bluuebunny/crossref_metadata_2025 huggingface dataset:
The Parallel Molecular Adaptations to the Antarctic Cold Environment in Two Psychrophilic Green Algae
Authors: Zhang Zhenhua , Qu Changfeng , Yao Ru , Nie Yuan , Xu Chenjie , Miao Jinlai , Zhong Bojian
Published: May 2019

Psychrophilic green algae from independent phylogenetic lines thrive in the polar extreme environments, but the hypothesis that their psychrophilic characteristics appeared through parallel routes of molecular evolution remains untested. The recent surge of transcriptome data enables large-scale evolutionary analyses to investigate the genetic basis for the adaptations to the Antarctic extreme environment, and the identification of the selective forces that drive molecular evolution is the foundation to understand the strategies of cold adaptation. Here, we conducted transcriptome sequencing of two Antarctic psychrophilic green algae (Chlamydomonas sp. ICE-L and Tetrabaena socialis) and performed positive selection and convergent substitution analyses to investigate their molecular convergence and adaptive strategies against extreme cold conditions. Our results revealed considerable shared positively selected genes and significant evidence of molecular convergence in two Antarctic psychrophilic algae. Significant evidence of positive selection and convergent substitution were detected in genes associated with photosynthetic machinery, multiple antioxidant systems, and several crucial translation elements in Antarctic psychrophilic algae. Our study reveals that the psychrophilic algae possess more stable photosynthetic apparatus and multiple protective mechanisms and provides new clues of parallel adaptive evolution in Antarctic psychrophilic green algae.
Development of a Combined Sensory-Cognitive Measure Based on the Common Cause Hypothesis: Heterogeneous Trajectories and Associated Risk Factors
Authors: de la Fuente Javier , Moreno-Agostino Dario , de la Torre-Luque Alejandro , Prina A Matthew , Haro Josep María , Caballero Francisco Félix , Ayuso-Mateos José Luis
Published: May 2019

Background and Objectives

There is a link between sensory and cognitive functioning across old age. However, there are no integrative measures for assessing common determinants of sensory-cognitive functioning. This study aims to develop a combined measure of sensory-cognitive functioning, and to identify heterogeneous trajectories and associated risk factors.

Research Design and Methods

Two thousand two hundred and fifty-five individuals aged 60 years and over selected from the first six waves (2002–2012) of the English Longitudinal Study of Ageing completed a set of five self-reported visual and hearing functioning items and four cognitive items. Several health-related outcomes were also collected.

Results

The common cause model presented longitudinal factorial invariance (Tucker-Lewis index [TLI] = 0.989; Comparative Fit Index [CFI] = 0.991; Root Mean Square Error of Approximation [RMSEA] = 0.026). A common factor explained 32%, 36%, and 26% of the visual, hearing, and cognitive difficulties, respectively. The developed sensory-cognitive measure predicted incident dementia over 10 years (area under the curve = .80; 95% confidence interval [CI] = .75, .86). A three-trajectory model was proved to fit better, according to growth mixture modeling. Low levels of education and household wealth, disability, diabetes, high blood pressure, depressive symptoms, and low levels of physical activity were risk factors associated with the classes showing trajectories with a steeper increase of sensory-cognitive difficulties.

Discussion and Implications

A time-invariant factor explains both sensory and cognitive functioning over 8 years. The sensory-cognitive measure derived from this factor showed a good performance for predicting dementia 10 years later. Several easily identifiable socioeconomic and health-related risk factors could be used as early markers of subsequent sensory-cognitive decline. Therefore, the proposed latent measure could be useful as a cost-effective indicator of sensory-cognitive functioning.
Salvage endovascular septectomy in patients with chronic abdominal aortic dissection after failed endovascular aneurysm repair
Authors: Zhuang Hui , Cai Fanggang , Wu Zhixian , Zhan Tenghui , Chen Hongyu , Chen Cheng , Zhang Hanyue , Guo Pingfan
Published: May 2019

This study aimed to investigate the efficacy and safety of salvage endovascular septectomy in patients with abdominal chronic aortic dissection (CAD) after endovascular aneurysm repair. A study cohort comprising 6 patients with chronic abdominal aortic dissection after failed endovascular aortic repair [mean age 62.5 (36–69) years] were enrolled to undergo salvage endovascular septectomy. The procedure involved entering the false lumen via the intrinsic visceral entry to perform a confined septectomy using a ‘Gigli wire’ to merge the true and false lumens. The outcomes were assessed by Digital angiography and computed tomography angiography. All 6 patients were successfully operated on; the diameters of the visceral abdominal aorta and the infrarenal abdominal aorta were similar at 1, 3, 6 and 12 months compared with the baseline; the patency of the visceral branch arteries was also stable at 1, 3, 6 and 12 months compared with the baseline; no occlusion of the visceral branch arteries was noted; no major vascular adverse events or deaths were observed. In this preliminary study, it was proven that salvage endovascular septectomy is a potentially advantageous technique that is safe and effective in the treatment of patients with CAD after failed endovascular aortic repair.
A magnetic resonance imaging-compatible small animal model under extracorporeal circulation
Authors: Assmann Anna Kathrin , Akhyari Payam , Demler Florian , Lichtenberg Artur , Assmann Alexander
Published: May 2019

The impact of different extracorporeal circulation (ECC) scenarios on arterial blood flow profiles has not yet been revealed. To allow for exact measurements, magnetic resonance imaging (MRI) during ECC is required. Therefore, the present study addressed the feasibility of a high-resolution MRI-compatible animal model of ECC. For usage in New Zealand White rabbits, we developed an ECC device, the tubes of which were long enough to eliminate impacts of the magnetic field on the blood pump and heart–lung control machine. The miniaturized ECC system via thoracic access comprised an infant oxygenator, a pulsatile centrifugal pump, 1/8″ tubes, a 10-Fr aortic cannula and a 12-Fr venous cannula for vacuum-assisted drainage. This miniaturized ECC system has very low priming volume (230–255 ml) to reduce the system-inherent haemodilution to 50%. Consequently, haemoglobin rates remained high enough to guarantee adequate oxygenation (arterial pressure of oxygen >200 mmHg). Optimized venous drainage by an additionally inserted pulmonary artery vent catheter resulted in sufficient blood flow (31.6–65.8 ml/min/kg) that was maintained for 60 min with pulsatility. The current study demonstrates the feasibility of MRI-compatible ECC in rabbits, and this model allows for real-time blood flow profile measurements during different ECC scenarios in future projects.
Sex hormone binding globulin and risk of breast cancer: a Mendelian randomization study
Authors: Dimou Niki L , Papadimitriou Nikos , Gill Dipender , Christakoudi Sofia , Murphy Neil , Gunter Marc J , Travis Ruth C , Key Tim J , Fortner Renee T , Haycock Philip C , Lewis Sarah J , Muir Kenneth , Martin Richard M , Tsilidis Konstantinos K
Published: May 2019

Background

There are observational data suggesting an inverse association between circulating concentrations of sex hormone binding globulin (SHBG) and risk of postmenopausal breast cancer. However, causality is uncertain and few studies have investigated this association by tumour receptor status. We aimed to investigate these associations under the causal framework of Mendelian randomization (MR).

Methods

We used summary association estimates extracted from published genome-wide association study (GWAS) meta-analyses for SHBG and breast cancer, to perform two-sample MR analyses. Summary statistics were available for 122 977 overall breast cancer cases, of which 69 501 were estrogen receptor positive (ER+ve) and 21 468 were ER-ve, and 105 974 controls. To control for potential horizontal pleiotropy acting via body mass index (BMI), we performed multivariable inverse-variance weighted (IVW) MR as the main analysis, with the robustness of this approach further tested in sensitivity analyses.

Results

The multivariable IVW MR analysis indicated a lower risk of overall (odds ratio [OR]: 0.94; 95% confidence interval [CI]: 0.90, 0.98; P: 0.006) and ER+ve (OR: 0.92; 95% CI: 0.87, 0.97; P: 0.003) breast cancer, and a higher risk of ER-ve disease (OR: 1.09; 95% CI: 1.00, 1.18; P: 0.047) per 25 nmol/L higher SHBG levels. Sensitivity analyses were consistent with the findings of the main analysis.

Conclusions

We corroborated the previous literature evidence coming from observational studies for a potentially causal inverse association between SHBG concentrations and risk of ER+ve breast cancer, but our findings also suggested a potential novel positive association with ER-ve disease that warrants further investigation, given the low prior probability of being true.
Treatment-Emergent Influenza Variant Viruses With Reduced Baloxavir Susceptibility: Impact on Clinical and Virologic Outcomes in Uncomplicated Influenza
Authors: Uehara Takeki , Hayden Frederick G , Kawaguchi Keiko , Omoto Shinya , Hurt Aeron C , De Jong Menno D , Hirotsu Nobuo , Sugaya Norio , Lee Nelson , Baba Keiko , Shishido Takao , Tsuchiya Kenji , Portsmouth Simon , Kida Hiroshi
Published: May 2019

Background

Single-dose baloxavir rapidly reduces influenza virus titers and symptoms in patients with uncomplicated influenza, but viruses with reduced in vitro susceptibility due to amino acid substitutions at position 38 of polymerase acidic protein (PA/I38X) sometimes emerge.

Methods

We evaluated the kinetics, risk factors, and effects on clinical and virologic outcomes of emergence of PA/I38X-substituted viruses.

Results

Viruses containing PA/I38X substitutions were identified 3–9 days after baloxavir treatment in 9.7% (36/370) of patients, of whom 85.3% had transient virus titer rises. Median time to sustained cessation of infectious virus detection was 192, 48, and 96 hours in the baloxavir recipients with PA/I38X-substituted viruses, without PA/I38X-substituted viruses, and placebo recipients, respectively. The corresponding median times to alleviation of symptoms were 63.1, 51.0, and 80.2 hours, respectively. After day 5, symptom increases occurred in 11.5%, 8.0%, and 13.0%, respectively, and in 8.9% of oseltamivir recipients. Variant virus emergence was associated with lower baseline neutralizing antibody titers.

Conclusions

The emergence of viruses with PA/I38X substitutions following baloxavir treatment was associated with transient rises in infectious virus titers, prolongation of virus detectability, initial delay in symptom alleviation, and uncommonly with symptom rebound. The potential transmissibility of PA/I38X-substituted viruses requires careful study.

Clinical Trial Registration

NCT02954354.
Risk factors for loss to follow-up in human immunodeficiency virus care in the Greater Accra Regional Hospital in Ghana: a retrospective cohort study
Authors: Sifa Jerry S , Manortey Stephen , Talboys Sharon , Ansa Gloria A , Houphouet Ekua E
Published: May 2019

Background

Loss of human immunodeficiency virus (HIV)-positive patients to follow-up increases HIV-related morbidity and mortality. This study identified the factors associated with loss to follow-up (LTFU) in an urban health facility in Ghana.

Methods

A 12-y retrospective study was conducted using routinely collected data from the National Acquired Immune Deficiency Syndrome (AIDS) Control Programme (NACP) on persons living with HIV/AIDS (PLWHA) who initiated antiretroviral therapy (ART) from 2006 to 2017 at the Greater Accra Regional Hospital. Convenience sampling was used to select the study area. All gathered data were exported to Stata 14 statistical software for analysis.

Results

A total of 4330 PLWHA initiated ART between January 2006 and December 2017. Of these, 1166 (26.9%) were lost to follow-up over the 12-y period. The factors associated with LTFU included being a Muslim (adjusted hazard ratio [aHR] 1.31 [95% confidence interval {CI} 1.05 to 1.65]), having CD4 <250 cells/ml (aHR 1.45 [95% CI 1.21 to 1.76]) and completing adherence counselling (aHR 1.58 [95% CI 1.31 to 1.92]). Having other sources of health care funding and disclosure of one’s disease status were found to be protective (aHR 0.74 [95% CI 0.58 to 0.94] and 0.80 [95% CI 0.65 to 0.98], respectively).

Conclusions

Some of the determinants of LTFU in the hospital are comparable to those found in other parts of Africa and could be addressed using existing interventions.
Population pharmacokinetics of dolutegravir: influence of drug–drug interactions in a real-life setting
Authors: Barcelo Catalina , Aouri Manel , Courlet Perrine , Guidi Monia , Braun Dominique L , Günthard Huldrych F , Piso Rein J , Cavassini Matthias , Buclin Thierry , Decosterd Laurent A , Csajka Chantal ,   Swiss HIV Cohort Study, Anagnostopoulos A , Battegay M , Bernasconi E , Böni J , Braun D L , Bucher H C , Calmy A , Cavassini M , Ciuffi A , Dollenmaier G , Egger M , Elzi L , Fehr J , Fellay J , Furrer H , Fux C A , Günthard H F , Haerry D , Hasse B , Hirsch H H , Hoffmann M , Hösli I , Huber M , Kahlert C R , Kaiser L , Keiser O , Klimkait T , Kouyos R D , Kovari H , Ledergerber B , Martinetti G , Martinez de Tejada B , Marzolini C , Metzner K J , Müller N , Nicca D , Paioni P , Pantaleo G , Perreau M , Rauch A , Rudin C , Scherrer A U , Schmid P , Speck R , Stöckle M , Tarr P , Trkola A , Vernazza P , Wandeler G , Weber R , Yerly S
Published: May 2019

Objectives

Dolutegravir is widely prescribed owing to its potent antiviral activity, high genetic barrier and good tolerability. The aim of this study was to characterize dolutegravir’s pharmacokinetic profile and variability in a real-life setting and to identify individual factors and co-medications affecting dolutegravir disposition.

Methods

A population pharmacokinetic model was developed using NONMEM®. Relevant demographic factors, clinical factors and co-medications were tested as potential covariates. Simulations based on the final model served to compare expected dolutegravir concentrations under standard and alternative dosage regimens in the case of drug–drug interactions.

Results

A total of 620 dolutegravir plasma concentrations were collected from 521 HIV-infected individuals under steady-state conditions. A one-compartment model with first-order absorption and elimination best characterized dolutegravir pharmacokinetics. Typical dolutegravir apparent clearance (CL/F) was 0.93 L/h with 32% between-subject variability, the apparent volume of distribution was 20.2 L and the absorption rate constant was fixed to 2.24 h−1. Older age, higher body weight and current smoking were associated with higher CL/F. Atazanavir co-administration decreased dolutegravir CL/F by 38%, while darunavir modestly increased CL/F by 14%. Rifampicin co-administration showed the largest impact on CL/F. Simulations suggest that average dolutegravir trough concentrations are 63% lower after 50 mg/12h with rifampicin compared with a standard dosage of 50 mg/24h without rifampicin. Average trough concentrations after 100 mg/24h and 100 mg/12h with rifampicin are 92% and 25% lower than the standard dosage without rifampicin, respectively.

Conclusions

Patients co-treated with dolutegravir and rifampicin might benefit from therapeutic drug monitoring and individualized dosage increase, up to 100 mg/12 h in some cases.
Secondary use of standardized nursing care data for advancing nursing science and practice: a systematic review
Authors: Macieira Tamara G R , Chianca Tania C M , Smith Madison B , Yao Yingwei , Bian Jiang , Wilkie Diana J , Dunn Lopez Karen , Keenan Gail M
Published: May 2019

Objective

The study sought to present the findings of a systematic review of studies involving secondary analyses of data coded with standardized nursing terminologies (SNTs) retrieved from electronic health records (EHRs).

Materials and Methods

We identified studies that performed secondary analysis of SNT-coded nursing EHR data from PubMed, CINAHL, and Google Scholar. We screened 2570 unique records and identified 44 articles of interest. We extracted research questions, nursing terminologies, sample characteristics, variables, and statistical techniques used from these articles. An adapted STROBE (Strengthening The Reporting of OBservational Studies in Epidemiology) Statement checklist for observational studies was used for reproducibility assessment.

Results

Forty-four articles were identified. Their study foci were grouped into 3 categories: (1) potential uses of SNT-coded nursing data or challenges associated with this type of data (feasibility of standardizing nursing data), (2) analysis of SNT-coded nursing data to describe the characteristics of nursing care (characterization of nursing care), and (3) analysis of SNT-coded nursing data to understand the impact or effectiveness of nursing care (impact of nursing care). The analytical techniques varied including bivariate analysis, data mining, and predictive modeling.

Discussion

SNT-coded nursing data extracted from EHRs is useful in characterizing nursing practice and offers the potential for demonstrating its impact on patient outcomes.

Conclusions

Our study provides evidence of the value of SNT-coded nursing data in EHRs. Future studies are needed to identify additional useful methods of analyzing SNT-coded nursing data and to combine nursing data with other data elements in EHRs to fully characterize the patient’s health care experience.
Characterization and comparison of cell-mediated immune responses following ex vivo stimulation with viral and bacterial respiratory pathogens in stressed and unstressed beef calves1
Authors: Buhler Veronica M , Cash Kaycee R , Hurley David J , Credille Brent C
Published: May 2019

The goal of this study was to compare the cell-mediated immune responses of highly commingled, sale-barn origin calves (STR; n = 10) to those of single source calves that had been weaned for 60 d (UNS; n = 10). Peripheral blood mononuclear cells and neutrophils (PMNs) were isolated from jugular venous blood of each calf. Peripheral blood mononuclear cells were stimulated with Concanavalin A (ConA), BVDV-1, BVDV-2, BHV-1, Mannheimia haemolytica, and Pasteurella multocida and evaluated for clonal proliferation and secretion of IL-8 into cell culture supernatants. The native functional capacities of PMNs were evaluated in response to stimulation with heat-killed Escherichia coli and Staphylococcus aureus. Complete blood counts and serum biochemical profiles were performed for each animal at the time of sample collection. Compared with STR calves, UNS calves had greater lymphocyte proliferative responses following stimulation BVDV1 (P = 0.041), BVDV2 (P = 0.002), BHV-1 (P = 0.001), M. haemolytica (P = 0.016), and P. multocida (P = 0.049). In addition, PMNs isolated from UNS calves had a greater ability to phagocytose E. coli (P = 0.001) and S. aureus (P = 0.003) when compared with STR calves. Serum nonesterified fatty acids were higher in STR calves (P < 0.001). Serum β-hydroxybutyrate was lower in STR calves (P < 0.003). These data suggest that immunologic and physiologic differences exist between STR and UNS calves. Although the underlying mechanisms for these differences are not clear, it is possible that combinations of energy imbalances, stress-induced immunosuppression, and general immune naiveté may predispose STR calves to an increased risk of morbidity and mortality due to bovine respiratory disease.
Social Participation of Burn Survivors and the General Population in Work and Employment: A Life Impact Burn Recovery Evaluation (LIBRE) Profile Study
Authors: Saret Cayla J , Ni Pengsheng , Marino Molly , Dore Emily , Ryan Colleen M , Schneider Jeffrey C , Kazis Lewis E
Published: May 2019

Introduction

Work integration and retention after burn injury is a key outcome. Little is known about how burn survivors reintegrate into the workplace. This article compares scores on the Life Impact Burn Recovery Evaluation (LIBRE) Profile, a burn-specific measure of social participation, between burn survivors and general population samples, focusing on the Work and Employment domain.

Methods

Convenience samples of burn survivors and the U.S. population were obtained. Differences in demographic and clinical characteristics and LIBRE Profile scores were assessed. To examine work and employment, we compared family and friends, social activities, and social interactions scores among working vs nonworking burn survivors.

Results

Six hundred and one burn survivors (320 employed) and 2000 U.S. residents (1101 employed) were surveyed. The mean age (P = .06), distributions of sex (P = .35), and Hispanic ethnicity (P = .07) did not differ significantly. Distributions of race (P < .01) and education (P = .01) differed significantly. The burn survivor sample had higher scores, demonstrating higher participation, for work and employment (mean = 49.5, SD = 9.42) than the general sample (mean = 46.94, SD = 8.94; P < .0001), which persisted after adjusting for demographic characteristics. Scores on the three domains administered to all respondents were higher (P < .001) for working than nonworking burn survivors.

Conclusion

Distributions indicated higher social participation in the burn survivor sample than the general sample. Possible explanations include sample bias; resilience, posttraumatic growth, or response-shift of survivors; and limitations of using items in the general sample. Working burn survivors scored higher than those not working. Future work can explore factors that mediate higher scores and develop interventions.
EAEPC v. Commission: Final Curtain for the GSK Spain Saga on so-called ‘dual-pricing’ for medicines
Authors: Komninos Assimakis
Published: May 2019

Following the CoJ’s 2009 judgment in the so-called GSK ‘dual-pricing’ case, the umbrella association of parallel traders complained to the Commission and requested a re-opening of the case. The Commission rejected the complaint and the General Court has now upheld that decision.
Joseph Eckhel (1737–1798) and the coin collection of Queen Christina of Sweden in Rome
Authors: Williams Daniela
Published: May 2019

On the basis of published and unpublished sources, this paper discusses the influence that the visit made by the Austrian numismatist Joseph Eckhel (1737–1798) to Rome in 1772–3 had on the late eighteenth-century arrangement of the coin collection assembled by Queen Christina of Sweden (1626–1689), then in possession of the Odescalchi family. Furthermore, the author tries to assess the impact of this collection on the work of Eckhel, a key figure in numismatic scholarship.
Predictive ability of prognostic nutritional index in surgically resected gastrointestinal stromal tumors: a propensity score matching analysis
Authors: Shi Wei-Kun , Zhang Xin-Hua , Zhang Jian , Yu Miao , Yuan Yu-Jie , Xiong Wei , Zhang Chang-Hua , He Yu-Long , Wei Zhe-Wei
Published: May 2019

Prognostic nutritional index was found to be correlated with prognosis in GISTs before and after propensity score matching and its incorporation improved the prognostic stratification of NIH risk criteria.
Partnership as Experimentation
Authors: Artunç Cihan , Guinnane Timothy W
Published: May 2019

Recent research disputes the view that the joint-stock corporation played a crucial role in historical economic development, but retains the idea that the costless firm dissolution implicit in non-corporate forms deterred investment. A multi-armed bandit model demonstrates the benefits of costless dissolution in an environment where potential business partners are not fully informed. Experimentation creates a spike in dissolution rates early in firms’ lives, as less productive matches break down and agents look for better matches. Many of the better matches adopt the corporate form, whose higher dissolution cost functions as a commitment device. We test the model’s predictions using firm-level data on 12,000 enterprises established in Egypt between 1910 and 1949. The partnership reflected a trade-off between committing to a partner and sorting into potentially better matches, fostering the formation of more productive enterprises (JEL D21, D22, L26, N15, O16).
Supergiant Fast X-ray Transients uncovered by the EXTraS project: flares reveal the development of magnetospheric instability in accreting neutron stars
Authors: Sidoli Lara , Postnov Konstantin A , Belfiore Andrea , Marelli Martino , Salvetti David , Salvaterra Ruben , De Luca Andrea , Esposito Paolo
Published: May 2019

The low luminosity, X-ray flaring activity, of the sub-class of high-mass X-ray binaries called Supergiant Fast X-ray Transients, has been investigated using XMM–Newton public observations, taking advantage of the products made publicly available by the EXTraS project. One of the goals of EXTraS was to extract from the XMM–Newton public archive information on the aperiodic variability of all sources observed in the soft X-ray range with EPIC (0.2–12 keV). Adopting a Bayesian block decomposition of the X-ray light curves of a sample of SFXTs, we picked out 144 X-ray flares, covering a large range of soft X-ray luminosities (1032–1036 erg s−1). We measured temporal quantities, like the rise time to and the decay time from the peak of the flares, their duration and the time interval between adjacent flares. We also estimated the peak luminosity, average accretion rate, and energy release in the flares. The observed soft X-ray properties of low-luminosity flaring activity from SFXTs is in qualitative agreement with what is expected by the application of the Rayleigh–Taylor instability model in accreting plasma near the neutron star magnetosphere. In the case of rapidly rotating neutron stars, sporadic accretion from temporary discs cannot be excluded.
On the detectability of transiting planets orbiting white dwarfs using LSST
Authors: Cortés Jorge , Kipping David
Published: May 2019

White dwarfs are one of the few types of stellar object for which we have yet to confirm the existence of companion planets. Recent evidence for metal contaminated atmospheres, circumstellar debris discs, and transiting planetary debris all indicates that planets may be likely. However, white dwarf transit surveys are challenging due to the intrinsic faintness of such objects, the short time-scale of the transits, and the low transit probabilities due to their compact radii. The Large Synoptic Survey Telescope (LSST) offers a remedy to these problems as a deep, half-sky survey with fast exposures encompassing approximately 10 million white dwarfs with r < 24.5 apparent magnitude (mr). We simulate LSST photometric observations of 3.5 million white dwarfs over a 10 yr period and calculate the detectability of companion planets with P < 10 d via transits. We find typical detection rates in the range of 5 × 10−6 to 4 × 10−4 for Ceres-sized bodies to Earth-sized worlds, yielding ∼50–$4000$ detections for a 100 per cent occurrence rate of each. For terrestrial planets in the continuously habitable zone, we find detection rates of ∼10−3 indicating that LSST would reveal hundreds of such worlds for occurrence rates in the range of 1–10 per cent.
RegulationSpotter: annotation and interpretation of extratranscriptic DNA variants
Authors: Schwarz Jana Marie , Hombach Daniela , Köhler Sebastian , Cooper David N , Schuelke Markus , Seelow Dominik
Published: May 2019

RegulationSpotter is a web-based tool for the user-friendly annotation and interpretation of DNA variants located outside of protein-coding transcripts (extratranscriptic variants). It is designed for clinicians and researchers who wish to assess the potential impact of the considerable number of non-coding variants found in Whole Genome Sequencing runs. It annotates individual variants with underlying regulatory features in an intuitive way by assessing over 100 genome-wide annotations. Additionally, it calculates a score, which reflects the regulatory potential of the variant region. Its dichotomous classifications, ‘functional’ or ‘non-functional’, and a human-readable presentation of the underlying evidence allow a biologically meaningful interpretation of the score. The output shows key aspects of every variant and allows rapid access to more detailed information about its possible role in gene regulation. RegulationSpotter can either analyse single variants or complete VCF files. Variants located within protein-coding transcripts are automatically assessed by MutationTaster as well as by RegulationSpotter to account for possible intragenic regulatory effects. RegulationSpotter offers the possibility of using phenotypic data to focus on known disease genes or genomic elements interacting with them. RegulationSpotter is freely available at https://www.regulationspotter.org.
Rouse model with transient intramolecular contacts on a timescale of seconds recapitulates folding and fluctuation of yeast chromosomes
Authors: Socol Marius , Wang Renjie , Jost Daniel , Carrivain Pascal , Vaillant Cédric , Le Cam Eric , Dahirel Vincent , Normand Christophe , Bystricky Kerstin , Victor Jean-Marc , Gadal Olivier , Bancaud Aurélien
Published: May 2019

DNA folding and dynamics along with major nuclear functions are determined by chromosome structural properties, which remain, thus far, elusive in vivo. Here, we combine polymer modeling and single particle tracking experiments to determine the physico-chemical parameters of chromatin in vitro and in living yeast. We find that the motion of reconstituted chromatin fibers can be recapitulated by the Rouse model using mechanical parameters of nucleosome arrays deduced from structural simulations. Conversely, we report that the Rouse model shows some inconsistencies to analyze the motion and structural properties inferred from yeast chromosomes determined with chromosome conformation capture techniques (specifically, Hi-C). We hence introduce the Rouse model with Transient Internal Contacts (RouseTIC), in which random association and dissociation occurs along the chromosome contour. The parametrization of this model by fitting motion and Hi-C data allows us to measure the kinetic parameters of the contact formation reaction. Chromosome contacts appear to be transient; associated to a lifetime of seconds and characterized by an attractive energy of –0.3 to –0.5 kBT. We suggest attributing this energy to the occurrence of histone tail-DNA contacts and notice that its amplitude sets chromosomes in ‘theta’ conditions, in which they are poised for compartmentalization and phase separation.
ProSNEx: a web-based application for exploration and analysis of protein structures using network formalism
Authors: Aydınkal Rasim Murat , Serçinoğlu Onur , Ozbek Pemra
Published: May 2019

ProSNEx (Protein Structure Network Explorer) is a web service for construction and analysis of Protein Structure Networks (PSNs) alongside amino acid flexibility, sequence conservation and annotation features. ProSNEx constructs a PSN by adding nodes to represent residues and edges between these nodes using user-specified interaction distance cutoffs for either carbon-alpha, carbon-beta or atom-pair contact networks. Different types of weighted networks can also be constructed by using either (i) the residue-residue interaction energies in the format returned by gRINN, resulting in a Protein Energy Network (PEN); (ii) the dynamical cross correlations from a coarse-grained Normal Mode Analysis (NMA) of the protein structure; (iii) interaction strength. Upon construction of the network, common network metrics (such as node centralities) as well as shortest paths between nodes and k-cliques are calculated. Moreover, additional features of each residue in the form of conservation scores and mutation/natural variant information are included in the analysis. By this way, tool offers an enhanced and direct comparison of network-based residue metrics with other types of biological information. ProSNEx is free and open to all users without login requirement at http://prosnex-tool.com.
web-rMKL: a web server for dimensionality reduction and sample clustering of multi-view data based on unsupervised multiple kernel learning
Authors: Röder Benedict , Kersten Nicolas , Herr Marius , Speicher Nora K , Pfeifer Nico
Published: May 2019

More and more affordable high-throughput techniques for measuring molecular features of biomedical samples have led to a huge increase in availability and size of different types of multi-omic datasets, containing, for example, genetic or histone modification data. Due to the multi-view characteristic of the data, established approaches for exploratory analysis are not directly applicable. Here we present web-rMKL, a web server that provides an integrative dimensionality reduction with subsequent clustering of samples based on data from multiple inputs. The underlying machine learning method rMKL-LPP performed best for clinical enrichment in a recent benchmark of state-of-the-art multi-view clustering algorithms. The method was introduced for a multi-omic cancer subtype discovery setting, however, it is not limited to this application scenario as exemplified by a presented use case for stem cell differentiation. web-rMKL offers an intuitive interface for uploading data and setting the parameters. rMKL-LPP runs on the back end and the user may receive notifications once the results are available. We also introduce a preprocessing tool for generating kernel matrices from tables containing numerical feature values. This program can be used to generate admissible input if no precomputed kernel matrices are available. The web server is freely available at web-rMKL.org.
PrankWeb: a web server for ligand binding site prediction and visualization
Authors: Jendele Lukas , Krivak Radoslav , Skoda Petr , Novotny Marian , Hoksza David
Published: May 2019

PrankWeb is an online resource providing an interface to P2Rank, a state-of-the-art method for ligand binding site prediction. P2Rank is a template-free machine learning method based on the prediction of local chemical neighborhood ligandability centered on points placed on a solvent-accessible protein surface. Points with a high ligandability score are then clustered to form the resulting ligand binding sites. In addition, PrankWeb provides a web interface enabling users to easily carry out the prediction and visually inspect the predicted binding sites via an integrated sequence-structure view. Moreover, PrankWeb can determine sequence conservation for the input molecule and use this in both the prediction and result visualization steps. Alongside its online visualization options, PrankWeb also offers the possibility of exporting the results as a PyMOL script for offline visualization. The web frontend communicates with the server side via a REST API. In high-throughput scenarios, therefore, users can utilize the server API directly, bypassing the need for a web-based frontend or installation of the P2Rank application. PrankWeb is available at http://prankweb.cz/, while the web application source code and the P2Rank method can be accessed at https://github.com/jendelel/PrankWebApp and https://github.com/rdk/p2rank, respectively.
ChEA3: transcription factor enrichment analysis by orthogonal omics integration
Authors: Keenan Alexandra B , Torre Denis , Lachmann Alexander , Leong Ariel K , Wojciechowicz Megan L , Utti Vivian , Jagodnik Kathleen M , Kropiwnicki Eryk , Wang Zichen , Ma’ayan Avi
Published: May 2019

Identifying the transcription factors (TFs) responsible for observed changes in gene expression is an important step in understanding gene regulatory networks. ChIP-X Enrichment Analysis 3 (ChEA3) is a transcription factor enrichment analysis tool that ranks TFs associated with user-submitted gene sets. The ChEA3 background database contains a collection of gene set libraries generated from multiple sources including TF–gene co-expression from RNA-seq studies, TF–target associations from ChIP-seq experiments, and TF–gene co-occurrence computed from crowd-submitted gene lists. Enrichment results from these distinct sources are integrated to generate a composite rank that improves the prediction of the correct upstream TF compared to ranks produced by individual libraries. We compare ChEA3 with existing TF prediction tools and show that ChEA3 performs better. By integrating the ChEA3 libraries, we illuminate general transcription factor properties such as whether the TF behaves as an activator or a repressor. The ChEA3 web-server is available from https://amp.pharm.mssm.edu/ChEA3.
CarD and RbpA modify the kinetics of initial transcription and slow promoter escape of the Mycobacterium tuberculosis RNA polymerase
Authors: Jensen Drake , Manzano Ana Ruiz , Rammohan Jayan , Stallings Christina L , Galburt Eric A
Published: May 2019

The pathogen Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, enacts unique transcriptional regulatory mechanisms when subjected to host-derived stresses. Initiation of transcription by the Mycobacterial RNA polymerase (RNAP) has previously been shown to exhibit different open complex kinetics and stabilities relative to Escherichia coli (Eco) RNAP. However, transcription initiation rates also depend on the kinetics following open complex formation such as initial nucleotide incorporation and subsequent promoter escape. Here, using a real-time fluorescence assay, we present the first in-depth kinetic analysis of initial transcription and promoter escape for the Mtb RNAP. We show that in relation to Eco RNAP, Mtb displays slower initial nucleotide incorporation but faster overall promoter escape kinetics on the Mtb rrnAP3 promoter. Furthermore, in the context of the essential transcription factors CarD and RbpA, Mtb promoter escape is slowed via differential effects on initially transcribing complexes. Finally, based on their ability to increase the rate of open complex formation and decrease the rate of promoter escape, we suggest that CarD and RbpA are capable of activation or repression depending on the rate-limiting step of a given promoter's basal initiation kinetics.
Who Speaks for Porn?
Authors: Padgett Esra
Published: May 2019

This chapter opens with the question “Who speaks for porn?” as a way to interrogate historical discourses on pornography and to reposition academic approaches to the subject. Taking a linguistic anthropological lens to academic work on pornography, the chapter provides a close examination of the ways in which ideologies about porn are constructed, focusing in particular on the discursive circulation of the social figures central to pornography: performers, producers, and consumers. The concept of porn literacy is introduced to stress the importance of developing informed reading practices in future academic work on porn. To this end, a case study of a porn performer is offered to demonstrate how an ethnographically informed approach to semiotic processes of authentication, branding, and mediatization may lead to new understandings of the political economic structure of pornography and broaden our definitions of authenticity, desire, and subjectivity.
Mediatizing Sex
Authors: Thurlow Crispin
Published: May 2019

This chapter focuses on sex/uality in the context of so-called new media and, specifically, digital discourse: technologically mediated linguistic or communicative practices, and mediatized representations of these practices. To help think through the relationship among sex, discourse, and (new) media, the discussion focuses on sexting and two instances of sexting “scandals” in the news. Against this backdrop, the chapter sets out four persistent binaries that typically shape public and academic writing about sex/uality and especially digital sex/uality: new-old, mediation-mediatization, private/real-public/fake, and personal-political. These either-or approaches are problematic, because they no longer account for the practical realities and lived experiences of both sex and media. Scholars interested in digital sex/uality are advised to adopt a “both-and” approach in which media (i.e., digital technologies and The Media) both create pleasurable, potentially liberating opportunities to use our bodies (sexually or otherwise) and simultaneously thwart us, shame us, or shut us down. In this sense, there is nothing that is really “new” after all.
Fiduciary Principles in Investment Advice
Authors: Laby Arthur B.
Published: May 2019

This chapter examines the fiduciary principles governing investment advice. Fiduciary principles in investment advice are both straightforward and complex. They are straightforward because most investment advisers are considered fiduciaries and subject to strict fiduciary duties under federal and state law. Their complex nature arises from the fact that many individuals and firms provide investment advice but are not deemed investment advisers and, therefore, are not subject to a fiduciary obligation. This chapter first explains whether and when an advisory relationship gives rise to fiduciary duties by focusing on both federal and state law, as well as the individuals and firms that typically provide investment advice. In particular, it looks at certain persons and entities excluded from the definition of investment adviser and thus not subject to the Investment Advisers Act of 1940, namely broker-dealers, banks, and family offices as well as accountants, lawyers, teachers, and engineers. The chapter also considers fiduciaries under ERISA, the Investment Company Act, and the Commodity Exchange Act before discussing the fiduciary duty of loyalty and how it is expressed and applied in investment advisory relationships; the fiduciary duty of care and how it differs from other standards of conduct, such as a duty of suitability; and other legal obligations imposed on investment advisers and how those obligations relate to an adviser’s fiduciary duty. Finally, the mandatory or default terms with regard to an investment adviser’s fiduciary duties are explored, along with remedies available for breach of fiduciary duty.
Fiduciary Principles in Surrogate Decision-Making
Authors: Kohn Nina A.
Published: May 2019

This chapter examines the fiduciary principles governing surrogate decision-making. Surrogate decision-making relationships arise when one person is appointed to make decisions for another, and are often used to make decisions for individuals with acute medical conditions or cognitive disabilities that make it difficult or impossible for the individuals to make decisions for themselves. A surrogate decision maker may be authorized by the individual for whom decisions are to be made or by a third party, including a court or a federal agency providing benefits to the individual. This chapter first considers how fiduciary duties are triggered in surrogate decision-making relationships and describes the requirements for appointment and acceptance by type of surrogate: guardians and conservators, agents acting under a power of attorney for finances or health care, and representative payees and other government fiduciaries. The discussion then turns to the surrogate decision maker’s duty of loyalty and duty of care, along with other fiduciary obligations. The chapter concludes with an overview of remedies available for a breach of fiduciary duty by a surrogate.
Fiduciary Principles in Employment Law
Authors: Bagchi Aditi
Published: May 2019

Employees are agents of their employers, and in some cases, are in a position to undermine the interests of their employers in ways that the employers cannot fully anticipate or contractually protect themselves against. While most jurisdictions historically treated all employees as fiduciaries of their employers, by now only a minority of jurisdictions regards all employees as fiduciaries. Most states treat only high-level employees of “trust and confidence” as fiduciaries, while other employees owe a lesser duty of loyalty. Some scholars have made arguments in support of recognizing employers as fiduciaries to employees, but as yet, employers owe neither fiduciary duties nor any lesser duty of loyalty to employees. Only employer-related entities such as pension funds and employee stock option programs owe fiduciary duties to employees under the Employee Retirement Income Security Act (ERISA). The doctrinal status and conceptual basis for the fiduciary duties of employees are discussed in Section I. Section II addresses fiduciary duties under ERISA. Section III touches on potential fiduciary duties of employers.
Fiduciary Principles in International Law
Authors: Criddle Evan J.
Published: May 2019

This chapter explores how fiduciary principles have shaped international law from colonial times to the present. Fiduciary principles are evident not only in the text of the League of Nations Covenant and the United Nations Charter, but also in various subfields of international law, including the law governing U.N. missions, military occupation, the legal status and duties of states, and the role and responsibilities of diplomatic officers. In each of these contexts, the international community has affirmed that certain offices and institutions attract fiduciary duties under international law. Nonetheless, the international community has struggled to develop credible mechanisms for enforcing these fiduciary duties.
Fiduciary Principles in Agency Law
Authors: DeMott Deborah A.
Published: May 2019

This chapter identifies the fiduciary principles that are integral to agency relationships as defined by the common law and explores their implications. In contrast to relationships in which a fact-specific assessment of a relationship and its circumstances trigger the application of fiduciary duties, agency relationships are categorically treated as fiduciary. When a relationship of common-law agency links two persons, one person’s actions can directly carry legal significance for the other. Agency doctrine defines and imposes formal structure on consensual relationships in which one actor has legally consequential power to represent the other, encompassing externally oriented consequences for the principal, the agent, and third parties, as well as internally oriented rights and duties between agent and principal. An agent functions not as a substitute for the principal but as an extension of the principal’s legal personality in dealings with third parties and other externally oriented conduct within the scope of the agency relationship, including knowledge of facts acquired by the agent when material to the agent’s duties. The potentially grave impact for the principal, plus the implications for personal autonomy when one person represents another, underlie the requisites that define an agency relationship, including its fiduciary character.
The Fiduciary Duty of Care
Authors: Goldberg John C. P.
Published: May 2019

Fiduciary duties of care are at once familiar and strange. They partake of many of the characteristics of duties of care in other domains of private law, particularly tort law. But they also bear the distinctive marks of the fiduciary context. This chapter identifies two ways in which fiduciary duties of care tend to be distinct from tort duties of care. First, with some important exceptions, they are less demanding and less vigorously enforced. Second, breaches of the fiduciary duty of care can give rise to liability even if no injury results to the beneficiary. These distinctive features, the chapter argues, reflect judicial efforts to harmonize the fiduciary’s duty of care with her duty of loyalty. As such, they are defensible, even if not in all respects justified.