bluuebunny/crossref_metadata_2025 huggingface dataset:
“Come on Down”: Using a Trivia Game to Teach the Concept of Organizational Justice
Authors: Swain Jordon E. , Bogardus Jason A. , Lin Eric
Published: December 2019

The three elements of organizational justice (distributive, procedural, and interactional justice) can be difficult for undergraduate students to grasp given variances in their personal experiences. To address this issue, we developed a novel approach to teach students these concepts by employing a trivia game show format in which students experience all three forms of injustice in a lighthearted and disarming context. We detail this experiential exercise and provide discussion points to help students grasp the important role organizational justice plays in leading effectively. We also provide suggestions for how to apply the concepts covered in the experiential exercise to different leadership challenges to deepen the learning experience.
Hemifacial Spasm in an Argus II Retinal Prosthesis Patient
Authors: Sun Susan Y. , Mammo Danny A. , Koozekanani Dara D. , Montezuma Sandra R.
Published: December 2019

Purpose:

A 59-year-old man with retinitis pigmentosa, who received an Argus II retinal prosthesis in the left eye 3 years prior, presented with left-sided involuntary facial contractions that occurred only after turning on the Argus II device.

Methods:

A case report.

Results:

Given that this patient's reported and visualized lower eyelid twitching corresponds to the location of the external region of the implanted coil, we hypothesize that heat or wirelessly transmitted electrical signals from the external coil to the implanted coil may induce spasm of the facial nerve and thus play a role in hemifacial spasm onset.

Conclusions:

To our knowledge, this is the first report of hemifacial spasm associated with Argus II use.
Cross-reactivity with Brazilian strains of Neisseria meningitidis B after immunization with outer membrane vesicles
Authors: Trzewikoswki de Lima Gabriela , Portilho Amanda Izeli , De Gaspari Elizabeth
Published: December 2019

Background:

Immunization against Neisseria meningitidis is important for public health. Vaccines composed of cross-reactivity antigens avoid strain-specific responses, ensuring more comprehensive protection.

Methods:

The cross-reactivity between three strains from the last outbreak of N. meningitidis in Brazil was assessed in our studies, using enzyme-linked immunosorbent assay (ELISA) and immunoblotting assays.

Results:

Both assays verifed a similar humoral response between the strains evaluated. Patterns of antigen recognition differed with each dose evaluated.

Conclusions:

We observed that immunization with N. meningitidis B outer membrane vesicles (OMVs) led to the production of antibodies that recognized antigens of heterologous strains, indicating possible protection against these evaluated strains.
Effect of chemical admixtures on the properties of grouting materials with high-volume mineral materials
Authors: Li Xianjun
Published: December 2019

Based on the preparation of grouting materials with high-volume mineral admixtures, the effects of chemical admixtures including early-strength components and retarding components on the grouts with volume mineral admixtures were investigated. The results show that early-strength components have little effect on the grouts with high-volume mineral admixtures. Retarding component sodium gluconate does not play a great role for the grouts with high-volume mineral admixtures. However, the incorporation of borax and sodium tripolyphosphate can greatly improve the properties of the grouts, mainly due to their composite effect. The appropriate compound content is 0.4 wt% borax and 0–0.2 wt% sodium tripolyphosphate of cementitious materials. When 0.4 wt% borax and 0.2 wt% sodium tripolyphosphate were added to the grouts with volume mineral admixtures, initial fluidity and 30-min fluidity are 340 mm, and 1-, 3-, and 28-day compressive strength are, respectively, 41.6, 57.1, and 81.5 MPa. These values far exceed the standard requirements. It also shows that early-strength components and sodium gluconate can be neglected when high-volume mineral admixtures are added to the grouts.
The Use of Sonography in a Mother and Fetus With Concordant Truncus Arteriosus
Authors: Fyock Danae G. , Downs Emily
Published: December 2019

Reported pregnancies in women with repaired truncus arteriosus are rare. As a result of improved surgical techniques, more women with conotruncal defects are now reaching reproductive age. Multifactorial inheritance rather than single gene mutation is the causative agent of most congenital heart disease. The environment can play an important and varied role in direct transmission, particularly in incidences where genes predispose a defect. This may be one of the first reported cases discussing a pregnant mother with repaired truncus arteriosus and her fetus, prenatally diagnosed with a concordant truncal defect.
Integrated drug profiling and CRISPR screening identify essential pathways for CAR T-cell cytotoxicity
Authors: Dufva Olli , Koski Jan , Maliniemi Pilvi , Ianevski Aleksandr , Klievink Jay , Leitner Judith , Pölönen Petri , Hohtari Helena , Saeed Khalid , Hannunen Tiina , Ellonen Pekka , Steinberger Peter , Kankainen Matti , Aittokallio Tero , Keränen Mikko A. I. , Korhonen Matti , Mustjoki Satu
Published: December 2019

Chimeric antigen receptor (CAR) T-cell therapy has proven effective in relapsed and refractory B-cell malignancies, but resistance and relapses still occur. Better understanding of mechanisms influencing CAR T-cell cytotoxicity and the potential for modulation using small-molecule drugs could improve current immunotherapies. Here, we systematically investigated druggable mechanisms of CAR T-cell cytotoxicity using >500 small-molecule drugs and genome-scale CRISPR-Cas9 loss-of-function screens. We identified several tyrosine kinase inhibitors that inhibit CAR T-cell cytotoxicity by impairing T-cell signaling transcriptional activity. In contrast, the apoptotic modulator drugs SMAC mimetics sensitized B-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma cells to anti-CD19 CAR T cells. CRISPR screens identified death receptor signaling through FADD and TNFRSF10B (TRAIL-R2) as a key mediator of CAR T-cell cytotoxicity and elucidated the RIPK1-dependent mechanism of sensitization by SMAC mimetics. Death receptor expression varied across genetic subtypes of B-cell malignancies, suggesting a link between mechanisms of CAR T-cell cytotoxicity and cancer genetics. These results implicate death receptor signaling as an important mediator of cancer cell sensitivity to CAR T-cell cytotoxicity, with potential for pharmacological targeting to enhance cancer immunotherapy. The screening data provide a resource of immunomodulatory properties of cancer drugs and genetic mechanisms influencing CAR T-cell cytotoxicity.
Association of asthma and smoking with lung function impairment in adolescence and early adulthood: the Isle of Wight Birth Cohort Study
Authors: Arshad S. Hasan , Hodgekiss Claire , Holloway John W. , Kurukulaaratchy Ramesh , Karmaus Wilfried , Zhang Hongmei , Roberts Graham
Published: December 2019

We investigated associations of asthma and smoking with lung function and airway reversibility from childhood to early adulthood.

The population-based Isle of Wight Birth Cohort (n=1456) was assessed at birth, and at 1, 2, 4, 10, 18 and 26 years. Asthma was defined as physician diagnosis plus current wheeze and/or treatment. Spirometry was conducted at 10 (n=981), 18 (n=839) and 26 years (n=547). Individuals were subdivided into nonsmokers without asthma, nonsmokers with asthma, smokers without asthma and smokers with asthma, based on asthma and smoking status at 26 years. Their lung function trajectories from 10 to 26 years were examined using longitudinal models.

Nonsmokers with asthma had smaller forced expiratory volume in 1 s (FEV1), FEF25–75%(forced expiratory flow at 25–75% of forced vital capacity (FVC)) and FEV1/FVC ratio compared to nonsmokers without asthma at age 10 and 18 years, with differences reduced after bronchodilator (pre-bronchodilator FEV1at 26 years 3.75 Lversus4.02 L, p<0.001; post-bronchodilator 4.02 Lversus4.16 L, p=0.08). This lung function deficit did not worsen after 18 years. Smokers without asthma had smaller FEF25–75%and FEV1/FVC ratio (but not FEV1) at 26 years compared to nonsmokers without asthma, with the deficit appearing after 18 years and persisting despite bronchodilator response (for FEV1/FVC ratio at 26 years 0.80versus0.81, p=0.002; post-bronchodilator 0.83versus0.85, p=0.005). Smokers with asthma had worse lung function compared to other groups.

Lung function deficits associated with asthma and smoking occur early in life. They are not fully responsive to bronchodilators, indicating a risk for long-term lung health, which highlights the need to institute preventive measures in adolescence and early adult life before irreversible damage occurs.
Donor surfactant protein A2 polymorphism and lung transplant survival
Authors: D'Ovidio Frank , Floros Joanna , Aramini Beatrice , Lederer David , DiAngelo Susan L. , Arcasoy Selim , Sonett Joshua R. , Robbins Hillary , Shah Lory , Costa Joseph , Urso Andreacarola
Published: December 2019

Purpose

Gene polymorphisms of surfactant proteins, key players in lung innate immunity, have been associated with various lung diseases. The aim of this study was to investigate the potential association between variations within the surfactant protein (SP)-A gene of the donor lung allograft and recipient post-transplant outcome.

Methods

Lung-transplant patients (n=192) were prospectively followed-up with pulmonary function tests, bronchoscopies with bronchoalveolar lavage and biopsies. Donor lungs were assayed for SP-A1 (6An) and SP-A2 (1An) gene polymorphism using the pyrosequencing method. Unadjusted and adjusted stratified Cox survival models are reported.

Results

SP-A1 and SP-A2 genotype frequency and lung transplant recipient and donor characteristics as well as cause of death are noted. Recipients were grouped per donor SP-A2 variants. Individuals that received lungs from donors with the SP-A2 1A0(n=102)versus1A1variant (n=68) or SP-A2 genotype 1A01A0(n=54)versus1A0A1(n=38) had greater survival at 1 year (log-rank p<0.025). No significant association was noted for SP-A1 variants. Stratified adjusted survival models for 1-year survival and diagnosis showed a reduced survival for 1A1variant and the 1A01A1genotype. Furthermore, when survival was conditional on 1-year survival no significance was observed, indicating that the survival difference was due to the first year's outcome associated with the 1A1variant.

Conclusion

Donor lung SP-A gene polymorphisms are associated with post-transplant clinical outcome. Lungs from donors with the SP-A2 variant 1A1had a reduced survival at 1 year. The observed donor genetic differences,viainnate immunity relate to the post-transplant clinical outcome.
Eight novel variants in theSLC34A2gene in pulmonary alveolar microlithiasis
Authors: Jönsson Åsa Lina M. , Bendstrup Elisabeth , Mogensen Susie , Kopras Elizabeth J. , McCormack Francis X. , Campo Ilaria , Mariani Francesca , Escribano-Montaner Amparo , Holm Are M. , Martinez-Colls Maria del Mar , Pintos-Morell Guillem , Taillé Camille , Crestani Bruno , Hilberg Ole , Hvarregaard Christensen Jane , Simonsen Ulf
Published: December 2019

Background

Pulmonary alveolar microlithiasis (PAM) is caused by genetic variants in theSLC34A2gene, which encodes the sodium-dependent phosphate transport protein 2B (NaPi-2b). PAM is characterised by deposition of calcium phosphate concretions (microliths) in the alveoli leading to pulmonary dysfunction. The variant spectrum ofSLC34A2has not been well investigated and it is not yet known whether a genotype–phenotype correlation exists.

Methods

We collected DNA from 14 patients with PAM and four relatives, and analysed the coding regions ofSLC34A2by direct DNA sequencing. To determine the phenotype characteristics, clinical data were collected and a severity score was created for each variant, based on type and localisation within the protein.

Results

We identified eight novel allelic variants ofSLC34A2in 14 patients with PAM. Four of these were nonsense variants, three were missense and one was a splice site variant. One patient was heterozygous for two different variants and all other patients were homozygous. Four patients were asymptomatic and 10 patients were symptomatic. The severity of the disease was associated with the variant severity.

Conclusions

Our findings support a significant role forSLC34A2in PAM and expand the variant spectrum of the disease. Thus,SLC34A2variants were detected in all patients and eight novel allelic variants were discovered. An association between disease severity and the severity of the variants was found; however, this needs to be investigated in larger patient populations.
PET/CT features of extrapulmonary tuberculosis at first clinical presentation: a cross-sectional observational18F-FDG imaging study across six countries
Authors: Bomanji Jamshed , Sharma Rajnish , Mittal Bhagwant R. , Gambhir Sanjay , Qureshy Ahmad , Begum Shamim M.F. , Paez Diana , Sathekge Mike , Vorster Mariza , Sobic Saranovic Dragana , Pusuwan Pawana , Mann Vera , Vinjamuri Sobhan , Zumla Alimuddin , Pascual Thomas N.B.
Published: December 2019

Background

A large proportion of the huge global burden of extrapulmonary tuberculosis (EPTB) cases are treated empirically without accurate definition of disease sites and extent of multi-organ disease involvement. Positron emission tomography (PET) imaging using 2-deoxy-2-(fluorine-18) fluoro-d-glucose (18F-FDG) in tuberculosis could be a useful imaging technique for localising disease sites and extent of disease.

Methods

We conducted a study of HIV-negative adult patients with a new clinical diagnosis of EPTB across eight centres located in six countries: India, Pakistan, Thailand, South Africa, Serbia and Bangladesh, to assess the extent of disease and common sites involved at first presentation.18F-FDG PET/computed tomography (CT) scans were performed within 2 weeks of presentation.

Findings

358 patients with EPTB (189 females; 169 males) were recruited over 45 months, with an age range of 18–83 years (females median 30 years; males median 38 years). 350 (98%) out of 358 patients (183 female, 167 male) had positive scans. 118 (33.7%) out of 350 had a single extrapulmonary site and 232 (66.3%) out of 350 had more than one site (organ) affected. Lymph nodes, skeleton, pleura and brain were common sites. 100 (28%) out of 358 EPTB patients had18F-FDG PET/CT-positive sites in the lung. 110 patients were18F-FDG PET/CT-positive in more body sites than were noted clinically at first presentation and 160 patients had the same number of positive body sites.

Interpretation

18F-FDG PET/CT scan has potential for further elucidating the spectrum of disease, pathogenesis of EPTB and monitoring the effects of treatment on active lesions over time, and requires longitudinal cohort studies, twinned with biopsy and molecular studies.
Transcriptional variation and divergence of host-finding behaviour in Steinernema carpocapsae infective juveniles
Authors: Warnock Neil D. , Cox Deborah , McCoy Ciaran , Morris Robert , Dalzell Johnathan J.
Published: December 2019

Background

Steinernema carpocapsaeis an entomopathogenic nematode that employs nictation and jumping behaviours to find potential insect hosts. Here we aimed to investigate the transcriptional basis of variant host-finding behaviours in the infective juvenile (IJ) stage of threeS. carpocapsaestrains (ALL, Breton and UK1), with a focus on neuronal genes known to influence behaviour in other nematode species. Identifying gene expression changes that correlate with variant host-finding behaviours will further our understanding of nematode biology.

Results

RNA-seq analysis revealed that whilst up to 28% of theS. carpocapsaetranscriptome was differentially expressed (P < 0.0001) between strains, remarkably few of the most highly differentially expressed genes (> 2 log2 fold change,P < 0.0001) were from neuronal gene families.S. carpocapsaeBreton displays increased chemotaxis toward the laboratory hostGalleria mellonella,relative to the other strains. This correlates with the up-regulation of four srsx chemosensory GPCR genes, and a sodium transporter gene,asic-2,relative to both ALL and UK1 strains. The UK1 strain exhibits a decreased nictation phenotype relative to ALL and Breton strains, which correlates with co-ordinate up-regulation of neuropeptide like protein 36 (nlp-36), and down-regulation of an srt family GPCR gene, and a distinctasic-2-likesodium channel paralogue.To further investigate the link between transcriptional regulation and behavioural variation, we sequenced microRNAs across IJs of each strain. We have identified 283 high confidence microRNA genes, yielding 321 predicted mature microRNAs inS. carpocapsae, and find that up to 36% of microRNAs are differentially expressed (P < 0.0001) between strains. Many of the most highly differentially expressed microRNAs (> 2 log2 fold, P < 0.0001) are predicted to regulate a variety of neuronal genes that may contribute to variant host-finding behaviours. We have also found evidence for differential gene isoform usage between strains, which alters predicted microRNA interactions, and could contribute to the diversification of behaviour.

Conclusions

These data provide insight to the transcriptional basis of behavioural variation inS. carpocapsae, supporting efforts to understand the molecular basis of complex behaviours in nematodes.
A review and synthesis of frameworks for engagement in health research to identify concepts of knowledge user engagement
Authors: Jull Janet E. , Davidson Laurie , Dungan Rachel , Nguyen Tram , Woodward Krista P. , Graham Ian D.
Published: December 2019

Background

Engaging those who influence, administer and/or who are active users (“knowledge users”) of health care systems, as co-producers of health research, can help to ensure that research products will better address real world needs. Our aim was to identify and review frameworks of knowledge user engagement in health research in a systematic manner, and to describe the concepts comprising these frameworks.

Methods

An international team sharing a common interest in knowledge user engagement in health research used a consensus-building process to: 1) agree upon criteria to identify articles, 2) screen articles to identify existing frameworks, 3) extract, analyze data, and 4) synthesize and report the concepts of knowledge user engagement described in health research frameworks. We utilized the Patient Centered Outcomes Research Institute Engagement in Health Research Literature Explorer (PCORI Explorer) as a source of articles related to engagement in health research. The search includes articles from May 1995 to December 2017.

Results

We identified 54 articles about frameworks for knowledge user engagement in health research and report on 15 concepts. The average number of concepts reported in the 54 articles isn = 7, and ranges fromn = 1 ton = 13 concepts. The most commonly reported concepts are: knowledge user - prepare, support (n = 44), relational process (n = 39), research agenda (n = 38). The least commonly reported concepts are: methodology (n = 8), methods (n = 10) and analysis (n = 18). In a comparison of articles that report how research was done (n = 26) versus how research should be done (n = 28), articles about how research was done report concepts more often and have a higher average number of concepts (n = 8 of 15) in comparison to articles about how research should be done (n = 6 of 15). The exception is the concept “evaluate” and that is more often reported in articles that describe how research should be done.

Conclusions

We propose that research teams 1) consider engagement with the 15 concepts as fluid, and 2) consider a form of partnered negotiation that takes place through all phases of research to identify and use concepts appropriate to their team needs. There is a need for further work to understand concepts for knowledge user engagement.
An AIDS patient with urine retention
Authors: Xu Lijun , Tao Ran , Zhao Qiyu , Cheng Jinlin , Zhu Biao
Published: December 2019

Background

Cryptococcal prostatitis is a rare clinical disease and has never been reported in China.

Case presentation

We report on a male HIV-infected patient with pulmonary and prostate cryptococcosis that was misdiagnosed (as tuberculosis) and delayed diagnosed. Although the patients accepted anti-fungal treatment and anti-retroviral treatment finally, the physician’s mistakes reflect the rarity of this condition in China.

Conclusion

Cryptococcal prostatitis is a rare disease that unusually presents in immunodeficient patients. Physicians should have a heightened awareness of this particular infection in the immunodeficient population.
Does having a pet influence the physical activity of their young female owners?
Authors: Machová Kristýna , Daďová Klára , Chaloupková Helena , Svobodová Ivona
Published: December 2019

Background

Many studies have shown that having a dog has an impact on the increase in physical activity (PA) of people. However, what is often not taken into account in many such studies is owning of other pets. The aim of this study was to compare PA levels between animal owners and non-owners and to research potential differences between owners of different kinds of animals.

Method

111 young females of mean age 21 ± 1.2 years enrolled in this cross-sectional study. Czech version of short International physical activity questionnaire (IPAQ) was used to assess PA level, supplemented with a question about whether they owned an animal and what kind.

Results

People who owned a pet had higher frequency and duration of moderate physical activity (MPA) and spent more MET/min/wk. (p < 0.05). This difference has projected into total PA duration and also into calories burned in a week. Furthermore, a statistically significant difference between subgroups of animal owners was also confirmed for MPA and total PA in favour of horse owners.

Conclusions

Animal owners generally reported higher PA levels compared to people who do not own any pets. However, similarly significant in this particular age group was the kind of animal these young women owned.
72 revision surgeries for aseptic failure after hip or knee arthroplasty: a prospective study with an extended diagnostic algorithm
Authors:   The PRIS Study group, Khalid Vesal , Schønheyder Henrik Carl , Nielsen Poul Torben , Kappel Andreas , Thomsen Trine Rolighed , Aleksyniene Ramune , Lorenzen Jan , Rasmussen Sten
Published: December 2019

Background

Unrecognized periprosthetic joint infections are a concern in revision surgery for aseptic failure (AF) after total hip (THA) or knee (TKA) arthroplasties. A gold diagnostic standard does not exist. The aim of the current study was to determine the prevalence of unrecognized periprosthetic joint infection (PJI) in a cohort of revision for AF, using an experimental diagnostic algorithm.

Methods

The surgeons’ suspicion of AF was based primarily on patient history and clinical evaluation. X-ray imaging was used to reveal mechanical problems. To rule out an infectious aetiology standard blood biochemical tests were ordered in most patients. Evaluation followed the existing practice in the institute. Cases were included if revision surgery was planned for suspected AF. Intraoperatively, five synovial tissue biopsies were obtained routinely. PJI was defined as ≥3 positive cultures with the same microorganism(s). Patients were followed for 1 year postoperatively. Protocol samples included joint fluid, additional synovial tissue biopsies, bone biopsy, swabs from the implant surface, and sonication of retrieved components. Routine and protocol samples were cultured with extended incubation (14 days) and preserved for batchwise 16SrRNAgene amplification. Patients were stratified based on culture results and a clinical status was obtained at study end.

Results

A total of 72 revisions were performed on 71 patients (35 THA and 37 TKA). We found five of 72 cases of unrecognized PJI. Extended culture and protocol samples accounted for two of these. One patient diagnosed with AF was treated for a PJI during follow-up. The remaining patients did not change status from AF during follow-up.

Conclusions

We found a low prevalence of unrecognized periprosthetic joint infections in patients with an AF diagnosis. The algorithm strengthens the surgeons’ preoperative diagnosis of a non-infective condition. Evaluation for a failing TKA or THA is complex. Distinguishing between AF and PJI pre-operatively was a clinical decision. Our data did not support additional testing in routine revision surgery for AF.
Falls and fear of falling in older adults with total joint arthroplasty: a scoping review
Authors: Chen Serena Kuangyi , Voaklander Don , Perry Danielle , Jones C. Allyson
Published: December 2019

Background

Patients waiting or recovering from total joint arthroplasty (TJA) are at risk for falls which can lead to restriction of activity and negatively impact recovery. The objective of this scoping review is to critically appraise and synthesize the evidence in the reported number of falls, fear of falling, and risk factors associated with falls in older patients waiting for or recovering from TJA.

Methods

Seven electronic databases were searched with no date limits and using language restriction (English). The inclusion criteria were 1) cohorts that included older adults 60+ years of age, 2) reported prevalence of falls, fear of falling, and/or risk factors for falls in patients who were waiting or recovering from TJA and 3) cross-sectional studies, cohort studies, and case control study designs. The quality assessment of selected articles was assessed using the SIGN Guidelines Checklist.

Results

Of the 866 citations identified, 12 studies met the inclusion criteria and were reviewed. Prevalence of falls in pre-operative TJA patients and post-operative TJA patients ranged from 23 to 63%, and 13 to 42%, respectively. Of those five studies that examined fear of falling, pre-operative TJA patients reported greater fear of falling than post-operative patients. Modifiable risk factors for falls included fear of falling, joint range of motion, and depression.

Conclusions

An increased risk of falls in patients with TJA was reported both for patients waiting for and recovering from surgery. A number of modifiable risk factors were identified including fear of falling that could be targeted in fall prevention programs for TJA.
Systematic computational identification of prognostic cytogenetic markers in neuroblastoma
Authors: Qin Chao , He Xiaoyan , Zhao Yanding , Tong Chun-Yip , Zhu Kenneth Y. , Sun Yongqi , Cheng Chao
Published: December 2019

Background

Neuroblastoma (NB) is the most common extracranial solid tumor found in children. The frequent gain/loss of many chromosome bands in tumor cells and absence of mutations found at diagnosis suggests that NB is a copy number-driven cancer. Despite the previous work, a systematic analysis that investigates the relationship between such frequent gain/loss of chromosome bands and patient prognosis has yet to be implemented.

Methods

First, we analyzed two NB CNV datasets to select chromosomal bands with a high frequency of gain or loss. Second, we applied a computational approach to infer sample-specific CNVs for each chromosomal band selected in step 1 based on gene expression data. Third, we applied univariate Cox proportional hazards models to examine the association between the resulting inferred copy number values (iCNVs) and patient survival. Finally, we applied multivariate Cox proportional hazards models to select chromosomal bands that remained significantly associated with prognosis after adjusting for critical clinical variables, including age, stage, gender, and MYCN amplification status.

Results

Here, we used a computational method to infer the copy number variations (CNVs) of sample-specific chromosome bands from NB patient gene expression profiles. The resulting inferred CNVs (iCNVs) were highly correlated with the experimentally determined CNVs, demonstrating CNVs can be accurately inferred from gene expression profiles. Using this iCNV metric, we identified 58 frequent gain/loss chromosome bands that were significantly associated with patient survival. Furthermore, we found that 7 chromosome bands were still significantly associated with patient survival even when clinical factors, such as MYCN status, were considered. Particularly, we found that the chromosome band chr11p14 has high potential as a novel candidate cytogenetic biomarker for clinical use.

Conclusion

Our analysis resulted in a comprehensive list of prognostic chromosome bands supported by strong statistical evidence. In particular, the chr11p14 gain event provided additional prognostic value in addition to well-established clinical factors, including MYCN status, and thereby represents a novel candidate cytogenetic biomarker with high clinical potential. Additionally, this computational framework could be readily extended to other cancer types, such as leukemia.
Process engineering of pH tolerant Ustilago cynodontis for efficient itaconic acid production
Authors: Hosseinpour Tehrani Hamed , Saur Katharina , Tharmasothirajan Apilaasha , Blank Lars M. , Wierckx Nick
Published: December 2019

Background

Ustilago cynodontis ranks among the relatively unknown itaconate production organisms. In comparison to the well-known and established organisms like Aspergillus terreus and Ustilago maydis, genetic engineering and first optimizations for itaconate production were only recently developed for U. cynodontis, enabling metabolic and morphological engineering of this acid-tolerant organism for efficient itaconate production. These engineered strains were so far mostly characterized in small scale shaken cultures.

Results

In pH-controlled fed-batch experiments an optimum pH of 3.6 could be determined for itaconate production in the morphology-engineered U. cynodontis Δfuz7. With U. cynodontis ∆fuz7r∆cyp3rPetefmttA Pria1ria1, optimized for itaconate production through the deletion of an itaconate oxidase and overexpression of rate-limiting production steps, titers up to 82.9 ± 0.8 g L−1 were reached in a high-density pulsed fed-batch fermentation at this pH. The use of a constant glucose feed controlled by in-line glucose analysis increased the yield in the production phase to 0.61 gITA gGLC−1, which is 84% of the maximum theoretical pathway yield. Productivity could be improved to a maximum of 1.44 g L−1 h−1 and cell recycling was achieved by repeated-batch application.

Conclusions

Here, we characterize engineered U. cynodontis strains in controlled bioreactors and optimize the fermentation process for itaconate production. The results obtained are discussed in a biotechnological context and show the great potential of U. cynodontis as an itaconate producing host.
Co-designing obesity prevention interventions together with children: intervention mapping meets youth-led participatory action research
Authors: Anselma Manou , Altenburg Teatske M. , Emke Helga , van Nassau Femke , Jurg Merlin , Ruiter Robert A. C. , Jurkowski Janine M. , Chinapaw Mai J. M.
Published: December 2019

Background

Youth-led Participatory Action Research (YPAR) involves children throughout the process of developing and implementing interventions. Combining YPAR with a structural approach for designing and planning interventions, such as Intervention Mapping (IM), may further improve implementation and effectiveness of interventions. This paper describes how YPAR and IM were combined in the Kids in Action study.

Methods

The Kids in Action study aims to improve health behaviors of 9–12-year old children living in a low socioeconomic neighborhood in Amsterdam, by co-designing interventions with these children. At each of four schools 6–8 children (N = 18–24 total per year) and two academic researchers formed participatory groups that met weekly or every fortnight during two school years. An IM expert panel advised the participatory groups on the application of IM.

Results

Following the IM protocol, we conducted a participatory needs assessment with children, parents and professionals, in IM-step 1. In IM-step 2, the IM expert panel constructed matrices of program objectives, and the children provided feedback. In collaboration with children programs were designed and produced using an iterative process during IM-steps 3–4. In IM-step 5, the participatory groups and professional community partners designed the implementation plan. Finally, in IM-step 6, the protocol of the process and effect evaluation – executed by academic researchers with input from children – was developed.

Conclusions

By combining YPAR and IM, several interventions have been developed and implemented, varying from a school water policy to extracurricular sports activities. Sharing responsibility with children was challenging when combining IM with YPAR. In YPAR children are given as much autonomy as possible, while traditional IM development work is primarily done by academic researchers. Strengths in combining IM and YPAR include the involvement of the end-users - children - throughout the process while at the same time developing interventions based on existing evidence. Time-management, a multidisciplinary team, and flexibility are important conditions when combining IM with YPAR. A strong community project group, with professionals who were willing to help children develop and execute their ideas, was an important success factor. This study can serve as an example to other YPAR studies developing interventions using the IM protocol.
Modelling the effects of glucagon during glucose tolerance testing
Authors: Kelly Ross A. , Fitches Molly J. , Webb Steven D. , Pop S. R. , Chidlow Stewart J.
Published: December 2019

Background

Glucose tolerance testing is a tool used to estimate glucose effectiveness and insulin sensitivity in diabetic patients. The importance of such tests has prompted the development and utilisation of mathematical models that describe glucose kinetics as a function of insulin activity. The hormone glucagon, also plays a fundamental role in systemic plasma glucose regulation and is secreted reciprocally to insulin, stimulating catabolic glucose utilisation. However, regulation of glucagon secretion by α-cells is impaired in type-1 and type-2 diabetes through pancreatic islet dysfunction. Despite this, inclusion of glucagon activity when modelling the glucose kinetics during glucose tolerance testing is often overlooked. This study presents two mathematical models of a glucose tolerance test that incorporate glucose-insulin-glucagon dynamics. The first model describes a non-linear relationship between glucagon and glucose, whereas the second model assumes a linear relationship.

Results

Both models are validated against insulin-modified and glucose infusion intravenous glucose tolerance test (IVGTT) data, as well as insulin infusion data, and are capable of estimating patient glucose effectiveness (sG) and insulin sensitivity (sI). Inclusion of glucagon dynamics proves to provide a more detailed representation of the metabolic portrait, enabling estimation of two new diagnostic parameters: glucagon effectiveness (sE) and glucagon sensitivity (δ).

Conclusions

The models are used to investigate how different degrees of pax‘tient glucagon sensitivity and effectiveness affect the concentration of blood glucose and plasma glucagon during IVGTT and insulin infusion tests, providing a platform from which the role of glucagon dynamics during a glucose tolerance test may be investigated and predicted.
The regulatory mechanism of p38/MAPK in the chondrogenic differentiation from bone marrow mesenchymal stem cells
Authors: Ma Ning , Teng Xiao , Zheng Qi , Chen Peng
Published: December 2019

Background

Osteoarthritis (OA) is a degenerative joint disease characterized by articular cartilage degradation and joint inflammation, in which growth factors are significantly involved. The extracellular signal-regulated p38 MAPK pathways play important roles in the regulation of osteogenic and chondrogenic differentiation in bone marrow mesenchymal stem cells (BMSCs). However, the exact mechanism remains unclear.

Methods

In this study, the chondrogenic differentiation of human BMSCs was initiated in micromass culture in the presence of TGF-β1 for 14 days. Quantitative RT-PCR and Western blot were performed to detect the transfection effect of shRNA-p38 interfering plasmid in BMSCs. The protein expressions of p/t-p38, SOX9, collagen II, Aggrecan, p/t-Smad1, and p/t-Smad4, as well as the kinase activities of p38/ERK/JNK pathway, were investigated using Western blot analysis. Additionally, the level of chondroitin sulfate and glycosaminoglycans (GAG) expression were measured by Alcian blue staining and GAG assay kit via qualitative and quantitative methods, respectively.

Results

The results demonstrated that p38 pathway was activated in the chondrogenic differentiation of BMSCs induced by TGF-β1. Cartilage-specific genes and chondrogenic regulators, such as SOX9, collagen II, Aggrecan, and GAG, were upregulated by TGF-β1, which could be reversed by predisposed with shRNA-p38 interfering plasmid and p38-MAPK inhibitors (SB203580). Moreover, the activation of p38/ERK/JNK pathways in the presence of TGF-β1 was suppressed by shRNA-p38 and SB203580 treatment.

Conclusion

Collectively, the activation of p38/ERK/JNK/Smad pathways plays a facilitated role in the chondrogenic differentiation induced by TGF-β1. After suppressing the p38 pathway, the chondrogenesis can be inhibited, which can be used to guide the treatment of osteoarthritis.
Nucleotide composition of transposable elements likely contributes to AT/GC compositional homogeneity of teleost fish genomes
Authors: Symonová Radka , Suh Alexander
Published: December 2019

Background

Teleost fish genome size has been repeatedly demonstrated to positively correlate with the proportion of transposable elements (TEs). This finding might have far-reaching implications for our understanding of the evolution of nucleotide composition across vertebrates. Genomes of fish and amphibians are GC homogenous, with non-teleost gars being the single exception identified to date, whereas birds and mammals are AT/GC heterogeneous. The exact reason for this phenomenon remains controversial. Since TEs make up significant proportions of genomes and can quickly accumulate across genomes, they can potentially influence the host genome with their own GC content (GC%). However, the GC% of fish TEs has so far been neglected.

Results

The genomic proportion of TEs indeed correlates with genome size, although not as linearly as previously shown with fewer genomes, and GC% negatively correlates with genome size in the 33 fish genome assemblies analysed here (excluding salmonids). GC% of fish TE consensus sequences positively correlates with the corresponding genomic GC% in 29 species tested. Likewise, the GC contents of the entire repetitive vs. non-repetitive genomic fractions correlate positively in 54 fish species in Ensembl. However, among these fish species, there is also a wide variation in GC% between the main groups of TEs. Class II DNA transposons, predominant TEs in fish genomes, are significantly GC-poorer than Class I retrotransposons. The AT/GC heterogeneous gar genome contains fewer Class II TEs, a situation similar to fugu with its extremely compact and also GC-enriched but AT/GC homogenous genome.

Conclusion

Our results reveal a previously overlooked correlation between GC% of fish genomes and their TEs. This applies to both TE consensus sequences as well as the entire repetitive genomic fraction. On the other hand, there is a wide variation in GC% across fish TE groups. These results raise the question whether GC% of TEs evolves independently of GC% of the host genome or whether it is driven by TE localization in the host genome. Answering these questions will help to understand how genomic GC% is shaped over time. Long-term accumulation of GC-poor(er) Class II DNA transposons might indeed have influenced AT/GC homogenization of fish genomes and requires further investigation.
Methods and efficacy of extracellular vesicles derived from mesenchymal stromal cells in animal models of disease: a preclinical systematic review protocol
Authors: Tieu Alvin , Slobodian Mitchell , Fergusson Dean A. , Montroy Joshua , Burger Dylan , Stewart Duncan J. , Shorr Risa , Allan David S. , Lalu Manoj M.
Published: December 2019

Background

Over the past decade, mesenchymal stromal cells have been increasingly investigated for their therapeutic potential in several different illnesses. However, cell therapy can be limited by potentially serious adverse events including cell embolus formation and tumorigenesis. Importantly, the protective effects of mesenchymal stromal cells are largely mediated by paracrine mechanisms including release of extracellular vesicles. This systematic review intends to synthesize the current knowledge of mesenchymal stromal cell-derived extracellular vesicles as a therapeutic option for preclinical models of disease, inflammation, or injury.

Methods

A systematic literature search of MEDLINE, Embase, and BIOSIS databases will be conducted. Interventional preclinical in vivo studies using extracellular vesicles derived from any tissue source of mesenchymal stromal cells will be included. Studies will be screened by abstract, and full-text by two independent reviewers. Eligible studies will undergo data extraction with subcategorization into domains based on disease. Methods utilized for extracellular vesicle characterization and isolation will be collected, as well as information on interventional traits, such as tissue source of mesenchymal stromal cells, dosage regimen, and vesicle modifications. Reported outcomes will be collected to determine which diseases studied may be impacted most from treatment with mesenchymal stromal cell-derived extracellular vesicles.

Discussion

This systematic review will summarize preclinical studies investigating the therapeutic efficacy of both small and large extracellular vesicles derived by mesenchymal stromal cells. Extracellular vesicles represent a possibility to harness the benefits of mesenchymal stromal cells with added benefits of reduced manufacturing costs and an improved safety profile. Hence, there has been an exponential increase in interest for developing this cell-free therapy with hundreds of preclinical studies published to date. However, a vast amount of heterogeneity between groups relates to methods of extracellular vesicle isolation, characterization, and study design. This review will capture this heterogeneity and identify the most commonly used and optimal approaches to evaluate mesenchymal stromal cell-derived extracellular vesicle treatment. A meta-analysis of outcomes within each disease domain will help elucidate which fields of research demonstrate promise for developing extracellular vesicles as a novel cell-free therapy. Summarizing this robust information on extracellular vesicles as an intervention can provide guidance for designing preclinical studies with hopes of future clinical translation.
Analyzing long-term empirical interactions between renewable energy generation, energy use, human capital, and economic performance in Pakistan
Authors: Fatima Nousheen , Li Yanbin , Ahmad Munir , Jabeen Gul , Li Xiaoyu
Published: December 2019

Background

The current research attempts to systematically investigate the causal interactions between renewable energy generation, aggregated energy use, human capital, and economic performance in Pakistan both in a short-term and long-term test for the period of 1990–2016.

Methods

As a primary step, a unit root analysis was conducted employing, among others, an augmented Dickey-Fuller-generalized least squares (ADF-GLS) test. Based on the order of integration I(1), the Johansen and Juselius (JJ) co-integration testing was employed to confirm a long-term causality analysis, which was followed by a vector error correction model (VECM) to calculate the short-run Granger causality analysis. Furthermore, the vector autoregressive (VAR)-based Cholesky test allowed the standard deviation impulse response functions to be generated to explain the responses of variables to arbitrary shocks in the data series under analysis.

Results

The empirical findings unearthed the bilateral causal connection between aggregated energy use and economic performance, renewable energy generation and economic performance, and human capital and economic performance. Thus, it confirmed the existence of feedback effects for aggregated energy use, renewable energy generation, and human capital in their relation to economic performance. Likewise, a unilateral positive causal connection was revealed running from renewable energy generation and human capital to aggregated energy use, and from human capital to renewable energy generation in both a long-term and short-term test. Additionally, the causal association running from aggregated energy use and renewable energy generation to economic performance was exposed in a long-term as well as short-term test, hence supporting the growth hypothesis.

Conclusions

The findings signified the importance of an enhanced generation of renewable energy along with the promotion of an aggregated energy use for the economic performance in Pakistan.
Aldehyde dehydrogenase 2 activity and aldehydic load contribute to neuroinflammation and Alzheimer’s disease related pathology
Authors: Joshi Amit U. , Van Wassenhove Lauren D. , Logas Kelsey R. , Minhas Paras S. , Andreasson Katrin I. , Weinberg Kenneth I. , Chen Che-Hong , Mochly-Rosen Daria
Published: December 2019

Aldehyde dehydrogenase 2 deficiency (ALDH2*2) causes facial flushing in response to alcohol consumption in approximately 560 million East Asians. Recent meta-analysis demonstrated the potential link between ALDH2*2 mutation and Alzheimer’s Disease (AD). Other studies have linked chronic alcohol consumption as a risk factor for AD. In the present study, we show that fibroblasts of an AD patient that also has an ALDH2*2 mutation or overexpression of ALDH2*2 in fibroblasts derived from AD patients harboring ApoE ε4 allele exhibited increased aldehydic load, oxidative stress, and increased mitochondrial dysfunction relative to healthy subjects and exposure to ethanol exacerbated these dysfunctions. In an in vivo model, daily exposure of WT mice to ethanol for 11 weeks resulted in mitochondrial dysfunction, oxidative stress and increased aldehyde levels in their brains and these pathologies were greater in ALDH2*2/*2 (homozygous) mice. Following chronic ethanol exposure, the levels of the AD-associated protein, amyloid-β, and neuroinflammation were higher in the brains of the ALDH2*2/*2 mice relative to WT. Cultured primary cortical neurons of ALDH2*2/*2 mice showed increased sensitivity to ethanol and there was a greater activation of their primary astrocytes relative to the responses of neurons or astrocytes from the WT mice. Importantly, an activator of ALDH2 and ALDH2*2, Alda-1, blunted the ethanol-induced increases in Aβ, and the neuroinflammation in vitro and in vivo. These data indicate that impairment in the metabolism of aldehydes, and specifically ethanol-derived acetaldehyde, is a contributor to AD associated pathology and highlights the likely risk of alcohol consumption in the general population and especially in East Asians that carry ALDH2*2 mutation.