bluuebunny/crossref_metadata_2025 huggingface dataset:
Winter Precipitation and Summer Temperature Predict Lake Water Quality at Macroscales
Authors: Collins S. M. , Yuan S. , Tan P. N. , Oliver S. K. , Lapierre J. F. , Cheruvelil K. S. , Fergus C. E. , Skaff N. K. , Stachelek J. , Wagner T. , Soranno P. A.
Published: March 2019

Climate change can have strong effects on aquatic ecosystems, including disrupting nutrient cycling and mediating processes that affect primary production. Past studies have been conducted mostly on individual or small groups of ecosystems, making it challenging to predict how future climate change will affect water quality at broad scales. We used a subcontinental‐scale database to address three objectives: (1) identify which climate metrics best predict lake water quality, (2) examine whether climate influences different nutrient and productivity measures similarly, and (3) quantify the potential effects of a changing climate on lakes. We used climate data to predict lake water quality in ~11,000 north temperate lakes across 17 U.S. states. We developed a novel machine learning method that jointly models different measures of water quality using 48 climate metrics and accounts for properties inherent in macroscale data (e.g., spatial autocorrelation). Our results suggest that climate metrics related to winter precipitation and summer temperature were strong predictors of lake nutrients and productivity. However, we found variation in the magnitude and direction of the relationship between climate and water quality. We predict that a likely future climate change scenario of warmer summer temperatures will lead to increased nutrient concentrations and algal biomass across lakes (median ~3%–9% increase), whereas increased winter precipitation will have highly variable effects. Our results emphasize the importance of heterogeneity in the response of individual ecosystems to climate and are a caution to extrapolating relationships across space.
Correction: Safety and utility of image-guided research biopsies in relapsed high-grade serous ovarian carcinoma—experience of the BriTROC consortium
Authors:   on behalf of the BriTROC investigators, Goranova T , Ennis D , Piskorz A M , Macintyre G , Lewsley L A , Stobo J , Wilson C , Kay D , Glasspool R M , Lockley M , Brockbank E , Montes A , Walther A , Sundar S , Edmondson R , Hall G D , Clamp A , Gourley C , Hall M , Fotopoulou C , Gabra H , Freeman S , Moore L , Jimenez-Linan M , Paul J , Brenton J D , McNeish I A
Published: March 2019

This article was originally published under a CC BY NC SA License, but has now been made available under a CC BY 4.0 License.
SUMOylation of G9a regulates its function as an activator of myoblast proliferation
Authors: Srinivasan Shruti , Shankar Shilpa Rani , Wang Yaju , Taneja Reshma
Published: March 2019

The lysine methyltransferase G9a plays a role in many cellular processes. It is a potent repressor of gene expression, a function attributed to its ability to methylate histone and non-histone proteins. Paradoxically, in some instances, G9a can activate gene expression. However, regulators of G9a expression and activity are poorly understood. In this study, we report that endogenous G9a is SUMOylated in proliferating skeletal myoblasts. There are four potential SUMOylation consensus motifs in G9a. Mutation of all four acceptor lysine residues [K79, K152, K256, and K799] inhibits SUMOylation. Interestingly, SUMOylation does not impact G9a-mediated repression of MyoD transcriptional activity or myogenic differentiation. In contrast, SUMO-defective G9a is unable to enhance proliferation of myoblasts. Using complementation experiments, we show that the proliferation defect of primary myoblasts from conditional G9a-deficient mice is rescued by re-expression of wild-type, but not SUMOylation-defective, G9a. Mechanistically, SUMOylation acts as signal for PCAF (P300/CBP-associated factor) recruitment at E2F1-target genes. This results in increased histone H3 lysine 9 acetylation marks at E2F1-target gene promoters that are required for S-phase progression. Our studies provide evidence by which SUMO modification of G9a influences the chromatin environment to impact cell cycle progression.
The lncRNA TP73-AS1 is linked to aggressiveness in glioblastoma and promotes temozolomide resistance in glioblastoma cancer stem cells
Authors: Mazor Gal , Levin Liron , Picard Daniel , Ahmadov Ulvi , Carén Helena , Borkhardt Arndt , Reifenberger Guido , Leprivier Gabriel , Remke Marc , Rotblat Barak
Published: March 2019

Glioblastoma multiform (GBM) is the most common brain tumor characterized by a dismal prognosis. GBM cancer stem cells (gCSC) or tumor-initiating cells are the cell population within the tumor-driving therapy resistance and recurrence. While temozolomide (TMZ), an alkylating agent, constitutes the first-line chemotherapeutic significantly improving survival in GBM patients, resistance against this compound commonly leads to GBM recurrence and treatment failure. Although the roles of protein-coding transcripts, proteins and microRNA in gCSC, and therapy resistance have been comprehensively investigated, very little is known about the role of long noncoding RNAs (lncRNAs) in this context. Using nonoverlapping, independent RNA sequencing and gene expression profiling datasets, we reveal that TP73-AS1 constitutes a clinically relevant lncRNA in GBM. Specifically, we demonstrate significant overexpression of TP73-AS1 in primary GBM samples, which is particularly increased in the gCSC. More importantly, we demonstrate that TP73-AS1 comprises a prognostic biomarker in glioma and in GBM with high expression identifying patients with particularly poor prognosis. Using CRISPRi to downregulate our candidate lncRNA in gCSC, we demonstrate that TP73-AS1 promotes TMZ resistance in gCSC and is linked to regulation of the expression of metabolism- related genes and ALDH1A1, a protein known to be expressed in cancer stem cell markers and protects gCSC from TMZ treatment. Taken together, our results reveal that high TP73-AS1 predicts poor prognosis in primary GBM cohorts and that this lncRNA promotes tumor aggressiveness and TMZ resistance in gCSC.
Amyloid β oligomers suppress excitatory transmitter release via presynaptic depletion of phosphatidylinositol-4,5-bisphosphate
Authors: He Yang , Wei Mengdi , Wu Yan , Qin Huaping , Li Weinan , Ma Xiaolin , Cheng Jingjing , Ren Jinshuai , Shen Ye , Chen Zhong , Sun Binggui , Huang Fu-De , Shen Yi , Zhou Yu-Dong
Published: March 2019

Amyloid β (Aβ) oligomer-induced aberrant neurotransmitter release is proposed to be a crucial early event leading to synapse dysfunction in Alzheimer’s disease (AD). In the present study, we report that the release probability (Pr) at the synapse between the Schaffer collateral (SC) and CA1 pyramidal neurons is significantly reduced at an early stage in mouse models of AD with elevated Aβ production. High nanomolar synthetic oligomeric Aβ42 also suppresses Pr at the SC-CA1 synapse in wild-type mice. This Aβ-induced suppression of Pr is mainly due to an mGluR5-mediated depletion of phosphatidylinositol-4,5-bisphosphate (PIP2) in axons. Selectively inhibiting Aβ-induced PIP2 hydrolysis in the CA3 region of the hippocampus strongly prevents oligomeric Aβ-induced suppression of Pr at the SC-CA1 synapse and rescues synaptic and spatial learning and memory deficits in APP/PS1 mice. These results first reveal the presynaptic mGluR5-PIP2 pathway whereby oligomeric Aβ induces early synaptic deficits in AD.
AKF-PD alleviates diabetic nephropathy via blocking the RAGE/AGEs/NOX and PKC/NOX Pathways
Authors: Qin Jiao , Peng Zhangzhe , Yuan QiongJing , Li Qian , Peng Yu , Wen Rui , Hu Zhaolan , Liu Jun , Xia Xiongfang , Deng Hong , Xiong Xuan , Hu Jinyue , Tao Lijian
Published: March 2019

Diabetic nephropathy (DN) is a major complication of diabetes. Currently, drugs are not available to effectively control the disease. Fluorofenidone (AKF-PD) is a recently developed drug; it possesses activities in reducing DN progression in preclinical research. Nonetheless, its renal protection and the underlying mechanisms have not been thoroughly investigated. We report here that AKF-PD significantly alleviatesrenal oxidative stress (OS) in db/dbmice through downregulation of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase and upregulation of glutathione peroxidase and superoxide dismutase, thereby protecting kidney from DN pathogenesis. AKF-PD likely reduces OS through the advanced glycation end products (AGE) and protein kinase C (PKC) pathways. While renal AGEs, PKCα, PKCβ, and NADPH oxidase 4 (NOX4) were all substantially upregulated in db/db mice compared to db/m animals, AKF-PD robustly downregulated all these events to the basal levelsdetected in db/m mice. In primary human renal mesangial cells (HMCs), high glucose (HG) elevated receptor for advanced glycation endproducts (RAGE), PKCα, PKCβ and NOX4 activity, and induced the production of reactive oxygen species (ROS); these events were all inhibited by AKF-PD. Furthermore, HG led to mitochondrial damagein HMCs;AKF-PD conferred protection on the damage. Knockdown of either PKCα or PKCβ reduced HG-induced ROS production and mitochondrial damage in HMCs. The knockdown significantly enhanced AKF-PD-mediated inhibition of ROS production and mitochondrial damage in HG-treated HMCs. Collectively, our study demonstrates that AKF-PD protects renal function under diabetes conditions in part through inhibition of OS during DN pathogenesis. AKF-PD can be explored for clinical applications in DN therapy.
The immunosuppressant drug azathioprine restrains adipogenesis of muscle Fibro/Adipogenic Progenitors from dystrophic mice by affecting AKT signaling
Authors: Reggio Alessio , Spada Filomena , Rosina Marco , Massacci Giorgia , Zuccotti Alessandro , Fuoco Claudia , Gargioli Cesare , Castagnoli Luisa , Cesareni Gianni
Published: March 2019

Fibro/Adipogenic Progenitors (FAPs) define a stem cell population playing a pro-regenerative role after muscle damage. When removed from their natural niche, FAPs readily differentiate into adipocytes or fibroblasts. This digressive differentiation potential, which is kept under tight control in the healthy muscle niche, contributes to fat and scar infiltrations in degenerative myopathies, such as in Duchenne Muscular Dystrophy (DMD). Controlling FAP differentiation by means of small molecules may contribute to delay the adverse consequences of the progressive pathological degeneration while offering, at the same time, a wider temporal window for gene therapy and cell-based strategies. In a high content phenotypic screening, we identified the immunosuppressant, azathioprine (AZA) as a negative modulator of FAP adipogenesis. We show here that AZA negatively affects the adipogenic propensity of FAPs purified from wild type and mdx mice by impairing the expression of the master adipogenic regulator, peroxisome proliferator-activated receptor γ (PPARγ). We show that this inhibition correlates with a decline in the activation of the AKT-mTOR axis, the main pathway that transduces the pro-adipogenic stimulus triggered by insulin. In addition, AZA exerts a cytostatic effect that has a negative impact on the mitotic clonal process that is required for the terminal differentiation of the preadipocyte-committed cells.
Effects of Black Raspberries and Their Ellagic Acid and Anthocyanin Constituents on Taxane Chemotherapy of Castration-Resistant Prostate Cancer Cells
Authors: Eskra Jillian N. , Schlicht Michael J. , Bosland Maarten C.
Published: March 2019

Cancer patients often use dietary supplements while on therapy, but little is known about interactions of supplements with cancer chemotherapy. Black raspberries (BRB) have anti-cancer effects, but have not been evaluated for interference with chemotherapy for castrate-resistant prostate cancer (CRPC). Here we studied whether BRB and some of their constituents interact with docetaxel and cabazitaxel on CRPC cells in culture and implanted into nude mice. Ellagic acid increased, but BRB extract inhibited, microtubule assembly. Ellagic acid decreased tubulin polymerization by cabazitaxel and bound to tubulin. Ellagic acid, its metabolite urolithin A, BRB extract, and the anthocyanin metabolite protocatechuic acid (PCA) did not alter cytotoxicity of taxanes. Ellagic acid inhibited drug efflux in CRPC cells, but BRB extract and PCA did not. None of these compounds altered CYP3A4 activity. Although dietary ellagic acid did not alter the tumor growth inhibition by docetaxel of xenografted 22Rv1 cells, ellagic acid has the potential to interfere with taxane chemotherapy by reducing tubulin polymerization while inhibiting P-glycoprotein drug efflux. These data are cause for concern of consuming ellagic acid during treatment for CRPC and indicate need for further research, but BRB consumption appears safe.
Early Detection of Tomato Spotted Wilt Virus by Hyperspectral Imaging and Outlier Removal Auxiliary Classifier Generative Adversarial Nets (OR-AC-GAN)
Authors: Wang Dongyi , Vinson Robert , Holmes Maxwell , Seibel Gary , Bechar Avital , Nof Shimon , Tao Yang
Published: March 2019

Tomato spotted wilt virus is a wide-spread plant disease in the world. It can threaten thousands of plants with a persistent and propagative manner. Early disease detection is expected to be able to control the disease spread, to facilitate management practice, and further to guarantee accompanying economic benefits. Hyperspectral imaging, a powerful remote sensing tool, has been widely applied in different science fields, especially in plant science domain. Rich spectral information makes disease detection possible before visible disease symptoms showing up. In the paper, a new hyperspectral analysis proximal sensing method based on generative adversarial nets (GAN) is proposed, named as outlier removal auxiliary classifier generative adversarial nets (OR-AC-GAN). It is an all-in-one method, which integrates the tasks of plant segmentation, spectrum classification and image classification. The model focuses on image pixels, which can effectively visualize potential plant disease positions, and keep experts’ attention on these diseased pixels. Meanwhile, this new model can improve the performances of classic spectrum band selection methods, including the maximum variance principle component analysis (MVPCA), fast density-peak-based clustering, and similarity-based unsupervised band selection. Selecting spectrum wavebands reasonably is an important preprocessing step in spectroscopy/hyperspectral analysis applications, which can reduce the computation time for potential in-field applications, affect the prediction results and make the hyperspectral analysis results explainable. In the experiment, the hyperspectral reflectance imaging system covers the spectral range from 395 nm to 1005 nm. The proprosed model makes use of 83 bands to do the analysis. The plant level classification accuracy gets 96.25% before visible symptoms shows up. The pixel prediction false positive rate in healthy plants gets as low as 1.47%. Combining the OR-AC-GAN with three existing band selection algorithms, the performance of these band selection models can be significantly improved. Among them, MVPCA can leverage only 8 spectrum bands to get the same plant level classification accuracy as OR-AC-GAN, and the pixel prediction false positive rate in healthy plants is 1.57%, which is also comparable to OR-AC-GAN. This new model can be potentially transferred to other plant diseases detection applications. Its property to boost the performance of existing band selection methods can also accelerate the in-field applications of hyperspectral imaging technology.
Community-Based Event Detection in Temporal Networks
Authors: Moriano Pablo , Finke Jorge , Ahn Yong-Yeol
Published: March 2019

We propose a method for detecting large events based on the structure of temporal communication networks. Our method is motivated by findings that viral information spreading has distinct diffusion patterns with respect to community structure. Namely, we hypothesize that global events trigger viral information cascades that easily cross community boundaries and can thus be detected by monitoring intra- and inter-community communications. By comparing the amount of communication within and across communities, we show that it is possible to detect events, even when they do not trigger a significantly larger communication volume. We demonstrate the effectiveness of our method using two examples—the email communication network of Enron and the Twitter communication network during the Boston Marathon bombing.
Earthquake segmentation in northern Chile correlates with curved plate geometry
Authors: Shrivastava Mahesh N. , González Gabriel , Moreno Marcos , Soto Hugo , Schurr Bernd , Salazar Pablo , Báez Juan Carlos
Published: March 2019

We performed an integrated analysis of the coseismic slip, afterslip and aftershock activity of the 2014 Mw8.1 Pisagua earthquake. This earthquake seems to be spatially located between two major historical earthquakes, the 1868 Mw8.8 earthquake in southern Peru and the 1877 Mw8.5 earthquake in northern Chile. Continuous GPS data were used to model the coseismic slip of the mainshock and the largest aftershock (Mw7.6). The afterslip was modeled for 273 days (end of year 2014) after the largest aftershock, revealing two patches of afterslip: a southern patch between the mainshock and the largest aftershock and a patch to the north of the mainshock. Observations from the seismic network indicate that aftershocks were concentrated near the southern patch. Conversely, the northern patch contained hardly any aftershocks, indicating a dominant aseismic slip. The Pisagua earthquake occurred within a prominent, curved section of the Andean subduction zone. This section may have acted as a barrier for the largest historical earthquakes and as an isolated segment during the Pisagua earthquake.
Prognostic Impact of Carboxylesterase 2 in Cholangiocarcinoma
Authors: Goeppert Benjamin , Renner Marcus , Singer Stephan , Albrecht Thomas , Zhang Qiangnu , Mehrabi Arianeb , Pathil Anita , Springfeld Christoph , Köhler Bruno , Rupp Christian , Weiss Karl Heinz , Kühl Anja A. , Arsenic Ruza , Pape Ulrich Frank , Vogel Arndt , Schirmacher Peter , Roessler Stephanie , Utku Nalân
Published: March 2019

Carboxylesterase 2 (CES2) is instrumental for conversion of ester-containing prodrugs in cancer treatment. Novel treatment strategies are exceedingly needed for cholangiocarcinoma (CCA) patients. Here, we assessed CES2 expression by immunohistochemistry in a CCA cohort comprising 171 non-liver fluke associated, intrahepatic (n = 72) and extrahepatic (perihilar: n = 56; distal: n = 43) CCAs. Additionally, 80 samples of high-grade biliary intraepithelial neoplastic tissues and 158 corresponding samples of histological normal, non-neoplastic biliary tract tissues were included. CES2 expression was highest in non-neoplastic biliary tissue and significantly decreased in CCA. Patients showing any CES2 expression in tumor cells had a significantly better overall survival compared to negative cases (p = 0.008). This survival benefit was also maintained after stratification of CES2-positive cases, by comparing low, medium and high CES2 expression levels (p-trend = 0.0006). Evaluation of CCA subtypes showed the survival difference to be restricted to extrahepatic tumors. Correlation of CES2 expression with data of tumor-infiltrating immune cells showed that particularly CD8+ T cells were more frequently detected in CES2-positive CCAs. Furthermore, treatment of CCA cell lines with the prodrug Irinotecan reduced cell viability, increased cytotoxicity and modulated inflammatory gene expression. In conclusion, reduced CES2 expression is associated with poor outcome and low CD8+ T cell infiltration in CCA patients. Further clinical studies could show, whether CES2 expression may serve as a predictive marker in patients treated with prodrugs converted by CES2.
Sustained response to symmetry in extrastriate areas after stimulus offset: An EEG study
Authors: Bertamini Marco , Rampone Giulia , Oulton Jennifer , Tatlidil Semir , Makin Alexis D. J.
Published: March 2019

Electrophysiological (EEG) studies of human perception have found that amplitude at posterior electrodes is more negative for symmetrical patterns compared to asymmetrical patterns. This negativity lasts for hundreds of milliseconds and it has been called sustained posterior negativity (SPN). Symmetry activates a network of visual areas, including the lateral occipital complex (LOC). The SPN is a response to presence of symmetry in the image. Given the sustained nature of this activation, in this study we tested the persistence of the SPN after stimulus offset. Two shapes were presented (for 0.5 s each) with a 1 s blank interval in between. We observed a sustained response after stimulus offset, irrespective of whether the task required processing of shape information. This supports the idea that the response to symmetry is generated by information in the image, independently of task, and that it is sustained over approximately one second post stimulus onset.
Deletion of hematopoietic Dectin-2 or CARD9 does not protect against atherosclerotic plaque formation in hyperlipidemic mice
Authors: Thiem Kathrin , Hoeke Geerte , van den Berg Susan , Hijmans Anneke , Jacobs Cor W. M. , Zhou Enchen , Mol Isabel M. , Mouktaroudi Maria , Bussink Johan , Kanneganti Thirumala D. , Lutgens Esther , Stienstra Rinke , Tack Cees J. , Netea Mihai G. , Rensen Patrick C. N. , Berbée Jimmy F. P. , van Diepen Janna A.
Published: March 2019

Inflammatory reactions activated by pattern recognition receptors (PRRs) on the membrane of innate immune cells play an important role in atherosclerosis. Whether the PRRs of the C-type lectin receptor (CLR) family including Dectin-2 may be involved in the pathogenesis of atherosclerosis remains largely unknown. Recently, the CLR-adaptor molecule caspase recruitment domain family member 9 (CARD9) has been suggested to play a role in cardiovascular pathologies as it provides the link between CLR activation and transcription of inflammatory cytokines as well as immune cell recruitment. We therefore evaluated whether hematopoietic deletion of Dectin-2 or CARD9 reduces inflammation and atherosclerosis development. Low-density lipoprotein receptor (Ldlr)-knockout mice were transplanted with bone marrow from wild-type, Dectin-2- or Card9-knockout mice and fed a Western-type diet containing 0.1% (w/w) cholesterol. After 10 weeks, lipid and inflammatory parameters were measured and atherosclerosis development was determined. Deletion of hematopoietic Dectin-2 or CARD9 did not influence plasma triglyceride and cholesterol levels. Deletion of hematopoietic Dectin-2 did not affect atherosclerotic lesion area, immune cell composition, ex vivo cytokine secretion by peritoneal cells or bone marrow derived macrophages. Unexpectedly, deletion of hematopoietic CARD9 increased atherosclerotic lesion formation and lesion severity. Deletion of hematopoietic CARD9 did also not influence circulating immune cell composition and peripheral cytokine secretion. Besides a tendency to a reduced macrophage content within these lesions, plasma MCP-1 levels decreased upon WTD feeding. Deletion of hematopoietic Dectin-2 did not influence atherosclerosis development in hyperlipidemic mice. The absence of CARD9 unexpectedly increased atherosclerotic lesion size and severity, suggesting that the presence of CARD9 may protect against initiation of atherosclerosis development.
Tsunamigenic potential of crustal faults and subduction zones in the Mediterranean
Authors: Petricca Patrizio , Babeyko Andrey Y.
Published: March 2019

We compiled a database and systematically evaluated tsunamigenic potential of all up-to-date known crustal fault systems and subduction zones in the entire Mediterranean region that has experienced several catastrophic tsunamis in historical times. The task is accomplished by means of numerical modeling of tsunami generation and propagation. We have systematically simulated all representative ruptures populating known crustal faults and subduction interfaces with magnitudes ranging from 6.1 up to expected Mwmax. Maximum tsunami heights calculated everywhere along the coasts allowed us to classify the sources in terms of their tsunamigenic potential and to estimate their minimum tsunamigenic magnitude. Almost every source in the Mediterranean, starting from Mw = 6.5, is capable to produce local tsunami at the advisory level (wave height >20 cm and ≤50 cm). In respect to the watch level (wave height >50 cm) larger magnitudes are needed (Mw ≥ 6.9). Faults behave more heterogeneously in the context of far field early warning. De-aggregation of the database at any selected coastal location can reveal relevant sources of tsunami hazard for this location. Our compilation blueprints methodology that, if completed with source recurrence rates and site-specific amplification factors, can be considered as a backbone for development of optimal early warning strategies by Mediterranean tsunami warning providers.
A comparison study of radiation effective dose in ECG-Gated Coronary CT Angiography and calcium scoring examinations performed with a dual-source CT scanner
Authors: Sabarudin Akmal , Siong Tiong Wei , Chin Ang Wee , Hoong Ng Kwan , Karim Muhammad Khalis Abdul
Published: March 2019

In this report we have evaluated radiation effective dose received by patients during ECG-gated CCTA examinations based on gender, heart rate, tube voltage protocol and body mass index (BMI). A total of 1,824 patients were retrospectively recruited (1,139 men and 685 women) and they were divided into Group 1 (CCTA with calcium scoring), Group 2 (CCTA without calcium scoring) and Group 3 (only calcium scoring), where the association between gender, heart rate, tube voltage protocol and body mass index (BMI) were analysed. Examinations were performed using a retrospective ECG-gated CCTA protocol and the effective doses were calculated from the dose length product with a conversion coefficient of 0.026 mSv.mGy−1cm−1. No significant differences were observed in the mean effective dose between gender in all groups. The mean estimated dose was significantly higher when the heart rate was lower in Group 1 (p < 0.001) and Group 2 (p = 0.002). There were also significant differences between the mean effective dose in tube voltage protocol and BMI among the three groups. The mean effective dose was positively correlated with BMI (p < 0.001), but inversely related to the heart rate. This study supported the theory that a high heart rate, low tube voltage and low BMI could significantly reduce radiation dose exposure.
Hexamethylene bisacetamide impairs NK cell-mediated clearance of acute T lymphoblastic leukemia cells and HIV-1-infected T cells that exit viral latency
Authors: Giuliani Erica , Desimio Maria Giovanna , Doria Margherita
Published: March 2019

The hexamethylene bisacetamide (HMBA) anticancer drug was dismissed due to limited efficacy in leukemic patients but it may re-enter into the clinics in HIV-1 eradication strategies because of its recently disclosed capacity to reactivate latent virus. Here, we investigated the impact of HMBA on the cytotoxicity of natural killer (NK) cells against acute T lymphoblastic leukemia (T-ALL) cells or HIV-1-infected T cells that exit from latency. We show that in T-ALL cells HMBA upmodulated MICB and ULBP2 ligands for the NKG2D activating receptor. In a primary CD4+ T cell-based latency model, HMBA did not reactivate HIV-1, yet enhanced ULBP2 expression on cells harboring virus reactivated by prostratin (PRO). However, HMBA reduced the expression of NKG2D and its DAP10 adaptor in NK cells, hence impairing NKG2D-mediated cytotoxicity and DAP10-dependent response to IL-15 stimulation. Alongside, HMBA dampened killing of T-ALL targets by IL-15-activated NK cells and impaired NK cell-mediated clearance of PRO-reactivated HIV-1+ cells. Overall, our results demonstrate a dominant detrimental effect of HMBA on the NKG2D pathway that crucially controls NK cell-mediated killing of tumors and virus-infected cells, providing one possible explanation for poor clinical outcome in HMBA-treated cancer patients and raising concerns for future therapeutic application of this drug.
Quantitative proteomic changes in LPS-activated monocyte-derived dendritic cells: A SWATH-MS study
Authors: Arya Swati , Wiatrek-Moumoulidis Dagmara , Synowsky Silvia A. , Shirran Sally L. , Botting Catherine H. , Powis Simon J. , Stewart Alan J.
Published: March 2019

Dendritic cells are key immune cells that respond to pathogens and co-ordinate many innate and adaptive immune responses. Quantitative mass spectrometry using Sequential Window Acquisition of all THeoretical fragment-ion spectra-Mass Spectrometry (SWATH-MS) was performed here to determine the global alterations in monocyte-derived dendritic cells (moDCs) in response to stimulation with lipopolysaccharide (LPS). A moDC library of 4,666 proteins was generated and proteins were quantified at 0, 6 and 24 h post-LPS stimulation using SWATH-MS. At 6 h and 24 h post-LPS exposure, the relative abundance of 227 and 282 proteins was statistically significantly altered (p-value ≤ 0.05), respectively. Functional annotation of proteins exhibiting significant changes in expression between the various time points led to the identification of clusters of proteins implicated in distinct cellular processes including interferon and interleukin signalling, endocytosis, the ER-phagosome pathway and antigen-presentation. In SWATH-MS major histocompatibility complex (MHC) class I proteins were highly upregulated at 24 h, whilst MHC class II proteins exhibited comparatively fewer changes over this period. This study provides new detailed insight into the global proteomic changes that occur in moDCs during antigen processing and presentation and further demonstrates the potential of SWATH-MS for the quantitative study of proteins involved in cellular processes.
TiO2 decorated functionalized halloysite nanotubes (TiO2@HNTs) and photocatalytic PVC membranes synthesis, characterization and its application in water treatment
Authors: Mishra Gourav , Mukhopadhyay Mausumi
Published: March 2019

In this study photocatalyst, TiO2@HNTs were prepared by  synthesizing TiO2 nanoparticles in situ on the  functionalized halloysite nanotubes (HNTs) surface. Photocatalytic PVC membrane TiO2@HNTs M2 (2 wt.%) and TiO2@HNTs M3 (3 wt.%) were also prepared. Photocatalyst TiO2@HNTs and photocatalytic PVC membranes were used to study the photocatalytic activity against the methylene blue (MB) and rhodamine B (RB) dyes in UV batch reactor. The structure and morphology of photocatalyst and photocatalytic PVC membrane were characterized by fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive X-ray (EDX), transmission electron microscopy (TEM), UV-Vis spectrophotometer and photoluminescence (PL). The PL study showed that the oxygen vacancies and surface hydroxyl groups present on the surface of TiO2@HNTs act as excellent traps for charge carrier, reducing the electron-hole recombination rate.TiO2@HNTs 2 (2 wt.%) and TiO2@HNTs 3 (3 wt.%) degraded MB dye up to 83.21%, 87.47% and RB dye up to 96.84% and 96.87%, respectively. TiO2@HNT photocatalyst proved to be stable during the three consecutive cycle of photocatalytic degradation of the RB dye. TiO2@HNTs M2 and TiO2@HNTs M3 degraded MB dye up to 27.19%, 42.37% and RB dye up to 30.78%, 32.76%, respectively. Photocatalytic degradation of both the dyes followed the first-order kinetic model. Degradation product analysis was done using the liquid chromatography–mass spectrometry (LC-MS) and the results showed that the dye degradation was initiated by demethylation of the molecule. MB and RB dye degradation reaction were tested by TBA and IPA as OH* and H+ scavengers respectively. Mechanism of photocatalytic activity of TiO2@HNTs and photocatalytic PVC membrane were also explained.
Subchronic low-dose 2,4-D exposure changed plasma acylcarnitine levels and induced gut microbiome perturbations in mice
Authors: Tu Pengcheng , Gao Bei , Chi Liang , Lai Yunjia , Bian Xiaoming , Ru Hongyu , Lu Kun
Published: March 2019

The gut microbiota critically confers various health benefits, whereas environmental chemicals can affect its constitution and functionality thereby increasing disease risk. In the present study, we aim to evaluate the toxic effects of a wildly-used herbicide 2,4-D (2,4-dichlorophenoxyacetic acid) on the gut microbiome and host using an occupationally relevant dose. A mouse model was used combined with metagenomic sequencing and metabolomic profiling to examine the alterations induced by subchronic low-dose 2,4-D exposure in fecal and plasma samples. The metagenomics results revealed a distinct gut microbial community with profound changes in diverse microbial pathways including urea degradation, amino acid and carbohydrate metabolism in 2,4-D-treated mice. Moreover, the metabolomics results revealed that the metabolic profiles in treatment group were differentiated from control group in both fecal and plasma samples. Toxic effects on the host of 2,4-D at an occupationally relevant dose were observed indicated by decreased acylcarnitine levels in plasma. These findings indicated that 2,4-D can cause toxicity and substantially impact the gut microbiome in mice at occupationally relevant doses, inferring that the relationship between environmental contaminants and microbiota is largely underestimated calling for more comprehensive consideration of the toxicity of occupational exposures.
The BRAF-inhibitor PLX4720 inhibits CXCL8 secretion in BRAFV600E mutated and normal thyroid cells: a further anti-cancer effect of BRAF-inhibitors
Authors: Coperchini Francesca , Croce Laura , Denegri Marco , Awwad Oriana , Ngnitejeu Samuel Tata , Muzza Marina , Capelli Valentina , Latrofa Francesco , Persani Luca , Chiovato Luca , Rotondi Mario
Published: March 2019

CXCL8 is a chemokine secreted by normal and thyroid cancer cells with proven tumor-promoting effects. The presence of BRAFV600E mutation is associated with a more aggressive clinical behavior and increased ability to secrete CXCL8 by papillary-thyroid-cancer cells. Aim of this study was to test the effect of the BRAF-inhibitor (PLX4720) on the basal and TNF-α-induced CXCL8 secretions in BRAFV600E mutated (BCPAP, 8305C, 8505C), in RET/PTC rearranged (TPC-1) thyroid-cancer-cell-lines and in normal-human-thyrocytes (NHT). Cells were incubated with increasing concentrations of PLX4720 alone or in combination with TNF-α for 24-hours. CXCL8 concentrations were measured in the cell supernatants. PLX4720 dose-dependently inhibited the basal and the TNF-α-induced CXCL8 secretions in BCPAP (F: 14.3, p < 0.0001 for basal and F: 12.29 p < 0.0001 for TNF-α), 8305C (F: 407.9 p < 0.0001 for basal and F: 5.76 p < 0.0001 for TNF-α) and 8505C (F:55.24 p < 0.0001 for basal and F: 42.85 p < 0.0001 for TNF-α). No effect was found in TPC-1 (F: 1.8, p = 0.134 for basal; F: 1.6, p = 0.178 for TNF-α). In NHT an inhibitory effect was found only at the highest concentration of PLX4720 (F: 13.13 p < 0.001 for basal and F: 2.5 p < 0.01 for TNF-α). Cell migration assays showed that PLX4720 reduced both basal and CXCL8-induced cell migration in BCPAP, 8305C, 8505C and NHT but not in TPC-1 cells. These results constitutes the first demonstration that PLX4720 is able to inhibit the secretion of CXCL8 in BRAFV600E mutated thyroid cancer cells indicating that, at least some, of the anti-tumor activities of PLX4720 could be exerted through a lowering of CXCL8 in the thyroid-cancer-microenvironment.
No Effect of Bt-transgenic Rice on the Tritrophic Interaction of the Stored Rice, the Maize Weevil Sitophilus Zeamais and the Parasitoid Wasp Theocolax elegans
Authors: Tang Qingfeng , Yang Zhipeng , Han Rongrong , Zhang Ying , Shen Chen , Wang Jian
Published: March 2019

During Bt transgenic rice storage, Bt Cry1Ab/Cry1Ac fused protein is exposed to the maize weevil Sitophilus zeamais and the parasitoid wasp Theocolax elegans. We have carried out a long-term risk assessment for Bt rice to these non-target organisms in the storehouse. Effects of Bt rice on S. zeamais and T. elegans have been carefully detected in a laboratory experiment of over 5 years. The survival, development, fecundity, and longevity of the maize weevil were compared between Bt rice and non-Bt rice treatments for every 5 generations from generation 1 to 25. Moreover, the development, adult body size and sex ratio of T. elegans were compared between them parasitizing S. zeamais feeding on Bt rice or non-Bt rice. We found that although Bt Cry1Ab/Cry1Ac fused protein exists in the Bt rice grains and S. zeamais digestive tracts, Bt rice is not harmful to the maize weevil S. zeamais and its parasitoid T. elegans.
Evidence for polarized nanoregions from the domain dynamics in multiferroic LiCuVO4
Authors: Grams Christoph P. , Kopatz Severin , Brüning Daniel , Biesenkamp Sebastian , Becker Petra , Bohatý Ladislav , Lorenz Thomas , Hemberger Joachim
Published: March 2019

LiCuVO4 is a model system of a 1D spin-1/2 chain that enters a planar spin-spiral ground state below its Néel temperature of 2.4 K due to competing nearest and next nearest neighbor interactions. The spin-spiral state is multiferroic with an electric polarization along the a axis which has been proposed to be caused purely by the spin supercurrent mechanism. With external magnetic fields in c direction TN can be suppressed down to 0 K at 7.4 T. Here we report dynamical measurements of the polarization from P(E)-hysteresis loops, magnetic field dependent pyro-current and non-linear dielectric spectroscopy as well as thermal expansion and magnetostriction measurements at very low temperatures. The multiferroic transition is accompanied by strong anomalies in the thermal expansion and magnetostriction coefficients and we find slow switching times of electric domain reversal. Both observations suggest a sizable magnetoelastic coupling in LiCuVO4. By analyzing the non-linear polarization dynamics we derive domain sizes in the nm range that are probably caused by Li defects.
Rice seed priming with sodium selenate: Effects on germination, seedling growth, and biochemical attributes
Authors: Du Bin , Luo Haowen , He Longxin , Zhang Lihe , Liu Yangfang , Mo Zhaowen , Pan Shenggang , Tian Hua , Duan Meiyang , Tang Xiangru
Published: March 2019

The aim of this study was to determine the effects of sodium selenate (15, 30, 45, 60, 75, 90, and 105 mg kg−1) on the germination and seedling growth of Changnongjing 1 rice (Oryza sativa L.) at 25 °C and 30 °C. Low selenate concentrations induced shorter and more uniform germination periods than did ultrapure water at both temperatures. Seedlings primed with low selenate concentrations were superior to those primed with ultrapure water in terms of plant height, fresh weight, dry matter accumulation, and soluble carbohydrate and protein contents. Lower selenate concentrations (15–75 mg kg−1) induced higher chlorophyll and phenol contents in seedlings than did ultrapure water. Lower selenate concentrations also increased the superoxide dismutase (SOD), peroxidase (POX), catalase (CAT), and glutathione peroxidase (GPx) contents in seedlings and significantly decreased the stress-related malondialdehyde (MDA) content compared to ultrapure water. In conclusion, rice seedling germination and growth were promoted by priming with low selenate concentrations (15–75 mg kg−1) but inhibited by priming with high selenate concentrations (90–105 mg kg−1).
Integrative approach detects natural hybridization of sympatric lambaris species and emergence of infertile hybrids
Authors: Pinheiro Ana Paula Barbosa , Melo Rafael Magno Costa , Teixeira Daniel Fonseca , Birindelli José Luís Olivan , Carvalho Daniel Cardoso , Rizzo Elizete
Published: March 2019

Despite its relevance for ecology, evolution and conservation of species, natural hybridization and hybrids biology are still poorly studied in freshwater fish. Here, we tested the hypothesis that sympatric species Astyanax paranae and A. fasciatus are able to interbreed in the natural environment and presented evidence for the first record of hybridization between these species. We analyzed anatomical traits, gametogenesis, reproductive biology, and genetic variations of the COI and S7 genes of both species and putative hybrids. Intermediate morphometric and meristic features were observed in hybrids when compared to A. paranae and A. fasciatus. Overlap in reproductive season was showed for these species, with greater reproductive activity from August to January, but hybrids did not present any sign of gonadal maturation. Oogonia and perinucleolar follicles as well as spermatogonia and primary spermatocytes were found in hybrids, but previtellogenic and vitellogenic follicles, spermatids, and spermatozoa were absent. Moreover, several alterations in gametogenesis were detected, such as interrupted meiosis in both males and females, vacuolated and degenerated germ cells, increased interstitial tissue, and presence of immune cells. Molecular analyses supported the hypothesis of hybridization between A. paranae and A. fasciatus. Overall, our multidisciplinary approach also provides strong evidence that hybrids are infertile.
Combined congenic mapping and nuclease-based gene targeting for studying allele-specific effects of Tnfrsf9 within the Idd9.3 autoimmune diabetes locus
Authors: Forsberg Matthew H. , Foda Bardees , Serreze David V. , Chen Yi-Guang
Published: March 2019

Rodent complex trait genetic studies involving a cross between two inbred strains are usually followed by congenic mapping to refine the loci responsible for the phenotype. However, progressing from a chromosomal region to the actual causal gene remains challenging because multiple polymorphic genes are often closely linked. The goal of this study was to develop a strategy that allows candidate gene testing by allele-specific expression without prior knowledge of the credible causal variant.Tnfrsf9(encoding CD137) is a candidate gene for theIdd9.3type 1 diabetes (T1D) susceptibility locus in the nonobese diabetic (NOD) mouse model. A C57BL/10Sn (B10)-derived diabetes resistanceIdd9.3congenic region has been shown to enhance accumulation of CD137+regulatory T cells and serum soluble CD137 in NOD mice. By combining the power of congenic mapping and nuclease-based gene targeting, we established a system where a pair of F1 hybrids expressed either the B10 or NODTnfrsf9allele mimicking coisogenic strains. Using this approach, we demonstrated that the allelic difference in B10 and NODTnfrsf9alone was sufficient to cause differential accumulation of CD137+regulatory T cells and serum soluble CD137 levels. This strategy can be broadly applied to other rodent genetic mapping studies.
GlcNAc6ST3 is a keratan sulfate sulfotransferase for the protein-tyrosine phosphatase PTPRZ in the adult brain
Authors: Narentuya  , Takeda-Uchimura Yoshiko , Foyez Tahmina , Zhang Zui , Akama Tomoya O. , Yagi Hirokazu , Kato Koichi , Komatsu Yukio , Kadomatsu Kenji , Uchimura Kenji
Published: March 2019

Keratan sulfate (KS) is a carbohydrate side chain covalently attached to extracellular proteoglycans. KS is composed of disaccharide units of 6-sulfated N-acetylglucosamine (GlcNAc) and galactose. We have previously shown that GlcNAc-6-O-sulfotransferase (GlcNAc6ST) 1 encoded by Chst2 is an enzyme necessary for the synthesis of GlcNAc-6-sulfated KS chains that are required for neuronal plasticity in the visual cortex of the mouse brain during the critical period, but not in adulthood. Here, we show that GlcNAc-6-sulfated KS recognized by the R-10G anti-KS antibody, of which the minimum epitope structure is Galß1-4GlcNAc(6S)ß1-3Galß1-4GlcNAc(6S), distributes diffusely in neuropils and presents densely in close proximity to the perineuronal region of the perineuronal net (PNN)-positive neurons in the adult visual cortex. Surprisingly, GlcNAc6ST3, which was discovered as an intestinal GlcNAc6ST encoded by Chst5, is a major brain KS sulfotransferase expressed in oligodendrocytes in adulthood. Moreover, we identified an isoform of the protein-tyrosine phosphatase PTPRZ as a R-10G-reactive KS proteoglycan. These results indicate that GlcNAc6ST3 may play a role in synthesis of a component of PNN in the adult brain, and that the KS-modified isoform of PTPRZ encoded by Ptprz1 could be an extracellular molecule associated with PNNs.
Photoacoustic Wavefront Shaping with High Signal to Noise Ratio for Light Focusing Through Scattering Media
Authors: Sun Jialin , Zhang Bin , Feng Qi , He Huimei , Ding Yingchun , Liu Qiang
Published: March 2019

Noninvasive light focusing and imaging through a scattering medium can be achieved by wavefront shaping using the photoacoustic signal as feedback. Unfortunately, the signal to noise ratio (SNR) of the traditional photoacoustic method is very low, which limits the wavefront shaping focusing speed and intensity. In this paper, we propose a completely new photoacoustic-signal-extraction method which combines wavelet denoising and correlation detection. With this method, the SNR of the photoacoustic signal reaches 25.2, 6.5 times higher than that of the unprocessed photoacoustic signal. Moreover, we achieve the simultaneous multipoint focusing, which is crucial for improving the speed of scanning imaging. The superior performance of the proposed method was experimentally demonstrated in extracting and denoising the photoacoustic signals deeply buried in noise, one critical step in in vivo photoacoustic imaging.
Non-Invasive Monitoring of Functional State of Articular Cartilage Tissue with Label-Free Unsupervised Hyperspectral Imaging
Authors: Mahbub Saabah B. , Guller Anna , Campbell Jared M. , Anwer Ayad G. , Gosnell Martin E. , Vesey Graham , Goldys Ewa M.
Published: March 2019

Damage and degradation of articular cartilage leads to severe pain and loss of mobility. The development of new therapies for cartilage regeneration for monitoring their effect requires further study of cartilage, ideally at a molecular level and in a minimally invasive way. Hyperspectral microscopy is a novel technology which utilises endogenous fluorophores to non-invasively assess the molecular composition of cells and tissue. In this study, we applied hyperspectral microscopy to healthy bovine articular cartilage and osteoarthritic human articular cartilage to investigate its capacity to generate informative molecular data and characterise disease state and treatment effects. We successfully demonstrated label-free fluorescence identification of collagen type I and II – isolated in cartilage here for the first time and the co-enzymes free NADH and FAD which together give the optical redox ratio that is an important measure of metabolic activity. The intracellular composition of chondrocytes was also examined. Differences were observed in the molecular ratios within the superficial and transitional zones of the articular cartilage which appeared to be influenced by disease state and treatment. These findings show that hyperspectral microscopy could be useful for investigating the molecular underpinnings of articular cartilage degradation and repair. As it is non-invasive and non-destructive, samples can be repeatedly assessed over time, enabling true time-course experiments with in-depth molecular data. Additionally, there is potential for the hyperspectral approach to be adapted for patient examination to allow the investigation of cartilage state. This could be of advantage for assessment and diagnosis as well as treatment monitoring.