bluuebunny/crossref_metadata_2025 huggingface dataset:
Toxoplasma gondii in house mice Mus musculus domesticus from Dakar, Senegal: clues for oral rather than vertical mode of infection
Authors: Galal Lokman , Stragier Claire , Boumediène Farid , Hamidović Azra , Maugrion Océane , Dardé Marie-Laure , Brouat Carine , Mercier Aurélien
Published: April 2019

Toxoplasma gondii is an ubiquitous highly prevalent zoonotic protozoan. Cats are the definitive hosts, while all other warm-blooded animals are intermediate hosts for this parasite. Commensal rodents, being the main preys of cats, are probably the major reservoir for T. gondii. Rodents often develop dormant tissue cysts after ingestion of oocysts shed in the environment by cats in the form of contaminated feces. Experimental evidence that vertical transmission can be sufficient to the perpetuation of transmission between generations of mice has also been found. In natural settings, the relative epidemiological importance of vertical transmission over oral transmission is a matter of debate and raises the question of the possibility of a T. gondii cycle in the absence of cats. In the present study, we took advantage of an extensive survey of commensal rodents in Dakar, Senegal, where the house mouse Mus musculus domesticus is the predominant putative reservoir of T. gondii. Host genotype and spatial location through GPS referencing of all trapping localizations were investigated in relation to T. gondii infection in 12 sites of the city of Dakar and on Goree Island. In each sampled site, the occurrence of over-prevalence zones of T. gondii infection was investigated through Kulldorf’s statistic using SaTScan software. For the sites where a possible over-prevalence zone was identified, mice family lines were inferred from Discriminant Analysis of Principal Components (DAPC). In 3 of the 4 identified possible over-prevalence zones, T. gondii infection was not confined to a single family line, which suggested no association between kinship and infection occurrence. This finding rather suggests an environmental source of infection for mice associated with localized putative foci of environmental contamination and supports an oral route of infection for mice from Dakar rather than a cycle based on vertical transmission.
Antibiotic-induced shifts in fecal microbiota density and composition during hematopoietic stem cell transplantation
Authors: Morjaria Sejal , Schluter Jonas , Taylor Bradford P. , Littmann Eric R. , Carter Rebecca A. , Fontana Emily , Peled Jonathan U. , van den Brink Marcel R.M. , Xavier Joao B. , Taur Ying
Published: April 2019

Background

Dramatic microbiota changes and loss of commensal anaerobic bacteria are associated with adverse outcomes in hematopoietic cell transplantation (HCT) recipients. In this study, we demonstrate these dynamic changes at high-resolution through daily stool sampling and assess the impact of individual antibiotics on those changes.

Methods

We collected 272 longitudinal stool samples (with mostly daily frequency) from 18 patients undergoing HCT and determined their composition by multi-parallel 16S rRNA gene sequencing, as well as density of bacteria in stool by qPCR. We calculated microbiota volatility to quantify rapid shifts and developed a new dynamic systems inference method to assess the specific impact of antibiotics.

Results

The greatest shifts in microbiota composition occurred between stem cell infusion and reconstitution of healthy immune cells. Piperacillin-tazobactam caused the most severe declines among obligate anaerobes.

Conclusions

Our approach of daily sampling, bacterial density determination and dynamic systems modeling allowed us to infer the independent effects of specific antibiotics on the microbiota of HCT patients.
Deep Learning of Markov Model Based Machines for Determination of Better Treatment Option Decisions for Infertile Women
Authors: Srinivasa Rao Arni S.R. , Diamond Michael P.
Published: April 2019

In this technical article, we are proposing ideas those we have been developing of how machine learning and deep learning techniques can potentially assist obstetricians / gynecologists in better clinical decision making using infertile women in their treatment options in combination with mathematical modeling in pregnant women as examples.
Hypotonic stress induces fast, reversible degradation of the vimentin cytoskeleton via intracellular calcium release
Authors: Pan Leiting , Zhang Ping , Hu Fen , Yan Rui , He Manni , Li Wan , Xu Jingjun , Xu Ke
Published: April 2019

The dynamic response of the cell to osmotic changes is critical to its physiology and has been widely exploited for cell manipulation. Using 3D-STORM super-resolution microscopy, here we examine the hypotonic stress-induced ultrastructural changes of the cytoskeleton of a common fibroblast cell type. Unexpectedly, we observe a fast, yet reversible dissolution of the vimentin intermediate filament system that precedes ultrastructural changes of the supposedly more dynamic actin and tubulin cytoskeletal systems, as well as changes in cell morphology. In combination with calcium imaging and biochemical analysis, we next show that the vimentin-specific fast cytoskeletal degradation under hypotonic stress is due to proteolysis by the calcium-dependent protease calpain. We find the process to be activated by the hypotonic stress-induced calcium release from intracellular stores, and so is efficiently suppressed by inhibiting any part of the IP3-Ca2+-calpain pathway we establish. Together, our findings highlight an unexpected, fast degradation mechanism for the vimentin cytoskeleton in response to the external stimuli, and point to the significant, yet previously overlooked physiological impacts of hypotonic stress-induced intracellular calcium release on cell ultrastructure and function.
Crippling the bacterial cell wall molecular machinery
Authors: Williams Allison H. , Wheeler Richard , Deghmane Ala-Eddine , Santecchia Ignacio , Impens Francis , Bastos Paulo André Dias , Hicham Samia , Nilges Maryse Moya , Malosse Christian , Chamot-Rooke Julia , Haouz Ahmed , Robins William P. , Taha Muhamed-Kheir , Boneca Ivo Gomperts
Published: April 2019

Lytic transglycosylases (LT) are redundant enzymes that play a critical role in peptidoglycan (PG) recycling and metabolism. LT(s) role in cell wall-modifying complexes and usefulness as antimicrobial drug targets remain elusive. We determined at high-resolution a structure of the membrane-bound homolog of the soluble LT fromNeisseriaspecies with a disordered active site helix (alpha helix 30). Alpha helix 30 is crucial for binding PG during catalysis1. Here we show using an alpha helix 30 deletion strain that LT (LtgA) determines the integrity of the cell wall, participates in cell division and separation, and can be manipulated to impair the fitness of the human pathogenNeisseria meningitidisduring infection. Characterization ofltgAhelix deleted strain interactome identified glycan chain remodeling enzymes whose function appear to be modulated by LTs. Targeting LTs can disrupt the PG machinery, which is fatal for the bacterium, a new approach for antibiotic development.
An electrophysiological approach to measure changes in the membrane surface potential in real time
Authors: Burtscher Verena , Hotka Matej , Freissmuth Michael , Sandtner Walter
Published: April 2019

Biological membranes carry fixed charges at their surfaces. These arise primarily from phospholipid head groups. In addition, membrane proteins contribute to the surface potential with their charged residues. Membrane lipids are asymmetrically distributed. Because of this asymmetry the net negative charge at the inner leaflet exceeds that at the outer leaflet. Changes in surface potential are predicted to shape the capacitive properties of the membrane (i.e. the ability of the membrane to store electrical charges). Here, we show that it is possible to detect changes in surface potential by an electrophysiological approach: the analysis of cellular currents relies on assuming that the electrical properties of a cell are faithfully described by a three-element circuit - i.e. the minimal equivalent circuit - comprised of two resistors and one capacitor. However, to account for changes in surface potential it is necessary to add a battery to this circuit connected in series with the capacitor. This extended circuit model predicts that the current response to a square-wave voltage pulse harbors information, which allows for separating the changes in surface potential from a true capacitance change. We interrogated our model by investigating changes in capacitance induced by ligand binding to the serotonin transporter (SERT) and to the glycine transporters (GlyT1 and GlyT2). The experimental observations were consistent with the predictions of the extended circuit. We conclude that ligand-induced changes in surface potential (reflecting the binding event) and in true membrane capacitance (reflecting the concomitant conformational change) can be detected in real time even in instances where they occur simultaneously.

Statement of Significance

The plasma membrane of a cell possesses fixed charges on both surfaces. Surface charges play an important role in many biological processes. However, the mechanisms, which regulate the surface charge densities at the plasma membrane, are poorly understood. This is in part due to lack of experimental approaches that allow for detecting changes in surface charges in real time. Here, we show that it is possible to track alterations in the electric potential at the membrane surface with high temporal resolution by an electrophysiological approach. Importantly, the described method allows for discriminating between a change in surface potential and a change in true membrane capacitance (e.g. a change in membrane area), even if these occur in parallel.
Slc7a11 modulated by POU2F1 is involved in pigmentation in rabbit
Authors: Chen Yang , Hu Shuaishuai , Mu Lin , Zhao Bohao , Wang Manman , Yang Naisu , Bao Guolian , Zhu Cigen , Wu Xinsheng
Published: April 2019

Solute carrier family 7 member 11 (Slc7a11) codes for a cystine/glutamate xCT transporter and can control production of pheomelanin pigment to change fur and skin colors of animals. Previous studies found that the skin expression levels of Slc7a11 varied significantly with the fur colors of the Rex Rabbit. However, it is not yet known the molecular regulation mechanism of Slc7a11 in pigmentation. Here rabbit melanocytes were first isolated and identified. The distribution and expression pattern of Slc7a11 was confirmed in rabbit skin with different fur colors. Slc7a11 could affect the expression of pigmentation related genes and thus affect melanogenesis. Meanwhile, Slc7a11 decreased melanocytes apoptosis, but inhibition of Slc7a11 enhanced apoptosis. Furthermore, it was found that POU2F1 protein bound to the -713 to -703 bp region of Slc7a11 promoter to inhibite its activity by dual-luciferase reporter and site-directed mutagenesis assay. This study uncover the function of the Slc7a11 in melanogenesis and provided in-depth analysis of the mechanism of fur pigmentation.
Daedalus and Gasz recruit Armitage to mitochondria, bringing piRNA precursors to the biogenesis machinery
Authors: Munafò Marzia , Manelli Vera , Falconio Federica A. , Sawle Ashley , Kneuss Emma , Eastwood Evelyn L. , Seah Jun Wen Eugene , Czech Benjamin , Hannon Gregory J.
Published: April 2019

The piRNA pathway is a small RNA-based immune system that silences mobile genetic elements in animal germlines. piRNA biogenesis requires a specialised machinery that converts long single-stranded precursors into small RNAs of ~25-nucleotides in length. This process involves factors that operate in two different subcellular compartments: the nuage/Yb-body and mitochondria. How these two sites communicate to achieve accurate substrate selection and efficient processing remains unclear. Here, we investigate a previously uncharacterized piRNA biogenesis factor, Daedalus (Daed), that is located on the outer mitochondrial membrane. Daed is essential for Zucchini-mediated piRNA production and for the correct localisation of the indispensable piRNA biogenesis factor, Armitage (Armi). We find that Gasz and Daed interact with each other and likely provide a mitochondrial “anchoring platform” to ensure that Armi is held in place, proximal to Zucchini, during piRNA processing. Our data suggest that Armi initially identifies piRNA precursors in nuage/Yb-bodies in a manner that depends upon Piwi and then moves to mitochondria to present precursors to the mitochondrial biogenesis machinery. These results represent a significant step in understanding a critical aspect of transposon silencing, namely how RNAs are chosen to instruct the piRNA machinery in the nature of its silencing targets.
Mitofusin 2 regulates neutrophil adhesive migration and the actin cytoskeleton
Authors: Zhou Wenqing , Hsu Alan Y. , Wang Yueyang , Wang Tianqi , Jeffries Jacob , Wang Xu , Mohammad Haroon , Seleem Mohamed N. , Umulis David , Deng Qing
Published: April 2019

Neutrophils rely on glycolysis for energy production. How mitochondria regulate neutrophil function is not fully understood. Here, we report that mitochondrial outer membrane protein Mitofusin 2 (Mfn2) regulates neutrophil homeostasis in vivo. Mfn2-deficient neutrophils are released from the hematopoietic tissue and trapped in the vasculature in zebrafish embryos. Human neutrophil-like cells deficient with MFN2 fail to arrest on activated endothelium under sheer stress or perform chemotaxis. Deletion of Mfn2 results in a significant reduction of neutrophil infiltration to the inflamed peritoneal cavity in mice. Mfn2, but not Mfn1, -null mouse embryonic fibroblast cells have altered actin structure and are impaired in wound closure. MFN2-deficient neutrophil-like cells display heightened intracellular calcium levels and Rac activation after chemokine stimulation. Mechanistically, MFN2 maintains mitochondria-ER interaction. Restoring mitochondria-ER tether rescues the chemotaxis defect and Rac activation resulted from MFN2 depletion. Finally, inhibition of Rac restores chemotaxis in MFN2-deficient neutrophils. Altogether, we identified that MFN2 regulates neutrophil migration via suppressing Rac activation and uncovered a previously unrecognized role of MFN2 in regulating the actin cytoskeleton.
How delayed treatment benefits and harms would impact the optimal timing of statin initiation for cardiovascular primary prevention
Authors: Hayward Rodney A. , Schell Greggory , Robinson Jennifer G. , Sussman Jeremy B. , Lavieri Mariel S.
Published: April 2019

Background

Genetic studies suggest that the relative risk reduction (RRR) of statins may increase over time, potentially resulting in much greater long-term benefit if statins are started before cardiovascular (CV) risk is high.

Methods

We used a nationally representative sample of American adults to estimate effects of initiating a statin when 10-year CV risk reaches 5%, 10% or 15%. We examined scenarios in which a statin’s initial RRR (30%) gradually doubles over 10 to 30 years of treatment.

Results

Initiating a statin when 10-year CV risk is 5% resulted in a mean of 20.1 years on a statin before age 75 (8 years more than starting when CV risk reaches 10%). If a statin’s RRR doubles over 20 years, starting when CV risk is 5% would save about 5.1 to 6.1 additional QALYs per 1000 additional treatment years than starting when CV risk is 10%. Most of this additional benefit was accrued by those who reach a 5% risk at a younger age. Due to the prolonged treatment period, however, early treatment could also result in net harm if the treatment slowly increased a major complication of aging, such as muscular or neurological aging.

Conclusions

In a thought experiment exploring the impact of delayed effects, we found that if the relative effectiveness of statin therapy gradually doubles over a 10 to 30 year period, starting a statin when 10-year CV risk is 5% could have much more long-term benefit than starting a statin when CV risk is 10%. Most of the additional benefit occurred in those at elevated age-adjusted CV risk. Unfortunately, given the long duration of treatment, substantial delayed statin harms, if present, could outweigh these potential benefits and result in substantial net harm.
Estimation of Peru’s sovereign yield curve: the role of macroeconomic and latent factors
Authors: Olivares Rios Alejandra , Rodríguez Gabriel , Ataurima Arellano Miguel
Published: April 2019

Purpose

Following Ang and Piazzesi’s (2003) study, the authors use an affine term structure model to study the relevance of macroeconomic (domestic and foreign) factors for Peru’s sovereign yield curve in the period from November 2005 to December 2015. The paper aims to discuss this issue.

Design/methodology/approach

Risk premia are modeled as time-varying and depend on both observable and unobservable factors; and the authors estimate a vector autoregressive model considering no-arbitrage assumptions.

Findings

The authors find evidence that macro factors help to improve the fit of the model and explain a substantial amount of variation in bond yields. However, their influence is very sensitive to the specification model. Variance decompositions show that macro factors explain a significant share of the movements at the short and middle segments of the yield curve (up to 50 percent), while unobservable factors are the main drivers for most of the movements at the long end of the yield curve (up to 80 percent). Furthermore, the authors find that international markets are relevant for the determination of the risk premium in the short term. Higher uncertainty in international markets increases bond yields, although this effect vanishes quickly. Finally, the authors find that no-arbitrage restrictions with the incorporation of macro factors improve forecasts.

Originality/value

To the authors’ knowledge this is the first application of this type of models using data from an emerging country such as Peru.
Re-examining the determinants of bank profitability in Nigeria
Authors: Bolarinwa Segun Thompson , Obembe Olufemi Bodunde , Olaniyi Clement
Published: April 2019

Purpose

The purpose of this paper is to re-examine the determinants of bank profitability in Nigeria. Specifically, the study investigates the effect of managerial cost efficiency on bank profitability. Also, since there exist mixed results and controversies in the literature, in both developed and developing countries, regarding the effect of efficiency on bank profitability, this study employs the standard measure of efficiency. In addition, the work incorporates the role of persistence, which is often neglected in the literature in developing countries.

Design/methodology/approach

This study employs system generalized method of moments.

Findings

The findings, using the case of Nigeria, show that cost efficiency is a strong determinant of bank profitability in developing countries. In addition, the profitability of banks in Nigeria persists over time; hence, the industry is fairly competitive.

Research limitations/implications

The recent policies of banking industry recapitalization meant to increase profitability and stability in Nigeria and other African countries’ banking industry will not be effective if the issue of managerial efficiency is not properly addressed.

Practical implications

Improving the banking managerial efficiency will positively reduce bad loans, hence leading to the stability in the banking system.

Originality/value

The authors introduce efficiency using standard measure of stochastic frontier analysis for its measurement. Also, this study introduces the role of persistence in the literature in developing countries.
Multiwell study of seismic attenuation at the CO2CRC Otway project geosequestration site: Comparison of amplitude decay, centroid frequency shift and 1D waveform inversion methods
Authors: Pirogova A. , Pevzner R. , Gurevich B. , Glubokovskikh S. , Tertyshnikov K.
Published: April 2019

At the CO2CRC Otway geosequestration site, the abundance of borehole seismic and logging data provides a unique opportunity to compare techniques of Q (measure of attenuation) estimation and validate their reliability. Specifically, we test conventional time‐domain amplitude decay and spectral‐domain centroid frequency shift methods versus the 1D waveform inversion constrained by well logs on a set of zero‐offset vertical seismic profiles. The amplitude decay and centroid frequency shift methods of Q estimation assume that a seismic pulse propagates in a homogeneous medium and ignore the interference of the propagating wave with short‐period multiples. The waveform inversion explicitly models multiple scattering and interference on a stack of thin layers using high‐resolution data from sonic and density logs. This allows for stable Q estimation in small depth windows (in this study, 150 m), and separation of the frequency‐dependent layer‐induced scattering from intrinsic absorption. Besides, the inversion takes into account band‐limited nature of seismic data, and thus, it is less dependent on the operating frequency bandwidth than on the other methods. However, all considered methods of Q estimation are unreliable in the intervals where subsurface significantly deviates from 1D geometry. At the Otway site, the attenuation estimates are distorted by sub‐vertical faults close to the boreholes. Analysis of repeated vertical seismic profiles reveals that 15 kt injection of the CO2‐rich fluid into a thin saline aquifer at 1.5 km depth does not induce detectable absorption of P‐waves at generated frequencies 5–150 Hz, most likely because the CO2 plume in the monitoring well is thin, <15 m. At the Otway research site, strong attenuation Q ≈ 30–50 is observed only in shaly formations (Skull Creek Mudstone, Belfast Mudstone). Layer‐induced scattering attenuation is negligible except for a few intervals, namely 500–650 m from the surface, and near the injection interval, at around 1400–1550 m, where Qscat ≈ 50–65.
Effect of plant chemical variation and mutualistic ants on the local population genetic structure of an aphid herbivore
Authors: Zytynska Sharon E. , Guenay Yasemin , Sturm Sarah , Clancy Mary V. , Senft Matthias , Schnitzler Jörg‐Peter , Dilip Pophaly Saurabh , Wurmser Christine , Weisser Wolfgang W.
Published: April 2019

Plants exhibit impressive genetic and chemical diversity, not just between species but also within species, and the importance of plant intraspecific variation for structuring ecological communities is well known. When there is variation at the local population level, this can create a spatially heterogeneous habitat for specialised herbivores potentially leading to non‐random distribution of individuals across host plants.

Plant variation can affect herbivores directly and indirectly via a third species, resulting in variable herbivore growth rates across different host plants. Herbivores also exhibit within‐species variation, with some genotypes better adapted to some plant variants than others.

We genotyped aphids collected across 2 years from a field site containing ~200 patchily distributed host plants that exhibit high chemical diversity. The distribution of aphid genotypes, their ant mutualists, and other predators was assessed across the plants.

We present evidence that the local distribution of aphid (Metopeurum fuscoviride) genotypes across host‐plant individuals is associated with variation in the plant volatiles (chemotypes) and non‐volatile metabolites (metabotypes) of their host plant tansy (Tanacetum vulgare). Furthermore, these interactions in the field were influenced by plant‐host preferences of aphid‐mutualist ants.

Our results emphasise that plant intraspecific variation can structure ecological communities not only at the species level but also at the genetic level within species and that this effect can be enhanced through indirect interactions with a third species.
Metabolic engineering of Bacillus subtilis for production of para‐aminobenzoic acid – unexpected importance of carbon source is an advantage for space application
Authors: Averesch Nils J. H. , Rothschild Lynn J.
Published: April 2019

High‐strength polymers, such as aramid fibres, are important materials in space technology. To obtain these materials in remote locations, such as Mars, biological production is of interest. The aromatic polymer precursor para‐aminobenzoic acid (pABA) can be derived from the shikimate pathway through metabolic engineering of Bacillus subtilis, an organism suited for space synthetic biology. Our engineering strategy included repair of the defective indole‐3‐glycerol phosphate synthase (trpC), knockout of one chorismate mutase isozyme (aroH) and overexpression of the aminodeoxychorismate synthase (pabAB) and aminodeoxychorismate lyase (pabC) from the bacteria Corynebacterium callunae and Xenorhabdus bovienii respectively. Further, a fusion‐protein enzyme (pabABC) was created for channelling of the carbon flux. Using adaptive evolution, mutants of the production strain, able to metabolize xylose, were created, to explore and compare pABA production capacity from different carbon sources. Rather than the efficiency of the substrate or performance of the biochemical pathway, the product toxicity, which was strongly dependent on the pH, appeared to be the overall limiting factor. The highest titre achieved in shake flasks was 3.22 g l−1 with a carbon yield of 12.4% [C‐mol/C‐mol] from an amino sugar. This promises suitability of the system for in situ resource utilization (ISRU) in space biotechnology, where feedstocks that can be derived from cyanobacterial cell lysate play a role.
Application of circulating tumor DNA for dynamic monitoring of advanced non‐small cell lung cancer treatment response: An open‐label, multicenter, prospective, observational study protocol
Authors: Gao Zhenlin , Shang Yanhong , Wang Xiaozhen , Ma Yuquan , Yang Fan , Wang Jun , Chen Kezhong , Zhang Yan
Published: April 2019

Response Evaluation Criteria in Solid Tumors version 1.1 is currently considered the indicator to assess the curative effect of cancer. However, radiographic measurements often fail to detect tiny lesions or changes in the tumor burden, while tumor biomarkers possess low sensitivity and stability. Circulating tumor DNA (ctDNA) is a potential noninvasive approach that can be used to make an earlier diagnosis, monitor disease progress, and determine treatment efficacy. Previous studies of non‐small cell lung cancer (NSCLC) have not clearly determined the optimum time to monitor ctDNA. Hence, the appropriate time to evaluate ctDNA to determine the curative effects of treatment in advanced NSCLC compared to conventional imaging and tumor markers should be explored in order to prevent unnecessary side effects and to avoid continuing ineffective therapies. This protocol outlines a prospective clinical trial in which advanced NSCLC patients will be recruited and longitudinal changes in ctDNA levels with changes in radiographic tumor size or tumor biomarkers will be assessed. ctDNA will be quantified by determining the allele fraction of cancer‐associated somatic mutations in plasma using multigene next‐generation sequencing assay. Conclusions will be drawn from data collection and analysis.
Quantifying habitat use of migratory fish across riverscapes using space‐time isotope models
Authors: Brennan Sean R. , Cline Timothy J. , Schindler Daniel E.
Published: April 2019

Migratory animals pose difficult challenges to conservation and management because identifying critical habitats used throughout their lives is rarely possible. Endogenous tracers (e.g. isotope ratios) recorded in sequentially growing biogenic tissues, however, represent a potential source of unique insights at the more elusive temporal and spatial scales central to understanding the ecology of mobile species. To this end, a general probabilistic framework has emerged that quantitatively compares predictive models of isotopic variation across landscapes (called isoscapes) to the isotopic composition recorded in a biological tissue to determine the provenance and movements of animals throughout their lives.

Although this spatially continuous approach to isotope‐based geographic assignment is becoming more common across taxa and ecosystems, adopting this framework to take advantage of serial isotope records stored within sequentially growing biogenic tissues (e.g. teeth or otoliths) is less common.

Here, we construct a novel space‐time isotope model of provenance (STIMP) that determines the habitat use through time of migratory fish across river basins. To do so, this model integrates: strontium isotope (87Sr/86Sr) ratios across a riverscape, the serial records of 87Sr/86Sr within otoliths, habitat geomorphology and the directional movement patterns of fish through river networks.

To illustrate an application of the model, we applied it to a published dataset from Chinook salmon (Oncorhynchus tshawytscha) harvested in 2011 during a coastal fishery in Bristol Bay, Alaska, U.S.A. Using this model, we show how individuals exploit an array of habitat types to achieve their juvenile growth prior to ocean migration, and that the intensity of habitat use among habitat types across the basin shifts spatially over the course of freshwater residence (e.g. from headwaters to migration corridors). The STIMP presented here integrates diverse information sources to reveal the cryptic juvenile movement patterns of a highly migratory species, providing new insights critical to their conservation. This general framework is applicable to any migratory taxa that use isotopically heterogeneous landscapes during their lives and record such variation in sequentially growing biogenic tissues.
When to go abroad: economic policy uncertainty and Chinese firms’ overseas investment
Authors: Wu Ji (George) , Zhang Jian , Wu Yiwen , Kong Dongmin
Published: April 2019

We study how economic policy uncertainty (EPU) influences firms’ overseas investments for Chinese listed companies. We find a significant negative relationship between EPU and firms’ overseas investments after controlling for firm characteristics and macroeconomic variables. Chinese firms seem to reduce their overseas investments on fixed income securities when facing domestic policy uncertainty. The negative relationship is pronounced for financially constrained firms, firms relying on government subsidies and with low overseas revenues, and SOEs. Firms operating in high marketisation regions can mitigate the negative effect of EPU on firms’ overseas investments. Our results remain significant when considering endogeneity problems.
Emerging new themes in environmental, social and governance investing: a systematic literature review
Authors: Daugaard Dan
Published: April 2019

Environmental, social and governance (ESG) investing is a large and influential industry. Its activities could be illuminated, appraised and improved by academic research. Unfortunately, research to date has focused on measuring return performance. A wider range of topics is necessary before research can properly inform investors, companies and regulators. This paper contributes to the challenge by systematically exploring the literature to reveal a richer array of topics: the heterogeneous nature of ESG investing, its costs and motivations, and its management literature origins. In addition to these established topics, five emerging themes are identified: the human element, climate change, fund flows, fixed income and the rise of non‐Western players.
Moderate alcohol consumption and depression – a longitudinal population‐based study in Sweden
Authors: Gémes K. , Forsell Y. , Janszky I. , László K. D. , Lundin A. , Ponce De Leon A. , Mukamal K. J. , Moller J.
Published: April 2019

Background and Aims

The interrelationship between alcohol consumption and depression is complex, and the direction of the association is unclear. We investigated whether alcohol consumption influences the risk of depression while accounting for this potential bidirectionality.

Methods

A total of 10 441 individuals participated in the PART study in 1998–2000, 8622 in 2001–2003, and 5228 in 2010. Participants answered questions on their alcohol consumption, symptoms of depression, childhood adversity, and sociodemographic, socioeconomic, psychosocial, and lifestyle factors. A total of 5087 participants provided repeated information on alcohol consumption. We used marginal structural models to analyze the association between alcohol consumption and depression while controlling for previous alcohol consumption and depressive symptoms and other time‐varying confounders.

Results

Non‐drinkers had a higher depression risk than light drinkers (≤7 drinks/week) (risk ratio: 1.7; 95% confidence interval 1.3–2.1). Consumers of seven–fourteen drinks/week had a depression risk similar to that of light drinkers. Hazardous drinking was associated with a higher risk of depression than non‐hazardous alcohol consumption (risk ratio: 1.8, 95% confidence interval: 1.4–2.4).

Conclusion

Light and moderate alcohol consumption and non‐hazardous drinking were associated with the lowest risk of subsequent depression after accounting for potential bidirectional effects. Hazardous drinking increased the risk of depression.
Internalizing and externalizing symptoms and suicidal behaviour in young people: a systematic review and meta‐analysis of longitudinal studies
Authors: Soto‐Sanz V. , Castellví P. , Piqueras J. A. , Rodríguez‐Marín J. , Rodríguez‐Jiménez T. , Miranda‐Mendizábal A. , Parés‐Badell O. , Almenara J. , Alonso I. , Blasco M. J. , Cebrià A. , Gabilondo A. , Gili M. , Lagares C. , Roca M. , Alonso J.
Published: April 2019

Objective

To assess internalizing and externalizing symptoms as risk factors for suicidal behaviour and suicide among adolescents and young adults.

Method

We conducted a systematic review of articles published until January 2017. We identified 26 883 potential papers; 1701 full‐text articles were assessed for eligibility, of which 1479 were excluded because of methodological reasons. Diverse meta‐analyses were performed for each group of symptoms. Odds ratios (ORs) and 95% confidence intervals (95% CI) or beta coefficients for categorical variables, and effect size (ES) were calculated for continuous variables.

Results

Finally, 41 studies were included, involving participants aged 12–26 years for a systematic review, and 24 articles were included for meta‐analysis. The meta‐analysis showed that youths with any internalizing (ES = 0.93) or externalizing symptoms (ES = 0.76 and OR = 2.59) were more likely to attempt suicide in future. This effect was also seen in depression symptoms (OR = 6.58 and ES = 1.00), legal problems (OR = 3.36), and anxiety (ES = 0.65).

Conclusion

Reported internalizing and externalizing symptoms are predictors of suicide behaviour in young people; therefore, the detection and management of these symptoms in young populations could be a crucial strategy for preventing suicidality in this group.
Ungulate browsing on introduced pines differs between plant communities: Implications for invasion process and management
Authors: Zamora‐Nasca Lucía B. , Relva M. Andrea , Núñez Martín A.
Published: April 2019

The effects of herbivory on plant invasions are broadly discussed, and many studies have led to widely debated theories. In particular, the effects of herbivores on pine invasion found in different studies vary; in some cases, they controlled their expansion, and in others, they promoted it. On the other hand, vulnerability to invasion by pines differs between community types. Sites with dunes and bare ground are the most heavily invaded, followed by grasslands, while shrublands and forests are least invaded. Because current evidence is mostly observational, some of the varying responses of pine invasions to herbivory should be examined further through replicated experiments. Here, we address experimentally the extent to which preference for the non‐native invasive Pinus contorta by domestic sheep (Ovis aries) depends on the vegetation type. We installed experimental enclosures within two adjacent communities, grassland and shrubland, and in each one, we planted seedlings of P. contorta Douglas and established a sheep density typically recommended for the study area. The number of browsed seedlings, the number and type of branches browsed per seedling, the reduction in height and probability of survival immediately after browsing period were recorded. The number of browsed seedlings and damage to the terminal bud were higher in grassland than in shrubland, while the number of browsed branches per seedling was higher in shrubland than grassland. The reductions in height and probability of survival immediately after browsing were similar in both communities. These results show that moderate levels of sheep herbivory could reduce 20% seedling survival in both communities; nevertheless, the damage patterns differ between them. The sheep browsed more substantial number of seedlings in grasslands than in shrublands. However, if sheep find the seedlings, they damage it more in shrublands. These results suggest that experimental studies comparing communities are important for pine invasion management.
Research priorities in residential aged care services: A statewide survey
Authors: Rayner Jo‐Anne , Fetherstonhaugh Deirdre , Cowen Sandra
Published: April 2019

Objectives

To ascertain the research priorities of staff working in Victorian residential aged care services (RACS).

Method

In October 2016, all 754 Victorian RACS were asked to list three most important research priorities in a confidential postal survey. Descriptive statistics and content analysis were used to analyse the data.

Results

One hundred and sixty‐two (21.5%) RACS participated. Research priorities, in order of importance, were grouped thematically as workforce issues, strategies to manage residents with dementia and funding to the sector. Staffing numbers and mix, particularly nurse‐to‐resident ratios, dominated workforce issues. The management of responsive behaviours was highlighted as a pressing clinical issue, and insufficient funding to the sector impacted on most issues reported.

Conclusions

The research priorities identified were inter‐related. Some were already well researched, suggesting RACS staff have little time and/or limited access to research evidence to inform the care and management of residents, possibly because of inadequate staffing and funding.
The importance of being rhythmic: Living in harmony with your body clocks
Authors: Dibner Charna
Published: April 2019

Circadian rhythms have developed in all light‐sensitive organisms, including humans, as a fundamental anticipatory mechanism that enables proactive adaptation to environmental changes. The circadian system is organized in a highly hierarchical manner, with clocks operative in most cells of the body ensuring the temporal coordination of physiological processes. Circadian misalignment, stemming from modern life style, draws increasing attention due to its tight association with the development of metabolic, cardiovascular, inflammatory and mental diseases as well as cancer. This review highlights recent findings emphasizing the role of the circadian system in the temporal orchestration of physiology, with a particular focus on implications of circadian misalignment in human pathologies.
Programmed cell death protein‐1 (PD‐1)‐targeted immunotherapy in advanced hepatocellular carcinoma: efficacy and safety data from an international multicentre real‐world cohort
Authors: Scheiner Bernhard , Kirstein Martha M. , Hucke Florian , Finkelmeier Fabian , Schulze Kornelius , von Felden Johann , Koch Sandra , Schwabl Philipp , Hinrichs Jan B. , Waneck Fredrik , Waidmann Oliver , Reiberger Thomas , Müller Christian , Sieghart Wolfgang , Trauner Michael , Weinmann Arndt , Wege Henning , Trojan Jörg , Peck‐Radosavljevic Markus , Vogel Arndt , Pinter Matthias
Published: April 2019

Background

Programmed cell death protein‐1‐targeted immunotherapy has shown promising results in phase II studies of hepatocellular carcinoma.

Aim

To evaluate safety and efficacy of nivolumab and pembrolizumab in an international, multicentre, real‐world cohort of patients with advanced hepatocellular carcinoma.

Methods

Sixty‐five patients treated with nivolumab (n = 34) or pembrolizumab (n = 31) between July 10, 2015 and December 31, 2018 (data cut‐off) across six centres in Austria and Germany were retrospectively analysed.

Results

Child‐Pugh class A/B/C was 32 (49%)/28 (43%)/5 (8%). Immunotherapy was used as systemic first‐/second‐/third‐/fourth‐line treatment in 9 (14%)/27 (42%)/26 (40%)/3 (5%) patients. Fifty‐four patients had at least one follow‐up imaging and were, therefore, available for radiological response assessment. The overall response and disease control rates were 12% and 49% respectively. Of 52 evaluable patients, four (8%) had hyperprogressive disease. Median time to progression was 5.5 (95% CI, 3.5‐7.4) months, median progression‐free survival was 4.6 (95% CI, 3.0‐6.2) months, and median overall survival was 11.0 (95% CI, 8.2‐13.8) months. Most common adverse events were infections (n = 7), rash (n = 6), pruritus (n = 3), fatigue (n = 3), diarrhoea (n = 3) and hepatitis (n = 3). Efficacy and safety results were comparable between Child‐Pugh A and B patients; however, median overall survival (OS) was shorter in Child‐Pugh B patients (16.7 vs 8.6 months; P = 0.065). There was no difference in terms of efficacy and adverse events between patients who received immunotherapy as first‐/second‐line and third‐/fourth‐line respectively.

Conclusions

Programmed cell death protein‐1‐targeted immunotherapy with nivolumab or pembrolizumab showed promising efficacy and safety in patients with advanced hepatocellular carcinoma, including subjects with Child‐Pugh stage B and patients with intensive pretreatment.
Methadone and buprenorphine pharmacokinetics and pharmacodynamics when coadministered with fostemsavir to opioid‐dependent, human immunodeficiency virus seronegative participants
Authors: Moore Katy , Magee Mindy , Sevinsky Heather , Chang Ming , Lubin Susan , Myers Elsa , Ackerman Peter , Llamoso Cyril
Published: April 2019

Aims

Regional human immunodeficiency virus (HIV) prevalence rates are high in people with history of injection drug use, including those managed with maintenance opioids. Fostemsavir (FTR) is an oral prodrug of temsavir, a first‐in‐class attachment inhibitor that binds HIV‐1 gp120, preventing initial HIV attachment and entry into host immune cells. Here we determine the impact of FTR on the pharmacokinetics of opioids methadone (MET: R‐, S‐ and total) or buprenorphine and norbuprenorphine (BUP and norBUP) when coadministered.

Methods

Study 206216 (NCT02666001) was a Phase I, open‐label study, assessing the effect of FTR 600 mg (extended‐release formulation) twice daily on pharmacokinetics of MET or BUP and norBUP, in non‐HIV‐infected participants on stable maintenance therapy with MET (40–120 mg; n = 16) or BUP plus naloxone (8–24 mg plus 2–6 mg; n = 16); pharmacodynamic response was assessed using standard opioid rating scales.

Results

Following coadministration with FTR, dose‐normalized MET (R‐, S‐ and total) exposures (maximum concentration in plasma, area under the plasma concentration–time curve over the dosing interval and concentration in plasma at 24 hours) increased 9–15% and BUP and norBUP exposures increased 24–39%. The 90% confidence interval ranges for MET (1.01–1.21) and BUP and norBUP (1.03–1.69) were within respective no‐effect ranges (0.7–1.43 and 0.5–2.0). Opioid pharmacodynamic scores were similar with and without MET/BUP with no symptoms of withdrawal/overdose; no new safety signal for FTR when combined with a stable opioid regimen.

Conclusions

FTR did not impact MET and had no clinically significant impact on BUP pharmacokinetics. Standardized assessments of opioid pharmacodynamics were unchanged throughout FTR administration with MET or BUP. FTR can be administered with MET or BUP without dose adjustment.
Dynamics of circulating vascular endothelial growth factor‐A predict benefit from antiangiogenic cediranib in metastatic or recurrent cervical cancer patients
Authors: Zhou Cong , Taylor Sarah , Tugwood Jonathan , Simpson Kathryn , Jayson Gordon C. , Symonds Paul , Paul James , Davidson Susan , Carty Karen , McCartney Elaine , Rai Debbie , Dive Caroline , West Catharine
Published: April 2019

Aims

There is a need for predictive and surrogate response biomarkers to support treatment with antiangiogenic vascular endothelial growth factor (VEGF) inhibitors. We aimed to identify a minimally‐invasive biomarker predicting benefit from cediranib pretreatment or early during treatment in patients with recurrent or metastatic cervical cancer.

Methods

Blood samples were collected before treatment, during treatment and upon disease progression where appropriate from patients enrolled in CIRCCa, a randomised phase II trial of carboplatin and paclitaxel with or without cediranib. Plasma concentrations of VEGF‐A, VEGF‐receptor 2, Ang1 and Tie2 were measured using multiplex enzyme‐linked immunosorbent assay. Pretreatment and temporal changes of the biomarkers were investigated using proportional hazard regression and unsupervised clustering analysis.

Results

Samples (n = 556) from 52 patients were analysed. VEGF‐receptor 2 (P = .0006) and Tie2 (P = .04) were downregulated following cediranib, while VEGF‐A (P = .0025) was upregulated. High Eastern Cooperative Oncology Group performance status (P = .02, hazard ratio [HR] = 2.15, 95% confidence interval [CI] 1.13–4.09) and low pretreatment Tie2 concentrations (P = .003, HR = 0.57, 95%CI 0.39–0.83) were independent prognostic factors associated with reduced progression‐free survival. Two patterns of changes in VEGF‐A following cediranib were identified. Patients with elevated VEGF‐A in the first 3 treatment cycles, regardless of magnitude, had reduced progression‐free survival in the placebo arm but improved survival with the addition of cediranib (P = .019, HR = 0.13, 95% CI 0.02–0.71).

Conclusion

Patterns of early elevation in plasma VEGF‐A should be studied further as a potential biomarker to predict treatment benefit from cediranib.