bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimized sample preparation strategy for the analysis of low molecular mass adducts of a fluorescent cisplatin analogue in cancer cell lines by CE‐dual‐LIF
Authors: Zabel Robert , Kullmann Maximilian , Kalayda Ganna V. , Jaehde Ulrich , Weber Günther
Published: December 2014

Pt‐based anticancer drugs, such as cisplatin, are known to undergo several (bio‐)chemical transformation steps after administration. Hydrolysis and adduct formation with small nucleophiles and larger proteins are their most relevant reactions on the way to the final reaction site (DNA), but there are still many open questions regarding the identity and pharmacological relevance of various proposed adducts and intermediates. Furthermore, the role of buffer components or additives, which are inevitably added to samples during any type of analytical measurement, has been frequently neglected in previous studies. Here, we report on adduct formation reactions of the fluorescent cisplatin analogue carboxyfluorescein diacetate platinum (CFDA‐Pt) in commonly used buffers and cell culture medium. Our results indicate that chelation reactions with noninnocent buffers (e.g., Tris) and components of the cell culture/cell lysis medium must be taken into account when interpreting results. Adduct formation kinetics was followed up to 60 h at nanomolar concentrations of CFDA‐Pt by using CE‐LIF. CE‐MS enabled the online identification of such unexpected adducts down to the nanomolar concentration range. By using an optimized sample preparation strategy, unwanted adducts can be avoided and several fluorescent adducts of CFDA‐Pt are detectable in sensitive and cisplatin‐resistant cancer cell lines. By processing samples rapidly after incubation, we could even identify the initial, but transient, Pt species in the cells as deacetylated CFDA‐Pt with unaltered complexing environment at Pt. Overall, the proposed procedure enables a very sensitive and accurate analysis of low molecular mass Pt species in cancer cells, involving a fast CE‐LIF detection within 5 min.
Single nucleotide polymorphisms of mitochondrial DNA HVS‐I and HVS‐II in Chinese Bai ethnic group
Authors: Chen Feng , Yin Cai‐Yong , Qian Xiao‐Qin , Fan Han‐Ting , Deng Ya‐Jun , Zhang Yu‐Dang , Meng Hao‐Tian , Shen Chun‐Mei , Yang Chun‐Hua , Jin Rui , Zhu Bo‐Feng , Xu Peng
Published: December 2014

For forensic and population genetic purposes, a total of 125 unrelated volunteers’ blood samples were collected from Chinese Bai ethnic minority group to analyze sequence variation of two hypervariable segments (HVS‐I and HVS‐II) in the mitochondrial DNA control region. Comparing the HVS‐I and HVS‐II sequences of the 125 Chinese Bais to the Anderson reference sequence, we found 86 polymorphic loci in HVS‐I and 40 in HVS‐II in mitochondrial DNA sequences of the Chinese Bai ethnic minority group, which defined 93 and 53 different haplotypes, respectively. Haplotype diversity and the mean pairwise differences were 0.992 ± 0.003 and 6.553 in HVS‐I, and 0.877 ± 0.027 and 2.407 in HVS‐II, respectively. We defined four macrohaplogroups R, M, N and D with the proportions ranging from 9.6% to 40.0%. With the analysis of the hypervariable domain from nucleotide 16 180–16 193 in HVS‐I, our study revealed new haplotypes of sequence variations. In addition, the Fst metric, phylogenetic tree, and principal component analysis demonstrated a close genetic relationship between the Bai group and Chinese Han populations from South China, Changsha, and Guangdong. The results support that the Bai group is a multiorigin ethnic minority that has merged with the Chinese Han population.
Effective periods and seismic performance of steel moment resisting frames designed for risk categories I and IV according to IBC2009
Authors: Jeong Seong‐Hoon , Kwon Oh‐Sung , Lee Kwang‐Ho
Published: December 2014

In current seismic design, structures that are essential for post‐disaster recovery, and hazardous facilities are classified as risk category IV and are designed with higher importance factors and stringent drift limits. These structures are expected to perform better in an earthquake event because a larger base shear and more stringent drift limit are used. Although this provision has been in the seismic design code over the last three decades, few studies have investigated the performance of essential structures. The aim of this study is to quantify the impact of higher importance factors and stringent drift limits on the seismic performance of steel moment resisting frames. A total of 16 steel structures are designed for Los Angeles and Seattle. Different risk categories are used for the design. The effects of the risk categories on the structural periods, and thus on the seismic force demand, are investigated. A suite of inelastic time history analyses are carried out to understand the probability of exceeding a specified limit state when the structures are subjected to different levels of earthquake events. The results show that the periods of the structures in risk category IV decrease by a factor of 0.5 to 0.8, and the strengths increase by a factor of 1.5 to 3.2. Seismic fragility analysis shows that the structures in risk category IV generally satisfy the probabilistic performance objectives. Copyright © 2014 John Wiley & Sons, Ltd.
The effect of CuO NPs on reactive oxygen species and cell cycle gene expression in roots of rice
Authors: Wang Shuling , Liu Hanzhu , Zhang Yuxi , Xin Hua
Published: December 2014

To evaluate the effect of CuO nanoparticles (NPs) on root growth, root reactive oxygen species (ROS) production, and the expression of 2 genes (OsCDC2 and OsCYCD) associated with root growth of Oryza sativa (rice), rice roots were treated with 5 mg/L CuO NP suspension, 5 mg/L CuO bulk particle suspension, and 0.27 mg/L CuSO4 · 5H2O solution, with distilled water as control. The results indicated that CuO NPs and Cu2+ severely inhibited the elongation and biomass of rice roots after 72-h exposure. Dyeing with 7′-dichlorodihydrofluorescein–diacetate (DCFH–DA) showed that in all 3 treatment groups, the fluorescence was primarily located in the meristem zone, demonstrating that the meristem zone was where ROS were primarily generated. In addition, a significant increase in ROS was detected in the meristem zone of roots treated with the CuO NP suspension and the CuSO4 · 5H2O solution, both of which greatly influenced the expression level of OsCDC2 and OsCYCD. The impact of Cu2+ on these 2 genes was smaller than that of CuO NPs. The Cu content in roots of rice after treatment with CuO NPs was much higher than that found after the other treatments, which indicated that CuO NPs may have been absorbed into root tissue. Collectively, these data suggest that growth inhibition, higher ROS production, and gene expression inhibition may be caused not only by the ions themselves, but also the NPs. Environ Toxicol Chem 2015;34:554–561. © 2014 SETAC
Lethal and sublethal measures of chronic copper toxicity in the eastern narrowmouth toad, Gastrophryne carolinensis
Authors: Flynn R. Wesley , Scott David E. , Kuhne Wendy , Soteropoulos Diana , Lance Stacey L.
Published: December 2014

Many metals are acutely toxic to aquatic organisms at high concentrations and for some metals, such as copper (Cu), even low-level chronic contamination may be cause for conservation concern. Amphibian susceptibility to Cu has been examined in only a few species, and susceptibility is highly variable. The lethal and sublethal effects were examined of chronic aqueous Cu exposure on embryonic and larval eastern narrowmouth toads, Gastrophryne carolinensis. Copper levels as low as 10 μg Cu/L reduced embryonic and larval survival. Embryonic survivorship varied within- and between-source populations, with embryos derived from uncontaminated-wetland parents having greater survival at lower Cu levels than embryos from parents from a metal-contaminated constructed wetland. At 30 μg/L, embryos from the contaminated site had greater survival. Overall survival from oviposition to metamorphosis was 68.9% at 0 μg/L and 5.4% at 10 μg/L. Similarly, embryos exposed to ≥50 μg/L demonstrated developmental delays in transition from embryo to free-swimming larva. These results demonstrate a negative population-specific response to environmentally relevant levels of Cu. Environ Toxicol Chem 2015;34:575–582. © 2014 SETAC
Transfer learning and cooperation management: balancing the quality of service and information exchange overhead in cognitive radio networks
Authors: Zhao Qiyang , Grace David , Clarke Tim
Published: December 2014

This paper introduces and studies a novel solution of transfer learning applied to spectrum management in cognitive radio networks in order to improve the Quality of Service (QoS) and convergence performance of conventional full distributed learning. Cooperation management has been investigated to enhance transfer learning as a novel way of reducing the need for control information exchange between distributed cognitive agents while providing the same effective QoS as that achieved in a fully coordinated network. A structured approach is taken to transfer learning, including a source agent selection function defining how the agents exchange learning information, and a target agent training function reinforcing the knowledgebase. It is demonstrated in simulation and analysis that transfer learning achieves a significantly higher QoS and throughput than distributed reinforcement learning. The cooperation management algorithm is shown to effectively reduce the need for information exchange by 90 per cent whilst still providing adequate QoS compared with a fully coordinated network. Copyright © 2014 John Wiley & Sons, Ltd.
PV electrical plants fire risk assessment and mitigation according to the Italian national fire services guidelines
Authors: Cancelliere Piergiacomo
Published: December 2014

Photovoltaic (PV) systems design and construction are generally focused on efficiency and reliability, in order to increase the amount of solar energy that can be converted into electrical energy. Therefore, in a PV electrical generation plant, fire risk is not taken into account by technical designers and, furthermore, is not considered by constructors of PV plant installation. This paper shows a procedure to assess and mitigate the fire risk as a result of a PV plant installation located over buildings, according to the Italian National Fire Services Guidelines. Firstly, an introduction to the main faulty modes of PV arrays and modules is reported in order to highlight how the pre‐existing level of fire risk is increased for a building or construction work where a PV electrical generation plant is installed. Hence, the paper explains how the guidelines point out fire risk assessment steps oriented to PV plant installation over buildings. In addition, the guidelines contain some useful fire risk mitigation technical solutions. The guidelines have been developed with safety as their main objective. The PV sector has been presented with certain limitations in roof or façade installations as a result of PV fire ignition characteristics and firefighting suppression techniques. The aim of the guidelines is to provide the solar PV industry with information and technical arrangements to aid the design, construction and installation of solar PV systems meeting the objectives of both solar PV industry and fire safety requirements. Copyright © 2014 John Wiley & Sons, Ltd.
Rediscovery of Lichen Genus Psorotheciopsis Rehm for India
Authors: Gupta Pooja , Sinha Gopal Prasad
Published: December 2014

The genus Psorotheciopsis Rehm recorded by Cunningham from Calcutta in 1879 has been rediscovered for India after a gap of 135 years. The taxonomic characters of Psorotheciopsis patellarioides (Rehm) Rolf Santesson are provided to facilitate the identification of the species. (© 2013 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Bayesian Analysis of Asymmetric Stochastic Conditional Duration Model
Authors: Men Zhongxian , Kolkiewicz Adam W. , Wirjanto Tony S.
Published: December 2014

This paper proposes Markov chain Monte Carlo methods to estimate the parameters and log durations of the correlated or asymmetric stochastic conditional duration models. Following the literature, instead of fitting the models directly, the observation equation of the models is first subjected to a logarithmic transformation. A correlation is then introduced between the transformed innovation and the latent process in an attempt to improve the statistical fits of the models. In order to perform one‐step‐ahead in‐sample and out‐of‐sample duration forecasts, an auxiliary particle filter is used to approximate the filter distributions of the latent states. Simulation studies and application to the IBM transaction dataset illustrate that our proposed estimation methods work well in terms of parameter and log duration estimation. Copyright © 2014 John Wiley & Sons, Ltd.
Semi‐Structural Forecasting of UK Inflation Based on the Hybrid New Keynesian Phillips Curve
Authors: Posch Johanna , Rumler Fabio
Published: December 2014

We develop a semi‐structural model for forecasting inflation in the UK in which the New Keynesian Phillips curve (NKPC) is augmented with a time series model for marginal cost. By combining structural and time series elements we hope to reap the benefits of both approaches, namely the relatively better forecasting performance of time series models in the short run and a theory‐consistent economic interpretation of the forecast coming from the structural model. In our model we consider the hybrid version of the NKPC and use an open‐economy measure of marginal cost. The results suggest that our semi‐structural model performs better than a random‐walk forecast and most of the competing models (conventional time series models and strictly structural models) only in the short run (one quarter ahead) but it is outperformed by some of the competing models at medium and long forecast horizons (four and eight quarters ahead). In addition, the open‐economy specification of our semi‐structural model delivers more accurate forecasts than its closed‐economy alternative at all horizons. Copyright © 2014 John Wiley & Sons, Ltd.
Distribution of injected CO2 in a stratified saline reservoir accounting for coupled wellbore‐reservoir flow
Authors: Rasmusson Kristina , Tsang Chin‐Fu , Tsang Yvonne , Rasmusson Maria , Pan Lehua , Fagerlund Fritjof , Bensabat Jacob , Niemi Auli
Published: December 2014

Geological storage in sedimentary basins is considered a viable technology in mitigating atmospheric CO2 emissions. Alternating high and low permeability strata are common in these basins. The distribution of injected CO2 among such layers affects e.g. CO2 storage efficiency, capacity and plume footprint. A numerical study on the distribution of injected CO2 into a multi‐layered reservoir, accounting for coupled wellbore‐reservoir flow, was carried out using the T2Well/ECO2N code. A site‐specific case as well as a more general case were considered. Properties and processes governing the distribution of sequestrated CO2 were identified and the potential to operationally modify the distribution was investigated. The distribution of CO2 was seen to differ from that of injected water, i.e. it was not proportional to the transmissivity of the layers. The results indicate that caution should be taken when performing numerical simulations of CO2 injection into layered formations. Ignoring coupled wellbore‐reservoir flow and instead adopting a simple boundary condition at the injection well, such as an inflow rate proportional to the transmissivity of each layer, may result in significant underestimation of the proportion of CO2 ending up in the shallower layers, as not all relevant processes are accounted for. This discrepancy has been thoroughly investigated and quantified for several CO2 sequestration scenarios.
Smoking and the developing brain: Altered white matter microstructure in attention‐deficit/hyperactivity disorder and healthy controls
Authors: van Ewijk Hanneke , Groenman Annabeth P. , Zwiers Marcel P. , Heslenfeld Dirk J. , Faraone Stephen V. , Hartman Catharina A. , Luman Marjolein , Greven Corina U. , Hoekstra Pieter J. , Franke Barbara , Buitelaar Jan , Oosterlaan Jaap
Published: December 2014

Brain white matter (WM) tracts, playing a vital role in the communication between brain regions, undergo important maturational changes during adolescence and young adulthood, a critical period for the development of nicotine dependence. Attention‐deficit/hyperactivity disorder (ADHD) is associated with increased smoking and widespread WM abnormalities, suggesting that the developing ADHD brain might be especially vulnerable to effects of smoking. This study aims to investigate the effect of smoking on (WM) microstructure in adolescents and young adults with and without ADHD. Diffusion tensor imaging was performed in an extensively phenotyped sample of nonsmokers (n = 95, 50.5% ADHD), irregular smokers (n = 41, 58.5% ADHD), and regular smokers (n = 50, 82.5% ADHD), aged 14–24 years. A whole‐brain voxelwise approach investigated associations of smoking, ADHD and their interaction, with WM microstructure as measured by fractional anisotropy (FA) and mean diffusivity (MD). Widespread alterations in FA and MD were found for regular smokers compared to irregular and nonsmokers, mainly located in the corpus callosum and WM tracts surrounding the basal ganglia. Several regions overlapped with regions of altered FA for ADHD versus controls, albeit in different directions. Irregular and nonsmokers did not differ, and ADHD and smoking did not interact. Results implicate that smoking and ADHD have independent effects on WM microstructure, and possibly do not share underlying mechanisms. Two mechanisms may play a role in the current results. First, smoking may cause alterations in WM microstructure in the maturing brain. Second, pre‐existing WM microstructure differences possibly reflect a risk factor for development of a smoking addiction. Hum Brain Mapp 36:1180–1189, 2015. © 2014 Wiley Periodicals, Inc.
Functional connectivity mapping of regions associated with self‐ and other‐processing
Authors: Murray Ryan J. , Debbané Martin , Fox Peter T. , Bzdok Danilo , Eickhoff Simon B.
Published: December 2014

Neuroscience literature increasingly suggests a conceptual self composed of interacting neural regions, rather than independent local activations, yet such claims have yet to be investigated. We, thus, combined task‐dependent meta‐analytic connectivity modeling (MACM) with task‐independent resting‐state (RS) connectivity analysis to delineate the neural network of the self, across both states. Given psychological evidence implicating the self's interdependence on social information, we also delineated the neural network underlying conceptual other‐processing. To elucidate the relation between the self‐/other‐networks and their function, we mined the MACM metadata to generate a cognitive–behavioral profile for an empirically identified region specific to conceptual self, the pregenual anterior cingulate (pACC), and conceptual other, posterior cingulate/precuneus (PCC/PC). Mining of 7,200 published, task‐dependent, neuroimaging studies, using healthy human subjects, yielded 193 studies activating the self‐related seed and were conjoined with RS connectivity analysis to delineate a differentiated self‐network composed of the pACC (seed) and anterior insula, relative to other functional connectivity. Additionally, 106 studies activating the other‐related seed were conjoined with RS connectivity analysis to delineate a differentiated other‐network of PCC/PC (seed) and angular gyrus/temporoparietal junction, relative to self‐functional connectivity. The self‐network seed related to emotional conflict resolution and motivational processing, whereas the other‐network seed related to socially oriented processing and contextual information integration. Notably, our findings revealed shared RS connectivity between ensuing self‐/other‐networks within the ventromedial prefrontal cortex and medial orbitofrontal cortex, suggesting self‐updating via integration of self‐relevant social information. We, therefore, present initial neurobiological evidence corroborating the increasing claims of an intricate self‐network, the architecture of which may promote social value processing.Hum Brain Mapp 36:1304–1324, 2015. ©2014 Wiley Periodicals, Inc.
Safety of contralateral submandibular gland sparing in locally advanced oropharyngeal cancers: A multicenter review
Authors: Robin Tyler P. , Gan Gregory N. , Tam Moses , Westerly David , Riaz Nadeem , Karam Sana D. , Lee Nancy , Raben David
Published: December 2014

Background

Previous groups have shown contralateral submandibular gland sparing to improve xerostomia with safe outcomes, but primarily in early‐stage disease. In this study, we present a large cohort of patients with locally advanced head and neck cancer that underwent contralateral submandibular gland‐sparing radiotherapy, to demonstrate feasibility and safety specifically in patients with locally advanced disease.

Methods

We retrospectively analyzed patients who were treated prospectively with contralateral submandibular gland sparing. Only patients who underwent bilateral neck radiotherapy with contralateral submandibular gland doses <39 Gy were included.

Results

We identified 71 patients. Approximately 80% of patients had ≥N2b disease. The contralateral submandibular gland mean dose was 33 Gy and, at a median follow‐up of 27.3 months, no patients experienced treatment failure in the contralateral level IB lymph nodes.

Conclusion

Xerostomia remains a significant morbidity despite parotid sparing and can be minimized further by contralateral submandibular gland sparing. These data provide important preliminary evidence that contralateral submandibular gland sparing is feasible and may be safe even in locally advanced cancers. © 2015 Wiley Periodicals, Inc. Head Neck 38: 506–511, 2016
Cost‐effectiveness of transoral robotic surgery versus (chemo)radiotherapy for early T classification oropharyngeal carcinoma: A cost‐utility analysis
Authors: de Almeida John R. , Moskowitz Alan J. , Miles Brett A. , Goldstein David P. , Teng Marita S. , Sikora Andrew G. , Gupta Vishal , Posner Marshall , Genden Eric M.
Published: December 2014

Background

The present study is an economic evaluation comparing transoral robotic surgery (TORS) to (chemo)radiotherapy for the management of early T‐classification oropharyngeal cancer.

Methods

A societal perspective was adopted. Treatment for TORS and (chemo)radiotherapy were modeled using decision analysis and recurrences were modeled over a 10 year horizon with a Markov model. Model parameters were derived from systematic review. Deterministic and probabilistic sensitivity analyses were used to test model robustness.

Results

TORS demonstrated a cost savings of $1366 and an increase of 0.25 quality‐adjusted life years (QALYs) per case in comparison to (chemo)radiotherapy. TORS was sensitive to variations in adjuvant therapy, costs, utilities, complications, and recurrence rates in deterministic and probabilistic sensitivity analysis. In two‐way sensitivity analysis, with increasing adjuvant therapy for TORS and decreasing concurrent chemotherapy for radiotherapy, TORS is decreasingly cost‐effective.

Conclusion

TORS is cost‐effective for treatment of early oropharyngeal cancer. Case selection to minimize adjuvant therapy ensures cost‐effective treatment. © 2015 Wiley Periodicals, Inc. Head Neck 38: 589–600, 2016
Collision tumors of the thyroid: A case report and review of the literature
Authors: Ryan Neil , Walkden Graham , Lazic Darko , Tierney Paul
Published: December 2014

Background

Collision tumors of the thyroid are a rare pathology that present a diagnostic and treatment challenge. In this report, we present an interesting case and a review of the current literature as to inform management.

Methods and Results

An 88‐year‐old woman presented with acute airway compromise and vocal cord paralysis. CT identified a thyroid mass and widespread metastasis. Histopathology identified the lesion as a collision tumor consisting of a squamous cell carcinoma (SCC) and papillary thyroid carcinoma. The patient was managed with surgery and palliative radiotherapy. However, she died from complications of a lower respiratory tract infection. We also present a review of the literature with 33 cases reviewed.

Conclusion

Management of collision tumors is complex because of the duality of the pathology. They should be managed in a multidisciplinary team setting and treatment should be patient specific. Generally, the most aggressive neoplasm should guide treatment. We recommend surgical management with adjunct therapy. © 2015 Wiley Periodicals, Inc. Head Neck 37: E125–E129, 2015
Oncologic outcome of hypopharyngeal carcinoma treated with different modalities at 2 different university hospitals
Authors: Bussu Francesco , Mura Federica , Miccichè Francesco , Bertino Giulia , Occhini Antonio , Almadori Giovanni , Galli Jacopo , Pandolfini Manlio , Gallus Roberto , Autorino Rosa , Guidi Maria Lavinia , Dinapoli Nicola , Valentini Vincenzo , Paludetti Gaetano , Benazzo Marco
Published: December 2014

Background

The hypopharynx is the site with the worst prognosis among head and neck squamous cell carcinomas (SCCs). The purpose of this study was to evaluate the oncologic outcomes of hypopharyngeal SCCs to identify the major clinical predictive factors and to compare the different primary therapeutic modalities.

Methods

The medical records of 123 consecutive patients diagnosed with primary resectable hypopharyngeal SCC were reviewed. The correlations of oncologic endpoints with tumor parameters and primary treatment were evaluated.

Results

The overall survival (OS) rate was 76% and the disease‐specific survival (DSS) rate was 80% at 3 years in the entire group. Sex and T and N classifications significantly influenced survival in both univariate and multivariate analyses. Seventy‐four percent of our patients underwent both surgery and radiotherapy (RT), and the temporal sequence of the 2 modalities did not affect prognosis.

Conclusion

The primary treatment modality in patients with resectable hypopharyngeal SCC did not affect prognosis in univariate and multivariate analyses for any stage considered. © 2015 Wiley Periodicals, Inc. Head Neck 38: 606–612, 2016
Dysregulated iron homeostasis is strongly associated with multiorgan failure and early mortality in acute‐on‐chronic liver failure
Authors: Maras Jaswinder Singh , Maiwall Rakhi , Harsha H.C. , Das Sukanta , Hussain Md.Shabir , Kumar Chandan , Bihari Chhagan , Rastogi Archana , Kumar Manoj , Trehanpati Nirupama , Sharma Shvetank , Pandey Akhilesh , Sarin Shiv Kumar
Published: December 2014

Acute‐on‐chronic liver failure (ACLF) is an ailment with high incidence of multiorgan failure (MOF) and consequent mortality. Dysregulated iron homeostasis and macrophage dysfunction are linked to increased incidence of MOF. We investigated whether a panel of circulating iron‐regulating proteins are associated with development of MOF and can predict 15‐ or 30‐day mortality in ACLF patients. One hundred twenty patients with ACLF, 20 patients with compensated cirrhosis, and 20 healthy controls were studied. Relative protein expression profiling was performed in the derivative cohort and confirmed in the validation cohort. A panel of iron regulators and indices were determined. Multiparametric flow cytometry for quantitation of labile iron pool (LIP) was performed. Validation studies confirmed lower serum transferrin (Tf) and ceruloplasmin levels in ACLF and ACLF‐MOF, compared to patients with cirrhosis and controls (P < 0.01). Serum iron and ferritin levels were markedly elevated (P < 0.001; P < 0.05) and hepcidin levels were lower (P < 0.001) in ACLF patients with MOF than those without and other groups (P < 0.001). Percentage Tf saturation (%SAT) was higher in ACLF‐MOF (39.2%; P < 0.001) and correlated with poor outcome (hazard ratio: 6.970; P < 0.01). Intracellular LIP indices were significantly elevated in the subsets of circulating macrophages in ACLF‐MOF, compared to other groups (P < 0.01). Whereas expression of iron‐regulatory genes was markedly down‐regulated, genes related to endoplasmic reticulum stress, apoptosis, and inflammation were up‐regulated in ACLF patients, compared to patients with cirrhosis. Severe dysregulation of autophagy mechanisms was also observed in the former. Conclusions: Iron metabolism and transport are severely deranged in ACLF patients and more so in those with MOF. %SAT, circulating hepcidin, and LIP in macrophages correlate with disease severity and %SAT could be used for early prognostication in ACLF patients. (Hepatology 2015;61:1306–1320)
Autoimmune hepatitis in a murine autoimmune polyendocrine syndrome type 1 model is directed against multiple autoantigens
Authors: Hardtke‐Wolenski Matthias , Taubert Richard , Noyan Fatih , Sievers Maren , Dywicki Janine , Schlue Jerome , Falk Christine S. , Ardesjö Lundgren Brita , Scott Hamish S. , Pich Andreas , Anderson Mark S. , Manns Michael P. , Jaeckel Elmar
Published: December 2014

Autoimmune polyendocrine syndrome type 1 (APS‐1) is caused by mutations of the autoimmune regulator (AIRE) gene. Mouse studies have shown that this results in defective negative selection of T cells and defective early seeding of peripheral organs with regulatory T cells (Tregs). Aire deficiency in humans and mice manifests as spontaneous autoimmunity against multiple organs, and 20% of patients develop an autoimmune hepatitis (AIH). To study AIH in APS‐1, we generated a murine model of human AIH on a BALB/c mouse background, in which Aire is truncated at exon 2. A subgroup of 24% of mice is affected by AIH, characterized by lymphoplasmacytic and periportal hepatic infiltrates, autoantibodies, elevated aminotransferases, and a chronic and progressive course of disease. Disease manifestation was dependent on specific Aire mutations and the genetic background of the mice. Though intrahepatic Treg numbers were increased and hyperproliferative, the intrahepatic CD4/CD8 ratio was decreased. The targets of the adaptive autoimmune response were polyspecific and not focussed on essential autoantigens, as described for other APS‐1‐related autoimmune diseases. The AIH could be treated with prednisolone or adoptive transfer of polyspecific Tregs. Conclusion: Development of AIH in APS‐1 is dependent on specific Aire mutations and genetic background genes. Autoimmune response is polyspecific and can be controlled by steroids or transfer with Tregs. This might enable new treatment options for patients with AIH. (Hepatology 2015;61:1295–1305)
Surviving mossy cells enlarge and receive more excitatory synaptic input in a mouse model of temporal lobe epilepsy
Authors: Zhang Wei , Thamattoor Ajoy K. , LeRoy Christopher , Buckmaster Paul S.
Published: December 2014

Numerous hypotheses of temporal lobe epileptogenesis have been proposed, and several involve hippocampal mossy cells. Building on previous hypotheses we sought to test the possibility that after epileptogenic injuries surviving mossy cells develop into super‐connected seizure‐generating hub cells. If so, they might require more cellular machinery and consequently have larger somata, elongate their dendrites to receive more synaptic input, and display higher frequencies of miniature excitatory synaptic currents (mEPSCs). To test these possibilities pilocarpine‐treated mice were evaluated using GluR2‐immunocytochemistry, whole‐cell recording, and biocytin‐labeling. Epileptic pilocarpine‐treated mice displayed substantial loss of GluR2‐positive hilar neurons. Somata of surviving neurons were 1.4‐times larger than in controls. Biocytin‐labeled mossy cells also were larger in epileptic mice, but dendritic length per cell was not significantly different. The average frequency of mEPSCs of mossy cells recorded in the presence of tetrodotoxin and bicuculline was 3.2‐times higher in epileptic pilocarpine‐treated mice as compared to controls. Other parameters of mEPSCs were similar in both groups. Average input resistance of mossy cells in epileptic mice was reduced to 63% of controls, which is consistent with larger somata and would tend to make surviving mossy cells less excitable. Other intrinsic physiological characteristics examined were similar in both groups. Increased excitatory synaptic input is consistent with the hypothesis that surviving mossy cells develop into aberrantly super‐connected seizure‐generating hub cells, and soma hypertrophy is indirectly consistent with the possibility of axon sprouting. However, no obvious evidence of hyperexcitable intrinsic physiology was found. Furthermore, similar hypertrophy and hyper‐connectivity has been reported for other neuron types in the dentate gyrus, suggesting mossy cells are not unique in this regard. Thus, findings of the present study reveal epilepsy‐related changes in mossy cell anatomy and synaptic input but do not strongly support the hypothesis that mossy cells develop into seizure‐generating hub cells. © 2014 Wiley Periodicals, Inc.
Low‐intensity daily walking activity is associated with hippocampal volume in older adults
Authors: Varma Vijay R. , Chuang Yi‐Fang , Harris Gregory C. , Tan Erwin J. , Carlson Michelle C.
Published: December 2014

Hippocampal atrophy is associated with memory impairment and dementia and serves as a key biomarker in the preclinical stages of Alzheimer's disease. Physical activity, one of the most promising behavioral interventions to prevent or delay cognitive decline, has been shown to be associated with hippocampal volume; specifically increased aerobic activity and fitness may have a positive effect on the size of the hippocampus. The majority of older adults, however, are sedentary and have difficulty initiating and maintaining exercise programs. A modestly more active lifestyle may nonetheless be beneficial. This study explored whether greater objectively measured daily walking activity was associated with larger hippocampal volume. We additionally explored whether greater low‐intensity walking activity, which may be related to leisure‐time physical, functional, and social activities, was associated with larger hippocampal volume independent of exercise and higher‐intensity walking activity. Segmentation of hippocampal volumes was performed using Functional Magnetic Resonance Imaging of the Brain's Software Library (FSL), and daily walking activity was assessed using a step activity monitor on 92, nondemented, older adult participants. After controlling for age, education, body mass index, cardiovascular disease risk factors, and the Mini Mental State Exam, we found that a greater amount, duration, and frequency of total daily walking activity were each associated with larger hippocampal volume among older women, but not among men. These relationships were specific to hippocampal volume, compared with the thalamus, used as a control brain region, and remained significant for low‐intensity walking activity, independent of moderate‐ to vigorous‐intensity activity and self‐reported exercise. This is the first study, to our knowledge, to explore the relationship between objectively measured daily walking activity and hippocampal volume in an older adult population. Findings suggest the importance of examining whether increasing nonexercise, lifestyle physical activities may produce measurable cognitive benefits and affect hippocampal volume through molecular pathways unique to those related to moderate‐intensity exercise. © 2014 Wiley Periodicals, Inc.
Hippocampus, delay discounting, and vicarious trial‐and‐error
Authors: Bett David , Murdoch Lauren H. , Wood Emma R. , Dudchenko Paul A.
Published: December 2014

In decision‐making, an immediate reward is usually preferred to a delayed reward, even if the latter is larger. We tested whether the hippocampus is necessary for this form of temporal discounting, and for vicarious trial‐and‐error at the decision point. Rats were trained on a recently developed, adjustable delay‐discounting task (Papale et al. (2012) Cogn Affect Behav Neurosci 12:513–526), which featured a choice between a small, nearly immediate reward, and a larger, delayed reward. Rats then received either hippocampus or sham lesions. Animals with hippocampus lesions adjusted the delay for the larger reward to a level similar to that of sham‐lesioned animals, suggesting a similar valuation capacity. However, the hippocampus lesion group spent significantly longer investigating the small and large rewards in the first part of the sessions, and were less sensitive to changes in the amount of reward in the large reward maze arm. Both sham‐ and hippocampus‐lesioned rats showed a greater amount of vicarious trial‐and‐error on trials in which the delay was adjusted. In a nonadjusting version of the delay discounting task, animals with hippocampus lesions showed more variability in their preference for a larger reward that was delayed by 10 s compared with sham‐lesioned animals. To verify the lesion behaviorally, rat were subsequently trained on a water maze task, and rats with hippocampus lesions were significantly impaired compared with sham‐lesioned animals. The findings on the delay discounting tasks suggest that damage to the hippocampus may impair the detection of reward magnitude. © 2014 Wiley Periodicals, Inc.
Modelling and assessment of hydrological changes in a developing urban catchment
Authors: Guan Mingfu , Sillanpää Nora , Koivusalo Harri
Published: December 2014

Urbanization strongly changes natural catchment by increasing impervious coverage and by creating a need for efficient drainage systems. Such land cover changes lead to more rapid hydrological response to storms and change distribution of peak and low flows. This study aims to explore and assess how gradual hydrological changes occur during urban development from rural area to a medium‐density residential catchment. The Stormwater Management Model (SWMM) is utilized to simulate a series of scenarios in a same developing urban catchment. Sub‐hourly hydro‐meteorological data in warm season is used to calibrate and validate the model in the fully developed catchment in 2006. The validated model is then applied to other cases in development stage and runoff management scenarios. Based on the simulations and observations, three key problems are solved: (1) how catchment hydrology changes with land cover change, (2) how urban development changes pre‐development flows, and (3) how stormwater management techniques affect catchment hydrology. The results show that the low‐frequency flow rates had remarkably increased from 2004 to 2006 along with the increase of impervious areas. Urbanization in the residential catchment expands the runoff contributing area, accelerates hydrological response, raises peak flows in an order of magnitude of over 10, and more than doubles the total runoff volume. The effects of several LID controls on runoff hydrograph were simulated, and the techniques were able to reduce flows towards the pre‐development levels. However, the partly restored flow regime was still clearly changed in comparison to the pre‐development flow conditions. Copyright © 2014 John Wiley & Sons, Ltd.
Conceptual modelling to assess how the interplay of hydrological connectivity, catchment storage and tracer dynamics controls nonstationary water age estimates
Authors: Birkel Christian , Soulsby Chris , Tetzlaff Doerthe
Published: December 2014

Although catchment storage is an intrinsic control on the rainfall–runoff response of streams, direct measurement remains a major challenge. Coupled models that integrate long‐term hydrometric and isotope tracer data are useful tools that can provide insights into the dynamics of catchment storage and the volumes of water involved. In this study, we use a tracer‐aided hydrological model to characterize catchment storage as a dynamic control on system function related to streamflow generation, which also allows direct estimation of the nonstationarity of water ages. We show that in a wet Scottish upland catchment dominated by runoff generation from riparian peats (histosols) with high water storage, nonstationarity in water age distributions is only clearly detectable during more extreme wet and dry periods. This is explained by the frequency and longevity of hydrological connectivity and the associated relative importance of flow paths contributing younger or older waters to the stream. Generally, these saturated riparian soils represent large mixing zones that buffer the time variance of water age and integrate catchment‐scale partial mixing processes. Although storage simulations depend on model performance, which is influenced by input variability and the degree of isotopic damping in the stream, a longer‐term storage analysis of this model indicates a system that is only sensitive to more extreme hydroclimatic variability. Copyright © 2014 John Wiley & Sons, Ltd.
CD24 activates the NLRP3 inflammasome through c‐Src kinase activity in a model of the lining epithelium of inflamed periodontal tissues
Authors: Guo Wei , Ye Ping , Yu Hong , Liu Zhonghao , Yang Pishan , Hunter Neil
Published: December 2014

Chronic periodontitis is characterized by perturbation of the epithelial attachment to the tooth with subsequent migration of the lining epithelium and formation of a cleft or pocket. This non‐keratinized lining epithelium provides initial responses to bacterial products by signalling through receptors of innate immunity to activate inflammasome pathways. These comprise an intracellular network of regulatory and effector molecules leading to synthesis and activation of pro‐inflammatory cytokines. Conversely, CD24 is characteristically strongly expressed by the pocket epithelium and is reported to function as an important negative regulator for danger signals, protecting tissues from excessive leukocyte activity. The objective of the study was to determine the impact of ligation of CD24 on expression of inflammasome components. An epithelial mimic of pocket epithelium was used to evaluate activation of the NLRP3 inflammasome pathway. Surprisingly, antibody ligation of CD24 enhanced expression of NLRP3 together with co‐activators ASC and caspase‐1 resulting in burst release of activated interleukin (IL)‐18. Potent product inhibition was detected with IL‐18 suppressing expression of NLRP3, ASC, and caspase‐1. Scant distribution of these products within pocket epithelium compared with healthy gingival attachment provided indication of potential cycling of NLRP3 inflammasome expression. As subjects with mild chronic periodontitis have increased titres of serum antibodies auto‐reactive with CD24 compared with those of subjects with severe periodontitis, a molecular mechanism for regulated expression of the NLRP3 inflammasome mediated by c‐Src kinase activity, is proposed. This pathway could be regionally disrupted by products of pathogenic bacteria with profound downregulation in the dysbiosis associated with severe disease.
Factors influencing ovulation and the risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers
Authors: Kotsopoulos Joanne , Lubinski Jan , Gronwald Jacek , Cybulski Cezary , Demsky Rochelle , Neuhausen Susan L. , Kim‐Sing Charmaine , Tung Nadine , Friedman Susan , Senter Leigha , Weitzel Jeffrey , Karlan Beth , Moller Pal , Sun Ping , Narod Steven A. ,   the Hereditary Breast Cancer Clinical Study Group
Published: December 2014

The role of the lifetime number of ovulatory cycles has not been evaluated in the context of BRCA‐associated ovarian cancer. Thus, we conducted a matched case–control study to evaluate the relationship between the cumulative number of ovulatory cycles (and contributing components) and risk of developing ovarian cancer in BRCA mutation carriers (1,329 cases and 5,267 controls). Information regarding reproductive and hormonal factors was collected from a routinely administered questionnaire. Conditional logistic regression was used to evaluate all associations. We observed a 45% reduction in the risk of developing ovarian cancer among women in the lowest vs. highest quartile of ovulatory cycles (OR = 0.55; 95% CI 0.41–0.75, p = 0.0001). Breastfeeding for more than 12 months was associated with a 38% (95% CI 0.48–0.79) and 50% (95% CI 0.29–0.84) reduction in risk among BRCA1 and BRCA2 mutation carriers, respectively. For oral contraceptive use, maximum benefit was seen with five or more years of use among BRCA1 mutation carriers (OR = 0.50; 95% CI 0.40–0.63) and three or more years for BRCA2 mutation carriers (OR = 0.42; 95% CI 0.22–0.83). Increasing parity was associated with a significant inverse trend among BRCA1 (OR = 0.87; 95% CI 0.79–0.96; p‐trend = 0.005) but not BRCA2 mutation carriers (OR 0.98; 95% CI 0.81–1.19; p‐trend = 0.85). A later age at menopause was associated with an increased risk in women with a BRCA1 mutation (OR trend = 1.18; 95% CI 1.03–1.35; p = 0.02). These findings support an important role of breastfeeding and oral contraceptive use for the primary prevention of ovarian cancer among women carrying BRCA mutations.
Early pregnancy IGF‐I and placental GH and risk of epithelial ovarian cancer: A nested case‐control study
Authors: Schock Helena , Fortner Renée T. , Surcel Heljä‐Marja , Grankvist Kjell , Pukkala Eero , Lehtinen Matti , Lundin Eva
Published: December 2014

Insulin‐like growth factor‐I (IGF‐I) signaling may promote ovarian tumor development by exerting mitotic, antiapoptotic and proangiogenic effects. During pregnancy, maternal production of IGF‐I is regulated by placental growth hormone (GH). Parity is an established protective factor for ovarian cancer, however, no prior study has evaluated placental GH and IGF‐I in pregnancy and epithelial ovarian cancer (EOC). Prior prospective studies on the association between IGF‐I and EOC in nonpregnant populations were inconclusive and did not address associations in subtypes of EOC. Among members of the Finnish Maternity Cohort and the Northern Sweden Maternity Cohort, we identified 1,045 EOC cases, diagnosed after recruitment (1975–2008) and before March 2011 and 2,658 individually matched controls. Placental GH and IGF‐I were measured in serum from the last pregnancy before EOC diagnosis or selection as control. We used conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for tertiles and a doubling of hormone concentrations. Higher IGF‐I was associated with a nonsignificant decrease in risk for invasive [ORT3 vs. T1: 0.79 (0.62–1.02); ptrend = 0.07] and endometrioid tumors [ORT3 vs. T1: 0.55 (0.28–1.07); ptrend = 0.07]. The protective association between higher IGF‐I levels and risk of invasive EOC was stronger in analyses limited to women aged <55 years at diagnosis [ORT3 vs. T1: 0.74 (0.57–0.96); ptrend = 0.03]. Our study provides the first data on placental GH and IGF‐I in pregnancy and EOC risk overall and by subtype. Our data suggest higher IGF‐I levels in pregnancy may be associated with lower risk of invasive and endometrioid EOC.