bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of Different Catalyst Supporters and Polymers on Electrical Behavior of MWCNT Composites
Authors: Park Suyoung , Lee Seoungsoo , Jeong Hakyung , Jin Changhyun
Published: June 2016

Four different polymer‐coated multi‐walled carbon nanotubes (MWCNTs) were prepared under various catalyst‐supporter conditions for examining the conductivity of the nanocomposites. The dimensions of the initial Al(OH)3 catalyst supporter, i.e., one of the final ternary catalysts, mainly determined the pristine MWCNT properties. The respective MWCNT‐based composites with polycarbonate, high‐density polyethylene, polypropylene, and low‐density polyethylene generally exhibited remarkable catalyst support‐dependent conductivity differences—approximately seven orders of magnitude, from 109.7 to 102.7. The degree of MWCNT dispersion is considered the key factor inducing the significant electrical differences.
Pharmacokinetic studies of a novel trioxane antimalarial (99/411) in rats and monkeys using LC–MS/MS
Authors: Pandey Saurabh , Gautam Nagsen , Kushwaha Hari Narayan , Singh Shio Kumar
Published: June 2016

The pharmacokinetic profile of 99/411, a novel anti‐malarial drug, was established in rats (12 mg/kg of body weight) and monkeys (20 mg/kg of body weight). Following oral administration, the presence of 99/411 was rapidly determined in rat plasma, tissues, urine, feces and monkey plasma using a validated LC–MS/MS method. The tissue distribution studies in rats indicated that the drug was partially distributed in all major tissues and plasma, and peak concentration levels were achieved within 0.5–4 h. Area under the curve in different rat tissues and plasma was found in order of blood > lung > intestine > heart > muscle > brain > kidney > spleen > liver. The total recoveries (within 86 h) of 99/411 were <0.0017% and <0.08% in urine and feces, respectively. The peak plasma concentration was 3499 ng/mL in rats after ~2 h of oral administration and 697–767 ng/mL in monkeys after ~6 h of oral administration. No plasma accumulation was observed in both male and female monkeys, even after multiple dosing. The preclinical pharmacokinetic profile and tissue distribution data are expected to assist in future clinical explorations of 99/411 as a promising anti‐malarial agent.
Review of clinical studies of perampanel in adolescent patients
Authors: Kim Heung Dong , Chi Ching‐Shiang , Desudchit Tayard , Nikanorova Marina , Visudtibhan Anannit , Nabangchang Charcrin , Chan Derrick W. S. , Fong Choong Yi , Chang Kai‐Ping , Kwan Shang‐Yeong , Reyes Fe De Los , Huang Chao‐Ching , Likasitwattanakul Surachai , Lee Wang‐Tso , Yung Ada , Dash Amitabh
Published: June 2016

Aim

To assess the clinical trial and real‐world data for adjunctive perampanel in adolescents and develop consensus recommendations to guide the use of perampanel in this population in clinical practice.

Methods

In May 2015, 15 epilepsy experts attended a Consensus Development Meeting to assess the clinical trial data for perampanel, specific to the adolescent age group (12‐17 years) and develop consensus treatment recommendations.

Results and Discussion

Analysis of the adolescent subgroup data of three pivotal placebo‐controlled, double‐blind, phase 3 trials investigating perampanel in patients with ongoing focal epileptic seizures despite receiving one to three antiepileptic drugs found that perampanel 4–12 mg was superior to placebo. The tolerability profile of perampanel was generally acceptable. Adolescent patients receiving long‐term treatment with perampanel in an open‐label extension study maintained improvements in seizure control compared with baseline, with a favorable risk‐benefit profile. A phase 2 study showed that perampanel had no clinically important effects on cognitive function, growth, and development.

Conclusion

Perampanel is a welcome addition to the armamentarium of existing antiepileptic drugs as it represents a new approach in the management of epilepsy, with a novel mechanism of action, and the potential to have a considerable impact on the treatment of adolescents with epilepsy.
Multiphase flow modelling in moderately rotating inclined porous media
Authors: Härting Hans‐Ulrich , Lange Rüdiger , Schubert Markus
Published: June 2016

Advective and diffusive multiphase flows through vertical porous media are well examined and discussed in the scientific literature. However, uncommon configurations with inclined porous media are examined to a lesser extent, while advanced configurations with superimposed motion have hitherto scarcely been addressed. An example of such configuration is the inclined rotating tubular fixed bed reactor, which is a novel intensified multiphase reactor for heterogeneous catalytic gas‐liquid‐solid reactions (H.‐U. Härting, R. Lange, F. Larachi, M. Schubert, Chem. Eng. J. 2015, 281, 931).

For the prediction of liquid saturation and two‐phase pressure drop in inclined and moderately rotating confined porous media, a two‐fluid model is presented. The model is one‐directional, isothermal, and considers incompressible Newtonian fluids. To account for the interphase momentum transfer, adopted Ergun‐type closures are formulated taking the peculiarities of stratified, dispersed, and annular flow into account. The effects of inclination and rotation are incorporated as additional body forces, whereby inclination is taken into account by the longitudinal gravity component and a semi‐empirical closure for the complex effects of the rotational velocity is presented. The applicability of the model is validated against experimental liquid saturation and two‐phase pressure drop data.
Reduction of Greenhouse Gas Emissions From Municipal Wastewater Treatment in Mexico Based on Technology Selection
Authors: Noyola Adalberto , Paredes María Guadalupe , Morgan‐Sagastume Juan Manuel , Güereca Leonor Patricia
Published: June 2016

As do many developing countries and emerging economies, Mexico needs to invest in wastewater treatment facilities, which has been neglected in the past. Currently, 45% of municipal sewage enters a treatment plant, so a significant fraction of untreated or partially treated water is discharged or used for crop irrigation. This has significant impacts on public health and the environment. In this context, the proper selection of treatment technologies may be an important opportunity for contributing to the ambitious national greenhouse gas (GHG) emission reduction goals in Mexico. Based on actual infrastructure data, the scenarios analyzed in this work show that emission reductions from sewage treatment plants in Mexico could be as high as 34% when compared to the baseline scenario, depending on the treatment technologies. The results show that the anaerobic + aerobic scenario is a better option than the full aerobic scenario, as it would achieve a 4% GHG emission reduction by the year 2030. Moreover, if methane is used for in situ electricity cogeneration in larger facilities, the reduction reaches 27% versus the full aerobic scenairo. The results may be helpful to policy and decision makers to evaluate the cost effectiveness and feasibility of possible GHG mitigation strategies for wastewater treatment facilities, mainly for new infrastructures in developing countries.
Equilibrium Modeling of Arsenic Adsorption in a Ternary Arsenic–Iron Oxide–Natural Organic Matter System
Authors: Fakour Hoda , Lin Tsair‐Fuh , Lo Shang‐Lien
Published: June 2016

The effect of natural organic matter (NOM) on the adsorption efficiency of arsenic (As) species by iron oxide‐based adsorbent (IBA) under different concentrations was investigated. To evaluate the sorption of As in the presence of humic materials, simple isotherm curves should be replaced by three‐dimensional sorption isotherm surfaces. In this study, a modified Langmuir‐type model was developed to describe the isotherm surfaces. The proposed model showed satisfactory predictions for the As uptake in different scenarios with the presence of As(V)/(III), organic matter fractions, and model adsorbent. The isotherms indicated a competitive uptake of the As species and humic substances, causing that less As was adsorbed on the adsorbent. The developed model for the ternary sorption system enabled quantitative estimation of As sorption onto iron oxide based adsorbents in complex natural water systems.
Ascertainment of postprostatectomy radiotherapy for prostate cancer in the Surveillance, Epidemiology, and End Results database
Authors: Wang Kyle , Sheets Nathan C. , Basak Ramsankar , Chen Ronald C.
Published: June 2016

BACKGROUND

Surveillance, Epidemiology, and End Results (SEER) data are frequently used to examine receipt of adjuvant radiotherapy (RT), but to the authors' knowledge the accuracy of data regarding second‐course treatments is unknown.

METHODS

Using SEER‐Medicare‐linked data, the authors identified a cohort of men who underwent radical prostatectomy for localized prostate cancer with indications for RT due to adverse pathologic risk factors. Receipt of RT was compared between the SEER database and Medicare claims, with the latter considered to be the “gold standard.” Multivariable logistic regression was used to assess factors associated with ascertainment of RT in SEER.

RESULTS

A total of 3842 men were analyzed, 749 of whom were found to have Medicare claims for RT within 1 year of undergoing prostatectomy. SEER ascertainment of postprostatectomy RT was 56% overall: 76% among patients who received RT within 2 months of prostatectomy, 73% among patients who received RT between 2 to 4 months after prostatectomy, 63% among patients who received RT between 4 to 6 months after prostatectomy, 44% among patients who received RT between 6 to 8 months after prostatectomy, and 21% among patients who received RT between 8 to 12 months after prostatectomy. On multivariable analysis, increasing time from prostatectomy to RT was found to be significantly associated with decreased SEER ascertainment (odds ratio, 0.70 per month; P<.001). There also was variation noted by SEER region and urban/rural locale.

CONCLUSIONS

SEER underascertains the receipt of postprostatectomy RT compared with Medicare claims, and the magnitude of the underascertainment increases with longer time between prostatectomy and RT. These findings have direct implications for the use of SEER data alone to assess patterns of care and guideline concordance for second‐course treatment. Cancer 2016;122:3069‐3074. © 2016 American Cancer Society.
Solar Water Oxidation by Multicomponent TaON Photoanodes Functionalized with Nickel Oxide
Authors: Gujral Satnam Singh , Simonov Alexandr N. , Fang Xi‐Ya , Higashi Masanobu , Abe Ryu , Spiccia Leone
Published: June 2016

Efficient solar‐powered water oxidation over the TaON‐based anodes requires coupling this photoactive n‐type semiconductor to an electrooxidation catalyst to improve the otherwise unsatisfactory activity and stability. Herein, we examine how functionalization with electrodeposited nickel oxide, NiOx, affects the performance of screen‐printed TaON photoanodes post‐necked with titania (TiO2–TaON). The effects of the NiOx photo‐electrodeposition parameters on the microstructure and photocatalytic performance of the resulting anodes are explored. Enhancements in the transient water oxidation photocurrent densities by sixfold vs. unmodified TiO2–TaON were achieved with the use of the NiOx/TiO2–TaON photoanodes. Long‐term stability tests reveal a slow but persistent degradation of the performance of the multicomponent photocatalysts under the severely oxidizing conditions of water photo‐oxidation coincident with continuous morphological changes in the NiOx deposits.
Making Every Subject Count: A Case Study of Drug Development Path for Medication in a Pediatric Rare Disease
Authors: Bhattacharya I , Manukyan Z , Chan P , Harnisch L , Heatherington A
Published: June 2016

Approximately 50% of rare diseases are evident in children. Fatal disease prognosis and lack of treatments causes 30% of affected children to not live past their fifth birthday. This clear sense of urgency demands innovation and acceleration in drug development. A case study is discussed highlighting the need for data‐rich phase I study design, extensive use of modeling and simulation, use of diverse data sources, and input from collaborators to respond to this urgent call.
Monocarboxylate Transporters: Therapeutic Targets and Prognostic Factors in Disease
Authors: Jones RS , Morris ME
Published: June 2016

Solute carrier (SLC) transporters represent 52 families of membrane transport proteins that function in endogenous compound homeostasis and xenobiotic disposition, and have been exploited in drug delivery and therapeutic targeting strategies. In particular, the SLC16 family that encodes for the 14 isoforms of the monocarboxylate transporter (MCT) family plays a significant role in the absorption, tissue distribution, and clearance of both endogenous and exogenous compounds. MCTs are required for the transport of essential cell nutrients and for cellular metabolic and pH regulation. Recent publications have indicated their novel roles in disease, and thus their potential as biomarkers and new therapeutic targets in disease are under investigation. More research into MCT isoform function, specificity, expression, and regulation will allow researchers to exploit the potential utility of MCTs in the clinic as therapeutic targets and prognostic factors of disease.
Assessing the sensitivity of avian species abundance to land cover and climate
Authors: LeBrun Jaymi J. , Thogmartin Wayne E. , Thompson Frank R. , Dijak William D. , Millspaugh Joshua J.
Published: June 2016

Climate projections for the Midwestern United States predict southerly climates to shift northward. These shifts in climate could alter distributions of species across North America through changes in climate (i.e., temperature and precipitation), or through climate‐induced changes on land cover. Our objective was to determine the relative impacts of land cover and climate on the abundance of five bird species in the Central United States that have habitat requirements ranging from grassland and shrubland to forest. We substituted space for time to examine potential impacts of a changing climate by assessing climate and land cover relationships over a broad latitudinal gradient. We found positive and negative relationships of climate and land cover factors with avian abundances. Habitat variables drove patterns of abundance in migratory and resident species, although climate was also influential in predicting abundance for some species occupying more open habitat (i.e., prairie warbler, blue‐winged warbler, and northern bobwhite). Abundance of northern bobwhite increased with winter temperature and was the species exhibiting the most significant effect of climate. Models for birds primarily occupying early successional habitats performed better with a combination of habitat and climate variables whereas models of species found in contiguous forest performed best with land cover alone. These varied species‐specific responses present unique challenges to land managers trying to balance species conservation over a variety of land covers. Management activities focused on increasing forest cover may play a role in mitigating effects of future climate by providing habitat refugia to species vulnerable to projected changes. Conservation efforts would be best served focusing on areas with high species abundances and an array of habitats. Future work managing forests for resilience and resistance to climate change could benefit species already susceptible to climate impacts.
Effects of a mining‐altered environment on individual fitness of amphibians and reptiles
Authors: Sasaki Kiyoshi , Lesbarrères David , Beaulieu Camille Tremblay , Watson Glen , Litzgus Jacqueline
Published: June 2016

Pollution can affect wildlife directly through toxicity and indirectly through changes in biotic and abiotic factors, however, how these mechanisms interact in affecting free‐ranging animals remains poorly understood. By examining effects on individual fitness proxies, we aimed to determine the mechanisms behind documented amphibian and reptile declines in barren landscapes where vegetation was nearly decimated due to atmospheric metal and sulfur deposition from smelting operations in Sudbury, Ontario, Canada. We examined individual characteristics of snakes (Thamnophis sirtalis, Storeria occipitomaculata) and frogs (Lithobates clamitans, L. pipiens, L. septentrionalis) in replicated barren and reference sites, including standard metabolic rates (in snakes), body condition (all species), female reproductive status (snakes), limb deformity (frogs), and fluctuating asymmetry (all species). Frogs in barren sites (except L. septentrionalis) were in poor body condition, and all but one case of limb deformities in frogs were found in barren sites. However, neither frogs nor snakes exhibited elevated frequency of fluctuating asymmetry in barren sites. Standard metabolic rates (SMR) were not elevated in either snake species, suggesting that metal toxicity does not present an energetic burden. Instead, female T. sirtalis from barren sites exhibited lower SMR and were in poor body condition, which is a predicted response to reduced food intake. By contrast, SMR and body condition of S. occipitomaculata were not different between barren and reference sites. While physiological responses differed between T. sirtalis and S. occipitomaculata, both species exhibited lower reproductive rates (proportion of pregnant females) in barren sites compared to reference sites. Thus, energy deficiency may explain reduced reproduction in T. sirtalis while reduced availability of suitable gestation microhabitat may be a limiting factor for S. occipitomaculata. Populations in smelting‐impacted habitats include individuals with potentially compromised fitness. The low values of our measured fitness proxies appear to have resulted from pollution‐induced changes in biotic and abiotic factors, in addition to (for frogs) or rather than (for snakes) from the direct toxicity. These results suggest that impact assessment based solely on toxicological data and species distributions can underestimate the full impacts of pollution, highlighting the need for integrated examination at multiple levels of biological organization.
A complex systems approach for multiobjective water quality regulation on managed wetland landscapes
Authors: Parrott Lael , Quinn Nigel
Published: June 2016

Management of wetland ecosystems that are tightly coupled with human systems typically requires balancing multiple objectives to ensure that a range of ecosystem services are provided for the benefit of society. We describe how adopting a complex systems approach may provide managers with the appropriate conceptual tools to achieve social and ecological objectives in a multifunctional wetland landscape. We illustrate the applicability of the approach using the Grasslands Ecological Area (GEA) in California as a case study. Human intervention has shaped and reshaped the GEA over the past century, affecting the ability of the landscape to provide ecosystem services. Ecological disaster in the 1980s precipitated transformative change in the management system toward an approach that adopts many of the recommended actions for complexity. Present‐day management, which balances multiple social and ecological objectives, has led to improved water quality, restoration of wetland habitats, and a general increase in system complexity at the landscape scale. New research and real‐time monitoring systems facilitate adaptive management and heterogeneous responses of wetland management entities. We argue that taking a complex systems approach to management in the GEA provides a common, and inclusive, conceptual model for all stakeholders and may lead to a more sustainable and ecologically resilient landscape over the long term.
How much effort is required to accurately describe the complex ecology of a rodent‐borne viral disease?
Authors: Douglass Richard J. , Vadell María Victoria
Published: June 2016

We use data collected on 18, 1‐ha live trapping grids monitored from 1994 through 2005 and on five of those grids through 2013 in the mesic northwestern United States to illustrate the complexity of the deer mouse (Peromyscus maniculatus)/Sin Nombre virus (SNV) host‐pathogen system. Important factors necessary to understand zoonotic disease ecology include those associated with distribution and population dynamics of reservoir species as well as infection dynamics. Results are based on more than 851,000 trap nights, 16,608 individual deer mice and 10,572 collected blood samples. Deer mice were distributed throughout every habitat we sampled and were present during every sampling period in all habitats except high altitude habitats over 1900 m. Abundance varied greatly among locations with peak numbers occurring mostly during fall. However, peak rodent abundance occurred during fall, winter and spring during various years on three grids trapped 12 months/yr. Prevalence of antibodies to SNV averaged 3.9% to 22.1% but no grids had mice with antibodies during every month. The maximum period without antibody‐positive mice ranged from 1 to 52 months, or even more at high altitude grids where deer mice were not always present. Months without antibody‐positive mice were more prevalent during fall than spring. Population fluctuations were not synchronous over broad geographic areas and antibody prevalences were not well spatially consistent, differing greatly over short distances. We observed an apparently negative, but nonstatistically significant relationship between average antibody prevalence and average deer mouse population abundance and a statistically significant positive relationship between the average number of antibody positive mice and average population abundance. We present data from which potential researchers can estimate the effort required to adequately describe the ecology of a rodent‐borne viral system. We address different factors affecting population dynamics and hantavirus antibody prevalence and discuss the path to understanding a complex rodent‐borne disease system as well as the obstacles in that path.
Disturbance, complexity, and succession of net ecosystem production in North America's temperate deciduous forests
Authors: Gough Christopher M. , Curtis Peter S. , Hardiman Brady S. , Scheuermann Cynthia M. , Bond‐Lamberty Ben
Published: June 2016

Century‐old forests in the U.S. upper Midwest and Northeast power much of North America's terrestrial carbon (C) sink, but these forests' production and C sequestration capacity are expected to soon decline as fast‐growing early successional species die and are replaced by slower growing late successional species. But will this really happen? Here we marshal empirical data and ecological theory to argue that substantial declines in net ecosystem production (NEP) owing to reduced forest growth, or net primary production (NPP), are not imminent in regrown temperate deciduous forests over the next several decades. Forest age and production data for temperate deciduous forests, synthesized from published literature, suggest slight declines in NEP and increasing or stable NPP during middle successional stages. We revisit long‐held hypotheses by EP Odum and others that suggest low‐severity, high‐frequency disturbances occurring in the region's aging forests will, against intuition, maintain NEP at higher‐than‐expected rates by increasing ecosystem complexity, sustaining or enhancing NPP to a level that largely offsets rising C losses as heterotrophic respiration increases. This theoretical model is also supported by biological evidence and observations from the Forest Accelerated Succession Experiment in Michigan, USA. Ecosystems that experience high‐severity disturbances that simplify ecosystem complexity can exhibit substantial declines in production during middle stages of succession. However, observations from these ecosystems have exerted a disproportionate influence on assumptions regarding the trajectory and magnitude of age‐related declines in forest production. We conclude that there is a wide ecological space for forests to maintain NPP and, in doing so, lessens the declines in NEP, with significant implications for the future of the North American carbon sink. Our intellectual frameworks for understanding forest C cycle dynamics and resilience need to catch up to our more complex and nuanced understanding of ecological succession.
Ungulate impacts on herbaceous‐layer plant communities in even‐aged and uneven‐aged managed forests
Authors: Murray Bryan D. , Webster Christopher R. , Jenkins Michael A. , Saunders Michael R. , Haulton G. Scott
Published: June 2016

Forest management and ungulate herbivory are extant drivers of herbaceous‐layer community composition and diversity. We conducted a white‐tailed deer (Odocoileus virginianus) exclosure experiment across a managed landscape to determine how deer impacts interact with the type of forest management system in influencing herb‐layer (all vascular plants < 0.5 m tall) species richness and composition. Our study took place 3 yr after harvest in a deciduous forest landscape being managed through even‐aged (~4.1 ha openings) and uneven‐aged (~1.4 ha openings) silvicultural systems. We expected the severity of deer impacts on herb layer species richness and composition to vary according to opening position, opening size, and the spatial scale of inference. At forest stand and landscape scales, species richness within silvicultural openings was greater outside compared to inside deer exclosures, and did not differ according to deer access in edges or the forest matrix. However, greater levels of species richness associated with deer access were driven by infrequently occurring forbs, and overall species composition did not differ. Notably, these species were not exotics or ferns. Deer reduced the density of large saplings and blackberry (Rubusspp.) shrubs in the smaller openings characteristic of uneven‐aged management stands, but had no effect on sapling density in the larger openings characteristic of even‐aged management stands. This result extends the forage maturation hypothesis to silvicultural systems, and is consistent with predictions that plant tolerance and avoidance of herbivory increase with resource availability. Deer may have facilitated the establishment of forbs in recently created silvicultural openings by temporarily slowing sapling regeneration, creating establishment sites through physical disturbance, and seed dispersal via epizoochory and endozoochory. This outcome is contingent upon declining deer visitation rates as woody vegetation matures as well as distance from source populations of exotic species. We conclude that ecological context, such as local ungulate abundance, disturbance, and landscape factors, influence how ungulates interact with forest management systems.
A mutation within the SH2 domain of slp‐76 regulates the tissue distribution and cytokine production of iNKT cells in mice
Authors: Danzer Claudia , Koller Anna , Baier Julia , Arnold Harald , Giessler Claudia , Opoka Robert , Schmidt Stephanie , Willers Maike , Mihai Sidonia , Parsch Hans , Wirtz Stefan , Daniel Christoph , Reinhold Annegret , Engelmann Swen , Kliche Stefanie , Bogdan Christian , Hoebe Kasper , Mattner Jochen
Published: June 2016

TCR ligation is critical for the selection, activation, and integrin expression of T lymphocytes. Here, we explored the role of the TCR adaptor protein slp‐76 on iNKT‐cell biology. Compared to B6 controls, slp‐76ace/ace mice carrying a missense mutation (Thr428Ile) within the SH2‐domain of slp‐76 showed an increase in iNKT cells in the thymus and lymph nodes, but a decrease in iNKT cells in spleens and livers, along with reduced ADAP expression and cytokine response. A comparable reduction in iNKT cells was observed in the livers and spleens of ADAP‐deficient mice. Like ADAP−/− iNKT cells, slp‐76ace/ace iNKT cells were characterized by enhanced CD11b expression, correlating with an impaired induction of the TCR immediate‐early gene Nur77 and a decreased adhesion to ICAM‐1. Furthermore, CD11b‐intrinsic effects inhibited cytokine release, concanavalin A‐mediated inflammation, and iNKT‐cell accumulation in the liver. Unlike B6 and ADAP−/− mice, the expression of the transcription factors Id3 and PLZF was reduced, whereas NP‐1‐expression was enhanced in slp‐76ace/ace mice. Blockade of NP‐1 decreased the recovery of iNKT cells from peripheral lymph nodes, identifying NP‐1 as an iNKT‐cell‐specific adhesion factor. Thus, slp‐76 contributes to the regulation of the tissue distribution, PLZF, and cytokine expression of iNKT cells via ADAP‐dependent and ‐independent mechanisms.
Mycobacterium tuberculosis‐associated synthetic mycolates differentially exert immune stimulatory adjuvant activity
Authors: Smet Muriel , Pollard Charlotte , De Beuckelaer Ans , Van Hoecke Lien , Vander Beken Seppe , De Koker Stefaan , Al Dulayymi Juma'a R. , Huygen Kris , Verschoor Jan , Baird Mark S. , Grooten Johan
Published: June 2016

Mycolic acids (MAs) are highly hydrophobic long‐chain α‐alkyl β‐hydroxy fatty acids present in the cell wall of Mycobacterium tuberculosis (Mtb) as a complex mixture of molecules with a common general structure but with variable functional groups in the meromycolate chain. In this study, we addressed the relationship between the MA molecular structure and their contribution to the development of T‐cell immune responses. Hereto, we used the model antigen ovalbumin and single synthetic MAs, differing in oxygenation class and cis versus trans proximal cyclopropane configuration, as immune stimulatory agents. Subcutaneous delivery of liposome‐formulated MAs with a proximal cis cyclopropane elicited antigen‐specific Th1 and cytotoxic T‐cell immune responses, whereas intratracheal immunization elicited pulmonary Th17 responses. These immune stimulatory activities depended not only on the cis versus trans proximal cyclopropane configuration but also on the MA oxygenation class. Our study thus shows that both the presence and nature of the functional groups in the meromycolate chain affect the immune stimulatory adjuvant activity of Mtb mycolates and suggests that Mtb bacilli may impact on the host protective immune response by modulating the cis versus trans stereochemistry of its mycolates as well as by altering the oxygenation class of the meromycolate functional group.
A Surface Grafting of Carbon Allotropes with in‐situ Generated 3‐aryl Diazonium Chlorides: Electrochemical Kinetic Studies
Authors: Radtke Mariusz , Ignaszak Anna
Published: June 2016

In this work three different carbon allotropes: multi‐walled carbon nanotubes (MWCNT), graphene and carbon nanohorns (CNH) were covalently bound with in‐situ generated 3‐diazonium aryl chlorides. These species were attached to the carbon surface using an electrochemically‐initiated radical coupling, similar to the Gomberg‐Bachman type reaction. An electrochemical grafting of the extended π‐systems at the carbon surface was performed in aqueous media in a simple 3‐electrode system and its kinetics was investigated by a modified Butler‐Volmer approach. The analysis of Hammett constants demonstrated a strong influence of the type of electron donating‐/withdrawing substituents on the reduction potential peak position and the peak current. Moderately or strong electron withdrawing groups like ‐carboxy or ‐nitro tend to shift reduction potential towards more positive values, which facilitates an electron uptake. The deposition time varies for different carbon allotropes and depends on the carbon graphitization and the surface area. The best surface coverage was obtained at 90–150 sec of the deposition. Although, the surface functionalities are less conductive than the carbon, the electrodes showed a low internal resistance and thus a high rate of electron transfer (high exchange current density and the electron transfer rate constant), with the most promising observed for carbon nanohorns. The best performing carbon revealed also superior mass transport of the redox active species toward the electrode surface, owing to their unique particle shapes and its very porous structure. The Tafel analysis complemented by an impedance spectroscopy allowed selecting the best carbon substrate for the functionalization with a 3‐aminobenzoic acid.
The Reductive Cleavage Mechanism and Complex Stability of Glutathionyl‐Cobalamin in Acidic Media
Authors: Sajan Abin , Birke Ronald L.
Published: June 2016

The mechanisms of the electrode reduction of vitamin B12a and the reductive cleavage of glutathionyl cobalamin (GSCbl) were investigated with digital simulations in acid media at pH 3.78 and 2.78. Even though the pH is quite acidic, the 1‐electron reduction of B12a goes through the base‐on form in a step‐wise sequence forming base‐on vitamin B12r which then is protonated to the base‐off form, and finally reduced in another 1‐electron step to vitamin B12s Unlike the case of B12a, the GSCbl is found to go by a 1‐electron overall mechanism. In this case, electronic structure calculations at the B3LYP/6‐311G(d,p) level for a model GSCbl complex show that the one‐electron adduct is a radical anion with the unpaired electron in a corrin ring π* orbital. When the axial 5,6‐dimethylbenzimidazole dissociates, the Co(III)‐S bond will break forming Vitamin B12s and the GS• radical. This reductive cleavage mechanism is the same as in the case of alkylcobalmins and is relevant to the biological mechanism of the B12 trafficking chaperone proteins, CblC, for processing GSCbl in B12 dependent enzyme reactions. Finally, we determined conditional stability constants for the formation of the GSCbl complex, Kobs, which are 4.4±0.5×103 M−1 and 9.9±0.1×102 M−1 at pH 3.78 and 2.78, respectively.
Use of the Acoustic Energy Meter (AEM) for rapid geomorphological field assessment of rock hardness: comparison with Schmidt hammer R‐value
Authors: Brook M. S. , Winkler S.
Published: June 2016

Rapid, field‐based assessments of rock hardness are required in a broad range of geomorphological investigations where rock intact strength is important. Several different methods are now available for taking such measurements, in particular the Schmidt hammer, which has seen increasing use in geomorphology in recent decades. This is despite caution from within the engineering literature regarding choice of Schmidt hammer type, normalization of rebound (R‐) values, surface micro‐roughness, weathering degree and moisture content, and data reduction/analysis procedures. We present a pilot study of the use of an Acoustic Energy Meter (AEM), originally produced, tested and developed within the field of underground mining engineering as a rapid measure of rock surface hardness, and compare it with results from a mechanical N‐Type Schmidt hammer. We assess its capabilities across six lithological study sites in southeast Queensland, Australia, in the Greater Brisbane area. Each rock exposure has been recently exposed in the 20th/21st century. Using a ‘paired’ sampling approach, the AEM G‐value shows an inverse relationship with Schmidt hammer R‐value. While both devices show variability with lithology, the AEM G‐values show less scatter than the Schmidt hammer. We conclude that each device can contribute to useful rock hardness testing in geomorphological research, but the AEM requires further field testing in a range of environments, and in particular on older and naturally‐exposed rock surfaces. Future evaluations can extend this pilot study by focusing on sampling procedures, energy sources, and data reduction protocols, within the framework of a comparison study with other rock hardness testing apparatus. Copyright © 2016 John Wiley & Sons, Ltd.
Nomogram for individualized prediction of hepatocellular carcinoma occurrence in hepatitis C virus cirrhosis (ANRS CO12 CirVir)
Authors: Ganne‐Carrié Nathalie , Layese Richard , Bourcier Valérie , Cagnot Carole , Marcellin Patrick , Guyader Dominique , Pol Stanislas , Larrey Dominique , de Lédinghen Victor , Ouzan Denis , Zoulim Fabien , Roulot Dominique , Tran Albert , Bronowicki Jean‐Pierre , Zarski Jean‐Pierre , Riachi Ghassan , Calès Paul , Péron Jean‐Marie , Alric Laurent , Bourlière Marc , Mathurin Philippe , Blanc Jean‐Frédéric , Abergel Armand , Serfaty Lawrence , Mallat Ariane , Grangé Jean‐Didier , Attali Pierre , Bacq Yannick , Wartelle Claire , Dao Thông , Benhamou Yves , Pilette Christophe , Silvain Christine , Christidis Christos , Capron Dominique , Bernard‐Chabert Brigitte , Zucman David , Di Martino Vincent , Trinchet Jean‐Claude , Nahon Pierre , Roudot‐Thoraval Françoise ,   the ANRS CO12 CirVir Study Group
Published: June 2016

The aim of this work was to develop an individualized score for predicting hepatocellular carcinoma (HCC) in patients with hepatitis C (HCV)‐compensated cirrhosis. Among 1,323 patients with HCV cirrhosis enrolled in the French prospective ANRS CO12 CirVir cohort, 720 and 360 were randomly assigned to training and validation sets, respectively. Cox's multivariate model was used to predict HCC, after which a nomogram was computed to assess individualized risk. During follow‐up (median, 51.0 months), 103 and 39 patients developed HCC in the training and validation sets, respectively. Five variables were independently associated with occurrence of HCC: age > 50 years (hazard ratio [HR], 1.94; 95% confidence interval [CI], 1.16; 3.25; P = 0.012); past excessive alcohol intake (HR, 1.55; 95% CI, 1.02; 2.36; P = 0.041); low platelet count (<100 Giga/mm3: HR, 2.70; 95% CI, 1.62; 4.51; P < 0.001; [100; 150] Giga/mm3: HR, 1.87; 95% CI, 1.10; 3.18; P = 0.021); gamma‐glutamyl transpeptidase above the upper limit of normal (HR, 1.96; 95% CI, 1.11; 3.47; P = 0.021); and absence of a sustained virological response during follow‐up (HR, 3.02; 95% CI, 1.67; 5.48; P < 0.001). An 11‐point risk score was derived from the training cohort and validated in the validation set. Based on this score, the population was stratified into three groups, in which HCC development gradually increased, from 0% to 30.1% at 5 years for patients with the lowest (≤3) and highest (≥8) scores (P < 0.001). Using this score, a nomogram was built enabling individualized prediction of HCC occurrence at 1, 3, and 5 years. Conclusion: This HCC score can accurately predict HCC at an individual level in French patients with HCV cirrhosis. (Hepatology 2016;64:1136‐1147)
Inhibition of mast cell‐secreted histamine decreases biliary proliferation and fibrosis in primary sclerosing cholangitis Mdr2−/− mice
Authors: Jones Hannah , Hargrove Laura , Kennedy Lindsey , Meng Fanyin , Graf‐Eaton Allyson , Owens Jennifer , Alpini Gianfranco , Johnson Christopher , Bernuzzi Francesca , Demieville Jennifer , DeMorrow Sharon , Invernizzi Pietro , Francis Heather
Published: June 2016

Hepatic fibrosis is marked by activation of hepatic stellate cells (HSCs). Cholestatic injury precedes liver fibrosis, and cholangiocytes interact with HSCs promoting fibrosis. Mast cells (MCs) infiltrate following liver injury and release histamine, increasing biliary proliferation. We evaluated if inhibition of MC‐derived histamine decreases biliary proliferation and fibrosis. Wild‐type and multidrug resistance 2 knockout mice (9‐11 weeks) were treated with cromolyn sodium for 1 week to block MC‐derived histamine. Biliary mass and proliferation were evaluated by immunohistochemistry for cytokeratin 19 and Ki‐67. Bile flow, bicarbonate excretion, and total bile acids were measured in all mice. Fibrosis was evaluated by sirius red/fast green staining and by quantitative polymerase chain reaction for alpha‐smooth muscle actin, fibronectin, collagen type 1a, and transforming growth factor‐beta 1. HSC activation was evaluated by quantitative polymerase chain reaction in total liver and immunofluorescent staining in tissues for synaptophysin 9. Histamine serum secretion was measured by enzymatic immunoassay. Mouse liver and human liver samples from control or primary sclerosing cholangitis patients were evaluated for MC markers by quantitative polymerase chain reaction and immunohistochemistry. In vitro, cultured MCs were transfected with histidine decarboxylase short hairpin RNA to decrease histamine secretion and subsequently cocultured with cholangiocytes or HSCs prior to measuring fibrosis markers, proliferation, and transforming growth factor‐beta 1 secretion. Treatment with cromolyn sodium decreased biliary proliferation, fibrosis, histamine secretion, and bile flow in multidrug resistance 2 knockout mice. Primary sclerosing cholangitis mice and patients have increased MCs. Knockdown of MC histidine decarboxylase decreased cholangiocyte and HSC proliferation/activation. Conclusion: MCs are recruited to proliferating cholangiocytes and promote fibrosis. Inhibition of MC‐derived histamine decreases fibrosis, and regulation of MC mediators may be therapeutic for primary sclerosing cholangitis. (Hepatology 2016;64:1202‐1216)
Ledipasvir plus sofosbuvir for 12 weeks in patients with hepatitis C genotype 4 infection
Authors: Abergel Armand , Metivier Sophie , Samuel Didier , Jiang Deyuan , Kersey Kathryn , Pang Phillip S. , Svarovskaia Evguenia , Knox Steven J. , Loustaud‐Ratti Veronique , Asselah Tarik
Published: June 2016

Genotype 4 hepatitis C virus (HCV) was considered difficult to treat in the era of pegylated interferon‐alpha (Peg‐IFN‐α) and ribavirin regimens. We evaluated the efficacy and safety of therapy with the nonstructural (NS) 5A inhibitor, ledipasvir, combined with the NS5B polymerase inhibitor, sofosbuvir, in patients with HCV genotype 4. In this phase 2, open‐label study, 44 patients (22 treatment naïve and 22 treatment experienced) received a fixed‐dose combination tablet of 90 mg of ledipasvir and 400 mg of sofosbuvir orally once‐daily for 12 weeks. The primary endpoint was the percentage of patients with HCV RNA <15 IU/mL 12 weeks after stopping therapy (SVR12). Among study participants, HCV genotype 4 subtypes were well represented (4a, n = 25; 4d, n = 10; other subtypes, n = 9). Ten patients (23%) had compensated cirrhosis. Of the 22 treatment‐experienced patients, 21 (95%) had a non‐CC IL‐28B genotype. All 44 patients completed the full 12 weeks of dosing. The SVR12 rate was 93% (41 of 44; 95% confidence interval, 81‐99). SVR12 rates were similar between treatment‐naïve (95%; 21 of 22) and treatment‐experienced (91%; 20 of 22) patients. All 3 patients who did not achieve SVR12 had virological relapse within 4 weeks of the end of treatment; all 3 had baseline HCV RNA ≥800,000 IU/mL, a non‐CC IL‐28B genotype, and pretreatment NS5A resistance‐associated variants. None of the patients who relapsed had cirrhosis. The most common adverse events were asthenia, headache, and fatigue. No patients experienced a serious adverse event. Conclusion: The all‐oral regimen of ledipasvir and sofosbuvir is an effective and safe treatment for a wide range of HCV 4 subtypes in both treatment‐naïve and ‐experienced patients, including those with compensated cirrhosis. (EudraCT number: 2013‐003978‐27; Clinicaltrials.gov NCT02081079) (Hepatology 2016;64:1049‐1056)
The use and interpretation of anthropometric measures in cancer epidemiology: A perspective from the world cancer research fund international continuous update project
Authors: Bandera Elisa V. , Fay Stephanie H. , Giovannucci Edward , Leitzmann Michael F. , Marklew Rachel , McTiernan Anne , Mullee Amy , Romieu Isabelle , Thune Inger , Uauy Ricardo , Wiseman Martin J. ,   on behalf of the World Cancer Research Fund International Continuous Update Project Panel
Published: June 2016

Anthropometric measures relating to body size, weight and composition are increasingly being associated with cancer risk and progression. Whilst practical in epidemiologic research, where population‐level associations with disease are revealed, it is important to be aware that such measures are imperfect markers of the internal physiological processes that are the actual correlates of cancer development. Body mass index (BMI), the most commonly used marker for adiposity, may mask differences between lean and adipose tissue, or fat distribution, which varies across individuals, ethnicities, and stage in the lifespan. Other measures, such as weight gain in adulthood, waist circumference and waist‐to‐hip ratio, contribute information on adipose tissue distribution and insulin sensitivity. Single anthropometric measures do not capture maturational events, including the presence of critical windows of susceptibility (i.e., age of menarche and menopause), which presents a challenge in epidemiologic work. Integration of experimental research on underlying dynamic genetic, hormonal, and other non‐nutritional mechanisms is necessary for a confident conclusion of the overall evidence in cancer development and progression. This article discusses the challenges confronted in evaluating and interpreting the current evidence linking anthropometric factors and cancer risk as a basis for issuing recommendations for cancer prevention.
Inverse Ubbelohde effect in the short hydrogen bond of photosystem II: Relation between H/D isotope effect and symmetry in potential energy profile
Authors: Kanematsu Yusuke , Tachikawa Masanori , Takano Yu
Published: June 2016

The short hydrogen bond between tyrosine Yz and D1‐His190 of photosystem II (PSII) was investigated using multicomponent quantum mechanics, where the quantum fluctuation of a hydrogen nucleus was incorporated into electronic structure calculation. Our computation demonstrated that the deuteration for hydrogen in the short hydrogen bond of PSII led to the reduction of the O…N distance. It indicated an inverse Ubbelohde effect typically recognized in strong and symmetric hydrogen‐bonding clusters such as FHF– and
. We confirmed that the relation between the geometric isotope effect and the symmetry of the potential energy profile of FHF– was reasonably agreed with that of PSII. According to this agreement, the short hydrogen bond in PSII can be regarded as a short strong hydrogen bond. © 2016 Wiley Periodicals, Inc.
Variant Inosine Triphosphatase Phenotypes Are Associated With Increased Ribavirin Triphosphate Levels
Authors: Jimmerson Leah C. , Urban Thomas J. , Truesdale Aimee , Baouchi‐Mokrane Fafa , Kottilil Shyam , Meissner Eric G. , Sims Zayani , Langness Jacob A. , Hodara Ariel , Aquilante Christina L. , Kiser Jennifer J.
Published: June 2016

Individuals with lower inosine triphosphatase (ITPA) enzyme activity have a reduced likelihood of experiencing hemolytic anemia during hepatitis C virus (HCV) treatment containing ribavirin (RBV). Because ITPA degrades purines and RBV is a purine analogue, it is conceivable that ITPA activity may affect intracellular RBV concentrations. Here we assessed the association between ITPA activity phenotype and concentrations of RBV triphosphate (RBV‐TP) in red blood cells (RBCs) during HCV treatment. RBV‐TP was quantified in the RBCs of 177 HCV‐infected individuals at a median (range) of 84 (19 to 336) days into HCV treatment that included RBV. Mean (SD) RBV‐TP concentrations were 92.8 (51.6), 101.3 (53.5), 184.8 (84.5), and 197.7 (64.6) pmol/106 cells for 100%, 60%, 30%, and ≤10% ITPA activity groups, respectively. Overall, RBV‐TP was approximately 2‐fold higher in patients with ≤30% ITPA activity compared to 100% activity (P < .0001). Despite higher RBV‐TP levels, individuals with variant ITPA phenotypes had less anemia. The 100% activity group had, on average, a –2.20 g/dL drop in hemoglobin vs –1.43 g/dL (P = .04) for 60% activity, –1.14 g/dL (P = .008) for 30% activity, and –0.70 g/dL (P = .06) for ≤10% activity. This finding of higher RBV‐TP concentrations in RBCs in ITPA variants was unexpected given that ITPA activity‐deficient individuals have a reduced likelihood of RBV‐induced anemia. It also refutes the hypothesis that the mechanism by which ITPA variants are protected against anemia is due to lower RBV‐TP levels in RBCs.