bluuebunny/crossref_metadata_2025_split huggingface dataset:
Griseofulvin impairs intraerythrocytic growth of Plasmodium falciparum through ferrochelatase inhibition but lacks activity in an experimental human infection study
Authors: Smith Clare M. , Jerkovic Ante , Truong Thy Thuc , Foote Simon J. , McCarthy James S. , McMorran Brendan J. 
Published: February 2017

AbstractGriseofulvin, an orally active antifungal drug used to treat dermatophyte infections, has a secondary effect of inducing cytochrome P450-mediated production of N-methyl protoporphyrin IX (N-MPP). N-MPP is a potent competitive inhibitor of the heme biosynthetic-enzyme ferrochelatase, and inhibits the growth of cultured erythrocyte stage Plasmodium falciparum. Novel drugs against Plasmodium are needed to achieve malaria elimination. Thus, we investigated whether griseofulvin shows anti-plasmodial activity. We observed that the intraerythrocytic growth of P. falciparum is inhibited in red blood cells pretreated with griseofulvin in vitro. Treatment with 100 μM griseofulvin was sufficient to prevent parasite growth and induce the production of N-MPP. Inclusion of the ferrochelatase substrate PPIX blocked the inhibitory activity of griseofulvin, suggesting that griseofulvin exerts its activity through the N-MPP-dependent inhibition of ferrochelatase. In an ex-vivo study, red blood cells from griseofulvin-treated subjects were refractory to the growth of cultured P. falciparum. However, in a clinical trial griseofulvin failed to show either therapeutic or prophylactic effect in subjects infected with blood stage P. falciparum. Although the development of griseofulvin as an antimalarial is not warranted, it represents a novel inhibitor of P. falciparum growth and acts via the N-MPP-dependent inhibition of ferrochelatase.
Structure of an octameric form of the minichromosome maintenance protein from the archaeon Pyrococcus abyssi
Authors: Cannone Giuseppe , Visentin Silvia , Palud Adeline , Henneke Ghislaine , Spagnolo Laura 
Published: February 2017

AbstractCell division is a complex process that requires precise duplication of genetic material. Duplication is concerted by replisomes. The Minichromosome Maintenance (MCM) replicative helicase is a crucial component of replisomes. Eukaryotic and archaeal MCM proteins are highly conserved. In fact, archaeal MCMs are powerful tools for elucidating essential features of MCM function. However, while eukaryotic MCM2-7 is a heterocomplex made of different polypeptide chains, the MCM complexes of manyArchaeaform homohexamers from a single gene product. Moreover, some archaeal MCMs are polymorphic, and both hexameric and heptameric architectures have been reported for the same polypeptide. Here, we present the structure of the archaeal MCM helicase fromPyrococcus abyssiin its single octameric ring assembly. To our knowledge, this is the first report of a full-length octameric MCM helicase.
Synthesis, Fungicidal Activity, and Structure Activity Relationship of β-Acylaminocycloalkylsulfonamides against Botrytis cinerea
Authors: Liu Chun-Hui , Chen Xiao-Yuan , Qin Pei-Wen , Qi Zhi-Qiu , Ji Ming-Shan , Liu Xing-Yu , Babu P. Vijaya , Li Xing-Hai , Cui Zi-Ning 
Published: February 2017

AbstractIn order to discover new antifungal agrochemicals that could have highly active and novel motifs, thirty-six new 2-acylaminocycloalkylsulfonamides (IV) were synthesized. Their structures were characterized and confirmed by 1H NMR, 13C NMR, IR, MS, elemental analysis and X-ray single crystal diffraction. In vitro and in vivo activities against various Botrytis cinerea strains were evaluated. Bioassay results revealed that most of the title compounds exhibited excellent in vitro fungicidal activity, in which compound IV-26 showed the highest activity against sensitive, low-resistant, moderate-resistant and high-resistant strains of B. cinerea compared with the positive fungicide procymidone. Meanwhile in vivo fungicidal activity of compound IV-31 was better than the commercial fungicides procymidone and chesulfamide in greenhouse trial. The structure activity relationship (SAR) was also discussed and the results were of importance to the structural optimization and development of more potent sulfonamides antifungal agents.
N,N Dimethylacetamide a drug excipient that acts as bromodomain ligand for osteoporosis treatment
Authors: Ghayor Chafik , Gjoksi Bebeka , Dong Jing , Siegenthaler Barbara , Caflisch Amedeo , Weber Franz E. 
Published: February 2017

AbstractN,N-Dimethylacetamide (DMA) is a water-miscible solvent, FDA approved as excipient and therefore widely used as drug-delivery vehicle. As such, DMA should be devoid of any bioactivity. Here we report that DMA is epigenetically active since it binds bromodomains and inhibits osteoclastogenesis and inflammation. Moreover, DMA enhances bone regeneration in vivo. Therefore, our in vivo and in vitro data reveal DMA’s potential as an anti-osteoporotic agent via the inhibition of osteoclast mediated bone resorption and enhanced bone regeneration. Our results highlight the potential therapeutic benefits of DMA and the need for reconsideration of previous reports where DMA was used as an ‘inactive’ drug-delivery vehicle.
Integrin α5β1 expression on dopaminergic neurons is involved in dopaminergic neurite outgrowth on striatal neurons
Authors: Izumi Yasuhiko , Wakita Seiko , Kanbara Chisato , Nakai Toshie , Akaike Akinori , Kume Toshiaki 
Published: February 2017

AbstractDuring development, dopaminergic neurons born in the substantia nigra extend their axons toward the striatum. However, the mechanisms by which the dopaminergic axons extend the striatum to innervate their targets remain unclear. We previously showed that paired-cultivation of mesencephalic cells containing dopaminergic neurons with striatal cells leads to the extension of dopaminergic neurites from the mesencephalic cell region to the striatal cell region. The present study shows that dopaminergic neurites extended along striatal neurons in the paired-cultures of mesencephalic cells with striatal cells. The extension of dopaminergic neurites was suppressed by the pharmacological inhibition of integrin α5β1. Using lentiviral vectors, short hairpin RNA (shRNA)-mediated knockdown of integrin α5 in dopaminergic neurons suppressed the neurite outgrowth to the striatal cell region. In contrast, the knockdown of integrin α5 in non-dopaminergic mesencephalic and striatal cells had no effect. Furthermore, overexpression of integrin α5 in dopaminergic neurons differentiated from embryonic stem cells enhanced their neurite outgrowth on striatal cells. These results indicate that integrin α5β1 expression on dopaminergic neurons plays an important role in the dopaminergic neurite outgrowth on striatal neurons.
The dynamic mechanism of noisy signal decoding in gene regulation
Authors: Liu Peijiang , Wang Haohua , Huang Lifang , Zhou Tianshou 
Published: February 2017

AbstractExperimental evidence supports that signaling pathways can induce different dynamics of transcription factor (TF) activation, but how an input signal is encoded by such a dynamic, noisy TF and further decoded by downstream genes remains largely unclear. Here, using a system of stochastic transcription with signal regulation, we show that (1) keeping the intensity of the signal noise invariant but prolonging the signal duration can both enhance the mutual information (MI) and reduce the energetic cost (EC); (2) if the signal duration is fixed, the larger MI needs the larger EC, but if the signal period is fixed, there is an optimal time that the signal spends at one lower branch, such that MI reaches the maximum; (3) if both the period and the duration are simultaneously fixed, increasing the input noise can always enhance MI in the case of transcription regulation rather than in the case of degradation regulation. In addition, we find that the input noise can induce stochastic focusing in a regulation-dependent manner. These results reveal not only the dynamic mechanism of noisy signal decoding in gene regulation but also the essential role of external noise in controlling gene expression levels.
Targeting the molecular chaperone SlyD to inhibit bacterial growth with a small molecule
Authors: Kumar Amit , Balbach Jochen 
Published: February 2017

AbstractMolecular chaperones are essential molecules for cell growth, whereby they maintain protein homeostasis. Because of their central cellular function, bacterial chaperones might be potential candidates for drug targets. Antimicrobial resistance is currently one of the greatest threats to human health, with gram-negative bacteria being of major concern. We found that a Cu2+ complex readily crosses the bacterial cell wall and inhibits SlyD, which is a molecular chaperone, cis/trans peptidyl prolyl isomerise (PPIase) and involved in various other metabolic pathways. The Cu2+ complex binds to the active sites of SlyD, which suppresses its PPIase and chaperone activities. Significant cell growth retardation could be observed for pathogenic bacteria (e.g., Staphylococcus aureus and Pseudomonas aeruginosa). We anticipate that rational development of drugs targeting molecular chaperones might help in future control of pathogenic bacterial growth, in an era of rapidly increasing antibiotic resistance.
ISL1 is a major susceptibility gene for classic bladder exstrophy and a regulator of urinary tract development
Authors: Zhang Rong , Knapp Michael , Suzuki Kentaro , Kajioka Daiki , Schmidt Johanna M. , Winkler Jonas , Yilmaz Öznur , Pleschka Michael , Cao Jia , Kockum Christina Clementson , Barker Gillian , Holmdahl Gundela , Beaman Glenda , Keene David , Woolf Adrian S. , Cervellione Raimondo M. , Cheng Wei , Wilkins Simon , Gearhart John P. , Sirchia Fabio , Di Grazia Massimo , Ebert Anne-Karolin , Rösch Wolfgang , Ellinger Jörg , Jenetzky Ekkehart , Zwink Nadine , Feitz Wout F. , Marcelis Carlo , Schumacher Johannes , Martinón-Torres Federico , Hibberd Martin Lloyd , Khor Chiea Chuen , Heilmann-Heimbach Stefanie , Barth Sandra , Boyadjiev Simeon A. , Brusco Alfredo , Ludwig Michael , Newman William , Nordenskjöld Agneta , Yamada Gen , Odermatt Benjamin , Reutter Heiko 
Published: February 2017

AbstractPreviously genome-wide association methods in patients with classic bladder exstrophy (CBE) found association with ISL1, a master control gene expressed in pericloacal mesenchyme. This study sought to further explore the genetics in a larger set of patients following-up on the most promising genomic regions previously reported. Genotypes of 12 markers obtained from 268 CBE patients of Australian, British, German Italian, Spanish and Swedish origin and 1,354 ethnically matched controls and from 92 CBE case-parent trios from North America were analysed. Only marker rs6874700 at the ISL1 locus showed association (p = 2.22 × 10−08). A meta-analysis of rs6874700 of our previous and present study showed a p value of 9.2 × 10−19. Developmental biology models were used to clarify the location of ISL1 activity in the forming urinary tract. Genetic lineage analysis of Isl1-expressing cells by the lineage tracer mouse model showed Isl1-expressing cells in the urinary tract of mouse embryos at E10.5 and distributed in the bladder at E15.5. Expression of isl1 in zebrafish larvae staged 48 hpf was detected in a small region of the developing pronephros. Our study supports ISL1 as a major susceptibility gene for CBE and as a regulator of urinary tract development.
Comparative study of the gut microbiome potentially related to milk protein in Murrah buffaloes (Bubalus bubalis) and Chinese Holstein cattle
Authors: Zhang Jiachao , Xu Chuanbiao , Huo Dongxue , Hu Qisong , Peng Qiannan 
Published: February 2017

AbstractPrevious studies suggested a close relationship between ruminant gut microbes and the mammary gland. In this study, shotgun metagenomic sequencing was used to reveal the differences in the intestinal microbiome potentially related to milk components in Murrah buffaloes and Chinese Holstein cattle. A PCoA based on the weighted Unifrac distances showed an apparent clustering pattern in the structure of intestinal microbiota between buffalo and cattle. We could attribute the structural difference to the genera of Sutterella, Coprococcus and Dorea. A further analysis of microbial functional features revealed that the biosynthesis of amino acids (including lysine, valine, leucine and isoleucine), lipopolysaccharide biosynthesis and cofactor/vitamin biosynthesis were enriched in the buffalo. In contrast, dairy cattle had higher levels of pyruvate metabolism and carbon fixation in photosynthetic organisms. A further correlation analysis based on different milk components and the typical microbiome uncovered a significant positive correlation between milk protein and the microbial biosynthesis of amino acids, which was also positively correlated in the genera of Parabacteroides, Dorea and Sutterella. This study will expand our understanding of the intestinal microbiome of buffalo and cattle as representative ruminants, as well as provide new views about how to improve the production and nutritional qualities of animal milk.
Millitesla magnetic field effects on the photocycle of an animal cryptochrome
Authors: Sheppard Dean M. W. , Li Jing , Henbest Kevin B. , Neil Simon R. T. , Maeda Kiminori , Storey Jonathan , Schleicher Erik , Biskup Till , Rodriguez Ryan , Weber Stefan , Hore P. J. , Timmel Christiane R. , Mackenzie Stuart R. 
Published: February 2017

AbstractDrosophila have been used as model organisms to explore both the biophysical mechanisms of animal magnetoreception and the possibility that weak, low-frequency anthropogenic electromagnetic fields may have biological consequences. In both cases, the presumed receptor is cryptochrome, a protein thought to be responsible for magnetic compass sensing in migratory birds and a variety of magnetic behavioural responses in insects. Here, we demonstrate that photo-induced electron transfer reactions in Drosophila melanogaster cryptochrome are indeed influenced by magnetic fields of a few millitesla. The form of the protein containing flavin and tryptophan radicals shows kinetics that differ markedly from those of closely related members of the cryptochrome–photolyase family. These differences and the magnetic sensitivity of Drosophila cryptochrome are interpreted in terms of the radical pair mechanism and a photocycle involving the recently discovered fourth tryptophan electron donor.
Metagenomic survey of the taxonomic and functional microbial communities of seawater and sea ice from the Canadian Arctic
Authors: Yergeau Etienne , Michel Christine , Tremblay Julien , Niemi Andrea , King Thomas L. , Wyglinski Joanne , Lee Kenneth , Greer Charles W. 
Published: February 2017

AbstractClimate change has resulted in an accelerated decline of Arctic sea ice since 2001 resulting in primary production increases and prolongation of the ice-free season within the Northwest Passage. The taxonomic and functional microbial community composition of the seawater and sea ice of the Canadian Arctic is not very well known. Bacterial communities from the bottom layer of sea ice cores and surface water from 23 locations around Cornwallis Island, NU, Canada, were extensively screened. The bacterial 16S rRNA gene was sequenced for all samples while shotgun metagenomics was performed on selected samples. Bacterial community composition showed large variation throughout the sampling area both for sea ice and seawater. Seawater and sea ice samples harbored significantly distinct microbial communities, both at different taxonomic levels and at the functional level. A key difference between the two sample types was the dominance of algae in sea ice samples, as visualized by the higher relative abundance of algae and photosynthesis-related genes in the metagenomic datasets and the higher chlaconcentrations. The relative abundance of various OTUs and functional genes were significantly correlated with multiple environmental parameters, highlighting many potential environmental drivers and ecological strategies.
Functional Coupling of Human Microphysiology Systems: Intestine, Liver, Kidney Proximal Tubule, Blood-Brain Barrier and Skeletal Muscle
Authors: Vernetti Lawrence , Gough Albert , Baetz Nicholas , Blutt Sarah , Broughman James R. , Brown Jacquelyn A. , Foulke-Abel Jennifer , Hasan Nesrin , In Julie , Kelly Edward , Kovbasnjuk Olga , Repper Jonathan , Senutovitch Nina , Stabb Janet , Yeung Catherine , Zachos Nick C. , Donowitz Mark , Estes Mary , Himmelfarb Jonathan , Truskey George , Wikswo John P. , Taylor D. Lansing 
Published: February 2017

AbstractOrgan interactions resulting from drug, metabolite or xenobiotic transport between organs are key components of human metabolism that impact therapeutic action and toxic side effects. Preclinical animal testing often fails to predict adverse outcomes arising from sequential, multi-organ metabolism of drugs and xenobiotics. Human microphysiological systems (MPS) can model these interactions and are predicted to dramatically improve the efficiency of the drug development process. In this study, five human MPS models were evaluated for functional coupling, defined as the determination of organ interactions via an in vivo-like sequential, organ-to-organ transfer of media. MPS models representing the major absorption, metabolism and clearance organs (the jejunum, liver and kidney) were evaluated, along with skeletal muscle and neurovascular models. Three compounds were evaluated for organ-specific processing: terfenadine for pharmacokinetics (PK) and toxicity; trimethylamine (TMA) as a potentially toxic microbiome metabolite; and vitamin D3. We show that the organ-specific processing of these compounds was consistent with clinical data, and discovered that trimethylamine-N-oxide (TMAO) crosses the blood-brain barrier. These studies demonstrate the potential of human MPS for multi-organ toxicity and absorption, distribution, metabolism and excretion (ADME), provide guidance for physically coupling MPS, and offer an approach to coupling MPS with distinct media and perfusion requirements.
Structural white matter and functional connectivity alterations in patients with shoulder apprehension
Authors: Zanchi Davide , Cunningham Gregory , Lädermann Alexandre , Ozturk Mehmet , Hoffmeyer Pierre , Haller Sven 
Published: February 2017

AbstractPrevious functional magnetic resonance imaging (fMRI) findings indicate that shoulder apprehension is more complex than a pure mechanical problem of the shoulder, showing a direct modification in functional brain networks associated with motor inhibition and emotional regulation. The current study extends these findings by investigating further structural alterations in patients with shoulder apprehension compared to controls. 14 aged patients with shoulder apprehension (27.3 ± 2.0 years) and 10 matched healthy controls (29.6 ± 1.3 years) underwent clinical and fMRI examination including fMRI and diffusion tensor imaging (DTI). Tract-based spatial statistics procedure was used to analyze white matter (WM) alterations. Functional images were analyzed investigating resting state network connectivity. DTI results were correlated with different shoulder clinical scores and functional connectivity networks. Fractional anisotropy (FA), representing white matter integrity, is increased in the left internal capsule and partially in the thalamus in patients compared to controls. Moreover, FA correlates negatively with simple shoulder test (SST) scores (p < .05) and positively with a functional connectivity network qualitatively replicating previous results (p < .01). This study extends previous findings, showing that in addition to functional changes, structural white matter changes are also present in patients with shoulder apprehension.
sPing: a user‐centred debugging mechanism for software defined networks
Authors: Tseng Fan‐Hsun , Chang Kai‐Di , Liao Shang‐Chuan , Chao Han‐Chieh , Leung Victor C.M. 
Published: February 2017

Software defined networking (SDN) paradigm currently does not integrate with any debugging or diagnosing mechanism. Services through Internet connection may not work properly due to network problems, such as loop and black hole problems. The study introduces sPing, a user‐centred debugging mechanism for users debugging and troubleshooting network problems in SDN. The sPing diagnoses problems in data plane by collecting and recording specific packets based on programmable capability. It not only detects network loop and black hole but also discovers the hidden information of data link layer. The discovery of layer 2 information is unachievable to existing SDN‐based debuggers. The authors experiment the sPing on three different brands of SDN switches for verifying its proof of concept, and simulate it in the Mininet emulator for evaluating its performance. Results showed that the proposed sPing mechanism assists SDN users in debugging network problems and in maintaining network functionalities.
Quantifying antiviral activity optimizes drug combinations against hepatitis C virus infection
Authors: Koizumi Yoshiki , Ohashi Hirofumi , Nakajima Syo , Tanaka Yasuhito , Wakita Takaji , Perelson Alan S. , Iwami Shingo , Watashi Koichi 
Published: February 2017

Significance
Introduction of new anti-hepatitis C virus (HCV) agents, so-called direct-acting antivirals (DAAs), has greatly changed treatment for HCV, and a variety of choices for anti-HCV drug combinations are available. For better management and control of this worldwide infectious disease with anti-HCV agents, it is critical to develop a method for precisely profiling the antiviral efficacy of possible combination drug regimens and seek the “best treatment” based on scientific evidence. In this study, we showed how cell culture data can be combined with a mathematical model and computer simulation to quantify the anti-HCV drug efficacy of different drug concentrations and combinations in a preclinical setting, and hence develop a quantitative basis for selecting drug combinations prior to costly clinical trials.
Synergistic antileukemic therapies in
NOTCH1
-induced T-ALL
Authors: Sanchez-Martin Marta , Ambesi-Impiombato Alberto , Qin Yue , Herranz Daniel , Bansal Mukesh , Girardi Tiziana , Paietta Elisabeth , Tallman Martin S. , Rowe Jacob M. , De Keersmaecker Kim , Califano Andrea , Ferrando Adolfo A. 
Published: February 2017

Significance
The clinical development of targeted therapies has been hampered by their limited intrinsic antitumor activity and the rapid emergence of resistance, highlighting the need to identify highly active and synergistic drug combinations. However, empirical synergistic drug-screening approaches are challenging, and elucidating the mechanisms that underlie such drug interactions is typically complex. Here, we performed an expression-based screen and network analyses to identify drugs amplifying the antitumor effects of NOTCH inhibition in T-cell acute lymphoblastic leukemia (T-ALL). These studies uncovered a druggable synthetic lethal interaction between suppression of protein translation and NOTCH inhibition in T-ALL. Our results illustrate the power of expression-based analyses toward the identification and functional characterization of antitumor drug combinations for the treatment of human cancer.
Quantum chaos on a critical Fermi surface
Authors: Patel Aavishkar A. , Sachdev Subir 
Published: February 2017

Significance
All high-temperature superconductors exhibit a remarkable “strange metal” state above their critical temperatures. A theory of the strange metal is a prerequisite for a deeper understanding of high-temperature superconductivity, but the ubiquitous quasiparticle theory of normal metals cannot be extended to the strange metal. Instead, strange metals exhibit many-body chaos over the shortest possible time allowed by quantum theory. We characterize the quantum chaos in a model of fermions at nonzero density coupled to an emergent gauge field. We find a universal relationship between the chaos parameters and the experimentally measurable thermal diffusivity. Our results establish a connection between quantum dephasing and energy transport in states of quantum matter without quasiparticles.