bluuebunny/crossref_metadata_2025 huggingface dataset:
Nrf1D is the first candidate secretory transcription factor in the blood plasma, with its precursor existing as a unique redox-sensitive transmembrane CNC-bZIP protein in somatic tissues
Authors: Yuan Jianxin , Wang Hongxia , Li Shaojun , Xiang Yuancai , Hu Shaofan , Wang Meng , Qiu Lu , Zhang Yiguo
Published: June 2018

Amongst multiple distinct isoforms, Nrf1D is synthesized from translation of an alternatively-spliced transcript of Nrf1 mRNA, with a naturally-occurring deletion of its stop codon-flanking 1466 nucleotides. This molecular event leads to the reading frameshift mutation, which results in a constitutive substitution of the intact Nrf1’s C-terminal 72 amino acids (aa, covering the second half of the leucine zipper motif to C-terminal Neh3L domain) by an additional extended 80-aa stretch to generate a unique variant Nrf1D. The C-terminal extra 80-aa region of Nrf1D was identified to fold into a redox-sensitive transmembrane domain that enables it to be tightly integrated within the endoplasmic reticulum (ER) membranes. Notably, the salient feature of Nrf1D confers it to be distinguishable from prototypic Nrf1, such that Nrf1D is endowed with only a less ability than wild-type Nrf1 at mediating target gene expression. Further evidence has been presented revealing that both mRNA and protein levels of Nrf1D were detected to varying extents in somatic tissues. Surprisingly, we also found the existence of Nrf1D-derived isoforms in the blood plasma, implying that it is a candidate secretory transcription factor, although its precursor acts as an integral transmembrane-bound CNC-bZIP protein that entails dynamic topologies, before being unleashed from the ER to enter the blood plasma.
Lipidomic and biophysical homeostasis of mammalian membranes in response to dietary lipids is essential for cellular fitness
Authors: Levental Kandice R , Malmberg Eric , Symons Jessica , Fan Yang-Yi , Chapkin Robert S. , Ernst Robert , Levental Ilya
Published: June 2018

Biological membranes form the functional, dynamic interface that hosts a major fraction of all cellular bioactivity. Proper membrane physiology requires maintenance of a narrow range of physicochemical properties, which must be buffered from external perturbations. While homeostatic adaptation of membrane fluidity to temperature variation is a ubiquitous design feature of ectothermic organisms, such responsive membrane adaptation to external inputs has not been directly observed in mammals. Here, we report that challenging mammalian membrane homeostasis by dietary lipids leads to robust lipidomic remodeling to preserve membrane physical properties. Specifically, exogenous polyunsaturated fatty acids (PUFAs) are rapidly and extensively incorporated into membrane lipids, inducing a reduction in membrane packing. These effects are rapidly compensated both in culture and in vivo by lipidome-wide remodeling, most notably upregulation of saturated lipids and cholesterol. These lipidomic changes result in recovery of membrane packing and permeability. This lipidomic and biophysical compensation is mediated in part by lipid regulatory machinery, whose pharmacological or genetic abrogation results in cytotoxicity when membrane homeostasis is challenged by dietary lipids. These results reveal an essential mammalian mechanism for membrane homeostasis wherein lipidome remodeling in response to dietary lipid inputs preserves functional membrane phenotypes.
Gut Microbiota Diversity across Ethnicities in the United States
Authors: Brooks Andrew W. , Priya Sambhawa , Blekhman Ran , Bordenstein Seth R.
Published: June 2018

Composed of hundreds of microbial species, the composition of the human gut microbiota can vary with chronic diseases underlying health disparities that disproportionally affect ethnic minorities. However, the influence of ethnicity on the gut microbiota remains largely unexplored and lacks reproducible generalizations across studies. By distilling associations between ethnicity and differences in two United States based 16S gut microbiota datasets including 1,673 individuals, we report 12 microbial genera and families that reproducibly vary by ethnicity. Interestingly, a majority of these microbial taxa, including the most heritable bacterial family, Christensenellaceae, overlap with genetically-associated taxa and form co-occurring clusters linked by similar fermentative and methanogenic metabolic processes. These results demonstrate recurrent associations between specific taxa in the gut microbiota and ethnicity, providing hypotheses for examining specific members of the gut microbiota as mediators of health disparities.
Isoform and protein region abnormalities of dysbindin and copper transporter proteins in postmortem schizophrenia substantia nigra
Authors: Schoonover Kirsten E. , Roberts Rosalinda C.
Published: June 2018

Objective

Dysbindin is downregulated in several schizophrenia brain regions and modulates copper transport required for myelination and monoamine metabolism. We sought to determine dysbindin and copper transporter protein expression in schizophrenia subjects.

Methods

We studied the substantia nigra (which exhibits one of the highest copper contents of the human brain) using Western blot analysis. We characterized specific protein domains of copper transporters ATP7A, CTR1, ATP7B, and dysbindin isoforms 1A and 1B/C in postmortem substantia nigra in schizophrenia subjects (n=15) and matched controls (n=11). As a preliminary investigation, we examined medication status in medicated (n=11) versus unmedicated schizophrenia subjects (n=4).

Results

The combined schizophrenia group exhibited increased levels of C-terminus, but not N-terminus, ATP7A. Schizophrenia subjects expressed less transmembrane CTR1 and dysbindin 1B/C than controls. When subdivided, the increased C-terminus ATP7A protein was present only in medicated subjects versus controls. Unmedicated subjects exhibited less N-terminus ATP7A protein than controls and medicated subjects, suggesting medication-induced rescue of the ATP7A N-terminus. Transmembrane CTR1 was decreased to a similar extent in both treatment groups versus controls, suggesting no medication effect.

Conclusions

These results provide the first evidence of disrupted copper transport into and within schizophrenia nigral cells that may be modulated by specific dysbindin isoforms and antipsychotic treatment.
PIKfyve/Fab1 is required for efficient V-ATPase and hydrolase delivery to phagosomes, phagosomal killing, and restriction ofLegionellainfection
Authors: Buckley Catherine M. , Heath Victoria L. , Guého Aurélie , Bosmani Cristina , Knobloch Paulina , Sikakana Phumzile , Personnic Nicolas , Dove Stephen K. , Michell Robert H. , Meier Roger , Hilbi Hubert , Soldati Thierry , Insall Robert H. , King Jason S.
Published: June 2018

By engulfing potentially harmful microbes, professional phagocytes are continually at risk from intracellular pathogens. To avoid becoming infected, the host must kill pathogens in the phagosome before they can escape or establish a survival niche. Here, we analyse the role of the phosphoinositide (PI) 5-kinase PIKfyve in phagosome maturation and killing, using the amoeba and model phagocyteDictyostelium discoideum.

PIKfyve plays important but poorly understood roles in vesicular trafficking by catalysing formation of the lipids phosphatidylinositol (3,5)-bisphosphate (PI(3,5)2) and phosphatidylinositol-5-phosphate (PI(5)P). Here we show that its activity is essential during early phagosome maturation inDictyostelium. Disruption ofPIKfyveinhibited delivery of both the vacuolar V-ATPase and proteases, dramatically reducing the ability of cells to acidify newly formed phagosomes and digest their contents. Consequently,PIKfyve-cells were unable to generate an effective antimicrobial environment and efficiently kill captured bacteria. Moreover, we demonstrate that cells lackingPIKfyveare more susceptible to infection by the intracellular pathogenLegionella pneumophila. We conclude that PIKfyve-catalysed phosphoinositide production plays a crucial and general role in ensuring early phagosomal maturation, protecting host cells from diverse pathogenic microbes.

Importance

Cells that capture or eat bacteria must swiftly kill them to prevent pathogens from surviving long enough to escape the bactericidal pathway and establish an infection. This is achieved by the rapid delivery of components that produce an antimicrobial environment in the phagosome, the compartment containing the captured microbe. This is essential both for the function of immune cells and for amoebae that feed on bacteria in their environment. Here we identify a central component of the pathway used by cells to deliver antimicrobial components to the phagosome and show that bacteria survive over three times as long within the host if this pathway is disabled. We show that this is of general importance for killing a wide range of pathogenic and non-pathogenic bacteria, and that it is physiologically important if cells are to avoid infection by the opportunistic human pathogenLegionella.
Win‐wins for biodiversity and ecosystem service conservation depend on the trophic levels of the species providing services
Authors: Xiao Hui , Dee Laura E. , Chadès Iadine , Peyrard Nathalie , Sabbadin Régis , Stringer Martin , McDonald‐Madden Eve
Published: June 2018

Confronted by significant impacts to ecosystems world‐wide, decision makers face the challenge of maintaining both biodiversity and the provision of ecosystem services (ES). However, the objectives of managing biodiversity and supplying ES may not always be in concert, resulting in the need for trade‐offs. Understanding these potential trade‐offs is crucial for identifying circumstances under which conservation strategies designed to maximise either biodiversity or ES will result in win‐win or win‐lose outcomes. One important factor that may influence these outcomes are species interactions and the structure of the networks in which they are embedded.

We combine optimisation and network theory to investigate the difference in species prioritisation and management outcomes when targeting biodiversity or ES, by considering trophic interactions between species. We analyse 360 simulated ecosystem networks with different ecosystem structures, including the trophic level of the species providing the ES, the number of ES considered, and the food web connectivity. We then illustrate the framework on a saltmarsh case study.

We find that trade‐offs between biodiversity and ES depend on the network structure of the ecosystem being managed. The trophic level of the species providing the ES is an important determinant of optimal species protection priorities and the biodiversity‐ES trade‐offs. A strategy targeting ES leads to similar levels of biodiversity conservation (a win‐win situation) only when basal species provide the services. In contrast, food web connectivity and the number of services considered have little impact on biodiversity‐ES trade‐offs.

Synthesis and applications. Our research provides the first optimisation model to examine trade‐offs between a biodiversity‐ or ecosystem service‐based approach for managing a network of interacting species that provide services. Importantly, results from considering species‐services interactions in ecosystem network dynamics can provide managers with quantitative insights to identify opportunities for win‐wins and or to avoid win‐loss outcomes, by focusing on the trophic level of the species providing services. Future research could build on our model to add multiple interaction types among species, ecosystem functions, and ecosystem services to analyse optimal ecosystem management for multiple conservation objectives.
A cost‐and‐time effective procedure to develop SNP markers for multiple species: A support for community genetics
Authors: Delord Chrystelle , Lassalle Gilles , Oger Adrien , Barloy Dominique , Coutellec Marie‐Agnes , Delcamp Adline , Evanno Guillaume , Genthon Clemence , Guichoux Erwan , Le Bail Pierre‐Yves , Le Quilliec Patricia , Longin Guillaume , Lorvelec Olivier , Massot Marie , Reveillac Elodie , Rinaldo Raphaelle , Roussel Jean‐Marc , Vigouroux Regis , Launey Sophie , Petit Eric J.
Published: June 2018

Multispecies population genetics is an emerging field that provides insight relevant to conservation biology and community ecology. However, to date, this approach is limited to species with available genetic resources. The use of thousands of single‐nucleotide polymorphism (SNP) markers developed from recent genotyping‐by‐sequencing (GBS) technologies is a roadmap for the study of nonmodel species, but remains cost prohibitive when several, distantly related species are involved.

We aimed to overcome this issue using a single HiSeq3000 run of restriction‐site associated DNA sequencing (RAD‐Seq) to retrieve SNP markers for 40 diverse species including plants, invertebrates, fish, and mammals. We developed a Python‐based pipeline to isolate c. 100–500 high‐quality SNP markers for each species that could be genotyped through classical PCR amplification methods. To assess the quality of these markers, we validated our approach on c. 160 of the characterized SNPs for each of 18 Neotropical fish species from the river Maroni (French Guiana, South America), using the MassARRAY iPLEX platform from Agena Bioscience (San Diego, CA, USA).

A run of the pipeline applying stringent filtering parameters enabled the successful design of between 130 and 3,492 SNP markers for 30 of the 40 study species. Relaxing pipeline parameters allows for an increase in the number of detected SNPs. Across the 18 species from French Guiana, an average of 85% of markers were successfully amplified, polymorphic, and scored in ≥90% of individuals (c. 200 individuals per species). The great majority (>98%) of these markers were at Hardy–Weinberg equilibrium in each sampling site from the river Maroni.

This SNP discovery was performed at the cost of c. $US110 for each of the 40 species. Genotyping was performed at the cost of c. $US6000 for each of the 18 fish species with an average of 200 individuals per species. This strategy was found cost‐and‐time efficient to develop hundreds of SNP markers for a large range of nonmodel species, which can be used to investigate ecological and evolutionary questions that do not require whole‐genome coverage.
Uncertainty in geographical estimates of performance and fitness
Authors: Woods H. Arthur , Kingsolver Joel G. , Fey Samuel B. , Vasseur David A.
Published: June 2018

Thermal performance curves (TPCs) have become key tools for predicting geographical distributions of performance by ectotherms. Such TPC‐based predictions, however, may be sensitive to errors arising from diverse sources.

We analysed potential errors that arise from common choices faced by biologists integrating TPCs with climate data by constructing case studies focusing on experimental sets of TPCs and simulating geographical patterns of mean performance. We first analysed differences in geographical patterns of performance derived from two pairs of commonly used TPCs. Mean performance differed most (up to 30%) in regions with relatively constant mean temperatures similar to those at which the TPCs diverged the most.

We also analysed the effects of thermal history by comparing geographical estimates derived from (a) a broad TPC based on short‐term measurements of insect larvae (Manduca sexta) with a history of exposure to thermal variation versus (b) a narrow TPC based on long‐term measurements of larvae held at constant temperatures. Estimated mean performance diverged by up to 40%, and differences were magnified in simulated future climates.

Finally, to quantify geographical error arising from statistical error in fitted TPCs, we propose and illustrate a bootstrapping technique for establishing 95% prediction intervals on mean performance at each location (pixel).

Collectively, our analyses indicate that error arising from several underappreciated sources can significantly affect the mean performance values derived from TPCs, and we suggest that the magnitudes of these errors should be estimated routinely in future studies.
Landscape history confounds the ability of the NDVI to detect fine‐scale variation in grassland communities
Authors: Löfgren Oskar , Prentice Honor C. , Moeckel Thomas , Schmid Barbara C. , Hall Karin
Published: June 2018

The NDVI is a remotely sensed vegetation index that is frequently used in ecological studies. There is, however, a lack of studies that evaluate the ability of the NDVI to detect fine‐scale variation in grassland plant community composition and species richness. Ellenberg indicators characterize the environmental preferences of plant species—and community‐mean Ellenberg values have been used to explore the environmental drivers of community assembly.

We used variation partitioning to test the ability of satellite‐based NDVI to explain community‐mean Ellenberg nutrient (mN) and moisture (mF) indices, and the richness of habitat‐specialist species in dry grasslands of different ages. The grasslands represent a gradient of decreasing soil nutrient status.

If community composition is determined by the responses of individual species to the underlying environmental conditions and if, at the same time, community composition determines the optical characteristics of the vegetation canopy, then positive relationships between the NDVI and mN and mF are expected. Many grassland specialists are intolerant of nutrient‐rich soils. If specialist richness is negatively related to soil‐nutrient levels, then a negative association between the NDVI and specialist richness is expected. However, because grassland community composition is not only influenced by abiotic variables but also by other spatial and temporal drivers, we included spatial variables and grassland age in the statistical analyses.

The NDVI explained the majority of the variation in mF, and also contributed to a substantial proportion of the variation in mN. However, variation in specialist richness and the lowest values of mN were explained by grassland age and spatial variables—but were poorly explained by the NDVI.

Synthesis and applications. The NDVI showed a good ability to detect variation in plant community composition, and should provide a valuable tool for assessing fine‐scale environmental variation in grasslands or for monitoring changes in grassland habitat properties. However, because the concentration of grassland specialists not only depends on environmental variables but also on the age and spatial context of the grasslands, the NDVI is unlikely to allow the identification of grasslands with high numbers of specialist species.
Why understanding the pioneering and continuing contributions ofBIOCLIMto species distribution modelling is important
Authors: Booth Trevor H.
Published: June 2018

Modern species distribution modelling (SDM) began in 1984 with the launch of theBIOCLIMprogram in Australia. With more than 900 papers mentioning ‘species distribution model’ published around the world to date,SDMis one of the most active areas of global ecology. Three books published in 2009, 2011 and 2017 have reviewedSDM, and the closely related areas of ecological niche modelling and habitat suitability modelling. All three books provide excellent introductions to these topics, but give very little information on the role thatBIOCLIMplayed in laying the foundation for these research areas. Understanding the history ofBIOCLIMis vital because it was the first package to implement the basicSDMprocess in an easy‐to‐use integrated system. It provided what are still the most commonly used set of 19 bioclimatic variables and contributed to the development of the interpolation routines used to prepare the most commonly used source of bioclimatic data (WorldClim). EarlyBIOCLIMstudies investigated important issues such as ecological niche, invasion risk, conservation planning and impacts of climate change. Although all three books acknowledge that theBIOCLIMpackage was important in earlySDMresearch, they all deal with the pioneering work very briefly and omit important details which are described here. Virtually all currentSDMstudies owe something to the pioneeringBIOCLIMwork, but this is rarely acknowledged.
Does an extreme age (≥80 years) affect outcomes in patients after liver cancer surgery? A meta‐analysis
Authors: Wei Fangqiang
Published: June 2018

Background

Increasing global life expectancy has resulted in a greater demand for cancer surgery in aged patients. However, whether extreme age causes poorer clinical outcomes remains unclear. This meta‐analysis aimed to evaluate the impact of extreme age (≥80 years) on outcomes in patients after liver cancer surgery.

Methods

A systematic search was performed to enrol relevant studies. Data were analysed using fixed‐effects or random‐effects models. Eight retrospective studies involving 253 participants older than 80 years were included.

Results

Compared with younger patients, patients of extreme age (≥80 years) who had undergone curative liver cancer surgery experienced less operating time and blood loss (both P < 0.0001); a larger size (weighted mean difference = 0.48 cm, 95% confidence interval (CI) 0.08–0.87 cm; P = 0.02) and more advanced stage of hepatocellular carcinoma (risk ratio (RR) = 1.20, 95% CI 1.04–1.39; P = 0.01); a higher overall morbidity (RR = 1.24, 95% CI 1.05–1.47; P = 0.01); and more post‐operative ileus (POI) (RR = 3.45, 95% CI 1.03–11.56; P = 0.04), delirium (RR = 3.04, 95% CI 1.36–6.78; P = 0.007) and cardiovascular events (RR = 6.17, 95% CI 2.79–13.60; P < 0.00001). No significant difference was noted in overall (hazard ratio (HR) = 1.15, 95% CI 0.87–1.53; P = 0.32) or disease‐free (HR = 0.96, 95% CI 0.75–1.24; P = 0.77) survival.

Conclusion

Although an extreme age may not be a contraindication for undertaking liver cancer surgery, it may cause more morbidity. Perioperative intervention should be considered for prevention and early treatment of POI, delirium and cardiovascular events.
Pattern of care for cancer of the oesophagus in a western population
Authors: Nguyen Thuy‐My N. , Hummel Richard , Bright Tim , Thompson Sarah K. , Tornqvist Bjorn , Watson David I.
Published: June 2018

Background

Most oesophageal outcome research focuses on surgical treatment, despite most patients not undergoing surgery as they are unfit or have metastatic disease. Few studies have evaluated the patterns of care for all patients presenting with oesophageal cancer.

Methods

All patients with oesophageal cancer, and high‐grade dysplasia (HGD), presented at the South Australian state‐wide upper gastrointestinal cancer multidisciplinary team from 2012 to 2015 were reviewed to determine the patterns of presentation and treatment.

Results

A total of 375 patients were included. Diagnosis was adenocarcinoma in 69.6%, squamous cell carcinoma in 24.8% and HGD in 5.6%. The majority of patients presented with stages II and III disease (56.8%). A total of 51.5% were treated with curative intent, with 28.8% undergoing surgery and/or neoadjuvant therapy. Treatment was palliative in 48.5%, with chemoradiotherapy utilized in 20.8%. Disease stage and age impacted treatment intent. All patients with HGD received curative treatment versus 89.7%/63.8%/1% of patients with stage I/II and III/IV disease, respectively. A total of 56.9% of patients <80 years received curative treatment versus 25% of those >80 years old.

Conclusion

Whilst approximately half of patients underwent treatment with curative intent, only a minority underwent surgery. Future efforts to improve survival outcomes for oesophageal cancer should address patients who are unfit for surgery and those presenting with metastatic disease.
Use of topical ocular antibiotics in young children: a Scandinavian drug utilization study
Authors: Andersson Jasmine , Hofsli Mikael , Gade Uffe Lomholt , Heegaard Steffen , Pottegård Anton
Published: June 2018

Purpose

Acute infectious conjunctivitis is a common disease. While usually self‐limiting, children often receive treatment to be accepted back into nursery, day care or school. We aimed to describe trends in the utilization of topical ocular antibiotics in young children aged 0–4 years in Denmark, Norway and Sweden.

Methods

Using individual‐level data from the Danish National Prescription Registry (2000–2015), we provided detailed descriptions of treatment patterns at the individual level, stratified by age (0–1 years, 2–4 years) and antibiotic substance. Aggregate‐level data for Danish, Norwegian and Swedish children (0–4 years) were obtained from publicly available data sources (2000–2016).

Results

We identified 107 581 Danish children aged 0–4 years receiving 271 980 treatment episodes. The incidence rate was relatively stable between 2000 and 2010 (on average, 637 and 283/1000 person‐years for 0‐ to 1‐ and 2‐ to 4‐year‐olds, respectively), after which it dropped by 37% until 2015. In the aggregated data, a markedly higher use was seen in Denmark (211/1000 children in 2016) compared with Sweden (42) and Norway (151). The decrease from 2010 onwards was observed in all three countries. Chloramphenicol and fusidic acid were the most commonly used topical ocular antibiotics across Scandinavia. Tobramycin was rarely used in Norway and Sweden (≤1/1000 children in 2016) compared with Denmark (24/1000 children).

Conclusion

Considerable variation is seen in the utilization of topical ocular antibiotics among children in Scandinavia, with Denmark having the highest use. Across the Scandinavian countries, however, a decline was noted from 2010 onwards.
Seasonality of birth affects paediatric coeliac disease
Authors: Daniel Sharon , Kalansky Adie , Tsur Avishai , Pinsk Vered , Ling Galina , Rannan Ronit , Yerushalmi Baruch
Published: June 2018

Aim

This study investigated the seasonality of birth in children diagnosed with coeliac disease (CD) at a tertiary University hospital in Southern Israel.

Methods

This was a population‐based retrospective time series analysis study from January 1988 to December 2014. There were 308 903 live births at Soroka University Medical Centre during the study period and 699 were diagnosed with CD. We combined three databases covering births, CD diagnoses and weather indices. The daily proportion of births that resulted in CD for the different four seasons and high seasons were compared to the weather indices on the day of birth using negative binomial regression.

Results

Statistically significant associations were found between the season of birth and the rate of CD, with autumn births being associated with a higher risk for the development of CD than births during the summer, with an incidence ratio of 1.22. The association was further increased when the defined summer and autumn high seasons were used, with an incidence ratio of 1.40. No association was found between CD and the mean temperature and global radiation.

Conclusion

Coeliac disease was associated with birth during the autumn and the autumn high season posed an even more significant risk factor.
A first‐in‐man safety and pharmacokinetics study of nangibotide, a new modulator of innate immune response through TREM‐1 receptor inhibition
Authors: Cuvier Valerie , Lorch Ulrike , Witte Stephan , Olivier Aurelie , Gibot Sebastien , Delor Isabelle , Garaud Jean‐Jacques , Derive Marc , Salcedo‐Magguilli Margarita
Published: June 2018

Aims

The peptide nangibotide is the first clinical‐stage agent targeting the immunoreceptor TREM‐1 (triggering receptor expressed on myeloid cells‐1) and is being investigated as a novel therapy for acute inflammatory disorders such as septic shock. This first‐in‐man, randomized, double‐blind, ascending dose, placebo‐controlled Phase I study evaluated the safety, tolerability and pharmacokinetics of nangibotide.

Methods

Twenty‐seven healthy subjects (aged 18–45 years) were randomized into eight groups. Nangibotide was administered as a single continuous intravenous infusion. The first two groups received a single i.v. dose of 1 and 10 mg, respectively, over 15 min. Subsequent groups were randomized in a product : placebo ratio of 3:1 at doses ranging from 0.03 to 6 mg kg−1 h−1 over 7 h 45 min, preceded by a 15‐minute loading dose of up to 5 mg kg−1.

Results

Nangibotide was safe and well tolerated up to the highest dose tested. There were only few adverse events and they were mild in severity and considered unrelated to treatment. Nangibotide displayed dose‐proportional PK properties, with a clearance of 6.6 l kg−1 h−1 for a subject of 70 kg and a 3 min effective half‐life, which are compatible with extensive enzymatic metabolism in blood. Central and peripheral volumes of distribution were 16.7 l and 15.9 l respectively, indicating limited distribution of the drug mainly in blood and interstitial fluid. No circulating anti‐drug antibodies were detectable up to 28 days after administration.

Conclusions

The novel immunomodulator nangibotide displayed favourable safety and PK profiles at all doses, including expected pharmacologically active doses, and warrants further clinical development.
Communication with children about sickle cell disease: A qualitative study of parent experience
Authors: Middleton Joanne , Calam Rachel , Ulph Fiona
Published: June 2018

Objectives

This study aimed to explore how parents communicate with children affected by sickle cell disease, a condition associated with social and cultural complexities that pose risks to open parent–child communication.

Design

A contextualist approach informed the qualitative exploration of parent experience using an individual interview design.

Methods

Twelve semi‐structured interviews were conducted with parents whose child had a diagnosis of sickle cell disease. Interviews were audio‐recorded, transcribed verbatim, and analysed using inductive thematic analysis.

Results

Parental communication was aimed at educating and protecting children from the physical and emotional effects of SCD in an age appropriate way. Parents commonly described avoidant communication and a small number described using this as a more predominant approach. This appeared to relate to fears about SCD, stigma, and uncertainty about how to best to respond.

Conclusions

As a known mediator of child outcomes, communication offers a promising target for intervention. The findings of this study suggest that parents of children with SCD are likely to benefit from formal support to adapt their communication to their child's needs. Parenting interventions should, in future, include the SCD parent population as a specific group to benefit child outcomes.

Statement of contribution

What is already known on this subject?

Talking openly with children who have genetic conditions is known to promote acceptance and adjustment to illness. Sickle cell disease (SCD) is a genetic condition that is surrounded by various sociocultural issues that may act as barriers to parent–child communication. For example, it is condition that affects only Black and Minority Ethnic (BME) groups and is associated with longstanding stigma within BME communities due to the hereditary nature of the disease.

What does this study add?

It adds a unique focus on communication in the SCD parent population (previous work has tended to study this group alongside parents of various other genetic conditions).

The findings provide a rich insight into parent experience of communication with children about SCD.

It reveals that many parents find it difficult to talk openly with children and often avoid sensitive issues such as inheritance, physical limitations, and risk of death which has important implications for child coping and adjustment.

It is therefore recommended that health care services are designed to support parents with communication about SCD with their child.
The association between liver cirrhosis and fracture risk: A systematic review and meta‐analysis
Authors: Liang Jie , Meng Wei‐Dong , Yang Jun‐Ming , Li Sheng‐Long , Zhong Mi‐Na , Hou Xuan‐Xuan , Wang Ran , Long Yu‐Ying , Bao Liang‐Xiao , Bao Ming
Published: June 2018

Objective

Liver cirrhosis (LC) was associated with an increased risk of osteoporosis; however, the association between LC and fracture risk was inconclusive. Therefore, this systematic review and meta‐analysis aims to explore the association between LC and fracture risk.

Design

To identify related literature, a systematic search of PubMed, EMBASE, Web of science and the Cochrane Library from 1965 to July 2017 without language limitation was performed. The random‐effects model described by DerSimonian and Laird was used to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs).

Results

Eventually, 5 cohort and 3 case‐control studies were identified, which included 321 035 subjects and 31 272 fracture cases. The pooled OR of the association between LC and any fracture risk, hip fracture, spine/trunk fracture and limb fracture was 1.94 (95% CI, 1.59‐2.37), 2.11 (95% CI, 1.34‐3.32), 2.00 (95% CI, 1.50‐2.67) and 1.82 (95% CI, 1.65‐2.01), respectively.

Conclusion

In conclusion, this study indicates that cirrhotic patients have an increased risk of fracture. Preventive measures should be instituted as early as possible.
Changes over time in hip fracture risk: Greater improvements in men compared to women
Authors: Smith Roger , Perera Buddhini K. , Chan Daniela W.C.
Published: June 2018

Purpose

The aim of this study was to determine whether there has been a change in the mean age and age‐standardized incidence of minimal trauma hip fractures in the Newcastle and Lake Macquarie population of Australia between 1998 and 2015.

Method

Patients with neck of femur fractures over 50 who presented to the regional referral centre were retrospectively identified using the ICD‐9 and ICD‐10 coding system.

Results

There were 233 and 308 eligible patients in 1998 and 2015, respectively. For females, the mean age for hip fracture of 83.2 years in 1998 was not significantly different from the mean age of 84.5 years in 2015 (P = .16). For males, the mean age for hip fracture was significantly older at 84.6 years in 2015 compared to 80.4 years in 1998 (P = .005). For females, the decrease in the rate of hip fracture from 1998 to 2015 was 13% and was weakly statistically significant (IRR = 0.86, P = .05). For males, there was a statistically significant decrease in the rate of hip fractures from 1998 to 2015 by 33% (IRR = 0.67, P = .001).

Conclusion

Our study shows a decrease in age‐standardized rates of hip fractures for men and women and suggests that men are demonstrating a greater improvement in bone health compared to women.
Direct Taxation and State–Society Relations in Lagos, Nigeria
Authors: Gatt Leah , Owen Oliver
Published: June 2018

Existing research suggests that external sources of finance, such as foreign aid and natural resource rents, allow states to generate revenue independently of their societies, disincentivizing them from forming close links with their citizens and severely problematizing the notion of a social contract. In Lagos, Nigeria's commercial capital, a series of personal income tax reforms have seen an increase in taxpayer compliance. Considering Lagosians’ perceptions of their relation with the state government, this study examines whether the state had to ‘earn’ its revenue by developing a closer relationship with its citizens, and whether citizens responded through a greater willingness to pay tax. It explores how citizens understand this relationship, what role they perceive themselves to fulfil, and what their expectations are for the future of state–society relations. The study shows how, through efforts to visibly link tax to service delivery, a social contract is emerging between Lagos State and its citizens — but that this relationship differs among groups, in that it is shaped by pre‐existing concepts of public organization and modes of political engagement.
Smallholder Adaptation to Drought in Costa Rica's Crony Capitalist Rice Economy
Authors: Warner Benjamin P. , Childers Daniel L. , Kuzdas Christopher , Stocks Gabriela
Published: June 2018

This article advances theoretical understanding of exclusionary politics in rural locations through an institutional analysis of adaptation to climate change in Costa Rica's rice economy. It describes how crony capitalism evolved in state‐sponsored rural development as the national economy moved towards a new neoliberal model. Cronies reorganized rice production and re‐appropriated capital flows. As smallholder farmers were marginalized in the rice economy, their reliance on the state for irrigation water made them vulnerable to drought. As the state adapted its water allocation scheme to drought conditions, it determined who would profit and who would lose their livelihood. The authors use this analysis to argue that climate change adaptation is a normative process that may be used to justify coercion and control of specific classes of people. To understand this process, current adaptation frames must be broadened to include the organization of production and the appropriation and realization of capital flows. This broadening facilitates an understanding of how climate change adaptation strategies produce stratified class structures; some classes are made vulnerable to climate change while others profit. Breaking with the common refrain in much of the critical literature on neoliberal development, the authors argue that state responses to neoliberal change — not just neoliberal change itself — must be increasingly incorporated into critical development studies of rural transformations.
Iloprost infusion prevents the insulin‐induced reduction in skeletal muscle microvascular blood volume but does not enhance peripheral glucose uptake in type 2 diabetic patients
Authors: Emanuel Anna L. , de Clercq Nicolien C. , Koopen Annefleur M. , van Poelgeest Erik , Serlie Mireille J. M. , van Raalte Daniel H. , Kramer Mark H. H. , Nieuwdorp Max , Eringa Etto C. , Serné Erik H.
Published: June 2018

Aims

In type 2 diabetes impaired insulin‐induced muscle perfusion is thought to contribute to reduced whole‐body glucose uptake. In this study, we examined the effects of iloprost, a stable prostacyclin analogue, on insulin‐induced muscle capillary recruitment and whole‐body glucose uptake.

Materials and Methods

In a randomized cross‐over design, 12 type 2 diabetes patients (age, 55 [46‐69] years; BMI, 33.1 [31.0‐39] kg/m2) underwent two hyperinsulinaemic‐euglycaemic clamps, one with and one without simultaneous low‐dose iloprost infusion. Contrast‐enhanced ultrasonography of the vastus lateralis muscle was performed before and during the clamp. Muscle capillary recruitment was calculated as percentage change in microvascular blood volume (MBV) before and during the clamp.

Results

Insulin infusion reduced skeletal muscle MBV by ~50% compared to the fasting state (fasting, 1.77·10−4 [1.54·10−5–2.44·10−3] arbitrary units (AU); hyperinsulinaemia, 6.69·10−5 [2.68·10−6–5.72·10−4] AU; P = 0.050). Infusion of iloprost prevented this insulin‐induced skeletal muscle capillary derecruitment, from (−49.5 [−89.5 to 55.3] %) to (8.0 [−68.8 to 306.6] %), for conditions without and with iloprost, respectively. The rate of glucose disappearance (Rd) did not change significantly during iloprost infusion (17.3 [10.0‐40.8] μmol/kg/min) compared with insulin infusion alone (17.6 [9.9‐68.7] μmol/kg/min).

Conclusions

Our data suggest that acute improvement in insulin‐stimulated muscle perfusion is not an attractive therapeutic approach to bypass cellular resistance to glucose uptake in type 2 diabetes. Whether long‐term improvements in insulin‐induced muscle perfusion may prove beneficial for glucose disposal remains to be determined.
WHY ARE U.S. WOMEN DECREASING THEIR LABOR FORCE PARTICIPATION IF THEIR WAGES ARE RISING?
Authors: Huang Chen
Published: June 2018

Given the traditional interpretation of women's labor force participation rate (LFPR) trends as movements along a positively sloped labor supply curve, it is surprising that the recent downward trend in U.S. women's LFPR has occurred over a period when women's real wages were commonly believed to be rising. I find that almost two‐thirds of the decline since 2000 is attributable to aging of the adult female population. The remainder, due to declining labor force participation for women under 55, becomes less puzzling in light of my evidence that the wage/education locus faced by women actually may have worsened since 2000. (JEL J21, J31, J82)
Social defeat stress induces hyperalgesia and increases truncated BDNF isoforms in the nucleus accumbens regardless of the depressive‐like behavior induction in mice
Authors: Pagliusi Jr Marco Oreste Finocchio , Bonet Ivan José Magayewski , Dias Elayne Vieira , Vieira André Schwambach , Tambeli Claudia Herrera , Parada Carlos Amilcar , Sartori Cesar Renato
Published: June 2018

Epidemiological studies have shown a close association between pain and depression. There is evidence showing this association as patients with depression show a high chronic pain prevalence and vice versa. Considering that social stress is critical for the development of depression in humans, we used a social defeat stress (SDS) model which induces depressive‐like behavior in mice. In this model, mice are exposed to an aggressor mouse for ten days, suffering brief periods of agonistic contact and long periods of sensory contact. Some mice display social avoidance, a depressive‐like behavior, and are considered susceptible, while some mice do not, and are considered resilient. Thus, we investigated the nociceptive behavior of mice submitted to SDS and the neuroplastic changes in dopaminergic mesolimbic system. Our results showed that the stressed mice (resilient and susceptible) presented a higher sensitivity to pain than the control mice in chemical and mechanical tests. We also verified that susceptible mice have higher Bdnf mRNA in the VTA compared to the resilient and control mice. The stressed mice had less mature BDNF and more truncated BDNF protein in the NAc compared with control mice. Although social stress may trigger the development of depression and hyperalgesia, these two conditions may manifest independently as social stress induced hyperalgesia even in mice that did not display depressive‐like behavior. Also, increased Bdnf in the VTA seems to be associated with depressive‐like behavior, whereas high levels of truncated BDNF and low mature BDNF appear to be associated with hyperalgesia induced by social defeat stress.
Positive externalities of CEO delta
Authors: Feng Hongrui , Jia Yuecheng
Published: June 2018

Increases in delta incentives are dramatic for a small group of firms (leader firms) but negligible for the majority. We show that leader firms have larger market capitalization and higher irreversibility, and are in industries with negative shocks. When leader firms experience substantial growth in delta incentives, industry peers experience positive abnormal returns and abnormal improvement in fundamentals despite no significant change in delta. Further, we provide evidence that abnormal returns are induced by peer CEOs’ extra efforts in response to the increasing competitive pressure caused by leader firms. To mitigate their competitive pressure and turnover threat, peer CEOs allocate their extra efforts to firms’ operating efficiency and product differentiation.
A microbial role in the construction of Mono Lake carbonate chimneys?
Authors: Brasier Alexander , Wacey David , Rogerson Mike , Guagliardo Paul , Saunders Martin , Kellner Siri , Mercedes‐Martin Ramon , Prior Tim , Taylor Colin , Matthews Anna , Reijmer John
Published: June 2018

Lacustrine carbonate chimneys are striking, metre‐scale constructions. If these were bioinfluenced constructions, they could be priority targets in the search for early and extraterrestrial microbial life. However, there are questions over whether such chimneys are built on a geobiological framework or are solely abiotic geomorphological features produced by mixing of lake and spring waters. Here, we use correlative microscopy to show that microbes were living around Pleistocene Mono Lake carbonate chimneys during their growth. A plausible interpretation, in line with some recent works by others on other lacustrine carbonates, is that benthic cyanobacteria and their associated extracellular organic material (EOM) formed tubular biofilms around rising sublacustrine spring vent waters, binding calcium ions and trapping and binding detrital silicate sediment. Decay of these biofilms would locally have increased calcium and carbonate ion activity, inducing calcite precipitation on and around the biofilms. Early manganese carbonate mineralisation was directly associated with cell walls, potentially related to microbial activity though the precise mechanism remains to be elucidated. Much of the calcite crystal growth was likely abiotic, and no strong evidence for either authigenic silicate growth or a clay mineral precursor framework was observed. Nevertheless, it seems likely that the biofilms provided initial sites for calcite nucleation and encouraged the primary organised crystal growth. We suggest that the nano‐, micro‐ and macroscale fabrics of these Pleistocene Mono Lake chimneys were affected by the presence of centimetre‐thick tubular and vertically stacked calcifying microbial mats. Such carbonate chimneys represent a promising macroscale target in the exploration for ancient or extraterrestrial life.
Combining stable isotope analysis and conventional techniques to improve knowledge of the diet of the European Roller Coracias garrulus
Authors: Catry Inês , Sampaio Ana , Silva Mónica C. , Moreira Francisco , Franco Aldina M. A. , Catry Teresa
Published: June 2018

Diet studies are crucial for understanding the ecology and evolution of species, as well as for establishing appropriate conservation and management strategies. However, they remain methodologically challenging due to variation between seasons, sites, sexes or age groups and even variation between individuals. Due to method‐specific characteristics and biases, a combination of existing techniques can overcome the inherent limitations of each technique and provide a more accurate and broad picture of species’ food preferences. Here, we examine diet information obtained using three different assessment methods to better understand the trophic ecology of the European Roller Coracias garrulus, a species targeted by conservation measures in Europe. First, we analysed regurgitated pellets and video‐recordings to report the diet composition of adult and nestling Rollers, respectively. Secondly, we used stable isotope analysis (SIA) to investigate adult sexual diet segregation as well as to confirm the main findings regarding adult and nestling diets obtained through conventional methods. Based on the analysis of pellets, the diet of adult Rollers was dominated by Coleoptera, whereas camera images revealed that the diet of nestlings was dominated by Orthoptera, mainly grasshoppers and bush crickets. Blood isotopic signatures of adult and nestling Rollers confirmed the results obtained through pellet and video‐recording techniques. Of the three methods, pellet analysis provided the most comprehensive trophic information regarding the detectable prey spectrum and prey species contribution, as well as basic diet information for the SIA. Our results also highlight the potential of SIA for assessing intraspecific variation in diet by sampling individuals of known age and sex, which is often unfeasible through conventional approaches. SIA analysis showed no differences in δ13C and δ15N ratios of blood between males and females and a high degree of overlap amongst isotopic niches, suggesting no sex‐specific partitioning in resource use. Overall, we showed that the combination of different methods could be used to gain new and clearer insights into avian trophic ecology that are essential for informing habitat management aiming to improve availability of foraging resources.