bluuebunny/crossref_metadata_2025 huggingface dataset:
Cell-type-specific chromatin occupancy by the pioneer factor Zelda drives key developmental transitions inDrosophila
Authors: Larson Elizabeth D. , Komori Hideyuki , Gibson Tyler J. , Ostgaard Cyrina M. , Hamm Danielle C. , Schnell Jack M. , Lee Cheng-Yu , Harrison Melissa M.
Published: March 2021

DuringDrosophilaembryogenesis, the essential pioneer factor Zelda defines hundreds ofcis-regulatory regions and in doing so reprograms the zygotic transcriptome. While Zelda is essential later in development, it is unclear how the ability of Zelda to definecis-regulatory regions is shaped by cell-type-specific chromatin architecture. Asymmetric division of neural stem cells (neuroblasts) in the fly brain provide an excellent paradigm for investigating the cell-type-specific functions of this pioneer factor. We show that Zelda synergistically functions with Notch to maintain neuroblasts in an undifferentiated state. Zelda misexpression reprograms progenitor cells to neuroblasts, but this capacity is limited by transcriptional repressors critical for progenitor commitment. Zelda genomic occupancy in neuroblasts is reorganized as compared to the embryo, and this reorganization is driven by differences in chromatin accessibility and cofactor availability. We propose that Zelda regulates essential transitions in the neuroblasts and embryo through a shared gene-regulatory network by defining cell-type-specific enhancers.
The NOTCH3 Downstream Target HEYL Regulates Human Airway Epithelial Club Cell Differentiation
Authors: Bodas Manish , Subramaniyan Bharathiraja , Moore Andrew R. , Metcalf Jordan P. , Ocañas Sarah R. , Freeman Willard M. , Georgescu Constantin , Wren Jonathan D. , Walters Matthew S.
Published: March 2021

Basal cells (BC) are the resident stem/progenitor cells of the adult pseudostratified airway epithelium, whose differentiation program is orchestrated by the NOTCH signaling pathway. NOTCH3 receptor mediated signaling regulates BC to club cell differentiation; however, the downstream responses that regulate this process are largely unknown. In the present study we used anin vitroair-liquid interface model of the human pseudostratified airway epithelium to identify the NOTCH3-dependent downstream genes/pathways that regulate human BC to club cell differentiation. Activation of NOTCH3 signaling in BC via lentivirus-mediated over-expression of the active NOTCH3 intracellular domain (NICD3) promoted club cell differentiation. Bulk RNA-seq analysis of controlvsNICD3-transduced cells, identified 692 NICD3 responsive genes enriched for pathways linked to airway epithelial biology and differentiation including Wnt/β-catenin Signaling. Expression of the classical NOTCH target HEYL increased in response to NOTCH3 activation and positively correlated with expression of the club cell marker SCGB1A1. Further, using single-cell RNA-seq, we report that HEYL+cells primarily clustered with SCGB1A1+and NOTCH3+cells. Moreover, HEYL protein co-localized with SCGB1A1 in ALI culturesin vitroand in the human and mouse airway epitheliumin vivo.siRNA-mediated knockdown of HEYL in BC led to changes in epithelial structure including altered morphology and significant reductions in transepithelial electrical resistance and expression of tight junction related genes. Finally, HEYL knockdown significantly reduced the number of SCGB1A1+club cells, along with a corresponding increase in KRT8+BC-intermediate cells. Overall, our data identifies NOTCH3-HEYL signaling as a key regulator of BC to club cell differentiation.
Antibody responses to SARS-CoV-2 mRNA vaccines are detectable in saliva
Authors: Ketas Thomas J. , Chaturbhuj Devidas , Cruz-Portillo Victor M , Francomano Erik , Golden Encouse , Chandrasekhar Sharanya , Debnath Gargi , Diaz-Tapia Randy , Yasmeen Anila , Leconet Wilhem , Zhao Zhen , Brouwer Philip J.M. , Cushing Melissa M. , Sanders Rogier W. , Cupo Albert , Klasse P. J. , Formenti Silvia C. , Moore John P.
Published: March 2021

Vaccines are critical for curtailing the COVID-19 pandemic (1, 2). In the USA, two highly protective mRNA vaccines are available: BNT162b2 from Pfizer/BioNTech and mRNA-1273 from Moderna (3, 4). These vaccines induce antibodies to the SARS-CoV-2 S-protein, including neutralizing antibodies (NAbs) predominantly directed against the Receptor Binding Domain (RBD) (1-4). Serum NAbs are induced at modest levels within ∼1 week of the first dose, but their titers are strongly boosted by a second dose at 3 (BNT162b2) or 4 weeks (mRNA-1273) (3, 4). SARS-CoV-2 is most commonly transmitted nasally or orally and infects cells in the mucosae of the respiratory and to some extent also the gastrointestinal tract (5). Although serum NAbs may be a correlate of protection against COVID-19, mucosal antibodies might directly prevent or limit virus acquisition by the nasal, oral and conjunctival routes (5). Whether the mRNA vaccines induce mucosal immunity has not been studied. Here, we report that antibodies to the S-protein and its RBD are present in saliva samples from mRNA-vaccinated healthcare workers (HCW). Within 1-2 weeks after their second dose, 37/37 and 8/8 recipients of the Pfizer and Moderna vaccines, respectively, had S-protein IgG antibodies in their saliva, while IgA was detected in a substantial proportion. These observations may be relevant to vaccine-mediated protection from SARS-CoV-2 infection and disease.
A plug and play microfluidic platform for standardized sensitive low-input chromatin immunoprecipitation
Authors: Dirks René A.M. , Thomas Peter C. , Wu Haoyu , Jones Robert C. , Stunnenberg Hendrik G. , Marks Hendrik
Published: March 2021

Epigenetic profiling by chromatin immunoprecipitation followed by sequencing (ChIP-seq) has become a powerful tool for genome-wide identification of regulatory elements, for defining transcriptional regulatory networks, and for screening for biomarkers. However, the ChIP-seq protocol for low-input samples is laborious and time-consuming and suffers from experimental variation, resulting in poor reproducibility and low throughput. Although prototypic microfluidic ChIP-seq platforms have been developed, these are poorly transferable as they require sophisticated custom-made equipment and in-depth microfluidic and ChIP expertise, while lacking parallelization. To enable standardized, automated ChIP-seq profiling of low-input samples, we constructed microfluidic PDMS-based plates capable of performing 24 sensitive ChIP reactions within 30 min of hands-on time and 4.5 h of machine-running time. These disposable plates can be conveniently loaded into a widely available controller for pneumatics and thermocycling. In light of the plug and play (PnP) ChIP plates and workflow, we named our procedure PnP-ChIP-seq. We show high-quality ChIP-seq on hundreds to a few thousand of cells for all six post-translational histone modifications that are included in the International Human Epigenome Consortium set of reference epigenomes. PnP-ChIP-seq robustly detects epigenetic differences on promoters and enhancers between naive and more primed mouse embryonic stem cells (mESCs). Furthermore, we used our platform to generate epigenetic profiles of rare subpopulations of mESCs that resemble the two-cell stage of embryonic development. PnP-ChIP-seq allows nonexpert laboratories worldwide to conveniently run robust, standardized ChIP-seq, whereas its high throughput, consistency, and sensitivity pave the way toward large-scale profiling of precious sample types such as rare subpopulations of cells or biopsies.
Retaining and supporting employees with mental illness through inclusive organizations: lessons from five Canadian case studies
Authors: Gewurtz Rebecca E. , Harlos Karen , Tompa Emile , Oldfield Margaret , Lysaght Rosemary , Moll Sandra , Kirsh Bonnie , Sultan-Taïeb Hélène , Cook Katie , Rueda Sergio
Published: March 2021

Purpose

Although awareness is growing of the importance of employee mental health and the value of inclusive work practices, less is known about how to support employees with mental illness (MI). We aimed to explore organizational strategies and work practices that promote retention and support of employees living with MI in relation to past theory-driven research by building and extending current theory.

Design/methodology/approach

We adopted a qualitative case-study approach focussed on organizations that have taken steps towards promoting workplace inclusion for employees with MI. Five diverse Canadian organizations were recruited based on their efforts to build psychologically safe and healthy workplaces, and actively support employees with MI. Data collection in each organization consisted of onsite observation and interviews with workplace stakeholders, including employees with MI, their co-workers, supervisors/managers and human resource professionals. Thirty interviews were conducted from across the five organizations. Data analysis was informed by interpretive description to identify challenges and opportunities.

Findings

Two key themes were noted in depictions of supportive workplaces: (1) relationship-focussed workplaces and (2) flexible, inclusive work practices.

Originality/value

These practices highlight how organizations support employees with MI. Despite our focus on organizations working towards inclusion, the stigma associated with MI and the rigidity of some workplace processes continue to limit support and retention. Our findings suggest that organizations should focus on communication processes, support mechanisms, how they reinforce flexibility, inclusion and oversight of employees with MI.
High-performance work practices do much, but H.E.R.O does more: an empirical investigation of employees' innovative behavior from the hospitality industry
Authors: Farrukh Muhammad , Ansari Nabeel Yunus , Raza Ali , Meng Fanchen , Wang Hong
Published: March 2021

Purpose

Drawing motivation from Lawrence Bossidy's quote and leaning on the conservation of resources (COR) theory, in this study, the authors aim to investigate the role of high-performance work practices (HPWPs) and psychological capital (H.E.R.O) in employee innovative work behavior (EIB).

Design/methodology/approach

The study is banked on a hypothetico-deductive approach. The relationships were measured by gathering data from 375 frontline service employees through structural equation modeling.

Findings

The study results indicate a positive impact of HPWPs on EIB. Moreover, the association between HPWPs-EIB is mediated by psychological capital (PsyCap).

Research limitations/implications

The current study contributed to the innovation research stream by determining driving forces that encourage employees to exhibit innovative work behaviors.

Originality/value

Employee innovative behavior has become imperative for organizational survival and success in an ever-changing global business environment. Owing to this organizational significance, employee innovative behavior continues to gain burgeoning research attention. Despite the rising scholarly interest in studying employee innovative behavior, there is a dearth of knowledge about how innovation can be fostered at the individual level, particularly among frontline service employees. Hence, to bridge this research gap, the present study intends to analyze the influence of high-performance work practices on employee innovative work behavior, mediated by psychological capital.
The influence of mobile QR code payment on payment pleasure: evidence from China
Authors: Liu Rong , Wu Jifei , Yu-Buck Grace Fang
Published: March 2021

Purpose

Drawing on self-determination theory, this paper compares the effects of QR code payment method (autonomous vs dependent payment) on payment pleasure, its mechanism and the boundary condition in the mobile payment setting.

Design/methodology/approach

Four studies were conducted to examine the effect of QR code payment method on payment pleasure. In study 1, 108 undergraduate students were asked to recall a recent experience when they made either autonomous payment or dependent payment. Study 2 assigned 74 undergraduate students to either the autonomous or dependent payment. Study 3 replicated study 2, but recruited 75 customers in the field. For study 4, a total of 134 undergraduate students participated in a 2 (payment method: autonomous payment vs dependent payment) × 2 (product involvement: high vs low) between-subjects design.

Findings

The results of these four studies demonstrate that (1) customers derive more payment pleasure from autonomous payment, compared with dependent payments (study 1); (2) the sense of control mediates the effect of the payment method on payment pleasure (study 2 and study 3); and (3) product involvement moderates the mediating effect of the sense of control (study 4).

Originality/value

These findings contribute to the literature on mobile payment and payment experience. These findings also provide insight to merchants when they select an appropriate payment method and manage the customer payment experience.
Worst Expected Best method for assessment of probabilistic network expected value at risk: application in supply chain risk management
Authors: Qazi Abroon , Simsekler Mecit Can Emre
Published: March 2021

Purpose

The purpose of this paper is to develop and operationalize a process for prioritizing supply chain risks that is capable of capturing the value at risk (VaR), the maximum loss expected at a given confidence level for a specified timeframe associated with risks within a network setting.

Design/methodology/approach

The proposed “Worst Expected Best” method is theoretically grounded in the framework of Bayesian Belief Networks (BBNs), which is considered an effective technique for modeling interdependency across uncertain variables. An algorithm is developed to operationalize the proposed method, which is demonstrated using a simulation model.

Findings

Point estimate-based methods used for aggregating the network expected loss for a given supply chain risk network are unable to project the realistic risk exposure associated with a supply chain. The proposed method helps in establishing the expected network-wide loss for a given confidence level. The vulnerability and resilience-based risk prioritization schemes for the model considered in this paper have a very weak correlation.

Originality/value

This paper introduces a new “Worst Expected Best” method to the literature on supply chain risk management that helps in assessing the probabilistic network expected VaR for a given supply chain risk network. Further, new risk metrics are proposed to prioritize risks relative to a specific VaR that reflects the decision-maker's risk appetite.
Land‐use legacies influence tree water‐use efficiency and nitrogen availability in recently established European forests
Authors: Guerrieri Rossella , Correia Marta , Martín‐Forés Irene , Alfaro‐Sánchez Raquel , Pino Joan , Hampe Arndt , Valladares Fernando , Espelta Josep Maria
Published: March 2021

Forest regrowth following farmland (agriculture and pasture) abandonment has been positively associated with a number of processes including the regulation of hydrological cycling, the enhancement of soil functioning and an increase in forest productivity and carbon (C) sequestration. Although these changes in ecosystem functioning post‐farmland abandonment have been observed in multiple locations and studies, the ecophysiological basis underpinning these patterns remains unclear. Here, we examine whether increased forest expansion following pastureland abandonment is associated with greater water‐use efficiency (WUE) and legacies from previous land use in terms of nitrogen (N) availability.

We thus explored differences in leaf traits and N availability between recently established (post‐1950) beech Fagus sylvatica (L.) forests on former pastureland and long‐established beech forests (pre‐1950). The investigated leaf traits were SLA, leaf N concentration (%N) and intrinsic WUE (iWUE, i.e. the ratio between photosynthesis and stomatal conductance); as well, leaf and soil stable N isotope composition (δ15N) and total %N were used to assess changes in N availability. Finally, we compared the correlation strength between the above‐mentioned parameters and those associated with tree productivity (wood density and basal area increment, BAI) and the richness of ectomycorrhizal fungi (ECM) in these two forest types.

Recent forests had greater iWUE than long‐established forests, which was associated more with lower SLA than leaf %N. Leaf and soil δ15N were more robust proxies than %N for detecting differences in N availability. Less negative leaf and soil δ15N values in recent versus long‐established forests suggest, on the one hand, greater N availability, probably due to higher historical N input originating from animal excreta on these former pasturelands, and, on the other hand, an increase in N loss pathways.

Our results point to greater correlations between leaf δ15N, tree iWUE and productivity in recent forests than in long‐established forests, thereby suggesting a close link between C and N cycles. Our findings also highlight different N dynamics between the two forest types, with recent forests showing ‘leaky’ N cycling wherever lower N retention by trees and associated ECM fungi occurs as a legacy of previous land use.

A free Plain Language Summary can be found within the Supporting Information of this article.
Resource allocation to a structural biomaterial: Induced production of byssal threads decreases growth of a marine mussel
Authors: Roberts Emily A. , Newcomb Laura A. , McCartha Michelle M. , Harrington Katie J. , LaFramboise Sam A. , Carrington Emily , Sebens Kenneth P.
Published: March 2021

The biomechanics of specialized mechanical structures produced by organisms provides crucial fitness advantages. The energetic cost associated with producing these structural materials and the resulting energetic trade‐off with growth, however, is rarely quantified. We integrate resource allocation to structural material production with an energetic framework by combining an experimental manipulation with an energetic model.

Mytilid bivalves produce byssus, a network of collagen‐like threads that tethers individuals to hard substrate. We hypothesized that a manipulation that induces the production of more byssal threads would result in increased energetic cost and decreased growth of the species Mytilus trossulus.

In month‐long field experiments in spring and autumn, we severed byssal threads across a range of frequencies (never, weekly, daily), and measured shell and tissue growth. We then quantified the costs associated with the production of byssal threads using a Scope for Growth model.

We found that byssal thread removal increased byssal thread production and decreased growth. The cost calculated per byssal thread was similar in the spring and autumn (~1 J/thread), but energy budget calculations differed by season, and depended on thread quantity and seasonal differences in assumptions of metabolic costs.

This work demonstrates that the cost of producing a structural material has a substantial effect on mussel energetic state. The energetic cost of producing byssal threads was 2%–8% percent of the energy budget in control groups that had low byssal thread production, and increased six to 11‐fold (up to 47%) in mussels induced to produce threads daily.

We propose that characterizing the trade‐off between the cost of biomaterial production and growth has implications for understanding the role of trade‐offs in adaptive evolution, and improved natural resource management and conservation practices.

A free Plain Language Summary can be found within the Supporting Information of this article.
Caching territoriality and site preferences by a scatter‐hoarder drive the spatial pattern of seed dispersal and affect seedling emergence
Authors: Martínez‐Baroja Loreto , Pérez‐Camacho Lorenzo , Villar‐Salvador Pedro , Rebollo Salvador , Leverkus Alexandro B. , Pesendorfer Mario B. , Molina‐Morales Mercedes , Castro Jorge , Rey‐Benayas José María
Published: March 2021

For plants with seeds dispersed by scatter‐hoarders, decision‐making by animals when caching determines the spatial pattern of seed dispersal and lays the initial template for recruitment, driving the regeneration of many plant species. However, the mechanism by which animal behaviour shapes seed distributions in spatially complex landscapes is not well understood. We investigated caching territoriality and site preferences to determine the spatial pattern of seed caching at different scales and whether scatter‐hoarding behaviour drives the spatial distribution of seedling emergence.

We used radio‐tracking and automatic wildlife cameras to monitor holm oak (Quercus ilex) acorn caching by Eurasian magpies (Pica pica), who are effective scatter‐hoarders in agroforestry systems. We assessed the effect of caching territories, distance to seed source, habitat, sub‐habitat, microsites and caching material in the spatial pattern of acorn dispersal by magpies. In addition, we analysed the relationship between the density of cached acorns and of emerged seedlings in different habitats.

Breeding magpies cached the acorns inside their caching territories, where they preferred tilled areas over oak plantations and mostly avoided old fields. These differences in habitat preference were maximized at relatively short to medium dispersal distances, where most acorns were cached, and decreased or disappeared at long distances. Within tree plantations, magpies preferred high plant‐productivity sites over low productivity ones. At the finest spatial scale, magpies preferred structures built by animals, such as rabbit grit mounds and latrines and ant litter mounds, to cache the acorns. In many sites, magpies selected uncommon materials such as stones and litter to cover caches. In the subsequent spring, seedling emergence was positively correlated with acorn cache density.

Synthesis. Scatter‐hoarding is a hierarchical process in which caching sites are selected using different criteria at different spatial scales driven by territoriality and site preferences. Territoriality constrained dispersal distance and the habitats available for acorn caching. Magpie territoriality therefore indirectly drives oak seedling emergence and can determine oak recruitment and forest regeneration.
Destroying one Public Service Bargain Without Making Another: A Comment on Lowe and Pemberton, The Official History of the British Civil Service, Volume II: 1982–1997
Authors: Diamond Patrick
Published: March 2021

This article responds to Lowe and Pemberton's second volume on the history of the civil service and analyses fundamental shifts in British governance at the centre that occurred during the 1980s and 1990s. The traditional ‘public service bargain’ (PSB) that underpinned the relationship between ministers and officials has been repeatedly undermined. The article examines how far prior civil service reforms relate to the changes of the contemporary era instigated by Conservative‐led governments since 2010. As Lowe and Pemberton's work illustrates, the impulse to reform the state and the managerial reforms it unleashed were long in the making. Their legacy can be traced to the emergence of Thatcherism after 1979. The core argument of the article is that the more recent efforts of the Johnson administration to transform the state and undermine the PBS were scarcely original. Rather, they consolidated and drew upon earlier initiatives.
Offices scarce but housing scarcer: Estimating the premium for London office conversions
Authors: Cheshire Paul Charles , Kaimakamis Katerina
Published: March 2021

British planning is among the most restrictive in the world and has been restrictive for longer than elsewhere. Restrictive regulation substantially increases the costs of office space and, especially in London, increases the house prices. Partly in response to the crisis in housing supply an automatic right to convert offices to residential use was introduced in 2013. Some major office locations in central London and Manchester were excluded from this relaxation. We exploit the resulting boundary discontinuities to estimate the impact on prices of the new right to convert offices to housing. Using a panel data set of some 2,000 office transactions between 2009 and 2016, we find a significant increase in the price of offices eligible for this automatic conversion: our central estimate is a premium of 50%. This result demonstrates that London's restrictions on the supply of housing were substantially more severe than those on offices–already estimated to have been tighter than anywhere else in Europe. This article contributes to the small literature analyzing the restrictive effect of regulation on offices and is, as far as we are aware, the first analyzing regulatory restriction on offices relative to housing.
Exploring patient satisfaction with hospital foodservice: A Swedish study using the Acute Care Hospital Foodservice Patient Satisfaction Questionnaire
Authors: Rapo Sofia , Mattson Sydner Ylva , Kautto Ethel , Hörnell Agneta
Published: March 2021

Aim

The aim of this study was to explore patient satisfaction with hospital foodservice in the Swedish setting, using a validated instrument, adding this context to the existing body of research.

Methods

The study was carried out at three hospitals employing cyclic menus and conventional cook‐serve foodservice systems with centralised tray assemblies and hot‐trolley distributions to the wards for service. Patient satisfaction was explored using a translated version of the validated Acute Care Hospital Foodservice Patient Satisfaction Questionnaire. Groups were compared with Mann‐Whitney U‐test and Kruskal Wallis test with a set significance level of P < .05.

Results

Questionnaires from 439 patients were included in the analysis. The majority (80%) reported an overall satisfaction of “good” or “very good.” Questions related to Staff and Service received mostly the highest possible ratings, while questions related to Food Quality and Meal Size had slightly lower ratings and higher variation. Comparisons between groups showed that differences were small even when statistically significant. Low appetite and a long hospital stay had an adverse effect on overall satisfaction and food quality‐related questions. Men and younger patients reported more often being hungry after and between meals.

Conclusions

Hospital foodservice faces the challenge of catering to multiple patient needs. Monitoring patient satisfaction is crucial to ensure that foodservice operations remain evidence based. The Acute Care Hospital Foodservice Patient Satisfaction Questionnaire provided a general overview that indicated foodservice areas with potential for improvement, although patient satisfaction overall was high. However, patient satisfaction is a complex measure and reflexivity is required when interpreting empirical results.
Rodent control to fight plague: field assessment of methods based on rat density reduction
Authors: RAHELINIRINA Soanandrasana , SCOBIE Kathryn , RAMASINDRAZANA Beza , ANDRIANAIVOARIMANANA Voahangy , RASOAMALALA Fanohinjanaharinirina , RANDRIANTSEHENO Lovasoa Nomena , RAKOTONIAINA Jerry Sylvio , GORGÉ Olivier , LAMBIN Xavier , VALADE Eric , TELFER Sandra , RAJERISON Minoarisoa
Published: March 2021

Rodents represent a serious threat to food security and public health. The extent to which rodent control can mitigate the risk from rodent‐borne disease depends on both the effectiveness of control in reducing rodent abundance and the impact on disease epidemiology. Focusing on a plague‐endemic region of Madagascar, this study compared the effectiveness of 3 methods: live‐traps, snap‐traps, and rodenticides. Control interventions were implemented inside houses between May and October 2019. Tracking tiles monitored rodent abundance. Rodent fleas, the vector involved in plague transmission, were collected. Rodent populations consisted of Rattus rattus and Mus musculus. In terms of trap success, we found that our live‐trap regime was more effective than snap‐traps. While all 3 control strategies appeared to reduce in‐house rodent activity in the short term, we found no evidence of a longer‐term effect, with in‐house rodent abundance in treated sites comparable to non‐treatment sites by the following month. Endemic flea, Synopsyllus fonquerniei, is a key plague vector usually found on rats living outdoors. Although we found no evidence that its abundance inside houses increased following control, this may have been due to a lack of power caused by significant variation in S. fonquerniei abundance. The presence of S. fonquerniei in houses was more likely when S. fonquerniei abundance on outdoor rats was higher, which in turn correlated with high rat abundance. Our results emphasize that control strategies need to consider this connectivity between in‐house rat–flea populations and the outdoor populations, and any potential consequences for plague transmission.
Evaluation of an ankylosing spondylitis education and self‐management program: Beneficial effects on ankylosing spondylitis specific outcomes
Authors: Inderjeeth Charles A. , Boland Emma , Connor Clara , Johnson Christina , Jacques Angela , McQuade Jean
Published: March 2021

Background

Self‐management programs have demonstrated significant health benefits in people with musculoskeletal diseases.

Aim

To examine the benefits of a tailored ankylosing spondylitis self‐management program (ASSMP) delivered by trained health professionals for people with ankylosing spondylitis (AS) relative to health status, quality of life and disease activity.

Methods

ASSMP was developed within a continuous quality improvement framework following a needs assessment and focus group discussions. Formal feedback from the group after each 6 week program cycle group by questionnaire helped refine the ASSMP. Patient health status, quality of life and disease activity were assessed at multiple time points up to 12 months.

Results

Fifty‐five percent were female; mean age 48.5 ± 15.2 years. Median time to AS diagnosis was 4 years (interquartile range: 1‐10). AS disease activity Bath Ankylosing Spondylitis Global Score scores improved at 3, 6 and 12 months (P < .001). Bath Ankylosing Spondylitis Disease Activity Index improved at 6 weeks and was sustained at 3, 6 and 12 months (P < .001). The Ankylosing Spondylitis Quality of Life improved at 3, 6 and 12 months (P < .001). Bath Ankylosing Spondylitis Functional Index improved by 12 months (P < .001). Participants reported less nocturnal back pain at 6 months and was sustained at 12 months (P < .001). Patients Global Disease Activity improved by 6 months (P = .012), Multi‐Dimensional Assessment of Fatigue and a Global Fatigue Index at 6 months (P = .003), Hospital Anxiety and Depression Scale ‐ Anxiety at 12 months (P = .001), Evaluation Ankylosing Spondylitis Quality of Life at 6 months (P = .001) and Pain Self‐Efficacy Questionnaire at 12 months (P = .002).

Conclusion

This ASSMP demonstrated significant and sustained benefit in symptoms, disease activity measures and quality of life in a condition that results in significant impairment, disability and poorer quality of life. The cost effectiveness and benefit of this program should be tested.
Alcohol‐associated intestinal dysbiosis alters mucosal‐associated invariant T‐cell phenotype and function
Authors: Gu Min , Samuelson Derrick R. , Taylor Christopher M. , Molina Patricia E. , Luo Meng , Siggins Robert W. , Shellito Judd E. , Welsh David A.
Published: March 2021

Background

Chronic alcohol consumption is associated with a compromised innate and adaptive immune responses to infectious disease. Mucosa‐associated invariant T (MAIT) cells play a critical role in antibacterial host defense. However, whether alcohol‐associated deficits in innate and adaptive immune responses are mediated by alterations in MAIT cells remains unclear.

Methods

To investigate the impact of alcohol on MAIT cells, mice were treated with binge‐on‐chronic alcohol for 10 days and sacrificed at day 11. MAIT cells in the barrier organs (lung, liver, and intestine) were characterized by flow cytometry. Two additional sets of animals were used to examine the involvement of gut microbiota on alcohol‐induced MAIT cell changes: (1) Cecal microbiota from alcohol‐fed (AF) mice were adoptive transferred into antibiotic‐pretreated mice and (2) AF mice were treated with antibiotics during the experiment. MAIT cells in the barrier organs were measured via flow cytometry.

Results

Binge‐on‐chronic alcohol feeding led to a significant reduction in the abundance of MAIT cells in the barrier tissues. However, CD69 expression on tissue‐associated MAIT cells was increased in AF mice compared with pair‐fed (PF) mice. The expression of Th1 cytokines and the corresponding transcriptional factor was tissue specific, showing downregulation in the intestine and increases in the lung and liver in AF animals. Transplantation of fecal microbiota from AF mice resulted in a MAIT cell profile aligned to that of AF mouse donor. Antibiotic treatment abolished the MAIT cell differences between AF and PF animals.

Conclusion

MAIT cells in the intestine, liver, and lung are perturbed by alcohol use and these changes are partially attributable to alcohol‐associated dysbiosis. MAIT cell dysfunction may contribute to alcohol‐induced innate and adaptive immunity and consequently end‐organ pathophysiology.
Approvals of type 2 diabetes drugs tested in cardiovascular outcome trials: A tripartite comparison
Authors: Shimazawa Rumiko , Ikeda Masayuki
Published: March 2021

Aims

In 2008, the US Food and Drug Administration (FDA) issued a guidance requiring that cardiovascular outcome trials (CVOTs) be conducted for newer hypoglycaemic drugs for type 2 diabetes (T2D). We aimed to examine the decisions by 3 regulatory authorities in response to identical CVOT data.

Methods

We surveyed ClinicalTrials.gov to identify CVOTs and examined the revision histories of drug labels in databases from the FDA, the European Medicines Agency, and the Pharmaceuticals and Medical Devices Agency in Japan.

Results

We selected 14 drugs and corresponding CVOTs, 12 of which were conducted as postmarketing trials. In the USA and the EU, the pre‐CVOT indication on all 14 labels was “improvement in glycaemic control”. Six drugs showed significant cardiovascular risk reduction, which led to an additional indication regarding reduction of cardiovascular adverse events in the USA, and a change to the EU indication to specify treatment of adults with T2D. The initial indication in Japan, T2D, remained unchanged. Regarding safety, significant increases in heart failure were observed only in the saxagliptin trial. A warning was added to the saxagliptin labels in the EU and Japan, whereas the FDA required a class effect warning to be added to the labels of all 4 dipeptidyl peptidase‐4 inhibitors.

Conclusions

Regulatory authorities using identical trial data made substantially different decisions regarding both safety and efficacy of hypoglycaemic drugs. The differences in initial indication wording between Japan and the other authorities suggest that trial data and T2D are interpreted differently in these regions.
Nonparametric estimation of Spearman's rank correlation with bivariate survival data
Authors: Eden Svetlana K. , Li Chun , Shepherd Bryan E.
Published: March 2021

We study rank‐based approaches to estimate the correlation between two right‐censored variables. With end‐of‐study censoring, it is often impossible to nonparametrically identify the complete bivariate survival distribution, and therefore it is impossible to nonparametrically compute Spearman's rank correlation. As a solution, we propose two measures that can be nonparametrically estimated. The first measure is Spearman's correlation in a restricted region. The second measure is Spearman's correlation for an altered but estimable joint distribution. We describe population parameters for these measures and illustrate how they are similar to and different from the overall Spearman's correlation. We propose consistent estimators of these measures and study their performance through simulations. We illustrate our methods with a study assessing the correlation between the time to viral failure and the time to regimen change among persons living with HIV in Latin America who start antiretroviral therapy.
Development of children’s metacognitive knowledge, reading, and writing in English as a foreign language: Evidence from longitudinal data using multilevel models
Authors: Teng Mark Feng , Zhang Lawrence Jun
Published: March 2021

Background

Limited studies have been conducted on delineating the rationale behind individual differences in children developing metacognitive knowledge, as well as reading and writing proficiency.

Aims

This study examined the dynamics of children’s development of metacognitive knowledge as well as reading and writing proficiency during their progression from Grade 1 to Grade 6.

Sample(s)

A total of 420 students participated in the study, who were tested 6 times to assess their metacognitive knowledge, reading, and writing proficiency.

Methods

The participants were invited to complete three tests: metacognitive knowledge, reading, and writing, which were administered at the end of each grade year.

Results and conclusions

Three variables (i.e., metacognitive knowledge, reading, and writing) showed high stability and increasing variance over time. These findings suggest individual differences in children’s development of metacognitive knowledge, as well as reading and writing proficiency. Students’ metacognitive knowledge grew more quickly among those who entered primary school with already strong metacognitive skills; the same was true for their reading and writing development. Results also revealed predictive effects of students’ metacognitive knowledge on their reading and writing performance. Implications are discussed based on these findings.
Do children use logic to spell logician? Implicit versus explicit teaching of morphological spelling rules
Authors: Burton Lauren , Nunes Terezinha , Evangelou Maria
Published: March 2021

Background

Intervention studies have reported the advantage of teaching children about morphemes for spelling, but direct comparisons between explicit and implicit teaching have been examined systematically in relation to only a few morphological rules.

Aims

This study compared explicit versus implicit teaching of the functional rule for the conservation of stem morphemes in derived words in English (e.g.,logicis conserved in the derivativelogicianin spite of changes in pronunciation).

Sample

Participants (n = 90; 7‐ to 9‐year‐olds) were drawn from three schools with a diverse intake.

Methods

The design included a pre‐test and two post‐intervention tests. Participants were randomly assigned to one of three groups: an explicit group, taught about stems and their conservation in derived words; an implicit group, exposed to the same stems and derivatives without explicit teaching; and an unseen control group. At pre‐ and post‐test, the children’s spelling of stems in derivatives was assessed. The interventions involved practice games in which the children spelled derived words after seeing the base forms; the explicit group discussed the connection between the spellings, whereas the implicit group did not.

Results

Analyses of variance revealed that explicit teaching led to more significant spelling improvements than implicit or no teaching, and this effect held at both post‐tests.

Conclusions

It was concluded that explicit teaching of the stem conservation rule in derived forms combined with appropriate practice games shows a sustained effect on spelling. The evidence supports explicit teaching of this morphological rule in classroom practice.
Pathogenesis of follicular lymphoma: genetics to the microenvironment to clinical translation
Authors: Kumar Emil , Pickard Lucy , Okosun Jessica
Published: March 2021

Follicular lymphoma (FL) represents a heterogeneous disease both clinically and biologically. The pathognomonic t(14;18) translocation can no longer be thought of as the primary genetic driver, with increasing recognition of the biological relevance of recurrent genetic alterations in epigenetic regulators that now feature as a pivotal hallmark of this lymphoma subtype. Furthermore, sequencing studies have provided a near complete catalogue of additional genetic aberrations. Longitudinal and spatial genetic studies add an additional layer to the biological heterogeneity, providing preliminary molecular insights into high‐risk phenotypes such as early progressors and transformation, and also supporting evidence for the existence of persisting re‐populating cells that act as lymphoma reservoirs and harbingers for FL recurrence. Simultaneously, understanding of the tumour microenvironmental cues promoting lymphomagenesis and disease progression continue to broaden. More recently, studies are beginning to unravel the convergence and co‐operation between the genetics, epigenetics and microenvironment. There is a pressing need to marry biology with therapeutics, especially with the burgeoning treatment landscape in FL, to aid in optimising patient selection and guiding the ‘right drug to the right patient’.
Halofuginone, a promising drug for treatment of pulmonary hypertension
Authors: Jain Pritesh P. , Zhao Tengteng , Xiong Mingmei , Song Shanshan , Lai Ning , Zheng Qiuyu , Chen Jiyuan , Carr Shane G. , Babicheva Aleksandra , Izadi Amin , Rodriguez Marisela , Rahimi Shamin , Balistrieri Francesca , Rahimi Shayan , Simonson Tatum , Valdez‐Jasso Daniela , Thistlethwaite Patricia A. , Shyy John Y.‐J. , Wang Jian , Makino Ayako , Yuan Jason X.‐J.
Published: March 2021

Background and Purpose

Halofuginone is a febrifugine derivative originally isolated from Chinese traditional herb Chang Shan that exhibits anti‐hypertrophic, anti‐fibrotic and anti‐proliferative effects. We sought to investigate whether halofuginone induced pulmonary vasodilation and attenuates chronic hypoxia‐induced pulmonary hypertension (HPH).

Experimental Approach

Patch‐clamp experiments were conducted to examine the activity of voltage‐dependent Ca2+ channels (VDCCs) in pulmonary artery smooth muscle cells (PASMCs). Digital fluorescence microscopy was used to measure intracellular Ca2+ concentration in PASMCs. Isolated perfused and ventilated mouse lungs were used to measure pulmonary artery pressure (PAP). Mice exposed to hypoxia (10% O2) for 4 weeks were used as model of HPH for in vivo experiments.

Key Results

Halofuginone increased voltage‐gated K+ (Kv) currents in PASMCs and K+ currents through KCNA5 channels in HEK cells transfected with KCNA5 gene. HF (0.03–1 μM) inhibited receptor‐operated Ca2+ entry in HEK cells transfected with calcium‐sensing receptor gene and attenuated store‐operated Ca2+ entry in PASMCs. Acute (3–5 min) intrapulmonary application of halofuginone significantly and reversibly inhibited alveolar hypoxia‐induced pulmonary vasoconstriction dose‐dependently (0.1–10 μM). Intraperitoneal administration of halofuginone (0.3 mg·kg−1, for 2 weeks) partly reversed established PH in mice.

Conclusion and Implications

Halofuginone is a potent pulmonary vasodilator by activating Kv channels and blocking VDCC and receptor‐operated and store‐operated Ca2+ channels in PASMCs. The therapeutic effect of halofuginone on experimental PH is probably due to combination of its vasodilator effects, via inhibition of excitation–contraction coupling and anti‐proliferative effects, via inhibition of the PI3K/Akt/mTOR signalling pathway.
N‐glycosylated GPNMB ligand independently activates mutated EGFR signaling and promotes metastasis in NSCLC
Authors: Han Chia‐Li , Chen Xuan‐Ren , Lan Albert , Hsu Yuan‐Ling , Wu Pei‐Shan , Hung Pei‐Fang , Hung Chung‐Lieh , Pan Szu‐Hua
Published: March 2021

Lung cancer is the leading cause of cancer‐related death worldwide. As well as the identified role of epidermal growth factor receptor (EGFR), its association with driver mutations has improved the therapeutics for patients with lung cancer harboring EGFR mutations. These patients usually display shorter overall survival and a higher tendency to develop distant metastasis compared with those carrying the wild‐type EGFR. Nevertheless, the way to control mutated EGFR signaling remains unclear. Here, we performed membrane proteomic analysis to determine potential components that may act with EGFR mutations to promote lung cancer malignancy. Expression of transmembrane glycoprotein non‐metastatic melanoma protein B (GPNMB) was positively correlated with the status of mutated EGFR in non‐small‐cell lung cancer (NSCLC). This protein was not only overexpressed but also highly glycosylated in EGFR‐mutated, especially EGFR‐L858R mutated, NSCLC cells. Further examination showed that GPNMB could activate mutated EGFR without ligand stimulation and could bind to the C‐terminus of EGFR, assist phosphorylation at Y845, turn on downstream STAT3 signaling, and promote cancer metastasis. Moreover, we also found that Asn134 (N134) glycosylation of GPNMB played a crucial role in this ligand‐independent regulation. Depleting N134‐glycosylation on GPNMB could dramatically inhibit binding of GPNMB to mutated EGFR, blocking its downstream signaling, and ultimately inhibiting cancer metastasis in NSCLC. Clarifying the role of N‐glycosylated GPNMB in regulating the ligand‐independent activation of mutated EGFR may soon give new insight into the development of novel therapeutics for NSCLC.
Investigating the in‐solution photodegradation pathway of Diamond Green G by chromatography and mass spectrometry
Authors: Sabatini Francesca , Degano Ilaria , van Bommel Maarten
Published: March 2021

Diamond Green G (CI 42040, Basic Green 1) is a triarylmethane dye mostly employed in the industrial dyeing of miscellaneous natural and artificial textile fibres, in the production of printing inks and as an anti‐fungal agent for aquaculture products. Diamond Green (DG) tends to fade under light irradiation, similar to several other dyes and pigments belonging to the triarylmethane family. In this paper, an in‐solution degradation study was carried out to shed light on DG photostability. The experiments were performed by artificially irradiating DG in water and dimethyl sulphoxide, and analysing aliquots sampled at different time intervals by ultra‐high performance liquid chromatography coupled with diode array detector quadrupole and time of flight tandem mass spectrometry. The degradation products formed were characterised and the product‐ion spectra discussed and interpreted. On the basis of the structure of the identified compounds and their kinetic trend in relation to the accelerated ageing time, degradation mechanisms were proposed for DG, taking into account the role played by the solvent. Finally, the dyeing formulation of an historical textile sample, collected from a stage costume worn in a Zeffirelli lyric opera, was determined utilising the information collected from the analysis of irradiated DG solutions.