bluuebunny/crossref_metadata_2025_split huggingface dataset:
The thiosemicarbazone Me2NNMe2 induces paraptosis by disrupting the ER thiol redox homeostasis based on protein disulfide isomerase inhibition
Authors: Hager Sonja , Korbula Katharina , Bielec Björn , Grusch Michael , Pirker Christine , Schosserer Markus , Liendl Lisa , Lang Magdalena , Grillari Johannes , Nowikovsky Karin , Pape Veronika F. S. , Mohr Thomas , Szakács Gergely , Keppler Bernhard K. , Berger Walter , Kowol Christian R. , Heffeter Petra 
Published: October 2018

AbstractDue to their high biological activity, thiosemicarbazones have been developed for treatment of diverse diseases, including cancer, resulting in multiple clinical trials especially of the lead compound Triapine. During the last years, a novel subclass of anticancer thiosemicarbazones has attracted substantial interest based on their enhanced cytotoxic activity. Increasing evidence suggests that the double-dimethylated Triapine derivative Me2NNMe2 differs from Triapine not only in its efficacy but also in its mode of action. Here we show that Me2NNMe2- (but not Triapine)-treated cancer cells exhibit all hallmarks of paraptotic cell death including, besides the appearance of endoplasmic reticulum (ER)-derived vesicles, also mitochondrial swelling and caspase-independent cell death via the MAPK signaling pathway. Subsequently, we uncover that the copper complex of Me2NNMe2 (a supposed intracellular metabolite) inhibits the ER-resident protein disulfide isomerase, resulting in a specific form of ER stress based on disruption of the Ca2+ and ER thiol redox homeostasis. Our findings indicate that compounds like Me2NNMe2 are of interest especially for the treatment of apoptosis-resistant cancer and provide new insights into mechanisms underlying drug-induced paraptosis.
Common mechanism of transcription termination at coding and noncoding RNA genes in fission yeast
Authors: Larochelle Marc , Robert Marc-Antoine , Hébert Jean-Nicolas , Liu Xiaochuan , Matteau Dominick , Rodrigue Sébastien , Tian Bin , Jacques Pierre-Étienne , Bachand François 
Published: October 2018

AbstractTermination of RNA polymerase II (RNAPII) transcription is a fundamental step of gene expression that is critical for determining the borders between genes. In budding yeast, termination at protein-coding genes is initiated by the cleavage/polyadenylation machinery, whereas termination of most noncoding RNA (ncRNA) genes occurs via the Nrd1–Nab3–Sen1 (NNS) pathway. Here, we find that NNS-like transcription termination is not conserved in fission yeast. Rather, genome-wide analyses show global recruitment of mRNA 3′ end processing factors at the end of ncRNA genes, including snoRNAs and snRNAs, and that this recruitment coincides with high levels of Ser2 and Tyr1 phosphorylation on the RNAPII C-terminal domain. We also find that termination of mRNA and ncRNA transcription requires the conserved Ysh1/CPSF-73 and Dhp1/XRN2 nucleases, supporting widespread cleavage-dependent transcription termination in fission yeast. Our findings thus reveal that a common mode of transcription termination can produce functionally and structurally distinct types of polyadenylated and non-polyadenylated RNAs.
DHX9 helicase promotes R-loop formation in cells with impaired RNA splicing
Authors: Chakraborty Prasun , Huang Jeffrey T. J. , Hiom Kevin 
Published: October 2018

AbstractR-loops are stable nucleic acid structures that have important physiological functions, but which also pose a significant threat to genomic stability. Increased R-loops cause replication stress and chromosome fragility and have been associated with diseases such as neurodegeneration and cancer. Although excessive R-loops are a feature of cells that are defective in RNA processing, what causes them to form is unclear. Here, we demonstrate that DHX9 (RNA helicase A) promotes the formation of pathological and non-pathological R-loops. In the absence of splicing factors, formation of R-loops correlates with the prolonged association of DHX9 with RNA Polymerase II (RNA Pol II). This leads to the production of DNA–RNA hybrid, which traps RNA Pol II on chromatin with the potential to block DNA replication. Our data provide a molecular mechanism for the formation of R-loops that is relevant to neurodegenerative diseases and cancers in which deregulated RNA processing is a feature.
The reaction of hydroxyl and methylperoxy radicals is not a major source of atmospheric methanol
Authors: Caravan Rebecca L. , Khan M. Anwar H. , Zádor Judit , Sheps Leonid , Antonov Ivan O. , Rotavera Brandon , Ramasesha Krupa , Au Kendrew , Chen Ming-Wei , Rösch Daniel , Osborn David L. , Fittschen Christa , Schoemaecker Coralie , Duncianu Marius , Grira Asma , Dusanter Sebastien , Tomas Alexandre , Percival Carl J. , Shallcross Dudley E. , Taatjes Craig A. 
Published: October 2018

AbstractMethanol is a benchmark for understanding tropospheric oxidation, but is underpredicted by up to 100% in atmospheric models. Recent work has suggested this discrepancy can be reconciled by the rapid reaction of hydroxyl and methylperoxy radicals with a methanol branching fraction of 30%. However, for fractions below 15%, methanol underprediction is exacerbated. Theoretical investigations of this reaction are challenging because of intersystem crossing between singlet and triplet surfaces – ∼45% of reaction products are obtained via intersystem crossing of a pre-product complex – which demands experimental determinations of product branching. Here we report direct measurements of methanol from this reaction. A branching fraction below 15% is established, consequently highlighting a large gap in the understanding of global methanol sources. These results support the recent high-level theoretical work and substantially reduce its uncertainties.
TRIP13 and APC15 drive mitotic exit by turnover of interphase- and unattached kinetochore-produced MCC
Authors: Kim Dong Hyun , Han Joo Seok , Ly Peter , Ye Qiaozhen , McMahon Moira A. , Myung Kyungjae , Corbett Kevin D. , Cleveland Don W. 
Published: October 2018

AbstractThe mitotic checkpoint ensures accurate chromosome segregation through assembly of the mitotic checkpoint complex (MCC), a soluble inhibitor of the anaphase-promoting complex/cyclosome (APC/C) produced by unattached kinetochores. MCC is also assembled during interphase by Mad1/Mad2 bound at nuclear pores, thereby preventing premature mitotic exit prior to kinetochore maturation and checkpoint activation. Using degron tagging to rapidly deplete the AAA+ ATPase TRIP13, we show that its catalytic activity is required to maintain a pool of open-state Mad2 for MCC assembly, thereby supporting mitotic checkpoint activation, but is also required for timely mitotic exit through catalytic disassembly of MCC. Strikingly, combining TRIP13 depletion with elimination of APC15-dependent Cdc20 ubiquitination/degradation results in a complete inability to exit mitosis, even when MCC assembly at unattached kinetochores is prevented. Thus, mitotic exit requires MCC produced either in interphase or mitosis to be disassembled by TRIP13-catalyzed removal of Mad2 or APC15-driven ubiquitination/degradation of its Cdc20 subunit.
Src regulates amino acid-mediated mTORC1 activation by disrupting GATOR1-Rag GTPase interaction
Authors: Pal Rituraj , Palmieri Michela , Chaudhury Arindam , Klisch Tiemo Jürgen , di Ronza Alberto , Neilson Joel R. , Rodney George G. , Sardiello Marco 
Published: October 2018

AbstractThe mechanistic target of rapamycin complex 1 (mTORC1) regulates cell survival and autophagy, and its activity is regulated by amino acid availability. Rag GTPase-GATOR1 interactions inhibit mTORC1 in the absence of amino acids, and GATOR1 release and activation of RagA/B promotes mTORC1 activity in the presence of amino acids. However, the factors that play a role in Rag-GATOR1 interaction are still poorly characterized. Here, we show that the tyrosine kinase Src is crucial for amino acid-mediated activation of mTORC1. Src acts upstream of the Rag GTPases by promoting dissociation of GATOR1 from the Rags, thereby determining mTORC1 recruitment and activation at the lysosomal surface. Accordingly, amino acid-mediated regulation of Src/mTORC1 modulates autophagy and cell size expansion. Finally, Src hyperactivation overrides amino acid signaling in the activation of mTORC1. These results shed light on the mechanisms underlying pathway dysregulation in many cancer types.
Enhanced diffusion by binding to the crosslinks of a polymer gel
Authors: Goodrich Carl P. , Brenner Michael P. , Ribbeck Katharina 
Published: October 2018

AbstractCreating a selective gel that filters particles based on their interactions is a major goal of nanotechnology, with far-reaching implications from drug delivery to controlling assembly pathways. However, this is particularly difficult when the particles are larger than the gel’s characteristic mesh size because such particles cannot passively pass through the gel. Thus, filtering requires the interacting particles to transiently reorganize the gel’s internal structure. While significant advances, e.g., in DNA engineering, have enabled the design of nano-materials with programmable interactions, it is not clear what physical principles such a designer gel could exploit to achieve selective permeability. We present an equilibrium mechanism where crosslink binding dynamics are affected by interacting particles such that particle diffusion is enhanced. In addition to revealing specific design rules for manufacturing selective gels, our results have the potential to explain the origin of selective permeability in certain biological materials, including the nuclear pore complex.
A cAMP/CRP-controlled mechanism for the incorporation of extracellular ADP-glucose in Escherichia coli involving NupC and NupG nucleoside transporters
Authors: Almagro Goizeder , Viale Alejandro M. , Montero Manuel , Muñoz Francisco José , Baroja-Fernández Edurne , Mori Hirotada , Pozueta-Romero Javier 
Published: October 2018

AbstractADP-glucose is the precursor of glycogen biosynthesis in bacteria, and a compound abundant in the starchy plant organs ingested by many mammals. Here we show that the enteric species Escherichia coli is capable of scavenging exogenous ADP-glucose for use as a glycosyl donor in glycogen biosynthesis and feed the adenine nucleotide pool. To unravel the molecular mechanisms involved in this process, we screened the E. coli single-gene deletion mutants of the Keio collection for glycogen content in ADP-glucose-containing culture medium. In comparison to wild-type (WT) cells, individual ∆nupC and ∆nupG mutants lacking the cAMP/CRP responsive inner-membrane nucleoside transporters NupC and NupG displayed reduced glycogen contents and slow ADP-glucose incorporation. In concordance, ∆cya and ∆crp mutants accumulated low levels of glycogen and slowly incorporated ADP-glucose. Two-thirds of the glycogen-excess mutants identified during screening lacked functions that underlie envelope biogenesis and integrity, including the RpoE specific RseA anti-sigma factor. These mutants exhibited higher ADP-glucose uptake than WT cells. The incorporation of either ∆crp, ∆nupG or ∆nupC null alleles sharply reduced the ADP-glucose incorporation and glycogen content initially witnessed in ∆rseA cells. Overall, the data showed that E. coli incorporates extracellular ADP-glucose through a cAMP/CRP-regulated process involving the NupC and NupG nucleoside transporters that is facilitated under envelope stress conditions.
Stimulus strength determines the BTK-dependence of the SHIP1-deficient phenotype in IgE/antigen-triggered mast cells
Authors: Zorn Carolin N. , Simonowski Anne , Huber Michael 
Published: October 2018

AbstractAntigen (Ag)-mediated crosslinking of IgE-loaded high-affinity receptors for IgE (FcεRI) on mast cells (MCs) triggers activation of proinflammatory effector functions relevant for IgE-associated allergic disorders. The cytosolic tyrosine kinase BTK and the SH2-containing inositol-5′-phosphatase SHIP1 are central positive and negative regulators of Ag-triggered MC activation, respectively, contrarily controlling Ca2+mobilisation, degranulation, and cytokine production. Using genetic and pharmacological techniques, we examined whether BTK activation inShip1−/− MCs is mandatory for the manifestation of the well-known hyperactive phenotype ofShip1−/− MCs. We demonstrate the prominence of BTK for theShip1−/− phenotype in a manner strictly dependent on the strength of the initial Ag stimulus; particular importance for BTK was identified inShip1−/− bone marrow-derived MCs in response to stimulation with suboptimal Ag concentrations. With respect to MAPK activation, BTK showed particular importance at suboptimal Ag concentrations, allowing for an analogous-to-digital switch resulting in full activation of ERK1/2 already at low Ag concentrations. Our data allow for a more precise definition of the role of BTK in FcεRI-mediated signal transduction and effector function in MCs. Moreover, they suggest that reduced activation or curtate expression of SHIP1 can be compensated by pharmacological inhibition of BTK andvice versa.
Estimation of Horizontal Eddy Heat Flux in Upper Mixed-Layer in the South China Sea by Using Satellite Data
Authors: Pan Jiayi , Sun Yujuan 
Published: October 2018

AbstractIn this study, the horizontal eddy heat flux in the upper mixed-layer in the South China Sea (SCS) is derived from satellite-derived observational data of sea surface height anomalies and optimally interpolated sea surface temperature, as well as a reanalysis dataset of mixed-layer depth. The long-term heat flux shows a northward transport on the west side of the SCS, comparable with that in the Kuroshio extension with strong eddy activities. The eddy flux in the SCS has a prominent semi-annual cycle and becomes the strongest in winter and summer with the inflow flux in the south and the outflow in the northwest into the East China Sea through the Taiwan Strait. The semi-annual cycle is related to the strong semi-annul variabilities of the velocity and the temperature in areas southeast of Vietnam and in the northern SCS, respectively. In some areas of the SCS, the eddy heat flux can reach more than ~ 60% of the mean flow heat flux. The convergence of the eddy flux indicates that heat accumulates southeast of Vietnam, which may result in heat storage increases in the upper mixed-layer.
Photocatalytic degradation of toxic aquatic pollutants by novel magnetic 3D-TiO2@HPGA nanocomposite
Authors: Santhosh Chella , Malathi A. , Daneshvar Ehsan , Kollu Pratap , Bhatnagar Amit 
Published: October 2018

AbstractIn this study, a series of photocatalysts were prepared, namely bare 3D-TiO2 (b-3D-T), magnetic 3D-TiO2: (m3D-T) and magnetic 3D-TiO2@Hierarchical Porous Graphene Aerogels (HPGA) nanocomposite: (m3D-T-HPGA NC) by solvothermal process. The prepared photocatalysts were analyzed by using X-ray diffraction (XRD), Field emission scanning electron microscope (FE-SEM), transmission electron microscope (TEM), Vibrating sample magnetometer (VSM), Brunauer–Emmett–Teller (BET) and Diffuse Reflectance Measurement – Ultraviolet (DRS-UV) to know their physical and chemical properties. The photocatalytic degradations of two toxic aquatic pollutants viz., Cr(VI) and bisphenol A (BPA) were tested by using the prepared photocatalysts. Parameters such as initial pollutant concentration, solution pH, photocatalyst dosage, wavelength and light intensity were investigated to optimize the process. The photocatalytic properties of prepared catalyst were analyzed based on the degradation of Cr(VI) and BPA under UV irradiation. The modified photocatalysts showed better performance as compared to b-3D-T photocatalyst. This better performance is ascribed to efficient charge transfer between b-3D-T nanoparticles to the porous graphene sheets. The maximum photocatalytic degradation of Cr(VI) was found to be 100% with m3D-T-HPGA NC within 140 min, whereas a removal efficacy of 100% and 57% was noticed in case of m3D-T and b-3D-T within 200 and 240 min, respectively. In the case of BPA, the maximum degradation efficiency was found to be 90% with m3D-T-HPGA NC within 240 min.
Porcine circovirus 2 (PCV-2) genetic variability under natural infection scenario reveals a complex network of viral quasispecies
Authors: Correa-Fiz Florencia , Franzo Giovanni , Llorens Anna , Segalés Joaquim , Kekarainen Tuija 
Published: October 2018

AbstractPorcine circovirus 2 (PCV-2) is a virus characterized by a high evolutionary rate, promoting the potential emergence of different genotypes and strains. Despite the likely relevance in the emergence of new PCV-2 variants, the subtle evolutionary patterns of PCV-2 at the individual-host level or over short transmission chains are still largely unknown. This study aimed to analyze the within-host genetic variability of PCV-2 subpopulations to unravel the forces driving PCV-2 evolution. A longitudinal weekly sampling was conducted on individual animals located in three farms after the first PCV-2 detection. The analysis of polymorphisms evaluated throughout the full PCV-2 genome demonstrated the presence of several single nucleotide polymorphisms (SNPs) especially in the genome region encoding for the capsid gene. The global haplotype reconstruction allowed inferring the virus transmission network over time, suggesting a relevant within-farm circulation. Evidences of co-infection and recombination involving multiple PCV-2 genotypes were found after mixing with pigs originating from other sources. The present study demonstrates the remarkable within-host genetic variability of PCV-2 quasispecies, suggesting the role of the natural selection induced by the host immune response in driving PCV-2 evolution. Moreover, the effect of pig management in multiple genotype coinfections occurrence and recombination likelihood was demonstrated.
Role of partial molar enthalpy of oxides on Soret effect in high-temperature CaO–SiO2 melts
Authors: Shimizu Masahiro , Matsuoka Jun , Kato Hiroshi , Kato Takeyuki , Nishi Masayuki , Visbal Heidy , Nagashima Kohji , Sakakura Masaaki , Shimotsuma Yasuhiko , Itasaka Hiroki , Hirao Kazuyuki , Miura Kiyotaka 
Published: October 2018

AbstractThe Soret effect or thermodiffusion is the temperature-gradient driven diffusion in a multicomponent system. Two important conclusions have been obtained for the Soret effect in multicomponent silicate melts: first, the SiO2 component concentrates in the hot region; and second, heavier isotopes concentrate in the cold region more than lighter isotopes. For the second point, the isotope fractionation can be explained by the classical mechanical collisions between pairs of particles. However, as for the first point, no physical model has been reported to answer why the SiO2 component concentrates in the hot region. We try to address this issue by simulating the composition dependence of the Soret effect in CaO–SiO2 melts with nonequilibrium molecular dynamics and determining through a comparison of the results with those calculated from the Kempers model that partial molar enthalpy is one of the dominant factors in this phenomenon.
Up-regulated miR-133a orchestrates epithelial-mesenchymal transition of airway epithelial cells
Authors: Chen Linjie , He Xiaobai , Xie Yan , Huang Yapei , Wolff Dennis W. , Abel Peter W. , Tu Yaping 
Published: October 2018

AbstractDysregulation of microRNAs (miRNAs) contributes to epithelial-mesenchymal transition (EMT) of cancer, but the pathological roles of miRNAs in airway EMT of lung diseases remains largely unknown. We performed sequencing and real-time PCR analysis of the miRNA expression profile of human airway epithelial cells undergoing EMT, and revealed miR-133a to be one of the most common up-regulated miRNAs. MiR-133a was previously reported to be persistently up-regulated in airway epithelial cells of smokers. We found that mice exposed to cigarette smoke (CS) showed airway hyper-responsiveness, a typical symptom occurring in CS-related lung diseases, up-regulation of miR-133a and EMT marker protein N-cadherin in airway epithelium. Importantly, miR-133a overexpression induces airway epithelial cells to undergo spontaneous EMT via down-regulation of grainyhead-like 2 (GRHL2), an epithelial specific transcriptional factor. Loss of GRHL2 causes down-regulation of epithelial splicing regulatory protein 1 (ESRP1), a central coordinator of alternative splicing processes that are critical in the regulation of EMT. Down-regulation of ESRP1 induces isoform switching of adherens junction-associated protein p120-catenin, and leads to the loss of E-cadherin. Our study is the first to demonstrate that up-regulated miR-133a orchestrates airway EMT via alternative splicing processes, which points to novel therapeutic possibilities for the treatment of CS-related lung disease.
Rational design W-doped Co-ZIF-9 based Co3S4 composite photocatalyst for efficient visible-light-driven photocatalytic H2 evolution
Authors: Wang Haiyu , jin Zhiliang 
Published: October 2018

Herein, a novel W doped Co3S4 composite photocatalyst was successfully prepared by MOF (metal organic framework), Co-ZIF-9, as a nanoscaled template via a hydrothermal treatment.
Ethical Considerations in Neurogenetic Testing
Authors: Su Xiaowei , Simmons Zachary 
Published: October 2018

AbstractRecent advances in the genetics of neurologic diseases coupled with improvements in sensitivity and specificity are making genetic testing an increasingly important part of diagnosis and management for neurologists. However, the complex nature of genetic testing, the nuances of multiple result types, and the short- and long-term consequences of genetic diagnoses raise important ethical issues for the clinician. Neurologists must balance the ethical principles of beneficence and nonmaleficence, on the one hand, with patient autonomy on the other hand, when ordering such tests by facilitating shared decision making, carrying out their fiduciary responsibilities to patients, and ensuring that patients have adequate counseling to make informed decisions. This review summarizes ethical issues related to genetic testing for neurologic diseases, with a focus on clinical practice. Informed consent for genetic testing of patients and asymptomatic at-risk family members is discussed. The roles and responsibilities of physicians as genetic counselors are reviewed, including the framing of incidental findings and variants of unknown significance that impact individuals' decisions about whether to pursue genetic testing and what results they wish to know. Disclosure and its consequences for the patient are placed within an ethical framework to permit a better understanding of why genetic testing is different from most other diagnostic testing ordered by physicians. The review ends with clinical vignettes that attempt to place ethical principles into familiar clinical settings involving physicians, patients and their families.
Ensuring Justice in Access to Investigational Neurological Drugs
Authors: Bateman-House Alison , Caplan Arthur , Kearns Lisa 
Published: October 2018

AbstractPatients who suffer from life-threatening illnesses or are stricken with conditions that could result in serious morbidity who have exhausted all appropriate treatments may choose to try, through the Food and Drug Administration's expanded access program, an investigational drug or device in development. The program has succeeded for decades in allowing patients to access potentially helpful but still experimental agents. Nevertheless, the administration of investigational drugs outside of clinical trials raises several ethical issues. Of particular concern are the validity of informed consent and the absence of a framework to ensure that experimental drugs are allocated justly and transparently. Although there are some safeguards to help protect the soundness of consent, little work to date has been done to guarantee that investigational medical products are allocated justly and transparently. We introduce a novel pilot project that seeks to address this issue.