bluuebunny/crossref_metadata_2025_split huggingface dataset:
Knocking out alpha-synuclein in melanoma cells dysregulates cellular iron metabolism and suppresses tumor growth
Authors: Shekoohi Sahar , Rajasekaran Santhanasabapathy , Patel Dhaval , Yang Shu , Liu Wang , Huang Shile , Yu Xiuping , Witt Stephan N. 
Published: March 2021

AbstractThe protein alpha-synuclein (α-syn) is unusual because, depending on its conformation and the type of cell in which it is expressed, it is pro-death or pro-survival, triggering neurodegeneration in Parkinson’s disease and enhancing cell survival of some melanomas. To probe the function of α-syn in melanoma, we used CRISPR/Cas9 to knockout SNCA, the gene that codes for α-syn, in SK-Mel-28 melanoma cells. The SNCA-knockout clones in culture exhibited a decrease in the transferrin receptor 1 (TfR1), an increase in ferritin, an increase of reactive oxygen species and proliferated slower than control cells. These SNCA-knockout clones grafted into SCID mice grew significantly slower than the SK-Mel-28 control cells that expressed α-syn. In the excised SNCA-knockout xenografts, TfR1 decreased 3.3-fold, ferritin increased 6.2-fold, the divalent metal ion transporter 1 (DMT1) increased threefold, and the iron exporter ferroportin (FPN1) decreased twofold relative to control xenografts. The excised SNCA-KO tumors exhibited significantly more ferric iron and TUNEL staining relative to the control melanoma xenografts. Collectively, depletion of α-syn in SK-Mel-28 cells dysregulates cellular iron metabolism, especially in xenografts, yielding melanoma cells that are deficient in TfR1 and FPN1, that accumulate ferric iron and ferritin, and that undergo apoptosis relative to control cells expressing α-syn.
Paracetamol modulates biofilm formation in Staphylococcus aureus clonal complex 8 strains
Authors: Sultan Andi R. , Lattwein Kirby R. , Lemmens-den Toom Nicole A. , Snijders Susan V. , Kooiman Klazina , Verbon Annelies , van Wamel Willem J. B. 
Published: March 2021

AbstractStaphylococcus aureus biofilms are a major problem in modern healthcare due to their resistance to immune system defenses and antibiotic treatments. Certain analgesic agents are able to modulate S. aureus biofilm formation, but currently no evidence exists if paracetamol, often combined with antibiotic treatment, also has this effect. Therefore, we aimed to investigate if paracetamol can modulate S. aureus biofilm formation. Considering that certain regulatory pathways for biofilm formation and virulence factor production by S. aureus are linked, we further investigated the effect of paracetamol on immune modulator production. The in vitro biofilm mass of 21 S. aureus strains from 9 genetic backgrounds was measured in the presence of paracetamol. Based on biofilm mass quantity, we further investigated paracetamol-induced biofilm alterations using a bacterial viability assay combined with N-Acetylglucosamine staining. Isothermal microcalorimetry was used to monitor the effect of paracetamol on bacterial metabolism within biofilms and green fluorescent protein (GFP) promoter fusion technology for transcription of staphylococcal complement inhibitor (SCIN). Clinically relevant concentrations of paracetamol enhanced biofilm formation particularly among strains belonging to clonal complex 8 (CC8), but had minimal effect on S. aureus planktonic growth. The increase of biofilm mass can be attributed to the marked increase of N-Acetylglucosamine containing components of the extracellular matrix, presumably polysaccharide intercellular adhesion. Biofilms of RN6390A (CC8) showed a significant increase in the immune modulator SCIN transcription during co-incubation with low concentrations of paracetamol. Our data indicate that paracetamol can enhance biofilm formation. The clinical relevance needs to be further investigated.
Bayesian network-driven clustering analysis with feature selection for high-dimensional multi-modal molecular data
Authors: Zhao Yize , Chang Changgee , Hannum Margaret , Lee Jasme , Shen Ronglai 
Published: March 2021

AbstractMulti-modal molecular profiling data in bulk tumors or single cells are accumulating at a fast pace. There is a great need for developing statistical and computational methods to reveal molecular structures in complex data types toward biological discoveries. Here, we introduce Nebula, a novel Bayesian integrative clustering analysis for high dimensional multi-modal molecular data to identify directly interpretable clusters and associated biomarkers in a unified and biologically plausible framework. To facilitate computational efficiency, a variational Bayes approach is developed to approximate the joint posterior distribution to achieve model inference in high-dimensional settings. We describe a pan-cancer data analysis of genomic, epigenomic, and transcriptomic alterations in close to 9000 tumor samples across canonical oncogenic signaling pathways, immune and stemness phenotype, with comparisons to state-of-the-art clustering methods. We demonstrate that Nebula has the unique advantage of revealing patterns on the basis of shared pathway alterations, offering biological and clinical insights beyond tumor type and histology in the pan-cancer analysis setting. We also illustrate the utility of Nebula in single cell data for immune cell decomposition in peripheral blood samples.
Ultrahigh-speed point scanning two-photon microscopy using high dynamic range silicon photomultipliers
Authors: Ching-Roa Vincent D. , Olson Eben M. , Ibrahim Sherrif F. , Torres Richard , Giacomelli Michael G. 
Published: March 2021

AbstractConventional two-photon microscopes use photomultiplier tubes, which enable high sensitivity but can detect relatively few photons per second, forcing longer pixel integration times and limiting maximum imaging rates. We introduce novel detection electronics using silicon photomultipliers that greatly extend dynamic range, enabling more than an order of magnitude increased photon detection rate as compared to state-of-the-art photomultiplier tubes. We demonstrate that this capability can dramatically improve both imaging rates and signal-to-noise ratio (SNR) in two-photon microscopy using human surgical specimens. Finally, to enable wider use of more advanced detection technology, we have formed the OpenSiPM project, which aims to provide open source detector designs for high-speed two-photon and confocal microscopy.
Accelerated crystal structure prediction of multi-elements random alloy using expandable features
Authors: Jin Taewon , Park Ina , Park Taesu , Park Jaesik , Shim Ji Hoon 
Published: March 2021

AbstractProperties of solid-state materials depend on their crystal structures. In solid solution high entropy alloy (HEA), its mechanical properties such as strength and ductility depend on its phase. Therefore, the crystal structure prediction should be preceded to find new functional materials. Recently, the machine learning-based approach has been successfully applied to the prediction of structural phases. However, since about 80% of the data set is used as a training set in machine learning, it is well known that it requires vast cost for preparing a dataset of multi-element alloy as training. In this work, we develop an efficient approach to predicting the multi-element alloys' structural phases without preparing a large scale of the training dataset. We demonstrate that our method trained from binary alloy dataset can be applied to the multi-element alloys' crystal structure prediction by designing a transformation module from raw features to expandable form. Surprisingly, without involving the multi-element alloys in the training process, we obtain an accuracy, 80.56% for the phase of the multi-element alloy and 84.20% accuracy for the phase of HEA. It is comparable with the previous machine learning results. Besides, our approach saves at least three orders of magnitude computational cost for HEA by employing expandable features. We suggest that this accelerated approach can be applied to predicting various structural properties of multi-elements alloys that do not exist in the current structural database.
The food additive EDTA aggravates colitis and colon carcinogenesis in mouse models
Authors: Evstatiev Rayko , Cervenka Adam , Austerlitz Tina , Deim Gunther , Baumgartner Maximilian , Beer Andrea , Krnjic Anita , Gmainer Christina , Lang Michaela , Frick Adrian , Schachner Helga , Khare Vineeta , Gasche Christoph 
Published: March 2021

AbstractInflammatory bowel disease is a group of conditions with rising incidence caused by genetic and environmental factors including diet. The chelator ethylenediaminetetraacetate (EDTA) is widely used by the food and pharmaceutical industry among numerous other applications, leading to a considerable environmental exposure. Numerous safety studies in healthy animals have revealed no relevant toxicity by EDTA. Here we show that, in the presence of intestinal inflammation, EDTA is surprisingly capable of massively exacerbating inflammation and even inducing colorectal carcinogenesis at doses that are presumed to be safe. This toxicity is evident in two biologically different mouse models of inflammatory bowel disease, the AOM/DSS and the IL10−/− model. The mechanism of this effect may be attributed to disruption of intercellular contacts as demonstrated by in vivo confocal endomicroscopy, electron microscopy and cell culture studies. Our findings add EDTA to the list of food additives that might be detrimental in the presence of intestinal inflammation, but the toxicity of which may have been missed by regulatory safety testing procedures that utilize only healthy models. We conclude that the current use of EDTA especially in food and pharmaceuticals should be reconsidered. Moreover, we suggest that intestinal inflammatory models should be implemented in the testing of food additives to account for the exposure of this primary organ to environmental and dietary stress.
The association between gestational diabetes and ASD and ADHD: a systematic review and meta-analysis
Authors: Rowland Jennifer , Wilson Claire A. 
Published: March 2021

AbstractThere is growing evidence for a role of maternal diabetes in the pathogenesis of neurodevelopmental disorders. However, the specific association between gestational diabetes (GDM), as opposed to pre-gestational diabetes, has been poorly isolated. Thus the aim was to systematically review and meta-analyse literature pertaining to prevalence and risk for two neurodevelopmental disorders: autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), when exposed to GDM. PubMed, Cochrane Library, EMBASE, PsycINFO and CINAHL were systematically searched for eligible literature, with forward and backward citation tracking. Screening for eligibility, risk of bias assessment and data extraction were performed by two independent reviewers. 18 studies measuring ASD and 15 measuring ADHD met inclusion criteria. On meta-analysis there was an increased risk of ASD (OR 1.42; 95% CI 1.22, 1.65) but not ADHD (OR 1.01; 95% CI 0.79, 1.28). We discuss potential mechanisms for these differing risks. Greater understanding of risk factors, including GDM, for these neurodevelopmental disorders and potential mechanisms may help inform strategies aimed at prevention of exposure to these adversities during pregnancy.
The incidence trends of liver cirrhosis caused by nonalcoholic steatohepatitis via the GBD study 2017
Authors: Zhai Mimi , Liu Zhide , Long Jianhai , Zhou Qingxiang , Yang Leping , Zhou Qin , Liu Sushun , Dai Yu 
Published: March 2021

AbstractNonalcoholic steatohepatitis (NASH) has rapidly become the most common cause of chronic liver diseases. We aimed to explore the incidence and distribution characteristics of NASH by sex, region and sociodemographic index (SDI). We collected data, including sex and region, on NASH-related liver cirrhosis from the 2017 GBD study. The age-standardized incidence rates (ASRs) and estimated annual percentage changes (EAPCs) were used to estimate the incidence trend and distribution characteristics. Globally, the incidence of liver cirrhosis caused by NASH increased from 178,430 cases in 1990 to 367,780 cases in 2017, an increase of approximately 105.56%. The ASR of NASH increased by an average of 1.35% per year (95% CI 1.28–1.42). Meanwhile, large differences in the ASR and the EAPC were observed across regions. The middle-high SDI region had the highest increase among all five SDI regions, followed by middle SDI region. In addition, Eastern Europe, Andean Latin America and Central Asia showed a more significant growth trend of ASR. In contrast, the high SDI region demonstrated the slowest increasing trend of ASR, and the high-income Asia Pacific demonstrated a decreasing trend among the 21 regions. Liver cirrhosis has caused a huge and rising health burden in many countries and regions. In addition, with the growth of obesity, population and aging, NASH might replace viral hepatitis as the most important cause of liver cirrhosis in the near future. Therefore, appropriate interventions are needed in coming decades to realize early diagnosis and prevention of NASH-related liver cirrhosis.
Persistent bone impairment despite long-term control of hyperprolactinemia and hypogonadism in men and women with prolactinomas
Authors: Andereggen Lukas , Frey Janine , Andres Robert H. , Luedi Markus M. , Widmer Hans Rudolf , Beck Jürgen , Mariani Luigi , Christ Emanuel 
Published: March 2021

AbstractWhile prolactinoma patients have high bone turnover, current data are inconclusive when it comes to determining whether correction of hyperprolactinemia and associated hypogandism improves osteodensitometric data in men and women over the long term. In a large cohort of including 40 men and 60 women, we studied the long-term impact of prolactinoma treatment on bone mineral density (BMD) in men versus women, assessed adverse effects of a primary surgical or medical approach, and evaluated data for risk factors for impaired BMD at last follow-up using multivariate regression analyses. Median duration of follow-up was 79 months (range 13–408 months). Our data indicate that the prevalence of impaired BMD remained significantly higher in men (37%) than in women (7%, p < 0.001), despite the fact that hyperprolactinemia and hypogonadism are under control in the majority of men. We found that persistent hyperprolactinemia and male sex were independent risk factors for long-term bone impairment. Currently, osteoporosis prevention and treatment focus primarily on women, yet special attention to bone loss in men with prolactinomas is advised. Bone impairment as “end organ” reflects the full range of the disease and could become a surrogate marker for the severity of long-lasting hyperprolactinemia and associated hypogonadism.
Exploratory classification of clinical phenotypes in Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis using cluster analysis
Authors: Watanabe Haruki , Sada Ken-ei , Harigai Masayoshi , Amano Koichi , Dobashi Hiroaki , Takasaki Yoshinari , Fujimoto Shouichi , Atsumi Tatsuya , Yamagata Kunihiro , Homma Sakae , Arimura Yoshihiro , Makino Hirofumi ,   Research Committee of Intractable Vasculitis Syndrome (JPVAS),   Research Committee of Intractable Renal Disease of the Ministry of Health, Labour, and Welfare of Japan
Published: March 2021

AbstractA novel patient cluster in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) may be identified in Japan. We performed multiple correspondence and cluster analysis regarding 427 clinically diagnosed AAV patients excluding eosinophilic granulomatosis with polyangiitis. Model 1 included the ANCA phenotype, items of the Birmingham Vasculitis Activity Score, and interstitial lung disease; model 2 included serum creatinine (s-Cr) and C-reactive protein (CRP) levels with model 1 components. In seven clusters determined in model 1, the ANCA-negative (n = 8) and proteinase 3-ANCA-positive (n = 41) groups emerged as two distinct clusters. The other five myeloperoxidase-ANCA-positive clusters were characterized by ear, nose, and throat (ENT) (n = 47); cutaneous (n = 36); renal (n = 256), non-renal (n = 33); and both ENT and cutaneous symptoms (n = 6). Four clusters in model 2 were characterized by myeloperoxidase-ANCA negativity (n = 42), without s-Cr elevation (< 1.3 mg/dL) (n = 157), s-Cr elevation (≥ 1.3 mg/dL) with high CRP (> 10 mg/dL) (n = 71), or s-Cr elevation (≥ 1.3 mg/dL) without high CRP (≤ 10 mg/dL) (n = 157). Overall, renal, and relapse-free survival rates were significantly different across the four clusters in model 2. ENT, cutaneous, and renal symptoms may be useful in characterization of Japanese AAV patients with myeloperoxidase-ANCA. The combination of s-Cr and CRP levels may be predictive of prognosis.
Polymorphisms of the matrix metalloproteinase genes are associated with essential hypertension in a Caucasian population of Central Russia
Authors: Moskalenko Maria , Ponomarenko Irina , Reshetnikov Evgeny , Dvornyk Volodymyr , Churnosov Mikhail 
Published: March 2021

AbstractThis study aimed to determine possible association of eight polymorphisms of seven MMP genes with essential hypertension (EH) in a Caucasian population of Central Russia. Eight SNPs of the MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, and MMP12 genes and their gene–gene (epistatic) interactions were analyzed for association with EH in a cohort of 939 patients and 466 controls using logistic regression and assuming additive, recessive, and dominant genetic models. The functional significance of the polymorphisms associated with EH and 114 variants linked to them (r2 ≥ 0.8) was analyzed in silico. Allele G of rs11568818 MMP7 was associated with EH according to all three genetic models (OR = 0.58–0.70, pperm = 0.01–0.03). The above eight SNPs were associated with the disorder within 12 most significant epistatic models (OR = 1.49–1.93, pperm < 0.02). Loci rs1320632 MMP8 and rs11568818 MMP7 contributed to the largest number of the models (12 and 10, respectively). The EH-associated loci and 114 SNPs linked to them had non-synonymous, regulatory, and eQTL significance for 15 genes, which contributed to the pathways related to metalloendopeptidase activity, collagen degradation, and extracellular matrix disassembly. In summary, eight studied SNPs of MMPs genes were associated with EH in the Caucasian population of Central Russia.
Neuron-specific spinal cord translatomes reveal a neuropeptide code for mouse dorsal horn excitatory neurons
Authors: Das Gupta Rebecca Rani , Scheurer Louis , Pelczar Pawel , Wildner Hendrik , Zeilhofer Hanns Ulrich 
Published: March 2021

AbstractThe spinal dorsal horn harbors a sophisticated and heterogeneous network of excitatory and inhibitory neurons that process peripheral signals encoding different sensory modalities. Although it has long been recognized that this network is crucial both for the separation and the integration of sensory signals of different modalities, a systematic unbiased approach to the use of specific neuromodulatory systems is still missing. Here, we have used the translating ribosome affinity purification (TRAP) technique to map the translatomes of excitatory glutamatergic (vGluT2+) and inhibitory GABA and/or glycinergic (vGAT+ or Gad67+) neurons of the mouse spinal cord. Our analyses demonstrate that inhibitory and excitatory neurons are not only set apart, as expected, by the expression of genes related to the production, release or re-uptake of their principal neurotransmitters and by genes encoding for transcription factors, but also by a differential engagement of neuromodulator, especially neuropeptide, signaling pathways. Subsequent multiplex in situ hybridization revealed eleven neuropeptide genes that are strongly enriched in excitatory dorsal horn neurons and display largely non-overlapping expression patterns closely adhering to the laminar and presumably also functional organization of the spinal cord grey matter.
High resolution biologging of breaching by the world’s second largest shark species
Authors: Rudd Jessica L. , Exeter Owen M. , Hall Jackie , Hall Graham , Henderson Suzanne M. , Kerry Christopher , Witt Matthew J. , Hawkes Lucy A. 
Published: March 2021

AbstractBasking sharks, the world’s second largest fish, are endangered globally following two centuries of large-scale exploitation for their oily livers. In the northeast Atlantic, they seasonally gather in key sites, including the western Scottish Isles, where they feed on plankton, but their breeding grounds are currently completely unknown. Using high-resolution three-axis accelerometry and depth logging, we present the first direct records of breaching by basking sharks over 41 days. We show that basking sharks breach both during the night and day, starting at approximately 20 m depth and can breach multiple times in short succession. We also present early evidence of potential lateralisation in basking sharks. Given the energetic nature of breaching, it should have an important biological function, but this remains unclear.
Hepatic lymphocytes involved in the pathogenesis of pediatric and adult non-alcoholic fatty liver disease
Authors: Cairoli Victoria , De Matteo Elena , Rios Daniela , Lezama Carol , Galoppo Marcela , Casciato Paola , Mullen Eduardo , Giadans Cecilia , Bertot Gustavo , Preciado María Victoria , Valva Pamela 
Published: March 2021

AbstractThe immune response is critical in NAFLD pathogenesis, but the liver infiltrate’s composition and the role of each T cell population is still up for debate. To characterize liver pathogenesis in pediatric and adult cases, frequency and localization of immune cell populations [Cytotoxic T Lymphocytes (CD8+), T helper Lymphocytes (CD4+), Regulatory T lymphocytes (Foxp3+) and Th17 (IL-17A+)] were evaluated. In portal/periportal (P/P) tracts, both age groups displayed a similar proportion of CD8+ and CD4+ lymphocytes. However, comparable Foxp3+ and IL-17A+ cell frequencies were observed in pediatric cases, meanwhile, in adults Foxp3+ was higher than IL-17A+ cells. Interestingly, IL-17A+ lymphocytes seemed to be nearly exclusive of P/P area in both age groups. In intralobular areas, both pediatric and adult cases showed CD8+ lymphocytes predominance with lower frequencies of CD4+ lymphocytes followed by Foxp3+ . Severe inflammation was associated with higher intralobular Foxp3+ lymphocytes (p = 0.026) in children, and lower P/P Foxp3+ and higher IL-17A+ lymphocytes in adults. All cases with fibrosis ≥ 2 displayed P/P low Foxp3+ and high IL-17A+ lymphocyte counts. Pediatric cases with worse steatosis showed high P/P CD4+ (p = 0.023) and intralobular CD8+ (p = 0.027) and CD4+ cells (p = 0.012). In NAFLD cases, the lymphocyte liver infiltrate composition differs between histological areas. Treg and Th17 balance seems to condition damage progression, denoting their important role in pathogenesis.