bluuebunny/crossref_metadata_2025 huggingface dataset:
Correction: Inotuzumab ozogamicin in pediatric patients with relapsed/refractory acute lymphoblastic leukemia
Authors: Bhojwani Deepa , Sposto Richard , Shah Nirali N. , Rodriguez Vilmarie , Yuan Constance , Stetler-Stevenson Maryalice , O’Brien Maureen M. , McNeer Jennifer L. , Quereshi Amrana , Cabannes Aurelie , Schlegel Paul , Rossig Claudia , Dalla-Pozza Luciano , August Keith , Alexander Sarah , Bourquin Jean-Pierre , Zwaan Michel , Raetz Elizabeth A. , Loh Mignon L. , Rheingold Susan R.
Published: March 2019

We thank the research coordinators and following physicians at pediatric cancer centers for contributing data to this project: Prashant Hiwarkar and Jayashree Motwani, Birmingham Women’s and Children’s Hospital, UK; Kelly Malone, Children’s Hospital of Colorado, USA; Mylene Bassal, Children’s Hospital of Eastern Ontario, Canada; Yoav Messinger and Joanna Perkins, Children’s Hospital of Minnesota, USA; Van Huynh, Children’s Hospital of Orange County, USA; Richard Ho, Children’s Hospital at Vanderbilt, USA; Joanne Chuah and Jessa Morales, Children’s Hospital at Westmead, Australia; Donald Wells, Dell Children’s Hospital, USA; Nicolas Boissel, Hospital Saint-Louis, France; Tannie Huang, Kaiser Permanente, USA; Stacey Marjerrison, McMaster Children’s Hospital, Canada; William Carroll and Joanna Pierro, New York University Langone Medical Center, USA; Ajay Vora, Sheffield Children’s Hospital, UK; Donna Lancaster, The Royal Marsden Hospital, UK; Lucie Šrámková, University Hospital Motol, Czech Republic; Chatchawin Assanasen, University of Texas Health Science Center, San Antonio, USA; Rupert Handgretinger, University of Tübingen, Germany.
Organic piezoelectric materials: milestones and potential
Authors: Guerin Sarah , Tofail Syed A. M. , Thompson Damien
Published: March 2019

Research on the piezoelectric response of biomolecules has intensified following demonstration of open circuit voltages of over 20 V in biopiezoelectric generators. Organic piezoelectric nanotubes, fibers, and micro-islands have been grown and studied; however, the lack of fundamental understanding of the piezoelectric effect in nature hinders the rational design of biomaterials to provide a tailor-made piezoelectric response. Advances in high performance computing have facilitated the use of quantum mechanical calculations to predict the full piezoelectric tensor of biomolecular crystals, including amino acids and small peptides. By identifying directions of high piezoelectric response, the simulations can guide experimental crystal growth, device fabrication and electrical testing, which have led to the demonstration of unprecedented piezoelectric responses in organic crystals on the order of 200 pC/N. These large responses arise from strong supramolecular dipoles, which can be tuned by molecular chemistry and packing, opening new opportunities for the realization of technologically useful piezoelectric devices from renewable materials. The amino acids predicted to exhibit the highest piezoelectric response, such as glycine, hydroxyproline and lysine, are anticipated to be used to engineer highly piezoelectric peptides in the future. With improved scaling of advanced computational methods, such as density functional perturbation theory, the research community can begin to efficiently screen peptide structures for enhanced electromechanical properties. This capability will accelerate the experimental development of devices and provide much-needed insight into the evolution of a hierarchical relation in biological materials starting from strongly piezoelectric building blocks.
Brain tyrosinase overexpression implicates age-dependent neuromelanin production in Parkinson’s disease pathogenesis
Authors: Carballo-Carbajal Iria , Laguna Ariadna , Romero-Giménez Jordi , Cuadros Thais , Bové Jordi , Martinez-Vicente Marta , Parent Annabelle , Gonzalez-Sepulveda Marta , Peñuelas Núria , Torra Albert , Rodríguez-Galván Beatriz , Ballabio Andrea , Hasegawa Takafumi , Bortolozzi Analía , Gelpi Ellen , Vila Miquel
Published: March 2019

In Parkinson’s disease (PD) there is a selective degeneration of neuromelanin-containing neurons, especially substantia nigra dopaminergic neurons. In humans, neuromelanin accumulates with age, the latter being the main risk factor for PD. The contribution of neuromelanin to PD pathogenesis remains unknown because, unlike humans, common laboratory animals lack neuromelanin. Synthesis of peripheral melanins is mediated by tyrosinase, an enzyme also present at low levels in the brain. Here we report that overexpression of human tyrosinase in rat substantia nigra results in age-dependent production of human-like neuromelanin within nigral dopaminergic neurons, up to levels reached in elderly humans. In these animals, intracellular neuromelanin accumulation above a specific threshold is associated to an age-dependent PD phenotype, including hypokinesia, Lewy body-like formation and nigrostriatal neurodegeneration. Enhancing lysosomal proteostasis reduces intracellular neuromelanin and prevents neurodegeneration in tyrosinase-overexpressing animals. Our results suggest that intracellular neuromelanin levels may set the threshold for the initiation of PD.
Regulation of atmospheric circulation controlling the tropical Pacific precipitation change in response to CO2 increases
Authors: Sohn Byung-Ju , Yeh Sang-Wook , Lee Ahreum , Lau William K. M.
Published: March 2019

The spatial pattern of precipitation responses to CO2 concentration increases significantly influences global weather and climate variability by altering the location of tropical heating in a warmer climate. In this study, we analyze the Coupled Model Intercomparison Project Phase 5 (CMIP5) climate model projections of tropical Pacific rainfall response to quadrupled increase of CO2. We found that the precipitation changes to the CO2 concentration increase cannot be interpreted by a weakening or strengthening of large-scale east–west coupling across the tropical Pacific basin, i.e., Walker circulation. By calculating the water vapor transport, we suggest instead that different responses of the Walker and Hadley circulations to the increasing CO2 concentration shape the details of the spatial pattern of precipitation in the tropical Pacific. Therefore, more regionally perturbed circulations over the tropical Pacific, which is influenced by the mean state change in the tropical Pacific and the enhanced precipitation outside the tropical Pacific, lead to greater increases in precipitation in the western equatorial Pacific as compared to the eastern tropical Pacific in a warmer climate.
Imaging inflammation using an activated macrophage probe with Slc18b1 as the activation-selective gating target
Authors: Park Sung-Jin , Kim Beomsue , Choi Sejong , Balasubramaniam Sivaraman , Lee Sung-Chan , Lee Jung Yeol , Kim Heon Seok , Kim Jun-Young , Kim Jong-Jin , Lee Yong-An , Kang Nam-Young , Kim Jin-Soo , Chang Young-Tae
Published: March 2019

Activated macrophages have the potential to be ideal targets for imaging inflammation. However, probe selectivity over non-activated macrophages and probe delivery to target tissue have been challenging. Here, we report a small molecule probe specific for activated macrophages, called CDg16, and demonstrate its application to visualizing inflammatory atherosclerotic plaques in vivo. Through a systematic transporter screen using a CRISPR activation library, we identify the orphan transporter Slc18b1/SLC18B1 as the gating target of CDg16.
A widely distributed diheme enzyme from Burkholderia that displays an atypically stable bis-Fe(IV) state
Authors: Rizzolo Kimberly , Cohen Steven E. , Weitz Andrew C. , López Muñoz Madeline M. , Hendrich Michael P. , Drennan Catherine L. , Elliott Sean J.
Published: March 2019

Bacterial diheme peroxidases represent a diverse enzyme family with functions that range from hydrogen peroxide (H2O2) reduction to post-translational modifications. By implementing a sequence similarity network (SSN) of the bCCP_MauG superfamily, we present the discovery of a unique diheme peroxidase BthA conserved in all Burkholderia. Using a combination of magnetic resonance, near-IR and Mössbauer spectroscopies and electrochemical methods, we report that BthA is capable of generating a bis-Fe(IV) species previously thought to be a unique feature of the diheme enzyme MauG. However, BthA is not MauG-like in that it catalytically converts H2O2 to water, and a 1.54-Å resolution crystal structure reveals striking differences between BthA and other superfamily members, including the essential residues for both bis-Fe(IV) formation and H2O2 turnover. Taken together, we find that BthA represents a previously undiscovered class of diheme enzymes, one that stabilizes a bis-Fe(IV) state and catalyzes H2O2 turnover in a mechanistically distinct manner.
Overeating, caloric restriction and breast cancer risk by pathologic subtype: the EPIGEICAM study
Authors: Lope Virginia , Martín Miguel , Castelló Adela , Ruiz Amparo , Casas Ana Mª , Baena-Cañada José Manuel , Antolín Silvia , Ramos-Vázquez Manuel , García-Sáenz José Ángel , Muñoz Montserrat , Lluch Ana , de Juan-Ferré Ana , Jara Carlos , Sánchez-Rovira Pedro , Antón Antonio , Chacón José Ignacio , Arcusa Angels , Jimeno Mª Angeles , Bezares Susana , Vioque Jesús , Carrasco Eva , Pérez-Gómez Beatriz , Pollán Marina
Published: March 2019

This study analyzes the association of excessive energy intake and caloric restriction with breast cancer (BC) risk taking into account the individual energy needs of Spanish women. We conducted a multicenter matched case-control study where 973 pairs completed lifestyle and food frequency questionnaires. Expected caloric intake was predicted from a linear regression model in controls, including calories consumed as dependent variable, basal metabolic rate as an offset and physical activity as explanatory. Overeating and caloric restriction were defined taking into account the 99% confidence interval of the predicted value. The association with BC risk, overall and by pathologic subtype, was evaluated using conditional and multinomial logistic regression models. While premenopausal women that consumed few calories (>20% below predicted) had lower BC risk (OR = 0.36; 95% CI = 0.21–0.63), postmenopausal women with an excessive intake (≥40% above predicted) showed an increased risk (OR = 2.81; 95% CI = 1.65–4.79). For every 20% increase in relative (observed/predicted) caloric intake the risk of hormone receptor positive (p-trend < 0.001) and HER2+ (p-trend = 0.015) tumours increased 13%, being this figure 7% for triple negative tumours. While high energy intake increases BC risk, caloric restriction could be protective. Moderate caloric restriction, in combination with regular physical activity, could be a good strategy for BC prevention.
Chimeric NANOG repressors inhibit glioblastoma growth in vivo in a context-dependent manner
Authors: Kuciak Monika , Mas Christophe , Borges Isabel , Sánchez-Gómez Pilar , Ruiz i Altaba Ariel
Published: March 2019

Targeting stemness promises new therapeutic strategies against highly invasive tumors. While a number of approaches are being tested, inhibiting the core transcription regulatory network of cancer stem cells is an attractive yet challenging possibility. Here we have aimed to provide the proof of principle for a strategy, previously used in developmental studies, to directly repress the targets of a salient stemness and pluripotency factor: NANOG. In doing so we expected to inhibit the expression of so far unknown mediators of pro-tumorigenic NANOG function. We chose NANOG since previous work showed the essential requirement for NANOG activity for human glioblastoma (GBM) growth in orthotopic xenografts, and it is apparently absent from many adult human tissues thus likely minimizing unwanted effects on normal cells. NANOG repressor chimeras, which we name NANEPs, bear the DNA-binding specificity of NANOG through its homeodomain (HD), and this is linked to transposable human repressor domains. We show that in vitro and in vivo, NANEP5, our most active NANEP with a HES1 repressor domain, mimics knock-down (kd) of NANOG function in GBM cells. Competition orthotopic xenografts also reveal the effectiveness of NANEP5 in a brain tumor context, as well as the specificity of NANEP activity through the abrogation of its function via the introduction of specific mutations in the HD. The transcriptomes of cells expressing NANEP5 reveal multiple potential mediators of pro-tumorigenic NANEP/NANOG action including intercellular signaling components. The present results encourage further studies on the regulation of context-dependent NANEP abundance and function, and the development of NANEP-based anti-cancer therapies.
Anomalous Release Kinetics of Prodigiosin from Poly-N-Isopropyl-Acrylamid based Hydrogels for The Treatment of Triple Negative Breast Cancer
Authors: Danyuo Y. , Ani C. J. , Salifu A. A. , Obayemi J. D. , Dozie-Nwachukwu S. , Obanawu V. O. , Akpan U. M. , Odusanya O. S. , Abade-Abugre M. , McBagonluri F. , Soboyejo W. O.
Published: March 2019

This paper presents the anomalous release kinetics of a cancer drug (prodigiosin) frompoly-n-isopropyl-acrylamide(P(NIPA))-based gels. The release exponents, n, which correspond to the drug release mechanisms, were found to be between 0.41 and 1.40. This is within a range that include Fickian case I (n = 0.45) and non-Fickian diffusion (case II) (n > 0.45) for cylindrical drug-loaded structures. The results, however, suggest that the release exponents, n, correspond mostly to anomalous case II and super case II transport mechanics with sigmoidal characteristics. The drug release kinetics of the P(NIPA)-based hydrogels are well described by bi-dose functions. The observed drug release behavour is related to the porosity of the hydrogels, which can be controlled by cross-linking and copolymerization with acrylamide, which also improves the hydrophilicity of the gels. The paper also presents the effects of cancer drug release on cell survival (%), as well as the cell metabolic activities of treated cells and non-treated cells. The implications of the results are discussed for the development of implantable thermosensitive gels for the controlled release of drugs for localized cancer treatment.
Role of metallic core for the stability of virus-like particles in strongly coupled electrostatics
Authors: Javidpour Leili , Lošdorfer Božič Anže , Podgornik Rudolf , Naji Ali
Published: March 2019

Electrostatic interactions play important roles in the formation and stability of viruses and virus-like particles (VLPs) through processes that often involve added, or naturally occurring, multivalent ions. Here, we investigate the electrostatic or osmotic pressure acting on the proteinaceous shell of a generic model of VLPs, comprising a charged outer shell and a metallic nanoparticle core, coated by a charged layer and bathed in an aqueous electrolyte solution. Motivated by the recent studies accentuating the role of multivalent ions for the stability of VLPs, we focus on the effects of multivalent cations and anions in an otherwise monovalent ionic solution. We perform extensive Monte-Carlo simulations based on appropriate Coulombic interactions that consistently take into account the effects of salt screening, the dielectric polarization of the metallic core, and the strong-coupling electrostatics due to multivalent ions. We specifically study the intricate roles these factors play in the electrostatic stability of the model VLPs. It is shown that while the insertion of a metallic nanoparticle by itself can produce negative, inward-directed, pressure on the outer shell, addition of only a small amount of multivalent counterions can robustly engender negative pressures, enhancing the VLP stability across a wide range of values for the system parameters.
Anastomosis Groups of Rhizoctonia solani associated with tomato foot rot in Pothohar Region of Pakistan
Authors: Gondal Amjad Shahzad , Rauf Abdul , Naz Farah
Published: March 2019

Rhizoctonia solani Kühn (teleomorph = Thanatephorus cucumeris (Frank) Donk) is one of the important soil-borne fungal pathogen, which infects tomato with typical symptoms of seedling damping-off and foot rot. During surveys (2014 and 2015 crop season) of nine tomato growing areas in Pothohar region of Pakistan, symptoms of foot rot were noted on approximately 33.4% of the plants observed at soil line level of the stem. Lesions on infected plant stems were irregular in shape, water-soaked, brown in colour manifesting sunken appearance. Fungal colonies isolated from stem portions of the diseased plants on malt extract agar medium were light grey to brown in colour with abundant mycelial growth and branched hyphae. A septum was always present in the branch of hyphae near the originating point with a slight constriction at the branch. No conidia or conidiophores were observed. All isolates were multinucleate when subjected to DAPI (4′,6-diamidino-2-phenylindole) stain. Based on morphological characteristics of fungal hyphae, isolates were identified as R. solani. Restriction analysis of PCR-amplified ribosomal DNA with four discriminant enzymes (MseI, AvaII, HincII, and MunI) and hyphal interactions with known tester strains confirmed these isolates belong to AG-3-PT (64.2%), AG-2-1 (14.2%), AG-2-2 (9.5%), AG-5 (7.1%) and AG-4-HGI (4.7%). AG-3-PT was widely distributed to major tomato growing areas while other groups were confined to distinct locations. Internal transcribed spacer (ITS) region of rDNA was amplified with the primers ITS1/ITS4 and sequenced which had 99–100% identity with the corresponding gene sequences of respective R. solani AGs. To confirm Koch’s postulates, four week old tomato plants were transplanted into 1.5 L plastic pots containing sterilized potting mixture i.e. sand: clay: farmyard manure, at the rate of 1:1:1. Soil inoculum containing 10 g of barley grains colonized with each isolate of R. solani for 14 days was mixed in the upper 2 cm layer of soil (Taheri and Tarighi, 2012). A set of uninoculated plants was used as a control. Ambient conditions were provided under the greenhouse. 21 days after inoculation, water-soaked greyish to brown lesions similar to the symptoms of the previous infection were observed on stem portions of all inoculated plants while control plants remained symptomless. Fungus re-isolated from infections was confirmed as R. solani by microscopic appearance of the hyphae. Present study is the first report of AG composition of R. solani infecting tomato in Pakistan which will be useful to breeding programs working on varietal evaluation.
Plasma cupping induces VEGF expression in skin cells through nitric oxide-mediated activation of hypoxia inducible factor 1
Authors: Lee Hyun-Young , Lee Hae-June , Kim Gyoo-Cheon , Choi Jeong-Hae , Hong Jin-Woo
Published: March 2019

Despite a long history, the clinical efficacy of cupping therapy is still under debate. This is likely due to the lack of direct evidence for the biological actions of cupping, since the short exposure of cells to vacuum condition rarely has affects cellular activity. In this study, the medicinal properties of a recent medical technology, non-thermal plasma, were added to classical cupping and designated as ‘plasma cupping’ (PC). In our results, the plasma-generating efficacy was increased under a cupping-like semi-vacuum condition (410 Torr) rather than normal atmospheric pressure (760 Torr). Notably, while cupping rarely affects the angiogenic factor vascular-endothelial growth factor (VEGF)-A, the PC treatment on HaCaT human keratinocytes significantly induced the expression of VEGF-A. The increased expression of the VEGF-A gene after the PC treatment was expected to be a result of PC-mediated ERK protein activation. The PC-mediated activation of ERK was essential for the activity of hypoxia inducible factor (HIF) 1 alpha, which is responsible for the PC-mediated expression of VEGF-A. The PC mediated increase of NO in the media was thought as a main reason for the elevated HIF-1 protein activity. In addition to the angiogenesis-promoting action of PC, it also showed anti-inflammatory activity by reducing TNF-α-mediated IL-1β and IL-6 expression. Taken together, this study indicates the potential for PC that could enhance the clinical efficacy of cupping by adding the effects of non-thermal plasma to traditional cupping.
Combined SIRT3 and SIRT5 deletion is associated with inner retinal dysfunction in a mouse model of type 1 diabetes
Authors: Lin Jonathan B. , Lin Joseph B. , Chen Howard C. , Chen Teresa , Apte Rajendra S.
Published: March 2019

Diabetic retinopathy (DR) is a major cause of blindness in working adults in the industrialized world. In addition to vision loss caused by macular edema and pathological angiogenesis, DR patients often exhibit neuronal dysfunction on electrophysiological testing, suggesting that there may be an independent neuronal phase of disease that precedes vascular disease. Given the tremendous metabolic requirements of the retina and photoreceptors in particular, we hypothesized that derangements in metabolic regulation may accelerate retinal dysfunction in diabetes. As such, we induced hyperglycemia with streptozotocin in mice with monoallelic Nampt deletion from rod photoreceptors, mice lacking SIRT3, and mice lacking SIRT5 and tested multiple components of retinal function with electroretinography. None of these mice exhibited accelerated retinal dysfunction after induction of hyperglycemia, consistent with normal-appearing retinal morphology in hyperglycemic Sirt3−/− or Sirt5−/− mice. However, mice lacking both SIRT3 and SIRT5 (Sirt3−/−Sirt5−/− mice) exhibited significant evidence of inner retinal dysfunction after induction of hyperglycemia compared to hyperglycemic littermate controls, although this dysfunction was not accompanied by gross morphological changes in the retina. These results suggest that SIRT3 and SIRT5 may be involved in regulating neuronal dysfunction in DR and provide a foundation for future studies investigating sirtuin-based therapies.
Quantifying Tip60 (Kat5) stratifies breast cancer
Authors: McGuire A. , Casey M. C. , Shalaby A. , Kalinina O. , Curran C. , Webber M. , Callagy G. , Holian E. , Bourke E. , Kerin M. J. , Brown J. A. L.
Published: March 2019

Breast cancer is stratified into four distinct clinical subtypes, using three key biomarkers (Her2/Neu gene status, Estrogen and Progesterone receptor status). However, each subtype is a heterogeneous group, displaying significant variation in survival rates and treatment response. New biomarkers are required to provide more precise stratification of breast cancer cohorts to inform personalised treatment options/predict outcomes. Tip60 is a member of the MYST sub-family of histone acetyltransferases (HATs), and is directly involved in genome maintenance, gene regulation and DNA damage response/repair pathways (key chemotherapeutic influencing mechanisms). We aimed to determine if quantifying Tip60 staining patterns improved breast cancer stratification. We defined Tip60 protein in vivo, quantifying location (cytoplasmic, nuclear), percent of cells and staining intensity in a breast cancer tissue microarray (n = 337). A significant association of specific Tip60 staining patterns with breast cancer subtype, ER or PR status and Tumour grade was found. Importantly, low Tip60 mRNA expression correlated with poor overall survival and relapse free survival. We found Tip60 is a biomarker able to stratify breast cancer patients, and low Tip60 expression is a significant risk factor indicating a higher chance of disease reoccurrence. This work highlights Tip60 regulation as a key factor influencing the development of breast cancer.
The epigenetic basis for the impaired ability of adult murine retinal pigment epithelium cells to regenerate retinal tissue
Authors: Dvoriantchikova Galina , Seemungal Rajeev J. , Ivanov Dmitry
Published: March 2019

The epigenetic plasticity of amphibian retinal pigment epithelium (RPE) allows them to regenerate the entire retina, a trait known to be absent in mammals. In this study, we investigated the epigenetic plasticity of adult murine RPE to identify possible mechanisms that prevent mammalian RPE from regenerating retinal tissue. RPE were analyzed using microarray, ChIP-seq, and whole-genome bisulfite sequencing approaches. We found that the majority of key genes required for progenitor phenotypes were in a permissive chromatin state and unmethylated in RPE. We observed that the majority of non-photoreceptor genes had promoters in a repressive chromatin state, but these promoters were in unmethylated or low-methylated regions. Meanwhile, the majority of promoters for photoreceptor genes were found in a permissive chromatin state, but were highly-methylated. Methylome states of photoreceptor-related genes in adult RPE and embryonic retina (which mostly contain progenitors) were very similar. However, promoters of these genes were demethylated and activated during retinal development. Our data suggest that, epigenetically, adult murine RPE cells are a progenitor-like cell type. Most likely two mechanisms prevent adult RPE from reprogramming and differentiating into retinal neurons: 1) repressive chromatin in the promoter regions of non-photoreceptor retinal neuron genes; 2) highly-methylated promoters of photoreceptor-related genes.
Peptide vaccine for semaphorin3E ameliorates systemic glucose intolerance in mice with dietary obesity
Authors: Yoshida Yohko , Shimizu Ippei , Hayashi Yuka , Ikegami Ryutaro , Suda Masayoshi , Katsuumi Goro , Wakasugi Takayuki , Nakao Masaaki , Nakagami Hironori , Morishita Ryuichi , Minamino Tohru
Published: March 2019

We previously demonstrated that cellular aging signals upregulated a secreted class 3 semaphorin E (Sema3E) and its receptor plexinD1 in the adipose tissue of a murine model of dietary obesity and that Sema3E was a chemoattractant, mediating its biological effects by inducing infiltration of plexinD1-positive inflammatory macrophages into the visceral white adipose tissue. This study was performed to develop a peptide vaccine for Sema3E and test its therapeutic potential in a murine model of dietary obesity. Two antigenic peptides were selected to generate neutralizing antibodies for a vaccine. These peptides were conjugated to keyhole limpet hemocyanin (KLH), and were administered with Freund’s adjuvant to obese wild-type male mice. The Sema3E antibody titer was analyzed by ELISA, and the biological effects of the peptides were tested in mice with dietary obesity. Among the two candidate peptides, the Sema3E antibody titer was significantly increased by injection of KLH-conjugated HKEGPEYHWS (Sema3E vaccine). Administration of Sema3E vaccine suppressed the infiltration of plexinD1-positive cells, ameliorated chronic inflammation in visceral white adipose tissue, and improved systemic glucose intolerance in mice with dietary obesity, suggesting that Sema3E vaccine has the potential to become a next generation therapy for obesity and diabetes.
Iws1 and Spt6 Regulate Trimethylation of Histone H3 on Lysine 36 through Akt Signaling and are Essential for Mouse Embryonic Genome Activation
Authors: Oqani Reza K. , Lin Tao , Lee Jae Eun , Kang Jeong Won , Shin Hyun Young , Il Jin Dong
Published: March 2019

The mRNA processing and export factor, Iws1, interacts with the histone H3/H4 chaperone, Spt6 (Supt6 in mouse gene ontology) and recruits the lysine methyltransferase, Setd2, to chromatin to regulate H3K36me3. This recruitment is known to be crucial for pre-mRNA splicing and Iws1 has been shown to interact with REF1/Aly to mediate mRNA export. However, the role of this complex has not yet been examined in embryonic development. Here, we show that knockdown of either Iws1 or Supt6 blocked embryo development, primarily at the 8/16-cell stage, indicating that Iws1 and Supt6 are crucial for mouse preimplantation development. In the knockdown embryos, we observed decreases in pre-mRNA splicing, mRNA export and the expression of the lineage-specific transcription factor, Nanog. We found that either Iws1 or Supt6 are required for H3K36 trimethylation and that concurrent knockdown of both Iws1 and Supt6 blocks embryonic development at the 2-cell stage. We show that H3K36me3 is modulated by the Pi3k/Akt pathway, as inhibition of this pathway reduced the global level of H3K36me3 while activation of the pathway increased the level of this modification in 2-cell embryos. We observed that Iws1 interacts with nuclear Akt in early embryos, and herein propose that Akt modulates H3K36me3 through interaction with Iws1. Together, our results indicate that the Iws1 and Supt6 play crucial roles in embryonic genome activation, lineage specification, and histone modification during mouse early development.
Interactive effects of drought and heat stresses on morpho-physiological attributes, yield, nutrient uptake and oxidative status in maize hybrids
Authors: Hussain Hafiz Athar , Men Shengnan , Hussain Saddam , Chen Yinglong , Ali Shafaqat , Zhang Sai , Zhang Kangping , Li Yan , Xu Qiwen , Liao Changqing , Wang Longchang
Published: March 2019

Maize is a sensitive crop to drought and heat stresses, particularly at the reproductive stages of development. The present study investigated the individual and interactive effects of drought (50% field capacity) and heat (38 °C/30 °C) stresses on morpho-physiological growth, yield, nutrient uptake and oxidative metabolism in two maize hybrids i.e., ‘Xida 889’ and ‘Xida 319’. The stress treatments were applied at tasseling stage for 15 days. Drought, heat and drought + heat stress caused oxidative stress by the over-production of ROS (O2−, H2O2, OH−) and enhanced malondialdehyde contents, which led to reduced photosynthetic components, nutrients uptake and yield attributes. The concurrent occurrence of drought and heat was more severe for maize growth than the single stress. However, both stresses induced the metabolites accumulation and enzymatic and non-enzymatic antioxidants to prevent the oxidative damage. The performance of Xida 899 was more prominent than the Xida 319. The greater tolerance of Xida 889 to heat and drought stresses was attributed to strong antioxidant defense system, higher osmolyte accumulation, and maintenance of photosynthetic pigments and nutrient balance compared with Xida 319.
Accumulation of magnetite by flotation on bubbles during decompression of silicate magma
Authors: Knipping Jaayke L. , Webster James D. , Simon Adam C. , Holtz François
Published: March 2019

Magnetite (Fe3O4) is an iron ore mineral that is globally mined especially for steel production. It is denser (5.15 g/cm3) than Earth’s crust (~2.7 g/cm3) and is expected to accumulate at the bottom of melt-rich magma reservoirs. However, recent studies revealed heterogeneous fluid bubble nucleation on oxide minerals such as magnetite during fluid degassing in volcanic systems. To test if the attachment on fluid bubbles is strong enough to efficiently float magnetite in silicate magma, decompression experiments were conducted at geologically relevant magmatic conditions with subsequent annealing to simulate re-equilibration after decompression. The results demonstrate that magnetite-bubble pairs do ascend in silicate melt, accumulating in an upper layer that grows during re-equilibration. This outcome contradicts the paradigm that magnetite must settle gravitationally in silicate melt.
Emergence of new antigenic epitopes in the glycoproteins of human respiratory syncytial virus collected from a US surveillance study, 2015–17
Authors: Bin Lu  , Liu Hui , Tabor David E. , Tovchigrechko Andrey , Qi Yanping , Ruzin Alexey , Esser Mark T. , Jin Hong
Published: March 2019

Respiratory syncytial virus (RSV) is a significant cause of lower respiratory tract infection in infants and elderly. To understand the evolution of neutralizing epitopes on the RSV glycoprotein (G) and fusion (F) proteins, we conducted a multi-year surveillance program (OUTSMART-RSV) in the US. Analysis of 1,146 RSV samples from 2015–2017 revealed a slight shift in prevalence from RSV A (58.7%) to B (53.7%) between the two seasons. RSV B was more prevalent in elderly (52.9% and 73.4%). Approximately 1% of the samples contained both RSV A and B viruses. All RSV A isolates were ON1 and almost all the B isolates were BA9 genotypes. Compared with the 2013 reference sequences, changes at the F antigenic sites of RSV B were greater than RSV A, which mainly occurred at antigenic sites V (L172Q/S173L at 99.6%), Ø (I206M/Q209K at 18.6%) and IV (E463D at 7%) of RSV B F. Sequence diversities in the G protein second hypervariable region were observed in the duplicated regions for RSV A and B, and at the G stop codon resulting in extension of 7 amino acids (22.1%) for RSV B in 2016–17. Thus, RSV surface glycoproteins are continuously evolving, and continued surveillance is important for the clinical evaluation of immunoprophylactic products.
Record-low coastal sea levels in the Northeast Pacific during the winter of 2013–2014
Authors: Wang Yaqi , Liu Hailong , Lin Pengfei , Yin Jianjun
Published: March 2019

During the winter of 2013–2014, the averaged tide gauge (TG) coastal sea level (CSL) anomaly north of 40°N was a record low of −107 mm for the period of 1948–2016. Statistical analysis indicates that this large drop was a once-in-a-century event and closely related to an unusual ocean warming event known as “The Blob”. The Blob developed in the NE Pacific during the winter of 2013–2014. Both the Blob and record-low CSL can be attributed to wind changes associated with an unusually high sea level pressure (SLP) pattern over the NE Pacific. The anomalous local longshore winds induced by the positive SLP anomalies caused strong offshore Ekman transport along the coast of NE Pacific, thereby leading to the record-low CSL. In addition, the steric sea level changes also contributed a significant part (17%) to the record-low CSL. The Pacific Decadal Oscillation (PDO), as the primary variability mode in the NE Pacific on decadal time scales, did not contribute to the emergence of this extreme CSL event.
The genetic legacy of continental scale admixture in Indian Austroasiatic speakers
Authors: Tätte Kai , Pagani Luca , Pathak Ajai K. , Kõks Sulev , Ho Duy Binh , Ho Xuan Dung , Sultana Gazi Nurun Nahar , Sharif Mohd Istiaq , Asaduzzaman Md , Behar Doron M. , Hadid Yarin , Villems Richard , Chaubey Gyaneshwer , Kivisild Toomas , Metspalu Mait
Published: March 2019

Surrounded by speakers of Indo-European, Dravidian and Tibeto-Burman languages, around 11 million Munda (a branch of Austroasiatic language family) speakers live in the densely populated and genetically diverse South Asia. Their genetic makeup holds components characteristic of South Asians as well as Southeast Asians. The admixture time between these components has been previously estimated on the basis of archaeology, linguistics and uniparental markers. Using genome-wide genotype data of 102 Munda speakers and contextual data from South and Southeast Asia, we retrieved admixture dates between 2000–3800 years ago for different populations of Munda. The best modern proxies for the source populations for the admixture with proportions 0.29/0.71 are Lao people from Laos and Dravidian speakers from Kerala in India. The South Asian population(s), with whom the incoming Southeast Asians intermixed, had a smaller proportion of West Eurasian genetic component than contemporary proxies. Somewhat surprisingly Malaysian Peninsular tribes rather than the geographically closer Austroasiatic languages speakers like Vietnamese and Cambodians show highest sharing of IBD segments with the Munda. In addition, we affirmed that the grouping of the Munda speakers into North and South Munda based on linguistics is in concordance with genome-wide data.
Epidemiologic features of enterovirus associated with hand, foot and mouth disease in 2013 and 2014 in Shenzhen, China
Authors: Xiao Kelin , Duan Lian , Peng Yun , Wu Maocai , Mai Guangxing , Yan Zehao , Chen Shuiwen , Lu Yihan
Published: March 2019

Hand, foot and mouth disease (HFMD) is responsible for a heavy economic and social burden in the Asia-Pacific region. Previous studies have shown that coxsackievirus A6 (CVA6) and coxsackievirus A10 (CVA10) have become the predominant agents of HFMD in mainland China in recent years, replacing enterovirus 71 (EV71) and coxsackievirus A16 (CVA16), although it is unclear if this is consistent throughout China. In this study, samples from 253 HFMD cases were collected in Shenzhen, China, from May 2013 through April 2014 to identify the etiological agent of HFMD. In total, 64.8% (164/253) of HFMD cases were enterovirus positive, in which 81.1% (133/164) were determined to be CVA6. The phylogenetic tree of the partial viral protein 1 sequence showed that the CVA6 isolates were divided into four clusters (Clusters A to D), and cluster D was further divided into four sub-clusters (Clusters D1 to D4). The 133 CVA6 samples isolated in our study were classified into cluster D4, in which the first identified sequence was isolated in Shenzhen in 2008. This study demonstrated that the CVA6 cluster D4, which is predominantly circulating in HFMD in mainland China, may have originated from a local strain identified in 2008 in Shenzhen.
Reactive centre loop dynamics and serpin specificity
Authors: Marijanovic Emilia M. , Fodor James , Riley Blake T. , Porebski Benjamin T. , Costa Mauricio G. S. , Kass Itamar , Hoke David E. , McGowan Sheena , Buckle Ashley M.
Published: March 2019

Serine proteinase inhibitors (serpins), typically fold to a metastable native state and undergo a major conformational change in order to inhibit target proteases. However, conformational lability of the native serpin fold renders them susceptible to misfolding and aggregation, and underlies misfolding diseases such as α1-antitrypsin deficiency. Serpin specificity towards its protease target is dictated by its flexible and solvent exposed reactive centre loop (RCL), which forms the initial interaction with the target protease during inhibition. Previous studies have attempted to alter the specificity by mutating the RCL to that of a target serpin, but the rules governing specificity are not understood well enough yet to enable specificity to be engineered at will. In this paper, we use conserpin, a synthetic, thermostable serpin, as a model protein with which to investigate the determinants of serpin specificity by engineering its RCL. Replacing the RCL sequence with that from α1-antitrypsin fails to restore specificity against trypsin or human neutrophil elastase. Structural determination of the RCL-engineered conserpin and molecular dynamics simulations indicate that, although the RCL sequence may partially dictate specificity, local electrostatics and RCL dynamics may dictate the rate of insertion during protease inhibition, and thus whether it behaves as an inhibitor or a substrate. Engineering serpin specificity is therefore substantially more complex than solely manipulating the RCL sequence, and will require a more thorough understanding of how conformational dynamics achieves the delicate balance between stability, folding and function required by the exquisite serpin mechanism of action.
IP-10 dried blood spots assay monitoring treatment efficacy in extrapulmonary tuberculosis in a low-resource setting
Authors: Hoel Ida Marie , Jørstad Melissa Davidsen , Marijani Msafiri , Ruhwald Morten , Mustafa Tehmina , Dyrhol-Riise Anne Ma
Published: March 2019

Treatment efficacy is difficult to evaluate in extrapulmonary tuberculosis (EPTB) patients. Interferon-γ inducible protein (IP-)10 has been suggested as a biomarker for response to treatment. We have investigated if IP-10 from dried plasma spots (DPS) or dried blood spots (DBS) can be used in treatment monitoring of EPTB patients in a low-resource setting of Zanzibar. IP-10 levels in plasma, DPS and DBS samples collected before, during (2 months) and after TB treatment of 36 EPTB patients (6 culture and/or Xpert MTB/RIF positive and 30 clinically diagnosed) and 8 pulmonary tuberculosis (PTB) patients, were quantified by an enzyme-linked immunosorbent assay. There was a high positive correlation between IP-10 measured in plasma and DPS and DBS, respectively. We found a significant decline in IP-10 levels from baseline to end of treatment in plasma, DPS and DBS, both in EPTB and PTB patients. The declines were observed already after 2 months in HIV negative patients. In conclusion, the DPS/DBS IP-10 assay allows for easy and manageable monitoring in low-resource settings and our findings suggest that IP-10 may serve as a biomarker for treatment efficacy in EPTB patients, albeit further studies in cohorts of patients with treatment failure and relapse are needed.
Egg-laying decisions based on olfactory cues enhance offspring fitness in Stomoxys calcitrans L. (Diptera: Muscidae)
Authors: Baleba Steve B. S. , Torto Baldwyn , Masiga Daniel , Weldon Christopher W. , Getahun Merid N.
Published: March 2019

Selection of oviposition substrate is critical in holometabolous insects. Female stable flies, Stomoxys calcitrans, locate and select vertebrate herbivore dung in which they lay their eggs. However, the preference for vertebrate herbivore dung by S. calcitrans females, its fitness consequences for offspring, and the semiochemicals used to locate and select oviposition substrates remain unclear. Using oviposition choice tests and life table bioassays we found that gravid female S. calcitrans prefer to oviposit on donkey and sheep dung, which also improves the performance of their offspring. GC-MS analysis followed by random forest classification identified β-citronellene and carvone as the most important predictive volatile organic compounds of donkey and sheep dung, respectively. In multiple choice oviposition bioassays, S. calcitrans laid more eggs in wet sand containing β-citronellene and carvone than in other treatments. The attractiveness of these compounds was confirmed in a field trial, with traps baited with β-citronellene and carvone catching more S. calcitrans. We conclude that gravid female S. calcitrans use semiochemical cues to choose oviposition substrates that maximise offspring fitness.
Acute effects of active breaks during prolonged sitting on subcutaneous adipose tissue gene expression: an ancillary analysis of a randomised controlled trial
Authors: Grace Megan S. , Formosa Melissa F. , Bozaoglu Kiymet , Bergouignan Audrey , Brozynska Marta , Carey Andrew L. , Veiga Camilla Bertuzzo , Sethi Parneet , Dillon Francis , Bertovic David A. , Inouye Michael , Owen Neville , Dunstan David W. , Kingwell Bronwyn A.
Published: March 2019

Active breaks in prolonged sitting has beneficial impacts on cardiometabolic risk biomarkers. The molecular mechanisms include regulation of skeletal muscle gene and protein expression controlling metabolic, inflammatory and cell development pathways. An active communication network exists between adipose and muscle tissue, but the effect of active breaks in prolonged sitting on adipose tissue have not been investigated. This study characterized the acute transcriptional events induced in adipose tissue by regular active breaks during prolonged sitting. We studied 8 overweight/obese adults participating in an acute randomized three-intervention crossover trial. Interventions were performed in the postprandial state and included: (i) prolonged uninterrupted sitting; or prolonged sitting interrupted with 2-minute bouts of (ii) light- or (iii) moderate-intensity treadmill walking every 20 minutes. Subcutaneous adipose tissue biopsies were obtained after each condition. Microarrays identified 36 differentially expressed genes between the three conditions (fold change ≥0.5 in either direction; p < 0.05). Pathway analysis indicated that breaking up of prolonged sitting led to differential regulation of adipose tissue metabolic networks and inflammatory pathways, increased insulin signaling, modulation of adipocyte cell cycle, and facilitated cross-talk between adipose tissue and other organs. This study provides preliminary insight into the adipose tissue regulatory systems that may contribute to the physiological effects of interrupting prolonged sitting.
The mechanics of abalone crawling on sharp objects without injury
Authors: Zhang Yun , Li Shanpeng , Zuo Pingcheng , Ji Jiaxin , Liu Jianlin
Published: March 2019

Despite the soft appearance of their feet, abalones can crawl quickly on sharp objects. Tests using rough substrates aligned with blades or posts found that the animal has two adaptations to guarantee its safety on these surfaces. Mechanical compression tests showed that the abalone foot muscle is inherently robust and can resist penetration by sharp objects. A finite element simulation indicated that to avoid being pierced, abalone controls the shape of its foot to wrap it around sharp objects, thereby greatly reducing the stress concentration. These analyses may aid the engineering of new materials and devices for fields including soft robotics and aircraft.
Phagosomal and mitochondrial alterations in RPE may contribute to KCNJ13 retinopathy
Authors: Toms Maria , Burgoyne Thomas , Tracey-White Dhani , Richardson Rose , Dubis Adam M. , Webster Andrew R. , Futter Clare , Moosajee Mariya
Published: March 2019

Mutations in KCNJ13 are associated with two retinal disorders; Leber congenital amaurosis (LCA) and snowflake vitreoretinal degeneration (SVD). We examined the retina of kcnj13 mutant zebrafish (obelixtd15, c.502T > C p.[Phe168Leu]) to provide new insights into the pathophysiology underlying these conditions. Detailed phenotyping of obelixtd15 fish revealed a late onset retinal degeneration at 12 months. Electron microscopy of the obelixtd15 retinal pigment epithelium (RPE) uncovered reduced phagosome clearance and increased mitochondrial number and size prior any signs of retinal degeneration. Melanosome distribution was also affected in dark-adapted 12-month obelixtd15 fish. At 6 and 12 months, ATP levels were found to be reduced along with increased expression of glial fibrillary acidic protein and heat shock protein 60. Quantitative RT-PCR of polg2, fis1, opa1, sod1/2 and bcl2a from isolated retina showed expression changes consistent with altered mitochondrial activity and retinal stress. We propose that the retinal disease in this model is primarily a failure of phagosome physiology with a secondary mitochondrial dysfunction. Our findings suggest that alterations in the RPE and photoreceptor cellular organelles may contribute to KCNJ13-related retinal degeneration and provide a therapeutic target.
Loading of AgNPs onto the surface of boron nitride nanosheets for determination of scopoletin in Atractylodes macrocephala
Authors: Yue Yinzi , Zeng Li , Wang Xiaopeng , Su Lianlin , Sun Mingming , Wu Bensheng , Yan Shuai
Published: March 2019

In this work, silver nanoparticles prepared by a molten salt method were deposited onto the surface of hexagonal boron nitride nanosheet (NS/AgNP) to from a composite. The synthesized nanocomposite was applied for surface modification of screen-printed electrode (SPE). The modified electrode showed a superior performance for electrochemical detection of scopoletin. The electrochemical behaviour of NS/AgNP/SPE was studied in detail. An electrocatalytic oxidation was observed and used for analytical determination of scopoletin concentration. The response of the proposed electrochemical sensing platform was linear over a wide detection range of 2 μM to 0.45 mM with a low limit of detection (LOD) of 0.89 μM. The NS/AgNP/SPE also showed excellent reproducibility and anti-interference property. In addition, the proposed scopoletin sensor was successfully used for the determination of scopoletin in Atractylodes macrocephala herb samples.