bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic Effects of Welding Fumes on the Development of Respiratory System Diseases
Authors: Rana Humayan Kabir , Akhtar Mst. Rashida , Islam M. Babul , Ahmed Mohammad Boshir , Lio’ Pietro , Quinn Julian M.W. , Huq Fazlul , Moni Mohammad Ali
Published: December 2018

Background

The welding process releases potentially hazardous gases and fumes, mainly composed of metallic oxides, fluorides and silicates. Long term welding fume (WF) inhalation is a recognized health issue that carries a risk of developing chronic health problems, particularly respiratory system diseases (RSDs). Aside from general airway irritation, WF exposure may drive direct cellular responses in the respiratory system which increase risk of RSD, but these are not well understood.

Methods

We developed a quantitative framework to identify gene expression effects of WF exposure that may affect RSD development. We analyzed gene expression microarray data from WF-exposed tissues and RSD-affected tissues, including chronic bronchitis (CB), asthma (AS), pulmonary edema (PE), lung cancer (LC) datasets. We built disease-gene (diseasome) association networks and identified dysregulated signaling and ontological pathways, and protein-protein interaction sub-network using neighborhood-based benchmarking and multilayer network topology.

Results

We observed many genes with altered expression in WF-exposed tissues were also among differentially expressed genes (DEGs) in RSD tissues; for CB, AS, PE and LC there were 34, 27, 50 and 26 genes respectively. DEG analysis, using disease association networks, pathways, ontological analysis and protein-protein interaction sub-network suggest significant links between WF exposure and the development of CB, AS, PE and LC.

Conclusions

Our network-based analysis and investigation of the genetic links of WFs and RSDs confirm a number of genes and gene products are plausible participants in RSD development. Our results are a significant resource to identify causal influences on the development of RSDs, particularly in the context of WF exposure.
Development and validation of serological markers for detecting recent exposure toPlasmodium vivaxinfection
Authors: Longley Rhea J. , White Michael T. , Takashima Eizo , Brewster Jessica , Morita Masayuki , Harbers Matthias , Robinson Leanne J. , Matsuura Fumie , Zoe Liu Shih-Jung , Li-Wai-Suen Connie S. N. , Tham Wai-Hong , Healer Julie , Huon Christele , Chitnis Chetan E. , Nguitragool Wang , Monteiro Wuelton , Proietti Carla , Doolan Denise L. , Ding Xavier C. , Gonzalez Iveth J. , Kazura James , Lacerda Marcus , Sattabongkot Jetsumon , Tsuboi Takafumi , Mueller Ivo
Published: December 2018

In order to accelerate towards malaria elimination, improved targeting of limited resources is essential. A major gap in our elimination toolkit forPlasmodium vivaxmalaria is the identification of individuals carrying arrested liver stages, called hypnozoites. These clinically silent but frequently relapsing hypnozoites are key toP. vivaxpersistence. Whilst hypnozoites cannot be directly detected, individuals who have had recent exposure toP. vivaxand have not been treated are likely to harbor these parasites. By measuring IgG antibody responses to over 300P. vivaxproteins, a panel of serological markers capable of detecting exposure toP. vivaxinfections in the prior 9-month period was identified and validated. Using antibody responses to 8P. vivaxproteins, 80% sensitivity and specificity for detecting recent infections were achieved in three independent studies conducted in Thailand, Brazil and the Solomon Islands. As these individuals have a high likelihood of harboring hypnozoites, the suite of these 8 antibody responses can serve as biomarkers for the identification of individuals who should be targeted for treatment with liver-stage drugs such as primaquine and tafenoquine in mass drug administration programs aimed at controlling and eliminatingP. vivaxmalaria.

One Sentence Summary

The manuscript describes identification and validation of a novel panel of P. vivax proteins that can be used to detect recent exposure to P. vivax infections within the prior 9 months.
Percolation in the resting zebrafish habenula
Authors: Suryadi  , Cheng Ruey-Kuang , Jesuthasan Suresh , Chew Lock Yue
Published: December 2018

The habenula is an evolutionarily conserved structure of the vertebrate brain that is essential for behavioural flexibility and mood control. It is spontaneously active and is able to access diverse states when the animal is exposed to sensory stimuli or reward. Here we analyze two-photon calcium imaging time-series of the habenula of larval zebrafish and find that percolation occurs, indicating the presence of long-range spatial correlations within each side of the habenula, with percolation occurring independently in each side. On the other hand, the analysis of neuronal avalanches suggests that the system is subcritical, implying that the flexibility in its dynamics may result from other dynamical processes.
Mining Significant Features of Diabetes Mellitus Applying Decision Trees: A Case Study In Bangladesh
Authors: Howlader Koushik Chandra , Satu Md. Shahriare , Barua Avijit , Moni Mohammad Ali
Published: December 2018

Diabetes is a chronic condition which is associated with an abnormally high level of sugar in the blood. It is a lifelong disease that causes harmful effects in human life. The goal of this research is to predict the severity of diabetes and find out significant features of it. In this work, we gathered diabetes patients records from Noakhali Diabetes Association, Noakhali, Bangladesh. Thus, We preprocessed our raw dataset by replacing and removing missing and wrong records respectively. Thus, CDT, J48, NBTree and REPtree decision tree based classification techniques were used to analyze this dataset. After this analysis, we evaluated classification outcomes of these decision tree classifiers and found the best decision tree model from them. In this work, CDT unpruned tree shows highest accuracy, precision, recall, f-measure, second highest AUROC and lowest RMSE than other models. Then, we extracted possible rules and significant features from this model and plasma glucose, plasma glucose 2hr after glucose and HDL-cholesterol have been found as the most significant features to predict the severity of Diabetes Mellitus. We hope this work will be beneficial to build a predictive system and complementary tool for diabetes treatment in future.
Evaluation of the performance of copy number variant prediction tools for the detection of deletions from whole genome sequencing data
Authors: Whitford Whitney , Lehnert Klaus , Snell Russell G. , Jacobsen Jessie C.
Published: December 2018

Background

Whole genome sequencing (WGS) has increased in popularity and decreased in cost over the past decade, rendering this approach as a viable and sensitive method for variant detection. In addition to its utility for single nucleotide variant detection, WGS data has the potential to detect Copy Number Variants (CNV) to fine resolution. Many CNV detection software packages have been developed exploiting four main types of data: read pair, split read, read depth, and assembly based methods. The aim of this study was to evaluate the efficiency of each of these main approaches in detecting deletions.

Methods

WGS data and high confidence deletion calls for the individual NA12878 from the Genome in a Bottle consortium were the benchmark dataset. The performance of Breakdancer, CNVnator, Delly, FermiKit, and Pindel was assessed by comparing the accuracy and sensitivity of each software package in detecting deletions exceeding 1kb.

Results

There was considerable variability in the outputs of the different WGS CNV detection programs. The best performance was seen from Breakdancer and Delly, with 92.6% and 96.7% sensitivity, respectively and 34.5% and 68.5% false discovery rate (FDR), respectively. In comparison, Pindel, CNVnator, and FermiKit were less effective with sensitivities of 69.1%, 66.0%, and 15.8%, respectively and FDR of 91.3%, 69.0%, and 31.7%, respectively. Concordance across software packages was poor, with only 27 of the total 612 benchmark deletions identified by all five methodologies.

Conclusions

The WGS based CNV detection tools evaluated show disparate performance in identifying deletions ≥1kb, particularly those utilising different input data characteristics. Software that exploits read pair based data had the highest sensitivity, namely Breakdancer and Delly. Breakdancer also had the second lowest false discovery rate. Therefore, in this analysis read pair methods (Breakdancer in particular) were the best performing approaches for the identification of deletions ≥1kb, balancing accuracy and sensitivity. There is potential for improvement in the detection algorithms, particularly for reducing FDR. This analysis has validated the utility of WGS based CNV detection software to reliably identify deletions, and these findings will be of use when choosing appropriate software for deletion detection, in both research and diagnostic medicine.
All in thirty milliseconds: EEG evidence of hierarchical and asymmetric phonological encoding of vowels
Authors: Manca Anna Dora , Russo Francesco Di , Sigona Francesco , Grimaldi Mirko
Published: December 2018

How the brain encodes the speech acoustic signal into phonological representations (distinctive features) is a fundamental question for the neurobiology of language. Whether this process is characterized by tonotopic maps in primary or secondary auditory areas, with bilateral or leftward activity, remains a long-standing challenge. Magnetoencephalographic and ECoG studies have previously failed to show hierarchical and asymmetric hints for speech processing. We employed high-density electroencephalography to map the Salento Italian vowel system onto cortical sources using the N1 auditory evoked component. We found evidence that the N1 is characterized by hierarchical and asymmetric indexes structuring vowels representation. We identified them with two N1 subcomponents: the typical N1 (N1a) peaking at 125-135 ms and localized in the primary auditory cortex bilaterally with a tangential distribution and a late phase of the N1 (N1b) peaking at 145-155 ms and localized in the left superior temporal gyrus with a radial distribution. Notably, we showed that the processing of distinctive feature representations begins early in the primary auditory cortex and carries on in the superior temporal gyrus along lateral-medial, anterior-posterior and inferior-superior gradients. It is the dynamical interface of both auditory cortices and the interaction effects between different distinctive features that generate the categorical representations of vowels.
Effectiveness of live attenuated monovalent human rotavirus vaccination in rural Ecuador, 2008-2013
Authors: Kraay Alicia N. M. , Ionides Edward L. , Lee Gwenyth O. , Cevallos Trujillo William F. , Eisenberg Joseph N.S.
Published: December 2018

Background

While live attenuated monovalent human rotavirus vaccine (Rotarix) efficacy has been characterized through randomized studies, its effectiveness, especially in non-clinical settings, is unclear. In this study, we estimate direct, indirect, and overall effectiveness of Rotarix vaccination.

Methods

We analyze 29 months of all-cause diarrhea surveillance from a child cohort (n=376) and ten years of serial population-based case-control lab-confirmed rotavirus data (n=2489) from rural Ecuador during which Rotarix vaccination was introduced. We estimate: 1) the direct effect of vaccination from a cohort of children born from 2008-2013 using Cox regression to compare time to first all-cause diarrhea case by vaccine status; and 2) the overall effect on all-cause diarrheal and symptomatic and asymptomatic rotavirus infection for all age groups, including indirect effects on adults, from the case-control data using weighted logistic regression.

Results

Rotarix vaccination provided direct protection against all-cause diarrhea among children 0.5 - 2 years (All-cause diarrhea reduction for receipt of 2 doses of Rotarix=57.1%, 95% CI: 16.6, 77.9%). Overall effectiveness against rotavirus infection was strong (Exposure to 100% coverage of Rotarix vaccination was associated with an 85.5% reduction, 95% CI: 61.1-94.6%) compared to 0% coverage. Indirect effects were observed among older, vaccine-ineligible children and adults (84.5% reduction, 95% CI: 48.2-95.4%). Vaccine effectiveness was high against both symptomatic (48.3% reduction,95% CI: 0.03-73.1%) and asymptomatic infection (90.1% reduction, 95% CI: 56.9-97.7%).

Conclusions

Rotarix vaccination suppresses overall transmission. It is highly effective among children in a rural community setting and provides population-level benefits through indirect protection among adults.
Hippocampal-neocortical interactions sharpen over time for predictive actions
Authors: Hindy Nicholas C. , Avery Emily W. , Turk-Browne Nicholas B.
Published: December 2018

When an action is familiar, we are able to anticipate how it will change the state of the world. These expectations can result from retrieval of action-outcome associations in the hippocampus and the reinstatement of anticipated outcomes in visual cortex. How does this role for the hippocampus in action-based prediction change over time? We used high-resolution fMRI and a dual-training behavioral paradigm to examine how the hippocampus interacts with visual cortex during predictive and nonpredictive actions learned either three days earlier or immediately before the scan. Just-learned associations led to comparable background connectivity between the hippocampus and V1/V2, regardless of whether actions predicted outcomes. However, three-day-old associations led to stronger background connectivity and greater differentiation between neural patterns for predictive vs. nonpredictive actions. Hippocampal prediction may initially reflect indiscriminate binding of co-occurring of events, with action information pruning weaker associations and leading to more selective and accurate predictions over time.
Genetic differences in host infectivity affect disease spread and survival in epidemics
Authors: Anacleto Osvaldo , Cabaleiro Santiago , Villanueva Beatriz , Saura María , Houston Ross D. , Woolliams John A. , Doeschl-Wilson Andrea B.
Published: December 2018

Survival during an epidemic is partly determined by host genetics. While quantitative genetic studies typically consider survival as an indicator for disease resistance, mortality rates of populations undergoing an epidemic are also affected by tolerance and infectivity (i.e. the propensity of an infected individual to transmit disease). Few studies have demonstrated genetic variation in disease tolerance, and no study has demonstrated genetic variation in host infectivity, despite strong evidence for considerable phenotypic variation in this trait. Here we propose an experimental design and statistical models for estimating genetic diversity in all three host traits. Using an infection model in fish we provide, for the first time, direct evidence for genetic variation in host infectivity, in addition to variation in resistance and tolerance. We also demonstrate how genetic differences in these three traits contribute to survival. Our results imply that animals can evolve different disease response types affecting epidemic survival rates, with important implications for understanding and controlling epidemics.
How to improve foraging efficiency for restocking measures of juvenile Baltic sturgeon (Acipenser oxyrinchus)
Authors: Cámara-Ruiz Maria , Santo Carlos Espirito , Gessner Joern , Wuertz Sven
Published: December 2018

Atlantic sturgeon (Acipenser oxyrinchus), also known as Baltic sturgeon, is considered missing or extinct in German waters. Current conservation efforts focus on re-stocking activities, but classical hatchery rearing may reduce the fitness of the respective juveniles. In this study, we evaluated if foraging efficiency can be improved by short term training. Over a period of 14 d, we kept individuals of the training group in a raceway and fed them chironomids buried in a small sand spot to stimulate benthic feeding behavior while fish of the control group were fed in tanks without substrate. Thereafter, each fish was transferred to a raceway entirely covered with sand. For feeding, chironomids were randomly buried in the sand. During the first 7 days, trained fish recovered the feed significantly faster than untrained fish of the control group. Gene expression revealed an up-regulation in neurod1 in all brain regions after 14 d of training. Thus, this study suggests that foraging efficiency can be improved through short-time training thus improve fitness upon restocking into the wild.
NucMerge: Genome assembly quality improvement assisted by alternative assemblies and paired-end Illumina reads
Authors: Khelik Ksenia , Nederbragt Alexander Johan , Sandve Geir Kjetil , Rognes Torbjørn
Published: December 2018

Background

In spite of the major breakthroughs in the second-generation sequencing technologies and the developments of a plethora of assemblers over the last ten years, the resulting genome assemblies may still be fragmented and contain errors. It is typical in genome projects with second-generation reads involved to run multiple assemblers with different parameters and choose the best assembly. However, such an approach is always a trade-off between the strengths and weaknesses of the assemblies. To exploit the advantages of different assemblers, an alternative approach that combines the best parts of several assemblies into one may be applied. The existing tools based on such an approach assist in elongation of assembly fragments and/or improvement of assembly accuracy. Though there has been progress with such a strategy, there is still room for improvement of the existing tools.

Results

We present NucMerge, a tool for improving genome assembly accuracy by incorporating information derived from an alternative assembly and paired-end Illumina reads from the same genome. The tool corrects insertion, deletion, substitution, and inversion errors and locates different inter- and intra-chromosomal rearrangement errors. NucMerge was compared to two existing alternatives, namely Metassembler and GAM-NGS.

Conclusions

The benchmarking results show that NucMerge has generally better performance than the other tools tested, providing accuracy improvement of more assemblies. NucMerge is freely available at https://github.com/uio-bmi/NucMerge under the MPL license.
A critical role for human ventromedial frontal lobe in value comparison based on multi-attribute configuration
Authors: Pelletier Gabriel , Fellows Lesley K.
Published: December 2018

Real-life decisions are often between options with multiple value-relevant attributes. Neuroeconomic models propose that the value associated with each attribute is integrated in a global value for each option. However, evidence from patients with ventromedial frontal (VMF) damage argues against a very general role for this region in value integration, suggesting instead that it contributes critically to specific value inference or comparison processes. Here, we tested value-based decision-making between artificial multi-attribute objects in 12 men and women with focal damage to VMF, compared to a healthy control group (N=24) and a control group with frontal lobe damage sparing VMF (N=12). In a ‘configural’ condition, overall object value was predicted by the conjunction of two attributes, while in an ‘elemental’ condition, object value could be assessed by combining the independent values of individual attributes. Patients with VMF damage were impaired in making choices when value was uniquely predicted by the configuration of attributes, but intact when choosing based on elemental attribute-values. This is evidence that VMF is critical for inferring the value of whole objects in multi-attribute choice. These findings have implications for models of value-based choice, and add to emerging views of how this region may interact with medial temporal lobe systems involved in configural object processing and relational memory.
Nanoparticle-based local translation reveals mRNA as translation-coupled scaffold with anchoring function
Authors: Kashida Shunnichi , Wang Dan Ohtan , Saito Hirohide , Gueroui Zoher
Published: December 2018

Spatial regulations of mRNA translation are central to cellular functions and relies on numerous complex processes. Biomimetic approaches could bypass the endogenous complex processes, improve our comprehension, and allow for controlling local translation regulations and functions. However, the causality between localizing translation and nascent protein function remains elusive. Here, we develop a novel nanoparticle-based strategy to magnetically control mRNA spatial patterns in mammalian cell extracts and investigate how local translation impacts nascent protein localization and function. By monitoring translation on magnetically localized mRNAs, we show that mRNA-nanoparticle operates as a source for the continuous production of proteins from defined positions. By applying magnetic localization of mRNAs coding for Actin Binding Proteins, we trigger the local formation of actin cytoskeleton and identify minimal requirements for spatial control of actin filament network. In addition, our bottom-up approach identifies a novel role of mRNA as translation-coupled scaffold for nascent N-terminal protein domain functions. Our approach will serve as a novel platform for regulating mRNA localization and investigating a functional role of nascent protein domains during translation.
Optimal metabolic states in cells
Authors: Liebermeister Wolfram
Published: December 2018

Cells, in order to thrive, make efficient use of metabolites, proteins, energy, membrane space, and time. How, for example, should they allocate the available amount of protein to different metabolic pathways or cell functions? To model metabolic behaviour as an economic problem, some flux analysis model, kinetic models, and cell models apply optimality principles. However, due to their different assumptions these models are hard to compare and combine. Benefits and costs of metabolic pathways – e.g. favouring high production fluxes and low metabolite and enzyme cost – can be derived from general fitness objectives such as fast cell growth. To define pathway objectives, we may assume “optimistically” that, given a pathway state, any cell variables outside the pathway will be chosen for maximal fitness. The resulting fitness defines an effective pathway objective as a function of the pathway variables. Here I propose a unified theory that considers kinetic models, describes the set of feasible states as a state manifold and score each state by cost and benefit functions for fluxes, metabolite concentrations, and enzyme levels. To screen the state manifold and to find optimal states, the problem can be projected into flux, metabolite, or enzyme space, where effective cost and benefit functions are used. We reobtain existing modelling approaches such as enzyme cost minimisation or nonlinear versions of Flux Balance Analysis. Due to their common origin, the different approaches share mathematical optimality conditions of the same form. A general theory of optimal metabolic states, as proposed here, provides a logical link between existing modelling approaches and can help justify, interconvert, and combine metabolic optimality problems.
Evolution of dispersal can rescue populations from expansion load
Authors: Peischl Stephan , Gilbert Kimberly J.
Published: December 2018

Understanding the causes and consequences of range expansions or range shifts has a long history in evolutionary biology. Recent theoretical, experimental, and empirical work has identified two particularly interesting phenomena in the context of species range expansions: (i) gene surfing and the relaxation of natural selection, and (ii) spatial sorting. The former can lead to an accumulation of deleterious mutations at range edges, causing an expansion load and slowing down expansion. The latter can create gradients in dispersal-related traits along the expansion axis and cause an acceleration of expansion. We present a theoretical framework that treats spatial sorting and gene surfing as spatial versions of natural selection and genetic drift, respectively. This model allows us to study analytically how gene surfing and spatial sorting interact, and to derive the probability of fixation of pleiotropic mutations at the expansion front. We use our results to predict the co-evolution of mean fitness and dispersal rates, taking into account the effects of random genetic drift, natural selection and spatial sorting, as well as correlations between fitnessand dispersal-related traits. We identify a “rescue effect” of spatial sorting, where the evolution of higher dispersal rates at the leading edge rescues the population from incurring expansion load.
The value structure of metabolic states
Authors: Liebermeister Wolfram
Published: December 2018

To improve their metabolic performance, cells need to find compromises between high metabolic fluxes, low enzyme investments, and well-adapted metabolite concentrations. In mathematical models, such compromises can be described by optimality problems that trade metabolic benefit against enzyme cost. While many such modelling frameworks exist, they are often hard to compare and combine. To unify these modelling approaches, I propose a theory that characterises metabolic systems by a value structure, that is, a pattern of local costs and benefits assigned to all elements in the network. The economic values of metabolites, fluxes, and enzymes are interlinked by local balance equations. Formally defined as shadow values, the economic variables serve as local proxies for benefits that arise anywhere in the network, but are represented as local costs or benefits in the reaction of interest. Here I derive economic variables and their balance equations for kinetic, stoichiometric, and cell models. Metabolic value theory provides a new perspective on biochemical networks, defines concepts for comparing and combining metabolic optimality problems, and is useful for semi-automatic, layered, and modular modelling.
Effects of FLOWERING LOCUS T on FD during the transition to flowering at the shoot apical meristem of Arabidopsis thaliana
Authors: Collani Silvio , Neumann Manuela , Yant Levi , Schmid Markus
Published: December 2018

The transition to flowering is a crucial step in the plant life cycle that is controlled by multiple endogenous and environmental cues, including hormones, sugars, temperature, and photoperiod. Permissive photoperiod induces FLOWERING LOCUS T (FT) in the phloem companion cells of leaves. The FT protein then acts as a florigen that is transported to the shoot apical meristem (SAM) where it physically interacts with the bZIP transcription factor FD and 14-3-3 proteins. However, despite the importance of FD for promoting flowering, its direct transcriptional targets are largely unknown. Here we combined ChIP-seq and RNA-seq to identify targets of FD at the genome-wide scale and assess the contribution of FT to binding DNA. We further investigated the ability of FD to form protein complexes with FT and TFL1 through the interaction with 14-3-3 proteins. Importantly, we observe direct binding of FD to targets involved in several aspects of the plant development not directly related to the regulation of flowering time. Our results confirm FD as central regulator of the floral transition at the shoot meristem and provides evidence for crosstalk between the regulation of flowering and other signaling pathways.

Material Distribution

The author responsible for distribution of materials integral to the findings presented in this article in accordance with the policy described in the Instructions for Authors (www.cell.com/molecular-plant/authors): Markus Schmid (markus.schmid@umu.se).

Contact Information

Umeå Plant Science Centre (UPSC), Dept. of Plant Physiology Umeå University, SE-901 87 Umeå, SWEDEN
Expanded genomic analyses for male voice-breaking highlights a shared phenotypic and genetic basis between puberty timing and hair colour
Authors: Hollis Ben , Day Felix R. , Busch Alexander S. , Thompson Deborah J. , Soares Ana Luiza G. , Timmers Paul R.H.J. , Kwong Alex , Easton Doug F. , Joshi Peter K. , Timpson Nicholas J. ,   The PRACTICAL Consortium,   23andMe Research Team, Ong Ken K. , Perry John R.B.
Published: December 2018

The timing of puberty is highly variable and has important consequences for long-term health. Most of our understanding of the genetic control of puberty timing is based on studies in women, as age at menarche is often recorded. Here, we report a multi-trait genome-wide association study for male puberty timing, based on recalled timing of voice breaking and facial hair, with an effective sample size of 205,354 men, nearly four-fold larger than previously reported. We identify 78 independent signals for male puberty timing, including 29 signals not previously associated with puberty in either sex. Novel mechanisms include an unexpected phenotypic and genetic link between puberty timing and natural hair colour, possibly reflecting common effects of pituitary hormones on puberty and pigmentation. Earlier male puberty timing is genetically correlated with several adverse health outcomes and, in Mendelian randomization analyses, shows causal relationships with higher risk of prostate cancer and shorter lifespan. These findings highlight the relationships between puberty timing and later health outcomes, and demonstrate the value of genetic studies of puberty timing in both sexes.
CDK12 loss in cancer cells affects DNA damage response genes through premature cleavage and polyadenylation
Authors: Krajewska Malgorzata , Dries Ruben , Grassetti Andrew V. , Dust Sofia , Gao Yang , Huang Hao , Sharma Bandana , Day Daniel S. , Kwiatkowski Nicholas , Pomaville Monica , Dodd Oliver , Chipumuro Edmond , Zhang Tinghu , Greenleaf Arno L. , Yuan Guo-Cheng , Gray Nathanael S. , Young Richard A. , Geyer Matthias , Gerber Scott A. , George Rani E.
Published: December 2018

The cyclin-dependent kinase 12 (CDK12) modulates transcription elongation by phosphorylating the carboxy-terminal domain of RNA polymerase II and appears to selectively affect the expression of DNA damage response (DDR) and mRNA processing genes. Yet, the mechanism(s) by which it achieves this selectivity remains unclear. Using a highly selective CDK12/13 inhibitor, THZ531, and nascent RNA sequencing, we show that CDK12 inhibition results in gene length-dependent elongation defects, leading to premature cleavage and polyadenylation (PCPA) as well as loss of expression of long (>45 kb) genes, a substantial proportion of which participate in the DDR. This early termination phenotype correlated with an increased proportion of intronic polyadenylation sites, a feature that was especially prominent among DDR genes. Finally, phosphoproteomic analysis indicated that pre-mRNA processing factors, including those involved in PCPA, are direct phosphotargets of CDKs 12 and 13. These results support a model in which DDR genes are uniquely susceptible to CDK12 inhibition due primarily to their relatively longer lengths and lower ratios of U1 snRNP binding to intronic polyadenylation sites.
Modelling cost-effectiveness of tenofovir for prevention of mother to child transmission of hepatitis B virus infection in South Africa
Authors: Mokaya Jolynne , Burn Edward , Tamandjou Cynthia Raissa , Goedhals Dominique , Barnes Eleanor , Andersson Monique , Pinedo-Villanueva Rafael , Matthews Philippa C
Published: December 2018

In light of sustainable development goals for 2030, an important priority for Africa is to have affordable, accessible and sustainable hepatitis B virus (HBV) prevention of mother to child transmission (PMTCT) programmes, delivering screening and treatment for antenatal women and implementing timely administration of HBV vaccine for their babies. We developed a decision-analytic model simulating 10,000 singleton pregnancies to assess the cost-effectiveness of three possible strategies for deployment of tenofovir in pregnancy, in combination with routine infant vaccination: S1: no screening nor antiviral therapy; S2: screening and antiviral prophylaxis for all women who test HBsAg-positive; S3: screening for HBsAg, followed by HBeAg testing and antiviral prophylaxis for women who are HBsAg-positive and HBeAg-positive. Our outcome was cost per infant HBV infection avoided and the analysis followed a healthcare perspective. S1 predicts 45 infants would be HBV-infected at six months of age, compared to 21 and 28 infants in S2 and S3, respectively. Relative to S1, S2 had an incremental cost of $3,940 per infection avoided. S3 led to more infections and higher costs. Given the long-term health burden for individuals and economic burden for society associated with chronic HBV infection, screening pregnant women and providing tenofovir for all who test HBsAg+ may be a cost-effective strategy for South Africa.
A cell-of-origin epigenetic tracer reveals clinically distinct subtypes of high grade serous ovarian cancer
Authors: Riso Pietro Lo , Villa Carlo Emanuele , Gasparoni Gilles , Luongo Raffaele , Manfredi Anna , Vingiani Andrea , Jungmann Annemarie , Garbi Annalisa , Lupia Michela , Laise Pasquale , Das Vivek , Pruneri Giancarlo , Viale Giuseppe , Colombo Nicoletta , Cavallaro Ugo , Cacchiarelli Davide , Walter Jörn , Testa Giuseppe
Published: December 2018

High grade serous ovarian cancer (HGSOC) is a major unmet need in oncology. The persistent uncertainty on its originating tissue has contributed to hamper the discovery of oncogenic pathways and effective therapies. Here we define the DNA methylation print that distinguishes the human fimbrial (FI) and ovarian surface epithelia (OSE) and develop a robust epigenetic cell-of-origin tracer that stratifies HGSOC in FI-and OSE-originated tumors across all available cohorts. We translate this origin-based stratification into a clinically actionable transcriptomic signature, demonstrating its prognostic impact on patients’ survival and identifying novel network level dysregulations specific for the two disease subtypes.
QTG-Finder: a machine-learning based algorithm to prioritize causal genes of quantitative trait loci
Authors: Lin Fan , Fan Jue , Rhee Seung Y.
Published: December 2018

Linkage mapping is one of the most commonly used methods to identify genetic loci that determine a trait. However, the loci identified by linkage mapping may contain hundreds of candidate genes and require a time-consuming and labor-intensive fine mapping process to find the causal gene controlling the trait. With the availability of a rich assortment of genomic and functional genomic data, it is possible to develop a computational method to facilitate faster identification of causal genes. We developed QTG-Finder, a machine learning based algorithm to prioritize causal genes by ranking genes within a quantitative trait locus (QTL). Two predictive models were trained separately based on known causal genes in Arabidopsis and rice. With an independent validation analysis, we demonstrate the models can correctly prioritize about 65% and 60% of Arabidopsis and rice causal genes when the top 20% ranked genes were considered. The models can prioritize different types of traits though at different efficiency. We also identified several important features of causal genes including paralog copy number, being a transporter, being a transcription factor, and containing SNPs that cause premature stop codon. This work lays the foundation for systematically understanding characteristics of causal genes and establishes a pipeline to predict causal genes based on public data.

One sentence summary

We systematically analyzed the genomic characteristics of causal genes in QTLs and developed a novel computational tool to prioritize causal genes.
A novel photoactivatable tool for intermediate filament disruption indicates a role for keratin filaments in early embryogenesis
Authors: Sanghvi-Shah Rucha , Paranjpe Shalaka , Baek Jiyeon , Dobrowolski Radek , Weber Gregory F.
Published: December 2018

The significance of cytoplasmic intermediate filament proteins has previously been examined largely through various genetic approaches, including knockdown, knockout and transgenic overexpression. Few studies to date have attempted to examine the role of specifically the filamentous intermediate filament network in orchestrating various cell functions. To directly assess the role of the filamentous keratin intermediate filament network in regulation of cellular behavior, we created aPhotoActivatabledisruptor of keratin IntermediateFilaments (PA-dIF). This genetically encoded construct consists of a peptide derived from the 2B2 region of Keratin 8 fused to the photosensitive LOV2 domain fromAvena sativaphototropin-1. Upon 458 nm photoirradiation, PA-dIF disrupts keratin intermediate filaments in multiple species and cell types. Marked remodeling of the keratin intermediate filament network accompanies collective cellular morphogenetic movements that occur during gastrulation and neurulation in theXenopus laevisfrog embryo. Light-based activation of PA-dIF was able to disrupt keratin intermediate filaments inXenopuscells and lead to tissue-specific disruption of morphogenetic processes. Altogether our data show a fundamental requirement for keratin intermediate filaments in orchestrating morphogenetic movements during early embryonic development that have yet to be revealed in other model systems. Moreover, our data validate the utility of a new genetically encoded photoactivatable tool for the disruption and examination of intermediate filaments.
A structure-based model for the electrostatic interaction of the N-terminus of protein tau with the fibril core of Alzheimer’s Disease filaments
Authors: Boyer David R. , Eisenberg David S.
Published: December 2018

Although portions of tau protein within the microtubule binding region have been shown to form the ordered core of tau filaments, the structural details of how other regions of tau participate in filament formation are so far unknown. In an attempt to understand how the N-terminus of tau may interact with fibril core, we crystallized and determined the structure of the N-terminal segment 5RQEFEV10 of tau. Several lines of evidence have shown the importance of this segment for fibril formation. The crystal structure reveals an out-of-register Class 5 steric zipper with a wet and a dry interface. To examine the possible interaction of 5RQEFEV10 with the tau fibril core, we modeled the binding of the wet interface of the 5RQEFEV10 structure with the 313VDLSKVTSKC322 region of the Alzheimer’s Disease tau filament structures. This model is consistent with, and helps to explain previous findings on the possible interaction of these two segments, distant in sequence. In addition, we discuss the possible conservation of this interaction across multiple polymorphs of tau.
When does uncertainty avoidance promote customer-to-customer intercultural service encounters?
Authors: Ghantous Nabil , Maher Amro A.
Published: December 2018

Purpose

Previous literature has reported inconsistent findings regarding the impact of uncertainty avoidance (UA) on intercultural experiences. This includes positive, negative and insignificant associations between UA on the one hand and cosmopolitanism or comfort with intercultural service encounters (ICSE) on the other hand. The purpose of this paper is to participate in addressing these contradictions. More specifically, this study examines how UA affects expatriate cosmopolitanism as well as approach of service environments patronized by local customers by introducing two moderators: national identification and perceived discrimination.

Design/methodology/approach

The authors propose a conceptual model based on the results of a literature review. The authors test it with survey data collected from Indian expatriates (n=341) living in Qatar, using structural equation modeling.

Findings

The results corroborate the moderating role of national identification. Under low identification, expatriate consumers engage in a prospective form of uncertainty management, leading them to adopt a more cosmopolitan stance. Under high identification, their uncertainty plays an inhibitory role, reducing their cosmopolitanism and negatively affecting their approach of service places patronized by local consumers. Perceived discrimination did not moderate the impact of UA as expected on either cosmopolitanism or approach.

Originality/value

This paper extends the prior research on UA by testing how two moderators could activate either a prospective or an inhibitory form of uncertainty. It also contributes to research on ICSE, by focusing on customer-to-customer interactions in a multicultural marketplace.
Impedance control of collaborative robots based on joint torque servo with active disturbance rejection
Authors: Ren Tianyu , Dong Yunfei , Wu Dan , Chen Ken
Published: December 2018

Purpose

The purpose of this paper is to present a simple yet effective force control scheme for collaborative robots by addressing the problem of disturbance rejection in joint torque: inherent actuator flexibility and nonlinear friction.

Design/methodology/approach

In this paper, a joint torque controller with an extended state observer is used to decouple the joint actuators from the multi-rigid-body system of a constrained robot and compensate the motor friction. Moreover, to realize robot force control, the authors embed this controller into the impedance control framework.

Findings

Results have been given in simulations and experiments in which the proposed joint torque controller with an extended state observer can effectively estimate and compensate the total disturbance. The overall control framework is analytically proved to be stable, and further it is validated in experiments with a robot testbed.

Practical implications

With the proposed robot force controller, the robot is able to change its stiffness in real time and therefore take variable tasks without any accessories, such as the RCC or 6-DOF F/T sensor. In addition, programing by demonstration can be realized easily within the proposed framework, which makes the robot accessible to unprofessional users.

Originality/value

The main contribution of the presented work is the design of a model-free robot force controller with the ability to reject torque disturbances from robot-actuator coupling effect and motor friction, applicable for both constrained and unconstrained environments. Simulation and experiment results from a 7-DOF robot are given to show the effectiveness and robustness of the proposed controller.
Endogenous consumers’ preferences as drivers of green corporate social responsibility
Authors: Barboza Gustavo
Published: December 2018

Purpose

This paper’s main objective is to expand the demand-driven strategic field by developing a model where endogenization of consumers’ preferences for clean(er) products becomes the driver of the firm green corporate social responsible (GCSR) profit maximization behavior.

Design/methodology/approach

The model proposes that in undifferentiated markets, firms using a conventional technology manage production-related negative externalities via information asymmetries. In turn, when consumer socially responsible individuals (CnSR) discover the nature of the information asymmetries, they then reveal their preferences. The building block of the model is that CnSR derive value both from intrinsic as well as extrinsic product features, and derive negative satisfaction from the production negative externalities. In turn, CnSR preferences offer a higher willingness to pay for a combined intrinsic (private good and direct utility) and extrinsic (public good and feel good–do good utility) product.

Findings

The model demonstrates that the firm’s GCSR behavior is a technological-driven process directly affecting the extrinsic component of the product through the development of a safe technology, and exclusively targeting CnSR type of consumers. The corollary of the model is that for the firm pursuing a GCSR behavior, the development of a competitive advantage with higher firm performance leads to profit maximization when exclusively serving the GCSR segment of the market. Thus, GCSR is the result of unusual innovation efforts.

Originality/value

This paper presents a model that expands the field of strategic management through the demand-driven incorporation and respective modeling. To the best of the author’s knowledge, this is the first model to explicitly develop this relationship in this format.
The discrete and differential impact of monetary policy
Authors: McCredie Bronwyn
Published: December 2018

This study exploits a unique feature of the Australian monetary policy environment to determine whether economic recovery can be stimulated via central bank communications. This study finds that unexpected monetary policy announcements and communications have a significant and comparable impact on the value and volatility of the Australian foreign exchange market, suggesting that they can be used interchangeably to stimulate economic recovery. However, further analysis reveals that the state of the economy influences this impact. Specifically, during poor economic states, monetary policy actions speak louder than words, an adage that in this context provides actionable information for central bank regulators.
Uterotonics in elective caesarean delivery: a randomised non‐inferiority study comparing carbetocin 20 μg and 100 μg
Authors: Tabl S. , Balki M. , Downey K. , Tomlinson G. , Farine D. , Seaward G. , Carvalho J. C. A.
Published: December 2018

Postpartum haemorrhage is the leading cause of maternal mortality worldwide and prophylactic uterotonic drug administration after the delivery of the infant is advised. Carbetocin is recommended as an uterotonic, but the minimum effective dose has not been verified. We compared the efficacy of two doses of intravenous carbetocin (20 μg and 100 μg) in women undergoing elective caesarean delivery. This was a randomised, double‐blind, non‐inferiority study in women at low risk of postpartum haemorrhage. Carbetocin was administered on delivery of the anterior shoulder of the neonate. Uterine tone was assessed by the obstetrician 2 min and 5 min after carbetocin administration according to an 11‐point numerical rating scale (0 = atonic uterus and 10 = firm uterus). The primary outcome was uterine tone 2 min after carbetocin administration. The pre‐specified non‐inferiority margin was 1 point on the 11‐point scale. Secondary outcomes included: uterine tone at 5 min; use of additional uterotonics within 24 h; blood loss; and adverse effects. Data were available for 53 women in the carbetocin‐20 group and for 55 women in the carbetocin‐100 group. The mean (SD) uterine tone at 2 min was 7.5 (1.9) in the carbetocin‐20 group and 8.0 (1.5) in the carbetocin‐100 group. The lower limit of the one‐sided 95%CI for the mean difference was outside the non‐inferiority margin (at −1.1; p = 0.11) meaning non‐inferiority of carbetocin 20 μg compared with carbetocin 100 μg could not be confirmed. However, the secondary outcome measures of uterine tone at 5 min, blood loss and use of additional uterotonics were similar in both groups.