bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical application of targeted next‐generation sequencing in fetuses with congenital heart defect
Authors: Hu P. , Qiao F. , Wang Y. , Meng L. , Ji X. , Luo C. , Xu T. , Zhou R. , Zhang J. , Yu B. , Wang L. , Wang T. , Pan Q. , Ma D. , Liang D. , Xu Z.
Published: March 2018

Objectives

To assess the value of targeted next‐generation sequencing (NGS) in prenatal diagnosis of congenital heart defects (CHD) and to investigate the genetic etiology of prenatal CHD.

Methods

Forty‐four fetuses with CHD, normal molecular karyotype and negative chromosomal microarray results underwent targeted NGS. Fetal genomic DNA was extracted directly from amniotic fluid cells in each prenatal case. A customized targeted‐NGS panel of 77 CHD‐associated genes was designed to detect variants in the coding regions and the splicing sites of these genes. The detected variants were classified as pathogenic, likely pathogenic, of uncertain significance, likely benign or benign, following the guidelines recommended by the American College of Medical Genetics and Genomics.

Results

The detection rates of targeted NGS for pathogenic and likely pathogenic variations were 13.6% (6/44) and 2.3% (1/44), respectively. The turnaround time of the test was 3 weeks. The six pathogenic variations were identified on the genes CHD7 (CHARGE syndrome), CITED2 (tetralogy of Fallot, ventricular septal defect and atrial septal defect), ZFPM2 (tetralogy of Fallot), MYH6 (atrial septal defect, familial isolated dilated cardiomyopathy) and, in two cases, KMT2D (Kabuki syndrome). The likely pathogenic variation was detected on JAG1, which is associated with tetralogy of Fallot and Alagille syndrome. Sanger sequencing in the fetuses and their parents indicated that all seven mutations were de novo. Variations of uncertain significance were detected in 79.5% of cases.

Conclusions

Targeted NGS in fetuses with isolated and non‐isolated CHD achieved a high diagnostic yield in our cohort, with an acceptable turnaround time for the prenatal setting. Our results have important implications for clinical management and genetic counseling. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.
Diagnostic accuracy of first‐trimester ultrasound in detecting abnormally invasive placenta in high‐risk women with placenta previa
Authors: Cali G. , Forlani F. , Foti F. , Minneci G. , Manzoli L. , Flacco M. E. , Buca D. , Liberati M. , Scambia G. , D'Antonio F.
Published: March 2018

Objective

To ascertain the diagnostic accuracy of ultrasound in detecting abnormally invasive placenta (AIP) during the first trimester of pregnancy (11–14 weeks' gestation) in women at risk for this condition.

Methods

This was a retrospective analysis of data collected prospectively from women at risk for AIP based upon the presence of at least one prior Cesarean section (CS) and/or uterine surgery and placenta previa, who had ultrasound assessment for AIP at the time of the 11–14‐week scan. The ultrasound signs explored in the present study were: loss of the clear zone, placental lacunae, bladder wall interruption and uterovesical hypervascularity. The potential of ultrasound and different ultrasound signs to predict the different types of AIP was assessed by computing summary estimates of sensitivity, specificity, diagnostic odds ratio (DOR) and positive (LR+) and negative (LR–) likelihood ratios.

Results

One hundred and eighty‐eight women with placenta previa and at least one previous CS or uterine surgery were included in the study. All the explored ultrasound signs were associated significantly with the occurrence of AIP. Overall, when at least one ultrasound sign was used to make the diagnosis, ultrasound had a sensitivity of 84.3% (95% CI, 74.7–91.4%), specificity of 61.9% (95% CI, 51.9–71.2%), DOR of 8.6 (95% CI, 4.1–19.3), LR+ of 2.2 (95% CI, 1.7–2.9) and LR– of 0.3 (95% CI, 0.1–0.4) in detecting AIP. Using two ultrasound signs to label a case as positive increased the diagnostic accuracy in terms of specificity, although it did not affect sensitivity. Among the different ultrasound signs, loss of the clear zone had a sensitivity of 84.3% (95% CI, 74.7–91.4%) and a specificity of 81.9% (95% CI, 73.2–88.7%) in detecting AIP, while sensitivities for placental lacunae and bladder wall interruption were 78.3% (95% CI, 67.9–86.6%) and 75.9% (95% CI, 65.3–84.6%), respectively, and specificities were 81.0% (95% CI, 72.1–88.0%) and 99.1% (95% CI, 94.8–100.0%), respectively. The optimal combination of sensitivity and specificity was achieved when at least two imaging signs of AIP were used in the diagnostic algorithm.

Conclusions

AIP can be detected from the first trimester of pregnancy in women at risk for this condition, and ultrasound performed between 11 and 14 weeks' gestation has an overall good diagnostic accuracy for detecting all types of AIP. However, these findings are applicable only to women with placenta previa and prior uterine scar. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.
Assessment of offshore wind farm characteristics with the cloud resolving storm simulator: A case study in Japan
Authors: Raak Fredrik , Susuki Yoshihiko , Tsuboki Kazuhisa , Kato Masaya , Eguchi Shinya , Hikihara Takashi
Published: March 2018

Wind conditions and output power characteristics of a wind farm in Japan are evaluated with highly resolved weather predictions from the so‐called cloud resolving storm simulator. One year of 30‐hour‐ahead predictions with 2‐km spatial resolution and 1‐hour time resolution are evaluated against 10‐minute averaged measurements (averaged to hourly data) from the wind farm. Also, extremely detailed shorter‐term predictions with 200‐m spatial resolution and 1‐second time resolution are evaluated against 1‐Hz measurements. For the hourly data, wind speeds are predicted with an RMSE of 3.0 to 3.5 m/s, and wind power with about 0.3 per unit. Wind direction is predicted with a standard deviation of errors of 16° to 28° for hourly data, and generally below 10° for the 1‐Hz data. We show that wind power variability—here in terms of increments—can be assessed on the timescale of several hours. The measured and predicted wind spectra are found similar on both short and long timescales.
Wildlife warning reflectors and white canvas reduce deer–vehicle collisions and risky road‐crossing behavior
Authors: Riginos Corinna , Graham Morgan W. , Davis Melanie J. , Johnson Andrew B. , May Alexander B. , Ryer Kevin W. , Hall L. Embere
Published: March 2018

Collisions between wildlife and vehicles are detrimental to both wildlife and human safety. A variety of mitigation methods have been deployed with the intent of increasing ungulate awareness of approaching vehicles. Wildlife warning reflectors are one such method. Roadside reflectors are designed to reflect headlights into the right‐of‐way and alert ungulates to approaching vehicles. Studies of the effectiveness of these reflectors have yielded mixed results. We conducted a robust test of reflectors in central Wyoming, USA, during 2013 and 2014, and unexpectedly discovered a potentially more effective method than the reflectors for reducing collisions between vehicles and mule deer (Odocoileus hemionus). In our initial experiment, we manipulated 10 1.6‐km segments of highway by leaving their reflectors exposed or covering them with a white canvas bag with the intention of neutralizing the reflector. The treatment configuration was swapped monthly. We counted deer carcasses under each treatment for 1 year and observed deer road‐crossing behavior using thermal video cameras. Carcass rates were 33% less in the white canvas treatment relative to uncovered reflectors. Deer in the white canvas treatment also stopped before entering the road 20% more often, ran into the road from the right‐of‐way 11% less often, and fled from the road 12% more often than when reflectors were uncovered. In a follow‐up experiment, we found that deer carcass rates were 32% less when reflectors were exposed versus covered with black canvas. We further found that deer road‐crossing behavior was least risky in a white canvas treatment, intermediate in a reflectors treatment, and most risky when reflectors were removed from posts. Taken together, these results indicate that, although reflectors were moderately effective, white canvas was substantially more effective in reducing deer–vehicle collisions. This unexpected finding suggests that new vigilance‐enhancing mitigation methods should be explored as a way to reduce wildlife–vehicle collisions. © 2018 The Wildlife Society.
Light dark Higgs boson in minimal sub-GeV dark matter scenarios
Authors: Darmé Luc , Rao Soumya , Roszkowski Leszek
Published: March 2018

Abstract

Minimal scenarios with light (sub-GeV) dark matter whose relic density is obtained from thermal freeze-out must include new light mediators. In particular, a very well-motivated case is that of a new “dark” massive vector gauge boson mediator. The mass term for such mediator is most naturally obtained by a “dark Higgs mechanism” which leads to the presence of an often long-lived dark Higgs boson whose mass scale is the same as that of the mediator. We study the phenomenology and experimental constraints on two minimal, self-consistent dark sectors that include such a light dark Higgs boson. In one the dark matter is a pseudo-Dirac fermion, in the other a complex scalar. We find that the constraints from BBN and CMB are considerably relaxed in the framework of such minimal dark sectors. We present detection prospects for the dark Higgs boson in existing and projected proton beam-dump experiments. We show that future searches at experiments like Xenon1T or LDMX can probe all the relevant parameter space, complementing the various upcoming indirect constraints from astrophysical observations.
Novel jet observables from machine learning
Authors: Datta Kaustuv , Larkoski Andrew J.
Published: March 2018

Abstract

Previous studies have demonstrated the utility and applicability of machine learning techniques to jet physics. In this paper, we construct new observables for the discrimination of jets from different originating particles exclusively from information identified by the machine. The approach we propose is to first organize information in the jet by resolved phase space and determine the effective N -body phase space at which discrimination power saturates. This then allows for the construction of a discrimination observable from the N -body phase space coordinates. A general form of this observable can be expressed with numerous parameters that are chosen so that the observable maximizes the signal vs. background likelihood. Here, we illustrate this technique applied to discrimination of

$$ H\to b\overline{b} $$

H
→
b

b
¯

decays from massive

$$ g\to b\overline{b} $$

g
→
b

b
¯

splittings. We show that for a simple parametrization, we can construct an observable that has discrimination power comparable to, or better than, widely-used observables motivated from theory considerations. For the case of jets on which modified mass-drop tagger grooming is applied, the observable that the machine learns is essentially the angle of the dominant gluon emission off of the

$$ b\overline{b} $$

b

b
¯

pair.
An integrated workflow for phenazine-modifying enzyme characterization
Authors: Coates R Cameron , Bowen Benjamin P , Oberortner Ernst , Thomashow Linda , Hadjithomas Michalis , Zhao Zhiying , Ke Jing , Silva Leslie , Louie Katherine , Wang Gaoyan , Robinson David , Tarver Angela , Hamilton Matthew , Lubbe Andrea , Feltcher Meghan , Dangl Jeffery L , Pati Amrita , Weller David , Northen Trent R , Cheng Jan-Fang , Mouncey Nigel J , Deutsch Samuel , Yoshikuni Yasuo
Published: March 2018

Increasing availability of new genomes and putative biosynthetic gene clusters (BGCs) has extended the opportunity to access novel chemical diversity for agriculture, medicine, environmental and industrial purposes. However, functional characterization of BGCs through heterologous expression is limited because expression may require complex regulatory mechanisms, specific folding or activation. We developed an integrated workflow for BGC characterization that integrates pathway identification, modular design, DNA synthesis, assembly and characterization. This workflow was applied to characterize multiple phenazine-modifying enzymes. Phenazine pathways are useful for this workflow because all phenazines are derived from a core scaffold for modification by diverse modifying enzymes (PhzM, PhzS, PhzH, and PhzO) that produce characterized compounds. We expressed refactored synthetic modules of previously uncharacterized phenazine BGCs heterologously in Escherichia coli and were able to identify metabolic intermediates they produced, including a previously unidentified metabolite. These results demonstrate how this approach can accelerate functional characterization of BGCs.
Use of Tunneled-Cuffed Central Catheters in Patients with Cancer: A Single-Center Experience
Authors: Madabhavi Irappa , Patel Apurva , Anand Asha , Kataria Pritam , Kadakol Nagaveni , Sarkar Malay
Published: March 2018

Background: Effective and reliable venous access is among the cornerstones of modern medical therapy in oncology.

Materials and Methods: This was a prospective observational study of collected data of patients with a diagnosis of any cancer, at a tertiary care oncology hospital in Ahmadabad, Gujarat, India, during a 2-year period.

Results: A Hickman catheter was inserted in 200 patients and most commonly used in solid malignancies (n = 103; 51.5%), followed by hematologic conditions (n = 93; 48.5%). Among solid malignancies, hepatoblastoma (n = 21; 10.5%) was the most common indication, whereas in hematologic malignancies acute lymphoblastic leukemia was the most common indication (n = 56; 28%) for Hickman catheter insertion. Hickman catheters were inserted most commonly in the right side (n = 170; 85%) of the venous system. The various complications in the Hickman study group in descending order were 28 patients (14%) developed arrhythmias, 15 patients (7.5%) developed infection, 12 patients (6%) developed bleeding, 8 patients (4%) developed pneumothorax, 7 patients (3.5%) developed catheter blockage, and 6 patients (3%) required premature catheter removal. The median time of Hickman catheter in situ was 207 days.

Conclusions: The most disturbing aspect of treatment of patients with cancer is multiple painful venipunctures made for administration of cytotoxic agents, antibiotics, blood products, and nutritional supplements. The focus of this prospective observational research was to study the various indications for Hickman catheter in different solid and hematologic malignancies as well as the various complications and outcomes in pediatric and adult cancer patients.
Lean Six Sigma for Intravenous Therapy Optimization: A Hospital Use of Lean Thinking to Improve Occlusion Management
Authors: Steere Lee , Rousseau Marc , Durland Lisa
Published: March 2018

Background: Continual improvement is a necessary part of hospital culture. This occurs by identifying opportunities for improvement that influence efficiency while saving money.

Methodology: An investigation of intravenous device-related practices was performed by the nurses of the intravenous access team, pharmacy, and hospital operations at Hartford Hospital using Lean Six Sigma methodology. Central venous access device occlusion and tissue plasminogen activator variability was identified. Using observation, measurement of performance, and root cause analysis, the hospital's practices, policies, and equipment were evaluated for the process of occlusion management. The team utilized a Six Sigma strategy employing the elements define, measure, analyze, improve, and control, which is a disciplined, data-driven methodology that focuses on eliminating defects (waste). Interventions initiated based on the assessment performed by the team using the define, measure, analyze, improve, and control approach included replacement of negative displacement needleless connectors with antireflux needleless connectors and specialty team assessment before tissue plasminogen activator use.

Results: Over the course of the 26-month study, Hartford Hospital experienced a 69% total reduction in tissue plasminogen activator use representing a total 26-month savings of $107,315. Other cost savings were reflected in areas of flushing, flushing disposables, and in a decrease in needleless connector consumption. Central line-associated bloodstream rates fell 36% following the intervention as an unexpected secondary gain, resulting in further savings related to treating this nonreimbursable hospital-acquired condition.

Conclusions: This study examined the influence of using Lean Thinking and Six Sigma methodology as a tool in saving hospital money, resulting in better patient outcomes.
Twisted waves and instabilities in a permeating dusty plasma
Authors: Bukhari S. , Ali S. , Khan S. A. , Mendonca J. T.
Published: March 2018

New features of the twisted dusty plasma modes and associated instabilities are investigated in permeating plasmas. Using the Vlasov–Poisson model equations, a generalized dispersion relation is obtained for a Maxwellian distributed plasma to analyse the dust-acoustic and dust-ion-acoustic waves with finite orbital angular momentum (OAM) states. Existence conditions for damping/growth rates are discussed and showed significant modifications in twisted dusty modes as compared to straight propagating dusty modes. Numerically, the instability growth rate, which depends on particle streaming and twist effects in the wave potential, is significantly modified due to the Laguerre–Gaussian profiles. Relevance of the study to wave excitations due to penetration of solar wind into cometary clouds or interstellar dusty plasmas is discussed.
Alcohol use and personality trait change: pooled analysis of six cohort studies
Authors: Hakulinen Christian , Jokela Markus
Published: March 2018

Background

Personality has been associated with alcohol use, but less is known about how alcohol use may influence long-term personality trait change.

Methods

The present study examines associations between alcohol use and change in the five major personality traits across two measurement occasions (mean follow-up of 5.6 years). A total of 39 722 participants (54% women) were pooled from six cohort studies for an individual-participant meta-analysis. Alcohol use was measured as (1) average alcohol consumption, (2) frequency of binge drinking, (3) symptoms of alcohol use disorder, and (4) a global indicator of risky alcohol use. Changes in the five major personality traits (extraversion, emotional stability, agreeableness, conscientiousness, and openness to experience) were used as outcomes.

Results

Risky alcohol use was associated with increasing extraversion [0.25 T-scores over the mean follow-up of 5.6 years; 95% confidence interval (CI) 0.07–0.44] and decreasing emotional stability (−0.28; 95% CI −0.48 to −0.08), agreeableness (−0.67; 95% CI −0.87 to −0.36), and conscientiousness (−0.58; 95% CI −0.79 to −0.38). Except the association between alcohol use and extraversion, these associations were consistent across cohort studies and across different measures of alcohol use.

Conclusions

These findings suggest that alcohol use is associated with personality trait changes in adulthood.
Focus on form and corrective feedback research at the University of Victoria, Canada
Authors: Chen Sibo , Nassaji Hossein
Published: March 2018

The Department of Linguistics at University of Victoria (UVic) in Canada has a long-standing tradition of empirical approaches to the study of theoretical and applied linguistics. As part of the Faculty of Humanities, the department caters to students with a wide range of backgrounds and interests, and provides crucial language teaching support in collaboration with other teaching units at UVic. Accordingly, some applied linguistics studies concern language teaching and learning, some of which are conducted in classroom settings. In this article, we provide a brief overview of recent corrective feedback research conducted by UVic Applied Linguistics Research Group.
L2 semantics from a formal linguistic perspective
Authors: Slabakova Roumyana
Published: March 2018

Ever since Aristotle and Plato (The Categories; Cratylus), linguists have considered language to be the pairing of form (sounds or gestures or written strings) and meaning. This is true for all meaningful linguistic units from morphemes, through words, phrases and sentences, to discourse. Generally speaking, semantics is the study of how form and meaning are related. However, semantics is more narrowly construed as excluding those meanings that derive from speaker intensions and psychological states, as well as sociocultural features of the context. Furthermore, the boundary between semantics proper and pragmatics is intensely debated and to some researchers constitutes an empirical question. Formal semantics came into being as a system describing formal languages, that is, the mathematical and logical languages of computing machines as opposed to the natural languages of human beings. However, in the late 1960s the philosopher Richard Montague argued that natural languages such as English could be fruitfully described using the same rigorous rules and correspondences utilized in the description of formal languages. Modern formal semantics was born and is currently prospering as a branch of linguistics.
Habitat selection by the black-tufted marmosetCallithrix penicillatain human-disturbed landscapes
Authors: Secco Helio , Grilo Clara , Bager Alex
Published: March 2018

There are several primate species with high risk of extinction in small forest fragments disturbed by human activities. However, some species exhibit high ecological plasticity, which allows them to persist in human-modified landscapes. The main goal of this study is to examine the relative roles of vegetation (mean distance among trees and mean canopy cover), human disturbance (distance to the road, distance to the fragment edge and edge type), and habitat spatial configuration (spatial autocorrelation index, category of quadrat – position within the fragment/fragment type) on the habitat selection of the black-tufted marmosetCallithrix penicillatain forest patches. We selected forest patches near and away from roads/urban areas, in southern Minas Gerais state, south-eastern Brazil. We used generalized linear mixed models to explain the presence of black-tufted marmoset in those patches. Our results show that black-tufted marmoset tend to occupy forest fragments closer to roads/urban areas, and consequently are under the influence of anthropic disturbance. In addition to the area delimited by these fragments, there is a preference for edge environments, where disturbances are exacerbated and the ecological conditions are suitable for exploitation by the black-tufted marmoset (supply of gum trees and reduced risk of competition). We suggest that a cross-habitat spillover by marmoset occur from forests to small habitat patches close to human-modified areas, such as those in proximity to roads and urban zones.
Acquisition of locative utterances in Norwegian: structure-building via lexical learning
Authors: MITROFANOVA Natalia , WESTERGAARD Marit
Published: March 2018

This paper focuses on the acquisition of locative prepositional phrases in L1 Norwegian. We report on two production experiments with children acquiring Norwegian as their first language and compare the results to similar experiments conducted with Russian children. The results of the experiments show that Norwegian children at age 2 regularly produce locative utterances lacking overt prepositions, with the rate of preposition omission decreasing significantly by age 3. Furthermore, our results suggest that phonologically strong and semantically unambiguous locative items appear earlier in Norwegian children's utterances than their phonologically weak and semantically ambiguous counterparts. This conclusion is confirmed by a corpus study. We argue that our results are best captured by the Underspecified P Hypothesis (UPH; Mitrofanova, 2017), which assumes that, at early stages of grammatical development, the underlying structure of locative utterances is underspecified, with more complex functional representations emerging gradually based on the input. This approach predicts that the rate of acquisition in the domain of locative PPs should be influenced by the lexical properties of individual language-specific grammatical elements (such as frequency, morphological complexity, phonological salience, or semantic ambiguity). Our data from child Norwegian show that this prediction is borne out. Specifically, the results of our study suggest that phonologically more salient and semantically unambiguous items are mastered earlier than their ambiguous and phonologically less salient counterparts, despite the higher frequency of the latter in the input (Clahsen et al., 1996).
Freedom to conduct a business and EU labour law
Authors: Giubboni Stefano
Published: March 2018

Critical-contextual analysis of case law of the European Court of Justice on employers’ contractual freedom – Fundamental right to be immunised against the alleged disproportional protection enjoyed by employees – Progressive ideological overthrow of the original constitutional assumptions of the founding treaties – Prominent example of ‘displacement of social Europe’ – Court of Justice’s case law on the relationship between freedom to conduct a business and labour law – Neoliberal understanding of the freedom of enterprise – Alternative interpretation of Article 16 of the EU Charter of Fundamental Rights
Does Low (vs. High) Subjective Socioeconomic Status Increase Both	Prosociality and Aggression?
Authors: Greitemeyer Tobias , Sagioglou Christina
Published: March 2018

Abstract. Previous research has shown that people of low subjective socioeconomic status (SES) are more likely to experience compassion and provide help to others than people of high SES. However, low subjective SES also appears to be related to more hostile and aggressive responding. Given that prosociality is typically an antagonist of aggression, we examined whether low subjective SES individuals could be indeed more prosocial and antisocial. Five studies – two correlational, three experimental – found that low subjective SES was related to increased aggression. In contrast, subjective SES was not negatively related to trait and state measures of prosociality.
Need for Cognitive Closure and Political Ideology
Authors: Panno Angelo , Carrus Giuseppe , Brizi Ambra , Maricchiolo Fridanna , Giacomantonio Mauro , Mannetti Lucia
Published: March 2018

Abstract. Little is known about epistemic motivations affecting political ideology when people make environmental decisions. In two studies, we examined the key role that political ideology played in the relationship between need for cognitive closure (NCC) and self-reported eco-friendly behavior. Study 1: 279 participants completed the NCC, pro-environmental, and political ideology measures. Mediation analyses showed that NCC was related to less pro-environmental behavior through more right-wing political ideology. Study 2: We replicated these results with a nonstudent sample (n = 240) and both social and economic conservatism as mediators. The results of Study 2 showed that social conservatism mediated the relationship between NCC and pro-environmental behavior. Finally, NCC was associated with pro-environmental attitude through both social and economic conservatism.
Cooperation, competition and antibiotic resistance in bacterial colonies
Authors: Frost Isabel , Smith William P J , Mitri Sara , Millan Alvaro San , Davit Yohan , Osborne James M , Pitt-Francis Joe M , MacLean R Craig , Foster Kevin R
Published: March 2018

Bacteria commonly live in dense and genetically diverse communities associated with surfaces. In these communities, competition for resources and space is intense, and yet we understand little of how this affects the spread of antibiotic-resistant strains. Here, we study interactions between antibiotic-resistant and susceptible strains using in vitro competition experiments in the opportunistic pathogen Pseudomonas aeruginosa and in silico simulations. Selection for intracellular resistance to streptomycin is very strong in colonies, such that resistance is favoured at very low antibiotic doses. In contrast, selection for extracellular resistance to carbenicillin is weak in colonies, and high doses of antibiotic are required to select for resistance. Manipulating the density and spatial structure of colonies reveals that this difference is partly explained by the fact that the local degradation of carbenicillin by β-lactamase-secreting cells protects neighbouring sensitive cells from carbenicillin. In addition, we discover a second unexpected effect: the inducible elongation of cells in response to carbenicillin allows sensitive cells to better compete for the rapidly growing colony edge. These combined effects mean that antibiotic treatment can select against antibiotic-resistant strains, raising the possibility of treatment regimes that suppress sensitive strains while limiting the rise of antibiotic resistance. We argue that the detailed study of bacterial interactions will be fundamental to understanding and overcoming antibiotic resistance.
Orchestrated control of filaggrin–actin scaffolds underpins cornification
Authors: Gutowska-Owsiak Danuta , de La Serna Jorge Bernardino , Fritzsche Marco , Naeem Aishath , Podobas Ewa I. , Leeming Michael , Colin-York Huw , O’Shaughnessy Ryan , Eggeling Christian , Ogg Graham S.
Published: March 2018

Epidermal stratification critically depends on keratinocyte differentiation and programmed death by cornification, leading to formation of a protective skin barrier. Cornification is dynamically controlled by the protein filaggrin, rapidly released from keratohyalin granules (KHGs). However, the mechanisms of cornification largely remain elusive, partly due to limitations of the observation techniques employed to study filaggrin organization in keratinocytes. Moreover, while the abundance of keratins within KHGs has been well described, it is not clear whether actin also contributes to their formation or fate. We employed advanced (super-resolution) microscopy to examine filaggrin organization and dynamics in skin and human keratinocytes during differentiation. We found that filaggrin organization depends on the cytoplasmic actin cytoskeleton, including the role for α- and β-actin scaffolds. Filaggrin-containing KHGs displayed high mobility and migrated toward the nucleus during differentiation. Pharmacological disruption targeting actin networks resulted in granule disintegration and accelerated cornification. We identified the role of AKT serine/threonine kinase 1 (AKT1), which controls binding preference and function of heat shock protein B1 (HspB1), facilitating the switch from actin stabilization to filaggrin processing. Our results suggest an extended model of cornification in which filaggrin utilizes actins to effectively control keratinocyte differentiation and death, promoting epidermal stratification and formation of a fully functional skin barrier.
JMJD5 is a human arginyl C-3 hydroxylase
Authors: Wilkins Sarah E. , Islam Md. Saiful , Gannon Joan M. , Markolovic Suzana , Hopkinson Richard J. , Ge Wei , Schofield Christopher J. , Chowdhury Rasheduzzaman
Published: March 2018

Oxygenase-catalysed post-translational modifications of basic protein residues, including lysyl hydroxylations and Nε-methyl lysyl demethylations, have important cellular roles. Jumonji-C (JmjC) domain-containing protein 5 (JMJD5), which genetic studies reveal is essential in animal development, is reported as a histone Nε-methyl lysine demethylase (KDM). Here we report how extensive screening with peptides based on JMJD5 interacting proteins led to the finding that JMJD5 catalyses stereoselective C-3 hydroxylation of arginine residues in sequences from human regulator of chromosome condensation domain-containing protein 1 (RCCD1) and ribosomal protein S6 (RPS6). High-resolution crystallographic analyses reveal overall fold, active site and substrate binding/product release features supporting the assignment of JMJD5 as an arginine hydroxylase rather than a KDM. The results will be useful in the development of selective oxygenase inhibitors for the treatment of cancer and genetic diseases.
A spliced latency-associated VZV transcript maps antisense to the viral transactivator gene 61
Authors: Depledge Daniel P. , Ouwendijk Werner J. D. , Sadaoka Tomohiko , Braspenning Shirley E. , Mori Yasuko , Cohrs Randall J. , Verjans Georges M. G. M. , Breuer Judith
Published: March 2018

Varicella-zoster virus (VZV), an alphaherpesvirus, establishes lifelong latent infection in the neurons of >90% humans worldwide, reactivating in one-third to cause shingles, debilitating pain and stroke. How VZV maintains latency remains unclear. Here, using ultra-deep virus-enriched RNA sequencing of latently infected human trigeminal ganglia (TG), we demonstrate the consistent expression of a spliced VZV mRNA, antisense to VZV open reading frame 61 (ORF61). The spliced VZV latency-associated transcript (VLT) is expressed in human TG neurons and encodes a protein with late kinetics in productively infected cells in vitro and in shingles skin lesions. Whereas multiple alternatively spliced VLT isoforms (VLTly) are expressed during lytic infection, a single unique VLT isoform, which specifically suppresses ORF61 gene expression in co-transfected cells, predominates in latently VZV-infected human TG. The discovery of VLT links VZV with the other better characterized human and animal neurotropic alphaherpesviruses and provides insights into VZV latency.
Strategically growing the urban forest will improve our world
Authors: Endreny Theodore A.
Published: March 2018

Growth in urban populations creates opportunities for urban forests to deliver ecosystem services critical to human wellbeing and biodiversity. Our challenge is to strategically expand urban forests and provide our international communities, particularly the vulnerable, with healthier, happier, and enriched lives.
Dietary butyrate glycerides modulate intestinal microbiota composition and serum metabolites in broilers
Authors: Yang Xiaojian , Yin Fugui , Yang Yuhui , Lepp Dion , Yu Hai , Ruan Zheng , Yang Chengbo , Yin Yulong , Hou Yongqing , Leeson Steve , Gong Joshua
Published: March 2018

Butyrate can modulate the immune response and energy expenditure of animals and enhance intestinal health. The present study investigated changes in the intestinal microbiota composition and serum metabolites of young broilers in response to 3,000 ppm butyrate in the form of butyrate glycerides (BG) via pyrosequencing of bacterial 16S rRNA genes and nuclear magnetic resonance (NMR). The dietary treatment did not affect the alpha diversity of intestinal microbiota, but altered its composition. Thirty-nine key operational taxonomic units (OTUs) in differentiating cecal microbiota community structures between BG treated and untreated chickens were also identified. Bifidobacterium was, in particular, affected by the dietary treatment significantly, showing an increase in not only the abundance (approximately 3 fold, P ≤ 0.05) but also the species diversity. The (NMR)-based analysis revealed an increase in serum concentrations of alanine, low-density and very low-density lipoproteins, and lipids (P ≤ 0.05) by BG. More interestingly, the dietary treatment also boosted (P ≤ 0.05) serum concentrations of bacterial metabolites, including choline, glycerophosphorylcholine, dimethylamine, trimethylamine, trimethylamine-N-oxide, lactate, and succinate. In conclusion, the data suggest the modulation of intestinal microbiota and serum metabolites by BG dietary treatment and potential contribution of intestinal bacteria to lipid metabolism/energy homeostasis in broilers.
Profiling walking dysfunction in multiple sclerosis: characterisation, classification and progression over time
Authors: Filli Linard , Sutter Tabea , Easthope Christopher S. , Killeen Tim , Meyer Christian , Reuter Katja , Lörincz Lilla , Bolliger Marc , Weller Michael , Curt Armin , Straumann Dominik , Linnebank Michael , Zörner Björn
Published: March 2018

Gait dysfunction is a common and relevant symptom in multiple sclerosis (MS). This study aimed to profile gait pathology in gait-impaired patients with MS using comprehensive 3D gait analysis and clinical walking tests. Thirty-seven patients with MS walked on the treadmill at their individual, sustainable speed while 20 healthy control subjects walked at all the different patient’s paces, allowing for comparisons independent of walking velocity. Kinematic analysis revealed pronounced restrictions in knee and ankle joint excursion, increased gait variability and asymmetry along with impaired dynamic stability in patients. The most discriminative single gait parameter, differentiating patients from controls with an accuracy of 83.3% (χ2 test; p = 0.0001), was reduced knee range of motion. Based on hierarchical cluster and principal component analysis, three principal pathological gait patterns were identified: a spastic-paretic, an ataxia-like, and an unstable gait. Follow-up assessments after 1 year indicated deterioration of walking function, particularly in patients with spastic-paretic gait patterns. Our findings suggest that impaired knee/ankle control is common in patients with MS. Personalised gait profiles and clustering algorithms may be promising tools for stratifying patients and to inform patient-tailored exercise programs. Responsive, objective outcome measures are important for monitoring disease progression and treatment effects in MS trials.
Sparse recovery of undersampled intensity patterns for coherent diffraction imaging at high X-ray energies
Authors: Maddali S. , Calvo-Almazan I. , Almer J. , Kenesei P. , Park J.-S. , Harder R. , Nashed Y. , Hruszkewycz S. O.
Published: March 2018

Coherent X-ray photons with energies higher than 50 keV offer new possibilities for imaging nanoscale lattice distortions in bulk crystalline materials using Bragg peak phase retrieval methods. However, the compression of reciprocal space at high energies typically results in poorly resolved fringes on an area detector, rendering the diffraction data unsuitable for the three-dimensional reconstruction of compact crystals. To address this problem, we propose a method by which to recover fine fringe detail in the scattered intensity. This recovery is achieved in two steps: multiple undersampled measurements are made by in-plane sub-pixel motion of the area detector, then this data set is passed to a sparsity-based numerical solver that recovers fringe detail suitable for standard Bragg coherent diffraction imaging (BCDI) reconstruction methods of compact single crystals. The key insight of this paper is that sparsity in a BCDI data set can be enforced by recognising that the signal in the detector, though poorly resolved, is band-limited. This requires fewer in-plane detector translations for complete signal recovery, while adhering to information theory limits. We use simulated BCDI data sets to demonstrate the approach, outline our sparse recovery strategy, and comment on future opportunities.
Impact of prenatal stress on offspring glucocorticoid levels: A phylogenetic meta-analysis across 14 vertebrate species
Authors: Thayer Zaneta M. , Wilson Meredith A. , Kim Andrew W. , Jaeggi Adrian V.
Published: March 2018

Prenatal exposure to maternal stress is commonly associated with variation in Hypothalamic Pituitary Adrenal (HPA)-axis functioning in offspring. However, the strength or consistency of this response has never been empirically evaluated across vertebrate species. Here we meta-analyzed 114 results from 39 studies across 14 vertebrate species using Bayesian phylogenetic mixed-effects models. We found a positive overall effect of prenatal stress on offspring glucocorticoids (d’ = 0.43) though the 95% Highest Posterior Density Interval overlapped with 0 (−0.16–0.95). Meta-regressions of potential moderators highlighted that phylogeny and life history variables predicted relatively little variation in effect size. Experimental studies (d’ = 0.64) produced stronger effects than observational ones (d’ = −0.01), while prenatal stress affected glucocorticoid recovery following offspring stress exposure more strongly (d’ = 0.75) than baseline levels (d’ = 0.48) or glucocorticoid peak response (d’ = 0.36). These findings are consistent with the argument that HPA-axis sensitivity to prenatal stress is evolutionarily ancient and occurs regardless of a species’ overall life history strategy. These effects may therefore be especially important for mediating intra-specific life-history variation. In addition, these findings suggest that animal models of prenatal HPA-axis programming may be appropriate for studying similar effects in humans.
Low temperature exposure induces browning of bone marrow stem cell derived adipocytes in vitro
Authors: Velickovic Ksenija , Lugo Leija Hilda Anaid , Bloor Ian , Law James , Sacks Harold , Symonds Michael , Sottile Virginie
Published: March 2018

Brown and beige adipocytes are characterised as expressing the unique mitochondrial uncoupling protein (UCP)1 for which the primary stimulus in vivo is cold exposure. The extent to which cold-induced UCP1 activation can also be achieved in vitro, and therefore perform a comparable cellular function, is unknown. We report an in vitro model to induce adipocyte browning using bone marrow (BM) derived mesenchymal stem cells (MSC), which relies on differentiation at 32 °C instead of 37 °C. The low temperature promoted browning in adipogenic cultures, with increased adipocyte differentiation and upregulation of adipogenic and thermogenic factors, especially UCP1. Cells exhibited enhanced uncoupled respiration and metabolic adaptation. Cold-exposed differentiated cells showed a marked translocation of leptin to adipocyte nuclei, suggesting a previously unknown role for leptin in the browning process. These results indicate that BM-MSC can be driven to forming beige-like adipocytes in vitro by exposure to a reduced temperature. This in vitro model will provide a powerful tool to elucidate the precise role of leptin and related hormones in hitherto functions in the browning process.
MFSD2B is a sphingosine 1-phosphate transporter in erythroid cells
Authors: Kobayashi Naoki , Kawasaki-Nishi Shoko , Otsuka Masato , Hisano Yu , Yamaguchi Akihito , Nishi Tsuyoshi
Published: March 2018

Sphingosine 1-phosphate (S1P) is an intercellular signaling molecule present in blood. Erythrocytes have a central role in maintaining the S1P concentration in the blood stream. We previously demonstrated that S1P is exported from erythrocytes by a glyburide-sensitive S1P transporter. However, the gene encoding the S1P transporter in erythrocytes is unknown. In this study, we found that the mouse erythroid cell line, MEDEP-E14, has S1P export activity and exhibits properties that are consistent with those of erythrocytes. Using microarray analysis of MEDEP-E14 cells and its parental cell line, E14TG2a, we identified several candidate genes for S1P export activity. Of those genes, only one gene, Mfsd2b, showed S1P transport activity. The properties of S1P release by MFSD2B were similar to those in erythrocytes. Moreover, knockout of MFSD2B in MEDEP-E14 cells decreased S1P export from the cells. These results strongly suggest that MFSD2B is a novel S1P transporter in erythroid cells.
Comparison of single cell sequencing data between two whole genome amplification methods on two sequencing platforms
Authors: Chen DaYang , Zhen HeFu , Qiu Yong , Liu Ping , Zeng Peng , Xia Jun , Shi QianYu , Xie Lin , Zhu Zhu , Gao Ya , Huang GuoDong , Wang Jian , Yang HuanMing , Chen Fang
Published: March 2018

Research based on a strategy of single-cell low-coverage whole genome sequencing (SLWGS) has enabled better reproducibility and accuracy for detection of copy number variations (CNVs). The whole genome amplification (WGA) method and sequencing platform are critical factors for successful SLWGS (<0.1 × coverage). In this study, we compared single cell and multiple cells sequencing data produced by the HiSeq2000 and Ion Proton platforms using two WGA kits and then comprehensively evaluated the GC-bias, reproducibility, uniformity and CNV detection among different experimental combinations. Our analysis demonstrated that the PicoPLEX WGA Kit resulted in higher reproducibility, lower sequencing error frequency but more GC-bias than the GenomePlex Single Cell WGA Kit (WGA4 kit) independent of the cell number on the HiSeq2000 platform. While on the Ion Proton platform, the WGA4 kit (both single cell and multiple cells) had higher uniformity and less GC-bias but lower reproducibility than those of the PicoPLEX WGA Kit. Moreover, on these two sequencing platforms, depending on cell number, the performance of the two WGA kits was different for both sensitivity and specificity on CNV detection. The results can help researchers who plan to use SLWGS on single or multiple cells to select appropriate experimental conditions for their applications.
Non-heuristic automatic techniques for overcoming low signal-to-noise-ratio bias of localization microscopy and multiple signal classification algorithm
Authors: Agarwal Krishna , Macháň Radek , Prasad Dilip K.
Published: March 2018

Localization microscopy and multiple signal classification algorithm use temporal stack of image frames of sparse emissions from fluorophores to provide super-resolution images. Localization microscopy localizes emissions in each image independently and later collates the localizations in all the frames, giving same weight to each frame irrespective of its signal-to-noise ratio. This results in a bias towards frames with low signal-to-noise ratio and causes cluttered background in the super-resolved image. User-defined heuristic computational filters are employed to remove a set of localizations in an attempt to overcome this bias. Multiple signal classification performs eigen-decomposition of the entire stack, irrespective of the relative signal-to-noise ratios of the frames, and uses a threshold to classify eigenimages into signal and null subspaces. This results in under-representation of frames with low signal-to-noise ratio in the signal space and over-representation in the null space. Thus, multiple signal classification algorithms is biased against frames with low signal-to-noise ratio resulting into suppression of the corresponding fluorophores. This paper presents techniques to automatically debias localization microscopy and multiple signal classification algorithm of these biases without compromising their resolution and without employing heuristics, user-defined criteria. The effect of debiasing is demonstrated through five datasets of invitro and fixed cell samples.
Broadband acoustic subwavelength imaging by rapidly modulated stratified media
Authors: Zhu Xing-Feng , Wei Qi , Wu Da-Jian , Liu Xiao-Jun
Published: March 2018

An acoustic anisotropic lens (AAL) based on large mass-density modulation depth (LMMD) medium is proposed for subwavelength imaging. The underlying mechanism for converting evanescent components into propagating waves is attributed to the strong suppression of the transverse velocity field component in LMMD medium. In addition, the proposed lens can operate in a broadband manner, which is more flexible in practical applications. Both transfer matrix method and finite element method are used to corroborate the subwavelength imaging capabilities of the proposed lens. The numerical simulations demonstrate that the proposed lens can clearly distinguish two Gaussian sources with equal width of λ0/25 and separation of λ0/5 in a broad frequency bandwidth. Medium losses decrease the transmission but cannot compromise the resolution of the lens.