bluuebunny/crossref_metadata_2025 huggingface dataset:
CRNET: an efficient sampling approach to infer functional regulatory networks by integrating large-scale ChIP-seq and time-course RNA-seq data
Authors: Chen Xi , Gu Jinghua , Wang Xiao , Jung Jin-Gyoung , Wang Tian-Li , Hilakivi-Clarke Leena , Clarke Robert , Xuan Jianhua
Published: December 2017

Motivation

NGS techniques have been widely applied in genetic and epigenetic studies. Multiple ChIP-seq and RNA-seq profiles can now be jointly used to infer functional regulatory networks (FRNs). However, existing methods suffer from either oversimplified assumption on transcription factor (TF) regulation or slow convergence of sampling for FRN inference from large-scale ChIP-seq and time-course RNA-seq data.

Results

We developed an efficient Bayesian integration method (CRNET) for FRN inference using a two-stage Gibbs sampler to estimate iteratively hidden TF activities and the posterior probabilities of binding events. A novel statistic measure that jointly considers regulation strength and regression error enables the sampling process of CRNET to converge quickly, thus making CRNET very efficient for large-scale FRN inference. Experiments on synthetic and benchmark data showed a significantly improved performance of CRNET when compared with existing methods. CRNET was applied to breast cancer data to identify FRNs functional at promoter or enhancer regions in breast cancer MCF-7 cells. Transcription factor MYC is predicted as a key functional factor in both promoter and enhancer FRNs. We experimentally validated the regulation effects of MYC on CRNET-predicted target genes using appropriate RNAi approaches in MCF-7 cells.

Availability and implementation

R scripts of CRNET are available at http://www.cbil.ece.vt.edu/software.htm.

Supplementary information

Supplementary data are available at Bioinformatics online.
mTM-align: an algorithm for fast and accurate multiple protein structure alignment
Authors: Dong Runze , Peng Zhenling , Zhang Yang , Yang Jianyi
Published: December 2017

Motivation

As protein structure is more conserved than sequence during evolution, multiple structure alignment can be more informative than multiple sequence alignment, especially for distantly related proteins. With the rapid increase of the number of protein structures in the Protein Data Bank, it becomes urgent to develop efficient algorithms for multiple structure alignment.

Results

A new multiple structure alignment algorithm (mTM-align) was proposed, which is an extension of the highly efficient pairwise structure alignment program TM-align. The algorithm was benchmarked on four widely used datasets, HOMSTRAD, SABmark_sup, SABmark_twi and SISY-multiple, showing that mTM-align consistently outperforms other algorithms. In addition, the comparison with the manually curated alignments in the HOMSTRAD database shows that the automated alignments built by mTM-align are in general more accurate. Therefore, mTM-align may be used as a reliable complement to construct multiple structure alignments for real-world applications.

Availability and implementation

http://yanglab.nankai.edu.cn/mTM-align

Supplementary information

Supplementary data are available at Bioinformatics online.
Initial in vitro testing of a paediatric continuous-flow total artificial heart
Authors: Fukamachi Kiyotaka , Karimov Jamshid H , Horvath David J , Sunagawa Gengo , Byram Nicole A , Kuban Barry D , Moazami Nader
Published: December 2017

OBJECTIVES

Mechanical circulatory support has become standard therapy for adult patients with end-stage heart failure; however, in paediatric patients with congenital heart disease, the options for chronic mechanical circulatory support are limited to paracorporeal devices or off-label use of devices intended for implantation in adults. Congenital heart disease and cardiomyopathy often involve both the left and right ventricles; in such cases, heart transplantation, a biventricular assist device or a total artificial heart is needed to adequately sustain both pulmonary and systemic circulations. We aimed to evaluate the in vitro performance of the initial prototype of our paediatric continuous-flow total artificial heart.

METHODS

The paediatric continuous-flow total artificial heart pump was downsized from the adult continuous-flow total artificial heart configuration by a scale factor of 0.70 (1/3 of total volume) to enable implantation in infants. System performance of this prototype was evaluated using the continuous-flow total artificial heart mock loop set to mimic paediatric circulation. We generated maps of pump performance and atrial pressure differences over a wide range of systemic vascular resistance/pulmonary vascular resistance and pump speeds.

RESULTS

Performance data indicated left pump flow range of 0.4–4.7 l/min at 100 mmHg delta pressure. The left/right atrial pressure difference was maintained within ±5 mmHg with systemic vascular resistance/pulmonary vascular resistance ratios between 1.4 and 35, with/without pump speed modulation, verifying expected passive self-regulation of atrial pressure balance.

CONCLUSIONS

The paediatric continuous-flow total artificial heart prototype met design requirements for self-regulation and performance; in vivo pump performance studies are ongoing.
Tool for filtering PubMed search results by sample size
Authors: Baladrón Carlos , Santos-Lozano Alejandro , Aguiar Javier M , Lucia Alejandro , Martín-Hernández Juan
Published: December 2017

Objective

The most used search engine for scientific literature, PubMed, provides tools to filter results by several fields. When searching for reports on clinical trials, sample size can be among the most important factors to consider. However, PubMed does not currently provide any means of filtering search results by sample size. Such a filtering tool would be useful in a variety of situations, including meta-analyses or state-of-the-art analyses to support experimental therapies. In this work, a tool was developed to filter articles identified by PubMed based on their reported sample sizes.

Materials and Methods

A search engine was designed to send queries to PubMed, retrieve results, and compute estimates of reported sample sizes using a combination of syntactical and machine learning methods. The sample size search tool is publicly available for download at http://ihealth.uemc.es. Its accuracy was assessed against a manually annotated database of 750 random clinical trials returned by PubMed.

Results

Validation tests show that the sample size search tool is able to accurately (1) estimate sample size for 70% of abstracts and (2) classify 85% of abstracts into sample size quartiles.

Conclusions

The proposed tool was validated as useful for advanced PubMed searches of clinical trials when the user is interested in identifying trials of a given sample size.
Dynamics of the Immune Response in Acute Hepatitis B Infection
Authors: Stelma Femke , Willemse Sophie B , Erken Robin , de Niet Annikki , Sinnige Marjan J , van Dort Karel , Zaaijer Hans L , van Leeuwen Ester M M , Kootstra Neeltje A , Reesink Hendrik W
Published: December 2017

Background

Acute hepatitis B virus infection in adults is generally self-limiting but may lead to chronicity in a minority of patients.

Methods

We included 9 patients with acute hepatitis B virus (HBV) infection and collected longitudinal follow-up samples. Natural killer (NK) cell characteristics were analyzed by flowcytometry. HBV-specific T-cell function was analyzed by in vitro stimulation with HBV peptide pools and intracellular cytokine staining.

Results

Median baseline HBV DNA load was 5.12 log IU/mL, and median ALT was 2652 U/mL. Of 9 patients, 8 cleared HBsAg within 6 months whereas 1 patient became chronically infected. Early time points after infection showed increased CD56bright NK cells and an increased proportion of cells expressing activation markers. Most of these had normalized at week 24, while the proportion of TRAIL-positive CD56bright NK cells remained high in the chronically infected patient. In patients who cleared HBV, functional HBV-specific CD8+ and CD4+ responses could be observed, whereas in the patient who developed chronic infection, only low HBV-specific T-cell responses were observed.

Conclusions

NK cells are activated early in the course of acute HBV infection. Broad and multispecific T-cell responses are observed in patients who clear acute HBV infection, but not in a patient who became chronically infected.
Discovery of Negative-Sense RNA Viruses in Trees Infected with Apple Rubbery Wood Disease by Next-Generation Sequencing
Authors: Rott Michael E. , Kesanakurti Prasad , Berwarth Constanze , Rast Heidi , Boyes Ian , Phelan James , Jelkmann Wilhelm
Published: December 2017

Apple rubbery wood is a disease of apple found around the world, often associated with Apple flat limb disease, and regulated in many countries. Despite its long history in apple cultivation, the disease’s causal agent has remained elusive. In this study, next-generation sequencing (NGS) was used to identify and characterize several related novel viral agents from apple rubbery wood-infected plants, which have been named Apple rubbery wood virus (ARWV) 1 and 2. Additional specimens with apple rubbery wood disease tested positive by polymerase chain reaction with primers designed to ARWV 1 and 2 genomic RNA segments. In an NGS-based screening of over 100 Malus and 100 Prunus specimens from a collection of virus-infected trees, only one Malus specimen was found to be infected with ARWV not known to be infected with the disease, which strongly suggests that ARWV is not commonly found in Malus spp. or other fruit trees. The two viruses are most closely related to members of the order Bunyavirales. Three RNA segments (large, medium, and small) were characterized and the viruses likely represent a new genus under the family Phenuiviridae, with a suggested name of Rubodvirus (Rubbery wood virus).
Surgical Treatment of Unicoronal Synostosis
Authors: Kalantar Hormozi Abdoljalil , Daryani Amir , Zali Alireza , Mohammadi Hasan Reza , Shahverediani Reza , Eskandarloo Mehdi
Published: December 2017

Background:

Although referrals for nonsyndromic frontal plagiocephaly have been increased during the past several years, successful surgical repair of unicoronal synostosis (UCS) remains a challenge for craniofacial surgeons. Most surgical techniques followed to correct supraorbital rim elevation and temporal constrictions are being noticed less and often require a secondary revision. But this new technique consists of correcting the affected ipsilateral frontal, temporal, and superior orbital rim areas in the first operation.

Methods:

From 1995 to 2016, a total of 154 cases of UCS were operated by first author. A total of 91 patients were operated with standard technique, whereas the new technique was applied on 63. Whitaker scoring system was used for evaluation of patients after surgery.

Results:

Data analysis shows a significant difference between 2 operation techniques results (P 
= 0.007). None of the patients from the new technique group required revision surgery.

Conlusions:

We believe that our new technique have less invasive osteotomy on the frontal bone and no manipulation of the orbital bone, so provide sufficient bone graft and is applicable even for younger patients (<6 months).
Inferior Parietal Cortex Hypoperfusion is the Most Specific Imaging Marker for AD Patients With Positive CSF Biomarker Assays in a Memory Clinic in France
Authors: Andriuta Daniela , Moullart Véronique , Schraen Susanna , Devendeville Agnes , Meyer Marc-Etienne , Godefroy Olivier
Published: December 2017

The diagnostic accuracy of hexamethylpropyleneamine oxime (HMPAo) single-photon emission computed tomography (SPECT) in Alzheimer disease (AD) remains undetermined in a “real-life” clinical population. The objective was to determine the HMPAo SPECT hypoperfusion pattern in cognitively impaired patients with positive CSF AD biomarker and to evaluate its diagnostic accuracy. This study included 120 patients referred to a university memory clinic assessed using HMPAo SPECT, MRI, and CSF biomarkers. Three biomarker signatures suggestive of AD were analyzed (1, Aß1-42; 2, Aß1-42+t-tau and/or p-tau; 3, Aß1-42/p-tau). The clinical diagnoses were possible AD (n=29) or other causes of cognitive impairment (n=91). All CSF AD signatures were significantly (1, P=0.004; 2, P=0.017; 3, P=0.024) associated with the difference between inferior parietal perfusion and lateral dorsal frontal cortex perfusion. The hypoperfusion pattern discriminated between patients with positive CSF AD biomarkers and those with other cognitive impairments with a sensitivity of 67% to 71% and a specificity of 63% to 65% and a greatest negative predictive value (NPV) of 90%. Inferior parietal cortex hypoperfusion was the most sensitive and specific feature in AD patients diagnosed using clinical and CSF biomarker criteria. This hypoperfusion pattern was associated with an NPV of 90% and therefore discriminated sharply between AD and other cognitive disorders.
Microwave-assisted direct synthesis of butene from high-selectivity methane
Authors: Lu Yi-heng , Li Kang , Lu Yu-wei
Published: December 2017

Methane was directly converted to butene liquid fuel by microwave-induced non-oxidative catalytic dehydrogenation under 0.1–0.2 MPa. The results show that, under microwave heating in a two-stage fixed-bed reactor, in which nickel powder and NiO

x

–MoO
y
/SiO
2
are used as the catalyst, the methane–hydrogen mixture is used as the raw material, with no acetylene detected. The methane conversion is more than 73.2%, and the selectivity of methane to butene is 99.0%. Increasing the hydrogen/methane feed volume ratio increases methane conversion and selectivity. Gas chromatography/electron impact ionization/mass spectrometry chromatographic analysis showed that the liquid fuel produced by methane dehydrogenation oligomerization contained 89.44% of butene, and the rest was acetic acid, ethanol, butenol and butyric acid, and the content was 1.0–3.0 wt%.
Triggerfish uses chromaticity and lightness for object segregation
Authors: Mitchell Laurie , Cheney Karen L. , Cortesi Fabio , Marshall N. Justin , Vorobyev Misha
Published: December 2017

Humans group components of visual patterns according to their colour, and perceive colours separately from shape. This property of human visual perception is the basis behind the Ishihara test for colour deficiency, where an observer is asked to detect a pattern made up of dots of similar colour with variable lightness against a background of dots made from different colour(s) and lightness. To find out if fish use colour for object segregation in a similar manner to humans, we used stimuli inspired by the Ishihara test. Triggerfish (Rhinecanthus aculeatus) were trained to detect a cross constructed from similarly coloured dots against various backgrounds. Fish detected this cross even when it was camouflaged using either achromatic or chromatic noise, but fish relied more on chromatic cues for shape segregation. It remains unknown whether fish may switch to rely primarily on achromatic cues in scenarios where target objects have higher achromatic contrast and lower chromatic contrast. Fish were also able to generalize between stimuli of different colours, suggesting that colour and shape are processed by fish independently.
Continuous dependence on modelling for temperature-dependent bidispersive flow
Authors: Franchi Franca , Nibbi Roberta , Straughan Brian
Published: December 2017

We consider a model for flow in a porous medium which has a double porosity structure. There is the usual porosity herein called macro porosity, but in addition, we allow for a porosity due to cracks or fissures in the solid skeleton. The cracks give rise to a micro porosity. The model considered also allows for temperature effects with a single temperature
T
. This paper analyses three aspects of structural stability. The first establishes continuous dependence of the solution on the interaction coefficient between the velocities associated with the macro and micro porosity. The second analyses continuous dependence on the viscosity coefficients, while the third establishes continuous dependence on the radiation constant when Newton’s law of cooling is involved on the boundary.
Predicting acoustic relaxation absorption in gas mixtures for extraction of composition relaxation contributions
Authors: Liu Tingting , Wang Shu , Zhu Ming
Published: December 2017

The existing molecular relaxation models based on both parallel relaxation theory and series relaxation theory cannot extract the contributions of gas compositions to acoustic relaxation absorption in mixtures. In this paper, we propose an analytical model to predict acoustic relaxation absorption and clarify composition relaxation contributions based on the rate-determining energy transfer processes in molecular relaxation in excitable gases. By combining parallel and series relaxation theory, the proposed model suggests that the vibration-translation process of the lowest vibrational mode in each composition provides the primary deexcitation path of the relaxation energy, and the rate-determining vibration–vibration processes between the lowest mode and others dominate the coupling energy transfer between different modes. Thus, each gas composition contributes directly one single relaxation process to the molecular relaxation in mixture, which can be illustrated by the decomposed acoustic relaxation absorption spectrum of the single relaxation process. The proposed model is validated by simulation results in good agreement with experimental data such as N2, O2, CO2, CH4and their mixtures.
Neonicotinoid pesticides and nutritional stress synergistically reduce survival in honey bees
Authors: Tosi Simone , Nieh James C. , Sgolastra Fabio , Cabbri Riccardo , Medrzycki Piotr
Published: December 2017

The honey bee is a major pollinator whose health is of global concern. Declines in bee health are related to multiple factors, including resource quality and pesticide contamination. Intensive agricultural areas with crop monocultures potentially reduce the quality and quantity of available nutrients and expose bee foragers to pesticides. However, there is, to date, no evidence for synergistic effects between pesticides and nutritional stress in animals. The neonicotinoids clothianidin (CLO) and thiamethoxam (TMX) are common systemic pesticides that are used worldwide and found in nectar and pollen. We therefore tested if nutritional stress (limited access to nectar and access to nectar with low-sugar concentrations) and sublethal, field-realistic acute exposures to two neonicotinoids (CLO and TMX at 1/5 and 1/25 of LD50) could alter bee survival, food consumption and haemolymph sugar levels. Bee survival was synergistically reduced by the combination of poor nutrition and pesticide exposure (−50%). Nutritional and pesticide stressors reduced also food consumption (−48%) and haemolymph levels of glucose (−60%) and trehalose (−27%). Our results provide the first demonstration that field-realistic nutritional stress and pesticide exposure can synergistically interact and cause significant harm to animal survival. These findings have implications for current pesticide risk assessment and pollinator protection.
Arboreality constrains morphological evolution but not species diversification in vipers
Authors: de Alencar Laura Rodrigues Vieira , Martins Marcio , Burin Gustavo , Quental Tiago Bosisio
Published: December 2017

An increase in ecological opportunities, either through changes in the environment or acquisition of new traits, is frequently associated with an increase in species and morphological diversification. However, it is possible that certain ecological settings might prevent lineages from diversifying. Arboreality evolved multiple times in vipers, making them ideal organisms for exploring how potentially new ecological opportunities affect their morphology and speciation regimes. Arboreal snakes are frequently suggested to have a very specialized morphology, and being too large, too small, too heavy, or having short tails might be challenging for them. Using trait-evolution models, we show that arboreal vipers are evolving towards intermediate body sizes, with longer tails and more slender bodies than terrestrial vipers. Arboreality strongly constrains body size and circumference evolution in vipers, while terrestrial lineages are evolving towards a broader range of morphological variants. Trait-dependent diversification models, however, suggest similar speciation rates between microhabitats. Thus, we show that arboreality might constrain morphological evolution but not necessarily affect the rates at which lineages generate new species.
Rabies elimination research: juxtaposing optimism, pragmatism and realism
Authors: Cleaveland Sarah , Hampson Katie
Published: December 2017

More than 100 years of research has now been conducted into the prevention, control and elimination of rabies with safe and highly efficacious vaccines developed for use in human and animal populations. Domestic dogs are a major reservoir for rabies, and although considerable advances have been made towards the elimination and control of canine rabies in many parts of the world, the disease continues to kill tens of thousands of people every year in Africa and Asia. Policy efforts are now being directed towards a global target of zero human deaths from dog-mediated rabies by 2030 and the global elimination of canine rabies. Here we demonstrate how research provides a cause for optimism as to the feasibility of these goals through strategies based around mass dog vaccination. We summarize some of the pragmatic insights generated from rabies epidemiology and dog ecology research that can improve the design of dog vaccination strategies in low- and middle-income countries and which should encourage implementation without further delay. We also highlight the need for realism in reaching the feasible, although technically more difficult and longer-term goal of global elimination of canine rabies. Finally, we discuss how research on rabies has broader relevance to the control and elimination of a suite of diseases of current concern to human and animal health, providing an exemplar of the value of a ‘One Health’ approach.
Scale dependencies and generalism in host use shape virus prevalence
Authors: McLeish Michael , Sacristán Soledad , Fraile Aurora , García-Arenal Fernando
Published: December 2017

Processes that generate the distribution of pathogens and their interactions with hosts are not insensitive to changes in spatial scale. Spatial scales and species traits are often selected intentionally, based on practical considerations, ignoring biases that the scale and type of observation may introduce. Specifically, these biases might change the interpretation of disease–diversity relationships that are reported as either ‘dilution’ or ‘amplification’ effects. Here, we combine field data of a host–pathogen community with empirical models to test the effects that (i) spatial scale and (ii) host range have on the relationship between plant–virus infection prevalence and diversity. We show that prevalence–diversity relationships are scale-dependent and can produce opposite effects associated with different habitats at sub-ecosystem scales. The total number of host species of each virus reflected generalism at the ecosystem scale. However, plasticity in host range resembled habitat-specific specialization and also changed model predictions. We show that habitat heterogeneity, ignored at larger (ecosystem) spatial scales, influences pathogen distributions. Hence, understanding disease distributions and the evolution of pathogens requires reconciling specific hypotheses of the study with an appropriate spatial scale, or scales, and consideration of traits, such as host range, that might strongly contribute to biotic interactions.
Bathyal feasting: post-spawning squid as a source of carbon for deep-sea benthic communities
Authors: Hoving H. J. T. , Bush S. L. , Haddock S. H. D. , Robison B. H.
Published: December 2017

In many oceanic carbon budgets there is a discrepancy between the energetic requirements of deep-sea benthic communities and the supply of organic matter. This suggests that there are unidentified and unmeasured food sources reaching the seafloor. During 11 deep-sea remotely operated vehicle (ROV) surveys in the Gulf of California, the remains (squid carcasses and hatched-out egg sheets) of 64 post-brooding squid were encountered. As many as 36 remains were encountered during a single dive. To our knowledge this is one of the largest numbers of natural food falls of medium-size deep-sea nekton described to date. Various deep-sea scavengers (Ophiuroidea, Holothuroidea, Decapoda, Asteroidea, Enteropneusta) were associated with the remains. Although many of the 80 examined ROV dives did not encounter dead squids or egg sheets (
n
= 69), and the phenomenon may be geographically and temporally restricted, our results show that dead, sinking squid transport carbon from the water column to the seafloor in the Gulf of California. Based on food fall observations from individual dives, we estimate that annual squid carcass depositions may regionally contribute from 0.05 to 12.07 mg C m
−2
d
−1
to the seafloor in the areas where we observed the remains. The sinking of squid carcasses may constitute a significant but underestimated carbon vector between the water column and the seafloor worldwide, because squid populations are enormous and are regionally expanding as a result of climate change and pressure on fish stocks. In the future, standardized methods and surveys in geographical regions that have large squid populations will be important for investigating the overall contribution of squid falls to regional carbon budgets.
Corals hosting symbiotic hydrozoans are less susceptible to predation and disease
Authors: Montano Simone , Fattorini Simone , Parravicini Valeriano , Berumen Michael L. , Galli Paolo , Maggioni Davide , Arrigoni Roberto , Seveso Davide , Strona Giovanni
Published: December 2017

In spite of growing evidence that climate change may dramatically affect networks of interacting species, whether—and to what extent—ecological interactions can mediate species' responses to disturbances is an open question. Here we show how a largely overseen association such as that between hydrozoans and scleractinian corals could be possibly associated with a reduction in coral susceptibility to ever-increasing predator and disease outbreaks. We examined 2455 scleractinian colonies (from both Maldivian and the Saudi Arabian coral reefs) searching for non-random patterns in the occurrence of hydrozoans on corals showing signs of different health conditions (i.e. bleaching, algal overgrowth, corallivory and different coral diseases). We show that, after accounting for geographical, ecological and co-evolutionary factors, signs of disease and corallivory are significantly lower in coral colonies hosting hydrozoans than in hydrozoan-free ones. This finding has important implications for our understanding of the ecology of coral reefs, and for their conservation in the current scenario of global change, because it suggests that symbiotic hydrozoans may play an active role in protecting their scleractinian hosts from stresses induced by warming water temperatures.
Balancing selection for aflatoxin inAspergillus flavusis maintained through interference competition with, and fungivory by insects
Authors: Drott Milton T. , Lazzaro Brian P. , Brown Dan L. , Carbone Ignazio , Milgroom Michael G.
Published: December 2017

The role of microbial secondary metabolites in the ecology of the organisms that produce them remains poorly understood. Variation in aflatoxin production byAspergillus flavusis maintained by balancing selection, but the ecological function and impact on fungal fitness of this compound are unknown. We hypothesize that balancing selection for aflatoxin production inA. flavusis driven by interaction with insects. To test this, we competed naturally occurring aflatoxigenic and non-aflatoxigenic fungal isolates againstDrosophilalarvae on medium containing 0–1750 ppb aflatoxin, using quantitative PCR to quantifyA. flavusDNA as a proxy for fungal fitness. The addition of aflatoxin across this range resulted in a 26-fold increase in fungal fitness. With no added toxin, aflatoxigenic isolates caused higher mortality ofDrosophilalarvae and had slightly higher fitness than non-aflatoxigenic isolates. Additionally, aflatoxin production increased an average of 1.5-fold in the presence of a single larva and nearly threefold when the fungus was mechanically damaged. We argue that the role of aflatoxin in protection from fungivory is inextricably linked to its role in interference competition. Our results, to our knowledge, provide the first clear evidence of a fitness advantage conferred toA. flavusby aflatoxin when interacting with insects.
Whole-genome resequencing reveals candidate mutations for pig prolificacy
Authors: Li Wen-Ting , Zhang Meng-Meng , Li Qi-Gang , Tang Hui , Zhang Li-Fan , Wang Ke-Jun , Zhu Mu-Zhen , Lu Yun-Feng , Bao Hai-Gang , Zhang Yuan-Ming , Li Qiu-Yan , Wu Ke-Liang , Wu Chang-Xin
Published: December 2017

Changes in pig fertility have occurred as a result of domestication, but are not understood at the level of genetic variation. To identify variations potentially responsible for prolificacy, we sequenced the genomes of the highly prolific Taihu pig breed and four control breeds. Genes involved in embryogenesis and morphogenesis were targeted in the Taihu pig, consistent with the morphological differences observed between the Taihu pig and others during pregnancy. Additionally, excessive functional non-coding mutations have been specifically fixed or nearly fixed in the Taihu pig. We focused attention on an oestrogen response element (ERE) within the first intron of the bone morphogenetic protein receptor type-1B gene (
BMPR1B
) that overlaps with a known quantitative trait locus (QTL) for pig fecundity. Using 242 pigs from 30 different breeds, we confirmed that the genotype of the ERE was nearly fixed in the Taihu pig. ERE function was assessed by luciferase assays, examination of histological sections, chromatin immunoprecipitation, quantitative polymerase chain reactions, and western blots. The results suggest that the ERE may control pig prolificacy via the cis-regulation of
BMPR1B
expression. This study provides new insight into changes in reproductive performance and highlights the role of non-coding mutations in generating phenotypic diversity between breeds.
The prognostic effects of somatic mutations in ER-positive breast cancer
Authors: Griffith Obi L , Spies Nicholas C , Anurag Meenakshi , Griffith Malachi , Luo Jingqin , Tu Dongsheng , Yeo Belinda , Kunisaki Jason , Miller Christopher A , Krysiak Kilannin , Hundal Jasreet , Ainscough Benjamin J , Skidmore Zachary L , Campbell Katie , Kumar Runjun , Fronick Catrina , Cook Lisa , Snider Jacqueline E , Davies Sherri , Kavuri Shyam M , Chang Eric C , Magrini Vincent , Larson David E , Fulton Robert S , Liu Shuzhen , Leung Samuel , Voduc David , Bose Ron , FMedSci Mitch Dowsett , Wilson Richard K , Nielsen Torsten O , Mardis Elaine R , Ellis Matthew J
Published: December 2017

More than 50 genes are recurrently affected by somatic mutation in estrogen receptor positive (ER+) breast cancer but prognostic effects have not been definitively established. Primary tumor DNA was therefore subjected to targeted sequencing from 625 postmenopausal (UBC-TAM series) and 328 premenopausal (MA12 trial) hormone receptor-positive (HR+) patients. Independent validation of prognostic interactions was achieved using independent data from the METABRIC study. Associations between MAP3K1 and PIK3CA with luminal A status and TP53 mutations with Luminal B/non-luminal tumors were observed, validating the methodological approach. In UBC-TAM, NF1 frame-shift nonsense (FS/NS) mutation was validated as a poor outcome driver. For MA12, poor outcome associated with PIK3R1 mutation was similarly validated. DDR1 mutations were strongly associated with poor prognosis in UBC-TAM despite stringent false-discovery correction (q=0.0003). In conclusion, uncommon recurrent somatic mutations should be further explored to create a more complete explanation of the highly variable outcomes that typify ER+ breast cancer.
Distribution of Sigma factors delineates segregation of virulent and avirulent Mycobacterium
Authors: Gupta Aayatti Mallick , Mandal Sukhendu
Published: December 2017

Sigma factors, in combination with RNA polymerase and several transcription factors play specific role in expression of housekeeping as well as various stress responsive genes in mycobacterial species. The genus Mycobacterium includes a wide range of species under major pathogens, opportunists and non-pathogens. The number and combination of sigma factors is extremely diversified among Mycobacterium. We have performed comparative genome analysis among 40 different species of Mycobacterium whose whole genome sequence is available, in order to identify the distribution of sigma factors. The study illustrate that SigC, SigD, SigG, SigH, SigK and SigI are dominant among the true pathogens. Moreover, 16S rDNA based phylogenetic analyses distinctly differentiate the slow growing Mycobacterium from the fast growers, and clusters the true pathogens from the opportunists and non-pathogens. While evaluating the similarity coefficient upon the allotment of sigma factors of different Mycobacterium species through UPGMA dendrogram analysis, it is apparent that the true pathogens are grouped separately following the similar trend observed from evolutionary approach. Sigma factors playing dominant role in pathogenicity are found stable in nature with high aliphatic index thereby remain flexible at a wide range of temperature. The comparative distribution of six well known virulence factors of Mycobacterium - PhoP, PcaA, FbpA, Mce1B, KatG and PE_PGRS and various sigma factors justify the allotment pattern of mycobacterial sigma factors among pathogenic species. The pathogenicity responsible sigma factors elicit close resemblance with few notable characters of the known virulence factors. Thus the analysis renders that the distribution of sigma factors of different species of Mycobacterium can be a potential tool to predict the pathogenicity index of this genus.
Conservation of separase N-terminal domain
Authors: Melesse Michael , Bembenek Joshua N. , Zhulin Igor B.
Published: December 2017

We report a reanalysis of the sequence conservation of the cell cycle regulatory protease, separase. The sequence and structural conservation of the protease domain has long been recognized. Here we reexamine the protein sequence conservation at the N-terminus using PSI-BLAST analysis and report our discovery of a cysteine rich motif (CxCXXC) conserved in nematodes and vertebrates. This motif is found in a solvent exposed linker region connecting two TPR-like helical motifs. Mutation of this motif in Caenorhabditis elegans separase leads to a temperature sensitive hypomorphic protein, and several N-terminal residues identified as intragenic suppressors are not conserved. Conservation of this motif in multiple organisms raises the possibility that the motif plays similar roles across species.
Functional Compensation Between Hematopoietic Stem CellsIn Vivo
Authors: Nguyen Lisa , Wang Zheng , Chu Elizabeth , Eerdeng Jiya , Chowdhury Adnan Y. , Lu Rong
Published: December 2017

In most organ systems, regeneration is a coordinated effort that involves many stem cells, but little is known about whether and how individual stem cells compensate for the functional deficiencies of other stem cells. Functional compensation between stem cells is critically important during disease progression and treatment. Here, we show how individual hematopoietic stem cells (HSCs) in a mouse heterogeneously compensate for the deficiencies of other HSCs’ during lymphopoiesis by increasing their clonal expansion at specific differentiation stages. This compensation rescues the overall blood supply and influences blood cell types outside of the deficient lineages in distinct patterns. We have identified the molecular regulators and signaling pathways in HSCs that are involved in this process. Our data demonstrate how stem cells interact with each other to constitute a coordinated network that is robust enough to withstand minor functional disruptions. Exploiting the innate compensation capacity of stem cell networks may improve the prognosis and treatment of many diseases.
Micropattern differentiation of mouse pluripotent stem cells recapitulates embryo regionalized cell fate patterning
Authors: Morgani Sophie M. , Metzger Jakob J. , Nichols Jennifer , Siggia Eric D. , Hadjantonakis Anna-Katerina
Published: December 2017

During gastrulation epiblast cells exit pluripotency as they specify and spatially arrange the three germ layers of the embryo. Similarly, human pluripotent stem cells (PSCs) undergo spatially organized fate specification on micropatterned surfaces. Since in vivo validation is not possible for the human, we developed a mouse PSC micropattern system and, with direct comparisons to mouse embryos, reveal the robust specification of distinct regional identities. BMP, WNT, ACTIVIN and FGF directed mouse epiblast-like cells to undergo an epithelial-to-mesenchymal transition and radially pattern posterior mesoderm fates. Conversely, WNT, ACTIVIN and FGF patterned anterior identities, including definitive endoderm. By contrast, epiblast stem cells, a developmentally advanced state, only specified anterior identities, but without patterning. The mouse micropattern system offers a robust scalable method to generate regionalized cell types present in vivo, resolve how signals promote distinct identities and generate patterns, and compare mechanisms operating in vivo and in vitro and across species.
Regulation of mitochondrial dynamics by Aurora A kinase
Authors: Grant Rhys , Abdelbaki Ahmed , Bertoldi Alessia , Gavilan Maria P , Mansfeld Jörg , Glover David M , Lindon Catherine
Published: December 2017

Aurora A kinase (AURKA) is a major regulator of mitosis and an important driver of cancer progression. The roles of AURKA outside of mitosis, and how these might contribute to cancer progression, are not well understood. Here we show that a fraction of cytoplasmic AURKA is associated with mitochondria, co-fractionating in cell extracts and interacting with mitochondrial proteins by reciprocal co-immunoprecipitation. We have also found that the dynamics of the mitochondrial network are sensitive to AURKA inhibition, depletion or overexpression. This can account for the different mitochondrial morphologies observed in RPE1 and U2OS cell lines, which show very different levels of expression of AURKA. We identify the mitochondrial fraction of AURKA as influencing mitochondrial morphology, since an N-terminally truncated version of the kinase that does not localize to mitochondria does not affect the mitochondrial network. We identify a cryptic mitochondrial targeting sequence in the AURKA N-terminus and discuss how alternative conformations of the protein may influence its cytoplasmic fate.
Cytosolic delivery of large supramolecular protein complexes arranged on DNA nanopegboards
Authors: Nikolov Pavel M. , Koßmann Katja J. , Schilling Alessa , Angelin Alessandro , Brglez Josipa , Klein Alina , Tampé Robert , Rabe Kersten S. , Niemeyer Christof M.
Published: December 2017

A generic methodology for cytosolic delivery of large supramolecular multiprotein complexes into living cells is described that takes advantage of the highly-controllable bottom-up fabrication of protein-decorated DNA nanostructures and the microfluidic “cell squeezing” technique. Therein, cells are deformed upon passage through a narrow constriction leading to formation of transient holes in the cell membrane that enable the diffusion of the protein-DNA nanostructures from the surrounding buffer into the cytosol. A diverse set of multiprotein complexes was assembled on DNA origami nanostructures using streptavidin and the sensitive glucose sensor protein FLIP as model systems. We demonstrate that our approach allows for the direct cytosolic delivery of these multifunctional protein complexes into the cytosol of HeLa cells. We also demonstrate that targeting groups can be incorporated into the protein-DNA nanoassemblies to enable their intracellular targeting to cytosolic compartments, such as the cytoskeleton or nucleus. We believe that this methodology will open up novel strategies for research in fundamental cell biology, such as the reverseengineering of the supramolecular machinery involved in gene regulation, cell signalling, or cell division. Furthermore, direct applications in immunotherapy can be foreseen.
Candidate cancer driver mutations in superenhancers and long-range chromatin interaction networks
Authors: Wadi Lina , Uusküla-Reimand Liis , Isaev Keren , Shuai Shimin , Huang Vincent , Liang Minggao , Thompson J. Drew , Li Yao , Ruan Luyao , Paczkowska Marta , Krassowski Michal , Dzneladze Irakli , Kron Ken , Murison Alexander , Mazrooei Parisa , Bristow Robert G. , Simpson Jared T. , Lupien Mathieu , Wilson Michael D. , Stein Lincoln D. , Boutros Paul C. , Reimand Jüri
Published: December 2017

A comprehensive catalogue of the mutations that drive tumorigenesis and progression is essential to understanding tumor biology and developing therapies. Protein-coding driver mutations have been well-characterized by large exome-sequencing studies, however many tumors have no mutations in protein-coding driver genes. Non-coding mutations are thought to explain many of these cases, however few non-coding drivers besides TERT promoter are known. To fill this gap, we analyzed 150,000 cis-regulatory regions in 1,844 whole cancer genomes from the ICGC-TCGA PCAWG project. Using our new method, ActiveDriverWGS, we found 41 frequently mutated regulatory elements (FMREs) enriched in non-coding SNVs and indels (FDR<0.05) characterized by aging-associated mutation signatures and frequent structural variants. Most FMREs are distal from genes, reported here for the first time and also recovered by additional driver discovery methods. FMREs were enriched in super-enhancers, H3K27ac enhancer marks of primary tumors and long-range chromatin interactions, suggesting that the mutations drive cancer by distally controlling gene expression through threedimensional genome organization. In support of this hypothesis, the chromatin interaction network of FMREs and target genes revealed associations of mutations and differential gene expression of known and novel cancer genes (e.g., CNNB1IP1, RCC1), activation of immune response pathways and altered enhancer marks. Thus distal genomic regions may include additional, infrequently mutated drivers that act on target genes via chromatin loops. Our study is an important step towards finding such regulatory regions and deciphering the somatic mutation landscape of the non-coding genome.
The cancer-mutation network and the number and specificity of driver mutations
Authors: Iranzo Jaime , Martincorena Iñigo , Koonin Eugene V.
Published: December 2017

Cancer genomics has produced extensive information on cancer-associated genes but the number and specificity of cancer driver mutations remains a matter of debate. We constructed a bipartite network in which 7665 tumors from 30 cancer types are connected via shared mutations in 198 previously identified cancer-associated genes. We show that 27% of the tumors can be assigned to statistically supported modules, most of which encompass 1-2 cancer types. The rest of the tumors belong to a diffuse network component suggesting lower gene-specificity of driver mutations. Linear regression of the mutational loads in cancer-associated genes was used to estimate the number of drivers required for the onset of different cancers. The mean number of drivers is ~2, with a range of 1 to 5. Cancers that are associated to modules had more drivers than those from the diffuse network component, suggesting that unidentified and/or interchangeable drivers exist in the latter.
Late diagnosis of a truncating WISP3 mutation entails a severe phenotype of progressive pseudorheumatoid dysplasia
Authors: Alawbathani Salem , Kawalia Amit , Karakaya Mert , Altmüller Janine , Nürnberg Peter , Cirak Sebahattin
Published: December 2017

Rare diseases are often misdiagnosed or receive a delayed diagnosis; thus, unfortunately, affected individuals may not receive optimal medical management. Here, we report a case of two siblings with a severe phenotype of progressive pseudorheumatoid dysplasia (PPD). Their onset of symptoms began at the age of 3 yr. Both were neglected in the past, and the patients presented with a very severe phenotype and unmitigated natural history. PPD is a rare autosomal recessive skeletal dysplasia characterized by progressive joint stiffness, swelling, and pain. Because of observed muscle wasting, weakness, and the lack of laboratory testing, the case had been initially misdiagnosed by the local physicians. We aimed to provide diagnostic support by a targeted next-generation sequencing gene panel (Illumina TruSight One) for Mendelian diseases (Mendeliome), and we identified a homozygous frameshift mutation in the gene WISP3 (c.868_869delAG, p.Ser290Leufs*12). Thus, early diagnosis and intervention may have decreased the severity and complication of the disease.
The use of a pedometer with or without a supervised exercise program for control of pre- to mild hypertension
Authors: Chongthawonsatid Sukanya , Chinjenpradit Wipawee
Published: December 2017

Purpose

Exercise training has been shown to be an effective and integral component of non-pharmacological intervention for the control of blood pressure. The purpose of this paper is to compare the effectiveness of a supervised modified exercise program of moderate-intensity exercise for one hour per week including the use of a pedometer, and with the use of a pedometer alone without additional exercise in reducing blood pressure.

Design/methodology/approach

The study was a randomized control trial, with an experimental group of 30 people and a control group of 26 people. Participants were males and females aged 30-65 years with pre- to mild hypertension, and who were not receiving any drugs for the treatment of hypertension. Participants of the experimental group were assigned to a fitness program with supervised exercise once a week at the Golden Jubilee Medical Fitness Center, given access to a pedometer, and provided with health education. Participants in the control group were assigned to use a pedometer only. All experimental and control group members participated in the study for three months, as well as a follow-up at the third and sixth month.

Findings

Comparison of the experimental and control groups at the first, third, and sixth month, using repeated measures analysis found that interaction effect groups and times were significantly different for mean systolic blood pressure (SBP), body mass index (BMI), hip circumference (HC), and high-density lipoprotein (HDL) (p<0.05). Mean SBP, diastolic blood pressure (DBP), BMI, waist circumference (WC), HC, and low-density lipoprotein (LDL) within groups were significantly different (p<0.05). Mean WC, cholesterol, LDL, and triglyceride between groups were significantly different (p<0.05). Both groups had SBP improved at the third and sixth month when compared with baseline data. Mean HDL increased in the experimental group and decreased in the control group. Multiple regression analysis showed that both groups were not statistically different after intervention, SBP was reduced in the experimental group when compared to the control group. However, at six months, members in the experimental group reported spending less time sitting or reclining on a typical day than members of the control group.

Originality/value

A supervised one-time per week fitness program combined with pedometer and pedometer alone were not different in reducing blood pressure, as both groups showed decreases in blood pressure. However, the group with the supervised exercise program tended to change sedentary behaviors in the longer term compared to those who used the pedometer alone.