bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activation of the reverse transsulfuration pathway through NRF2/CBS confers erastin-induced ferroptosis resistance
Authors: Liu Nan , Lin Xiaoli , Huang Chengying 
Published: December 2019

AbstractBackgroundFerroptosis is an iron-dependent, lipid peroxide-mediated cell death that may be exploited to selective elimination of damaged and malignant cells. Recent studies have identified that small-molecule erastin specifically inhibits transmembrane cystine–glutamate antiporter system xc−, prevents extracellular cystine import and ultimately causes ferroptosis in certain cancer cells. In this study, we aimed to investigate the molecular mechanism underlying erastin-induced ferroptosis resistance in ovarian cancer cells.MethodsWe treated ovarian cancer cells with erastin and examined cell viability, cellular ROS and metabolites of the transsulfuration pathway. We also depleted cystathionine β-synthase (CBS) and NRF2 to investigate the CBS and NRF2 dependency in erastin-resistant cells.ResultsWe found that prolonged erastin treatment induced ferroptosis resistance. Upon exposure to erastin, cells gradually adapted to cystine deprivation via sustained activation of the reverse transsulfuration pathway, allowing the cells to bypass erastin insult. CBS, the biosynthetic enzyme for cysteine, was constantly upregulated and was critical for the resistance. Knockdown of CBS by RNAi in erastin-resistant cells caused ferroptotic cell death, while CBS overexpression conferred ferroptosis resistance. We determined that the antioxidant transcriptional factor, NRF2 was constitutively activated in erastin-resistant cells and NRF2 transcriptionally upregulated CBS. Genetically repression of NRF2 enhanced ferroptosis susceptibility.ConclusionsBased on these results, we concluded that constitutive activation of NRF2/CBS signalling confers erastin-induced ferroptosis resistance. This study demonstrates a new mechanism underlying ferroptosis resistance, and has implications for the therapeutic response to erastin-induced ferroptosis.
Novel clinical and genetic insight into CXorf56-associated intellectual disability
Authors: Rocha Maria Eugenia , Silveira Tainá Regina Damaceno , Sasaki Erina , Sás Daíse Moreno , Lourenço Charles Marques , Kandaswamy Krishna K. , Beetz Christian , Rolfs Arndt , Bauer Peter , Reardon Willie , Bertoli-Avella Aida M. 
Published: December 2019

AbstractIntellectual disability (ID) is one of most frequent reasons for genetic consultation. The complex molecular anatomy of ID ranges from complete chromosomal imbalances to single nucleotide variant changes occurring de novo, with thousands of genes identified. This extreme genetic heterogeneity challenges the molecular diagnosis, which mostly requires a genomic approach. CXorf56 is largely uncharacterized and was recently proposed as a candidate ID gene based on findings in a single Dutch family. Here, we describe nine cases (six males and three females) from three unrelated families. Exome sequencing and combined database analyses, identified family-specific CXorf56 variants (NM_022101.3:c.498_503del, p.(Glu167_Glu168del) and c.303_304delCTinsACCC, p.(Phe101Leufs*20)) that segregated with the ID phenotype. These variants are presumably leading to loss-of-function, which is the proposed disease mechanism. Clinically, CXorf56-related disease is a slowly progressive neurological disorder. The phenotype is more severe in hemizygote males, but might also manifests in heterozygote females, which showed skewed X-inactivation patterns in blood. Male patients might present previously unreported neurological features such as epilepsy, abnormal gait, tremor, and clonus, which extends the clinical spectrum of the disorder. In conclusion, we confirm the causative role of variants in CXorf56 for an X-linked form of intellectual disability with additional neurological features. The gene should be considered for molecular diagnostics of patients with ID, specifically when family history is suggestive of X-linked inheritance. Further work is needed to understand the role of this gene in neurodevelopment and intellectual disability.
Atlas of quantitative single-base-resolution N6-methyl-adenine methylomes
Authors: Koh Casslynn W. Q. , Goh Yeek Teck , Goh W. S. Sho 
Published: December 2019

AbstractVarious methyltransferases and demethylases catalyse methylation and demethylation of N6-methyladenosine (m6A) and N6,2′-O-dimethyladenosine (m6Am) but precise methylomes uniquely mediated by each methyltransferase/demethylase are still lacking. Here, we develop m6A-Crosslinking-Exonuclease-sequencing (m6ACE-seq) to map transcriptome-wide m6A and m6Am at quantitative single-base-resolution. This allows for the generation of a comprehensive atlas of distinct methylomes uniquely mediated by every individual known methyltransferase or demethylase. Our atlas reveals METTL16 to indirectly impact manifold methylation targets beyond its consensus target motif and highlights the importance of precision in mapping PCIF1-dependent m6Am. Rather than reverse RNA methylation, we find that both ALKBH5 and FTO instead maintain their regulated sites in an unmethylated steady-state. In FTO’s absence, anomalous m6Am disrupts snRNA interaction with nuclear export machinery, potentially causing aberrant pre-mRNA splicing events.
Electronic heat flow and thermal shot noise in quantum circuits
Authors: Sivre E. , Duprez H. , Anthore A. , Aassime A. , Parmentier F. D. , Cavanna A. , Ouerghi A. , Gennser U. , Pierre F. 
Published: December 2019

AbstractWhen assembling individual quantum components into a mesoscopic circuit, the interplay between Coulomb interaction and charge granularity breaks down the classical laws of electrical impedance composition. Here we explore experimentally the thermal consequences, and observe an additional quantum mechanism of electronic heat transport. The investigated, broadly tunable test-bed circuit is composed of a micron-scale metallic node connected to one electronic channel and a resistance. Heating up the node with Joule dissipation, we separately determine, from complementary noise measurements, both its temperature and the thermal shot noise induced by the temperature difference across the channel. The thermal shot noise predictions are thereby directly validated, and the electronic heat flow is revealed. The latter exhibits a contribution from the channel involving the electrons’ partitioning together with the Coulomb interaction. Expanding heat current predictions to include the thermal shot noise, we find a quantitative agreement with experiments.
Deciphering protein evolution and fitness landscapes with latent space models
Authors: Ding Xinqiang , Zou Zhengting , Brooks III Charles L. 
Published: December 2019

AbstractProtein sequences contain rich information about protein evolution, fitness landscapes, and stability. Here we investigate how latent space models trained using variational auto-encoders can infer these properties from sequences. Using both simulated and real sequences, we show that the low dimensional latent space representation of sequences, calculated using the encoder model, captures both evolutionary and ancestral relationships between sequences. Together with experimental fitness data and Gaussian process regression, the latent space representation also enables learning the protein fitness landscape in a continuous low dimensional space. Moreover, the model is also useful in predicting protein mutational stability landscapes and quantifying the importance of stability in shaping protein evolution. Overall, we illustrate that the latent space models learned using variational auto-encoders provide a mechanism for exploration of the rich data contained in protein sequences regarding evolution, fitness and stability and hence are well-suited to help guide protein engineering efforts.
Hyperconjugative aromaticity and protodeauration reactivity of polyaurated indoliums
Authors: Xiao Kui , Zhao Yu , Zhu Jun , Zhao Liang 
Published: December 2019

AbstractAromaticity generally describes a cyclic structure composed of sp2-hybridized carbon or hetero atoms with remarkable stability and unique reactivity. The doping of even one sp3-hybridized atom often damages the aromaticity due to the interrupted electron conjugation. Here we demonstrate the occurrence of an extended hyperconjugative aromaticity (EHA) in a metalated indole ring which contains two gem-diaurated tetrahedral carbon atoms. The EHA-involved penta-aurated indolium shows extended electron conjugation because of dual hyperconjugation. Furthermore, the EHA-induced low electron density on the indolyl nitrogen atom enables a facile protodeauration reaction for the labile Au-N bond. In contrast, the degraded tetra-aurated indolium with a single gem-dimetalated carbon atom exhibits poor bond averaging and inertness in the protodeauration reaction. The aromaticity difference in such two polyaurated indoliums is discussed in the geometrical and electronic perspectives. This work highlights the significant effect of metalation on the aromaticity of polymetalated species.
Integrative systematics and ecology of a new deep-sea family of tanaidacean crustaceans
Authors: Błażewicz Magdalena , Jóźwiak Piotr , Jennings Robert M. , Studzian Maciej , Frutos Inmaculada 
Published: December 2019

AbstractA new family of paratanaoidean Tanaidacea – Paranarthrurellidae fam. nov. – is erected to accommodate two genera without family classification (Paratanaoideaincertae sedis), namelyArmatognathiaKudinova-Pasternak, 1987 andParanarthrurellaLang, 1971. Seven new species ofParanarthrurellaand two ofArmatognathiaare described from material taken in different deep-sea areas of the Atlantic and Pacific oceans. The type species ofParanarthrurella—P. caudata(Kudinova-Pasternak, 1965) — is redescribed based on the paratype. The genusCheliasetosatanaisLarsen and Araújo-Silva, 2014 originally classified within Colletteidae is synonymised withParanarthrurella, andArthrura shiinoiKudinova-Pasternak, 1973 is transferred toArmatognathia. Amended diagnoses ofArmatognathiaandParanarthrurellagenera are given. Choosing characters for distinguishing and defining both genera was supported by Principal Component Analysis. Designation of the new family is supported by molecular phylogenetic analysis of COI and 18S datasets. The distribution of all species currently included in the new family was visualised and their bathymetric distribution analysed.
Fuzhenghuayu Decoction ameliorates hepatic fibrosis by attenuating experimental sinusoidal capillarization and liver angiogenesis
Authors: Liu Hong-liang , Lv Jing , Zhao Zhi-min , Xiong An-ming , Tan Ye , Glenn Jeffrey S. , Tao Yan-yan , Weng Hong-lei , Liu Cheng-hai 
Published: December 2019

AbstractFuzhenghuayu (FZHY) is a compound extracted from natural plants. Its anti-fibrotic effect has been confirmed in experimental and clinical studies. However, precise effects and underlying mechanisms of FZHY in liver angiogenesis largely remain understood. In this study, we investigated the effects of FZHY on sinusoidal capillarization and angiogenesis with mice challenged for Carbon tetrachloride (CCl4) and dimethylnitrosamine (DMN), in vitro human hepatic sinusoidal endothelial cells (HHSEC) and Human Umbilical Vein Endothelial Cell (HUVEC) 3D fibrin gel model. Besides its anti-fibrotic effect, FZHY ameliorated CCl4 and DMN-induced sinusoidal capillarization, angiogenesis and expression of angiogenesis-associated factors, i.e. CD31, VEGF, VEGF receptor II, phosphor-ERK and HIF-1α. Consistent with the findings based on animal models, inhibitory effects of FZHY on capillarization and angiogenesis were further confirmed in HHSEC and the HUVEC 3D fibrin gel model, respectively. These data suggest that FZHY ameliorates not only liver fibrosis but also vessel remodeling in experimental models. Therefore, FZHY might be a potentially useful drug to treat liver cirrhosis in clinical practice.
The emissions of CO2 and other volatiles from the world’s subaerial volcanoes
Authors: Fischer Tobias P. , Arellano Santiago , Carn Simon , Aiuppa Alessandro , Galle Bo , Allard Patrick , Lopez Taryn , Shinohara Hiroshi , Kelly Peter , Werner Cynthia , Cardellini Carlo , Chiodini Giovanni 
Published: December 2019

AbstractVolcanoes are the main pathway to the surface for volatiles that are stored within the Earth. Carbon dioxide (CO2) is of particular interest because of its potential for climate forcing. Understanding the balance of CO2 that is transferred from the Earth’s surface to the Earth’s interior, hinges on accurate quantification of the long-term emissions of volcanic CO2 to the atmosphere. Here we present an updated evaluation of the world’s volcanic CO2 emissions that takes advantage of recent improvements in satellite-based monitoring of sulfur dioxide, the establishment of ground-based networks for semi-continuous CO2-SO2 gas sensing and a new approach to estimate key volcanic gas parameters based on magma compositions. Our results reveal a global volcanic CO2 flux of 51.3 ± 5.7 Tg CO2/y (11.7 × 1011 mol CO2/y) for non-eruptive degassing and 1.8 ± 0.9 Tg/y for eruptive degassing during the period from 2005 to 2015. While lower than recent estimates, this global volcanic flux implies that a significant proportion of the surface-derived CO2 subducted into the Earth’s mantle is either stored below the arc crust, is efficiently consumed by microbial activity before entering the deeper parts of the subduction system, or becomes recycled into the deep mantle to potentially form diamonds.
Plasma metabolomics in tuberculosis patients with and without concurrent type 2 diabetes at diagnosis and during antibiotic treatment
Authors: Vrieling Frank , Alisjahbana Bachti , Sahiratmadja Edhyana , van Crevel Reinout , Harms Amy C. , Hankemeier Thomas , Ottenhoff Tom H. M. , Joosten Simone A. 
Published: December 2019

AbstractTuberculosis (TB) and type 2 diabetes mellitus (DM), a major TB risk factor, are both accompanied by marked alterations in metabolic processes. Dissecting the specific metabolic changes induced by disease through metabolomics has shown potential to improve our understanding of relevant pathophysiological mechanisms of disease, which could lead to improved treatment. Targeted tandem liquid chromatography–mass spectrometry (LC-MS/MS) was used to compare amine and acylcarnitine levels in plasma samples of patients with TB or TB-DM from Indonesia at time of diagnosis and during antibiotic treatment. Partial least squares discrimination analysis (PLS-DA) showed good separation of patient groups. Amine levels were strongly altered in both disease groups compared to healthy controls, including low concentrations of citrulline and ornithine. Several amino acid ratios discriminated TB from controls (phenylalanine/histidine; citrulline/arginine; kynurenine/tryptophan), possibly reflecting changes in indoleamine-pyrrole 2,3-dioxygenase (IDO) and nitric oxide synthase (NOS) activity. Choline, glycine, serine, threonine and homoserine levels were lower in TB-DM compared to TB, and, in contrast to other analytes, did not normalize to healthy control levels during antibiotic treatment. Our results not only provide important validation of previous studies but also identify novel biomarkers, and significantly enhance our understanding of metabolic changes in human TB and TB-DM.
The perception of time is dynamically interlocked with the facial muscle activity
Authors: Fernandes Alexandre C. , Garcia-Marques Teresa 
Published: December 2019

AbstractTime perception relies on the motor system. Involves core brain regions of this system, including those associated with feelings generated from sensorimotor states. Perceptual timing is also distorted when movement occurs during timing tasks, possibly by interfering with sensorimotor afferent feedback. However, it is unknown if the perception of time is an active process associated with specific patterns of muscle activity. We explored this idea based on the phenomenon of electromyographic gradients, which consists of the dynamic increase of muscle activity during cognitive tasks that require sustained attention, a critical function in perceptual timing. We aimed to determine whether facial muscle dynamic activity indexes the subjective representation of time. We asked participants to judge stimuli durations (varying in familiarity) while we monitored the time course of the activity of the zygomaticus-major and corrugator-supercilii muscles, both associated with cognitive and affective feelings. The dynamic electromyographic activity in corrugator-supercilii over time reflected objective time and this relationship predicted subjective judgments of duration. Furthermore, the zygomaticus-major muscle signaled the bias that familiarity introduces in duration judgments. This suggests that subjective duration could be an embodiment process based in motor information changing over time and their associated feelings.
Virtual clinical trials identify effective combination therapies in ovarian cancer
Authors: Kozłowska Emilia , Vallius Tuulia , Hynninen Johanna , Hietanen Sakari , Färkkilä Anniina , Hautaniemi Sampsa 
Published: December 2019

AbstractA major issue in oncology is the high failure rate of translating preclinical results in successful clinical trials. Using a virtual clinical trial simulations approach, we present a mathematical framework to estimate the added value of combinatorial treatments in ovarian cancer. This approach was applied to identify effective targeted therapies that can be combined with the platinum-taxane regimen and overcome platinum resistance in high-grade serous ovarian cancer. We modeled and evaluated the effectiveness of three drugs that target the main platinum resistance mechanisms, which have shown promising efficacy in vitro, in vivo, and early clinical trials. Our results show that drugs resensitizing chemoresistant cells are superior to those aimed at triggering apoptosis or increasing the bioavailability of platinum. Our results further show that the benefit of using biomarker stratification in clinical trials is dependent on the efficacy of the drug and tumor composition. The mathematical framework presented herein is suitable for systematically testing various drug combinations and clinical trial designs in solid cancers.
Intracellular delivery of therapeutic antibodies into specific cells using antibody-peptide fusions
Authors: Gaston Julie , Maestrali Nicolas , Lalle Guilhem , Gagnaire Marie , Masiero Alessandro , Dumas Bruno , Dabdoubi Tarik , Radošević Katarina , Berne Pierre-François 
Published: December 2019

AbstractBecause of their favorable properties as macromolecular drugs, antibodies are a very successful therapeutic modality for interfering with disease-relevant targets in the extracellular space or at the cell membrane. However, a large number of diseases involve cytosolic targets and designing antibodies able to efficiently reach intracellular compartments would expand the antibody-tractable conditions. Here, we genetically fused cell penetrating peptides (CPPs) at various positions to an antibody targeting cancer cells, evaluated the developability features of the resulting antibody-peptide fusions and the ability of selected constructs to reach the cytosol. We first determined positions in the IgG structure that were permissive to CPP incorporation without destabilizing the antibody. Fusing CPPs to the C-terminus of the light chain and either before or after the hinge had the least effect on antibody developability features. These constructs were further evaluated for cell penetration efficiency. Two out of five tested CPPs significantly enhanced antibody penetration into the cytosol, in particular when fused before or after the hinge. Finally, we demonstrate that specific antibody binding to the cell surface target is necessary for efficient cell penetration of the CPP-antibody fusions. This study provides a solid basis for further exploration of therapeutic antibodies for intracellular targets.
Transscleral cyclophotocoagulation and its histological effects on the conjunctiva
Authors: Tan Nicholas Y. Q. , Ang Marcus , Chan Anita S. Y. , Barathi Veluchamy A. , Tham Clement C. , Barton Keith , Sng Chelvin C. A. 
Published: December 2019

AbstractMicropulse transscleral cyclophotocoagulation (MP-TCP) is increasingly being used as an initial procedure prior to conjunctival filtration surgeries. However, it is uncertain whether MP-TCP may cause inflammation and scarring of the bulbar conjunctiva. Thus, we aimed to study the histological effects of MP-TCP (compared to controls and continuous wave [CW]-TCP) on the conjunctiva. Our study included 10 Dutch Belted Rabbits that underwent TCP in their right eyes (n = 5, MP-TCP; n = 5, CW-TCP), while their left eyes served as controls. The rabbits were euthanised at 4 weeks, and their dissected globes underwent histopathological and immunohistochemical examination. We observed greater conjunctival inflammation in MP-TCP or CW-TCP-treated eyes compared to controls, but not between each other. The majority of the lymphocytic infiltrates were CD4 T-cells. Increased conjunctival fibrosis was evident in MP-TCP or CW-TCP-treated eyes, to similar extents, compared to controls. However, the increased staining for myofibroblasts was not statistically significant in TCP-treated eyes. We concluded that MP-TCP causes significantly greater overall conjunctival inflammation and scarring compared to controls, similar to CW-TCP. As these are risk-factors for fibrosis and failure of the conjunctival bleb, further studies are required to explore the effect, if any, of post-TCP conjunctival changes on future bleb morphology and survival.
Genome analysis of deep sea piezotolerant Nesiotobacter exalbescens COD22 and toluene degradation studies under high pressure condition
Authors: Ganesh Kumar A. , Mathew Noelin Chinnu , Sujitha K. , Kirubagaran R. , Dharani G. 
Published: December 2019

AbstractA marine isolate, Nesiotobacter exalbescens COD22, isolated from deep sea sediment (2100 m depth) was capable of degrading aromatic hydrocarbons. The Nesiotobacter sp. grew well in the presence of toluene at 0.1 MPa and 10 MPa at a rate of 0.24 h−1 and 0.12 h−1, respectively, in custom designed high pressure reactors. Percentage of hydrocarbon degradation was found to be 87.5% at ambient pressure and it reached 92% under high pressure condition within a short retention period of 72 h. The biodegradation of hydrocarbon was confirmed by the accumulation of dicarboxylic acid, benzoic acid, benzyl alcohol and benzaldehyde which are key intermediates in toluene catabolism. The complete genome sequence consists of 4,285,402 bp with 53% GC content and contained 3969 total coding genes. The complete genome analysis revealed unique adaptation and degradation capabilities for complex aromatic compounds, biosurfactant synthesis to facilitate hydrocarbon emulsification, advanced mechanisms for chemotaxis and presence of well developed flagellar assembly. The genomic data corroborated with the results of hydrocarbon biodegradation at high pressure growth conditions and confirmed the biotechnological potential of Nesiotobacter sp. towards bioremediation of hydrocarbon polluted deep sea environments.