bluuebunny/crossref_metadata_2025 huggingface dataset:
Generation of
Fad2
and
Fad3
transgenic mice that produce n-6 and n-3 polyunsaturated fatty acids
Authors: Song Lishuang , Yang Lei , Wang Jiapeng , Liu Xuefei , Bai Lige , Di Anqi , Li Guangpeng
Published: October 2019

Linoleic acid (18 : 2, n-6) and α-linolenic acid (18 : 3, n-3) are polyunsaturated fatty acids (PUFAs), which are essential for mammalian health, development and growth. However, the majority of mammals, including humans, are incapable of synthesizing n-6 and n-3 PUFAs. Mammals must obtain n-6 and n-3 PUFAs from their diet. Fatty acid desaturase (Fad) plays a critical role in plant PUFA biosynthesis. Therefore, we generated plant-derived
Fad3
single and
Fad2–Fad3
double transgenic mice. Compared with wild-type mice, we found that PUFA levels were greatly increased in the single and double transgenic mice by measuring PUFA levels. Moreover, the concentration of n-6 and n-3 PUFAs in the
Fad2–Fad3
double transgenic mice were greater than in the
Fad3
single transgenic mice. These results demonstrate that the plant-derived
Fad2
and
Fad3
genes can be expressed in mammals. To clarify the mechanism for
Fad2
and
Fad3
genes in transgenic mice, we measured the PUFAs synthesis-related genes. Compared with wild-type mice, these
Fad
transgenic mice have their own n-3 and n-6 PUFAs biosynthetic pathways. Thus, we have established a simple and efficient method for
in vivo
synthesis of PUFAs.
Meiotic drive mechanisms: lessons fromDrosophila
Authors: Courret Cécile , Chang Ching-Ho , Wei Kevin H.-C. , Montchamp-Moreau Catherine , Larracuente Amanda M.
Published: October 2019

Meiotic drivers are selfish genetic elements that bias their transmission into gametes, often to the detriment of the rest of the genome. The resulting intragenomic conflicts triggered by meiotic drive create evolutionary arms races and shape genome evolution. The phenomenon of meiotic drive is widespread across taxa but is particularly prominent in theDrosophilagenus. Recent studies inDrosophilahave provided insights into the genetic origins of drivers and their molecular mechanisms. Here, we review the current literature on mechanisms of drive with an emphasis on sperm killers inDrosophilaspecies. In these systems, meiotic drivers often evolve from gene duplications and targets are generally linked to heterochromatin. While dense in repetitive elements and difficult to study using traditional genetic and genomic approaches, recent work inDrosophilahas made progress on the heterochromatic compartment of the genome. Although we still understand little about precise drive mechanisms, studies of male drive systems are converging on common themes such as heterochromatin regulation, small RNA pathways, and nuclear transport pathways. Meiotic drive systems are therefore promising models for discovering fundamental features of gametogenesis.
Altered lentiviral infection dynamics follow genetic rescue of the Florida panther
Authors: Malmberg Jennifer L. , Lee Justin S. , Gagne Roderick B. , Kraberger Simona , Kechejian Sarah , Roelke Melody , McBride Roy , Onorato Dave , Cunningham Mark , Crooks Kevin R. , VandeWoude Sue
Published: October 2019

Wildlife translocations are a commonly used strategy in endangered species recovery programmes. Although translocations require detailed assessment of risk, their impact on parasite distribution has not been thoroughly assessed. This is despite the observation that actions that alter host–parasite distributions can drive evolution or introduce new parasites to previously sequestered populations. Here, we use a contemporary approach to amplify viral sequences from archived biological samples to characterize a previously undocumented impact of the successful genetic rescue of the Florida panther (Puma concolor coryi). Our efforts reveal transmission of feline immunodeficiency virus (FIV) during translocation of pumas from Texas to Florida, resulting in extirpation of a historic Florida panther FIV subtype and expansion of a genetically stable subtype that is highly conserved in Texas and Florida. We used coalescent theory to estimate viral demography across time and show an exponential increase in the effective population size of FIV coincident with expansion of the panther population. Additionally, we show that FIV isolates from Texas are basal to isolates from Florida. Interestingly, FIV genomes recovered from Florida and Texas demonstrate exceptionally low interhost divergence. Low host genomic diversity and lack of additional introgressions may underlie the surprising lack of FIV evolution over 2 decades. We conclude that modern FIV in the Florida panther disseminated following genetic rescue and rapid population expansion, and that infectious disease risks should be carefully considered during conservation efforts involving translocations. Further, viral evolutionary dynamics may be significantly altered by ecological niche, host diversity and connectivity between host populations.
Forest-type specialization strongly predicts avian responses to tropical agriculture
Authors: Socolar Jacob B. , Wilcove David S.
Published: October 2019

Species’ traits influence how populations respond to land-use change. However, even in well-characterized groups such as birds, widely studied traits explain only a modest proportion of the variance in response across species. Here, we show that associations with particular forest types strongly predict the sensitivity of forest-dwelling Amazonian birds to agriculture. Incorporating these fine-scale habitat associations into models of population response dramatically improves predictive performance and markedly outperforms the functional traits that commonly appear in similar analyses. Moreover, by identifying habitat features that support assemblages of unusually sensitive habitat-specialist species, our model furnishes straightforward conservation recommendations. In Amazonia, species that specialize on forests along a soil–nutrient gradient (i.e. both rich-soil specialists and poor-soil specialists) are exceptionally sensitive to agriculture, whereas species that specialize on floodplain forests are unusually insensitive. Thus, habitat specializationper sedoes not predict disturbance sensitivity, but particular habitat associations do. A focus on conserving specific habitats that harbour highly sensitive avifaunas (e.g. poor-soil forest) would protect a critically threatened component of regional biodiversity. We present a conceptual model to explain the divergent responses of habitat specialists in the different habitats, and we suggest that similar patterns and conservation opportunities probably exist for other taxa and regions.
Cross-scale cooperation enables sustainable use of a common-pool resource
Authors: Ringsmuth Andrew K. , Lade Steven J. , Schlüter Maja
Published: October 2019

In social-ecological systems (SESs), social and biophysical dynamics interact within and between the levels of organization at multiple spatial and temporal scales. Cross-scale interactions (CSIs) are interdependences between processes at different scales, generating behaviour unpredictable at single scales. Understanding CSIs is important for improving SES governance, but they remain understudied. Theoretical models are needed that capture essential features while being simple enough to yield insights into mechanisms. In a stylized model, we study CSIs in a two-level system of weakly interacting communities harvesting a common-pool resource. Community members adaptively conform to, or defect from, a norm of socially optimal harvesting, enforced through social sanctioning both within and between communities. We find that each subsystem’s dynamics depend sensitively on the other despite interactions being much weaker between subsystems than within them. When interaction is purely biophysical, stably high cooperation in one community can cause cooperation in the other to collapse. However, even weak social interaction can prevent the collapse of cooperation and instead cause collapse of defection. We identify conditions under which subsystem-level cooperation produces desirable system-level outcomes. Our findings expand evidence that collaboration is important for sustainably managing shared resources, showing its importance even when resource sharing and social relationships are weak.
Transcriptional analysis of insect extreme freeze tolerance
Authors: Des Marteaux Lauren E. , Hůla Petr , Koštál Vladimír
Published: October 2019

Few invertebrates can survive cryopreservation in liquid nitrogen, and the mechanisms by which some species do survive are underexplored, despite high application potential. Here, we turn to the drosophilid
Chymomyza costata
to strengthen our fundamental understanding of extreme freeze tolerance and gain insights about potential avenues for cryopreservation of biological materials. We first use RNAseq to generate transcriptomes of three
C. costata
larval phenotypic variants: those warm-acclimated in early or late diapause (weak capacity to survive cryopreservation), and those undergoing cold acclimation after diapause entry (extremely freeze tolerant, surviving cryopreservation). We identify mRNA transcripts representing genes and processes that accompany the physiological transition to extreme freeze tolerance and relate cryopreservation survival to the transcriptional profiles of select candidate genes using extended sampling of phenotypic variants. Enhanced capacity for protein folding, refolding and processing appears to be a central theme of extreme freeze tolerance and may allow cold-acclimated larvae to repair or eliminate proteins damaged by freezing (thus mitigating the toxicity of denatured proteins, endoplasmic reticulum stress and subsequent apoptosis). We also find a number of candidate genes (including both known and potentially novel, unannotated sequences) whose expression profiles tightly mirror the change in extreme freeze tolerance status among phenotypic variants.
Sex biases in bird and mammal natural history collections
Authors: Cooper Natalie , Bond Alexander L. , Davis Joshua L. , Portela Miguez Roberto , Tomsett Louise , Helgen Kristofer M.
Published: October 2019

Natural history specimens are widely used across ecology, evolutionary biology and conservation. Although biological sex may influence all of these areas, it is often overlooked in large-scale studies using museum specimens. If collections are biased towards one sex, studies may not be representative of the species. Here, we investigate sex ratios in over two million bird and mammal specimen records from five large international museums. We found a slight bias towards males in birds (40% females) and mammals (48% females), but this varied among orders. The proportion of female specimens has not significantly changed in 130 years, but has decreased in species with showy male traits like colourful plumage and horns. Body size had little effect. Male bias was strongest in name-bearing types; only 27% of bird and 39% of mammal types were female. These results imply that previous studies may be impacted by undetected male bias, and vigilance is required when using specimen data, collecting new specimens and designating types.
Age associated microbiome modulation and its association with systemic inflammation in a Rhesus Macaque Model
Authors: Pallikkuth Suresh , Russell Kyle , Sirupangi Tirupataiah , Mendez Roberto , Kvistad Daniel , Pahwa Rajendra , Villinger Francois , Banerjee Santanu , Pahwa Savita
Published: October 2019

Background

As the individual ages, the immune system decreases in activity while chronic systemic inflammation increases. The microbiome is also affected by age, decreasing in beneficial microbes while increasing in pathogenic, inflammation inducing microbes with corresponding changes in their metabolic profile. While aging is known to affect both, links between the two have been hard to uncover.

Methods

Four young (age 3-6 years) and 12 old (age>18 years) Rhesus macaques were recruited for the study. PBMCs and plasma were collected to investigate immune cell subsets by flow cytometry and plasma cytokines by bead based multiplex cytokine analysis respectively. Stool samples were collected by ileal loop for microbiome analysis by shotgun metagenomics and serum, gut microbial lysate and microbe-free fecal extract was used to determine metabolomics by mass-spectrometry.

Results

Our aging NHP model recaptured many of the features of the age-associated immune alterations, with increased inflammation and alterations in immune cells subsets with lower number of CD4 T cells and a trend of age associated alterations in maturation subsets in older animals with lower naïve and higher central memory CD4 T cells. Older animals showed a significantly different microbiome from young animals with lower abundance of Firmicutes and higher Archaeal and Proteobacterial species. Correlation analysis showed a link between microbes in older animals with systemic inflammation. Analysis of metabolites in the serum and feces showed significant differences between specific metabolites between young and older animals that can influence age-associated morbidities.

Conclusion

These data support the age associated alterations in microbiome profile and its association with persistent systemic inflammation and metabolome changes. Further mechanistic studies are needed to understand the relationship between inflammation and microbiome. Nevertheless, this NHP model recapitulates human age associated changes in immune, inflammatory and microbiome profiles and can be useful for designing future studies targeting microbiome modulations in aging.
TreeFix-TP: Phylogenetic Error-Correction for Infectious Disease Transmission Network Inference
Authors: Sledzieski Samuel , Zhang Chengchen , Mandoiu Ion , Bansal Mukul S
Published: October 2019

Background

Many existing methods for estimation of infectious disease transmission networks use a phylogeny of the infecting strains as the basis for transmission network inference, and accurate network inference relies on accuracy of this underlying evolutionary history. However, phylogenetic reconstruction can be highly error prone and more sophisticated methods can fail to scale to larger outbreaks, negatively impacting downstream transmission network inference. Additionally, there are no currently available methods which are able to use within-host diversity to improve phylogenetic reconstruction.

Results

We introduce a new method, TreeFix-TP, for accurate and scalable reconstruction of transmission phylogenies based on an error-correction framework. Our method uses intra-host strain diversity and host information to balance a parsimonious evaluation of the implied transmission network with statistical hypothesis testing on sequence data likelihood. The reconstructed tree minimizes the number of required disease transmissions while being as well supported by sequence data as the maximum likelihood phylogeny. We use a simulation framework for viral transmission and evolution to demonstrate that TreeFix-TP improves phylogenetic accuracy and downstream transmission network accuracy. We also use real data from ten HCV outbreaks and demonstrate how error-correction improves source detection.

Conclusions

Our results show that using TreeFix-TP can lead to significant improvement in transmission phylogeny inference and that its performance is robust to variations in transmission and evolutionary parameters. Our experiments also demonstrate the importance of sampling multiple strain sequences from each infected host for accurate transmission network inference. TreeFix-TP is freely available open-source fromhttps://compbio.engr.uconn.edu/software/treefix-tp/.
An aphid host-responsive RNA transcript that migrates systemically in plants promotes aphid reproduction
Authors: Chen Yazhou , Singh Archana , Kaithakottill Gemy G. , Mathers Thomas C. , Gravino Matteo , Mugford Sam T. , Oosterhout Cock van , Swarbreck David , Hogenhout Saskia A.
Published: October 2019

Aphids are sap-feeding insects that colonize a broad range of plant species and often cause feeding damage and transmit plant pathogens, including bacteria, viruses and viroids. These insects feed from the plant vascular tissue, predominantly the phloem. However, it remains largely unknown how aphids, and other sap-feeding insects, establish intimate long-term interactions with plants. To identify aphid virulence factors, we took advantage of the ability of the green peach aphidMyzus persicaeto colonize divergent plant species. We found that aM. persicaeclone of near-identical females establishes stable colonies on nine plant species of five representative plant eudicot and monocot families that span the angiosperm phylogeny. Members of the novel aphidYafamily are differentially expressed in aphids on the nine plant species, are co-regulated and organized as tandem repeats in aphid genomes. Interestingly, aphids translocateYatranscripts into plants and some transcripts migrate systemically within several plant species. RNAi-mediated knock down ofYagenes reducesM. persicaefecundity andM. persicaeproduces more progeny on transgenic plants that heterologously produce one of the systemically migratingYatranscripts as a long non-coding (lnc)RNA. Taken together, our work led to the discovery of a new host-responsive aphid gene family that operate as virulence factors. Transcripts of this family translocate into plants, including a lncRNA that migrates systemically and promotes aphid reproduction.

Significance Statement

The green peach aphidMyzus persicaecauses yield losses of a diverse range of economically important crops primarily as a vector of more than 100 different plant pathogens. We found that a single genotype ofM. persicaeis able to colonize nine plant species, including diverse dicots and maize, indicating that this aphid is truly polyphagous. Members of a new aphidYafamily undergoes coordinated expression changes inM. persicaedepending on the plant species. The aphids translocateYatranscripts into plants during feeding and these RNAs migrate to systemic leaves. Moreover, heterologousin plantaexpression ofM. persicae Ya1as a long non-coding RNA promotes aphid reproduction. Our findings indicate that cross kingdom deployment of RNA is more common than thought.
Genetic and clinical analyses of psychosis spectrum symptoms in a large multi-ethnic youth cohort reveal significant link with ADHD
Authors: Loohuis Loes Olde , Mennigen Eva , Ori Anil , Perkins Diana , Robinson Elise , Addington Jean , Cadenhead Kristin S. , Cornblatt Barbara A. , Mathalon Daniel H. , McGlashan Thomas H. , Seidman Larry J. , Keshavan Matcheri , Stone William , Tsuang Ming T. , Walker Elaine F. , Woods Scott W. , Cannon Tyrone D. , Gur Ruben C. , Gur Raquel E. , Bearden Carrie E. , Ophoff Roel A.
Published: October 2019

Objective

Psychotic symptoms are an important feature of severe neuropsychiatric disorders, but are also common in the general population, especially in youth. The genetic etiology of psychosis symptoms in youth remains poorly understood. To characterize genetic risk for psychosis spectrum symptoms (PS), we leverage a community-based multi-ethnic sample of children and adolescents aged 8-22 years, the Philadelphia Neurodevelopmental Cohort (n = 7,225, 20% PS).

Methods

Using an elastic net regression model, we aim to classify PS status using polygenic scores (PGS) based on a range of heritable psychiatric and brain-related traits in a multi-PGS model. We also perform univariate PGS associations and evaluate age-specific effects.

Results

The multi-PGS analyses do not improve prediction of PS status over univariate models, but reveal that the attention deficit hyperactivity disorder (ADHD) PGS is robustly and uniquely associated with PS (OR 1.12 (1.05, 1.18) P = 0.0003). This association is: i) driven by subjects of European ancestry (OR=1.23 (1.14, 1.34), P=4.15×10−7) but is not observed in African American subjects (P=0.65) and ii) independent of phenotypic overlap. We also find a significant interaction with age (P=0.01), with a stronger association in younger children. In an independent sample, we replicate an increased ADHD PGS in 328 youth at clinical high risk for psychosis, compared to 216 unaffected controls (OR 1.06, CI(1.01, 1.11), P= 0.02).

Conclusions

Our findings suggest that PS in youth may reflect a different genetic etiology than psychotic symptoms in adulthood, one more akin to ADHD, and shed light on how genetic risk can be investigated across early disease trajectories.
Whole genome sequencing and the application of a SNP panel reveal primary evolutionary lineages and genomic variation in the lion (Panthera leo)
Authors: Bertola L.D. , Vermaat M. , Lesilau F. , Chege M. , Tumenta P.N. , Sogbohossou E.A. , Schaap O.D. , Bauer H. , Patterson B.D. , White P.A. , de Iongh H.H. , Laros J.F.J. , Vrieling K.
Published: October 2019

Background

Previous phylogeographic studies of the lion (Panthera leo) have improved our insight into the distribution of genetic variation, as well as a revised taxonomy which now recognizes a northern (Panthera leo leo) and a southern (Panthera leo melanochaita) subspecies. However, existing whole range phylogeographic studies on lions either consist of very limited numbers of samples, or are focused on mitochondrial DNA and/or a limited set of microsatellites. The geographic extent of genetic lineages and their phylogenetic relationships remain uncertain, clouded by massive sampling gaps, sex-biased dispersal and incomplete lineage sorting.

Results

In this study we present results of low depth whole genome sequencing and subsequent variant calling in ten lions sampled throughout the geographic range, resulting in the discovery of >150,000 Single Nucleotide Polymorphisms (SNPs). Phylogenetic analyses revealed the same basal split between northern and southern populations as well as four population clusters on a more local scale. Further, we designed a SNP panel, including 125 autosomal and 14 mitochondrial SNPs, which was tested on >200 lions from across their range. Results allow us to assign individuals to one of these four major clades (West & Central Africa, India, East Africa, or Southern Africa) and delineate these clades in more detail.

Conclusions

The results presented here, particularly the validated SNP panel, have important applications, not only for studying populations on a local geographic scale, but also for tracing samples of unknown origin for forensic purposes, and for guiding conservation management ofex situpopulations. Thus, these genomic resources not only contribute to our understanding of the evolutionary history of the lion, but may also play a crucial role in conservation efforts aimed at protecting the species in its full diversity.
Phenotypic clustering reveals distinct subtypes of polycystic ovary syndrome with novel genetic associations
Authors: Dapas Matthew , Lin Frederick T. J. , Nadkarni Girish N. , Sisk Ryan , Legro Richard S. , Urbanek Margrit , Hayes M. Geoffrey , Dunaif Andrea
Published: October 2019

Background

Polycystic ovary syndrome (PCOS) is a common, complex genetic disorder affecting up to 15% of reproductive age women worldwide, depending on the diagnostic criteria applied. These diagnostic criteria are based on expert opinion and have been the subject of considerable controversy. The phenotypic variation observed in PCOS is suggestive of an underlying genetic heterogeneity, but a recent meta-analysis of European ancestry PCOS cases found that the genetic architecture of PCOS defined by different diagnostic criteria was generally similar, suggesting that the criteria do not identify biologically distinct disease subtypes. We performed this study to test the hypothesis that there are biologically relevant subtypes of PCOS.

Methods and Findings

Unsupervised hierarchical cluster analysis was performed on quantitative anthropometric, reproductive, and metabolic traits in a genotyped discovery cohort of 893 PCOS cases and an ungenotyped validation cohort of 263 PCOS cases. We identified two PCOS subtypes: a “reproductive” group (21-23%) characterized by higher luteinizing hormone (LH) and sex hormone binding globulin (SHBG) levels with relatively low body mass index (BMI) and insulin levels; and a “metabolic” group (37-39%), characterized by higher BMI, glucose, and insulin levels with lower SHBG and LH levels. We performed a GWAS on the genotyped cohort, limiting the cases to either the reproductive or metabolic subtypes. We identified alleles in four novel loci that were associated with the reproductive subtype at genome-wide significance (PRDM2/KAZN1, P=2.2×10-10;IQCA1, P=2.8×10-9;BMPR1B/UNC5C, P=9.7×10-9;CDH10,P=1.2×10-8) and one locus that was significantly associated with the metabolic subtype (KCNH7/FIGN, P=1.0×10-8). We have previously reported that rare variants inDENND1A, a gene regulating androgen biosynthesis, were associated with PCOS quantitative traits in a family-based whole genome sequencing analysis. We classified the reproductive and metabolic subtypes in this family-based PCOS cohort and found that the subtypes tended to cluster in families and that carriers of rareDENND1Avariants were significantly more likely to have the reproductive subtype of PCOS. Limitations of our study were that only PCOS cases of European ancestry diagnosed by NIH criteria were included, the sample sizes for the subtype GWAS were small, and the GWAS findings were not replicated.

Conclusions

In conclusion, we have found stable reproductive and metabolic subtypes of PCOS. Further, these subtypes were associated with novel susceptibility loci. Our results suggest that these subtypes are biologically relevant since they have distinct genetic architectures. This study demonstrates how precise phenotypic delineation can be more powerful than increases in sample size for genetic association studies.
Shape coding in occipito-temporal cortex relies on object silhouette, curvature and medial-axis
Authors: Papale Paolo , Leo Andrea , Handjaras Giacomo , Cecchetti Luca , Pietrini Pietro , Ricciardi Emiliano
Published: October 2019

Object recognition relies on different transformations of the retinal input, carried out by the visual system, that range from local contrast to object shape and category. While some of those transformations are thought to occur at specific stages of the visual hierarchy, the features they represent are correlated (e.g., object shape and identity) and selectivity for the same feature overlaps in many brain regions. This may be explained either by collinearity across representations, or may instead reflect the coding of multiple dimensions by the same cortical population. Moreover, orthogonal and shared components may differently impact on distinctive stages of the visual hierarchy. We recorded functional MRI (fMRI) activity while participants passively attended to object images and employed a statistical approach that partitioned orthogonal and shared object representations to reveal their relative impact on brain processing. Orthogonal shape representations (silhouette, curvature and medial-axis) independently explained distinct and overlapping clusters of selectivity in occitotemporal (OTC) and parietal cortex. Moreover, we show that the relevance of shared representations linearly increases moving from posterior to anterior regions. These results indicate that the visual cortex encodes shared relations between different features in a topographic fashion and that object shape is encoded along different dimensions, each representing orthogonal features.

New & Noteworthy

There are several possible ways of characterizing the shape of an object. Which shape description better describes our brain responses while we passively perceive objects? Here, we employed three competing shape models to explain brain representations when viewing real objects. We found that object shape is encoded in a multi-dimensional fashion and thus defined by the interaction of multiple features.
Exploiting the GTEx resources to decipher the mechanisms at GWAS loci
Authors: Barbeira Alvaro N , Bonazzola Rodrigo , Gamazon Eric R , Liang Yanyu , Park YoSon , Kim-Hellmuth Sarah , Wang Gao , Jiang Zhuoxun , Zhou Dan , Hormozdiari Farhad , Liu Boxiang , Rao Abhiram , Hamel Andrew R , Pividori Milton D , Aguet François ,   GTEx GWAS Working Group, Bastarache Lisa , Jordan Daniel M , Verbanck Marie , Do Ron ,   GTEx Consortium, Stephens Matthew , Ardlie Kristin , McCarthy Mark , Montgomery Stephen B , Segrè Ayellet V , Brown Christopher D. , Lappalainen Tuuli , Wen Xiaoquan , Im Hae Kyung
Published: October 2019

The resources generated by the GTEx consortium offer unprecedented opportunities to advance our understanding of the biology of human diseases. Here, we present an in-depth examination of the phenotypic consequences of transcriptome regulation and a blueprint for the functional interpretation of genome-wide association study-discovered loci. Across a broad set of complex traits and diseases, we demonstrate widespread dose-dependent effects of RNA expression and splicing. We develop a data-driven framework to benchmark methods that prioritize causal genes and find no single approach outperforms the combination of multiple approaches. Using colocalization and association approaches that take into account the observed allelic heterogeneity of gene expression, we propose potential target genes for 47% (2,519 out of 5,385) of the GWAS loci examined. Our results demonstrate the translational relevance of the GTEx resources and highlight the need to increase their resolution and breadth to further our understanding of the genotype-phenotype link.
Up-regulation of autophagy by low concentration of salicylic acid delays methyl jasmonate-induced leaf senescence
Authors: Yin Runzhu , Yu Jingfang , Ji Yingbin , Liu Jian , Cheng Lixin , Zhou Jun
Published: October 2019

Crosstalk between salicylic acid (SA) and jasmonic acid (JA) signaling plays an important role in molecular regulation of plant senescence. Our previous works found that SA could delay methyl jasmonate (MeJA)-induced leaf senescence in a concentration-dependent manner. Here, the effect of low concentration of SA (LCSA) application on MeJA-induced leaf senescence was further assessed. High-throughput sequencing (RNA-Seq) results showed that LCSA did not have dominant effects on the genetic regulatory pathways of basal metabolism like nitrogen metabolism, photosynthesis and glycolysis. The ClusterONE was applied to identify discrete gene modules based on protein-protein interaction (PPI) network. Interestingly, an autophagy-related (ATG) module was identified in the differentially expressed genes (DEGs) that exclusively induced by MeJA together with LCSA. RT-qPCR confirmed that the expression of most of the determined ATG genes were upregulated by LCSA. Remarkably, in contrast to wild type (Col-0), LCSA cannot alleviate the leaf yellowing phenotype in autophagy defective mutants (atg5-1 and atg7-2) upon MeJA treatment. Confocal and western blot results showed that LCSA increased the number of autophagic bodies and autophagic flux during MeJA-induced leaf senescence. Collectively, our work revealed up-regulation of autophagy by LCSA as a key regulator to alleviate MeJA-induced leaf senescence.
A biosynthetic platform for antimalarial drug discovery
Authors: Wilkinson Mark D. , Lai Hung-En , Freemont Paul S. , Baum Jake
Published: October 2019

Advances in synthetic biology have enabled production of a variety of compounds using bacteria as a vehicle for complex compound biosynthesis. Violacein, a naturally occurring indole pigment with antibiotic properties, can be biosynthetically engineered in Escherichia coli expressing its non-native synthesis pathway. To explore whether this synthetic biosynthesis platform could be used for drug discovery, here we have screened bacterially-derived violacein against the main causative agent of human malaria, Plasmodium falciparum. We show the antiparasitic activity of bacterially-derived violacein against the P. falciparum 3D7 laboratory reference strain as well as drug-sensitive and resistant patient isolates, confirming the potential utility of this drug as an antimalarial. We then screen a biosynthetic series of violacein derivatives against P. falciparum growth. The demonstrated varied activity of each derivative against asexual parasite growth points to potential for further development of violacein as an antimalarial. Towards defining its mode of action, we show that biosynthetic violacein affects the parasite actin cytoskeleton, resulting in an accumulation of actin signal that is independent of actin polymerization. This activity points to a target that modulates actin behaviour in the cell either in terms of its regulation or its folding. More broadly, our data show that bacterial synthetic biosynthesis is a suitable platform for antimalarial drug discovery with potential applications in high-throughput and cost-effective drug screening with otherwise chemically-intractable natural products.
Bayesian statistics show a lack of change in excitability following bihemispheric HD-TDCS over the primary somatosensory cortices
Authors: Selene Gallo , Baaijen Thijs J. , Judith Suttrup , Carolina Fernandes-Henriques , Christian Keysers , Valeria Gazzola
Published: October 2019

Background

High Definition transcranial Direct Current Stimulation (HD-tDCS) is a method meant to explore the causal structure-function relationship of brain areas, developed to improve the spatial resolution of tDCS, but the validity of tDCS results is currently under intense debate

Objective

The goal of this study is to validate a new HD-tDCS protocol for bilateral modulation of the Somatosensory Cortex (SI). The new montage is meant to increase the focus of the stimulation while limiting the area of the scalp covered by electrodes. We aim to characterize the effect of the stimulation in terms of directionality, consistency and reproducibility.

Methods

We aim to leverage a 1 × 1 montage to most focally stimulate the primary somatosensory cortex (SI) and measure modulation via Somatosensory Evoked Potentials (SEP) triggered by median nerve stimulation.

Results

The results of Experiment1 suggest that our montage increases the amplitude of the SEP component N30. In Experiment2, we aim to replicate our finding and to assess the duration of the modulatory effect on N30 over time. Data from Experiment2 fails to replicate N30 modulation. A sequential Bayesian analysis performed on N30 data from both experiments indicates that the effect fluctuates across participants, without a clear homogenous directionality.

Conclusion

This study sets boundaries on the effect size that can be expected for this montage and illustrates the need to include replication samples or larger sample sizes to avoid overestimating effect sizes. We conclude that our montage has insufficient effect size for use in moderately sample-sized experimental studies and clinical applications.
Hox genes are essential for the development of novel serial homologous eyespots on the wings of Bicyclus anynana butterflies
Authors: Matsuoka Yuji , Monteiro Antónia
Published: October 2019

The eyespot patterns found on the wings of nymphalid butterflies are novel serial homologous traits that originated first in hindwings and subsequently in forewings, suggesting that eyespot development might be dependent on Hox genes. Hindwings differ from forewings in the expression of Ultrabithorax (Ubx), but the function of this Hox gene in eyespot development as well as that of another Hox gene Antennapedia (Antp), expressed specifically in eyespots centers on both wings, are still unclear. We used CRISPR-Cas9 to target both genes in Bicyclus anynana butterflies. We show that Antp is essential for eyespot development on the forewings and for the differentiation of white centers and larger eyespots on hindwings, whereas Ubx is essential for the development of at least some hindwing eyespots but also for repressing the size of other eyespots. Additionally, Antp is essential for the development of silver scales in male wings. In summary, Antp and Ubx, in addition to their conserved roles in modifying serial homologous traits along the anterior-posterior axis of animals, have acquired a novel role in promoting the development of a new set of serial homologs, the eyespot patterns, in both forewings (Antp) and hindwings (Antp and Ubx) of B. anynana butterflies. We propose that the peculiar pattern of eyespot origins on hindwings first, followed by forewings, could be due to an initial co-option of Ubx into eyespot development, followed by a later, partially redundant co-option of Antp into the same network.
In vivo and in vitro human gene essentiality estimations capture contrasting functional constraints
Authors: Caldu-Primo JL , Verduzco-Martínez JA , Alvarez-Buylla ER , Davila-Velderrain J
Published: October 2019

Gene essentiality estimation is a popular empirical approach to link genotypes to phenotypes. In humans, essentiality is estimated based on loss-of-function (LoF) mutation intolerance, either from population exome sequencing (in vivo) data or CRISPR-based in vitro perturbation experiments. Both approaches identify genes presumed to have strong detrimental consequences on the organism upon mutation. Are these genes functionally distinct and constrained by having key roles? Do in vivo and in vitro estimations equally recover these constraints? To address these questions, here we integrated disparate genome-scale datasets and compared structural, functional, and evolutionary features of essential genes versus genes with extremely high mutational tolerance and proteome expectation. We found that essentiality estimates do recover functional constraints. However, the organismal or cellular context of estimation leads to functionally contrasting properties underlying the constraint. Our results suggest that depletion of LoF mutations in human populations effectively captures developmental, organismal-level functional constraints not experimentally accessible through CRISPR-based screens. Finally, we identify a new set of genes (OrgEssential), which are intolerant of LoF mutation in vivo but highly tolerant in vitro. These genes drive observed functional constraint differences and have an unexpected preference for nervous system expression.
EEG correlates of perceived food product similarity in a cross-modal taste-visual task
Authors: Domracheva M. , Kulikova S.
Published: October 2019

The most common tools to understand perception of food products are hall-tests, surveys, observations, etc. However to get reliable results these approaches require large samples, making them costly and time-consuming. Furthermore, they are also highly expert-dependent and rely on the assumption that study participants can express their preferences consciously and explicitly. Here we suggested an EEG-based approach to evaluate perceived product similarity in a cross-modal taste-visual task. Two candidate neurometrics measured from Fz electrode were tested: the amplitude of N430-620 from evoked response potentials (ERP) and the power of induced gamma oscillations during 400-600 ms period after visual stimulus presentation. Both suggested metrics showed a strong correlation with the perceived similarity scores at both individual and group levels, however N430-630 had greater inter-subject variability making it less suitable for practical applications. The results based on the power of induced gamma oscillations (N=18) not only reflected the results from traditional hall-tests (N=200) but also allowed better discrimination between different food products.
Variation in host home range decreases rabies vaccination effectiveness by increasing the spatial spread of rabies
Authors: McClure Katherine M. , Gilbert Amy T. , Chipman Richard B. , Rees Erin , Pepin Kim M.
Published: October 2019

Animal movement influences the spatial spread of wildlife infectious diseases through host-host contact structure and hence pathogen transmission. Wildlife disease hosts vary in characteristics related to pathogen transmission, which can increase the spread and intensity of disease outbreaks. The consequences of home range size variation on wildlife disease dynamics are poorly understood, but could help to predict disease spread and determine more effective disease management strategies.

We developed a spatially-explicit individual-based model to examine the effect of variation in host home range size on the spatial spread rate, persistence, and incidence of rabies virus (RABV) in raccoons (Procyon lotor). We tested the hypothesis that host home range area variation decreases vaccination effectiveness in wildlife host populations following pathogen invasion into a vaccination zone.

We simulated raccoon demography and RABV dynamics across a range of magnitudes and variances in weekly home range radius distributions for raccoons, and compared results to conditions that assumed a fixed host home range area. We examined how variable host home range radius distributions influenced the relative effectiveness of three components of orally-baited raccoon RABV vaccination (ORV) programs—timing and frequency of bait delivery, width of the zone where ORV baits were delivered, and proportion of hosts immunized.

Variability in home range radius distributions increased RABV spread rates by 1.2 - 5.2-fold compared to simulations with fixed radii. More variable host home range radius distributions decreased relative vaccination effectiveness by 71% compared to less variable host home range radius distributions under conventional vaccination conditions. We found that vaccination timing was more influential for vaccination effectiveness than vaccination frequency or vaccination zone width.

Our results suggest that variation in wildlife home range exploration increases the spatial spread and incidence of wildlife disease. Our vaccination results underscore the importance of prioritizing individual-level space use data collection to understand the dynamics of wildlife diseases and plan their effective control and elimination.
Spontaneous mutations that confer resistance to 2-deoxyglucose act through Hxk2 and Snf1 pathways to regulate gene expression and HXT endocytosis
Authors: Soncini Samantha R. , Chandrashekarappa Dakshayini G. , Augustine David A. , Callahan Kenny P. , O’Donnell Allyson F. , Schmidt Martin C.
Published: October 2019

Yeast and fast-growing human tumor cells share metabolic similarities in that both cells use fermentation of glucose for energy and both are highly sensitive to the glucose analog 2-deoxyglucose. Spontaneous mutations inS. cerevisiaethat conferred resistance to 2-deoxyglucose were identified by whole genome sequencing. In addition to three aneuploid strains, we detected missense alleles of theHXK2, REG1, GLC7andSNF1genes that were shown to confer significant resistance to 2-deoxyglucose. All three missense alleles inHXK2resulted in significantly reduced catalytic activity. Missense alleles affecting the Snf1 kinase pathway (REG1,GLC7andSNF1)exhibited different capacities to affect the regulation of invertase expression. Of the seven missense alleles identified in this study, all but one affected hexose transporter endocytosis by increasing plasma membrane occupancy of the Hxt3 protein. Increased expression of the DOG (deoxyglucose) phosphatases has been associated with resistance to 2-deoxyglucose. Expression of both theDOG1andDOG2mRNA was elevated after treatment with 2-deoxyglucose. Deletion of theHXK2andREG1genes confers resistance to 2-deoxyglucose and causes increased expression of theDOG2mRNA. We conclude that Snf1 kinase-mediated regulation of the endocytosis of the hexose transporters and regulation ofDOG2expression are important mechanisms for resistance to 2-deoxyglucose. However, the dominantSNF1-G53Rallele can confer additional 2-deoxyglucose resistance in cells that are genetically compromised in both the endocytosis andDOGpathways. Thus at least one more mechanism for conferring resistance to this glucose analog remains to be discovered.

Author Summary

Yeast and fast-growing human tumor cells share metabolic similarities in that both cells use fermentation of glucose for energy and both are highly sensitive to the glucose analog 2-deoxyglucose. Another similarity between yeast cells and human tumor cells is that both cells can acquire resistance to 2-deoxyglucose, an outcome that can limit the usefulness of some cancer therapeutics. In this study, we used bakers’ yeast as a model organism to better understand the mechanism of toxicity and acquisition of resistance to 2-deoxyglucose. Spontaneous mutations in S. cerevisiae that conferred resistance to 2-deoxyglucose were isolated and identified by whole genome sequencing, a technology that was not available until recently. Our studies indicate that 2-deoxyglucose becomes toxic after it is phosphorylated by an enzyme called hexokinase. One important route to resistance is to reduce hexokinase activity. Other parallel pathways to resistance include increased expression of a hydrolase that degrades the toxic metabolite, altered localization of glucose transporters and altered glucose signal transduction pathways.
Correlation between increased atrial expression of genes related to fatty acid metabolism and autophagy in patients with chronic atrial fibrillation
Authors: Shingu Yasushige , Takada Shingo , Yokota Takashi , Shirakawa Ryosuke , Yamada Akira , Ooka Tomonori , Katoh Hiroki , Kubota Suguru , Matsui Yoshiro
Published: October 2019

Atrial metabolic disturbance contributes to the onset and development of atrial fibrillation (AF). Autophagy plays a role in maintaining the cellular energy balance. We examined whether the altered atrial expression of genes related to fatty acid metabolism is linked to that related to autophagy in chronic AF. Right atrial tissue was obtained during heart surgery from 51 patients with sinus rhythm (SR, n=38) or chronic AF (n=13). Preoperative fasting serum free-fatty-acid levels were significantly higher in the AF patients. The atrial gene expression of fatty acid binding protein 3 (FABP3), which is involved in the cells’ fatty acid uptake and intracellular fatty acid transport, was significantly increased in AF patients compared to SR patients; in the SR patients it was positively correlated with the right atrial diameter and intra-atrial EMD, parameters of structural and electrical atrial remodeling that was evaluated by an echocardiography. In contrast, the two groups’ atrial contents of diacylglycerol (DAG), a toxic fatty acid metabolite, were comparable. Importantly, the atrial gene expression of microtubule-associated protein light chain 3 (LC3) was significantly increased in the AF patients, and autophagy-related genes including LC3 were positively correlated with the atrial expression of FABP3. In conclusion, in chronic AF patients, the atrial expression of FABP3 was upregulated in association with autophagy-related genes without altered atrial DAG content. Our findings may support the hypothesis that dysregulated cardiac fatty acid metabolism contributes to the progression of AF and induction of autophagy has a cardioprotective effect against cardiac lipotoxicity in chronic AF.