bluuebunny/crossref_metadata_2025 huggingface dataset:
Variants in the degron ofAFF3cause a multi-system disorder with mesomelic dysplasia, horseshoe kidney and developmental and epileptic encephalopathy
Authors: Voisin Norine , Schnur Rhonda E. , Douzgou Sofia , Hiatt Susan M. , Rustad Cecilie F. , Brown Natasha J. , Earl Dawn L. , Keren Boris , Levchenko Olga , Geuer Sinje , Amor David , Brusco Alfredo , Bebin E. Martina , Cappuccio Gerarda , Charrow Joel , Chatron Nicolas , Cooper Gregory M. , Dadali Elena , Delafontaine Julien , Del Giudice Ennio , Douglas Ganka , Funari Tara , Giannuzzi Giuliana , Guex Nicolas , Heron Delphine , Holla Øystein L. , Hurst Anna C.E. , Juusola Jane , Kronn David , Lavrov Alexander , Lee Crystle , Merckoll Else , Mikhaleva Anna , Norman Jennifer , Pradervand Sylvain , Sanders Victoria , Sirchia Fabio , Takenouchi Toshiki , Tanaka Akemi J. , Taska-Tench Heidi , Tønne Elin , Tveten Kristian , Vitiello Giuseppina , Uehara Tomoko , Nava Caroline , Yalcin Binnaz , Kosaki Kenjiro , Donnai Dian , Mundlos Stefan , Brunetti-Pierri Nicola , Chung Wendy K. , Reymond Alexandre
Published: July 2019

The ALF transcription factor paralogs,AFF1, AFF2, AFF3andAFF4, are components of the transcriptional super elongation complex that regulates expression of genes involved in neurogenesis and development. We describe a new autosomal dominant disorder associated withde novomissense variants in the degron of AFF3, a nine amino acid sequence important for its degradation. Consistent with a causative role ofAFF3variants, the mutated AFF3 proteins show reduced clearance. Ten affected individuals were identified, and present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoeKIdney, NS forNievergelt/Savarirayan type of mesomelic dysplasia, S forSeizures, H forHypertrichosis, I forIntellectual disability and P forPulmonary involvement), partially overlapping theAFF4associated CHOPS syndrome. An eleventh individual with a microdeletion encompassing only the transactivation domain and degron motif ofAFF3exhibited overlapping clinical features. A zebrafish overexpression model that shows body axis anomalies provides further support for the pathological effect of increased amount of AFF3 protein.

Whereas homozygousAff3knockout mice display skeletal anomalies, kidney defects, brain malformation and neurological anomalies, knock-in animals modeling the microdeletion and the missense variants identified in affected individuals presented with lower mesomelic limb deformities and early lethality, respectively.

Transcriptome analyses as well as the partial phenotypic overlap of syndromes associated withAFF3andAFF4variants suggest that ALF transcription factors are not redundant in contrast to what was previously suggested
Integrative prediction of gene expression with chromatin accessibility and conformation data
Authors: Schmidt Florian , Kern Fabian , Schulz Marcel H.
Published: July 2019

Background

Enhancers play a fundamental role in orchestrating cell state and development. Although several methods have been developed to identify enhancers, linking them to their target genes is still an open problem. Several theories have been proposed on the functional mechanisms of enhancers, which triggered the development of various methods to infer promoter enhancer interactions (PEIs). The advancement of high-throughput techniques describing the three-dimensional organisation of the chromatin, paved the way to pinpoint long-range PEIs. Here we investigated whether including PEIs in computational models for the prediction of gene expression improves performance and interpretability.

Results

We have extended our Tepic framework to include DNA contacts deduced from chromatin conformation capture experiments and compared various methods to determine PEIs using predictive modelling of gene expression from chromatin accessibility data and predicted transcription factor (TF) motif data. We found that including long-range PEIs deduced from both HiC and HiChIP data indeed improves model performance. We designed a novel machine learning approach that allows to prioritize TFs in distal loop and promoter regions with respect to their importance for gene expression regulation. Our analysis revealed a set of core TFs that are part of enhancer-promoter loops involving YY1 in different cell lines.

Conclusion

We show that the integration of chromatin conformation data improves gene expression prediction, underlining the importance of enhancer looping for gene expression regulation. Our general approach can be used to prioritize TFs that are involved in distal and promoter-proximal regulation using accessibility, conformation and expression data.
Leveraging Gene Co-expression Patterns to Infer Trait-Relevant Tissues in Genome-wide Association Studies
Authors: Shang Lulu , Smith Jennifer A. , Zhou Xiang
Published: July 2019

Genome-wide association studies (GWASs) have identified many SNPs associated with various common diseases. Understanding the biological functions of these identified SNP associations requires identifying disease/trait relevant tissues or cell types. Here, we develop a network method, CoCoNet, to facilitate the identification of trait-relevant tissues or cell types. Different from existing approaches, CoCoNet incorporates tissue-specific gene co-expression networks constructed from either bulk or single cell RNA sequencing (RNAseq) studies with GWAS data for trait-tissue inference. In particular, CoCoNet relies on a covariance regression network model to express gene-level effect sizes for the given GWAS trait as a function of the tissue-specific co-expression adjacency matrix. With a composite likelihood-based inference algorithm, CoCoNet is scalable to tens of thousands of genes. We validate the performance of CoCoNet through extensive simulations. We apply CoCoNet for an in-depth analysis of four neurological disorders and four autoimmune diseases, where we integrate the corresponding GWASs with bulk RNAseq data from 38 tissues and single cell RNAseq data from 10 cell types. In the real data applications, we show how CoCoNet can help identify specific glial cell types relevant for neurological disorders and identify disease-targeted colon tissues as relevant for autoimmune diseases. Our results also provide empirical evidence supporting one hypothesis of the omnigenic model: that trait-relevant gene co-expression networks underlie disease etiology.
Identification of selection and inhibition components in a Go/NoGo task from EEG spectra using a machine learning model
Authors: DeLaRosa Bambi L. , Spence Jeffrey S. , Motes Michael A. , To Wing , Vanneste Sven , Hart John , Kraut Michael A.
Published: July 2019

Abstract

Prior Go/NoGo studies have localized specific regions and EEG spectra for which traditional approaches have distinguished between Go and NoGo conditions. A more detailed characterization of the spatial distribution and timing of the synchronization of frequency bands would contribute substantially to the clarification of neural mechanisms that underlie performance of the Go/NoGo task. The present study used a machine learning approach to learn the features that distinguish between ERSPs involved in selection and inhibition in a Go/NoGo task. A neural network classifier was used to predict task conditions for each subject to characterize ERSPs associated with Go versus NoGo trials. The final model accurately identified individual task conditions at an overall rate of 92%, estimated by 5-fold cross-validation. The detailed accounting of EEG time-frequency patterns localized to brain sources (i.e., thalamus, preSMA, orbitofrontal cortex, and superior parietal cortex) provides elaboration on previous findings from fMRI and EEG studies and more information about EEG power changes in multiple frequency bands (i.e., primarily theta power increase, alpha decreases, and beta increases and decreases) within these regions underlying the selection and inhibition processes engaged in the Go and NoGo trials. This extends previous findings, providing more information about neural mechanisms underlying selection and inhibition processes engaged in the Go and NoGo trials, respectively, and may offer insight into therapeutic uses of neuromodulation in neural dysfunction.
Cortical bone gain following loading is site-specifically enhanced by prior and concurrent disuse in aged male mice
Authors: Galea Gabriel , Delisser Peter J , Meakin Lee , Lanyon Lance E , Price Joanna S , Windahl Sara H
Published: July 2019

The primary aim of bone anabolic therapies is to strategically increase bone mass in skeletal regions likely to experience high strains. This is naturally achieved by mechanical loading of the young healthy skeleton. However, these bone anabolic responses fail with age. Here, we applied site specificity analysis to map regional differences in bone anabolic responses to axial loading of the tibia (tri-weekly, for two weeks) between young (19-week-old) and aged (19-month-old), male and female mice. Loading increased bone mass specifically in the proximal tibia in both sexes and ages. Young female mice gained more cortical bone than young males in specific regions of the tibia. However, these site-specific sex difference were lost with age such that bone gain following loading was not significantly different between old males and females. Having previously demonstrated that prior and concurrent disuse enhances bone gain following loading in old females, we established whether this “rescue” is sex-specific. Old male mice were subjected to sciatic neurectomy or sham surgery, and tri-weekly loading was initiated four days after surgery. Disuse augmented cortical bone gain in response to loading in old male mice, but only in the regions of the tibia which were load-responsive in the young. Increased understanding of how locally-activated load-responsive processes lead to site-specific bone formation, and how the age-related diminution of these processes can be site-specifically enhanced by disuse, may lead to the next generation of strategic bone anabolic therapies.

Highlights

Sex differences in cortical tissue area of young and old mice are not site-specific

The loading response in young, but not old, mice is sex- and site-specific

The cortical loading response is site-specifically enhanced by disuse in old mice of both sexes

The trabecular loading response can be rescued by disuse in old male, but not female, mice
Fitness and community feedbacks: the two axes that drive long-term invasion impacts
Authors: Arnoldi Jean-François , Barbier Matthieu , Kelly Ruth , Barabás György , Jackson Andrew L.
Published: July 2019

Many facets of ecological theory rely on the analysis of invasion processes, and general approaches exist to understand the early stages of an invasion. However, predicting the long-term transformations of communities following an invasion remains a challenging endeavour. We propose an analytical method that uses community structure and invader dynamical features to predict when these impacts can be large, and show it to be applicable across a wide class of dynamical models. Our approach reveals that short-term invasion success and long-term consequences are two distinct axes of variation controlled by different properties of both invader and resident community. Whether a species can invade is controlled by its invasion fitness, which depends on environmental conditions and direct interactions with resident species. But whether this invasion will cause significant transformations, such as extinctions or a regime shift, depends on a specific measure of indirect feedbacks that may involve the entire resident community. Our approach applies to arbitrarily complex communities, from few competing phenotypes in adaptive dynamics to large nonlinear food webs. It hints at new questions to ask as part of any invasion analysis, and suggests that long-term indirect interactions are key determinants of invasion outcomes.
Weak and uneven associations of home, neighborhood and school environments with stress hormone output across multiple time scales
Authors: Malanchini Margherita , Engelhardt Laura E. , Raffington Laurel , Sabhlok Aditi , Grotzinger Andrew D. , Briley Daniel A. , Madole James W. , Freis Samantha M. , Patterson Megan W. , Harden K. Paige , Tucker-Drob Elliot M.
Published: July 2019

The progression of lifelong trajectories of socioeconomic inequalities in health and mortality begins in childhood. Dysregulation in cortisol, a stress hormone that is the primary output of the hypothalamus-pituitary-adrenal (HPA) axis, has been hypothesized to be a mechanism for how early environmental adversity compromises health. However, despite the popularity of cortisol as a biomarker for stress and adversity, little is known about whether cortisol output differs in children being raised in socioeconomically disadvantaged environments. Here, we show that there are few differences between advantaged and disadvantaged children in their cortisol output. In 8- to 14-year-old children from the population-based Texas Twin Project, we measured cortisol output at three different time-scales: (1) diurnal fluctuation in salivary cortisol (n= 400), (2) salivary cortisol reactivity and recovery after exposure to the Trier Social Stress Test (n= 444), and (3) and cortisol concentration in hair (n= 1,210). These measures converged on two moderately correlated, yet distinguishable, dimensions of HPA function. We then tested differences in cortisol output across nine aspects of social disadvantage at the home (e.g., family socioeconomic status), school (e.g., average levels of academic achievement), and neighborhood (e.g., concentrated poverty). Children living in neighborhoods with higher concentrated poverty had higher diurnal cortisol output, as measured in saliva; otherwise, child cortisol output was unrelated to any other aspect of social disadvantage. Overall, we find limited support for alteration in HPA axis functioning as a general mechanism for the health consequences of socioeconomic inequality in childhood.
Seeing distinct groups where there are none: spurious patterns from between-group PCA
Authors: Cardini Andrea , O’Higgins Paul , Rohlf F. James
Published: July 2019

Using sampling experiments, we found that, when there are fewer groups than variables, between-groups PCA (bgPCA) may suggest surprisingly distinct differences among groups for data in which none exist. While apparently not noticed before, the reasons for this problem are easy to understand. A bgPCA captures the g-1 dimensions of variation among the g group means, but only a fraction of the ∑ni − g dimensions of within-group variation (ni are the sample sizes), when the number of variables, p, is greater than g-1. This introduces a distortion in the appearance of the bgPCA plots because the within-group variation will be underrepresented, unless the variables are sufficiently correlated so that the total variation can be accounted for with just g-1 dimensions. The effect is most obvious when sample sizes are small relative to the number of variables, because smaller samples spread out less, but the distortion is present even for large samples. Strong covariance among variables largely reduces the magnitude of the problem, because it effectively reduces the dimensionality of the data and thus enables a larger proportion of the within-group variation to be accounted for within the g-1-dimensional space of a bgPCA. The distortion will still be relevant though its strength will vary from case to case depending on the structure of the data (p, g, covariances etc.). These are important problems for a method mainly designed for the analysis of variation among groups when there are very large numbers of variables and relatively small samples. In such cases, users are likely to conclude that the groups they are comparing are much more distinct than they really are. Having many variables but just small sample sizes is a common problem in fields ranging from morphometrics (as in our examples) to molecular analyses.
The role of the pre-commissural fornix in episodic autobiographical memory and simulation
Authors: Williams Angharad N. , Ridgeway Samuel , Postans Mark , Graham Kim S. , Lawrence Andrew D. , Hodgetts Carl J.
Published: July 2019

Neuropsychological and functional magnetic resonance imaging (MRI) evidence suggests that the ability to vividly remember our personal past, and imagine future scenarios, involves two closely connected regions: the hippocampus and ventromedial prefrontal cortex (vmPFC). Despite evidence of a direct anatomical connection from hippocampus to vmPFC, it is unknown whether hippocampal-vmPFC structural connectivity supports both past and future-oriented episodic thinking. To address this, we applied diffusion-weighted magnetic resonance imaging (dMRI) and a novel deterministic tractography protocol to reconstruct distinct subdivisions of the fornix previously detected in axonal tracer studies, namely pre-commissural (connecting the hippocampus to vmPFC) and post-commissural (linking the hippocampus and medial diencephalon) fornix, in a group of healthy young adult humans who undertook an adapted past-future autobiographical interview. As predicted, we found that inter-individual differences in pre-commissural - but not post-commissural - fornix microstructure (fractional anisotropy) was significantly correlated with the episodic richness of both past and future autobiographical narratives. Notably, these results remained significant when controlling for both non-episodic narrative content and grey matter volumes of the hippocampus and vmPFC. This study provides novel evidence that reconstructing events from one’s personal past, and constructing possible future events, involves a distinct, structurally-instantiated hippocampal-vmPFC pathway.

Significance Statement

A novel anatomically-guided protocol that allows the pre-commissural and post-commissural fornix fibers to be separately reconstructed in vivo (Christiansen et al., 2016) was applied to reconstruct the pre-commissural subdivision of the white matter fornix tract (anatomically linking the hippocampal formation to the vmPFC) and investigate its contribution to episodic memory and future simulation. We demonstrated that the amount of episodic details contained in past and future narratives, collected via an adapted autobiographical interview, was positively correlated with pre-, but not post-, commissural fornix microstructure. These findings highlight how inter-individual variation in the pre-commissural subdivision of the fornix underpins the construction of self-reflective, contextual events – for both the past and future.
Neural correlates of the DMT experience as assessed via multivariate EEG
Authors: Timmermann Christopher , Roseman Leor , Schartner Michael , Milliere Raphael , Williams Luke , Erritzoe David , Muthukumaraswamy Suresh , Ashton Michael , Bendrioua Adam , Kaur Okdeep , Turton Samuel , Nour Matthew M , Day Camilla M , Leech Robert , Nutt David , Carhart-Harris Robin
Published: July 2019

Studying transitions in and out of the altered state of consciousness caused by intravenous (IV) N,N-Dimethyltryptamine (DMT – a fast-acting tryptamine psychedelic) offers a safe and powerful means of advancing knowledge on the neurobiology of conscious states. Here we sought to investigate the effects of IV DMT on the power spectrum and signal diversity of human brain activity (6 female, 7 male) recorded via multivariate EEG, and plot relationships between subjective experience, brain activity and drug plasma concentrations across time. Compared with placebo, DMT markedly reduced oscillatory power in the alpha and beta bands and robustly increased spontaneous signal diversity. Time-referenced analyses revealed close relationships between changes in various aspects of subjective experience and changes in brain activity. Importantly, the emergence of oscillatory activity within the delta and theta frequency bands was found to correlate with the peak of the experience, and particularly its eyes-closed visual component. These findings highlight marked changes in oscillatory activity and signal diversity with DMT that parallel broad and specific components of the relevant subjective experience and thus further our understanding of the neurobiological underpinnings of immersive states of consciousness.
Urgency, Leakage, and the Relative Nature of Information Processing in Decision-making
Authors: Trueblood Jennifer S. , Heathcote Andrew , Evans Nathan J. , Holmes William R.
Published: July 2019

Over the last decade, there has been a robust debate in decision neuroscience and psychology about what mechanism governs the time course of decision making. Historically, the most prominent hypothesis is that neural architectures accumulate information over time until some threshold is met, the so-called Evidence Accumulation hypothesis. However, most applications of this theory rely on simplifying assumptions, belying a number of potential complexities. Is changing stimulus information perceived and processed in an independent manner or is there a relative component? Does urgency play a role? What about evidence leakage? Although the latter questions have been the subject of recent investigations, most studies to date have been piecemeal in nature, addressing one aspect of the decision process or another. Here we develop a modeling framework, an extension of the Urgency Gating Model, in conjunction with a changing information experimental paradigm to simultaneously probe these aspects of the decision process. Using state-of-the-art Bayesian methods to perform parameter-based inference, we find that 1) information processing is relative with early information influencing the perception of late information, 2) time varying urgency and evidence accumulation are of roughly equal importance in the decision process, and 3) leakage is present with a time scale of ~200-250ms. To our knowledge, this is the first comprehensive study to utilize a changing information paradigm to jointly and quantitatively estimate the temporal dynamics of human decision-making.
Peripheral blood cell immunophenotyping reveals distinct subgroups of inflamed depression
Authors: Lynall Mary-Ellen , Turner Lorinda , Bhatti Junaid , Cavanagh Jonathan , de Boer Peter , Mondelli Valeria , Jones Declan , Drevets Wayne C. , Cowen Philip , Harrison Neil A. , Pariante Carmine M. , Pointon Linda ,   NIMA Consortium, Clatworthy Menna R. , Bullmore Ed
Published: July 2019

Depression has been associated with increased inflammatory proteins but changes in circulating immune cells are less well defined. We used multi-parametric flow cytometry to investigate 14 subsets of peripheral blood cells in 206 cases of major depressive disorder (MDD) and 77 age- and sex-matched controls. There were significant case-control differences, by univariate and multivariate analysis: cases showed increased immune cell counts, especially neutrophils, CD4+ T cells and monocytes, and increased inflammatory proteins (C-reactive protein and interleukin-6). Within-group analysis demonstrated significant association between the severity of depressive symptoms and increased myeloid and CD4+ cell counts. MDD cases could be partitioned into two groups by forced binary clustering of cell counts: the inflamed depression group (N=81 out of 206; 39%) had increased monocyte, CD4+ and neutrophil counts, increased C-reactive protein (CRP) and interleukin 6 (IL-6), and was more depressed than the uninflamed majority of cases. Relaxing the presumption of a binary classification, data-driven clustering identified four subgroups of MDD cases: two of these subgroups (N=38 and N=100; 67% collectively) were associated with increased inflammatory proteins and more severe depression, but differed from each other in the relative weighting of myeloid and lymphoid cell counts. Case-control and within-group results were robust to statistical control for the potentially confounding effects of age, sex, BMI, recent infection status, and tobacco use. Peripheral blood immunophenotyping can be used to identify a candidate cellular biomarker of inflamed depression, and to further decompose that binary partition, suggesting that there is more than one mechanistic pathway underlying inflamed depression.

One Sentence Summary

Two subgroups of depressed cases (about two-thirds of all 206 cases) were identified by peripheral blood biomarker evidence of distinctive cellular immunophenotypes, biased towards the myeloid or lymphoid lineages in different subgroups, but consistently associated with increased blood concentrations of inflammatory proteins and greater severity of depressive symptoms.
IQGAP1 connects phosphoinositide signaling to cytoskeletal reorganization
Authors: Yerramilli V. Siddartha , Ross Alonzo H. , Lindberg Samantha K. , Scarlata Suzanne , Gericke Arne
Published: July 2019

IQGAP1 is a multi-domain protein that acts as a scaffold for multiple signaling pathways. IQGAP1 generates the lipid messenger PI(3,4,5)P3 by scaffolding the phosphoinositide kinases PIPKIs and PI3K. The dynamics of this scaffolding protein complex in intact, living cells are unknown. Here, we delineate the role of IQGAP1 in PI(3,4,5)P3-mediated signaling in live cells under basal and stimulated conditions using fluorescence lifetime imaging microscopy. We demonstrate that IQGAP1 interacts strongly with PIPKIγ at intracellular entities and on the plasma membrane, and scaffolds PI3K and PIPKIγ in response to physiological changes. Additionally, we show that IQGAP1 scaffolds phosphoinositides with PI3K, PIPKIγ and EGFR, and forms clusters upon cell stimulation with epidermal growth factor. Importantly, we show that IQGAP1 connects PI(3,4,5)P3-mediated signaling and cytoskeletal signaling pathways by binding PIPKIγ in proximity of the cytoskeletal proteins talin and Cdc42. Our results support a model in which IQGAP1 mediates crosstalk between phosphoinositide signaling and the cytoskeleton to promote directed cell movement.
Context-dependent gene regulation by transcription factor complexes
Authors: Kribelbauer Judith F. , Loker Ryan E. , Feng Siqian , Rastogi Chaitanya , Abe Namiko , Rube H. Tomas , Bussemaker Harmen J. , Mann Richard S.
Published: July 2019

Eukaryotic transcription factors (TFs) form complexes with various partner proteins to recognize their genomic target sites. Yet, how the DNA sequence determines which TF complex forms at any given site is poorly understood. Here we demonstrate that high-throughputin vitrobinding assays coupled with unbiased computational analysis provides unprecedented insight into how complexes of homeodomain proteins adapt their stoichiometry and configuration to the bound DNA. Using inferred knowledge about minor groove width readout, we design targeted protein mutations that destabilize homeodomain binding in a complex-specific manner. By performing parallel SELEX-seq, ChIP-seq, RNA-seq and Hi-C assays, we not only reveal complex-specific functions, but also show that TF binding sites that lack a canonical sequence motif emerge as a consequence of direct interaction with functionally bound sites.
PacBio amplicon sequencing method to measure pilin antigenic variation frequencies ofNeisseria gonorrhoeae
Authors: Ozer Egon A. , Prister Lauren L. , Yin Shaohui , Ward Billy H. , Ivanov Stanimir , Seifert H Steven
Published: July 2019

Gene diversification is a common mechanism pathogens use to alter surface structures to aid in immune avoidance.Neisseria gonorrhoeaeuses a gene conversion-based diversification system to alter the primary sequence of the gene encoding the major subunit of the pilus, pilE. Antigenic variation occurs when one of the non-expressed 19 silent copies donates part of its DNA sequence topilE. We have developed a method using Pacific Biosciences amplicon sequencing and custom software to determine pilin antigenic variation frequencies. The program analyzes 37 variable regions across the strain FA1090 1-81-S2pilEgene and can be modified to determine sequence variation from other startingpilEsequences or other diversity generation systems. Using this method, we measured pilin antigenic variation frequencies for various derivatives of strain FA1090 and showed we can also analyze pilin antigenic variation frequencies during macrophage infection.
Single-gene resolution of locally adaptive genetic variation in Mexican maize
Authors: Gates Daniel J , Runcie Dan , Janzen Garrett M. , Navarro Alberto Romero , Willcox Martha , Sonder Kai , Snodgrass Samantha J. , Rodríguez-Zapata Fausto , Sawers Ruairidh J. H. , Rellán-Álvarez Rubén , Buckler Edward S. , Hearne Sarah , Hufford Matthew B. , Ross-Ibarra Jeffrey
Published: July 2019

Threats to crop production due to climate change are one of the greatest challenges facing plant breeders today. While considerable adaptive variation exists in traditional landraces, natural populations of crop wild relatives, and ex situ germplasm collections, separating adaptive alleles from linked deleterious variants that impact agronomic traits is challenging and has limited the utility of these diverse germplasm resources. Modern genome editing techniques such as CRISPR offer a potential solution by targeting specific alleles for transfer to new backgrounds, but such methods require a higher degree of precision than traditional mapping approaches can achieve. Here we present a high-resolution genome-wide association analysis to identify loci exhibiting adaptive patterns in a large panel of more than 4500 traditional maize landraces representing the breadth of genetic diversity of maize in Mexico. We evaluate associations between genotype and plant performance in 13 common gardens across a range of environments, identifying hundreds of candidate genes underlying genotype by environment interaction. We further identify genetic associations with environment across Mexico and show that such loci are associated with variation in yield and flowering time in our field trials and predict performance in independent drought trials. Our results indicate that the variation necessary to adapt crops to changing climate exists in traditional landraces that have been subject to ongoing environmental adaptation and can be identified by both phenotypic and environmental association.
Interaction between induced and natural variation atoil yellow1delays reproductive maturity in maize
Authors: Khangura Rajdeep S. , Venkata Bala P. , Marla Sandeep R. , Mickelbart Michael V. , Dhungana Singha , Braun David M. , Dilkes Brian P. , Johal Gurmukh S.
Published: July 2019

We previously demonstrated that maize (Zea mays) locusvery oil yellow1 (vey1)encodes a putative cis-regulatory expression polymorphism at the magnesium chelatase subunit I gene (akaoil yellow1) that strongly modifies the chlorophyll content of the semi-dominantOy1-N1989mutants. Thevey1allele of Mo17 inbred line reduces chlorophyll content in the mutants leading to reduced photosynthetic output.Oy1-N1989mutants in B73 reached reproductive maturity four days later than wild-type siblings. Enhancement ofOy1-N1989by the Mo17 allele at thevey1QTL delayed maturity further, resulting in detection of a flowering time QTL in two bi-parental mapping populations crossed toOy1-N1989. The near isogenic lines of B73 harboring thevey1allele from Mo17 delayed flowering ofOy1-N1989mutants by twelve days. Just as previously observed for chlorophyll content,vey1had no effect on reproductive maturity in the absence of theOy1-N1989allele. Loss of chlorophyll biosynthesis inOy1-N1989mutants and enhancement byvey1reduced CO2assimilation. We attempted to separate the effects of photosynthesis on the induction of flowering from a possible impact of chlorophyll metabolites and retrograde signaling by manually reducing leaf area. Removal of leaves, independent of theOy1-N1989mutant, delayed flowering but surprisingly reduced chlorophyll contents of emerging leaves. Thus, defoliation did not completely separate the identity of the signal(s) that regulates flowering time from changes in chlorophyll content in the foliage. These findings illustrate the necessity to explore the linkage between metabolism and the mechanisms that connect it to flowering time regulation.
Societal attention toward extinction threats
Authors: Jarić Ivan , Bellard Céline , Courchamp Franck , Kalinkat Gregor , Meinard Yves , Roberts David L. , Correia Ricardo A.
Published: July 2019

Public attention and interest in the fate of endangered species is a crucial prerequisite for effective conservation programs. Societal awareness and values will largely determine whether conservation initiatives receive necessary support and lead to adequate policy change. Using text data mining, we assessed general public attention toward climate change and biological invasions, which represent two key threats for endangered amphibian, reptile, bird and mammal species in three European countries (France, Germany and the United Kingdom). Our analysis revealed that public attention patterns differed among species groups and countries but was globally higher for climate change than for biological invasions. Both threats received better recognition in threatened than in non-threatened species, as well as in native species than in species from other countries and regions. The relative level of attention toward the two threats corresponded well with the listing of the threats and their severity within the IUCN Red List. We conclude that more efficient communication regarding the threat from biological invasions should be developed, and that conservation practitioners should take advantage of the existing attention toward the threat of climate change.
Engineered Dendritic Cell-Directed Concurrent Activation of Multiple T cell Inhibitory Pathways Induces Robust Immune Tolerance
Authors: Gudi Radhika R. , Karumuthil-Melethil Subha , Perez Nicolas , Li Gongbo , Vasu Chenthamarakshan
Published: July 2019

Inhibitory/repressor-receptors are upregulated significantly on activated T cells, and have been the molecules of attention as targets for inducing immune tolerance. Induction of effective antigen specific tolerance depends on concurrent engagement of the TCR and one or more of these inhibitory receptors. Here, we show, for the first time that dendritic cells (DCs) can be efficiently engineered to express multiple T cell inhibitory ligands, and enhanced engagement of T cell inhibitory receptors, upon antigen presentation, by these DCs can induce effective CD4+ T cell tolerance and suppress autoimmunity. Compared to control DCs, antigen presentation by DCs that ectopically express CTLA4, PD1 and BTLA selective ligands (B7.1wa, PD-L1, and HVEM-CRD1 respectively) individually (mono-ligand DCs) or in combination (multi-ligand DCs) causes an inhibition of CD4+ T cell proliferation and pro-inflammatory cytokine response, as well as increase in Foxp3+ Treg frequency and immune regulatory cytokine production. Administration of self-antigen (mouse thyroglobulin; mTg) loaded multi-ligand DCs caused hyporesponsiveness to mTg challenge, suppression of autoantibody production, and amelioration of experimental autoimmune thyroiditis. Overall, this study shows that engineered DC-directed enhanced concurrent activation of multiple T cell coinhibitory pathways is an effective way to induce self-antigen specific T cell tolerance to suppress ongoing autoimmunity.
Crystal structure of Sulfolobus solfataricus topoisomerase III reveals a novel carboxyl-terminal zinc finger domain essential for decatenation activity
Authors: Wang Hanqian , Zhang Junhua , Gao Zengqiang , Zheng Xin , Zhu Keli , Zhang Zhenfeng , Zhang Zhiyong , Dong Yuhui , Huang Li , Gong Yong
Published: July 2019

DNA topoisomerases are essential enzymes for a variety of cellular processes involved in DNA transactions. Mechanistic insights into type IA DNA topoisomerases have come principally from studies on bacterial and eukaryotic enzymes. A structural understanding of type IA topoisomerases in Archaea is lacking. Here, we present a 2.1-angstrom crystal structure of full-length Sulfolobus solfataricus topoisomerase III (Sso topo III), an archaeal member of type IA topoisomerases. The structure shows that Sso topo III adopts a characteristic torus-like architecture consisting of a four-domain core region and a novel carboxyl-terminal zinc finger domain (domain V). Structure-based mutation analyses reveal that a novel zinc-binding motif in domain V is essential for the DNA decatenation activity of Sso topo III. Our data indicate that Sso topo III represents a subclass of Type IA topoisomerases capable of resolving DNA catenates using a domain V-dependent mechanism.

IMPORTANCE

Type IA topoisomerases are omnipresent in all cellular life forms and serve pivotal roles in cellular processes involved in DNA transactions. While considerable insights have been gained into Type IA topoisomerases from bacteria and eukaryotes, a structural understanding of type IA topoisomerases in Archaea remains elusive. we first determined the crystal structure of full-length Sulfolobus solfataricus topoisomerase III (Sso topo III), an archaeal member of type IA topoisomerases. Our structure provides the first molecular view of this archaeal topoisomerase, which removes negative supercoils and decatenates DNA catenane. Our findings manifest that Sso topo III may serve as an alternative prototype of type IA topoisomerases, whose decatenation mechanism differs from that of known bacterial and eukaryotic topoisomerases III such as Escherichia coli topoisomerase III (EcTOP3).
Visual speed compensation of pitch-constrained blue-bottle flies under retinal-image velocity perturbation in a flight mill
Authors: Hsu Shih-Jung , Cheng Bo
Published: July 2019

In the presence of wind or background image motion, flies are able to maintain a constant retinal-image velocity via regulating flight speed to the extent permitted by their locomotor capacity. Here we investigated the speed regulation of semi-tethered blue-bottle flies (Calliphora vomitoria) flying along an annular corridor in a magnetically levitated flight mill enclosed by two motorized cylindrical walls. We perturbed the flies’ retinal-image motion via spinning the cylindrical walls, generating bilaterally-averaged velocity perturbations from -0.3 to 0.3 m·s-1. Flies compensated retinal-image velocity perturbations by adjusting airspeed up to 20%, thereby maintaining a relatively constant retinal-image velocity. When the retinal-image velocity perturbation became greater than ∼0.1 m·s-1, the compensation weakened as airspeed plateaued, suggesting that flies were unable to further change airspeed. The compensation gain, i.e., the ratio of airspeed compensation and retinal-image velocity perturbation, depended on the spatial frequency of the grating patterns, being the largest at 12 m-1.
TheC. elegansRIG-I homologdrh-1mediates the Intracellular Pathogen Response upon viral infection
Authors: Sowa Jessica N. , Jiang Hongbing , Somasundaram Lakshmi , Xu Guorong , Wang David , Troemel Emily R.
Published: July 2019

Mammalian RIG-I-like receptors detect viral dsRNA and 5’ triphosphorylated RNA to activate transcription of interferon genes and promote antiviral defense. TheC. elegansRIG-I-like receptor DRH-1 promotes defense through antiviral RNA interference, but less is known about its role in regulating transcription. Here we describe a role fordrh-1in directing a transcriptional response inC. eleganscalled the Intracellular Pathogen Response (IPR), which is associated with increased pathogen resistance. The IPR includes a set of genes induced by diverse stimuli including intracellular infection and proteotoxic stress. Previous work suggested that the proteotoxic stress caused by intracellular infections might be the common trigger of the IPR, but here we demonstrate that different stimuli act through distinct pathways. Specifically, we demonstrate that DRH-1/RIG-I is required for inducing the IPR in response to Orsay virus infection, but not in response to other triggers like microsporidian infection or proteotoxic stress. Furthermore,drh-1appears to be acting independently of its known role in RNAi. Interestingly, expression of the replication competent Orsay virus RNA1 segment alone is sufficient to induce most of the IPR genes in a manner dependent on RNA dependent RNA polymerase activity and ondrh-1. Altogether, these results suggest that DRH-1 is a pattern-recognition receptor that detects viral replication products to activate the IPR stress/immune program inC. elegans.

Importance

C. eleganslacks homologs of most mammalian pattern recognition receptors, and how nematodes detect pathogens is poorly understood. We show that theC. elegansRIG-I homologdrh-1mediates induction of the Intracellular Pathogen Response (IPR), a novel transcriptional defense program, in response to infection by the naturalC. elegansviral pathogen Orsay virus.drh-1appears to act as a pattern-recognition receptor to induce the IPR transcriptional defense program by sensing the products of viral RNA-dependent RNA polymerase activity. Interestingly, this signaling role ofdrh-1is separable from its previously known role in antiviral RNAi. In addition, we show that there are multiple host pathways for inducing the IPR, shedding light on the regulation of this novel transcriptional immune response.
Rapid evolution of antiviral APOBEC3 genes driven by the conflicts with ancient retroviruses
Authors: Ito Jumpei , Gifford Robert J. , Sato Kei
Published: July 2019

The evolution of antiviral genes has been fundamentally shaped by antagonistic interactions with ancestral viruses. The AID/APOBEC family genes (AID and APOBEC1-4) encode cellular cytosine deaminases that target nucleic acids and catalyze C-to-U mutations. In the case of retroviral replication, APOBEC3 proteins induce C-to-U mutations in minus-stranded viral DNA, which results in G-to-A mutations in the viral genome. Previous studies have indicated that the expansion and rapid evolution of mammalian APOBEC3 genes has been driven by an arms race with retroviral parasites, but this has not been thoroughly investigated. Endogenous retroviruses (ERVs) are retrotransposons originated from ancient retroviral infections. These sequences sometimes bear the hallmarks of APOBEC3-mediated mutations, and therefore serve as a record of the ancient conflict between retroviruses and APOBEC3 genes. Here we systematically investigated the sequences of ERVs and APOBEC3 genes in mammals to reconstruct details of the evolutionary conflict between them. We identified 1,420 AID/APOBEC family genes in a comprehensive screen of mammalian genome. Of the AID/APOBEC family genes, APOBEC3 genes have been selectively amplified in mammalian genomes and disclose evidence of strong positive selection - whereas the catalytic domain was highly conserved across species, the structure loop 7, which recognizes viral DNA/RNA substrates, was shown to be evolving under strong positive selection. Although APOBEC3 genes have been amplified by tandem gene duplication in most mammalian lineages, the retrotransposition-mediated gene amplification was found in several mammals including New World monkeys and prosimian primates. Comparative analysis revealed that G-to-A mutations are accumulated in ERVs, and that the G-to-A mutation signatures on ERVs is concordant with the target preferences of APOBEC3 proteins. Importantly, the number of APOBEC3 genes was significantly correlated with the frequency of G-to-A mutations in ERVs, suggesting that the amplification of APOBEC3 genes led to stronger attacks on ERVs and/or their ancestral retroviruses by APOBEC3 proteins. Furthermore, the numbers of APOBEC3 genes and ERVs in mammalian genomes were positively correlated, and in primates, the timings of APOBEC3 gene amplification was concordant with that of ERV invasions. Our findings suggest that conflict with ancient retroviruses was a major selective pressure driving the rapid evolution of APOBEC3 genes in mammals.
Kinase inhibition of G2019S-LRRK2 restores autolysosome formation and function to reduce endogenous alpha-synuclein intracellular inclusions
Authors: Obergasteiger Julia , Frapporti Giulia , Lamonaca Giulia , Pizzi Sara , Picard Anne , Pischedda Francesca , Piccoli Giovanni , Lobbestael Evy , Baekelandt Veerle , Hicks Andrew A. , Corti Corrado , Pramstaller Peter P. , Volta Mattia
Published: July 2019

The Parkinson’s disease (PD)-associated kinase Leucine-Rich Repeat Kinase 2 (LRRK2) is a potent modulator of autophagy and impacts on lysosome biology and function, but unclarity exists on the precise mechanics of its role and the direction of this modulation. LRRK2 is also involved in the degradation of pathological alpha-synuclein, with pathogenic mutations precipitating neuropathology in cellular and animal models of PD, and most LRRK2 familial cases manifesting with Lewy neuropathology. Defects in autophagic processing and lysosomal degradation of alpha-synuclein have been postulated to underlie its accumulation and onset of neuropathology. Thus, it is critical to reconcile these independent pieces of information to obtain a comprehensive knowledge on LRRK2-associated pathology that could also be generalized to the idiopathic disease.

Here, we report a focused investigation on the role of PD-causing G2019S-LRRK2 in the autophagy-lysosome pathway in a recombinant cell line model. Initially, we evaluated the effect of LRRK2 expression on autophagy-related transcriptome. Then, we found that G2019S-LRRK2 leads to accumulation of autophagosomes with no net effect on autophagy induction. This is linked to abnormalities in lysosome morphology and proteolytic activity that are associated with a decrease in the successful formation of autolysosomes. Despite some of these features being shared by WT-LRRK2, alpha-synuclein intracellular inclusions are specifically found in G2019S-LRRK2 cells. Pharmacological kinase inhibition is capable of rescuing defects in the autophagy-lysosome pathway and reducing the number of inclusions. Notably, this effect is prevented by upstream blockade of autophagosome-lysosome fusion events, highlighting this step of the process as critical for alpha-synuclein clearance.
DNA Methylation Biomarkers Of Myocardial Infarction And Cardiovascular Disease
Authors: Fernández-Sanlés Alba , Sayols-Baixeras Sergi , Subirana Isaac , Sentí Mariano , Pérez-Fernández S , de Moura Manuel Castro , Esteller Manel , Marrugat Jaume , Elosua Roberto
Published: July 2019

Objective

To assess the association between DNA methylation and acute myocardial infarction, the predictive added value of the identified methylation marks, and the causality of those associations.

Approach and Results

We conducted a case-control, two-stage, epigenome-wide association study on acute myocardial infarction (ndiscovery=391, nvalidation=204). DNA methylation was assessed using the Infinium MethylationEPIC BeadChip (over 850,000 CpGs). DNA methylation was the exposure variable and myocardial infarction the outcome of interest. After a fixed-effects meta-analysis, 34 CpGs fulfilled Bonferroni significance. These findings were also analysed in two independent cohort studies (n∼1,800 and n∼2,500) with incident coronary (CHD) and cardiovascular disease (CVD). The Infinium HumanMethylation450 BeadChip was used in these two studies (over 480,000 CpGs) and only 12 of the 34 CpGs were available in those samples. Finally, we validated four of them in association with incident CHD:AHRR-mapping cg05575921,PTCD2-mapping cg25769469, intergenic cg21566642 andMPO-mapping cg04988978. The four CpGs were also associated with classical cardiovascular risk factors. A methylation risk score based on those CpGs did not improve the predictive capacity of the Framingham risk function. To assess the causal effects of those CpGs we performed Mendelian randomization analysis but only one metQTL could be identified and the results were not conclusive.

Conclusions

We have identified 34 CpGs related to acute myocardial infarction. These loci highlight the relevance of smoking, lipid metabolism, and inflammation in the biological mechanisms related to myocardial infarction. Four were additionally associated with incident CHD and CVD but did not provide additional predictive information.