bluuebunny/crossref_metadata_2025 huggingface dataset:
Sequence-structure-function relationships in class I MHC: a local frustration perspective
Authors: Serçinoğlu Onur , Ozbek Pemra
Published: December 2019

Class I Major Histocompatibility Complex (MHC) binds short antigenic peptides with the help of Peptide Loading Complex (PLC), and presents them to T-cell Receptors (TCRs) of cytotoxic T-cells and Killer-cell Immunglobulin-like Receptors (KIRs) of Natural Killer (NK) cells. With more than 10000 alleles, the Human Leukocyte Antigen (HLA) chain of MHC is the most polymorphic protein in humans. This allelic diversity provides a wide coverage of peptide sequence space, yet does not affect the three-dimensional structure of the complex. Moreover, TCRs mostly interact with pMHC in a common diagonal binding mode, and KIR-pMHC interaction is allele-dependent. With the aim of establishing a framework for understanding the relationships between polymorphism (sequence), structure (conserved fold) and function (protein interactions) of the MHC, we performed here a local frustration analysis on pMHC homology models covering 1436 HLA I alleles. An analysis of local frustration profiles indicated that (1) variations in MHC fold are unlikely due to minimally-frustrated and relatively conserved residues within the HLA peptide-binding groove, (2) high frustration patches on HLA helices are either involved in or near interaction sites of MHC with the TCR, KIR, or Tapasin of the PLC, and (3) peptide ligands mainly stabilize the F-pocket of HLA binding groove.

Author Summary

A protein complex called the Major Histocompatibility Complex (MHC) plays a critical role in our fight against pathogens via presentation of antigenic peptides to receptor molecules of our immune system cells. Our knowledge on genetics, structure and protein interactions of MHC revealed that the peptide-binding groove of Human Leukocyte Chain (HLA I) of this complex is highly polymorphic and interacts with different proteins for peptide-binding and presentation over the course of its lifetime. Although the relationship between polymorphism and peptide-binding is well-known, we still lack a proper framework to understand how this polymorphism affects the overall MHC structure and protein interactions. Here, we used computational biophysics methods to generate structural models of 1436 HLA I alleles, and quantified local frustration within the HLA I, which indicates energetic optimization levels of contacts between amino acids. We identified a group of minimally frustrated and conserved positions which may be responsible for the conserved MHC structure, and detected high frustration patches on HLA surface positions taking part in interactions with other immune system proteins. Our results provide a biophysical basis for relationships between sequence, structure, and function of MHC I.
Mycolactone-independent pathogenicity ofMycobacterium ulcerans: an experimental study in plants
Authors: Bouam A. , Drancourt M.
Published: December 2019

Mycobacterium ulcerans, the etiologic agent of Buruli ulcer in humans and animals, secretes macrolide exotoxins mycolactones which damage tissues after a cascade of cellular effects.M. ulcerans, an environmental organism with still elusive reservoirs and sources has been detected in soil and water in endemic areas where it could be in contact with plants. Symptom observations, microscopy and molecular biology were used to investigateM. ulceranscontact with plants in an experimental model mimicking the known pathology of Buruli ulcer in humans.Solanum lycopereum(tomato) plants with scarified or intact roots were transplanted into pots containing contaminated soil withM. ulceransor a mixture of mycolactones A/B and C in the presence of negative control groups. Whereas plants with intact roots remained asymptomatic,M. ulcerans-infected plants with scarified roots had significantly more diseased leaves than controls (p = 0.004). Optic microscopy examination showed significantly more mycobacteria in the secondary and main roots than in controls (p=0.0008). Real-time PCRs detectedM. ulceransDNA in 7/12 (58%) of infected root samples versus none in the control plants (p = 0.04). Further study of plants with mycolactones A/B and C yielded no significant difference with negative controls. These results suggest that in this model,M. ulceransexhibits a mycolactone-independent pathogenicity whose mechanism remains to be elucidated.
Diffusion MRI free water is a sensitive marker of age-related changes in the cingulum
Authors: Edde Manon , Theaud Guillaume , Rheault François , Dilharreguy Bixente , Helmer Catherine , Dartigues Jean-François , Amieva Hélène , Allard Michèle , Descoteaux Maxime , Catheline Gwénaëlle
Published: December 2019

Diffusion MRI is extensively used to investigate changes in white matter microstructure. However, diffusion measures within white matter tissue can be affected by partial volume effects due to cerebrospinal fluid and white matter hyperintensities, especially in the aging brain. In previous aging studies, the cingulum bundle that plays a central role in the architecture of the brain networks supporting cognitive functions has been associated with cognitive deficits. However, most of these studies did not consider the partial volume effects on diffusion measures. The aim of this study was to evaluate the effect of free water elimination on diffusion measures of the cingulum in a group of 68 healthy elderly individuals. We first determined the effect of free water elimination on conventional DTI measures and then examined the effect of free water elimination on verbal fluency performance over 12 years. The cingulum bundle was reconstructed with a tractography pipeline including a white matter hyperintensities mask to limit the negative impact of hyperintensities on fiber tracking algorithms. We observed that free water elimination improved the sensitivity of conventional DTI measures to detect associations between tissue-specific diffusion measures of the cingulum and changes in verbal fluency in older individuals. Moreover, free water content measured along the cingulum was independently strongly associated with changes in verbal fluency. These observations suggest the importance of using free water elimination when studying brain aging and indicate that free water itself could be a relevant marker for age-related cingulum white matter modifications and cognitive decline.
Longitudinal change in executive function is associated with impaired top-down frontolimbic regulation during reappraisal in older adults
Authors: Lloyd William K. , Morriss Jayne , Macdonald Birthe , Joanknecht Karin , Nihouarn Julie , van Reekum Carien M.
Published: December 2019

Networks in the prefrontal cortex (PFC) that are important for executive function are also engaged in adaptive responding to negative events. These networks are particularly vulnerable to age-related structural atrophy and an associated loss of executive function, yet existing evidence suggests preserved emotion processing ability in aging. Using longitudinally acquired data from a battery of cognitive tasks, we defined a metric for the rate of decline of executive function. With this metric, we investigated relationships between changes in executive function and emotion reappraisal ability and brain structure, in older adults using functional and structural MRI. During task-based fMRI, participants were asked to cognitively reappraise negatively valenced images. We hypothesised one of two associations with decreasing executive function over time: 1) a decreased ability to reappraise reflected in decreased PFC and increased amygdala activation, or 2) a neural compensation mechanism characterised by increased PFC activation but no differential amygdala activation. Structurally, for a decreased reappraisal ability, we predicted a decrease in grey matter in PFC and/or a decrease of white matter integrity in amygdala-PFC pathways. Neither of the two hypotheses relating to brain function were completely supported, with the findings indicating a steeper decline in executive function associated with both increased PFC and increased left amygdala activity when reappraising negative stimuli. In addition, white matter integrity of the uncinate fasciculus, a primary white matter tract connecting the amygdala and ventromedial areas of PFC, was lower in those individuals who demonstrated a greater decrease in executive function. These findings highlight that when cognitive ability diminishes, active top-down emotional control is compromised.
Mitophagy contributes to alpha-tocopheryl succinate toxicity in GSNOR-deficient hepatocellular carcinoma
Authors: Rizza Salvatore , Di Leo Luca , Mandatori Sara , De Zio Daniela , Filomeni Giuseppe
Published: December 2019

The denitrosylating enzymeS-nitrosoglutathione reductase (GSNOR), has been reported to control the selective degradation of mitochondria through mitophagy, by modulating the extent of nitric oxide-modified proteins (S-nitrosylation). The accumulation ofS-nitrosylated proteins due to GSNOR downregulation is a feature of hepatocellular carcinoma, causing mitochondrial defects that sensitize these tumors to mitochondrial toxins, in particular to mitochondrial complex II inhibitor alpha-tocopheryl succinate (αTOS). However, it is not known if mitophagy defects contribute to GSNOR-deficient cancer cells sensitivity to αTOS, nor if mitophagy inhibition could be used as a common mechanism to sensitize liver cancers to this toxin. Here, we provide evidence that GSNOR-deficient cancer cells show defective mitophagy. Furthermore, we show that αTOS is a mitophagy inducer and that mitophagy defects of GSNOR-deficient liver cancer cells contribute to its toxicity. We finally prove that the inhibition of mitophagy by depletion of Parkin, a pivotal ubiquitin ligase targeting mitochondria for degradation, enhances αTOS toxicity, thus suggesting that this drug could be effective in treating mitophagy-defective tumors.
Minimally Complex Nucleic Acid Feedback Control Systems for First Experimental Implementations
Authors: Paulino Nuno M. G. , Foo Mathias , de Greef Tom F. A. , Kim Jongmin , Bates Declan G.
Published: December 2019

Chemical reaction networks based on catalysis, degradation, and annihilation may be used as building blocks to construct a variety of dynamical and feedback control systems in Synthetic Biology. DNA strand-displacement, which is based on DNA hybridisation programmed using Watson-Crick base pairing, is an effective primitive to implement such reactions experimentally. However, experimental construction, validation and scale-up of nucleic acid control systems is still significantly lagging theoretical developments, due to several technical challenges, such as leakage, crosstalk, and toehold sequence design. To help the progress towards experimental implementation, we provide here designs representing two fundamental classes of reference tracking control circuits (integral and state-feedback control), for which the complexity of the chemical reactions required for implementation has been minimised. The supplied ‘minimally complex’ control circuits should be ideal candidates for first experimental validations of nucleic acid controllers.
High resolution mapping of aHordeum bulbosum-derived powdery mildew resistance locus in barley using distinct homologous introgression lines
Authors: Hoseinzadeh Parastoo , Ruge-Wehling Brigitte , Schweizer Patrick , Stein Nils , Pidon Hélène
Published: December 2019

Powdery mildew caused byBlumeria graminisf.sp.hordei (Bgh)is one of the main foliar diseases in barley (Hordeum vulgareL.;Hv). Naturally occurring resistance genes used in barley breeding are a cost effective and environmentally sustainable strategy to minimize the impact of pathogens, however, the primary gene pool ofH. vulgarecontains limited diversity owing to recent domestication bottlenecks. To ensure durable resistance against this pathogen, more genes are required that could be unraveled by investigation of secondary barley gene-pool. A large set ofHordeum bulbosum(Hb) introgression lines (ILs) harboring a diverse set of desirable resistance traits have been developed and are being routinely used as source of novel diversity in gene mapping studies. Nevertheless, this strategy is often compromised by a lack of recombination between the introgressed fragment and the orthologous chromosome of the barley genome. In this study, we fine-mapped aHbgene conferring resistance to barley powdery mildew. The initial genotyping of twoHbILs mapping populations with differently sized 2HS introgressions revealed severely reduced interspecific recombination in the region of the introgressed segment, preventing precise localization of the gene. To overcome this difficulty, we developed an alternative strategy, exploiting intraspecific recombination by crossing twoHv/HbILs with collinearHbintrogressions, one of which carries a powdery mildew resistance gene, while the other doesn’t. The intraspecific recombination rate in theHb-introgressed fragment of 2HS was approximately 20 times higher than it was in the initial simple ILs mapping populations. Using high-throughput genotyping-by-sequencing (GBS), we allocated the resistance gene to a 1.4 Mb interval, based on an estimate using theHvgenome as reference, in populations of only 103 and 146 individuals respectively, similar to what is expected at this locus in barley. The most likely candidate resistance gene within this interval encodes a legume-type lectin-receptor-like protein (LecRLP). Like other LecRLPs that have been implicated in resistance, this gene could be a good candidate forHbresistance. The reported strategy can be applied as a general strategic approach for identifying genes underlying traits of interest in crop wild relatives.
ZBED2 is an antagonist of Interferon Regulatory Factor 1 and modulates cell identity in pancreatic cancer
Authors: Somerville Tim D.D. , Xu Yali , Wu Xiaoli S. , Vakoc Christopher R.
Published: December 2019

Lineage plasticity is a prominent feature of pancreatic ductal adenocarcinoma (PDA) cells, which can occur via deregulation of lineage-specifying transcription factors. Here, we show that the zinc finger protein ZBED2 is aberrantly expressed in PDA and alters tumor cell identity in this disease. Unexpectedly, our epigenomic experiments reveal that ZBED2 is a sequence-specific transcriptional repressor of interferon-stimulated genes, which occurs through antagonism of Interferon Regulatory Factor 1 (IRF1)-mediated transcriptional activation at co-occupied promoter elements. Consequently, ZBED2 attenuates the transcriptional output and growth arrest phenotypes downstream of interferon signaling in multiple PDA cell line models. We also found that ZBED2 is preferentially expressed in the squamous molecular subtype of human PDA, in association with inferior patient survival outcomes. Consistent with this observation, we show that ZBED2 can repress the pancreatic progenitor transcriptional program, enhance motility, and promote invasion in PDA cells. Collectively, our findings suggest that high ZBED2 expression is acquired during PDA progression to suppress the interferon response pathway and to promote lineage plasticity in this disease.

SIGNIFICANCE STATEMENT

Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancies, attributed in part to lineage infidelity downstream of deregulated lineage-specifying transcription factors (TFs). Here we define the biological effects of a poorly understood TF ZBED2 in the most aggressive subtype of PDA, defined by the expression of squamous lineage markers. Our study reveals two molecular functions of ZBED2 in PDA cells: an inhibitor of interferon response genes and a modifier of epithelial lineage programs. Both functions can be explained by the ability of ZBED2 to antagonize the functional output of Interferon Regulatory Factor-1 (IRF1). Our study reinforces the concept of aberrant lineage identity in cancer and highlights an unexpected connection between interferon response pathways and squamous-subtype PDA.
Allopatric speciation is more prevalent than parapatric ecological divergence in a recent high-Andean diversification (Asteraceae:Linochilus)
Authors: Vargas Oscar M. , Madriñán Santiago , Simpson Beryl B.
Published: December 2019

Elucidating how species accumulate in diversity hotspots is an ongoing debate in evolutionary biology. The páramo, in the Northern Andes, has remarkably high indices of plant diversity, endemicity, and diversification rates. A hypothesis for explaining such indices is that allopatric speciation is high in the páramo given its island-like distribution; an alternative hypothesis is that the altitudinal gradient of the Andean topography provides a variety of niches that drive vertical parapatric ecological speciation. A formal test for evaluating the relative roles of allopatric speciation and parapatric ecological divergence is lacking. The main aim of our study is to test which kind of speciation is more common in an endemic páramo genus. We developed a framework incorporating phylogenetics, species’ distributions, and a morpho-ecological trait (leaf area) to compare sister species and infer whether allopatric or parapatric ecological divergence caused their speciation. We applied our framework to the species-rich genusLinochilus(63 spp.) and found that the majority of recent speciation events in it (12, 80%) have been driven by allopatric speciation, while a smaller fraction (1, 6.6%) is attributed to parapatric ecological divergence; two pairs produced inconclusive results (13.3%). We conclude that páramo autochthonous diversification is primarily driven by allopatric speciation.
Structural analysis of nonapeptides derived from elastin
Authors: Hernandez B , Crowet JM , Thiery J , Kruglik SG , Belloy N , Baud S , Dauchez M , Debelle L
Published: December 2019

Elastin-derived peptides are released from the extracellular matrix remodeling by numerous proteases and seem to regulate many biological processes, notably cancer progression. The canonical elastin peptide is VGVAPG which harbors the XGXXPG consensus pattern allowing interaction with the elastin receptor complex located at the surface of cells. Besides these elastokines, another class of peptides has been identified. This group of bioactive elastin peptides presents the XGXPGXGXG consensus sequence but the reason for their bioactivity remains unexplained. In order to better understand their nature and structure-function relationships, herein we searched the current databases for this nonapeptide motif and observed that the XGXPGXGXG elastin peptides define a specific group of tandemly repeated patterns. Further, we focused on four tandemly repeated human elastin nonapeptides,i.e.AGIPGLGVG, VGVPGLGVG, AGVPGLGVG and AGVPGFGAG. These peptides were analysed by means of optical spectroscopies and molecular dynamics. UV-circular dichroism and Raman spectra are consistent with a conformational equilibrium between β-turn, β-strand and random chain secondary elements in aqueous media. This equilibrium was found to be concentration-independent. Quantitative analysis of their conformations suggested that turns corresponded to half of the total population of structural elements while the remaining half was equally distributed between β-strand and unordered chains. These distributions were confirmed by molecular dynamics simulations. Altogether, our data suggest that these peptides harbor a type II β-turn located in their central part. We hypothesize that this structural element could explain their specific bioactivity.

Statement of Significance

Elastin fragmentation products, the so-called elastin peptides, may exhibit a bioactivity towards normal and tumor cells. This phenomenon depends on the sequence motif they harbor. While XGXXPG sequences bioactivity is explained by the presence of a type VIII β-turn allowing interaction with the elastin receptor complex, the structural reasons for XGXPGXGXG specific activity remain unexplained. Using data mining, we show that elastin nonapeptides define a specific class of tandemly repeated features. Further, spectroscopic and numerical simulations methods suggest the presence of a type II β-turn in their conformation. This structural element could explain their bioactivity.
Quantifying the polygenic architecture of the human cerebral cortex: Extensive genetic overlap between cortical thickness and surface area
Authors: van der Meer Dennis , Frei Oleksandr , Kaufmann Tobias , Chen Chi-Hua , Thompson Wesley K. , O’Connell Kevin S. , Monereo Sánchez Jennifer , Linden David E.J. , Westlye Lars T. , Dale Anders M. , Andreassen Ole A.
Published: December 2019

Introduction

The thickness of the cerebral cortical sheet and its surface area are highly heritable traits thought to have largely distinct polygenic architectures. Despite large-scale efforts, the majority of their genetic determinants remains unknown. Our ability to identify causal genetic variants can be improved by employing better delineated, less noisy brain measures that better map onto the biology we seek to understand. Such measures may have fewer variants but with larger effects, i.e. lower polygenicity and higher discoverability.

Methods

Using Gaussian mixture modeling, we estimated the number of causal variants shared between mean cortical thickness and total surface area. We further determined the polygenicity and discoverability of regional cortical measures from five often-employed parcellation schemes. We made use of UK Biobank data from 31,312 healthy White European individuals (mean age 55.5, standard deviation (SD) 7.4, 52.1% female).

Results

Contrary to previous reports, we found large genetic overlap between total surface area and mean thickness, sharing 4427 out of 7150 causal variants. Regional surface area was more discoverable (p=4.1×10−6) and less polygenic (p=.007) than regional thickness measures. We further found that genetically-informed and less granular parcellation schemes had highest discoverability, with no differences in polygenicity.

Conclusions

These findings may serve as a roadmap for improved future GWAS studies; Knowledge of which measures or parcellations are most discoverable, as well as the genetic overlap between these measures, may be used to boost identification of genetic predictors and thereby gain a better understanding of brain morphology.
The α-synuclein hereditary mutation E46K unlocks a more stable, pathogenic fibril structure
Authors: Boyer David R. , Li Binsen , Sun Chuanqi , Fan Weijia , Zhou Kang , Hughes Michael P. , Sawaya Michael R. , Jiang Lin , Eisenberg David S.
Published: December 2019

Aggregation of α-synuclein is a defining molecular feature of Parkinson’s disease, Lewy Body Dementia, and Multiple Systems Atrophy. Hereditary mutations in α-synuclein are linked to both Parkinson’s disease and Lewy Body Dementia; in particular, patients bearing the E46K disease mutation manifest a clinical picture of parkinsonism and Lewy Body Dementia, and E46K creates more pathogenic fibrils in vitro. Understanding the effect of these hereditary mutations on α-synuclein fibril structure is fundamental to α-synuclein biology. We therefore determined the cryoEM structure of α-synuclein fibrils containing the hereditary E46K mutation. The 2.5 Å structure reveals a symmetric double protofilament in which the molecules adopt a vastly re-arranged, lower energy fold compared to wild-type fibrils. We propose that the E46K misfolding pathway avoids electrostatic repulsion between K46 and K80, a residue pair which forms the E46-K80 salt-bridge in the wild-type fibril structure. We hypothesize that under our conditions the wild-type fold does not reach this deeper energy well of the E46K fold because the E46-K80 salt bridge diverts α-synuclein into a kinetic trap – a shallower, more accessible energy minimum. The E46K mutation apparently unlocks a more stable and pathogenic fibril structure.

Significance Statement

Parkinson’s is the second most prevalent neurodegenerative condition, leading to movement disorders, and dementia in some cases. Because of the strong association of this condition with amyloid aggregates of the protein α-synuclein, structural understanding of these amyloid aggregates may be the path to eventual therapies. Our study of the structure of a variant α-synuclein inherited in families afflicted with a clinical picture of parkinsonism and Lewy Body Dementia supplements recent structures of the wild type structure, and shows how a single residue change can result in a greatly changed structure that may underlie the inherited form of the disease.
Microbial single-cell RNA sequencing by split-pool barcoding
Authors: Kuchina Anna , Brettner Leandra M. , Paleologu Luana , Roco Charles M. , Rosenberg Alexander B. , Carignano Alberto , Kibler Ryan , Hirano Matthew , DePaolo R. William , Seelig Georg
Published: December 2019

Single-cell RNA-sequencing (scRNA-seq) has become an essential tool for characterizing multi-celled eukaryotic systems but current methods are not compatible with bacteria. Here, we introduce microSPLiT, a low cost and high-throughput scRNA-seq method that works for gram-negative and gram-positive bacteria and can resolve transcriptional states that remain hidden at a population level. We applied microSPLiT to >25,000Bacillus subtiliscells sampled from different growth stages, creating a detailed atlas of changes in metabolism and lifestyle. We not only retrieve detailed gene expression profiles associated with known but rare states such as competence and PBSX prophage induction, but also identify novel and unexpected gene expression states including heterogeneous activation of a niche metabolic pathway in a subpopulation of cells. microSPLiT empowers high-throughput analysis of gene expression in complex bacterial communities.
Wars, public finances and interest rates for rural lending: evidence from 19th-century Lima
Authors: Zegarra Luis Felipe
Published: December 2019

Purpose

The purpose of this paper is to analyze the effect of political instability on rural credit in Lima between 1835 and 1865. In particular, it explores the effects of wars on interest rates for the agricultural sector.

Design/methodology/approach

The paper relies on primary sources for the study of the early credit market of Lima. In particular, the study relies on a sample of more than 800 notarized loans for 1835–1865, collected from the National Archives of Peru, to determine the effect of wars on the cost of credit.

Findings

The evidence shows that wars increased interest rates on rural loans and that the impact of wars on the cost of credit was greater when the State lacked fiscal resources. Political instability made funding more costly for landlords and farmers, especially in the late 1830s and early 1840s.

Originality/value

This paper is one of the few historical studies on the role of wars on rural credit in Latin America. It contributes to our understanding of the linkages between political instability and financial development.
The effect of government spending innovations on the Ethiopian economy
Authors: Gereziher Hayelom Yrgaw , Nuru Naser Yenus
Published: December 2019

Purpose

The purpose of this paper is to estimate the size of government spending components’ multipliers for the Ethiopian economy over the sample period of 2001Q1 up to 2017Q4.

Design/methodology/approach

The effects of government spending are analyzed by applying short-run contemporaneous restrictions for the identification of shocks in an SVAR in order to estimate multipliers for the small open economy. Accordingly, recursive identification scheme is used in this study.

Findings

From the impulse response functions, the authors found that aggregate government spending is less effective in stimulating the economy for the study period as evidenced by almost zero multipliers. This can be due to many structural and conjunctural factors that tend to lower the multiplier effects. At a disaggregate level, real GDP responds negatively to capital spending while its effect on recurrent spending is positive and insignificant on impact. The variation to real GDP is best explained by the variation in capital spending as compared to recurrent spending.

Originality/value

Though almost none in number, little research has been conducted in Ethiopia related to the effect of government spending shock on output. But this research deviates from the previous study by introducing a new methodology which is SVAR with cholesky decomposition. The previous study, however, used Bayesian VAR. Besides to that, using cholesky identification scheme, government spending is decomposed in to recurrent and capital spending to see the effect of government spending components on output and government spending multipliers are also computed both at an aggregate and disaggregate level.
Modeling and numerical simulation for flow of hybrid nanofluid (SiO2/C3H8O2) and (MoS2/C3H8O2) with entropy optimization and variable viscosity
Authors: Khan Muhammad Ijaz , Ahmad Khan Sohail , Hayat Tasawar , Waqas Muhammad , Alsaedi Ahmed
Published: December 2019

Purpose

The purpose of this paper is to investigate the entropy optimization in magnetohydrodynamic hybrid nanomaterials flows toward a stretchable surface. The energy expression is modeled subject to dissipation, heat generation/absorption and Joule heating. Here silicon dioxide (SiO2) and molybdenum disulfide (MoS2) as nanoparticles and propylene glycol (C3H8O2) as base fluid, respectively. Furthermore, the authors discussed the comparative study of molybdenum disulfide and silicon dioxide diluted in propylene glycol. The total entropy optimization rate is computed through implementation of the second law of thermodynamics.

Design/methodology/approach

The nonlinear partial differential system is reduced to an ordinary one through implementation of transformation. Newton built-in shooting method is used for computational results for the given system. Influences of various flow variables on the temperature, Bejan number, velocity, concentration and entropy generation rate are examined graphically for both nanoparticles (SiO2 and MoS2). Gradients of velocity and temperature are computed numerically for various physical parameters. Also, take the comparison between the present and previously published results in tabulated form.

Findings

For higher estimation of ϕ both temperature and velocity are enhanced. Entropy optimization and Bejan number have the opposite outcome for viscosity parameter. Temperature and velocity have opposite behaviors for larger values of magnetic parameter. Molybdenum disulfide (MoS2) is more efficient than silicon dioxide (SiO2).

Originality/value

No such work is yet published in the literature.
Practitioner perspectives of multi-agency safeguarding hubs (MASH)
Authors: Shorrock Sarah , McManus Michelle M. , Kirby Stuart
Published: December 2019

Purpose

The challenges of transferring the theoretical requirements of an effective multi-agency partnership into everyday practices are often overlooked, particularly within safeguarding practices. Therefore, the purpose of this paper is to explore practitioner perspectives of working within a multi-agency safeguarding hub (MASH) and those factors that encourage or hinder a multi-agency approach to safeguarding vulnerable individuals.

Design/methodology/approach

Semi-structured interviews with 23 practitioners from one MASH location in the North of England were conducted, with a thematic analysis being used to analyse findings.

Findings

The interviews with practitioners illustrated the complexity of establishing a multi-agency approach to safeguarding. It was inferred that whilst information sharing and trust between agencies had improved, the absence of a common governance structure, unified management system, formalisation of practices and procedures and shared pool of resources limited the degree to which MASH could be considered a multi-agency approach to safeguarding.

Practical implications

Establishing a multi-agency approach to safeguarding is complex and does not occur automatically. Rather, the transition to collaborative practices needs to be planned, with agreed practices and processes implemented from the beginning and reviewed regularly.

Originality/value

Few studies have investigated the implementation of MASH into safeguarding practices, with this paper providing a unique insight into practitioner opinions regarding the transition to multi-agency practices. Whilst there is a focus on MASH, the challenges to arise from the research may be reflective of other multi-agency partnerships, providing a foundation for best practice to emerge.
Healing work
Authors: Suiter Sarah V. , Wilfong C. Danielle
Published: December 2019

Purpose

The purpose of this paper is to explore women’s experiences in one such social enterprise, and to analyze the ways in which this social enterprise supports and/or undermines its employees’ health and well-being. Finding and keeping employment during recovery from addiction is a strong predictor of women’s ability to maintain sobriety and accomplish other important life goals. Many treatment organizations have programs that support job readiness and acquisition; however, less priority is placed on the quality of the workplaces and their consequences for continued health and well-being. Social enterprises that exist for the purpose of employing women in recovery have the potential to be health-promoting workspaces, but understanding how health is supported for this particular population is important.

Design/methodology/approach

This paper provides an ethnographic account of Light Collective, a social enterprise run by women in recovery from addiction. Data were collected through 2 years of participant observation, 38 interviews and 2 focus groups. Data were analysed using a grounded theory approach.

Findings

Light Collective provides a health-promoting workplace by keeping barriers to employment low and making work hours and expectations individualized and flexible. Furthermore, the organization creates a setting in which work is developmentally nurturing, provides the opportunity for meaningful mastery and serves to build community amongst women who are often marginalized and isolated in more traditional contexts.

Originality/value

This study contributes to literature exploring the potential for social enterprises to create health-promoting workplaces by focusing the types of workplace commitments required to support a particularly vulnerable population. This study also explores some of the challenges and contradictions inherent in trying to create health-promoting work environments vis-à-vis the constraints of broader economic systems.
Ibuprofen Plus Acetaminophen Versus Ibuprofen Alone for Acute Low Back Pain: An Emergency Department–based Randomized Study
Authors: Friedman Benjamin W. , Irizarry Eddie , Chertoff Andrew , Feliciano Carmen , Solorzano Clemencia , Zias Eleftheria , Gallagher E. John
Published: December 2019

Objectives

Patients with low back pain (LBP) are often treated with nonsteroidal anti‐inflammatory drugs (NSAIDs). NSAIDs are modestly effective for LBP, but many patients with LBP continue to suffer despite treatment with these medications. We compared pain and functional outcomes 1 week after emergency department (ED) discharge among patients randomized to a 1‐week course of ibuprofen plus acetaminophen versus ibuprofen plus placebo.

Methods

This was a randomized, double‐blind study conducted in two urban EDs. Patients presenting with acute, nontraumatic, nonradicular LBP of no more than 2 weeks’ duration were eligible for enrollment immediately prior to discharge from an ED if they had a score > 5 on the Roland Morris Disability Questionnaire (RMDQ), a 24‐item validated instrument, indicating more than minimal functional impairment. All patients were given a standardized 10‐minute LBP educational session prior to discharge. The primary outcome was improvement on the RMDQ between ED discharge and 1 week later. One secondary outcome was pain intensity, as measured on a 4‐point descriptive scale (severe, moderate, mild, none) at 1 week.

Results

Enrollment began in October 2018. A total of 120 patients met selection criteria and were randomized. Baseline demographic characteristics were comparable between the two groups. By 1 week after the ED visit, patients randomized to ibuprofen plus placebo reported a mean (±SD) improvement in the RMDQ of 11.9 (±9.7), while those randomized to ibuprofen plus acetaminophen reported a mean (±SD) improvement of 11.1 (±10.7). The 95% CI for the between‐group difference of 0.8 was −3.0 to 4.7. At 1 week, moderate or severe pain was reported by 15 of 53 (28%) patients in the ibuprofen plus placebo group and 16 of 57 (28%) patients in the ibuprofen plus acetaminophen group (95% CI for between‐group difference of 0% = −17% to 17%).

Conclusion

Among ED patients with acute, nontraumatic, nonradicular LBP, adding acetaminophen to ibuprofen does not improve outcomes within 1 week.
Automatic aspects of response selection remain unchanged during high‐dose alcohol intoxication
Authors: Stock Ann‐Kathrin , Bensmann Wiebke , Zink Nicolas , Münchau Alexander , Beste Christian
Published: December 2019

Regular binge‐drinking increases the risk of developing alcohol use disorder (AUD) and induces similar acute effects on behavioral control, particularly in case of response selection conflicts. No such effects have been reported for automatic/bottom‐up response selection, even though AUD alters automaticity. However, it has never been reliably tested whether this domain is truly unchanged during high‐dose alcohol intoxication. To investigate this question with the help of Bayesian analyses, we subjected n=31 young healthy male participants to a within‐subject design, where each participant was tested twice in a counter‐balanced order (ie, once sober and once intoxicated at 1.1‰). On each appointment, the participants performed the S‐R paradigm, which assesses automatic stimulus‐response (S‐R) binding within the framework of the theory of event coding (TEC). In short, the TEC states that stimulus features and responses become encoded in an event file when they occur simultaneously. These event files will be reactivated by any matching stimulus feature, thus facilitating the encoded response (and hampering different responses). Alcohol led to a general decrease in behavioral performance, as demonstrated by significant main effects of intoxication status on accuracy and response times (all P ≤ .009). We also reproduced typical task effects, but did not find any significant interactions with the intoxication factor (all P ≥ .099). The latter was further substantiated by Bayesian analyses providing positive to strong evidence for the null hypothesis. Taken together, our results demonstrate that even high‐dose alcohol intoxication does not impair automatic response selection/S‐R associations.
Challenging Silences: Democratic Citizenship Education and Historical Memory in Poland and Guatemala
Authors: Rubin Beth C. , Cervinkova Hana
Published: December 2019

This paper draws upon data from two youth‐focused, ethnographically informed inquiries—one in Poland, the other in Guatemala—to describe how historical memory can conflict with both state historical narratives and with globalized approaches to democratic citizenship education. This analysis helps us to better understand the ways that, in post‐conflict societies, schools function as spaces in which overlapping claims of community, nation, and world frame the development of youth citizenship and belonging.
Infiltration of tumor‐associated macrophages is involved in tumor programmed death‐ligand 1 expression in early lung adenocarcinoma
Authors: Shima Toshiyuki , Shimoda Masayuki , Shigenobu Takao , Ohtsuka Takashi , Nishimura Tomoyasu , Emoto Katsura , Hayashi Yuichiro , Iwasaki Tatsuro , Abe Takayuki , Asamura Hisao , Kanai Yae
Published: December 2019

Programmed death‐ligand 1 (PD‐L1) is an immune modulator that promotes immunosuppression by binding to programmed death‐1 of T‐lymphocytes. Although tumor cell PD‐L1 expression has been shown to be associated with the clinical response to anti–PD‐L1 antibodies, its concise regulatory mechanisms remain elusive. In this study, we evaluated the associations of tumor PD‐L1 expression and immune cell infiltrating patterns in 146 cases of early lung adenocarcinoma (AC) to investigate the possible extrinsic regulation of tumor PD‐L1 by immune cells. Using immunohistochemistry, cell surface PD‐L1 expression in tumor cells was observed in 18.5% of stage 0‐IA lung AC patients. Tumor PD‐L1 positivity was significantly associated with stromal invasion, which was accompanied by increased tumor‐associated macrophages (TAM), CD8+ cytotoxic T cells and FoxP3+ regulatory T cells. Among these immune cells, TAM and CD8+ T cells significantly accumulated in PD‐L1‐positive carcinoma cell areas, which showed a tumor cell nest‐infiltrating pattern. Although CD8+ T cells are known to induce tumor PD‐L1 expression via interferon‐ɣ production, the increased TAM within tumors were also associated with tumor cell PD‐L1 positivity, independently of CD8+ T cell infiltration. Our in vitro experiments revealed that PD‐L1 expression in lung cancer cell lines was significantly upregulated by co–culture with M2‐differentiated macrophages; expression of PD‐L1 was reduced to baseline levels following treatment with a transforming growth factor‐β inhibitor. These results demonstrated that tumor‐infiltrating TAM are extrinsic regulators of tumor PD‐L1 expression, indicating that combination therapy targeting both tumor PD‐L1 and stromal TAM might be a possible strategy for effective treatment of lung cancer.
Young children are more likely to cheat after overhearing that a classmate is smart
Authors: Zhao Li , Chen Lulu , Sun Wenjin , Compton Brian J. , Lee Kang , Heyman Gail D.
Published: December 2019

Research on moral socialization has largely focused on the role of direct communication and has almost completely ignored a potentially rich source of social influence: evaluative comments that children overhear. We examined for the first time whether overheard comments can shape children's moral behavior. Three‐ and 5‐year‐old children (N = 200) participated in a guessing game in which they were instructed not to cheat by peeking. We randomly assigned children to a condition in which they overheard an experimenter tell another adult that a classmate who was no longer present is smart, or to a control condition in which the overheard conversation consisted of non‐social information. We found that 5‐year‐olds, but not 3‐year‐olds, cheated significantly more often if they overheard the classmate praised for being smart. These findings show that the effects of ability praise can spread far beyond the intended recipient to influence the behavior of children who are mere observers, and they suggest that overheard evaluative comments can be an important force in shaping moral development.
Hypoglycaemia is reduced with use of inhaled Technosphere® Insulin relative to insulin aspart in type 1 diabetes mellitus
Authors: Seaquist E. R. , Blonde L. , McGill J. B. , Heller S. R. , Kendall D. M. , Bumpass J. B. , Pompilio F. M. , Grant M. L.
Published: December 2019

Aim

To evaluate the effect of final HbA1c levels on the incidences of hypoglycaemia in participants with type 1 diabetes treated with inhaled Technosphere® Insulin or subcutaneous insulin aspart, reported in alignment with the International Hypoglycaemia Study Group recommendations.

Methods

In the randomized, phase 3, multicentre AFFINITY‐1 study, adults (N = 375) who had type 1 diabetes for ≥ 12 months and an HbA1c level of 58–86 mmol/mol (7.5–10.0%) were randomized to receive basal insulin plus either inhaled Technosphere Insulin or subcutaneous insulin aspart. This was a post‐hoc regression analysis on a subset (N = 279) of the randomized AFFINITY‐1 cohort for whom baseline and end‐of‐treatment HbA1c values were reported. Primary outcome measures were incidence and event rates for levels 1, 2 and 3 hypoglycaemia, respectively defined as blood glucose levels of ≤ 3.9 mmol/l, < 3.0 mmol/l or requiring external assistance for recovery.

Results

Participants treated with Technosphere Insulin experienced statistically significantly fewer level 1 and 2 hypoglycaemic events and a lower incidence of level 3 hypoglycaemia than participants treated with insulin aspart. The lower rate of hypoglycaemia with Technosphere Insulin was observed across the range of end‐of‐treatment HbA1c levels. Technosphere Insulin was associated with higher rates of hypoglycaemia 30–60 min after meals, but significantly lower rates 2–6 h after meals.

Conclusions

Participants using Technosphere Insulin experienced clinically non‐inferior glycaemic control and lower hypoglycaemia rates across a range of HbA1c levels compared with participants receiving insulin aspart. ClinicalTrials.gov: NCT01445951.
Increased risk of long‐term sickness absence, lower rate of return to work and higher risk of disability pension among people with type 1 and type 2 diabetes mellitus: a Danish retrospective cohort study with up to 17 years’ follow‐up
Authors: Nexø M. A. , Pedersen J. , Cleal B. , Bjorner J. B.
Published: December 2019

Aim

To evaluate labour market outcomes in type 1 or type 2 diabetes.

Methods

Individuals with type 1 (n = 431) and type 2 diabetes (n = 4047) were identified in Danish national registers from 1994 to 2011 and compared with individuals without diabetes (n = 101 295). Multi‐state Cox proportional hazards analyses estimated hazard ratios (HR) with 95% confidence intervals (CI) for transitions between work, sickness absence, unemployment and disability pension.

Results

We observed significantly higher HR of sickness absence in type 1 diabetes (women: 1.34, 95% CI 1.12–1.62; men: 1.43, 1.01–2.03) and type 2 diabetes (women: 1.46, 95% CI 1.35–1.58; men: 1.64, 1.46–1.85) compared with people without diabetes. HR of unemployment was higher for men with type 1 diabetes (1.25, 95% CI 1.01–1.53) and women with type 2 diabetes (1.09, 95% CI 1.03–1.16) and men with type 2 diabetes (1.17, 95% CI 1.08–1.27). HR of disability pension was higher in type 1 diabetes (women: 1.90, 95% CI 1.46–2.46; men: 2.09, 1.38–3.18) and type 2 diabetes (women: 1.78, 95% CI 1.62–1.96; men: 2.11, 1.86–2.40). Only women with type 2 diabetes were less likely to return to work from sickness absence (HR 0.91, 95% CI 0.86–0.98) or unemployment (0.89, 95% CI 0.85–0.94). We found no significant difference between the two types of diabetes. Hazard ratios for diabetes regarding unemployment, sickness absence while unemployed and disability pension were significantly higher for men than for women.

Conclusions

Both type 1 and type 2 diabetes affect labour market outcomes, but future studies should also consider comorbidity and social gradient.