bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationship between pubertal timing and chronic nonspecific pain in adolescent girls: the Young-HUNT3 study (2006-2008)
Authors: Kløven Barbro , Hoftun Gry B. , Romundstad Pål R. , Rygg Marite
Published: May 2017

The aim of this study was to examine a possible relationship between early puberty and chronic nonspecific pain in 13- to 18-year-old girls. All adolescents in Nord-Trøndelag County, Norway, were invited to participate in the Young-HUNT3 study (2006-2008). Of the invited girls, 81% answered the questionnaire and of these 3982 were 13 to 18 years of age. Menarche and perceived physical maturation were used as exposure measures. Early menarche was defined as <12 years, normal menarche as ≥12 and <14 years, and late menarche as ≥14 years. Perceived physical maturation was divided into maturing earlier, the same or later than others of their own age. The main outcome measure was chronic nonspecific pain, defined as pain in at least one location not related to any known disease or injury, for at least once a week during the last 3 months. The median age at menarche was 13.2 years. Chronic nonspecific pain was more prevalent among girls with early menarche (68%, 95% CI: 64%-72%) compared to girls with either normal (55%, 95% CI: 53%-57%), late (50%, 95% CI: 46%-54%), or no menarche (35%, 95% CI: 29%-40%). The association persisted after adjusting for age, body mass index, socioeconomic factors, and anxiety and depression. A similar association was found between girls that perceived themselves as earlier physically matured than their peers and chronic nonspecific pain. Headache/migraine was the most common type of chronic nonspecific pain regardless of menarcheal age. In all reported locations, pain was more prevalent in the group with early menarche compared to normal or late menarche.
Altered brain structure and function associated with sensory and affective components of classic trigeminal neuralgia
Authors: Wang Yuan , Cao Dong-yuan , Remeniuk Bethany , Krimmel Samuel , Seminowicz David A. , Zhang Ming
Published: May 2017

Classic trigeminal neuralgia (CTN) is a chronic neuropathic pain state characterized by intense, piercing spasms of the orofacial region, and may be attributable to abnormal pain processing in the central nervous system. Our study investigated neuronal alterations using voxel-based morphometry (VBM), diffuse tensor imaging (DTI), and resting-state functional connectivity in 38 patients with CTN and 38 matched healthy controls. For voxel-based morphometry analyses, patients with CTN displayed gray matter volume (GMV) reductions in the anterior-cingulate cortex (ACC) and mid-cingulate cortex, insula, secondary somatosensory cortex (S2), primary motor cortex (M1), premotor area, and several regions in the temporal lobe. For DTI analysis, patients compared with controls had increased mean diffusivity (MD) and decreased fractional anisotropy (FA) in the corpus callosum and the bilateral corona radiata, and increased mean diffusivity with no fractional anisotropy changes across the bilateral superior longitudinal fasciculus, the internal and external capsule, the thalamus and brainstem. Additionally, patients with CTN had enhanced functional connectivity between the right insula/S2 and ACC, medial prefrontal cortex, posterior cingulate cortex, and bilateral dorsolateral prefrontal cortex. Furthermore, gray matter volume of left inferior temporal gyrus negatively correlated with current pain intensity and disease duration in patients, and connectivity of the right insula/S2-ACC was negatively correlated with pain intensity, depression, and anxiety ratings. This study provides multiple lines of evidence supporting aberrant structural and functional patterns that are observed in patients with CTN, which may help us better understand the pathophysiology of CTN and facilitate the development of new therapies for this disease.
Age-Group and Gender Differences in Stroke Knowledge in an Israeli Jewish Adult Population
Authors: Melnikov Semyon , Itzhaki Michal , Koton Silvia
Published: May 2017

Background:

Stroke is a leading cause of long-term disability and the fifth leading cause of death in Israel. Knowledge of stroke warning signs has been linked to early seeking of medical help. Little is known about knowledge of stroke warning signs in Israeli Jewish adults.

Methods:

Stroke knowledge was examined among Jewish Israeli adults. Using a structured questionnaire, registered nurses interviewed a convenience sample of the respondents, 18 years or older, with no stroke history. Stroke knowledge and demographics were examined by 3 age groups (<45, 45–64, and >64 years) in men and women.

Results:

In total, 1137 Jewish Israelis were interviewed, 457 (40.2%) men and 680 women (59.8%); 493 (43.4%) were younger than 45 years, 541 (47.6%) were aged 45 to 64 years, and 102 (9%) were older than 64 years; 1 (0.1%) did not report age. On average, each interview lasted for 25 to 30 minutes. Participants younger than 45 years showed the lowest knowledge of stroke cause. Women younger than 45 years were less likely to identify at least 2 stroke warning signs. Participants younger than 45 years were less likely to identify at least 2 risk factors, compared with participants aged 45 to 64 years and older than 64 years. Women younger than 45 years were less likely to identify at least 2 stroke prevention strategies.

Conclusion:

Participants younger than 45 years showed the lowest levels of stroke knowledge. The highest stroke knowledge was found in the 45 to 64 years age group. Stroke knowledge among different age groups was similar in both genders. Educational campaigns aimed at increasing knowledge of stroke among the general population and targeting the younger population are recommended.
Growth hormone treatment for growth hormone deficiency and idiopathic short stature: new guidelines shaped by the presence and absence of evidence
Authors: Grimberg Adda , Allen David B.
Published: May 2017

Purpose of review

The Pediatric Endocrine Society recently published new guidelines for the use of human growth hormone (hGH) and human insulin-like growth factor-I (hIGF-I) treatment for growth hormone deficiency, idiopathic short stature, and primary IGF-I deficiency in children and adolescents. This review places the new guidelines in historical contexts of the life cycle of hGH and the evolution of US health care, and highlights their future implications.

Recent findings

The new hGH guidelines, the first to be created by the Grading of Recommendations Assessment, Development and Evaluation approach, are more conservative than their predecessors. They follow an extended period of hGH therapeutic expansion at a time when US health care is pivoting toward value-based practice. There are strong supporting evidence and general agreement regarding the restoration of hormonal normalcy in children with severe deficiency of growth hormone or hIGF-I. More complex are issues related to hGH treatment to increase growth rates and heights of otherwise healthy short children with either idiopathic short stature or ‘partial’ isolated idiopathic growth hormone deficiency.

The guidelines-developing process revealed fundamental questions about hGH treatment that still need evidence-based answers. Unless and until such research is performed, a more restrained hGH-prescribing approach is appropriate.
Diagnosis and management of allergic contact dermatitis in children: common allergens that can be easily missed
Authors: Jacob Sharon E. , Brankov Nikoleta , Kerr Alastair
Published: May 2017

Purpose of review

Contact dermatitis is an economically burdensome pediatric disease, and it is important to know the top allergens that have remained as top offenders for over the last decade.

Recent findings

A comparative analysis of the 20-allergen screen was done against the current top 40 pediatric allergens, and it revealed that the 20-allergen screening series would have theoretically only captured 47.5% of the relevant contact allergens (52.5% failure to detect rate). In addition, the T.R.U.E. Test (SmartPractice, Phoenix, Arizona, USA) would have revealed 60% of the top 40 allergens (40% failure to detect rate).

Patch testing in children has become a more common practice, and management requires the identification and avoidance of the offending allergen from the sensitized person's environment.
Outbreaks in the adult ICUs
Authors: Al-Dorzi Hasan M. , Arabi Yaseen M.
Published: May 2017

Purpose of review

Infectious disease outbreaks in the critical care setting are common and serious consequence. This article reviews and summarizes recent outbreaks in the adult ICUs.

Recent findings

Outbreaks of multidrug-resistant bacteria, fungi, and emerging viruses in ICUs from different countries are common. Outbreak investigation relies on epidemiologic methods, microbiologic studies, and molecular typing methods. Overuse of antibiotics, gaps in implementing infection prevention measures, and contaminated environment are common causes of ICU outbreaks. ICU staff awareness of and preparedness for such outbreaks are crucial for outbreak prevention and control. Specific infection control measures vary according to outbreak transmission mode and cause.

Outbreaks remain a significant threat to healthcare systems. Proper implementation of infection prevention practices and judicious use of antibiotics are needed for outbreak prevention in adult ICUs. Surveillance, proper outbreak investigation, adherence to infection prevention and control measures, and thorough disinfection of contaminated areas are required to successfully manage outbreaks.
Metabolic Inflammatory Complex in Sepsis: Septic Cachexia as a Novel Potential Therapeutic Target
Authors: Kaneki Masao
Published: May 2017

Despite several decades of focused investigation, sepsis remains a major cause of mortality in critically ill patients. Advancements in intensive care have enabled more patients to survive the acute phase of sepsis than previously, but a growing number of them progress to chronic critical illness. The failure of previous randomized clinical trials of anti-inflammatory agents to show any pro-survival benefit in septic patients underscores current thought that simple anti-inflammatory strategies are ineffective because the inhibitory effect of anti-inflammatory agents undermines the immune response to pathogens. New strategies with the dual capability of ameliorating inflammation in organs while stimulating antimicrobial activity are eagerly awaited. On the other hand, the metabolic alterations associated with systemic inflammatory response, including mitochondrial dysfunction and metabolic shift, are closely linked through a nexus of signaling pathways and signaling molecules. Preventing these metabolic derangements may be an alternative way to control excessive inflammation, an intriguing possibility that has not been fully explored. New insight into the molecular pathogenesis of sepsis and sepsis-associated chronic critical illness has led to the recognition of septic cachexia, a life-threatening form of metabolic inflammatory complex associated with multiple organ dysfunction. The potential for septic cachexia to serve as a novel target disease state to improve the clinical outcome of septic patients is discussed in this review.
Focal Capillary Dropout Associated With Optic Disc Drusen Using Optical Coherence Tomographic Angiography
Authors: Gaier Eric D. , Rizzo Joseph F. , Miller John B. , Cestari Dean M.
Published: May 2017

Optic disc drusen may be a cause of visual field defects and visual loss. The mechanism by which this occurs is unclear. We report a patient who developed decreased vision in the right eye and was found to have a heavy burden of superficial optic disc drusen. Optical coherence tomography (OCT) confirmed focal retinal nerve fiber layer thinning that corresponded with the distribution of drusen. OCT angiography, with superficial laminar segmentation, showed focal capillary attenuation overlying the most prominent drusen. These findings demonstrate alterations in the superficial retinal capillary network associated with optic disc drusen.
Clues for two-step virion infectivity factor regulation by core binding factor beta
Authors: Ai Youwei , Ma Jianzhang , Wang Xiaojun
Published: May 2017

Lentiviruses threaten human and animal health. Virion infectivity factor (Vif) is essential for the infectivity of most lentiviruses, except for the equine infectious anaemia virus (EIAV). Vif promotes viral infectivity by recruiting a Cullin-based E3 ligase to induce the degradation of a class of host restriction factors, named APOBEC3. Core binding factor beta (CBF-β) is necessary for several primate lentiviral Vif functions, including HIV-1 Vif. Although much progress has been made in understanding the contribution of CBF-β to Vif function, the precise mechanism has not yet been fully elucidated. In this study, we found that an interaction with CBF-β altered the oligomerization and subcellular distribution pattern and increased the stability of two primate lentiviral Vifs, HIV-1 Vif and Macaca simian immunodeficiency virus (SIVmac) Vif. Moreover, using a CBF-β loss-of-function mutant, we demonstrated that the interaction between CBF-β and Vif was not sufficient for Vif assistance; a region including F68 in CBF-β was also required for the stability and function of Vif. For the first time, this study separates the binding and regulating processes of CBF-β when it is promoting Vif function, which further extends our understanding of the biochemical regulation of Vif by CBF-β.
Effects of olanexidine gluconate on preoperative skin preparation: an experimental study in cynomolgus monkeys
Authors: Nakata Hikaru , Tsubotani Yoshie , Nii Takuya , Hagi Akifumi , Inoue Yasuhide , Imamura Tadashi
Published: May 2017

Purpose.To determine the bactericidal efficacy of a new topical antiseptic for preoperative skin preparation, olanexidine gluconate (development code: OPB-2045G), against transient or resident bacterial flora on the skin of cynomolgus monkeys.

Methodology.After measuring baseline bacterial counts on test sites marked on the abdomens, we applied olanexidine, chlorhexidine or povidone–iodine. After 10 min (fast-acting effect) and 6 h (long-lasting effect), bacterial counts were measured again and log10reductions were calculated. In addition, we determined the bactericidal effects on the skin contaminated with blood before or after applying the antiseptics.

Results.In the non-blood-contaminated condition, the mean log10reductions of olanexidine at doses of 1–2 % were significantly higher than those of saline (negative control), but did not significantly differ from those of 0.5 % chlorhexidine and 10 % povidone–iodine at either time point. But olanexidine was significantly more effective at both time points than chlorhexidine and povidone–iodine when applied after the site was contaminated with blood. Olanexidine was also significantly more effective than chlorhexidine and as effective as or more effective than povidone-iodine at both time points when skin was contaminated with blood after the antiseptics were applied.

Conclusion.The bactericidal effects of olanexidine were comparable to those of commercial antiseptics such as chlorhexidine and povidone–iodine in non-blood-contaminated conditions. More importantly, the effect of olanexidine was hardly affected by blood unlike commercial antiseptics. Thus, it is considered that olanexidine has a favourable property for skin preparation in various types of surgical treatments.
Laser-free super-resolution microscopy
Authors: Prakash Kirti
Published: May 2017

We report that high-density single-molecule super-resolution microscopy can be achieved with a conventional epifluorescence microscope setup and a Mercury arc lamp. The configuration termed as laser-free super-resolution microscopy (LFSM), is an extension of single molecule localisation microscopy (SMLM) techniques and allows single molecules to be switched on and off (a phenomenon termed as “blinking”), detected and localised. The use of a short burst of deep blue excitation (350-380 nm) can be further used to reactivate the blinking, once the blinking process has slowed or stopped. A resolution of 90 nm is achieved on test specimens (mouse and amphibian meiotic chromosomes). Finally, we demonstrate that STED and LFSM can be performed on the same biological sample using a simple commercial mounting medium. It is hoped that this type of correlative imaging will provide a basis for a further enhanced resolution.
Polygenic Link Between Blood Lipids And Amyotrophic Lateral Sclerosis
Authors: Chen Xu , Yazdani Solmaz , Piehl Fredrik , Magnusson Patrik K.E. , Fang Fang
Published: May 2017

Dyslipidemia is common among patients with amyotrophic lateral sclerosis (ALS). We aimed to test the association and causality between blood lipids and ALS, using polygenic analyses on the summary results of genome-wide association studies. Polygenic risk scores (PRS) based on low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) risk alleles were significantly associated with a higher risk of ALS. Using single nucleotide polymorphisms (SNPs) specifically associated with LDL-C and TC as the instrumental variables, statistically significant causal effects of LDL-C and TC on ALS risk were identified in Mendelian randomization analysis. No significant association was noted between PRS based on triglycerides or high-density lipoprotein cholesterol risk alleles and ALS, and the PRS based on ALS risk alleles were not associated with any studied lipids. This study supports that high levels of LDL-C and TC are risk factors for ALS, and it also suggests a causal relationship of LDL-C and TC to ALS.
Towards selective-alignment: Bridging the accuracy gap between alignment-based and alignment-free transcript quantification
Authors: Sarkar Hirak , Zakeri Mohsen , Malik Laraib , Patro Rob
Published: May 2017

Motivation

We introduce an algorithm for selectively aligning high-throughput sequencing reads to a transcriptome, with the goal of improving transcript-level quantification. This algorithm attempts to bridge the gap between fast “mapping” algorithms and more traditional alignment procedures.

Results

We adopt a hybrid approach that is able to increase mapping accuracy while still retaining much of the efficiency of fast mapping algorithms. To achieve this, we introduce a new approach that explores the candidate search space with high sensitivity as well as a collection of carefully-engineered heuristics to efficiently filter these candidates. Additionally, unlike the strategies adopted in most aligners which first align the ends of paired-end reads independently, we introduce a notion of co-mapping. This procedure exploits relevant information between the “hits” from the left and right ends of paired-end reads before full alignments or mappings for each are generated, which improves the efficiency of filtering likely-spurious alignments. Finally, we demonstrate the utility of selective alignment in improving the accuracy of efficient transcript-level quantification from RNA-seq reads. Specifically, we show that selective-alignment is able to resolve certain complex mapping scenarios that can confound existing fast mapping procedures, while simultaneously eliminating spurious alignments that fast mapping approaches can produce.

Availability

Selective-alignment is implemented in C++11 as a part ofSalmon, and is available as open source software, under GPL v3, at:https://github.com/COMBINE-lab/salmon/tree/selective-alignment

Contact

rob.patro@cs.stonybrook.edu
The AWSEM-Amylometer: predicting amyloid propensity and fibril topology using an optimized folding landscape model
Authors: Chen Mingchen , Schafer Nicholas P , Zheng Weihua , Wolynes Peter G
Published: May 2017

Amyloids are fibrillar protein aggregates with simple repeated structural motifs in their cores, usuallyβ-strands but sometimesα-helices. Identifying the amyloid-prone regions within protein sequences is important both for understanding the mechanisms of amyloid-associated diseases and for understanding functional amyloids. Based on the crystal structures of seven cross-βamyloidogenic peptides with different topologies and one recently solved cross-αfiber structure, we have developed a computational approach for identifying amyloidogenic segments in protein sequences using the Associative memory, Water mediated, Structure and Energy Model. The AWSEM-Amylometer performs favorably in comparison with other predictors in predicting aggregation-prone sequences in multiple datasets. The method also predicts the specific topologies (the relative arrangement ofβ-strands in the core) of the amyloid fibrils well. An important advantage of the AWSEM-Amylometer over other existing methods is its direct connection with an efficient, optimized protein folding simulation model, AWSEM. This connection allows one to combine efficient and accurate search of protein sequences for amyloidogenic segments with the detailed study of the thermodynamic and kinetic roles that these segments play in folding and aggregation in the context of the entire protein sequence. We present new simulation results that highlight the free energy landscapes of peptides that can take on multiple fibril topologies. We also demonstrate how the Amylometer methodology can be straightforwardly extended to the study of functional amyloids that have the recently discovered cross-αfibril architecture.
On the importance of being stable ‒ evolutionarily frozen species can win in fluctuating environment
Authors: Flegr Jaroslav , Ponížil Petr
Published: May 2017

The ability of organisms to adaptively respond to environmental changes (evolvability) is usually considered to be an important advantage in interspecific competition. It has been suggested, however, that evolvability could be a double-edged sword that could present a serious handicap in fluctuating environments. The authors of this counterintuitive idea have published only verbal models to support their claims.

Here we present the results of individual-based stochastic modelling of competition between two asexual species differing only by their evolvability. They show that, in changeable environments, less evolvable species could outperform their more evolvable competitors in a broad area of a parameter space, regardless of whether the conditions fluctuated periodically or aperiodically. Highly evolvable species prospered better nearly all the time; however, they sustained a higher probability of extinction during rare events of the rapid transient change of conditions.

Our results offer an explanation of why sexually reproducing species, with their reduced capacity to respond adaptively to local or temporal environmental changes, prevail in most eukaryotic taxa in nearly all biotopes on the surface of Earth. These species may suffer several important disadvantages in direct competitive battles with asexual species; however, they might win in changeable environments in the more important sorting-according-to-stability war.
Identifying parameters of host cell vulnerability duringSalmonellainfection by quantitative image analysis and modeling
Authors: Voznica Jakub , Gardella Christophe , Belotserkovsky Ilia , Dufour Alexandre , Enninga Jost , Stévenin Virginie
Published: May 2017

Salmonellatarget and enter epithelial cells at permissive entry sites: some cells are more likely to be infected than others. However the parameters that lead to host cell heterogeneity are not known. Here, we quantitatively characterized host cell “vulnerability” towardsSalmonellainfection based on imaged parameters. We performed successive infections of the same host cell population followed by automated high-throuput microscopy and observed that infected cells have higher probability of being re-infected. Establishing a predictive model we identified two combined origins of host cell vulnerability: the pathogen-induced cellular vulnerability emerging fromSalmonellauptake and persisting at later stage of the infection, and the host cell-inherent vulnerability. We linked the host cell inherent vulnerability with its morphological attributes such as the local cell crowding, and with host cell cholesterol content. This showed that the probability ofSalmonellainfection success can be forecast from morphological or molecular host cell parameters.
Isolation and characterization of key genes that promote flavonoid accumulation in purple-leaf tea (Camellia sinensisL.)
Authors: He Xiujuan , Zhao Xuecheng , Gao Liping , Shi Xingxing , Dai Xinlong , Liu Yajun , Xia Tao , Wang Yunsheng
Published: May 2017

There were several high concentrations of flavonoid components in tea leaves that present health benefits. A novel purple-leaf tea variety, ‘Mooma1’, was obtained from the natural hybrid population of Longjing 43 variety. The buds and young leaves of ‘Mooma1’ were displayed in bright red. HPLC and LC-MS analysis showed that anthocyanins and O-Glycosylated flavonols were remarkably accumulated in the leaves of ‘Mooma1’, while the total amount of catechins in purple-leaf leaves was slightly decreased compared with the control. A R2R3-MYB transcription factor (CsMYB6A) and a novel UGT gene (CsUGT72AM1), that were highly expressed in purple leaf were isolated and identified by transcriptome sequencing. The over-expression of transgenic tobacco confirmed thatCsMYB6Acan activate the expression of flavonoid-related structural genes, especiallyCHS and 3GT,controlling the accumulation of anthocyanins in the leaf of transgenic tobacco. Enzymatic assaysin vitroconfirmed that CsUGT72AM1 has catalytic activity as a flavonol 3-O-glucosyltransferase, and displayed broad substrate specificity. The results were useful for further elucidating the molecular mechanisms of the flavonoid metabolic fluxes in the tea plant.
Interdependence, Reflexivity, Fidelity, Impedance Matching, and the Evolution of Genetic Coding
Authors: Carter Charles W. , Wills Peter
Published: May 2017

Genetic coding is generally thought to have required ribozymes whose functions were taken over by polypeptide aminoacyl-tRNA synthetases (aaRS). Two discoveries about aaRS and their tRNA substrates now furnish a unifying rationale for the opposite conclusion: that the key processes of the Central Dogma of molecular biology emerged simultaneously and naturally from simple origins in a peptide•RNA partnership, eliminating the epistemological need for a prior RNA world. First, the two aaRS classes likely arose from opposite strands of the same ancestral gene, implying a simple genetic alphabet. Inversion symmetries in aaRS structural biology arising from genetic complementarity would have stabilized the initial and subsequent differentiation of coding specificities and hence rapidly promoted diversity in the proteome. Second, amino acid physical chemistry maps onto tRNA identity elements, establishing reflexivity in protein aaRS. Bootstrapping of increasingly detailed coding is thus intrinsic to polypeptide aaRS, but impossible in an RNA world. These notions underline the following concepts that contradict gradual replacement of ribozymal aaRS by polypeptide aaRS: (i) any set of aaRS must be interdependent; (ii) reflexivity intrinsic to polypeptide aaRS production dynamics promotes bootstrapping; (iii) takeover of RNA-catalyzed aminoacylation by enzymes will necessarily degrade specificity; (iv) the Central Dogma’s emergence is most probable when replication and translation error rates remain comparable. These characteristics are necessary and sufficient for the essentiallyde novoemergence of a coupled gene-replicase-translatase system of genetic coding that would have continuously preserved the functional meaning of genetically encoded protein genes whose phylogenetic relationships match those observed today.
Improved estimation of SNP heritability using Bayesian multiple-phenotype models
Authors: Elhezzani Najla Saad
Published: May 2017

Linear mixed models (LMM) are widely used to estimate narrow sense heritability explained by tagged single-nucleotide polymorphisms (SNPs). However, those estimates are valid only if large sample sizes are used. We propose a Bayesian matrix-variate model that takes into account the genetic correlation among phenotypes and genetic correlation among individuals. The use of multivariate Bayesian methods allows us to circumvent some issues related to small sample sizes, mainly overfitting and boundary estimates. Using gene expression pathways, we demonstrate a significant improvement in SNP-based heritability estimates over univariate and likelihood-based methods, thus explaining why recent progress in eQTL identification has been limited.
A non-parametric Bayesian prior for causal inference of auditory streaming
Authors: Yates Tim , Larigaldie Nathanael , Beierholm Ulrik R.
Published: May 2017

Human perceptual grouping of sequential auditory cues has traditionally been modeled using a mechanistic approach. The problem however is essentially one of source inference – a problem that has recently been tackled using statistical Bayesian models in visual and auditory-visual modalities. Usually the models are restricted to performing inference over just one or two possible sources, but human perceptual systems have to deal with much more complex scenarios. To characterize human perception we have developed a Bayesian inference model that allows an unlimited number of signal sources to be considered: it is general enough to allow any discrete sequential cues, from any modality. The model uses a non-parametric prior, hence increased complexity of the signal does not necessitate more parameters. The model not only determines the most likely number of sources, but also specifies the source that each signal is associated with. The model gives an excellent fit to data from an auditory stream segregation experiment in which the pitch and presentation rate of pure tones determined the perceived number of sources.
De novomutations implicate novel genes with burden of rare variants in Systemic Lupus Erythematosus
Authors: Pullabhatla Venu , Roberts Amy L. , Lewis Myles J. , Mauro Daniele , Morris David L. , Odhams Christopher A. , Tombleson Philip , Liljedahl Ulrika , Vyse Simon , Simpson Michael A. , Sauer Sascha , Rinaldis Emanuele de , Syvänen Ann-Christine , Vyse Timothy J.
Published: May 2017

The omnigenic model of complex diseases stipulates that the majority of the heritability will be explained by the effects of common variation on genes in the periphery of core disease pathways. Rare variant associations, expected to explain far less of the heritability, may be enriched in core disease genes and thus will be instrumental in the understanding of complex disease pathogenesis and their potential therapeutic targets. Here, using complementary whole-exome sequencing (WES), high-density imputation, andin vitrocellular assays, we identify three candidate core genes in the pathogenesis of Systemic Lupus Erythematosus (SLE). Using extreme-phenotype sampling, we sequenced the exomes of 30 SLE parent-affected-offspring trios and identified 14 genes with missensede novomutations (DNM), none of which are within the >80 SLE susceptibility loci implicated through genome-wide association studies (GWAS). In a follow-up cohort of 10,995 individuals of matched European ancestry, we imputed genotype data to the density of the combined UK10K-1000 genomes Phase III reference panel across the 14 candidate genes. We identify a burden of rare variants acrossPRKCDassociated with SLE risk (P=0.0028), and acrossDNMT3Aassociated with two severe disease prognosis sub-phenotypes (P=0.0005 andP=0.0033). Both genes are functional candidates and significantly constrained against missense mutations in gene-level analyses, along withC1QTNF4. We further characterise the TNF-dependent functions of candidate geneC1QTNF4on NF-κB activation and apoptosis, which are inhibited by the p.His198Gln DNM. Our results support extreme-phenotype sampling and DNM gene discovery to aid the search for core disease genes implicated through rare variation.

Significance Statement

Rare variants, present in <1% in population, are expected to explain little of the heritability of complex diseases, such as Systemic Lupus Erythematosus (SLE), yet are likely to identify core genes crucial to disease mechanisms. Their rarity, however, limits the power to show their statistical association with disease. Through sequencing the exomes of SLE patients and their parents, we identified non-inheritedde novomutations in 14 genes and hypothesised that these are prime candidates for harbouring additional disease-associated rare variants. We demonstrate that two of these genes also carry a significant excess of rare variants in an independent, large cohort of SLE patients. Our findings will influence future study designs in the search for the ‘missing heritability’ of complex diseases.
Health Status by Gender, Hair Color, and Eye Color: Red-Haired Women are the Most Divergent with the Lowest Viability and the Highest Fertility
Authors: Frost P. , Kleisner K. , Flegr J.
Published: May 2017

Background

Red hair is associated with pain sensitivity, and more so in women than in men. Hair redness may thus interact with a female-specific factor. We tested this hypothesis on a large sample of Czech and Slovak respondents. They were asked about the natural redness and darkness of their hair, their natural eye color, their physical and mental health (24 categories), and other personal attributes (height, weight, number of children, lifelong number of sexual partners, frequency of smoking).

Results

We found that red-haired women did worse than other women in ten health categories and better in only three. In particular, they were more prone to colorectal, cervical, uterine, and ovarian cancer. Cancer risk increased steadily with increasing hair redness except for the reddest shade. Red-haired men showed a balanced pattern of health effects, doing better than other men in three categories and worse in three. Number of children was the only category where both male and female redheads did better than other respondents. We also confirmed earlier findings that red hair is naturally more frequent in women than in men.

Conclusion

Red-haired women had higher fecundity and sexual attractiveness, but this selective advantage seems offset by worse health outcomes and therefore lower viability. The resulting equilibrium between these two counterbalancing forces might explain why red hair has remained less common than other hair and eye colors. Of the ‘new’ hair and eye colors, red hair diverges the most from the ancestral state of black hair and brown eyes. It is the most sexually dimorphic variant, not only in population frequency but also in health outcomes. This sexual dimorphism seems to have resulted from a selection pressure that acted primarily on early European women and which led to a general and apparently rapid diversification of hair and eye colors.
Genetic load makes cancer cells more sensitive to common drugs: evidence from Cancer Cell Line Encyclopedia
Authors: Pavel Ana B. , Korolev Kirill S.
Published: May 2017

Genetic alterations initiate tumors and enable the evolution of drug resistance. The pro-cancer view of mutations is however incomplete, and several studies show that mutational load can reduce tumor fitness. Given its negative effect, genetic load should make tumors more sensitive to anticancer drugs. Here, we test this hypothesis across all major types of cancer from the Cancer Cell Line Encyclopedia, that provides genetic and expression data of 496 cell lines together with their response to 24 common anticancer drugs. We found that the efficacy of 9 out of 24 drugs showed significant association with genetic load in a pan-cancer analysis. The associations for some tissue-drug combinations were remarkably strong with genetic load explaining up to 83% of the variance in the drug response. Overall, the role of genetic load depended on both the drug and the tissue type with 10 tissues being particularly vulnerable to genetic load. We also identified changes in gene expression associated with increased genetic load, which included cell-cycle checkpoints, DNA damage and apoptosis. Our results show that genetic load is an important component of tumor fitness and can predict drug sensitivity. Beyond being a biomarker, genetic load might be a new, unexplored vulnerability of cancer.
Diagnostic Yield and Treatment Impact of Targeted Exome Sequencing in Early-onset Epilepsy
Authors: Demos Michelle , Guella Ilaria , McKenzie Marna B. , Buerki Sarah E. , Evans Daniel M. , Toyota Eric B. , Boelman Cyrus , Huh Linda L. , Datta Anita , Michoulas Aspasia , Selby Kathryn , Bjornson Bruce H. , Horvath Gabriella , Lopez-Rangel Elena , van Karnebeek Clara DM , Salvarinova Ramona , Slade Erin , Eydoux Patrice , Adam Shelin , Van Allen Margot. I. , Nelson Tanya N. , Bolbocean Corneliu , Connolly Mary B. , Farrer Matthew J.
Published: May 2017

Background

To examine the impact on diagnosis, treatment and cost with early use of targeted whole-exome sequencing (WES) in early-onset epilepsy.

Methods

WES was performed on 50 patients with early-onset epilepsy (≤ 5 years) of unknown cause. Patients were classified as retrospective (epilepsy diagnosis > 6 months) or prospective (epilepsy diagnosis < 6 months). WES was performed on an Ion ProtonTM and variant reporting was restricted to the sequences of 565 known epilepsy genes. Diagnostic yield and time to diagnosis were calculated. An analysis of cost and impact on treatment was also performed.

Results

A likely/definite diagnosis was made in 17/50 patients (34%) with immediate treatment implications in 8/17 (47%). A possible diagnosis was identified in 9 additional patients (18%) for whom supporting evidence is pending. Time from epilepsy onset to genetic diagnosis was faster when WES was performed early in the diagnostic process (mean: 143 days prospective versus 2,172 days retrospective). Costs of prior negative tests averaged $8,344 in the retrospective group, suggesting savings of up to $5,110 per patient.

Interpretation

These results support the clinical utility and potential cost-effectiveness of using targeted WES early in the diagnostic workup of patients with unexplained early-onset epilepsy. The costs and clinical benefits are likely to continue to improve. Advances in precision medicine and further studies regarding impact on long-term clinical outcome will be important.
Research Advance: Extending chemical perturbations of the Ubiquitin fitness landscape in a classroom setting
Authors: Mavor David , Barlow Kyle A. , Asarnow Daniel , Birman Yuliya , Britain Derek , Chen Weilin , Green Evan M. , Kenner Lillian R. , Mensa Bruk , Morinishi Leanna S. , Nelson Charlotte , Poss Erin M. , Suresh Pooja , Tian Ruilin , Arhar Taylor , Ary Beatrice , Bauer David , Bergman Ian , Brunetti Rachel , Chio Cynthia , Dai Shizhong , Dickinson Miles , Elledge Susanna , Helsell Cole , Hendel Nathan , Kang Emily , Kern Nadja , Khoroshkin Matvei , Kirkemo Lisa , Lewis Greyson , Lou Kevin , Marin Wesley , Maxwell Alison , McTigue Peter , Myers-Turnbull Douglas , Nagy Tamas , Natale Andrew , Oltion Keely , Pourmal Sergei , Reder Gabriel , Rettko Nicholas , Rohweder Peter , Schwarz Daniel , Tan Sophia , Thomas Paul , Tibble Ryan , Town Jason , Tsai Kaitlyn , Ugur Fatima , Wassarmann Douglas R. , Wolff Alexander , Wu Taia , Bogdanoff Derrick , Li Jennifer , Thorn Kurt S. , O’Conchúir Shane , Swaney Danielle L. , Chow Eric D. , Madhani Hiten , Redding Sy , Bolon Daniel N. , Kortemme Tanja , DeRisi Joseph L. , Kampmann Martin , Fraser James S.
Published: May 2017

Although the primary protein sequence of ubiquitin (Ub) is extremely stable over evolutionary time, it is highly tolerant to mutation during selection experiments performed in the laboratory. We have proposed that this discrepancy results from the difference between fitness under laboratory culture conditions and the selective pressures in changing environments over evolutionary time scales. Building on our previous work (Mavor et al 2016), we used deep mutational scanning to determine how twelve new chemicals (3-Amino-1,2,4-triazole, 5-fluorocytosine, Amphotericin B, CaCl2, Cerulenin, Cobalt Acetate, Menadione, Nickel Chloride, p-fluorophenylalanine, Rapamycin, Tamoxifen, and Tunicamycin) reveal novel mutational sensitivities of ubiquitin residues. We found sensitization of Lys63 in eight new conditions. In total, our experiments have uncovered a sensitizing condition for every position in Ub except Ser57 and Gln62. By determining the Ubiquitin fitness landscape under different chemical constraints, our work helps to resolve the inconsistencies between deep mutational scanning experiments and sequence conservation over evolutionary timescales.

Builds on

Mavor D, Barlow KA, Thompson S, Barad BA, Bonny AR, Cario CL, Gaskins G, Liu Z, Deming L, Axen SD, Caceres E, Chen W, Cuesta A, Gate R, Green EM, Hulce KR, Ji W, Kenner LR, Mensa B, Morinishi LS, Moss SM, Mravic M, Muir RK, Niekamp S, Nnadi CI, Palovcak E, Poss EM, Ross TD, Salcedo E, See S, Subramaniam M, Wong AW, Li J, Thorn KS, Conchúir SÓ, Roscoe BP, Chow ED, DeRisi JL, Kortemme T, Bolon DN, Fraser JS. Determination of Ubiquitin Fitness Landscapes Under Different Chemical Stresses in a Classroom Setting.eLife. 2016.

Impact Statement

We organized a project-based course that used deep mutational scanning in multiple chemical conditions to resolve the inconsistencies between tolerance to mutations in laboratory conditions and sequence conservation over evolutionary timescales.
Benchmarking green chemistry adoption by “big pharma” and generics manufacturers
Authors: Veleva Vesela , W. Cue Jr Berkeley
Published: May 2017

Purpose

The purpose of this paper is to benchmark current adoption of green chemistry (GC) practices by the innovative and generic pharmaceutical companies and examine the drivers, barriers and future opportunities.

Design/methodology/approach

The authors examined publicly available data for the top 10 “big pharma” and top ten generic drug manufacturers. Using the IQ Green Chemistry working group framework for effective GC programs, they scored each of the 20 companies in seven key areas.

Findings

The study finds that generic drug companies have not embraced GC at the level of the innovative pharmaceutical companies (average GC score of 2 vs 11 for “big pharma”). Top two barriers for them include: lack of pressure and incentives, and the burdensome regulatory process for making changes in the manufacturing process.

Research limitations/implications

The research is based on publicly disclosed information. It is possible that some generic drug manufacturers have begun to work internally on GC but have not disclosed externally yet. Future research should include a survey or interviews of generic drug manufacturers.

Practical implications

The company-level analysis, benchmarking framework and results are of value for researchers and practitioners interested in advancing greater adoption of GC by the pharmaceutical industry.

Originality/value

This study provides the first company-level benchmarking of GC adoption by the largest innovative and generics drug manufacturers. It contributes to the literature on the barriers and drivers for greater adoption of GC.
To examine the relationships between supplier development practices and supplier-buyer relationship practices from the supplier’s perspective
Authors: Joshi Sarang , Kharat Manoj , Raut Rakesh , Kamble Sachin , Kamble Sheetal
Published: May 2017

Purpose

The purpose of this paper is to examine the relationships between supplier development practices (SDPs) and supplier-buyer relationship practices from the supplier’s perspective (SBRSP), and seek to understand how specific SDPs may impact a buyer’s operational performance as well as supplier-buyer relationship practices.

Design/methodology/approach

The authors conducted a survey of 512 respondents from the different manufacturing firms in India and applied structural equation modelling to test a structural model that proposes the impacts of various efforts of SDPs on a buyer’s performance as well as SBRSP.

Findings

The study concludes that SDPs and SBRSP together improve the relationship between a buyer and supplier, and this improved relationship leads to competitive advantages (CAs) followed by profitability. Results indicate that supplier perspective of buyer-supplier relationship can be improved under the condition of SDPs and SBRSP together. SDPs are driven by productive measure and competitive pressure, whereas customer uncertainty is found to be statistically insignificant.

Research limitations/implications

The study was carried out in North Maharashtra Industrial Zone of India, where the auto sector and machine/components manufacturing firms have been established for a considerable period of time. Results of the study are limited to manufacturing organizations predominantly focussing on the automobile sector and machine/components manufacturing firms.

Practical implications

This study provides significant insights into the specific impact of various SDPs and SBRSP for both academics and practitioners. SDPs along with SBRSP practices lead to improvement in the relationship leading to CAs. SBRSP suggests that trust, long-term commitments and the supplier’s perspective are important practices for relationship improvement.

Originality/value

The current study attempts to identify what are the success factors for the supplier-buyer relationship from the supplier’s perspective and SDPs and how the supplier-buyer relationship can be improved under the condition of SDPs and SBRSP. Hence, the aim is to develop a more thorough understanding of the outcomes of a supplier-buyer relationship improvement from both buyer’s and supplier’s perspective, under the conditions of supplier development to achieve CAs leading to profitability. Furthermore, the study analyses the effect of the improved supplier-buyer relationship for achieving CAs leading to profitability.