bluuebunny/crossref_metadata_2025 huggingface dataset:
Mutation in noncoding RNA RNU12 causes early onset cerebellar ataxia
Authors: Elsaid Mahmoud Fawzi , Chalhoub Nader , Ben‐Omran Tawfeg , Kumar Pankaj , Kamel Hussein , Ibrahim Khalid , Mohamoud Yasmin , Al‐Dous Eman , Al‐Azwani Iman , Malek Joel A. , Suhre Karsten , Ross M. Elizabeth , Aleem Alice Abdel
Published: November 2016

Objective

Exome sequences account for only 2% of the genome and may overlook mutations causing disease. To obtain a more complete view, whole genome sequencing (WGS) was analyzed in a large consanguineous family in which members displayed autosomal recessively inherited cerebellar ataxia manifesting before 2 years of age.

Methods

WGS from blood‐derived genomic DNA was used for homozygosity mapping and a rare variant search. RNA from isolated blood leukocytes was used for quantitative polymerase chain reaction (PCR), RNA sequencing, and comparison of the transcriptomes of affected and unaffected family members.

Results

WGS revealed a point mutation in noncoding RNA RNU12 that was associated with early onset cerebellar ataxia. The U12‐dependent minor spliceosome edits 879 known transcripts. Reverse transcriptase PCR demonstrated minor intron retention in all of 9 randomly selected RNAs from this group, and RNAseq showed splicing disruption specific to all U12‐type introns detected in blood monocytes from affected individuals. Moreover, 144 minor intron–containing RNAs were differentially expressed, including transcripts for 3 genes previously associated with cerebellar neurodegeneration.

Interpretation

Interference with particular spliceosome components, including small nuclear RNAs, cause reproducible uniquely distributed phenotypic and transcript‐specific effects, making this an important category of disease‐associated mutation. Our approach to differential expression analysis of minor intron–containing genes is applicable to other diseases involving altered transcriptome processing. ANN NEUROL 2017;81:68–78
Mitigating Tensions over Land Conversion in Papua, Indonesia
Authors: Indrawan Mochamad , Caldecott Julian , Ermayanti
Published: November 2016

In the south of the biodiversity‐rich Indonesian province of Papua, a large agricultural program is planned for the districts around Merauke, with the ostensible aim of helping to meet Indonesia's food requirements. Questions arise over the scheme's compliance with national laws and sustainability policies, as well as its likely impacts on indigenous livelihoods and biodiversity. It is also contrary to the recent low‐carbon development priorities of the provincial and national governments. For the initiative to be consistent with law and policy, therefore, considerably improved planning effort would be needed, taking into account many factors that have so far been ignored.
Highly Fluorescent Non‐Conventional Boron‐Difluoride‐Based π Organogel with Gelation‐Assisted Piezochromism
Authors: Wang Sa , Lan Haichuang , Xiao Shuzhang , Tan Ronghua , Lu Yunxiang
Published: November 2016

Triphenylamine‐functionalized boron 2‐(2′‐pyridyl)imidazole complex bearing no alkyl chains or H‐bond unit was found to be able to gelate a series of solvents, and the balanced intermolecular π–π interactions play an important role in its supramolecular self‐assembly. The gelator molecule is piezochromic, and the dried gel responded to pressure more sensitively than regular crystalline powder.
Measurement of caffeine and its three primary metabolites in human plasma by HPLC‐ESI‐MS/MS and clinical application
Authors: Chen Feng , Hu Zhe‐Yi , Parker Robert B. , Laizure S. Casey
Published: November 2016

Caffeine is a mild stimulant with significant potential for abuse, being consumed in larger doses with the widespread availability of energy drinks and by novel routes of administration such as inspired powder, oral sprays and electronic cigarettes. How these recent changes in caffeine consumption affecting caffeine disposition and abuse potential is of growing concern. In the study of caffeine disposition in humans, it is common to only measure the caffeine concentration; however, caffeine's three major metabolites (paraxanthine, theobromine and theophylline) retain central nervous system stimulant activity that may contribute to the overall pharmacological activity and toxicity. Therefore, it would be scientifically more rigorous to measure caffeine and its major metabolites in the evaluation of caffeine disposition in human subjects. Herein, we report a method for the simultaneous quantification of caffeine and its three major metabolites in human plasma by high‐performance liquid chromatography coupled to electrospray tandem mass spectrometry (HPLC‐ESI‐MS/MS). Human plasma samples were treated by simple protein precipitation and the analytes were separated using a 6 min gradient program. Precision and accuracy were well within in the 15% acceptance range. The simple sample preparation, short runtime, sensitivity and the inclusion of caffeine's major metabolites make this assay methodology optimal for the study of caffeine's pharmacokinetics and pharmacodynamics in human subjects.
Planar PtPd3 Complexes Stabilized by Three Bridging Silylene Ligands
Authors: Tanabe Makoto , Yumoto Ryouhei , Yamada Tetsuyuki , Fukuta Tomoko , Hoshino Tsuyoshi , Osakada Kohtaro , Tanase Tomoaki
Published: November 2016

A heterobimetallic PtPd3 complex supported by three bridging diphenylsilylene ligands, [Pt{Pd(dmpe)}3(μ3‐SiPh2)3] (1, dmpe=1,2‐bis(dimethylphosphino)ethane), has been synthesized from mononuclear Pd and Pt complexes. The hexagonal core composed of Pt, Pd, and Si atoms is slightly larger than that of the tetrapalladium complex, [Pd{Pd(dmpe)}3(μ3‐SiPh2)3] (2). Reaction of PhSiH3 with complex 1 in the presence and absence of Ph2SiH2 results in the formation of a tetranuclear complex with silyl and hydride ligands at the Pt center, [PtH(SiPh2H){Pd(dmpe)}3(μ3‐SiHPh)3] (3), and an octanuclear complex, [{Pt{Pd(dmpe)}3(μ3‐SiHPh)3}2(κ2‐dmpe)] (5), respectively. Both M−Si (M=Pt, Pd) bond lengths and the 29Si NMR chemical shifts of 1 and 2 are located between those of mononuclear late transition‐metal complexes with a silylene ligand and complexes with donor‐stabilized silylene ligands. CuI and AgI adducts of 1 and 2, formulated as [M(μ‐M′I){Pd(dmpe)}3(μ3‐SiPh2)3] (M=Pt, Pd; M′=Cu, Ag), undergo elimination of CuI (AgI) and regenerate the tetrametallic complexes upon heating or addition of a chelating diphosphine. Elimination of AgI from 2‐AgI occurs more rapidly than elimination of CuI from 2‐CuI, as determined from the results of kinetics experiments.
Aberrant mTOR signaling and disrupted autophagy: The missing link in potential vigabatrin‐associated ocular toxicity?
Authors: Vogel KR , Ainslie GR , Pearl PL , Gibson KM
Published: November 2016

Vigabatrin (VGB; γ‐vinylGABA) is a unique antiepileptic directly elevating CNS GABA via inactivation of the GABA metabolic enzyme GABA‐transaminase. VGB is effective in treating infantile spasms, a rare seizure disorder associated with significant morbidity. The potential for unexplained bilateral constriction of the visual field associated with VGB intervention can severely limit its temporal utility. Removal of this potential adverse effect with adjuvant intervention(s) would represent a significant advance in epilepsy therapeutics.
Colistin Reduces LPS‐Triggered Inflammation in a Human Sepsis Model In Vivo: A Randomized Controlled Trial
Authors: Matzneller P , Strommer S , Drucker C , Petroczi K , Schörgenhofer C , Lackner E , Jilma B , Zeitlinger M
Published: November 2016

The previously described anti‐endotoxin effect of colistin has not been investigated in humans yet. We performed a randomized, double‐blind, placebo‐controlled crossover trial to determine the degree of colistin‐driven modulation of inflammatory response in blood of lipopolysaccharide (LPS)‐challenged healthy volunteers in a human endotoxemia model. After a single intravenous dose of 2.5 million IU colistin methanesulfonate, interleukin (IL)‐6, IL‐8, tumor necrosis factor alpha (TNF‐α), and IL‐1β concentrations as well as other biomarkers of inflammation such as C‐reactive protein, differential leukocyte counts, and body temperature were measured up to 24 h postdose. Colistin significantly decreased the inflammatory cytokine response to LPS in blood of healthy volunteers. This effect was most evident for IL‐6, IL‐8, and TNF‐α. This study is the first to confirm the anti‐endotoxin effect of colistin in humans in vivo. Further studies might increase our knowledge on the interaction between colistin and the effectors of the immune system.
Carbon lost and carbon gained: a study of vegetation and carbon trade‐offs among diverse land uses inPhoenix,Arizona
Authors: McHale Melissa R. , Hall Sharon J. , Majumdar Anandamayee , Grimm Nancy B.
Published: November 2016

Human modification and management of urban landscapes drastically alters vegetation and soils, thereby altering carbon (C) storage and rates of net primary productivity (NPP). Complex social and ecological processes drive vegetation cover in cities, leading to heterogeneity in C dynamics depending on regional climate, land use, and land cover. Recent work has demonstrated homogenization in ecological processes within human‐dominated landscapes (the urban convergence hypothesis) in soils and biotic communities. However, a lack of information on vegetation in arid land cities has hindered an understanding of potential C storage andNPPconvergence across a diversity of ecosystem types. We estimated C storage andNPPof trees and shrubs for six different land‐use types in the arid metropolis of Phoenix, Arizona,USA, and compared those results to native desert ecosystems, as well as other urban and natural systems around the world. Results from Phoenix do not support the convergence hypothesis. In particular, C storage in urban trees and shrubs was 42% of that found in desert vegetation, whileNPPwas only 20% of the totalNPPestimated for comparable natural ecosystems. Furthermore, the overall estimates of C storage andNPPassociated with urban trees in theCAPecosystem were much lower (8–63%) than the other cities included in this analysis. We also found that C storage (175.25–388.94 g/m2) andNPP(8.07–15.99 g·m−2·yr−1) were dominated by trees in the urban residential land uses, while in the desert, shrubs were the primary source for pools (183.65 g/m2) and fluxes (6.51 g·m−2·yr−1). These results indicate a trade‐off between shrubs and trees in arid ecosystems, with shrubs playing a major role in overall C storage andNPPin deserts and trees serving as the dominant C pool in cities. Our research supports current literature that calls for the development of spatially explicit and standardized methods for analyzing C dynamics associated with vegetation in urbanizing areas.
Spatial vegetation patterns and neighborhood competition among woody plants in an East African savanna
Authors: Dohn Justin , Augustine David J. , Hanan Niall P. , Ratnam Jayashree , Sankaran Mahesh
Published: November 2016

The majority of research on savanna vegetation dynamics has focused on the coexistence of woody and herbaceous vegetation. Interactions among woody plants in savannas are relatively poorly understood. We present data from a 10‐yr longitudinal study of spatially explicit growth patterns of woody vegetation in an East African savanna following exclusion of large herbivores and in the absence of fire. We examined plant spatial patterns and quantified the degree of competition among woody individuals. Woody plants in this semiarid savanna exhibit strongly clumped spatial distributions at scales of 1–5 m. However, analysis of woody plant growth rates relative to their conspecific and heterospecific neighbors revealed evidence for strong competitive interactions at neighborhood scales of up to 5 m for most woody plant species. Thus, woody plants were aggregated in clumps despite significantly decreased growth rates in close proximity to neighbors, indicating that the spatial distribution of woody plants in this region depends on dispersal and establishment processes rather than on competitive, density‐dependent mortality. However, our documentation of suppressive effects of woody plants on neighbors also suggests a potentially important role for tree‐tree competition in controlling vegetation structure and indicates that the balanced‐competition hypothesis may contribute to well‐known patterns in maximum tree cover across rainfall gradients in Africa.
Estimates of local biodiversity change over time stand up to scrutiny
Authors: Vellend Mark , Dornelas Maria , Baeten Lander , Beauséjour Robin , Brown Carissa D. , De Frenne Pieter , Elmendorf Sarah C. , Gotelli Nicholas J. , Moyes Faye , Myers‐Smith Isla H. , Magurran Anne E. , McGill Brian J. , Shimadzu Hideyasu , Sievers Caya
Published: November 2016

We present new data and analyses revealing fundamental flaws in a critique of two recent meta‐analyses of local‐scale temporal biodiversity change. First, the conclusion that short‐term time series lead to biased estimates of long‐term change was based on two errors in the simulations used to support it. Second, the conclusion of negative relationships between temporal biodiversity change and study duration was entirely dependent on unrealistic model assumptions, the use of a subset of data, and inclusion of one outlier data point in one study. Third, the finding of a decline in local biodiversity, after eliminating post‐disturbance studies, is not robust to alternative analyses on the original data set, and is absent in a larger, updated data set. Finally, the undebatable point, noted in both original papers, that studies in the ecological literature are geographically biased, was used to cast doubt on the conclusion that, outside of areas converted to croplands or asphalt, the distribution of biodiversity trends is centered approximately on zero. Future studies may modify conclusions, but at present, alternative conclusions based on the geographic‐bias argument rely on speculation. In sum, the critique raises points of uncertainty typical of all ecological studies, but does not provide an evidence‐based alternative interpretation.
“Hummingbird” floral traits interact synergistically to discourage visitation by bumble bee foragers
Authors: Gegear Robert J. , Burns Rebecca , Swoboda‐Bhattarai Katharine A.
Published: November 2016

Pollination syndromes are suites of floral traits presumed to reflect adaptations to attract and utilize a “primary” type of animal pollinator. However, syndrome traits may also function to deter “secondary” flower visitors that reduce plant fitness through their foraging activities. Here we use the hummingbird‐pollinated plant species Mimulus cardinalis as a model to investigate the potential deterrent effects of classic bird syndrome traits on bumble bee foragers. To establish that M. cardinalis flowers elicit an avoidance response in bees, we assessed the choice behavior of individual foragers on a mixed experimental array of M. cardinalis and its bee‐pollinated sister species M. lewisii. As expected, bees showed a strong preference against M. cardinalis flowers (only 22% of total bee visits were to M. cardinalis), but surprisingly also showed a high degree of individual specialization (95.2% of total plant transitions were between conspecifics). To determine M. cardinalis floral traits that discourage bee visitation, we then assessed foraging responses of individuals to M. cardinalis‐like and M. lewisii‐like floral models differing in color, orientation, reward, and combinations thereof. Across experiments, M. cardinalis‐like trait combinations consistently produced a higher degree of flower avoidance behavior and individual specialization than expected based on bee responses to each trait in isolation. We then conducted a series of flower discrimination experiments to assess the ability of bees to utilize traits and trait combinations associated with each species. Relative to M. lewisii‐like alternatives, M. cardinalis‐like traits alone had a minimal effect on bee foraging proficiency but together increased the time bees spent searching for rewarding flowers from 1.49 to 2.65 s per visit. Collectively, our results show that M. cardinalis flowers impose foraging costs on bumble bees sufficient to discourage visitation and remarkably, generate such costs through synergistic color‐orientation and color‐reward trait interactions. Floral syndromes therefore represent complex adaptations to multiple pollinator groups, rather than simply the primary pollinator.
Woody plant richness does not influence invertebrate community reassembly trajectories in a tree diversity experiment
Authors: Yeeles Peter , Lach Lori , Hobbs Richard J. , van Wees Mary , Didham Raphael K.
Published: November 2016

Understanding the relationship between plant diversity and diversity at higher trophic levels is important from both conservation and restoration perspectives. Although there is strong evidence for bottom‐up maintenance of biodiversity, this is based largely on studies of simplified grassland systems. Recently, studies in the TreeDivNet global network of tree diversity experiments have begun to test whether these findings are generalizable to more complex ecosystems, such as woodlands. We monitored invertebrate community reassembly over 5 yr of experimental woodland restoration at the TreeDivNet Ridgefield site in southwest Australia, testing the effects of woody plant species richness and herb‐layer manipulation on invertebrate community structure and ant species composition. From 2010 to 2014, we sampled ground‐dwelling invertebrates using pitfall traps in herbicide vs. no‐herbicide subplots nested within each of 10 woody plant treatments varying in richness from zero (bare controls) to eight species, which produced a total of 211, 235 invertebrates, including 98, 979 ants belonging to 74 species. In mixed model analyses, the presence of woody plants was an important driver of faunal community reassembly (relative to bare control plots), but faunal responses to woody plant treatment combinations were idiosyncratic and unrelated to woody plant richness across treatments. We also found that a herbicide‐induced reduction in herbaceous plant cover and richness had a positive effect on ant richness and caused more rapid convergence of invertebrate community composition toward the composition of a woodland reference site. These findings show that woody plant richness did not have direct positive effects on the diversity and community reassembly trajectories of higher trophic levels in our woodland system. From a management perspective, this suggests that even low‐diversity restoration or carbon sequestration plantings can potentially lead to faunal reassembly outcomes that are comparable to more complex re‐planting designs.
l‐Rhamnosylation: The Solvent is the Solution
Authors: Elferink Hidde , Pedersen Christian Marcus
Published: November 2016

Herein we present a systematic study of l‐rhamnosylation. The influence of protective groups, reactivity, solvents and glycosylation method, i.e. catalytic versus promoted glycosylation, are studied. It was found that the selectivity can be controlled to a large extend, by varying these parameters and hence the same donor can give both anomers. A reversal of the influence of the participating solvents is observed, and hence ethereal solvents increase the β selectivity, whereas nitrile solvents give almost exclusive α‐selectively.
Derivation of Kinetics and Design Parameters for a Carbonator Reactor in a Greenhouse Calcium Looping Process
Authors: Ramezani Mohammad , Tremain Priscilla , Shah Kalpit , Doroodchi Elham , Moghtaderi Behdad
Published: November 2016

The carbonation/calcination reaction cycle of a limestone sorbent was studied experimentally by using a thermogravimetric analyzer for unique conditions, such as low temperature (400 to 500 °C) and low CO2 partial pressure (0.05 to 0.1 %), pertinent to a novel greenhouse calcium looping process. The kinetic parameters were obtained and compared with those reported in the literature. Various gas–solid reaction mechanisms were considered to determine the best reaction mechanism for the carbonation reaction. The diffusion function, or G(x)=x2, had the best least‐squares linear fit, which resulted in a first‐order reaction for the carbonation reaction in the greenhouse calcium looping process. Moreover, the activation energy and pre‐exponential factor of the carbonation reaction were established to be 19.7 kJ mol−1 and 295.8 min−1 kPa−1, respectively. The derived kinetic parameters were used in Aspen Plus to optimize the carbonator reactor size. The required size of the reactor decreased with increasing operating temperature of the reactor. Exergy analysis revealed that the overall exergetic efficiency of greenhouse calcium looping could be more than 80 %.
Platinum Nanoparticles Supported on TiO2 Photonic Crystals as Highly Active Photocatalyst for the Reduction of CO2 in the Presence of Water
Authors: Jiao Jinqing , Wei Yuechang , Chi Kebin , Zhao Zhen , Duan Aijun , Liu Jian , Jiang Guiyuan , Wang Yajun , Wang Xilong , Han Changcun , Zheng Peng
Published: November 2016

Photonic crystals can delay the propagation of light and increase its path length through a slow‐light effect, which could have immense potential in improving photocatalytic conversion efficiencies. We employed a colloidal crystal template method to synthesize TiO2 photonic crystals (PC‐TiO2), with platinum nanoparticles (Pt NPs) being deposited on the surface of the PC‐TiO2 support at different loading amounts by the gas bubbling‐assisted membrane reduction (GBMR) method. A series of Pt/PC‐TiO2 photocatalysts with well‐defined inverse‐opal structure have uniform Pt NPs (about 2.5 nm) homogeneously dispersed on the pore walls of the support. The slow‐light effect of photonic crystals effectively enhances the absorption efficiency of solar irradiation. Moreover, the Pt deposition significantly extends the spectral response and reduces the recombination rates of photoinduced electron–hole pairs. As a result, the Ptx/PC‐TiO2 catalysts exhibit excellent photocatalytic activity for the reduction of CO2 in the presence of H2O. In addition, we propose a reaction mechanism for the photoreduction of CO2 under light irradiation.
The elements and richness of particle diffusion during sediment transport at small timescales
Authors: Furbish David Jon , Fathel Siobhan L. , Schmeeckle Mark W. , Jerolmack Douglas J. , Schumer Rina
Published: November 2016

The ideas of advection and diffusion of sediment particles are probabilistic constructs that emerge when the Master equation, a precise, probabilistic description of particle conservation, is approximated as a Fokker–Planck equation. The diffusive term approximates nonlocal transport. It ‘looks’ upstream and downstream for variations in particle activity and velocities, whose effects modify the advective term. High‐resolution measurements of bedload particle motions indicate that the mean squared displacement of tracer particles, when treated as a virtual plume, primarily reflects a nonlinear increase in the variance in hop distances with increasing travel time, manifest as apparent anomalous diffusion. In contrast, an ensemble calculation of the mean squared displacement involving paired coordinate positions independent of starting time indicates a transition from correlated random walks to normal (Fickian) diffusion. This normal behavior also is reflected in the particle velocity autocorrelation function. Spatial variations in particle entrainment produce a flux from sites of high entrainment toward sites of low entrainment. In the case of rain splash transport, this leads to topographic roughening, where differential rain splash beneath the canopy of a desert shrub contributes to the growth of a soil mound beneath the shrub. With uniform entrainment, rain splash transport, often described as a diffusive process, actually represents an advective particle flux that is proportional to the land surface slope. Particle diffusion during both bedload and rain splash transport involves motions that mostly are patchy, intermittent and rarefied. The probabilistic framework of the Master equation reveals that continuous formulations of the flux and its divergence (the Exner equation) represent statistically expected behavior, analogous to Reynolds‐averaged conditions. Key topics meriting clarification include the mechanical basis of particle diffusion, effects of rarefied conditions involving patchy, intermittent motions, and effects of rest times on diffusion of tracer particles and particle‐borne substances. Copyright © 2016 John Wiley & Sons, Ltd.
Using a landform evolution model to study ephemeral gullying in agricultural fields: the effects of rainfall patterns on ephemeral gully dynamics
Authors: Hoober David , Svoray Tal , Cohen Sagy
Published: November 2016

Water driven soil erosion is a major cause of land degradation worldwide. Ephemeral gullies (EGs) are considered key contributors to agricultural catchment soil loss. Despite their importance, the parameters and drivers controlling EG dynamics have not been adequately quantified. Here we investigate the effects of rainfall characteristics on EGs, using the physically based landform evolution model (LEM) CAESAR‐Lisflood. An initial goal of this study was to test the feasibility of using a LEM to estimate EG dynamics based on an easily obtainable and moderate spatial resolution (2 × 2 m) Digital Elevation Model (DEM). EG evolution was simulated for two rainfall seasons in a 0.37 km2 agricultural plot situated in a semiarid catchment in central Israel. The 2014 rainfall season was used to calibrate the model and the 2015 season was used for validation. The model overall well predicted the EG network structure and average depth but tended to underestimate the EG length. The effects of rainfall characteristics on EG dynamics were investigated by comparing simulations employing seven rainfall scenarios. Four of these scenarios differ in their overall rainfall volume relative to observed precipitation (+20%, +10%, −10%, −20%). The remaining three scenarios vary in the temporal distribution of rainfall during each storm, allowing us to isolate the effect of rainfall intensity on EG evolution. The results show that: (1) EG dynamics strongly correlated with changes in rainfall volume; (2) small‐scale morphological behavior varies between rainfall scenarios, resulting in different meandering and connectivity variability; (3) EG evolution is divided into two main stages, an initial rapid development occurring after the first two weeks of the rainy season, followed by a stable development period; (4) a 12 mm h−1 intensity threshold was observed to initiate and, later, modify EGs; and (5) inner storm rainfall variability can have a considerable effect on EG evolution. Copyright © 2016 John Wiley & Sons, Ltd.
IL6‐mediated inflammatory loop reprograms normal to epithelial‐mesenchymal transition+ metastatic cancer stem cells in preneoplastic liver of transforming growth factor beta–deficient β2‐spectrin+/− mice
Authors: Mitra Abhisek , Yan Jun , Xia Xueqing , Zhou Shouhao , Chen Jian , Mishra Lopa , Li Shulin
Published: November 2016

Hepatocellular carcinoma (HCC) is the second‐leading cause of cancer‐related deaths worldwide with a poor survival rate. As many as 40% of HCCs are clonal, with alteration of key tumor‐suppressor pathways in stem cells as the primary cause of HCC initiation. However, mechanisms that generate metastatic stem cells in preneoplastic liver tissue are not well understood. We hypothesized that chronic inflammation is a major driver of the transformation of genetically defective liver stem cells (LSCs) into highly metastatic liver cancer cells in premalignant liver tissue. We developed models of chronic inflammation in wild‐type (WT) and β2‐spectrin (β2SP)+/− (SPTBN1) mice. CD133+ LSCs derived from preneoplastic livers of β2SP+/− mice treated with interleukin‐6 (pIL6; IL6β2SP+/− LSCs) were highly tumorigenic and metastatic, whereas those derived from WT mice treated with pIL6 (IL6WT LSCs) had significantly less proliferation and no tumorigenic properties. IL6β2SP+/− LSCs not only exhibited nuclear localization of Twist and Slug, markers of epithelial‐mesenchymal transition (EMT), but also constitutive activation of nuclear factor kappa B (NFκB; RELA). Knockdown of NFκB decreased the EMT phenotypes and metastatic capacity of these cells. NFκB in IL6β2SP+/− LSCs was activated by transforming growth factor β (TGFβ)‐activated kinase 1 (TAK1; MAP3K7), which is associated with poor survival in HCC and interleukin‐6 (IL6) expression. The amount of constitutively activated NFκB increased dramatically from normal to cirrhotic to HCC tissues from human patients. Conclusion: IL6‐mediated inflammation programs constitutive activation of the TAK1‐NFκB signaling cascade in CD133+ LSCs, and this program interacts with deficient TGFβ signaling, thereby accelerating the transformation of normal LSCs to metastatic cancer stem cells (mCSCs). Indeed, this study delineates the development of EMT‐positive mCSCs in HCC‐free liver tissue upon chronic inflammation. (Hepatology 2017;65:1222‐1236).
A new class of hepatitis B and D virus entry inhibitors, proanthocyanidin and its analogs, that directly act on the viral large surface proteins
Authors: Tsukuda Senko , Watashi Koichi , Hojima Taichi , Isogawa Masanori , Iwamoto Masashi , Omagari Katsumi , Suzuki Ryosuke , Aizaki Hideki , Kojima Soichi , Sugiyama Masaya , Saito Akiko , Tanaka Yasuhito , Mizokami Masashi , Sureau Camille , Wakita Takaji
Published: November 2016

Introduction of direct‐acting antivirals against hepatitis C virus (HCV) has provided a revolutionary improvement in the treatment outcome. In contrast to HCV, however, the strategy for developing new antiviral agents against hepatitis B virus (HBV), especially viral‐targeting compounds, is limited because HBV requires only four viral genes for its efficient replication/infection. Here, we identify an oligomeric flavonoid, proanthocyanidin (PAC) and its analogs, which inhibit HBV entry into host cells by targeting the HBV large surface protein (LHBs). Through cell‐based chemical screening, PAC was identified to inhibit HBV infection with little cytotoxic effect. PAC prevented the attachment of the preS1 region in the LHBs to its cellular receptor, sodium taurocholate cotransporting polypeptide (NTCP). PAC was shown to target HBV particles and impair their infectivity, whereas it did not affect the NTCP‐mediated bile acid transport activity. Chemical biological techniques demonstrated that PAC directly interacted with the region essential for receptor binding in the preS1 region in the LHBs protein. Importantly, PAC had a pan‐genotypic anti‐HBV activity and was also effective against a clinically relevant nucleoside analog‐resistant HBV isolate. We further showed that PAC augmented the ability of a nucleoside analog, tenofovir, to interrupt HBV spread over time in primary human hepatocytes by cotreatment. Moreover, derivative analysis could identify small molecules that demonstrated more‐potent anti‐HBV activity over PAC. Conclusion: PAC and its analogs represent a new class of anti‐HBV agents that directly target the preS1 region of the HBV large surface protein. These agents could contribute to the development of a potent, well‐tolerated, and broadly active inhibitor of HBV infection. (Hepatology 2017;65:1104‐1116).
Lipid zonation and phospholipid remodeling in nonalcoholic fatty liver disease
Authors: Hall Zoe , Bond Nicholas J. , Ashmore Tom , Sanders Francis , Ament Zsuzsanna , Wang Xinzhu , Murray Andrew J. , Bellafante Elena , Virtue Sam , Vidal‐Puig Antonio , Allison Michael , Davies Susan E. , Koulman Albert , Vacca Michele , Griffin Julian L.
Published: November 2016

Nonalcoholic fatty liver disease (NAFLD) can progress from simple steatosis (i.e., nonalcoholic fatty liver [NAFL]) to nonalcoholic steatohepatitis (NASH), cirrhosis, and cancer. Currently, the driver for this progression is not fully understood; in particular, it is not known how NAFLD and its early progression affects the distribution of lipids in the liver, producing lipotoxicity and inflammation. In this study, we used dietary and genetic mouse models of NAFL and NASH and translated the results to humans by correlating the spatial distribution of lipids in liver tissue with disease progression using advanced mass spectrometry imaging technology. We identified several lipids with distinct zonal distributions in control and NAFL samples and observed partial to complete loss of lipid zonation in NASH. In addition, we found increased hepatic expression of genes associated with remodeling the phospholipid membrane, release of arachidonic acid (AA) from the membrane, and production of eicosanoid species that promote inflammation and cell injury. The results of our immunohistochemistry analyses suggest that the zonal location of remodeling enzyme LPCAT2 plays a role in the change in spatial distribution for AA‐containing lipids. This results in a cycle of AA‐enrichment in pericentral hepatocytes, membrane release of AA, and generation of proinflammatory eicosanoids and may account for increased oxidative damage in pericentral regions in NASH. Conclusion: NAFLD is associated not only with lipid enrichment, but also with zonal changes of specific lipids and their associated metabolic pathways. This may play a role in the heterogeneous development of NAFLD. (Hepatology 2017;65:1165‐1180)
Dissociable profiles of generalization/discrimination in the human hippocampus during associative retrieval
Authors: De Shetler Natalie G. , Rissman Jesse
Published: November 2016

When encountering stimuli that vary slightly from previous experiences, neural signals within the CA3 and dentate gyrus (CA3DG) hippocampal subfields are thought to facilitate mnemonic discrimination, whereas CA1 may be less sensitive to minor stimulus changes, allowing for generalization across similar events. Studies have also posited a critical role for CA1 in the comparison of events to memory‐derived expectations, but the degree to which these processes are impacted by explicit retrieval demands is yet unclear. To evaluate extant accounts of hippocampal subfield function, we acquired high‐resolution fMRI data as participants performed a task in which famous names were used to cue the retrieval of previously paired images. Although both left CA3DG and CA1 showed match enhancement effects, responding more to original paired images (targets) than to never‐before‐seen images (novels), the sensitivity of these subfields to stimulus changes and task demands diverged. CA3DG showed a goal‐independent, yet highly specific, preference for previously encountered stimuli, responding equally strongly to targets and mispaired associates, while showing equally weak responses to close lures and novels. In contrast, recognition signals in CA1 were goal‐dependent (i.e., not evoked by mispaired associates), yet accommodating of subtle stimulus differences, such that close lures evoked comparable activity as targets. © 2016 Wiley Periodicals, Inc.
Surface water quality in a sulfide mineral‐rich arid zone in North‐Central Chile: Learning from a complex past, addressing an uncertain future
Authors: Flores Mauricio , Núñez Jorge , Oyarzún Jorge , Freixas Gustavo , Maturana Hugo , Oyarzún Ricardo
Published: November 2016

This study presents an analysis of up to 30 years of hydrological variables and selected water quality parameters (pH, SO4, Fe, Cu, and As) in the upper area of the Elqui River basin in North‐Central Chile. A correlation analysis determined statistically significant positive relationship for SO4‐Cu, Fe‐As, and Fe‐Cu. In terms of historical behaviour, no statistically significant trends were detected for precipitation or temperature. In contrast, for flow, there is an overall decreasing pattern for the entire area of study, although only in one case this trend was statistically significant. Along with the aforementioned analysis, a characterization of the flow‐water quality relationships is considered for the time period analyzed. Although erratic behaviours were confirmed, a negative (i.e., inverse) flow‐concentration relationship was identified for SO4, a positive (i.e., direct) relationship for Fe, and undefined relationships for As and Cu were obtained. From these analyses and based on previous studies on projections regarding climate change for the Andean region, and in particular for the upper Elqui zone, an estimation of the possible effects of the change in water regimes on water quality in the area of study is developed. It is likely that a decrease in surface flow, as a consequence of climate change could translate into improvements in water quality in terms of Fe and eventually As and Cu, but into an impairment in the case of SO4. In any case, this is a complex situation that demands special attention in the face of industrial activities that could be developed in tributaries like the Claro River, which currently play an important role in depurating or diluting contaminants in the waters of the Elqui River. Finally, it should be noted that this study addresses an issue that goes beyond the local interest and could be used as a reference to compare other transitional environments containing sulphide ores or areas of hydrothermal alterations, which are considered to be highly vulnerable to climate change and variability.
Goal-Directed Treatment for Osteoporosis: A Progress Report From the ASBMR-NOF Working Group on Goal-Directed Treatment for Osteoporosis
Authors: Cummings Steven R , Cosman Felicia , Lewiecki E Michael , Schousboe John T , Bauer Douglas C , Black Dennis M , Brown Thomas D , Cheung Angela M , Cody Kathleen , Cooper Cyrus , Diez-Perez Adolfo , Eastell Richard , Hadji Peyman , Hosoi Takayuki , Jan De Beur Suzanne , Kagan Risa , Kiel Douglas P , Reid Ian R , Solomon Daniel H , Randall Susan
Published: November 2016

The American Society for Bone and Mineral Research and the United States National Osteoporosis Foundation (NOF) formed a working group to develop principles of goal-directed treatment and identify gaps that need to be filled to implement this approach. With goal-directed treatment, a treatment goal would first be established and choice of treatment determined by the probability of achieving that goal. Goals of treatment would be freedom from fracture, a T-score > –2.5, which is above the NOF threshold for initiating treatment, or achievement of an estimated risk level below the threshold for initiating treatment. Progress toward reaching the patient's goal would be periodically and systematically assessed by estimating the patient's compliance with treatment, reviewing fracture history, repeating vertebral imaging when indicated, and repeating measurement of bone mineral density (BMD). Using these data, a decision would be made to stop, continue, or change therapy. Some of these approaches can now be applied to clinical practice. However, the application of goal-directed treatment cannot be fully achieved until medications are available that provide greater increases in BMD and greater reduction in fracture risk than those that are currently approved; only then can patients with very high fracture risk and very low BMD achieve such goals. Furthermore, assessing future fracture risk in patients on treatment requires a new assessment tool that accurately captures the change in fracture risk associated with treatment and should also be sensitive to the importance of recent fractures as predictors of imminent fracture risk. Lastly, evidence is needed to confirm that selecting and switching treatments to achieve goals reduces fracture risk more effectively than current standard care. © 2016 American Society for Bone and Mineral Research.

Abstract

The fundamental principle of treat-to-goal for osteoporosis is that treatment should be selected according to having a high likelihood of achieving an acceptable level of fracture risk. This is different than but complementary to the current paradigm of monitoring for response to therapy, usually with bone density testing by DXA or bone turnover markers. A patient may respond to therapy yet continue to have an unacceptably high fracture risk. Response to treatment is essential but not necessarily sufficient in achieving an acceptable level of fracture risk.
N‐Glycosylation at Asn 402 Stabilizes N‐Cadherin and Promotes Cell–Cell Adhesion of Glioma Cells
Authors: Xu Yaolin , Chang Ruiqi , Xu Fulin , Gao Yan , Yang Fuming , Wang Can , Xiao Jin , Su Zuopeng , Bi Yongyan , Wang Liying , Zha Xiliang
Published: November 2016

Cadherin is crucial for cell–cell adhesion and N‐glycosylation of N‐cadherin has been implicated in the process of mammary, renal, and ovarian carcinogenesis. However, whether N‐glycosylation of N‐cadherin plays a role in glioma remains unknown. Previous studies had indicated that N‐glycosylation could occur at three asparagine residues of N‐cadherin. By generating and over‐expressing N‐glycosylation‐deficient N‐cadherin mutants in the human glioma cell lines SHG66 and U87, we found that mutation of N402 but not of the other potentially N‐glycosylated residues destabilized N‐cadherin and led to its ubiquitylation and subsequent proteasomal degradation. Furthermore, destabilized N‐cadherin inhibited cadherin‐mediated cell–cell adhesion and promoted cell migration. Our findings reveal that N‐glycosylation controls N‐cadherin stability and plays a role in glioma migration. J. Cell. Biochem. 118: 1423–1431, 2017. © 2016 Wiley Periodicals, Inc.
Ethical use of animal models in musculoskeletal research
Authors: Allen Matthew J. , Hankenson Kurt D. , Goodrich Laurie , Boivin Gregory P. , von Rechenberg Brigitte
Published: November 2016

The use of animals in research is under increasing scrutiny from the general public, funding agencies, and regulatory authorities. Our ability to continue to perform in‐vivo studies in laboratory animals will be critically determined by how researchers respond to this new reality. This Perspectives article summarizes recent and ongoing initiatives within ORS and allied organizations to ensure that musculoskeletal research is performed to the highest ethical standards. It goes on to present an overview of the practical application of the 3Rs (reduction, refinement, and replacement) into experimental design and execution, and discusses recent guidance with regard to improvements in the way in which animal data are reported in publications. The overarching goal of this review is to challenge the status quo, to highlight the absolute interdependence between animal welfare and rigorous science, and to provide practical recommendations and resources to allow clinicians and scientists to optimize the ways in which they undertake preclinical studies involving animals. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:740–751, 2017.
Diversification of the kinetic properties of yeast NADP‐glutamate‐dehydrogenase isozymes proceeds independently of their evolutionary origin
Authors: Campero‐Basaldua Carlos , Quezada Héctor , Riego‐Ruíz Lina , Márquez Dariel , Rojas Erendira , González James , El‐Hafidi Mohammed , González Alicia
Published: November 2016

In the yeastSaccharomyces cerevisiae, theScGDH1andScGDH3encoded glutamate dehydrogenases (NADP‐GDHs) catalyze the synthesis of glutamate from ammonium and α‐ketoglutarate (α‐KG). Previous kinetic characterization showed that these enzymes displayed different allosteric properties and respectively high or low rate of α‐KGutilization. Accordingly, the coordinated action ofScGdh1 andScGdh3, regulated balanced α‐KGutilization for glutamate biosynthesis under either fermentative or respiratory conditions, safeguarding energy provision. Here, we have addressed the question of whether there is a correlation between the regulation and kinetic properties of theNADP‐GDHisozymes present inS. cerevisiae(ScGdh1 andScGdh3),Kluyveromyces lactis(KlGdh1), andLachancea kluyveri(LkGdh1) and their evolutionary history. Our results show that the kinetic properties ofK. lactisandL. kluyverisingleNADP‐GDHs are respectively similar to eitherScGDH3orScGDH1, which arose from the whole genome duplication event of theS. cerevisiaelineage, although,KlGDH1andLkGDH1originated from aGDHclade, through an ancient interspecies hybridization event that preceded the divergence between theSaccharomycesclade and the one containing the generaKluyveromyces,Lachancea, andEremothecium. Thus, the kinetic properties which determine theNADP‐GDHs capacity to utilize α‐KGand synthesize glutamate do not correlate with their evolutionary origin.
E2F transcription factor 2 variants as predictive biomarkers for recurrence risk in patients with squamous cell carcinoma of the oropharynx
Authors: Li Yuncheng , Sturgis Erich M. , Zhu Lijun , Cao Xiaoli , Wei Qingyi , Zhang Hua , Li Guojun
Published: November 2016

Because E2F transcription factor 2 (E2F2) promoter polymorphisms have been implicated in carcinogenesis and prognosis, we investigated associations between genetic variants in five E2F2 promoter polymorphisms and recurrence risk of squamous cell carcinoma of the oropharynx (SCCOP) in 1 008 patients. A log‐rank test and multivariable Cox models were used to assess the associations. Compared with patients with variant genotypes of E2F2‐rs2742976 and E2F2‐rs3218123, patients with common homozygous genotypes had better disease‐free survival (both log‐rank, P < 0.001) and lower SCCOP recurrence risk (HR, 0.4, 95% CI, 0.3–0.6 and HR, 0.3, 95% CI, 0.2–0.5, respectively) after multivariable adjustment. Furthermore, among patients with HPV16‐positive tumors, those with common homozygous genotypes of E2F2‐rs2742976 and E2F2‐rs3218123 had better disease‐free survival rates (both log‐rank, P < 0.001) and lower recurrence risk (HR, 0.1, 95% CI, 0.1–0.4 and HR, 0.1, 95% CI, 0.0–0.2, respectively) than patients with variant genotypes. However, no significant differences were found for the other three polymorphisms. After combining the risk genotypes of the five polymorphisms and using the high‐risk group (2–5 risk genotypes) as the reference group, we found that the low‐risk groups (0 or 1 risk genotype) had significantly lower recurrence risk among all patients (HR, 0.4, 95% CI, 0.3–0.6) and among HPV16‐positive patients (HR, 0.2, 95% CI, 0.1–0.5). Our findings suggest that E2F2 polymorphisms may individually or jointly modify SCCOP recurrence risk, particularly for SCCOP patients with HPV16‐positive tumors. © 2017 Wiley Periodicals, Inc.
Anti‐EGFR monoclonal antibodies enhance sensitivity to DNA‐damaging agents in BRCA1‐mutated and PTEN‐wild‐type triple‐negative breast cancer cells
Authors: El Guerrab Abderrahim , Bamdad Mahchid , Bignon Yves‐Jean , Penault‐Llorca Frédérique , Aubel Corinne
Published: November 2016

Increased epidermal growth factor receptor (EGFR) expression in triple‐negative breast cancer (TNBC) is recognized as a promising therapeutic target, specifically through the use of selective EGFR inhibitors combined with chemotherapies. TNBC is characterized by genetic instability that leads to increased sensitivity to cytotoxic agents. We analyzed the effect of anti‐EGFR monoclonal antibodies (mAbs; cetuximab and panitumumab) in combination with chemotherapeutic agents (docetaxel, cisplatin, and epirubicin) on EGFR‐expressing TNBC cell lines that have different mutation statuses for one oncogene (KRAS) and two tumor suppressor genes (PTEN and BRCA1). Both mAbs failed to improve the cytotoxic effect of chemotherapies in the KRAS mutant cell line (MDA‐MB‐231) and PTEN‐null cell lines (HCC‐1937 and MDA‐MB‐468). In contrast, mAbs combined with DNA‐damaging agents (cisplatin or epirubicin) had a synergistic effect in the BRCA1‐mutant cell line SUM‐1315 (wild‐type KRAS and PTEN). The reintroduction of wild‐type BRCA1 into SUM‐1315 cells abolished this synergism. The improved effect of combination therapy was associated with cell cycle arrest at G1 phase and inhibition of the phosphorylation of EGFR and ERK1/2 proteins. These results suggest that patients with BRCA1‐associated TNBC without genetic alterations in the PTEN and KRAS genes may have improved therapeutic responses to anti‐EGFR mAbs combined with DNA‐damaging agents. © 2017 Wiley Periodicals, Inc.