bluuebunny/crossref_metadata_2025 huggingface dataset:
CD123 target validation and preclinical evaluation of ADCC activity of anti-CD123 antibody CSL362 in combination with NKs from AML patients in remission
Authors: Xie L H , Biondo M , Busfield S J , Arruda A , Yang X , Vairo G , Minden M D
Published: June 2017

Despite the heterogeneity of acute myeloid leukemia (AML), overexpression of the interleukin-3 receptor-α (CD123) on both the more differentiated leukemic blast and leukemic stem cells (LSCs) provides a therapeutic target for antibody treatment. Here we present data on the potential clinical activity of the monoclonal antibody CSL362, which binds to CD123 with high affinity. We first validated the expression of CD123 by 100% (52/52) of patient samples and the correlation of NPM1 and FLT3-ITD mutations with the high frequency of CD123 in AML. In vitro studies demonstrated that CSL362 potently induced antibody-dependent cell cytotoxicity (ADCC) of AML blasts including CD34+CD38−CD123+ LSCs by natural killer cells (NKs). Importantly, compared with healthy donor (HD) NKs, NKs drawn from AML patients in remission had a comparable ADCC activity against leukemic cells; of note, during remission, immature NKs were five times higher in AML patients than that in HDs. Significantly, we report a case where leukemic cells were resistant to autologous ADCC; however, the blasts were effectively lysed by CSL362 together with donor-derived NKs after allogeneic hematopoietic stem cell transplantation. These studies highlight CSL362 as a promising therapeutic option following chemotherapy and transplant so as to improve the outcome of AML patients.
Near-infrared absorption of π-stacking columns composed of trioxotriangulene neutral radicals
Authors: Ikabata Yasuhiro , Wang Qi , Yoshikawa Takeshi , Ueda Akira , Murata Tsuyoshi , Kariyazono Kazuki , Moriguchi Miki , Okamoto Hiroshi , Morita Yasushi , Nakai Hiromi
Published: June 2017

A long-wavelength photoabsorption of organic molecules has been noticed because of the potential as materials. In addition to the extension of π conjugation, molecular aggregation has been utilized to realize the elongation of absorption wavelength. We report strong near-infrared absorptions of trioxotriangulene neutral radicals in the crystalline state and large-scale theoretical calculations of the radical assemblies interpreting the mechanism of optical properties. Polarized absorption spectra and X-ray diffraction of the crystals clarified that an unusual π-stacking column consisting of π-dimers is key for this absorption. Quantum chemical calculations based on time-dependent density functional theory revealed that the π-dimer shows an electronic transition between frontier orbitals generated by strong coupling of the delocalized singly occupied orbitals of monomers. The interdimer interaction of transition dipole moments, which are parallel to the column, elucidated the increase of absorption wavelength. The divide-and-conquer Green function method enabled the large-scale time-dependent density functional theory calculation up to a 60mer, where the maximum number of atoms is 4380, reproducing the near-infrared absorptions of trioxotriangulene crystals. The present method to investigate the mechanism of the long-wavelength photoabsorption is useful for developing organic materials consisting of stable neutral radicals.
H5N1 influenza vaccine induces a less robust neutralizing antibody response than seasonal trivalent and H7N9 influenza vaccines
Authors: Wong Sook-San , DeBeauchamp Jennifer , Zanin Mark , Sun Yilun , Tang Li , Webby Richard
Published: June 2017

Conventional inactivated avian influenza vaccines have performed poorly in past vaccine trials, leading to the hypothesis that they are less immunogenic than seasonal influenza vaccines. We tested this hypothesis by comparing the immunogenicity of the H5N1 and H7N9 vaccines (avian influenza vaccines) to a seasonal trivalent inactivated influenza vaccine in naïve ferrets, administered with or without the adjuvants MF59 or AS03. Vaccine immunogenicity was assessed by measuring neutralizing antibody titers against hemagglutinin and neuraminidase and by hemagglutinin -specific IgG levels. Two doses of unadjuvanted vaccines induced low or no HA-specific IgG responses and hemagglutination-inhibiting titers. Adjuvanted vaccines induced comparable IgG-titers, but poorer neutralizing antibody titers for the H5 vaccine. All adjuvanted vaccines elicited detectable anti- neuraminidase -antibodies with the exception of the H5N1 vaccine, likely due to the low amounts of neuraminidase in the vaccine. Overall, the H5N1 vaccine had poorer capacity to induce neutralizing antibodies, but not HA-specific IgG, compared to H7N9 or trivalent inactivated influenza vaccine.
Protection against inhalation anthrax by immunization with Salmonella enterica serovar Typhi Ty21a stably producing protective antigen of Bacillus anthracis
Authors: Sim B. Kim Lee , Li Minglin , Osorio Manuel , Wu Yun , Wai Tint T. , Peterson Johnny W. , James Eric R. , Chakravarty Sumana , Gao Lixin , Xu Rui , KC Natasha , Stafford Richard E. , Lawrence William S. , Yeager Linsey A. , Peel Jennifer E. , Sivasubramani Satheesh K. , Chopra Ashok K. , Filippova Svetlana , Hoffman Stephen L.
Published: June 2017

The national blueprint for biodefense concluded that the United States is underprepared for biological threats. The licensed anthrax vaccine absorbed vaccine, BioThrax, requires administration of at least 3–5 intramuscular doses. The anthrax vaccine absorbed vaccine consists of complex cell-free culture filtrates of a toxigenic Bacillus anthracis strain and causes tenderness at the injection site and significant adverse events. We integrated a codon-optimized, protective antigen gene of B. anthracis (plus extracellular secretion machinery), into the chromosome of the licensed, oral, live-attenuated typhoid fever vaccineTy21a to form Ty21a-PA-01 and demonstrated excellent expression of the gene encoding protective antigen. We produced the vaccine in a 10-L fermenter; foam-dried and vialed it, and characterized the dried product. The vaccine retained ~50% viability for 20 months at ambient temperature. Sera from animals immunized by the intraperitoneal route had high levels of anti-protective antigen antibodies by enzyme-linked immunosorbent assay and anthrax lethal toxin-neutralizing activity. Immunized mice were fully protected against intranasal challenge with ~5 LD50 of B. anthracis Sterne spores, and 70% (7/10) of vaccinated rabbits were protected against aerosol challenge with 200 LD50 of B. anthracis Ames spores. There was a significant correlation between protection and antibody levels determined by enzyme-linked immunosorbent assay and toxin-neutralizing activity. These data provide the foundation for achievement of our ultimate goal, which is to develop an oral anthrax vaccine that is stable at ambient temperatures and induces the rapid onset of durable, high-level protection after a 1-week immunization regimen.
mTFkb: a knowledgebase for fundamental annotation of mouse transcription factors
Authors: Sun Kun , Wang Huating , Sun Hao
Published: June 2017

Transcription factors (TFs) are well-known important regulators in cell biology and tissue development. However, in mouse, one of the most widely-used model species, currently the vast majority of the known TFs have not been functionally studied due to the lack of sufficient annotations. To this end, we collected and analyzed the whole transcriptome sequencing data from more than 30 major mouse tissues and used the expression profiles to annotate the TFs. We found that the expression patterns of the TFs are highly correlated with the histology of the tissue types thus can be used to infer the potential functions of the TFs. Furthermore, we found that as many as 30% TFs display tissue-specific expression pattern, and these tissue-specific TFs are among the key TFs in their corresponding tissues. We also observed signals of divergent transcription associated with many TFs with unique expression pattern. Lastly, we have integrated all the data, our analysis results as well as various annotation resources to build a web-based database named mTFkb freely accessible at htt﻿p://www.m﻿yogenesisdb.org/mTFkb/. We believe that mTFkb could serve as a useful and valuable resource for TF studies in mouse.
Leukocyte Bim deficiency does not impact atherogenesis in ldlr
−/− mice, despite a pronounced induction of autoimmune inflammation
Authors: Temmerman Lieve , Westra Marijke M. , Bot Ilze , van Vlijmen Bart J. M. , van Bree Niek , Bot Martine , Habets Kim L. L. , Keulers Tom G. H. , van der Vlag Johan , Cotter Thomas G. , van Berkel Theo J. C. , Biessen Erik A. L.
Published: June 2017

Proapoptotic Bcl-2 family member Bim is particularly relevant for deletion of autoreactive and activated T and B cells, implicating Bim in autoimmunity. As atherosclerosis is a chronic inflammatory process with features of autoimmune disease, we investigated the impact of hematopoietic Bim deficiency on plaque formation and parameters of plaque stability. Bim−/− or wild type bone marrow transplanted ldlr−/− mice were fed a Western type diet (WTD) for 5 or 10 weeks, after which they were immunophenotyped and atherosclerotic lesions were analyzed. Bim−/− transplanted mice displayed splenomegaly and overt lymphocytosis. CD4+ and CD8+ T cells were more activated (increased CD69 and CD71 expression, increased interferon gamma production). B cells were elevated by 147%, with a shift towards the pro-atherogenic IgG-producing B2 cell phenotype, resulting in a doubling of anti-oxLDL IgG1 antibody titers in serum of bim−/− mice. Bim−/− mice displayed massive intraplaque accumulation of Ig complexes and of lesional T cells, although this did not translate in changes in plaque size or stability features (apoptotic cell and macrophage content). The surprising lack in plaque phenotype despite the profound pro-atherogenic immune effects may be attributable to the sharp reduction of serum cholesterol levels in WTD fed bim−/− mice.
Controlled functional expression of the bacteriocins pediocin PA-1 and bactofencin A in Escherichia coli
Authors: Mesa-Pereira Beatriz , O’Connor Paula M. , Rea Mary C. , Cotter Paul D. , Hill Colin , Ross R. Paul
Published: June 2017

The bacteriocins bactofencin A (class IId) and pediocin PA-1 (class IIa) are encoded by operons with a similarly clustered gene organization including a structural peptide, an immunity protein, an ABC transporter and accessory bacteriocin transporter protein. Cloning of these operons in E. coli TunerTM (DE3) on a pETcoco-2 derived vector resulted in successful secretion of both bacteriocins. A corresponding approach, involving the construction of vectors containing different combinations of these genes, revealed that the structural and the transporter genes alone are sufficient to permit heterologous production and secretion in this host. Even though the accessory protein, usually associated with optimal disulfide bond formation, was not required for bacteriocin synthesis, its presence did result in greater pediocin PA-1 production. The simplicity of the system and the fact that the associated bacteriocins could be recovered from the extracellular medium provides an opportunity to facilitate protein engineering and the overproduction of biologically-active bacteriocins at industrial scale. Additionally, this system could enable the characterization of new bacteriocin operons where genetic tools are not available for the native producers.
RCAN-11R peptide provides immunosuppression for fully mismatched islet allografts in mice
Authors: Noguchi Hirofumi , Sugimoto Koji , Miyagi-Shiohira Chika , Nakashima Yoshiki , Kobayashi Naoya , Saitoh Issei , Watanabe Masami , Noguchi Yasufumi
Published: June 2017

Calcineurin inhibitors have been used for transplant therapy. However, the inhibition of calcineurin outside the immune system has a number of side effects. We previously developed a cell-permeable inhibitor of NFAT (nuclear factor of activated T cells) using the polyarginine peptide delivery system. This peptide (11R-VIVIT) selectively interferes with calcineurin-NFAT interaction without affecting the activity of calcineurin phosphatase and provides immunosuppression for fully mismatched islet allografts in mice. However, our recent study showed that 11R-VIVIT affected cell viability in vitro when it was used at higher concentration because of the VIVIT sequence. The aim of this study is to develop a safer NFAT inhibitor (RCAN-11R) that does not affect cell viability, and which is less toxic than calcineurin inhibitors. The minimal sequence of the protein family of regulators of calcineurin (RCAN) that is responsible for the inhibition of calcineurin-NFAT signaling was recently characterized. The peptide could selectively interfere with the calcineurin-NFAT interaction without affecting the activity of calcineurin phosphatase, similar to 11R-VIVIT. RCAN-11R did not affect cell viability when it was used at a higher concentration than the toxic concentration of 11R-VIVIT. RCAN-11R could therefore be useful as a therapeutic agent that is less toxic than current drugs or 11R-VIVIT.
Geographic variation in pneumococcal vaccine efficacy estimated from dynamic modeling of epidemiological data post-PCV7
Authors: Gjini Erida
Published: June 2017

Although mean efficacy of multivalent pneumococcus vaccines has been intensively studied, variance in vaccine efficacy (VE) has been overlooked. Different net individual protection across settings can be driven by environmental conditions, local serotype and clonal composition, as well as by socio-demographic and genetic host factors. Understanding efficacy variation has implications for population-level effectiveness and other eco-evolutionary feedbacks. Here I show that realized VE can vary across epidemiological settings, by applying a multi-site-one-model approach to data post-vaccination. I analyse serotype prevalence dynamics following PCV7, in asymptomatic carriage in children attending day care in Portugal, Norway, France, Greece, Hungary and Hong-Kong. Model fitting to each dataset provides site-specific estimates for vaccine efficacy against acquisition, and pneumococcal transmission parameters. According to this model, variable serotype replacement across sites can be explained through variable PCV7 efficacy, ranging from 40% in Norway to 10% in Hong-Kong. While the details of how this effect is achieved remain to be determined, here I report three factors negatively associated with the VE readout, including initial prevalence of serotype 19F, daily mean temperature, and the Gini index. The study warrants more attention on local modulators of vaccine performance and calls for predictive frameworks within and across populations.
Storage of neural histamine and histaminergic neurotransmission is VMAT2 dependent in the zebrafish
Authors: Puttonen Henri A. J. , Semenova Svetlana , Sundvik Maria , Panula Pertti
Published: June 2017

Monoaminergic neurotransmission is greatly dependent on the function of the vesicular monoamine transporter VMAT2, which is responsible for loading monoamines into secretory vesicles. The role of VMAT2 in histaminergic neurotransmission is poorly understood. We studied the structure and function of the histaminergic system in larval zebrafish following inhibition of VMAT2 function by reserpine. We found that reserpine treatment greatly reduced histamine immunoreactivity in neurons and an almost total disappearance of histamine-containing nerve fibers in the dorsal telencephalon and habenula, the most densely innervated targets of the hypothalamic histamine neurons. The reserpine treated larvae had an impaired histamine-dependent dark-induced flash response seen during the first second after onset of darkness, implying that function of the histaminergic network is VMAT2 dependent. Levels of histamine and other monoamines were decreased in reserpine treated animals. This study provides conclusive evidence of the relevance of VMAT2 in histaminergic neurotransmission, further implying that the storage and release mechanism of neural histamine is comparable to that of other monoamines. Our results also reveal potential new insights about the roles of monoaminergic neurotransmitters in the regulation of locomotion increase during adaptation to darkness.
Detection of DNA Amplicons of Polymerase Chain Reaction Using Litmus Test
Authors: Chang Dingran , Tram Kha , Li Ben , Feng Qian , Shen Zhifa , Lee Christine H. , Salena Bruno J. , Li Yingfu
Published: June 2017

We report on a new colorimetric DNA detection method that takes advantage of the power of polymerase chain reaction (PCR) and the simplicity of the classic litmus test. The strategy makes use of a modified set of primers for PCR to facilitate ensuing manipulations of resultant DNA amplicons: their tagging with urease and immobilization onto magnetic beads. The amplicon/urease-laden beads are then used to hydrolyze urea, resulting in the increase of pH that can be conveniently reported by a pH-sensitive dye. We have successfully applied this strategy for the detection of two hypervirulent strains of the bacterium Clostridium difficile that are responsible for the recent increase in the global incidence and severity of C. difficile infections. Furthermore, the viability of this test for diagnostic applications is demonstrated using clinically validated stool samples from C. difficile infected patients.
Comprehensive study of excess phosphate response reveals ethylene mediated signaling that negatively regulates plant growth and development
Authors: Shukla Devesh , Rinehart Claire A. , Sahi Shivendra V.
Published: June 2017

Excess Phosphorus (P) in agriculture is causing serious environmental problems like eutrophication of lakes and rivers. Unlike the enormous information available for phosphate starvation response (P0), very few information is available for the effect of excess phosphate Pi on plants. Characterization of Excess Phosphate Response (EPiR) is essential for designing strategies to increase phosphate accumulation and tolerance. We show a significant modulation in the root developmental plasticity under the increasing supply of excess Pi. An excess supply of 20 mM Pi (P20) produces a shallow root system architecture (RSA), reduces primary root growth, root apical meristem size, and meristematic activity in Arabidopsis. The inhibition of primary root growth and development is indeterminate in nature and caused by the decrease in number of meristematic cortical cells due to EPiR. Significant changes occurred in metal nutrients level due to excess Pi supply. A comparative microarray investigation of the EPiR response reveals a modulation in ethylene biosynthesis and signaling, metal ions deficiency response, and root development related genes. We used ethylene-insensitive or sensitive mutants to provide more evidence for ethylene-mediated signaling. A new role of EPiR in regulating the developmental responses of plants mediated by ethylene has been demonstrated.
Optical mapping of neuronal activity during seizures in zebrafish
Authors: Turrini L. , Fornetto C. , Marchetto G. , Müllenbroich M. C. , Tiso N. , Vettori A. , Resta F. , Masi A. , Mannaioni G. , Pavone F. S. , Vanzi F.
Published: June 2017

Mapping neuronal activity during the onset and propagation of epileptic seizures can provide a better understanding of the mechanisms underlying this pathology and improve our approaches to the development of new drugs. Recently, zebrafish has become an important model for studying epilepsy both in basic research and in drug discovery. Here, we employed a transgenic line with pan-neuronal expression of the genetically-encoded calcium indicator GCaMP6s to measure neuronal activity in zebrafish larvae during seizures induced by pentylenetretrazole (PTZ). With this approach, we mapped neuronal activity in different areas of the larval brain, demonstrating the high sensitivity of this method to different levels of alteration, as induced by increasing PTZ concentrations, and the rescuing effect of an anti-epileptic drug. We also present simultaneous measurements of brain and locomotor activity, as well as a high-throughput assay, demonstrating that GCaMP measurements can complement behavioural assays for the detection of subclinical epileptic seizures, thus enabling future investigations on human hypomorphic mutations and more effective drug screening methods. Notably, the methodology described here can be easily applied to the study of many human neuropathologies modelled in zebrafish, allowing a simple and yet detailed investigation of brain activity alterations associated with the pathological phenotype.
Prenatal chromium exposure and risk of preterm birth: a cohort study in Hubei, China
Authors: Pan Xinyun , Hu Jie , Xia Wei , Zhang Bin , Liu Wenyu , Zhang Chuncao , Yang Jie , Hu Chen , Zhou Aifen , Chen Zhong , Cao Jiangxia , Zhang Yiming , Wang Youjie , Huang Zheng , Lv Bin , Song Ranran , Zhang Jianduan , Xu Shunqing , Li Yuanyuan
Published: June 2017

Few studies have investigated the association of environmental chromium exposure and preterm birth in general population. This study was designed to investigate whether maternal chromium exposure during pregnancy is associated with reduced gestational age or risk of preterm birth using the data from Healthy Baby Cohort study conducted in Hubei, China between 2012 and 2014 (n = 7290). Chromium concentrations in maternal urine samples collected at delivery were measured with inductively coupled plasma mass spectrometry. Tertiles of chromium concentrations was negatively associated with gestational age in multivariable linear regression analyses [β (95% CI): low = reference; middle = −0.67 days (−1.14, −0.20); high = −2.30 days (−2.93, −1.67); p trend <0.01]. Logistic regression analyses also indicated that higher maternal chromium [adjusted odds ratio (OR) (95% CI): 1.55(0.99, 2.42) for the medium tertile; 1.89(1.13, 3.18) for the highest tertile; p trend <0.01] was associated with increased risk of preterm birth. The associations appeared to be more pronounced in male infants (adjusted OR (95% CI): 2.54 (1.29, 4.95) for the medium tertile; 2.92 (1.37, 6.19) for the highest tertile; p trend <0.01). Our findings suggest maternal exposure to higher chromium levels during pregnancy may potentially increase the risk of delivering preterm infants, particularly for male infants.
Lapatinib potentiates cytotoxicity of YM155 in neuroblastoma via inhibition of the ABCB1 efflux transporter
Authors: Radic-Sarikas Branka , Halasz Melinda , Huber Kilian V. M. , Winter Georg E. , Tsafou Kalliopi P. , Papamarkou Theodore , Brunak Søren , Kolch Walter , Superti-Furga Giulio
Published: June 2017

Adverse side effects of cancer agents are of great concern in the context of childhood tumors where they can reduce the quality of life in young patients and cause life-long adverse effects. Synergistic drug combinations can lessen potential toxic side effects through lower dosing and simultaneously help to overcome drug resistance. Neuroblastoma is the most common cancer in infancy and extremely heterogeneous in clinical presentation and features. Applying a systematic pairwise drug combination screen we observed a highly potent synergy in neuroblastoma cells between the EGFR kinase inhibitor lapatinib and the anticancer compound YM155 that is preserved across several neuroblastoma variants. Mechanistically, the synergy was based on a lapatinib induced inhibition of the multidrug-resistance efflux transporter ABCB1, which is frequently expressed in resistant neuroblastoma cells, which allowed prolonged and elevated cytotoxicity of YM155. In addition, the drug combination (i.e. lapatinib plus YM155) decreased neuroblastoma tumor size in an in vivo model.
Characterization of a new murine cell line of sarcomatoid hepatocellular carcinoma and its application for biomarker/therapy development
Authors: Yen Chia-Hung , Lai Chih-Chung , Liao Chen-Chung , Wang Sheng-Fan , Liao Yi-Jen , Tung Chien-Yi , Hung Jung-Hsien , Huang Shiu-Feng , Chen Yi-Ming Arthur
Published: June 2017

Sarcomatoid hepatocellular carcinoma (SHC) is a rare type of HCC with significantly poorer survival than ordinary HCC. Little is known about the mechanism associated with SHC and its biomarkers and therapy. Here, we established a mouse liver cancer cell line and designated as Ymac-1. A sarcomatous appearance was observed in the allograft tumor arose from Ymac-1. Liver-secreted plasma proteins were found in Ymac-1 cultured supernatant by proteomics analysis. The positive staining of CK7, CK8, Vimentin and the suppressed expression of AFP indicated that Ymac-1 is a SHC cell line. Compared to its original tumor, an elevated level of EMT markers, N-cadherin and Vimentin, was found in Ymac-1. Ymac-1 displayed a higher migration rate and side population percentage than a mouse ordinary HCC cell line-Hepa1-6. Microarray analysis was performed to identify potential biomarkers/therapeutic targets for SHC. G6pd, a vital enzyme in pentose phosphate pathway, is highly expressed in Ymac-1. Depletion of G6pd in Ymac-1 reduced CD133 expression and sphere formation. Positive correlations between G6PD and CD133 were observed in human specimen. Higher expression of both G6PD and CD133 in tumor were associated with poor survival. In summary Ymac-1 can be a useful SHC cell model for novel biomarker and therapy development.
Sortase A-mediated crosslinked short-chain dehydrogenases/reductases as novel biocatalysts with improved thermostability and catalytic efficiency
Authors: Li Kunpeng , Zhang Rongzhen , Xu Yan , Wu Zhimeng , Li Jing , Zhou Xiaotian , Jiang Jiawei , Liu Haiyan , Xiao Rong
Published: June 2017

(S)-carbonyl reductase II (SCRII) from Candida parapsilosis is a short-chain alcohol dehydrogenase/reductase. It catalyses the conversion of 2-hydroxyacetophenone to (S)-1-phenyl-1,2-ethanediol with low efficiency. Sortase was reported as a molecular “stapler” for site-specific protein conjugation to strengthen or add protein functionality. Here, we describe Staphylococcus aureus sortase A-mediated crosslinking of SCRII to produce stable catalysts for efficient biotransformation. Via a native N-terminal glycine and an added GGGGSLPETGG peptide at C-terminus of SCRII, SCRII subunits were conjugated by sortase A to form crosslinked SCRII, mainly dimers and trimers. The crosslinked SCRII showed over 6-fold and 4-fold increases, respectively, in activity and kcat/Km values toward 2-hydroxyacetophenone compared with wild-type SCRII. Moreover, crosslinked SCRII was much more thermostable with its denaturation temperature (Tm) increased to 60 °C. Biotransformation result showed that crosslinked SCRII gave a product optical purity of 100% and a yield of >99.9% within 3 h, a 16-fold decrease in transformation duration with respect to Escherichia coli/pET-SCRII. Sortase A-catalysed ligation also obviously improved Tms and product yields of eight other short-chain alcohol dehydrogenases/reductases. This work demonstrates a generic technology to improve enzyme function and thermostability through sortase A-mediated crosslinking of oxidoreductases.
Intrinsic functional connectivity reduces after first-time exposure to short-term gravitational alterations induced by parabolic flight
Authors: Van Ombergen Angelique , Wuyts Floris L. , Jeurissen Ben , Sijbers Jan , Vanhevel Floris , Jillings Steven , Parizel Paul M. , Sunaert Stefan , Van de Heyning Paul H. , Dousset Vincent , Laureys Steven , Demertzi Athena
Published: June 2017

Spaceflight severely impacts the human body. However, little is known about how gravity and gravitational alterations affect the human brain. Here, we aimed at measuring the effects of acute exposure to gravity transitions. We exposed 28 naïve participants to repetitive alterations between normal, hyper- and microgravity induced by a parabolic flight (PF) and measured functional MRI connectivity changes. Scans were acquired before and after the PF. To mitigate motion sickness, PF participants received scopolamine prior to PF. To account for the scopolamine effects, 12 non-PF controls were scanned prior to and after scopolamine injection. Changes in functional connectivity were explored with the Intrinsic Connectivity Contrast (ICC). Seed-based analysis on the regions exhibiting localized changes was subsequently performed to understand the networks associated with the identified nodes. We found that the PF group was characterized by lower ICC scores in the right temporo-parietal junction (rTPJ), an area involved in multisensory integration and spatial tasks. The encompassed network revealed PF-related decreases in within- and inter-hemispheric anticorrelations between the rTPJ and the supramarginal gyri, indicating both altered vestibular and self-related functions. Our findings shed light on how the brain copes with gravity transitions, on gravity internalization and are relevant for the understanding of bodily self-consciousness.
Mathematical modeling and stability analysis of Pine Wilt Disease with optimal control
Authors: Khan M. A. , Ali K. , Bonyah E. , Okosun K. O. , Islam S. , Khan A.
Published: June 2017

This paper presents and examine a mathematical system of equations which describes the dynamics of pine wilt disease (PWD). Firstly, we examine the model with constant controls. Here, we investigate the disease equilibria and calculate the basic reproduction number of the disease. Secondly, we incorporate time dependent controls into the model and then analyze the conditions that are necessary for the disease to be controlled optimally. Finally, the numerical results for the model are presented.
Fusaric Acid immunotoxicity and MAPK activation in normal peripheral blood mononuclear cells and Thp-1 cells
Authors: Dhani Shanel , Nagiah Savania , Naidoo Dhaneshree B. , Chuturgoon Anil A.
Published: June 2017

Fusaric acid (FA), a food-borne mycotoxin, is a potent divalent metal chelator. The human immune system is complex and susceptible to environmental insult however, the immunotoxity of FA remains unknown. We investigated the immunotoxicity of FA on human peripheral blood mononuclear cells (PBMCs) and Thp-1 cells. FA was cytotoxic to PBMCs (IC50-240.8 μg/ml) and Thp-1 (IC50-107.7 μg/ml) cells at 24 h. FA induced early apoptosis but significantly decreased caspase activity in PBMCs, a characteristic of paraptosis. In Thp-1 cells, FA induced apoptosis and increased caspase −9 and −3/7 activities. In PBMCs, FA maintained mitochondrial membrane potential and decreased protein expression of Bax whilst increasing expression of p-Bcl-2; FA induced oxidative stress and depleted ATP levels in both cell types. In Thp-1 cells, FA increased mitochondrial membrane depolarization and decreased p-Bcl-2 expression. In PBMCs, FA significantly up-regulated the MAPK protein expression of p-ERK and p-JNK but down-regulated p-p38 expression. In Thp-1 cells, FA up-regulated MAPK protein expression of p-ERK whilst p-JNK and p-p38 expression were down-regulated. In conclusion FA induced programmed cell death and altered MAPK signaling in healthy PBMCs and Thp-1 cells strongly suggesting a possible mechanism of FA induced immunotoxicity in vitro.
Improving randomness characterization through Bayesian model selection
Authors: Díaz Hernández Rojas Rafael , Solís Aldo , Angulo Martínez Alí M. , U’Ren Alfred B. , Hirsch Jorge G. , Marsili Matteo , Pérez Castillo Isaac
Published: June 2017

Random number generation plays an essential role in technology with important applications in areas ranging from cryptography to Monte Carlo methods, and other probabilistic algorithms. All such applications require high-quality sources of random numbers, yet effective methods for assessing whether a source produce truly random sequences are still missing. Current methods either do not rely on a formal description of randomness (NIST test suite) on the one hand, or are inapplicable in principle (the characterization derived from the Algorithmic Theory of Information), on the other, for they require testing all the possible computer programs that could produce the sequence to be analysed. Here we present a rigorous method that overcomes these problems based on Bayesian model selection. We derive analytic expressions for a model’s likelihood which is then used to compute its posterior distribution. Our method proves to be more rigorous than NIST’s suite and Borel-Normality criterion and its implementation is straightforward. We applied our method to an experimental device based on the process of spontaneous parametric downconversion to confirm it behaves as a genuine quantum random number generator. As our approach relies on Bayesian inference our scheme transcends individual sequence analysis, leading to a characterization of the source itself.
Measuring multisensory integration: from reaction times to spike counts
Authors: Colonius Hans , Diederich Adele
Published: June 2017

A neuron is categorized as “multisensory” if there is a statistically significant difference between the response evoked, e.g., by a crossmodal stimulus combination and that evoked by the most effective of its components separately. Being responsive to multiple sensory modalities does not guarantee that a neuron has actually engaged in integrating its multiple sensory inputs: it could simply respond to the stimulus component eliciting the strongest response in a given trial. Crossmodal enhancement is commonly expressed as a proportion of the strongest mean unisensory response. This traditional index does not take into account any statistical dependency between the sensory channels under crossmodal stimulation. We propose an alternative index measuring by how much the multisensory response surpasses the level obtainable by optimally combining the unisensory responses, with optimality defined as probability summation under maximal negative stochastic dependence. The new index is analogous to measuring crossmodal enhancement in reaction time studies by the strength of violation of the “race model inequality’, a numerical measure of multisensory integration. Since the new index tends to be smaller than the traditional one, neurons previously labeled as “multisensory’ may lose that property. The index is easy to compute and it is sensitive to variability in data.
Characterizing haploinsufficiency of SHELL gene to improve fruit form prediction in introgressive hybrids of oil palm
Authors: Teh Chee-Keng , Muaz Siti Dalila , Tangaya Praveena , Fong Po-Yee , Ong Ai-Ling , Mayes Sean , Chew Fook-Tim , Kulaveerasingam Harikrishna , Appleton David
Published: June 2017

The fundamental trait in selective breeding of oil palm (Eleais guineensis Jacq.) is the shell thickness surrounding the kernel. The monogenic shell thickness is inversely correlated to mesocarp thickness, where the crude palm oil accumulates. Commercial thin-shelled tenera derived from thick-shelled dura × shell-less pisifera generally contain 30% higher oil per bunch. Two mutations, sh
MPOB
(M1) and sh
AVROS
(M2) in the SHELL gene – a type II MADS-box transcription factor mainly present in AVROS and Nigerian origins, were reported to be responsible for different fruit forms. In this study, we have tested 1,339 samples maintained in Sime Darby Plantation using both mutations. Five genotype-phenotype discrepancies and eight controls were then re-tested with all five reported mutations (sh
AVROS
, sh
MPOB
, sh
MPOB2
, sh
MPOB3
and sh
MPOB4
) within the same gene. The integration of genotypic data, pedigree records and shell formation model further explained the haploinsufficiency effect on the SHELL gene with different number of functional copies. Some rare mutations were also identified, suggesting a need to further confirm the existence of cis-compound mutations in the gene. With this, the prediction accuracy of fruit forms can be further improved, especially in introgressive hybrids of oil palm. Understanding causative variant segregation is extremely important, even for monogenic traits such as shell thickness in oil palm.
Transgenic overexpression of GTP cyclohydrolase 1 in cardiomyocytes ameliorates post-infarction cardiac remodeling
Authors: Liu Yanan , Baumgardt Shelley L. , Fang Juan , Shi Yang , Qiao Shigang , Bosnjak Zeljko J. , Vásquez-Vivar Jeannette , Xia Zhengyuan , Warltier David C. , Kersten Judy R. , Ge Zhi-Dong
Published: June 2017

GTP cyclohydrolase 1 (GCH1) and its product tetrahydrobiopterin play crucial roles in cardiovascular health and disease, yet the exact regulation and role of GCH1 in adverse cardiac remodeling after myocardial infarction are still enigmatic. Here we report that cardiac GCH1 is degraded in remodeled hearts after myocardial infarction, concomitant with increases in the thickness of interventricular septum, interstitial fibrosis, and phosphorylated p38 mitogen-activated protein kinase and decreases in left ventricular anterior wall thickness, cardiac contractility, tetrahydrobiopterin, the dimers of nitric oxide synthase, sarcoplasmic reticulum Ca2+ release, and the expression of sarcoplasmic reticulum Ca2+ handling proteins. Intriguingly, transgenic overexpression of GCH1 in cardiomyocytes reduces the thickness of interventricular septum and interstitial fibrosis and increases anterior wall thickness and cardiac contractility after infarction. Moreover, we show that GCH1 overexpression decreases phosphorylated p38 mitogen-activated protein kinase and elevates tetrahydrobiopterin levels, the dimerization and phosphorylation of neuronal nitric oxide synthase, sarcoplasmic reticulum Ca2+ release, and sarcoplasmic reticulum Ca2+ handling proteins in post-infarction remodeled hearts. Our results indicate that the pivotal role of GCH1 overexpression in post-infarction cardiac remodeling is attributable to preservation of neuronal nitric oxide synthase and sarcoplasmic reticulum Ca2+ handling proteins, and identify a new therapeutic target for cardiac remodeling after infarction.
Targeting Bacillus anthracis toxicity with a genetically selected inhibitor of the PA/CMG2 protein-protein interaction
Authors: Male Abigail L. , Forafonov Fedor , Cuda Francesco , Zhang Gong , Zheng Siqi , Oyston Petra C. F. , Chen Peng R. , Williamson E. Diane , Tavassoli Ali
Published: June 2017

The protein-protein interaction between the human CMG2 receptor and the Bacillus anthracis protective antigen (PA) is essential for the transport of anthrax lethal and edema toxins into human cells. We used a genetically encoded high throughput screening platform to screen a SICLOPPS library of 3.2 million cyclic hexapeptides for inhibitors of this protein-protein interaction. Unusually, the top 3 hits all contained stop codons in the randomized region of the library, resulting in linear rather than cyclic peptides. These peptides disrupted the targeted interaction in vitro; two act by binding to CMG2 while one binds PA. The efficacy of the most potent CMG2-binding inhibitor was improved through the incorporation of non-natural phenylalanine analogues. Cell based assays demonstrated that the optimized inhibitor protects macrophages from the toxicity of lethal factor.
A Comprehensive Prediction Model of Hydraulic Extended-Reach Limit Considering the Allowable Range of Drilling Fluid Flow Rate in Horizontal Drilling
Authors: Li Xin , Gao Deli , Chen Xuyue
Published: June 2017

Hydraulic extended-reach limit (HERL) model of horizontal extended-reach well (ERW) can predict the maximum measured depth (MMD) of the horizontal ERW. The HERL refers to the well’s MMD when drilling fluid cannot be normally circulated by drilling pump. Previous model analyzed the following two constraint conditions, drilling pump rated pressure and rated power. However, effects of the allowable range of drilling fluid flow rate (Q
min
 ≤ Q ≤ Q
max
) were not considered. In this study, three cases of HERL model are proposed according to the relationship between allowable range of drilling fluid flow rate and rated flow rate of drilling pump (Q
r
). A horizontal ERW is analyzed to predict its HERL, especially its horizontal-section limit (L
h
). Results show that when Q
min
 ≤ Q
r
 ≤ Q
max
(Case I), L
h
depends both on horizontal-section limit based on rated pump pressure (L
h1
) and horizontal-section limit based on rated pump power (L
h2
); when Q
min
 < Q
max
 < Q
r
(Case II), L
h
is exclusively controlled by L
h1
; while L
h
is only determined by L
h2
when Q
r
 < Q
min
 < Q
max
(Case III). Furthermore, L
h1
first increases and then decreases with the increase in drilling fluid flow rate, while L
h2
keeps decreasing as the drilling fluid flow rate increases. The comprehensive model provides a more accurate prediction on HERL.
Synthesis of porous polymer/tissue paper hybrid membranes for switchable oil/water separation
Authors: Cao Cong-Xiao , Yuan Jiayin , Cheng Jin-Pei , Han Bao-Hang
Published: June 2017

The unusually broad physical and chemical property window of ionic liquids allows for a wide range of applications, which gives rise to the recent spring-up of ionic liquid-based functional materials. Via solvothermal copolymerization of a monomeric ionic liquid and divinylbenzene in the presence of a tissue paper in autoclave, we fabricated a flexible porous polymer/paper hybrid membrane. The surface areas of the hybrid membranes depend on the weight fraction of the copolymer impregnated inside the tissue paper. The as-prepared hybrid membrane shows controlled surface wettability in terms of ethanol wetting and ethanol removal by harsh drying condition. This unique property provides the hybrid membrane with switchable oil/water separation function, thus of practical values for real life application.
Booster immunizations with DNA plasmids encoding HER-2/neu prevent spontaneous mammary cancer in HER-2/neu transgenic mice over life span
Authors: Provinciali Mauro , Barucca Alessandra , Orlando Fiorenza , Pierpaoli Elisa
Published: June 2017

Cancer vaccines are less effective at old than at young age because of immunosenescence. Besides, in preliminary observations we showed that the immunization with HER-2/neu DNA plasmid in transgenic young mice (standard immunization, SI) delays but not abrogate spontaneous mammary tumours progressively appearing during aging. In this study we evaluated whether booster immunizations (BI) of HER-2/neu transgenic mice with HER-2/neu DNA plasmids every 6 (ECD6), 3 (ECD3), or 1.5 (ECD1.5) months after SI induce a protective immunity that could be maintained over life span. The long term BI significantly improved the effect of SI increasing the number of tumour free mice at 110 weeks of age from 13% (SI) to 58% (BI). Both the number and the volume of tumour masses were reduced in BI than in SI groups. The protective effect of BI was associated with increased antibody production with isotype switching to IgG2a, augmented CD4 T cells, and increased in vivo cytotoxicity of HER-2/neu specific cytotoxic T lymphocytes, mainly in ECD1.5 and ECD3 groups. The transfer of sera from ECD1.5 mice to untreated HER-2/neu mice highly protected against tumour development than sera from SI mice. We conclude that BI induce a protective immunity effective over life span.
Mitochondrial biogenesis dysfunction and metabolic dysfunction from a novel mitochondrial tRNAMet 4467 C>A mutation in a Han Chinese family with maternally inherited hypertension
Authors: Liu Yuqi , Li Yang , Zhu Chao , Tian Liuyang , Guan Minxin , Chen Yundai
Published: June 2017

To investigate the relationship between mitochondrial DNA (mtDNA) and hypertension as well as the mechanism involved in mitochondrial metabolic dysfunction. We identified a novel tRNAMet C4467A mutation in a Han Chinese family with hypertension. The maternal members presented with increased glucose, total cholesterol, low-density lipoprotein, and serum sodium as well as decreased potassium compared with non-maternal members (P < 0.05). Segregation analysis showed this mutation was maternally inherited. We analyzed lymphocyte cell lines derived from three maternal and three non-maternal family members. Reactive oxygen species production in the mutant cell lines was 114.5% higher compared with that in controls (P < 0.05) while ATP was 26.4% lower. The mitochondrial membrane potential of the mutated cell lines was 26.2% lower than that in controls (P < 0.05). Oxygen consumption rates were decreased in the mutant cell lines (P < 0.05). The activation of caspase-3/7 was 104.1% higher in the mutant cell lines compared with controls (P < 0.05). The expression of voltage-dependent anion channel (VDAC), Bax and apoptosis-inducing factor (AIF) in the mutant cell lines was higher compared with that in controls, with the increased colocalization of VDAC and Bax. Therefore, this mutation contributes to oxidative stress and mitochondrial biogenesis dysfunction, which may be involved in the pathogenesis of hypertension.
Preparing local strain patterns in graphene by atomic force microscope based indentation
Authors: Nemes-Incze Péter , Kukucska Gergő , Koltai János , Kürti Jenő , Hwang Chanyong , Tapasztó Levente , Biró László P.
Published: June 2017

Patterning graphene into various mesoscopic devices such as nanoribbons, quantum dots, etc. by lithographic techniques has enabled the guiding and manipulation of graphene’s Dirac-type charge carriers. Graphene, with well-defined strain patterns, holds promise of similarly rich physics while avoiding the problems created by the hard to control edge configuration of lithographically prepared devices. To engineer the properties of graphene via mechanical deformation, versatile new techniques are needed to pattern strain profiles in a controlled manner. Here we present a process by which strain can be created in substrate supported graphene layers. Our atomic force microscope-based technique opens up new possibilities in tailoring the properties of graphene using mechanical strain.
Widom Lines in Binary Mixtures of Supercritical Fluids
Authors: Raju Muralikrishna , Banuti Daniel T. , Ma Peter C. , Ihme Matthias
Published: June 2017

Recent experiments on pure fluids have identified distinct liquid-like and gas-like regimes even under supercritical conditions. The supercritical liquid-gas transition is marked by maxima in response functions that define a line emanating from the critical point, referred to as Widom line. However, the structure of analogous state transitions in mixtures of supercritical fluids has not been determined, and it is not clear whether a Widom line can be identified for binary mixtures. Here, we present first evidence for the existence of multiple Widom lines in binary mixtures from molecular dynamics simulations. By considering mixtures of noble gases, we show that, depending on the phase behavior, mixtures transition from a liquid-like to a gas-like regime via distinctly different pathways, leading to phase relationships of surprising complexity and variety. Specifically, we show that miscible binary mixtures have behavior analogous to a pure fluid and the supercritical state space is characterized by a single liquid-gas transition. In contrast, immiscible binary mixture undergo a phase separation in which the clusters transition separately at different temperatures, resulting in multiple distinct Widom lines. The presence of this unique transition behavior emphasizes the complexity of the supercritical state to be expected in high-order mixtures of practical relevance.