bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanisms ofIgf2inhibition in thymic epithelial cells infected by coxsackievirus CV-B4
Authors: Michaux Hélène , Halouani Aymen , Trussart Charlotte , Renard Chantal , Jaïdane Hela , Martens Henri , Hober Didier , Geenen Vincent
Published: January 2020

Epidemiological studies have evidenced a link between type 1 diabetes (T1D) and infections by enteroviruses, especially with coxsackievirus B4 (CV-B4). CV-B4 is able to infect human and murine thymic epithelial cells (TECs) and, in a murine TEC line, we have shown that the diabetogenic strain CV-B4 E2 decreases transcription of insulin-like growth factor 2 gene (Igf2), coding for the self-peptide of the insulin family. Here we show that in CV-B4 infection of mice altersIgf2transcripts isoforms in TECs, followed by a decrease of pro-IGF2 precursor in the thymus. CV-B4 infection of a murine TEC line decreasesIgf2P3 promoter activity by targeting the region −68 to −22 upstream of the transcription start site (TSS) whereasIgf2transcripts stability is not affected, pointing towards a regulation ofIgf2transcription. Our data also show that CV-B4 decreases IL-6/STAT3 signalingin vitro. This study provides new knowledge about the regulation of intrathymicIgf2transcription by CV-B4 and reinforces the hypothesis that CV-B4 infection of the thymus could break central self-tolerance of the insulin family by decreasingIgf2transcription and IGF2 presentation in thymus epithelium.

IMPORTANCE

Coxsackievirus B4 represents one of the most important environmental factors associated to type 1 diabetes, autoimmune disease for which no curative treatment exist. The diabetogenic strain Coxsackievirus B4 E2 was previously shown to decreaseIgf2expression, important player for central tolerance towards insulin, in a thymic epithelial cell line. The understanding ofIgf2regulation mechanisms during coxsackievirus B4 infection represents an interest for the understanding of central tolerance development but also forIgf2transcriptional regulation itself, still poorly understood.

Here we demonstrate that, some transcripts isoforms ofIgf2are also decreased in thymic epithelial cellsin vivo. Moreover, we show that this decrease is induced by an alteration of specific regions ofIgf2P3 promoter and may be linked by a decrease of STAT3 signaling.In finewe hope that this work could lead to future therapies leading to reprogramming central tolerance towards β cells antigens viaIgf2expression.
NRF1 and NRF3 complementarily maintain a basal proteasome activity in cancer cells through CPEB3-mediated translational repression
Authors: Waku Tsuyoshi , Katayama Hiroyuki , Hiraoka Miyako , Hatanaka Atsushi , Nakamura Nanami , Tanaka Yuya , Tamura Natsuko , Watanabe Akira , Kobayashi Akira
Published: January 2020

Proteasomes are protease complexes essential for cellular homeostasis, and their activity is crucial for cancer cell growth. However, the mechanism of how proteasome activity is maintained in cancer cells has remained unclear. The CNC family transcription factor NRF1 induces the expression of almost all proteasome-related genes under proteasome inhibition.NRF1and its phylogenetically closest homologNRF3are both highly expressed in several types of cancers, such as colorectal cancer. Herein, we demonstrate that NRF1 and NRF3 complementarily maintain basal proteasome activity in cancer cells. A double knockdown ofNRF1andNRF3impaired the basal proteasome activity in cancer cells and the cancer cell resistance to a proteasome inhibitor anticancer drug bortezomib by significantly reducing basal expression of seven proteasome-related genes, includingPSMB3, PSMB7, PSMC2, PSMD3, PSMG2, PSMG3, andPOMP. Interestingly, the molecular basis behind these cellular consequences was that NRF3 repressed NRF1 translation by the gene induction of translational regulator CPEB3, which binds toNRF1-3′UTR and decreases polysome formation onNRF1mRNA. Consistent results were obtained from clinical analysis, wherein patients with cancer having higherCPEB3/NRF3-expressing tumors exhibit poor prognosis. These results provide the novel regulatory mechanism of basal proteasome activity in cancer cells through an NRF3-CPEB3-NRF1 translational repression axis.
Macromolecular and cytological changes in fission yeast G0 nuclei
Authors: Tan Zhi Yang , Cai Shujun , Paithankar Saayli A. , Nie Xin , Shi Jian , Gan Lu
Published: January 2020

When starved of nitrogen, fission yeastSchizosaccharomyces pombecells enter a quiescent “G0” state with smaller nuclei and transcriptional repression. The genomics ofS. pombeG0 cells has been well studied, but much of its nuclear cell biology remains unknown. Here we use confocal microscopy, immunoblots, and electron cryotomography to investigate the cytological, biochemical, and ultrastructural differences betweenS. pombeproliferating, G1-arrested, and G0 cell nuclei, with an emphasis on the histone acetylation, RNA polymerase II fates, and macromolecular complex packing. Compared to proliferating cells, G0 cells have lower levels of histone acetylation, nuclear RNA polymerase II, and active transcription. The G0 nucleus has similar macromolecular crowding yet fewer chromatin-associated multi-megadalton globular complexes. Induced histone hyperacetylation in G0 results in cells that have larger nuclei and therefore less compact chromatin. However, these histone-hyperacetylated G0 cells remain transcriptionally repressed with similar nuclear crowding. Canonical nucleosomes – those that resemble the crystal structure – are rare in proliferating, G1-arrested, and G0 cells. Our study therefore shows that extreme changes in nucleus physiology are possible without extreme reorganisation at the macromolecular level.

We use multiple cell-biological techniques to compare proliferating and quiescent G0 fission yeast cell nucleus transcription, histone acetylation, macromolecular packing.
Size regulation of multiple organelles competing for a shared subunit pool
Authors: Banerjee Deb Sankar , Banerjee Shiladitya
Published: January 2020

How cells regulate the size of intracellular structures and organelles, despite continuous turnover in their component parts, is a longstanding question. Recent experiments suggest that size control of many intracellular assemblies is achieved through the depletion of a limiting subunit pool in the cytoplasm. While the limiting pool model ensures organelle size scaling with cell size, it does not provide a mechanism for robust size control of multiple co-existing structures. Here we propose a kinetic theory for size regulation of multiple structures that are assembled from a shared pool of subunits. We demonstrate that a negative feedback between the growth rate and the size of individual structures underlies size regulation of a wide variety of intracellular assemblies, from cytoskeletal filaments to three-dimensional organelles such as centrosomes and the nucleus. We identify the feedback motifs for size control in these structures, based on known molecular interactions, and quantitatively compare our theory with available experimental data. Furthermore, we show that a positive feedback between structure size and growth rate can lead to bistable size distributions arising from autocatalytic growth. In the limit of high subunit concentration, autocatalytic growth of multiple structures leads to stochastic selection of a single structure, elucidating a mechanism for polarity establishment.
Scalable generation of mesenchymal stem cells and adipocytes from human pluripotent stem cells
Authors: Karam Manale , Younis Ihab , Abdelalim Essam M.
Published: January 2020

Human pluripotent stem cells (hPSCs) can provide unlimited supply for mesenchymal stem cells (MSCs) and adipocytes that can be used for therapeutic applications. Here we developed a simple and highly efficient All-trans-retinoic acid (RA)-based method for generating an off-the-shelf and scalable number of human pluripotent stem cell (hPSC)-derived MSCs with enhanced adipogenic potential. We showed that short exposure of multiple hPSC lines (hESCs/ hiPSCs) to a high RA concentration (10 μM) dramatically enhances embryoid body (EB) formation through regulation of genes activating signaling pathways associated with cell proliferation, survival and adhesion, among others. Disruption of cell adhesion induced the subsequent differentiation of the highly expanded RA-derived EB-forming cells into a pure population of multipotent MSCs (up to 1542-fold increase in comparison to RA-untreated counterparts). Interestingly, the RA-derived MSCs displayed enhanced differentiation potential into adipocytes. Thus, these findings present a novel RA-based approach for providing an unlimited source of MSCs and adipocytes that can be used for regenerative medicine, drug screening, and disease modeling applications.
Crystal structures of (E)-5-(4-methylphenyl)-1-(pyridin-2-yl)pent-2-en-4-yn-1-one and [3,4-bis(phenylethynyl)cyclobutane-1,2-diyl]bis(pyridin-2-ylmethanone)
Authors: Ushakov Ivan E. , Odin Ivan S. , Gloukhov Pavel A. , Golovanov Alexander A. , Dorovatovskii Pavel V. , Vologzhanina Anna V.
Published: January 2020

Recrystallization of (E)-5-phenyl-1-(pyridin-2-yl)pent-2-en-4-yn-1-one at room temperature from ethylene glycol in daylight afforded [3,4-bis(phenylethynyl)cyclobutane-1,2-diyl)bis(pyridin-2-ylmethanone], C32H22N2O2 (3), while (E)-5-(4-methylphenyl)-1-(pyridin-2-yl)pent-2-en-4-yn-1-one, C17H13NO (2), remained photoinert. This is the first experimental evidence that pentenynones can be photoreactive when fixed in nearly coplanar parallel positions. During the photoreaction, the bond lengths and angles along the pentenyne chain changed significantly, while the disposition of the pyridyl ring towards the keto group was almost unchanged. The cyclobutane ring adopts an rctt conformation.
Evaluating complementary synergies in integrated crop-livestock systems in Ghana
Authors: Asante Bright O. , Villano Renato A. , Battese George E.
Published: January 2020

Purpose

The purpose of this paper is to investigate the characteristics of crop-livestock diversification among smallholders in the forest-savannah agroecological zone of Ghana.

Design/methodology/approach

The study uses a stochastic input distance function to investigate the evidence of economies of diversification and its effect on determining diversification decisions of smallholders in Ghana. Furthermore, this study also explores evidence of scale economies in integrated crop-livestock systems among smallholder farmers.

Findings

The empirical results show that economies of diversification are significant in determining diversification decisions of smallholders. The economies of scale are evident in integrated crop-livestock systems in Ghana, suggesting that opportunities exist to expand crop-livestock outputs without employing additional inputs or improved production technologies. Crop-livestock diversification is a desirable strategy for improving overall farm productivity among smallholders in Ghana. Economies of diversification were found to be significant among the output combinations, maize with other crops and other crops with livestock, in integrated crop-livestock production systems.

Research limitations/implications

This study is based on a cross-sectional data set. Hence, the findings may be subject to some limitations; however, the authors have sought to minimise such limitations.

Practical implications

The results imply that crop-livestock diversification is a desirable strategy for improving overall farm productivity. Therefore, the findings are useful for policymakers to design appropriate strategies for enhancing the production of specific output combinations in crop-livestock diversification systems among smallholders in Ghana. Specifically, such policies should promote the production and integration of crops such as legumes with other crops, and livestock with other crops in diversified farming systems to enhance overall farm productivity. This will reduce food insecurity and poverty among rural farm households and the entire rural population.

Originality/value

These results indicate that to improve crop-livestock productivity through diversification, and reduce the effect of climate variability, it is imperative to provide the enabling environment that will facilitate and encourage production of these output combinations among smallholders in Ghana. The empirical results enhance the literature by providing empirical evidence of the complementary synergies and economies of diversification in integrated farming systems and, hence, make recommendations for improving these farming systems.

Peer review

The peer review history for this paper is available at:https://publons.com/publon/10.1108/IJSE-04-2019-0274.
Social courage fosters both voice and silence in the workplace
Authors: Howard Matt C. , Holmes Philip E.
Published: January 2020

Purpose

One of the strongest and most important outcomes of trait social courage is employee voice, but researchers have only studied this relationship with unidimensional conceptualizations of voice. The purpose of this paper is to apply Van Dyneet al.’s (2003) three-dimensional conceptualization of voice, which also distinguishes three dimensions of silence, to provide a nuanced understanding of the relationship of social courage with voice and silence. The authors also test for the moderating effect of three contextual influences: top management attitudes toward voice and silence, supervisor attitudes toward voice and silence, as well as communication opportunities.

Design/methodology/approach

The authors conducted a four-timepoint survey with each measurement occasion separated by one week. A total of 134 participants completed all four timepoints.

Findings

The results support that social courage positively relates to prosocial voice and silence, whereas it negatively relates to defensive voice and silence as well as acquiescent voice and silence. In other words, social courage positively relates to beneficial voice and silence as well as negatively relates to detrimental voice and silence. The results also failed to support any moderating effects, suggesting that the relationships of social courage are very resilient to outside forces.

Practical implications

These findings both test prior results and discover new relationships of social courage, which can further stress the importance of courage. The authors also draw direct connections between the influence of social courage on the surrounding workplace environment – as well as the influences of the environment on social courage. While the current paper provides insights into social courage, it also directs future researchers toward new insights of their own.

Originality/value

Courage is an emergent research topic within organizations. While many authors have assumed that courage is important to work, the current paper is among the few to empirically support this notion.
The Problematic Development of the Stalking Protection Order
Authors: Kelly Rory
Published: January 2020

In 2019, Parliament enacted the Stalking Protection Act. The Act introduces the stalking protection order (SPO); a civil measure the breach of which is an offence. The role of courts in assessing whether similar behaviour orders are penalties has attracted significant scholarly attention. This article examines instead the roles of Government and Parliament in developing the stalking protection order. My central contention is that the Home Office undertook a problematic consultation and the issues to which it gave rise were not addressed in later parliamentary debates. The result was the enactment of a coercive measure of unclear purpose and questionable efficacy. Assessing the roles of the executive and legislature in developing the SPO also allows for fresh insight into wider discussions of behaviour orders. Specifically, I question the language of ‘prevention’ that is ever‐present in such discussions and describe an important development for debates on whether behaviour orders are penalties.
Texture, physicochemical and sensory properties of artisanal Adobera cheese from Los Altos de Jalisco, a genuine Mexican cheese
Authors: Ruvalcaba‐Gómez José M , Ruiz‐Espinosa Héctor , Arteaga‐Garibay Ramón I , Rojas‐López Marlon , Amador‐Espejo Genaro G , Anaya‐Esparza Luis M , Delgado‐Macuil Raúl J
Published: January 2020

Physicochemical and sensory properties of Adobera, a genuine, understudied Mexican raw‐milk cheese, were explored by analysing commercial samples from different manufacturers and seasons. Composition‐wise, Adobera could be considered a fresh cheese with a high moisture content (42.5%), although its relatively low water activity (0.953) and pH (5.14) and high free amino acid content (0.46 mmol/g, dry basis) could indicate otherwise. Instrumental texture corresponded to that of a semifirm cheese, while its colour was whitish‐to‐ivory. Both texture and composition were significantly affected by sampling season and cheese composition, while some attributes of sensory acceptability significantly varied with brand.
Development of a novel metric of timely care access to primary care services
Authors: Batten Adam J. , Augustine Matthew R. , Nelson Karin M. , Kaboli Peter J.
Published: January 2020

Objective

To develop a model for identifying clinic performance at fulfilling next‐day and walk‐in requests after adjusting for patient demographics and risk.

Data Source

Using Department of Veterans Affairs (VA) administrative data from 160 VA primary care clinics from 2014 to 2017.

Study Design

Using a retrospective cohort design, we applied Bayesian hierarchical regression models to predict provision of timely care, with clinic‐level random intercept and slope while adjusting for patient demographics and risk status. Timely care was defined as the provision of an appointment within 48 hours of any patient requesting the clinicʼs next available appointment or walking in to receive care.

Data Collection/Extraction Methods

We extracted 1 841 210 timely care requests from 613 263 patients.

Principal Findings

Across 160 primary care clinics, requests for timely care were fulfilled 86 percent of the time (range 83 percent‐88 percent). Our model of timely care fit the data well, with a Bayesian R2 of .8. Over the four years of observation, we identified 25 clinics (16 percent) that were either struggling or excelling at providing timely care.

Conclusion

Statistical models of timely care allow for identification of clinics in need of improvement after adjusting for patient demographics and risk status. VA primary care clinics fulfilled 86 percent of timely care requests.
Anxiety boosts progression of prediabetes to type 2 diabetes: findings from the prospective Cooperative Health Research in the Region of Augsburg F4 and FF4 studies
Authors: Jiang L. , Atasoy S. , Johar H. , Herder C. , Peters A. , Kruse J. , Ladwig K.‐H.
Published: January 2020

Aim

To investigate the association between anxiety symptoms and the progression from prediabetes to type 2 diabetes.

Methods

A sample of 1708 participants aged 31–82 years from the population‐based Cooperative Health Research in the Region of Augsburg F4 and the follow‐up Cooperative Health Research in the Region of Augsburg FF4 studies was included. Prediabetes was defined as impaired fasting glucose and/or impaired glucose tolerance, and anxiety status was measured by the generalized anxiety disorder‐7 questionnaire. Newly diagnosed type 2 diabetes cases were identified after 6.5 years (11 102 person‐years) and confirmed by medical records. Multivariate logistic regression analyses were employed to estimate the effect of prediabetes and anxiety on the incidence of type 2 diabetes with different levels of adjustments for potential confounders. The population attributable risk of type 2 diabetes in participants with prediabetes and anxiety was estimated.

Results

Prediabetes at baseline was prevalent in 247 participants, of whom 77 developed diabetes after follow‐up, accounting for a progression rate of 31%. In participants with prediabetes, high anxiety was associated with a 3‐fold increased risk of progression to type 2 diabetes in comparison with low anxiety, even after accounting for socio‐demographic, lifestyle and metabolic risk factors (OR = 2.82, 95% CI = 0.95–8.37, P = 0.06). A significant proportion of incident type 2 diabetes was attributed to having anxiety in addition to prediabetes (attributable risk proportion: 0.52; 95% CI = 0.004–1.04, P = 0.05).

Conclusions

Anxiety symptoms independently increase the progression risk of prediabetes to type 2 diabetes and should be routinely considered alongside the traditional risk factors in people with prediabetes.
The pomegranate butterfly Deudorix livia (Lepidoptera: Lycaenidae): an emerging pest on dates in Tunisia
Authors: Abbes K. , Zouba A. , Harbi A. , Ghrissi N. , Ksantini M. , Chermiti B.
Published: January 2020

The pomegranate butterfly Deudorix (=Virachola) livia Klug 1834 (Lepidoptera: Lycaenidae) was encountered for the first time infesting dates (Phoenix dactylifera, variety Deglet Nour) in the oasis of Gafsa, Southern Tunisia in September 2011. Larvae of D. livia only caused damage on date fruits at the phenological stages kimiri (green fruits) and khalal (yellow fruits). The average infestation rate of dates was 10%. In addition, 7.1% of the infested fruits dropped to the ground. Damage caused by this insect on dates is described, the current situation in Tunisia is provided and possible control methods in Tunisia are briefly discussed. Although this pest has previously been reported in Tunisia on pomegranate this is the first report of D. livia on dates in the country.
Deciphering the molecular mechanism of FLT3 resistance mutations
Authors: Georgoulia Panagiota S. , Bjelic Sinisa , Friedman Ran
Published: January 2020

FMS‐like tyrosine kinase 3 (FLT3) has been found to be mutated in ~ 30% of acute myeloid leukaemia patients. Small‐molecule inhibitors targeting FLT3 that are currently approved or still undergoing clinical trials are subject to drug resistance due to FLT3 mutations. How these mutations lead to drug resistance is hitherto poorly understood. Herein, we studied the molecular mechanism of the drug resistance mutations D835N, Y842S and M664I, which confer resistance against the most advanced inhibitors, quizartinib and PLX3397 (pexidartinib), using enzyme kinetics and computer simulations. In vitro kinase assays were performed to measure the comparative catalytic activity of the native protein and the mutants, using a bacterial expression system developed to this aim. Our results reveal that the differential drug sensitivity profiles can be rationalised by the dynamics of the protein–drug interactions and perturbation of the intraprotein contacts upon mutations. Drug binding induced a single conformation in the native protein, whereas multiple conformations were observed otherwise (in the mutants or in the absence of drugs). The end‐point kinetics measurements indicated that the three resistant mutants conferred catalytic activity that is at least as high as that of the reference without such mutations. Overall, our calculations and measurements suggest that the structural dynamics of the drug‐resistant mutants that affect the active state and the increased conformational freedom of the remaining inactive drug‐bound population are the two major factors that contribute to drug resistance in FLT3 harbouring cancer cells. Our results explain the mechanism of drug resistance mutations and can aid to the design of more effective tyrosine kinase inhibitors.
Use of Amitriptyline in the Treatment of Headache After Traumatic Brain Injury: Lessons Learned From a Clinical Trial
Authors: Hurwitz Max , Lucas Sylvia , Bell Kathleen R. , Temkin Nancy , Dikmen Sureyya , Hoffman Jeanne
Published: January 2020

Objectives

The primary outcome of this study was to assess the efficacy and safety of preventive treatment with amitriptyline on headache frequency and severity after mild traumatic brain injury (mTBI).

Background

Despite the fact that headache is the most common and persistent physical symptom after TBI, there has been little research on the longitudinal course or pharmacologic treatment of this disorder. Of those who have headache after injury, about 60% continue to complain of headache at 3 months post injury, with higher levels of disability than those without headache. There have been no prospective, randomized, controlled trials of a pharmacologic agent for headache after TBI. Additionally, a brain‐injured population may be more susceptible to side effects of medication.

Design

This is a single‐center phase II trial of amitriptyline to prevent persistent headache after an mTBI. Medication dose was gradually increased from 10 to 50 mg daily.

Results

Fifty participants were enrolled and 33 who completed the 90‐day assessment were included in the final analysis. In order to detect a possible cognitive impact of the study drug, 24 participants were randomly assigned to start amitriptyline immediately after study enrollment and 26 were assigned to start 30 days after enrollment. Forty‐nine percent (18/37) of those assigned to take medication took none throughout the study period, with less compliance in younger participants with mean ages of 32.7 in those who did not take any medication, 33.4 who were less than 80% compliant, and 42.3 who were compliant (P = .013). Compliance in keeping a daily headache diary was low, with 29/50 participants (58%) meeting daily entry completion, and only 10 participants maintaining 100% diary completion. No differences were found between those who started medication immediately vs at day 30 in headache frequency or severity.

Conclusions

While headache is the most common symptom following mTBI, current evidence does not support a specific treatment. No differences were noted in headache frequency compared to our prior study. However, the current sample had significantly lower headache severity (15% vs 36% with pain rating of 6 or above, P = .015) compared to our prior study. Our current study was not able to determine whether there is any benefit for the use of amitriptyline as a headache preventive because of difficulty with study recruitment and compliance. The challenges with recruitment and retention in the mTBI population were instructive, and future research in this area will need to identify strategies to improve recruitment, diary compliance, and medication adherence in this population.
Can imperial radio be transnational? British‐affiliated Arabic radio broadcasting in the interwar period
Authors: Stanton Andrea L.
Published: January 2020

This media history article uses the development of the British Broadcasting Corporation's Arabic radio broadcasting service in 1938 as a case study for considering the intersections and overlaps between transnationalism and imperialism in the early mid‐20th century. Archival evidence suggests that the British Broadcasting Corporation's Arabic broadcasting service, which was based in London, relied for human resources, programming, and other forms of expertise on the Palestine Broadcasting Service in Jerusalem and the Egyptian State Broadcasting Service in Cairo—as well as on British government officials in those countries. Yet scholarly literature on these stations tends to treat them as free‐standing institutions with minimal interaction. How might recent scholarship on entangled media histories productively problematize the treatment of radio histories as institutional histories within nation‐state boundaries? How might it capture both the transnational and the colonial or imperial connections of these stations? It closes by suggesting how this case study might be useful for scholars working in other arenas.
Strategy to design high performance TiB2‐based materials: Strengthen grain boundaries by solid solute segregation
Authors: Dai Fu‐Zhi , Xiang Huimin , Zhou Yanchun
Published: January 2020

TiB2 exhibits a unique combination of excellent properties that make it promising candidate for applications in extreme environments, where retention of strength at high temperatures is essential. Tailoring grain boundary properties by segregation is believed a prominent way to design high‐temperature performance of ceramics. In this work, segregation tendencies of solute elements, including Sc, Y, Zr, Hf, V, Nb, Ta, Cr, Mo, and W, in TiB2 grain boundaries and the strengthening/weakening effects induced by segregations are investigated by first‐principles calculations. The results reveal that small atoms tend to segregate to grain boundary sites with local compression strains, while large atoms prefer grain boundary sites with local expansion strains. Deteriorated grain boundary strength is usually caused by additional expansion strain induced by segregation, while improved grain boundary strength results from either enhanced local bonding induced by segregation of small atoms or increased fracture strain due to segregation of large atoms. Cr and V, especially Cr, exhibit strong segregation tendency and improvement on grain boundary strength, which provides useful guidelines for the design of high performance TiB2‐based materials.
The combination of FLT3 and SYK kinase inhibitors is toxic to leukaemia cells with CBL mutations
Authors: Weisberg Ellen , Meng Chengcheng , Case Abigail E. , Tiv Hong L. , Gokhale Prafulla C. , Toure Anthia A. , Buhrlage Sara , Liu Xiaoxi , Wang Jinhua , Gray Nathanael , Stone Richard , Adamia Sophia , Winer Eric , Sattler Martin , Griffin James D.
Published: January 2020

Mutations in the E3 ubiquitin ligase CBL, found in several myeloid neoplasms, lead to decreased ubiquitin ligase activity. In murine systems, these mutations are associated with cytokine‐independent proliferation, thought to result from the activation of hematopoietic growth receptors, including FLT3 and KIT. Using cell lines and primary patient cells, we compared the activity of a panel of FLT3 inhibitors currently being used or tested in AML patients and also evaluated the effects of inhibition of the non‐receptor tyrosine kinase, SYK. We show that FLT3 inhibitors ranging from promiscuous to highly targeted are potent inhibitors of growth of leukaemia cells expressing mutant CBL in vitro, and we demonstrate in vivo efficacy of midostaurin using mouse models of mutant CBL. Potentiation of effects of targeted FLT3 inhibition by SYK inhibition has been demonstrated in models of mutant FLT3‐positive AML and AML characterized by hyperactivated SYK. Here, we show that targeted SYK inhibition similarly enhances the effects of midostaurin and other FLT3 inhibitors against mutant CBL‐positive leukaemia. Taken together, our results support the notion that mutant CBL‐expressing myeloid leukaemias are highly sensitive to available FLT3 inhibitors and that this effect can be significantly augmented by optimum inhibition of SYK kinase.
Process and outcome evaluation of a CBME intervention guided by program theory
Authors: Hamza Deena M. , Ross Shelley , Oandasan Ivy
Published: January 2020

Rationale

Competency‐based medical education (CBME) has gained momentum as an improved training model, but literature on outcomes of CBME, including evaluation of implementation processes, is minimal. We present a case for the following: (a) the development of a program theory is essential prior to or in the initial stages of implementation of CBME; (b) the program theory should guide the strategies and methods for evaluation that will answer questions about anticipated and unintended outcomes; and (c) the iterative process of testing assumptions and hypotheses will lead to modifications to the program theory to inform best practices of implementing CBME.

Methods

We use the Triple C Competency‐based Curriculum as a worked example to illustrate how process and outcome evaluation, guided by a program theory, can lead to meaningful enhancement of CBME curriculum, assessment, and implementation strategies. Using a mixed methods design, the processes and outcomes of Triple C were explored through surveys, interviews, and historical document review, which captured the experiences of various stakeholders.

Findings

The theory‐led program evaluation process was able to identify areas that supported CBME implementation: the value of a strong nondirective national vertical core supporting the transformation in education, program autonomy, and adaptability to pre‐existing local context. Areas in need of improvement included the need for ongoing support from College of Family Physicians of Canada (CFPC) and better planning for shifts in program leadership over time.

Conclusions

Deliberately pairing evaluation alongside change is an important activity and, when accomplished, yields valuable information from the experiences of those implementing and experiencing a program. Evaluation and the development of an updated program theory facilitate the introduction of new changes and theories that build on these findings, which also supports the desired goal of contributing toward cumulative science rather than “reinventing the wheel.”
Incidence of myeloproliferative neoplasms – trends by subgroup and age in a population‐based study in Sweden
Authors: Hultcrantz M. , Ravn Landtblom A. , Andréasson B. , Samuelsson J. , Dickman P. W. , Kristinsson S. Y. , Björkholm M. , Andersson T. M.‐L.
Published: January 2020

Background

The reported incidence of Philadelphia‐negative myeloproliferative neoplasms (MPNs) differs substantially between previous reports, likely due to true regional differences in incidence and/or variations in the quality and coverage of the cancer registers.

Objective

We therefore assessed MPN incidence in Sweden during recent years using prospectively collected information captured in Swedish health registers.

Methods

Patients with MPNs were identified through the Swedish Cancer Register and Swedish Blood Cancer Register between 2000 and 2014. Information on the Swedish population was obtained from the Human Mortality Database. Crude and age‐standardized incidence rates of MPNs with 95% confidence intervals (CIs) were calculated.

Results

A total of 6281 MPN cases were reported to the Swedish Cancer Register and Swedish Blood Cancer Register during 2000–2014. The age‐standardized, to the Swedish population in 2000, incidence for all MPNs was 4.45 (95% confidence interval [CI] 4.34–4.56)/100 000 person‐years. The age‐standardized incidence for polycythemia vera was 1.48 (1.42–1.54), for essential thrombocythemia 1.60 (1.53–1.66) and for primary myelofibrosis 0.52 (0.48–0.56)/100 000 person‐years, respectively. The incidence rate of MPNs was substantially higher in the older compared to the younger age groups. The incidence increased during the study period, likely to do better reporting and increasing age of the general population.

Conclusion

The reported MPN incidences in our study, which were in the higher interval of previously published studies, are likely more accurate compared to previous reports due to the population‐based setting and high level of coverage in the Swedish Cancer and Blood Cancer Registers.
Melatonin alleviates vascular calcification and ageing through exosomal miR‐204/miR‐211 cluster in a paracrine manner
Authors: Xu Feng , Zhong Jia‐Yu , Lin Xiao , Shan Su‐Kang , Guo Bei , Zheng Ming‐Hui , Wang Yi , Li Fuxingzi , Cui Rong‐Rong , Wu Feng , Zhou En , Liao Xiao‐Bo , Liu You‐Shuo , Yuan Ling‐Qing
Published: January 2020

In the elderly with atherosclerosis, hypertension and diabetes, vascular calcification and ageing are ubiquitous. Melatonin (MT) has been demonstrated to impact the cardiovascular system. In this study, we have shown that MT alleviates vascular calcification and ageing, and the underlying mechanism involved. We found that both osteogenic differentiation and senescence of vascular smooth muscle cells (VSMCs) were attenuated by MT in a MT membrane receptor‐dependent manner. Moreover, exosomes isolated from VSMCs or calcifying vascular smooth muscle cells (CVSMCs) treated with MT could be uptaken by VSMCs and attenuated the osteogenic differentiation and senescence of VSMCs or CVSMCs, respectively. Moreover, we used conditional medium from MT‐treated VSMCs and Transwell assay to confirm exosomes secreted by MT‐treated VSMCs attenuated the osteogenic differentiation and senescence of VSMCs through paracrine mechanism. We also found exosomal miR‐204/miR‐211 mediated the paracrine effect of exosomes secreted by VSMCs. A potential target of these two miRs was revealed to be BMP2. Furthermore, treatment of MT alleviated vascular calcification and ageing in 5/6‐nephrectomy plus high‐phosphate diet‐treated (5/6 NTP) mice, while these effects were partially reversed by GW4869. Exosomes derived from MT‐treated VSMCs were internalised into mouse artery detected by in vivo fluorescence image, and these exosomes reduced vascular calcification and ageing of 5/6 NTP mice, but both effects were largely abolished by inhibition of exosomal miR‐204 or miR‐211. In summary, our present study revealed that exosomes from MT‐treated VSMCs could attenuate vascular calcification and ageing in a paracrine manner through an exosomal miR‐204/miR‐211.
Do psychologists understand honor cultures when they operationalize them?
Authors: Barnes Collin D.
Published: January 2020

This paper brings the thought of philosopher and world‐class chemist Michael Polanyi to bear on psychologists' study of honor cultures. After reviewing some fundamentals of Polanyi's outlook on science and persons, the paper develops a heuristic involving two dimensions to the process of knowing others—one that is integrative, another that is affective—in which seeing with honor cultures only characterizes one side of the intersection between these dimensions. This leads on to consideration of the Honor Ideology for Manhood scale (Barnes, Brown, & Osterman, 2012), an operationalization of honor in the southern U.S. that misses understanding because of impairments it naturally suffers as an instrument of detachment. The possibility follows that understanding as seeing with another culture most readily succeeds when that culture's way of life is personally indwelt so that the psychologist directly encounters what its members can speak of and only convey by showing. The distinction Polanyi makes between explicit and tacit knowledge informs this proposal, and his vision of apprenticing—such as occurs between masters and pupils in the training of a science or an art—is presented as an exemplary form of such encounters.
Is Excess Weight Penalised or Rewarded in Middle‐Income Countries’ Labour Markets? Comparative Evidence from China, India and Mexico
Authors: Clément Matthieu , Levasseur Pierre , Seetahul Suneha
Published: January 2020

This comparative study examines the relationship between excess weight and hourly wages in the unprecedented context of middle‐income countries. We compare three countries that are at different stages of the nutrition transition: India (at an early stage), China (at an intermediate stage) and Mexico (at an advanced stage). To do so, we use three distinct household surveys and combine different estimation procedures. Our results emphasise a wage penalty of underweight together with a wage reward of excess weight in India, pointing towards the persistence of pro‐fat social norms in a country where hunger is still highly prevalent. Conversely, we observe significant overweight and obesity wage penalties in China, especially in non‐manual jobs, probably due to a large diffusion of anti‐fat social norms in a country where hunger is residual and normal weight predominant. In Mexico, we find an overweight wage premium in manual jobs and no effect in non‐manual jobs. We speculate that the large‐scale diffusion of excess weight may lead to its greater social acceptance (i.e. ‘new’ pro‐fat norms). Finally, we explore the potential transmission channels through which bodyweight may affect wages. We provide evidence of potential anti‐fat discrimination in China and pro‐fat‐discrimination in India and Mexico. Our results have important implications in terms of public health policy.
Suppression of tooth movement‐induced sclerostin expression using β‐adrenergic receptor blockers
Authors: Uchibori Shiho , Sekiya Takeo , Sato Takuma , Hayashi Kaori , Takeguchi Atsushi , Muramatsu Ryujiro , Ishizuka Kyoko , Kondo Hisataka , Miyazawa Ken , Togari Akifumi , Goto Shigemi
Published: January 2020

Objective

Regulation of bone metabolism by the sympathetic nervous system has recently been clarified. Tooth movement is increased by increased bone metabolic turnover due to sympathetic activation. This study aimed to compare the effects of the β‐adrenergic receptor (β‐AR) blockers atenolol (β1‐AR blocker), butoxamine (β2‐AR blocker) and propranolol (non‐selective β‐AR blocker) on tooth movement in spontaneously hypertensive rats (SHR) with sympathicotonia.

Materials and Methods

Spontaneously hypertensive rats were divided into the following four groups: an SHR control group and groups treated with 0.1 mg/kg atenolol, 1 mg/kg butoxamine or 1 mg/kg propranolol (n = 6 rats/group). Atenolol, butoxamine or propranolol was administered daily to each treatment group, and orthodontic force was applied using a closed‐coil spring. Finally, immunohistochemical analysis was performed for receptor activator of nuclear factor kappa‐B ligand (RANKL) and sclerostin (SOST).

Results

Atenolol, butoxamine and propranolol inhibited tooth movement and increased maxillary alveolar bone volume. Histological analysis revealed that these β‐AR blockers decreased osteoclast activity on the compression side. Furthermore, immunohistochemical analysis revealed that atenolol, butoxamine and propranolol decreased the number of RANKL‐ and SOST‐positive osteocytes on the compression side.

Conclusions

β‐AR blockers decreased tooth movement and downregulated SOST in osteocytes, accompanied by increasing alveolar bone resorption.
Epicutaneous immunogenicity of partially hydrolyzed whey protein evaluated using tape‐stripped mouse model
Authors: Iwamoto Hiroshi , Matsubara Takeshi , Okamoto Tomoyuki , Yoshikawa Mayu , Matsumoto Takuya , Kono Gaku , Takeda Yasuhiro
Published: January 2020

Background

Hydrolyzed cow's milk protein formulas are widely used for infants with a history or risk of cow's milk allergy. Based on the current theory that food allergen sensitization occurs via the skin, we investigated the epicutaneous immunogenicity of partially hydrolyzed whey proteins, which are ingredients in infant formulas.

Methods

BALB/c mice were exposed epicutaneously to whey protein concentrate (WPC) or partial whey protein hydrolysates (PWH1 or PWH2) on tape‐stripped skin. Sensitization was assessed by evaluating serum β‐lactoglobulin (β‐LG)‐specific antibodies, basophil activation, and cytokine production from β‐LG‐stimulated lymphoid cells. The anaphylaxis reaction was evaluated by measuring the rectal temperature and plasma level of mouse mast cell protease‐1 after oral β‐LG challenge. Immune cell accumulation in the skin was also analyzed.

Results

Substantive sensitization and β‐LG‐induced anaphylaxis reaction were observed in WPC‐exposed mice, whereas no significant changes were observed in PWH1‐ or PWH2‐exposed mice. The basophil and eosinophil counts increased in WPC‐exposed murine skin, not but in PWH1‐ or PWH2‐exposed mice.

Conclusion

The epicutaneous immunogenicity of PWH1 and PWH2 is markedly decreased, which may reduce the risk of allergen sensitization. Further studies are required to investigate the clinical value of these partial hydrolysates for high‐risk infants.
The influence of species richness in primary school surroundings on children lung function and allergic disease development
Authors: Cavaleiro Rufo João , Ribeiro Ana Isabel , Paciência Inês , Delgado Luís , Moreira André
Published: January 2020

Background

Primary schools represent important environments for biodiversity exposure and thus may play a crucial role on early‐life immunomodulation, protecting against allergic sensitization. The aim of this study was to understand how the exposure to different levels of species richness surrounding urban primary schools may influence the development of allergic diseases and asthma in children.

Methods

A species richness index (SRI), evaluating habitat diversity in terms of amphibians, birds, reptiles, and small mammals, was estimated and attributed to 20 primary schools in the city of Porto, Portugal. The SRI was measured considering a 100 m straight‐line buffer around the schools. Children who attended the participating schools were invited to participate in the study, performed spirometry with bronchodilation and skin‐prick tests, and had their parents fill a questionnaire concerning allergy and asthma symptoms, as well as demographic and socioeconomic data. Asthma was defined according to three distinct criteria.

Results

The study results showed significant and positive associations between the exposure to species richness in schools and the forced expiratory volume at the first second (FEV1) and forced vital capacity (FVC) parameters both before and after bronchodilation, independently of the asthma and atopic status. Fully adjusted models revealed that a unitary increment in the SRI was associated with an average increase of approximately 2 and 3 mL in FEV1 and FVC, respectively.

Conclusion

Species richness in school surroundings may impact lung function development in children. However, this increase in lung function was not associated with any clinically relevant protective effect on allergy and asthma development.
Health education interventions for older adults with hypertension: A systematic review and meta‐analysis
Authors: Chen Yajing , Li Xiuxia , Jing Guangzhuang , Pan Bei , Ge Long , Bing ZhiTong , Yang Kehu , Han Xuemei
Published: January 2020

Objective

The study aimed to evaluate the effectiveness of health education intervention for the control of blood pressure (BP) in older adults with hypertension.

Methods

Five databases were searched in March 2018 for randomized controlled trials to manage hypertension in older adults by health education. The primary outcomes were changes in systolic and diastolic BP. RevMan5 was used for meta‐analysis.

Results

Seven articles with 1,105 participants were included. In them, 393 (35.56%) older adults participated in health education interventions in the form of courses, and 226 (20.45%), in health education sessions. The meta‐analysis suggested an overall reduction in systolic BP after health education courses (SMD, standardized mean difference = 4.80, 95% CI: 7.01–2.59, p < .05). Similar results were observed after health education sessions (SMD = 11.73, 95% CI: 17.63–5.82, p < .05). The diastolic BP reduction showed no difference after the health education course (p = .09). The random effects meta‐analysis suggested an overall reduction in diastolic BP after health education sessions (SMD = 5.39, 95% CI: 7.98–2.79, p < .05).

Conclusion

Although different health education methods had different effects on hypertension control, overall, educational interventions can potentially lead to improved BP control.