylase activity
Authors: Adamopoulos Athanassios , Heidebrecht Tatjana , Roosendaal Jeroen , Touw Wouter G , Phan Isabelle , Beijnen Jos , Perrakis Anastassis
Published: December 2018

JBP1 (J-DNA Binding Protein 1) contributes to biosynthesis and maintenance of base J (β-D-glucosyl-hydroxymethyluracil), a modification of thymidine (T) confined to pathogenic protozoa. JBP1 has two known functional domains: an N-terminal thymidine hydroxylase (TH) homologous to the 5-methylcytosine hydroxylase domain in TET proteins; and a J-DNA binding domain (JDBD) that resides in the middle of JBP1. Here we show that removing JDBD from JBP1 results in a soluble protein (Δ-JDBD) with the N- and C-terminal regions tightly associated together in a well-ordered domain. This Δ-JDBD domain retains thymidine hydroxylation activity in vitro, but displays a fifteen-fold lower apparent rate of hydroxylation compared to JBP1. Small Angle X-ray Scattering (SAXS) experiments on JBP1 and JDBD in the presence and absence of J-DNA, and on Δ-JDBD, allowed us to generate low-resolution three-dimensional models. We conclude that Δ-JDBD, and not the N-terminal region of JBP1 alone, is a distinct folding unit. Our SAXS-based model supports the notion that binding of JDBD specifically to J-DNA can facilitate hydroxylation a T 12-14 bp downstream on the complementary strand of the J-recognition site. We postulate that insertion of the JDBD module in the Δ-JDBD scaffold during evolution provided a mechanism to synergize between J recognition and T hydroxylation, ensuring inheritance of J in specific sequence patterns following DNA replication.
The sensory coding of warm perception
Authors: Paricio-Montesinos Ricardo , Schwaller Frederick , Udhayachandran Annapoorani , Walcher Jan , Evangelista Roberta , Poulet James F.A. , Lewin Gary R.
Published: December 2018

Humans easily discriminate tiny skin temperature changes that are perceived as warming or cooling. Dedicated thermoreceptors forming distinct thermosensory channels or “labelled lines” are thought to underlie thermal perception. We show that mice have similar perceptual thresholds for forepaw warming to humans (~1 °C change) and do not mistake warming for cooling. Mice perform warm discrimination tasks without dedicated thermoreceptors, but use information carried by unmyelinated polymodal C-fibers. Deletion of the heat-sensitive transduction channels TRPM2 and TRPV1 did not impact warming perception or afferent coding of warm. However, without the cold sensitive TRPM8 channel, afferent coding of cooling was impaired and these mice cannot perceive warming or cooling. Our data is incompatible with the existence of thermospecific labelled lines, but can be reconciled by the existence of central circuits that compare and integrate the input from at least two types of polymodal afferents, hitherto thought to exclusively signal pain.
The translatome of adult cortical axons is regulated by learning in vivo
Authors: Ostroff Linnaea E. , Santini Emanuela , Sears Robert , Deane Zachary , LeDoux Joseph E. , Lhakhang Tenzin , Tsirigos Aristotelis , Heguy Adriana , Klann Eric
Published: December 2018

Local translation can support memory consolidation by supplying new proteins to synapses undergoing plasticity. Translation in adult forebrain dendrites is an established mechanism of synaptic plasticity and is regulated by learning, yet there is no evidence for learning-regulated protein synthesis in adult forebrain axons, which have traditionally been believed to be incapable of translation. Here we show that axons in the adult rat amygdala contain translation machinery, and use translating ribosome affinity purification (TRAP) with RNASeq to identify mRNAs in cortical axons projecting to the amygdala, over 1200 of which were regulated during consolidation of associative memory. Mitochondrial and translation-related genes were upregulated, whereas synaptic, cytoskeletal, and myelin-related genes were downregulated; the opposite effects were observed in the cortex. Our results demonstrate that learning-regulated axonal translation occurs in the adult forebrain, and support the likelihood that local translation is more a rule than an exception in neuronal processes.
Evolution of photochemical reaction centres: more twists?
Authors: Cardona Tanai , Rutherford A. William
Published: December 2018

The earliest event recorded in the molecular evolution of photosynthesis is the structural and functional specialisation of Type I (ferredoxin-reducing) and Type II (quinone-reducing) reaction centres. Here we point out that the homodimeric Type I reaction centre of Heliobacteria has a Ca2+-binding site with a number of striking parallels to the Mn4CaO5 cluster of cyanobacterial Photosystem II. This structural parallels indicate that water oxidation chemistry originated at the divergence of Type I and Type II reaction centres. We suggests that this divergence was triggered by a structural rearrangement of a core transmembrane helix resulting in a shift of the redox potential of the electron donor side and electron acceptor side at the same time and in the same redox direction.
Alkane and wax ester production from lignin derived molecules
Authors: Salmela Milla , Lehtinen Tapio , Efimova Elena , Santala Suvi , Santala Ville
Published: December 2018

Lignin has potential as a sustainable feedstock for microbial production of industrially relevant molecules. However, the required lignin depolymerization yields a heterogenic mixture of aromatic monomers that are challenging substrates for the microorganisms commonly used in industry. Here, we investigated the properties of lignin-derived molecules (LDMs), namely coumarate, ferulate, and caffeate, in the synthesis of biomass and products in a LDM-utilizing bacterial hostAcinetobacter baylyiADP1. The biosynthesis products, wax esters and alkanes, are relevant compounds for the chemical and fuel industries. InA. baylyiADP1, wax esters are produced by a native pathway, whereas alkanes are produced by a synthetic pathway introduced to the host. Using individual LDMs as substrates, the growth, product formation, and toxicity to cells were monitored with internal biosensors. Of the tested LDMs, coumarate was the most propitious in terms of product synthesis. Wax esters were produced from coumarate with a yield and titer of 40 mg /gcoumarateand 221 mg/L, whereas alkanes were produced with a yield of 62.3 μg /gcoumarateand titer of 152 μg/L. This study demonstrates the microbial preference for certain LDMs, and highlights the potential ofA. baylyiADP1 as a convenient host for LDM upgrading to value-added products.
Dual language experience enhances neural activation variability during an fMRI reading and language task
Authors: Malins Jeffrey G. , D'Silva Hailey , Luk Gigi , Hernandez Arturo E. , Frost Stephen J. , Pugh Kenneth R. , Mencl W. Einar , Mehta Chintan , Bosson-Heenan Joan , Gruen Jeffrey R.
Published: December 2018

Previous work has shown that experience speaking more than one language in childhood is associated with decreased intra-individual neural variability in electrophysiological responses during a low-level speech perception task. However, no study has yet evaluated the impact of dual language experience on variability in fMRI responses during a higher-level spoken and written language processing task. In the current study, we calculated trial-by-trial variability in neural activation during an fMRI task that involved deciding whether spoken or printed English words matched pictures of items. We compared trial-by-trial neural activation variability between two groups of 8-15 year-old children: a group of dual language learners (N = 24; 11 female) who were Spanish-dominant and acquiring English, and a group of monolingual learners who were English-dominant (N = 17; 9 female). We found that when controlling for a variety of language, general cognitive, and demographic measures, neural activation variability for printed words was greater in the dual language learners compared to the monolingual learners in the right middle frontal gyrus, a brain region previously associated with attentional control. This finding highlights how neural variability offers a window of opportunity to examine experience-dependent mechanisms during human development, and motivates future research on bilingual language processing.
Nessys: a novel method for accurate nuclear segmentation in 3D
Authors: Blin Guillaume , Sadurska Daina , Portero Migueles Rosa , Chen Naiming , Watson Julia Alice , Lowell Sally
Published: December 2018

Methods for measuring the properties of individual cells within their native 3D environment will enable a deeper understanding of embryonic development, tissue regeneration, and tumorigenesis. However current methods for segmenting nuclei in 3D tissues are not designed for situations where nuclei are densely packed, non-spherical, heterogeneous in shape, size, or texture, all of which are true of many embryonic and adult tissue types as well as in many cases for cells differentiating in culture. Here we overcome this bottleneck by devising a novel method based on labelling the nuclear envelope (NE) and automatically distinguishing individual nuclei using a tree structured ridge tracing method followed by shape ranking according to a trained classifier. The method is fast and makes it possible to process images that are larger than computer memory. We consistently obtain accurate segmentation rates of >90% even for challenging images such as mid-gestation embryos or 3D cultures. We provide a 3D editor and inspector for the manual curation of the segmentation results as well as a program to assess the accuracy of the segmentation. We have also generated a live reporter of the NE that can be used to track live cells in three dimensions over time. We use this to monitor the history of cell interactions and occurrences of neighbour exchange within cultures of pluripotent cells during differentiation. We provide these tools in an open-access user-friendly format.
Evolution of metabolic novelty: a trichome-expressed invertase creates specialized metabolic diversity in wild tomato
Authors: Leong Bryan J. , Lybrand Daniel , Lou Yann-Ru , Fan Pengxiang , Schilmiller Anthony L. , Last Robert L.
Published: December 2018

Plants produce myriad taxonomically restricted specialized metabolites. This diversity – and our ability to correlate genotype with phenotype – makes the evolution of these ecologically and medicinally important compounds interesting and experimentally tractable. Trichomes of tomato and other nightshade family plants produce structurally diverse protective compounds termed acylsugars. While cultivated tomato (Solanum lycopersicum) accumulates strictly acylsucroses, the South American wild relativeSolanum pennelliiproduces copious amounts of acylglucoses. Genetic, transgenic and biochemical dissection of theS. pennelliiacylglucose biosynthetic pathway identified a trichome gland cell expressed invertase-like enzyme that hydrolyzes acylsucroses (Sopen03g040490). This enzyme acts on the pyranose ring-acylated acylsucroses found in the wild tomato but not the furanose ring-decorated acylsucroses of cultivated tomato. These results show that modification of the core acylsucrose biosynthetic pathway leading to loss of furanose ring acylation set the stage for co-option of a general metabolic enzyme to produce a new class of protective compounds.
Molecular Evolution ofPseudomonas syringaeType III Secreted Effector Proteins
Authors: Dillon Marcus M. , Almeida Renan N.D. , Laflamme Bradley , Martel Alexandre , Weir Bevan S. , Desveaux Darrell , Guttman David S.
Published: December 2018

Diverse Gram-negative pathogens likePseudomonas syringaeemploy type III secreted effector (T3SE) proteins as primary virulence factors that combat host immunity and promote disease. T3SEs can also be recognized by plant hosts and activate an effector triggered immune (ETI) response that shifts the interaction back towards plant immunity. Consequently, T3SEs are pivotal in determining the virulence potential of individualP. syringaestrains, and ultimately restrictP. syringaepathogens to a subset of potential hosts that are unable to recognize their repertoires of T3SEs. While a number of effector families are known to be present in theP. syringaespecies complex, one of the most persistent challenges has been documenting the complex variation in T3SE contents across a diverse collection of strains. Using the entire pan-genome of 494P. syringaestrains isolated from more than 100 hosts, we conducted a global analysis of all known and putative T3SEs. We identified a total of 14,613 T3SEs, 4,636 of which were unique at the amino acid level, and show that T3SE repertoires of differentP. syringaestrains vary dramatically, even among strains isolated from the same hosts. We also find that dramatic diversification has occurred within many T3SE families, and in many cases find strong signatures of positive selection. Furthermore, we identify multiple gene gain and loss events for several families, demonstrating an important role of horizontal gene transfer (HGT) in the evolution ofP. syringaeT3SEs. These analyses provide insight into the evolutionary history ofP. syringaeT3SEs as they co-evolve with the host immune system, and dramatically expand the database ofP. syringaeT3SEs alleles.
Viral metagenomic analysis of the cheese surface: a comparative study of rapid procedures for extracting virus-like particles
Authors: Dugat-Bony Eric , Lossouarn Julien , De Paepe Marianne , Sarthou Anne-Sophie , Fedala Yasmina , Petit Marie-Agnes , Chaillou Stephane
Published: December 2018

The structure and functioning of microbial communities from fermented foods, including cheese, have been extensively studied during the past decade. However, there is still a lack of information about both the occurrence and the role of viruses in modulating the function of this type of spatially structured and solid ecosystems. Viral metagenomics was recently applied to a wide variety of environmental samples and standardized procedures for recovering virus-like particles from different type of materials has emerged. In this study, we adapted a procedure originally developed to extract viruses from fecal samples, in order to enable efficient virome analysis of cheese surface. We tested and validated the positive impact of both addition of a filtration step prior to virus concentration and substitution of purification by density gradient ultracentrifugation by a simple chloroform treatment to eliminate membrane vesicles. Viral DNA extracted from the several procedures, as well as a vesicle sample, were sequenced using Illumina paired-end MiSeq technology and the subsequent clusters assembled from the virome were analyzed to assess those belonging to putative phages, plasmid-derived DNA, or even from bacterial chromosomal DNA. The best procedure was then chosen, and used to describe the Epoisses cheese virome. This study provides the basis of future investigations regarding the ecological importance of viruses in cheese microbial ecosystems.
Identifying small molecule probes of ENTPD5 through high throughput screening
Authors: Durst Matthew A , Ratia Kiira , Lavie Arnon
Published: December 2018

Ectonucleoside Triphosphate Diphosphohydrolase 5 (ENTPD5) has been shown to be important in maintaining cellular function in cancer, and its expression is upregulated through multiple, unique pathways in certain cancers, including laryngeal, glioblastoma multiforme, breast, testicular, and prostate. ENTPD5 supports cancer growth by promoting the import of UDP-glucose, a metabolite used for protein glycosylation and hence proper glycoprotein folding, into the ER by providing the counter molecule, UMP, to the ER antiporter. Despite its cancer-supporting function, no small molecule inhibitors of ENTPD5 are commercially available, and few studies have been performed in tissue culture to understand the effects of chemical inhibition of ENTPD5. We performed a high-throughput screen (HTS) of 21,120 compounds to identify small molecule inhibitors of ENPTD5 activity. Two hits were identified, and we performed a structure activity relationship (SAR) screen around these hits. Further validation of these probes were done in an orthogonal assay and then assayed in cell culture to assess their effect on prostate cancer cell lines. Notably, treatment with the novel ENTPD5 inhibitor reduced the amount of glycoprotein produced in treated cells, consistent with the hypothesis that ENTPD5 is important for glycoprotein folding. This work serves as an important step in designing new molecular probes for ENTPD5 as well as further probing the utility of targeting ENTPD5 to combat cancer cell proliferation.