bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predicting long-term disease control in transplant-ineligible patients with multiple myeloma: impact of an MGUS-like signature
Authors: Rodríguez-Otero Paula , Mateos María Victoria , Martínez-López Joaquín , Hernández Miguel-Teodoro , Ocio Enrique M. , Rosiñol Laura , Martínez Rafael , Teruel Ana-Isabel , Gutiérrez Norma C. , Bargay Joan , Bengoechea Enrique , González Yolanda , de Oteyza Jaime Pérez , Gironella Mercedes , Nuñez-Córdoba Jorge M. , Encinas Cristina , Martín Jesús , Cabrera Carmen , Palomera Luis , de Arriba Felipe , Cedena María Teresa , Puig Noemí , Oriol Albert , Paiva Bruno , Bladé Joan , Lahuerta Juan José , San Miguel Jesús F. 
Published: March 2019

AbstractDisease control at 5 years would be a desirable endpoint for elderly multiple myeloma (MM) patients, but biomarkers predicting this are not defined. Therefore, to gain further insights in this endpoint, a population of 498 newly diagnosed transplant-ineligible patients enrolled in two Spanish trials (GEM2005MAS65 and GEM2010MAS65), has been analyzed. Among the 435 patients included in this post-hoc study, 18.6% remained alive and progression free after 5 years of treatment initiation. In these patients, overall survival (OS) rate at 10 years was 60.8% as compared with 11.8% for those progressing within the first 5 years. Hemoglobin (Hb) ≥ 12 g/dl (OR 2.74, p = 0.001) and MGUS-like profile (OR 4.18, p = 0.005) were the two baseline variables associated with long-term disease-free survival. Upon including depth of response (and MRD), Hb ≥ 12 g/dl (OR 2.27) and MGUS-like signature (OR 7.48) retained their predictive value along with MRD negativity (OR 5.18). This study shows that despite the use of novel agents, the probability of disease control at 5 years is still restricted to a small fraction (18.6%) of elderly MM patients. Since this endpoint is associated with higher rates of OS, this study provides important information about diagnostic and post-treatment biomarkers helpful in predicting the likelihood of disease control at 5 years.
LRRK2 deficiency induced mitochondrial Ca2+ efflux inhibition can be rescued by Na+/Ca2+/Li+ exchanger upregulation
Authors: Ludtmann Marthe H. R. , Kostic Marko , Horne Amy , Gandhi Sonia , Sekler Israel , Abramov Andrey Y. 
Published: March 2019

AbstractVariants of leucine-rich repeat kinase 2 (lrrk2) are associated with an increased risk in developing Parkinson’s disease (PD). Mitochondrial dysfunction and specifically mitochondrial Ca2+ handling has been linked to the pathogenesis of PD. Here we describe for the second time a mitochondrial Ca2+ efflux deficiency in a model displaying alterations in a PD-associated risk protein. LRRK2 deletion, inhibition and mutations led to an impaired mitochondrial Ca2+ extrusion via Na+/Ca2+/Li+ exchanger (NCLX) which in turn lowered mitochondrial permeability transition pore (PTP) opening threshold and increased cell death. The mitochondrial membrane potential was found not to be the underlying cause for the Ca2+ extrusion deficiency. NCLX activity was rescued by a direct (phosphomimetic NCLX mutant) and indirect (protein kinase A) activation which in turn elevated the PTP opening threshold. Therefore, at least two PD-associated risk protein pathways appear to converge on NCLX controlling mitochondrial Ca2+ extrusion and therefore mitochondrial health. Since mitochondrial Ca2+ overload has been described in many neurological disorders this study warrants further studies into NCLX as a potential therapeutic target.
TIAM1 promotes chemoresistance and tumor invasiveness in colorectal cancer
Authors: Izumi Daisuke , Toden Shusuke , Ureta Elsie , Ishimoto Takatsugu , Baba Hideo , Goel Ajay 
Published: March 2019

AbstractAccumulating evidence suggests that cancer cells with stem cell-like features have higher resistance to chemotherapeutic agents. Herein, we identified T-lymphoma invasion and metastasis-inducing protein-1 (TIAM1) as one of the Wnt-signaling associated genes which drives self-renewal and its expression is upregulated by cancer associated fibroblasts (CAFs). TIAM1 expression was assessed in resected colorectal cancer (CRC) tissues from 300 patients who did or did not respond to chemotherapy. siRNA and CRISPR/Cas9 was used to examine whether the inhibition of TIAM1 affects chemosensitivity of CRC. We demonstrate that stemness through Wnt signaling regulates chemosensitivity and this phenomenon occurs exclusively in cancer stem cells. Subsequently, we established patient-derived CAFs and tested whether the drug sensitivity of CRC cell lines is altered with CAF-derived conditioned medium. High-TIAM1 expression correlated significantly with poor prognosis of CRC patients, and was overexpressed in patients who did not respond to chemotherapy. We demonstrated that the inhibition of TIAM1 enhanced sensitivity to chemotherapeutic drugs and reduced tumor invasiveness in a series of experiments in vitro. Moreover, CAF-derived conditioned media increased stemness and chemoresistance in CRC cell lines through TIAM1 overexpression. In addition, we validated TIAM1 associated drug sensitivity using a xenograft model. We have demonstrated that TIAM1 is overexpressed in CRC tumors from patients who did not respond to chemotherapeutic drugs and levels of TIAM1 expression served as an independent prognostic factor. Mechanistically, CAFs enhanced CRC chemoresistance through TIAM1 overexpression. Collectively, these results suggest that TIAM1 regulates chemosensitivity in tumors and stroma and thus may be an attractive therapeutic target.
von Hippel-Lindau mutants in renal cell carcinoma are regulated by increased expression of RSUME
Authors: Tedesco Lucas , Elguero Belén , Pacin David Gonilski , Senin Sergio , Pollak Cora , Garcia Marchiñena Patricio A. , Jurado Alberto M. , Isola Mariana , Labanca María J. , Palazzo Martin , Yankilevich Patricio , Fuertes Mariana , Arzt Eduardo 
Published: March 2019

AbstractRenal cell carcinoma (RCC) is the major cause of death among patients with von Hippel-Lindau (VHL) disease. Resistance to therapies targeting tumor angiogenesis opens the question about the underlying mechanisms. Previously we have described that RWDD3 or RSUME (RWD domain-containing protein SUMO Enhancer) sumoylates and binds VHL protein and negatively regulates HIF degradation, leading to xenograft RCC tumor growth in mice. In this study, we performed a bioinformatics analysis in a ccRCC dataset showing an association of RSUME levels with VHL mutations and tumor progression, and we demonstrate the molecular mechanism by which RSUME regulates the pathologic angiogenic phenotype of VHL missense mutations. We report that VHL mutants fail to downregulate RSUME protein levels accounting for the increased RSUME expression found in RCC tumors. Furthermore, we prove that targeting RSUME in RCC cell line clones carrying missense VHL mutants results in decreased early tumor angiogenesis. The mechanism we describe is that RSUME sumoylates VHL mutants and beyond its sumoylation capacity, interacts with Type 2 VHL mutants, reduces HIF-2α-VHL mutants binding, and negatively regulates the assembly of the Type 2 VHL, Elongins and Cullins (ECV) complex. Altogether these results show RSUME involvement in VHL mutants deregulation that leads to the angiogenic phenotype of RCC tumors.
Generic synthesis of small-sized hollow mesoporous organosilica nanoparticles for oxygen-independent X-ray-activated synergistic therapy
Authors: Fan Wenpei , Lu Nan , Shen Zheyu , Tang Wei , Shen Bo , Cui Zhaowen , Shan Lingling , Yang Zhen , Wang Zhantong , Jacobson Orit , Zhou Zijian , Liu Yijing , Hu Ping , Yang Weijing , Song Jibin , Zhang Yang , Zhang Liwen , Khashab Niveen M. , Aronova Maria A. , Lu Guangming , Chen Xiaoyuan 
Published: March 2019

AbstractThe success of radiotherapy relies on tumor-specific delivery of radiosensitizers to attenuate hypoxia resistance. Here we report an ammonia-assisted hot water etching strategy for the generic synthesis of a library of small-sized (sub-50 nm) hollow mesoporous organosilica nanoparticles (HMONs) with mono, double, triple, and even quadruple framework hybridization of diverse organic moieties by changing only the introduced bissilylated organosilica precursors. The biodegradable thioether-hybridized HMONs are chosen for efficient co-delivery of tert-butyl hydroperoxide (TBHP) and iron pentacarbonyl (Fe(CO)5). Distinct from conventional RT, radiodynamic therapy (RDT) is developed by taking advantage of X-ray-activated peroxy bond cleavage within TBHP to generate •OH, which can further attack Fe(CO)5 to release CO molecules for gas therapy. Detailed in vitro and in vivo studies reveal the X-ray-activated cascaded release of •OH and CO molecules from TBHP/Fe(CO)5 co-loaded PEGylated HMONs without reliance on oxygen, which brings about remarkable destructive effects against both normoxic and hypoxic cancers.
Network-based prediction of protein interactions
Authors: Kovács István A. , Luck Katja , Spirohn Kerstin , Wang Yang , Pollis Carl , Schlabach Sadie , Bian Wenting , Kim Dae-Kyum , Kishore Nishka , Hao Tong , Calderwood Michael A. , Vidal Marc , Barabási Albert-László 
Published: March 2019

AbstractDespite exceptional experimental efforts to map out the human interactome, the continued data incompleteness limits our ability to understand the molecular roots of human disease. Computational tools offer a promising alternative, helping identify biologically significant, yet unmapped protein-protein interactions (PPIs). While link prediction methods connect proteins on the basis of biological or network-based similarity, interacting proteins are not necessarily similar and similar proteins do not necessarily interact. Here, we offer structural and evolutionary evidence that proteins interact not if they are similar to each other, but if one of them is similar to the other’s partners. This approach, that mathematically relies on network paths of length three (L3), significantly outperforms all existing link prediction methods. Given its high accuracy, we show that L3 can offer mechanistic insights into disease mechanisms and can complement future experimental efforts to complete the human interactome.
Effects of infection history on dengue virus infection and pathogenicity
Authors: Tsang Tim K. , Ghebremariam Samson L. , Gresh Lionel , Gordon Aubree , Halloran M. Elizabeth , Katzelnick Leah C. , Rojas Diana Patricia , Kuan Guillermina , Balmaseda Angel , Sugimoto Jonathan , Harris Eva , Longini Ira M. , Yang Yang 
Published: March 2019

AbstractThe understanding of immunological interactions among the four dengue virus (DENV) serotypes and their epidemiological implications is often hampered by the lack of individual-level infection history. Using a statistical framework that infers full infection history, we analyze a prospective pediatric cohort in Nicaragua to characterize how infection history modulates the risks of DENV infection and subsequent clinical disease. After controlling for age, one prior infection is associated with 54% lower, while two or more are associated with 91% higher, risk of a new infection, compared to DENV-naive children. Children >8 years old have 55% and 120% higher risks of infection and subsequent disease, respectively, than their younger peers. Among children with ≥1 prior infection, intermediate antibody titers increase, whereas high titers lower, the risk of subsequent infection, compared with undetectable titers. Such complex dependency needs to be considered in the design of dengue vaccines and vaccination strategies.
Clonal architectures predict clinical outcome in clear cell renal cell carcinoma
Authors: Huang Yi , Wang Jiayin , Jia Peilin , Li Xiangchun , Pei Guangsheng , Wang Changxi , Fang Xiaodong , Zhao Zhongming , Cai Zhiming , Yi Xin , Wu Song , Zhang Baifeng 
Published: March 2019

AbstractThe genetic landscape of clear cell renal cell carcinoma (ccRCC) had been investigated extensively but its evolution patterns remained unclear. Here we analyze the clonal architectures of 473 patients from three different populations. We find that the mutational signatures vary substantially across different populations and evolution stages. The evolution patterns of ccRCC have great inter-patient heterogeneities, with del(3p) being regarded as the common earliest event followed by three early departure points: VHL and PBRM1 mutations, del(14q) and other somatic copy number alterations (SCNAs) including amp(7), del(1p) and del(6q). We identify three prognostic subtypes of ccRCC with distinct clonal architectures and immune infiltrates: long-lived patients, enriched with VHL but depleted of BAP1 mutations, have high levels of Th17 and CD8+ T cells while short-lived patients with high burden of SCNAs have high levels of Tregs and Th2 cells, highlighting the importance of evaluating evolution patterns in the clinical management of ccRCC.
Nitric oxide-dependent anaerobic ammonium oxidation
Authors: Hu Ziye , Wessels Hans J. C. T. , van Alen Theo , Jetten Mike S. M. , Kartal Boran 
Published: March 2019

AbstractNitric oxide (NO) has important functions in biology and atmospheric chemistry as a toxin, signaling molecule, ozone depleting agent and the precursor of the greenhouse gas nitrous oxide (N2O). Although NO is a potent oxidant, and was available on Earth earlier than oxygen, it is unclear whether NO can be used by microorganisms for growth. Anaerobic ammonium-oxidizing (anammox) bacteria couple nitrite reduction to ammonium oxidation with NO and hydrazine as intermediates, and produce N2 and nitrate. Here, we show that the anammox bacterium Kuenenia stuttgartiensis is able to grow in the absence of nitrite by coupling ammonium oxidation to NO reduction, and produce only N2. Under these growth conditions, the transcription of proteins necessary for NO generation is downregulated. Our work has potential implications in the control of N2O and NO emissions from natural and manmade ecosystems, where anammox bacteria contribute significantly to N2 release to the atmosphere. We hypothesize that microbial NO-dependent ammonium oxidation may have existed on early Earth.
Estimation of microbial phosphate-accumulation abilities
Authors: Anand Ajeeta , Aoyagi Hideki 
Published: March 2019

AbstractPhosphate binders and dialysis can have harmful side-effects during the treatments of hyperphosphatemia. Therefore, we evaluated the capability of intestinal bacteria (lactic acid bacteria and bifidobacteria) as phosphate-accumulating organisms (PAOs) for phosphate accumulation, with the aim of determining whether PAO-formulated food can prevent hyperphosphatemia in the early stages. However, methods for estimating microbial phosphate-accumulation capacities require significant improvements regarding specificity, cost, and simplicity. The presented method analyzed cell-free broth to assess the phosphate accumulation capability of cells. Active cells and the constructed phosphate-deficient cells were incubated in assay salt media. After incubation, phosphate-deficient cell-free broth was taken as sample and the blank was the active cell-free broth. Therefore, effects of interfering agents and other metabolites were avoided and enhanced the specificity remarkably. Phosphate contents were assessed by reactions with toluidine blue O. In contrast to the case in previous studies, the shift in the first absorbance peak was found to be inversely proportional to the phosphate concentration. The minimum detectable phosphate concentrations for the 11th isolate of Lactobacillus casei JCM 1134 and 8th isolate of Bifidobacterium adolescentis JCM 1275 were determined to be 1.24 and 0.4 mg/L, respectively. Further, the validation results were found to be significant (p-value < 0.05).
Low oxygen post conditioning prevents thalamic secondary neuronal loss caused by excitotoxicity after cortical stroke
Authors: Pietrogrande Giovanni , Zalewska Katarzyna , Zhao Zidan , Abdolhoseini Mahmoud , Chow Wei Zhen , Sanchez-Bezanilla Sonia , Ong Lin Kooi , Johnson Sarah J. , Nilsson Michael , Walker Frederick R. 
Published: March 2019

AbstractIn the current study, we were interested in investigating whether Low oxygen post-conditioning (LOPC) was capable of limiting the severity of stroke-induced secondary neurodegeneration (SND). To investigate the effect of LOPC we exposed adult male C57/BL6 mice to photothrombotic occlusion (PTO) of the motor and somatosensory cortex. This is known to induce progressive neurodegeneration in the thalamus within two weeks of infarction. Two days after PTO induction mice were randomly assigned to one of four groups: (i) LOPC-15 day exposure group; (ii) a LOPC 15 day exposure followed by a 15 day exposure to normal atmosphere; (iii) normal atmosphere for 15 days and (iv) normal atmosphere for 30 days (n = 20/group). We observed that LOPC reduced the extent of neuronal loss, as indicated by assessment of both area of loss and NeuN+ cell counts, within the thalamus. Additionally, we identified that LOPC reduced microglial activity and decreased activity within the excitotoxic signalling pathway of the NMDAR axis. Together, these findings suggest that LOPC limits neuronal death caused by excitotoxicity in sites of secondary damage and promotes neuronal survival. In conclusion, this work supports the potential of utilising LOPC to intervene in the sub-acute phase post-stroke to restrict the severity of SND.
Norcorrole as a Delocalized, Antiaromatic System
Authors: Conradie Jeanet , Foroutan-Nejad Cina , Ghosh Abhik 
Published: March 2019

AbstractNickel norcorrole provides an unusual example of a molecule that is strongly antiaromatic according to the magnetic criterion, but which exhibits, according to high-quality DFT calculations, a symmetric, delocalized structure with no difference in bond length between adjacent Cmeso-Cα bonds. A fragment molecular orbital analysis suggests that these discordant observations are a manifestation of the high stability of the dipyrrin fragments, which retain their electronic and structural integrity even as part of the norcorrole ring system.
Sex-specific Effects of Music Listening on Couples’ Stress in Everyday Life
Authors: Wuttke-Linnemann A. , Nater U. M. , Ehlert U. , Ditzen B. 
Published: March 2019

AbstractMusic listening in daily life is associated with stress-reducing effects on the individual with increasing effects when music listening occurs in a social context. As little is known about effects on couples, we investigated whether beneficial effects can be found in couples. Forty heterosexual couples were investigated using ambulatory assessment. Participants completed six assessments on music listening and subjective stress per day for five consecutive days. With each assessment, saliva samples for the later analysis of cortisol and alpha-amylase were collected. Music listening affected biopsychological stress markers in women and men, however in different ways: While music listening reduced cortisol in women, it increased alpha-amylase in men. Dyadic effects of music listening on stress markers were found. Men showed lower secretion of cortisol if women listened to music which was more pronounced when couples shared musical preferences. Both men and women showed higher alpha-amylase activity when their partner had listened to music. Music listening influences couples’ psychobiological stress levels in a sex-dependent manner with evidence of dyadic co-variation in physiological responses to music. Interventions for promoting stress reduction should consider that women and men differ in their use of music in everyday life.
Fabrication of capacitive pressure sensor using single crystal diamond cantilever beam
Authors: Fu Jiao , Zhu Tianfei , Liang Yan , Liu Zhangcheng , Wang Ruozheng , Zhang Xiaofan , Wang Hong-Xing 
Published: March 2019

AbstractFabrication of single crystal diamond capacitive pressure sensor is presented. Firstly, the single crystal diamond cantilever beam was formed on HPHT diamond substrate by using selective high-energy ion implantation, metal patterning, ICP etching and electrochemical etching techniques. Secondly, on this diamond cantilever beam, the desired electrode patterns were processed with photolithography and metal evaporation methods. Furthermore, the displacements of cantilever beam under different pressure conditions were investigated by atomic force microscopy. The capacitance-voltage curves of single crystal diamond cantilever beam and substrate under different force loading conditions were measured by using Agilent B1505A parameter analyzer. The results show that sensitivity increases with the enlargement of electrode area of cantilever beam, and decreases with the rise of measurement frequency.
The deubiquitinating enzyme USP25 binds tankyrase and regulates trafficking of the facilitative glucose transporter GLUT4 in adipocytes
Authors: Sadler Jessica B. A. , Lamb Christopher A. , Welburn Cassie R. , Adamson Iain S. , Kioumourtzoglou Dimitrios , Chi Nai-Wen , Gould Gwyn W. , Bryant Nia J. 
Published: March 2019

AbstractKey to whole body glucose homeostasis is the ability of fat and muscle cells to sequester the facilitative glucose transporter GLUT4 in an intracellular compartment from where it can be mobilized in response to insulin. We have previously demonstrated that this process requires ubiquitination of GLUT4 while numerous other studies have identified several molecules that are also required, including the insulin-responsive aminopeptidase IRAP and its binding partner, the scaffolding protein tankyrase. In addition to binding IRAP, Tankyrase has also been shown to bind the deubiquinating enzyme USP25. Here we demonstrate that USP25 and Tankyrase interact, and colocalise with GLUT4 in insulin-sensitive cells. Furthermore depletion of USP25 from adipocytes reduces cellular levels of GLUT4 and concomitantly blunts the ability of insulin to stimulate glucose transport. Collectively, these data support our model that sorting of GLUT4 into its insulin-sensitive store involves a cycle of ubiquitination and subsequent deubiquitination.
Aerobic methane oxidation under copper scarcity in a stratified lake
Authors: Guggenheim Carole , Brand Andreas , Bürgmann Helmut , Sigg Laura , Wehrli Bernhard 
Published: March 2019

AbstractAerobic methane-oxidizing bacteria (MOB) substantially reduce methane fluxes from freshwater sediments to the atmosphere. Their metalloenzyme methane monooxygenase (MMO) catalyses the first oxidation step converting methane to methanol. Its most prevalent form is the copper-dependent particulate pMMO, however, some MOB are also able to express the iron-containing, soluble sMMO under conditions of copper scarcity. So far, the link between copper availability in different forms and biological methane consumption in freshwater systems is poorly understood. Here, we present high-resolution profiles of MOB abundance and pMMO and sMMO functional genes in relation to copper, methane and oxygen profiles across the oxic-anoxic boundary of a stratified lake. We show that even at low nanomolar copper concentrations, MOB species containing the gene for pMMO expression are present at high abundance. The findings highlight the importance of copper as a micronutrient for MOB species and the potential usage of copper acquisition strategies, even under conditions of abundant iron, and shed light on the spatial distribution of these microorganisms.