bluuebunny/crossref_metadata_2025 huggingface dataset:
Comprehensive evaluation of transcriptome-based cell-type quantification methods for immuno-oncology
Authors: Sturm Gregor , Finotello Francesca , Petitprez Florent , Zhang Jitao David , Baumbach Jan , Fridman Wolf H , List Markus , Aneichyk Tatsiana
Published: May 2019

Motivation

The composition and density of immune cells in the tumor microenvironment (TME) profoundly influence tumor progression and success of anti-cancer therapies. Flow cytometry, immunohistochemistry staining or single-cell sequencing are often unavailable such that we rely on computational methods to estimate the immune-cell composition from bulk RNA-sequencing (RNA-seq) data. Various methods have been proposed recently, yet their capabilities and limitations have not been evaluated systematically. A general guideline leading the research community through cell type deconvolution is missing.

Results

We developed a systematic approach for benchmarking such computational methods and assessed the accuracy of tools at estimating nine different immune- and stromal cells from bulk RNA-seq samples. We used a single-cell RNA-seq dataset of ∼11 000 cells from the TME to simulate bulk samples of known cell type proportions, and validated the results using independent, publicly available gold-standard estimates. This allowed us to analyze and condense the results of more than a hundred thousand predictions to provide an exhaustive evaluation across seven computational methods over nine cell types and ∼1800 samples from five simulated and real-world datasets. We demonstrate that computational deconvolution performs at high accuracy for well-defined cell-type signatures and propose how fuzzy cell-type signatures can be improved. We suggest that future efforts should be dedicated to refining cell population definitions and finding reliable signatures.

Availability and implementation

A snakemake pipeline to reproduce the benchmark is available at https://github.com/grst/immune_deconvolution_benchmark. An R package allows the community to perform integrated deconvolution using different methods (https://grst.github.io/immunedeconv).

Supplementary information

Supplementary data are available at Bioinformatics online.
Persistent neuropathological effects 14 years following amyloid-β immunization in Alzheimer’s disease
Authors: Nicoll James A R , Buckland George R , Harrison Charlotte H , Page Anton , Harris Scott , Love Seth , Neal James W , Holmes Clive , Boche Delphine
Published: May 2019

We performed a 15-year post-mortem neuropathological follow-up of patients in the first trial of amyloid-β immunotherapy for Alzheimer’s disease. Twenty-two participants of a clinical trial of active amyloid-β42 immunization (AN1792, Elan Pharmaceuticals) or placebo were studied. Comprehensive post-mortem neuropathological assessments were performed from 4 months to 15 years after the trial. We analysed the relationships between the topographical distribution of amyloid-β removal from the cerebral cortex and tau pathology, cerebrovascular territories, plasma anti-AN1792 antibody titres and late cognitive status. Seventeen of 22 (77%) participants had Alzheimer’s neuropathological change, whereas 5 of 22 (23%) had alternative causes for dementia (progressive supranuclear palsy = 1, Lewy body disease = 1, vascular brain injury = 1, and frontotemporal lobar degeneration = 2). Nineteen of the 22 participants had received the active agent, three the placebo. Fourteen of 16 (88%) patients with Alzheimer’s disease receiving the active agent had evidence of plaque removal (very extensive removal = 5, intermediate = 4, very limited = 5, no removal = 2). Of particular note, two Alzheimer’s patients who died 14 years after immunization had only very sparse or no detectable plaques in all regions examined. There was a significant inverse correlation between post-vaccination peripheral blood anti-AN1792 antibody titres and post-mortem plaque scores (ρ = − 0.664, P = 0.005). Cortical foci cleared of plaques contained less tau than did cortex with remaining plaques, but the overall distribution of tangles was extensive (Braak V/VI). In conclusion, patients with Alzheimer’s disease actively immunized against amyloid-β can remain virtually plaque-free for 14 years. The extent of plaque removal is related to the immune response. This long duration of efficacy is important in support of active immunization protocols as therapy for, or potentially prevention of, neurodegeneration-associated protein accumulations. Inclusion of patients without Alzheimer’s disease in Alzheimer’s therapy trials is a problem for assessing the efficacy of treatment. Despite modification of Alzheimer’s pathology, most patients had progressed to severe dementia, notably including the five with very extensive plaque removal, possibly due to continued tau propagation. Neuropathology follow-up of patients in therapeutic trials provides valuable information on the causes of dementia and effects of treatment.
Protective effects of Alda-1, an ALDH2 activator, on alcohol-derived DNA damage in the esophagus of human ALDH2*2 (Glu504Lys) knock-in mice
Authors: Hirohashi Kenshiro , Ohashi Shinya , Amanuma Yusuke , Nakai Yukie , Ida Tomomi , Baba Kiichiro , Mitani Yosuke , Mizumoto Ayaka , Yamamoto Yoshihiro , Kikuchi Osamu , Matsubara Junichi , Yamada Atsushi , Miyamoto Shin’ichi , Seno Hiroshi , Matsuda Tomonari , Muto Manabu
Published: May 2019

Alcohol consumption is the key risk factor for the development of esophageal squamous cell carcinoma (ESCC), and acetaldehyde, a metabolite of alcohol, is an alcohol-derived major carcinogen that causes DNA damage. Aldehyde dehydrogenase2 (ALDH2) is an enzyme that detoxifies acetaldehyde, and its activity is reduced by ALDH2 gene polymorphism. Reduction in ALDH2 activity increases blood, salivary and breath acetaldehyde levels after alcohol intake, and it is deeply associated with the development of ESCC. Heavy alcohol consumption in individuals with ALDH2 gene polymorphism significantly elevates the risk of ESCC; however, effective prevention has not been established yet. In this study, we investigated the protective effects of Alda-1, a small molecule ALDH2 activator, on alcohol-mediated esophageal DNA damage. Here, we generated novel genetically engineered knock-in mice that express the human ALDH2*1 (wild-type allele) or ALDH2*2 gene (mutant allele). Those mice were crossed, and human ALDH2*1/*1, ALDH2*1/*2 and ALDH2*2/*2 knock-in mice were established. They were given 10% ethanol for 7 days in the presence or absence of Alda-1, and we measured the levels of esophageal DNA damage, represented by DNA adduct (N2-ethylidene-2′-deoxyguanosine). Alda-1 significantly increased hepatic ALDH2 activity both in human ALDH2*1/*2 and/or ALDH2*2/*2 knock-in mice and reduced esophageal DNA damage levels after alcohol drinking. Conversely, cyanamide, an ALDH2-inhibitor, significantly exacerbated esophageal DNA adduct level in C57BL/6N mice induced by alcohol drinking. These results indicate the protective effects of ALDH2 activation by Alda-1 on esophageal DNA damage levels in individuals with ALDH2 gene polymorphism, providing a new insight into acetaldehyde-mediated esophageal carcinogenesis and prevention.
HyDeploy: The UK’s First Hydrogen Blending Deployment Project
Authors: Isaac Tommy
Published: May 2019

The HyDeploy project is the UK’s first practical project to demonstrate that hydrogen can be safely blended into the natural-gas distribution system without requiring changes to appliances and the associated disruption. The project is funded under Ofgem’s Network Innovation Competition and is a collaboration between Cadent Gas, Northern Gas Networks, Progressive Energy Ltd, Keele University (Keele), Health & Safety Laboratory and ITM Power. Cadent and Northern Gas Networks are the Gas Distribution Network sponsors of the project. Keele University is the host site, providing the gas-distribution network, which will receive the hydrogen blend. Keele University is the largest campus university in the UK. Health & Safety Laboratory provides the scientific laboratories and experimental expertise. ITM Power provides the electrolyser that produces the hydrogen. Progressive Energy Ltd is the project developer and project manager. HyDeploy is structured into three distinct phases. The first is an extensive technical programme to establish the necessary detailed evidence base in support of an application to the Health & Safety Executive for Exemption to Schedule 3 of the Gas Safety (Management) Regulations (GS(M)R) to permit the injection of hydrogen at 20 mol%. This is required to allow hydrogen to be blended into a natural-gas supply above the current British limit of 0.1 mol%. The second phase comprises the construction of the electrolyser and grid entry unit, along with the necessary piping and valves, to allow hydrogen to be mixed and injected into the Keele University gas-distribution network and to ensure all necessary training of operatives is conducted before injection. The third phase is the trial itself, which is due to start in the summer of 2019 and last around 10 months. The trial phase also provides an opportunity to undertake further experimental activities related to the operational network to support the pathway to full deployment of blended gas. The outcome of HyDeploy is principally developing the initial evidence base that hydrogen can be blended into a UK operational natural-gas network without disruption to customers and without prejudicing the safety of end users. If deployed at scale, hydrogen blending at 20 mol% would unlock 29 TWh pa of decarbonized heat and provide a route map for deeper savings. The equivalent carbon savings of a national roll-out of a 20-mol% hydrogen blend would be to remove 2.5 million cars from the road. HyDeploy is a seminal UK project for the decarbonization of the gas grid via hydrogen deployment and will provide the first stepping stone for setting technical, operational and regulatory precedents of the hydrogen vector.
Effect of Cannabis Use on Human Immunodeficiency Virus DNA During Suppressive Antiretroviral Therapy
Authors: Chaillon Antoine , Nakazawa Masato , Anderson Christy , Christensen-Quick Aaron , Ellis Ronald J , Franklin Donald , Morris Sheldon R , Gianella Sara
Published: May 2019

Cannabis use is frequent among people living with human immunodeficiency virus (HIV) and is associated with reduced systemic inflammation. We observed a faster HIV DNA decay during antiretroviral therapy among cannabis users, compared to those with no drug use. No cannabis effect was observed on cellular HIV RNA transcription.
Interpretation of volumetric laser endomicroscopy in Barrett's esophagus using image enhancement software
Authors: Kamboj A K , Hoversten P , Kahn A K , Trindade A J , Iyer P G , Wang K K , Leggett C L
Published: May 2019

Image interpretation of Barrett's esophagus (BE) with volumetric laser endomicroscopy (VLE) can be enhanced by image processing software that highlights established features using a color-graded scale (intelligent real-time image segmentation, IRIS). This study aims to provide a description of IRIS features of various gastroesophageal tissue types using histologic correlation. A database of 80 VLE laser-marked targets with histologic correlation was reviewed for various tissue types. IRIS was applied off-line to the VLE scans, laser-marked targets were identified, and feature review was performed. Squamous epithelium targets (N = 7) showed IRIS layered architecture with lack of surface hyper-reflectivity and epithelial glands. Gastric cardia targets (N = 10) showed absent layering (100%) and surface hyper-reflectivity with epithelial glands (40%). Nondysplastic BE targets (N = 39) showed surface hyper-reflectivity (64%), epithelial glands (51%), and lack of layering (74%). Targets of BE with early neoplasia (N = 24), showed surface hyper-reflectivity (96%), epithelial glands (67%), and lack of layering (96%). IRIS features that characterize each tissue type appear to mirror the nonenhanced VLE counterparts that define them.
Impact of new pacemaker implantation following surgical and transcatheter aortic valve replacement on 1-year outcome
Authors: Fujita Buntaro , Schmidt Tobias , Bleiziffer Sabine , Bauer Timm , Beckmann Andreas , Bekeredjian Raffi , Möllmann Helge , Walther Thomas , Landwehr Sandra , Hamm Christian , Beyersdorf Friedhelm , Katus Hugo A , Harringer Wolfgang , Ensminger Stephan , Frerker Christian ,   GARY Executive Board
Published: May 2019

OBJECTIVES

The purpose of this study was to evaluate the incidence of new pacemaker implantation (NPMI) after surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR), and investigate its influence on 1-year mortality.

METHODS

Patients who were enrolled in ‘The German Aortic Valve Registry’ undergoing isolated TAVR or SAVR between 2011 and 2015 were analysed. The rate of NPMI was analysed for both groups and multivariable Cox regression analysis was performed to investigate the possible independent association between NPMI and 1-year mortality.

RESULTS

Twenty thousand eight hundred and seventy-two patients who underwent TAVR and 17 750 patients who received SAVR were included in this study. The rate of NPMI was 16.6% after TAVR and 3.6% after SAVR. In the TAVR group, NPMI was associated with significantly increased 1-year mortality in univariable Cox regression analysis [hazard ratio (HR) 1.29, confidence interval (CI) 1.18–1.41; P < 0.001]. This association persisted after adjustment for confounding factors (HR 1.29, CI 1.16–1.43; P < 0.001). In the SAVR group, NPMI significantly increased 1-year mortality in univariable analysis as well (HR 1.55, CI 1.08–2.22; P = 0.02), whereas after multivariable adjustment, NPMI did not emerge as an independent risk factor (HR 1.29, 0.88–1.89; P = 0.19). NPMI was not associated with 30-day mortality in both procedure groups.

CONCLUSIONS

The rate of NPMI was markedly higher after TAVR compared with SAVR and was independently associated with 1-year mortality after TAVR, whereas this was not significant after SAVR. As 30-day mortality was not different for TAVR and SAVR, the subsequent procedure of an NPMI itself seems not to increase the risk of mortality.
Learning EAP at university: perceptions of high-achieving first-year ESL undergraduates
Authors: Yung Kevin Wai-Ho , Fong Natalie
Published: May 2019

This study focuses on the perceptions of learning EAP of first-year undergraduates with high ESL proficiency admitted to an English-medium university in Hong Kong. Two in-depth individual interviews were conducted with nine participants and their written assignments were analysed. The data reveal several challenges facing the high achievers in learning EAP. One evident aspect is how to properly cite academic sources. The participants struggled with selecting suitable texts from sources, paraphrasing them, and using them to support their arguments. They also perceived a need to abandon the recited formulaic expressions which may have helped them score highly in the secondary school examination. This study reveals gaps between the English learnt in secondary school and EAP and offers insight into what first-year students need when they transition from secondary school to university studies. It argues that EAP should be made an essential component of first-year undergraduate programmes.
Augmented reality
Authors: Hockly Nicky
Published: May 2019

In this series, we explore technology-related themes and topics. The series aims to discuss and demystify what may be new areas for some readers and to consider their relevance for English language teachers.
Forced diuresis with matched hydration during transcatheter aortic valve implantation for Reducing Acute Kidney Injury: a randomized, sham-controlled study (REDUCE-AKI)
Authors: Arbel Yaron , Ben-Assa Eyal , Puzhevsky Daniela , Litmanowicz Batia , Galli Naama , Chorin Ehud , Halkin Amir , Sadeh Ben , Konigstein Maayan , Bassat Orit Kliuk-Ben , Steinvil Arie , Bazan Samuel , Banai Shmuel , Finkelstein Ariel
Published: May 2019

Aims

Acute kidney injury (AKI) is a common complication following transcatheter aortic valve implantation (TAVI) and is associated with increased risk for short- and long-term mortality. In patients undergoing percutaneous coronary intervention (PCI), forced diuresis with matched hydration has been shown to reduce the incidence of AKI by ∼50%. The aim of the present study was to evaluate whether forced diuresis with matched intravenous hydration reduces AKI in patients undergoing TAVI.

Methods and results

Reducing Acute Kidney Injury (REDUCE-AKI) was a single-centre, prospective, randomized, double-blind sham-controlled clinical trial, designed to examine the effect of an automated matched saline infusion with urine output for the prevention of AKI in patients undergoing TAVI. A total of 136 TAVI patients were randomized, 68 in each group. Mean age was 83.9 ± 5 years and 41.2% were males. There were no differences in baseline characteristics between the two groups. The rate of AKI was not statistically different between the groups (25% in the active group vs. 19.1% in the sham group, P = 0.408). There was a significant increase in long-term mortality in the active group (27.9% vs. 13. 2% HR 3.744, 95% CI 1.51–9.28; P = 0.004). The study was terminated prematurely by the Data Safety Monitoring Board for futility and a possible signal of harm.

Conclusions

Unlike in PCI, forced diuresis with matched hydration does not prevent AKI in patients undergoing TAVI, and might be associated with increased long-term mortality. Future studies should focus on understanding the mechanisms behind these findings.

Clinicaltrials.gov registration

NCT01866800, 30 April 2013.
Omics-based comparative analysis of putative mobile genetic elements in Lactococcus lactis
Authors: Andersen Joakim Mark , Pedersen Christine Møller , Bang-Berthelsen Claus Heiner
Published: May 2019

Lactococcus lactis is globally used in food fermentation. Genomics is useful to investigate speciation and differential occurrence of (un)desired gene functions, often related to mobile DNA. This study investigates L. lactis for putative chromosomal mobile genetic elements through comparative genomics, and analyses how they contribute to chromosomal variation at strain level. Our work identified 95 loci that may range over 10% of the chromosome size when including prophages, and the loci display a marked differential occurrence in the analysed strains. Analysis of differential transcriptomics data revealed how mobile genetic elements may impact the host physiology in response to conditional changes. This insight in the genetic variation of mobile genetic elements in L. lactis holds potential to further identify important functions related to food and biotechnology applications within this important species.
Working with Older Adults Scale: Application of the Theory of Planned Behavior
Authors: Graham Kirsten L , Rosén Lee A
Published: May 2019

Background and Objectives

The expanding population of older adults in the United States, coupled with provider hesitance to work with this population, is expected to result in a large service gap, particularly in the health care field. Research on provider hesitancy has largely focused on the impact of attitudes toward older adults and professional competency, with some recent explorations of social influences. There is currently no comprehensive measure that includes all of these areas.

Research Design and Methods

The present study outlines the development of the Working with Older Adults Scale (WOAS), which is grounded in the theory of planned behavior as applied to working with older adults. The WOAS is composed of 20 items, rated on a 7-point Likert scale, that make up four subscales: (i) Attitude, (ii) Subjective Norm, (iii) Perceived Behavioral Control, and (iv) Intention.

Results

Results indicated that, for the young adult college student sample it was developed with, the measure has an excellent factor structure and good internal reliability and construct validity. Consistent with the theory of planned behavior model, intention to work with older adults was significantly predicted by attitudes, subjective norm, and perceived behavioral control. Subjective norm accounted for the greatest amount of variance. Further analyses revealed differential effects of age, gender, and experience on the WOAS subscales.

Discussion and Implications

The WOAS, and underlying theory, offers new insights and ideas for future exploration of the service gap between older adults’ needs and professional availability across health service fields.
Participatory Action Research With Older Adults: A Critical Interpretive Synthesis
Authors: Corrado Ann Marie , Benjamin-Thomas Tanya Elizabeth , McGrath Colleen , Hand Carri , Laliberte Rudman Debbie
Published: May 2019

Background and Objectives

Given population aging, the meaningful involvement of older adults in influencing policy and programs through participatory action research (PAR) is increasingly vital. PAR holds promise for equitable participation, co-learning, community mobilization, and personal and social transformation, however, little scholarly attention has been given to critically evaluating how PAR has been taken up with older adults. The objective of this review was to critically evaluate the use of PAR with older adults.

Research Design and Methods

A critical interpretive synthesis (CIS) of 40 PAR studies with older adults was conducted. Critical engagement with the articles identified dominant tendencies, limits of these tendencies, and proposed ways forward.

Results

Within the majority of articles reviewed, older adults were not prominent partners in PAR given their often limited involvement in designing the research questions, learning research skills and knowledge, and implementing findings for change. Furthermore, power differentials between researchers and older adults were evident, as older adults were often positioned as participants rather than partners. Finally, this article demonstrates various boundaries on the foci of studies related to inclusivity and sustainability.

Discussion and Implications

This study revealed that the promises PAR holds are often not fully realized in projects with older adults, given that they are rarely positioned as equitable partners, co-learners, or agents for change. The findings have the potential to stimulate further uptake of PAR research with an older adult population, highlighting areas for change in systems and research practices.
Thoracoscopy-assisted repair of comminuted sternal fracture with bioresorbable plates
Authors: Imanishi Naoko , Takeda Yusuke , Ichiki Yoshinobu , Tanaka Fumihiro
Published: May 2019

We present a case of comminuted sternal fracture with posterior displacement, which was successfully repaired by ‘sandwich’ fixation using 2 bioresorbable plates that were placed anterior to and posterior to the sternum. All procedures including retro-sternal dissection for placement of the posterior plate were performed using video-assisted thoracoscopic surgery. The minimally invasive thoracoscopic technique provided effective repair and rigid fixation with immediate relief from intractable chest pain that had persisted before surgery.
Inducing Super-Approximation
Authors: Salehi Golsefidy Alireza , Zhang Xin
Published: May 2019

Let $\Gamma _2\subseteq \Gamma _1$ be finitely generated subgroups of ${\operatorname{GL}}_{n_0}({\mathbb{Z}}[1/q_0])$ where $q_0$ is a positive integer. For $i=1$ or $2$, let ${\mathbb{G}}_i$ be the Zariski-closure of $\Gamma _i$ in $({\operatorname{GL}}_{n_0})_{{\mathbb{Q}}}$, ${\mathbb{G}}_i^{\circ }$ be the Zariski-connected component of ${\mathbb{G}}_i$, and let $G_i$ be the closure of $\Gamma _i$ in $\prod _{p\nmid q_0}{\operatorname{GL}}_{n_0}({\mathbb{Z}}_p)$. In this article we prove that if ${\mathbb{G}}_1^{\circ }$ is the smallest closed normal subgroup of ${\mathbb{G}}_1^{\circ }$ that contains ${\mathbb{G}}_2^{\circ }$ and $\Gamma _2\curvearrowright G_2$ has spectral gap, then $\Gamma _1\curvearrowright G_1$ has spectral gap.
Contribution of Functional Antimalarial Immunity to Measures of Parasite Clearance in Therapeutic Efficacy Studies of Artemisinin Derivatives
Authors: O’Flaherty Katherine , Ataíde Ricardo , Zaloumis Sophie G , Ashley Elizabeth A , Powell Rosanna , Feng Gaoqian , Reiling Linda , Dondorp Arjen M , Day Nicholas P , Dhorda Mehul , Fairhurst Rick M , Lim Pharath , Amaratunga Chanaki , Pukrittayakamee Sasithon , Hien Tran Tinh , Htut Ye , Mayxay Mayfong , Faiz M Abul , Beeson James G , Nosten Francois , Simpson Julie A , White Nicholas J , Fowkes Freya J I
Published: May 2019

Background

Antibodies to the blood stages of malaria parasites enhance parasite clearance and antimalarial efficacy. The antibody subclass and functions that contribute to parasite clearance during antimalarial treatment and their relationship to malaria transmission intensity have not been characterized.

Methods

Levels of immunoglobulin G (IgG) subclasses and C1q fixation in response to Plasmodium falciparum merozoite antigens (erythrocyte-binding antigen [EBA] 175RIII-V, merozoite surface protein 2 [MSP-2], and MSP-142) and opsonic phagocytosis of merozoites were measured in a multinational trial assessing the efficacy of artesunate therapy across 11 Southeast Asian sites. Regression analyses assessed the effects of antibody seropositivity on the parasite clearance half-life (PC½), having a PC½ of ≥5 hours, and having parasitemia 3 days after treatment.

Results

IgG3, followed by IgG1, was the predominant IgG subclass detected (seroprevalence range, 5%–35% for IgG1 and 27%–41% for IgG3), varied across study sites, and was lowest in study sites with the lowest transmission intensity and slowest mean PC½. IgG3, C1q fixation, and opsonic-phagocytosis seropositivity were associated with a faster PC½ (range of the mean reduction in PC½, 0.47–1.16 hours; P range, .001–.03) and a reduced odds of having a PC½ of ≥5 hours and having parasitemia 3 days after treatment.

Conclusions

The prevalence of IgG3, complement-fixing antibodies, and merozoite phagocytosis vary according to transmission intensity, are associated with faster parasite clearance, and may be sensitive surrogates of an augmented clearance capacity of infected erythrocytes. Determining the functional immune mechanisms associated with parasite clearance will improve characterization of artemisinin resistance.
CELL BIOLOGY SYMPOSIUM: METABOLIC RESPONSES TO STRESS: FROM ANIMAL TO CELL: Poor maternal nutrition during gestation: effects on offspring whole-body and tissue-specific metabolism in livestock species1,2
Authors: Govoni Kristen E , Reed Sarah A , Zinn Steven A
Published: May 2019

Poor maternal nutrition, both restricted-feeding and overfeeding, during gestation can negatively affect offspring growth, body composition, and metabolism. The effects are observed as early as the prenatal period and often persist through postnatal growth and adulthood. There is evidence of multigenerational effects demonstrating the long-term negative impacts on livestock production. We and others have demonstrated that poor maternal nutrition impairs muscle growth, increases adipose tissue, and negatively affects liver function. In addition to altered growth, changes in key metabolic factors, increased glucose concentrations, insulin insensitivity, and hyperleptinemia are observed during the postnatal period. Furthermore, there is recent evidence of altered metabolism in specific tissues (e.g., muscle, adipose, and liver) and stem cells. The systemic and local changes in metabolism demonstrate the importance of determining the mechanism(s) by which maternal diet programs offspring growth and metabolism in an effort to develop novel management practices to improve the efficiency of growth and health in these offspring.
Relative Prices and Sectoral Productivity
Authors: Duarte Margarida , Restuccia Diego
Published: May 2019

The relative price of services rises with development. A standard interpretation of this fact is that productivity differences across countries are larger in manufacturing than in services. The service sector comprises heterogeneous categories and we document that many disaggregated service categories feature a negative income elasticity of relative prices. We divide service industries into two broad categories based on the income gradient of its relative price: traditional services with positive income elasticities and nontraditional services with negative income elasticities of relative prices. Using an otherwise standard multisector development accounting framework extended to include an input–output structure, we find that the cross-country income elasticity of sectoral productivity is large in nontraditional services (1.15), smaller in manufacturing (1.05), and much smaller in traditional services (0.67). Eliminating cross-country productivity differences in nontraditional services reduces aggregate income disparity by 58%, a 7.9-fold reduction in aggregate productivity differences. Heterogeneity between traditional and nontraditional services also has a substantial impact on aggregate productivity.
Adaptive Alignment of Plasticity With Genetic Variation and Selection
Authors: Berdal Monica Anderson , Dochtermann Ned A
Published: May 2019

Theoretical research has outlined how selection may shape both genetic variation and the expression of phenotypic plasticity in multivariate trait space. Specifically, research regarding the evolution of patterns of additive genetic variances and covariances (summarized in matrix form as G) and complementary research into how selection may shape adaptive plasticity lead to the general prediction that G, plasticity, and selection surfaces are all expected to align with each other. However, less well discussed is how this prediction might be assessed and how the modeled theoretical processes are expected to manifest in actual populations. Here, we discuss the theoretical foundations of the overarching prediction of alignment, what alignment mathematically means, how researchers might test for alignment and important caveats to this testing. The most important caveat concerns the fact that, for plasticity, the prediction of alignment only applies to cases where plasticity is adaptive, whereas organisms express considerable plasticity that may be neutral or even maladaptive. We detail the ramifications of these alternative expressions of plasticity vis-à-vis predictions of alignment. Finally, we briefly highlight some important interpretations of deviations from the prediction of alignment and what alignment might mean for populations experiencing environmental and selective changes.
The Heritability of Behavior: A Meta-analysis
Authors: Dochtermann Ned A , Schwab Tori , Anderson Berdal Monica , Dalos Jeremy , Royauté Raphaël
Published: May 2019

The contribution of genetic variation to phenotypes is a central factor in whether and how populations respond to selection. The most common approach to estimating these influences is via the calculation of heritabilities, which summarize the contribution of genetic variation to phenotypic variation. Heritabilities also indicate the relative effect of genetic variation on phenotypes versus that of environmental sources of variation. For labile traits like behavioral responses, life history traits, and physiological responses, estimation of heritabilities is important as these traits are strongly influenced by the environment. Thus, knowing whether or not genetic variation is present within populations is necessary to understand whether or not these populations can evolve in response to selection. Here we report the results of a meta-analysis summarizing what we currently know about the heritability of behavior. Using phylogenetically controlled methods we assessed the average heritability of behavior (0.235)—which is similar to that reported in previous analyses of physiological and life history traits—and examined differences among taxa, behavioral classifications, and other biologically relevant factors. We found that there was considerable variation among behaviors as to how heritable they were, with migratory behaviors being the most heritable. Interestingly, we found no effect of phylogeny on estimates of heritability. These results suggest, first, that behavior may not be particularly unique in the degree to which it is influenced by factors other than genetics and, second, that those factors influencing whether a behavioral trait will have low or high heritability require further consideration.
Professional judgment and legitimacy work in an organizationally embedded profession
Authors: Suddaby Roy , Bévort Frans , Strandgaard Pedersen Jesper
Published: May 2019

Professions have been traditionally understood as an alternative way of organizing work that stands in opposition to the corporate or bureaucratic organizational form. Increasingly, however, corporations are seen to be the source of new forms of expert knowledge and occupational categories. Yet we have little understanding of how expert judgement forms and is legitimated inside a large organization. In this study, we examine the emergence of standards of professional judgement in a government organization. Using archival and interview data between 2000 and 2012 we examine how experts in the Danish Film Institute generated professional standards of decision making against the backdrop of intense bureaucratic control. Our analysis demonstrates that norms of professional judgement emerge in a process that is inextricably linked to the emergence of professional role identities. Our core theoretical contribution is the discovery that the legitimacy work of managerial professions operates in two spheres; by first grounding claims of professional legitimacy in broad societal norms, and second, by grounding claims of professional identity in localized but increasingly abstract expressions of professional expertise.
The response of human mesenchymal stem cells to internal exposure to tritium β-rays
Authors: Quan Yi , Lin Jinxian , Deng Bing
Published: May 2019

There is no doubt that estimating the exposure risk of external and internal low-dose radiation is an imperative issue in radiobiological study. Human mesenchymal stem cells (hMSCs) are multipotent and self-renewing, supporting the regeneration of damaged tissue, including tissue damaged by radiation. However, the responses of hMSCs to internal exposure to radionuclides are still insufficiently understood. In order to evaluate the adverse effects produced by internal exposure to tritiated water (HTO) at a low dose, hMSCs were exposed to 2 × 107 Bq/ml HTO, and the biological effects after the exposure were examined. Apoptosis and DNA double-strand breaks (DSBs) were assayed to analyze the cellular response to the damage induced by HTO. Slight enhancement of apoptosis was found after treatment, except at the dose of 9 mGy. The number of DSBs at 24 h post-irradiation showed that the DNA damage was able to be efficiently repaired by the hMSCs. Moreover, the increasing proportion of the cell population in S phase proved that the persistence of residual γH2AX foci at lower concentrations of HTO was attributable to the secondary production of DSBs in DNA replication. Our work adds to the available data, helping us understand the risk of stem cell transformation due to internal exposure and its correlation with low-dose radiation–induced carcinogenesis.
Sequential star formation in the filamentary structures of the Planck Galactic cold clump G181.84+0.31
Authors: Yuan Lixia , Zhu Ming , Liu Tie , Yuan Jinghua , Wu Yuefang , Kim Kee-Tae , Wang Ke , Zhou Chenlin , Tatematsu Ken’ichi , Kuno Nario
Published: May 2019

We present a multiwavelength study of the Planck Galactic cold clump G181.84+0.31, which is located at the northern end of the extended filamentary structure S242. We have extracted nine compact dense cores from the SCUBA-2 850-$\hbox{$\mu $m}$ map, and we have identified 18 young stellar objects (YSOs; four Class I and 14 Class II) based on their Spitzer, Wide-field Infrared Survey Explorer(WISE) and Two-Micron All-Sky Survey (2MASS) near- and mid-infrared colours. The dense cores and YSOs are mainly distributed along the filamentary structures of G181.84 and are well traced by HCO+(1–0) and N2H+(1–0) spectral-line emission. We find signatures of sequential star formation activities in G181.84: dense cores and YSOs located in the northern and southern substructures are younger than those in the central region. We also detect global velocity gradients of about 0.8 ± 0.05 and 1.0 ± 0.05 km s−1 pc−1 along the northern and southern substructures, respectively, and local velocity gradients of 1.2 ± 0.1 km s−1 pc−1 in the central substructure. These results might be due to the fact that the global collapse of the extended filamentary structure S242 is driven by an edge effect, for which the filament edges collapse first and then further trigger star formation activities inward. We identify three substructures in G181.84 and estimate their critical masses per unit length, which are ∼101 ± 15, 56 ± 8 and 28 ± 4 M⊙ pc−1, respectively. These values are all lower than the observed values (∼200 M⊙ pc−1), suggesting that these substructures are gravitationally unstable.
RETRACTED: A 5′ fragment of Xist can sequester RNA produced from adjacent genes on chromatin
Authors: Lee David M , Trotman Jackson B , Cherney Rachel E , Inoue Kaoru , Schertzer Megan D , Bischoff Steven R , Cowley Dale O , Calabrese J Mauro
Published: May 2019

Xist requires Repeat-A, a protein-binding module in its first two kilobases (2kb), to repress transcription. We report that when expressed as a standalone transcript in mouse embryonic stem cells (ESCs), the first 2kb of Xist (Xist-2kb) does not induce transcriptional silencing. Instead, Xist-2kb sequesters RNA produced from adjacent genes on chromatin. Sequestration does not spread beyond adjacent genes, requires the same sequence elements in Repeat-A that full-length Xist requires to repress transcription and can be induced by lncRNAs with similar sequence composition to Xist-2kb. We did not detect sequestration by full-length Xist, but we did detect it by mutant forms of Xist with attenuated transcriptional silencing capability. Xist-2kb associated with SPEN, a Repeat-A binding protein required for Xist-induced transcriptional silencing, but SPEN was not necessary for sequestration. Thus, when expressed in mouse ESCs, a 5′ fragment of Xist that contains Repeat-A sequesters RNA from adjacent genes on chromatin and associates with the silencing factor SPEN, but it does not induce transcriptional silencing. Instead, Xist-induced transcriptional silencing requires synergy between Repeat-A and additional sequence elements in Xist. We propose that sequestration is mechanistically related to the Repeat-A dependent stabilization and tethering of Xist near actively transcribed regions of chromatin.
Conformational communication mediates the reset step in t6A biosynthesis
Authors: Luthra Amit , Paranagama Naduni , Swinehart William , Bayooz Susan , Phan Phuc , Quach Vanessa , Schiffer Jamie M , Stec Boguslaw , Iwata-Reuyl Dirk , Swairjo Manal A
Published: May 2019

The universally conserved N6-threonylcarbamoyladenosine (t6A) modification of tRNA is essential for translational fidelity. In bacteria, t6A biosynthesis starts with the TsaC/TsaC2-catalyzed synthesis of the intermediate threonylcarbamoyl adenylate (TC–AMP), followed by transfer of the threonylcarbamoyl (TC) moiety to adenine-37 of tRNA by the TC-transfer complex comprised of TsaB, TsaD and TsaE subunits and possessing an ATPase activity required for multi-turnover of the t6A cycle. We report a 2.5-Å crystal structure of the T. maritima TC-transfer complex (TmTsaB2D2E2) bound to Mg2+-ATP in the ATPase site, and substrate analog carboxy-AMP in the TC-transfer site. Site directed mutagenesis results show that residues in the conserved Switch I and Switch II motifs of TsaE mediate the ATP hydrolysis-driven reactivation/reset step of the t6A cycle. Further, SAXS analysis of the TmTsaB2D2-tRNA complex in solution reveals bound tRNA lodged in the TsaE binding cavity, confirming our previous biochemical data. Based on the crystal structure and molecular docking of TC–AMP and adenine-37 in the TC-transfer site, we propose a model for the mechanism of TC transfer by this universal biosynthetic system.
Effective mismatch repair depends on timely control of PCNA retention on DNA by the Elg1 complex
Authors: Paul Solomon Devakumar Lovely Jael , Gaubitz Christl , Lundblad Victoria , Kelch Brian A , Kubota Takashi
Published: May 2019

Proliferating cell nuclear antigen (PCNA) is a sliding clamp that acts as a central co-ordinator for mismatch repair (MMR) as well as DNA replication. Loss of Elg1, the major subunit of the PCNA unloader complex, causes over-accumulation of PCNA on DNA and also increases mutation rate, but it has been unclear if the two effects are linked. Here we show that timely removal of PCNA from DNA by the Elg1 complex is important to prevent mutations. Although premature unloading of PCNA generally increases mutation rate, the mutator phenotype of elg1Δ is attenuated by PCNA mutants PCNA-R14E and PCNA-D150E that spontaneously fall off DNA. In contrast, the elg1Δ mutator phenotype is exacerbated by PCNA mutants that accumulate on DNA due to enhanced electrostatic PCNA–DNA interactions. Epistasis analysis suggests that PCNA over-accumulation on DNA interferes with both MMR and MMR-independent process(es). In elg1Δ, over-retained PCNA hyper-recruits the Msh2–Msh6 mismatch recognition complex through its PCNA-interacting peptide motif, causing accumulation of MMR intermediates. Our results suggest that PCNA retention controlled by the Elg1 complex is critical for efficient MMR: PCNA needs to be on DNA long enough to enable MMR, but if it is retained too long it interferes with downstream repair steps.
Effects of 5-hydroxytryptophan on distinct types of depression: a systematic review and meta-analysis
Authors: Javelle Florian , Lampit Amit , Bloch Wilhelm , Häussermann Peter , Johnson Sheri L , Zimmer Philipp
Published: May 2019

Context

Serotonergic dysfunction, including reduced central serotonin levels, is associated with different psychiatric syndromes, including depression. As a serotonin precursor, 5-hydroxytryptophan has long been used as a nonpharmacological treatment for depression.

Objective

A systematic review and meta-analysis was conducted to determine the antidepressant effects of 5-hydroxytryptophan in depressed patients.

Data sources

MEDLINE (via PubMed) and Google Scholar were searched from inception to May 2018.

Data extraction

Thirteen investigations were included in the systematic review (using PRISMA guidelines), and 7 in the full meta-analysis (pre-registered on PROSPERO: CRD42018104415).

Data analysis

Analyses revealed a depression remission rate of 0.65 (95% confidence interval [CI], 0.55–0.78; remission rate [k] = 13), and this was confirmed by the questionnaire results, which revealed a large Hedges’ g (1.11; 95%CI, 0.53–1.69). Methodological variability (in treatment duration, type of depression studied, experimental design, 5-hydroxytryptophan dosage) contributes to heterogeneity in the results (I2 = 76%, τ2 = 0.379). In addition, the OHAT (Office of Health Assessment and Translation risk of bias rating) tool suggested that, on the whole, current studies are relatively weak (few include placebo groups).

Conclusion

Further trials should overcome these limitations by using placebo-controlled studies that include patients with well-defined depression diagnoses, along with strong characterization of psychological and physiological patient characteristics.
Nut consumption and incidence of cardiovascular diseases and cardiovascular disease mortality: a meta-analysis of prospective cohort studies
Authors: Becerra-Tomás Nerea , Paz-Graniel Indira , W.C. Kendall Cyril , Kahleova Hana , Rahelić Dario , Sievenpiper John L , Salas-Salvadó Jordi
Published: May 2019

Context

Previous meta-analyses evaluating the association between nut consumption and the risk of cardiovascular disease (CVD) had substantial methodological limitations and lacked recently published large prospective studies; hence, making an updated meta-analysis highly desirable.

Objective

To update the clinical guidelines for nutrition therapy in relation to the European Association for the Study of Diabetes (EASD), a systematic review and meta-analysis of prospective studies was conducted using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to summarize the evidence of the association between total nuts, specific types of nuts, and the incidence of, and mortality from, CVD outcomes.

Data sources

Relevant articles were identified by searching the PubMed and Cochrane databases.

Data extraction

Two independent researchers screened the articles to identify those that met the inclusion criteria.

Data analysis

The inverse variance method with fixed-effect or random-effects models was used to pool data across studies (expressed as risk ratio [RR] and 95% confidence interval [CI]). Heterogeneity was tested and quantified using the Cochrane Q test and I2-statistic, respectively. The GRADE system was used to assess the quality of the evidence.

Results

Nineteen studies were included in the analyses. The results revealed an inverse association between total nut consumption (comparing highest vs lowest categories) and CVD incidence (RR, 0.85; 95%CI, 0.800.91; I2, 0%), CVD mortality (RR, 0.77; 95%CI, 0.72–0.82; I2, 3%), coronary heart disease (CHD) incidence (RR, 0.82; 95%CI, 0.69–0.96; I2, 74%), CHD mortality (RR, 0.76; 95%CI, 0.67–0.86; I2, 46%), stroke mortality (RR, 0.83; 95%CI, 0.75–0.93; I2, 0%), and atrial fibrillation (RR, 0.85; 95%CI, 0.73–0.99; I2, 0%). No association was observed with stroke incidence and heart failure. The certainty of the evidence ranged from moderate to very low.

Conclusions

This systematic review and meta-analysis revealed a beneficial role of nut consumption in reducing the incidence of, and mortality from, different CVD outcomes.
Mediated Discourse Analysis in Language and Sexuality Research
Authors: Jones Rodney H.
Published: May 2019

This chapter outlines some of the main theoretical principles and analytical procedures of mediated discourse analysis and illustrates how they can be applied to studies of language and sexuality. Where mediated discourse analysis differs from other approaches to language and sexuality is its focus on the concrete social actions that people take in their lives, like putting on a condom or sharing a dick pic. The approach asks how language and other cultural tools that people have available to them make these actions possible, and, how through their actions, people reproduce or “technologize” these cultural tools so that they can be taken up and used in future actions. Sexuality emerges through a process of making our bodies (and parts of our bodies) meaningful in the ongoing negotiation of mediated actions through processes of entextualization, appropriation, and recontextualization.