bluuebunny/crossref_metadata_2025 huggingface dataset:
Computational homogenization of liquid‐phase sintering based on a mixed variational format
Authors: Öhman Mikael , Larsson Fredrik , Runesson Kenneth
Published: November 2016

In this paper a mixed velocity‐pressure variational formulation is adopted for the subscale modeling of sintering stemming from micropores with surface tension. The macroscopic response is obtained from variationally consistent homogenization. As to the driving force for sintering, the model framework allows for a non‐spherical sintering stress, derived via the homogenization procedure, which contrasts traditional macroscopic modeling. The proposed method can seamlessly handle the transition from macroscopically compressible to incompressible response.

For the Representative Volume Elements (RVEs) the weakly periodic, Neumann, and Dirichlet type boundary conditions are established, and it is shown that the Hill‐Mandel condition is satisfied. The numerical examples show the transient behavior of a 2D unit‐cell subjected to free sintering. Effective macroscale properties pertinent to different boundary conditions are compared for a 3D microstructure. (© 2016 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
The role of the pallidothalamic fibre tracts in deep brain stimulation for dystonia: A diffusion MRI tractography study
Authors: Rozanski Verena Eveline , da Silva Nadia Moreira , Ahmadi Seyed‐Ahmad , Mehrkens Jan , da Silva Cunha Joao , Houde Jean‐Christophe , Vollmar Christian , Bötzel Kai , Descoteaux Maxime
Published: November 2016

Background

Deep Brain Stimulation (DBS) of the Globus pallidus internus (GPi) is gold standard treatment in medically refractory dystonia. Recent evidence indicates that stimulation effects are also due to axonal modulation and affection of a fibre network. For the GPi, the pallidothalamic tracts are known to be the major motor efferent pathways. The aim of this study is to explore the anatomic vicinity of these tracts and DBS electrodes in dystonia applying diffusion tractography.

Methods

Diffusion MRI was acquired in ten patients presenting for DBS for dystonia. We applied both a conventionally used probabilistic tractography algorithm (FSL) as well as a probabilistic streamline tracking approach, based on constrained spherical deconvolution and particle filtering with anatomic priors, to the datasets. DBS electrodes were coregistered to the diffusion datasets.

Results

We were able to delineate the pallidothalamic tracts in all patients. Using the streamline approach, we were able to distinguish between the two sub‐components of the tracts, the ansa lenticularis and the fasciculus lenticularis. Clinically efficient DBS electrodes displayed a close anatomic vicinity pathway of the pallidothalamic tracts, and their course was consistent with previous tracer labelling studies. Although we present only anatomic data, we interpret these findings as evidence of the possible involvement of fibre tracts to the clinical effect in DBS. Electrophysiological intraoperative recordings would be needed to complement our findings. In the future, a clear and individual delineation of the pallidothalamic tracts could optimize the stereotactic process of optimal electrode localization. Hum Brain Mapp 38:1224–1232, 2017. © 2016 Wiley Periodicals, Inc.
Multiple‐region directed functional connectivity based on phase delays
Authors: Goelman Gadi , Dan Rotem
Published: November 2016

Network analysis is increasingly advancing the field of neuroimaging. Neural networks are generally constructed from pairwise interactions with an assumption of linear relations between them. Here, a high‐order statistical framework to calculate directed functional connectivity among multiple regions, using wavelet analysis and spectral coherence has been presented. The mathematical expression for 4 regions was derived and used to characterize a quartet of regions as a linear, combined (nonlinear), or disconnected network. Phase delays between regions were used to obtain network's temporal hierarchy and directionality. The validity of the mathematical derivation along with the effects of coupling strength and noise on its outcomes were studied by computer simulations of the Kuramoto model. The simulations demonstrated correct directionality for a large range of coupling strength and low sensitivity to Gaussian noise compared with pairwise coherences. The analysis was applied to resting‐state fMRI data of 40 healthy young subjects to characterize the ventral visual system, motor system and default mode network (DMN). It was shown that the ventral visual system was predominantly composed of linear networks while the motor system and the DMN were composed of combined (nonlinear) networks. The ventral visual system exhibits its known temporal hierarchy, the motor system exhibits center ↔ out hierarchy and the DMN has dorsal ↔ ventral and anterior ↔ posterior organizations. The analysis can be applied in different disciplines such as seismology, or economy and in a variety of brain data including stimulus‐driven fMRI, electrophysiology, EEG, and MEG, thus open new horizons in brain research. Hum Brain Mapp 38:1374–1386, 2016. © 2016 Wiley Periodicals, Inc.
Serotonergic modulation of orbitofrontal activity and its relevance for decision making and impulsivity
Authors: Mavrogiorgou Paraskevi , Enzi Björn , Klimm Ann‐Kristin , Köhler Elke , Roser Patrik , Norra Christine , Juckel Georg
Published: November 2016

Background

The orbitofrontal cortex seems to play a crucial role in reward‐guided learning and decision making, especially for impulsive choice procedures including delayed reward discounting. The central serotonergic system is closely involved in the regulation of impulsivity, but how the serotonergic firing rate and release, best investigated by the loudness dependence of auditory evoked potentials (LDAEP), interact with orbitofrontal activity is still unknown.

Methods

Twenty healthy volunteers (11 males, 9 females, 31.3 ± 10.6 years old) were studied in a 3T MRI scanner (Philips, Hamburg, Germany) during a delay discounting task, after their LDAEP was recorded using a 32 electrodes EEG machine (Brain Products, Munich, Germany).

Results

Significant positive correlations were only found between the LDAEP and the medial orbitofrontal part of the superior frontal gyrus (SFG/MO) [Δ immediate reward – delayed reward] for the right (r = 0.519; P = 0.019) and left side (r = 0.478; P = 0.033). This relationship was stronger for females compared with males. Orbitofrontal activity was also related to the Barratt Impulsivity Scale.

Conclusions

This study revealed that low serotonergic activity as measured by a strong LDAEP was related to a high fMRI signal intensity of SFG/MO during immediate reward behavior which is related to impulsivity. Since this relationship was only found for the infralimbic medial and not for the middle or lateral part of the orbitofrontal cortex, an exclusive projection tract of the serotonergic system to this cortical region can be assumed to regulate impulsive reward‐orientated decision making. Hum Brain Mapp 38:1507–1517, 2017. © 2016 Wiley Periodicals, Inc.
Mutual epithelium‐macrophage dependency in liver carcinogenesis mediated by ST18
Authors: Ravà Micol , D'Andrea Aleco , Doni Mirko , Kress Theresia R. , Ostuni Renato , Bianchi Valerio , Morelli Marco J. , Collino Agnese , Ghisletti Serena , Nicoli Paola , Recordati Camilla , Iascone Maria , Sonzogni Aurelio , D'Antiga Lorenzo , Shukla Ruchi , Faulkner Geoffrey J. , Natoli Gioacchino , Campaner Stefano , Amati Bruno
Published: November 2016

The ST18 gene has been proposed to act either as a tumor suppressor or as an oncogene in different human cancers, but direct evidence for its role in tumorigenesis has been lacking thus far. Here, we demonstrate that ST18 is critical for tumor progression and maintenance in a mouse model of liver cancer, based on oncogenic transformation and adoptive transfer of primary precursor cells (hepatoblasts). ST18 messenger RNA (mRNA) and protein were detectable neither in normal liver nor in cultured hepatoblasts, but were readily expressed after subcutaneous engraftment and tumor growth. ST18 expression in liver cells was induced by inflammatory cues, including acute or chronic inflammation in vivo, as well as coculture with macrophages in vitro. Knocking down the ST18 mRNA in transplanted hepatoblasts delayed tumor progression. Induction of ST18 knockdown in pre‐established tumors caused rapid tumor involution associated with pervasive morphological changes, proliferative arrest, and apoptosis in tumor cells, as well as depletion of tumor‐associated macrophages, vascular ectasia, and hemorrhage. Reciprocally, systemic depletion of macrophages in recipient animals had very similar phenotypic consequences, impairing either tumor development or maintenance, and suppressing ST18 expression in hepatoblasts. Finally, RNA sequencing of ST18‐depleted tumors before involution revealed down‐regulation of inflammatory response genes, pointing to the suppression of nuclear factor kappa B–dependent transcription. Conclusion: ST18 expression in epithelial cells is induced by tumor‐associated macrophages, contributing to the reciprocal feed‐forward loop between both cell types in liver tumorigenesis. Our findings warrant the exploration of means to interfere with ST18‐dependent epithelium–macrophage interactions in a therapeutic setting. (Hepatology 2017;65:1708‐1719).
Associations between adherence to the World Cancer Research Fund/American Institute for Cancer Research cancer prevention recommendations and biomarkers of inflammation, hormonal, and insulin response
Authors: Tabung Fred K. , Fung Teresa T. , Chavarro Jorge E. , Smith‐Warner Stephanie A. , Willett Walter C. , Giovannucci Edward L.
Published: November 2016

Adherence to the 2007 WCRF/AICR cancer prevention recommendations has been associated with lower cancer risk but the underlying biological mechanisms have not been elucidated. We utilized dietary and lifestyle data from 11,342 women in the Nurses' Health Study and 8,136 men in the Health Professionals Follow‐up Study, to investigate associations between adherence scores and markers of inflammation, hormonal and insulin response. Two scores ranging from 0 to 3 were constructed to assess adherence to the energy balance‐related recommendations (weight management, physical activity, energy density); and the plant, animal foods and alcohol intake recommendations; with higher scores indicating greater adherence. The following biomarkers were assessed in plasma samples donated by chronic disease‐free women (1990) and men (1994): C‐reactive protein (CRP), interleukin (IL)−6, tumor necrosis factor (TNF)‐α receptor 2 (TNFαR2) and adiponectin for inflammation; estrone and estradiol for hormonal response in women, C‐peptide for hyperinsulinemia; and triglycerides/high density lipoprotein‐cholesterol (TG/HDL) ratio for insulin resistance. In multivariable‐adjusted linear regression analyses, we estimated relative concentrations of biomarkers across adherence categories. There was a significant trend of lower (higher for adiponectin) biomarker concentrations with higher adherence to the energy balance recommendations (all p trend <0.0001). Comparing the highest (3) to the lowest recommendation category (0–1), the percent difference in relative concentrations of biomarkers was CRP, −69%; IL6, −41%; TNFαR2, −13%; adiponectin, +36%; C‐peptide, −43%; TG/HDL, −43%; estrone, −31%; and estradiol, −43%; in women; and CRP, −59%; IL6, −42%; TNFαR2, −10%; adiponectin, +22%; C‐peptide, −44%; and TG/HDL, −40%; in men. In contrast, associations between adherence to the plant, animal foods and alcohol intake recommendations and biomarker concentrations were weaker, and mostly nonsignificant. The healthier biomarker profile associated with greater adherence to the WCRF/AICR cancer prevention recommendations is driven mainly by adherence to the energy balance‐related recommendations.
Antiglioma effects of N6‐isopentenyladenosine, an endogenous isoprenoid end product, through the downregulation of epidermal growth factor receptor
Authors: Ciaglia Elena , Abate Mario , Laezza Chiara , Pisanti Simona , Vitale Mario , Seneca Vincenzo , Torelli Giovanni , Franceschelli Silvia , Catapano Giuseppe , Gazzerro Patrizia , Bifulco Maurizio
Published: November 2016

Malignant gliomas are highly dependent on the isoprenoid pathway for the synthesis of lipid moieties critical for cell proliferation. The isoprenoid derivative N6‐isopentenyladenosine (iPA) displays pleiotropic biological effects, including a direct anti‐tumor activity in several tumor models. The antiglioma effects of iPA was then explored in U87MG cells both in vitro and grafted in mice and the related molecular mechanism confirmed in primary derived patients' glioma cells. iPA powerfully inhibited tumor cell growth and induced caspase‐dependent apoptosis through a mechanism involving a marked accumulation of the pro‐apoptotic BIM protein and inhibition of EGFR. Indeed, activating AMPK following conversion into its iPAMP active form, iPA stimulated EGFR phosphorylation and ubiquitination along a proteasome‐mediated pathway which was responsible for receptor degradation and its downstream signaling pathways inhibition, including the STAT3, ERK and AKT cascade. The inhibition of AMPK by compound C prevented iPA‐mediated phosphorylation of EGFR, known to precede receptor loss. As expected the block of EGFR degradation, by exposure to the proteasome inhibitor MG132, significantly reduced iPA‐induced cell death. Given the importance of receptor degradation in iPA‐mediated cytotoxicity, we also documented that the EGFR expression levels in a panel of primary glioma cells confers them a high sensitivity to iPA treatment. In conclusion our study provides the first evidence of iPA antiglioma effect. Indeed, as glioma is driven by aberrant signaling of growth factor receptors, particularly the EGFR, iPA, alone or in association with EGFR targeted therapies, might be a promising therapeutic tool to achieve a potent anti‐tumoral effect.
Cost‐effectiveness of the Norwegian breast cancer screening program
Authors: van Luijt P.A. , Heijnsdijk E.A.M. , de Koning H.J.
Published: November 2016

The Norwegian Breast Cancer Screening Programme (NBCSP) has a nation‐wide coverage since 2005. All women aged 50–69 years are invited biennially for mammography screening. We evaluated breast cancer mortality reduction and performed a cost‐effectiveness analysis, using our microsimulation model, calibrated to most recent data. The microsimulation model allows for the comparison of mortality and costs between a (hypothetical) situation without screening and a situation with screening. Breast cancer incidence in Norway had a steep increase in the early 1990s. We calibrated the model to simulate this increase and included recent costs for screening, diagnosis and treatment of breast cancer and travel and productivity loss. We estimate a 16% breast cancer mortality reduction for a cohort of women, invited to screening, followed over their complete lifetime. Cost‐effectiveness is estimated at NOK 112,162 per QALY gained, when taking only direct medical costs into account (the cost of the buses, examinations, and invitations). We used a 3.5% annual discount rate. Cost‐effectiveness estimates are substantially below the threshold of NOK 1,926,366 as recommended by the WHO guidelines. For the Norwegian population, which has been gradually exposed to screening, breast cancer mortality reduction for women exposed to screening is increasing and is estimated to rise to ∼30% in 2020 for women aged 55–80 years. The NBCSP is a highly cost‐effective measure to reduce breast cancer specific mortality. We estimate a breast cancer specific mortality reduction of 16–30%, at the cost of 112,162 NOK per QALY gained.
Cardiac glycosides and breast cancer risk: A systematic review and meta‐analysis of observational studies
Authors: Karasneh Reema A. , Murray Liam J. , Cardwell Chris R.
Published: November 2016

Cardiac glycosides are phytoestrogens and have been linked to the risk of estrogen sensitive cancers such as uterus cancer. However, the association between use of cardiac glycosides and risk of breast cancer remains unclear. We investigated the association between cardiac glycosides use and the risk of breast cancer by systematically reviewing the published literature and performing meta‐analyses. A comprehensive literature search was performed using MEDLINE, EMBASE, Web of Science and SCOPUS to identify all relevant articles published up to November 2015. Risk estimates, and accompanying standard errors, for the association between cardiac glycoside use and breast cancer were extracted from identified studies. Meta‐analysis models were used to calculate a combined hazard ratio (HR), and 95% confidence interval (CI), and to investigate heterogeneity between studies. In total, nine studies were identified investigating cardiac glycosides use and risk of developing breast cancer. Overall, there was evidence to suggest an association between cardiac glycosides use and breast cancer risk (HR = 1.34; 95% CI 1.25, 1.44; p < 0.001) with little variation in the association between studies (I2 = 16%, p for heterogeneity = 0.30). Results were little altered when analysis was restricted to studies with high quality scores or cohort studies. Overall, there was a 34% increase in breast risk with use of cardiac glycosides but it is unclear whether this association reflects confounding or is causal. Further observational studies are required to examine this association particularly for estrogen receptor positive breast cancer and to explore the role of potential confounding variables.
In vivo biocompatibility, vascularization, and incorporation of Integra® dermal regenerative template and flowable wound matrix
Authors: Später Thomas , Frueh Florian S. , Metzger Wolfgang , Menger Michael D. , Laschke Matthias W.
Published: November 2016

Integra® matrix wound dressing (MWD) is used for the reconstruction of full‐thickness skin defects. For the treatment of complex wounds, this dermal substitute is available as a flowable wound matrix (FWM) of identical composition. To clarify whether variations in sample preparation and consistency affect the biocompatibility and tissue incorporation, we herein compared MWD and FWM. The matrices were characterized using scanning electron microscopy and histology. Moreover, they were implanted in mouse dorsal skinfold chambers to analyze their in vivo performance over 2 weeks. Scanning electron microscopy showed a planar surface of MWD whereas FWM presented an irregular, fissured morphology. However, histology of the two matrices revealed an identical fiber thickness, fiber length, and interfiber distance. Repetitive stereo‐microscopy and immunohistochemical analyses of MWD and FWM showed a comparable epithelialization of the implants in the dorsal skinfold chamber model. At day 14, both matrices exhibited a low collagen content and microvessel density. Moreover, they were infiltrated by a high number of myeloperoxidase (MPO)‐positive neutrophilic granulocytes and a lower number of MAC387‐positive macrophages and CD3‐positive lymphocytes. These findings demonstrate that differences in preparation and consistency do not affect the tissue response to MWD and FWM, indicating a comparable regenerative capacity in wound healing. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 52–60, 2018.
Gene Expression and Activity Profiling Reveal a Significant Contribution of Exo‐Phosphotransferases to the Extracellular Nucleotides Metabolism in HUVEC Endothelial Cells
Authors: Wujak Magdalena , Hetmann Anna , Porowińska Dorota , Roszek Katarzyna
Published: November 2016

Purinergic signaling maintains local tissue homeostasis in blood vessels via the regulation of vascular tone, blood platelet aggregation, cell proliferation, and differentiation as well as inflammatory responses. Extracellular purines are important signaling molecules in the vasculature, and both purine‐hydrolysing as well as ‐phosphorylating enzymes are considered to selectively govern extracellular nucleotide/nucleoside metabolism. Recent studies have provided some evidence for the existence of these enzymes in a soluble form in human blood and their secretion into the extracellular space under physiological and pathological conditions. However, the comprehensive analysis of endothelium‐derived enzymes involved in purine metabolic pathways has received no attention so far. In the presented study, in vitro cultured human umbilical vein endothelial cells (HUVEC) are shown to be an abundant source of exo‐nucleotidases comprising 5′‐nucleotidase (exo‐5′‐NT), and nucleoside triphosphate diphosphohydrolases (exo‐NTPDase) as well as phosphotransferases, represented by nucleoside diphosphate kinase (exo‐NDPK) and adenylate kinase (exo‐AK). An attempt is also made to demonstrate that, in contrast to the metabolic pattern determined on the endothelial cell surface, exo‐phosphorylating activities markedly predominate over exo‐hydrolytic ones. We present for the first time the expression profiles of genes encoding isoenzymes belonging to distinct nucleotide kinase and nucleotidase families. The genes encoding NDPK1, NDPK2, AK1, and AK2 phosphotransferases have been shown to be expressed at the highest level in HUVEC cells. The data indicate the coexistence of secreted and cell‐associated factors of endothelial origin mediating ATP‐consuming and ATP‐generating pathways with the predominance of exo‐phosphotransferases activity. The described enzymes contribute to the regulation of purinergic signal duration and extent in the venous vasculature. J. Cell. Biochem. 118: 1341–1348, 2017. © 2016 Wiley Periodicals, Inc.
Genome‐Wide Transcriptome Profiling of the Neoplastic Giant Cell Tumor of Bone Stromal Cells by RNA Sequencing
Authors: Lau Carol P.Y. , Kwok Jamie S.L. , Tsui Joseph C.C. , Huang Lin , Yang Kevin Y. , Tsui Stephen K.W. , Kumta Shekhar Madhukar
Published: November 2016

Giant cell tumor of bone (GCTB) is the most common non‐malignant primary bone tumor reported in Hong Kong. Failure of treatment in advanced GCTB with aggressive local recurrence remains a clinical challenge. In order to reveal the molecular mechanism underlying the pathogenesis of this tumor, we aimed to examine the transcriptome profiling of the neoplastic stromal cells of GCTB in this study. RNA‐sequencing was performed on three GCTB stromal cell samples and one bone marrow‐derived MSC sample and 174 differentially expressed genes (DEGs) were identified between these two cell types. The top five up‐regulated genes are SPP1, F3, TSPAN12, MMP13, and LGALS3BP and further validated by qPCR and Western Blotting. Knockdown of SPP1 was found to induce RUNX2 and OPG expression in GCTB stromal cells but not the MSCs. Ingenuity pathway analysis (IPA) of the 174 DEGs revealed significant alternations in 23 pathways; variant calling analysis revealed 1915 somatic variants of 384 genes with high or moderate impacts. Interestingly, four canonical pathways were found overlapping in both analyses; from which VEGFA, CSF1, PLAUR, and F3 genes with somatic mutation were found up‐regulated in GCTB stromal cells. The STRING diagram showed two main clusters of the DEGs; one cluster of histone genes that are down‐regulated in GCTB samples and another related to osteoblast differentiation, angiogenesis, cell cycle progression, and tumor growth. The DEGs and somatic mutations found in our study warrant further investigation and validation, nevertheless, our study add new insights in the search for new therapeutic targets in treating GCTB. J. Cell. Biochem. 118: 1349–1360, 2017. © 2016 Wiley Periodicals, Inc.
The “Mechanostat” Principle and the Osteoprotegerin—OPG/RANKL/RANK System PART II. The Role of the Hypothalamic—Pituitary Axis
Authors: Tyrovola Joanna B.
Published: November 2016

Recent literature provides us with the indication that the ratio of OPG/RANKL concentrations fluctuate in a non‐linear (bell‐shaped) mode, according to Frost's “mechanostat” theory, during the application of mechanical strain. A similar cellular signal transduction mechanism to mechanical loading, that may also regulate bone resorptive activities, has nowdays been proposed. Since the skeleton is considered to be an endocrine organ, as such, it may likewise be subject to hypothalamic control. This central regulatory system may continually modulate the adaptation of the bone homeostatic system to external challenges. The hypothalamic‐pituitary‐gonadal axis may play a role in the regulation of OPG/RANKL secretion. The “mechanostat” principle may well characterize the oscillatory properties of the signal transduction mechanism that controls hard tissue metabolism and includes biochemical apart from mechanical stimuli. J. Cell. Biochem. 118: 962–966, 2017. © 2016 Wiley Periodicals, Inc.
Escalating Methamphetamine Regimen Induces Compensatory Mechanisms, Mitochondrial Biogenesis, and GDNF Expression, in Substantia Nigra
Authors: Valian Neda , Ahmadiani Abolhassan , Dargahi Leila
Published: November 2016

Methamphetamine (MA) produces long‐lasting deficits in dopaminergic neurons in the long‐term use via several neurotoxic mechanisms. The effects of MA on mitochondrial biogenesis is less studied currently. So, we evaluated the effects of repeated escalating MA regimen on transcriptional factors involved in mitochondrial biogenesis and glial‐derived neurotrophic factor (GDNF) expression in substantia nigra (SN) and striatum of rat. In male Wistar rats, increasing doses of MA (1–14 mg/kg) were administrated twice a day for 14 days. At the 1st, 14th, 28th, and 60th days after MA discontinuation, we measured the PGC1α, TFAM and NRF1 mRNA levels, indicator of mitochondrial biogenesis, and GDNF expression in SN and striatum. Furthermore, we evaluated the glial fibrillary acidic protein (GFAP) and Iba1 mRNA levels, and the levels of tyrosine hydroxylase (TH) and α‐synuclein (α‐syn) using immunohistochemistry and real‐time polymerase chain reaction (PCR). We detected increments in PGC1α and TFAM mRNA levels in SN, but not striatum, and elevations in GDNF levels in SN immediately after MA discontinuation. We also observed increases in GFAP and Iba1 mRNA levels in SN on day 1 and increases in Iba1 mRNA on days 1 and 14 in striatum. Data analysis revealed that the number of TH+ cells in the SN did not reduce in any time points, though TH mRNA levels was increased on day 1 after MA discontinuation in SN. These data show that repeated escalating MA induces several compensatory mechanisms, such as mitochondrial biogenesis and elevation in GDNF in SN. These mechanisms can reverse MA‐induced neuroinflammation and prevent TH‐immunoreactivity reduction in nigrostriatal pathway. J. Cell. Biochem. 118: 1369–1378, 2017. © 2016 Wiley Periodicals, Inc.
Molecular simulations to delineate functional conformational transitions in the HCV polymerase
Authors: Sesmero Ester , Brown Jodian A. , Thorpe Ian F.
Published: November 2016

Hepatitis C virus (HCV) is a global health concern for which there is no vaccine available. The HCV polymerase is responsible for the critical function of replicating the RNA genome of the virus. Transitions between at least two conformations (open and closed) are necessary to allow the enzyme to replicate RNA. In this study, molecular dynamic simulations were initiated from multiple crystal structures to understand the free energy landscape (FEL) explored by the enzyme as it interconverts between these conformations. Our studies reveal the location of distinct states within the FEL as well as the molecular interactions associated with these states. Specific hydrogen bonds appear to play a key role in modulating conformational transitions. This knowledge is essential to elucidate the role of these conformations in replication and may also be valuable in understanding the basis by which this enzyme is inhibited by small molecules. © 2016 Wiley Periodicals, Inc.
The role of different sampling methods in improving biological activity prediction using deep belief network
Authors: Ghasemi Fahimeh , Fassihi Afshin , Pérez‐Sánchez Horacio , Mehri Dehnavi Alireza
Published: November 2016

Thousands of molecules and descriptors are available for a medicinal chemist thanks to the technological advancements in different branches of chemistry. This fact as well as the correlation between them has raised new problems in quantitative structure activity relationship studies. Proper parameter initialization in statistical modeling has merged as another challenge in recent years. Random selection of parameters leads to poor performance of deep neural network (DNN). In this research, deep belief network (DBN) was applied to initialize DNNs. DBN is composed of some stacks of restricted Boltzmann machine, an energy‐based method that requires computing log likelihood gradient for all samples. Three different sampling approaches were suggested to solve this gradient. In this respect, the impact of DBN was applied based on the different sampling approaches mentioned above to initialize the DNN architecture in predicting biological activity of all fifteen Kaggle targets that contain more than 70k molecules. The same as other fields of processing research, the outputs of these models demonstrated significant superiority to that of DNN with random parameters. © 2016 Wiley Periodicals, Inc.
Synthesis, Enzyme Inhibition, and Molecular Docking Studies of Hydrazones from Dichlorophenylacetic Acids
Authors: Abid Obaid‐ur‐Rahman , Ayaz Muhammad , Rehman Wajid , Mehdi Kamran , Ali Arif , Wadood Abdul , Rahim Fazal , Sultan Aneesa , Ghufran Mehreen , Mir Sadullah , Qureshi Muhammad Tauseef
Published: November 2016

A series of hydrazones 5a–i were synthesized by the condensation of hydrazides derived from dichlorophenylacetic acids with different aromatic aldehydes and ketones. Their structures were confirmed by spectroscopic data and elemental analysis. Hydrazones 5a–i were evaluated for α‐glucosidase and urease inhibition activities. Five compounds exhibited potent α‐glucosidase inhibitory potential with IC50
values 8.5 ± 0.3, 22.2 ± 0.78, 32.9 ± 1.5, 34 ± 2.4, and 170.6 ± 7.5 μM, respectively, which are many times better than that of the standard inhibitor acarbose (IC50 = 840 ± 1.73 μM). Furthermore, molecular docking study was performed to explore the binding mode in the active sites of α‐glucosidase and urease enzymes.
A Novel Hyperbranched Phase Transporter for Extraction of Water‐soluble Dyes in Industrial Wastewater
Authors: Fan Zhen Zhong , Wang Ji Gang , Zhang Li Feng , Zhan Ning Ning , He Gui Jin
Published: November 2016

Methacrylated hyperbranched polyglycerol (HPG‐MA) is successfully synthesized through transesterification by controlling the ratio of HPG to glycidyl methacrylate (GMA). The concentration of the dye or phase transporter, temperature, contact time, and molecular weight of phase transporter were taken into consideration to evaluate the removal ratio and transfer capability. With malachite green optimized as a model dye, HPG‐MA could reach a maximum adsorption of 990 mg/g at the feed concentration of 1 g/L, and the removal ratio is 99% compared with ~20 h for other reported phase transporters, which indicates that HPG‐MA is a novel phase transporter. HPG‐MA can absorb dyes in aqueous solutions, which can be ascribed to the existence of a cavity structure and abundant ether groups. We believe that HPG‐MA can have potential applications in the removal of dyes from aqueous solutions due to its high adsorption capacity and eco‐friendly nature.
4th European Seminars in Virology on Oncogenic and Oncolytic Viruses, in Bertinoro (Bologna), Italy
Authors: Reale Alberto , Messa Lorenzo , Vitiello Adriana , Loregian Arianna , Palù Giorgio
Published: November 2016

The 4th European Seminars in Virology (EuSeV), which was focused on oncogenic and oncolytic viruses, was held in Bertinoro (Bologna), Italy, from June 10 to 12, 2016. This article summarizes the plenary lectures and aims to illustrate the main topics discussed at 4th EuSeV, which brought together knowledge and expertise in the field of oncogenic and oncolytic viruses from all over the world. The meeting was divided in two parts, “Mechanisms of Viral Oncogenesis” and “Viral Oncolysis and Immunotherapy,” which were both focused on dissecting the complex and multi‐factorial interplay between cancer and human viruses and on exploring new anti‐cancer strategies. J. Cell. Physiol. 232: 2641–2648, 2017. © 2016 Wiley Periodicals, Inc.
Impact of Target‐Mediated Elimination on the Dose and Regimen of Evolocumab, a Human Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9)
Authors: Gibbs John P. , Doshi Sameer , Kuchimanchi Mita , Grover Anita , Emery Maurice G. , Dodds Michael G. , Gibbs Megan A. , Somaratne Ransi , Wasserman Scott M. , Blom Dirk
Published: November 2016

Understanding the pharmacokinetic (PK) and pharmacodynamic (PD) relationship of a therapeutic monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9) exhibiting target‐mediated drug disposition (TMDD) is critical for selecting optimal dosing regimens. We describe the PK/PD relationship of evolocumab using a mathematical model that captures evolocumab binding and removal of unbound PCSK9 as well as reduction in circulating low‐density lipoprotein cholesterol (LDL‐C). Data were pooled from 2 clinical studies: a single‐dose escalation study in healthy subjects (7‐420 mg SC; n = 44) and a multiple‐dose escalation study in statin‐treated hypercholesterolemic patients (14 mg weekly to 420 mg monthly [QM] SC; n = 57). A TMDD model described the time course of unbound evolocumab concentrations and removal of unbound PCSK9. The estimated linear clearance and volume of evolocumab were 0.256 L/day and 2.66 L, respectively, consistent with other monoclonal antibodies. The time course of LDL‐C reduction was described by an indirect response model with the elimination rate of LDL‐C being modulated by unbound PCSK9. The concentration of unbound PCSK9 associated with half‐maximal inhibition (IC50) of LDL‐C elimination was 1.46 nM. Based on simulations, 140 mg every 2 weeks (Q2W) and 420 mg QM were predicted to achieve a similar time‐averaged effect of 69% reduction in LDL‐C in patients on statin therapy, suggesting that an approximate 3‐fold dose increase is required for a 2‐fold extension in the dosing interval. Evolocumab dosing regimens of 140 mg Q2W or 420 mg QM were predicted to result in comparable reductions in LDL‐C over a monthly period, consistent with results from recently completed phase 3 studies.
The influence of very small doses of alpha radiation on the stability of erythrocytes
Authors: Kaczmarska Magdalena , Żydek Dominika , Wilkłacz‐Potoczny Justyna , Fornal Maria , Grodzicki Tomasz , Kochowska Elżbieta , Kozak Krzysztof , Gocal Łukasz , Pohorecki Władysław , Matlak Krzysztof , Korecki Józef , Burda Květoslava
Published: November 2016

Our aim was to study the influence of low doses (0.2–4 μGy) of α radiation on the stability of human erythrocytes isolated from healthy and diabetic erythrocytes. Absorption spectroscopy was used to measure the level of red blood cell (RBC) hemolysis, along with Mössbauer spectroscopy, which is a highly specific method suited to monitoring various hemoglobin forms. States of hemoglobin are sensitive to a homeostatic imbalance in red blood cells. Changes in the membrane skeleton organization of irradiated erythrocytes isolated from healthy donors were studied using atomic force microscopy (AFM). Hemolysis, in healthy red blood cells, showed characteristic discontinuities, depending on the α particle flux and the exposure time to the low doses applied. This phenomenon was not observed in severe diabetic cases, which could be a result of modified protein–lipid–sugar complexes and the attenuation/absence of some antioxidative enzymatic processes in their RBC membranes. Similar effects were also observed for red blood cells treated with low doses of neutron and γ‐radiation. AFM measurements demonstrated a reorganization of the RBC membrane skeleton network depending on the time of RBC exposure to α radiation. This suggests that the changes in the activity of the acute defense processes against free radicals which are activated within the erythrocyte membrane irradiated with α‐particles could additionally be up‐ or down regulated by modifications to the membrane–skeleton network. However, even the highest dose of α radiation applied in these studies did not cause any significant changes in the ability of hemoglobin to transport oxygen. Microsc. Res. Tech. 80:131–143, 2017. © 2016 Wiley Periodicals, Inc.
Morphological changes induced in erythrocyte membrane by the antiepileptic treatment: An atomic force microscopy study
Authors: Oprisan Bogdan , Stoica Iuliana , Avadanei Mihaela Iuliana
Published: November 2016

Atomic force microscopy (AFM), a powerful characterization tool widely applied in problems in a large range of disciplines of the natural sciences, including cellular biology, was used to obtain information about the morphological changes induced in the erythrocyte membrane at the patients with epilepsy that undergo a long time treatment that operates upon one or several neuronal ionic channels, comparative with a healthy donor. This technique allowed non‐invasive imaging of erythrocyte membrane, revealing details and specific characteristics down to the nanometer level with characterization of surface texture parameters, such as average height, average roughness and coefficient of kurtosis at micrometer/nanometer resolution. For the healthy donor the AFM morphology appears to have all the characteristics of a normal red blood cell membrane. Instead, the closer examination of the erythrocytes membrane surface morphology for the samples collected from the patients diagnosed with epilepsy and treated with specific drugs did not reveal similar structures with those obtained for the healthy donor. The nanostructure of the membrane was drastically damaged, depending on the administrated treatment, and probably in time will affect their functionality. Therefore, the anticomital drugs have influence not only at the neuronal level, but also at the red blood cell level.
Genotypic profiles of hepatitis B in African immigrants and their clinical relevance
Authors: Thurnheer Maria Christine , Edwards Rosalind , Schulz Thomas Ray , Yuen Lilly , Littlejohn Margaret , Revill Peter , Bannister Elizabeth , Chu Melissa , Tanyeri Firuz , Wade Amanda , Biggs Beverley‐Ann , Sasadeusz Joseph
Published: November 2016

Hepatitis B virus (HBV) from 40 adult African immigrants in Australia was characterized to determine the prevalence of different HBV genotypes and subgenotypes. A mutational analysis was then performed to determine the presence of clinically significant mutations and correlate them to clinical outcomes. Initial sequencing analysis revealed 13 with genotype A (32.5%), 13 with genotype D (32.5%), and 14 with genotype E (35%). Serology showed that 37 were HBeAg negative. Phylogenetic analysis identified a high prevalence (25%) of HBV subgenotype A1 in our cohort, a subgenotype which has been associated with more aggressive clinical disease. BCP/PC sequencing was obtained for 38 patients. BCP and/or PC mutations were identified in 36/38 (95%). The median viral load of all patients was 2995 IU/mL and most of the pathology results were within the normal range. Only one patient had an increased APRI score of 1.1 suggestive of cirrhosis. We present novel information on the HBV genotypes amongst the African population in Australia along with clinical correlates. The high prevalence of A1 subgenotype in this population supports the current Australian recommendation to commence hepatocellular carcinoma screening in Africans with chronic HBV from 20 years old.
The antiviral cytokine interferon‐gamma restricts neural stem/progenitor cell proliferation through activation of STAT1 and modulation of retinoblastoma protein phosphorylation
Authors: Kulkarni Apurva , Scully Taylor J. , O'Donnell Lauren A.
Published: November 2016

Neural stem/progenitor cells (NPSCs) express receptors for many inflammatory cytokines, with varying effects on differentiation and proliferation depending on the stage of development and the milieu of inflammatory mediators. In primary neurons and astrocytes, we recently showed that interferon gamma (IFNγ), a potent antiviral cytokine that is required for the control and clearance of many central nervous system (CNS) infections, could differentially affect cell survival and cell cycle progression depending upon the cell type and the profile of activated intracellular signaling molecules. Here, we show that IFNγ inhibits proliferation of primary NSPCs through dephosphorylation of the tumor suppressor Retinoblastoma protein (pRb), which is dependent on activation of signal transducers and activators of transcription‐1 (STAT1) signaling pathways. Our results show i) IFNγ inhibits neurosphere growth and proliferation rate in a dose‐dependent manner; ii) IFNγ blocks cell cycle progression through a late‐stage G1/S phase restriction; iii) IFNγ induces phosphorylation and expression of STAT1 and STAT3; iv) IFNγ decreases cyclin E/cdk2 expression and reduces phosphorylation of cyclin D1 and pRb on serine residue 795; and v) the effects of IFNγ on NSPC proliferation, cell cycle protein expression, and pRb phosphorylation are STAT1‐dependent. These data define a mechanism by which IFNγ could contribute to a reduction in NSPC proliferation in inflammatory conditions. Further delineation of the effects of inflammatory cytokines on NSPC growth could improve our understanding of how CNS infections and other inflammatory events disrupt brain development and NSPC function. © 2016 The Authors. Journal of Neuroscience Research Published by Wiley Periodicals, Inc.
Simulation and fabrication of a fast fringe‐field switching liquid crystal with enhanced surface anchoring enabled by controlled polymer topology
Authors: Weng Libo , Varanytsia Andrii , Chang Kai‐Han , Chien Liang‐Chy
Published: November 2016

We demonstrate a fringe‐field switching nematic liquid crystal with electro‐optical behavior modulated by both bulk and surface polymer stabilization. The polymer is formed by ultraviolet irradiation‐induced phase separation of various amounts of a reactive monomer in the planar‐aligned nematic liquid crystal. Simulation is carried out to verify the effect of anchoring energy. Experimental evidence validates the effect of monomer concentration on transmittance–voltage and response times curves of fringe‐field switching cells. The polymer‐stabilized alignment with a higher polymer concentration escalates the interaction between the liquid crystal and the polymer structure and increases the surface anchoring energy. The polymer stabilization also improves the dynamic response times of liquid crystal. The enabling polymer‐stabilized alignment technique has excellent electro‐optical properties such as a very good dark state, high optical contrast, and fast rise and decay times that may lead to development of a wide range of applications.
Propionibacterium skull base osteomyelitis complicated by internal carotid artery pseudoaneurysm
Authors: Kreicher Kathryn L. , Hatch Jonathan L. , Lohia Shivangi , Meyer Ted A.
Published: November 2016

The microbiology of skull base osteomyelitis (SBO) is evolving. We present here the first case of SBO caused by Propionibacterium acnes leading to the development of a pseudoaneurysm of the internal carotid artery. Otolaryngologists should recognize this pathogen as a potential cause of invasive temporal bone infection to optimize prompt diagnosis and treatment. Laryngoscope, 127:2337–2339, 2017
Hearing loss associated with enlarged vestibular aqueduct and zero or one mutant allele of SLC26A4
Authors: Rose Jane , Muskett Julie A. , King Kelly A. , Zalewski Christopher K. , Chattaraj Parna , Butman John A. , Kenna Margaret A. , Chien Wade W. , Brewer Carmen C. , Griffith Andrew J.
Published: November 2016

Objectives/Hypothesis

To characterize the severity and natural history of hearing loss, and the prevalence of having a cochlear implant in a maturing cohort of individuals with enlarged vestibular aqueduct (EVA) and zero or one mutant allele of SLC26A4.

Study Design

Prospective cohort study of subjects ascertained between 1998 and 2015 at the National Institutes of Health Clinical Center.

Methods

Study subjects were 127 individuals (median age, 8 years; range, 0–59 years) with EVA in at least one ear.

Results

Ears with EVA and zero or one mutant allele of SLC26A4 had mean 0.5/1/2/4‐kHz pure‐tone averages of 62.6 and 52.9 dB HL, respectively, in contrast to EVA ears with two mutant alleles of SLC26A4 (88.1 dB HL; P < .01). This association was independent of age, sex, or side of EVA (P < .001). Natural history of hearing loss was not associated with number of mutant alleles (P = .94). The prevalence of having a cochlear implant was nine (12%) of 76, two (13%) of 15, and 12 (38%) of 32 subjects with zero, one, and two mutant alleles, respectively (P = .00833). This association was not independent (P = .534) but reflected underlying correlations with age at time of first audiogram (P = .003) or severity of hearing loss (P = .000).

Conclusions

Ears with EVA and zero or one mutant allele of SLC26A4 have less severe hearing loss, no difference in prevalence of fluctuation, and a lower prevalence of cochlear implantation in comparison to ears with two mutant alleles of SLC26A4.

Level of Evidence

NA Laryngoscope, 127:E238–E243, 2017
Predator driven changes in prey size distribution stabilize secondary production in lacustrine food webs
Authors: Detmer Thomas M. , McCutchan James H. , Lewis William M.
Published: November 2016

Data from 12 Colorado mountain lakes, some containing invertivorous fish and some without fish, show that fish suppressed biomass of benthic invertebrates and zooplankton and reduced their mean and maximum body size, but did not alter invertebrate production. Resilience of invertebrate production occurred because the smaller body size of invertebrates in lakes with fish raised the community P/B ratio and simultaneously caused an increase in abundance of small invertebrates (<10 mm benthic invertebrates; < 1.5 mm zooplankton), probably by releasing small invertebrates from competition with large invertebrates. Together, these two changes in the invertebrate communities stabilized secondary production even though total invertebrate biomass was reduced. Compensatory stability of herbivore production in response to size selective predation by fish may be a common phenomenon in aquatic food webs. Because it involves both an increase in P/B ratio and an increase in biomass of invertebrates with high P/B ratio, compensation may to some degree explain the commonly observed failure of predation pressure by primary consumers to cause an increase in biomass of primary producers for trophic cascades with three levels, even when invertebrate biomass is reduced by predation. Addition of a fourth trophic level consisting of piscivorous fish would likely have less predictable effects because piscivores produce offspring that are invertivorous predators, thus potentially adding a qualitatively different compensatory mechanism to the trophic cascade.