bluuebunny/crossref_metadata_2025 huggingface dataset:
Shared mechanisms between coronary heart disease and depression: findings from a large UK general population-based cohort
Authors: Khandaker Golam M. , Zuber Verena , Rees Jessica M. B. , Carvalho Livia , Mason Amy M. , Foley Christopher N. , Gkatzionis Apostolos , Jones Peter B. , Burgess Stephen
Published: March 2019

While comorbidity between coronary heart disease (CHD) and depression is evident, it is unclear whether the two diseases have shared underlying mechanisms. We performed a range of analyses in 367,703 unrelated middle-aged participants of European ancestry from UK Biobank, a population-based cohort study, to assess whether comorbidity is primarily due to genetic or environmental factors, and to test whether cardiovascular risk factors and CHD are likely to be causally related to depression using Mendelian randomization. We showed family history of heart disease was associated with a 20% increase in depression risk (95% confidence interval [CI] 16–24%, p < 0.0001), but a genetic risk score that is strongly associated with CHD risk was not associated with depression. An increase of 1 standard deviation in the CHD genetic risk score was associated with 71% higher CHD risk, but 1% higher depression risk (95% CI 0–3%; p = 0.11). Mendelian randomization analyses suggested that triglycerides, interleukin-6 (IL-6), and C-reactive protein (CRP) are likely causal risk factors for depression. The odds ratio for depression per standard deviation increase in genetically-predicted triglycerides was 1.18 (95% CI 1.09–1.27; p = 2 × 10−5); per unit increase in genetically-predicted log-transformed IL-6 was 1.35 (95% CI 1.12–1.62; p = 0.0012); and per unit increase in genetically-predicted log-transformed CRP was 1.18 (95% CI 1.07–1.29; p = 0.0009). Our analyses suggest that comorbidity between depression and CHD arises largely from shared environmental factors. IL-6, CRP and triglycerides are likely to be causally linked with depression, so could be targets for treatment and prevention of depression.
Pharmacologic or genetic activation of SIRT1 attenuates the fat-induced decrease in beta-cell function in vivo
Authors: Desai Tejas , Koulajian Khajag , Ivovic Aleksandar , Breen Danna M. , Luu Lemieux , Tsiani Evangelia L. , Wheeler Michael B. , Giacca Adria
Published: March 2019

Background

There is evidence that sirtuin 1 (SIRT1), a key regulator of nutrient metabolism, increases β-cell secretory function. Excess circulating fat, as seen in obesity, has been shown to decrease β-cell function, an effect that may involve decreased SIRT1 activity. Consequently, SIRT1 activation may increase β-cell function in conditions of elevated plasma-free fatty acid levels. Here we attempted to attenuate the lipid-induced decrease in β-cell function in vivo using pharmacological and genetic models of SIRT1 activation.

Methods

Our pharmacologic model involved 48 h intravenous infusion of Wistar rats with either saline or oleate with or without the SIRT1 activator resveratrol. Additionally, we used β-cell-specific SIRT1 overexpressing (BESTO) mice and wild-type littermates infused for 48 h intravenously with either saline or oleate. In both models, the infusion period was followed by assessment of β-cell function using the hyperglycemic clamp method.

Results

Lipid infusion resulted in a significant decrease in β-cell function as expected in both rats (p < 0.05) and mice (p < 0.001). Both models of SIRT1 activation, which did not alter β-cell function in the absence of fat, resulted in partial protection from the fat-induced decrease in β-cell function (NS vs. control).

Conclusion

These results suggest that SIRT1 is a therapeutic target in decreased β-cell function specifically induced by fat.
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

Disease 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

Variants 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

Accumulating 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

Renal 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

The 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

Despite 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

The 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

The 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

Nitric 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

Phosphate 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

In 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

Nickel 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

Music 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

Fabrication 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

Key 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

Aerobic 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.
Dissolved organic carbon contribution to oxygen respiration in the central Red Sea
Authors: Calleja Maria Ll. , Al-Otaibi Najwa , Morán Xosé Anxelu G.
Published: March 2019

In oligotrophic waters, dissolved organic carbon (DOC) is mostly produced in the surface layers by phytoplankton and remineralized by heterotrophic prokaryotes throughout the water column. DOC surface excess is subducted and exported to deeper layers where a semi-labile fraction is further processed contributing to oxygen consumption. How this cycling of DOC occurs in the Red Sea, one of the warmest oligotrophic marine basins, is virtually unknown. We examined DOC vertical and seasonal variability in a mesopelagic station (ca. 700 m depth) of the central Red Sea performing monthly profile samplings over a two-year period. Together with DOC vertical and seasonal distribution we evaluated the interaction with heterotrophic prokaryotes and contribution to oxygen respiration. DOC values ranged from 41.4 to 95.4 µmol C L−1, with concentrations in the epipelagic (70.0 ± 7.5 µmol C L−1) 40% higher on average than in the mesopelagic (50.7 ± 4.1 µmol C L−1). Subduction of seasonally accumulated semi-labile DOC was estimated to be responsible for ∼20% of the oxygen consumption mostly occurring at the low epipelagic-upper mesopelagic boundary layer. Variability in mesopelagic waters was higher than expected (ca. 20 µmol C L−1) evidencing a more active realm than previously thought, with consequences for carbon sequestration.
Sizing biological cells using a microfluidic acoustic flow cytometer
Authors: Strohm Eric M. , Gnyawali Vaskar , Sebastian Joseph A. , Ngunjiri Robert , Moore Michael J. , Tsai Scott S. H. , Kolios Michael C.
Published: March 2019

We describe a new technique that combines ultrasound and microfluidics to rapidly size and count cells in a high-throughput and label-free fashion. Using 3D hydrodynamic flow focusing, cells are streamed single file through an ultrasound beam where ultrasound scattering events from each individual cell are acquired. The ultrasound operates at a center frequency of 375 MHz with a wavelength of 4 μm; when the ultrasound wavelength is similar to the size of a scatterer, the power spectra of the backscattered ultrasound waves have distinct features at specific frequencies that are directly related to the cell size. Our approach determines cell sizes through a comparison of these distinct spectral features with established theoretical models. We perform an analysis of two types of cells: acute myeloid leukemia cells, where 2,390 measurements resulted in a mean size of 10.0 ± 1.7 μm, and HT29 colorectal cancer cells, where 1,955 measurements resulted in a mean size of 15.0 ± 2.3 μm. These results and histogram distributions agree very well with those measured from a Coulter Counter Multisizer 4. Our technique is the first to combine ultrasound and microfluidics to determine the cell size with the potential for multi-parameter cellular characterization using fluorescence, light scattering and quantitative photoacoustic techniques.
The DNA damage induced by the Cytosine Deaminase APOBEC3A Leads to the production of ROS
Authors: Niocel Mathilde , Appourchaux Romain , Nguyen Xuan-Nhi , Delpeuch Mathilde , Cimarelli Andrea
Published: March 2019

Human apolipoprotein B mRNA-editing catalytic polypeptide-like 3 proteins (APOBEC3s or A3s) are cytosine deaminases that protect cells by introducing promutagenic uraciles in invading retro-elements. However as a drawback of this protective activity, A3s can also target cellular DNA, leading to DNA damage and to the accumulation of somatic mutations that may contribute to tumorigenesis. Among A3s, A3A has been shown to be particularly proficient at mutagenizing cellular DNA, but whether this enzyme exerts additional effects on the cellular physiology remains unclear. Here, we show that A3A editing of cellular DNA leads to reactive oxygen species (ROS) production through Nox-enzymes. ROS production occurs in two distinct model cell lines and it is contingent upon DNA replication and intact enzymatic properties of A3A. For the first time, our results indicate that the editing activity of A3A results in the induction of a pro-inflammatory state that may possibly contribute to the constitution of a tumorigenic-prone environment.
Extensive conservation of the proneuropeptide and peptide prohormone complement in mollusks
Authors: De Oliveira A. L. , Calcino A. , Wanninger A.
Published: March 2019

As one of the most diverse groups of invertebrate animals, mollusks represent powerful models for neurobiological and developmental studies. Neuropeptides and peptide hormones are a heterogeneous class of signalling molecules involved in chemical communication between neurons and in neuroendocrine regulation. Here we present a fine-grained view of the molluscan neuropeptide and peptide hormone toolkit. Our results expand the distribution of several peptide families (e.g., prokineticin, insulin-related peptides, prohormone-4, LFRFamide) within Lophotrochozoa and provide evidence for an early origin of others (e.g., GNXQN/prohormone-2, neuroparsin). We identified a new peptide family broadly distributed among conchiferan mollusks, the PXRX family. We found the Wnt antagonist dickkopf1/2/4 ortholog in lophotrochozoans and nematodes and reveal that the egg-laying hormone family is a DH44 homolog restricted to gastropods. Our data demonstrate that numerous peptides evolved much earlier than previously assumed and that key signalling elements are extensively conserved among extant mollusks.
Burden of unique and low prevalence somatic mutations correlates with cancer survival
Authors: Klebanov Nikolai , Artomov Mykyta , Goggins William B. , Daly Emma , Daly Mark J. , Tsao Hensin
Published: March 2019

Tumor mutational burden correlates with improved survival and immunotherapy response in some malignancies, and with tumor aggressiveness in others. To study the link between mutational burden and survival, we analyzed survival effects of tumor exonic missense mutation burden (TEMMB) across 6947 specimens spanning 31 cancers which have undergone whole exome sequencing as part of TCGA. We adjusted TEMMB for age, sex, stage, and recruitment center, and computed Cox-proportional models of TEMMB survival effects. We assigned a recurrence score (RS) to each cohort, defining RS as the burden of recurrent mutations exceeding 1% population prevalence. High TEMMB was associated with improved survival in cutaneous melanoma: hazard ratio (HR) = 0.71 [0.60–0.85], p = 0.0002, urothelial bladder carcinoma: HR = 0.74 [0.59–0.93], p = 0.01, and ovarian carcinoma: HR = 0.80 [0.70–0.93], p = 0.003. High TEMMB was associated with decreased survival in colorectal adenocarcinoma: HR = 1.32 [1.00–1.74], p < 0.05. We identified that TEMMB survival effects were governed by the balance of recurrent and non-recurrent mutations. In cancers with a low RS, high TEMMB was correlated with better survival outcomes (r = 0.49, p = 0.02). In conclusion, TEMMB effects on survival depend on recurrent mutation enrichment; tumor types that are highly enriched in passenger mutations show a survival benefit in the setting of high tumor mutational burden.
Application of PMCA to screen for prion infection in a human cell line used to produce biological therapeutics
Authors: Lyon Adam , Mays Charles E. , Borriello Frank , Telling Glenn C. , Soto Claudio , Pritzkow Sandra
Published: March 2019

Advances in biotechnology have led to the development of a number of biological therapies for the treatment of diverse human diseases. Since these products may contain or are made using human or animal (e.g. cattle) derived materials, it is crucial to test their safety by ensuring the absence of infectious agents; specifically prions, which are highly resilient to elimination and produce fatal diseases in humans. Many cases of iatrogenic Creutzfeldt-Jakob disease have been caused by the use of biological materials (e.g. human growth hormone) contaminated with prions. For this reason, it is important to screen cells and biological materials for the presence of prions. Here we show the utility of the Protein Misfolding Cyclic Amplification (PMCA) technology as a screening tool for the presence of human (vCJD) and bovine (BSE) prions in a human cell therapy product candidate. First, we demonstrated the sensitivity of PMCA to detect a single cell infected with prions. For these experiments, we used RKM7 cells chronically infected with murine RML prions. Serial dilutions of an infected cell culture showed that PMCA enabled prion amplification from a sample comprised of only one cell. Next, we determined that PMCA performance was robust and uncompromised by the spiking of large quantities of uninfected cells into the reaction. Finally, to demonstrate the practical application of this technology, we analyzed a human cell line being developed for therapeutic use and found it to be PMCA-negative for vCJD and BSE prions. Our findings demonstrate that the PMCA technology has unparalleled sensitivity and specificity for the detection of prions, making it an ideal quality control procedure in the production of biological therapeutics.
Outcomes of surgery and/or combination chemotherapy for extraskeletal osteosarcoma: a single-center retrospective study from China
Authors: Liao Zhichao , Qiu Minghan , Yang Jilong , Yang Yun , Zhu Lei , Yang Bo , Bai Xu , Xing Peipei , Zhang Jin , Xing Ruwei , Teng Sheng , Zhao Jun
Published: March 2019

Extraskeletal osteosarcoma (ESOS) is an extremely rare malignancy with poor prognosis, accounting for 2–4% of all osteogenic sarcomas. The purpose of this study was to examine the oncological outcomes of this disease related to surgical treatment and/or combined adjuvant therapies and to analyze the associated prognostic factors in ESOS. From January 1990 to June 2016, 22 patients with primary ESOS were analyzed in this retrospective study. Overall survival (OS) and progression-free survival (PFS) rates were calculated by Kaplan-Meier methods and compared with log-rank test. 22 patients were diagnosed with ESOS, 19 showed localized diseases and 3 presented with metastatic lesions. The median age at diagnosis was 55.5 years. Surgery resection was performed for all patients, 18 of whom received adjuvant chemotherapy. The median follow-up time was 48.5 months. There were 10 cases of recurrence and 9 patients developed new metastases. The 5-year OS rate for all patients was 58%. For localized cohort, the 5-year OS rate was 62%, and the 3-year PFS rate was 31% with a median PFS of 16 months. Univariate analysis of related prognosis factors showed that larger size of tumor (>5.5 cm) and higher histologic grade emerged as significant factors associated with worse OS. The addition of combination chemotherapy has no effect found on OS or PFS in this study. In summary, for patients who presented with ESOS, larger tumor size and higher histologic grade indicate a lower OS rate. The combination chemotherapy does not improve the OS or PFS.
Numerical and Experimental Investigation into LWIR Transmission Performance of Complementary Silicon Subwavelength Antireflection Grating (SWARG) Structures
Authors: Cetin Ramazan , Akin Tayfun
Published: March 2019

This paper presents a detailed comparison between the long wave infrared (LWIR) transmission performances of binary, silicon based, structurally complementary pillar and groove type antireflective gratings that can be used for wafer level vacuum packaging (WLVP) of uncooled microbolometer detectors. Both pillar and groove type gratings are designed with various topological configurations changing in various period sizes (Λ) from 1.0 μm to 2.0 μm, various heights/depths (h) from 0.8 μm to 1.8 μm, and various pillar/groove width-to-period (w/Λ) ratios from 0.6 to 1.0. The transmission performance of gratings is simulated with a hybrid simulation technique based on the modification of the reflection term within the Fresnel transmission equation, which combines both numerical and analytical approaches in a unique way for the first time in literature. Simulation results are experimentally verified with 19 different fabricated structures where a spectral agreement is achieved with an absolute root-mean-square (RMS) error less than 5.4% within the subwavelength (SW) regime, proving the effectiveness of the proposed hybrid technique. These results show first time in the literature that both pillar and groove type silicon based gratings present similar spectral IR transmission characteristics, and they are also structurally complementary when optimum configurations are employed to maximize the transmission.
Ataxia-Telangiectasia Mutated is located in cardiac mitochondria and impacts oxidative phosphorylation
Authors: Blignaut Marguerite , Loos Ben , Botchway Stanley W. , Parker Anthony W. , Huisamen Barbara
Published: March 2019

The absence of Ataxia-Telangiectasia mutated protein kinase (ATM) is associated with neurological, metabolic and cardiovascular defects. The protein has been associated with mitochondria and its absence results in mitochondrial dysfunction. Furthermore, it can be activated in the cytosol by mitochondrial oxidative stress and mediates a cellular anti-oxidant response through the pentose phosphate pathway (PPP). However, the precise location and function of ATM within mitochondria and its role in oxidative phosphorylation is still unknown. We show that ATM is found endogenously within cardiac myocyte mitochondria under normoxic conditions and is consistently associated with the inner mitochondrial membrane. Acute ex vivo inhibition of ATM protein kinase significantly decreased mitochondrial electron transfer chain complex I-mediated oxidative phosphorylation rate but did not decrease coupling efficiency or oxygen consumption rate during β-oxidation. Chemical inhibition of ATM in rat cardiomyoblast cells (H9c2) significantly decreased the excited-state autofluorescence lifetime of enzyme-bound reduced NADH and its phosphorylated form, NADPH (NAD(P)H; 2.77 ± 0.26 ns compared to 2.57 ± 0.14 ns in KU60019-treated cells). This suggests an interaction between ATM and the electron transfer chain in the mitochondria, and hence may have an important role in oxidative phosphorylation in terminally differentiated cells such as cardiomyocytes.
Effect of statins on the association between high temperature and all-cause mortality in a socioeconomically disadvantaged population: a cohort study
Authors: Nam Young Hee , Bilker Warren B. , Leonard Charles E. , Bell Michelle L. , Alexander Lacy M. , Hennessy Sean
Published: March 2019

High temperature increases all-cause mortality. Thermoregulatory ability is impaired in persons with elevated serum cholesterol, but can be improved by the administration of statins, even in the short-term. We investigated whether the impact of high temperature (≥24 °C) on all-cause mortality among socioeconomically disadvantaged adults with a current or past indication for a statin is attenuated by current use of a statin with temperature dependence, by using claims data from five US Medicaid programs supplemented with Medicare claims for dual-enrollees and meteorological data from 1999–2010. We identified 3,508,948 persons (3,181,752 person-years) in a 1:1 propensity score-matched cohort. The incidence rate of all-cause mortality (deaths per 1,000 person-years) was 21.9 (95% confidence interval [CI]: 21.6 to 22.3) in current statin users and 30.1 (95% CI: 30.2 to 30.6) in former users. The adjusted odds ratios of mortality for current vs. former statin use were statistically significantly lower than 1.0, suggesting a protective effect of current statin use, on days with high temperature, with either daily average temperature or daily maximum temperature, and declined as daily average temperature increased from 29 °C and daily maximum temperature increased from 34 °C. These results were robust to the adjustment for daily relative humidity.
Breast cancer cells exhibits specific dielectric signature in vitro using the open-ended coaxial probe technique from 200 MHz to 13.6 GHz
Authors: Hussein Mousa , Awwad Falah , Jithin Dwija , El Hasasna Husain , Athamneh Khawlah , Iratni Rabah
Published: March 2019

Here we investigated the feasibility of using microwave spectroscopy for characterization of normal and breast cancer cell lines cultured in vitro. Healthy non-tumorigenic, MCF-10A and breast cancer, MDA-MB-231, Hs578T, T47D and MCF-7 cell lines were electrically characterized using the open-ended coaxial probe technique from 200 MHz to 13.6 GHz. The dielectric constant, dielectric loss and conductivity between breast non-tumorigenic and breast cancer cells lines were analyzed and their differences determined. Our results showed that the four breast cancer cell lines analyzed exhibited higher dielectric properties when compared to healthy cells. Interestingly, we found that breast and colon cancer cells have different dielectric properties as well, thus suggesting that each type of cancer has a unique microwave signature. This study shows that microwave characterization of breast cancer cell lines is reliable with potential in biomedical applications such as designing electromagnetic models for detection of tumorous cells in healthy tissues.
Interactive influences of intercropping by nitrogen on flavonoid exudation and nodulation in faba bean
Authors: Liu Yingchao , Yin Xinhua , Xiao Jingxiu , Tang Li , Zheng Yi
Published: March 2019

In order to address the question of how flavonoids affected root nodulation of faba bean in a wheat and faba bean intercropping system, we set up soil and hydroponic experiments comprising two cropping pattern treatments (intercropped and monocropped) and three nitrogen (N) supply treatments at the deficient (50% N), adequate (100% N), and excessive (150% N) levels with three replicates in a randomized complete block design. Across the three N treatments and two experiments, it was frequently observed that intercropping increased but N fertilization decreased the nodule number and nodule dry weight of faba bean. Six types of flavonoids were detected in the faba bean root secretion, but only genistein, hesperetin, and naringenin often had significant correlations with the nodule number and nodule dry weight. Intercropping increased faba bean root secretions of genistein, hesperetin, and naringenin compared to monoculture only at the deficient and adequate N supply levels. The differences in flavonoids of faba bean caused by the intercropped patterns, N supply levels, and their interactions were mainly significant at flowering stage. In conclusion, interspecies and N supply interactively altered the contents and proportions of flavonoids in faba bean root exudations under wheat and faba bean intercropping. These findings provide insight into flavonoids-nodule-yield interactions in cereal and legume intercropping systems.
Oxygen diffusion and vacancy migration thermally-activated govern high-temperature magnetism in ceria
Authors: Varalda J. , Dartora C. A. , de Camargo P. C. , de Oliveira A. J. A. , Mosca D. H.
Published: March 2019

Several experimental works currently demonstrate that metallic nano-oxides and carbon nanomaterials expected to be diamagnets, in fact, behave as ferromagnets at room temperature. More than scientifically intriguing, this unconventional and unexpected ferromagnetism pave the way for innovation products and novel nanotechnological applications, gathering the magnetism to interesting functionalities of these nanomaterials. Here, we investigate the non-conventional ferromagnetism observed at high temperatures in nanocrystalline cerium dioxide (CeO2or nanoceria) thin films that are optically transparent to visible light. Nanoceria exhibits several concrete applications in catalytic processes, photovoltaic cells, solid-state fuel cells, among others, which are mostly due to natural presence of oxygen vacancies and easy migration of the oxygen through the structure. The ferromagnetism in non-stoichiometric nanocrystaline ceria can be consistently described by ab initio electronic structure calculations, which support that oxygen vacancies cause the formation of magnetic moments and can provide a robust interconnectivity within magnetic polarons theoretical framework. Additionally, we present a conceptual model to account the oxygen transport to the non-conventional ferromagnetism at temperatures well above room temperature. The approach is complementary to the thermally-activated effective transfers of charge and spin around oxygen vacancy centers.