bluuebunny/crossref_metadata_2025_split huggingface dataset:
Insights into the pathophysiology of DFNA10 hearing loss associated with novel EYA4 variants
Authors: Morín Matias , Borreguero Lucía , Booth Kevin T , Lachgar María , Huygen Patrick , Villamar Manuela , Mayo Fernando , Barrio Luis Carlos , Santos Serrão de Castro Luciana , Morales Carmelo , del Castillo Ignacio , Arellano Beatriz , Tellería Dolores , Smith Richard J. H. , Azaiez Hela , Moreno Pelayo M. A. 
Published: April 2020

AbstractThe mutational spectrum of many genes and their contribution to the global prevalence of hereditary hearing loss is still widely unknown. In this study, we have performed the mutational screening of EYA4 gene by DHLPC and NGS in a large cohort of 531 unrelated Spanish probands and one Australian family with autosomal dominant non-syndromic hearing loss (ADNSHL). In total, 9 novel EYA4 variants have been identified, 3 in the EYA4 variable region (c.160G > T; p.Glu54*, c.781del; p.Thr261Argfs*34 and c.1078C > A; p.Pro360Thr) and 6 in the EYA-HR domain (c.1107G > T; p.Glu369Asp, c.1122G > T; p.Trp374Cys, c.1281G > A; p.Glu427Glu, c.1282-1G > A, c.1601C > G; p.S534* and an heterozygous copy number loss encompassing exons 15 to 17). The contribution of EYA4 mutations to ADNSHL in Spain is, therefore, very limited (~1.5%, 8/531). The pathophysiology of some of these novel variants has been explored. Transient expression of the c-myc-tagged EYA4 mutants in mammalian COS7 cells revealed absence of expression of the p.S534* mutant, consistent with a model of haploinsufficiency reported for all previously described EYA4 truncating mutations. However, normal expression pattern and translocation to the nucleus were observed for the p.Glu369Asp mutant in presence of SIX1. Complementary in silico analysis suggested that c.1107G > T (p.Glu369Asp), c.1281G > A (p.Glu427Glu) and c.1282-1G > A variants alter normal splicing. Minigene assays in NIH3T3 cells further confirmed that all 3 variants caused exon skipping resulting in frameshifts that lead to premature stop codons. Our study reports the first likely pathogenic synonymous variant linked to DFNA10 and provide further evidence for haploinsufficiency as the common underlying disease-causing mechanism for DFNA10-related hearing loss.
MicroRNA-520f-3p inhibits proliferation of gastric cancer cells via targeting SOX9 and thereby inactivating Wnt signaling
Authors: Chen Jian-qing , Huang Zhi-ping , Li Hui-fen , Ou Yang-liu , Huo Feng , Hu Liang-kai 
Published: April 2020

AbstractMicroRNAs (miRNAs) are known to be important in a variety of cancer types. The specific expression and roles of miR-520f-3p in the context of gastric cancer (GC), however, remains unknown. Herein we determined miR-520f-3p expression to be significantly reduced in human GC cells compared to cells of the gastric epithelium, with comparable down-regulation also being evident in gastric cancer tissue samples and the low expression of this miRNA was positively correlated with features of more aggressive large tumor size (p = 0.019), depth of invasion (p = 0.008), and distant metastasis (p = 0.037). We further found that lower levels of miR-520f-3p corresponded with poorer GC patient overall (p = 0.003) and disease-free (p = 0.036) survival. When over-expressed in GC cells, miR-520f-3p was able to impair their growth, proliferation, and survival, instead leading to the induction of apoptosis. We further found that miR-520f-3p was able to bind the SOX9 3′-UTR, thereby negatively regulating its expression in GC cells. Consistent with this model, SOX9 and miR-520f-3p expression were negatively correlated with one another in GC tissues. When SOX9 was upregulated, this was also able to abrogate miR-520f-3p-mediated inactivation of Wnt/β-catenin signaling. Together our findings thus suggest that miR-520f-3p can act to suppress GC progression, at least in part via suppressing SOX9 expression and thus disrupting Wnt/β-catenin signaling. Our results thus highlight potential novel therapeutic targets in GC worthy of future investigation.
The SLC6A3 gene polymorphism is related to the development of attentional functions but not to ADHD
Authors: Kuc Katarzyna , Bielecki Maksymilian , Racicka-Pawlukiewicz Ewa , Czerwinski Michał B. , Cybulska-Klosowicz Anita 
Published: April 2020

AbstractNeuropharmacological and human clinical studies have suggested that the brain dopaminergic system is substantively involved in normal and pathological phenotypes of attention. Dopamine transporter gene (SLC6A3) was proposed as a candidate gene for Attention-Deficit/Hyperactivity Disorder (ADHD). We investigated the effect of theSLC6A3variants on cognitive performance in ADHD and healthy children and teenagers. Participants completed cognitive tasks measuring attentional switching, selective and sustained attention, and effectiveness of alerting, orienting and executive attention. We estimated the effects of 40 bp variable number of tandem repeat (VNTR) polymorphism located in the 3′ untranslated region (3′ UTR) (9-repeat vs 10-repeat allele) of theSLC6A3gene, ADHD diagnosis, age, and their interactions as predictors of cognitive performance. ADHD children demonstrated deficits in most of the examined attention processes, persistent within the examined age range (9–16 years). No significant effects were observed for the interaction of ADHD and theSLC6A3polymorphism, but the results revealed a significant main effect ofSLC6A3genotype in the entire research sample. Subjects carrying 9R allele performed the switching task significantly worse in comparison to children with 10R/10R or 10R/11R genotype.SLC6A3polymorphism moderated age-related improvements in orienting and attentional switching. Results suggest thatSLC6A3genotype influence these attentional/cognitive functions which deficits are not the key symptoms in ADHD.
Red List of vascular plants of Tajikistan – the core area of the Mountains of Central Asia global biodiversity hotspot
Authors: Nowak Arkadiusz , Świerszcz Sebastian , Nowak Sylwia , Hisorev Hikmat , Klichowska Ewelina , Wróbel Anna , Nobis Agnieszka , Nobis Marcin 
Published: April 2020

AbstractCentral Pamir-Alai, which is located almost entirely within the area of Tajikistan, is one of the world hotspots of biodiversity, harbouring ca. 4,300 species and 1,400 endemic plants. The first application of the IUCN Red List criteria reveals that among all native species occurring in Tajikistan 1,627 taxa (38.11%) are threatened, including 23 extinct (0.54%), 271 (6.34%) critically endangered (CR), 717 (16.79%) endangered (EN) and 639 (14.96%) vulnerable (VU). Globally, 20 taxa are extinct, 711 (16.65%) threatened, including 144 (3.37%) critically endangered, 322 (7.54%) endangered and 245 (5.73%) vulnerable. As we found positive correlation between human density and the number of threatened species, we suspect this indirect factor responsible for the species diversity decline. Extinct or threatened taxa have short blooming periods in spring or early summer, have limited geographical range and inhabit mainly valley bottoms at lower altitudes. Threatened taxa occupy extremely dry or wet habitats, such as deserts, semi-deserts, water reservoirs and fens. The group of threatened plants consists mostly of Central Asian, Indo-Indochinese and Arctic species. Ornamental plants have a higher extinction risk than other plants, but species collected for medicinal reasons and used for forage or food reveal lower retreatment rate. Our assessment fills a gap for important plant area and provides the data for raising the effectiveness of plant diversity conservation.
In vitro immune responses of human PBMCs against Candida albicans reveals fungal and leucocyte phenotypes associated with fungal persistence
Authors: Alvarez-Rueda Nidia , Rouges Célia , Touahri Adel , Misme-Aucouturier Barbara , Albassier Marjorie , Pape Patrice Le 
Published: April 2020

AbstractAlthough there is a growing understanding of immunity againstCandida albicans, efforts need to be pursued in order to decipher the cellular mechanisms leading to an uncontrolled immune response that eventually oppose disease eradication. We describe here significant intra- and inter-subject variations in immune response patterns of major human leucocyte subsets following anin vitrochallenge withC. albicansclinical isolates. We also observed that there areCandidaisolate-dependent changes in leucocyte phenotypes. Through a combination of multiple fungal growth and flow cytometric measurements, coupled to the tSNE algorithm, we showed that significant proliferation differences exist amongC. albicansisolates, leading to the calculation of a strain specific persistent index. Despite substantial inter-subject differences in T cells and stability of myeloid cells at baseline, our experimental approach highlights substantial immune cell composition changes and cytokine secretion profiles afterC. albicanschallenge. The significant secretion of IL-17 by CD66+ cells, IFN-γ and IL-10 by CD4+ T cells 2 days afterC. albicanschallenge was associated with fungal control. Fungal persistence was associated with delayed secretion of IFN-γ, IL-17, IL-4, TNF-α and IL-10 by myeloid cells and IL-4 and TNF-α secretion by CD4+ and CD8+ T cells. Overall, this experimental and analytical approach is available for the monitoring of such fungal and human immune responses.
Temperature and Size Effect on the Electrical Properties of Monolayer Graphene based Interconnects for Next Generation MQCA based Nanoelectronics
Authors: Debroy Sanghamitra , Sivasubramani Santhosh , Vaidya Gayatri , Acharyya Swati Ghosh , Acharyya Amit 
Published: April 2020

AbstractGraphene interconnects have been projected to out-perform Copper interconnects in the next generation Magnetic Quantum-dot Cellular Automata (MQCA) based nano-electronic applications. In this paper a simple two-step lithography process for patterning CVD monolayer graphene on SiO2/Si substrate has been used that resulted in the current density of one order higher magnitude as compared to the state-of-the-art graphene-based interconnects. Electrical performances of the fabricated graphene interconnects were evaluated, and the impact of temperature and size on the current density and reliability was investigated. The maximum current density of 1.18 ×108 A/cm2 was observed for 0.3 μm graphene interconnect on SiO2/Si substrate, which is about two orders and one order higher than that of conventionally used copper interconnects and CVD grown graphene respectively, thus demonstrating huge potential in outperforming copper wires for on-chip clocking. The drop in current at 473 K as compared to room temperature was found to be nearly 30%, indicating a positive temperature coefficient of resistivity (TCR). TCR for all cases were studied and it was found that with decrease in width, the sensitivity of temperature also reduces. The effect of resistivity on the breakdown current density was analysed on the experimental data using Matlab and found to follow the power-law equations. The breakdown current density was found to have a reciprocal relationship to graphene interconnect resistivity suggesting Joule heating as the likely mechanism of breakdown.
Gene-expression profiles of abdominal perivascular adipose tissue distinguish aortic occlusive from stenotic atherosclerotic lesions and denote different pathogenetic pathways
Authors: Piacentini Luca , Saccu Claudio , Bono Elisa , Tremoli Elena , Spirito Rita , Colombo Gualtiero Ivanoe , Werba José Pablo 
Published: April 2020

AbstractPerivascular adipose tissue (PVAT) helps regulate arterial homeostasis and plays a role in the pathogenesis of large vessel diseases. In this study, we investigated whether the PVAT of aortic occlusive lesions shows specific gene-expression patterns related to pathophysiology. By a genome-wide approach, we investigated the PVAT transcriptome in patients with aortoiliac occlusive disease. We compared the adipose layer surrounding the distal aorta (atherosclerotic lesion) with the proximal aorta (plaque-free segment), both within and between patients with complete aortoiliac occlusion (Oc) and low-grade aortic stenosis (St). We found that PVAT of the distal versus proximal aorta within both Oc- and St-patients lacks specific, locally restricted gene-expression patterns. Conversely, singular gene-expression profiles distinguished the PVAT between Oc- and St-patients. Functional enrichment analysis revealed that these signatures were associated with pathways related to metabolism of cholesterol, vessel tone regulation, and remodeling, including TGF-β and SMAD signaling. We finally observed that gene-expression profiles in omental-visceral or subcutaneous fat differentiated between Oc- and St-patients, suggesting that the overall adipose component associates with a different atherosclerosis burden. Our work points out the role of PVAT and, likely, other adipose tissues play in the pathophysiological mechanisms underlying atherosclerotic disease, including the abdominal aortic occlusive forms.
YAP Activity is Not Associated with Survival of Uveal Melanoma Patients and Cell Lines
Authors: Kim Yong Joon , Lee Sung Chul , Kim Sung Eun , Kim Seo Hee , Kim Sang Kyum , Lee Christopher Seungkyu 
Published: April 2020

AbstractRecent experimental studies have demonstrated an essential role for the Hippo-Yes-associated protein (YAP) pathway in GNAQ/GNA11-induced tumorigenesis in uveal melanoma (UM). However, the association between YAP activity and clinical outcomes remains elusive. We investigated possible associations between YAP activity and clinicopathological features including survival outcomes in patients with UM using The Cancer Genome Atlas (TCGA) cohort and our local cohort. We estimated YAP activity by mRNA expression levels, Gene Set Variation Analysis (GSVA) for the TCGA cohort, and immunohistochemical YAP staining for the local cohort. In the TCGA cohort, most clinicopathological features including tumor stage, mitotic counts, mutation of genes, and tumor sizes did not significantly differ between low and high YAP activity groups. In the local cohort, YAP nuclear-positive staining was observed in 30 (42%) of 72 patients with primary UM. UM-specific survival was not significantly different between tumors with low and high YAP activities. Unlike mesothelioma cells harboring a mutation of negative regulators of YAP, the survival of multiple UM cell lines was not significantly reduced by YAP/TAZ depletion. Our results suggest that the effect of YAP on development, growth, and invasion of UM in actual patients is less than previously demonstrated in experimental studies.
Molecular mechanism of the dual regulatory roles of ATP on the αγ heterodimer of human NAD-dependent isocitrate dehydrogenase
Authors: Sun Pengkai , Bai Tuya , Ma Tengfei , Ding Jianping 
Published: April 2020

AbstractHuman NAD-dependent isocitrate dehydrogenase (NAD-IDH) is responsible for the catalytic conversion of isocitrate into α-ketoglutarate in the Krebs cycle. This enzyme exists as the α2βγ heterotetramer composed of the αβ and αγ heterodimers. Our previous biochemical data showed that the αγ heterodimer and the holoenzyme can be activated by low concentrations of ATP but inhibited by high concentrations of ATP; however, the molecular mechanism was unknown. Here, we report the crystal structures of the αγ heterodimer with ATP binding only to the allosteric site (αMgγMg+CIT+ATP) and to both the allosteric site and the active site (αMg+ATPγMg+CIT+ATP). Structural data show that ATP at low concentrations can mimic ADP to bind to the allosteric site, which stabilizes CIT binding and leads the enzyme to adopt an active conformation, revealing why the enzyme can be activated by low concentrations of ATP. On the other hand, at high concentrations ATP is competitive with NAD for binding to the catalytic site. In addition, our biochemical data show that high concentrations of ATP promote the formation of metal ion-ATP chelates. This reduces the concentration of free metal ion available for the catalytic reaction, and thus further inhibits the enzymatic activity. The combination of these two effects accounts for the inhibition of the enzyme at high concentrations of ATP. Taken together, our structural and biochemical data reveal the molecular mechanism for the dual regulatory roles of ATP on the αγ heterodimer of human NAD-IDH.
Hydrogen sulfide increases copper-dependent neurotoxicityviaintracellular copper accumulation
Authors: Goto Norika , Hara Hirokazu , Kondo Mao , Yasuda Naomi , Kamiya Tetsuro , Okuda Kensuke , Adachi Tetsuo 
Published: April 2020

AbstractCopper (Cu) is an essential trace element and acts as a redox cofactor for many enzymes; however, excess Cu is toxic to cells. Hydrogen sulfide (H2S) is a well-known toxic gaseous molecule, but it has various biological effects such as neuromodulation and vasodilation. H2S was recently demonstrated to be involved in the detoxification of heavy metals, including zinc and cadmium, suggesting that H2S helps to maintain the homeostasis of heavy metals in cells. However, it is unclear how H2S impacts cellular Cu dynamics. In this study, we examined the effects of H2S on Cu cytotoxicity. Human neuroblastoma SH-SY5Y cells were exposed to CuSO4 in the presence of the H2S donor NaHS. CuSO4 alone slightly induced cell injury, whereas the combination of CuSO4 and NaHS (Cu/NaHS) increased Cu cytotoxicity. The Cu chelator bathocuproinedisulfonic acid mitigated Cu/NaHS-induced cytotoxicity. Compared with CuSO4 alone, Cu/NaHS markedly promoted ROS generation, mitochondrial dysfunction, and a decrease in ATP production. In addition, reporter assay using the metal responsive element (MRE)-driven reporter plasmid revealed that Cu/NaHS augmented Cu-dependent MRE activation. The amount of intracellular Cu was significantly higher in cells treated with Cu/NaHS than in those treated with CuSO4 alone. Moreover, Cu/NaHS markedly suppressed the level of the Cu exporter ATP7A, but not ATP7B, protein, whereas the combination did not affect that of the Cu importer CTR1 protein. Taken together, we conclude that the marked decrease in the ATP7A protein level by Cu/NaHS promotes intracellular Cu accumulation and leads to increased Cu cytotoxicity.
Psychische Probleme in der Pandemie – Beobachtungen während der COVID-19-Krise
Authors: Fatke Bastian , Hölzle Patricia , Frank Andreas , Förstl Hans 
Published: April 2020

AbstractWe have recently observed several clusters of psychiatric symptoms in the context of COVID-19: (1) increased anxiety in psychiatric in- and outpatients with different diagnoses; (2) more cases of domestic violence often associated with increased drug- or alcohol-consumption in offenders and victims; (3) a nihilistic “apocalyptic” syndrome of elderly patients cut-off from their families; (4) visual and acoustic hallucinoses due to pneumonia and sepsis-related confusional states. Cases of chloroquine-related toxicity have been reported elsewhere, but have not been observed in our hospital so far. Mental issues related to COVID-19 reported from China and practical recommendations are briefly summarized. Many patients with serious mental disorders will suffer world-wide due to a reallocation of medical, social and financial ressources.
Alkynyl Prins and Alkynyl Aza-Prins Annulations: Scope and Synthetic Applications
Authors: Frontier Alison J. , Abdul-Rashed Shukree , Holt Connor 
Published: April 2020

This review focuses on alkynyl Prins and alkynyl aza-Prins cyclization­ processes, which involve intramolecular coupling of an alkyne with either an oxocarbenium or iminium electrophile. The oxocarbenium or iminium species can be generated through condensation- or elimination-type processes, to achieve an overall bimolecular annulation that enables the synthesis of both oxygen- and nitrogen-containing­ saturated heterocycles with different ring sizes and substitution patterns. Also discussed are cascade processes in which alkynyl Prins heterocyclic adducts react to trigger subsequent pericyclic reactions, including [4+2] cycloadditions and Nazarov electrocyclizations, to rapidly construct complex small molecules. Finally, examples of the use of alkynyl Prins and alkynyl aza-Prins reactions in the synthesis of natural products are described. The review covers the literature through the end of 2019.1	Introduction1.1	Alkyne-Carbonyl Coupling Pathways1.2	Coupling/Cyclization Cascades Using the Alkynyl Prins Reaction2	Alkynyl Prins Annulation (Oxocarbenium Electrophiles)2.1	Early Work2.2	Halide as Terminal Nucleophile2.3	Oxygen as Terminal Nucleophile2.4	Arene as Terminal Nucleophile (Intermolecular)2.5	Arene Terminal Nucleophile (Intramolecular)2.6	Cyclizations Terminated by Elimination3	Synthetic Utility of Alkynyl Prins Annulation3.1	Alkynyl Prins-Mediated Synthesis of Dienes for a [4+2] Cyclo­-	addition­-Oxidation Sequence3.2	Alkynyl Prins Cyclization Adducts as Nazarov Cyclization Precursors3.3	Alkynyl Prins Cyclization in Natural Product Synthesis4	Alkynyl Aza-Prins Annulation4.1	Iminium Electrophiles4.2	Activated Iminium Electrophiles5	Alkynyl Aza-Prins Cyclizations in Natural Product Synthesis6	Summary and Outlook
Newborn Infant Parasympathetic Evaluation Index for the Assessment of Procedural Pain in Nonanesthetized Infants: A Multicenter Pilot Study
Authors: Walas Wojciech , Latka-Grot Julita , Maroszyńska Iwona , Malinowska Ewelina , Rutkowska Magdalena , Piotrowski Andrzej , Wrońska Monika , Szczapa Tomasz , Kubiaczyk Agata , Skrzypek Michał , De Jonckheere Julien , Halaba Zenon P. 
Published: April 2020

Abstract
Objective The aim of this study is to evaluate the ability of the Newborn Infant Parasympathetic Evaluation (NIPE) index to detect the response to nociceptive stimuli in nonanesthetized infants and to compare these results to simultaneous scoring by behavioral scales.
Study Design Thirty-six nonanesthetized infants admitted to neonatal/pediatric intensive care unit (N/PICUs) were enrolled to the study. Due to faulty records of the data, three patients had to be excluded. To detect pain caused by noxious stimuli, the heart-rate-variability-derived NIPE index and behavioral pain scales designed for measuring procedural pain in nonverbal children were used.
Results Forty-one painful events were available for analysis. We observed in the whole group a statistically significant decrease in NIPE values at 1, 2, and 3 minutes after a painful stimulus, in comparison to the NIPE value at rest and the statistically significant differences between the minimum NIPE value within 3 minutes after the stimulus in comparison to NIPE value at rest in the whole group, as well as in the subgroups of moderate and severe pain. Receiver operating characteristic (ROC) analysis has shown the strong sensitivity and specificity of the NIPE in detecting the noxious stimuli (ROC AUC: 0.767). We also found that the stronger the sensation of pain was, the more rapidly NIPE reached its lowest value.
Discussion Our study indicates that the painful procedures are associated with a significant decrease in the NIPE value within 3 minutes after a noxious stimulus. Based on our observation, the minimum value within 3 minutes from the painful procedure seems to be the most distinctive value.
PSGL-1 restricts HIV-1 infectivity by blocking virus particle attachment to target cells
Authors: Fu Yajing , He Sijia , Waheed Abdul A. , Dabbagh Deemah , Zhou Zheng , Trinité Benjamin , Wang Zhao , Yu Jieshi , Wang Dan , Li Feng , Levy David N. , Shang Hong , Freed Eric O. , Wu Yuntao 
Published: April 2020

Significance
PSGL-1 and CD43 are surface glycoproteins expressed on blood CD4 T cells to bind to selectins for T cell tethering, rolling, and migration into inflamed tissues. The PSGL-1 level is greatly up-regulated during inflammation. Here we found that PSGL-1 and CD43 expression inhibits HIV spreading infection. Mechanistically, PSGL-1 blocks the binding of virus particles to target cells. PSGL-1–mediated suppression of virus infectivity extends to another retrovirus—murine leukemia virus—and to influenza A virus. These results further our understanding of virus–host interactions and help elucidate mechanisms by which cellular host factors regulate viral infection and pathogenesis.