bluuebunny/crossref_metadata_2025 huggingface dataset:
The Oligomerization Landscape of Histones
Authors: Zhao Haiqing , Winogradoff David , Dalal Yamini , Papoian Garegin A.
Published: September 2018

In eukaryotes, DNA is packaged within nucleosomes. The DNA of each nucleosome is typically centered around an octameric histone protein core: one central tetramer plus two separate dimers. Studying the assembly mechanisms of histones is essential for understanding the dynamics of entire nucleosomes and higher-order DNA packaging. Here we investigate canonical histone assembly and that of the centromere-specific histone variant CENP-A using molecular dynamics simulations. We quantitatively characterize their thermodynamical and dynamical features, showing that two H3/H4 dimers form a structurally floppy, weakly-bound complex, the latter exhibiting large instability around the central interface manifested via a swiveling motion of two halves. This finding is consistent with the recently observed DNA handedness flipping of the tetrasome. In contrast, the variant CENP-A encodes distinctive stability to its tetramer with a rigid but twisted interface compared to the crystal structure, implying diverse structural possibilities of the histone variant. Interestingly, the observed tetramer dynamics alter significantly and appear to reach a new balance when H2A/H2B dimers are present. Furthermore, we found that the preferred structure for the (CENP-A/H4)2 tetramer is incongruent with the octameric structure, explaining many of the unusual dynamical behaviors of the CENP-A nucleosome. In all, these data reveal key mechanistic insights and structural details for the assembly of canonical and variant histone tetramers and octamers, providing theoretical quantifications and physical interpretations for longstanding and recent experimental observations. Based on these findings, we propose different chaperone-assisted binding and nucleosome assembly mechanisms for the canonical and CENP-A histone oligomers.
BRICseq bridges brain-wide interregional connectivity to neural activity and gene expression in single animals
Authors: Huang Longwen , Kebschull Justus M , Furth Daniel , Musall Simon , Kaufman Matthew T , Churchland Anne K , Zador Anthony M
Published: September 2018

Comprehensive analysis of neuronal networks requires brain-wide measurement of connectivity, activity, and gene expression. Although high-throughput methods are available for mapping brain-wide activity and transcriptomes, comparable methods for mapping region-to-region connectivity remain slow and expensive because they require averaging across hundreds of brains. Here we describe BRICseq, which leverages DNA barcoding and sequencing to map connectivity from single individuals in a few weeks and at low cost. Applying BRICseq to the mouse neocortex, we find that region-to-region connectivity provides a simple bridge relating transcriptome to activity: The spatial expression patterns of a few genes predict region-to-region connectivity, and connectivity predicts activity correlations. We also exploited BRICseq to map the mutant BTBR mouse brain, which lacks a corpus callosum, and recapitulated its known connectopathies. BRICseq allows individual laboratories to compare how age, sex, environment, genetics and species affect neuronal wiring, and to integrate these with functional activity and gene expression.
Evidence that disruption of apicoplast protein import in malaria parasites evades delayed-death growth inhibition
Authors: Boucher Michael J. , Yeh Ellen
Published: September 2018

Malaria 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.

Importance

Malaria 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

Although 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

Pancreatic 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

The 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

Background

Silene 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.

Results

We 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.

Conclusions

Frequent 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

Background

Transposable 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.

Results

To 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.

Conclusions

We 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

Bacterial 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

The 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

Background

Imprinted genes are epigenetically modified during gametogenesis and maintain the established epigenetic signatures after fertilization, causing parental-specific gene expression.

Results

In 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.

Conclusions

The 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

The 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

The 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

Previous 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.
Detecting mosaic patterns in macroevolutionary disparity
Authors: Parins-Fukuchi Caroline
Published: September 2018

Evolutionary biologists have long sought to understand the full complexity in pattern and process that shapes organismal diversity. Although phylogenetic comparative methods are often used to reconstruct complex evolutionary dynamics, they are typically limited to a single phenotypic trait. Extensions that accommodate multiple traits lack the ability to partition multidimensional datasets into a set of mosaic suites of evolutionarily linked characters. I introduce a comparative framework that identifies heterogeneity in evolutionary patterns across large datasets of continuous traits. Using a model of continuous trait evolution based on the differential accumulation of disparity across lineages in a phylogeny, the approach algorithmically partitions traits into a set of character suites that best explains the data, where each suite displays a distinct pattern in phylogenetic morphological disparity. When applied to empirical data, the approach revealed a mosaic pattern predicted by developmental biology. The evolutionary distinctiveness of individual suites can be investigated in more detail, either by fitting conventional comparative models or by directly studying the phylogenetic patterns in disparity recovered during the analysis. This framework can supplement existing comparative approaches by inferring the complex, integrated patterns that shape evolution across the body plan from disparate developmental, morphometric, and environmental sources of phenotypic data.
Extended hopanoid loss reduces bacterial motility and surface attachment and leads to heterogeneity in root nodule growth kinetics in a Bradyrhizobium-Aeschynomene symbiosis
Authors: Belin B.J. , Tookmanian E.T , de Anda J. , Wong G. C. L , Newman D.K.
Published: September 2018

Hopanoids are steroid-like bacterial lipids that enhance membrane rigidity and promote bacterial growth under diverse stresses. Hopanoid biosynthesis genes are conserved in nitrogen-fixing plant symbionts, and we previously found that the extended (C35) class of hopanoids in Bradyrhizobium diazoefficiens are required for efficient symbiotic nitrogen fixation in the tropical legume host Aeschynomene afraspera. Here we demonstrate that the nitrogen fixation defect conferred by extended loss can fully be explained by a reduction in root nodule sizes rather than per-bacteroid nitrogen fixation levels. Using a single-nodule tracking approach to track A. afraspera nodule development, we provide a quantitative model of root nodule development in this host, uncovering both the baseline growth parameters for wild-type nodules and a surprising heterogeneity of extended hopanoid mutant developmental phenotypes. These phenotypes include a delay in root nodule initiation and presence of a subpopulation of nodules with slow growth rates and low final volumes, which are correlated with reduced motility and surface attachment in vitro and lower bacteroid densities in planta, respectively. This work provides a quantitative reference point for understanding the phenotypic diversity of ineffective symbionts in A. afraspera and identifies specific developmental stages affected by extended hopanoid loss for future mechanistic work.
RUNX proteins desensitize multiple myeloma to lenalidomide via protecting IKZFs from degradation
Authors: Zhou Nan , Uzquiza Alvaro Gutierrez , Zheng Xiang Yu , Vogl Dan , Garfall Alfred L. , Bernabei Luca , Saraf Anita , Florens Laurence , Washburn Michael P. , Illendula Anuradha , Bushweller John H. , Busino Luca
Published: September 2018

Ikaros family zinc finger protein 1 and 3 (IKZF1 and IKZF3) are transcription factors that promote multiple myeloma (MM) proliferation. The immunomodulatory imide drug (IMiD) lenalidomide promotes myeloma cell death via Cereblon (CRBN)-dependent ubiquitylation and proteasome-dependent degradation of IKZF1 and IKZF3. Although IMiDs have been used as first-line drugs for MM, the overall survival of refractory MM patients remains poor and demands the identification of novel agents to potentiate the therapeutic effect of IMiDs. Using an unbiased screen based on mass spectrometry, we identified the Runt-related transcription factor 1 and 3 (RUNX1 and RUNX3) as interactors of IKZF1 and IKZF3. Interaction with RUNX1 and RUNX3 inhibits CRBN-dependent binding, ubiquitylation and degradation of IKZF1 and IKZF3 upon lenalidomide treatment. Inhibition of RUNXs, via genetic ablation or a small molecule (AI-10-104), results in sensitization of myeloma cell lines and primary tumors to lenalidomide. Thus, RUNX inhibition represents a valuable therapeutic opportunity to potentiate IMiDs therapy for the treatment of multiple myeloma.
De novoassembly, delivery and expression of a 101 kb human gene in mouse cells
Authors: Mitchell Leslie A. , McCulloch Laura H. , Pinglay Sudarshan , Berger Henri , Bosco Nazario , Brosh Ran , Bulajic Milica , Huang Emily , Hogan Megan S. , Martin James A. , Mazzoni Esteban O. , Davoli Teresa , Maurano Matthew T. , Boeke Jef D.
Published: September 2018

Design and large-scale synthesis of DNA has been applied to the functional study of viral and microbial genomes. New and expanded technology development is required to unlock the transformative potential of such bottom-up approaches to the study of larger mammalian genomes. Two major challenges include assembling and delivering long DNA sequences. Here we describe a pipeline forde novoDNA assembly and delivery that enables functional evaluation of mammalian genes on the length scale of 100 kb. The DNA assembly step is supported by an integrated robotic workcell. We assembled the 101 kb humanHPRT1gene in yeast, delivered it to mouse embryonic stem cells, and showed expression of the human protein from its full-length gene. This pipeline provides a framework for producing systematic, designer variants of any mammalian gene locus for functional evaluation in cells.

Significance Statement

Mammalian genomes consist of a tiny proportion of relatively well-characterized coding regions and vast swaths of poorly characterized “dark matter” containing critical but much less well-defined regulatory sequences. Given the dominant role of noncoding DNA in common human diseases and traits, the interconnectivity of regulatory elements, and the importance of genomic context,de novodesign, assembly, and delivery can enable large-scale manipulation of these elements on a locus scale. Here we outline a pipeline forde novoassembly, delivery and expression of mammalian genes replete with native regulatory sequences. We expect this pipeline will be useful for dissecting the function of non-coding sequence variation in mammalian genomes.
New method for runoff estimation under different soil management practices
Authors: Bashagakule Janvier Bigabwa , Logah Vincent , Opoku Andrews , Tuffour Henry Oppong , Sarkodie-Addo Joseph , Quansah Charles
Published: September 2018

Soil erosion has been widely measured using different approaches based on models, direct runoff and sediment collections. However, most of the methods are, poorly applied due to the cost, the accuracy and their tedious nature. This study aimed to develop and test a new method for runoff characterization, which may be more applicable and adaptable to different situations of soil and crop management. An experiment was carried out on runoff plots under different cropping systems (sole maize, sole soybean and maize intercropped with soybean) and soil amendments (NPK, Biochar, NPK + Biochar and Control) in the Semi-deciduous forest zone of Ghana. The study was a two-factor experiment (split-plot) in which cropping systems constituted the main plot whereas soil management the subplot. To assess the quality of the method, different statistical parameters were used: p-values, coefficient of determination (R2), Nash-Sutcliffe efficiency (NSE), root mean square (RMSE) and, root square ratio (RSR). The NPK + Biochar under each cropping system reduced surface runoff than all other treatments. At p < 0.001, R2 ranged from 0.88 to 0.94 which showed good accuracy of the method developed. The dispersion between the predicted and observed values was low with RMSE varying from 1.68 to 2.66 mm which was less than 10 % of the general mean of the runoff. Moreover, the low variability between parameters was confirmed by the low values of RSR ranging from 0.38 to 0.46 (with 0.00 ≤ RSR ≤ 0.50 for perfect prediction). NSE values varied from 0.79 to 0.86 (≥0.75 being the threshold for excellent prediction). Though the sensitivity analysis showed that the method under high amount of runoff (especially on bare plots) was poorly adapted, the dimensions of runoff plots could be based on runoff coefficient of the region by analyzing the possible limits of an individual rainfall amount of the site. The findings provide alternative approach for monitoring soil degradation.
Comparative structure analysis of the ETSi domain of ERG3 and its complex with the E74 promoter DNA sequence
Authors: Sharma Ruby , Gangwar Shanti P. , Saxena Ajay K.
Published: September 2018

ERG3 (ETS-related gene) is a member of the ETS (erythroblast transformation-specific) family of transcription factors, which contain a highly conserved DNA-binding domain. The ETS family of transcription factors differ in their binding to promoter DNA sequences, and the mechanism of their DNA-sequence discrimination is little known. In the current study, crystals of the ETSi domain (the ETS domain of ERG3 containing a CID motif) in space group P41212 and of its complex with the E74 DNA sequence (DNA9) in space group C2221 were obtained and their structures were determined. Comparative structure analysis of the ETSi domain and its complex with DNA9 with previously determined structures of the ERGi domain (the ETS domain of ERG containing inhibitory motifs) in space group P65212 and of the ERGi–DNA12 complex in space group P41212 were performed. The ETSi domain is observed as a homodimer in solution as well as in the crystallographic asymmetric unit. Superposition of the structure of the ETSi domain on that of the ERGi domain showed a major conformational change at the C-terminal DNA-binding autoinhibitory (CID) motif, while minor changes are observed in the loop regions of the ETSi-domain structure. The ETSi–DNA9 complex in space group C2221 forms a structure that is quite similar to that of the ERG–DNA12 complex in space group P41212. Upon superposition of the complexes, major conformational changes are observed at the 5′ and 3′ ends of DNA9, while the conformation of the core GGA nucleotides was quite conserved. Comparison of the ETSi–DNA9 structure with known structures of ETS class 1 protein–DNA complexes shows the similarities and differences in the promoter DNA binding and specificity of the class 1 ETS proteins.
3-Acetyl-7-[2-(morpholin-4-yl)ethoxy]chromen-2-one
Authors: Wang Junjun , Zhu Yin , Wang Haiyan , Yang Mingdi
Published: September 2018

In the title compound, C17H19NO5, the morpholine ring adopts a chair conformation with the exocyclic N—C bond in an equatorial orientation. In the crystal, the molecules are linked by C—H...O and weak aromatic π–π stacking interactions, thereby generating a layered structure.
The location of comprehensive income reporting – does it pass the financial analyst revision test?
Authors: Banks Louis , Hodgson Allan , Russell Mark
Published: September 2018

Purpose

This paper aims to test whether a change in the reporting location of income, and other comprehensive income (OCI) components, in a statement of comprehensive income (SoCI) under International Financial Reporting Standards affects their value-relevance and use by financial analysts.

Design/methodology/approach

The study tests the associations between CI, OCI, share returns and financial analyst forecast revisions.

Findings

Results show that comprehensive income is less value-relevant than net income, regardless of reporting location. Changing the reporting location of OCI components to the SoCI does not provide incremental improvement for financial analysts or stock prices. Finally, the paper finds that analysts use OCI components to revise forecasts.

Originality/value

The paper addresses the question of which OCI components should be reported, and the importance of reporting location. The paper extends the examination of OCI components to financial analysts as expert financial report users.
Overlapping membership on audit and compensation committees, equity holdings of overlapping members and audit outcomes
Authors: Habib Ahsan , Bhuiyan Md. Borhan Uddin
Published: September 2018

Purpose

This paper aims to examine the question of whether external auditors incorporate equity holdings by overlapping audit committee members as a priced governance factor and tests whether this attribute, as a mechanism for ensuring good governance, affects the propensity for external auditors to issue modified audit opinions.

Design/methodology/approach

Overlapping membership in this context refers to the arrangement where at least one audit committee member also sits on the compensation committee. Both ordinarily least square and logistic regression are used to capture the impact of overlapping committee members and equity holding of those overlapping committee members.

Findings

Using archival data from Australian Stock Exchange listed companies, the authors find support for the beneficial effect of having overlapping audit committee members with equity holdings. The authors also find that auditor propensity to issue modified audit opinions is lower for firms with equity holdings by overlapping audit committee members.

Practical implications

The finding has practical implication to the investors and regulators as overlapping audit committee members with equity holdings may provide especially effective oversight by monitoring opportunistic accounting policy choices for maximizing compensation pay. To the extent that this occurs, audit risk will decrease, requiring less audit effort and lower audit fees than would otherwise be necessary. Similarly, such oversight is likely to make financial reporting more credible and will reduce the possibility of receiving modified audit opinions by reporting organizations.

Originality/value

Both audit and compensation committees are equally important in modern organizations. While both of the committee have distinctive responsibilities, questions remain on the desirability of overlapping audit committee. Also, this is the first study to the authors’ knowledge that incorporates overlapping membership on audit and compensation committee as an important component of auditor risk perception which regards in pricing the audit fees.
Local responses to disasters: recent lessons from zero-order responders
Authors: Briones Fernando , Vachon Ryan , Glantz Michael
Published: September 2018

Purpose

The purpose of this paper is to define and discuss the concept of zero-order responders (ZOR). It explores the potential lessons and the additive value that assimilation of responses of disaster-affected people into disaster risk reduction (DRR) and disaster risk management (DRM) programs can provide.

Design/methodology/approach

In order to support this concept, the authors review two recent extreme hydrometeorological events, illustrating how local populations cope with disasters during the period before external support arrives. Additionally, the authors address their under-leveraged role in the management of recovery. The empirical evidence was collected by direct observations during the 2017 El Niño Costero-related floods in Peru, and by the review of press following 2017 hurricanes Irma and Maria destruction in Puerto Rico.

Findings

During disasters, there is a window of time before official and/or external support arrives. During this period, citizens must act unsupported by first responders – devising self-coping strategies in order to survive. In the days, weeks and months following a disaster, local populations are still facing recovery with creativity.

Research limitations/implications

Citing references arguing for or against the value of documenting survivor methods to serve as a testimony for the improvement of DRR programming.

Practical implications

DRR and DRM must integrate local populations and knowledge into DRR planning to improve partnerships between communities and organizations.

Social implications

The actions and experiences of citizens pro-acting to pave fruitful futures is a valuable commentary on improvements for DRR and management.

Originality/value

This paper proposes a citizen-centered contribution to future disaster risk reducing actions. This approach emphasizes the reinterpretation of local responses to disasters. DRRs and DRMs growth as fields would value from heralding ZOR coping and improvisation skills, illustrated under stressful disaster-related conditions, as an additive resource to programming development.
Connecting the poor: the internet, mobile phones and financial inclusion in Africa
Authors: Evans Olaniyi
Published: September 2018

Purpose

The increased adoption of internet-enabled phones in Africa has caused much speculation and optimism concerning its effects on financial inclusion. Policymakers, the media and various studies have all flaunted the potentials of internet and mobile phones for financial inclusion. An important question therefore is “Can the internet and mobile phones spur the inclusion of the financially excluded poor? This study therefore aims to examine the relationship and causality between internet, mobile phones and financial inclusion in Africa for the 2000-2016 period.

Design/methodology/approach

The empirical analysis followed these three steps: examination of the stationarity of the variables; testing for the cointegration; and evaluation of the effects of the internet and mobile phones on financial inclusion in Africa for the 2000-2016 period using three outcomes of panel FMOLS approach and Granger causality tests.

Findings

The empirical evidence shows that internet and mobile phones have significant positive relationship with financial inclusion, meaning that rising levels of internet and mobile phones are associated with increased financial inclusion. There is also uni-directional causality from internet and mobile phones to financial inclusion, implying that internet and mobile phones cause financial inclusion. The study also shows that macroeconomic factors such as capital formation, primary enrollment, bank credit, broad money, population growth, remittances, agriculture and interest rate, as well as institutional factors such as regulatory quality are important underlying factors for financial inclusion in Africa.

Originality/value

In the literature, there is a dearth of research on the internet, mobile phones and financial inclusion, especially in Africa. Most of the related studies are conceptual and micro-based, with little empirical attention to the relationship and causality between internet, mobile phones and financial inclusion. In fact, this dearth of rigorous empirical studies has been attributed as the main cause of inadequate policy guidance in enhancing information communication technologies (Roycroft and Anantho, 2003), despite saturation levels in developed economies. This study fills the gap by evaluating the effects of the Internet and mobile phones on financial inclusion for 44 African countries for the 2000-2016 period.