bluuebunny/crossref_metadata_2025_split huggingface dataset:
The absence of (TCAGGG)n repeats in some telomeres, combined with variable responses to NR2F2 depletion, suggest that this nuclear receptor plays an indirect role in the alternative lengthening of telomeres
Authors: Alhendi Ahmed S. N. , Royle Nicola J. 
Published: November 2020

AbstractThe alternative lengthening of telomeres (ALT) facilitates telomere lengthening by a DNA strand invasion and copying mechanism. The nuclear receptors (NRs), NR2F2 and NR2C2, can bind to (TCAGGG)n variant repeats within telomeres and it has been proposed that this facilitates telomere interactions in ALT+ cells. Here we show that the frequency of cells with detectable NR2F2 and NR2C2 nuclear foci varies considerably between ALT+ cell lines and does not correlate with the level of protein expression. In addition, four of five ALT+ cell lines lack (TCAGGG)n repeats in some telomeres, indicating that direct NR binding does not play a role in ALT at these telomeres. NR2F2-depletion altered the abundance of C-circles and APBs but the direction of the response was inconsistent between three ALT+ cell lines. Moreover, transcriptome analysis following NR2F2-depletion in the ALT+ cell lines revealed different very responses. For example, NR2F2-depletion down-regulated many genes in U2OS cells, consistent with the cell cycle arrest and changes to ALT markers, but these features were not shared by the other two ALT+ cell lines. Among 86 ALT-associated genes, only MND1 showed consistent down-regulation across three NR2F2-depleted ALT+ cell lines. Altogether our data suggest that NR2F2 does not play a direct role in ALT and we speculate about an alternative role for this NR in a DNA damage response at telomeres.
UBC9 coordinates inflammation affecting development of bladder cancer
Authors: Huang Xiaoliang , Tao Yuting , Gao Jiamin , Zhou Xianguo , Tang Shaomei , Deng Caiwang , Lai Zhiyong , Lin Xinggu , Wang Qiuyan , Li Tianyu 
Published: November 2020

AbstractDysregulation of SUMO modification is linked to carcinogenesis. UBC9 is the sole conjugating enzyme in sumoylation and plays a pivotal role in maintaining homeostasis and restraining stress reactions. However, the clinical significance and function of UBC9 in bladder cancer remain unclear. In this study, immunohistochemistry was used to determine the expression of UBC9. UBC9 knock-down and SUMO inhibition were conducted followed by proliferation, migration, and cell cycle assays. RNA sequencing and bioinformatic analysis were used to identify potential mechanisms of UBC9. Cytokine membrane antibody array was used to detect the expression of cytokine. The mass cytometry TOF (CyTOF) was used to explore the association between bladder cancer stem cell-like population and UBC9 expression. Our results showed that UBC9 played a dual role in bladder cancer. UBC9 was up-regulated in bladder cancer, but was negatively correlated with TNM stage and grade. Knocking-down of UBC9 resulted in dramatic activation of inflammatory gene expression, which might cause inhibition of cell proliferation and inducing cell apoptosis. IL6 was the hub gene in UBC9 regulatory network. Markedly up-regulated IL6 after knocking-down of UBC9 activated the expression of CD44, which was a prominent marker of cancer stem cells. Thus, our results revealed an important and previously undescribed role for UBC9 in modulation of inflammatory signaling of bladder cancer. UBC9 in bladder cancer cells is required to maintain high sumoylation levels and alleviate stress-related inflammation threats to cell survival. Lacking UBC9 contributes to inflammation activation, epithelial–mesenchymal transition and stem cell-like population formation, leading to cancer progression.
A holistic approach in herbicide resistance research and management: from resistance detection to sustainable weed control
Authors: Liu Chun , Jackson Lucy V. , Hutchings Sarah-Jane , Tuesca Daniel , Moreno Raul , Mcindoe Eddie , Kaundun Shiv S. 
Published: November 2020

AbstractAgricultural weeds can adapt rapidly to human activities as exemplified by the evolution of resistance to herbicides. Despite its multi-faceted nature, herbicide resistance has rarely been researched in a holistic manner. A novel approach combining timely resistance confirmation, investigation of resistance mechanisms, alternative control solutions and population modelling was adopted for the sustainable management of the Amaranthus palmeri weed in soybean production systems in Argentina. Here, we show that resistance to glyphosate in the studied population from Cordoba province was mainly due to a P106S target-site mutation in the 5-enolpyruvylshikimate 3-phosphate synthase (EPSPS) gene, with minor contributions from EPSPS gene duplication/overexpression. Alternative herbicides, such as fomesafen, effectively controlled the glyphosate-resistant plants. Model simulations revealed the tendency of a solo herbicidal input to primarily select for a single resistance mechanism and suggested that residual herbicides, alongside chemical diversity, were important for the sustainable use of these herbicides. We also discuss the value of an interdisciplinary approach for improved understanding of evolving weeds.
Mirtazapine exerts astrocyte-mediated dopaminergic neuroprotection
Authors: Kikuoka Ryo , Miyazaki Ikuko , Kubota Natsuki , Maeda Megumi , Kagawa Daiki , Moriyama Masaaki , Sato Asuka , Murakami Shinki , Kitamura Yoshihisa , Sendo Toshiaki , Asanuma Masato 
Published: November 2020

AbstractMirtazapine, a noradrenergic and specific serotonergic antidepressant (NaSSA), is known to activate serotonin (5-HT) 1A receptor. Our recent study demonstrated that stimulation of astrocytic 5-HT1A receptors promoted astrocyte proliferation and upregulated antioxidative property in astrocytes to protect dopaminergic neurons against oxidative stress. Here, we evaluated the neuroprotective effects of mirtazapine against dopaminergic neurodegeneration in models of Parkinson’s disease (PD). Mirtazapine administration attenuated the loss of dopaminergic neurons in the substantia nigra and increased the expression of the antioxidative molecule metallothionein (MT) in the striatal astrocytes of 6-hydroxydopamine (6-OHDA)-injected parkinsonian mice via 5-HT1A receptors. Mirtazapine protected dopaminergic neurons against 6-OHDA-induced neurotoxicity in mesencephalic neuron and striatal astrocyte cocultures, but not in enriched neuronal cultures. Mirtazapine-treated neuron-conditioned medium (Mir-NCM) induced astrocyte proliferation and upregulated MT expression via 5-HT1A receptors on astrocytes. Furthermore, treatment with medium from Mir-NCM-treated astrocytes protected dopaminergic neurons against 6-OHDA neurotoxicity, and these effects were attenuated by treatment with a MT-1/2-specific antibody or 5-HT1A antagonist. Our study suggests that mirtazapine could be an effective disease-modifying drug for PD and highlights that astrocytic 5-HT1A receptors may be a novel target for the treatment of PD.
Influence of pycnocline on settling behaviour of non-spherical particle and wake evolution
Authors: Mrokowska Magdalena M. 
Published: November 2020

AbstractSettling of non-spherical particles in a stratified fluid exhibits complex dynamics in a low-to-moderate inertia regime. Although this process is involved in a wide variety of phenomena in natural fluid systems, its fundamental mechanisms are still unexplored. Understanding of particle settling in microscale is particularly important to explain challenging problems associated with ecological and biogeochemical processes in the ocean due to the delayed settling of particulate matter at pycnoclines. Here, I explore interactions between disk-shaped particles and a stratified fluid with a density transition. By laboratory experiments, I demonstrate that the settling dynamics of the disk crossing a density transition are tightly coupled with the wake structure evolution, and I observe for the first time in a two-layer ambient configuration a bell-shaped structure that forms on a jet after the wake has detached from the particle. Furthermore, I identify hydrodynamic conditions for the variations of settling velocity and particle orientation instabilities. These findings shed light on particle settling mechanisms necessary to explain dynamics of marine particles such as plankton, faecal pellets, and microplastics and may improve the estimation methods of sedimentation processes in various areas of earth sciences and engineering.
Development and validation of a nomogram for predicting the probability of nontraumatic osteonecrosis of the femoral head in Chinese population
Authors: Xu Qiang , Chen Hangjun , Chen Sihai , Shan Jing , Xia Guoming , Cao Zhiyou , Liu Xuqiang , Dai Min 
Published: November 2020

AbstractAlthough corticosteroids and alcohol are two major risk factors for nontraumatic osteonecrosis of the femoral head (NONFH), the effects of other factors have rarely been studied, thereby making early diagnosis and treatment of NONFH difficult. This study aimed to develop and validate a nomogram to NONFH, but patients with alcohol- and steroid-related NONFH are not at all taken into account in this study. A training cohort of 790 patients (n = 434, NONFH; n = 356, femoral neck fractures [non-NONFH]) diagnosed in our hospital from January 2011 to December 2016 was used for model development. A least absolute shrinkage and selection operator (lasso) regression model was used for date dimension reduction and optimal predictor selection. A predictive model was developed from univariate and multivariate logistic regression analyses. Performance characterisation of the resulting nomogram included calibration, discriminatory ability, and clinical usefulness. After internal validation, the nomogram was further evaluated in a separate cohort of 300 consecutive patients included between January 2017 and December 2018. The simple prediction nomogram included five predictors from univariate and multivariate analyses, including gender, total cholesterol levels, triglyceride levels, white blood cell count, and platelet count. Internal validation showed that the model had good discrimination [area under the receiver operating characteristic curve (AUC) = 0.80] and calibration. Good discrimination (AUC = 0.81) and calibration were preserved in the validation cohort. Decision curve analysis showed that the predictive nomogram was clinically useful. The simple diagnostic nomogram, which combines demographic data and laboratory blood test results, was able to quantify the probability of NONFH in cases of early screening and diagnosis.
Wireless localization with diffusion maps
Authors: Ghafourian Amin , Georgiou Orestis , Barter Edmund , Gross Thilo 
Published: November 2020

AbstractIn the Wireless Localization Matching Problem (WLMP) the challenge is to match pieces of equipment with a set of candidate locations based on wireless signal measurements taken by the pieces of equipment. This challenge is complicated by the noise that is inherent in wireless signal measurements. Here we propose the use of diffusion maps, a manifold learning technique, to obtain an embedding of positions and equipment coordinates in a space that enables coordinate comparison and reliable evaluation of assignment quality at very low computational cost. We show that the mapping is robust to noise and using diffusion maps allows for accurate matching in a realistic setting. This suggests that the diffusion-map-based approach could significantly increase the accuracy of wireless localization in applications.
Cryo-EM structures and functional characterization of homo- and heteropolymers of human ferritin variants
Authors: Irimia-Dominguez Jose , Sun Chen , Li Kunpeng , Muhoberac Barry B. , Hallinan Grace I. , Garringer Holly J. , Ghetti Bernardino , Jiang Wen , Vidal Ruben 
Published: November 2020

AbstractThe role of abnormal brain iron metabolism in neurodegenerative diseases is still insufficiently understood. Here, we investigate the molecular basis of the neurodegenerative disease hereditary ferritinopathy (HF), in which dysregulation of brain iron homeostasis is the primary cause of neurodegeneration. We mutagenized ferritin’s three-fold pores (3FPs), i.e. the main entry route for iron, to investigate ferritin’s iron management when iron must traverse the protein shell through the disrupted four-fold pores (4FPs) generated by mutations in the ferritin light chain (FtL) gene in HF. We assessed the structure and properties of ferritins using cryo-electron microscopy and a range of functional analyses in vitro. Loss of 3FP function did not alter ferritin structure but led to a decrease in protein solubility and iron storage. Abnormal 4FPs acted as alternate routes for iron entry and exit in the absence of functional 3FPs, further reducing ferritin iron-storage capacity. Importantly, even a small number of MtFtL subunits significantly compromises ferritin solubility and function, providing a rationale for the presence of ferritin aggregates in cell types expressing different levels of FtLs in patients with HF. These findings led us to discuss whether modifying pores could be used as a pharmacological target in HF.
Cancer education matters: a report on testicular cancer knowledge, awareness, and self-examination practice among young Polish men
Authors: Pietrzyk Łukasz , Denisow-Pietrzyk Marta , Czeczelewski Marcin , Ślizień-Kuczapski Konrad , Torres Kamil 
Published: November 2020

AbstractThe objective of the study was to assess the level of testicular cancer (TC) knowledge and awareness as well as the altitude and practice towards testicular self-examination (TSE) among Polish male high school and medical students. An original questionnaire survey was conducted in SE Poland with a representative sample of 1077 male students: 335 from high school and 742 medical students. The results indicate the knowledge about TC epidemiology and the awareness of risk factors responsible for the TC was low. The knowledge of the signs and symptoms of TC was significantly higher among the medical students, compared to the high school students. The level of education was associated with the awareness of methods for early detection and symptoms of TC. A satisfactory level of awareness of the TSE practice was exhibited only by the medical students. The main reason for not performing self-examination was the lack of knowledge and practical skills. The deficits of knowledge of TC in young men should motivate the education policy makers in Poland to implement education in the field of TC issues more widely in high schools. Moreover, cancer prevention modules and/or teaching methods should be improved in medical schools.
Rheometer enabled study of cartilage frequency-dependent properties
Authors: Perni Stefano , Prokopovich Polina 
Published: November 2020

AbstractDespite the well-established dependence of cartilage mechanical properties on the frequency of the applied load, most research in the field is carried out in either load-free or constant load conditions because of the complexity of the equipment required for the determination of time-dependent properties. These simpler analyses provide a limited representation of cartilage properties thus greatly reducing the impact of the information gathered hindering the understanding of the mechanisms involved in this tissue replacement, development and pathology. More complex techniques could represent better investigative methods, but their uptake in cartilage research is limited by the highly specialised training required and cost of the equipment. There is, therefore, a clear need for alternative experimental approaches to cartilage testing to be deployed in research and clinical settings using more user-friendly and financial accessible devices. Frequency dependent material properties can be determined through rheometry that is an easy to use requiring a relatively inexpensive device; we present how a commercial rheometer can be adapted to determine the viscoelastic properties of articular cartilage. Frequency-sweep tests were run at various applied normal loads on immature, mature and trypsinased (as model of osteoarthritis) cartilage samples to determine the dynamic shear moduli (G*, G′ G″) of the tissues. Moduli increased with increasing frequency and applied load; mature cartilage had generally the highest moduli and GAG depleted samples the lowest. Hydraulic permeability (KH) was estimated from the rheological data and decreased with applied load; GAG depleted cartilage exhibited higher hydraulic permeability than either immature or mature tissues. The rheometer-based methodology developed was validated by the close comparison of the rheometer-obtained cartilage characteristics (G*, G′, G″, KH) with results obtained with more complex testing techniques available in literature. Rheometry is relatively simpler and does not require highly capital intensive machinery and staff training is more accessible; thus the use of a rheometer would represent a cost-effective approach for the determination of frequency-dependent properties of cartilage for more comprehensive and impactful results for both healthcare professional and R&D.
Antagonistic effects of activin A and TNF-α on the activation of L929 fibroblast cells via Smad3-independent signaling
Authors: Jiang Lingling , Liu Boyang , Qi Yan , Zhu Linru , Cui Xueling , Liu Zhonghui 
Published: November 2020

AbstractFibroblasts play an important role in inflammation and tissue fibrosis. Both activin A and TNF-α can activate immune cells, however, the roles and relationship of them in activating fibroblasts in inflammation remain unclear. Here, this study revealed that TNF-α promoted the release of NO and IL-6 by L929 fibroblast cells, but co-treatment with activin A attenuated these effects. In contrast, activin A induced cell migration and increased the production of tissue fibrosis-related TGF-β1 and fibronectin, while TNF-α inhibited these function changes of L929 cells induced by activin A. Moreover, this study revealed that activin A and TNF-α regulated the activities of L929 cells via ERK1/2/MAPK pathway, rather than Smad3-dependent signaling pathway. Taken together, these data indicate that activin A and TNF-α exert mutually antagonistic effects on regulating fibroblasts activities, and the balance between their action may determine the process and outcome of fibroblasts-mediated inflammation.
Loading Imatinib inside targeted nanoparticles to prevent Bronchiolitis Obliterans Syndrome
Authors: Pandolfi Laura , Fusco Roberta , Frangipane Vanessa , D’Amico Ramona , Giustra Marco , Bozzini Sara , Morosini Monica , D’Amato Maura , Cova Emanuela , Ferrario Giuseppina , Morbini Patrizia , Colombo Miriam , Prosperi Davide , Viglio Simona , Piloni Davide , Di Paola Rosanna , Cuzzocrea Salvatore , Meloni Federica 
Published: November 2020

AbstractBronchiolitis Obliterans Syndrome seriously reduces long-term survival of lung transplanted patients. Up to now there is no effective therapy once BOS is established. Nanomedicine introduces the possibility to administer drugs locally into lungs increasing drug accumulation in alveola reducing side effects. Imatinib was loaded in gold nanoparticles (GNP) functionalized with antibody against CD44 (GNP-HCIm). Lung fibroblasts (LFs) were derived from bronchoalveolar lavage of BOS patients. GNP-HCIm cytotoxicity was evaluated by MTT assay, apoptosis/necrosis and phosphorylated-cAbl (cAbl-p). Heterotopic tracheal transplantation (HTT) mouse model was used to evaluate the effect of local GNP-HCIm administration by Alzet pump. GNP-HCIm decreased LFs viability compared to Imatinib (44.4 ± 1.8% vs. 91.8 ± 3.2%, p < 0.001), inducing higher apoptosis (22.68 ± 4.3% vs. 6.43 ± 0.29; p < 0.001) and necrosis (18.65 ± 5.19%; p < 0.01). GNP-HCIm reduced cAbl-p (0.41 GNP-HCIm, 0.24 Imatinib vs. to control; p < 0.001). GNP-HCIm in HTT mouse model by Alzet pump significantly reduced tracheal lumen obliteration (p < 0.05), decreasing apoptosis (p < 0.05) and TGF-β-positive signal (p < 0.05) in surrounding tissue. GNP-HCIm treatment significantly reduced lymphocytic and neutrophil infiltration and mast cells degranulation (p < 0.05). Encapsulation of Imatinib into targeted nanoparticles could be considered a new option to inhibit the onset of allograft rejection acting on BOS specific features.
PKN1 promotes synapse maturation by inhibiting mGluR-dependent silencing through neuronal glutamate transporter activation
Authors: Yasuda Hiroki , Yamamoto Hikaru , Hanamura Kenji , Mehruba Mona , Kawamata Toshio , Morisaki Hiromi , Miyamoto Masaaki , Takada Shinji , Shirao Tomoaki , Ono Yoshitaka , Mukai Hideyuki 
Published: November 2020

AbstractAbnormal metabotropic glutamate receptor (mGluR) activity could cause brain disorders; however, its regulation has not yet been fully understood. Here, we report that protein kinase N1 (PKN1), a protein kinase expressed predominantly in neurons in the brain, normalizes group 1 mGluR function by upregulating a neuronal glutamate transporter, excitatory amino acid transporter 3 (EAAT3), and supports silent synapse activation. Knocking out PKN1a, the dominant PKN1 subtype in the brain, unmasked abnormal input-nonspecific mGluR-dependent long-term depression (mGluR-LTD) and AMPA receptor (AMPAR) silencing in the developing hippocampus. mGluR-LTD was mimicked by inhibiting glutamate transporters in wild-type mice. Knocking out PKN1a decreased hippocampal EAAT3 expression and PKN1 inhibition reduced glutamate uptake through EAAT3. Also, synaptic transmission was immature; there were more silent synapses and fewer spines with shorter postsynaptic densities in PKN1a knockout mice than in wild-type mice. Thus, PKN1 plays a critical role in regulation of synaptic maturation by upregulating EAAT3 expression.
GRID2 Mutation-Related Spinocerebellar Ataxia Type 18: A New Report and Literature Review
Authors: Panda Prateek Kumar , Sharawat Indar Kumar , Dawman Lesa 
Published: November 2020

AbstractSpinocerebellar ataxias (SCAs) are heterogeneous disorders with multiple genetic etiology. Mutations in the GRID2 gene are associated with spinocerebellar ataxia type 18 (SCA-18). We report the first Indian case of SCA-18. The proband is a 7-year-old boy with motor delay, cerebellar signs, and cerebellar atrophy. Whole exome and direct sequencing identified compound heterozygous mutations of the coding and noncoding regions of the GRID2 gene. A literature review of the published cases with pathogenic GRID2 variants was performed. Beside our patients, 32 cases were identified. The majority of reported cases were males, of consanguineous kindreds, with autosomal recessive inheritance. However, a proportion of cases (39%) had autosomal dominant/semidominant inheritance with heterozygous variants. In addition to childhood-onset cerebellar ataxia, other reported features were: early-onset dementia, complicated spastic paraparesis, retinal dystrophy, hearing loss, lower motor neuron signs, and severe global developmental delay in some homozygous cases. Cerebellar atrophy was the commonest neuroimaging finding, with few cases demonstrating brain stem, supratentorial, and white matter abnormalities. Although SCA-18 should be suspected in patients with early-onset cerebellar ataxia, eye movement abnormalities, and motor delay, clinicians should be aware of late-onset, variable presentations with pyramidal signs, dementia, and hearing loss. In suspected cases, if mutations were not detected by whole-exome sequencing, direct sequencing of noncoding regions and chromosomal microarray should be considered.