bluuebunny/crossref_metadata_2025 huggingface dataset:
Recombining your way out of trouble: The genetic architecture of hybrid fitness under environmental stress
Authors: Zhang Zebin , Bendixsen Devin P. , Janzen Thijs , Nolte Arne W. , Greig Duncan , Stelkens Rike
Published: May 2019

Hybridization between species is a fundamental evolutionary force that can both promote and delay adaptation. There is a deficit in our understanding of the genetic basis of hybrid fitness, especially in non-domesticated organisms. We also know little about how hybrid fitness changes as a function of environmental stress. Here, we made genetically variable F2 hybrid populations from two divergentSaccharomycesyeast species, exposed populations to ten toxins, and sequenced the most resilient hybrids on low coverage using ddRADseq. We expected to find strong negative epistasis and heterozygote advantage in the hybrid genomes. We investigated three aspects of hybridness: 1) hybridity, 2) interspecific heterozygosity, and 3) epistasis (positive or negative associations between non-homologous chromosomes). Linear mixed effect models revealed strong genotype-by-environment interactions with many chromosomes and chromosomal interactions showing species-biased content depending on the environment. Against our predictions, we found extensive selection against heterozygosity such that homozygous allelic combinations from the same species were strongly overrepresented in an otherwise hybrid genomic background. We also observed multiple cases of positive epistasis between chromosomes from opposite species, confirmed by epistasis- and selection-free simulations, which is surprising given the large divergence of the parental species (~15% genome-wide). Together, these results suggest that stress-resilient hybrid genomes can be assembled from the best features of both parents, without paying high costs of negative epistasis across large evolutionary distances. Our findings illustrate the importance of measuring genetic trait architecture in an environmental context when determining the evolutionary potential of hybrid populations.
RSAT Var-tools: an accessible and flexible framework to predict the impact of regulatory variants on transcription factor binding
Authors: Santana-Garcia Walter , Rocha-Acevedo Maria , Ramirez-Navarro Lucia , Mbouamboua Yvon , Thieffry Denis , Thomas-Chollier Morgane , Contreras-Moreira Bruno , van Helden Jacques , Medina-Rivera Alejandra
Published: May 2019

Gene regulatory regions contain short and degenerated DNA sites recognized by transcription factors (TFs). When such regions harbor SNPs, the DNA motifs where TFs bind may be affected, thereby altering the transcriptional regulation of the target genes. Such regulatory SNPs have been implicated as causal variants in GWAS studies. In this study, we describe the application of the programs Var-tools designed to predict regulatory variants, and present four case studies to illustrate their usage and applications. In brief, Var-tools facilitate i) obtaining variation information, ii) interconversion of variation file formats, iii) retrieval of sequences surrounding variants, and iv) calculating the change on predicted TF affinity scores between alleles, using motif scanning approaches. Notably, the tools support the analysis of haplotypes. The tools are included within the well-maintained suite Regulatory Sequence Analysis Tools (RSAT, http://rsat.eu), and accessible through a web interface that currently enables analysis of five metazoa and ten plant genomes. Vart-tools can also be used in command-line with any locally-installed Ensembl genome. Users can input personal collections of variants and motifs, providing flexibility in the analysis.
Emotional valence modulates the topology of the parent-infant inter-brain network
Authors: Santamaria Lorena , Noreika Valdas , Georgieva Stanimira , Clackson Kaili , Wass Sam , Leong Victoria
Published: May 2019

Emotional communication between parents and children is crucial during early life, yet little is known about its neural underpinnings. Here, we adopt a dual-brain connectivity approach to assess how emotional valence modulates the parent-infant neural network. Fifteen mothers modelled positive and negative emotions toward pairs of objects during social interaction with their infants (aged 10.3 months) whilst their neural activity was concurrently measured using dual-EEG. Intra-brain and inter-brain network connectivity in the 6-9 Hz (infant Alpha) range was computed during maternal expression of positive and negative emotions using directed (partial directed coherence) and non-directed (phase-locking value) connectivity metrics. Graph theoretical metrics were used to quantify differences in network topology as a function of emotional valence. Inter-brain network indices (Density, Strength and Divisibility) consistently revealed that the integration of parents’ and childrens’ neural processes was significantly stronger during maternal demonstrations of positive than negative emotions. Further, directed inter-brain metrics indicated that mother-to-infant directional influences were stronger during the expression of positive than negative emotions. These results suggest that the parent-infant inter-brain network is modulated by the emotional quality and tone of dyadic social interactions, and that inter-brain graph metrics may be successfully applied to examine these changes in interpersonal network topology.
Growth defects and loss-of-function in synthetic gene circuits
Authors: Nikolados Evangelos-Marios , Weiße Andrea Y. , Ceroni Francesca , Oyarzún Diego A.
Published: May 2019

Synthetic gene circuits perturb the physiology of their cellular host. The extra load on endogenous processes shifts the equilibrium of resource allocation in the host, leading to slow growth and reduced biosynthesis. Here we built integrated host-circuit models to quantify growth defects caused by synthetic gene circuits. Simulations reveal a complex relation between circuit output and cellular capacity for gene expression. For weak induction of heterologous genes, protein output can be increased at the expense of growth defects. Yet for stronger induction, cellular capacity reaches a tipping point, beyond which both gene expression and growth rate drop sharply. Extensive simulations across various growth conditions and large regions of the design space suggest that the critical capacity is a result of ribosomal scarcity. We studied the impact of growth defects on various gene circuits and transcriptional logic gates, which highlights the extent to which cellular burden can limit, shape and even break down circuit function. Our approach offers a comprehensive framework to assess the impact of host-circuit interactions in silico, with wide-ranging implications for the design and optimization of bacterial gene circuits.
A transient time window for early predispositions in newborn chicks
Authors: Versace Elisabetta , Ragusa Morgana , Vallortigara Giorgio
Published: May 2019

Neonates of different species are born with a set of predispositions that influence their early orienting responses toward the first stimuli encountered in their life. Human neonates and domestic chicks exhibit several similarities in the predisposition for attending to objects that move with speed changes, face-like stimuli and biological motion. Although early predispositions are connected to physiological development, little is known on the temporal course of early predispositions (whether they are stable or change in time) and on their genetic basis. To address these issues, we tested the preference for objects that change in speed vs. linear motion in three chicken breeds (Padovana, Polverara and Robusta maculata) within one day after hatching and three days after hatching. We found that the predisposition to preferentially attend to changes in speed is fixed at the species level on the first day of life and that it disappears by day three. These results indicate the existence of a short and transient time window of early predispositions that does not depend on visual experience.
Treatment-seeking for vaginal fistula in sub-Saharan Africa
Authors: Gebremedhin Samson , Asefa Anteneh
Published: May 2019

Background

There is dearth of data regarding the treatment-seeking practice of women living with vaginal fistula. The paper describes the health-seeking behaviour of fistula cases in the sub-Saharan Africa (SSA) where the burden of the problem is high.

Methods

We analysed the data of 1,317 women who ever experienced vaginal fistula, extracted from 16 national Demographic and Health Surveys carried out in SSA between 2010 and 2017. The association between treatment-seeking and basic socio-demographic characteristics assessed via mixed-effects logistic regression and the outputs are provided using adjusted odds ratio (AOR) with 95% confidence intervals (CI).

Results

Two-thirds (67.6%) of the women encountered the fistula soon after delivery implying obstetric fistula. Fewer identified sexual assault (3.8%) and pelvic surgery (2.7%) as the cause. In 25.8% of the cases clear-cut causes couldn’t be ascertained and excluding these ambiguous causes, 91.2% of the women had obstetric fistula. Among those who ever had fistula, 60.3% (95% CI: 56.9-63.6%) sought treatment and 28.5% (95% CI: 25.3-31.6%) underwent fistula-repair surgery. The leading reasons for not seeking treatment were: unaware that it can be repaired (21.4%), don’t know where to get the treatment (17.4%), economic constraints (11.9%), healed by itself (11.9%) and embarrassment (7.9%). The regression analysis indicated, teenagers as compared to adults 35 years or older [AOR=0.31 (95 % CI: 0.20-47)]; and women devoid of formal education when compared to women with any formal education [AOR=0.69 (95% CI: 0.51-0.93)], had reduced odds of treatment-seeking. In 25.9% of the women who underweight fistula-repair surgery, complete continence after surgery was not achieved.

Conclusion

Treatment-seeking for fistula remains low and it should be augmented via mix of strategies for abridging health-system, psycho-social, economic and awareness barriers.
Parasite-induced shifts in host movement may explain the transient coexistence of high- and low-pathogenic disease strains
Authors: Fofana Abdou Moutalab , Hurford Amy
Published: May 2019

Many parasites induce decreased host movement, known as lethargy, which can impact disease spread and the evolution of virulence. Mathematical models have investigated virulence evolution when parasites cause host death, but disease-induced decreased host movement has received relatively less attention. Here, we consider a model where, due to the within-host parasite replication rate, an infected host can become lethargic and shift from a moving to a resting state, where it can die. We find that when the lethargy and disease-induced mortality costs to the parasites are not high, then evolutionary bistability can arise, and either moderate or high virulence can evolve depending on the initial virulence and the magnitude of mutation. These results suggest, firstly, the transient coexistence of strains with different virulence, which may explain the coexistence of low- and high-pathogenic strains of avian influenza and human immunodeficiency viruses, and secondly, that medical interventions to treat the symptoms of lethargy or prevent disease-induced host deaths can result in a large jump in virulence and the rapid evolution of high virulence. In complement to existing results that show bistability when hosts are heterogeneous at the population-level, we show that evolutionary bistability may arise due to transmission heterogeneity at the individual host-level.
Multi-trait genome-wide association meta-analysis of dietary intake identifies new loci and genetic and functional links with metabolic traits
Authors: Merino Jordi , Dashti Hassan S. , Sarnowski Chloé , Lane Jacqueline M. , Udler Miriam S. , Todorov Petar V. , Song Yanwei , Wang Heming , Kim Jaegil , Tucker Chandler , Campbell John , Tanaka Toshiko , Chu Audrey Y. , Tsai Linus , Pers Tune H. , Chasman Daniel I. , Dupuis Josée , Rutter Martin K. , Florez Jose C. , Saxena Richa
Published: May 2019

Dietary intake, a major contributor to the global obesity epidemic1–5, is a complex phenotype partially affected by innate physiological processes.6–11 However, previous genome-wide association studies (GWAS) have only implicated a few loci in variability of dietary composition.12–14 Here, we present a multi-trait genome-wide association meta-analysis of inter-individual variation in dietary intake in 283,119 European-ancestry participants from UK Biobank and CHARGE consortium, and identify 96 genome-wide significant loci. Dietary intake signals map to different brain tissues and are enriched for genes expressed in β1-tanycytes and serotonergic and GABAergic neurons. We also find enrichment of biological pathways related to neurogenesis. Integration of cell-line and brain-specific epigenomic annotations identify 15 additional loci. Clustering of genome-wide significant variants yields three main genetic clusters with distinct associations with obesity and type 2 diabetes (T2D). Overall, these results enhance biological understanding of dietary composition, highlight neural mechanisms, and support functional follow-up experiments.
Water for sterol: an unusual mechanism of sterol egress from a StARkin domain
Authors: Khelashvili George , Pandey Kalpana , Chauhan Neha , Eliezer David , Menon Anant K.
Published: May 2019

Previously we identified a new family of endoplasmic reticulum membrane proteins that possess sterol-binding StARkin domains (Gatta et al. eLife 2015). These Lam/GramD1 proteins are implicated in intracellular sterol homeostasis, a function that requires them to be able to bind sterols. Here we show how these proteins exchange sterol molecules with membranes. An aperture at one end of the StARkin domain enables sterol to enter/exit the binding pocket. Strikingly, the wall of the pocket is fractured along its length, exposing bound sterol to solvent. We considered whether hydration of the pocket could mediate sterol entry/exit. Large-scale atomistic molecular dynamics simulations reveal that sterol egress involves widening of the fracture, penetration of water into the cavity and consequent destabilization of the bound sterol. The simulations also identify polar residues along the fracture that are important for sterol release. Their replacement with alanine affects the ability of the StARkin domain to bind sterol, catalyze inter-vesicular sterol exchange and alleviate the nystatin-sensitivity of lam2Δ yeast cells. These data suggest an unprecedented, water-controlled mechanism of sterol acquisition and discharge from a StARkin domain.
Targeted photostimulation uncovers circuit motifs supporting short-term memory
Authors: Daie Kayvon , Svoboda Karel , Druckmann Shaul
Published: May 2019

Short-term memory is associated with persistent neural activity without sustained input, arising from the interactions between neurons with short time constants1,2. A variety of neural circuit motifs could account for measured neural activity3–7. A mechanistic understanding of the neural circuits supporting short-term memory requires probing network connectivity between functionally characterized neurons8. We performed targeted photostimulation of small (< 10) groups of neurons, while imaging the response of hundreds of other neurons9,10, in anterior-lateral motor cortex (ALM) of mice performing a delayed response task11. Mice were instructed with brief auditory stimuli to make directional movements (lick left or lick right), but only after a three second delay epoch. ALM contains neurons with delay epoch activity that is selective for left or right choices. Targeted photostimulation of groups of neurons during the delay epoch allowed us to observe the functional organization of population activity and recurrent interactions underlying short-term memory. These experiments revealed strong coupling between neurons sharing similar selectivity. Brief photostimulation of functionally related neurons produced changes in activity in sparse subpopulations of nearby neurons that persisted for several seconds following stimulus offset, far outlasting the duration of the perturbation. Photostimulation produced behavioral biases that were predictable based on the selectivity of the perturbed neuronal population. These results suggest that ALM contains multiple intercalated modules, consisting of recurrently coupled neurons, that can independently maintain persistent activity.
Lipocalin-2 is a Sensitive and Specific Marker of Bacterial Infection in Children
Authors: Herberg Jethro , Huang Honglei , Thezenas Marie L. , Janes Victoria , Carter Michael , Gormley Stuart , Hamilton Melisa S. , Kessler Benedikt , Levin Michael , Casals-Pascual Climent
Published: May 2019

Introduction

Bacterial infection is the leading cause of death in children globally. Clinical algorithms to identify children who are likely to benefit from antimicrobial treatment remain suboptimal. Biomarkers that accurately identify serious bacterial infection (SBI) could improve diagnosis and clinical management. Lipocalin 2 (LCN2) and neutrophil collagenase (MMP-8) are neutrophil-derived biomarkers associated with bacterial infection.

Methods

We evaluated LCN2 and MMP-8 as candidate biomarkers in 40 healthy controls and 151 febrile children categorised confirmed SBI, probable SBI, or viral infection. The diagnostic performance of LCN2 and MMP-8 to predict SBI was estimated by the area under the receiver operating characteristic curve (AUROC) and compared to the performance of C-reactive protein (CRP).

Results

Plasma LCN2 and MMP-8 concentration were predictive of SBI. The AUROC (95% CI) for LCN2, MMP8 and CRP to predict SBI was 0.88 (0.82-0.94); 0.80 (0.72-0.87) and 0.89 (0.84-0.94), respectively. The diagnostic performance of LCN2 in combination with CRP was significantly superior to either marker alone: AUROC 0.92 (95% CI: 0.88-0.96).

Conclusion

LCN2 is a sensitive and specific predictor of SBI in children which could be used to improve clinical management and antimicrobial stewardship. LCN2 should be further evaluated in prospective clinical studies.
Impulse responses reveal unimodal and bimodal access to visual and auditory working memory
Authors: Wolff M. J. , Kandemir G. , Stokes M. G. , Akyürek E. G.
Published: May 2019

It is unclear to what extent sensory processing areas are involved in the maintenance of sensory information in working memory (WM). Previous studies have thus far relied on finding neural activity in the corresponding sensory cortices, neglecting potential activity-silent mechanisms such as connectivity-dependent encoding. It has recently been found that visual stimulation during visual WM maintenance reveals WM-dependent changes through a bottom-up neural response. Here, we test whether this impulse response is uniquely visual and sensory-specific. Human participants (both sexes) completed visual and auditory WM tasks while electroencephalography was recorded. During the maintenance period, the WM network was perturbed serially with fixed and task-neutral auditory and visual stimuli. We show that a neutral auditory impulse-stimulus presented during the maintenance of a pure tone resulted in a WM-dependent neural response, providing evidence for the auditory counterpart to the visual WM findings reported previously. Interestingly, visual stimulation also resulted in an auditory WM-dependent impulse response, implicating the visual cortex in the maintenance of auditory information, either directly, or indirectly as a pathway to the neural auditory WM representations elsewhere. In contrast, during visual WM maintenance only the impulse response to visual stimulation was content-specific, suggesting that visual information is maintained in a sensory-specific neural network, separated from auditory processing areas.

Significance Statement

Working memory is a crucial component of intelligent, adaptive behaviour. Our understanding of the neural mechanisms that support it has recently shifted: rather than being dependent on an unbroken chain of neural activity, working memory may rely on transient changes in neuronal connectivity, which can be maintained efficiently in activity-silent brain states. Previous work using a visual impulse stimulus to perturb the memory network has implicated such silent states in the retention of line orientations in visual working memory. Here, we show that auditory working memory similarly retains auditory information. We also observed a sensory-specific impulse response in visual working memory, while auditory memory responded bi-modally to both visual and auditory impulses, possibly reflecting visual dominance of working memory.
A novel mechanism for amplification of sensory responses by the amygdala-TRN projections
Authors: Aizenberg Mark , Martinez Solymar Rolon , Pham Tuan , Rao Winnie , Haas Julie , Geffen Maria N.
Published: May 2019

Many forms of behavior require selective amplification of neuronal representations of relevant environmental signals. Following emotional learning, sensory stimuli drive enhanced responses in the sensory cortex. However, the brain circuits that underlie emotionally driven control of the sensory representations remain poorly understood. Here we identify a novel pathway between the basolateral amygdala (BLA), an emotional learning center in the mouse brain, and the inhibitory nucleus of the thalamus (TRN). We demonstrate that activation of this pathway amplifies sound-evoked activity in the central auditory pathway. Optogenetic activation of BLA suppressed spontaneous, but not tone-evoked activity in the auditory cortex (AC), effectively amplifying tone-evoked responses in AC. Anterograde and retrograde viral tracing identified robust BLA projections terminating at TRN. Optogenetic activation of amygdala-TRN pathway mimicked the effect of direct BLA activation, amplifying tone-evoked responses in the auditory thalamus and cortex. The results are explained by a computational model of the thalamocortical circuitry. In our model, activation of TRN by BLA suppresses spontaneous activity in thalamocortical cells, and as a result, thalamocortical neurons are primed to relay relevant sensory input. These results demonstrate a novel circuit mechanism for shining a neural spotlight on behaviorally relevant signals and provide a potential target for treatment of neuropsychological disorders, in which emotional control of sensory processing is disrupted.
Significant enrichment of Herpesvirus interactors in GWAS data suggests causal inferences for the association between Epstein Barr virus and multiple sclerosis
Authors: Mechelli Rosella , Umeton Renato , Srinivasan Sundararajan , Fornasiero Arianna , Ferraldeschi Michela ,   IMSGC and WTCCC2, Centonze Diego , Farina Cinthia , Salvetti Marco , Ristori Giovanni
Published: May 2019

We exploited genetic information to assess the role of non-genetic factors in multifactorial diseases. To this aim we isolated candidate “interactomes” (i.e. groups of genes whose products are known to physically interact with environmental exposures and biological processes, plausibly relevant for disease pathogenesis) and analyzed nominal statistical evidence of association with genetic predisposition to multiple sclerosis (MS) and other inflammatory and non-inflammatory complex disorders. The interaction between genotype and Herpesviruses emerged as specific for MS, with Epstein Barr virus (EBV) showing higher levels of significance compared to Human Herpesvirus 8 (HHV8) and, more evidently, to cytomegalovirus (CMV). In accord with this result, when we classified the MS-associated genes contained in the interactomes into canonical pathways, the analysis converged towards biological functions of B cells, in particular the CD40 pathway. When we analyzed peripheral blood transcriptomes in persons with MS, we found a significant dysregulation of MS-associated genes belonging to the EBV interactome in primary progressive MS. This study indicates that the interaction between herpesviruses and predisposing genetic background is of causal significance in MS, and provides a mechanistic explanation for the long-recognized association between EBV and this condition.
Targeting Fe3O4 Au nanoparticles in photoacoustic nuclear magnetic dual-mode imaging
Authors: Protealo David , Smith John
Published: May 2019

Multi-mode complementary imaging can improve the accuracy of medical diagnosis. Multi-mode probes are a bridge between various imaging modes, which means that the development of multi-mode, multi-functional nano-probes is very necessary. This paper develops a targeted as a probe for nuclear magnetic and photoacoustic dual-mode imaging, Fe3O4@Au nanoparticles have superparamagnetism and can enhance the nuclear magnetic signal of T2 sequence. The needle has optical absorption properties and can enhance photoacoustic signals. After modifying the surface of Integrin monoclonal antibody, the probe has selective targeting to U87-MG tumor cells. Nuclear magnetic based on Fe3O4@Au nanoparticles /Photoacoustic dual-mode imaging will play a major role in tumor diagnosis.
A flexible simulation toolkit for designing and evaluating ChIP-sequencing experiments
Authors: Zheng An , Lamkin Michael , Qiu Yutong , Ren Kevin , Goren Alon , Gymrek Melissa
Published: May 2019

A major challenge in evaluating quantitative ChIP-seq analyses, such as peak calling and differential binding, is a lack of reliable ground truth data. We present Tulip, a toolkit for rapidly simulating ChIP-seq data using statistical models of the experimental steps. Tulip may be used for a range of applications, including power analysis for experimental design, benchmarking of analysis tools, and modeling effects of processes such as replication on ChIP-seq signals.
Sperm-particle interactions and their prospects for charge mapping
Authors: Magdanz Veronika , Gebauer Johannes , Sharan Priyanka , Eltoukhy Samar , Voigt Dagmar , Simmchen Juliane
Published: May 2019

In this article, we demonstrate a procedure to investigate sperm charge distribution by electrostatic sperm-particle interactions. We fabricated and investigated differently charged particles and their attachment distribution on the bovine sperm membrane. We observed the sperm-particle attachment sites using bright field and cryo-scanning electron microscopy combined with energy-dispersive X-ray analysis. Our findings suggest that the charge distribution of the sperm membrane is not uniform and although the overall net charge of the sperm cell is negative, positively charged areas are especially found on the sperm heads. We test the newly developed method to investigate the dynamic charge distribution of the sperm cell membrane upon maturation induced by heparin, as a representation of the multitude of changes during the development of a sperm.
Feedback inhibition and its control in an insect olfactory circuit
Authors: Ray Subhasis , Aldworth Zane N. , Stopfer Mark A.
Published: May 2019

Inhibitory neurons play critical roles in regulating and shaping olfactory responses in vertebrates and invertebrates. In insects, these roles are performed by relatively few neurons, which can be interrogated efficiently, revealing fundamental principles of olfactory coding. Here, with electrophysiological recordings from the locust and a large-scale biophysical model, we analyzed the properties and functions of GGN, a unique giant GABAergic neuron that plays a central role in structuring olfactory codes in the locust mushroom body. Analysis of our in vivo recordings and simulations of our model of the olfactory network suggests that GGN extends the dynamic range of KCs, and leads us to predict the existence of a yet undiscovered olfactory pathway. Our analysis of GGN’s intrinsic properties, inputs, and outputs, in vivo and in silico, reveals basic new features of this critical neuron and the olfactory network that surrounds it.
Prevalence, awareness and control of hypertension in Malaysia 1980 – 2017: A Systematic Review and Meta-Analysis
Authors: Chow Zhen Yee , Jun Soo Man , Ching Siew Mooi , Tan Chun Han , Lee Kai Wei , Devaraj Navin Kumar , Syahida Hani , Ramachandran Vasudevan , Hoo Fan Kee , Cheong Ai Theng , Chia Yook Chin
Published: May 2019

Background

Hypertension is a common public health problem worldwide and is a well-known risk factor for increased risk of cardiovascular diseases, contributing to high morbidity and mortality. However, there is no systematic review and meta-analysis that has been done in a multi-ethnic population like Malaysia. This systematic review aims to determine the trend in prevalence, awareness and control of hypertension in Malaysia.

Methods

Systematic searches were conducted in PubMed, Scopus, Ovid, Cumulative Index to Nursing and Allied Health Literature, Malaysian Medical Repository and Malaysia Citation Index published between 1980 and 2017. All original articles in English were included. Studies included were those on adults aged 18 years and above. Studies of prevalence in children and adolescents and pregnancy related hypertension were excluded. Two authors independently reviewed the studies, carried out data extraction and performed quality assessment. Heterogeneity between studies and publication bias was assessed and effect size was pooled by the random effect model.

Results

Fifty-six studies with a total of 241,796 subjects were included. The prevalence of hypertension throughout Malaysia varied (I2= 99.3%). The overall pooled prevalence of hypertension over the past 4 decades was 28.2% in adults aged 18 years and older (95% CI: 26.1 – 33.3) and the prevalence in those 30 years and older was 40.0% (95% CI: 35.3-44.8).

For subgroup analysis, the prevalence of hypertension in male aged 18 and above was 31.4% (95% CI: 26.5 - 36.2) and 27.8% in female (95% CI: 20.7 – 34.9). The prevalence of hypertension among the ethnic groups aged 18 years and above were 37.3% in Malays (95% CI: 32.9 – 41.7); 36.4% in Chinese (95% CI 31.6 - 41.2) and 34.8% in Indians (95% CI: 31.2-38.4). The prevalence of hypertension was the lowest in the 1980s (16.2%, 95% CI: 13.4-19.0%), increases up to 36.8% in the 1990s (95% CI: 6.1-67.5), then came down to 28.7% (95% CI: 21.7-35.8) in the 2000s and 29.2% (95% CI: 24.0-34.4) in the 2010s. The prevalence of awareness was 38.7% (95% CI: 31.7 – 45.8) whereas the control of hypertension of those on treatment was 33.3% (95% CI: 28.4 – 38.2).

Conclusion

Three in 10 adults aged 18 years old and above have hypertension, whereas four in 10 adults aged 30 years old and above have hypertension. Four out of 10 are aware of their hypertension status and only one-third of them who were under treatment achieved control of their hypertension. Concerted efforts by policymakers and healthcare professionals to improve the awareness and control of hypertension should be of high priority.
Variant Analysis Pipeline for Accurate Detection of Genomic Variants from Transcriptome Sequencing Data
Authors: Adetunji Modupeore O. , Schmidt Carl J. , Lamont Susan J. , Abasht Behnam
Published: May 2019

The wealth of information deliverable from transcriptome sequencing (RNA-seq) is significant, however current applications for variant detection still remain a challenge due to the complexity of the transcriptome. Given the ability of RNA-seq to reveal active regions of the genome, detection of RNA-seq SNPs can prove valuable in understanding the phenotypic diversity between populations. Thus, we present a novel computational workflow named VAP (Variant Analysis Pipeline) that takes advantage of multiple RNA-seq splice aware aligners to call SNPs in non-human models using RNA-seq data only. We applied VAP to RNA-seq from a highly inbred chicken line and achieved >97% precision and >99% sensitivity when compared with the matching whole genome sequencing (WGS) data. Over 65% of WGS coding variants were identified from RNA-seq. Further, our results discovered SNPs resulting from post translational modifications, such as RNA editing, which may reveal potentially functional variation that would have otherwise been missed in genomic data. Even with the limitation in detecting variants in expressed regions only, our method proves to be a reliable alternative for SNP identification using RNA-seq data.
Maternal biomarker patterns for metabolism and inflammation in pregnancy are influenced by multiple micronutrient supplementation and associated with childrens’s biomarker patterns and nutritional status at 9-12 years of age in Lombok, Indonesia
Authors: Priliani Lidwina , Oktavianthi Sukma , Prado Elizabeth L. , Malik Safarina G. , Shankar Anuraj H.
Published: May 2019

Maternal nutritional status influences fetal development and long-term risk for adult non-communicable diseases. The underlying mechanisms of these long-term effects remain poorly understood. We examined whether maternal biomarkers for metabolism and inflammation during pregnancy were associated with child biomarkers in the Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT, ISRCTN34151616) in Lombok, Indonesia wherein archived blood specimens and relevant data were available from pregnant women and their children 9-12 years after birth. Forty-four mother-child dyads comprising 132 specimens were analyzed by multiplex microbead immunoassays to quantify vitamin D-binding protein (D), adiponectin (A), retinol-binding protein 4 (R), C-reactive protein (C), and leptin (L). Principal component analysis (PCA) revealed distinct variance patterns, i.e. principal components (PC), for baseline pregnancy bp.pc1.D↓A↓R↓ and bp.pc2.C↓L↑; combined follow-up and post-partum dp-pp.pc1.D↑↓A↑R↑↓L↓ and dp-pp.pc2.A↑C↑L↑; and children ch.pc1.D↑R↑C↑ and ch.pc2.D↓A↑L↑. Maternal multiple micronutrient (MMN) supplementation modified the association between baseline maternal bp.pc2.C↓L↑ and post-supplementation maternal dp-pp.pc2.A↓C↑L↑ (p=0.022). Significant associations were found between maternal dp-pp.pc2.A↑C↑L↑ and increased child ‘s ch.pc1.D↑R↑C↑ (p=0.036), and decreased child ‘s BMI z-score (BMIZ) (p=0.022); and between maternal dp-pp.pc1.D↑↓A↑R↑↓L↑ and increased child ‘s BMIZ (p=0.036). Child ‘s ch.pc1.D↑R↑C↑ was associated with decreased birth weight (p=0.036), and increased child’s BMIZ (p=0.002); and ch.pc2.D↓A↑L↑ was associated with increased child’s BMIZ (p=0.005), decreased maternal height (p=0.030) and girls (p=0.002). Elevated adiponectin and leptin pattern in pregnancy was associated with increased C-reactive protein and vitamin A and D binding proteins pattern in children, suggesting biomarkers acting in concert may be more important than single biomarker effects. Patterns in pregnancy proximal to birth were more associated with child status, and child patterns were most frequently associated with child status, particularly child BMI. Although MMN supplementation and certain maternal biomarker patterns have effects on metabolism and inflammation in pregnancy and in the child, nevertheless, nutrition conditions after birth may have a greater impact.
R Functions for Analysis of Continuous Glucose Monitor Data
Authors: Vigers Tim , Chan Christine L. , Snell-Bergeon Janet , Bjornstad Petter , Zeitler Philip S. , Forlenza Gregory , Pyle Laura
Published: May 2019

Continuous glucose monitoring (CGM) is an essential part of diabetes care. Real-time CGM data are beneficial to patients for daily glucose management, and aggregate summary statistics of CGM measures are valuable to direct insulin dosing and as a tool for researchers in clinical trials. Yet, the various commercial systems still report CGM data in disparate, non-standard ways. Accordingly, there is a need for a standardized, free, open-source approach to CGM data management and analysis. Functions were developed in the free programming language R to provide a rapid, easy, and consistent methodology for CGM data management and analysis. Summary variables calculated by our package compare well to those generated by various CGM software, and our functions provide a more comprehensive list of summary measures available to clinicians and researchers. Consistent handling of CGM data using our R package may facilitate collaboration between research groups and contribute to a better understanding of free-living glucose patterns.
Role of ethnicity and socio-economic status (SES) in the presentation of retinoblastoma: findings from the UK
Authors: Bourkiza Rabia , Cumberland Phillippa , Abeysekera Hiranya , Parulekar Manoj , Sagoo Mandeep S , Rahi Jugnoo , Reddy M. Ashwin
Published: May 2019

Purpose

The aim of this study was to investigate if there was a relationship between ethnicity or socioeconomic status and the presentation of advanced non-familial retinoblastoma in the UK.

Methods

A cross sectional study based at the two centres providing retinoblastoma care in the UK. Non-familial cases of retinoblastoma (Rb) presenting between January 2006 and December 2011 were included. Data collected included: age at diagnosis, gender, child’s ethnicity, International Intraocular Retinoblastoma Classification (IIRC) stage with Groups D and E being considered advanced, laterality, treatment, and postcodes. Individual postcode (ZIP code) data was used to obtain the Index of Multiple Deprivation (IMD) score. A postal questionnaire was sent to participants’ parents to collect further, person-level, information on languages spoken and household socioeconomic position. Measures of severity of retinoblastoma also included: requirement for primary enucleation; the use of adjuvant chemotherapy; and mortality.

Results

189 cases were analyzed. 98 (52%) male and 91 (48%) female. Median age at diagnosis was 16 months [IQR 8 – 34 months]. 153/189 (81%) of cases presented with advanced retinoblastoma; 75 (40%) group E, 78 (41%) group D. 134 (72%) of cases were treated with enucleation.

Multivariable analysis showed that older age at presentation was associated with enucleation and bilateral disease was associated with adjuvant chemotherapy. There was some indication that South Asian ethnicity and being in the most deprived IMD quintile were associated with a higher likelihood of presentation with advanced disease, but these estimates did not reach statistical significance.

Conclusions

In this first national UK study of patients with non-familial retinoblastoma, there was no evidence of an association of ethnicity or socio-economic status and the risk of presenting with advanced disease. This may reflect equality in access of health care in the UK. As a result, awareness campaigns should continue.
Transcriptome-wide map of m6A circRNAs identified in hypoxic pulmonary hypertension rat model
Authors: Su Hua , Zhou Lin , Li Na , Wang Guowen , Wu Lingfang , Ma Xiuqing , Ying Kejing , Zhang Ruifeng
Published: May 2019

Hypoxic pulmonary hypertension (HPH) is a lethal disease. CircRNAs and m6A circRNAs have been reported to be associated with cancer progression, but the expression profiling of m6A circRNAs has not been identified in HPH. This study was to investigate the transcriptome-wide map of m6A circRNAs in HPH. In this study, hypoxia-induced PH rat model was established. Total RNA was extracted and purified from lungs of rats, then circRNAs were detected and annotated by RNA-seq analysis. m6A RNA Immunoprecipitation (MeRIP) was performed following rRNA depletion, and RNA-seq library was constructed. CircRNA–miRNA–mRNA co-expression network was also constructed. In vitro, total m6A was measured. m6A circXpo6 and m6A circTmtc3 were detected in pulmonary artery smooth muscle cells (PASMCs) and pulmonary artery endothelial cells (PAECs) exposed to 21% O2 and 1% O2 for 48 h, respectively. m6A abundance in 166 circRNAs was significantly upregulated and m6A abundance in 191 circRNAs was significantly downregulated in lungs of HPH rats. m6A abundance in circRNAs was significantly reduced in hypoxia in vitro. m6A circRNAs were mainly derived from single exons of protein-coding genes. m6A influenced the circRNA–miRNA–mRNA co-expression network in hypoxia. m6A circXpo6 and m6A circTmtc3 were downregulated in hypoxia. In general, our study firstly identified the transcriptome-wide map of m6A circRNAs in HPH. m6A level in circRNAs was decreased in lungs of HPH rats and in PASMCs and PAECs exposed to hypoxia. Downregulated or upregulated m6A level influenced circRNA–miRNA–mRNA co-expression network in HPH. Moreover, we firstly identified two downregulated m6A circRNAs in HPH: circXpo6 and circTmtc3. We suggested that m6A circRNAs may be used as a potential diagnostic marker or therapy target in the future.

Author summary

HPH is a disease with great morbidity and mortality. It is often caused by chronic hypoxic lung diseases, such as chronic obstructive pulmonary disease and interstitial lung diseases. It lacks effective therapy methods so far. CircRNAs are a type of non-coding RNAs and can be used as biomarkers because they are differentially enriched in specific cell types or tissues and not easily degraded. m6A is identified as the most universal modification on non-coding RNAs in eukaryotes. CircRNAs can be modified by m6A. m6A circRNAs in HPH is not well understood yet. Here we identify the transcriptome-wide map of m6A circRNAs in HPH. We elucidate that m6A level in circRNAs is decreased in lungs of HPH rats and in PASMCs and PAECs exposed to hypoxia. We find that downregulated or upregulated m6A level influences circRNA– miRNA–mRNA co-expression network in HPH. Moreover, we are the first to identify two downregulated m6A circRNAs in HPH: circXpo6 and circTmtc3. We suggest that m6A circRNAs may be used as a potential diagnostic marker or therapy target in the future.
HES1, two programs: promoting the quiescence and proliferation of adult neural stem cells
Authors: Harris Lachlan , Guillemot François
Published: May 2019

Adult neural stem cells are mostly quiescent and only rarely enter the cell cycle to self-renew and generate neuronal or glial progenies. The Notch signaling pathway is essential for both the quiescent and proliferative states of neural stem cells. However, these are mutually exclusive cellular states; thus, how Notch promotes both of these programs within adult neural stem cells has remained unclear. In this issue of Genes & Development, Sueda and colleagues (pp. 511–523) use an extensive repertoire of mouse genetic tools and techniques to demonstrate that it is the levels and dynamic expression of the Notch transcriptional effector Hairy and Enhancer of Split 1 that enables this dual role.
Observation of Fluorescent Proteins in Fixed Cells
Authors: Behringer Richard , Gertsenstein Marina , Nagy Kristina Vintersten , Nagy Andras
Published: May 2019

Fluorescent proteins (FPs) are popular reporters available for gene expression detection and determination of cellular identities in the mouse. This protocol can be used to detect green fluorescent protein spectral variants and proteins labeled with the fusion tag dsRed in fixed cells.
Construction of Recombinant Adenovirus Genomes by Direct Cloning
Authors: Zhou Xiangyang , Sena-Esteves Miguel , Gao Guangping
Published: May 2019

This protocol describes how to generate an infectious adenovirus vector by direct ligation and cloning. This is the first step in the production of a recombinant adenovirus vector. The protocol begins with a convenient and efficient double-selection procedure based on antibiotic resistance and identification of green fluorescent protein (GFP)-negative bacterial colonies. In this protocol, the prokaryotic expression cassette for GFP in the shuttle plasmid pSh-pkGFP is replaced with the transgene. The resulting pShuttle–transgene plasmid is then used to clone the transgene expression cassette into pAd-pkGFP, using the same double-selection procedure.
Purification of the Recombinant Adenovirus by Cesium Chloride Gradient Centrifugation
Authors: Su Qin , Sena-Esteves Miguel , Gao Guangping
Published: May 2019

Cesium chloride gradient centrifugation is the most widely used method for purification of recombinant adenovirus. This protocol describes the entire process, from the preparation and clarification of crude viral lysate to the formulation and storage of purified virus.
Peptide Affinity Purification of Antibodies
Authors: Fishman Jordan B. , Berg Eric A.
Published: May 2019

This protocol describes antibody purification using a peptide affinity column. Peptides can be designed that use naturally occurring cysteines within the protein target's primary sequence, or a cysteine can be added to either end of the peptide to provide free thiols for attachment. The peptides can then be covalently attached to resins bearing thiol-reactive linkers. The most commonly used thiol-reactive moieties are iodoacetyl and maleimide, both of which react selectively with peptides containing cysteine thiols. Although gravity can be used to cycle the antibody solution (e.g., serum) over the column (it is recommended that the antibody be cycled multiple times to obtain maximal yield), the use of a pump to apply the serum to the column in a continuous flow manner improves the yield of antibody. Similarly, washing the column after application of the antibody without and with 0.5 m NaCl should be performed with at least 20 column volumes.
Product market competition and efficiency of corporate tax management
Authors: Wang Tina
Published: May 2019

Purpose

The purpose of this paper is to test the economic theory that product market competition should enhance firm performance in the US corporate tax management setting. It identifies one mechanism through which corporate management can improve firm performance. The paper also identifies business conditions that may facility or impede effective corporate tax management.

Design/methodology/approach

The paper tests the relationship between product market competition and corporate tax efficiency using large archival data. The primary data source is COMPUSTAT, which contains annual and quarterly accounting data for US public firms. Other data sources include accounting comparability data generously shared by Professor Vedi.

Findings

The paper finds that firms in competitive industries are more efficient in managing taxes. Specifically, the paper documents that firms in competitive industries exhibit lower effective tax rates than their non-competitive counterparts. Furthermore, the paper finds that the positive link between competition and the efficiency of tax management is much stronger for firms with lower cash flow volatility and for firms with fewer industry investment opportunities. The lack of financial statement comparability may weaken this link.

Research limitations/implications

Tax laws vary greatly from country to country. Readers should interpret the results within the US tax environments.

Practical implications

Results in this paper have implications for multinational corporations that are interested in investing and doing business in the USA.

Originality/value

This paper sheds light on how competition influences firm performance through efficient tax management, a specific mechanism through which competition improves firm performance. To the best of the author’s knowledge, this study provides the first documentation of how product market competition affects tax planning for US publicly traded companies.