bluuebunny/crossref_metadata_2025 huggingface dataset:
Whole-genome sequencing of human malignant mesothelioma tumours and cell lines
Authors: Oey Harald , Daniels Marissa , Relan Vandana , Chee Tian Mun , Davidson Morgan R , Yang Ian A , Ellis Jonathan J , Fong Kwun M , Krause Lutz , Bowman Rayleen V
Published: April 2019

Pleural mesothelioma is a cancer of serosal surfaces caused by environmental exposure to asbestos. Clinical outcome remains poor and while trials of new treatments are ongoing it remains an understudied cancer. Mesothelioma cell lines can readily be grown from primary tumour and from tumour cells shed into pleural effusion with the latter representing a particularly valuable source of DNA in clinical settings, procurable without the need for additional invasive procedures. However, it is not well understood how accurately patient-derived cultured tumour cells represent the molecular characteristics of their primary tumour. We used whole-genome sequencing of primary tumour and matched cultured cells to comprehensively characterize mutations and structural alterations. Most cases had complex rearranged genomes with evidence of chromoanagenesis and rearrangements reminiscent of chromoplexy. Many of the identified driver mutations were structural, indicating that mesothelioma is often caused by structural alterations and catastrophic genomic events, rather than point mutations. Because the majority of genomic changes detected in tumours were also displayed by the genomes of cultured tumour cells, we conclude that low-passage cultured tumour cells are generally suitable for molecular characterization of mesothelioma and may be particularly useful where tissue samples with high tumour cell content are not available. However, the subclonal compositions of the cell lines did not fully recapitulate the subclonal diversity of the primary tumours. Furthermore, longitudinal acquisition of major alterations in subclonal cell populations was observed after long-term passaging. These two factors define limitations of tumour-derived cell lines as genomic substrate for clinical purposes.
The Impact of Varicella Vaccination on the Incidence of Varicella and Herpes Zoster in the United States: Updated Evidence From Observational Databases, 1991–2016
Authors: Wolfson Lara J , Daniels Vincent J , Altland Alexandra , Black Wynona , Huang Wanjing , Ou Wanmei
Published: April 2019

Background

Universal childhood vaccination against varicella began in the United States as a 1-dose schedule in 1996, changing to a 2-dose schedule in 2006. The exogenous boosting hypothesis, which postulates that reexposure to circulating wild-type varicella delays the onset of herpes zoster, predicts a transient increase in the incidence of herpes zoster, peaking in adults 15–35 years after the start of varicella vaccination.

Methods

This was a retrospective study of administrative claims data from the MarketScan Commercial and Medicare databases between 1991–2016. Outcome measures were the incidences of herpes zoster per 100 000 person-years, by calendar year and age category, and the annual rates of change in herpes zoster by age category, in an interrupted time series regression analysis, for the periods of 1991–1995 (prevaccine), 1996–2006 (1-dose vaccination period), and 2007–2016 (2-dose vaccination period).

Results

The annual incidences of herpes zoster increased throughout the period of 1991–2012 in all adult age categories, with a plateau in 2013–2016 that was most evident in the ≥65 age group. In 1991–1995, the herpes zoster incidences increased at annual rates of 4–6% in age categories 18–34, 35–44, 45–54, and 55–64 years. In the same age categories during 1996–2006 and 2007–2016, the herpes zoster incidences increased at annual rates of 1–5%.

Conclusions

Although the annual incidence of herpes zoster in adults has continued to increase, the rates of change decreased during both the 1- and 2-dose vaccination periods. The hypothesized increase in herpes zoster predicted from modelling of the exogenous boosting hypothesis was not observed.
Trimethyllysine, a trimethylamine N-oxide precursor, provides near- and long-term prognostic value in patients presenting with acute coronary syndromes
Authors: Li Xinmin S , Obeid Slayman , Wang Zeneng , Hazen Benjamin J , Li Lin , Wu Yuping , Hurd Alex G , Gu Xiaodong , Pratt Alan , Levison Bruce S , Chung Yoon-Mi , Nissen Steven E , Tang Wai Hong Wilson , Mach François , Räber Lorenz , Nanchen David , Matter Christian M , Lüscher Thomas F , Hazen Stanley L
Published: April 2019

Aims 

Trimethyllysine (TML) serves as a nutrient precursor of the gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) and is associated with incident cardiovascular (CV) events in stable subjects. We examined the relationship between plasma TML levels and incident CV events in patients presenting with acute coronary syndromes (ACS).

Methods and results 

Plasma levels of TML were quantified in two independent cohorts using mass spectrometry, and its relationship with CV events was investigated. In a Cleveland Cohort (N = 530), comprised of patients presenting to the emergency department with chest pain and suspected ACS, TML was associated with major adverse cardiac events (MACE, myocardial infarction, stroke, need for revascularization, or all-cause mortality) over both 30 days [3rd tertile (T3), adjusted odds ratio (OR) 1.77, 95% confidence interval (CI) 1.04–3.01; P < 0.05] and 6 months (T3, adjusted OR 1.95, 95% CI 1.15–3.32; P < 0.05) of follow-up independent of traditional CV risk factors and indices of renal function. Elevated TML levels were also associated with incident long-term (7-year) all-cause mortality [T3, adjusted hazard ratio (HR) 2.52, 95% CI 1.50–4.24; P < 0.001], and MACE even amongst patients persistently negative for cardiac Troponin T at presentation (e.g. 30-day MACE, T3, adjusted OR 4.49, 95% CI 2.06–9.79; P < 0.001). Trimethyllysine in combination with TMAO showed additive significance for near- and long-term CV events, including patients with ‘negative’ high-sensitivity Troponin T levels. In a multicentre Swiss Cohort (N = 1683) comprised of ACS patients, similar associations between TML and incident 1-year adverse cardiac risks were observed (e.g. mortality, adjusted T3 HR 2.74, 95% CI 1.28–5.85; P < 0.05; and MACE, adjusted T3 HR 1.55, 95% CI 1.04–2.31; P < 0.05).

Conclusion 

Plasma TML levels, alone and together with TMAO, are associated with both near- and long-term CV events in patients with chest pain and ACS.
Characteristics, transcriptional patterns and possible physiological significance of glycoside hydrolase family 16 members in Coprinopsis cinerea
Authors: Kang Liqin , Zhu Yiting , Bai Yang , Yuan Sheng
Published: April 2019

The glycoside hydrolase (GH) 16 family of Coprinopsis cinerea includes 15 members distributed in four subgroups (A1, A2, B and D) by phylogenetic analysis. The expression patterns match well with the requirement of wall-softening in the germination of basidiospores, hyphal growth and branching, primordium formation, stipe elongation, pileus expansion and autolysis. Remarkably, expression levels of different GH16 members varied with different morphogenetic events. Like orthologs of Aspergillus fumigatus GH16 glucanases (ENG2–5), which were expressed in the dormant conidia and conidiogenesis, and essential for segregation of conidia, some members such as ENG in the subgroup A1 in C. cinerea were also predominantly expressed in dormant basidiospores, primordia and maturing pilei during basidiosporogenesis. In contrast, other members in subgroup A2, subgroup B or D were dominantly expressed in the germinating basidiospores, the growing mycelia, and the elongating stipes. We did not find the members of the GH81 or GH55 family in C. cinerea genome, which was different from A. fumigatus. However, C. cinerea contains an extra three subgroups (A2, B and D) compared with A. fumigatus. These extra subgroups of GH16 family members may function as those endo-β-1,3-glucanases belonging to other GH families in the development and growth of C. cinerea.
Music Hall, Jigs and Strippers: English Low-Brow Music in French Nineteenth-Century Travel Writing
Authors: Scott Hannah
Published: April 2019

It is a commonplace to remark that nineteenth-century England was a land without music. Yet French travel writers in the fin de siècle remark again and again on their astonishing, low-brow musical encounters in the nation’s capital. The present article examines such experiences in the writing of Jules Vallès and Hector France, as they turn their steps away from the refinement of Covent Garden to seek out more esoteric musical experiences in the music halls, tawdry bars, minor theatres and strip joints of London. These texts present an intriguing and ambivalent textual form to the reader. Though being based on – and structured as – travel anecdotes, they no less insistently reach beyond the anecdotal experience to extrapolate overarching conclusions about the English and their character relative to France. Yet in doing so, their texts reveal inconsistencies and contradictions as they try to reconcile these strange musical experiences with the stereotypes of Englishness that had solidified over the generations; these alien musical experiences resist conceptualization and challenge the tropes that had for so long underwritten French ideas of the English Other.
Simulation of fine-scale electrical conductivity fields using resolution-limited tomograms and area-to-point kriging
Authors: Nussbaumer Raphaël , Linde Niklas , Mariethoz Grégoire , Holliger Klaus
Published: April 2019

Deterministic geophysical inversion approaches yield tomographic images with strong imprints of the regularization terms required to solve otherwise ill-posed inverse problems. While such tomograms enable an adequate assessment of the larger-scale features of the probed subsurface, the finer-scale details tend to be unresolved. Yet, representing these fine-scale structural details is generally desirable and for some applications even mandatory. To address this problem, we have developed a two-step methodology based on area-to-point kriging to generate fine-scale multi-Gaussian realizations from smooth tomographic images. Specifically, we use a co-kriging system in which the smooth, low-resolution tomogram is related to the fine-scale heterogeneity through a linear mapping operation. This mapping is based on the model resolution and the posterior covariance matrices computed using a linearization around the final tomographic model. This, in turn, allows us for analytical computations of covariance and cross-covariance models. The methodology is tested on a heterogeneous synthetic 2-D distribution of electrical conductivity that is probed with a surface-based electrical resistivity tomography (ERT) survey. The results demonstrate the ability of this technique to reproduce a known geostatistical model characterizing the fine-scale structure, while simultaneously preserving the large-scale structures identified by the smoothness-constrained tomographic inversion. Small discrepancies between the geophysical forward responses of the realizations and the reference synthetic data are attributed to the underlying linearization. Overall, the method provides an effective and fast alternative to more comprehensive, but computationally more expensive approaches, such as, for example, Markov chain Monte Carlo techniques. Moreover, the proposed method can be used to generate fine-scale multivariate Gaussian realizations from virtually any smoothness-constrained inversion results given the corresponding resolution and posterior covariance matrices.
Citrullus ecirrhosus: Wild Source of Resistance Against Bemisia tabaci (Hemiptera: Aleyrodidae) for Cultivated Watermelon
Authors: Simmons Alvin M , Jarret Robert L , Cantrell Charles L , Levi Amnon
Published: April 2019

Members of the highly polyphagous Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae) species complex cause major crop damage by feeding and by transmitting plant viruses. The Middle East-Asia Minor 1 (MEAM1) of the B. tabaci complex is by far the most problematic whitefly affecting crops including cultivated watermelon (Citrullus lanatus; Cucurbitaceae: Cucurbitales). Watermelon cultivars share a narrow genetic base and are highly susceptible to whiteflies. We studied the potential of C. ecirrhosus, a perennial desert species that can be hybridized with C. lanatus, as a source of whitefly resistance for cultivated watermelon. The results of this study indicate that C. ecirrhosus offers resistance (although not total) against the MEAM1 B. tabaci based on, at least, antibiosis and antixenosis. Whitefly performance concerning developmental survival, body size attainment, and nonpreference were suppressed on C. ecirrhosus compared with the watermelon cultivar ‘Sugar Baby’. Also, our olfactometer results indicated that the adults were less attracted to leaf volatiles of C. ecirrhosus. Although there is a pungent odor associated with the leaves of C. ecirrhosus, the leaf volatiles had no toxic effect on adult whitefly survival as compared with cultivated watermelon. We also demonstrated that plants of C. ecirrhosus can be clonally propagated from vine cuttings of the parent plant. Using traditional breeding procedures, C. ecirrhosus was hybridized with C. lanatus and viable F1 and F2 seeds were produced. This is the first report of pest resistance in C. ecirrhosus. This wild species offers a source of resistance against whiteflies for the improvement of cultivated watermelon.
A Data Analysis of the Iran–US Claims Tribunal’s Jurisprudence—Lessons for International Dispute-Settlement Today
Authors: Charlotin Damien
Published: April 2019

The Iran–US Claims Tribunal was instituted in 1–981 to hear claims from the two governments and their nationals after they broke diplomatic and economic ties. Upon deciding hundreds of cases, the Tribunal has been hailed as an example of a successful international adjudicative body, and as a source of inspiration for international dispute-settlement scholars. Less often acknowledged, however, the Tribunal’s output also constitutes a formidable and under-investigated dataset, ripe for empirical and data-oriented analysis. Such an analysis confirms the Tribunal’s enduring relevance and sheds light on older and newer debates in international dispute-settlement scholarship. The oft-mentioned charge that the Tribunal’s party-appointed members were ‘political’, or the practice of issuing dissenting opinions, can be reviewed under this lens, as they lessons for international law scholars and practitioners today.
Developmental Trajectories of Feeding Problems in Children with Autism Spectrum Disorder
Authors: Peverill Sarah , Smith Isabel M , Duku Eric , Szatmari Peter , Mirenda Pat , Vaillancourt Tracy , Volden Joanne , Zwaigenbaum Lonnie , Bennett Teresa , Elsabbagh Mayada , Georgiades Stelios , Ungar Wendy J
Published: April 2019

Objective

Although feeding problems are a common concern in children with autism spectrum disorder (ASD), few longitudinal studies have examined their persistence over time. The purpose of this study was to examine the developmental progression of feeding problems across four time points in preschoolers with ASD.

Methods

Group-based trajectory analyses revealed four distinct trajectories of feeding problems in our sample (N = 396).

Results

The majority of children showed levels of feeding problems that were low from the outset and stable (Group 1; 26.3%) or moderate and declining over time (Group 2; 38.9%). A third group (26.5%) showed high levels of feeding problems as preschoolers that declined to the average range by school age. Few participants (8.3%) showed evidence of severe chronic feeding problems. Feeding problems were more highly correlated with general behavior problems than with autism symptom severity.

Conclusions

Overall, our findings demonstrated that in our sample of children with ASD, most feeding problems remitted over time, but a small subgroup showed chronic feeding problems into school age. It is important to consider and assess feeding problems in ASD against the backdrop of typical development, as many children with ASD may show improvement with age.
The multi-allelic APRR2 gene is associated with fruit pigment accumulation in melon and watermelon
Authors: Oren Elad , Tzuri Galil , Vexler Lea , Dafna Asaf , Meir Ayala , Faigenboim Adi , Kenigswald Merav , Portnoy Vitaly , Schaffer Arthur A , Levi Amnon , Buckler Edward S , Katzir Nurit , Burger Joseph , Tadmor Yaakov , Gur Amit
Published: April 2019

Color and pigment contents are important aspects of fruit quality and consumer acceptance of cucurbit crops. Here, we describe the independent mapping and cloning of a common causative APRR2 gene regulating pigment accumulation in melon and watermelon. We initially show that the APRR2 transcription factor is causative for the qualitative difference between dark and light green rind in both crops. Further analyses establish the link between sequence or expression level variations in the CmAPRR2 gene and pigment content in the rind and flesh of mature melon fruits. A genome-wide association study (GWAS) of young fruit rind color in a panel composed of 177 diverse melon accessions did not result in any significant association, leading to an earlier assumption that multiple genes are involved in shaping the overall phenotypic variation in this trait. Through resequencing of 25 representative accessions and allelism tests between light rind accessions, we show that multiple independent single nucleotide polymorphisms in the CmAPRR2 gene are causative of the light rind phenotype. The multi-haplotypic nature of this gene explains the lack of detection power obtained through genotyping by sequencing-based GWAS and confirms the pivotal role of this gene in shaping fruit color variation in melon. This study demonstrates the power of combining bi- and multi-allelic designs with deep sequencing, to resolve lack of power due to high haplotypic diversity and low allele frequencies. Due to its central role and broad effect on pigment accumulation in fruits, the APRR2 gene is an attractive target for carotenoid bio-fortification of cucurbit crops.
Nitric oxide accelerates germination via the regulation of respiration in chickpea
Authors: Pandey Sonika , Kumari Aprajita , Shree Manu , Kumar Vinod , Singh Pooja , Bharadwaj Chellapilla , Loake Gary J , Parida Swarup K , Masakapalli Shyam Kumar , Gupta Kapuganti Jagadis
Published: April 2019

Seed germination is crucial for the plant life cycle. We investigated the role of nitric oxide (NO) in two chickpea varieties that differ in germination capacity: Kabuli, which has a low rate of germination and germinates slowly, and Desi, which shows improved germination properties. Desi produced more NO than Kabuli and had lower respiratory rates. As a result of the high respiration rates, Kabuli had higher levels of reactive oxygen species (ROS). Treatment with the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP) reduced respiration in Kabuli and decreased ROS levels, resulting in accelerated germination rates. These findings suggest that NO plays a key role in the germination of Kabuli. SNAP increased the levels of transcripts encoding enzymes involved in carbohydrate metabolism and the cell cycle. Moreover, the levels of amino acids and organic acids were increased in Kabuli as a result of SNAP treatment. 1H-nuclear magnetic resonance analysis revealed that Kabuli has a higher capacity for glucose oxidation than Desi. An observed SNAP-induced increase in 13C incorporation into soluble alanine may result from enhanced oxidation of exogenous [13C]glucose via glycolysis and the pentose phosphate pathway. A homozygous hybrid that originated from a recombinant inbred line population of a cross between Desi and Kabuli germinated faster and had increased NO levels and a reduced accumulation of ROS compared with Kabuli. Taken together, these findings demonstrate the importance of NO in chickpea germination via the control of respiration and ROS accumulation.
Structural and functional imaging of large and opaque plant specimens
Authors: Hesse Linnea , Bunk Katharina , Leupold Jochen , Speck Thomas , Masselter Tom
Published: April 2019

Three- and four-dimensional imaging techniques are a prerequisite for spatially resolving the form–structure–function relationships in plants. However, choosing the right imaging method is a difficult and time-consuming process as the imaging principles, advantages and limitations, as well as the appropriate fields of application first need to be compared. The present study aims to provide an overview of three imaging methods that allow for imaging opaque, large and thick (>5 mm, up to several centimeters), hierarchically organized plant samples that can have complex geometries. We compare light microscopy of serial thin sections followed by 3D reconstruction (LMTS3D) as an optical imaging technique, micro-computed tomography (µ-CT) based on ionizing radiation, and magnetic resonance imaging (MRI) which uses the natural magnetic properties of a sample for image acquisition. We discuss the most important imaging principles, advantages, and limitations, and suggest fields of application for each imaging technique (LMTS, µ-CT, and MRI) with regard to static (at a given time; 3D) and dynamic (at different time points; quasi 4D) structural and functional plant imaging.
A missense mutation in Large Grain Size 1 increases grain size and enhances cold tolerance in rice
Authors: Chen Xiaolong , Jiang Liangrong , Zheng Jingsheng , Chen Fangyu , Wang Tiansheng , Wang Meiling , Tao Yi , Wang Houcong , Hong Zonglie , Huang Yumin , Huang Rongyu
Published: April 2019

Grain shape is controlled by quantitative trait loci (QTLs) in rice (Oryza sativa L.). A rice mutant (JF178) with long and large grains has been used in a breeding program for over a decade, but its genetic basis has been unclear. Here, a semi-dominant QTL, designated Large Grain Size 1 (LGS1), was cloned and the potential molecular mechanism of LGS1 function was studied. Near-isogenic lines (NILs) and a map-based approach were employed to clone the LGS1 locus. LGS1 encodes the OsGRF4 transcription factor and contains a 2 bp missense mutation in the coding region that coincides with the putative pairing site of miRNA396. The LGS1 transcript levels in the mutant line were found to be higher than the lgs1 transcript levels in the control plants, suggesting that the mutation might disrupt the pairing of the LGS1 mRNA with miR396. In addition to producing larger grains, LGS1 also enhanced cold tolerance at the seedling stage and increased the survival rate of seedlings after cold stress treatment. These findings indicate that the mutation in LGS1 appears to disturb the GRF4–miR396 stress response network and results in the development of enlarged grains and enhancement of cold tolerance in rice.
StMYB44 negatively regulates anthocyanin biosynthesis at high temperatures in tuber flesh of potato
Authors: Liu Yuhui , Lin-Wang Kui , Espley Richard V , Wang Li , Li Yuanming , Liu Zhen , Zhou Ping , Zeng Lihui , Zhang Xiaojing , Zhang Junlian , Allan Andrew C
Published: April 2019

High temperatures are known to reduce anthocyanin accumulation in a number of diverse plant species. In potato (Solanum tuberosum L.), high temperature significantly reduces tuber anthocyanin pigment content. However, the mechanism of anthocyanin biosynthesis in potato tuber under heat stress remains unknown. Here we show that high temperature causes reduction of anthocyanin biosynthesis in both potato tuber skin and flesh, with white areas forming between the vasculature and periderm. Heat stress reduced the expression of the R2R3 MYB transcription factors (TFs) StAN1 and StbHLH1, members of the transcriptional complex responsible for coordinated regulation of the skin and flesh pigmentation, as well as anthocyanin biosynthetic pathway genes in white regions. However, the core phenylpropanoid pathway, lignin, and chlorogenic acid (CGA) pathway genes were up-regulated in white areas, suggesting that suppression of the anthocyanin branch may result in re-routing phenylpropanoid flux into the CGA or lignin biosynthesis branches. Two R2R3 MYB TFs, StMYB44-1 and StMYB44-2, were highly expressed in white regions under high temperature. In transient assays, StMYB44 represses anthocyanin accumulation in leaves of Nicotiana tabacum and N. benthamiana by directly suppressing the activity of the dihydroflavonol reductase (DFR) promoter. StMYB44-1 showed stronger repressive capacity than StMYB44-2, with both predicted proteins containing the repression-associated EAR motif with some variation. StMYB44-1 conferred repression without a requirement for a basic helix–loop–helix (bHLH) partner, suggesting a different repression mechanism from that of reported anthocyanin repressors. We propose that temperature-induced reduction of anthocyanin accumulation in potato flesh is caused by down-regulation of the activating anthocyanin regulatory complex, by enhancing the expression of flesh-specific StMYB44 and alteration of phenylpropanoid flux.
A cytorhabdovirus phosphoprotein forms mobile inclusions trafficked on the actin/ER network for viral RNA synthesis
Authors: Fang Xiao-Dong , Yan Teng , Gao Qiang , Cao Qing , Gao Dong-Min , Xu Wen-Ya , Zhang Zhen-Jia , Ding Zhi-Hang , Wang Xian-Bing
Published: April 2019

As obligate parasites, plant viruses usually hijack host cytoskeletons for replication and movement. Rhabdoviruses are enveloped, negative-stranded RNA viruses that infect vertebrates, invertebrates, and plants, but the mechanisms of intracellular trafficking of plant rhabdovirus proteins are largely unknown. Here, we used Barley yellow striate mosaic virus (BYSMV), a plant cytorhabdovirus, as a model to investigate the effects of the actin cytoskeleton on viral intracellular movement and viral RNA synthesis in a mini-replicon (MR) system. The BYSMV P protein forms mobile inclusion bodies that are trafficked along the actin/endoplasmic reticulum network, and recruit the N and L proteins into viroplasm-like structures. Deletion analysis showed that the N terminal region (aa 43–55) and the remaining region (aa 56–295) of BYSMV P are essential for the mobility and formation of inclusions, respectively. Overexpression of myosin XI-K tails completely abolishes the trafficking activity of P bodies, and is accompanied by a significant reduction of viral MR RNA synthesis. These results suggest that BYSMV P contributes to the formation and trafficking of viroplasm-like structures along the ER/actin network driven by myosin XI-K. Thus, rhabdovirus P appears to be a dynamic hub protein for efficient recruitment of viral proteins, thereby promoting viral RNA synthesis.
The effect of dust bias on the census of neutral gas and metals in the high-redshift Universe due to SDSS-II quasar colour selection
Authors: Krogager Jens-Kristian , Fynbo Johan P U , Møller Palle , Noterdaeme Pasquier , Heintz Kasper E , Pettini Max
Published: April 2019

We present a systematic study of the impact of a dust bias on samples of damped Ly α absorbers (DLAs). This bias arises as an effect of the magnitude and colour criteria utilized in the Sloan Digital Sky Survey (SDSS) quasar target selection up until data release 7 (DR7). The bias has previously been quantified assuming only a contribution from the dust obscuration. In this work, we apply the full set of magnitude and colour criteria used up until SDSS-DR7 in order to quantify the full impact of dust biasing against dusty and metal-rich DLAs. We apply the quasar target selection algorithm on a modelled population of intrinsic colours, and by exploring the parameter space consisting of redshift, ($z_{\rm{\small QSO}}$and zabs), optical extinction, and H i column density, we demonstrate how the selection probability depends on these variables. We quantify the dust bias on the following properties derived for DLAs at z ≈ 3: the incidence rate, the mass density of neutral hydrogen and metals, and the average metallicity. We find that all quantities are significantly affected. When considering all uncertainties, the mass density of neutral hydrogen is underestimated by 10–50 per cent, and the mass density in metals is underestimated by 30–200 per cent. Lastly, we find that the bias depends on redshift. At redshift z = 2.2, the mass density of neutral hydrogen and metals might be underestimated by up to a factor of 2 and 5, respectively. Characterizing such a bias is crucial in order to accurately interpret and model the properties and metallicity evolution of absorption-selected galaxies.
Accurate prediction of boundaries of high resolution topologically associated domains (TADs) in fruit flies using deep learning
Authors: Henderson John , Ly Vi , Olichwier Shawn , Chainani Pranik , Liu Yu , Soibam Benjamin
Published: April 2019

Genomes are organized into self-interacting chromatin regions called topologically associated domains (TADs). A significant number of TAD boundaries are shared across multiple cell types and conserved across species. Disruption of TAD boundaries may affect the expression of nearby genes and could lead to several diseases. Even though detection of TAD boundaries is important and useful, there are experimental challenges in obtaining high resolution TAD locations. Here, we present computational prediction of TAD boundaries from high resolution Hi-C data in fruit flies. By extensive exploration and testing of several deep learning model architectures with hyperparameter optimization, we show that a unique deep learning model consisting of three convolution layers followed by a long short-term-memory layer achieves an accuracy of 96%. This outperforms feature-based models’ accuracy of 91% and an existing method's accuracy of 73–78% based on motif TRAP scores. Our method also detects previously reported motifs such as Beaf-32 that are enriched in TAD boundaries in fruit flies and also several unreported motifs.
Unprecedented tunability of riboswitch structure and regulatory function by sub-millimolar variations in physiological Mg2+
Authors: McCluskey Kaley , Boudreault Julien , St-Pierre Patrick , Perez-Gonzalez Cibran , Chauvier Adrien , Rizzi Adrien , Beauregard Pascale B , Lafontaine Daniel A , Penedo J Carlos
Published: April 2019

Riboswitches are cis-acting regulatory RNA biosensors that rival the efficiency of those found in proteins. At the heart of their regulatory function is the formation of a highly specific aptamer–ligand complex. Understanding how these RNAs recognize the ligand to regulate gene expression at physiological concentrations of Mg2+ ions and ligand is critical given their broad impact on bacterial gene expression and their potential as antibiotic targets. In this work, we used single-molecule FRET and biochemical techniques to demonstrate that Mg2+ ions act as fine-tuning elements of the amino acid-sensing lysC aptamer's ligand-free structure in the mesophile Bacillus subtilis. Mg2+ interactions with the aptamer produce encounter complexes with strikingly different sensitivities to the ligand in different, yet equally accessible, physiological ionic conditions. Our results demonstrate that the aptamer adapts its structure and folding landscape on a Mg2+-tunable scale to efficiently respond to changes in intracellular lysine of more than two orders of magnitude. The remarkable tunability of the lysC aptamer by sub-millimolar variations in the physiological concentration of Mg2+ ions suggests that some single-aptamer riboswitches have exploited the coupling of cellular levels of ligand and divalent metal ions to tightly control gene expression.
Ways to be Blameworthy
Authors: Mason Elinor
Published: April 2019

This book examines the relationship between our deontic notions, rightness and wrongness, and our responsibility notions, praise- and blameworthiness. The book presents a pluralistic view of both our deontic concepts and our responsibility concepts, identifying three different ways to be blameworthy. First, ordinary blameworthiness is essentially connected to subjective rightness and wrongness. Subjective obligation and ordinary blameworthiness apply only to those who are within our moral community, that is to say, those who understand and share our value system. By contrast, the second sort of blameworthiness, detached blameworthiness, can apply even when the agent is outside our moral community, and has no sense that her act is morally wrong. We blame agents for acting objectively wrongly, even if we do not have any view about their state of mind in so doing. Finally, the third sort of blameworthiness is ‘extended blameworthiness’, which applies in some contexts where the agent has acted wrongly, and understands the wrongness, but has acted wrongly entirely inadvertently. In such cases the agent is not personally at fault but the social context may be such that she should take responsibility, and thus become blameworthy.
Diversity of information sources: An evaluation of global think tanks knowledge construct
Authors: Ahmad Mahmood , Jan Muhammad Ayub
Published: April 2019

In the realm of policy making, place and prestige of think tanks is acknowledged for their contribution in policy analysis and recommendations. Governments around the world consider the reports and recommendations of leading global think tanks when developing their policies. However, in spite of there being a comprehensive list of typologies and functions of think tanks, much less is known about these ‘machineries of knowledge’ and what enables them ‘to know what they know, and the key sources of variation among them’. Drawing on the theory of epistemic knowledge, this study aims to provide insights about how knowledge is produced inside these machineries of knowledge by looking at source citations’ pattern of reports produced by the top 50 global think tanks. For this purpose, a total of 365 research reports on one country, i.e. Pakistan, published between 2007 and 2016 were retrieved. A total of 17,801 references were extracted and analyzed. The study finds that there is great variation across think tanks in the use of diverse information sources and the use also varies considerably over time even for the same organization.
Integrating Robotic Technology Into Resident Training: Challenges and Recommendations From the Front Lines
Authors: Green Courtney A. , Mahuron Kelly M. , Harris Hobart W. , O’Sullivan Patricia S.
Published: April 2019

Purpose

To develop recommendations for improving the integration of robotic technology into today’s apprentice-based resident training.

Method

During a national meeting in 2017, 24 robotic surgeons were interviewed about their experiences integrating robotic technology into resident training. Qualitative thematic analysis of interview notes and recordings revealed themes related to challenges and recommendations.

Results

Four themes emerged, each corresponding to a general recommendation for integrating robotic technology into training. The first, surgical techniques versus tools, contrasts faculty’s sequential mastery—surgical techniques first, then the robotic tool—with residents’ simultaneous learning. The recommendation is to create separate learning opportunities for focused skill acquisition. The second theme, timing of exposure to the robotic tool, describes trainees’ initial focus on tool use for basic surgical steps. The recommendation is to increase access to basic robotic cases. The third theme covers the relationship of laparoscopic and robotic surgery. The recommendation is to emphasize similar and dissimilar features during all minimally invasive surgical cases. The fourth theme, use of the dual console (which enables two consoles to operate the robot, the primary determines the secondary’s functionality), highlights the unique teaching opportunities this console creates. The recommendation is for surgeons to give verbal guidance so residents completely understand surgical techniques.

Conclusions

Surgical educators should consider technique versus tool, timing of exposure to the tool, overlapping and varying features of robotic and laparoscopic surgery, and use of the dual console as they develop curricula to ensure thorough acquisition and synthesis of all elements of robotic surgery.
What Can the Giant Do? Defining the Path to Unsupervised Primary Care Practice by Competence, Not Time
Authors: Warm Eric J. , Kinnear Benjamin
Published: April 2019

In this issue of Academic Medicine, Dewan and Norcini examine the significant variability of time-in-training between patient care “giants”—the physicians, nurse practitioners, and physician assistants who practice primary care—and they call for further studies to determine optimal training duration and eventual scope of practice. They ask, what is the minimum education and training required to practice primary care, or “how tall is the shortest giant?” In this Invited Commentary, the authors reframe the question from identifying the minimum length of training required, to identifying desired patient care outcomes. Primary care is not a uniform entity. It ranges from complex elderly chronically ill patients, to twentysomething millennials with acute problems, to pregnant women, to families, and everything in between. The authors argue that training should be fit for purpose and produce high-quality outcomes for patients. Competence should be defined by these outcomes. Drawing parallels with Major League Baseball, the authors note that time to competence development will be variable for different training programs depending on purpose, and also variable for people within those programs, even with shared purpose. While time is a tool for competence attainment, it should not be the metric by which readiness for practice is measured.
The Curse of the All-Star Team: A Single-Season Prospective Shoulder MRI Study of Little League Baseball Players
Authors: Holt Joshua B. , Stearns Philip H. , Bastrom Tracey P. , Dennis M. Morgan , Dwek Jerry R. , Pennock Andrew T.
Published: April 2019

Background:

Throwing guidelines have been implemented in Little League baseball in an attempt to minimize injuries in young baseball players. We hypothesized that playing pitcher or catcher and increased innings played during the season would result in dominant shoulder magnetic resonance imaging (MRI) abnormalities.

Methods:

A prospective evaluation of Little League players aged 10 to 12 years was performed. Players recruited before the start of the season underwent bilateral preseason and dominant shoulder postseason MRI, physical examination, and questionnaires addressing their playing history and arm pain. Innings played, player position, pitch counts, and all-star team selection were recorded.

Results:

In total, 23 players were enrolled. The majority (19/23, 82.6%) were right-handed and 16 of 23 (69.6%) played at least 10 innings as pitcher or catcher. Sixteen were selected for the all-star team. Fourteen players (60.9%) had positive dominant shoulder MRI findings not present in their nondominant shoulder. Eight players (34.8%) had new or worsening postseason MRI findings. Thirteen players (81.3%) selected to the all-star team had abnormal MRI findings whereas only one (14.3%) player not selected as an all-star had MRI abnormalities (P=0.005). Year-round play (P=0.016), innings pitched (P=0.046), innings catcher (P=0.039), and number of pitches (P=0.033) were associated with any postseason MRI abnormality, but not for new or worsening MRI changes. Single sport athletes and players playing for multiple teams were significantly more likely to have abnormal MRI findings (P=0.043 and 0.040, respectively) when compared with multisport athletes playing on a single team.

Conclusions:

MRI abnormalities involving the dominant shoulder are common in Little League baseball players and often develop or worsen during the season. Contrary to our hypothesis, MRI abnormalities were not associated with player position and pitch counts. Instead, they were most closely associated with year round play, single sports participation, and all-star team selection. The increased demands required for all-star selection comes at a price to the young athlete as the majority of players selected for this honor had abnormal MRI findings in their throwing shoulder while few non all-stars demonstrated such pathology.

Level of Evidence:

Level II.
Patient and Family Centered Actionable Processes of Care and Performance Measures for Persistent and Chronic Critical Illness: A Systematic Review
Authors: Rose Louise , Istanboulian Laura , Allum Laura , Burry Lisa , Dale Craig , Hart Nicholas , Kydonaki Kalliopi , Ramsay Pam , Pattison Natalie , Connolly Bronwen
Published: April 2019

Objectives:

To identify actionable processes of care, quality indicators, or performance measures and their evidence base relevant to patients with persistent or chronic critical illness and their family members including themes relating to patient/family experience.

Data Sources:

Two authors independently searched electronic, systemic review, and trial registration databases (inception to November 2016).

Study Selection:

We included studies with an ICU length of stay of greater than or equal to 7 days as an inclusion criterion and reported actionable processes of care; quality improvement indicators, measures, or tools; or patient/family experience. We excluded case series/reports of less than 10 patients.

Data Extraction:

Paired authors independently extracted data and performed risk of bias assessment.

Data Synthesis:

We screened 13,130 references identifying 114 primary studies and 102 relevant reviews. Primary studies reported data on 24,252 participants; median (interquartile range) sample size of 70 (32–182). We identified 42 distinct actionable processes of care, the most commonly investigated related to categories of 1) weaning methods (21 studies; 27 reviews); 2) rehabilitation, mobilization, and physiotherapy (20 studies; 40 reviews); and 3) provision of information, prognosis, and family communication (14 studies; 11 reviews). Processes with limited evidence were generally more patient-centered categories such as communication, promotion of sleep, symptom management, or family support. Of the 21 randomized controlled trials, only two were considered at low risk of bias across all six domains, whereas just two cohort studies and one qualitative study were considered of high quality.

Conclusions:

We identified 42 distinct actionable processes of care relevant to patients with persistent or chronic critical illness and their families, with most frequently studied processes relating to weaning, rehabilitation/mobilization, and family communication. Qualitative studies highlighted the need to address psychologic needs and distressing symptoms as well as enabling patient communication. Our findings are informative for clinicians and decision-makers when planning high-quality patient and family-focused care.
Fresh Red Cells for Transfusion in Critically Ill Adults: An Economic Evaluation of the Standard Issue Transfusion Versus Fresher Red-Cell Use in Intensive Care (TRANSFUSE) Clinical Trial
Authors: Irving Adam , Higgins Alisa , Ady Bridget , Bellomo Rinaldo , Cooper D. James , French Craig , Gantner Dashiell , Harris Anthony , Irving David O. , Murray Lynne , Nichol Alistair , Petrie Dennis , McQuilten Zoe K.
Published: April 2019

Objectives:

Trials comparing the effects of transfusing RBC units of different storage durations have considered mortality or morbidity as outcomes. We perform the first economic evaluation alongside a full age of blood clinical trial with a large population assessing the impact of RBC storage duration on quality-of-life and costs in critically ill adults.

Design:

Quality-of-life was measured at 6 months post randomization using the EuroQol 5-dimension 3-level instrument. The economic evaluation considers quality-adjusted life year and cost implications from randomization to 6 months. A generalized linear model was used to estimate incremental costs (2016 U.S. dollars) and quality-adjusted life years, respectively while adjusting for baseline characteristics.

Setting:

Fifty-nine ICUs in five countries.

Patients:

Adults with an anticipated ICU stay of at least 24 hours when the decision had been made to transfuse at least one RBC unit.

Interventions:

Patients were randomized to receive either the freshest or oldest available compatible RBC units (standard practice) in the hospital transfusion service.

Measurements and Main Results:

EuroQol 5-dimension 3-level utility scores were similar at 6 months—0.65 in the short-term and 0.63 in the long-term storage group (difference, 0.02; 95% CI, –0.00 to 0.04; p = 0.10). There were no significant differences in resource use between the two groups apart from 3.0 fewer hospital readmission days (95% CI, –5.3 to –0.8; p = 0.01) during follow-up in the short-term storage group. There were no significant differences in adjusted total costs or quality-adjusted life years between the short- and long-term storage groups (incremental costs, –$2,358; 95% CI, –$5,586 to $711) and incremental quality-adjusted life years: 0.003 quality-adjusted life years (95% CI, –0.003 to 0.008).

Conclusions:

Without considering the additional supply cost of implementing a freshest available RBC strategy for critical care patients, there is no evidence to suggest that the policy improves quality-of-life or reduces other costs compared with standard transfusion practice.
The impact of depression on adherence to organized and opportunistic breast cancer screening
Authors: Montagna Giacomo , Schneeberger Andres R. , Rossi Lorenzo , Reina Hubertina , Schwab Fabienne D. , Schoetzau Andreas , Eichholzer Monika , Pagani Olivia , Weber Walter P. , Kurzeder Christian , Güth Uwe , Huber Christian G.
Published: April 2019

One in five women will experience depression over her lifetime, and one out of eight will develop breast cancer. We evaluated the effect of depression on adherence to mammography in Switzerland, where opportunistic and organized screening programs coexist. We analyzed data from 3206 women aged 50–69 who participated in the Swiss Health Survey 2012. We compared mammographic rates among women with no to mild versus moderate to severe depressive symptoms. The effect of the type of screening on the odds of undertaking a mammography was calculated using multivariable logistic regression analysis. Women with moderate to severe major depressive symptoms were more likely to have had a mammography in the previous 2 years than their nondepressed or less-depressed counterparts (51 vs. 39.2%, respectively, P = 0.005). In the multivariable analysis, women with no to mild major depression living in cantons with an organized screening program had an adjusted odds ratio of 2.7 (95% confidence interval: 2.30–3.17, P < 0.001) of having had a mammography within the past 24 months compared with those living in the regions with an opportunistic screening. The adjusted odds ratio for women with moderate to severe major depression was 4.21 (95% confidence interval: 2.13–8.33, P < 0.001). In Switzerland. adherence to mammographic screening among women with moderate to severe major depression is higher than among women with no or minimal major depressive symptoms. This increased adherence is even more pronounced in regions with organized screening.