bluuebunny/crossref_metadata_2025 huggingface dataset:
Repeatability of Cardiac Magnetic Resonance Radiomics: A Multi-Centre Multi-Vendor Test-Retest Study
Authors: Raisi-Estabragh Zahra , Gkontra Polyxeni , Jaggi Akshay , Cooper Jackie , Augusto João , Bhuva Anish N. , Davies Rhodri H. , Manisty Charlotte H. , Moon James C. , Munroe Patricia B. , Harvey Nicholas C. , Lekadir Karim , Petersen Steffen E.
Published: December 2020

Aims: To evaluate the repeatability of cardiac magnetic resonance (CMR) radiomics features on test-retest scanning using a multi-centre multi-vendor dataset with a varied case-mix.

Methods and Results: The sample included 54 test-retest studies from the VOLUMES resource (thevolumesresource.com). Images were segmented according to a pre-defined protocol to select three regions of interest (ROI) in end-diastole and end-systole: right ventricle, left ventricle (LV), and LV myocardium. We extracted radiomics shape features from all three ROIs and, additionally, first-order and texture features from the LV myocardium. Overall, 280 features were derived per study. For each feature, we calculated intra-class correlation coefficient (ICC), within-subject coefficient of variation, and mean relative difference. We ranked robustness of features according to mean ICC stratified by feature category, ROI, and cardiac phase, demonstrating a wide range of repeatability. There were features with good and excellent repeatability (ICC ≥ 0.75) within all feature categories and ROIs. A high proportion of first-order and texture features had excellent repeatability (ICC ≥ 0.90), however, these categories also contained features with the poorest repeatability (ICC < 0.50).

Conclusion: CMR radiomic features have a wide range of repeatability. This paper is intended as a reference for future researchers to guide selection of the most robust features for clinical CMR radiomics models. Further work in larger and richer datasets is needed to further define the technical performance and clinical utility of CMR radiomics.
Genomic and Proteomic Study of the Inflammatory Pathway in Patients With Atrial Fibrillation and Cardiometabolic Syndrome
Authors: Itani Hana A. , Jaffa Miran A. , Elias Joseph , Sabra Mohammad , Zakka Patrick , Ballout Jad , Bekdash Amira , Ibrahim Rand , Al Hariri Moustafa , Ghemrawi Mirna , Abi-Saleh Bernard , Khoury Maurice , Alam Samir , Mahfouz Rami , Jaffa Ayad A. , Azar Sami T. , Refaat Marwan M.
Published: December 2020

Atrial fibrillation (AF) and cardiometabolic syndrome (CMS) have been linked to inflammation and fibrosis. However, it is still unknown which inflammatory cytokines contribute to the pathogenesis of AF. Furthermore, cardiometabolic syndrome (CMS) risk factors such as obesity, hypertension, insulin resistance/glucose intolerance are also associated with inflammation and increased level of cytokines and adipokines. We hypothesized that the inflammatory immune response is exacerbated in patients with both AF and CMS compared to either AF or CMS alone. We investigated inflammatory cytokines and fibrotic markers as well as cytokine genetic profiles in patients with lone AF and CMS. CMS, lone AF patients, patients with both lone AF and CMS, and control patients were recruited. Genetic polymorphisms in inflammatory and fibrotic markers were assessed. Serum levels of connective tissue growth factor (CTGF) were tested along with other inflammatory markers including platelet-to-lymphocyte ratio (PLR), monocyte-to-HDL ratio (MHR) in three groups of AF+CMS, AF, and CMS patients. There was a trend in the CTGF levels for statistical significance between the AF and AF+CMS group (P = 0.084). Genotyping showed high percentages of patients in all groups with high secretor genotypes of Interleukin-6 (IL-6) (P = 0.037). Genotyping of IFN-γ and IL-10 at high level showed an increase in expression in the AF + CMS group compared to AF and CMS alone suggesting an imbalance between the inflammatory and anti-inflammatory cytokines which is exacerbated by AF. Serum cytokine inflammatory cytokine levels showed that IL-4, IL-5, IL-10, IL-17F, and IL-22 were significant between the AF, AF+CMS, and CMS patients. Combination of both CMS and AF may be associated with a higher degree of inflammation than what is seen in either CMS or AF alone. Thus, the identification of a biomarker capable of identifying metabolic syndrome associated with disease will help in identification of a therapeutic target in treating this devastating disease.
Skin Immunity to Dermatophytes: From Experimental Infection Models to Human Disease
Authors: Burstein Verónica L. , Beccacece Ignacio , Guasconi Lorena , Mena Cristian J. , Cervi Laura , Chiapello Laura S.
Published: December 2020

Dermatophytoses (ringworms) are among the most frequent skin infections and are a highly prevalent cause of human disease worldwide. Despite the incidence of these superficial mycoses in healthy people and the compelling evidence on chronic and deep infections in immunocompromised individuals, the mechanisms controlling dermatophyte invasion in the skin are scarcely known. In the last years, the association between certain primary immunodeficiencies and the susceptibility to severe dermatophytosis as well as the evidence provided by novel experimental models mimicking human disease have significantly contributed to deciphering the basic immunological mechanisms against dermatophytes. In this review, we outline the current knowledge on fungal virulence factors involved in the pathogenesis of dermatophytoses and recent evidence from human infections and experimental models that shed light on the cells and molecules involved in the antifungal cutaneous immune response. The latest highlights emphasize the contribution of C-type lectin receptors signaling and the cellular immune response mediated by IL-17 and IFN-γ in the anti-dermatophytic defense and skin inflammation control.
Heparin Attenuates Histone-Mediated Cytotoxicity in Septic Acute Kidney Injury
Authors: Wang Ziyi , Wang Lijun , Cao Chao , Jin Heng , Zhang Yan , Liu Yancun , Gao Yulei , Liang Xue , Li Guangping , Shou Songtao
Published: December 2020

Histones are considered potential risk factors that contribute to the development of septic acute kidney injury (SAKI) by inducing apoptosis and inflammation. This study aimed to explore the protective effects of heparin on septic acute kidney injury through the neutralization of extracellular histones (EH) and to uncover the underlying mechanism. C57BL mice (16 each) were randomly divided into the sham group, the sepsis group (established by cecal ligation and puncture operation, CLP), and the heparin intervention group. Mice in the heparin intervention group received a subcutaneous injection of unfractionated heparin (0.03 IU/g) 4 h after CLP. At 6 h after the operation, nine mice from each group were sacrificed by the removal of the eyeballs to harvest blood samples; the upper half of the right kidney was used as the study sample. Mice renal tubular epithelial cells cultivated in six-well plates were equally divided into five groups. We cultured cells treated with either histone (40 U), histone (40 U) + heparin (25 IU/ml), histone(40U) + lipopolysaccharides (LPS; 10 μg/ml), or histone (40 U) + LPS (10 μg/ml) + heparin (25 IU/ml) for 6 h. For the histone + heparin group and the histone + LPS + heparin group, histone (and LPS) were treated with heparin simultaneously. Mice in the heparin intervention group showed decreased levels of EH4, neutrophil gelatinase-associated lipocalin (NAGL), kidney injury molecule-1 (KIM-1), tumor necrosis factor-α (TNF-α), and interleukin (IL)-6 in the blood serum, longer average 72-h survival rate, significantly decreased kidney tissue edema, and a clearer glomerular structure coupled with decreased protein and mRNA expression levels of kidney apoptosis-related proteins (cleaved Caspase-3/Caspase-3 and Bax/Bcl-2) compared with those in the sepsis group at 6 h after CLP (P < 0.05). Meanwhile, cells in the heparin intervention group exhibited lower expression levels of serum EH4 and inflammatory cytokines, a lower apoptosis rate, and decreased expression of apoptosis-related proteins, both at protein and mRNA levels, than those in the histone-stimulated group at 6 h after stimulation (P < 0.05). Heparin may alleviate apoptosis and inflammation through the neutralization of histones, thus playing a protective role against septic acute kidney injury.
γ-Secretase Modulatory Proteins: The Guiding Hand Behind the Running Scissors
Authors: Wong Eitan , Frost Georgia R. , Li Yue-Ming
Published: December 2020

Described as the “proteasome of the membrane” or the “scissors in the membrane,” γ-secretase has notoriously complicated biology, and even after decades of research, the full extent of its regulatory mechanism remains unclear. γ-Secretase is an intramembrane aspartyl protease complex composed of four obligatory subunits: Nicastrin (NCT), Presenilin (PS), Presenilin Enhancer-2 (Pen-2), and Anterior pharynx-defective-1 (Aph-1). γ-Secretase cleaves numerous type 1 transmembrane substrates, with no apparent homology, and plays major roles in broad biological pathways such as development, neurogenesis, and cancer. Notch and the amyloid precursor protein (APP) and are undoubtedly the best-studied γ-secretase substrates because of their role in cancer and Alzheimer’s disease (AD) and therefore became the focus of increasing studies as an attractive therapeutic target. The regulation of γ-secretase is intricate and involves the function of multiple cellular entities. Recently, γ-secretase modulatory proteins (GSMPs), which are non-essential subunits and yet modulate γ-secretase activity and specificity, have emerged as an important component in guiding γ-secretase. GSMPs are responsive to cellular and environmental changes and therefore, provide another layer of regulation of γ-secretase. This type of enzymatic regulation allows for a rapid and fine-tuning of γ-secretase activity when appropriate signals appear enabling a temporal level of regulation. In this review article, we discuss the latest developments on GSMPs and implications on the development of effective therapeutics for γ-secretase-associated diseases such as AD and cancer.
Breast Subtypes and Prognosis of Breast Cancer Patients With Initial Bone Metastasis: A Population-Based Study
Authors: Liu Deyue , Wu Jiayi , Lin Caijin , Andriani Lisa , Ding Shuning , Shen Kunwei , Zhu Li
Published: December 2020

Background

Metastatic breast cancer (MBC) is a highly heterogeneous disease and bone is one of the most common metastatic sites. This retrospective study was conducted to investigate the clinical features, prognostic factors and benefits of surgery of breast cancer patients with initial bone metastases.

Methods

From 2010 to 2015, 6,860 breast cancer patients diagnosed with initial bone metastasis were analyzed from Surveillance, Epidemiology, and End Results (SEER) database. Univariate and Multivariable analysis were used to identify prognostic factors. A nomogram was performed based on the factors selected from cox regression result. Survival curves were plotted according to different subtypes, metastatic burdens and risk groups differentiated by nomogram.

Results

Hormone receptor (HR) positive/human epidermal growth factor receptor 2 (HER2) positive patients showed the best outcome compared to other subtypes. Patients of younger age (<60 years old), white race, lower grade, lower T stage (<=T2), not combining visceral metastasis tended to have better outcome. About 37% (2,249) patients received surgery of primary tumor. Patients of all subtypes could benefit from surgery. Patients of bone-only metastases (BOM), bone and liver metastases, bone and lung metastases also showed superior survival time if surgery was performed. However, patients of bone and brain metastasis could not benefit from surgery (p = 0.05). The C-index of nomogram was 0.66. Cutoff values of nomogram point were identified as 87 and 157 points, which divided all patients into low-, intermediate- and high-risk groups. Patients of all groups showed better overall survival when receiving surgery.

Conclusion

Our study has provided population-based prognostic analysis in patients with initial bone metastatic breast cancer and constructed a predicting nomogram with good accuracy. The finding of potential benefit of surgery to overall survival will cast some lights on the treatment tactics of this group of patients.
Case Report: A Unique Case of Pediatric Central Nervous System Embryonal Tumor Harboring the CIC–LEUTX Fusion, Germline NBN Variant and Somatic TSC2 Mutation: Expanding the Spectrum of CIC-Rearranged Neoplasia
Authors: Hu Wanming , Wang Juan , Yuan Li , Zhang Xing , Ji Yuhang , Song Chao , Zeng Jing , Sun Xiaofei
Published: December 2020

Central nervous system (CNS) embryonal tumors (WHO grade IV) are a heterogeneous group of rare, poorly differentiated neuroepithelial malignant neoplasms that commonly occur in children, and they have a poor prognosis. The 2016 WHO (World Health Organization) classification of CNS tumors created a major shift in paradigm of the classification of embryonal tumors. However, some cases were still difficult to classify. Further integrative genomic analysis is needed to improve the precise classification, diagnosis and treatment of CNS embryonal tumors. Herein, we firstly report a case of CNS embryonal tumor harboring the pathogenicCIC–LEUTXgene fusion. A 2-year-old male infant presented with a solid cystic mass in the left temporal lobe-basal ganglia and left parietal lobe (maximum diameter, 75 mm) and underwent gross tumor resection. The tumor was classified as a poorly differentiated embryonal neoplasm of neuroectodermal origin that lacked specific features and rosettes. By immunohistochemistry, the tumor cells were strongly positive for synaptophysin, and the Ki67 proliferation index was high (>50%). FISH (Fluorescence in situ hybridization) results indicated no change in the copy number at the 19q13.42 C19MC locus. Next generation sequencing showed aCIC–LEUTXgene fusion, a somaticTSC2c.G2714A mutation, and a heterozygous germlineNBNc.C127T mutation. One month after surgery, there was recurrence of the intracranial tumor (maximum diameter, 55 mm) as well as spinal cord implantation metastasis. The patient received chemotherapy (CTX+CBP+VCR/DDP+VP-16), radiotherapy, and a drug targeting theTSC2gene (everolimus). At the time of this writing, the patient is alive without evidence of disease for 11 months. This is the first report of theCIC–LEUTXgene fusion in a case of CNS embryonal tumor.
The Epigenetics of Glioma Stem Cells: A Brief Overview
Authors: Valor Luis M. , Hervás-Corpión Irati
Published: December 2020

Glioma stem cells (GSCs) are crucial in the formation, perpetuation and recurrence of glioblastomas (GBs) due to their self-renewal and proliferation properties. Although GSCs share cellular and molecular characteristics with neural stem cells (NSCs), GSCs show unique transcriptional and epigenetic features that may explain their relevant role in GB and may constitute druggable targets for novel therapeutic approaches. In this review, we will summarize the most important findings in GSCs concerning epigenetic-dependent mechanisms.
Brain-Age Prediction Using Shallow Machine Learning: Predictive Analytics Competition 2019
Authors: Da Costa Pedro F. , Dafflon Jessica , Pinaya Walter H. L.
Published: December 2020

As we age, our brain structure changes and our cognitive capabilities decline. Although brain aging is universal, rates of brain aging differ markedly, which can be associated with pathological mechanism of psychiatric and neurological diseases. Predictive models have been applied to neuroimaging data to learn patterns associated with this variability and develop a neuroimaging biomarker of the brain condition. Aiming to stimulate the development of more accurate brain-age predictors, the Predictive Analytics Competition (PAC) 2019 provided a challenge that included a dataset of 2,640 participants. Here, we present our approach which placed between the top 10 of the challenge. We developed an ensemble of shallow machine learning methods (e.g., Support Vector Regression and Decision Tree-based regressors) that combined voxel-based and surface-based morphometric data. We used normalized brain volume maps (i.e., gray matter, white matter, or both) and features of cortical regions and anatomical structures, like cortical thickness, volume, and mean curvature. In order to fine-tune the hyperparameters of the machine learning methods, we combined the use of genetic algorithms and grid search. Our ensemble had a mean absolute error of 3.7597 years on the competition, showing the potential that shallow methods still have in predicting brain-age.
Factors Associated With Health-Related Quality of Life of Parents Who Lost Their Only Child: A Cross-Sectional Study in Central China
Authors: Rong Chao , Zheng Li-Jie , Zhang Qian , Cao Yi-Dan , Shen Shu-Hua , Gao Zheng-Qing , Wan Duo , Shen Wei-Wei , Xu Cai-Ming , Wang Xiao-Lan
Published: December 2020

Purpose: The number of families who lost their only child was over one million in 2012 in China, and it is growing rapidly every year. Without their only child, they will inevitably worry about their health and life for their later years. It is important to explore the quality of life and influencing factors of the parents.

Methods: The cluster sampling method was adopted to select the participants in Wuhu city, Anhui province, central China. The generalized linear regression models were performed to analyze factors influencing EQ-VAS scores.

Results: The parents with different monthly income (P = 0.001) and self-rated health status (P < 0.001) had different EQ-VAS scores. Educational level, self-rated health status, number of chronic diseases, depression and having grandchildren were significantly associated with their EQ-VAS score.

Conclusion: The government should encourage public medical institutions to provide convenient health management and medical services to this vulnerable group. Priority treatment should be given to the parents who already have multiple diseases. The parents who were depressed should be given timely intervention. The government should give more financial subsidies to the parents who need to raise their grandchildren.
Algae-Derived Polysaccharides Promote Growth Performance by Improving Antioxidant Capacity and Intestinal Barrier Function in Broiler Chickens
Authors: Liu Wen-Chao , Guo Yan , Zhao Zhi-Hui , Jha Rajesh , Balasubramanian Balamuralikrishnan
Published: December 2020

This study aimed to determine the efficacy of dietary algae-derived polysaccharides (ADPs) from Enteromorpha on growth performance, intestinal morphology, intestinal permeability, and antioxidant capacity in serum, liver, and intestinal mucosa of broilers. Three hundred and ninety six day-old male chicks were randomly assigned to six dietary treatments containing 0 (Control), 1,000, 2,500, 4,000, 5,500, and 7,000 mg ADP/kg basal diet in a 35 day feeding trial. During day 1–21, compared with the control group, dietary 1,000–7,000 mg/kg ADP supplementation improved the average daily gain (ADG) and feed conversion ratio (p < 0.05). Overall (day 1–35), dietary inclusion of 1,000 mg/kg ADP increased the final body weight and ADG (p < 0.05). Besides, on day 21, dietary 2,500 mg/kg ADP supplementation increased the serum catalase (CAT) and liver total superoxide dismutase (T-SOD) activities (p < 0.05), whereas dietary 1,000–5,500 mg/kg ADP supplementation decreased malondialdehyde (MDA) contents in serum and liver (p < 0.05). On day 35, supplementation of 1,000 mg/kg ADP increased the serum glutathione peroxidase and CAT activities and liver T-SOD activities (p < 0.05). It decreased the MDA level of serum and liver (p < 0.05). Also, dietary 2,500 mg/kg ADP increased the villus height of jejunum and ileum on day 21 (p < 0.05), and dietary 4,000 mg/kg ADP increased the villus height of duodenum and ileum on day 35 (p < 0.05). On day 21, dietary 4,000 mg/kg ADP increased the CAT activities of the duodenum and T-SOD activities of jejunum and ileum and decreased the MDA contents in the duodenum, jejunum, and ileum (p < 0.05). On day 35, dietary inclusion of 1,000–7,000 mg/kg ADP reduced MDA contents of duodenum and jejunum (p < 0.05). Furthermore, dietary inclusion of ADP at 1,000–7,000 mg/kg decreased serum DAO activities at day 21 and day 35 (p < 0.05), and the serum D-lactic acid concentration was reduced by dietary supplementation of 1,000, 2,500, and 7,000 mg/kg ADP on day 21. In conclusion, dietary ADP exerted beneficial effects on growth performance, antioxidant capacity, and gut health in broilers; based on the studied parameters, the appropriate recommended dose is 1,000–4,000 mg/kg. These findings provided new insights into the potential application of ADP as natural growth promoters in broilers.
Influence of Feeding Quinoa (Chenopodium quinoa) Seeds and Prickly Pear Fruit (Opuntia ficus indica) Peel on the Immune Response and Resistance to Aeromonas sobria Infection in Nile Tilapia (Oreochromis niloticus)
Authors: Ahmed Shaimaa A. A. , Abd El-Rahman Ghada I. , Behairy Amany , Beheiry Rasha R. , Hendam Basma M. , Alsubaie Faisal M. , Khalil Samah R.
Published: December 2020

In recent times, nutraceuticals have been used extensively to identify promising feed additives for the improvement of the aquaculture industry through the enhancement of growth and survival rates, potentiation of the immune responses, and fortification of the resistance against infectious bacterial diseases. In this study, Nile tilapia (Oreochromis niloticus) were fed with diets supplemented with quinoa seeds (QU) or prickly pear fruit peel (PP) at the dose levels of 10% or 20% of the diet. After 45 days of the feeding trial, the fish were exposed to Aeromonas sobria (A. sobria) challenge. The pre-challenge indices indicated that both supplements mediated a significant improvement in most of the estimated parameters, including survival rate, antioxidant status, hematological and immunological indices, and hepatoprotective potential. These effects were recorded in the groups fed with high doses of the supplements (20%). The least changes were observed in the QU10-supplemented fish. In the spleen tissue, the TGF-β gene was upregulated in the PP10-, PP20- and QU20-supplemented groups, while the expression of the IFN-γ gene remained unaffected in all the supplemented groups, except for the PP20-supplemented group, which showed an upregulation. After the challenge with A. sobria, the relative survival percentage was improved by the supplementation of PP and QU, particularly in the PP20-supplemented group, possibly via the promotion of immunological responses, hepatoprotective potency, and modulation of the studied genes. Moreover, the morphological structure of the tissues showed marked recovery. The findings suggest that Nile tilapia fed with different levels of PP peel and QU seeds, particularly at the level of 20%, enhanced the immune response in fish and improved their resistance against A. sobria infection.
Concentrations of Circulating Irisin and Myostatin in Race and Endurace Purebred Arabian Horses—Preliminary Study
Authors: Kowalik Sylwester , Wiśniewska Anna , Kędzierski Witold , Janczarek Iwona
Published: December 2020

Skeletal muscle is considered to be the largest endocrine organ determining the maintenance of energy homeostasis. Adaptive changes in skeletal muscles in response to physical exercise influence the production as well as secretion of myokines, which are bioactive factors that play a crucial role in energy expenditure processes. The aim of the study was to investigate the impact of two different types of exercise on the circulating level of two of these, myostatin and irisin, in trained horses. Twenty purebred Arabian horses were involved in the study: 10 three-year-old horses trained on the racetrack and 10 endurance horses aged 7.4 ± 1.9 years. The horses from both groups were regularly trained throughout the entire season, during which they also participated in Polish National competitions. To assess the influence of the training sessions on plasma myostatin and irisin concentrations, blood samples taken at rest and 30 min after the end of exercise were analyzed. In the studied horses, the single bout of exercise did not influence plasma irisin but induced an increase in plasma myostatin concentration. In racehorses, plasma irisin concentration decreased with the length of the training season. Plasma myostatin was higher in endurance horses than in three-year-old racehorses. Lack of exercise-induced fluctuation in circulating irisin in studied horses suggests that myostatin released in response to exercise provides a negative feedback signal to irisin release.
Best of Both Hydrogel Worlds: Harnessing Bioactivity and Tunability by Incorporating Glycosaminoglycans in Collagen Hydrogels
Authors: Walimbe Tanaya , Panitch Alyssa
Published: December 2020

Collagen, the most abundant protein in mammals, has garnered the interest of scientists for over 50 years. Its ubiquitous presence in all body tissues combined with its excellent biocompatibility has led scientists to study its potential as a biomaterial for a wide variety of biomedical applications with a high degree of success and widespread clinical approval. More recently, in order to increase their tunability and applicability, collagen hydrogels have frequently been co-polymerized with other natural and synthetic polymers. Of special significance is the use of bioactive glycosaminoglycans—the carbohydrate-rich polymers of the ECM responsible for regulating tissue homeostasis and cell signaling. This review covers the recent advances in the development of collagen-based hydrogels and collagen-glycosaminoglycan blend hydrogels for biomedical research. We discuss the formulations and shortcomings of using collagen in isolation, and the advantages of incorporating glycosaminoglycans (GAGs) in the hydrogels. We further elaborate on modifications used on these biopolymers for tunability and discuss tissue specific applications. The information presented herein will demonstrate the versatility and highly translational value of using collagen blended with GAGs as hydrogels for biomedical engineering applications.
TNF-α Priming Elicits Robust Immunomodulatory Potential of Human Tonsil-Derived Mesenchymal Stem Cells to Alleviate Murine Colitis
Authors: Shin Tae-Hoon , Ahn Ji-Su , Oh Su-Jeong , Shin Ye Young , Yang Ji Won , Kang Min-Jung , Kim Ji Min , Lee Byung-Joo , Seo Yoojin , Kim Hyung-Sik
Published: December 2020

Mesenchymal stem cells (MSCs) have been spotlighted in the field of cell therapies as a promising tool for the treatment of intractable inflammatory diseases. However, their therapeutic potency still shows a gap between preclinical and clinical settings, and distinctive characteristics of specific tissue-derived MSCs and definitive ways to maximize their beneficial functions have not been fully elucidated yet. We previously identified the unique MSCs population from human palatine tonsil (TMSCs) and revealed their superior properties in proliferation and ROS regulation. Based on these findings, we explored further characteristics of TMSCs particularly focused on immunomodulatory function. We found the merit of TMSCs as a therapeutic agent that retains favorable MSCs properties until relatively late passages and revealed that pre-treatment of TNF-α can enhance the immunomodulatory abilities of TMSCs through the upregulation of the PTGS2/PGE2 axis. TMSCs primed with TNF-α effectively restrained the proliferation and differentiation of T lymphocytes and macrophages in vitro, and more interestingly, these TNF-α-licensed TMSCs exhibited significant prophylactic and therapeutic efficacy in a murine model of autoimmune-mediated acute colitis via clinical and histopathological assessment compared to unprimed naïve TMSCs. These findings provide novel insight into the optimization and standardization of MSCs-based anti-inflammatory therapies, especially targeting inflammatory bowel disease (IBD).
Angiogenesis-Related Functions of Wnt Signaling in Colorectal Carcinogenesis
Authors: Kasprzak Aldona
Published: December 2020

Aberrant activation of the Wnt/Fzd/β-catenin signaling pathway is one of the major molecular mechanisms of colorectal cancer (CRC) development and progression. On the other hand, one of the most common clinical CRC characteristics include high levels of angiogenesis, which is a key event in cancer cell dissemination and distant metastasis. The canonical Wnt/β-catenin downstream signaling regulates the most important pro-angiogenic molecules including vascular endothelial growth factor (VEGF) family members, matrix metalloproteinases (MMPs), and chemokines. Furthermore, mutations of the β-catenin gene associated with nuclear localization of the protein have been mainly detected in microsatellite unstable CRC. Elevated nuclear β-catenin increases the expression of many genes involved in tumor angiogenesis. Factors regulating angiogenesis with the participation of Wnt/β-catenin signaling include different groups of biologically active molecules including Wnt pathway components (e.g., Wnt2, DKK, BCL9 proteins), and non-Wnt pathway factors (e.g., chemoattractant cytokines, enzymatic proteins, and bioactive compounds of plants). Several lines of evidence argue for the use of angiogenesis inhibition in the treatment of CRC. In the context of this paper, components of the Wnt pathway are among the most promising targets for CRC therapy. This review summarizes the current knowledge about the role of the Wnt/Fzd/β-catenin signaling pathway in the process of CRC angiogenesis, aiming to improve the understanding of the mechanisms of metastasis as well as improvements in the management of this cancer.
Optimal Systemic Treatment of Advanced Bladder Cancer—A Moving Target
Authors: Pappot Helle , Ullén Anders
Published: December 2020

n/a
Revealing Temozolomide Resistance Mechanisms via Genome-Wide CRISPR Libraries
Authors: Rocha Clarissa Ribeiro Reily , Rocha Alexandre Reily , Silva Matheus Molina , Gomes Luciana Rodrigues , Latancia Marcela Teatin , Andrade-Tomaz Marina , de Souza Izadora , Monteiro Linda Karolynne Seregni , Menck Carlos Frederico Martins
Published: December 2020

Glioblastoma is a severe type of brain tumor with a poor prognosis and few therapy options. Temozolomide (TMZ) is one of these options, however, with limited success, and failure is mainly due to tumor resistance. In this work, genome-wide CRISPR-Cas9 lentiviral screen libraries for gene knockout or activation were transduced in the human glioblastoma cell line, aiming to identify genes that modulate TMZ resistance. The sgRNAs enriched in both libraries in surviving cells after TMZ treatment were identified by next-generation sequencing (NGS). Pathway analyses of gene candidates on knockout screening revealed several enriched pathways, including the mismatch repair and the Sonic Hedgehog pathways. Silencing three genes ranked on the top 10 list (MSH2, PTCH2, and CLCA2) confirm cell protection from TMZ-induced death. In addition, a CRISPR activation library revealed that NRF2 and Wnt pathways are involved in TMZ resistance. Consistently, overexpression of FZD6, CTNNB1, or NRF2 genes significantly increased cell survival upon TMZ treatment. Moreover, NRF2 and related genes detected in this screen presented a robust negative correlation with glioblastoma patient survival rates. Finally, several gene candidates from knockout or activation screening are targetable by inhibitors or small molecules, and some of them have already been used in the clinic.
Spontaneous Depolarization-Induced Action Potentials of ON-Starburst Amacrine Cells during Cholinergic and Glutamatergic Retinal Waves
Authors: Yan Rong-Shan , Yang Xiong-Li , Zhong Yong-Mei , Zhang Dao-Qi
Published: December 2020

Correlated spontaneous activity in the developing retina (termed “retinal waves”) plays an instructive role in refining neural circuits of the visual system. Depolarizing (ON) and hyperpolarizing (OFF) starburst amacrine cells (SACs) initiate and propagate cholinergic retinal waves. Where cholinergic retinal waves stop, SACs are thought to be driven by glutamatergic retinal waves initiated by ON-bipolar cells. However, the properties and function of cholinergic and glutamatergic waves in ON- and OFF-SACs still remain poorly understood. In the present work, we performed whole-cell patch-clamp recordings and Ca2+ imaging from genetically labeled ON- and OFF-SACs in mouse flat-mount retinas. We found that both SAC subtypes exhibited spontaneous rhythmic depolarization during cholinergic and glutamatergic waves. Interestingly, ON-SACs had wave-induced action potentials (APs) in an age-dependent manner, but OFF-SACs did not. Simultaneous Ca2+ imaging and patch-clamp recordings demonstrated that, during a cholinergic wave, APs of an ON-SAC appeared to promote the dendritic release of acetylcholine onto neighboring ON- and OFF-SACs, which enhances their Ca2+ transients. These results advance the understanding of the cellular mechanisms underlying correlated spontaneous activity in the developing retina.
Proteomic Characterization of Synaptosomes from Human Substantia Nigra Indicates Altered Mitochondrial Translation in Parkinson’s Disease
Authors: Plum Sarah , Eggers Britta , Helling Stefan , Stepath Markus , Theiss Carsten , Leite Renata E. P. , Molina Mariana , Grinberg Lea T. , Riederer Peter , Gerlach Manfred , May Caroline , Marcus Katrin
Published: December 2020

The pathological hallmark of Parkinson’s disease (PD) is the loss of neuromelanin-containing dopaminergic neurons within the substantia nigra pars compacta (SNpc). Additionally, numerous studies indicate an altered synaptic function during disease progression. To gain new insights into the molecular processes underlying the alteration of synaptic function in PD, a proteomic study was performed. Therefore, synaptosomes were isolated by density gradient centrifugation from SNpc tissue of individuals at advanced PD stages (N = 5) as well as control subjects free of pathology (N = 5) followed by mass spectrometry-based analysis. In total, 362 proteins were identified and assigned to the synaptosomal core proteome. This core proteome comprised all proteins expressed within the synapses without regard to data analysis software, gender, age, or disease. The differential analysis between control subjects and PD cases revealed that CD9 antigen was overrepresented and fourteen proteins, among them Thymidine kinase 2 (TK2), mitochondrial, 39S ribosomal protein L37, neurolysin, and Methionine-tRNA ligase (MARS2) were underrepresented in PD suggesting an alteration in mitochondrial translation within synaptosomes.
Novel PET Biomarkers to Disentangle Molecular Pathways across Age-Related Neurodegenerative Diseases
Authors: Wilson Heather , Politis Marios , Rabiner Eugenii A. , Middleton Lefkos T.
Published: December 2020

There is a need to disentangle the etiological puzzle of age-related neurodegenerative diseases, whose clinical phenotypes arise from known, and as yet unknown, pathways that can act distinctly or in concert. Enhanced sub-phenotyping and the identification of in vivo biomarker-driven signature profiles could improve the stratification of patients into clinical trials and, potentially, help to drive the treatment landscape towards the precision medicine paradigm. The rapidly growing field of neuroimaging offers valuable tools to investigate disease pathophysiology and molecular pathways in humans, with the potential to capture the whole disease course starting from preclinical stages. Positron emission tomography (PET) combines the advantages of a versatile imaging technique with the ability to quantify, to nanomolar sensitivity, molecular targets in vivo. This review will discuss current research and available imaging biomarkers evaluating dysregulation of the main molecular pathways across age-related neurodegenerative diseases. The molecular pathways focused on in this review involve mitochondrial dysfunction and energy dysregulation; neuroinflammation; protein misfolding; aggregation and the concepts of pathobiology, synaptic dysfunction, neurotransmitter dysregulation and dysfunction of the glymphatic system. The use of PET imaging to dissect these molecular pathways and the potential to aid sub-phenotyping will be discussed, with a focus on novel PET biomarkers.
Pitfalls in Monitoring Mitochondrial Temperature Using Charged Thermosensitive Fluorophores
Authors: Chrétien Dominique , Bénit Paule , Leroy Christine , El-Khoury Riyad , Park Sunyou , Lee Jung Yeol , Chang Young-Tae , Lenaers Guy , Rustin Pierre , Rak Malgorzata
Published: December 2020

Mitochondria are the source of internal heat which influences all cellular processes. Hence, monitoring mitochondrial temperature provides a unique insight into cell physiology. Using a thermosensitive fluorescent probe MitoThermo Yellow (MTY), we have shown recently that mitochondria within human cells are maintained at close to 50 °C when active, increasing their temperature locally by about 10 °C. Initially reported in the HEK293 cell line, we confirmed this finding in the HeLa cell line. Delving deeper, using MTY and MTX (MitoThermo X), a modified version of MTY, we unraveled some caveats related to the nature of these charged fluorophores. While enabling the assessment of mitochondrial temperature in HEK and HeLa cell lines, the reactivity of MTY to membrane potential variations in human primary skin fibroblasts precluded local temperature monitoring in these cells. Chemical modification of MTY into MTX did not result in a temperature probe unresponsive to membrane potential variations that could be universally used in any cell type to determine mitochondrial temperature. Thus, the cell-type dependence of MTY in measuring mitochondrial temperature, which is likely due to the variable binding of this dye to specific internal mitochondrial components, should imply cautiousness while using these nanothermometers for mitochondrial temperature analysis.
Beyond Amitriptyline: A Pediatric and Adolescent Oriented Narrative Review of the Analgesic Properties of Psychotropic Medications for the Treatment of Complex Pain and Headache Disorders
Authors: Windsor Robert Blake , Sierra Michael , Zappitelli Megan , McDaniel Maria
Published: December 2020

Children and adolescents with recurrent or chronic pain and headache are a complex and heterogenous population. Patients are best served by multi-specialty, multidisciplinary teams to assess and create tailored, individualized pain treatment and rehabilitation plans. Due to the complex nature of pain, generalizing pharmacologic treatment recommendations in children with recurrent or chronic pains is challenging. This is particularly true of complicated patients with co-existing painful and psychiatric conditions. There is an unfortunate dearth of evidence to support many pharmacologic therapies to treat children with chronic pain and headache. This narrative review hopes to supplement the available treatment options for this complex population by reviewing the pediatric and adult literature for analgesic properties of medications that also have psychiatric indication. The medications reviewed belong to medication classes typically described as antidepressants, alpha 2 delta ligands, mood stabilizers, anti-psychotics, anti-sympathetic agents, and stimulants.
Magnetic Phase Transition, Elastic and Thermodynamic Properties of L12-(Ni,Cu)3(Al,Fe,Cr) in 3d High-Entropy Alloys
Authors: Ma Li , Wang Zhi-Peng , Huang Guo-Hua , Huang Jin-Li , Tang Ping-Ying , Fan Tou-Wen
Published: December 2020

The phase stability and elastic properties of paramagnetic (PM), ferromagnetic (FM) and antiferromagnetic (AFM) phases in L12-(Ni,Cu)3(Al,Fe,Cr) alloy are first investigated using the exact muffin-tin orbitals (EMTO) method in combination with the coherent potential approximation (CPA). The result shows the AFM structure phase of the three is the most stable in the ground state. Calculated elastic constants show that all the phases are mechanically stable, and have uncovered that L12-(Ni,Cu)3(Al,Fe,Cr) can achieve good strength and ductility simultaneously. Then, crucial thermal properties are described satisfactorily using the Debye–Grüneisen model, showing heat capacity, Gibbs free energy G, the competitive contribution of entropy −TS and enthalpy H exhibiting significant temperature dependences. Moreover, the magnetic phase transition thermodynamics was studied, which suggests that −TS has a primary contribution to Gibbs free energy and may play a key role in the phase transition. The present results can benefit the understanding of the mechanical, thermodynamic and magnetic properties of the L12 structure phase in 3d high-entropy alloys.
Macroinvertebrate Taxonomic Richness in Minimally Disturbed Streams on the Southeastern USA Coastal Plain
Authors: Paller Michael H. , Blas Susan A. , Kelley Robert W.
Published: December 2020

Collections made over 20 years with a multiple habitat sampling protocol and Hester–Dendy artificial substrate samplers were used to assess macroinvertebrate genera richness in first- to fourth-order streams on the Savannah River Site (SRS), a 780-km2, U.S. government reservation on the upper South Carolina, USA, coastal plain. We collected 312 genera representing 114 families including 268 genera and 87 families of insects. The total number of genera from each stream averaged 139 (97–194) with totals of 171–261 for drainages with more than one stream. Larger streams supported more macroinvertebrate genera, but small headwater streams supported genera not found in higher-order streams and contributed to drainage-wide richness. Sampling effort expressed as number of individuals collected or sites sampled and sampling duration influenced genera richness more than other factors. Genera accumulation curves showed that full representation of richness required several years of sampling and the inclusion of sampling sites that represented all habitats. Upper Three Runs, known for high insect species richness, was the most genera-rich stream, but richness was nearly comparable in other streams after adjusting for sampling effort. Some SRS streams are minimally exposed to anthropogenic disturbance, making them relatively unique in the southeastern USA Sand Hills and valuable as reference models.
Carbon Nanoparticles as Sources for a Cost-Effective Water Purification Method: A Comprehensive Review
Authors: Kotia Ankit , Yadav Aman , Rohit Raj Tata , Gertrud Keischgens Maria , Rathore Happy , Sarris Ioannis E.
Published: December 2020

As the global population grows, the demand for cost-effective and eco-friendly water purification methods is increasing, which presently is at its peak due to the increase of impurities in water and the increasing awareness of waterborne disease. Carbon-based materials, which includes activated carbon, carbon nanotubes (CNTs), graphene, graphene oxide (GO), reduced graphene oxide (rGO), fullerene, and carbon dots, are observed as potential candidates for water treatment. In the present review, developments related to water purification methods using carbon nanomaterials over the last decade are critically summarized, with an emphasis on their thermophysical properties. The fabrication techniques for activated carbon, CNTs, graphene, and graphene oxide are presented, with an emphasis on the properties of carbon materials that allow their usage for water purification. Then, an extensive review of 71 patents dedicated to water purification using carbon materials such as activated carbon and cotton fibers is performed. Subsequently, the more important research studies on water purification using carbon nanomaterials are discussed, showing that CNTs, GO, and rGO are widely used in water treatment processes. The present review critically discusses the recent developments and provides important information on water purification using carbon materials.
Analysis of Gluten in Dried Yeast and Yeast-Containing Products
Authors: Allred Laura K. , Nye-Wood Mitchell G. , Colgrave Michelle L.
Published: December 2020

Yeast are commonly used in the preparation of foods and beverages such as beer and bread and may also be used on their own as a source of nutrients and flavoring. Because of the historical connection of yeast to products made from wheat and barley, consumers maintaining a gluten-free diet can have concerns about the safety of yeast ingredients. Analyzing the safety of yeast and yeast-containing products presents some difficulties, as the yeast organisms actively degrade any gluten in the product, raising questions on the appropriateness of detection by traditional antibody-based methods. This study examines a variety of yeast and yeast-containing products by competitive ELISA and liquid chromatography-mass spectrometry for the estimated level of gluten proteins. While samples such as yeast extracts and nutritional yeast contained gluten levels below the 20 mg/kg (or parts per million, ppm) threshold defined by Codex Alimentarius, one baking yeast and a nutritional yeast supplement sample contained higher levels of gluten. This study demonstrates that both competitive ELISA and liquid chromatography-mass spectrometry provide similar results in the detection of wheat and barley gluten in yeast-containing products.
Identification of Novel Genomic Associations and Gene Candidates for Grain Starch Content in Sorghum
Authors: Sapkota Sirjan , Boatwright J. Lucas , Jordan Kathleen , Boyles Richard , Kresovich Stephen
Published: December 2020

Starch accumulated in the endosperm of cereal grains as reserve energy for germination serves as a staple in human and animal nutrition. Unraveling genetic control for starch metabolism is important for breeding grains with high starch content. In this study, we used a sorghum association panel with 389 individuals and 141,557 single nucleotide polymorphisms (SNPs) to fit linear mixed models (LMM) for identifying genomic regions and potential candidate genes associated with starch content. Three associated genomic regions, one in chromosome (chr) 1 and two novel associations in chr-8, were identified using combination of LMM and Bayesian sparse LMM. All significant SNPs were located within protein coding genes, with SNPs ∼ 52 Mb of chr-8 encoding a Casperian strip membrane protein (CASP)-like protein (Sobic.008G111500) and a heat shock protein (HSP) 90 (Sobic.008G111600) that were highly expressed in reproductive tissues including within the embryo and endosperm. The HSP90 is a potential hub gene with gene network of 75 high-confidence first interactors that is enriched for five biochemical pathways including protein processing. The first interactors of HSP90 also showed high transcript abundance in reproductive tissues. The candidates of this study are likely involved in intricate metabolic pathways and represent candidate gene targets for source-sink activities and drought and heat stress tolerance during grain filling.