bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence that disruption of apicoplast protein import in malaria parasites evades delayed-death growth inhibition
Authors: Boucher Michael J. , Yeh Ellen 
Published: September 2018

AbstractMalaria parasites (Plasmodium spp.) contain a nonphotosynthetic plastid organelle called the apicoplast, which houses essential metabolic pathways and is required throughout the parasite life cycle. Hundreds of proteins are imported across 4 membranes into the apicoplast to support its function and biogenesis. The machinery that mediates this import process is distinct from proteins in the human host and may serve as ideal drug targets. However, a significant concern is whether inhibition of apicoplast protein import will result in a “delayed-death” phenotype that limits clinical use, as observed for inhibitors of apicoplast housekeeping pathways. To assess the growth inhibition kinetics of disrupting apicoplast protein import, we targeted a murine dihydrofolate reductase (mDHFR) domain, which is stabilized by the compound WR99210, to the apicoplast to enable inducible blocking of apicoplast-localized protein translocons. We show that stabilization of this apicoplast-targeted mDHFR disrupts parasite growth within a single lytic cycle in an apicoplast-specific manner. Consistent with inhibition of apicoplast protein import, stabilization of this fusion protein disrupted transit peptide processing of endogenous apicoplast proteins and caused defects in apicoplast biogenesis. These results indicate that disruption of apicoplast protein import avoids delayed-death growth inhibition and that target-based approaches to develop inhibitors of import machinery may yield viable next-generation antimalarials.ImportanceMalaria is a major cause of global childhood mortality. To sustain progress in disease control made in the last decade, new antimalarial therapies are needed to combat emerging drug resistance. Malaria parasites contain a relict chloroplast called the apicoplast, which harbors new targets for drug discovery, including import machinery that transports hundreds of critical proteins into the apicoplast. Unfortunately, some drugs targeting apicoplast pathways show delayed growth inhibition, which results in a slow onset-of-action that precludes their use as fast-acting, frontline therapies. We used a chemical biology approach to disrupt apicoplast protein import and showed that chemical disruption of this pathway avoids delayed growth inhibition. Our finding indicates that prioritization of proteins involved in apicoplast protein import for target-based drug discovery efforts may aid in the development of novel fast-acting antimalarials.
The Evolutionary Landscape of Pan-Cancer Drives Clinical Aggression
Authors: Pang Shichao , Wu Leilei , Shen Xin , Sun Yidi , Wang Jingfang , Zhao Yi-Lei , Wang Zhen , Li Yixue 
Published: September 2018

AbstractAlthough cancer mechanisms differ from occurrence and development, some of them have similar oncogenesis, which leads to similar clinical phenotypes. Most existing genotyping studies look at “omics” data, but intentionally or unintentionally avoided that cancer is a time-dependent evolutionary process, biologically represented by the time evolution of tumor clones. We used the Bayesian mutation landscape approach to reconstruct the evolutionary process of cancer by acquiring somatic mutation data consisting of 21 cancer types. Four representative evolution patterns of pan-cancer have been discovered: trees, chaos, biconvex, and Cambrian, and a strong correlation between these four evolutionary patterns and clinical aggressivity. We further explained the characteristics of the corresponding biological systems in the evolution of pan cancer by analyzing the function of differentially expressed protein-protein interaction networks. Our results explained the difference in clinical aggressivity between cancer evolution patterns from the evolution of tumor clones and exposed the functional mechanism behind.
Detection of early stage pancreatic cancer using 5-hydroxymethylcytosine signatures in circulating cell free DNA
Authors: Collin Francois , Ning Yuhong , Phillips Tierney , McCarthy Erin , Scott Aaron , Ellison Chris , Ku Chin-Jen , Guler Gulfem D , Chau Kim , Ashworth Alan , Quake Stephen R , Levy Samuel 
Published: September 2018

AbstractPancreatic cancers are typically diagnosed at late stage where disease prognosis is poor as exemplified by a 5-year survival rate of 8.2%. Earlier diagnosis would be beneficial by enabling surgical resection or earlier application of therapeutic regimens. We investigated the detection of pancreatic ductal adenocarcinoma (PDAC) in a non-invasive manner by interrogating changes in 5-hydroxymethylation cytosine status (5hmC) of circulating cell free DNA in the plasma of a PDAC cohort (n=51) in comparison with a non-cancer cohort (n=41). We found that 5hmC sites are enriched in a disease and stage specific manner in exons, 3’UTRs and transcription termination sites. Our data show that 5hmC density is reduced in promoters and histone H3K4me3-associated sites with progressive disease suggesting increased transcriptional activity. 5hmC density is differentially represented in thousands of genes, and a stringently filtered set of the most significant genes points to biology related to pancreas (GATA4, GATA6, PROX1, ONECUT1) and/or cancer development (YAP1, TEAD1, PROX1, ONECUT1, ONECUT2, IGF1 and IGF2). Regularized regression models were built using 5hmC densities in statistically filtered genes or a comprehensive set of highly variable 5hmC counts in genes and performed with an AUC = 0.94-0.96 on training data. We were able to test the ability to classify PDAC and non-cancer samples with the Elastic net and Lasso models on two external pancreatic cancer 5hmC data sets and found validation performance to be AUC = 0.74-0.97. The findings suggest that 5hmC changes enable classification of PDAC patients with high fidelity and are worthy of further investigation on larger cohorts of patient samples.
Twist-bend coupling and the statistical mechanics of DNA: perturbation theory and beyond
Authors: Nomidis Stefanos K. , Skoruppa Enrico , Carlon Enrico , Marko John F. 
Published: September 2018

AbstractThe simplest model of DNA mechanics describes the double helix as a continuous rod with twist and bend elasticity. Recent work has discussed the relevance of a little-studied coupling G between twisting and bending, known to arise from the groove asymmetry of the DNA double helix. Here, the effect of G on the statistical mechanics of long DNA molecules subject to applied forces and torques is investigated. We present a perturbative calculation of the effective torsional stiffness Ceff for small twist-bend coupling. We find that the “bare” G is “screened” by thermal fluctuations, in the sense that the low-force, long-molecule effective free energy is that of a model with G = 0, but with long-wavelength bending and twisting rigidities that are shifted by G-dependent amounts. Using results for torsional and bending rigidities for freely-fluctuating DNA, we show how our perturbative results can be extended to a nonperturbative regime. These results are in excellent agreement with numerical calculations for Monte Carlo “triad” and molecular dynamics “oxDNA” models, characterized by different degrees of coarse-graining, validating the perturbative and non-perturbative analyses. While our theory is in generally-good quantitative agreement with experiment, the predicted torsional stiffness does systematically deviate from experimental data, suggesting that there are as-yet-uncharacterized aspects of DNA twisting-stretching mechanics relevant to low-force, long-molecule mechanical response, which are not captured by widely-used coarse-grained models.
Homologous recombination changes the context of Cytochrome b transcription in the mitochondrial genome of Silene vulgaris KRA
Authors: Štorchová Helena , Stone James D. , Sloan Daniel B. , Abeyawardana Oushadee , Müller Karel , Walterová Jana , Pažoutová Marie 
Published: September 2018

AbstractBackgroundSilene vulgaris (bladder campion) is a gynodioecious species existing as two genders – male-sterile females and hermaphrodites. Cytoplasmic male sterility (CMS) is generally encoded by mitochondrial genes, which interact with nuclear fertility restorer genes. Mitochondrial genomes of this species vary in DNA sequence, gene order and gene content. Multiple CMS genes are expected to exist in S. vulgaris, but little is known about their molecular identity.ResultsWe assembled the complete mitochondrial genome from the haplotype KRA of S. vulgaris. It consists of five chromosomes, two of which recombine with each other. Two small non-recombining chromosomes exist in linear, supercoiled and relaxed circle forms. We compared the mitochondrial transcriptomes from females and hermaphrodites and confirmed the differentially expressed chimeric gene bobt as the strongest CMS candidate gene in S. vulgaris KRA. The chimeric gene bobt is co-transcribed with the Cytochrome b (cob) gene in some genomic configurations. The co-transcription of a CMS factor with an essential gene may constrain transcription inhibition as a mechanism for fertility restoration because of the need to maintain appropriate production of the necessary protein. Homologous recombination places the gene cob outside the control of bobt, which allows for the suppression the CMS gene by the fertility restorer genes. In addition, by analyzing RNA editing, we found the loss of three editing sites in the KRA mitochondrial genome and identified four sites with highly distinct editing rates between KRA and another S. vulgaris haplotypes (KOV). Three of these highly differentially edited sites were located in the transport membrane protein B (mttB) gene. They resulted in differences in MttB protein sequences between haplotypes despite completely identical gene sequences.ConclusionsFrequent homologous recombination events that are widespread in plant mitochondrial genomes may change chromosomal configurations and also the control of gene transcription including CMS gene expression. Posttranscriptional processes, e.g RNA editing shall be evaluated in evolutionary and co-evolutionary studies of mitochondrial genes, because they may change protein composition despite the sequence identity of the respective genes. The investigation of natural populations of wild species such as S. vulgaris are necessary to reveal important aspects of CMS missed in domesticated crops, the traditional focus of the CMS studies.
A series of constitutive expression vectors to accurately measure the rate of DNA transposition and correct for auto-inhibition
Authors: Tellier Michael , Chalmers Ronald 
Published: September 2018

AbstractBackgroundTransposable elements (TEs) form a diverse group of DNA sequences encoding functions for their own mobility. This ability has been exploited as a powerful tool for molecular biology and genomics techniques. However, their use is sometimes limited because their activity is auto-regulated to allow them to cohabit within their hosts without causing excessive genomic damage. To overcome these limitations, it is important to develop efficient and simple screening assays for hyperactive transposases.ResultsTo widen the range of transposase expression normally accessible with inducible promoters, we have constructed a set of vectors based on constitutive promoters of different strengths. We characterized and validated our expression vectors with Hsmar1, a member of themarinertransposon family. We observed the highest rate of transposition with the weakest promoters. We went on to investigate the effects of mutations in the Hsmar1 transposase dimer interface and of covalently linking two transposase monomers in a single-chain dimer. We also tested the severity of mutations in the lineage leading to the humanSETMARgene, in which one copy of the Hsmar1 transposase has contributed a domain.ConclusionsWe generated a set of vectors to provide a wide range of transposase expression which will be useful for screening libraries of transposase mutants. We also found that mutations in the Hsmar1 dimer interface provides resistance to overproduction inhibition in bacteria, which could be valuable for improving bacterial transposon mutagenesis techniques.
Comparative analysis of PknB inhibitors for reactivity and toxicity
Authors: Wlodarchak Nathan , Beczkiewicz Jeff , Seitz Steven , Ye Zhengqing , Feltenberger John , Davis J Muse , Striker Rob 
Published: September 2018

ABSTRACTBacterial serine/threonine kinases are increasingly sought after as drug targets for new antibiotics. PknB, an essential kinase in Mycobacteria tuberculosis, is intensely targeted, and many inhibitors are in the developmental pipeline. These inhibitors typically are derived from screens of known kinase inhibitors and most share similar chemical properties as their parent compounds were all designed for optimal pharmacokinetic properties in the human body. Here, we investigate the reactivity and toxicity of a proposed PknB inhibitor, YH-8, which does not follow traditional drug design rules. We found that the compound is highly reactive with thiolating agents and has appreciable toxicity in a zebrafish animal model. Furthermore, we find minimal anti-mycobacterial activity with non-tubercular mycobacteria strains. These data suggest that further investigation is needed into its efficacy and physiochemical properties if it is to be further developed as an effective antibiotic.
Paleolithic DNA from the Caucasus reveals core of West Eurasian ancestry
Authors: Lazaridis Iosif , Belfer-Cohen Anna , Mallick Swapan , Patterson Nick , Cheronet Olivia , Rohland Nadin , Bar-Oz Guy , Bar-Yosef Ofer , Jakeli Nino , Kvavadze Eliso , Lordkipanidze David , Matzkevich Zinovi , Meshveliani Tengiz , Culleton Brendan J. , Kennett Douglas J. , Pinhasi Ron , Reich David 
Published: September 2018

AbstractThe earliest ancient DNA data of modern humans from Europe dates to ∼40 thousand years ago1-4, but that from the Caucasus and the Near East to only ∼14 thousand years ago5,6, from populations who lived long after the Last Glacial Maximum (LGM) ∼26.5-19 thousand years ago7. To address this imbalance and to better understand the relationship of Europeans and Near Easterners, we report genome-wide data from two ∼26 thousand year old individuals from Dzudzuana Cave in Georgia in the Caucasus from around the beginning of the LGM. Surprisingly, the Dzudzuana population was more closely related to early agriculturalists from western Anatolia ∼8 thousand years ago8than to the hunter-gatherers of the Caucasus from the same region of western Georgia of ∼13-10 thousand years ago5. Most of the Dzudzuana population’s ancestry was deeply related to the post-glacial western European hunter-gatherers of the ‘Villabruna cluster’3, but it also had ancestry from a lineage that had separated from the great majority of non-African populations before they separated from each other, proving that such ‘Basal Eurasians’6,9were present in West Eurasia twice as early as previously recorded5,6. We document major population turnover in the Near East after the time of Dzudzuana, showing that the highly differentiated Holocene populations of the region6were formed by ‘Ancient North Eurasian’3,9,10admixture into the Caucasus and Iran and North African11,12admixture into the Natufians of the Levant. We finally show that the Dzudzuana population contributed the majority of the ancestry of post-Ice Age people in the Near East, North Africa, and even parts of Europe, thereby becoming the largest single contributor of ancestry of all present-day West Eurasians.
Epigenetic signatures associated with imprinted paternally-expressed genes in the Arabidopsis endosperm
Authors: Moreno-Romero Jordi , Toro-De León Gerardo Del , Yadav Vikash Kumar , Santos-González Juan , Köhler Claudia 
Published: September 2018

ABSTRACTBackgroundImprinted genes are epigenetically modified during gametogenesis and maintain the established epigenetic signatures after fertilization, causing parental-specific gene expression.ResultsIn this study, we show that imprinted paternally-expressed genes (PEGs) in the Arabidopsis endosperm are marked by an epigenetic signature of Polycomb Repressive Complex2 (PRC2)-mediated H3K27me3 together with heterochromatic H3K9me2 and CHG methylation, which specifically mark the silenced maternal alleles of PEGs. The co-occurrence of H3K27me3 and H3K9me2 on defined loci in the endosperm drastically differs from the strict separation of both pathways in vegetative tissues, revealing tissue-specific employment of repressive epigenetic pathways in plants. Based on the presence of this epigenetic signature on maternal alleles we were able to predict known PEGs at high accuracy and identified several new PEGs that we confirmed using INTACT-based transcriptomes generated in this study.ConclusionsThe presence of the three repressive epigenetic marks, H3K27me3, H3K9me2, and CHG methylation on the maternal alleles in the endosperm serves as a specific epigenetic signature that allows to predict genes with parental-specific gene expression. Our study reveals that there are substantially more PEGs than previously identified, indicating that paternal-specific gene expression is of higher functional relevance than currently estimated. The combined activity of PRC2-mediated H3K27me3 together with the heterochromatic H3K9me3 has also been reported to silence the maternal Xist locus in mammalian preimplantation embryos, suggesting convergent employment of both pathways during the evolution of genomic imprinting.
Changes in rearing conditions rapidly modify gut microbiota structure in Tenebrio molitor larvae
Authors: Cambon Marine , Ogier Jean-Claude , Lanois Anne , Ferdy Jean-Baptiste , Gaudriault Sophie 
Published: September 2018

AbstractThe gut microbiota of multicellular organisms has been shown to play a key role in their host biology. In mammals, it has an invariant component, responsible for establishing a mutualistic relationship with the host. It also contains a dynamic fraction which facilitates adaptation in response to changes in the environment. These features have been well described in mammals, but little is known about microbiota stability or plasticity in insects. We assessed changes in microbiota composition and structure in a reared insect after a change in rearing conditions. We reared Tenebrio molitor (Coleoptera, Tenebrioninae) larvae for five days in soil samples from two river banks and analyzed their gut microbial communities by a metabarcoding technique, using the V3-V4 region of the 16S rRNA gene and the housekeeping gene gyrB. We found that soil-reared insects had a significantly more diverse microbiota than the control insects and that insects reared in soil from different sites had significantly different microbiota. We confirmed this trend by absolute quantification of the two mains fluctuating taxonomic groups: the Enterobacteriaceae family and the Pseudomonas genus, dominant in the soil-reared insects and in the control insects, respectively. Our results suggest the existence of a resident microbiota in T. molitor gut, but indicate that rearing changes can induce rapid and profound changes in the relative abundance of some of the members of this resident microbiota.
Speciation in a biodiversity hotspot: phylogenetic relationships, species delimitation, and divergence times of the Patagonian ground frogs ofEupsophus roseusgroup (Alsodidae)
Authors: Suárez-Villota Elkin Y. , Quercia Camila A. , Díaz Leila M. , Vera-Sovier Victoria A. , Nuñez José J. 
Published: September 2018

AbstractThe alsodid ground frogs genusEupsophusis divided into theroseus(2n=30) andvertebralis(2n=28) groups, distributed throughout the temperateNothofagusforests of South America. Currently, theroseusgroup is composed by four species, while thevertebralisgroup consists of two. Phylogenetic relationships and species delimitation within each group are controversial. In fact, previous analyses considered thatroseusgroup was composed between four to nine species. In this work, we evaluated phylogenetic relationships, diversification times, and species delimitation withinroseusgroup using a multi-locus dataset. For this purpose, mitochondrial (D-loop, Cytb, and COI) and nuclear (POMC and CRYBA1) partial sequences, were amplified from 164 individuals, representing all species. Maximum Likelihood (ML) and Bayesian approaches were used to reconstruct phylogenetic relationships. Species tree was estimated using BEAST and singular value decomposition scores for species quartets (SVDquartets). Species limits were evaluated with six coalescent approaches. Diversification times were estimated using mitochondrial and nuclear rates with LogNormal relaxed clock in BEAST. Nine well-supported monophyletic lineages were recovered in Bayesian, ML, and SVDquartets, including eight named species and a lineage composed by specimens from Villarrica population (Bootstrap: >90, PP:> 0.9). Single-locus species delimitation analyses overestimated the species number inE. migueli, E. calcaratusandE. roseuslineages, while multi-locus analyses recovered as species the nine lineages observed in phylogenetic analyses (>0.95). It is hypothesized thatEupsophusdiversification occurred during Mid-Pleistocene (0.42-0.14 Mya), with most species originated after of the Last Southern Patagonian Glaciation (0.18 Mya). Our results revitalize the hypothesis thatE. roseusgroup is composed by eight species and support to Villarrica lineage as a new putative species.
Survival protection mechanisms and genetic variability induction after stress: two sides of the same Hsp70 coin
Authors: Cappucci Ugo , Noro Fabrizia , Casale Assunta Maria , Fanti Laura , Berloco Maria , Alagia Angela Alessandra , Grassi Luigi , Pera Loredana Le , Piacentini Lucia , Pimpinelli Sergio 
Published: September 2018

AbstractPrevious studies have shown that heat shock stress may increase transcription levels and, in some cases, also the transposition of certain transposable elements (TEs) in Drosophila and other organisms. Other studies have also demonstrated that heat shock chaperones as Hsp90 and Hop are involved in repressing transposon’s activity in Drosophila melanogaster by their involvement in crucial steps of the biogenesis of Piwi-interacting RNAs (piRNAs), the largest class of germline-enriched small non-coding RNA implicated in the epigenetic silencing of TEs. However, a satisfying picture of how many chaperones and their respective functional roles could be involved in repressing transposons in germ cell is still unknown. Here we show that in Drosophila heat shock activates transposon′s expression at post-transcriptional level by disrupting a repressive chaperone complex by a decisive role of the stress-inducible chaperone Hsp70. We found that stress-induced transposons activation is triggered by an interaction of Hsp70 with the Hsc70-Hsp90 complex and other factors all involved in piRNA biogenesis in both ovaries and testes. Such interaction induces a displacement of all such factors to the lysosomes resulting in a functional collapse of piRNA biogenesis. In support of a significant role of Hsp70 in transposon activation after stress, we found that the expression under normal conditions of Hsp70 in transgenic flies increases the amount of transposon transcripts and displaces the components of chaperon machinery outside the nuage as observed after heat shock. So that, our results demonstrate that heat shock stress is capable to increase the expression of transposons at post-transcriptional level by affecting piRNA biogenesis through the action of the inducible chaperone Hsp70. We think that such mechanism proposes relevant evolutionary implications. In presence of drastic environmental changes, Hsp70 plays a key dual role in increasing both the survival probability of individuals and the genetic variability in their germ cells. This in turn should be translated into an increase of genetic variability inside the populations thus potentiating their evolutionary plasticity and evolvability.