bluuebunny/crossref_metadata_2025 huggingface dataset:
Saliva analysis combining membrane protein purification with surface-enhanced Raman spectroscopy for nasopharyngeal cancer detection
Authors: Feng Shangyuan , Lin Duo , Lin Juqiang , Huang Zufang , Chen Guannan , Li Yongzeng , Huang Shaohua , Zhao Jianhua , Chen Rong , Zeng Haishan
Published: February 2014

A method for saliva analysis combining membrane protein purification with silver nanoparticle-based surface-enhanced Raman spectroscopy (SERS) for non-invasive nasopharyngeal cancer detection was present in this paper. In this method, cellulose acetate membrane was used to obtain purified whole proteins from human saliva while removing other native saliva constituents and exogenous substances. The purified proteins were mixed with silver nanoparticle for SERS analysis. A diagnostic accuracy of 90.2% can be achieved by principal components analysis combined with linear discriminate analysis, for saliva samples obtained from patients with nasopharyngeal cancer (n = 62) and healthy volunteers (n = 30). This exploratory study demonstrated the potential for developing non-invasive, rapid saliva SERS analysis for nasopharyngeal cancer detection.
Synthesis of few layer graphene by direct exfoliation of graphite and a Raman spectroscopic study
Authors: Gayathri S. , Jayabal P. , Kottaisamy M. , Ramakrishnan V.
Published: February 2014

The exfoliation of graphene from pristine graphite in a liquid phase was achieved successfully via sonication followed by centrifugation method. Ultraviolet–visible (UV–vis) spectra of the obtained graphene dispersions at different exfoliation time indicated that the concentration of graphene dispersion increased markedly with increasing exfoliation time. The sheet-like morphology of the exfoliated graphene was revealed by Scanning Electron Microscopy (SEM) image. Further, the morphological change in different exfoliation time was investigated by Atomic Force Microscopy (AFM). A complete structural and defect characterization was probed using micro-Raman spectroscopic technique. The shape and position of the 2D band of Raman spectra revealed the formation of bilayer to few layer graphene. Also, Raman mapping confirmed the presence of uniformly distributed bilayer graphene sheets on the substrate.
Ppd1, Vrn1, ALMT1 and Rht genes and their effects on grain yield in lower rainfall environments in southern Australia
Authors: Eagles H. A. , Cane Karen , Trevaskis Ben , Vallance Neil , Eastwood R. F. , Gororo N. N. , Kuchel Haydn , Martin P. J.
Published: February 2014

Allele-specific markers for important genes can improve the efficiency of plant breeding. Their value can be enhanced if effects of the alleles for important traits can be estimated in identifiable types of environment. Provided potential bias can be minimised, large, unbalanced, datasets from previous plant-breeding and agronomic research can be used. Reliable, allele-specific markers are now available for the phenology genes Ppd-D1, Vrn-A1, Vrn-B1 and Vrn-D1, the aluminium-tolerance gene TaALMT1, and the plant-stature genes Rht-B1 and Rht-D1. We used a set of 208 experiments with growing-season rainfall of <347 mm from southern Australia to estimate the effects of seven frequent combinations of the phenology genes, an intolerant and a tolerant allele of TaALMT1, and two semi-dwarf combinations Rht-B1b + Rht-D1a (Rht-ba) and Rht-B1a + Rht-D1b (Rht-ab) on grain yield in lower rainfall, Mediterranean-type environments in southern Australia. There were 775 lines in our analyses and a relationship matrix was used to minimise bias.
Differences among the phenology genes were small, but the spring allele Vrn-B1a might be desirable. The tolerant allele, TaALMT1-V, was advantageous in locations with alkaline soils, possibly because of toxic levels of aluminium ions in subsoils. The advantage of TaALMT1-V is likely to be highest when mean maximum temperatures in spring are high. Rht-ab (Rht2 semi-dwarf) was also advantageous in environments with high mean maximum temperatures in spring, suggesting that for these stress environments, the combination of Vrn-B1a plus TaALMT1-V plus Rht-ab should be desirable. Many successful cultivars carry this combination.
Scaling up: fulfilling the promise of X-ray microprobe for biogeochemical research
Authors: Toner Brandy M. , Nicholas Sarah L. , Wasik Jill K. Coleman
Published: February 2014

Environmental context
Although biogeochemical processes in the environment are often considered on large spatial scales, critical processes can occur at fine-spatial scales. Quantifying these processes is a challenge, but significant recent developments in microprobe X-ray absorption spectroscopy in terms of data collection and analysis greatly facilitate micro-scale observations at the sample-level. These mapping methods create datasets that can be integrated with bulk observations with the potential for widespread application to biogeochemical research.

Abstract
Biogeochemists measure and model fluxes of materials among environmental compartments, often considering large spatial-scales within and among ecosystems. However, critical biogeochemical processes occur at fine-spatial scales, and quantifying these processes is a challenge. Recent developments in microprobe X-ray absorption spectroscopy (XAS) data collection and analysis allow for micro-scale observations and quantification of chemical species at the sample-level. These speciation mapping methods create datasets that can be integrated with bulk observations through empirical and theoretical modelling. Speciation mapping approaches are possible with existing instrumentation, but the widespread application to biogeochemical research is hindered by the small number of instruments currently available.
Shp2/MAPK signaling controls goblet/paneth cell fate decisions in the intestine
Authors: Heuberger Julian , Kosel Frauke , Qi Jingjing , Grossmann Katja S. , Rajewsky Klaus , Birchmeier Walter
Published: February 2014

Significance

The mammalian intestine is covered by an extended villus epithelium that contains absorptive enterocytes and secretory cell types that are replenished from stem cells in the lower parts of crypts. Signals that control stem cells are known, but those that regulate differentiation of secretory lineages are less well understood. Here we used mouse genetics and intestinal organoid cultures to characterize the intricate signaling networks in the crypts that regulate the choice between secretory goblet and paneth cells and stem cells. MAPK suppression in the crypts increases Wnt/β-catenin signaling and promotes paneth and stem cells. High MAPK signals in the crypts decreases paneth cells and stem cells and favors goblet cell properties. Mechanistically, MAPK regulates Wnt/β-catenin signaling on the posttranslational level.
Equitability, mutual information, and the maximal information coefficient
Authors: Kinney Justin B. , Atwal Gurinder S.
Published: February 2014

Significance

Attention has recently focused on a basic yet unresolved problem in statistics: How can one quantify the strength of a statistical association between two variables without bias for relationships of a specific form? Here we propose a way of mathematically formalizing this “equitability” criterion, using core concepts from information theory. This criterion is naturally satisfied by a fundamental information-theoretic measure of dependence called “mutual information.” By contrast, a recently introduced dependence measure called the “maximal information coefficient” is seen to violate equitability. We conclude that estimating mutual information provides a natural and practical method for equitably quantifying associations in large datasets.
Small distances can keep bacteria at bay for days
Authors: van Bunnik Bram A. D. , Ssematimba Amos , Hagenaars Thomas J. , Nodelijk Gonnie , Haverkate Manon R. , Bonten Marc J. M. , Hayden Mary K. , Weinstein Robert A. , Bootsma Martin C. J. , De Jong Mart C. M.
Published: February 2014

Significance

The failure to identify avoidable contacts makes indirect transmission the prime cause of difficulties in controlling epidemic spread (e.g., bacteria in hospitals, livestock infections). Our results from tailored indirect transmission experiments show that there is a clear delay in onset of transmission when there is a small distance between sender and recipient, and that this delay differs considerably between bacterium species. We showed that the observed patterns can, as we understand it, only be explained by taking into account the slow (random) transport of infectious material from sender to recipient and mortality of the bacterium during that transport. The implication of this is that hygiene measures can influence indirect transmission as shown for an antibiotic-resistance bacterium in a hospital.
A glioma classification scheme based on coexpression modules of EGFR and PDGFRA
Authors: Sun Yingyu , Zhang Wei , Chen Dongfeng , Lv Yuhong , Zheng Junxiong , Lilljebjörn Henrik , Ran Liang , Bao Zhaoshi , Soneson Charlotte , Sjögren Hans Olov , Salford Leif G. , Ji Jianguang , French Pim J. , Fioretos Thoas , Jiang Tao , Fan Xiaolong
Published: February 2014

Significance

Classification of cancer provides crucial guidance for clinical treatment and mechanistic studies. Our work extends previous glioma classification studies in that we established
EGFR
module (EM)/
PDGFRA
module (PM) glioma classification scheme based on gene coexpression modules around key signaling pathways conserved in neural development and gliomagenesis. We identified coexpressed EM and PM genes as classifiers. Based on the EM and PM signatures, our classification scheme robustly assigns adult low-grade and high-grade diffuse gliomas into three major subtypes that are distinct in patient survival, and in transcriptomic and genomic patterns. Our work suggests that EM and PM genes may play currently unrecognized roles in gliomagenesis. EM/PM glioma classification scheme forms a framework toward establishing molecular diagnostic tools and identifying new therapeutic targets to combat gliomas.
A dynamically assembled cell wall synthesis machinery buffers cell growth
Authors: Lee Timothy K. , Tropini Carolina , Hsin Jen , Desmarais Samantha M. , Ursell Tristan S. , Gong Enhao , Gitai Zemer , Monds Russell D. , Huang Kerwyn Casey
Published: February 2014

Significance

For complex biological processes, the formation of protein complexes is a strategy for coordinating the activities of many enzymes in space and time. It has been hypothesized that growth of the bacterial cell wall involves stable synthetic complexes, but neither the existence of such complexes nor the consequences of such a mechanism for growth efficiency have been demonstrated. Here, we use single-molecule tracking to demonstrate that the association between an essential cell wall synthesis enzyme and the cytoskeleton is highly dynamic, which allows the cell to buffer growth rate against large fluctuations in enzyme abundance. This indicates that dynamic association can be an efficient strategy for coordination of multiple enzymes, especially those for which excess abundance can be harmful to cells.
OGFOD1 catalyzes prolyl hydroxylation of RPS23 and is involved in translation control and stress granule formation
Authors: Singleton Rachelle S. , Liu-Yi Phebee , Formenti Fabio , Ge Wei , Sekirnik Rok , Fischer Roman , Adam Julie , Pollard Patrick J. , Wolf Alexander , Thalhammer Armin , Loenarz Christoph , Flashman Emily , Yamamoto Atsushi , Coleman Mathew L. , Kessler Benedikt M. , Wappner Pablo , Schofield Christopher J. , Ratcliffe Peter J. , Cockman Matthew E.
Published: February 2014

Significance

Members of the 2-oxoglutarate (2OG)-dependent oxygenase superfamily catalyze a range of important biological oxidations. Structurally informed bioinformatic predictions suggest that the human genome encodes as yet unassigned members of the superfamily. We describe work demonstrating that 2OG and Fe(II)-dependent oxygenase domain-containing protein 1 (OGFOD1) is a protein hydroxylase that modifies the small ribosomal subunit protein RPS23 at a conserved prolyl residue in the ribosome-decoding center and that suppression or deletion of OGFOD1 is associated with the activation of translational stress pathways. Together with studies of homologous genes in flies and yeast described in accompanying manuscripts, the work identifies a unique function for 2OG oxygenase-catalyzed hydroxylation in ribosome biology.
Sudestada1, a
Drosophila
ribosomal prolyl-hydroxylase required for mRNA translation, cell homeostasis, and organ growth
Authors: Katz Maximiliano J. , Acevedo Julieta M. , Loenarz Christoph , Galagovsky Diego , Liu-Yi Phebee , Pérez-Pepe Marcelo , Thalhammer Armin , Sekirnik Rok , Ge Wei , Melani Mariana , Thomas María G. , Simonetta Sergio , Boccaccio Graciela L. , Schofield Christopher J. , Cockman Matthew E. , Ratcliffe Peter J. , Wappner Pablo
Published: February 2014

Significance

Emerging evidence indicates that posttranslational hydroxylation of intracellularly localized proteins is more prevalent than once thought. We identify
Drosophila melanogaster sudestada1 (sud1)
as a gene that is needed for normal growth in the fly and show that
sud1
encodes a prolyl-hydroxylase that catalyzes posttranslational hydroxylation of a conserved residue in the small ribosomal subunit protein RPS23. Knockdown of Sud1 results in growth impairment and reduced RPS23 hydroxylation, which is associated with activation of the unfolded protein response, induction of apoptosis, and increased autophagy. Together with findings in humans and yeast reported in the companion articles, the work reveals a new type of posttranslational ribosome modification that is highly conserved in eukaryotes.
Gene regulation by substoichiometric heterocomplex formation of undecameric TRAP and trimeric anti-TRAP
Authors: Ihms Elihu C. , Zhou Mowei , Zhang Yun , Kleckner Ian R. , McElroy Craig A. , Wysocki Vicki H. , Gollnick Paul , Foster Mark P.
Published: February 2014

Significance

Noncovalent interactions between proteins modulate their functions and occur widely in biological regulation. A large proportion of such regulatory proteins are homo-oligomeric, with multiple copies of a single polypeptide assembled into higher-order quaternary structures. Understanding the regulatory interactions between homo-oligomeric proteins is difficult because their periodic structural configuration may allow different modes of interaction with differing functions. We apply a powerful combination of analytical techniques to study the interaction between TRAP (

t
rp

R
NA-binding
a
ttenuation
p
rotein), an 11-mer that regulates tryptophan metabolism by binding RNA, and its trimeric inhibitor protein anti-TRAP. We show that anti-TRAP condenses multiple TRAP oligomers into heterocomplexes, thereby blocking TRAP’s RNA-binding sites. These findings and our approach may have broad implications for other oligomeric regulatory proteins.
Approach for targeting Ras with small molecules that activate SOS-mediated nucleotide exchange
Authors: Burns Michael C. , Sun Qi , Daniels R. Nathan , Camper DeMarco , Kennedy J. Phillip , Phan Jason , Olejniczak Edward T. , Lee Taekyu , Waterson Alex G. , Rossanese Olivia W. , Fesik Stephen W.
Published: February 2014

Significance

Ras is one of the most highly validated targets in cancer; however, the discovery of potent inhibitors of Ras has been difficult to achieve. We report the discovery of small molecules that bind to a pocket on the Ras:Son of Sevenless:Ras complex and alter Ras activity in biochemical and cell-based experiments. High-resolution cocrystal structures define the protein–ligand interactions, and the lead compounds provide a starting point for the discovery of potent inhibitors of Ras signaling.
Effects of polymerization and nucleotide identity on the conformational dynamics of the bacterial actin homolog MreB
Authors: Colavin Alexandre , Hsin Jen , Huang Kerwyn Casey
Published: February 2014

Significance

Cytoskeletal filaments drive many dynamic cellular processes, such as the regulation of shape by actin networks in eukaryotes and by the actin homolog MreB in rod-shaped bacteria. Here, we use all-atom molecular dynamics simulations to demonstrate close parallels between the conformational dynamics of actin and MreB, in which polymerization induces flattening of MreB subunits that restructures the ATP binding pocket to promote hydrolysis. We also find that ATP-bound MreB filaments are substantially more curved than ADP-bound filaments, and this bending is highly correlated with the degree of flattening of the subunits. Our results provide molecular-scale insight into the diverse structural states of MreB during its assembly process, revealing properties that may be general to the broad actin family.
Mossy fiber-evoked subthreshold responses induce timing-dependent plasticity at hippocampal CA3 recurrent synapses
Authors: Brandalise Federico , Gerber Urs
Published: February 2014

Significance

Dentate mossy fibers represent the main conduit for information transfer from the cerebral cortex to the hippocampus, a structure essential for learning and memory. It is generally accepted that the information conveyed by mossy fibers must take the form of powerful all-or-none digital signals, known as action potentials, to ensure the formation of stable memory traces; however, experiments in behaving rodents have revealed that mossy fibers might not generate sufficient numbers of action potentials in hippocampal cells to support memory function. Here we show that analog signals elicited by mossy fiber activity, which are weaker but much more frequent than action potentials, can compensate for the paucity of digital signaling and effectively control hippocampal circuits important for memory.
Compartmentalized cyanophycin metabolism in the diazotrophic filaments of a heterocyst-forming cyanobacterium
Authors: Burnat Mireia , Herrero Antonia , Flores Enrique
Published: February 2014

Significance

The heterocyst-forming cyanobacteria represent a true multicellular system found in the bacterial world that adds unique features to biodiversity. They grow as chains of cells containing two metabolically interdependent cellular types, the vegetative cells that fix carbon dioxide performing oxygenic photosynthesis and the dinitrogen-fixing heterocysts. Heterocysts accumulate a cell inclusion, cyanophycin [multi-L-arginyl-poly (L-aspartic acid)], as a nitrogen reservoir. We have found that the second enzyme of cyanophycin catabolism, isoaspartyl dipeptidase, is present at significantly higher levels in vegetative cells than in heterocysts, identifying the nitrogen-rich dipeptide β-aspartyl-arginine as a nitrogen vehicle to the vegetative cells and showing that compartmentalization of a catabolic route is used to improve the physiology of nitrogen fixation.
Liquid metal enabled pump
Authors: Tang Shi-Yang , Khoshmanesh Khashayar , Sivan Vijay , Petersen Phred , O’Mullane Anthony P. , Abbott Derek , Mitchell Arnan , Kalantar-zadeh Kourosh
Published: February 2014

Significance

The utilization of small-scale pumps is presently hampered by their limited flow rates with respect to the input power or their rather complicated fabrication process. These issues arise as many conventional pumping effects rely on moving elements. Here, we demonstrate the concept of a liquid metal enabled pump with no mechanical parts by simply incorporating droplets of Galinstan. The liquid metal enabled pump creates high flow rates (>5,000 µL/min) at exceptionally low powers (<15 mW) by electrowetting/deelectrowetting the surface upon application of electric field. The presented pump is both efficient and simple; hence, it has the potential to advance the field of actuation in small-scale systems.
Evolutionary history and metabolic insights of ancient mammalian uricases
Authors: Kratzer James T. , Lanaspa Miguel A. , Murphy Michael N. , Cicerchi Christina , Graves Christina L. , Tipton Peter A. , Ortlund Eric A. , Johnson Richard J. , Gaucher Eric A.
Published: February 2014

Significance

Human susceptibility to gout is driven by the fact that we have a pseudogene for uricase that prevents a functional enzyme from being produced. Our inability to convert highly insoluble uric acid into a more soluble molecule makes us vulnerable to disease and other health complications. We have exploited ancestral sequence reconstruction to better understand how and why apes lost this functional enzyme. Our ancient proteins support one hypothesis that the progressive loss of uricase activity allowed our ancestors to readily accumulate fat via the metabolism of fructose from fruits. This adaptation may have provided our ancestors with an advantage when the energy-rich rainforests of Europe and Asia were displaced by temperate forests by the end of the Oligocene.
IL-1 receptor blockade restores autophagy and reduces inflammation in chronic granulomatous disease in mice and in humans
Authors: de Luca Antonella , Smeekens Sanne P. , Casagrande Andrea , Iannitti Rossana , Conway Kara L. , Gresnigt Mark. S. , Begun Jakob , Plantinga Theo S. , Joosten Leo A. B. , van der Meer Jos W. M. , Chamilos Georgios , Netea Mihai G. , Xavier Ramnik J. , Dinarello Charles A. , Romani Luigina , van de Veerdonk Frank L.
Published: February 2014

Significance

Chronic granulomatous disease (CGD) has an immunodeficiency component and, in addition, an autoinflammatory component in which autophagy and inflammasome activation are linked and amenable to IL-1 blockade. This study provides a rationale to perform clinical trials to investigate the efficacy of blocking IL-1 in CGD colitis and expands the therapeutic potential of IL-1 antagonists to inflammatory diseases with defective autophagy.
Form, function, and evolution of living organisms
Authors: Banavar Jayanth R. , Cooke Todd J. , Rinaldo Andrea , Maritan Amos
Published: February 2014

Significance

Understanding the origin and evolution of the shapes observed in nature remains an exciting challenge. Even from a cursory inspection, it is clear that the shapes of animals and plants, as determined by the distribution of mass over volume, are distinct. Animals are able to move and are approximately homogeneous in their mass distribution. Plants are rooted organisms endowed with heterogeneous self-similar geometry where the mass is concentrated in the stem and branches rather than in the leaves. By addressing the fundamental physics underlying the relation between form and physiology and the origins of Kleiber’s law, we discuss how the two divergent life forms of plants and animals may have independently evolved to achieve equivalent energetic efficiencies.
Structural motif of polyglutamine amyloid fibrils discerned with mixed-isotope infrared spectroscopy
Authors: Buchanan Lauren E. , Carr Joshua K. , Fluitt Aaron M. , Hoganson Andrew J. , Moran Sean D. , de Pablo Juan J. , Skinner James L. , Zanni Martin T.
Published: February 2014

Significance

Expanded polyglutamine (polyQ) tracts in proteins are associated with many neurodegenerative diseases, including Huntington disease. The structure and dynamics of polyQ peptides are difficult to study due to the homogenous nature of the sequence and their high propensity to aggregate into amyloid fibrils. In this manuscript, we study mixtures of isotope-labeled peptides with 2D IR spectroscopy to resolve the structure of individual monomers within the polyQ. These results, in combination with spectra calculated from molecular-dynamics simulations, determine the dominant structure of polyQ fibrils consists of stacked β-hairpins.
Transcription factors IIS and IIF enhance transcription efficiency by differentially modifying RNA polymerase pausing dynamics
Authors: Ishibashi Toyotaka , Dangkulwanich Manchuta , Coello Yves , Lionberger Troy A. , Lubkowska Lucyna , Ponticelli Alfred S. , Kashlev Mikhail , Bustamante Carlos
Published: February 2014

Significance

Regulation of gene expression controls fundamental cellular processes, such as growth and differentiation. Gene expression begins at transcription, in which the eukaryotic RNA polymerase (Pol II) synthesizes the precursors of mRNA during the elongation phase. The speed and fidelity of the process are regulated by many transcription elongation factors, including transcription factors IIS (TFIIS) and IIF (TFIIF), which directly interact with the enzyme. Using a single-molecule optical-tweezers assay, we have quantified the effects of these factors on the dynamics of transcription elongation by Pol II on both bare and nucleosomal DNA. We showed that TFIIF mainly prevents Pol II from pause entering, whereas TFIIS assists with pause recovery, and quantitatively described these effects on the kinetics of transcription elongation by Pol II.
Calpain-generated natural protein fragments as short-lived substrates of the N-end rule pathway
Authors: Piatkov Konstantin I. , Oh Jang-Hyun , Liu Yuan , Varshavsky Alexander
Published: February 2014

Significance

Calpains are a family of intracellular proteases that have in common their dependence on Ca
2+
and their ability to make a small number of specific cuts in their natural protein substrates. Although many calpain-generated protein fragments have been identified, understanding their functions is just beginning. This study shows that natural C-terminal fragments of a variety of proteins, including transmembrane ion channels, transcriptional regulators, apoptosis controllers, kinases, and phosphatases, are short-lived substrates of the N-end rule pathway, a ubiquitin-dependent processive proteolytic system that recognizes destabilizing N-terminal residues of protein substrates. This advance illuminates functional aspects of specific calpain fragments and suggests a specific molecular basis for many of the previously identified, mechanistically unclear roles of the N-end rule pathway.
Susceptibility breakpoints and target values for therapeutic drug monitoring of voriconazole and Aspergillus fumigatus in an in vitro pharmacokinetic/pharmacodynamic model
Authors: Siopi Maria , Mavridou Eleftheria , Mouton Johan W. , Verweij Paul E. , Zerva Loukia , Meletiadis Joseph
Published: February 2014

Background

Although voriconazole reached the bedside 10 years ago and became the standard care in the treatment of invasive aspergillosis, reliable clinical breakpoints are still in high demand. Moreover, this has increased due to the recent emergence of azole resistance.

Methods

Four clinical wild-type and non-wild-type A. fumigatus isolates with voriconazole CLSI MICs in the range of 0.125–2 mg/L were tested in an in vitro pharmacokinetic (PK)/pharmacodynamic (PD) model. Mouse PK was simulated and in vitro data were compared with in vivo outcome. Human PK was simulated and susceptibility breakpoints and trough levels required for optimal treatment were determined for the CLSI and EUCAST methods after 48 h and the gradient concentration MIC test strip (MTS) method after 24 h using the in vitro PK/PD relationship and Monte Carlo simulation.

Results

The in vitro PK/PD target (95% CI) associated with 50% of the maximal antifungal activity (EC50) was 28.61 (16.18–50.61), close to the in vivo EC50 of 14.67 (9.31–21.58) fAUC0–24/CLSI MIC. When human PK was simulated, the EC50 was 24.7 (17.9–35.6) fAUC0–12/CLSI MIC and it was associated with 6 week survival in clinical studies of invasive pulmonary aspergillosis. Target attainment rates were ≤5% (0%–24%), 42% (16%–58%), 68% (54%–75%) and ≥79% (73%–86%) for isolates with CLSI MICs ≥2, 1, 0.5 and ≤0.25 mg/L, respectively. A trough/CLSI MIC ratio of 2 was required for optimal treatment. The susceptible/intermediate/resistant breakpoints were determined to be 0.25/0.5–1/2 mg/L for CLSI, 0.5/1–2/4 mg/L for EUCAST and 0.25/0.375–1/1.5 mg/L for MTS.

Conclusions

These susceptibility breakpoints and target values for therapeutic drug monitoring could be used to optimize voriconazole therapy against A. fumigatus.
Ferritin and LIC
Authors: Smith Erika , Lebensburger Jeffrey , Hilliard Lee , Kelly David , Fineberg Naomi , Bai Shuting , Howard Tom
Published: February 2014

Objective:

Chronic blood transfusion therapy reduces clinical events in children with sickle cell anemia but increases risk for an iron‐related liver injury. Liver biopsy is the gold standard technique for quantifying liver iron content (LIC) and evaluating liver pathology. Ferritin, liver enzymes, and R2* magnetic resonance imaging of the liver are obtained as surrogate markers. In this study we compared surrogate markers with the gold standard, liver biopsy, in assessing liver histology.

Methods:

We conducted a retrospective review of 259 liver biopsies in 109 children with sickle cell anemia on chronic transfusion therapy and chelation therapy during a 9‐year period at a single center. Liver pathology was compared with LIC, ferritin, and alanine aminotransferase.

Results:

Ferritin correlates with LIC (r = 0.74, P < 0.001), although there is a broad range of ferritin values for a given LIC. Furthermore, patients with a high LIC (≥7 mg Fe/g dry weight) demonstrated significantly higher ferritin as compared to the patients with lower LIC <7 (P < 0.001). Periportal/portal inflammation also showed a significant relation. There was no significance when comparing ferritin and lobular inflammation or ferritin and alanine aminotransferase. When evaluating LIC in relation to fibrosis, the present study revealed that there was only a significant correlation with severe fibrosis (F = 36, P < 0.001).

Conclusions:

The results suggest that although correlations exist among ferritin and LIC and severe fibrosis and LIC, caution should be taken when they are used in isolation. Liver biopsy provides important pathologic information that cannot be obtained through surrogate markers.
Objective Assessment of Swallow Function in Children With Suspected Aspiration Using Pharyngeal Automated Impedance Manometry
Authors: Rommel Nathalie , Selleslagh Margot , Hoffman Ilse , Smet Maria H. , Davidson Geoffrey , Tack Jan , Omari Taher Imad
Published: February 2014

Objectives:

The purpose of the present study was to apply a new method, pharyngeal automated impedance manometry (AIM), as an objective assessment tool of swallow function relevant to aspiration, in a cohort of paediatric patients with dysphagia.

Methods:

We studied 20 children (mean age 6 years [5 months to 13.4 years]) referred for videofluoroscopy to assess aspiration risk with simultaneous manometry–impedance. Fluoroscopic evidence of aspiration was scored using a validated aspiration–penetration score. Pressure–flow profiles were analysed using AIM analysis measuring peak pressure, pressure at nadir impedance, time from nadir impedance to peak pressure, and flow interval. These variables were combined into a swallow risk index (SRI).

Results:

Six of 20 children presented with deglutitive aspiration during videofluoroscopic assessment of swallowing. Of 58 liquid swallows analysed, in 9 aspiration was observed. Multiple logistic regression identified longer flow interval (P < 0.05), higher SRI (P < 0.05) and increased pressure in the upper oesophageal sphincter during maximal bolus flow (P < 0.05) to be the dominant risk variables predictive of aspiration in children. Each of these nonradiologically derived pressure–flow variables correlated with higher aspiration scores on videofluoroscopy (P < 0.01).

Conclusions:

We present novel, preliminary findings in children with deglutitive aspiration, suggesting that pharyngeal AIM can detect alterations in pressure–flow characteristics of swallowing that predispose to aspiration risk.
Alteration of Tight Junction Gene Expression in Celiac Disease
Authors: Jauregi‐Miguel Amaia , Fernandez‐Jimenez Nora , Irastorza Iñaki , Plaza‐Izurieta Leticia , Vitoria Juan Carlos , Bilbao Jose Ramon
Published: February 2014

Objective:

The aim of the present study was to characterize the deregulation of epithelial tight junction genes and investigate its reversibility on removal of dietary gluten in small intestinal mucosa in celiac disease (CD).

Methods:

The expression levels of 23 genes related to tight junctions were studied in biopsies from 16 patients with active CD and compared with biopsies from the same patients taken after 2 years on gluten‐free diet (GFD) and with 16 non‐CD controls.

Results:

Nine genes showed altered expression levels in patients with active disease (CLDN2, PARD6A, ZAK, SYMPK, MYH14, and ACTB were upregulated, whereas MAGI1, TJP1, and PPP2R3A were downregulated). Alterations were reversible after 2 years on treatment, except for PPP2R3A, implicated in the negative control of cell growth and division. At the biological network level, important dysfunctions in several processes within the pathway were observed, including intestinal permeability, apicobasal polarity, and cell proliferation.

Conclusions:

Our work confirms the involvement of tight junction genes related to permeability, polarity, and cell proliferation in the epithelial destruction observed in CD. Coexpression patterns of several genes support the idea of a common regulatory mechanism that seems to be altered in active CD. In general, GFD normalization confirms the reversibility of the process, except for the constitutive downregulation of PPP2R3A suggestive of a genetic implication. Further studies in proteins and cells or tissues are necessary to confirm these findings.
Relevance relations for the concept of reproducibility
Authors: Atmanspacher H. , Bezzola Lambert L. , Folkers G. , Schubiger P. A.
Published: February 2014

The concept of reproducibility is widely considered a cornerstone of scientific methodology. However, recent problems with the reproducibility of empirical results in large-scale systems and in biomedical research have cast doubts on its universal and rigid applicability beyond the so-called basic sciences. Reproducibility is a particularly difficult issue in interdisciplinary work where the results to be reproduced typically refer to different levels of description of the system considered. In such cases, it is mandatory to distinguish between more and less relevant features, attributes or observables of the system, depending on the level at which they are described. For this reason, we propose a scheme for a general ‘relation of relevance’ between the level of complexity at which a system is considered and the granularity of its description. This relation implies relevance criteria for particular selected aspects of a system and its description, which can be operationally implemented by an interlevel relation called ‘contextual emergence’. It yields a formally sound and empirically applicable procedure to translate between descriptive levels and thus construct level-specific criteria for reproducibility in an overall consistent fashion. Relevance relations merged with contextual emergence challenge the old idea of one fundamental ontology from which everything else derives. At the same time, our proposal is specific enough to resist the backlash into a relativist patchwork of unconnected model fragments.
Learning dynamics explains human behaviour in Prisoner's Dilemma on networks
Authors: Cimini Giulio , Sánchez Angel
Published: February 2014

Cooperative behaviour lies at the very basis of human societies, yet its evolutionary origin remains a key unsolved puzzle. Whereas reciprocity or conditional cooperation is one of the most prominent mechanisms proposed to explain the emergence of cooperation in social dilemmas, recent experimental findings on networked Prisoner's Dilemma games suggest that conditional cooperation also depends on the previous action of the player—namely on the ‘mood’ in which the player is currently in. Roughly, a majority of people behave as conditional cooperators if they cooperated in the past, whereas they ignore the context and free ride with high probability if they did not. However, the ultimate origin of this behaviour represents a conundrum itself. Here, we aim specifically to provide an evolutionary explanation of moody conditional cooperation (MCC). To this end, we perform an extensive analysis of different evolutionary dynamics for players' behavioural traits—ranging from standard processes used in game theory based on pay-off comparison to others that include non-economic or social factors. Our results show that only a dynamic built upon reinforcement learning is able to give rise to evolutionarily stable MCC, and at the end to reproduce the human behaviours observed in the experiments.
Staying sticky: contact self-cleaning of gecko-inspired adhesives
Authors: Mengüç Yiğit , Röhrig Michael , Abusomwan Uyiosa , Hölscher Hendrik , Sitti Metin
Published: February 2014

The exceptionally adhesive foot of the gecko remains clean in dirty environments by shedding contaminants with each step. Synthetic gecko-inspired adhesives have achieved similar attachment strengths to the gecko on smooth surfaces, but the process of contact self-cleaning has yet to be effectively demonstrated. Here, we present the first gecko-inspired adhesive that has matched both the attachment strength and the contact self-cleaning performance of the gecko's foot on a smooth surface. Contact self-cleaning experiments were performed with three different sizes of mushroom-shaped elastomer microfibres and five different sizes of spherical silica contaminants. Using a load–drag–unload dry contact cleaning process similar to the loads acting on the gecko foot during locomotion, our fully contaminated synthetic gecko adhesives could recover lost adhesion at a rate comparable to that of the gecko. We observed that the relative size of contaminants to the characteristic size of the microfibres in the synthetic adhesive strongly determined how and to what degree the adhesive recovered from contamination. Our approximate model and experimental results show that the dominant mechanism of contact self-cleaning is particle rolling during the drag process. Embedding of particles between adjacent fibres was observed for particles with diameter smaller than the fibre tips, and further studied as a temporary cleaning mechanism. By incorporating contact self-cleaning capabilities, real-world applications of synthetic gecko adhesives, such as reusable tapes, clothing closures and medical adhesives, would become feasible.
Processes entangling interactions in communities: forbidden links are more important than abundance in a hummingbird–plant network
Authors: Vizentin-Bugoni Jeferson , Maruyama Pietro Kiyoshi , Sazima Marlies
Published: February 2014

Understanding the relative importance of multiple processes on structuring species interactions within communities is one of the major challenges in ecology. Here, we evaluated the relative importance of species abundance and forbidden links in structuring a hummingbird–plant interaction network from the Atlantic rainforest in Brazil. Our results show that models incorporating phenological overlapping and morphological matches were more accurate in predicting the observed interactions than models considering species abundance. This means that forbidden links, by imposing constraints on species interactions, play a greater role than species abundance in structuring the ecological network. We also show that using the frequency of interaction as a proxy for species abundance and network metrics to describe the detailed network structure might lead to biased conclusions regarding mechanisms generating network structure. Together, our findings suggest that species abundance can be a less important driver of species interactions in communities than previously thought.
Wild deer as potential vectors of anthelmintic-resistant abomasal nematodes between cattle and sheep farms
Authors: Chintoan-Uta C. , Morgan E. R. , Skuce P. J. , Coles G. C.
Published: February 2014

Gastrointestinal (GI) nematodes are among the most important causes of production loss in farmed ruminants, and anthelmintic resistance is emerging globally. We hypothesized that wild deer could potentially act as reservoirs of anthelmintic-resistant GI nematodes between livestock farms. Adult abomasal nematodes and faecal samples were collected from fallow (
n
= 24), red (
n
= 14) and roe deer (
n
= 10) from venison farms and areas of extensive or intensive livestock farming. Principal components analysis of abomasal nematode species composition revealed differences between wild roe deer grazing in the areas of intensive livestock farming, and fallow and red deer in all environments. Alleles for benzimidazole (BZ) resistance were identified in
β-tubulin
of
Haemonchus contortus
of roe deer and phenotypic resistance confirmed
in vitro
by an egg hatch test (EC
50
= 0.149 µg ml
−1
± 0.13 µg ml
−1
) on
H. contortus
eggs from experimentally infected sheep. This BZ-resistant
H. contortus
isolate also infected a calf experimentally. We present the first account of
in vitro
BZ resistance in wild roe deer, but further experiments should firmly establish the presence of phenotypic BZ resistance
in vivo.
Comprehensive in-field studies should assess whether nematode cross-transmission between deer and livestock occurs and contributes, in any way, to the development of resistance on livestock farms.
D1/D5 receptors and histone deacetylation mediate the Gateway Effect of LTP in hippocampal dentate gyrus
Authors: Huang Yan-You , Levine Amir , Kandel Denise B. , Yin Deqi , Colnaghi Luca , Drisaldi Bettina , Kandel Eric R.
Published: February 2014

The dentate gyrus (DG) of the hippocampus is critical for spatial memory and is also thought to be involved in the formation of drug-related associative memory. Here, we attempt to test an aspect of the Gateway Hypothesis, by studying the effect of consecutive exposure to nicotine and cocaine on long-term synaptic potentiation (LTP) in the DG. We find that a single injection of cocaine does not alter LTP. However, pretreatment with nicotine followed by a single injection of cocaine causes a substantial enhancement of LTP. This priming effect of nicotine is unidirectional: There is no enhancement of LTP if cocaine is administrated prior to nicotine. The facilitation induced by nicotine and cocaine can be blocked by oral administration of the dopamine D1/D5 receptor antagonist (SKF 83566) and enhanced by the D1/D5 agonist (SKF 38393). Application of the histone deacetylation inhibitor suberoylanilide hydroxamic acid (SAHA) simulates the priming effect of nicotine on cocaine. By contrast, the priming effect of nicotine on cocaine is blocked in genetically modified mice that are haploinsufficient for the CREB-binding protein (CBP) and possess only one functional CBP allele and therefore exhibit a reduction in histone acetylation. These results demonstrate that the DG of the hippocampus is an important brain region contributing to the priming effect of nicotine on cocaine. Moreover, both activation of dopamine-D1 receptor/PKA signaling pathway and histone deacetylation/CBP mediated transcription are required for the nicotine priming effect in the DG.
What periodicities can be found in diffraction patterns of quasicrystals?
Authors: Wolny Janusz , Kozakowski Bartlomiej , Kuczera Pawel , Pytlik Lucjan , Strzalka Radoslaw
Published: February 2014

The structure of quasicrystals is aperiodic. Their diffraction patterns, however, can be considered periodic. They are composed solely of series of peaks which exhibit a fully periodic arrangement in reciprocal space. Furthermore, the peak intensities in each series define the so-called `envelope function'. A Fourier transform of the envelope function gives an average unit cell, whose definition is based on the statistical distribution of atomic coordinates in physical space. If such a distribution is lifted to higher-dimensional space, it becomes the so-called atomic surface – the most fundamental feature of higher-dimensional analysis.
Cocaine induces DNA damage in distinct brain areas of female rats under different hormonal conditions
Authors: de Souza Marilise F , Gonçales Tierre A , Steinmetz Aline , Moura Dinara J , Saffi Jenifer , Gomez Rosane , Barros Helena MT
Published: February 2014

We evaluated levels of neuronal DNA damage after acute or repeated cocaine treatment in different brain areas of female rats after ovariectomy or sham surgery. Rats in the control and acute groups were given saline i.p., whereas in the repeated group were given 15 mg/kg, i.p., cocaine for 8 days. After a 10 day washout period, the control group was given saline i.p., whereas rats in the acute and repeated groups were given a challenge dose of 15 mg/kg, i.p., cocaine. After behavioural assessment, rats were killed and the cerebellum, hippocampus, hypothalamus, prefrontal cortex and striatum were dissected for the Comet assay. Acute cocaine exposure induced DNA damage in all brain areas. This effect persisted after repeated administration, except in the hypothalamus, where repeated treatment did not cause increased DNA damage. Sexual hormones exhibited a neuroprotective effect, decreasing cocaine‐induced DNA damage in cycling rats in all brain areas.
ATP‐binding cassette transporter A1 (ABCA1) promotes arsenic tolerance in human cells by reducing cellular arsenic accumulation
Authors: Tan Xiaohua , Yang Li , Xian Lingling , Huang Jin , Di Chunhong , Gu Wenyi , Guo Shuli , Yang Lei
Published: February 2014

Arsenic is a toxic element widely distributed in nature, such as water and soil. To survive this metalloid in the environment, nearly all organisms develop strategies to tolerate arsenic toxicity to some degree. Some arsenic‐resistance genes have been identified in bacteria and yeast, but for mammals, especially humans, these genes are largely unknown.

The aim of the present study was to identify these genes and benefit our intervention of arsenic resistance. We first established a human arsenic‐resistant ECV‐304 (AsRE) cell line and then used suppression subtractive hybridization and microarray analysis to identify arsenic‐resistant genes in these cells. Of the significantly upregulated genes, three ATP‐binding cassette (ABC) subfamily members, namely ABCA1, ABCE1 and ABCF1, were chosen for further study with RNA interference and overexpression analyses. The 3‐(4,5‐dimethyl‐2 thiazoyl)‐2,5‐diphenyl‐2H‐tetrazolium bromide assay was used to determine the cell survival rate and the IC50, whereas atomic fluorescence spectrophotometry was used to determine intracellular arsenic levels.

We found that among the three ABC genes, only when ABCA1 gene expression was silenced did cells obviously lose their arsenic tolerance. The arsenic accumulation in ABCA1 deficiency AsRE cells was greater than that in wild type AsRE cells. Overexpression of ABCA1 in HeLa cells decreased arsenic accumulation in the cells and the cells were more resistant to As(III) than control cells transfected with empty vector.

These results suggest a new functional role for ABCA1 in the development of arsenic resistance in human cells.
Environmental Kuznets Curve: Conclusive Econometric Evidence for CO2
Authors: Chow Gregory C. , Li Jie
Published: February 2014

This paper begins with a statistical formulation of the Environmental Kuznets Curve (EKC) and discusses the major econometric problems raised in the literature in testing this hypothesis using panel data. A simple t‐test is then presented that avoids these econometric problems. The result from applying the t‐test confirms conclusively the EKC for CO2 as formulated.
China's Capital Controls: Through the Prism of Covered Interest Differentials
Authors: Cheung Yin‐Wong , Herrala Risto
Published: February 2014

We study the renminbi covered interest differential, an indicator of the effectiveness of capital controls. It is found that the differential is not shrinking over time and, in fact, appears larger after the global financial crisis than before. That is, capital controls in China are still substantial and effective. In addition to exchange rate changes and volatilities, the renminbi covered interest differential is affected by credit market tightness indicators. The marginal explanatory power of these macroeconomic factors, however, is small relative to the autoregressive component and the dummy variables that capture changes in China's policy.