bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chloride intracellular channel 1 activity is not required for glioblastoma development but its inhibition dictates glioma stem cell responsivity to novel biguanide derivatives
Authors: Barbieri Federica , Bosio Alessia Graziana , Pattarozzi Alessandra , Tonelli Michele , Bajetto Adriana , Verduci Ivan , Cianci Francesca , Cannavale Gaetano , Palloni Luca M. G. , Francesconi Valeria , Thellung Stefano , Fiaschi Pietro , Mazzetti Samanta , Schenone Silvia , Balboni Beatrice , Girotto Stefania , Malatesta Paolo , Daga Antonio , Zona Gianluigi , Mazzanti Michele , Florio Tullio 
Published: February 2022

Abstract
Background
Chloride intracellular channel-1 (CLIC1) activity controls glioblastoma proliferation. Metformin exerts antitumor effects in glioblastoma stem cells (GSCs) inhibiting CLIC1 activity, but its low potency hampers its translation in clinical settings.

Methods
We synthesized a small library of novel biguanide-based compounds that were tested as antiproliferative agents for GSCs derived from human glioblastomas, in vitro using 2D and 3D cultures and in vivo in the zebrafish model. Compounds were compared to metformin for both potency and efficacy in the inhibition of GSC proliferation in vitro (MTT, Trypan blue exclusion assays, and EdU labeling) and in vivo (zebrafish model), migration (Boyden chamber assay), invasiveness (Matrigel invasion assay), self-renewal (spherogenesis assay), and CLIC1 activity (electrophysiology recordings), as well as for the absence of off-target toxicity (effects on normal stem cells and toxicity for zebrafish and chick embryos).

Results
We identified Q48 and Q54 as two novel CLIC1 blockers, characterized by higher antiproliferative potency than metformin in vitro, in both GSC 2D cultures and 3D spheroids. Q48 and Q54 also impaired GSC self-renewal, migration and invasion, and displayed low systemic in vivo toxicity. Q54 reduced in vivo proliferation of GSCs xenotransplanted in zebrafish hindbrain. Target specificity was confirmed by recombinant CLIC1 binding experiments using microscale thermophoresis approach. Finally, we characterized GSCs from GBMs spontaneously expressing low CLIC1 protein, demonstrating their ability to grow in vivo and to retain stem-like phenotype and functional features in vitro. In these GSCs, Q48 and Q54 displayed reduced potency and efficacy as antiproliferative agents as compared to high CLIC1-expressing tumors. However, in 3D cultures, metformin and Q48 (but not Q54) inhibited proliferation, which was dependent on the inhibition dihydrofolate reductase activity.

Conclusions
These data highlight that, while CLIC1 is dispensable for the development of a subset of glioblastomas, it acts as a booster of proliferation in the majority of these tumors and its functional expression is required for biguanide antitumor class-effects. In particular, the biguanide-based derivatives Q48 and Q54, represent the leads to develop novel compounds endowed with better pharmacological profiles than metformin, to act as CLIC1-blockers for the treatment of CLIC1-expressing glioblastomas, in a precision medicine approach.
Tracheostomy timing and clinical outcomes in ventilated COVID-19 patients: a systematic review and meta-analysis
Authors: Ji Yun , Fang Yumin , Cheng Baoli , Li Libin , Fang Xiangming 
Published: February 2022

AbstractBackgroundThe association of tracheostomy timing and clinical outcomes in ventilated COVID-19 patients remains controversial. We performed a meta-analysis to evaluate the impact of early tracheostomy compared to late tracheostomy on COVID-19 patients’ outcomes.MethodsWe searched Medline, Embase, Cochrane, and Scopus database, along with medRxiv, bioRxiv, and Research Square, from December 1, 2019, to August 24, 2021. Early tracheostomy was defined as a tracheostomy conducted 14 days or less after initiation of invasive mechanical ventilation (IMV). Late tracheostomy was any time thereafter. Duration of IMV, duration of ICU stay, and overall mortality were the primary outcomes of the meta-analysis. Pooled odds ratios (OR) or the mean differences (MD) with 95%CIs were calculated using a random-effects model.ResultsFourteen studies with a cumulative 2371 tracheostomized COVID-19 patients were included in this review. Early tracheostomy was associated with significant reductions in duration of IMV (2098 patients; MD − 9.08 days, 95% CI − 10.91 to − 7.26 days,p < 0.01) and duration of ICU stay (1224 patients; MD − 9.41 days, 95% CI − 12.36 to − 6.46 days,p < 0.01). Mortality was reported for 2343 patients and was comparable between groups (OR 1.09, 95% CI 0.79–1.51,p = 0.59).ConclusionsThe results of this meta-analysis suggest that, compared with late tracheostomy, early tracheostomy in COVID-19 patients was associated with shorter duration of IMV and ICU stay without modifying the mortality rate. These findings may have important implications to improve ICU availability during the COVID-19 pandemic.Trial registrationThe protocol was registered at INPLASY (INPLASY202180088).
Analysis of a delay-induced mathematical model of cancer
Authors: Das Anusmita , Dehingia Kaushik , Sarmah Hemanta Kumar , Hosseini Kamyar , Sadri Khadijeh , Salahshour Soheil 
Published: February 2022

AbstractIn this paper, the dynamical behavior of a mathematical model of cancer including tumor cells, immune cells, and normal cells is investigated when a delay term is induced. Though the model was originally proposed by De Pillis et al. (Math. Comput. Model. 37:1221–1244, 2003), to make the model more realistic, we have added a delay term into the model, and it has incorporated novelty in our present work. The stability of existing equilibrium points in the delay-induced system is studied in detail. Global stability conditions of the tumor-free equilibrium point have been found. It is shown that due to this delay effect, the coexisting equilibrium point may lose its stability through a Hopf bifurcation. The implicit function theorem is applied to characterize a complex function in a neighborhood of delay terms. Additionally, the presence of Hopf bifurcation is demonstrated when the transversality conditions are satisfied. The length of delay for which the solutions preserve the stability of the limit cycle is estimated. Finally, through a series of numerical simulations, the theoretical results are formally examined.
Interaction of potential and effective entrepreneurial capabilities in adolescents: modeling youth entrepreneurship structure using structural equation modeling
Authors: Campo-Ternera Lilia , Amar-Sepúlveda Paola , Olivero-Vega Enohemit 
Published: February 2022

AbstractThis article emphasizes entrepreneurial skills in adolescents, in order to determine the relationship between entrepreneurial skills (dependent variable) and the key factors for their development: personal, social, and educational (independent variables). It has an empirical‒analytical design which is explanatory in nature. After the design, validation, and application of the evaluation instrument, the estimation was carried out using Structural Equation Modeling (SEM). The results show great impact of potential entrepreneurial capacity on effective entrepreneurial capacity, determined by the direct effect of personal traits and life skills, the family as a moderating element, as well as the mediating role of entrepreneurship training processes. The complex nature of entrepreneurship is highlighted, which is influenced by multiple factors as possible boosters for the success of entrepreneurial initiatives.
Anti-inflammatory components isolated from Atractylodes macrocephala in LPS-induced RAW264.7 macrophages and BV2 microglial cells
Authors: Jin Hong-Guang , Kim Kwan-Woo , Li Jing , Lee Dae Young , Yoon Dahye , Jeong Jin Tae , Kim Geum-Soog , Oh Hyuncheol , An Ren-Bo , Kim Youn-Chul 
Published: February 2022

AbstractThe phytochemical investigation on the methanol extract of the rhizomes of Atractylodes macrocephala resulted in the discovery of one new compound 9α-hydroxyatractylenolide (1) and 21 known compounds including atractylone (2), 3β-acetoxyatractylon (3), atractylenolide I (4), atractylenolide II (5), 8-epiasterolid (6), atractylenolide III (7), atractylenolide VII (8), 8-epiatractylenolide III (9), eudesm-4(15)-ene-7α,11-diol (10), linoleic acid (11), myristic acid (12), 3-O-caffeoyl-1-methyquinic acid (13), (2E,8E,10E)-tetradecatriene-4,6-diyne-1,14-diol (14), 14-aceroxy-12-senecioyloxytetradeca-2E,8Z,10E-trien-4,6-diyn-1-ol (15), isoscopoletin (16), caffeic acid (17), protocatechic acid (18), 3-O-caffeoylquinic acid (19), 4-O-caffeoylquinic acid (20), 1,5-di-O-caffeoylquinic acid (21), and nicotinic acid (22). Their structures were identified using nuclear magnetic resonance (NMR) and mass spectroscopy, and by comparison with previously published data. Compounds 4, 5, 6, 8, and 10–22 significantly inhibited lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 macrophages, and compounds 4, 5, 6, 16, and 17 showed those responses in BV2 microglial cells. Especially, compound 6 showed the second-best effect, and inhibited the LPS-induced production of prostaglandin E2 (PGE2), the protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, and the production of cytokines including interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in both cells. These inhibitory effects were mediated by the inactivation of nuclear factor kappa B (NF-κB) signaling pathway.
The inflammatory pathology of dysferlinopathy is distinct from calpainopathy, Becker muscular dystrophy, and inflammatory myopathies
Authors: Becker Nicole , Moore Steven A. , Jones Karra A. 
Published: February 2022

AbstractThe descriptions of muscle pathology in dysferlinopathy patients have classically included an inflammatory infiltrate that can mimic inflammatory myopathies. Based on over 20 years of institutional experience in evaluating dystrophic and inflammatory myopathy muscle biopsies at the University of Iowa, we hypothesized the inflammatory histopathology of dysferlinopathy is more similar to limb-girdle pattern muscular dystrophies such as calpainopathy and Becker muscular dystrophy, and distinct from true inflammatory myopathies. Muscle biopsies from 32 dysferlinopathy, 30 calpainopathy, 30 Becker muscular dystrophy, and 30 inflammatory myopathies (15 each of dermatomyositis and inclusion body myositis) were analyzed through digital quantitation of CD3, CD4, CD8, CD20, and PU.1 immunostaining. The expression of MHC class I and deposition of complement C5b-9 was also evaluated. Dysferlinopathy, calpainopathy, and Becker muscular dystrophy muscle biopsies had similar numbers of inflammatory cell infiltrates and significantly fewer CD3+ T-lymphocytes than dermatomyositis (p = 0.05) and inclusion body myositis (p < 0.0001) biopsies. There was no statistically significant difference in the number of PU.1+ macrophages identified in any diagnostic group. MHC class I expression was significantly lower in the limb-girdle pattern muscular dystrophies compared to the inflammatory myopathies (p < 0.0001). In contrast, complement C5b-9 deposition was similar among dysferlinopathy, dermatomyositis, and inclusion body myositis biopsies but significantly greater than calpainopathy and Becker muscular dystrophy biopsies (p = 0.05). Compared to calpainopathy, Becker muscular dystrophy, and inflammatory myopathies, the unique profile of minimal inflammatory cell infiltrates, absent to focal MHC class I, and diffuse myofiber complement C5b-9 deposition is the pathologic signature of dysferlinopathy muscle biopsies.
Cluster analysis of personality traits in psychiatric patients with borderline personality disorder
Authors: Oladottir Kristin , Wolf-Arehult Martina , Ramklint Mia , Isaksson Martina 
Published: February 2022

Abstract
Background
Though the heterogeneous expression of symptoms of borderline personality disorder (BPD) is well-known, it is far from fully understood. Hybrid models combining dimensional and categorical ways of diagnosing BPD have been suggested to better handle this heterogeneity, but more research is needed. The aim of this study was to identify potential clusters in BPD, and evaluate if these clusters differed in diagnostic composition, severity, psychiatric symptoms, emotion regulation and control, or sociodemographic features.

Methods
Clusters were based on personality traits measured with the Swedish universities Scales of Personality (SSP) in 141 psychiatric patients diagnosed with BPD. Hierarchical cluster analysis was performed using Ward’s method. We used one-way analysis of variance to explore the different clusters’ properties. Effect sizes were calculated using partial eta squared.

Results
We found three distinct clusters: the lower psychopathology cluster (N = 67), the externalizing cluster (N = 28), and the internalizing cluster (N = 46). The clusters differed regarding trait composition, severity, and emotion regulation and control.

Conclusions
Our findings support hybrid models for diagnosing BPD by showing that clusters differed in terms of both severity (lower and higher psychopathology) and personality traits/style (internalizing and externalizing). Assessment of personality traits may be a feasible way to differentiate between clusters. In the future, this knowledge might be used to personalize treatment.
Enhanced l-ornithine production from glucose and sucrose via manipulation of the fructose metabolic pathway in Corynebacterium glutamicum
Authors: Nie Libin , Xu Kexin , Zhong Bin , Wu Xiaoyu , Ding Zhongtao , Chen Xuelan , Zhang Bin 
Published: February 2022

Abstractl-Ornithine, an important non-essential amino acid, has considerable medicinal value in the treatment of complex liver diseases. Microbial fermentation strategies using robust engineered strains have remarkable potential for producing l-ornithine. We showed that glucose and sucrose co-utilization accumulate more l-ornithine in Corynebacterium glutamicum than glucose alone. Further manipulating the expression of intracellular fructose-1-phosphate kinase through the deletion of pfkB1resulted in the engineered strain C. glutamicum SO30 that produced 47.6 g/L of l-ornithine, which represents a 32.8% increase than the original strain C. glutamicum SO26 using glucose as substrate (35.88 g/L). Moreover, fed-batch cultivation of C. glutamicum SO30 in 5-L fermenters produced 78.0 g/L of l-ornithine, which was a 78.9% increase in yield compared with that produced by C. glutamicum SO26. These results showed that manipulating the fructose metabolic pathway increases l-ornithine accumulation and provides a reference for developing C. glutamicum to produce valuable metabolites.
Graphical Abstract
SimUniversity at a distance: a descriptive account of a team-based remote simulation competition for health professions students
Authors: Major Stella , Krage Ralf , Lazarovici Marc 
Published: February 2022

Abstract
Background
SimUniversity competition is an innovative Society in Europe for Simulation Applied to Medicine (SESAM) initiative which has existed since 2014, with the aim of creating opportunities for undergraduate healthcare students to take part in a formative educational experience on an international platform. The main educational focus is on promoting non-technical skills such as leadership, situation awareness, decision making, communication, and assertiveness, but also clinical reasoning within a team. In preparation for the 2021 virtual conference, the team designed a new methodology to meet the same mission, and yet be offered remotely.

Main text
In this article, we describe the way in which we transformed the SimUniversity competition activity from face to face to a remote simulation. We relied on Zoom as the main communication technology to enable the distance component and followed the key elements of pre-briefing, simulation, and debriefing with the students being onsite together in one location and the faculty and simulator technologists in distant locations. Thirty-eight medical and nursing students formed 8 teams from 7 different countries. Two participating teams were based in Germany and one in Italy, Belgium, the Netherlands, Romania, Portugal, and Syria. Each team consisted of between 4 and 5 members and was self-selected to consist of either medical students alone or medical and nursing students together. The SimUniversity faculty team was composed of 5 physician educators, one nurse educator, one paramedic simulation technologist, and one industry simulation technologist. The faculty members facilitated each simulation synchronously in Zoom, while being based in different geographical locations within Europe (Germany, Switzerland, and the Netherlands) and the Middle East (Qatar and Lebanon).

Conclusion
We conclude that assuming there is access to adequate internet connectivity and minimal technical setup, conducting a remote simulation with virtual debriefing is achievable in supporting team-based learning, particularly when learners and/or faculty members are in distant locations. While the authors do not recommend this method to be superior to a face-to-face experience, we propose this model to be an alternative method to consider when educators are faced with imposed restrictions such as what we faced during the COVID-19 pandemic. We discuss lessons learned and highlight other potential benefits that this method may provide, to consider even when the restrictions are lifted.
Missense mutation of a class B heat shock factor is responsible for the tomato bushy root-2 phenotype
Authors: Kevei Zoltan , Ferreira Silva Demetryus Silva , Casenave Cristina Maria Perez , Kurowski Tomasz , Mohareb Fady , Rickett Daniel , Stain Chris , Thompson Andrew J. 
Published: February 2022

AbstractThebushy root-2(brt-2) tomato mutant has twisting roots, and slower plant development. Here we used whole genome resequencing and genetic mapping to show thatbrt-2is caused by a serine to cysteine (S75C) substitution in the DNA binding domain (DBD) of a heat shock factor class B (HsfB) encoded bySolycHsfB4a. This gene is orthologous to the ArabidopsisSCHIZORIZAgene, also known asAtHsfB4. Thebrt-2phenotype is very similar toArabidopsislines in which the function ofAtHsfB4is altered: a proliferation of lateral root cap and root meristematic tissues, and a tendency for lateral root cap cells to easily separate. Thebrt-2S75C mutation is unusual because all other reported amino acid substitutions in the highly conserved DBD of eukaryotic heat shock factors are dominant negative mutations, butbrt-2is recessive. We further show through reciprocal grafting thatbrt-2exerts its effects predominantly through the root genotype even throughBRT-2is expressed at similar levels in both root and shoot meristems. SinceAtHsfB4is induced by root knot nematodes (RKN), and loss-of-function mutants of this gene are resistant to RKNs,BRT-2could be a target gene for RKN resistance, an important trait in tomato rootstock breeding.Gene & accession numbersSolycHsfB4a-Solyc04g078770.
Racial Disparities in Diabetes-Related Emergency Department Visits and Hospitalizations Among Cancer Survivors
Authors: Pinheiro Laura C. , Soroka Orysya , Kern Lisa M. , Leonard John P. , Safford Monika M. 
Published: February 2022

PURPOSE: Black and Hispanic individuals with diabetes receive less recommended diabetes care after cancer diagnosis than non-Hispanic Whites (NHW). We sought to determine whether racial/ethnic minorities with diabetes and cancer were at increased risk of diabetes-related emergency department (ED) visits and hospitalizations compared with NHW. METHODS: Using SEER cancer registry data linked to Medicare claims from 2006 to 2014, we included Medicare beneficiaries age 66+ years diagnosed with incident nonmetastatic breast, prostate, or colorectal cancer between 2007 and 2012 who had diabetes. Our primary outcome was any diabetes-related ED visit or hospitalization 366-731 days after cancer diagnosis. Using Fine-Gray subdistribution hazard models, we examined whether risk of ED visits or hospitalizations was higher for racial/ethnic minorities compared with NHW. RESULTS: We included 40,059 beneficiaries with mean age 75.5 years (standard deviation 6.3), 45.6% were women, and 28.9% were non-White. Overall, 825 (2.1%) had an ED visit and 3,324 (8.3%) had a hospitalization related to diabetes in the 366-731 days after cancer diagnosis. Compared with NHW, Black individuals were more likely to have ED visits (2.9% v 2.0%; P < .0001) and hospitalizations (11.7% v 7.8%; P < .0001). Adjusting for potential confounders, Black (adjusted hazard ratio, 1.22; 95% CI, 1.12 to 1.35) individuals had a higher risk of any ED visit or hospitalization compared with NHW. CONCLUSION: Black individuals with diabetes and cancer were at increased risk for diabetes-related ED visits and hospitalizations in the second year after cancer diagnosis compared with NHW even after accounting for confounders.
Association of Incidence of Acid-related Upper Gastrointestinal Disorders With Glycated Hemoglobin Level
Authors: Tseng Ping-Huei , Hung Chi-Sheng , Tu Chia-Hung , Chen Chien-Chuan , Liao Wan-Chung , Lee Yi-Chia , Chiu Han-Mo , Yang Wei-Shiung , Wu Ming-Shiang 
Published: February 2022

Abstract

Context
Previous cross-sectional studies show diabetes and higher levels of plasma hemoglobin A1c (HbA1c) are associated with a higher prevalence of gastrointestinal (GI) complications. However, whether the glycemic status is associated with incident acid-related upper GI disorders remains unclear.

Objective
We aimed to determine the effect of hyperglycemia per se, in terms of HbA1c, on the incidence of acid-related disorders.

Methods
We analyzed consecutive subjects who had undergone repeated upper endoscopies as part of the health examinations at the National Taiwan University Hospital from 2005 to 2011. Acid-related endoscopic abnormalities were defined as erosive esophagitis (EE), Barrett’s esophagus (BE), and peptic ulcer disease (PUD), which included gastric ulcers (GUs) and duodenal ulcers (DUs). All subjects were categorized by 3 tertiles of HbA1c levels. We analyzed the occurrence of respective acid-related disorders during the follow-up period.

Results
A total of 11 391 participants (mean HbA1c level 5.6 ± 0.7%) were enrolled in this longitudinal study. During the 38 426.3 person-years of follow-up (mean duration 3.37 ± 1.59 years), the incidence of EE, BE, GU, DU, PUD, and any acid-related disorders were 22.1%, 0.5%, 4.5%, 8.6%, 12.3%, and 30.3%, respectively. The higher HbA1c level was associated with higher risk of disease incidents, except BE, during the follow-up (all log-rank P &lt; .001). In the Cox regression analyses with confounding factors fully adjusted, the hazard ratios for EE, GU, DU, PUD, and acid-related disorders were 1.174, 1.339, 1.24, 1.24, and 1.186, respectively, for the third tertile of HbA1c (all P &lt; .05).

Conclusion
Higher HbA1c level was associated with a higher risk of acid-related upper GI endoscopic abnormalities. Efforts toward better glycemic control may help to prevent the development of late GI complications.