bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mycolactone-independent pathogenicity ofMycobacterium ulcerans: an experimental study in plants
Authors: Bouam A. , Drancourt M. 
Published: December 2019

ABSTRACTMycobacterium ulcerans, the etiologic agent of Buruli ulcer in humans and animals, secretes macrolide exotoxins mycolactones which damage tissues after a cascade of cellular effects.M. ulcerans, an environmental organism with still elusive reservoirs and sources has been detected in soil and water in endemic areas where it could be in contact with plants. Symptom observations, microscopy and molecular biology were used to investigateM. ulceranscontact with plants in an experimental model mimicking the known pathology of Buruli ulcer in humans.Solanum lycopereum(tomato) plants with scarified or intact roots were transplanted into pots containing contaminated soil withM. ulceransor a mixture of mycolactones A/B and C in the presence of negative control groups. Whereas plants with intact roots remained asymptomatic,M. ulcerans-infected plants with scarified roots had significantly more diseased leaves than controls (p = 0.004). Optic microscopy examination showed significantly more mycobacteria in the secondary and main roots than in controls (p=0.0008). Real-time PCRs detectedM. ulceransDNA in 7/12 (58%) of infected root samples versus none in the control plants (p = 0.04). Further study of plants with mycolactones A/B and C yielded no significant difference with negative controls. These results suggest that in this model,M. ulceransexhibits a mycolactone-independent pathogenicity whose mechanism remains to be elucidated.
Diffusion MRI free water is a sensitive marker of age-related changes in the cingulum
Authors: Edde Manon , Theaud Guillaume , Rheault François , Dilharreguy Bixente , Helmer Catherine , Dartigues Jean-François , Amieva Hélène , Allard Michèle , Descoteaux Maxime , Catheline Gwénaëlle 
Published: December 2019

AbstractDiffusion MRI is extensively used to investigate changes in white matter microstructure. However, diffusion measures within white matter tissue can be affected by partial volume effects due to cerebrospinal fluid and white matter hyperintensities, especially in the aging brain. In previous aging studies, the cingulum bundle that plays a central role in the architecture of the brain networks supporting cognitive functions has been associated with cognitive deficits. However, most of these studies did not consider the partial volume effects on diffusion measures. The aim of this study was to evaluate the effect of free water elimination on diffusion measures of the cingulum in a group of 68 healthy elderly individuals. We first determined the effect of free water elimination on conventional DTI measures and then examined the effect of free water elimination on verbal fluency performance over 12 years. The cingulum bundle was reconstructed with a tractography pipeline including a white matter hyperintensities mask to limit the negative impact of hyperintensities on fiber tracking algorithms. We observed that free water elimination improved the sensitivity of conventional DTI measures to detect associations between tissue-specific diffusion measures of the cingulum and changes in verbal fluency in older individuals. Moreover, free water content measured along the cingulum was independently strongly associated with changes in verbal fluency. These observations suggest the importance of using free water elimination when studying brain aging and indicate that free water itself could be a relevant marker for age-related cingulum white matter modifications and cognitive decline.
Longitudinal change in executive function is associated with impaired top-down frontolimbic regulation during reappraisal in older adults
Authors: Lloyd William K. , Morriss Jayne , Macdonald Birthe , Joanknecht Karin , Nihouarn Julie , van Reekum Carien M. 
Published: December 2019

AbstractNetworks in the prefrontal cortex (PFC) that are important for executive function are also engaged in adaptive responding to negative events. These networks are particularly vulnerable to age-related structural atrophy and an associated loss of executive function, yet existing evidence suggests preserved emotion processing ability in aging. Using longitudinally acquired data from a battery of cognitive tasks, we defined a metric for the rate of decline of executive function. With this metric, we investigated relationships between changes in executive function and emotion reappraisal ability and brain structure, in older adults using functional and structural MRI. During task-based fMRI, participants were asked to cognitively reappraise negatively valenced images. We hypothesised one of two associations with decreasing executive function over time: 1) a decreased ability to reappraise reflected in decreased PFC and increased amygdala activation, or 2) a neural compensation mechanism characterised by increased PFC activation but no differential amygdala activation. Structurally, for a decreased reappraisal ability, we predicted a decrease in grey matter in PFC and/or a decrease of white matter integrity in amygdala-PFC pathways. Neither of the two hypotheses relating to brain function were completely supported, with the findings indicating a steeper decline in executive function associated with both increased PFC and increased left amygdala activity when reappraising negative stimuli. In addition, white matter integrity of the uncinate fasciculus, a primary white matter tract connecting the amygdala and ventromedial areas of PFC, was lower in those individuals who demonstrated a greater decrease in executive function. These findings highlight that when cognitive ability diminishes, active top-down emotional control is compromised.
Mitophagy contributes to alpha-tocopheryl succinate toxicity in GSNOR-deficient hepatocellular carcinoma
Authors: Rizza Salvatore , Di Leo Luca , Mandatori Sara , De Zio Daniela , Filomeni Giuseppe 
Published: December 2019

AbstractThe denitrosylating enzymeS-nitrosoglutathione reductase (GSNOR), has been reported to control the selective degradation of mitochondria through mitophagy, by modulating the extent of nitric oxide-modified proteins (S-nitrosylation). The accumulation ofS-nitrosylated proteins due to GSNOR downregulation is a feature of hepatocellular carcinoma, causing mitochondrial defects that sensitize these tumors to mitochondrial toxins, in particular to mitochondrial complex II inhibitor alpha-tocopheryl succinate (αTOS). However, it is not known if mitophagy defects contribute to GSNOR-deficient cancer cells sensitivity to αTOS, nor if mitophagy inhibition could be used as a common mechanism to sensitize liver cancers to this toxin. Here, we provide evidence that GSNOR-deficient cancer cells show defective mitophagy. Furthermore, we show that αTOS is a mitophagy inducer and that mitophagy defects of GSNOR-deficient liver cancer cells contribute to its toxicity. We finally prove that the inhibition of mitophagy by depletion of Parkin, a pivotal ubiquitin ligase targeting mitochondria for degradation, enhances αTOS toxicity, thus suggesting that this drug could be effective in treating mitophagy-defective tumors.
Minimally Complex Nucleic Acid Feedback Control Systems for First Experimental Implementations
Authors: Paulino Nuno M. G. , Foo Mathias , de Greef Tom F. A. , Kim Jongmin , Bates Declan G. 
Published: December 2019

AbstractChemical reaction networks based on catalysis, degradation, and annihilation may be used as building blocks to construct a variety of dynamical and feedback control systems in Synthetic Biology. DNA strand-displacement, which is based on DNA hybridisation programmed using Watson-Crick base pairing, is an effective primitive to implement such reactions experimentally. However, experimental construction, validation and scale-up of nucleic acid control systems is still significantly lagging theoretical developments, due to several technical challenges, such as leakage, crosstalk, and toehold sequence design. To help the progress towards experimental implementation, we provide here designs representing two fundamental classes of reference tracking control circuits (integral and state-feedback control), for which the complexity of the chemical reactions required for implementation has been minimised. The supplied ‘minimally complex’ control circuits should be ideal candidates for first experimental validations of nucleic acid controllers.
High resolution mapping of aHordeum bulbosum-derived powdery mildew resistance locus in barley using distinct homologous introgression lines
Authors: Hoseinzadeh Parastoo , Ruge-Wehling Brigitte , Schweizer Patrick , Stein Nils , Pidon Hélène 
Published: December 2019

AbstractPowdery mildew caused byBlumeria graminisf.sp.hordei (Bgh)is one of the main foliar diseases in barley (Hordeum vulgareL.;Hv). Naturally occurring resistance genes used in barley breeding are a cost effective and environmentally sustainable strategy to minimize the impact of pathogens, however, the primary gene pool ofH. vulgarecontains limited diversity owing to recent domestication bottlenecks. To ensure durable resistance against this pathogen, more genes are required that could be unraveled by investigation of secondary barley gene-pool. A large set ofHordeum bulbosum(Hb) introgression lines (ILs) harboring a diverse set of desirable resistance traits have been developed and are being routinely used as source of novel diversity in gene mapping studies. Nevertheless, this strategy is often compromised by a lack of recombination between the introgressed fragment and the orthologous chromosome of the barley genome. In this study, we fine-mapped aHbgene conferring resistance to barley powdery mildew. The initial genotyping of twoHbILs mapping populations with differently sized 2HS introgressions revealed severely reduced interspecific recombination in the region of the introgressed segment, preventing precise localization of the gene. To overcome this difficulty, we developed an alternative strategy, exploiting intraspecific recombination by crossing twoHv/HbILs with collinearHbintrogressions, one of which carries a powdery mildew resistance gene, while the other doesn’t. The intraspecific recombination rate in theHb-introgressed fragment of 2HS was approximately 20 times higher than it was in the initial simple ILs mapping populations. Using high-throughput genotyping-by-sequencing (GBS), we allocated the resistance gene to a 1.4 Mb interval, based on an estimate using theHvgenome as reference, in populations of only 103 and 146 individuals respectively, similar to what is expected at this locus in barley. The most likely candidate resistance gene within this interval encodes a legume-type lectin-receptor-like protein (LecRLP). Like other LecRLPs that have been implicated in resistance, this gene could be a good candidate forHbresistance. The reported strategy can be applied as a general strategic approach for identifying genes underlying traits of interest in crop wild relatives.
ZBED2 is an antagonist of Interferon Regulatory Factor 1 and modulates cell identity in pancreatic cancer
Authors: Somerville Tim D.D. , Xu Yali , Wu Xiaoli S. , Vakoc Christopher R. 
Published: December 2019

ABSTRACTLineage plasticity is a prominent feature of pancreatic ductal adenocarcinoma (PDA) cells, which can occur via deregulation of lineage-specifying transcription factors. Here, we show that the zinc finger protein ZBED2 is aberrantly expressed in PDA and alters tumor cell identity in this disease. Unexpectedly, our epigenomic experiments reveal that ZBED2 is a sequence-specific transcriptional repressor of interferon-stimulated genes, which occurs through antagonism of Interferon Regulatory Factor 1 (IRF1)-mediated transcriptional activation at co-occupied promoter elements. Consequently, ZBED2 attenuates the transcriptional output and growth arrest phenotypes downstream of interferon signaling in multiple PDA cell line models. We also found that ZBED2 is preferentially expressed in the squamous molecular subtype of human PDA, in association with inferior patient survival outcomes. Consistent with this observation, we show that ZBED2 can repress the pancreatic progenitor transcriptional program, enhance motility, and promote invasion in PDA cells. Collectively, our findings suggest that high ZBED2 expression is acquired during PDA progression to suppress the interferon response pathway and to promote lineage plasticity in this disease.SIGNIFICANCE STATEMENTPancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancies, attributed in part to lineage infidelity downstream of deregulated lineage-specifying transcription factors (TFs). Here we define the biological effects of a poorly understood TF ZBED2 in the most aggressive subtype of PDA, defined by the expression of squamous lineage markers. Our study reveals two molecular functions of ZBED2 in PDA cells: an inhibitor of interferon response genes and a modifier of epithelial lineage programs. Both functions can be explained by the ability of ZBED2 to antagonize the functional output of Interferon Regulatory Factor-1 (IRF1). Our study reinforces the concept of aberrant lineage identity in cancer and highlights an unexpected connection between interferon response pathways and squamous-subtype PDA.
Allopatric speciation is more prevalent than parapatric ecological divergence in a recent high-Andean diversification (Asteraceae:Linochilus)
Authors: Vargas Oscar M. , Madriñán Santiago , Simpson Beryl B. 
Published: December 2019

ABSTRACTElucidating how species accumulate in diversity hotspots is an ongoing debate in evolutionary biology. The páramo, in the Northern Andes, has remarkably high indices of plant diversity, endemicity, and diversification rates. A hypothesis for explaining such indices is that allopatric speciation is high in the páramo given its island-like distribution; an alternative hypothesis is that the altitudinal gradient of the Andean topography provides a variety of niches that drive vertical parapatric ecological speciation. A formal test for evaluating the relative roles of allopatric speciation and parapatric ecological divergence is lacking. The main aim of our study is to test which kind of speciation is more common in an endemic páramo genus. We developed a framework incorporating phylogenetics, species’ distributions, and a morpho-ecological trait (leaf area) to compare sister species and infer whether allopatric or parapatric ecological divergence caused their speciation. We applied our framework to the species-rich genusLinochilus(63 spp.) and found that the majority of recent speciation events in it (12, 80%) have been driven by allopatric speciation, while a smaller fraction (1, 6.6%) is attributed to parapatric ecological divergence; two pairs produced inconclusive results (13.3%). We conclude that páramo autochthonous diversification is primarily driven by allopatric speciation.
Structural analysis of nonapeptides derived from elastin
Authors: Hernandez B , Crowet JM , Thiery J , Kruglik SG , Belloy N , Baud S , Dauchez M , Debelle L 
Published: December 2019

AbstractElastin-derived peptides are released from the extracellular matrix remodeling by numerous proteases and seem to regulate many biological processes, notably cancer progression. The canonical elastin peptide is VGVAPG which harbors the XGXXPG consensus pattern allowing interaction with the elastin receptor complex located at the surface of cells. Besides these elastokines, another class of peptides has been identified. This group of bioactive elastin peptides presents the XGXPGXGXG consensus sequence but the reason for their bioactivity remains unexplained. In order to better understand their nature and structure-function relationships, herein we searched the current databases for this nonapeptide motif and observed that the XGXPGXGXG elastin peptides define a specific group of tandemly repeated patterns. Further, we focused on four tandemly repeated human elastin nonapeptides,i.e.AGIPGLGVG, VGVPGLGVG, AGVPGLGVG and AGVPGFGAG. These peptides were analysed by means of optical spectroscopies and molecular dynamics. UV-circular dichroism and Raman spectra are consistent with a conformational equilibrium between β-turn, β-strand and random chain secondary elements in aqueous media. This equilibrium was found to be concentration-independent. Quantitative analysis of their conformations suggested that turns corresponded to half of the total population of structural elements while the remaining half was equally distributed between β-strand and unordered chains. These distributions were confirmed by molecular dynamics simulations. Altogether, our data suggest that these peptides harbor a type II β-turn located in their central part. We hypothesize that this structural element could explain their specific bioactivity.Statement of SignificanceElastin fragmentation products, the so-called elastin peptides, may exhibit a bioactivity towards normal and tumor cells. This phenomenon depends on the sequence motif they harbor. While XGXXPG sequences bioactivity is explained by the presence of a type VIII β-turn allowing interaction with the elastin receptor complex, the structural reasons for XGXPGXGXG specific activity remain unexplained. Using data mining, we show that elastin nonapeptides define a specific class of tandemly repeated features. Further, spectroscopic and numerical simulations methods suggest the presence of a type II β-turn in their conformation. This structural element could explain their bioactivity.
Quantifying the polygenic architecture of the human cerebral cortex: Extensive genetic overlap between cortical thickness and surface area
Authors: van der Meer Dennis , Frei Oleksandr , Kaufmann Tobias , Chen Chi-Hua , Thompson Wesley K. , O’Connell Kevin S. , Monereo Sánchez Jennifer , Linden David E.J. , Westlye Lars T. , Dale Anders M. , Andreassen Ole A. 
Published: December 2019

ABSTRACTIntroductionThe thickness of the cerebral cortical sheet and its surface area are highly heritable traits thought to have largely distinct polygenic architectures. Despite large-scale efforts, the majority of their genetic determinants remains unknown. Our ability to identify causal genetic variants can be improved by employing better delineated, less noisy brain measures that better map onto the biology we seek to understand. Such measures may have fewer variants but with larger effects, i.e. lower polygenicity and higher discoverability.MethodsUsing Gaussian mixture modeling, we estimated the number of causal variants shared between mean cortical thickness and total surface area. We further determined the polygenicity and discoverability of regional cortical measures from five often-employed parcellation schemes. We made use of UK Biobank data from 31,312 healthy White European individuals (mean age 55.5, standard deviation (SD) 7.4, 52.1% female).ResultsContrary to previous reports, we found large genetic overlap between total surface area and mean thickness, sharing 4427 out of 7150 causal variants. Regional surface area was more discoverable (p=4.1×10−6) and less polygenic (p=.007) than regional thickness measures. We further found that genetically-informed and less granular parcellation schemes had highest discoverability, with no differences in polygenicity.ConclusionsThese findings may serve as a roadmap for improved future GWAS studies; Knowledge of which measures or parcellations are most discoverable, as well as the genetic overlap between these measures, may be used to boost identification of genetic predictors and thereby gain a better understanding of brain morphology.
The α-synuclein hereditary mutation E46K unlocks a more stable, pathogenic fibril structure
Authors: Boyer David R. , Li Binsen , Sun Chuanqi , Fan Weijia , Zhou Kang , Hughes Michael P. , Sawaya Michael R. , Jiang Lin , Eisenberg David S. 
Published: December 2019

AbstractAggregation of α-synuclein is a defining molecular feature of Parkinson’s disease, Lewy Body Dementia, and Multiple Systems Atrophy. Hereditary mutations in α-synuclein are linked to both Parkinson’s disease and Lewy Body Dementia; in particular, patients bearing the E46K disease mutation manifest a clinical picture of parkinsonism and Lewy Body Dementia, and E46K creates more pathogenic fibrils in vitro. Understanding the effect of these hereditary mutations on α-synuclein fibril structure is fundamental to α-synuclein biology. We therefore determined the cryoEM structure of α-synuclein fibrils containing the hereditary E46K mutation. The 2.5 Å structure reveals a symmetric double protofilament in which the molecules adopt a vastly re-arranged, lower energy fold compared to wild-type fibrils. We propose that the E46K misfolding pathway avoids electrostatic repulsion between K46 and K80, a residue pair which forms the E46-K80 salt-bridge in the wild-type fibril structure. We hypothesize that under our conditions the wild-type fold does not reach this deeper energy well of the E46K fold because the E46-K80 salt bridge diverts α-synuclein into a kinetic trap – a shallower, more accessible energy minimum. The E46K mutation apparently unlocks a more stable and pathogenic fibril structure.Significance StatementParkinson’s is the second most prevalent neurodegenerative condition, leading to movement disorders, and dementia in some cases. Because of the strong association of this condition with amyloid aggregates of the protein α-synuclein, structural understanding of these amyloid aggregates may be the path to eventual therapies. Our study of the structure of a variant α-synuclein inherited in families afflicted with a clinical picture of parkinsonism and Lewy Body Dementia supplements recent structures of the wild type structure, and shows how a single residue change can result in a greatly changed structure that may underlie the inherited form of the disease.
Microbial single-cell RNA sequencing by split-pool barcoding
Authors: Kuchina Anna , Brettner Leandra M. , Paleologu Luana , Roco Charles M. , Rosenberg Alexander B. , Carignano Alberto , Kibler Ryan , Hirano Matthew , DePaolo R. William , Seelig Georg 
Published: December 2019

AbstractSingle-cell RNA-sequencing (scRNA-seq) has become an essential tool for characterizing multi-celled eukaryotic systems but current methods are not compatible with bacteria. Here, we introduce microSPLiT, a low cost and high-throughput scRNA-seq method that works for gram-negative and gram-positive bacteria and can resolve transcriptional states that remain hidden at a population level. We applied microSPLiT to >25,000Bacillus subtiliscells sampled from different growth stages, creating a detailed atlas of changes in metabolism and lifestyle. We not only retrieve detailed gene expression profiles associated with known but rare states such as competence and PBSX prophage induction, but also identify novel and unexpected gene expression states including heterogeneous activation of a niche metabolic pathway in a subpopulation of cells. microSPLiT empowers high-throughput analysis of gene expression in complex bacterial communities.