bluuebunny/crossref_metadata_2025 huggingface dataset:
Enhancer-associated long non-coding RNA LEENE regulates endothelial nitric oxide synthase and endothelial function
Authors: Miao Yifei , Ajami Nassim E. , Huang Tse-Shun , Lin Feng-Mao , Lou Chih-Hong , Wang Yun-Ting , Li Shuai , Kang Jian , Munkacsi Hannah , Maurya Mano R. , Gupta Shakti , Chien Shu , Subramaniam Shankar , Chen Zhen
Published: January 2018

The optimal expression of endothelial nitric oxide synthase (eNOS), the hallmark of endothelial homeostasis, is vital to vascular function. Dynamically regulated by various stimuli, eNOS expression is modulated at transcriptional, post-transcriptional, and post-translational levels. However, epigenetic modulations of eNOS, particularly through long non-coding RNAs (lncRNAs) and chromatin remodeling, remain to be explored. Here we identify an enhancer-associated lncRNA that enhances eNOS expression (LEENE). Combining RNA-sequencing and chromatin conformation capture methods, we demonstrate that LEENE is co-regulated with eNOS and that its enhancer resides in proximity to eNOS promoter in endothelial cells (ECs). Gain- and Loss-of-function of LEENE differentially regulate eNOS expression and EC function. Mechanistically, LEENE facilitates the recruitment of RNA Pol II to the eNOS promoter to enhance eNOS nascent RNA transcription. Our findings unravel a new layer in eNOS regulation and provide novel insights into cardiovascular regulation involving endothelial function.
Harnessing insulin- and leptin-induced oxidation of PTP1B for therapeutic development
Authors: Krishnan Navasona , Bonham Christopher A. , Rus Ioana A. , Shrestha Om Kumar , Gauss Carla M. , Haque Aftabul , Tocilj Ante , Joshua-Tor Leemor , Tonks Nicholas K.
Published: January 2018

The protein tyrosine phosphatase PTP1B is a major regulator of glucose homeostasis and energy metabolism, and a validated target for therapeutic intervention in diabetes and obesity. Nevertheless, it is a challenging target for inhibitor development. Previously, we generated a recombinant antibody (scFv45) that recognizes selectively the oxidized, inactive conformation of PTP1B. Here, we provide a molecular basis for its interaction with reversibly oxidized PTP1B. Furthermore, we have identified a small molecule inhibitor that mimics the effects of scFv45. Our data provide proof-of-concept that stabilization of PTP1B in an inactive, oxidized conformation by small molecules can promote insulin and leptin signaling. This work illustrates a novel paradigm for inhibiting the signaling function of PTP1B that may be exploited for therapeutic intervention in diabetes and obesity.
Order enables efficient electron-hole separation at an organic heterojunction with a small energy loss
Authors: Menke S. Matthew , Cheminal Alexandre , Conaghan Patrick , Ran Niva A. , Greehnam Neil C. , Bazan Guillermo C. , Nguyen Thuc-Quyen , Rao Akshay , Friend Richard H.
Published: January 2018

Donor–acceptor organic solar cells often show low open-circuit voltages (VOC) relative to their optical energy gap (Eg) that limit power conversion efficiencies to ~12%. This energy loss is partly attributed to the offset between Eg and that of intermolecular charge transfer (CT) states at the donor–acceptor interface. Here we study charge generation occurring in PIPCP:PC61BM, a system with a very low driving energy for initial charge separation (Eg−ECT ~ 50 meV) and a high internal quantum efficiency (ηIQE ~ 80%). We track the strength of the electric field generated between the separating electron-hole pair by following the transient electroabsorption optical response, and find that while localised CT states are formed rapidly (<100 fs) after photoexcitation, free charges are not generated until 5 ps after photogeneration. In PIPCP:PC61BM, electronic disorder is low (Urbach energy <27 meV) and we consider that free charge separation is able to outcompete trap-assisted non-radiative recombination of the CT state.
Dysbindin links presynaptic proteasome function to homeostatic recruitment of low release probability vesicles
Authors: Wentzel Corinna , Delvendahl Igor , Sydlik Sebastian , Georgiev Oleg , Müller Martin
Published: January 2018

Here we explore the relationship between presynaptic homeostatic plasticity and proteasome function at the Drosophila neuromuscular junction. First, we demonstrate that the induction of homeostatic plasticity is blocked after presynaptic proteasome perturbation. Proteasome inhibition potentiates release under baseline conditions but not during homeostatic plasticity, suggesting that proteasomal degradation and homeostatic plasticity modulate a common pool of vesicles. The vesicles that are regulated by proteasome function and recruited during homeostatic plasticity are highly EGTA sensitive, implying looser Ca2+ influx-release coupling. Similar to homeostatic plasticity, proteasome perturbation enhances presynaptic Ca2+ influx, readily-releasable vesicle pool size, and does not potentiate release after loss of specific homeostatic plasticity genes, including the schizophrenia-susceptibility gene dysbindin. Finally, we provide genetic evidence that Dysbindin levels regulate the access to EGTA-sensitive vesicles. Together, our data suggest that presynaptic protein degradation opposes the release of low-release probability vesicles that are potentiated during homeostatic plasticity and whose access is controlled by dysbindin.
Quantitative optical nanophysiology of Ca2+ signaling at inner hair cell active zones
Authors: Neef Jakob , Urban Nicolai T. , Ohn Tzu-Lun , Frank Thomas , Jean Philippe , Hell Stefan W. , Willig Katrin I. , Moser Tobias
Published: January 2018

Ca2+ influx triggers the release of synaptic vesicles at the presynaptic active zone (AZ). A quantitative characterization of presynaptic Ca2+ signaling is critical for understanding synaptic transmission. However, this has remained challenging to establish at the required resolution. Here, we employ confocal and stimulated emission depletion (STED) microscopy to quantify the number (20–330) and arrangement (mostly linear 70 nm × 100–600 nm clusters) of Ca2+ channels at AZs of mouse cochlear inner hair cells (IHCs). Establishing STED Ca2+ imaging, we analyze presynaptic Ca2+ signals at the nanometer scale and find confined elongated Ca2+ domains at normal IHC AZs, whereas Ca2+ domains are spatially spread out at the AZs of bassoon-deficient IHCs. Performing 2D-STED fluorescence lifetime analysis, we arrive at estimates of the Ca2+ concentrations at stimulated IHC AZs of on average 25 µM. We propose that IHCs form bassoon-dependent presynaptic Ca2+-channel clusters of similar density but scalable length, thereby varying the number of Ca2+ channels amongst individual AZs.
Dot1 regulates nucleosome dynamics by its inherent histone chaperone activity in yeast
Authors: Lee Soyun , Oh Seunghee , Jeong Kwiwan , Jo Hyelim , Choi Yoonjung , Seo Hogyu David , Kim Minhoo , Choe Joonho , Kwon Chang Seob , Lee Daeyoup
Published: January 2018

Dot1 (disruptor of telomeric silencing-1, DOT1L in humans) is the only known enzyme responsible for histone H3 lysine 79 methylation (H3K79me) and is evolutionarily conserved in most eukaryotes. Yeast Dot1p lacks a SET domain and does not methylate free histones and thus may have different actions with respect to other histone methyltransferases. Here we show that Dot1p displays histone chaperone activity and regulates nucleosome dynamics via histone exchange in yeast. We show that a methylation-independent function of Dot1p is required for the cryptic transcription within transcribed regions seen following disruption of the Set2–Rpd3S pathway. Dot1p can assemble core histones to nucleosomes and facilitate ATP-dependent chromatin-remodeling activity through its nucleosome-binding domain, in vitro. Global analysis indicates that Dot1p appears to be particularly important for histone exchange and chromatin accessibility on the transcribed regions of long-length genes. Our findings collectively suggest that Dot1p-mediated histone chaperone activity controls nucleosome dynamics in transcribed regions.
Cigarette smoking is associated with an altered vaginal tract metabolomic profile
Authors: Nelson T. M. , Borgogna J. C. , Michalek R. D. , Roberts D. W. , Rath J. M. , Glover E. D. , Ravel J. , Shardell M. D. , Yeoman C. J. , Brotman R. M.
Published: January 2018

Cigarette smoking has been associated with both the diagnosis of bacterial vaginosis (BV) and a vaginal microbiota lacking protective Lactobacillus spp. As the mechanism linking smoking with vaginal microbiota and BV is unclear, we sought to compare the vaginal metabolomes of smokers and non-smokers (17 smokers/19 non-smokers). Metabolomic profiles were determined by gas and liquid chromatography mass spectrometry in a cross-sectional study. Analysis of the 16S rRNA gene populations revealed samples clustered into three community state types (CSTs) ---- CST-I (L. crispatus-dominated), CST-III (L. iners-dominated) or CST-IV (low-Lactobacillus). We identified 607 metabolites, including 12 that differed significantly (q-value < 0.05) between smokers and non-smokers. Nicotine, and the breakdown metabolites cotinine and hydroxycotinine were substantially higher in smokers, as expected. Among women categorized to CST-IV, biogenic amines, including agmatine, cadaverine, putrescine, tryptamine and tyramine were substantially higher in smokers, while dipeptides were lower in smokers. These biogenic amines are known to affect the virulence of infective pathogens and contribute to vaginal malodor. Our data suggest that cigarette smoking is associated with differences in important vaginal metabolites, and women who smoke, and particularly women who are also depauperate for Lactobacillus spp., may have increased susceptibilities to urogenital infections and increased malodor.
Directional sound beam emission from a configurable compact multi-source system
Authors: Zhao Jiajun , Jahdali Rasha Al , Zhang Likun , Wu Ying
Published: January 2018

We propose to achieve efficient emission of highly directional sound beams from multiple monopole sources embedded in a subwavelength enclosure. Without the enclosure, the emitted sound fields have an indistinguishable or omnidirectional radiation directivity in far fields. The strong directivity formed in the presence of the enclosure is attributed to interference of sources under degenerate Mie resonances in the enclosure of anisotropic property. Our numerical simulations of sound emission from the sources demonstrate the radiation of a highly directed sound beam of unidirectional or bidirectional patterns, depending on how the sources are configured inside the enclosure. Our scheme, if achieved, can solve the challenging problem of poor directivity of a subwavelength sound system, and can guide beam forming and collimation by miniaturized devices.
Genomic and transcriptomic analysis of the Asian honeybee Apis cerana provides novel insights into honeybee biology
Authors: Diao Qingyun , Sun Liangxian , Zheng Huajun , Zeng Zhijiang , Wang Shengyue , Xu Shufa , Zheng Huoqing , Chen Yanping , Shi Yuanyuan , Wang Yuezhu , Meng Fei , Sang Qingliang , Cao Lianfei , Liu Fang , Zhu Yongqiang , Li Wenfeng , Li Zhiguo , Dai Congjie , Yang Minjun , Chen Shenglu , Chen Runsheng , Zhang Shaowu , Evans Jay D. , Huang Qiang , Liu Jie , Hu Fuliang , Su Songkun , Wu Jie
Published: January 2018

The Asian honeybee Apis cerana is one of two bee species that have been commercially kept with immense economic value. Here we present the analysis of genomic sequence and transcriptomic exploration for A. cerana as well as the comparative genomic analysis of the Asian honeybee and the European honeybee A. mellifera. The genome and RNA-seq data yield new insights into the behavioral and physiological resistance to the parasitic mite Varroa the evolution of antimicrobial peptides, and the genetic basis for labor division in A. cerana. Comparison of genes between the two sister species revealed genes specific to A. cerana, 54.5% of which have no homology to any known proteins. The observation that A. cerana displayed significantly more vigilant grooming behaviors to the presence of Varroa than A. mellifera in conjunction with gene expression analysis suggests that parasite-defensive grooming in A. cerana is likely triggered not only by exogenous stimuli through visual and olfactory detection of the parasite, but also by genetically endogenous processes that periodically activates a bout of grooming to remove the ectoparasite. This information provides a valuable platform to facilitate the traits unique to A. cerana as well as those shared with other social bees for health improvement.
Loss of disease tolerance during Citrobacter rodentium infection is associated with impaired epithelial differentiation and hyperactivation of T cell responses
Authors: Kang Eugene , Zhou Guangyan , Yousefi Mitra , Cayrol Romain , Xia Jianguo , Gruenheid Samantha
Published: January 2018

Citrobacter rodentium is an intestinal mouse pathogen widely used as a model to study the mucosal response to infection. Inbred mouse strains suffer one of two fates following infection: self-limiting colitis or fatal diarrheal disease. We previously reported that Rspo2 is a major genetic determinant of the outcome of C. rodentium infection; Rspo2 induction during infection of susceptible mice leads to loss of intestinal function and mortality. Rspo2 induction does not impact bacterial colonization, but rather, impedes the ability of the host to tolerate C. rodentium infection. Here, we performed deep RNA sequencing and systematically analyzed the global gene expression profiles of C. rodentium-infected colon tissues from susceptible and resistant congenic mice strains to determine the common responses to infection and the Rspo2-mediated dysfunction pathway signatures associated with loss of disease tolerance. Our results highlight changes in metabolism, tissue remodeling, and host defence as common responses to infection. Conversely, increased Wnt and stem cell signatures, loss of epithelial differentiation, and exaggerated CD4+ T cell activation through increased antigen processing and presentation were specifically associated with the response to infection in susceptible mice. These data provide insights into the molecular mechanisms underlying intestinal dysfunction and disease tolerance during C. rodentium infection.
Phenotype and Functional Features of Human Telomerase Reverse Transcriptase Immortalized Human Airway Smooth Muscle Cells from Asthmatic and Non-Asthmatic Donors
Authors: Burgess J. K. , Ketheson A. , Faiz A. , Limbert Rempel K. A. , Oliver B. G. , Ward J. P. T. , Halayko A. J.
Published: January 2018

Asthma is an obstructive respiratory disease characterised by chronic inflammation with airway hyperresponsiveness. In asthmatic airways, there is an increase in airway smooth muscle (ASM) cell bulk, which differs from non-asthmatic ASM in characteristics. This study aimed to assess the usefulness of hTERT immortalisation of human ASM cells as a research tool. Specifically we compared proliferative capacity, inflammatory mediator release and extracellular matrix (ECM) production in hTERT immortalised and parent primary ASM cells from asthmatic and non-asthmatic donors. Our studies revealed no significant differences in proliferation, IL-6 and eotaxin-1 production, or CTGF synthesis between donor-matched parent and hTERT immortalised ASM cell lines. However, deposition of ECM proteins fibronectin and fibulin-1 was significantly lower in immortalised ASM cells compared to corresponding primary cells. Notably, previously reported differences in proliferation and inflammatory mediator release between asthmatic and non-asthmatic ASM cells were retained, but excessive ECM protein deposition in asthmatic ASM cells was lost in hTERT ASM cells. This study shows that hTERT immortalised ASM cells mirror primary ASM cells in proliferation and inflammatory profile characteristics. Moreover, we demonstrate both strengths and weaknesses of this immortalised cell model as a representation of primary ASM cells for future asthma pathophysiological research.
Detection of antimicrobial resistance genes associated with the International Space Station environmental surfaces
Authors: Urbaniak C. , Sielaff A. Checinska , Frey K. G. , Allen J. E. , Singh N. , Jaing C. , Wheeler K. , Venkateswaran K.
Published: January 2018

Antimicrobial resistance (AMR) is a global health issue. In an effort to minimize this threat to astronauts, who may be immunocompromised and thus at a greater risk of infection from antimicrobial resistant pathogens, a comprehensive study of the ISS “resistome’ was conducted. Using whole genome sequencing (WGS) and disc diffusion antibiotic resistance assays, 9 biosafety level 2 organisms isolated from the ISS were assessed for their antibiotic resistance. Molecular analysis of AMR genes from 24 surface samples collected from the ISS during 3 different sampling events over a span of a year were analyzed with Ion AmpliSeq™ and metagenomics. Disc diffusion assays showed that Enterobacter bugandensis strains were resistant to all 9 antibiotics tested and Staphylococcus haemolyticus being resistant to none. Ion AmpliSeq™ revealed that 123 AMR genes were found, with those responsible for beta-lactam and trimethoprim resistance being the most abundant and widespread. Using a variety of methods, the genes involved in antimicrobial resistance have been examined for the first time from the ISS. This information could lead to mitigation strategies to maintain astronaut health during long duration space missions when return to Earth for treatment is not possible.
A tissue-mimetic nano-fibrillar hybrid injectable hydrogel for potential soft tissue engineering applications
Authors: Latifi Neda , Asgari Meisam , Vali Hojatollah , Mongeau Luc
Published: January 2018

While collagen type I (Col-I) is commonly used as a structural component of biomaterials, collagen type III (Col-III), another fibril forming collagen ubiquitous in many soft tissues, has not previously been used. In the present study, the novel concept of an injectable hydrogel with semi-interpenetrating polymeric networks of heterotypic collagen fibrils, with tissue-specific Col-III to Col-I ratios, in a glycol-chitosan matrix was investigated. Col-III was introduced as a component of the novel hydrogel, inspired by its co-presence with Col-I in many soft tissues, its influence on the Col-I fibrillogenesis in terms of diameter and mechanics, and its established role in regulating scar formation. The hydrogel has a nano-fibrillar porous structure, and is mechanically stable under continuous dynamic stimulation. It was found to provide a longer half-life of about 35 days than similar hyaluronic acid-based hydrogels, and to support cell implantation in terms of viability, metabolic activity, adhesion and migration. The specific case of pure Col-III fibrils in a glycol-chitosan matrix was investigated. The proposed hydrogels meet many essential requirements for soft tissue engineering applications, particularly for mechanically challenged tissues such as vocal folds and heart valves.
SLAF-based high-density genetic map construction and QTL mapping for major economic traits in sea urchin Strongylocentrotus intermedius
Authors: Chang Yaqing , Ding Jun , Xu Yuhui , Li Dan , Zhang Weijie , Li Lei , Song Jian
Published: January 2018

Sea urchin (Strongylocentrotus intermedius) has long been a model species for developmental and evolutionary research, but only a few studies have focused on gene mapping. Here, we reported a high-density genetic map containing 4,387 polymorphism specific-length amplified fragment (SLAF) markers spanning 21 linkage groups (LG) for sea urchin. Based on this genetic map and phenotyping data for eight economic traits, 33 potentially significant QTLs were detected on ten different LGs with explanations ranging from 9.90% to 46.30%, partly including 10 QTLs for test diameter, six QTLs for body weight and eight QTLs for Aristotle’s lantern weight. Moreover, we found a QTL enrichment LG, LG15, gathering QTLs for test diameter, body weight, gonad weight, light orange-yellow color difference (≥E1) and light yellow color difference (≥E2). Among all QTLs, we genotyped four QTLs for test diameter, Aristotle’s lantern weight and body weight using High Resolution Melting (HRM) technology. Finally, we used the verified SNP marker (detected using SLAF sequencing) to explore their marker-assisted selection (MAS) breeding application potential and found that SNP-29 associated tightly with body weight and that heterozygous genotype was a dominant genotype, indicating that SNP-29 was a promising marker for MAS.
Band gap maps beyond the delocalization limit: correlation between optical band gaps and plasmon energies at the nanoscale
Authors: Zhan Wei , Venkatachalapathy Vishnukanthan , Aarholt Thomas , Kuznetsov Andrej Yu. , Prytz Øystein
Published: January 2018

Recent progresses in nanoscale semiconductor technology have heightened the need for measurements of band gaps with high spatial resolution. Band gap mapping can be performed through a combination of probe-corrected scanning transmission electron microscopy (STEM) and monochromated electron energy-loss spectroscopy (EELS), but are rare owing to the complexity of the experiments and the data analysis. Furthermore, although this method is far superior in terms of spatial resolution to any other techniques, it is still fundamentally resolution-limited due to inelastic delocalization of the EELS signal. In this work we have established a quantitative correlation between optical band gaps and plasmon energies using the Zn1−xCd
x
O/ZnO system as an example, thereby side-stepping the fundamental resolution limits of band gap measurements, and providing a simple and convenient approach to achieve band gap maps with unprecedented spatial resolution.
Error-related cardiac response as information for visibility judgements
Authors: Łukowska Marta , Sznajder Michał , Wierzchoń Michał
Published: January 2018

Interoception provides information about the saliency of external or internal sensory events and thus may inform perceptual decision-making. Error in performance is an example of a motivationally significant internal event that evokes autonomic nervous system response resembling the orienting response: heart rate deceleration, increased skin conductance response, and pupil dilation. Here, we investigate whether error-related cardiac activity may serve as a source of information when making metacognitive judgments in an orientation discrimination backward masking task. In the first experiment, we found that the heart accelerates less after an incorrect stimuli discrimination than after a correct one. Moreover, this difference becomes more pronounced with increasing subjective visibility of the stimuli. In the second experiment, this accuracy-dependent pattern of cardiac activity was found only when participants listened to their own heartbeats, but not someone else’s. We propose that decision accuracy coded in cardiac activity may be fed as a cue to subjective visibility judgments.
Oxidative stress via inhibition of the mitochondrial electron transport and Nrf-2-mediated anti-oxidative response regulate the cytotoxic activity of plumbagin
Authors: Kapur Arvinder , Beres Thomas , Rathi Kavya , Nayak Amruta P. , Czarnecki Austin , Felder Mildred , Gillette Amani , Ericksen Spencer S. , Sampene Emmanuel , Skala Melissa C. , Barroilhet Lisa , Patankar Manish S.
Published: January 2018

Plumbagin, an anti-cancer agent, is toxic to cells of multiple species. We investigated if plumbagin targets conserved biochemical processes. Plumbagin induced DNA damage and apoptosis in cells of diverse mutational background with comparable potency. A 3–5 fold increase in intracellular oxygen radicals occurred in response to plumbagin. Neutralization of the reactive oxygen species by N-acetylcysteine blocked apoptosis, indicating a central role for oxidative stress in plumbagin-mediated cell death. Plumbagin docks in the ubiquinone binding sites (Q0 and Qi) of mitochondrial complexes I–III, the major sites for oxygen radicals. Plumbagin decreased oxygen consumption rate, ATP production and optical redox ratio (NAD(P)H/FAD) indicating interference with electron transport downstream of mitochondrial Complex II. Oxidative stress induced by plumbagin triggered an anti-oxidative response via activation of Nrf2. Plumbagin and the Nrf2 inhibitor, brusatol, synergized to inhibit cell proliferation. These data indicate that while inhibition of electron transport is the conserved mechanism responsible for plumbagin’s chemotoxicity, activation of Nrf2 is the resulting anti-oxidative response that allows plumbagin to serve as a chemopreventive agent. This study provides the basis for designing potent and selective plumbagin analogs that can be coupled with suitable Nrf2 inhibitors for chemotherapy or administered as single agents to induce Nrf2-mediated chemoprevention.
Glucocorticoid receptor GRβ regulates glucocorticoid-induced ocular hypertension in mice
Authors: Patel Gaurang C. , Liu Yang , Millar J. Cameron , Clark Abbot F.
Published: January 2018

Prolonged glucocorticoid (GC) therapy can cause GC-induced ocular hypertension (OHT), which if left untreated progresses to iatrogenic glaucoma and permanent vision loss. The alternatively spliced isoform of glucocorticoid receptor GRβ acts as dominant negative regulator of GR activity, and it has been shown that overexpressing GRβ in trabecular meshwork (TM) cells inhibits GC-induced glaucomatous damage in TM cells. The purpose of this study was to use viral vectors to selectively overexpress the GRβ isoform in the TM of mouse eyes treated with GCs, to precisely dissect the role of GRβ in regulating steroid responsiveness. We show that overexpression of GRβ inhibits GC effects on MTM cells in vitro and GC-induced OHT in mouse eyes in vivo. Ad5 mediated GRβ overexpression reduced the GC induction of fibronectin, collagen 1, and myocilin in TM of mouse eyes both in vitro and in vivo. GRβ also reversed DEX-Ac induced IOP elevation, which correlated with increased conventional aqueous humor outflow facility. Thus, GRβ overexpression reduces effects caused by GCs and makes cells more resistant to GC treatment. In conclusion, our current work provides the first evidence of the in vivo physiological role of GRβ in regulating GC-OHT and GC-mediated gene expression in the TM.
Cardiac glycoside/aglycones inhibit HIV-1 gene expression by a mechanism requiring MEK1/2-ERK1/2 signaling
Authors: Wong Raymond W. , Lingwood Clifford A. , Ostrowski Mario A. , Cabral Tyler , Cochrane Alan
Published: January 2018

The capacity of HIV-1 to develop resistance to current drugs calls for innovative strategies to control this infection. We aimed at developing novel inhibitors of HIV-1 replication by targeting viral RNA processing—a stage dependent on conserved host processes. We previously reported that digoxin is a potent inhibitor of this stage. Herein, we identify 12 other cardiac glycoside/aglycones or cardiotonic steroids (CSs) that impede HIV growth in HIV-infected T cells from clinical patients at IC50s (1.1–1.3 nM) that are 2–26 times below concentrations used in patients with heart conditions. We subsequently demonstrate that CSs inhibit HIV-1 gene expression in part through modulation of MEK1/2-ERK1/2 signaling via interaction with the Na+/K+-ATPase, independent of alterations in intracellular Ca2+. Supporting this hypothesis, depletion of the Na+/K+-ATPase or addition of a MEK1/2-ERK1/2 activator also impairs HIV-1 gene expression. Similar to digoxin, all CSs tested induce oversplicing of HIV-1 RNAs, reducing unspliced (Gag) and singly spliced RNAs (Env/p14-Tat) encoding essential HIV-1 structural/regulatory proteins. Furthermore, all CSs cause nuclear retention of genomic/unspliced RNAs, supporting viral RNA processing as the underlying mechanism for their disruption of HIV-1 replication. These findings call for further in vivo validation and supports the targeting of cellular processes to control HIV-1 infection.
New virulence factor CSK29544_02616 as LpxA binding partner in Cronobacter sakazakii
Authors: Kim Seongok , Yoon Hyunjin , Ryu Sangryeol
Published: January 2018

Cronobacter sakazakii is an opportunistic pathogen that can cause meningitis and necrotizing enterocolitis in premature infants, but its virulence determinants remain largely unknown. In this study, a transposon-mediated random-mutant library of C. sakazakii was used to identify new virulence factors. Compared to wild-type bacteria, a mutant lacking CSK29544_02616 (referred to as labp) was defective in invasion into intestinal epithelial cells (by at least 1000-fold) and showed less phagocytosis by macrophages (by at least 50-fold). The lack of labp in C. sakazakii changed the profile of outer membrane proteins, decreased the production of lipopolysaccharides, and increased the production of membrane phospholipids. Bacterial physiological characteristics including surface hydrophobicity and motility were also altered in the absence of labp, presumably because of changes in the bacterial-envelope structure. To systematically determine the role of labp, ligand fishing was conducted using Labp as a bait, which revealed LpxA as a binding partner of Labp. LpxA is UDP-N-acetylglucosamine (GlcNAc) acyltransferase, the first enzyme in the pathway of lipid A biosynthesis. Labp increased the enzymatic activity of LpxA without influencing lpxA expression. Considering multifaceted roles of lipopolysaccharides in virulence regulation, Labp is a novel virulence factor that promotes the production of lipid A by LpxA in Cronobacter.
Quail egg homogenate alleviates food allergy induced eosinophilic esophagitis like disease through modulating PAR-2 transduction pathway in peanut sensitized mice
Authors: Lianto Priscilia , Han Shiwen , Li Xinrui , Ogutu Fredrick Onyango , Zhang Yani , Fan Zhuoyan , Che Huilian
Published: January 2018

The present pharmacotherapy for eosinophilic esophagitis (EoE) fundamentally depend on inhaled corticosteroids. Despite the fact that oral intake of topical steroids can be successful in restricting EoE-related inflammation, there are concerns with respect to the long term utilization of steroids, especially in kids. In the current research, we assess the effect of quail egg, which is reportedly a known serine protease inhibitor, on symptomatology and immune responses in a peanut-sensitized mouse model of food allergy induced EoE. Daily oral treatment with quail egg attenuated mice symptomatology and immune response. Treatment with quail egg inhibited antigen-prompted increments in mouse tryptase and eosinophil cationic protein (ECP) in serum and eosinophil in inflamed tissues like oesophagus, lung, and digestive system. Quail egg treatment resulted in decreased antibody specific IgE and IgG1 and a variety of inflammatory genes that were abnormally expressed in EoE. Other effects included increased IL-10, decreased PAR-2 activation and NF-kB p65 in inflamed tissues. Our results suggest that quail egg treatment may have therapeutic potential in attenuating the symptoms of food allergy induced EoE like disease through regulating PAR-2 downstream pathway by blocking the activation of the transcription factor NF-kB p65 activity.
Relationship between brachial-ankle and heart-femoral pulse wave velocities and the rapid decline of kidney function
Authors: Lee Sung Woo , Han Seung Hyeok , Yoo Tae Hyun , Chung Wookyung , Park Sue K. , Chae Dong Wan , Ahn Curie , Oh Kook-Hwan
Published: January 2018

The impact of brachial-ankle pulse wave velocity (baPWV) and heart-femoral pulse wave velocity (hfPWV) on rapid decline of estimated glomerular filtration rate (eGFR) has been inconclusive. The database of a multicenter prospective study of 2238 patients in Korea enrolled from 2011 to 2016 was reviewed. After excluding patients with missing baPWV (n = 257) and eGFR change (n = 180), the study included 1801 non-dialysis chronic kidney disease (CKD) patients. The eGFR change <−5ml/min/1.73 m2/year was defined as rapid decline. During a mean of 2.2 years, the mean eGFR change was −3.6 ml/min/1.73 m2/year, and 31.6% of patients were classified as having rapid decline. Older age, causes of CKD, increased heart rate, systolic blood pressures, and proteinuria were associated with the highest baPWV quintile. In multivariate logistic regression analyses, the odds of a rapid decline in eGFR was 1.9 times higher in the fifth quintile than in the first quintile (P = 0.013). In a subset with baPWV and hfPWV (n = 1182), high baPWV was associated with rapid eGFR decline only when accompanied by a high hfPWV. These findings suggest that central and peripheral PWVs may simultaneously affect rapid eGFR decline.
High strength nanostructured Al-based alloys through optimized processing of rapidly quenched amorphous precursors
Authors: Kim Song-Yi , Lee Gwang-Yeob , Park Gyu-Hyeon , Kim Hyeon-Ah , Lee A-Young , Scudino Sergio , Prashanth Konda Gokuldoss , Kim Do-Hyang , Eckert Jürgen , Lee Min-Ha
Published: January 2018

We report the methods increasing both strength and ductility of aluminum alloys transformed from amorphous precursor. The mechanical properties of bulk samples produced by spark-plasma sintering (SPS) of amorphous Al-Ni-Co-Dy powders at temperatures above 673 K are significantly enhanced by in-situ crystallization of nano-scale intermetallic compounds during the SPS process. The spark plasma sintered Al84Ni7Co3Dy6 bulk specimens exhibit 1433 MPa compressive yield strength and 1773 MPa maximum strength together with 5.6% plastic strain, respectively. The addition of Dy enhances the thermal stability of primary fcc Al in the amorphous Al-TM -RE alloy. The precipitation of intermetallic phases by crystallization of the remaining amorphous matrix plays important role to restrict the growth of the fcc Al phase and contributes to the improvement of the mechanical properties. Such fully crystalline nano- or ultrafine-scale Al-Ni-Co-Dy systems are considered promising for industrial application because their superior mechanical properties in terms of a combination of very high room temperature strength combined with good ductility.
The effect of foreign language in fear acquisition
Authors: García-Palacios Azucena , Costa Albert , Castilla Diana , del Río Eva , Casaponsa Aina , Duñabeitia Jon Andoni
Published: January 2018

Emotions are at the core of human nature. There is evidence that emotional reactivity in foreign languages compared to native languages is reduced. We explore whether this emotional distance could modulate fear conditioning, an essential mechanism for the understanding and treatment of anxiety disorders. A group of participants was verbally informed (either in a foreign or in a native language) that two different stimuli could be either cueing the potential presence of a threat stimulus or its absence. We registered pupil size and electrodermal activity and calculated the difference in psychophysiological responses to conditioned and to unconditioned stimuli. Our findings provided evidence that verbal conditioning processes are affected by language context in this paradigm. We report the first experimental evidence regarding how the use of a foreign language may reduce fear conditioning. This observation opens the avenue to the potential use of a foreign language in clinical contexts.
Stress-induced TRBP phosphorylation enhances its interaction with PKR to regulate cellular survival
Authors: Chukwurah Evelyn , Patel Rekha C.
Published: January 2018

Transactivation response element RNA-binding protein (TRBP or TARBP2) initially identified to play an important role in human immunodeficiency virus (HIV) replication also has emerged as a regulator of microRNA biogenesis. In addition, TRBP functions in signaling pathways by negatively regulating the interferon-induced double-stranded RNA (dsRNA)-activated protein kinase (PKR) during viral infections and cell stress. During cellular stress, PKR is activated and phosphorylates the α subunit of the eukaryotic translation factor eIF2, leading to the cessation of general protein synthesis. TRBP inhibits PKR activity by direct interaction as well as by binding to PKR’s two known activators, dsRNA and PACT, thus preventing their interaction with PKR. In this study, we demonstrate for the first time that TRBP is phosphorylated in response to oxidative stress and upon phosphorylation, inhibits PKR more efficiently promoting cell survival. These results establish that PKR regulation through stress-induced TRBP phosphorylation is an important mechanism ensuring cellular recovery and preventing apoptosis due to sustained PKR activation.
The ten-year evolutionary trajectory of a highly recurrent paediatric high grade neuroepithelial tumour with MN1:BEND2 fusion
Authors: Burford Anna , Mackay Alan , Popov Sergey , Vinci Maria , Carvalho Diana , Clarke Matthew , Izquierdo Elisa , Avery Aimee , Jacques Thomas S. , Ingram Wendy J. , Moore Andrew S. , Frawley Kieran , Hassall Timothy E. , Robertson Thomas , Jones Chris
Published: January 2018

Astroblastomas are rare brain tumours which predominate in children and young adults, and have a controversial claim as a distinct entity, with no established WHO grade. Reports suggest a better outcome than high grade gliomas, though they frequently recur. Recently, they have been described to overlap with a newly-discovered group of tumours described as’high grade neuroepithelial tumour with MN1 alteration’ (CNS HGNET-MN1), defined by global methylation patterns and strongly associated with gene fusions targeting MN1. We have studied a unique case of astroblastoma arising in a 6 year-old girl, with multiple recurrences over a period of 10 years, with the pathognomonic MN1:BEND2 fusion. Exome sequencing allowed for a phylogenetic reconstruction of tumour evolution, which when integrated with clinical, pathological and radiological data provide for a detailed understanding of disease progression, with initial treatment driving tumour dissemination along four distinct trajectories. Infiltration of distant sites was associated with a later genome doubling, whilst there was evidence of convergent evolution of different lesions acquiring distinct alterations targeting NF-κB. These data represent an unusual opportunity to understand the evolutionary history of a highly recurrent childhood brain tumour, and provide novel therapeutic targets for astroblastoma/CNS HGNET-MN1.
Quantifying the Risk and Cost of Active Monitoring for Infectious Diseases
Authors: Reich Nicholas G. , Lessler Justin , Varma Jay K. , Vora Neil M.
Published: January 2018

During outbreaks of deadly emerging pathogens (e.g., Ebola, MERS-CoV) and bioterror threats (e.g., smallpox), actively monitoring potentially infected individuals aims to limit disease transmission and morbidity. Guidance issued by CDC on active monitoring was a cornerstone of its response to the West Africa Ebola outbreak. There are limited data on how to balance the costs and performance of this important public health activity. We present a framework that estimates the risks and costs of specific durations of active monitoring for pathogens of significant public health concern. We analyze data from New York City’s Ebola active monitoring program over a 16-month period in 2014–2016. For monitored individuals, we identified unique durations of active monitoring that minimize expected costs for those at “low (but not zero) risk” and “some or high risk”: 21 and 31 days, respectively. Extending our analysis to smallpox and MERS-CoV, we found that the optimal length of active monitoring relative to the median incubation period was reduced compared to Ebola due to less variable incubation periods. Active monitoring can save lives but is expensive. Resources can be most effectively allocated by using exposure-risk categories to modify the duration or intensity of active monitoring.
Dynamic all-optical drug screening on cardiac voltage-gated ion channels
Authors: Streit Jonas , Kleinlogel Sonja
Published: January 2018

Voltage-gated ion channels (VGCs) are prime targets for the pharmaceutical industry, but drug profiling on VGCs is challenging, since drug interactions are confined to specific conformational channel states mediated by changes in transmembrane potential. Here we combined various optogenetic tools to develop dynamic, high-throughput drug profiling assays with defined light-step protocols to interrogate VGC states on a millisecond timescale. We show that such light-induced electrophysiology (LiEp) yields high-quality pharmacological data with exceptional screening windows for drugs acting on the major cardiac VGCs, including hNav1.5, hKv1.5 and hERG. LiEp-based screening remained robust when using a variety of optogenetic actuators (ChR2, ChR2(H134R), CatCh, ChR2-EYFP-βArchT) and different types of organic (RH421, Di-4-ANBDQPQ, BeRST1) or genetic voltage sensors (QuasAr1). The tractability of LiEp allows a versatile and precise alternative to state-of-the-art VGC drug screening platforms such as automated electrophysiology or FLIPR readers.
SDF1 gradient associates with the distribution of c-Kit+ cardiac cells in the heart
Authors: Renko Outi , Tolonen Anna-Maria , Rysä Jaana , Magga Johanna , Mustonen Erja , Ruskoaho Heikki , Serpi Raisa
Published: January 2018

Identification of the adult cardiac stem cells (CSCs) has offered new therapeutic possibilities for treating ischemic myocardium. CSCs positive for the cell surface antigen c-Kit are known as the primary source for cardiac regeneration. Accumulating evidence shows that chemokines play important roles in stem cell homing. Here we investigated molecular targets to be utilized in modulating the mobility of endogenous CSCs. In a four week follow-up after experimental acute myocardial infarction (AMI) with ligation of the left anterior descending (LAD) coronary artery of Sprague-Dawley rats c-Kit+ CSCs redistributed in the heart. The number of c-Kit+ CSCs in the atrial c-Kit niche was diminished, whereas increased amount was observed in the left ventricle and apex. This was associated with increased expression of stromal cell-derived factor 1 alpha (SDF1α), and a significant positive correlation was found between c-Kit+ CSCs and SDF1α expression in the heart. Moreover, the migratory capacity of isolated c-Kit+ CSCs was induced by SDF1 treatment in vitro. We conclude that upregulation of SDF1α after AMI associates with increased expression of endogenous c-Kit+ CSCs in the injury area, and show induced migration of c-Kit+ cells by SDF1.
Redundancy of protein disulfide isomerases in the catalysis of the inactivating disulfide switch in A Disintegrin and Metalloprotease 17
Authors: Krossa Sebastian , Scheidig Axel J. , Grötzinger Joachim , Lorenzen Inken
Published: January 2018

A Disintegrin and Metalloprotease 17 (ADAM17) can cause the fast release of growth factors and inflammatory mediators from the cell surface. Its activity has to be turned on which occurs by various stimuli. The active form can be inactivated by a structural change in its ectodomain, related to the pattern of the formed disulphide bridges. The switch-off is executed by protein disulfide isomerases (PDIs) that catalyze an isomerization of two disulfide bridges and thereby cause a disulfide switch. We demonstrate that the integrity of the CGHC-motif within the active site of PDIs is indispensable. In particular, no major variation is apparent in the activities of the two catalytic domains of PDIA6. The affinities between PDIA1, PDIA3, PDIA6 and the targeted domain of ADAM17 are all in the nanomolar range and display no significant differences. The redundancy between PDIs and their disulfide switch activity in ectodomains of transmembrane proteins foundin vitroappears to be a basic characteristic. However, different PDIs might be requiredin vivofor disulfide switches in different tissues and under different cellular and physiological situations.
Stingless Bee Larvae Require Fungal Steroid to Pupate
Authors: Paludo Camila R. , Menezes Cristiano , Silva-Junior Eduardo A. , Vollet-Neto Ayrton , Andrade-Dominguez Andres , Pishchany Gleb , Khadempour Lily , do Nascimento Fabio S. , Currie Cameron R. , Kolter Roberto , Clardy Jon , Pupo Mônica T.
Published: January 2018

The larval stage of the stingless beeScaptotrigona depilismust consume a specific brood cell fungus in order to continue development. Here we show that this fungus is a member of the genusZygosaccharomycesand provides essential steroid precursors to the developing bee. Insect pupation requires ecdysteroid hormones, and as insects cannot synthesize sterolsde novo, they must obtain steroids in their diet. Larvalin vitroculturing assays demonstrated that consuming ergosterol recapitulates the developmental effects onS. depilisas ingestion ofZygosaccharomycessp. cells. Thus, we determined the molecular underpinning of this intimate mutualistic symbiosis. Phylogenetic analyses showed that similar cases of bee-Zygosaccharomyces symbiosis may exist. This unprecedented case of bee-fungus symbiosis driven by steroid requirement brings new perspectives regarding pollinator-microbiota interaction and preservation.
Natriuretic peptides promote glucose uptake in a cGMP-dependent manner in human adipocytes
Authors: Coué Marine , Barquissau Valentin , Morigny Pauline , Louche Katie , Lefort Corinne , Mairal Aline , Carpéné Christian , Viguerie Nathalie , Arner Peter , Langin Dominique , Rydén Mikael , Moro Cedric
Published: January 2018

Robust associations between low plasma level of natriuretic peptides (NP) and increased risk of type 2 diabetes (T2D) have been recently reported in humans. Adipose tissue (AT) is a known target of NP. However it is unknown whether NP signalling in human AT relates to insulin sensitivity and modulates glucose metabolism. We here show in two European cohorts that the NP receptor guanylyl cyclase-A (GC-A) expression in subcutaneous AT was down-regulated as a function of obesity grade while adipose NP clearance receptor (NPRC) was up-regulated. Adipose GC-A mRNA level was down-regulated in prediabetes and T2D, and negatively correlated with HOMA-IR and fasting blood glucose. We show for the first time that NP promote glucose uptake in a dose-dependent manner. This effect is reduced in adipocytes of obese individuals. NP activate mammalian target of rapamycin complex 1/2 (mTORC1/2) and Akt signalling. These effects were totally abrogated by inhibition of cGMP-dependent protein kinase and mTORC1/2 by rapamycin. We further show that NP treatment favoured glucose oxidation and de novo lipogenesis independently of significant gene regulation. Collectively, our data support a role for NP in blood glucose control and insulin sensitivity by increasing glucose uptake in human adipocytes. This effect is partly blunted in obesity.
Enhanced bone defect repairing effects in glucocorticoid-induced osteonecrosis of the femoral head using a porous nano-lithium-hydroxyapatite/gelatin microsphere/erythropoietin composite scaffold
Authors: Li Donghai , Xie Xiaowei , Yang Zhouyuan , Wang Changde , Wei Zhun , Kang Pengde
Published: January 2018

Glucocorticoid-induced osteonecrosis of the femoral head (GIONFH) is a common debilitating disease that occurs in young and middle-aged adults.
11-Azaartemisinin cocrystals with preserved lactam : acid heterosynthons
Authors: Nisar Madiha , Sung Herman H.-Y. , Puschmann Horst , Lakerveld Richard , Haynes Richard K. , Williams Ian D.
Published: January 2018

The R22(8) lactam : acid hetero-synthon, found in several new 1 : 1 and 2 : 1 cocrystals between the anti-malarial 11-azaartemisinin and organic acids.
Antiferromagnetic exchange and long-range magnetic ordering in supramolecular networks constructed of hexacyanido-bridged LnIII(3-pyridone)–CrIII (Ln = Gd, Tb) chains
Authors: Chorazy Szymon , Rams Michał , Wyczesany Maciej , Nakabayashi Koji , Ohkoshi Shin-ichi , Sieklucka Barbara
Published: January 2018

Exchange interactions and magnetic phase transitions are observed in novel cyanido-bridged lanthanide(iii)–chromium(iii) chains as proved by magnetic and calorimetric studies.
Ultrafast dynamics of the ESIPT photoswitchN-(3-pyridinyl)-2-pyridinecarboxamide
Authors: Böhnke Hendrik , Bahrenburg Julia , Ma Xiaonan , Röttger Katharina , Näther Christian , Rode Michał F. , Sobolewski Andrzej L. , Temps Friedrich
Published: January 2018

A potential ESIPT photoswitch has been investigated by femtosecond time-resolved electronic and vibrational absorption spectroscopy.