bluuebunny/crossref_metadata_2025 huggingface dataset:
Mitochondrial Genome Study Identifies Association Between Primary Open-Angle Glaucoma and Variants in MT-CYB, MT-ND4 Genes and Haplogroups
Authors: Lo Faro Valeria , Nolte Ilja M. , Ten Brink Jacoline B. , Snieder Harold , Jansonius Nomdo M. , Bergen Arthur A. , Lifelines Cohort Study
Published: December 2021

Background and purpose: Primary open-angle glaucoma (POAG) is an optic neuropathy characterized by death of retinal ganglion cells and atrophy of the optic nerve head. The susceptibility of the optic nerve to damage has been shown to be mediated by mitochondrial dysfunction. In this study, we aimed to determine a possible association between mitochondrial SNPs or haplogroups and POAG.

Methods: Mitochondrial DNA single nucleotide polymorphisms (mtSNPs) were genotyped using the Illumina Infinium Global Screening Array-24 (GSA) 700K array set. Genetic analyses were performed in a POAG case-control study involving the cohorts, Groningen Longitudinal Glaucoma Study-Lifelines Cohort Study and Amsterdam Glaucoma Study, including 721 patients and 1951 controls in total. We excluded samples not passing quality control for nuclear genotypes and samples with low call rate for mitochondrial variation. The mitochondrial variants were analyzed both as SNPs and haplogroups. These were determined with the bioinformatics software HaploGrep, and logistic regression analysis was used for the association, as well as for SNPs.

Results: Meta-analysis of the results from both cohorts revealed a significant association between POAG and the allele A of rs2853496 [odds ratio (OR) = 0.64; p = 0.006] within the MT-ND4 gene, and for the T allele of rs35788393 (OR = 0.75; p = 0.041) located in the MT-CYB gene. In the mitochondrial haplogroup analysis, the most significant p-value was reached by haplogroup K (p = 1.2 × 10−05), which increases the risk of POAG with an OR of 5.8 (95% CI 2.7–13.1).

Conclusion: We identified an association between POAG and polymorphisms in the mitochondrial genes MT-ND4 (rs2853496) and MT-CYB (rs35788393), and with haplogroup K. The present study provides further evidence that mitochondrial genome variations are implicated in POAG. Further genetic and functional studies are required to substantiate the association between mitochondrial gene polymorphisms and POAG and to define the pathophysiological mechanisms of mitochondrial dysfunction in glaucoma.
Real-Life Cause-Effect Relations Between Urinary IL-6 Levels and Specific and Nonspecific Symptoms in a Patient With Mild SLE Disease Activity
Authors: Schubert Christian , Seizer Lennart , Chamson Emil , König Paul , Sepp Norbert , Ocaña-Peinado Francisco M. , Schnapka-Köpf Mirjam , Fuchs Dietmar
Published: December 2021

Background

Little is known about the real-time cause-effect relations between IL-6 concentrations and SLE symptoms.

Methods

A 52-year-old woman with mild SLE activity collected her entire urine for the determination of IL-6/creatinine and protein/creatinine levels (ELISA, HPLC) for a period of 56 days in 12 h intervals (total: 112 measurements). Additionally, she answered questionnaires (VAS) on oral ulceration, facial rash, joint pain, fatigue and tiredness and measured her temperature orally twice a day. Time-series analyses consisted of ARIMA modeling and cross-correlational analyses (one lag = 12 h, significance level = p < 0.05).

Results

Statistical analyses showed that increased urinary IL-6 concentrations preceded increased urinary protein levels by 36–48 h (lag3: r=+.225; p=.017) and that, in the opposite direction of effect, increased urinary protein preceded urinary IL-6 decreases by 12–24 h (lag1: r=–.322; p<.001). Moreover, urinary IL-6 increases co-occurred with increased oral ulceration (lag0: r=+.186; p=.049); after 48–60 h, however, IL-6 increases showed a strong tendency to precede oral ulceration decreases (lag4: r=–.170; p=.072). Increases in facial rash preceded decreases in urinary IL-6 after 84–96 h (lag7: r=–.215; p=.023). As to fatigue, increases in urinary IL-6 co-occurred with decreased fatigue (lag0: r=–.193; p=.042); after 84–96 h, however, IL-6 increases preceded fatigue increases (+lag7: r=+.189; p=.046). Finally, joint pain, tiredness and body temperature did not significantly correlate with urinary IL-6 concentrations in either direction of effect.

Conclusions

The results of this evaluation point to real-life feedback mechanisms between immune activity and SLE symptoms. Comparison with a previous evaluation of this patient suggests a counterregulatory mechanism between Th1 activity and IL-6. These findings are preliminary and require replication to draw firm conclusions about the real-time relation between IL-6 and SLE disease activity.
Chronic IL-15 Stimulation and Impaired mTOR Signaling and Metabolism in Natural Killer Cells During Acute Myeloid Leukemia
Authors: Bou-Tayeh Berna , Laletin Vladimir , Salem Nassim , Just-Landi Sylvaine , Fares Joanna , Leblanc Raphael , Balzano Marielle , Kerdiles Yann M. , Bidaut Ghislain , Hérault Olivier , Olive Daniel , Aurrand-Lions Michel , Walzer Thierry , Nunès Jacques A. , Fauriat Cyril
Published: December 2021

Natural Killer (NK) cells are potent anti-leukemic immune effectors. However, they display multiple defects in acute myeloid leukemia (AML) patients leading to reduced anti-tumor potential. Our limited understanding of the mechanisms underlying these defects hampers the development of strategies to restore NK cell potential. Here, we have used a mouse model of AML to gain insight into these mechanisms. We found that leukemia progression resulted in NK cell maturation defects and functional alterations. Next, we assessed NK cell cytokine signaling governing their behavior. We showed that NK cells from leukemic mice exhibit constitutive IL-15/mTOR signaling and type I IFN signaling. However, these cells failed to respond to IL-15 stimulation in vitro as illustrated by reduced activation of the mTOR pathway. Moreover, our data suggest that mTOR-mediated metabolic responses were reduced in NK cells from AML-bearing mice. Noteworthy, the reduction of mTOR-mediated activation of NK cells during AML development partially rescued NK cell metabolic and functional defects. Altogether, our data strongly suggest that NK cells from leukemic mice are metabolically and functionally exhausted as a result of a chronic cytokine activation, at least partially IL-15/mTOR signaling. NK cells from AML patients also displayed reduced IL-2/15Rβ expression and showed cues of reduced metabolic response to IL-15 stimulation in vitro, suggesting that a similar mechanism might occur in AML patients. Our study pinpoints the dysregulation of cytokine stimulation pathways as a new mechanism leading to NK cell defects in AML.
Characterization of m6A RNA Methylation Regulators Predicts Survival and Immunotherapy in Lung Adenocarcinoma
Authors: Zhu Minggao , Cui Yachao , Mo Qi , Zhang Junwei , Zhao Ting , Xu Yujie , Wu Zhenpeng , Sun Donglin , Zhang Xiaoren , Li Yingchang , You Qiang
Published: December 2021

N6-methyladenosine (m6A) RNA modification is a reversible mechanism that regulates eukaryotic gene expression. Growing evidence has demonstrated an association between m6A modification and tumorigenesis and response to immunotherapy. However, the overall influence of m6A regulators on the tumor microenvironment and their effect on the response to immunotherapy in lung adenocarcinoma remains to be explored. Here, we comprehensively analyzed the m6A modification patterns of 936 lung adenocarcinoma samples based on 24 m6A regulators. First, we described the features of genetic variation in these m6A regulators. Many m6A regulators were aberrantly expressed in tumors and negatively correlated with most tumor-infiltrating immune cell types. Furthermore, we identified three m6A modification patterns using a consensus clustering method. m6A cluster B was preferentially associated with a favorable prognosis and enriched in metabolism-associated pathways. In contrast, m6A cluster A was associated with the worst prognosis and was enriched in the process of DNA repair. m6A cluster C was characterized by activation of the immune system and a higher stromal cell score. Surprisingly, patients who received radiotherapy had a better prognosis than patients without radiotherapy only in the m6A cluster C group. Subsequently, we constructed an m6A score model that qualified the m6A modification level of individual samples by using principal component analysis algorithms. Patients with high m6A score were characterized by enhanced immune cell infiltration and prolonged survival time and were associated with lower tumor mutation burden and PD-1/CTLA4 expression. The combination of the m6A score and tumor mutation burden could accurately predict the prognosis of patients with lung adenocarcinoma. Furthermore, patients with high m6A score exhibited greater prognostic benefits from radiotherapy and immunotherapy. This study demonstrates that m6A modification is significantly associated with tumor microenvironment diversity and prognosis. A comprehensive evaluation of m6A modification patterns in single tumors will expand our understanding of the tumor immune landscape. In addition, our m6A score model demonstrated that the level of immune cell infiltration plays a significant role in cancer immunotherapy and provides a basis to increase the efficiency of current immune therapies and promote the clinical success of immunotherapy.
Anti-SARS-CoV-2 Immunoglobulin Isotypes, and Neutralization Activity Against Viral Variants, According to BNT162b2-Vaccination and Infection History
Authors: Tarkowski Maciej , de Jager Wilco , Schiuma Marco , Covizzi Alice , Lai Alessia , Gabrieli Arianna , Corbellino Mario , Bergna Annalisa , Ventura Carla Della , Galli Massimo , Riva Agostino , Antinori Spinello
Published: December 2021

Purpose

To compare SARS-CoV-2 antigen-specific antibody production and plasma neutralizing capacity against B.1 wild-type-like strain, and Gamma/P.1 and Delta/B.1.617.2 variants-of-concern, in subjects with different Covid-19 disease and vaccination histories.

Methods

Adult subjects were: 1) Unvaccinated/hospitalized for Covid-19; 2) Covid-19-recovered followed by one BNT162b2 vaccine dose; and 3) Covid-19-naïve/2-dose BNT162b2 vaccinated. Multiplex Luminex® immunoassays measured IgG, IgA, and IgM plasma levels against SARS-CoV-2 receptor-binding domain (RBD), spike-1 (S), and nucleocapsid proteins. Neutralizing activity was determined in Vero E6 cytopathic assays.

Results

Maximum anti-RBD IgG levels were similar in Covid-19‑recovered individuals 8‒10 days after single-dose vaccination and in Covid-19-naïve subjects 7 days after 2nd vaccine dosing; both groups had ≈2‑fold higher anti-RBD IgG levels than Unvaccinated/Covid-19 subjects tracked through 2 weeks post-symptom onset. Anti-S IgG expression patterns were similar to RBD within each group, but with lower signal strengths. Viral antigen-specific IgA and IgM levels were more variable than IgG patterns. Anti-nucleocapsid immunoglobulins were not detected in Covid-19-naïve subjects. Neutralizing activity against the B.1 strain, and Gamma/P.1 and Delta/B.1.617.2 variants, was highest in Covid‑19-recovered/single-dose vaccinated subjects; although neutralization against the Delta variant in this group was only 26% compared to B.1 neutralization, absolute anti-Delta titers suggested maintained protection. Neutralizing titers against the Gamma and Delta variants were 33‒77% and 26‒67%, respectively, versus neutralization against the B.1 strain (100%) in the three groups.

Conclusion

These findings support SARS-CoV-2 mRNA vaccine usefulness regardless of Covid-19 history, and confirm remarkable protection provided by a single vaccine dose in people who have recovered from Covid-19.
Summertime M2 Internal Tides in the Northern Yellow Sea
Authors: Lin Fan , Asplin Lars , Wei Hao
Published: December 2021

The summertime M2 internal tide in the northern Yellow Sea is investigated with moored current meter observations and numerical current model results. The hydrodynamic model, which is implemented from the Regional Ocean Model System (ROMS) with 1 km horizontal resolution, is capable of resolving the internal tidal dynamics and the results are validated in a comparison with observations. The vertical pattern of a mode-1, semi-diurnal internal tide is clearly captured by the moored ADCP as well as in the simulation results. Spectral analysis of the current results shows that the M2 internal tide is dominant in the northern Yellow Sea. Analysis of the major M2 internal tide energetics demonstrated a complex spatial pattern. The tidal mixing front along the Korean coast and on the northern shelf provided proper conditions for the generation and propagation of the internal tides. Near the Changshan islands, the M2 internal tide is mainly generated near the local topography anomalies with relatively strong current magnitude, equal to about 30% of the barotropic component, thus modifying the local current field. These local internal tides are short-lived phenomena rapidly being dissipated along the propagation pathway, restricting their influence within a few kilometers around the islands.
Mobile Responsive App—A Useful Additional Tool for Data Collection in the German Pregnancy Register Rhekiss?
Authors: Richter Jutta G. , Weiß Anja , Bungartz Christina , Fischer-Betz Rebecca , Zink Angela , Schneider Matthias , Strangfeld Anja
Published: December 2021

Background: The German pregnancy register Rhekiss is designed as a nationwide, web-based longitudinal observational cohort established in 2015. The register follows women with inflammatory rheumatic disease prospectively from child wish or early pregnancy until 2 years post-partum. Information on clinical and laboratory parameters, drug treatment, and (adverse) pregnancy outcomes are documented in pre-specified intervals. Physicians and patients report data for the same time periods via separated accounts and forms into a web-based application (app). As data entry on mobile devices might improve response rates of patients, a responsive app as a further convenient documentation option was developed.

Methods: The Rhekiss-app is available for self-reported data retrieval since August 2017 from the App stores. For the current analysis, Rhekiss register data were used from the start of the register until 30 September 2020. The analyses were performed for forms containing information on devices. Outcome parameters were compared for mobile and desktop users for the quantity and quality of filled forms.

Results: In total, 5,048 forms were received and submitted by 966 patients. About 57% of forms were sent from mobile devices with the highest numbers in patients with child wishes (63%). Users of mobile devices were slightly younger and often had less high-education level (62 vs. 79%) compared with desktop users. The proportion of forms submitted via mobile devices increased steadily from 48% in the fourth quarter of 2018 to 64% in the third quarter of 2020. The proportion of forms received before and after the Rhekiss-app implementation increased with the highest increase of 12% for forms filled at time point 12 months post-partum. Mobile users submitted significantly more forms than desktop users (2.9 vs. 2.1), data sent via desktops were more often complete (88 vs. 86%).

Conclusion: The responsive app is a valuable additional tool for data collection and is well-accepted by patients as indicated by its increasing use in Rhekiss. Apart from desktop/browser developments, the technological adoptions within observational cohorts and registries should take smartphone requirements and developments into account, especially when patient-reported data in young, mobile patients are collected, bearing in mind that data quality could be compromised and concepts for improving data quality should be implemented.
Living Donor Kidney Transplantation in Patients With Donor-Specific HLA Antibodies After Desensitization With Immunoadsorption
Authors: Kälble Florian , Süsal Caner , Pego da Silva Luiza , Speer Claudius , Benning Louise , Nusshag Christian , Pham Lien , Tran Hien , Schaier Matthias , Sommerer Claudia , Beimler Jörg , Mehrabi Arianeb , Zeier Martin , Morath Christian
Published: December 2021

Due to the current organ shortage, living donor kidney transplantation is increasingly performed across HLA (human leukocyte antigen) or ABO antibody barriers. There is still uncertainty about the risk of antibody-mediated rejection (AMR) episodes, which may limit long-term graft survival. From March 2007 to December 2016, 58 sensitized living donor kidney transplant candidates were identified and 38 patients eventually included in the study: 36 patients (95%) had pre-transplant and pre-desensitization Luminex-detected donor-specific HLA antibodies (DSA), and 17/36 patients (47%) in addition had a positive crossmatch result. Two patients had no detectable DSA but a positive CDC B-cell crossmatch result. Patients were treated with pre- and post-transplant apheresis and powerful immunosuppression including the anti-CD20 antibody rituximab (N = 36) in combination with thymoglobulin (N = 20) or anti-IL2 receptor antibody (N = 18). The results of the 38 successfully desensitized and transplanted patients were retrospectively compared to the results of 76 matched standard-risk recipients. Desensitized patients showed patient and graft survival rates similar to that of standard-risk recipients (P = 0.55 and P = 0.16, respectively). There was a trend toward reduced death-censored graft survival in desensitized patients (P = 0.053) which, however, disappeared when the 34 patients who were transplanted after introduction of sensitive Luminex testing were analyzed (P = 0.43). The incidence of rejection episodes without borderline changes were in desensitized patients with 21% similar to the 18% in standard-risk patients (P = 0.74). Thirty-six patients had pre-transplant HLA class I and/or II DSA that were reduced by 85 and 81%, respectively, during pre-transplant desensitization (P < 0.001 for both). On day 360 after transplantation, 20 of 36 (56%) patients had lost their DSA. The overall AMR rate was 6% in these patients, but as high as 60% in 5 (14%) patients with persistent and de novo DSA during year 1; 2 (40%) of whom lost their graft due to AMR. Eleven (31%) patients with persistent DSA but without de novo DSA had an AMR rate of 18% without graft loss while one patient lost her graft without signs of AMR. Our desensitization protocol for pre-sensitized living donor kidney transplant recipients with DSA resulted in good graft outcomes with side effects and rejection rates similar to that of standard-risk recipients. Adequate patient selection prior to transplantation and frequent immunological monitoring thereafter is critical to minimize rejection episodes and subsequent graft loss.
Urinary Incontinence and Alzheimer’s Disease: Insights From Patients and Preclinical Models
Authors: Bartolone Sarah N. , Sharma Prasun , Chancellor Michael B. , Lamb Laura E.
Published: December 2021

Alzheimer’s disease effects a large percentage of elderly dementia patients and is diagnosed on the basis of amyloid plaques and neurofibrillary tangles (NFTs) present in the brain. Urinary incontinence (UI) is often found in the elderly populations and multiple studies have shown that it is more common in Alzheimer’s disease patients than those with normal cognitive function. However, the link between increased UI and Alzheimer’s disease is still unclear. Amyloid plaques and NFTs present in micturition centers of the brain could cause a loss of signal to the bladder, resulting in the inability to properly void. Additionally, as Alzheimer’s disease progresses, patients become less likely to recognize the need or understand the appropriate time and place to void. There are several treatments for UI targeting the muscarinic and β3 adrenergic receptors, which are present in the bladder and the brain. While these treatments may aid in UI, they often have effects on the brain with cognitive impairment side-effects. Acetylcholine esterase inhibitors are often used in treatment of Alzheimer’s disease and directly oppose effects of anti-muscarinics used for UI, making UI management in Alzheimer’s disease patients difficult. There are currently over 200 pre-clinical models of Alzheimer’s disease, however, little research has been done on voiding disfunction in these models. There is preliminary data suggesting these models have similar voiding behavior to Alzheimer’s disease patients but much more research is needed to understand the link between UI and Alzheimer’s disease and discover better treatment options for managing both simultaneously.
Proteomics-Based Approach to Identify Novel Blood Biomarker Candidates for Differentiating Intracerebral Hemorrhage From Ischemic Stroke—A Pilot Study
Authors: Malicek David , Wittig Ilka , Luger Sebastian , Foerch Christian
Published: December 2021

Background: A reliable distinction between ischemic stroke (IS) and intracerebral hemorrhage (ICH) is required for diagnosis-specific treatment and effective secondary prevention in patients with stroke. However, in resource-limited settings brain imaging, which is the current diagnostic gold standard for this purpose, is not always available in time. Hence, an easily accessible and broadly applicable blood biomarker-based diagnostic test differing stroke subtypes would be desirable. Using an explorative proteomics approach, this pilot study aimed to identify novel blood biomarker candidates for distinguishing IS from ICH.

Material and Methods: Plasma samples from patients with IS and ICH were drawn during hospitalization and were analyzed by using liquid chromatography/mass spectrometry. Proteins were identified using the human reference proteome database UniProtKB, and label-free quantification (LFQ) data were further analyzed using bioinformatic tools.

Results: Plasma specimens of three patients with IS and four patients with ICH with a median National Institute of Health Stroke Scale (NIHSS) of 12 [interquartile range (IQR) 10.5–18.5] as well as serum samples from two healthy volunteers were analyzed. Among 495 identified protein groups, a total of 368 protein groups exhibited enough data points to be entered into quantitative analysis. Of the remaining 22 top-listed proteins, a significant difference between IS and ICH was found for Carboxypeptidase N subunit 2 (CPN2), Coagulation factor XII (FXII), Plasminogen, Mannan-binding lectin serine protease 1, Serum amyloid P-component, Paraoxonase 1, Carbonic anhydrase 1, Fibulin-1, and Granulins.

Discussion: In this exploratory proteomics-based pilot study, nine candidate biomarkers for differentiation of IS and ICH were identified. The proteins belong to the immune system, the coagulation cascade, and the apoptosis system, respectively. Further investigations in larger cohorts of patients with stroke using additional biochemical analysis methods, such as ELISA or Western Blotting are now necessary to validate these markers, and to characterize diagnostic accuracy with regard to the development of a point-of-care-system for use in resource-limited areas.
Analysis of Career-Advancement for Medical School Graduates During the COVID-19 Pandemic at a Chinese Teaching Hospital
Authors: Zhu Xiaoyan , Xie Mingxuan , Xia Xiaobo , Li Xiangping , Zhang Le
Published: December 2021

The COVID-19 pandemic has led to widespread social and economic disruptions in the balance of labor market. Our study aims to analyze the career-advancement of medical school graduates during the COVID-19 pandemic and the associated influencing factors. We collected and compared the career-advancement data of medical school graduates at a Chinese teaching hospital from 2016 to 2020. A self-designed 20-element medical graduates employment questionnaire and a Chinese adaptation of the General self-efficacy scale were distributed by the Questionnaire Star platform. Univariate analysis (Pearson's Chi-square-test and Fisher's exact-test) and subsequent binary logistic regression were used. Findings demonstrated that the career-advancement rate of medical graduate students in 2020 is 71.3%, which is significantly lower than that for the preceding 4 years from 2016 to 2019 (p < 0.001). Of the 251 employed medical school graduates, 159 (63.3%) have signed an employment agreement or contract, 83 (33.1%) are pursuing continued education domestically, and 9 (3.6%) have offers from foreign institutions. Univariate analysis revealed statistical differences of medical graduates' employment among various specialties, oral defense completion, job search start date, CV submission times, participation in a probationary period, and self-efficacy. Significant predictors for successful employment were early job search and self-efficacy by logistic regression model (χ2 = 12.719, p < 0.001). Most medical graduates assumed that the COVID-19 pandemic had a major (40.6%) or moderate (48%) impact on career-advancement. The COVID-19 pandemic has profoundly impacted the career-advancement of medical school graduates in 2020. We should make adaptive changes to improve the career-advancement of medical graduates.
GLP-1 Suppresses Feeding Behaviors and Modulates Neuronal Electrophysiological Properties in Multiple Brain Regions
Authors: Chen Xin-Yi , Chen Lei , Yang Wu , Xie An-Mu
Published: December 2021

The glucagon-like peptide-1 (GLP-1) plays important roles in the regulation of food intake and energy metabolism. Peripheral or central GLP-1 suppresses food intake and reduces body weight. The electrophysiological properties of neurons in the mammalian central nervous system reflect the neuronal excitability and the functional organization of the brain. Recent studies focus on elucidating GLP-1-induced suppression of feeding behaviors and modulation of neuronal electrophysiological properties in several brain regions. Here, we summarize that activation of GLP-1 receptor (GLP-1R) suppresses food intake and induces postsynaptic depolarization of membrane potential and/or presynaptic modulation of glutamatergic or GABAergic neurotransmission in brain nuclei located within the medulla oblongata, pons, mesencephalon, diencephalon, and telencephalon. This review may provide a background to guide future research about the cellular mechanisms of GLP-1-induced feeding inhibition.
Epithelial–Mesenchymal Transition Participates in the Formation of Vestibular Flat Epithelium
Authors: He Lu , Wang Guo-Peng , Guo Jing-Ying , Chen Zhong-Rui , Liu Ke , Gong Shu-Sheng
Published: December 2021

The vestibular sensory epithelium of humans and mice may degenerate into a layer of flat cells, known as flat epithelium (FE), after a severe lesion. However, the pathogenesis of vestibular FE remains unclear. To determine whether the epithelial–mesenchymal transition (EMT) participates in the formation of vestibular FE, we used a well-established mouse model in which FE was induced in the utricle by an injection of streptomycin into the inner ear. The mesenchymal and epithelial cell markers and cell proliferation were examined using immunofluorescence staining and quantitative reverse transcription polymerase chain reaction (qRT-PCR). The function of the EMT was assessed through transcriptome microarray analysis. The results demonstrated that mesenchymal cell markers (α-SMA, S100A4, vimentin, and Fn1) were upregulated in vestibular FE compared with the normal utricle. Robust cell proliferation, which was absent in the normal status, was observed in the formation of FE. Microarray analysis identified 1,227 upregulated and 962 downregulated genes in vestibular FE. Gene Ontology (GO) analysis revealed that differentially expressed genes (DEGs) were highly associated with several EMT-related GO terms, such as cell adhesion, cell migration, and extracellular matrix. Pathway enrichment analysis revealed that DEGs were enriched in the EMT-related signaling pathways, including extracellular matrix (ECM)-receptor interaction, focal adhesion, PI3K/Akt signaling pathway and cell adhesion molecule. Protein–protein interaction networks screened 20 hub genes, which were Akt, Casp3, Col1a1, Col1a2, Fn1, Hgf, Igf1,Il1b, Irs1, Itga2, Itga5, Jun, Mapk1, Myc, Nras, Pdgfrb, Tgfb1, Thbs1, Trp53, and Col2a1. Most of these genes are reportedly involved in the EMT process in various tissues. The mRNA expression level of hub genes was validated using qRT-PCR. In conclusion, the present study indicates that EMT plays a significant role in the formation of vestibular FE and provides an overview of transcriptome characteristics in vestibular FE.
Infant Iodine and Selenium Status in Relation to Maternal Status and Diet During Pregnancy and Lactation
Authors: Stråvik Mia , Gustin Klara , Barman Malin , Skröder Helena , Sandin Anna , Wold Agnes E. , Sandberg Ann-Sofie , Kippler Maria , Vahter Marie
Published: December 2021

Iodine and selenium are essential trace elements. Recent studies indicate that pregnant and lactating women often have insufficient intake of iodine and selenium, but the impact on fetal and infant status is unclear. Here, we assessed iodine and selenium status of infants in relation to maternal intake and status of these trace elements in the birth cohort NICE, conducted in northern Sweden (n = 604). Iodine was measured in urine (UIC) in gestational week 29, and in breast milk and infant urine 4 months postpartum, while selenium was measured in maternal plasma and erythrocytes in gestational week 29, and in breast milk and infant erythrocytes 4 months postpartum, in both cases using ICP-MS. Maternal intake was assessed with semi-quantitative food frequency questionnaires in gestational week 34 and at 4 months postpartum. The median intake of iodine and selenium during pregnancy (98 and 40 μg/d, respectively) and lactation (108 and 39 μg/d, respectively) was below recommended intakes, reflected in insufficient status (median UIC of 113 μg/L, median plasma selenium of 65 μg/L). Also, breast milk concentrations (median iodine 77 μg/L, median selenium 9 μg/L) were unlikely to meet infant requirements. Median UIC of the infants was 114 μg/L and median erythrocyte selenium 96 μg/kg, both similar to the maternal concentrations. Infant UIC correlated strongly with breast milk levels (rho = 0.64, p < 0.001). Their erythrocyte selenium correlated with maternal erythrocyte selenium in pregnancy (rho = 0.38, p < 0.001), but not with breast milk selenium, suggesting formation of prenatal reserves. Our results indicate that the transport of iodine and selenium to the fetus and infant is prioritized. Still, it is uncertain whether most infants had sufficient intakes. Further, the results might indicate an involvement of iodine in asthma development during the first year of life, which is essential to follow up. The low maternal and infant dietary intake of both iodine and selenium, especially when the mothers did not use supplements or iodized table salt, suggest a need for a general screening of women and young children.
A Comparative Study of Radiomics and Deep-Learning Based Methods for Pulmonary Nodule Malignancy Prediction in Low Dose CT Images
Authors: Astaraki Mehdi , Yang Guang , Zakko Yousuf , Toma-Dasu Iuliana , Smedby Örjan , Wang Chunliang
Published: December 2021

Objectives

Both radiomics and deep learning methods have shown great promise in predicting lesion malignancy in various image-based oncology studies. However, it is still unclear which method to choose for a specific clinical problem given the access to the same amount of training data. In this study, we try to compare the performance of a series of carefully selected conventional radiomics methods, end-to-end deep learning models, and deep-feature based radiomics pipelines for pulmonary nodule malignancy prediction on an open database that consists of 1297 manually delineated lung nodules.

Methods

Conventional radiomics analysis was conducted by extracting standard handcrafted features from target nodule images. Several end-to-end deep classifier networks, including VGG, ResNet, DenseNet, and EfficientNet were employed to identify lung nodule malignancy as well. In addition to the baseline implementations, we also investigated the importance of feature selection and class balancing, as well as separating the features learned in the nodule target region and the background/context region. By pooling the radiomics and deep features together in a hybrid feature set, we investigated the compatibility of these two sets with respect to malignancy prediction.

Results

The best baseline conventional radiomics model, deep learning model, and deep-feature based radiomics model achieved AUROC values (mean ± standard deviations) of 0.792 ± 0.025, 0.801 ± 0.018, and 0.817 ± 0.032, respectively through 5-fold cross-validation analyses. However, after trying out several optimization techniques, such as feature selection and data balancing, as well as adding context features, the corresponding best radiomics, end-to-end deep learning, and deep-feature based models achieved AUROC values of 0.921 ± 0.010, 0.824 ± 0.021, and 0.936 ± 0.011, respectively. We achieved the best prediction accuracy from the hybrid feature set (AUROC: 0.938 ± 0.010).

Conclusion

The end-to-end deep-learning model outperforms conventional radiomics out of the box without much fine-tuning. On the other hand, fine-tuning the models lead to significant improvements in the prediction performance where the conventional and deep-feature based radiomics models achieved comparable results. The hybrid radiomics method seems to be the most promising model for lung nodule malignancy prediction in this comparative study.
Case Report: Unilateral Sixth Cranial Nerve Palsy Associated With COVID-19 in a 2-year-old Child
Authors: Knoflach Katrin , Holzapfel Eva , Roser Timo , Rudolph Lieselotte , Paolini Marco , Muenchhoff Maximilian , Osterman Andreas , Griese Matthias , Kappler Matthias , von Both Ulrich
Published: December 2021

Children have been described to show neurological symptoms in acute coronavirus disease 2019 (COVID-19) and multisystemic inflammatory syndrome in children (MIS-C). We present a 2-year-old boy's clinical course of unilateral acute sixth nerve palsy in the context of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Onset of the palsy in the otherwise healthy boy occurred seven days after symptoms attributed to acute infection had subsided respectively 3 weeks after onset of respiratory symptoms. SARS-CoV-2 specific IgG was detected in serum as well as in cerebrospinal fluid. The patient showed a prolonged but self-limiting course with a full recovery after three and a half months. This case illustrates in a detailed chronological sequence that sixth cranial nerve involvement may occur as post-infectious, self-limiting complication of pediatric SARS-CoV-2-infection thus expanding the neurological spectrum of symptoms for children with COVID-19. Clinicians should be aware of the possibility of post-infectious sixth nerve palsy related to SARS-CoV-2-infection particularly in view of recent respiratory tract infection or confirmed cases of SARS-CoV-2-infection amongst the patient's close contacts.
Factors Influencing Implementation of Blood Transfusion Recommendations in Pediatric Critical Care Units
Authors: Steffen Katherine M. , Spinella Philip C. , Holdsworth Laura M. , Ford Mackenzie A. , Lee Grace M. , Asch Steven M. , Proctor Enola K. , Doctor Allan
Published: December 2021

Purpose:Risks of red blood cell transfusion may outweigh benefits for many patients in Pediatric Intensive Care Units (PICUs). The Transfusion and Anemia eXpertise Initiative (TAXI) recommendations seek to limit unnecessary and potentially harmful transfusions, but use has been variable. We sought to identify barriers and facilitators to using the TAXI recommendations to inform implementation efforts.

Materials and Methods:The integrated Promoting Action on Research Implementation in Health Services (iPARIHS) framework guided semi-structured interviews conducted in 8 U.S. ICUs; 50 providers in multiple ICU roles completed interviews. Adapted Framework analysis, a form of content analysis, used the iPARIHS innovation, recipient, context and facilitation constructs and subconstructs to categorize data and identify patterns as well as unique informative statements.

Results:Providers perceived that the TAXI recommendations would reduce transfusion rates and practice variability, but adoption faced challenges posed by attitudes around transfusion and care in busy and complex units. Development of widespread buy-in and inclusion in implementation, integration into workflow, designating committed champions, and monitoring outcomes data were expected to enhance implementation.

Conclusions:Targeted activities to create buy-in, educate, and plan for use are necessary for TAXI implementation. Recognition of contextual challenges posed by the PICU environment and an approach that adjusts for barriers may optimize adoption.
Initial-State Temperature of Light Meson Emission Source From Squared Momentum Transfer Spectra in High-Energy Collisions
Authors: Wang Qi , Liu Fu-Hu , Olimov Khusniddin K.
Published: December 2021

The squared momentum transfer spectra of light mesons, π0, π+, η, and ρ0, produced in high-energy virtual photon-proton (γ*p) → meson + nucleon process in electron-proton (ep) collisions measured by the CLAS Collaboration are analyzed by the Monte Carlo calculations, where the transfer undergoes from the incident γ* to emitted meson or equivalently from the target proton to emitted nucleon. In the calculations, the Erlang distribution from a multi-source thermal model is used to describe the transverse momentum spectra of emitted particles. Our results show that the average transverse momentum (⟨pT⟩) and the initial-state temperature (Ti) increase from lower squared photon virtuality (Q2) and Bjorken variable (xB) to higher one. This renders that the excitation degree of emission source, which is described by ⟨pT⟩ and Ti, increases with increasing of Q2 and xB.
Advances in Nursery Production of Hazelnut Plants in Serbia − Successful Grafting of Different Corylus avellana L. Cultivars and Clones Onto Corylus colurna L. Rootstock
Authors: Bijelić Sandra , Magazin Nenad , Džankić Sava , Janković Draža , Bogdanović Borivoje , Jaćimović Goran
Published: December 2021

The latest trends in hazelnut production are moving in the direction of selection and breeding of more productive cultivars, isolation of native clones, and more intensive clonal selection of rootstocks aimed at enhancing the agronomic performance of plants. Serbia stands out in the production of quality planting material by grafting on Turkish filbert (Corylus colurna L.), which does not form shoots and develops in the form of a tree. The aim of this research was to investigate the success achieved by grafting leading Italian cultivars (Tonda gentile romana, Tonda di Giffoni, and Tonda Gentile della Langhe) and their clones on Turkish filbert seedlings using technology developed at the University of Novi Sad, Faculty of Agriculture, Serbia, as well as determine possible differences in the quality and variability of the obtained planting material. For this purpose, from the end of March to the end of April, two-year-old C. colurna generative rootstocks (seedlings) were grafted by the whip and tongue method. At the beginning of September, the grafted plants were counted, and after the plants entered the dormant period (autumn in the year of grafting), they were taken out of the soil and classified. The obtained results revealed that the chosen hazel cultivars and clones exhibited excellent grafting success rate. In both analyzed years, as well as throughout the entire study period, greater grafting success was achieved using clones relative to the main cultivars. Over the two-year study period, the highest grafting success was achieved by clone AD17. Class I grafted plants were obtained in 80% of the cases, especially with Tombesi and AD17 clones, while significantly fewer Class I grafted plants were produced by grafting basic cultivars. Clones AD17 and Tombesi also produced grafted plants of greatest height and graft union diameter. All clones exhibited superior uniformity (i.e., a more stable grafting success) relative to their basic cultivars.
Mechanical Performances of Isolated Cuticles Along Tomato Fruit Growth and Ripening
Authors: Benítez José J. , Guzmán-Puyol Susana , Vilaplana Francisco , Heredia-Guerrero José A. , Domínguez Eva , Heredia Antonio
Published: December 2021

The cuticle is the most external layer that protects fruits from the environment and constitutes the first shield against physical impacts. The preservation of its mechanical integrity is essential to avoid the access to epidermal cell walls and to prevent mass loss and damage that affect the commercial quality of fruits. The rheology of the cuticle is also very important to respond to the size modification along fruit growth and to regulate the diffusion of molecules from and toward the atmosphere. The mechanical performance of cuticles is regulated by the amount and assembly of its components (mainly cutin, polysaccharides, and waxes). In tomato fruit cuticles, phenolics, a minor cuticle component, have been found to have a strong influence on their mechanical behavior. To fully characterize the biomechanics of tomato fruit cuticle, transient creep, uniaxial tests, and multi strain dynamic mechanical analysis (DMA) measurements have been carried out. Two well-differentiated stages have been identified. At early stages of growth, characterized by a low phenolic content, the cuticle displays a soft elastic behavior. Upon increased phenolic accumulation during ripening, a progressive stiffening is observed. The increment of viscoelasticity in ripe fruit cuticles has also been associated with the presence of these compounds. The transition from the soft elastic to the more rigid viscoelastic regime can be explained by the cooperative association of phenolics with both the cutin and the polysaccharide fractions.
Indirect in vitro Regeneration of the Medicinal Plant, Aspilia africana, and Histological Assessment at Different Developmental Stages
Authors: Okello Denis , Yang Sungyu , Komakech Richard , Chung Yuseong , Rahmat Endang , Gang Roggers , Omujal Francis , Lamwaka Alice V. , Kang Youngmin
Published: December 2021

The medicinal plant, Aspilia africana, has been traditionally used in several African countries to treat many diseases such as tuberculosis, cough, inflammation, malaria, osteoporosis, and diabetes. In this study, we developed a protocol for in vitro propagation of A. africana using indirect shoot organogenesis from leaf and root explants of in vitro-grown seedlings and assessed the tissues at different developmental stages. The highest callus induction (91.9 ± 2.96%) from leaf explants was in the Murashige and Skoog (MS) medium augmented with 1.0 mg/L 6-Benzylaminopurine (BAP) and 1.0 mg/L 2,4-dichlorophenoxyacetic acid (2,4-D) while from root explants, the highest callus induction (92.6 ± 2.80%) was in the same plant tissue culture medium augmented with 0.5 mg/L BAP and 1.0 mg/L 2,4-D. The best shoot regeneration capacity from leaf-derived calli (i.e., 80.0 ± 6.23% regeneration percentage and 12.0 ± 6.23 shoots per callus) was obtained in medium augmented with 1.0 mg/L BAP and 0.05 mg/L α-Naphthaleneacetic acid (NAA); the best regeneration capacity for root-derived calli (i.e., 86.7 ± 6.24% shoot regeneration percentage and 14.7 ± 1.11 shoots per callus) was obtained in the MS medium augmented with 1.0 mg/L BAP, 0.05 mg/L NAA, and 0.1 mg/L Thidiazuron (TDZ). Regenerated plantlets developed a robust root system in 1/2 MS medium augmented with 0.1 mg/L NAA and had a survival rate of 93.6% at acclimatization. The in vitro regenerated stem tissue was fully differentiated, while the young leaf tissue consisted of largely unorganized and poorly differentiated cells with large intercellular airspaces typical of in vitro leaf tissues. Our study established a protocol for the indirect regeneration of A. africana and offers a basis for its domestication, large-scale multiplication, and germplasm preservation. To the best of our knowledge, this is the first study to develop an indirect regeneration protocol for A. africana and conduct anatomical assessment through the different stages of development from callus to a fully developed plantlet.
Physiological and Biochemical Responses, and Comparative Transcriptome Profiling of Two Angelica sinensis Cultivars Under Enhanced Ultraviolet-B Radiation
Authors: Peng Tong , Wang Yinquan , Yang Tao , Wang Fusheng , Luo Jun , Zhang Yali
Published: December 2021

In this study, we explored the adaptive mechanism of two varieties of Angelica sinensis exposed to enhanced Ultraviolet-B (UV-B) radiation. The radiation had different effects on the biomass, photosynthetic performance, oxidative damage, antioxidant defense system, and levels of bioactive compounds of Mingui 1 (C1) and Mingui 2 (C2). C2 outperformed C1 under enhanced UV-B radiation, compared to natural light. Using the Illumina RNA-seq, we obtained 6,326 and 2,583 DEGs in C1 and C2, respectively. Under enhanced UV-B radiation, the mRNA levels of genes involved in photosynthesis, antennae protein synthesis, carbon fixation, chlorophyll synthesis, and carotenoid synthesis were decreased in C1 but stable in C2, involving few DEGs. TFs were widely involved in the response of C1 to enhanced UV-B radiation; almost all bHLH and MYB coding genes were downregulated whereas almost all genes encoded WRKY22, WRKY50, WRKY72, NCF, and HSF were upregulated. These results indicate that enhanced UV-B radiation was not conducive to the synthesis of flavonoids, while disease resistance was enhanced. Regarding the ROS scavenging system, upregulated DEGs were mainly found in the AsA-GSH cycle and PrxR/Trx pathways. Remarkably, DEGs that those encoding biosynthetic key enzymes, including ferulic acid (CHS, CHI, DFR, and ANS) and flavonoid (CHS, CHI, DFR, and ANS), most upregulation in C2, leading to increased accumulation of ferulic acid and flavonoids and adversely affecting C1. Genes encoding key enzymes involved in the synthesis of lactone components (ACX, PXG) were mostly up-regulated in C1, increasing the content of lactone components. Our results reveal the DEGs present between C1 and C2 under enhanced UV-B radiation and are consistent with the observed differences in physiological and biochemical indexes. C1 was more sensitive to enhanced UV-B radiation, and C2 was more tolerant to it under moderate enhanced UV-B radiation stress. In addition, the large amount of A. sinensis transcriptome data generated here will serve as a source for finding effective ways to mitigate UV-B enhancement, and also contribute to the well-established lack of genetic information for non-model plant species.
Working Memory Depletion Affects Intertemporal Choice Among Internet Addicts and Healthy Controls
Authors: Li Hongxia
Published: December 2021

Addiction to the Internet has emerged as a new kind of addictive behavior. Although previous studies have revealed that impairments in working memory led to suboptimal decision making (e.g., a greater willingness to choose smaller, more immediate rewards), little is known about how working memory affects intertemporal choice in Internet addicts and normal users. Thus, this study’s aim was to investigate the effect of working memory task on intertemporal choice in 33 participants addicted to internet and 25 healthy controls. Participants were administered (a) a test for Internet Addiction, (b) a single delay discounting self-report questionnaire (c) a working memory task. Differences between the Internet addicts and the control group were observed in terms of delay discounting rates, reaction times, and in memory accuracy rates. We observed significantly higher delay discounting rates among individuals addicted to the Internet. Moreover, it was documented that reaction times follow the 4-level working memory condition were significantly longer than follow the 2-level condition, in both the Internet addicts and the control group. The current findings suggest that Internet addicts are more likely to make short-sighted decisions than normal Internet users. The higher the level of working memory, the more likely an individual is to choose the present smaller reward, thus making short-sighted decisions, and have longer response times.