bluuebunny/crossref_metadata_2025 huggingface dataset:
Saturn's Ionosphere: Electron Density Altitude Profiles and D‐Ring Interaction From The Cassini Grand Finale
Authors: Hadid L. Z. , Morooka M. W. , Wahlund J.‐E. , Persoon A. M. , Andrews D. J. , Shebanits O. , Kurth W. S. , Vigren E. , Edberg N. J. T. , Nagy A. F. , Eriksson A. I.
Published: September 2018

We present the electron density (ne) altitude profiles of Saturn's ionosphere at near‐equatorial latitudes from all 23 orbits of Cassini's Grand Finale. The data are collected by the Langmuir probe part of the Radio and Plasma Wave Science investigation. A high degree of variability in the electron density profiles is observed. However, organizing them by consecutive altitude ranges revealed clear differences between the southern and northern hemispheres. The ne profiles are shown to be more variable and connected to the D‐ring below 5,000 km in the southern hemisphere compared to the northern hemisphere. This observed variability is explained to be a consequence of an electrodynamic interaction with the D‐ring. Moreover, a density altitude profile is constructed for the northern hemisphere indicating the presence of three different ionospheric layers. Similar properties were observed during Cassini's final plunge, where the main ionospheric peak is crossed at ∼1,550‐km altitude.
Role of miR-223 in the pathophysiology of liver diseases
Authors: Ye Dan , Zhang Tianbao , Lou Guohua , Liu Yanning
Published: September 2018

MiRNAs are small, noncoding RNAs, which can regulate gene expression posttranscriptionally, and they have emerged as key factors in disease biology by aiding in disease development and progression. MiR-223 is highly conserved during evolution and it was first described as a modulator of hematopoietic lineage differentiation. MiR-223 has an essential part in inflammation by targeting the nuclear factor-κB pathway and the nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome. Recent studies have shown that miR-223 expression is deregulated in various types of liver diseases, including hepatitis virus infections, alcohol-induced liver injury, drug-induced liver injury, non-alcoholic fatty liver disease, cirrhosis, and hepatocellular carcinoma. As inflammatory and immune factors are involved in the occurrence and progress of liver diseases, deregulated miR-223 may participate in the pathogenesis of these conditions by influencing neutrophil infiltration, macrophage polarization, and inflammasome activation. This review first summarizes the present understanding of the biological functions of miR-223, including its gene location and transcription regulation, as well as its physiological role in hematopoietic differentiation. This review then focuses on the role of miR-223 in liver pathophysiology and its potential applications as a diagnostic biomarker and therapeutic target in liver diseases.
Bacterial contributions to delignification and lignocellulose degradation in forest soils with metagenomic and quantitative stable isotope probing
Authors: Wilhelm Roland C , Singh Rahul , Eltis Lindsay D , Mohn William W
Published: September 2018

Delignification, or lignin-modification, facilitates the decomposition of lignocellulose in woody plant biomass. The extant diversity of lignin-degrading bacteria and fungi is underestimated by culture-dependent methods, limiting our understanding of the functional and ecological traits of decomposers populations. Here, we describe the use of stable isotope probing (SIP) coupled with amplicon and shotgun metagenomics to identify and characterize the functional attributes of lignin, cellulose and hemicellulose-degrading fungi and bacteria in coniferous forest soils from across North America. We tested the extent to which catabolic genes partitioned among different decomposer taxa; the relative roles of bacteria and fungi, and whether taxa or catabolic genes correlated with variation in lignocellulolytic activity, measured as the total assimilation of 13C-label into DNA and phospholipid fatty acids. We found high overall bacterial degradation of our model lignin substrate, particularly by gram-negative bacteria (Comamonadaceae and Caulobacteraceae), while fungi were more prominent in cellulose-degradation. Very few taxa incorporated 13C-label from more than one lignocellulosic polymer, suggesting specialization among decomposers. Collectively, members of Caulobacteraceae could degrade all three lignocellulosic polymers, providing new evidence for their importance in lignocellulose degradation. Variation in lignin-degrading activity was better explained by microbial community properties, such as catabolic gene content and community structure, than cellulose-degrading activity. SIP significantly improved shotgun metagenome assembly resulting in the recovery of several high-quality draft metagenome-assembled genomes and over 7500 contigs containing unique clusters of carbohydrate-active genes. These results improve understanding of which organisms, conditions and corresponding functional genes contribute to lignocellulose decomposition.
Neuroprotective efficacy of P7C3 compounds in primate hippocampus
Authors: Bauman Melissa D. , Schumann Cynthia M. , Carlson Erin L. , Taylor Sandra L. , Vázquez-Rosa Edwin , Cintrón-Pérez Coral J. , Shin Min-Kyoo , Williams Noelle S. , Pieper Andrew A.
Published: September 2018

There is a critical need for translating basic science discoveries into new therapeutics for patients suffering from difficult to treat neuropsychiatric and neurodegenerative conditions. Previously, a target-agnostic in vivo screen in mice identified P7C3 aminopropyl carbazole as capable of enhancing the net magnitude of postnatal neurogenesis by protecting young neurons from death. Subsequently, neuroprotective efficacy of P7C3 compounds in a broad spectrum of preclinical rodent models has also been observed. An important next step in translating this work to patients is to determine whether P7C3 compounds exhibit similar efficacy in primates. Adult male rhesus monkeys received daily oral P7C3-A20 or vehicle for 38 weeks. During weeks 2–11, monkeys received weekly injection of 5′-bromo-2-deoxyuridine (BrdU) to label newborn cells, the majority of which would normally die over the following 27 weeks. BrdU+ cells were quantified using unbiased stereology. Separately in mice, the proneurogenic efficacy of P7C3-A20 was compared to that of NSI-189, a proneurogenic drug currently in clinical trials for patients with major depression. Orally-administered P7C3-A20 provided sustained plasma exposure, was well-tolerated, and elevated the survival of hippocampal BrdU+ cells in nonhuman primates without adverse central or peripheral tissue effects. In mice, NSI-189 was shown to be pro-proliferative, and P7C3-A20 elevated the net magnitude of hippocampal neurogenesis to a greater degree than NSI-189 through its distinct mechanism of promoting neuronal survival. This pilot study provides evidence that P7C3-A20 safely protects neurons in nonhuman primates, suggesting that the neuroprotective efficacy of P7C3 compounds is likely to translate to humans as well.
The antipsychotic agent trifluoperazine hydrochloride suppresses triple-negative breast cancer tumor growth and brain metastasis by inducing G0/G1 arrest and apoptosis
Authors: Feng Zhanzhan , Xia Yong , Gao Tiantao , Xu Fuyan , Lei Qian , Peng Cuiting , Yang Yufei , Xue Qiang , Hu Xi , Wang Qianqian , Wang Ranran , Ran Zhiqiang , Zeng Zhilin , Yang Nan , Xie Zixin , Yu Luoting
Published: September 2018

Women with aggressive triple-negative breast cancer (TNBC) are at high risk of brain metastasis, which has no effective therapeutic option partially due to the poor penetration of drugs across the blood−brain barrier. Trifluoperazine (TFP) is an approved antipsychotic drug with good bioavailability in brain and had shown anticancer effect in several types of cancer. It drives us to investigate its activities to suppress TNBC, especially the brain metastasis. In this study, we chose three TNBC cell lines MDA-MB-468, MDA-MB-231, and 4T1 to assess its anticancer activities along with the possible mechanisms. In vitro, it induced G0/G1 cell cycle arrest via decreasing the expression of both cyclinD1/CDK4 and cyclinE/CDK2, and stimulated mitochondria-mediated apoptosis. In vivo, TFP suppressed the growth of subcutaneous xenograft tumor and brain metastasis without causing detectable side effects. Importantly, it prolonged the survival of mice bearing brain metastasis. Immunohistochemical analysis of Ki67 and cleaved caspase-3 indicated TFP could suppress the growth and induce apoptosis of cancer cells in vivo. Taken together, TFP might be a potential available drug for treating TNBC with brain metastasis, which urgently needs novel treatment options.
Dye-incorporated coordination polymers for direct photocatalytic trifluoromethylation of aromatics at metabolically susceptible positions
Authors: Zhang Tiexin , Guo Xiangyang , Shi Yusheng , He Cheng , Duan Chunying
Published: September 2018

Direct trifluoromethylation of unactivated aromatic rings at metabolically susceptible positions is highly desirable in pharmaceutical applications. By incorporating thiophenes into the backbone of triphenylamine to enlarge its π-system, a new approach for constructing coordination polymers is reported for direct trifluoromethylation without prefunctionalization of the aryl precursors. The improved light-harvesting ability and well-modulated excited state redox potential of the designed polymers endow the generated CF3 radicals with suitable reactivity and enhance radical adduct oxidation in pores. The well-configurated interactions between the organic ligands distort the coordination geometry to create active interaction sites within the coordination polymer; thus, the substrates could be docked near the photoredox-active centres. The synergistic electronic and spatial effects in the confined pores balance the contradictory demands of electronic effects and reaction dynamics, achieving regio- and diastereoselective discrimination among reaction sites with unremarkable electronic/steric differences.
LOTUS domain protein MARF1 binds CCR4-NOT deadenylase complex to post-transcriptionally regulate gene expression in oocytes
Authors: Zhu Li , Kandasamy Suresh K. , Liao Susan E. , Fukunaga Ryuya
Published: September 2018

Post-transcriptional regulation of gene expression plays an essential role during oocyte maturation. Here we report that Drosophila MARF1 (Meiosis Regulator And mRNA Stability Factor 1), which consists of one RNA-recognition motif and six tandem LOTUS domains with unknown molecular function, is essential for oocyte maturation. When tethered to a reporter mRNA, MARF1 post-transcriptionally silences reporter expression by shortening reporter mRNA poly-A tail length and thereby reducing reporter protein level. This activity is mediated by the MARF1 LOTUS domain, which binds the CCR4-NOT deadenylase complex. MARF1 binds cyclin A mRNA and shortens its poly-A tail to reduce Cyclin A protein level during oocyte maturation. This study identifies MARF1 as a regulator in oocyte maturation and defines the conserved LOTUS domain as a post-transcriptional effector domain that recruits CCR4-NOT deadenylase complex to shorten target mRNA poly-A tails and suppress their translation.
Correcting glucose-6-phosphate dehydrogenase deficiency with a small-molecule activator
Authors: Hwang Sunhee , Mruk Karen , Rahighi Simin , Raub Andrew G. , Chen Che-Hong , Dorn Lisa E. , Horikoshi Naoki , Wakatsuki Soichi , Chen James K. , Mochly-Rosen Daria
Published: September 2018

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, one of the most common human genetic enzymopathies, is caused by over 160 different point mutations and contributes to the severity of many acute and chronic diseases associated with oxidative stress, including hemolytic anemia and bilirubin-induced neurological damage particularly in newborns. As no medications are available to treat G6PD deficiency, here we seek to identify a small molecule that corrects it. Crystallographic study and mutagenesis analysis identify the structural and functional defect of one common mutant (Canton, R459L). Using high-throughput screening, we subsequently identify AG1, a small molecule that increases the activity of the wild-type, the Canton mutant and several other common G6PD mutants. AG1 reduces oxidative stress in cells and zebrafish. Furthermore, AG1 decreases chloroquine- or diamide-induced oxidative stress in human erythrocytes. Our study suggests that a pharmacological agent, of which AG1 may be a lead, will likely alleviate the challenges associated with G6PD deficiency.
Vibrational control of selective bond cleavage in dissociative chemisorption of methanol on Cu(111)
Authors: Chen Jialu , Zhou Xueyao , Zhang Yaolong , Jiang Bin
Published: September 2018

Controlling product branching ratios in a chemical reaction represents a desired but difficult achievement in chemistry. In this work, we demonstrate the first example of altering the branching ratios in a multichannel reaction, i.e., methanol dissociative chemisorption on Cu(111), via selectively exciting specific vibrational modes. To this end, we develop a globally accurate full-dimensional potential energy surface for the CH3OH/Cu(111) system and perform extensive vibrational state-selected molecular dynamics simulations. Our results show that O–H/C–H/C–O stretching vibrational excitations substantially enhance the respective bond scission processes, representing extraordinary bond selectivity. At a given total energy, the branching ratio of C–O/C–H dissociation can increase by as large as 100 times by exciting the C–O stretching mode which possesses an unprecedentedly strong vibrational efficacy on reactivity. This vibrational control can be realized by the well-designed experiment using a linearly polarized laser.
Computational design of chemogenetic and optogenetic split proteins
Authors: Dagliyan Onur , Krokhotin Andrey , Ozkan-Dagliyan Irem , Deiters Alexander , Der Channing J. , Hahn Klaus M. , Dokholyan Nikolay V.
Published: September 2018

Controlling protein activity with chemogenetics and optogenetics has proven to be powerful for testing hypotheses regarding protein function in rapid biological processes. Controlling proteins by splitting them and then rescuing their activity through inducible reassembly offers great potential to control diverse protein activities. Building split proteins has been difficult due to spontaneous assembly, difficulty in identifying appropriate split sites, and inefficient induction of effective reassembly. Here we present an automated approach to design effective split proteins regulated by a ligand or by light (SPELL). We develop a scoring function together with an engineered domain to enable reassembly of protein halves with high efficiency and with reduced spontaneous assembly. We demonstrate SPELL by applying it to proteins of various shapes and sizes in living cells. The SPELL server (spell.dokhlab.org) offers an automated prediction of split sites.
Chemogenetic generation of hydrogen peroxide in the heart induces severe cardiac dysfunction
Authors: Steinhorn Benjamin , Sorrentino Andrea , Badole Sachin , Bogdanova Yulia , Belousov Vsevolod , Michel Thomas
Published: September 2018

Oxidative stress plays an important role in the pathogenesis of many disease states. In the heart, reactive oxygen species are linked with cardiac ischemia/reperfusion injury, hypertrophy, and heart failure. While this correlation between ROS and cardiac pathology has been observed in multiple models of heart failure, the independent role of hydrogen peroxide (H2O2) in vitro and in vivo is unclear, owing to a lack of tools for precise manipulation of intracellular redox state. Here we apply a chemogenetic system based on a yeast D-amino acid oxidase to show that chronic generation of H2O2 in the heart induces a dilated cardiomyopathy with significant systolic dysfunction. We anticipate that chemogenetic approaches will enable future studies of in vivo H2O2 signaling not only in the heart, but also in the many other organ systems where the relationship between redox events and physiology remains unclear.
Tensorial neutron tomography of three-dimensional magnetic vector fields in bulk materials
Authors: Hilger A. , Manke I. , Kardjilov N. , Osenberg M. , Markötter H. , Banhart J.
Published: September 2018

Knowing the distribution of a magnetic field in bulk materials is important for understanding basic phenomena and developing functional magnetic materials. Microscopic imaging techniques employing X-rays, light, electrons, or scanning probe methods have been used to quantify magnetic fields within planar thin magnetic films in 2D or magnetic vector fields within comparable thin volumes in 3D. Some years ago, neutron imaging has been demonstrated to be a unique tool to detect magnetic fields and magnetic domain structures within bulk materials. Here, we show how arbitrary magnetic vector fields within bulk materials can be visualized and quantified in 3D using a set of nine spin-polarized neutron imaging measurements and a novel tensorial multiplicative algebraic reconstruction technique (TMART). We first verify the method by measuring the known magnetic field of an electric coil and then investigate the unknown trapped magnetic flux within the type-I superconductor lead.
Spatio-temporal dynamics and aetiology of proliferative leg skin lesions in wild British finches
Authors: Lawson Becki , Robinson Robert A. , Fernandez Julia Rodriguez-Ramos , John Shinto K. , Benitez Laura , Tolf Conny , Risely Kate , Toms Mike P. , Cunningham Andrew A. , Williams Richard A. J.
Published: September 2018

Proliferative leg skin lesions have been described in wild finches in Europe although there have been no large-scale studies of their aetiology or epizootiology to date. Firstly, disease surveillance, utilising public reporting of observations of live wild finches was conducted in Great Britain (GB) and showed proliferative leg skin lesions in chaffinches (Fringilla coelebs) to be widespread. Seasonal variation was observed, with a peak during the winter months. Secondly, pathological investigations were performed on a sample of 39 chaffinches, four bullfinches (Pyrrhula pyrrhula), one greenfinch (Chloris chloris) and one goldfinch (Carduelis carduelis) with proliferative leg skin lesions and detected Cnemidocoptes sp. mites in 91% (41/45) of affected finches and from all species examined. Fringilla coelebs papillomavirus (FcPV1) PCR was positive in 74% (23/31) of birds tested: a 394 base pair sequence was derived from 20 of these birds, from all examined species, with 100% identity to reference genomes. Both mites and FcPV1 DNA were detected in 71% (20/28) of birds tested for both pathogens. Histopathological examination of lesions did not discriminate the relative importance of mite or FcPV1 infection as their cause. Development of techniques to localise FcPV1 within lesions is required to elucidate the pathological significance of FcPV1 DNA detection.
Simvastatin Protects Cardiomyocytes Against Endotoxin-induced Apoptosis and Up-regulates Survivin/NF-κB/p65 Expression
Authors: Nežić Lana , Škrbić Ranko , Amidžić Ljiljana , Gajanin Radoslav , Kuča Kamil , Jaćević Vesna
Published: September 2018

This study is aimed to investigate whether simvastatin induces cardiomyocytes survival signaling in endotoxin (lipopolysaccharide, LSP)-induced myocardial injury, and if so, further to determine a role of survivin in simvastatin-anti-apoptotic effect. Wistar rats were pretreated with simvastatin (10–40 mg/kg po) before a single non-lethal dose of LPS. In myocardial tissue, LPS induced structural disorganization of myofibrils with significant inflammatory infiltrate (cardiac damage score, CDS = 3.87 ± 0.51, p < 0.05), whereas simvastatin dose-dependently abolished structural changes induced by LPS (p < 0.01). Simvastatin in 20 mg/kg and 40 mg/kg pretreatment, dose dependently, attenuated myocardial apoptosis determined as apoptotic index (28.8 ± 4.5% and 18.9 ± 3.5, p < 0.05), decreased cleaved caspase-3 expression (32.1 ± 5.8%, p < 0.01), along with significant Bcl-xL expression in the simvastatin groups (p < 0.01). Interestingly, in the simvastatin groups were determined significantly increased expression of survivin (p < 0.01), but in negative correlation with cleaved caspase-3 and apoptotic indices (p < 0.01). Simvastatin has a cardioprotective effects against LPS induced apoptosis. The effect may be mediated by up-regulation of survivin via activation of NF-κB, which leads to reduced activation of caspase-3 and consequent apoptosis of cardiomyocytes in experimental sepsis.
Discovery of Novel Soluble Epoxide Hydrolase Inhibitors as Potent Vasodilators
Authors: Tripathi Neetika , Paliwal Sarvesh , Sharma Swapnil , Verma Kanika , Gururani Ritika , Tiwari Akanksha , Verma Amrita , Chauhan Monika , Singh Aarti , Kumar Dipak , Pant Aditya
Published: September 2018

In view of the role of sEH (soluble epoxide hydrolase) in hypertension, we have developed a rigorously validated pharmacophore model containing one HBA (Hydrogen Bond Acceptor), two HY (Hydrophobic) and one RA (Ring Aromatic) features. The model was used as a query to search the NCI (National Cancer Institute) and Maybridge database leading to retrieval of many compounds which were sorted on the basis of predicted activity, fit value and Lipinski’s violation. The selected compounds were docked into the active site of enzyme soluble epoxide hydrolase. Potential interactions were observed between the features of the identified hits and the amino acids present in the docking site. The three selected compounds were subjected to in vitro evaluation using enzyme- based assay and the isolated rat aortic model followed by cytotoxicity studies. The results demonstrate that the identified compounds are potent, safe and novel soluble epoxide hydrolase inhibitors.
Control of proline utilization by the Lrp-like regulator PutR in Caulobacter crescentus
Authors: Mouammine Annabelle , Eich Katharina , Frandi Antonio , Collier Justine
Published: September 2018

Cellular metabolism recently emerged as a central player modulating the bacterial cell cycle. The Alphaproteobacterium Caulobacter crescentus appears as one of the best models to study these connections, but its metabolism is still poorly characterized. Considering that it lives in oligotrophic environments, its capacity to use amino-acids is often critical for its growth. Here, we characterized the C. crescentus PutA bi-functional enzyme and showed that it is required for the utilization of proline as a carbon source. We also found that putA transcription and proline utilization by PutA are strictly dependent on the Lrp-like PutR activator. The activation of putA by PutR needs proline, which most likely acts as an effector molecule for PutR. Surprisingly, we also observed that an over-production of PutR leads to cell elongation in liquid medium containing proline, while it inhibits colony formation even in the absence of proline on solid medium. These cell division and growth defects were equally pronounced in a ΔputA mutant background, indicating that PutR can play other roles beyond the control of proline catabolism. Altogether, these findings suggest that PutR might connect central metabolism with cell cycle processes.
Reconstructing the evolutionary history of pandemic foot-and-mouth disease viruses: the impact of recombination within the emerging O/ME-SA/Ind-2001 lineage
Authors: Bachanek-Bankowska Katarzyna , Di Nardo Antonello , Wadsworth Jemma , Mioulet Valerie , Pezzoni Giulia , Grazioli Santina , Brocchi Emiliana , Kafle Sharmila Chapagain , Hettiarachchi Ranjani , Kumarawadu Pradeep Lakpriya , Eldaghayes Ibrahim M. , Dayhum Abdunaser S. , Meenowa Deodass , Sghaier Soufien , Madani Hafsa , Abouchoaib Nabil , Hoang Bui Huy , Vu Pham Phong , Dukpa Kinzang , Gurung Ratna Bahadur , Tenzin Sangay , Wernery Ulrich , Panthumart Alongkorn , Seeyo Kingkarn Boonsuya , Linchongsubongkoch Wilai , Relmy Anthony , Bakkali-Kassimi Labib , Scherbakov Alexei , King Donald P. , Knowles Nick J.
Published: September 2018

Foot-and-mouth disease (FMD) is a highly contagious disease of livestock affecting animal production and trade throughout Asia and Africa. Understanding FMD virus (FMDV) global movements and evolution can help to reconstruct the disease spread between endemic regions and predict the risks of incursion into FMD-free countries. Global expansion of a single FMDV lineage is rare but can result in severe economic consequences. Using extensive sequence data we have reconstructed the global space-time transmission history of the O/ME-SA/Ind-2001 lineage (which normally circulates in the Indian sub-continent) providing evidence of at least 15 independent escapes during 2013–2017 that have led to outbreaks in North Africa, the Middle East, Southeast Asia, the Far East and the FMD-free islands of Mauritius. We demonstrated that sequence heterogeneity of this emerging FMDV lineage is accommodated within two co-evolving divergent sublineages and that recombination by exchange of capsid-coding sequences can impact upon the reconstructed evolutionary histories. Thus, we recommend that only sequences encoding the outer capsid proteins should be used for broad-scale phylogeographical reconstruction. These data emphasise the importance of the Indian subcontinent as a source of FMDV that can spread across large distances and illustrates the impact of FMDV genome recombination on FMDV molecular epidemiology.
Lymphocyte activation gene 3 (Lag3) expression is increased in prion infections but does not modify disease progression
Authors: Liu Yingjun , Sorce Silvia , Nuvolone Mario , Domange Julie , Aguzzi Adriano
Published: September 2018

Prion diseases, Alzheimer’s disease and Parkinson’s disease (PD) are fatal degenerative disorders that share common neuropathological and biochemical features, including the aggregation of pathological protein conformers. Lymphocyte activation gene 3 (Lag3, also known as CD223) is a member of the immunoglobulin superfamily of receptors expressed on peripheral immune cells, microglia and neurons, which serves as a receptor for α-synuclein aggregates in PD. Here we examined the possible role of Lag3 in the pathogenesis of prion diseases. Through quantitative real-time PCR and RNA-sequencing, we found that the expression levels of Lag3 were relatively low in the adult mouse brains, yet its expression was increased after prion infection. However, we failed finding significant differences regarding the incubation time, PrPSc load, neurodegeneration, astrocyte and microglia reactions and inflammatory gene expression between the Lag3 knockout mice and wild-type littermate controls after prion infection. We conclude that loss of Lag3 has no significant influence on prion disease pathogenesis. Considering that Lag3 is an immune checkpoint receptor, our results suggest that immune checkpoint inhibition (an increasingly prevalent therapeutic modality against many types of cancer) might not exert positive or negative effects on the progression of prion diseases.
Developmental transitions in amygdala PKC isoforms and AMPA receptor expression associated with threat memory in infant rats
Authors: Opendak Maya , Zanca Roseanna M. , Anane Eben , Serrano Peter A. , Sullivan Regina M.
Published: September 2018

Although infants learn and remember, they rapidly forget, a phenomenon known as infantile amnesia. While myriad mechanisms impact this rapid forgetting, the molecular events supporting memory maintenance have yet to be explored. To explore memory mechanisms across development, we used amygdala-dependent odor-shock conditioning and focused on mechanisms important in adult memory, the AMPA receptor subunits GluA1/2 and upstream protein kinases important for trafficking AMPAR, protein kinase M zeta (PKMζ) and iota/lambda (PKCι/λ). We use odor-shock conditioning in infant rats because it is late-developing (postnatal day, PN10) and can be modulated by corticosterone during a sensitive period in early life. Our results show that memory-related molecules did not change in pups too young to learn threat (PN8) but were activated in pups old enough to learn (PN12), with increased PKMζ-PKCι/λ and GluA2 similar to that observed in adult memory, but with an uncharacteristic decrease in GluA1. This molecular signature and behavioral avoidance of the conditioned odor was recapitulated in PN8 pups injected with CORT before conditioning to precociously induce learning. Blocking learning via CORT inhibition in older pups (PN12) blocked the expression of these molecules. PN16 pups showed a more adult-like molecular cascade of increased PKMζ-PKCι/λ and GluA1–2. Finally, at all ages, zeta inhibitory peptide (ZIP) infusions into the amygdala 24 hr after conditioning blocked memory. Together, these results identify unique features of memory processes across early development: AMPAR subunits GluA1/2 and PKC isoform expression are differentially used, which may contribute to mechanisms of early life forgetting.
Design of polarization-insensitive high-visibility silicon-on-insulator quantum interferometer
Authors: Zhang Jingjing , Guo Kai , Gao Minghong , Gao Yang , Yang Junbo
Published: September 2018

We based on integrated silicon-on-insulator platforms design the key components of an on-chip interferometer, beam splitter and directional coupler included, valid in high-visibility interference at telecommunication wavelengths. Special attention is given to the equal-proportion beam splitting and directional coupling, which is achieved by carefully designing the geometric dimension of multi-mode interferometer structure. The proposed interferometer facilitates low loss, broad operating bandwidth, anticipated large tolerance on size variation induced in fabrication procedures, based on a particular wafer with silicon layer thickness of 320 nm. The most highlight property of polarization-insensitive, enables the path-selective qubits generation for bi-polarization that further makes possible quantum key distribution using high dimensional protocols. We numerically demonstrate interference at 1550 nm with visibilities of 99.50% and 93.99% for transverse-electric and transverse-magnetic polarization, respectively, revealing that the proposed interferometer structure is well capable of on-chip optical control especially in quantum optics regime.
Arc/Arg3.1 has an activity-regulated interaction with PICK1 that results in altered spatial dynamics
Authors: Goo Brandee M. S. S. , Sanstrum Bethany J. , Holden Diana Z. Y. , Yu Yi , James Nicholas G.
Published: September 2018

Activity-regulated cytoskeleton-associated protein (Arc; also known as Arg3.1) is an immediate early gene product that is transcribed in dendritic spines and, to date, has been best characterized as a positive regulator of AMPAR endocytosis during long-term depression (LTD) through interaction with endocytic proteins. Here, we show that protein interacting with C terminal kinase 1 (PICK1), a protein known to bind to the GluA2 subunit of AMPARs and associated with AMPAR trafficking, was pulled-down from brain homogenates and synaptosomes when using Arc as immobilized bait. Fluctuation and FLIM-FRET-Phasor analysis revealed direct interaction between these proteins when co-expressed that was increased under depolarizing conditions in live cells. At the plasma membrane, Arc-mCherry oligomerization was found to be concentration dependent. Additionally, co-expression of Arc-mCherry and EGFP-PICK1 followed by depolarizing conditions resulted in significant increases in the number and size of puncta containing both proteins. Furthermore, we identified the Arc binding region to be the first 126 amino acids of the PICK1 BAR domain. Overall, our data support a novel interaction and model where PICK1 mediates Arc regulation of AMPARs particularly under depolarizing conditions.
Development of multi-layered and multi-sensitive polymeric nanocontainers for cancer therapy: in vitro evaluation
Authors: Toniolo Gianluca , Efthimiadou Eleni K. , Kordas George , Chatgilialoglu Chryssostomos
Published: September 2018

Nanoscale drug delivery systems represent a promising strategy to treat cancer and to overcome the side effects of chemotherapy. In particular, hollow polymeric nanocontainers have attracted great interest because of their structural and morphological advantages and the variety of polymers that can be used, allowing the synthesis of stimuli-responsive materials capable of responding to the biochemical alterations of the tumour microenvironment. Here are reported the synthesis, characterization and in vitro evaluation of a three-stimuli-sensitive hollow nanocontainer consisting of three different shells, each one sensitive to a specific tumoral stimulus: in order pH, temperature and reducing environment. To test its properties, daunorubicin was used as a model drug, for which the nanocontainers exhibited excellent encapsulation ability. The in vitro drug release behaviour was studied under different conditions, where the system proved capable of responding to the selected tumoral stimuli by releasing a larger amount of drug than in physiological environment. The hollow system itself showed negligible cytotoxicity but the loaded nanocontainers and free drug showed identical cytotoxicity and intracellular localization. Therefore, this formulation can be considered as a promising platform to develop an injectable delivery system capable of improving systematic toxicity without affecting or reducing the activity of the encapsulated drug.
Pyrophosphate inhibits gluconeogenesis by restricting UDP-glucose formation in vivo
Authors: Ferjani Ali , Kawade Kensuke , Asaoka Mariko , Oikawa Akira , Okada Takashi , Mochizuki Atsushi , Maeshima Masayoshi , Hirai Masami Yokota , Saito Kazuki , Tsukaya Hirokazu
Published: September 2018

Pyrophosphate (PPi) is produced by anabolic reactions and serves as an energy donor in the cytosol of plant cells; however, its accumulation to toxic levels disrupts several common biosynthetic pathways and is lethal. Before acquiring photosynthetic capacity, young seedlings must endure a short but critical heterotrophic period, during which they are nourished solely by sugar produced from seed reserves by the anabolic process of gluconeogenesis. Previously, we reported that excess PPi in H+-PPase-knockout fugu5 mutants of Arabidopsis thaliana severely compromised gluconeogenesis. However, the precise metabolic target of PPi inhibition in vivo remained elusive. Here, CE-TOF MS analyses of major metabolites characteristic of gluconeogenesis from seed lipids showed that the Glc6P;Fru6P level significantly increased and that Glc1P level was consistently somewhat higher in fugu5 compared to wild type. In contrast, the UDP-Glc level decreased significantly in the mutants. Importantly, specific removal of PPi in fugu5, and thus in AVP1pro:IPP1 transgenic lines, restored the Glc1P and the Glc6P;Fru6P levels, increased the UDP-Glc level ~2.0-fold, and subsequently increased sucrose synthesis. Given the reversible nature of the Glc1P/UDP-Glc reaction, our results indicate that UGP-Glc pyrophosphorylase is the major target when excess PPi exerts inhibitory effects in vivo. To validate our findings, we analyzed metabolite responses using a mathematical theory called structural sensitivity analysis (SSA), in which the responses of concentrations in reaction systems to perturbations in enzyme activity are determined from the structure of the network alone. A comparison of our experimental data with the results of pure structural theory predicted the existence of unknown reactions as the necessary condition for the above metabolic profiles, and confirmed the above results. Our data support the notion that H+-PPase plays a pivotal role in cytosolic PPi homeostasis in plant cells. We propose that the combination of metabolomics and SSA is powerful when seeking to identify and predict metabolic targets in living cells.
A Frequency Independent Framework for Synthesis of Programmable Non-reciprocal Networks
Authors: Lu Ruochen , Krol Jack , Gao Liuqing , Gong Songbin
Published: September 2018

Passive and linear nonreciprocal networks at microwave frequencies hold great promises in enabling new front-end architectures for wireless communication systems. Their non-reciprocity has been achieved by disrupting the time-reversal symmetry using various forms of biasing schemes, but only over a limited frequency range. Here we demonstrate a framework for synthesizing theoretically frequency-independent multi-port nonreciprocal networks. The framework is highly expandable and can have an arbitrary number of ports while simultaneously sustaining balanced performance and providing unprecedented programmability of non-reciprocity. A 4-port circulator based on such a framework is implemented and tested to produce a broadband nonreciprocal performance from 10 MHz to 900 MHz with a temporal switching effort at 23.8 MHz. With the combination of broad bandwidth, low temporal effort, and high programmability, the framework could inspire new ways of implementing multiple input multiple output (MIMO) communication systems for 5G.
Riemerella anatipestifer AS87_RS09170 gene is responsible for biotin synthesis, bacterial morphology and virulence
Authors: Ren Xiaomei , Wang Xiaolan , Shi Huoying , Zhang Xuemei , Chen Zongchao , Malhi Kanwar Kumar , Ding Chan , Yu Shengqing
Published: September 2018

Riemerella anatipestifer is a bacterial pathogen responsible for major economic losses within the duck industry. Recent studies have revealed that biotin biosynthesis is critical for the bacterium’s survival and virulence. We previously found that R. anatipestifer AS87_RS09170, a putative bioF gene, is important for bacterial virulence. In the present study, we characterized the AS87_RS09170 gene in R. anatipestifer strain Yb2. Sequence analysis indicated that the AS87_RS09170 gene is highly conserved among R. anatipestifer strains; the deduced protein harbored the conserved pyridoxal 5′-phosphate binding pocket of 8-amino-7-oxononanoate synthase. Western blot analysis demonstrated that the biotin-dependent enzyme was present in smaller quantities in the mutant strain Yb2ΔbioF compared to that of the wide-type strain Yb2, suggesting that the biotin biosynthesis was defective. The mutant strain Yb2ΔbioF displayed a decreased growth rate at the exponential phase in tryptic soy broth culture and in BeaverBeads Streptavidin treated tryptic soy broth culture, but recovered when biotin was supplemented. In addition, the mutant strain Yb2ΔbioF showed an enhanced biofilm formation, as well as increased adhesion and invasion capacities to duck embryo fibroblasts. Moreover, the mutant strain Yb2ΔbioF exhibited irregular shapes with budding vegetations and relatively thickened cell walls under scanning and transmission electron microscope observation, as well as a reduced capacity to establish systemic infection in a duck infection model. These results provide the first evidence that the R. anatipestifer AS87_RS09170 gene is responsible for biotin synthesis, bacterial morphology and virulence.
Cationic domains in particle-forming and assembly-deficient HBV core antigens capture mammalian RNA that stimulates Th1-biased antibody responses by DNA vaccination
Authors: Krieger Jana , Stifter Katja , Riedl Petra , Schirmbeck Reinhold
Published: September 2018

The HBV core protein self-assembles into particles and encapsidates immune-stimulatory bacterial RNA through a cationic COOH-terminal (C150–183) domain. To investigate if different cationic domains have an impact on the endogenous RNA-binding of HBV-C antigens in mammalian cells, we developed a strep-tag (st) based expression/purification system for HBV-C/RNA antigens in vector-transfected HEK-293 cells. We showed that HBV-stC but not HBV-stC149 particles (lacking the cationic domain) capture low amounts of mammalian RNA. Prevention of specific phosphorylation in cationic domains, either by exchanging the serine residues S155, S162 and S170 with alanines (HBV-stCAAA) or by exchanging the entire cationic domain with a HIV-tat48–57-like sequence (HBV-stC149tat) enhanced the encapsidation of RNA into mutant core particles. Particle-bound mammalian RNA functioned as TLR-7 ligand and induced a Th1-biased humoral immunity in B6 but not in TLR-7−/− mice by exogenous (protein) and endogenous (DNA) vaccines. Compared to core particles, binding of mammalian RNA to freely exposed cationic domains in assembly-deficient antigens was enhanced. However, RNA bound to non-particulate antigens unleash its Th1-stimulating adjuvant activity by DNA- but not protein-based vaccination. Mammalian RNAs targeted by an endogenously expressed antigen thus function as a natural adjuvant in the host that facilitates priming of Th1-biased immune responses by DNA-based immunization.
Risk factors of chronic kidney diseases in Chinese adults with type 2 diabetes
Authors: Yang Lin , Chu Tsun Kit , Lian Jinxiao , Lo Cheuk Wai , Lau Pak Ki , Nan Hairong , Liang Jun
Published: September 2018

In this study we conducted a cross sectional study to comprehensively evaluated the risk factors of chronic kidney disease (CKD) in a large sample of Chinese adults under primary care for type 2 diabetes mellitus (T2DM). We investigated the risk factors associated with the prevalence of CKD in adults with T2DM, who were enrolled in the Risk Factor Assessment and Management Programme for Patients with Diabetes Mellitus (RAMP-DM) of Hong Kong from July 2014 to June 2017. We collected the individual data of 31,574 subjects, with mean age of 63.0 (±10.8) years and mean DM duration of 7.4 (±6.4) years. Of them 9,386 (29.7%) had CKD and 7,452 (23.6%) had micro- or macro-albuminuria. After adjustment for multiple demographic and lifestyle confounders, we identified several modifiable risk factors associated with higher rate of CKD: obesity (OR = 1.54), current smoking (OR = 1.33), higher systolic blood pressure (OR = 1.01), dyslipidemia (OR = 1.32 and 0.61 for triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C)), hyperglycemia (OR = 1.11 for HbA1c), diabetic retinopathy (OR = 1.36 and 2.60 for non-sight and sight threatening retinopathy), and stroke (OR = 1.43). The risk factors of lower dialytic blood pressure and coronary heart disease were identified only in men, whereas peripheral arterial disease only in women. In conclusion, several modifiable and gender specific risk factors were significantly associated with higher prevalence of CKD in Chinese adults with T2DM. The high-risk populations identified in this study shall receive regular screening for renal functions to achieve better patient management in primary care settings.
Computational analysis of the amino acid interactions that promote or decrease protein solubility
Authors: Hou Qingzhen , Bourgeas Raphaël , Pucci Fabrizio , Rooman Marianne
Published: September 2018

The solubility of globular proteins is a basic biophysical property that is usually a prerequisite for their functioning. In this study, we probed the solubility of globular proteins with the help of the statistical potential formalism, in view of objectifying the connection of solubility with structural and energetic properties and of the solubility-dependence of specific amino acid interactions. We started by setting up two independent datasets containing either soluble or aggregation-prone proteins with known structures. From these two datasets, we computed solubility-dependent distance potentials that are by construction biased towards the solubility of the proteins from which they are derived. Their analysis showed the clear preference of amino acid interactions such as Lys-containing salt bridges and aliphatic interactions to promote protein solubility, whereas others such as aromatic, His-π, cation-π, amino-π and anion-π interactions rather tend to reduce it. These results indicate that interactions involving delocalized π-electrons favor aggregation, unlike those involving no (or few) dispersion forces. Furthermore, using our potentials derived from either highly or weakly soluble proteins to compute protein folding free energies, we found that the difference between these two energies correlates better with solubility than other properties analyzed before such as protein length, isoelectric point and aliphatic index. This is, to the best of our knowledge, the first comprehensive in silico study of the impact of residue-residue interactions on protein solubility properties.The results of this analysis provide new insights that will facilitate future rational protein design applications aimed at modulating the solubility of targeted proteins.
The role of scene summary statistics in object recognition
Authors: Lauer Tim , Cornelissen Tim H. W. , Draschkow Dejan , Willenbockel Verena , Võ Melissa L.-H.
Published: September 2018

Objects that are semantically related to the visual scene context are typically better recognized than unrelated objects. While context effects on object recognition are well studied, the question which particular visual information of an object’s surroundings modulates its semantic processing is still unresolved. Typically, one would expect contextual influences to arise from high-level, semantic components of a scene but what if even low-level features could modulate object processing? Here, we generated seemingly meaningless textures of real-world scenes, which preserved similar summary statistics but discarded spatial layout information. In Experiment 1, participants categorized such textures better than colour controls that lacked higher-order scene statistics while original scenes resulted in the highest performance. In Experiment 2, participants recognized briefly presented consistent objects on scenes significantly better than inconsistent objects, whereas on textures, consistent objects were recognized only slightly more accurately. In Experiment 3, we recorded event-related potentials and observed a pronounced mid-central negativity in the N300/N400 time windows for inconsistent relative to consistent objects on scenes. Critically, inconsistent objects on textures also triggered N300/N400 effects with a comparable time course, though less pronounced. Our results suggest that a scene’s low-level features contribute to the effective processing of objects in complex real-world environments.
Facial expression and oxytocin as possible markers of positive emotions in horses
Authors: Lansade Léa , Nowak Raymond , Lainé Anne-Lyse , Leterrier Christine , Bonneau Coralie , Parias Céline , Bertin Aline
Published: September 2018

Behavioural and physiological markers of discrete positive emotions remain little investigated in animals. To characterise new markers in horses, we used tactile stimulations to induce emotional situation of contrasting valence. In the Gentle grooming group (G, N = 13) horses were gently groomed during 11 sessions on the body areas they appreciated the most. Horses in the Standard grooming group (S, N = 14) were groomed using a fixed procedure, reported to induce avoidance reactions in some horses. At session 11, G horses expressed significantly more contact-seeking behaviours than S horses, which expressed significantly more avoidance behaviours. This result suggests positive emotions in G horses and negative emotions in S horses. Blood cortisol, oxytocin, heart rate and heart rate variability never differed between before and after the grooming session. However, after the 11 sessions, basal oxytocin levels were lower in the G than in the S group. This difference was unexpected, but supports studies showing that a low level of basal oxytocin could be a marker of better well-being. Analyses of facial expressions during grooming revealed significant differences between groups. These expressions appear to be more sensitive than behavioural indicators because they alone enabled differentiating emotions according to the group when horses were re-exposed to neutral grooming one year after the treatment.