bluuebunny/crossref_metadata_2025 huggingface dataset:
Global-scale CRISPR gene editor specificity profiling by ONE-seq identifies population-specific, variant off-target effects
Authors: Petri Karl , Kim Daniel Y. , Sasaki Kanae E. , Canver Matthew C. , Wang Xiao , Shah Hina , Lee Hyunho , Horng Joy E. , Clement Kendell , Iyer Sowmya , Garcia Sara P. , Guo Jimmy A. , Newby Gregory A. , Pinello Luca , Liu David R. , Aryee Martin J. , Musunuru Kiran , Keith Joung J. , Pattanayak Vikram
Published: April 2021

Defining off-target profiles of gene-editing nucleases and CRISPR base editors remains an important challenge for use of these technologies, therapeutic or otherwise. Existing methods can identify off-target sites induced by these gene editors on an individual genome but are not designed to account for the broad diversity of genomic sequence variation that exists within populations of humans or other organisms. Here we describe OligoNucleotide Enrichment and sequencing (ONE-seq), a novelin vitromethod that leverages customizable, high-throughput DNA synthesis technology instead of purified genomic DNA (gDNA) from individual genomes to profile gene editor off-target sites. We show that ONE-seq matches or exceeds the sensitivity of existing single-genome methods for identifyingbona fideCRISPR-Cas9 off-target sites in cultured human cells andin vivoin a liver-humanized mouse model. In addition, ONE-seq outperforms existing best-in-class single-genome methods for defining off-target sites of CRISPR-Cas12a nucleases, cytosine base editors (CBEs), and adenine base editors (ABEs), unveiling previously undescribedbona fideoff-target sites for all these editors in human cells. Most importantly, we leveraged ONE-seq to generate the first experimentally-derived population-scale off-target profiles for Cas9 nucleases that define the impacts of sequence variants from >2,500 individual human genome sequences in the 1000 Genomes Project database. Notably, some of the variants we identified that lead to increased mutation frequencies at off-target sites are enriched in specific human populations. We validated that novel population-specific, variant-sensitive off-target sites nominated by ONE-seqin vitrocan show increased frequencies of mutations in human lymphoblastoid cells (LCLs) harboring these sequence variants. Collectively, our results demonstrate that ONE-seq is a highly sensitive off-target nomination method that can uniquely be used to identify population subgroup-linked differences in off-target profiles of gene editors. ONE-seq provides an important new pathway by which to assess the impacts of global human genetic sequence diversity on the specificities of gene editors, thereby enabling a broader and more all-inclusive approach for profiling off-target effects of these transformative therapeutic technologies.
Cue overlap supports pre-retrieval selection in episodic memory: ERP evidence
Authors: Moccia Arianna , Morcom Alexa M.
Published: April 2021

People often want to recall only currently relevant events, but this selective remembering is not always possible. We contrasted two candidate mechanisms: the overlap between retrieval cues and stored memory traces, and the ease of recollection. In two preregistered experiments (Ns = 28) we used event-related potentials (ERPs) to quantify pre-retrieval selection and the goal states – retrieval orientations – thought to achieve this selection. Participants viewed object pictures or heard object names, and one of these sources was designated as targets in each memory test. We manipulated cue overlap by probing memory with visual names (Experiment 1) or line drawings (Experiment 2). Results revealed that regardless of which source was targeted, the left parietal ERP effect indexing recollection was selective when test cues overlapped more with the targeted than non-targeted information, despite consistently better memory for pictures. ERPs for unstudied items were also more positive-going when cue overlap was high, suggesting that engagement of retrieval orientations reflected availability of external cues matching the targeted source. The data support the view that selection can act prior to recollection if there is sufficient overlap between retrieval cues and targeted versus competing memory traces.
In Silico Analysis and Characterization of Differentially Expressed Genes to Distinguish Glioma Stem Cells from Normal Neural Stem Cells
Authors: Parekh Urja , Mazumder Mohit , Kaur Harpreet , Brodsky Elia
Published: April 2021

Glioblastoma multiforme (GBM) is a heterogeneous, invasive primary brain tumor that develops chemoresistance post therapy. Theories regarding the aetiology of GBM focus on transformation of normal neural stem cells (NSCs) to a cancerous phenotype or tumorigenesis driven via glioma stem cells (GSCs). Comparative RNA-Seq analysis of GSCs and NSCs can provide a better understanding of the origin of GBM. Thus, in the current study, we performed various bioinformatics analyses on transcriptional profiles of a total 40 RNA-seq samples including 20 NSC and 20 GSC, that were obtained from the NCBI-SRA (SRP200400). First, differential gene expression (DGE) analysis using DESeq2 revealed 348 significantly differentially expressed genes between GSCs and NSCs (padj. value <0.05, log2fold change ≥ 3.0 (for GSCs) and ≤ −3.0 (for NSCs)) with 192 upregulated and 156 downregulated genes in GSCs in comparison to NSCs. Subsequently, exploratory data analysis using principal component analysis (PCA) based on key significant genes depicted the clear separation between both the groups. Further, Hierarchical clustering confirmed the distinct clusters of GSC and NSC samples. Eventually, the biological enrichment analysis of the significant genes showed their enrichment in tumorigenesis pathways such as Wnt-signalling, VEGF-signalling and TGF-β-signalling pathways. Conclusively, our study depicted significant differences in the gene expression patterns between NSCs and GSCs. Besides, we also identified novel genes and genes previously unassociated with gliomagenesis that may prove to be valuable in establishing diagnostic, prognostic biomarkers and therapeutic targets for GBM.
Bioinformatic and mechanistic analysis of the palmerolide PKS-NRPS biosynthetic pathway from the microbiome of an Antarctic ascidian
Authors: Avalon Nicole E. , Murray Alison E. , Daligault Hajnalka E. , Lo Chien-Chi , Davenport Karen W. , Dichosa Armand E.K. , Chain Patrick S.G. , Baker Bill J.
Published: April 2021

Complex interactions exist between microbiomes and their hosts. Increasingly, defensive metabolites that have been attributed to host biosynthetic capability are now being recognized as products of host-associated microbes. These unique metabolites often have bioactivity targets in human disease and can be purposed as pharmaceuticals. Polyketides are a complex family of natural products that often serve as defensive metabolites for competitive or pro-survival purposes for the producing organism, while demonstrating bioactivity in human diseases as cholesterol lowering agents, anti-infectives, and anti-tumor agents. Marine invertebrates and microbes are a rich source of polyketides. Palmerolide A, a polyketide isolated from the Antarctic ascidianSynoicum adareanum, is a vacuolar-ATPase inhibitor with potent bioactivity against melanoma cell lines. The biosynthetic gene clusters (BGCs) responsible for production of secondary metabolites are encoded in the genomes of the producers as discrete genomic elements. A candidate palmerolide BGC was identified from aS. adareanummicrobiome-metagenome based on a high degree of congruence with a chemical structure-based retrobiosynthetic prediction. Protein family homology analysis, conserved domain searches, active site and motif identification were used to identify and propose the function of the ∼75 kbtrans-acyltransferase (AT) polyketide synthase-non-ribosomal synthase (PKS-NRPS) domains responsible for the stepwise synthesis of palmerolide A. Though PKS systems often act in a predictable co-linear sequence, this BGC includes multipletrans-acting enzymatic domains, a non-canonical condensation termination domain, a bacterial luciferase-like monooxygenase (LLM), and is found in multiple copies within the metagenome-assembled genome (MAG). Detailed inspection of the five highly similar pal BGC copies suggests the potential for biosynthesis of other members of the palmerolide chemical family. This is the first delineation of a biosynthetic gene cluster from an Antarctic microbial species, recently proposed asCandidatusSynoicohabitans palmerolidicus. These findings have relevance for fundamental knowledge of PKS combinatorial biosynthesis and could enhance drug development efforts of palmerolide A through heterologous gene expression.
A novel SNF2 ATPase complex inTrypanosoma bruceiwith a role in H2A.Z-mediated chromatin remodelling
Authors: Vellmer Tim , Hartleb Laura , Sola Albert Fradera , Kramer Susanne , Meyer-Natus Elisabeth , Butter Falk , Janzen Christian J
Published: April 2021

A cascade of histone acetylation events with subsequent incorporation of a histone H2A variant plays an essential part in transcription regulation in various model organisms. A key player in this cascade is the chromatin remodelling complex SWR1, which replaces the canonical histone H2A with its variant H2A.Z. Transcriptional regulation of polycistronic transcription units in the unicellular parasiteTrypanosoma bruceihas been shown to be highly dependent on acetylation of H2A.Z, which is mediated by the histone-acetyltransferase HAT2. The chromatin remodelling complex which mediates H2A.Z incorporation is not known and an SWR1 orthologue in trypanosomes has not yet been reported.

In this study, we identified and characterised an SWR1-like remodeller complex inT. bruceithat is responsible for Pol II-dependent transcriptional regulation. Bioinformatic analysis of potential SNF2 DEAD/Box helicases, the key component of SWR1 complexes, identified a 1211 amino acids-long protein that exhibits key structural characteristics of the SWR1 subfamily. Systematic protein-protein interaction analysis revealed the existence of a novel complex exhibiting key features of an SWR1-like chromatin remodeller. RNAi-mediated depletion of the ATPase subunit of this complex resulted in a significant reduction of H2A.Z incorporation at transcription start sites and a subsequent decrease of steady-state mRNA levels. Furthermore, depletion of SWR1 and RNA-polymerase II (Pol II) caused massive chromatin condensation. The potential function of several proteins associated with the SWR1-like complex and with HAT2, the key factor of H2A.Z incorporation, is discussed.

Author summary

Trypanosoma bruceiis the causative agent of African trypanosomiasis (sleeping sickness) in humans and nagana in cattle. Its unusual genomic organisation featuring large polycistronic units requires a general mechanism of transcription initiation, because individual gene promoters are mostly absent. Despite the fact that the histone variant H2A.Z has previously been identified as a key player of transcription regulation, the complex responsible for correct H2A.Z incorporation at transcription start sites (TSS) remains elusive. In other eukaryotes, SWR1, a SNF2 ATPase-associated chromatin remodelling complex, is responsible for correct incorporation of this histone variant. This study identified a SWR1-like complex inT. brucei. Depletion of the SNF2 ATPase resulted in a reduction of H2A.Z incorporation at the TSS and decreased steady-state mRNA levels accompanied by chromatin condensation. In addition to the SWR1-like complex, we also identified a trypanosome-specific HAT2 complex that includes the histone acetyltransferases HAT2, a key player in the H2A.Z incorporation process. This complex has a trypanosome-specific composition that is different from the NuA4/TIP60 complex inSaccharomyces cerevisiae.
Temporal resolution of melanogenesis determine fatty acid metabolism as key skin pigment regulator
Authors: Sultan Farina , Basu Reelina , Murthy Divya , Kochar Manisha , Attri Kuldeep S. , Aggrawal Ayush , Kumari Pooja , Dnyane Pooja , Singh Archana , Gadgil Chetan , Bhavesh Neel S. , Singh Pankaj K. , Natarajan Vivek T. , Gokhale Rajesh S.
Published: April 2021

Therapeutic methods to modulate skin pigmentation has important implications for skin cancer prevention and for treating meta-inflammatory-triggered cutaneous conditions. Modulators of cAMP signalling of melanocyte have met with minimal clinical efficacy. Towards defining new potential targets, we followed temporal dynamics orchestrating melanocyte differentiation by using a cell-autonomous pigmentation model. Our study elucidates three dominant phases of synchronized metabolic and transcriptional reprogramming. The induction phase is concomitant with a paradoxical decrease in MITF levels, reduced proliferation, and increased anabolic metabolism mediated by AKT phosphorylation. The melanogenic phase shows rapid uptake of glucose and fatty acid, transiently forming lipid droplets through SREBF1-mediated regulation of fatty acid metabolism. This heightened bioenergetic activity impairs mitochondria and the recovery phase is marked by a shift to aerobic glycolysis and activation of the NRF2 detoxication pathway. Finally, we show that inhibitors of lipid metabolism indeed resolve hyper-pigmentary conditions in a guinea pig UV-tanning model. Our studies reveal metabolic control mechanisms of melanocytes that could govern the balance between differentiation and proliferation in a variety of cutaneous diseases.
Structural basis for how sMAC is packaged for clearance
Authors: Menny Anaïs , Lukassen Marie V. , Couves Emma C. , Franc Vojtech , Heck Albert J.R. , Bubeck Doryen
Published: April 2021

Unregulated complement activation causes inflammatory and immunological pathologies with consequences for human disease. To prevent bystander damage during an immune response, extracellular chaperones (clusterin and vitronectin) capture and clear soluble precursors to the membrane attack complex (sMAC). However, how these chaperones block further polymerization of MAC and prevent the complex from binding target membranes remains unclear. Here, we address that question by combining cryo electron microscopy (cryoEM) and cross-linking mass spectrometry (XL-MS) to solve the structure of sMAC. Together our data reveal how clusterin recognizes and inhibits polymerizing complement proteins by binding a negatively charged surface of sMAC. Furthermore, we show that the pore-forming C9 protein is trapped in an intermediate conformation whereby only one of its two transmembrane β-hairpins has unfurled. This structure provides molecular details for immune pore formation and helps explain a complement control mechanism that has potential implications for how cell clearance pathways mediate immune homeostasis.
Does a Clarke-Groves type tax prevent free riding when implementing Eurobonds?
Authors: Contreras Carlos , Angulo Julio
Published: April 2021

Purpose

The purpose of this paper is to propose a Clarke-Groves Tax (CGT) type as a remedy to the criticism that the implementation of Eurobonds has raised regarding the risk of undermining fiscal discipline. In this model, a government minimizes its sovereign debt-to-GDP ratio in a given period and decides whether to join a common sovereign debt club. In doing so, it exposes itself to a positive or negative tax burden while benefiting from the liquidity premium involved in creating a secure asset. The authors found that the introduction of this tax may prevent free riding behaviours if Eurobonds were to be implemented. To illustrate this, the authors provide some numerical simulations for the Eurozone.

Design/methodology/approach

In the model presented, a government which optimizes a social utility function decides whether to join the common debt club.

Findings

The adoption of the proposed tax could prevent free-riding behaviours and, therefore, encourages participation by those countries with lower debt levels that would have not otherwise taken part in this common debt mechanism. Under certain circumstances, we can expect the utility of all members of this club to improve. The bias in the distribution of gains might be mitigated by regulating the tax rule determining the magnitude of payment/reward. The proportion of the liquidity premium, arising from the implementation of a sovereign safe asset, has a decisive impact on the degree of the governments’ utility enhancement.

Research limitations/implications

The adoption of a CGT would require Eurobonds club members to reach an agreement on “the” theoretical model for determining the sovereign debt yield. One of the limitations of this model is considering the debt-to-GDP ratio as the sole determinant of public debt yields. Moreover, the authors assumed the relationship between the debt-to-GDP ratio and funding costs to be identical for all countries. Any progress in the implementation of the proposed transfer scheme would require a more realistic and in-depth analysis.

Practical implications

A new fiscal rule based on compensating countries with lower public debt levels could be a way to mitigate free-riding problems if a Eurobond mechanism is to be established.

Originality/value

This fiscal rule has not been proposed or analysed before in a context such as that considered by this paper.
Innovative m-car rental service quality in India
Authors: Shah Tejas R. , Shah Tejal T.
Published: April 2021

Purpose

The purpose of the study is to explore and analyze m-car rental service quality dimensions.

Design/methodology/approach

Exploratory factor analysis method is applied to explore the m-car rental service quality dimensions. Further, confirmatory factor analysis is done to prove the reliability and validity of the factors using AMOS 22.0.

Findings

The results reveal the m-car rental service quality dimensions: ambient quality, technical quality, comfort, safety and employee service, mobile convenience, mobile responsiveness, mobile efficiency and reliability and mobile safety and billing.

Research limitations/implications

The explored dimensions of car rental services are in Indian environment. So, these dimensions can be further validated in other similar cultural context.

Practical implications

The proposed measurements can also be applied to measure and compare the service quality performance of car rental firms.

Originality/value

Current literature does not confirm the stable factor structure of m-car rental service quality. This study confirms the reliable and valid dimensions of care rental service through mobile app.
Numerical study on the dynamic characteristics of water-lubricated rubber bearing under asperity contact
Authors: Xiang Guo , Wang Yijia , Wang Cheng , Lv Zhongliang
Published: April 2021

Purpose

In this study, the dynamic characteristics of the water-lubricated rubber bearing considering asperity contact are numerically studied, including water-film stiffness and damping coefficients and plastic-elastic contact stiffness coefficient.

Design/methodology/approach

The Kogut-Etsion elastic-plastic contact model is applied to calculate the contact stiffness coefficient at the bearing-bush interface and the perturbed method is used to calculate the stiffness and damping coefficients of water-film. In addition, the rubber deformation is determined by the finite element method (FEM) during the simulation. Parametric studies are conducted to assess the effects of the radial clearance, rubber thickness and elastic modulus on the dynamic characteristic of water-lubricated rubber bearing.

Findings

Numerical results indicate that stiffness and damping coefficients of water film and the contact stiffness of asperity are increased with the decreasing of the radial clearance and the dynamic coefficients are less sensitive to the rubber thickness compared with the elastic modulus of rubber. Furthermore, due to the existed groove, a sudden change of the water film direct stiffness and damping coefficients is observed when the eccentricity ratio ranges from 0.6 to 1.0.

Originality/value

It is expected this study can provide more information to establish a dynamic equation of water-lubricated rubber bearings exposed to mixed lubrication conditions.
The goal is attainable: the effects of goal gradient and sub-goals on escalation of commitment in a new product evaluation
Authors: Liang Beichen
Published: April 2021

Purpose

The purpose of this study is to investigate whether, in the context of making a go/no-go decision regarding a failing new product, the use of a stopping rule and/or a new decision-maker would reduce the escalation of commitment (EOC).

Design/methodology/approach

This study uses a classroom experiment design and uses logistic regression and a chi-square test to analyze its data.

Findings

The findings show that both responsible and non-responsible participants are more likely to perceive the negative performance of a new product as less negative and believe that the goal for the product can be reached when there is a stopping rule and proximal negative feedback indicates a level of performance below but very close to it than when there is no stopping rule. Therefore, they are more likely to continue the failing new product, whether they are responsible for the product or not. However, non-responsible decision-makers are more likely than their responsible counterparts to discontinue the failing new product in the absence of a stopping rule.

Research limitations/implications

This paper extends the theory of EOC by showing that the use of a stopping rule and/or a new decision-maker may not reduce EOC.

Practical implications

This paper provides useful guidelines for managers on how to reduce EOC.

Originality/value

The originality and value of this paper are found in the investigation of a situation in which the use of a stopping rule and/or a new decision-maker may not reduce the EOC.
Innovation in the subsistence marketplace: an analysis considering multiple concepts and approaches
Authors: Nogami Vitor Koki da Costa , Veloso Andres Rodriguez
Published: April 2021

Purpose

The purpose of this paper is to explore the different concepts of innovation in the subsistence marketplace from top-down and bottom-up approaches. This study analyzes the literature on the theme and identified research gaps by constructing a framework based on approaches and innovation concepts, which can guide future research efforts. Additionally, this paper presents two case studies, which can improve the way innovation is developed and diffused in the subsistence marketplace.

Design/methodology/approach

Through a literature review, this study develops a framework by analyzing innovation concepts in the subsistence marketplace (i.e. base of the pyramid innovation, disruptive innovation, frugal innovation, reverse innovation and inclusive innovation) in light of subsistence marketplace approaches (top-down and bottom-up).

Findings

The analysis showed critical research gaps, especially a lack of studies involving disruptive and frugal innovations from a bottom-up approach. This paper also concludes that the top-down approach is more common than the bottom-up one. To fill these gaps, this study presents two business plans by illustrating disruptive innovation vs bottom-up approach and frugal innovation vs bottom-up approach.

Originality/value

The use of real business plans to illustrate proposals having an actual impact on subsistence marketplace regions sheds light on how to address these challenges. By doing so, this paper intends to fill the theoretical gap in disruptive and frugal innovations within a bottom-up approach to promote the development and diffusion of different types of innovation in the subsistence marketplace, and thus provide solutions to alleviate poverty.
B2B engagement within an internet of things ecosystem
Authors: Soltani Sadia
Published: April 2021

Purpose

This study aims to investigate business-to-business (B2B) engagement within an internet of things (IoT) ecosystem. A conceptual framework is proposed that can be used for building engagement strategies considering key actors within an IoT ecosystem.

Design/methodology/approach

The study used an integrative literature review as a research method and investigated engagement across several disciplines along with antecedents and outcomes of engagement to form an understanding of IoT engagement.

Findings

The findings in this study revealed IoT engagement antecedents as IoT readiness, commitment, communication, involvement and support and, consequently, the outcomes of IoT engagement as trust, loyalty, better performance and satisfaction. Furthermore, IoT engagement needs to be considered from three perspectives, namely, from a multidimensional perspective, beyond a dyad perspective and from the service-dominant logic perspective, which suggests thinking of goods as services and highlights the importance of value co-creation.

Research limitations/implications

As the study of B2B engagement within the IoT ecosystem is conceptual, empirical investigations are suggested for elaborating on the findings.

Practical implications

The conceptual framework provides managers within an IoT ecosystem with thorough recommendations on why to change their perspectives toward engagement; it points out drivers of engagement that need to be maintained and adds IoT readiness as a new antecedent to engagement literature.

Originality/value

This study contributes a coherent conceptualization of actors’ engagement within IoT ecosystems and enhances both the theoretical and practical domain of B2B engagement.
Advanced cuttlefish optimizer-random decision forest (ACORDF) based design of fractional order PID controller for higher-order time-delay system
Authors: George Thomas , Ganesan V.
Published: April 2021

Purpose

The purpose of this manuscript, a state feedback gain depends on the optimal design of fractional order PID controller to time-delay system is established. In established optimal design known as advanced cuttlefish optimizer and random decision forest that is combined performance of random decision forest algorithm (RDFA) and advanced cuttlefish optimizer (ACFO).

Design/methodology/approach

The proposed ACFO uses the concept of crossover and mutation operator depend on position upgrading to enhance its search behavior, calculational speed as well as convergence profile at basic cuttlefish optimizer.

Findings

Fractional order proportional-integrator-derivative (FOPID) controller, apart from as tuning parameters (kp, ki and kd) it consists of two extra tuning parameters λ and µ. In established technology, the increase of FOPID controller is adjusted to reach needed responses that demonstrated using RDFA theory as well as RDF weight matrices is probable to the help of the ACFO method. The uniqueness of the established method is to decrease the failure of the FOPID controller at greater order time delay method with the help of controller maximize restrictions. The objective of the established method is selected to consider parameters set point as well as achieved parameters of time-delay system.

Originality/value

In the established technique used to evade large order delays as well as reliability restrictions such as small excesses, time resolution, as well as fixed condition defect. These methods is implemented at MATLAB/Simulink platform as well as outcomes compared to various existing methods such as Ziegler-Nichols fit, curve fit, Wang method, regression and invasive weed optimization and linear-quadratic regression method.
How do forensic inpatients’ interpersonal sensitivity to dominance and perceptions of staff coercion impact upon anger and rates of aggression?
Authors: Holley Jessica , Tapp James , Draycott Simon
Published: April 2021

Purpose

Coercive practices – which are used as means to manage violent/aggressive behaviour in secure forensic settings – have come under scrutiny in recent years due to their paradoxical effects on provoking further service user aggression and violence. Previous research has found relationships between increased service user aggression with both service users’ interpersonal styles and perceptions of staff coercion (i.e. staff limit setting). This paper aims to investigate whether forensic service users’ levels of interpersonal sensitivity to dominance increase levels of self-reported anger and rates of aggression towards staff through perceptions of staff coercion.

Design/methodology/approach

In a cross-sectional quantitative study design, 70 service users were recruited from one high and two medium secure forensic hospitals. Standardised measures were completed by service users and recorded incident data was collected within the past year. Correlation and mediation analyses were run to investigate the relationship between study variables.

Findings

A significant relationship was found between service users’ interpersonal sensitivity to dominance and self-reported rates of anger, where forensic service users’ who had higher levels of interpersonal sensitivity to others’ dominance were likely to report higher rates of anger. No significant relationships were found between all other study variables.

Practical implications

The findings from this study contradict previous research where coercive practices may not necessarily increase rates of aggression towards staff but, in the context of service users’ interpersonal sensitivities to dominance, it may be more useful to consider the way in which coercive practices are implemented.

Originality/value

There is a gap in the literature, which looks at the way in which forensic service users perceive coercive practices in relation to their interpersonal sensitivities and whether this too has an impact upon service user aggression.
Plenary Indulgence for the Personal Participation in Crusades to the Holy Land as Presented by Crusade Preachers
Authors: PORTNYKH VALENTIN L.
Published: April 2021

This article discusses one of the main phenomena of the crusading movement: how preachers of the crusades to the Holy Land made the crusade indulgence attractive to would‐be crusaders. Since a plenary indulgence for the participants of the crusades is likely to have been introduced by the papacy at the beginning of the crusading movement in the eleventh century, this was used in crusade preaching throughout the whole period of crusading to the Holy Land. Given that the plenary indulgence is omnipresent in almost all sources related to crusade preaching, it is highly likely to have been deemed a useful argument to attract people to the crusading movement. Drawing on a large body of scholarship concerning the motivations of crusaders to the Holy Land, this article focuses on the ways in which preachers invented a number of ways to make the indulgence very attractive for sermon listeners.
Neoadjuvant radiotherapy for locally advanced and high‐risk breast cancer
Authors: Chidley Phoebe , Foroudi Farshad , Tacey Mark , Khor Richard , Yeh Janice , Bevington Elaine , Hyett Anthony , Loh Su Wen , Chew Grace , McCracken James , Neoh Derek , Yeo Belinda , Baker Caroline , Jassal Sunil , Law Michael , Zantuck Natalie , Cokelek Margaret , Guerrieri Mario , Brown Belinda , Stoney David , Ng Michael , Chao Michael
Published: April 2021

Introduction

Neoadjuvant radiotherapy (NART) as part of a multi‐modality approach for locally advanced breast cancer (LABC) requires further investigation. Importantly, this approach may allow for a single‐staged surgical procedure, with mastectomy and immediate autologous reconstruction. Multiple other potential benefits of NART include improved pathological downstaging of breast disease, reduced overall treatment time, elimination of time period with breast tissue deficit and improved patient satisfaction.

Methods

This is a retrospective multi‐institutional review of patients with LABC and high‐risk breast disease undergoing NART. Eligible patients sequentially underwent neoadjuvant chemotherapy (NACT) with or without HER2‐targeted therapy, NART, followed by mastectomy with immediate autologous breast reconstruction (BR) 4‐ to 6 weeks post‐completion of radiotherapy. Patient and tumour characteristics were analysed using descriptive statistics. Surgical complications were assessed using the Clavien–Dindo Classification (Ann Surg 2004; 240: 205).

Results

From 3/2013 to 9/2019, 153 patients were treated with NART. The median age was 47 years (IQR 42–52), with median body mass index of 27. Eighteen patients experienced Grade 3 acute surgical complications. This included 13 Grade 3B breast‐site events and 9 Grade 3B donor‐site events, where further surgical intervention was required for management of wound infection, wound dehiscence, flap or mastectomy skin necrosis, haematoma and internal mammary venous anastomotic thrombosis. No autologous flap loss was observed.

Conclusion

Neoadjuvant radiotherapy facilitates a single‐stage surgical procedure with mastectomy and immediate autologous BR, eliminating the delay to reconstructive surgery and thus shortening a woman’s breast cancer journey. The findings of this review support the use of NART, with comparable rates of surgical complications to standard sequencing.
Climate Ambition and Sustainable Development for a New Decade: A Catalytic Framework
Authors: Chan Sander , Boran Idil , van Asselt Harro , Ellinger Paula , Garcia Miriam , Hale Thomas , Hermwille Lukas , Liti Mbeva Kennedy , Mert Ayşem , Roger Charles B. , Weinfurter Amy , Widerberg Oscar , Bynoe Paulette , Chengo Victoria , Cherkaoui Ayman , Edwards Todd , Gütschow Malin , Hsu Angel , Hultman Nathan , Levaï David , Mihnar Saffran , Posa Sara , Roelfsema Mark , Rudyk Bryce , Scobie Michelle , Shrivastava Manish Kumar
Published: April 2021

This paper examines the Global Climate Action Agenda (GCAA) and discusses options to improve sub‐ and non‐state involvement in post‐2020 climate governance. A framework that stimulates sub‐ and non‐state action is a necessary complement to national governmental action, as the latter falls short of achieving low‐carbon and climate‐resilient development as envisaged in the Paris Agreement. Applying design principles for an ideal‐type orchestration framework, we review literature and gather expert judgements to assess whether the GCAA has been collaborative, comprehensive, evaluative and catalytic. Results show that there has been greater coordination among orchestrators, for instance in the organization of events. However, mobilization efforts remain event‐driven and too little effort is invested in understanding the progress of sub‐ and non‐state action. Data collection has improved, although more sophisticated indicators are needed to evaluate climate and sustainable development impacts. Finally, the GCAA has recorded more action, but relatively little by actors in developing countries. As the world seeks to recover from the COVID‐19 crisis and enters a new decade of climate action, the GCAA could make a vital contribution in challenging times by helping governments keep and enhance climate commitments; strengthening capacity for sub‐ and non‐state action; enabling accountability; and realizing sustainable development.
Cardiac‐specific experiential avoidance predicts change in general psychological well‐being among patients completing cardiac rehabilitation
Authors: Spatola Chiara A.M. , Giusti Emanuele Maria , Rapelli Giada , Goodwin Christina , Cattivelli Roberto , Pietrabissa Giada , Malfatto Gabriella , Facchini Mario , Castelnuovo Gianluca , Molinari Enrico
Published: April 2021

Previous studies have shown that experiential avoidance (EA) is associated with physical and psychological well‐being in medical and non‐medical samples. The aims of the present study were to evaluate the reciprocal association between psychological well‐being and EA over time among cardiac rehabilitation (CR) patients with moderately to severely low levels of psychological well‐being. Pre‐CR data on demographic characteristics, measures of psychological well‐being, and cardiac‐specific EA were collected from 915 CR patients, as well as post‐CR psychological well‐being and EA data, from 800 of these patients. A cross‐lagged model was estimated to examine the relationship between EA and psychological well‐being among patients with moderately to severely low levels of psychological well‐being based on questionnaire scores. Both EA and psychological well‐being significantly changed during CR and were negatively associated with each other at both pre‐ and post‐CR. Results from cross‐lagged structural equation modeling supported a nonreciprocal association between EA and psychological well‐being during CR. Pre‐CR assessment of EA in patients showing low levels of well‐being at the beginning of CR could help to identify patients at risk for worse psychological outcomes. EA could be a promising target of psychological treatments administered during CR.
Metabolic responses and benefits of glucagon‐like peptide‐1 (GLP‐1) receptor ligands
Authors: Tanday Neil , Flatt Peter R. , Irwin Nigel
Published: April 2021

Glucagon‐like peptide‐1 (GLP‐1) is an incretin hormone that has undergone a revolutionary turnaround from discovery to clinically approved therapeutic. Rapid progress in drug design and formulation has led from initial development of short‐ and long‐acting drugs suitable for daily or weekly parenteral administration, respectively, through to the most recent approval of an orally active GLP‐1 agent. The current review outlines the biological action profile of GLP‐1 including the various beneficial metabolic responses in pancreatic and extra‐pancreatic tissues, including the gastrointestinal tract, liver, bone and kidney as well as the reproductive cardiovascular and CNS. We then briefly consider clinically approved GLP‐1 receptor ligands and recent advances in this field. Given the sustained evolution in the area of GLP‐1 drug development and excellent safety profile, as well as the plethora of metabolic benefits, clinical approval for use in diseases beyond diabetes and obesity is very much conceivable.

LINKED ARTICLES

This article is part of a themed issue on GLP1 receptor ligands (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.4/issuetoc
What can we teach Lymnaea and what can Lymnaea teach us?
Authors: Rivi Veronica , Benatti Cristina , Lukowiak Ken , Colliva Chiara , Alboni Silvia , Tascedda Fabio , Blom Johanna M.C.
Published: April 2021

This review describes the advantages of adopting a molluscan complementary model, the freshwater snail Lymnaea stagnalis, to study the neural basis of learning and memory in appetitive and avoidance classical conditioning; as well as operant conditioning of its aerial respiratory and escape behaviour. We firstly explored ‘what we can teach Lymnaea’ by discussing a variety of sensitive, solid, easily reproducible and simple behavioural tests that have been used to uncover the memory abilities of this model system. Answering this question will allow us to open new frontiers in neuroscience and behavioural research to enhance our understanding of how the nervous system mediates learning and memory. In fact, from a translational perspective, Lymnaea and its nervous system can help to understand the neural transformation pathways from behavioural output to sensory coding in more complex systems like the mammalian brain. Moving on to the second question: ‘what can Lymnaea teach us?’, it is now known that Lymnaea shares important associative learning characteristics with vertebrates, including stimulus generalization, generalization of extinction and discriminative learning, opening the possibility to use snails as animal models for neuroscience translational research.
Liquidity constraints and debts: Implications for the saving behavior of the middle class
Authors: Toussaint‐Comeau Maude
Published: April 2021

Savings are essential for families to respond to risks against adverse financial shocks and reduce costs of uncertainties in the future. However, personal savings have been decreasing among US households. This study analyzes the determinants of liquidity constraints and savings for the relatively understudied middle class. The study finds evidence of substantial liquidity constraints—Eighty percent of households in the middle class are liquidity constrained. Furthermore, the results suggest that high‐debt payments and high‐interest‐rate credit cards amplify the effects of liquidity tightness and hinder savings for children's education, a first‐home purchase, or later‐on‐in‐life medical spending.
Feasibility study for online assessment on fatigue failure of aluminum cable steel reinforced conductors based on DC resistance measurement method
Authors: Mao Hanling , Li Xiaokang , Mao Hanying , Lan Shun , Li Siyue , Wang Bang , Huang Zhenfeng , Li Xinxin , Tang Weili
Published: April 2021

The strength of aluminum cable steel reinforced (ACSR) is an important index of loading capacity and safety of cables and will decrease with fatigue damage. However, the strength of ACSR used in transmission lines would be difficultly measured online. Hence the objective of this work is to investigate online measurement parameters employed to characterize fatigue damage of transmission lines. The resistance and strength characteristics of ACSR conductors in long‐term service were experimental studied; it revealed that strength loss rate is positively correlated with DC resistance growth rate. Then the DC resistance growth rate may be used as a fatigue damage evaluation index. Although the DC resistance of transmission lines is difficultly measured online, a resistance and inductance (RL) distributed parameter model simplified and an online measurement scheme were proposed. The simulation and experimental results showed that the DC resistance can be effectively and accurately measured online.
Conducting public involvement in dementia research: The contribution of the European Working Group of People with Dementia to the ROADMAP project
Authors: Diaz Ana , Gove Dianne , Nelson Mia , Smith Michael , Tochel Claire , Bintener Christophe , Ly Amanda , Bexelius Christin , Gustavsson Anders , Georges Jean , Gallacher John , Sudlow Cathie
Published: April 2021

Background

Dementia outcomes include memory loss, language impairment, reduced quality of life and personality changes. Research suggests that outcomes selected for dementia clinical trials might not be the most important to people affected.

Objective

One of the goals of the ‘Real world Outcomes across the Alzheimer's Disease spectrum for better care: Multi‐modal data Access Platform’ (ROADMAP) project was to identify important outcomes from the perspective of people with dementia and their caregivers. We review how ROADMAP's Public Involvement shaped the programme, impacted the research process and gave voice to people affected by dementia.

Design

The European Working Group of People with Dementia (EWGPWD) were invited to participate. In‐person consultations were held with people with dementia and caregivers, with advance information provided on ROADMAP activities. Constructive criticism of survey content, layout and accessibility was sought, as were views and perspectives on terminology and key concepts around disease progression.

Results

The working group provided significant improvements to survey accessibility and acceptability. They promoted better understanding of concepts around disease progression and how researchers might approach measuring and interpreting findings. They effectively expressed difficult concepts through real‐world examples.

Conclusions

The role of the EWGPWD in ROADMAP was crucial, and its impact was highly influential. Involvement from the design stage helped shape the ethos of the programme and ultimately its meaningfulness.

Public contribution

People with dementia and their carers were involved through structured consultations and invited to provide feedback on project materials, methods and insight into terminology and relevant concepts.
Evidence of an increasing trend in earnings surprises over the past two decades: The role of positive manager‐initiated non‐GAAP adjustments
Authors: Griffin Paul A. , Lont David H.
Published: April 2021

We explore patterns of street earnings surprises over time. We find a steady increasing trend in positive street earnings surprises over the past two decades. This trend reflects an asymmetric shift to the right—from substantially fewer small earnings surprises around zero to many more and larger ones well above zero. A difference‐in‐differences analysis reveals that this pattern cannot be explained by a similar pattern in the distribution of generally accepted accounting principles (GAAP) earnings surprises. The increasing trend is also steeper for firms with earnings guidance. We suggest that the shift in the pattern of street earnings surprises over time is best attributed to analysts’ increasing inclusion of positive manager‐initiated and other similar non‐GAAP adjustments in street earnings per share. This behavior has produced an ever‐increasing stream of positive street earnings surprises.
Knockdown of long non‐coding RNA small nucleolar RNA host gene 9 or hexokinase 2 both suppress endometrial cancer cell proliferation and glycolysis
Authors: Wang Lianhua , Huang Qiming , Lin Qingqing , Chen Lvxuan , Shi Qiyang
Published: April 2021

Aim

Endometrial cancer (EC) is a common type of malignant gynecological cancer. Small nucleolar RNA host gene 9 (SNHG9) has been discovered to serve a role in several types of cancer; however, the role of SNHG9 in EC remains unclear. The present study aimed to investigate the effects of lncRNA SNHG9 on cell proliferation and glycolysis in EC cells.

Methods

SNHG9 and hexokinase 2 (HK2) mRNA expression levels were measured by reverse transcription‐quantitative PCR. Glucose consumption and lactate production were detected by the glycolysis cell‐based assay kit. Cell Counting Kit‐8 and colony formation assays were conducted to detect cell proliferation. The knockdown experiments of SNHG9 and HK2 were carried out by transfection of corresponding small interference RNAs (siRNA). The SNHG9‐overexpressed plasmid was transfected into the cells to upregulate SNHG9. HK2 protein levels were analyzed by western blotting assay.

Results

SNHG9 expression levels were significantly upregulated in EC tissues and cells. The knockdown of SNHG9 subsequently effectively attenuated cell proliferation and glycolysis in vitro, while SNHG9 overexpression reported the opposite effects. Notably, the transfection of 2‐DG partially reversed the promoting effect of SNHG9 on glycolysis. Downregulation of HK2 markedly decreased cell proliferation and glycolysis in EC cells antagonized SNHG9.

Conclusion

Either downregulation of SNHG9 or HK2 inhibits EC cell proliferation and glycolysis via repressing EC cell proliferation and glycolysis.