bluuebunny/crossref_metadata_2025 huggingface dataset:
Stress and early experience underlie dominance status and division of labour in a clonal insect
Authors: Bernadou Abel , Schrader Lukas , Pable Julia , Hoffacker Elisabeth , Meusemann Karen , Heinze Jürgen
Published: August 2018

Cooperation and division of labour are fundamental in the ‘major transitions’ in evolution. While the factors regulating cell differentiation in multi-cellular organisms are quite well understood, we are just beginning to unveil the mechanisms underlying individual specialization in cooperative groups of animals. Clonal ants allow the study of which factors influence task allocation without confounding variation in genotype and morphology. Here, we subjected larvae and freshly hatched workers of the clonal ant
Platythyrea punctata
to different rearing conditions and investigated how these manipulations affected division of labour among pairs of oppositely treated, same-aged clonemates. High rearing temperature, physical stress, injury and malnutrition increased the propensity of individuals to become subordinate foragers rather than dominant reproductives. This is reflected in changed gene regulation: early stages of division of labour were associated with different expression of genes involved in nutrient signalling pathways, metabolism and the phenotypic response to environmental stimuli. Many of these genes appear to be capable of responding to a broad range of stressors. They might link environmental stimuli to behavioural and phenotypic changes and could therefore be more broadly involved in caste differentiation in social insects. Our experiments also shed light on the causes of behavioural variation among genetically identical individuals.
Context-dependent colonization of terrestrial habitat ‘islands’ by a long-distance migrant bird
Authors: Whytock Robin C. , Fuentes-Montemayor Elisa , Watts Kevin , Macgregor Nicholas A. , Williams Lefora , Park Kirsty J.
Published: August 2018

Landscape context can affect how individuals perceive patch quality during colonization. However, although context-dependent colonization has been observed in aquatic environments, it has rarely been studied in terrestrial environments or at large spatial scales. In this paper, we assessed how landscape context influenced colonization rates in a large-scale (ca7000 km2) terrestrial system where colonizers (Willow WarblerPhylloscopus trochilus) are capable of rapid, long-distance movements. Bioacoustic recorders were used to detect first song dates (an indicator of colonization or re-colonization) and settlement in 23 naturally replicated habitat patches. We compared support for three competing hypotheses describing colonization patterns that depend on landscape context (‘redirection’, ‘landscape-selection’ and ‘relative patch size’) with two patch-level hypotheses (patch ‘quality’ and ‘heterospecific attraction’). First song was earlier when habitat availability in the landscape was low, supporting the ‘redirection’ hypothesis. Settlement probability was best predicted by patch ‘quality’ and was lower in woodlands with a dense understorey. Results suggest that colonization of habitat patches by maleP. trochilusafter spring migration is spatially hierarchical. First, initial colonization depends on landscape context, and settlement is then determined by fine-scale vegetation characteristics. More broadly, we suggest that patterns observed in fragmented aquatic environments (e.g. ‘redirection’) can, in some circumstances, be extended to large-scale terrestrial environments.
Microparasite dispersal in metapopulations: a boon or bane to the host population?
Authors: Tadiri Christina P. , Scott Marilyn E. , Fussmann Gregor F.
Published: August 2018

Although connectivity can promote host species persistence in a metapopulation, dispersal may also enable disease transmission, an effect further complicated by the impact that parasite distribution may have on host–parasite population dynamics. We investigated the effects of connectivity and initial parasite distribution (clustered or dispersed) on microparasite–host dynamics in experimental metapopulations, using guppies andGyrodactylus turnbulli. We created metapopulations of guppies divided into four subpopulations and introduced either a low level of parasites to all subpopulations (dispersed) or a high level of parasites to one subpopulation (clustered). Controlled migration among subpopulations occurred every 10 days. In additional trials, we introduced low or high levels of parasites to isolated populations. Parasites persisted longer in metapopulations than in isolated populations. Mortality was lowest in isolated populations with low-level introductions. The interaction of connectivity and initial parasite distribution influenced parasite abundance. With low-level introductions, connectivity helped the parasite persist longer but had little effect on the hosts. With high levels, connectivity also benefited the hosts, lowering parasite burdens. These findings have implications for disease management and species conservation.
Testing the sensory trade-off hypothesis in New World bats
Authors: Wu Jinwei , Jiao Hengwu , Simmons Nancy B. , Lu Qin , Zhao Huabin
Published: August 2018

Detection of evolutionary shifts in sensory systems is challenging. By adopting a molecular approach, our earlier study proposed a sensory trade-off hypothesis between a loss of colour vision and an origin of high-duty-cycle (HDC) echolocation in Old World bats. Here, we test the hypothesis in New World bats, which include HDC echolocators that are distantly related to Old World HDC echolocators, as well as vampire bats, which have an infrared sensory system apparently unique among bats. Through sequencing the short-wavelength opsin gene (
SWS1
) in 16 species (29 individuals) of New World bats, we identified a novel
SWS1
polymorphism in an HDC echolocator: one allele is pseudogenized but the other is intact, while both alleles are either intact or pseudogenized in other individuals. Strikingly, both alleles were found to be pseudogenized in all three vampire bats. Since pseudogenization, transcriptional or translational changes could separately result in functional loss of a gene, a pseudogenized
SWS1
indicates a loss of dichromatic colour vision in bats. Thus, the same sensory trade-off appears to have repeatedly occurred in the two divergent lineages of HDC echolocators, and colour vision may have also been traded off against the infrared sense in vampire bats.
Difference in control between spring and autumn migration in birds: insight from seasonal changes in hypothalamic gene expression in captive buntings
Authors: Sharma Aakansha , Singh Devraj , Malik Shalie , Gupta Neelu Jain , Rani Sangeeta , Kumar Vinod
Published: August 2018

We hypothesized differences in molecular strategies for similar journeys that migrants undertake to reproduce in spring and to overwinter in autumn. We tested this in redheaded buntings (
Emberiza bruniceps
) photoinduced into spring and autumn migratory states, with winter and summer non-migratory states as controls. Compared with controls, buntings fattened, gained weight and showed
Zugunruhe
(nocturnal migratory restlessness) in the migratory state. Spring migration was associated with greater fat and body mass, and higher intensity of
Zugunruhe
, compared with autumn migration. Circulating corticosterone levels were higher in spring, while T3 levels were higher in autumn. Hypothalamic expression of thyroid hormone-responsive (
dio2
,
dio3
), light-responsive (
per2
,
cry1
,
adcyap1
) and
th
(tyrosine hydroxylase, involved in dopamine biosynthesis) genes showed significant changes with transition from non-migratory to the migratory state. There were significantly higher mRNA expressions in autumn, except for higher
th
levels in the spring. Furthermore, the expression patterns of
dnmt3a
(not
dnmt3b
) and
tet2
genes suggested an epigenetic difference between the non-migrant and migrant periods, and the spring and autumn migrant periods. These results demonstrate for the first time seasonal transition in hypothalamic gene expressions, and suggest differences in regulatory strategies at the transcriptional level for spring and autumn migrations in songbirds.
Detecting overlapping spatial clusters of high sugar-sweetened beverage intake and high body mass index in a general population: a cross-sectional study
Authors: Joost Stéphane , Ridder David De , Marques-Vidal Pedro , Bacchilega Beatrice , Theler Jean-Marc , Gaspoz Jean-Michel , Guessous Idris
Published: August 2018

Objective

To identify populations and areas presenting higher consumption of sugar-sweetened beverages (SSB) and their overlap with populations and areas presenting higher body mass index (BMI).

Design

Cross-sectional population-based study.

Setting

State of Geneva, Switzerland.

Participants

15,767 non-institutionalized residents aged between 35 and 74 years (20 and 74 since 2011) of the state of Geneva, Switzerland.

Main outcome measures

Spatial indices of sugar-sweetened beverage intake frequency and body mass index. Median regression analysis was used to control for characteristics of patients.

Results

The SSB intake frequency and the BMI were not randomly distributed across the state. Among the 15,423 participants retained for the analyses, 2,034 (13.2%) were within clusters of high SSB intake frequency and 1,651 (10.7%) was within clusters of low SSB intake frequency, 11,738 (76.1%) showed no spatial dependence. We also identified clusters of BMI, 4,014 (26.0%) participants were within clusters of high BMI and 3,591 (23.3%) were within clusters of low BMI, 7,818 (50.7%) showed no spatial dependence. We found that clusters of SSB intake frequency and BMI overlap in specific areas. 1,719 (11.1%) participants were within high SSB intake frequency and high BMI clusters. After adjustment for covariates (education level, gender, age, nationality, and the median income of the area), the identified clusters persisted and were only slightly attenuated.

Conclusion

A fine-scale spatial approach allows identifying specific populations and areas presenting higher SSB consumption and, for some areas, higher SSB consumption associated with higher BMI. These findings could guide legislators to develop targeted interventions such as prevention campaigns and pave the way for precision public health.

What is already known on this topic

The consumption of sugar-sweetened beverages (SSBs) is an important contributory factor of obesity and obesity-related diseases.

SSB consumption varies according to socioeconomic status, which could explain the higher prevalence of obesity in specific areas.

SSB taxation faces resistance in many countries due to its potential regressive nature.

What this study adds

The spatial analysis of individual-level SSB consumption in the state of Geneva provides a clear identification of populations and areas presenting higher SSB consumption and, for some areas, higher SSB consumption along with higher body mass index (BMI).

The results demonstrate the persistence of SSB clustering in the geographic space after adjusting for education level, gender, nationality, age, and neighborhood-level median income.

The findings provide guidance for future public health interventions to reduce SSB consumption by better targeting vulnerable populations.
Author-Reviewer Homophily in Peer Review
Authors: Murray Dakota , Siler Kyle , Larivière Vincent , Chan Wei Mun , Collings Andrew M. , Raymond Jennifer , Sugimoto Cassidy R.
Published: August 2018

The fairness of scholarly peer review has been challenged by evidence of disparities in publication outcomes based on author demographic characteristics. To assess this, we conducted an exploratory analysis of peer review outcomes of 23,876 initial submissions and 7,192 full submissions that were submitted to the biosciences journal eLife between 2012 and 2017. Women and authors from nations outside of North America and Europe were underrepresented both as gatekeepers (editors and peer reviewers) and authors. We found evidence of a homophilic relationship between the demographics of the gatekeepers and authors and the outcome of peer review; that is, there were higher rates of acceptance in the case of gender and country homophily. The acceptance rate for manuscripts with male last authors was seven percent, or 3.5 percentage points, greater than for female last authors (95% CI = [0.5, 6.4]); this gender inequity was greatest, at nine percent or about 4.8 percentage points (95% CI = [0.3, 9.1]), when the team of reviewers was all male; this difference was smaller and not significantly different for mixed-gender reviewer teams. Homogeny between countries of the gatekeeper and the corresponding author was also associated with higher acceptance rates for many countries. To test for the persistence of these effects after controlling for potentially confounding variables, we conducted a logistic regression including document and author metadata. Disparities in acceptance rates associated with gender and country of affiliation and the homophilic associations remained. We conclude with a discussion of mechanisms that could contribute to this effect, directions for future research, and policy implications. Code and anonymized data have been made available at https://github.com/murrayds/elife-analysis

Author summary

Peer review, the primary method by which scientific work is evaluated, is ideally a fair and equitable process in which scientific work is judged solely on its own merit. However, the integrity of peer review has been called into question based on evidence that outcomes often differ between male and female authors, and for authors in different countries. We investigated such disparities at the biosciences journal eLife by analyzing the demographics of authors and gatekeepers (editors and peer reviewers), and peer review outcomes of all submissions between 2012 and 2017. Outcomes were more favorable for male authors and those affiliated with institutions in North America and Europe; these groups were also over-represented among gatekeepers. There was evidence that peer review outcomes were influenced by homophily —a preference of gatekeepers for manuscripts from authors with shared characteristics. We discuss mechanisms that could contribute to this effect, directions for future research, and policy implications.
Expression of a recombinant, 4’-Phosphopantetheinylated, active M. tuberculosis Fatty acid Synthase I in E. coli
Authors: Baron Szilvia , Peleg Yoav , Grunwald Jacob , Morgenstern David , Elad Nadav , Peretz Moshe , Albeck Shira , Levin Yishai , Welch John T. , Deweerd Kim A. , Schwartz Alon , Burstein Yigal , Diskin Ron , Shakked Zippora , Zimhony Oren
Published: August 2018

Fatty acid synthase 1 (FAS I) from Mycobacterium. tuberculosis (Mtb) is an essential protein and a promising drug target. FAS I is a multi-functional, multi-domain protein that is organized as a large (1.9 MDa) homohexameric complex. Acyl intermediates produced during fatty acid elongation are attached covalently to an acyl carrier protein (ACP) domain. This domain is activated by the transfer of a 4’-Phosphopantetheine (4’-PP, also termed P-pant) group from CoA to ACP catalyzed by a 4’-PP transferase, termed acyl carrier protein synthase (AcpS). In order to obtain an activated FAS I in E. coli, we transformed E. coli with tagged Mtb fas1 and acpS genes encoded by a separate plasmid.

We induced the expression of Mtb FAS I following induction of AcpS expression. FAS I was purified by Strep-Tactin affinity chromatography. Activation of Mtb FAS I was confirmed by the identification of a bound P-pant group on serine at position 1808 by mass spectrometry. The purified FAS I displayed biochemical activity shown by spectrophotometric analysis of NADPH oxidation and by CoA production, using the Ellman reaction. The purified Mtb FAS I forms a hexameric complex shown by negative staining and cryo-EM. Purified hexameric and active Mtb FAS I is required for binding and drug inhibition studies and for structurefunction analysis of this enzyme. This relatively simple and short procedure for Mtb FAS I production should facilitate studies of this enzyme.
Self-Limiting Factors in Pandemics and Multi-Disease Syndemics
Authors: Manheim David
Published: August 2018

The potential for an infectious disease outbreak that is much worse than those which have been observed in human history, whether engineered or natural, has been the focus of significant concern in biosecurity. Fundamental dynamics of disease spread make such outbreaks much less likely than they first appear. Here we present a slightly modified formulation of the typical SEIR model that illustrates these dynamics more clearly, and shows the unlikely cases where concern may still be warranted. This is then applied to an extreme version of proposed pandemic risk, multi-disease syndemics, to show that (absent much clearer reasons for concern) the suggested dangers are overstated.

The models used in this paper are available here:https://github.com/davidmanheim/Infectious-Disease-Models
Disease persistence on temporal contact networks accounting for heterogeneous infectious periods
Authors: Darbon Alexandre , Colombi Davide , Valdano Eugenio , Savini Lara , Giovannini Armando , Colizza Vittoria
Published: August 2018

The infectious period of a transmissible disease is a key factor for disease spread and persistence. Epidemic models on networks typically assume an identical average infectious period for all individuals, thus allowing an analytical treatment. This simplifying assumption is however often unrealistic, as hosts may have different infectious periods, due, for instance, to individual host-pathogen interactions or inhomogeneous access to treatment. While previous work accounted for this heterogeneity in static networks, a full theoretical understanding of the interplay of varying infectious periods and time-evolving contacts is still missing. Here we consider an SIS epidemic on a temporal network with host-specific average infectious periods, and develop an analytical framework to estimate the epidemic threshold, i.e. the critical transmissibility for disease spread in the host population. Integrating contact data for transmission with outbreak data and epidemiological estimates, we apply our framework to three real-world case studies exploring different epidemic contexts – the persistence of bovine tuberculosis in southern Italy, the spread of nosocomial infections in a hospital, and the diffusion of pandemic influenza in a school. We find that the homogeneous parameterization may cause important biases in the assessment of the epidemic risk of the host population. Our approach is also able to identify groups of hosts mostly responsible for disease diffusion who may be targeted for prevention and control, aiding public health interventions.
Development and validation of the Evaluation Platform In COPD (EPIC): a population-based outcomes model of COPD for Canada
Authors: Sadatsafavi Mohsen , Ghanbarian Shahzad , Adibi Amin , Johnson Kate , FitzGerald J Mark , Flanagan William , Bryan Stirling , Sin Don ,   for the Canadian Respiratory Research Network#
Published: August 2018

Background

We report the development, validation, and implementation of an open-source population-based outcomes model of Chronic Obstructive Pulmonary Disease (COPD) for Canada.

Methods

Evaluation Platform in COPD (EPIC) is a discrete event simulation model of Canadians 40 years of age or older. Three core features of EPIC are its open-population design (incorporating projections of future population growth, aging, and smoking trends), its incorporation of heterogeneity in lung function decline and burden of exacerbations, and its modeling of the natural history of COPD from inception. Multiple original data analyses, as well as values reported in the literature, were used to populate the model. Extensive face validity as well as internal and external validity evaluations were performed.

Results

The model was internally validated on demographic projections, mortality rates, lung function trajectories, COPD exacerbations, and stability of COPD prevalence over time within strata of risk factors. In external validation, it moderately overestimated rate of overall exacerbations in two independent trials, but generated consistent estimates of rate of severe exacerbations and mortality.

Limitations

In its current version, EPIC does not consider uncertainty in the evidence. Several components such as additional (e.g., environmental and occupational) risk factors, treatment, symptoms, and comorbidity will have to be added in future iterations.

Conclusions

EPIC is the first multi-purpose outcome- and policy-focused model of COPD for Canada. By modeling the natural history of COPD from its inception, it is capable of modeling the outcomes of decisions across the entire care pathway of COPD. Platforms of this type have the capacity to be iteratively updated to incorporate the latest evidence and to project the outcomes of many different scenarios within a consistent framework.
Mapping drinking water and quality of life aspects in urban settings: an application of the urban exposome
Authors: Andrianou Xanthi D. , der Lek Chava van , Charisiadis Pantelis , Ioannou Solomon , Fotopoulou Kalliopi N. , Papapanagiotou Zoe , Botsaris George , Beumer Carijn , Makris Konstantinos C.
Published: August 2018

Cities face rapid changes leading to increasing inequalities and emerging public health issues that require cost-effective interventions. The urban exposome framework constitutes a novel approach in tackling city-wide challenges, such as those of drinking water quality and quality of life. In this proof-of-concept study, we presented part of the urban exposome of Limassol (Cyprus) focusing on chemical and microbial drinking water quality parameters and their association with urban neighborhood indicators. A perceptions study and an urban population study was conducted. We mapped the water quality parameters and participants’ opinions on city life (i.e. neighborhood life, health care and green space access) using quarters (small administrative areas) as the reference unit of the city. In an exploratory environment-wide association study analysis, we used all variables (questionnaire responses and water quality metrics) to describe correlations between them accounting, also, for self-reported health status. Overall, urban drinking-water quality using conventional indicators of chemical (disinfection byproducts-trihalomethanes) and microbial (coliforms, E. coli, and Enterococci) quality did not raise particular concerns. The general health and chronic health status of the urban participants were significantly (all >FDR corrected p value of 0.1) associated with different health conditions such as hypertension and asthma, or having financial issues in access to dental care. Additionally, correlations between trihalomethanes and participant characteristics (e.g. household cleaning, drinking water habits) were documented. This proof-of-concept study showed the potential of using integrative approaches to develop urban exposomic profiles and identifying within-city differentiated environmental and health indicators. The characterization of the urban exposome of Limassol will be expanded via the inclusion of biomonitoring tools and untargeted metabolomics platforms.
Genetic structure of invasive baby’s breath (Gypsophila paniculata) populations in a freshwater Michigan dune system
Authors: Leimbach – Maus Hailee B. , Parks Syndell R. , Partridge Charlyn G.
Published: August 2018

Coastal sand dunes are dynamic ecosystems with elevated levels of disturbance, and as such they are highly susceptible to plant invasions. One such invasion that is of major concern to the Great Lakes dune systems is that of perennial baby’s breath (Gypsophila paniculata). The invasion of baby’s breath negatively impacts native species such as the federal threatened Pitcher’s thistle (Cirsium pitcheri) that occupy the open sand habitat of the Michigan dune system. Our research goals were to (1) quantify the genetic diversity of invasive baby’s breath populations in the Michigan dune system, and (2) estimate the genetic structure of these invasive populations. We analyzed 12 populations at 14 nuclear and 2 chloroplast microsatellite loci. We found strong genetic structure among populations of baby’s breath sampled along Michigan’s dunes (global FST= 0.228), and also among two geographic regions that are separated by the Leelanau peninsula. Pairwise comparisons using the nSSR data among all 12 populations yielded significant FSTvalues. Results from a Bayesian clustering analysis suggest two main population clusters. Isolation by distance was found over all 12 populations (R = 0.755, P < 0.001) and when only cluster 2 populations were included (R = 0.523, P = 0.030); populations within cluster 1 revealed no significant relationship (R = 0.205, P = 0.494). Private nSSR alleles and cpSSR haplotypes within each cluster suggest the possibility of at least two separate introduction events to Michigan.
Human Epigenetic Aging is Logarithmic with Time across the Entire LifeSpan
Authors: Snir Sagi , Pellegrini Matteo
Published: August 2018

It is well established that organisms undergo epigenetic changes both during development and aging. Developmental changes have been extensively studied to characterize the differentiation of stem cells into diverse lineages. Epigenetic changes during aging have been characterized by multiple epigenetic clocks, that allow the prediction of chronological age based on methylation status. Despite their accuracy and utility, epigenetic age biomarkers leave many questions about epigenetic aging unanswered. Specifically, they do not permit the unbiased characterization of non-linear epigenetic aging trends across entire life spans, a critical question underlying this field of research. Here we a provide an integrated framework to address this question. Our model, inspired from evolutionary models, is able to account for acceleration/deceleration in epigenetic changes by fitting an individuals model age, theepigenetic age, which is related to chronological age in a non-linear fashion. We have devised a two stage procedure leveraging these model ages to infer aging trends over the entire lifespan of a population. Application of this procedure to real data measured across broad age ranges, from before birth to old age, and from two tissue types, suggests a universal logarithmic trend characterizes epigenetic aging across entire lifespans. This observation may have important implications for the development and application of future, more accurate, aging biomarkers.
Metabolic Flux Hierarchy Prioritizes the Entner-Doudoroff Pathway for Carbohydrate Co-Utilization inPseudomonas protegensPf-5
Authors: Wilkes Rebecca A. , Mendonca Caroll M. , Aristilde Ludmilla
Published: August 2018

The genetic characterization ofPseudomonas protegensPf-5 was recently completed. However, the inferred metabolic network structure has not yet been evaluated experimentally. Here we employed13C-tracers and quantitative flux analysis to investigate the intracellular network for carbohydrate metabolism. Similar to otherPseudomonasspecies,P. protegensPf-5 relied primarily on the Entner-Doudoroff (ED) pathway to connect initial glucose catabolism to downstream metabolic pathways. Flux quantitation determined that, in lieu of the direct phosphorylation of glucose by glucose kinase, phosphorylation of oxidized products of glucose (gluconate and 2-ketogluconate) towards the ED pathway accounted for over 90% of consumed glucose and greater than 35% of consumed glucose was secreted as gluconate and 2-ketogluconate. Consistent with the lack of annotated pathways for the initial catabolism of pentoses and galactose inP. protegensPf-5, only glucose was assimilated into intracellular metabolites in the presence of xylose, arabinose, or galactose. However, when glucose was fed simultaneously with fructose or mannose, co-uptake of the hexoses was evident but glucose was preferred over fructose (3 to 1) and over mannose (4 to 1). Despite gene annotation of mannose catabolism toward fructose 6-phosphate, metabolite labeling patterns revealed that mannose-derived carbons specifically entered central carbon metabolism via fructose-1,6-bisphosphate, similarly to fructose catabolism. Remarkably, carbons from mannose and fructose were found to cycle backward through the upper Emden-Meyerhof-Parnas pathway to feed into the ED pathway. Therefore, the operational metabolic network for processing carbohydrates inP. protegensPf-5 prioritizes flux through the ED pathway to channel carbons to downstream metabolic pathways.

IMPORTANCE

Species of thePseudomonasgenus thrive in various nutritional environments and have strong biocatalytic potential due to their diverse metabolic capabilities. Carbohydrate substrates are ubiquitous both in environmental matrices and in feedstocks for engineered bioconversion. Here we investigated the metabolic network for carbohydrate metabolism inP. protegensPf-5. Metabolic flux quantitation revealed the relative involvement of different catabolic routes in channeling carbohydrate carbons through the network. We also uncovered that mannose catabolism was similar to fructose catabolism, despite the gene annotation of two different pathways in the genome. Elucidation of the constitutive metabolic network inP. protegensis important for understanding its innate carbohydrate processing, thus laying the foundation for targeting metabolic engineering of this untappedPseudomonasspecies.
Dissecting differential signals in high-throughput data from complex tissues
Authors: Li Ziyi , Wu Zhijin , Jin Peng , Wu Hao
Published: August 2018

Samples from clinical practices are often mixtures of different cell types. The high-throughput data obtained from these samples are thus mixed signals. The cell mixture brings complications to data analysis, and will lead to biased results if not properly accounted for. We develop a method to model the high-throughput data from mixed, heterogeneous samples, and to detect differential signals. Our method allows flexible statistical inference for detecting a variety of cell-type specific changes. Extensive simulation studies and analyses of two real datasets demonstrate the favorable performance of our proposed method compared with existing ones serving similar purpose.
Assessment of population differentiation and linkage disequilibrium in Solanum pimpinellifolium using genome-wide high-density SNP markers
Authors: Lin Ya-Ping , Liu Chu-Yin , Chen Kai-Yi
Published: August 2018

To mine new favorable alleles for tomato breeding, we investigated the feasibility of utilizing Solanum pimpinellifolium as a diverse panel of genome-wide association study through the restriction site-associated DNA sequencing technique. Previous attempts to conduct genome-wide association study using S. pimpinellifolium were impeded by an inability to correct for population stratification and by lack of high-density markers to address the issue of rapid linkage disequilibrium decay. In the current study, a set of 24,330 SNPs was identified using 99 S. pimpinellifolium accessions from the Tomato Genetic Resource Center. Approximately 84% PstI site-associated DNA sequencing regions were located in the euchromatic regions, resulting in the tagging of most SNPs on or near genes. Our genotypic data suggested that the optimum number of S. pimpinellifolium ancestral subpopulations was three, and accessions were classified into seven groups. In contrast to the SolCAP SNP genotypic data of previous studies, our SNP genotypic data consistently confirmed the population differentiation, achieving a relatively uniform correction of population stratification. Moreover, as expected, rapid linkage disequilibrium decay was observed in S. pimpinellifolium, especially in euchromatic regions. Approximately two-thirds of the flanking SNP markers did not display linkage disequilibrium. Our result suggests that higher density of molecular markers and more accessions are required to conduct the genome-wide association study utilizing the Solanum pimpinellifolium collection.
Climatic stability and resource availability explains dung beetles (Scarabaeinae) richness patternon the Americas
Authors: Medina Anderson Matos
Published: August 2018

Climatic conditions are the main driver of species richness. Specifically, the increase in climatic instability may reduce species richness directly and indirectly by reducing resources available. This hypothesis is evaluated here using a producer-consumer interaction to explain dung beetle richness on a continental scale (America) using mammal richness as resource proxy and temperature and precipitation seasonality as a proxy for climatic instability. A spatial path analysis was built in order to evaluate this hypothesis while controlling for spatial autocorrelation and differences in the sampling effort and abundance of each study (n=115) gathered from the literature. Dung beetle richness was directly explained by temperature seasonality, precipitation seasonality, and mammal richness, whereas only precipitation seasonality had an effect modulated by mammal richness. This result reinforces the notion that species richness can be explained by climatic conditions, but also reveals the importance of biotic interactions in order to understand the mechanisms behind such patterns.
Visual experience regulates the intrinsic excitability of visual cortical neurons to maintain sensory function
Authors: Brown Alexander P.Y. , Cossell Lee , Margrie Troy W.
Published: August 2018

This in vivo study shows that both intrinsic and sensory-evoked synaptic properties of layer 2/3 neurons in mouse visual cortex are modified by ongoing visual input. Following visual deprivation, intrinsic properties are significantly altered, although orientation selectivity across the population remains unchanged. We therefore suggest that cortical cells adjust their intrinsic excitability in an activity-dependent manner to compensate for changes in synaptic drive and maintain sensory network function.
Decoupling of timescales reveals sparse convergent CPG network in the adult spinal cord
Authors: Radosevic Marija , Willumsen Alex , Petersen Peter C. , Lindén Henrik , Vestergaard Mikkel , Berg Rune W.
Published: August 2018

During the generation of rhythmic movements, most spinal neurons receive an oscillatory synaptic drive. The neuronal architecture underlying this drive is unknown, and the corresponding network size and sparseness have not yet been addressed. If the input originates from a small central pattern generator (CPG) with dense divergent connectivity, it will induce correlated input to all receiving neurons, while sparse convergent wiring will induce a weak correlation, if any. Here, we use pairwise recordings of spinal neurons to measure synaptic correlations and thus infer the wiring architecture qualitatively. A strong correlation on a slow timescale implies functional relatedness and a common source, which will also cause correlation on fast timescale due to shared synaptic connections. However, we consistently find marginal coupling between slow and fast correlations regardless of neuronal identity. This suggests either sparse convergent connectivity or a CPG network with recurrent inhibition that actively decorrelates common input.
Structures in multiple conformations reveal distinct transition metal and proton pathways in an Nramp transporter
Authors: Bozzi Aaron T. , Zimanyi Christina M. , Nicoludis John M. , Lee Brandon K. , Zhang Casey H. , Gaudet Rachelle
Published: August 2018

Nramp family transporters—expressed in organisms from bacteria to humans—enable uptake of essential divalent transition metals via an alternating-access mechanism that includes proton co-transport. We present high-resolution structures ofDeinococcus radiodurans(Dra)Nramp at complementary stages of its transport cycle to provide a thorough description of the Nramp transport cycle by identifying the key intramolecular rearrangements and changes to the metal coordination sphere. Strikingly, while metal transport requires cycling from outward-to inward-open states, efficient proton transport still occurs in outward-locked (but not inward-locked) DraNramp. We propose a model in which metal and proton enter the transporter via the same external pathway to the binding site, but follow separate routes to the cytoplasm, thus resolving the electrostatic dilemma of using a cation co-substrate to drive a cation primary substrate. Our results illustrate the flexibility of the LeuT fold to support a broad range of co-substrate coupling and conformational change mechanisms.
Convergent evolution of bird-mammal shared characteristics for adapting to nocturnality
Authors: Wu Yonghua , Wang Haifeng
Published: August 2018

The diapsid lineage (birds) and synapsid lineage (mammals), share a suite of functionally similar characteristics (e.g., endothermy) that are considered to be a result of their convergent evolution, but the candidate selections leading to this convergent evolution are still under debates. Here, we used a newly developed molecular phyloecological approach to reconstruct the diel activity pattern of the common ancestors of living birds. Our results strongly suggest that they had adaptations to nocturnality during their early evolution, which is remarkably similar to that of ancestral mammals. Given their similar adaptation to nocturnality, we propose that the shared traits in birds and mammals may have evolved as a result of the convergent evolution of their early ancestors adapting to ecological factors (e.g., low ambient temperature) associated with nocturnality. Finally, a conceptually unifying ecological model on the evolution of endothermy in diverse organisms with an emphasis on low ambient temperature is proposed. We reason that endothermy may evolve as an adaptive strategy to enable organisms to effectively implement various life cycle activities under relatively low-temperature environments. In particular, a habitat shift from high-temperature to relatively low-temperature environments is identified as a common factor underlying the evolution of endothermy.
Selective volume illumination microscopy offers synchronous volumetric imaging with high contrast
Authors: Truong Thai V. , Holland Daniel B. , Madaan Sara , Andreev Andrey , Troll Josh V. , Koo Daniel E. S. , Keomanee-Dizon Kevin , McFall-Ngai Margaret J. , Fraser Scott E.
Published: August 2018

Light field microscopy provides an efficient means to collect 3D images in a single acquisition, as its plenoptic detection captures an extended image volume in one snapshot. The ability of light field microscopy to simultaneously capture image data from a volume of interest, such as a functioning brain or a beating heart, is compromised by inadequate contrast and effective resolution, due, in large part, to light scattering by the tissue. Surprisingly, a major contribution to the image degradation is the signal scattered into the volume of interest by the typical wide-field illumination that excites the sample region outside the volume of interest. Here, we minimize this degradation by employing selective volume illumination, using a modified light sheet approach to illuminate preferentially the volume of interest. This minimizes the unavoidable background generated when extraneous regions of the sample are illuminated, dramatically enhancing the contrast and effective resolution of the captured and reconstructed images. Light Field Selective Volume Illumination Microscopy (LF-SVIM, SVIM for short) dramatically improves the performance of light field microscopy, and offers an unprecedented combination of synchronous z-depth coverage, lateral and axial resolution, and imaging speed.
Efficient implementation of penalized regression for genetic risk prediction
Authors: Privé Florian , Aschard Hugues , Blum Michael G.B.
Published: August 2018

Polygenic Risk Scores (PRS) consist in combining the information across many single-nucleotide polymorphisms (SNPs) in a score reflecting the genetic risk of developing a disease. PRS might have a major impact on public health, possibly allowing for screening campaigns to identify high-genetic risk individuals for a given disease. The “Clumping+Thresholding” (C+T) approach is the most common method to derive PRS. C+T uses only univariate genome-wide association studies (GWAS) summary statistics, which makes it fast and easy to use. However, previous work showed that jointly estimating SNP effects for computing PRS has the potential to significantly improve the predictive performance of PRS as compared to C+T.

In this paper, we present an efficient method to jointly estimate SNP effects, allowing for practical application of penalized logistic regression (PLR) on modern datasets including hundreds of thousands of individuals. Moreover, our implementation of PLR directly includes automatic choices for hyper-parameters. The choice of hyper-parameters for a predictive model is very important since it can dramatically impact its predictive performance. As an example, AUC values range from less than 60% to 90% in a model with 30 causal SNPs, depending on the p-value threshold in C+T.

We compare the performance of PLR, C+T and a derivation of random forests using both real and simulated data. PLR consistently achieves higher predictive performance than the two other methods while being as fast as C+T. We find that improvement in predictive performance is more pronounced when there are few effects located in nearby genomic regions with correlated SNPs; for instance, AUC values increase from 83% with the best prediction of C+T to 92.5% with PLR. We confirm these results in a data analysis of a case-control study for celiac disease where PLR and the standard C+T method achieve AUC of 89% and of 82.5%.

In conclusion, our study demonstrates that penalized logistic regression can achieve more discriminative polygenic risk scores, while being applicable to large-scale individual-level data thanks to the implementation we provide in the R package bigstatsr.
FRMPD2: a novel GluN2A-interacting scaffold protein in synaptic excitatory transmission
Authors: Lu Xi , Zhang Haiqing , Tian Xin , Wang Xuefeng
Published: August 2018

The scaffold proteins FRMPD2 is localized at the basolateral membranes of polarized epithelial cells and associated with tight junction formation. But the expression and function of FRMPD2 in vivo remain unknown. Here, we found that postsynaptic FRMPD2 effectively alters the neuronal excitability by regulating NMDARs-component excitatory synaptic transmission in adult hippocampus. FRMPD2 anchors the NMDAR subunit GluN2A at the synapses without changing the total NMDAR expression. By using of Co-IP, Pull Down and SPR, the second PDZ (PDZ2) domain of FRMPD2 direct and binds to the C-terminus of GluN2A. Our study discover that a novel scaffold protein FRMPD2 regulates synaptic excitatory in a PDZ2 domain-dependent manner in adult hippocampus.
Anatomical and physiological foundations of cerebello-hippocampal interactions
Authors: Watson TC , Obiang P , Torres-Herraez A , Wattilliaux A , Coulon P , Rochefort C , Rondi-Reig L
Published: August 2018

Multiple lines of evidence suggest that functionally intact cerebello-hippocampal interactions are required for appropriate spatial processing. However, how the cerebellum anatomically and physiologically engages with the hippocampus to sustain such interactions remains unknown. Using rabies virus as retrograde transneuronal tracer, we reveal that the dorsal hippocampus receives input from topographically restricted and disparate regions of the cerebellum. By simultaneously recording local field potential from both the dorsal hippocampus and anatomically connected cerebellar regions, we additionally demonstrate that the two structures interact, in a behaviorally dynamic manner, through subregion-specific synchronization of neuronal oscillations in the 6-12Hz frequency range. Together, these results reveal a novel neural network macro-architecture through which we can understand how a brain region classically associated with motor control, the cerebellum, may influence hippocampal neuronal activity and related functions, such as spatial navigation.
Autoantibodies and anti-microbial antibodies: Homology of the protein sequences of human autoantigens and the microbes with implication of microbial etiology in autoimmune diseases
Authors: Zhang Peilin
Published: August 2018

Autoimmune disease is a group of diverse clinical syndromes with defining autoantibodies within the circulation. The pathogenesis of autoantibodies in autoimmune disease is poorly understood. In this study, human autoantigens in all known autoimmune diseases were examined for the amino acid sequences in comparison to the microbial proteins including bacterial and fungal proteins by searching Genbank protein databases. Homologies between the human autoantigens and the microbial proteins were ranked high, medium, and low based on the default search parameters at the NCBI protein databases. Totally 64 human protein autoantigens important for a variety of autoimmune diseases were examined, and 26 autoantigens were ranked high, 19 ranked medium to bacterial proteins (69%) and 27 ranked high and 16 ranked medium to fungal proteins (66%) in their respective amino acid sequence homologies. There are specific autoantigens highly homologous to specific bacterial or fungal proteins, implying potential pathogenic roles of these microbes in specific autoimmune diseases. The computational examination of the primary amino acid sequences of human autoantigens in comparison to the microbial proteins suggests that the environmental exposure to the commensal or pathogenic microbes is potentially important in pathogenesis of a majority of autoimmune diseases, providing a new direction for further experimental investigation in searching for new diagnostic and therapeutic targets for autoimmune diseases.
Integrated single cell analysis of blood and cerebrospinal fluid leukocytes in multiple sclerosis
Authors: Schafflick David , Xu Chenling A. , Hartlehnert Maike , Cole Michael , Lautwein Tobias , Schulte-Mecklenbeck Andreas , Wolbert Jolien , Heming Michael , Meuth Sven G. , Kuhlmann Tanja , Gross Catharina C. , Wiendl Heinz , Yosef Nir , Horste Gerd Meyer zu
Published: August 2018

Cerebrospinal fluid (CSF) protects the central nervous system (CNS) and analyzing CSF aids the diagnosis of CNS diseases, but our understanding of CSF leukocytes remains superficial. Here, we firstly provide a transcriptional map of single leukocytes in CSF compared to blood. Leukocyte composition and transcriptome were compartment-specific with CSF-enrichment of myeloid dendritic cells and a border-associated phenotype of monocytes.

We secondly tested how multiple sclerosis (MS) - an autoimmune disease of the CNS - affected both compartments. MS increased transcriptional diversity in blood, while it preferentially increased cell type diversity in CSF. In addition to the known expansion of B lineage cells, we identified an increase of cytotoxic-phenotype and follicular T helper (TFH) cells in the CSF. In mice, TFH cells accordingly promoted B cell infiltration into the CNS and severity of MS animal models. Immune mechanisms in MS are thus highly compartmentalized and indicate local T/B cell interaction.