bluuebunny/crossref_metadata_2025 huggingface dataset:
Batch effects and the effective design of single-cell gene expression studies
Authors: Tung Po-Yuan , Blischak John D. , Hsiao Chiaowen Joyce , Knowles David A. , Burnett Jonathan E. , Pritchard Jonathan K. , Gilad Yoav
Published: July 2016

Single cell RNA sequencing (scRNA-seq) can be used to characterize variation in gene expression levels at high resolution. However, the sources of experimental noise in scRNA-seq are not yet well understood. We investigated the technical variation associated with sample processing using the single cell Fluidigm C1 platform. To do so, we processed three C1 replicates from three human induced pluripotent stem cell (iPSC) lines. We added unique molecular identifiers (UMIs) to all samples, to account for amplification bias. We found that the major source of variation in the gene expression data was driven by genotype, but we also observed substantial variation between the technical replicates. We observed that the conversion of reads to molecules using the UMIs was impacted by both biological and technical variation, indicating that UMI counts are not an unbiased estimator of gene expression levels. Based on our results, we suggest a framework for effective scRNA-seq studies.
Coding translational rates: the hidden genetic code
Authors: Diambra Luis
Published: July 2016

In this paper we propose that translational rate is modulated by pairs of consecutive codons or bicodons. By a statistical analysis of coding sequences, associated with low or with high abundant proteins, we found some bicodons with significant preference usage for either of these sets. These usage preferences cannot be explained by the frequency usage of the single codons. We compute a pause propensity measure of all bicodons in nine organisms, which reveals that in many cases bicodon preference is shared between related organisms. We found that bicodons associated with sequences encoding low abundant proteins are involved in translational attenuation reported in SufIprotein inE. coli.Furthermore, we observe that the misfolding in the drug-transport protein, encoded byMDR1gene, is better explained by a big change in the pause propensity due to the synonymous bicodon variant, rather than by a relatively small change in the codon usage. These findings suggest that bicodon usage can be a more powerful framework to understand translational speed, protein folding efficiency, and to improve protocols to optimize heterologous gene expression.
VarMatch: robust matching of small variant datasets using flexible scoring schemes
Authors: Sun Chen , Medvedev Paul
Published: July 2016

Motivation

Small variant calling is an important component of many analyses, and, in many instances, it is important to determine the set of variants which appear in multiple callsets. Variant matching is complicated by variants that have multiple equivalent representations. Normalization and decomposition algorithms have been proposed, but are not robust to different representation of complex variants. Variant matching is also usually done to maximize the number of matches, as opposed to other optimization criteria.

Results

We present the VarMatch algorithm for the variant matching problem. Our algorithm is based on a theoretical result which allows us to partition the input into smaller subproblems without sacrificing accuracy VarMatch is robust to different representation of complex variants and is particularly effective in low complexity regions or those dense in variants. VarMatch is able to detect more matches than either the normalization or decomposition algorithms on tested datasets. It also implements different optimization criteria, such as edit distance, that can improve robustness to different variant representations. Finally the VarMatch software provides summary statistics, annotations, and visualizations that are useful for understanding callers’ performance.

Availability

VarMatch is freely available at:https://github.com/medvedevgroup/varmatch

Contact

chensun@cse.psu.edu
Genome-wide Variants of Eurasian Facial Shape Differentiation and a prospective model of DNA based Face Prediction
Authors: Qiao Lu , Yang Yajun , Fu Pengcheng , Hu Sile , Zhou Hang , Peng Shouneng , Tan Jingze , Lu Yan , Lou Haiyi , Lu Dongsheng , Wu Sijie , Guo Jing , Jin Li , Guan Yaqun , Wang Sijia , Xu Shuhua , Tang Kun
Published: July 2016

It is a long standing question as to which genes define the characteristic facial features among different ethnic groups. In this study, we use Uyghurs, an ancient admixed population to query the genetic bases why Europeans and Han Chinese look different. Facial traits were analyzed based on high-dense 3D facial images; numerous biometric spaces were examined for divergent facial features between European and Han Chinese, ranging from inter-landmark distances to dense shape geometrics. Genome-wide association analyses were conducted on a discovery panel of Uyghurs. Six significant loci were identified four of which, rs1868752, rs118078182, rs60159418 at or near UBASH3B, COL23A1, PCDH7 and rs17868256 were replicated in independent cohorts of Uyghurs or Southern Han Chinese. A prospective model was also developed to predict 3D faces based on top GWAS signals, and tested in hypothetic forensic scenarios.
A nonsense mutation in theCOL7A1gene causes epidermolysis bullosa in Vorderwald cattle
Authors: Pausch Hubert , Ammermüller Simon , Wurmser Christine , Hamann Henning , Tetens Jens , Drögemüller Cord , Fries Ruedi
Published: July 2016

Background

The widespread use of individual sires for artificial insemination promotes the propagation of recessive conditions. Inadvertent matings between unnoticed carriers of deleterious alleles may result in the manifestation of fatal phenotypes in their progeny. Breeding consultants and farmers reported on Vorderwald calves with a congenital skin disease. The clinical findings in affected calves were compatible with epidermolysis bullosa.

Results

Pedigree analysis indicated autosomal recessive inheritance of epidermolysis bullosa in Vorderwald cattle. We genotyped two diseased and 41 healthy animals at 41,436 single nucleotide polymorphisms and performed whole-genome haplotype-based association testing, which allowed us to map the locus responsible for the skin disease to the distal end of bovine chromosome 22 (P=8.0×10−14). The analysis of whole-genome re-sequencing data of one diseased calf, three obligate mutation carriers and 1682 healthy animals from various bovine breeds revealed a nonsense mutation (rs876174537, p.Arg1588X) in theCOL7A1gene that segregates with the disease. The same mutation was previously detected in three calves with dystrophic epidermolysis bullosa from the Rotes Hӧehenvieh cattle breed. We show that diseased animals from Vorderwald and Rotes Hӧehenvieh cattle are identical by descent for an 8.72 Mb haplotype encompassing rs876174537 indicating they inherited the deleterious allele from a recent common ancestor.

Conclusions

Autosomal recessive epidermolysis bullosa in Vorderwald and Rotes Hӧehenvieh cattle is caused by a nonsense mutation in theCOL7A1gene. Our findings demonstrate that recessive deleterious alleles may segregate across cattle populations without apparent admixture. The identification of the causal mutation now enables the reliable detection of carriers of the defective allele. Genome-based mating strategies can avoid inadvertent matings of carrier animals thereby preventing the birth of homozygous calves that suffer from a painful skin disease.
Competition between continuously evolving lineages in asexual populations
Authors: Ribeck Noah , Mulka Joseph S. , Zaman Luis , Connelly Brian D. , Lenski Richard E.
Published: July 2016

In an asexual population, the fate of a beneficial mutation depends on how its lineage competes against other mutant lineages in the population. With high beneficial mutation rates or large population sizes, competition between contending mutations is strong, and successful lineages can accumulate multiple mutations before any single one achieves fixation. Most current theory about asexual population dynamics either neglects this multiple-mutations regime or introduces simplifying assumptions that may not apply. Here, we develop a theoretical framework that describes the dynamics of adaptation and substitution over all mutation-rate regimes by conceptualizing the population as a collection of continuously adapting lineages. This model of “lineage interference” shows that each new mutant’s advantage over the rest of the population must be above a critical threshold in order to likely achieve fixation, and we derive a simple expression for that threshold. We apply this framework to examine the role of beneficial mutations with different effect sizes across the transition to the multiple-mutations regime.
Functional Connectivity Patterns Underlying the Experience of Auditory Verbal Hallucinations in Patients with Schizophrenia
Authors: Pravesh Parekh , John John P. , Menon Sangeetha , Halahalli Harsha N. , Kutty Bindu M.
Published: July 2016

Abstract

Schizophrenia is characterized by functional connectivity aberrations between brain regions that mediate different cognitive processes. The characteristic symptoms of schizophrenia such as delusions, hallucinations, passivity experiences etc. are suggested to reflect a disordered self-awareness. In the present study, we used a novel fMRI paradigm, the ‘Hallucination Attentional Modulation Task (HAMT)”, to examine the functional connectivity patterns underlying the experience of auditory verbal hallucinations in contrast to the patterns associated with processing of visual stimuli. We found that there was substantial overlap amongst healthy (n=8) and schizophrenia (n=6) subjects with respect to the functional connectivity patterns during the ‘free attention’ and ‘visual attention’ conditions of the paradigm. In patients with schizophrenia having continuous auditory verbal hallucinations, the connectivity between the bilateral superior parietal lobules and bilateral thalami were stronger during the ‘hallucination attention’ condition. These results provide preliminary leads that link auditory verbal hallucinations to an underlying disorder of self-agency.
Past climate changes, population dynamics and the origin of Bison in Europe
Authors: Massilani Diyendo , Guimaraes Silvia , Brugal Jean-Philip , Bennett E. Andrew , Tokarska Malgorzata , Arbogast Rose-Marie , Baryshnikov Gennady , Boeskorov Gennady , Castel Jean-Christophe , Davydov Sergey , Madelaine Stephane , Putelat Olivier , Spasskaya Natalia , Uerpmann Hans-Peter , Grange Thierry , Geigl Eva-Maria
Published: July 2016

Climatic and environmental fluctuations as well as anthropogenic pressure have led to the extinction of much of Europe’s megafauna. Here we show that the emblematic European bison has experienced several waves of population expansion, contraction and extinction during the last 50,000 years in Europe, culminating in a major reduction of genetic diversity during the Holocene. Fifty-seven complete and partial ancient mitogenomes from throughout Europe, the Caucausus and Siberia reveal that three populations of wisent (Bison bonasus) and steppe bison (B. priscus) alternated in Western Europe correlating with climate-induced environmental changes. The Late Pleistocene European steppe bison originated from northern Eurasia whereas the modern wisent population emerged from a refuge in the southern Caucasus after the last glacial maximum. A population overlap in a transition period is reflected in ca. 36,000 year-old paintings in the French Chauvet cave. Bayesian analyses of these complete ancient mitogenomes yielded new dates of the various branching events during the evolution of Bison and its radiation with Bos that lead us to propose that the genetic affiliation between the wisent and cattle mitogenomes result from incomplete lineage sorting rather than post-speciation gene flow.

Significance

Climatic fluctuations during the Pleistocene had a major impact on the environment and led to multiple megafaunal extinctions. Through ancient DNA analyses we decipher these processes for one of the largest megafauna of Eurasia, the bison. We show that Western Europe was successively populated during the Late Pleistocene by three different bison clades or species originating from the Caucasus and North-Eastern Europe that can be correlated to major climatic fluctuations and environmental changes. Aurignacian cave artists were witnesses to the first replacement of bison species ~35,000 years ago. All of these populations went extinct except for one that survived into the Holocene where it experienced severe reductions of its genetic diversity due to anthropogenic pressure.
Regulation of the JMJD3 (KDM6B) histone demethylase in glioblastoma stem cells by STAT3
Authors: Sherry-Lynes Maureen M. , Sengupta Sejuti , Kulkarni Shreya , Cochran Brent H.
Published: July 2016

The growth factor and cytokine regulated transcription factor STAT3 is required for the self-renewal of several stem cell types including tumor stem cells from glioblastoma. Here we show that STAT3 inhibition leads to the upregulation of the histone H3K27me2/3 demethylase Jmjd3 (KDM6B), which can reverse polycomb complex-mediated repression of tissue specific genes. STAT3 binds to the Jmjd3 promoter, suggesting that Jmjd3 is a direct target of STAT3. Overexpression of Jmjd3 slows glioblastoma stem cell growth and neurosphere formation, whereas knockdown of Jmjd3 rescues the STAT3 inhibitor-induced neurosphere formation defect. Consistent with this observation, STAT3 inhibition leads to histone H3K27 demethylation of neural differentiation genes, such as Myt1, FGF21, and GDF15. These results demonstrate that the regulation of Jmjd3 by STAT3 maintains repression of differentiation specific genes and is therefore important for the maintenance of self-renewal of normal neural and glioblastoma stem cells.
RNA sequencing-based cell proliferation analysis across 19 cancers identifies a subset of proliferation-informative cancers with a common survival signature
Authors: Ramaker Ryne C. , Lasseigne Brittany N. , Hardigan Andrew A. , Palacio Laura , Gunther David S. , Kirby Marie K. , Myers Richard M. , Cooper Sara J.
Published: July 2016

Despite advances in cancer diagnosis and treatment strategies, robust prognostic signatures remain elusive in most cancers. Cell proliferation has long been recognized as a prognostic marker in cancer, but it has not been thoroughly investigated across multiple cancers. Here we explore the role of cell proliferation across 19 cancers (n=6,581 patients) using tissue-based RNA sequencing from The Cancer Genome Atlas project by employing a ‘proliferative index’ derived from gene expression associated withPCNAexpression. This proliferative index is significantly associated with patient survival (Cox, p-value<0.05) in 7/19 cancers, which we have defined as ‘proliferation-informative cancers’ (PICs). In PICs the proliferative index is strongly correlated with tumor stage and nodal invasion. PICs paradoxically demonstrate reduced baseline expression of proliferation machinery relative to non-PICs suggesting that non-PICs saturate their proliferative capacity early in tumor development and allow other factors to dictate prognostic outcomes. We also identify chemotherapies whose efficacy is correlated with proliferation index and highlight drugs capable of inhibiting proliferation associated expression. Additionally, we find that proliferative index is significantly associated with gross somatic mutation burden (Spearman, p=1.76×10−23) as well mutations in individual driver genes. This analysis provides a comprehensive characterization of tumor proliferation rates and their association with disease progression and prognosis across cancer types and highlights specific cancers that may be particularly susceptible to improved targeting of this classic cancer hallmark.
Measuring experimental cyclohexane-water distribution coefficients for the SAMPL5 challenge
Authors: Rustenburg Ariën S. , Dancer Justin , Lin Baiwei , Feng Jianwen A. , Ortwine Daniel F. , Mobley David L. , Chodera John D.
Published: July 2016

Small molecule distribution coefficients between immiscible nonaqueuous and aqueous phases—such as cyclohexane and water—measure the degree to which small molecules prefer one phase over another at a given pH. As distribution coefficients capture both thermodynamic effects (the free energy of transfer between phases) and chemical effects (protonation state and tautomer effects in aqueous solution), they provide an exacting test of the thermodynamic and chemical accuracy of physical models without the long correlation times inherent to the prediction of more complex properties of relevance to drug discovery, such as protein-ligand binding affinities. For the SAMPL5 challenge, we carried out a blind prediction exercise in which participants were tasked with the prediction of distribution coefficients to assess its potential as a new route for the evaluation and systematic improvement of predictive physical models. These measurements are typically performed for octanol-water, but we opted to utilize cyclohexane for the nonpolar phase. Cyclohexane was suggested to avoid issues with the high water content and persistent heterogeneous structure of water-saturated octanol phases, since it has greatly reduced water content and a homogeneous liquid structure. Using a modified shake-flask LC-MS/MS protocol, we collected cyclohexane/water distribution coefficients for a set of 53 druglike compounds at pH 7.4. These measurements were used as the basis for the SAMPL5 Distribution Coefficient Challenge, where 18 research groups predicted these measurements before the experimental values reported here were released. In this work, we describe the experimental protocol we utilized for measurement of cyclohexane-water distribution coefficients, report the measured data, propose a new bootstrap-based data analysis procedure to incorporate multiple sources of experimental error, and provide insights to help guide future iterations of this valuable exercise in predictive modeling.

Abbreviations used in this paper

SAMPL

Statistical Assessment of the Modeling of Proteins and Ligands

log P

log10partition coefficient

log D

log10distribution coefficient

LC-MS/MS

Liquid chromatography - tandem mass spectrometry

HPLC

High-pressure liquid chromatography

MRM

Multiple reaction monitoring

DMSO

Dimethyl sulfoxide

PBS

Phosphate buffered saline

RPM

Revolutions per minute

CV

Coefficient of variation

MAP

Maximuma posteriori

MCMC

Markov chain Monte Carlo
Deconvolution model for cytometric microbial subgroups along a freshwater hydrologic continuum
Authors: Amalfitano Stefano , Fazi Stefano , Romani Anna M. , Andrea Butturini
Published: July 2016

Flow cytometry is suitable to discriminate and quantify aquatic microbial cells within a spectrum of fluorescence and light scatter signals. Using fixed operational and gating settings, a mixture model, coupled to Laplacian operator and Nelder-Mead optimization algorithm, allowed deconvolving bivariate cytometric profiles into single cell subgroups. This procedure was applied to outline recurrent patterns and quantitative changes of the aquatic microbial community along a river hydrologic continuum. We found five major persistent subgroups within each of the commonly retrieved populations of cells with Low and High content of Nucleic Acids (namely, LNA and HNA cells). Moreover, we assessed changes of the cytometric community profile over-imposed by water inputs from a wastewater treatment plant. Our approach for multiparametric data deconvolution confirmed that flow cytometry could represent a prime candidate technology for assessing microbial community patterns in flowing waters.
Coordinates and Intervals in Graph-based Reference Genomes
Authors: Rand Knut D. , Grytten Ivar , Nederbragt Alexander J. , Storvik Geir O. , Glad Ingrid K. , Sandve Geir K.
Published: July 2016

Motivation

It has been proposed that future reference genomes should be graph structures in order to better represent the sequence diversity present in a species. However, there is currently no standard method to represent genomic intervals, such as positions of genes, on graph-based reference genomes.

Results

We formalize offset-based coordinate systems on graph-based reference genomes and introduce a method for representing intervals on these reference structures. We show the advantage of our method by representing genes on a graph-based representation of the GRCh38 version of the human genome and its alternative loci for regions that are highly variable.

Conclusion

More complex reference genomes, containing alternative loci, require methods to represent genomic data on these structures. Our proposed notation for genomic intervals makes it possible to fully utilize the alternative loci of GRCh38 and potential future graph-based reference genomes. We illustrate our notation for genomic intervals, as well as the offset-based coordinate systems, through a web tool at:https://github.com/uio-cels/gen-graph-coords.
Shared predation: positive effects of predator distraction
Authors: Teixeira Alves Mickaël , Grognard Frédéric , Calcagno Vincent , Mailleret Ludovic
Published: July 2016

Simple rules based on population equilibria can characterize indirect interactions in three-species systems but fail to predict them when considering behavioral mechanisms. In this paper, we revisit the effects of shared predation,i.e. the situation in which two prey are consumed by a common predator. Such predation usually induces negative indirect interactions between prey, or apparent competition, through an increase of predator density and thus of predation pressure. Two mechanisms can however weaken apparent competition and lead to equivocal signs of indirect interactions. On the one hand, predator distraction, which stems from the difficulty to efficiently forage for different prey at the same moment in time and diminishes the number of prey capturedperpredator. On the other hand, predator negative density dependence limits predator growth. To get further insights into simple rules describing indirect interactions brought about by shared predation, we studied two classes of one-predator-two-prey models exhibiting these two mechanisms. We found robust simple rules derived from predator equilibria which state that at least one prey is favored by the presence of the other when the predators partition their foraging effort between them. These rules thus characterize a surprising wide range of indirect effects including apparent predation, apparent commensalism and apparent mutualism. They also highlight different situations in which larger predator populations do not entail smaller prey populations and in which neither prey species can be negatively affected by the other.
Benzoate and Salicylate Tolerant Strains Lose Antibiotic Resistance during Laboratory Evolution ofEscherichia coliK-12
Authors: Creamer Kaitlin E. , Ditmars Frederick S. , Basting Preston J. , Kunka Karina S. , Hamdallah Issam N. , Bush Sean P. , Scott Zachary , He Amanda , Penix Stephanie R. , Gonzales Alexandra S. , Eder Elizabeth K. , Camperchioli Dominic , Berndt Adama , Clark Michelle W. , Rouhier Kerry A. , Slonczewski Joan L.
Published: July 2016

Escherichia coliK-12 W3110 grows in the presence of membrane-permeant organic acids that can depress cytoplasmic pH and accumulate in the cytoplasm. We conducted experimental evolution by daily diluting cultures in increasing concentrations of benzoic acid (up to 20 mM) buffered at external pH 6.5, a pH at which permeant acids concentrate in the cytoplasm. By 2,000 generations, clones isolated from evolving populations showed increasing tolerance to benzoate but were sensitive to chloramphenicol and tetracycline. Sixteen clones grew to stationary phase in 20 mM benzoate, whereas the ancestral strain W3110 peaked and declined. Similar growth occurred in 10 mM salicylate. Benzoate-evolved strains grew like W3110 in the absence of benzoate; in media buffered at pH 4.8, pH 7.0, or pH 9.0; or in 20 mM acetate or sorbate at pH 6.5. Genomes of 16 strains revealed over 100 mutations including SNPs, large deletions, and insertion knockouts. Most strains acquired deletions in the benzoate-induced multiple antibiotic resistance (Mar) regulon or in associated regulators such asrobandcpxA, as well as MDR efflux pumpsemrA,emrY, andmdtA. Strains also lost or down-regulated the Gad acid fitness regulon. In 5 mM benzoate, or in 2 mM salicylate (2-hydroxybenzoate), most strains showed increased sensitivity to the antibiotics chloramphenicol and tetracycline; some strains were more sensitive than amarAknockout. Thus, our benzoate-evolved strains may reveal additional unknown drug resistance components. Benzoate or salicylate selection pressure may cause general loss of MDR genes and regulators.

IMPORTANCE

Benzoate is a common food preservative, and salicylate is the primary active metabolite of aspirin. In the gut microbiome, genetic adaptation to salicylate may involve loss or downregulation of inducible multidrug resistance systems. This discovery implies that aspirin therapy may modulate the human gut microbiome to favor salicylate tolerance at the expense of drug resistance. Similar aspirin-associated loss of drug resistance might occur in bacterial pathogens found in arterial plaques.
The Nrd1-like protein Seb1 coordinates cotranscriptional 3′ end processing and polyadenylation site selection
Authors: Lemay Jean-François , Marguerat Samuel , Larochelle Marc , Liu Xiaochuan , van Nues Rob , Hunyadkürti Judit , Hoque Mainul , Tian Bin , Granneman Sander , Bähler Jürg , Bachand François
Published: July 2016

Termination of RNA polymerase II (RNAPII) transcription is associated with RNA 3′ end formation. For coding genes, termination is initiated by the cleavage/polyadenylation machinery. In contrast, a majority of noncoding transcription events in Saccharomyces cerevisiae does not rely on RNA cleavage for termination but instead terminates via a pathway that requires the Nrd1–Nab3–Sen1 (NNS) complex. Here we show that the Schizosaccharomyces pombe ortholog of Nrd1, Seb1, does not function in NNS-like termination but promotes polyadenylation site selection of coding and noncoding genes. We found that Seb1 associates with 3′ end processing factors, is enriched at the 3′ end of genes, and binds RNA motifs downstream from cleavage sites. Importantly, a deficiency in Seb1 resulted in widespread changes in 3′ untranslated region (UTR) length as a consequence of increased alternative polyadenylation. Given that Seb1 levels affected the recruitment of conserved 3′ end processing factors, our findings indicate that the conserved RNA-binding protein Seb1 cotranscriptionally controls alternative polyadenylation.
RB1: a prototype tumor suppressor and an enigma
Authors: Dyson Nicholas J.
Published: July 2016

The retinoblastoma susceptibility gene (RB1) was the first tumor suppressor gene to be molecularly defined.RB1mutations occur in almost all familial and sporadic forms of retinoblastoma, and this gene is mutated at variable frequencies in a variety of other human cancers. Because of its early discovery, the recessive nature ofRB1mutations, and its frequency of inactivation,RB1is often described as a prototype for the class of tumor suppressor genes. Its gene product (pRB) regulates transcription and is a negative regulator of cell proliferation. Although these general features are well established, a precise description of pRB's mechanism of action has remained elusive. Indeed, in many regards, pRB remains an enigma. This review summarizes some recent developments in pRB research and focuses on progress toward answers for the three fundamental questions that sit at the heart of the pRB literature: What does pRB do? How does the inactivation of RB change the cell? How can our knowledge of RB function be exploited to provide better treatment for cancer patients?
Toward the mechanism of eIF4F-mediated ribosomal attachment to mammalian capped mRNAs
Authors: Kumar Parimal , Hellen Christopher U.T. , Pestova Tatyana V.
Published: July 2016

Ribosomal attachment to mammalian capped mRNAs is achieved through the cap–eukaryotic initiation factor 4E (eIF4E)–eIF4G–eIF3–40S chain of interactions, but the mechanism by which mRNA enters the mRNA-binding channel of the 40S subunit remains unknown. To investigate this process, we recapitulated initiation on capped mRNAs in vitro using a reconstituted translation system. Formation of initiation complexes at 5′-terminal AUGs was stimulated by the eIF4E–cap interaction and followed “the first AUG” rule, indicating that it did not occur by backward scanning. Initiation complexes formed even at the very 5′ end of mRNA, implying that Met-tRNAiMet inspects mRNA from the first nucleotide and that initiation does not have a “blind spot.” In assembled initiation complexes, the cap was no longer associated with eIF4E. Omission of eIF4A or disruption of eIF4E–eIF4G–eIF3 interactions converted eIF4E into a specific inhibitor of initiation on capped mRNAs. Taken together, these results are consistent with the model in which eIF4E–eIF4G–eIF3–40S interactions place eIF4E at the leading edge of the 40S subunit, and mRNA is threaded into the mRNA-binding channel such that Met-tRNAiMet can inspect it from the first nucleotide. Before entering, eIF4E likely dissociates from the cap to overcome steric hindrance. We also found that the m7G cap specifically interacts with eIF3l.
Time to move the fat
Authors: Weaver Benjamin P. , Sewell Aileen K. , Han Min
Published: July 2016

In this issue of Genes & Development, Dowen and colleagues (pp. 1515–1528) elegantly unify two previously unconnected aspects of physiology. The investigators provide significant genetic evidence to support a critical link between developmental timing decisions and the regulation of lipid mobilization at the transition to adulthood in Caenorhabditis elegans. This novel connection involves cross-tissue signaling from the hypodermis (epidermis) to the intestine to promote reproductive success in the germline.
Testing ERBB2 p.L755S kinase domain mutation as a druggable target in a patient with advanced colorectal cancer
Authors: Aung Kyaw L. , Stockley Tracy L. , Serra Stefano , Kamel-Reid Suzanne , Bedard Philippe L. , Siu Lillian L.
Published: July 2016

Recent advances in molecular profiling technologies allow genetic driver events in individual tumors to be identified. The hypothesis behind this ongoing molecular profiling effort is that improvement in patients’ clinical outcomes will be achieved by inhibiting these discovered genetic driver events with matched targeted drugs. This hypothesis is currently being tested in oncology clinics with variable early results. Herein, we present our experience with a case of advanced colorectal cancer (CRC) with an ERBB2 p.L755S kinase domain mutation, a BRAF p.N581S mutation, and an APC p.Q1429fs mutation, together with a brief review of the literature describing the biological and clinical significance of ERRB2 kinase domain mutations in CRC. The patient was treated with trastuzumab combined with infusional 5-fluorouracil and leucovorin based on the presence of ERBB2 p.L755S kinase mutation in the tumor and based on the available evidence at the time when standard treatment options had been exhausted. However, there was no therapeutic response illustrating the challenges we face in managing patients with potentially targetable mutations where results from functional in vitro and in vivo studies lag behind those of genomic sequencing studies. Also lagging behind are clinical utility data from oncology clinics, hampering rapid therapeutic advances. Our case also highlights the logistical barriers associated with getting the most optimal therapeutic agents to the right patient in this era of personalized therapeutics based on cancer genomics.
Crystal structure of bis(2-methyl-1H-imidazole-κN3)(meso-tetra-p-tolylporphyrinato-κ4N)iron(III) perchlorate tetrahydrofuran sesquisolvate
Authors: Sun Wenyan , Li Jianfeng
Published: July 2016

In the title compound, [Fe(C48H36N4)(C4H6N2)2]ClO4·1.5C4H8O, the iron(III) metal is coordinated in a distorted octahedral geometry by four pyrrole N atoms of the porphyrin ligand in the equatorial plane and two N atoms of 2-methylimidazole ligands in the axial sites. The complex has a highly ruffled porphyrin core with mean absolute core-atom displacementsCa,Cb,CmandCavof 0.25 (5), 0.17 (12), 0.432 (16) and 0.25 (13) Å, respectively. One of the four phenyl groups of the porphyrin is disordered over two sets of sites with refined occupancy ratio of 0.718 (7):0.282 (7). The mean Fe—Np(Npis a porphyrin N atom) bond length [1.975 (9) Å] indicates the low-spin state of the iron atom. The two 2-methylimidazole ligands are nearly perpendicular and form a dihedral angle of 86.93 (10)°. The dihedral angles between the 2-methylimidazole ligands and the closest Fe—Npvector are 38.04 (9) and 35.00 (7)°. In the crystal, the complex cations interact with the perchlorate anions through N—H...O hydrogen bonds, forming chains running parallel to [110].
[μ2-trans-1,2-Bis(pyridin-4-yl)ethene-κ2N:N′]bis{[1,2-bis(pyridin-4-yl)ethene-κN]bis[N-(2-hydroxyethyl)-N-isopropyldithiocarbamato-κ2S,S′]cadmium} acetonitrile tetrasolvate: crystal structure and Hirshfeld surface analysis
Authors: Jotani Mukesh M. , Poplaukhin Pavel , Arman Hadi D. , Tiekink Edward R. T.
Published: July 2016

The asymmetric unit of the title compound, [Cd2(C12H10N2)3(C6H12NOS2)4]·4C2H3N, comprises a CdIIatom, two dithiocarbamate (dtc) anions, one and a halftrans-1,2-dipyridin-4-ylethylene (bpe) molecules and two acetonitrile solvent molecules. The full binuclear complex is generated by the application of a centre of inversion. The dtc ligands are chelating, one bpe molecule coordinates in a monodentate mode while the other is bidentate bridging. The resultingcis-N2S4coordination geometry is based on an octahedron. Supramolecular layers, sustained by hydroxy-O—H...O(hydroxy) and hydroxy-O—H...N(bpe) hydrogen bonding, interpenetrate to form a three-dimensional architecture; voids in this arrangement are occupied by the acetonitrile solvent molecules. Additional intermolecular interactions falling within the specified framework have been analysed by Hirshfeld surface analysis, including π–π interactions.
Crystal structures of a copper(II) and the isotypic nickel(II) and palladium(II) complexes of the ligand (E)-1-[(2,4,6-tribromophenyl)diazenyl]naphthalen-2-ol
Authors: Chetioui Souheyla , Rouag Djamil-Azzeddine , Djukic Jean-Pierre , Bochet Christian G. , Touzani Rachid , Bailly Corinne , Crochet Aurélien , Fromm Katharina M.
Published: July 2016

In the copper(II) complex, bis{(E)-1-[(2,4,6-tribromophenyl)diazenyl]naphthalen-2-olato}copper(II), [Cu(C16H8Br3N2O)2], (I), the metal cation is coordinated by two N atoms and two O atoms from two bidentate (E)-1-[(2,4,6-tribromophenyl)diazenyl]naphthalen-2-olate ligands, forming a slightly distorted square-planar environment. In one of the ligands, the tribromobenzene ring is inclined to the naphthalene ring system by 37.4 (5)°, creating a weak intramolecular Cu...Br interaction [3.134 (2) Å], while in the other ligand, the tribromobenzene ring is inclined to the naphthalene ring system by 72.1 (6)°. In the isotypic nickel(II) and palladium(II) complexes, namely bis{(E)-1-[(2,4,6-tribromophenyl)diazenyl]naphthalen-2-olato}nickel(II), [Ni(C16H8Br3N2O)2], (II), and bis{(E)-1-[(2,4,6-tribromophenyl)diazenyl]naphthalen-2-olato}palladium(II), [Pd(C16H8Br3N2O)2], (III), respectively, the metal atoms are located on centres of inversion, hence the metal coordination spheres have perfect square-planar geometries. The tribromobenzene rings are inclined to the naphthalene ring systems by 80.79 (18)° in (II) and by 80.8 (3)° in (III). In the crystal of (I), molecules are linked by C—H...Br hydrogen bonds, forming chains along [010]. The chains are linked by C—H...π interactions, forming sheets parallel to (011). In the crystals of (II) and (III), molecules are linked by C—H...π interactions, forming slabs parallel to (10-1). For the copper(II) complex (I), a region of disordered electron density was corrected for using the SQUEEZE routine inPLATON[Spek (2015).Acta Cryst.C71, 9–18]. The formula mass and unit-cell characteristics of the disordered solvent molecules were not taken into account during refinement.
Crystal structures of three substituted 3-aryl-2-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-ones
Authors: Yennawar Hemant P. , Coyle David J. , Noble Duncan J. , Yang Ziwei , Silverberg Lee J.
Published: July 2016

Three ring-substituted 3-aryl analogs of 2-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-one, namely 3-(4-methoxyphenyl)-2-phenyl-4H-1,3-benzothiazin-4-one, C21H17NO2S, (I), 2-phenyl-3-[4-(trifluoromethyl)phenyl]-2,3-dihydro-4H-1,3-benzothiazin-4-one toluene hemisolvate, C21H14F3NOS·0.5C7H8, (II), and 3-(3-bromophenyl)-2-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-one toluene hemisolvate, C20H14BrNOS·0.5C7H8, (III), were synthesized and their crystal structures determined. The hemisolvates differ in that in (II), the asymmetric unit comprises two molecules of the benzothiazinone compound and a toluene solvent molecule, whereas in (III), the unit comprises one benzothiazinone molecule and a half-occupancy toluene solvent molecule. All crystals are of racemic mixtures of the chiral 2-C atom of the thiazine moiety, which in all structures has a screw-boat puckering, with the puckering amplitude values within the range 0.575–0.603 Å. In all three structures, the benzene plane of the benzothiazine system makes a dihedral angle in the range 78.60 (5) to 98.40 (5)° with the unsubstituted benzene plane and in the range 70.50 (1) to 121.00 (5)° with the substituted benzene plane. The CF3substituent group in one of the molecules of (II) shows positional disorder, with an occupancy ratio of 0.57 (3):0.43 (3). In the crystals of (I) and (II), weak intermolecular C—H...O interactions are present, giving in (I), molecules arranged in a plane parallel to (010), and in (II), chains alonga. In addition, all three structures show weak C—H...π interactions involving various aromatic rings.
Crystal structure of 2-methyl-1H-imidazol-3-ium hydrogen oxalate dihydrate
Authors: Diop Mouhamadou Birame , Diop Libasse , Plasseraud Laurent , Cattey Hélène
Published: July 2016

Single crystals of the title molecular salt, C4H7N2+·HC2O4−·2H2O, were isolated from the reaction of 2-methyl-1H-imidazole and oxalic acid in a 1:1 molar ratio in water. In the crystal, the cations and anions are positioned alternately along an infinite [010] ribbon and linked together through bifurcated N—H...(O,O) hydrogen bonds. The water molecules of crystallization link the chains into (10-1) bilayers, with the methyl groups of the cations organized in an isotactic manner.
1H-Benzo[d]imidazol-3-ium (Z)-3-carboxyprop-2-enoate
Authors: Amudha M. , Gunasekaran B. , Kumar P. Praveen , Chakkaravarthi G.
Published: July 2016

In the anion of the title molecular salt, C7H7N2+.C4H3O4−, an O—H...O hydrogen bond generates anS(7) graph-set motif while a pair of intermolecular N—H...O and C—H...O hydrogen bonds generate anR44(10) ring-motif. Adjacent anions and cations are further connected through N—H...O hydrogen bonds into infinite chains along [101] and these chains are linked by C—H...O hydrogen bonds, forming a three-dimensional network.
Ethyl 1-benzyl-2-(3-chlorophenyl)-1H-benzimidazole-5-carboxylate
Authors: Kumar S. Madan , Manasa D. , Kumar Vasantha , Poojary Boja , Byrappa K. , Abdoh M. M. M.
Published: July 2016

In the title compound, C23H19ClN2O2, the dihedral angles between the imidazole ring system and the chlorobenzene and phenyl rings are 48.05 (14) and 82.53 (15)°, respectively. In the crystal, inversion dimers linked by pairs of C—H...O hydrogen bonds generateR22(22) loops. Weak C—H...π and π–π stacking interactions are also observed.
Poly[[tetramethanolbis[4-oxo-3-(pyridin-4-yl)-1-(2,4,6-trichlorophenyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-olato]disodium]–diethyl ether–methanol (1/1/2)]
Authors: Abu Thaher Bassam , Schollmeyer Dieter , Laufer Stefan
Published: July 2016

In the title compound, [Na2(C16H7Cl3N5O2)2(CH3OH)4]·C4H10O·2CH3OH, the central pyrazolo[3,4-d]pyrimidine system makes dihedral angles of 82.98 (7)° with the trichlorophenyl ring and 13.11 (15)° with the pyridine ring. The sodium ion has an octahedral environment, being coordinated by four methanol molecules and one O and one N atom of two different heterocyclic ring systems.
2-Amino-4-methylpyridinium 2-(3-methylphenyl)acetate
Authors: Sivakumar P. , Sudhahar S. , Israel S. , Chakkaravarthi G.
Published: July 2016

In the title molecular salt, C6H9N2+·C9H9O2−, the cation is protonated at the pyridine N atom and the anion is deprotonated at the hydroxy O atom. The dihedral angle between the benzene and pyridine rings is 66.58 (10)°. In the molecular structure, a pair of N—H...O hydrogen bonds links the anion and cation, generating anR22(8) ring motif. These ring motifs are connected to adjacent anions and cationsviaintermolecular N—H...O hydrogen bonding, generating a bifurcatedR22(8) ring motif. C—H...O, C—H...π and π–π [centroid-to-centroid distances = 3.7053 (11) and 3.9547 (13) Å] interactions lead to the formation of a three-dimensional network.
Opposing influences on construction plant and machinery health and safety innovations
Authors: Holt Gary D.
Published: July 2016

Purpose

This paper aims to consider opposing influences on workplace plant and machinery health and safety (PMH&S) innovations, highlight examples of these to model PMH&S innovations’ effectiveness at the workplace, develop guidance for improvement of same and for construction of health and safety (H&S) performance.

Design/methodology/approach

This study is a qualitative meta-analysis of data distributed among a sample of published research in the field, and it uses inductive reasoning based on informal, qualitative and interpretative analysis.

Findings

Nearly all PMH&S innovations (positive influences) originate from original equipment manufacturers and specialist companies throughout the supply chain. Negative influences that can counter these potential H&S benefits result mainly from human (in) action(s) at the workplace. These are classified (and analysed) in terms of “error”, “indifference” and “lack of training”. “Tolerant” H&S management is another negative influence found among these classifications.

Originality/value

The study draws from a targeted meta-sample of research in the field, a model of positive and negative influences on PMH&S innovations that emphasises workers’ (in) action(s).
Right-time vs real-time pro-active construction safety and health system architecture
Authors: Teizer Jochen
Published: July 2016

Purpose

The purpose of this paper is to investigate the critical time window for pro-active construction accident prevention and response. Large to small organisations throughout the entire construction supply chain continue to be challenged to adequately prevent accidents. Construction worker injuries and fatalities represent significant waste of resources. Although the five C’s (culture, competency, communication, controls and contractors) have been focusing on compliance, good practices and best-in-class strategies, even industry leaders have only marginal improvements in recorded safety statistics for many years.

Design/methodology/approach

Right-time vs real-time construction safety and health identifies three major focus areas to aid in the development of a strategic, as opposed to tactical, response. Occupational safety and health by design, real-time safety and health monitoring and alerts and education, training and feedback leveraging state-of-the-art technology provide meaningful predictive, quantitative and qualitative measures to identify, correlate and eliminate hazards before workers get injured or incidents cause collateral damage.

Findings

The current state and development of existing innovative initiatives in the occupational construction safety and health domain are identified. A framework for right-time vs real-time construction safety and health presents the specific focus on automated safety and health data gathering, analysis and reporting to achieve better safety performance. The developed roadmap for right-time vs real-time safety and health is finally tested in selected application scenarios of high concern in the construction industry.

Originality/value

A strategic roadmap to eliminate hazards and accidents through right-time vs real-time automation is presented that has practical as well as social implications on conducting a rigorous safety culture and climate in a construction business and its entire supply chain.
Librarians and scientists partner to address data management
Authors: Medina-Smith Andrea , Tryka Kimberly A. , Silcox Barbara , Hanisch Robert J.
Published: July 2016

Purpose

This study aims to look at the changing way in which the Information Services Office (ISO) at the National Institute of Standards and Technology (NIST) provides services to NIST scientific and technical staff throughout their research and publishing cycles. These services include the more traditional services of a research library and publishing NIST technical reports and The Journal of Research of NIST and preserving and exhibiting scientific instruments and other artifacts. ISO has always prided itself on having a close relationship with its customers, providing a high level of service and developing new services to stay in front of NIST researcher needs. Through a concerted, strategic effort since the late 1990s, ISO has developed and promoted relationships with its key customers through its Lab Liaison Program.

Design/methodology/approach

This paper discusses the relationship ISO has developed with the Office of Data and Informatics (ODI), how this relationship was forged and how this collaboration will serve as a model for working with the other labs and programs at NIST. It will also discuss the risks and opportunities of this new collaborative service model, how ISO positioned itself to become an equal partner with ODI in the exploration of solutions to data management issues and the benefits of the relationship from ODI’s perspective.

Findings

A pattern of strategic changes to the services and activities offered by the Lab Liaison program has put ISO in the position to collaborate as peers with researchers at NIST.

Originality/value

This study provides an overview of how ISO made strategic decisions to incorporate non-traditional services to support data management at NIST.