bluuebunny/crossref_metadata_2025 huggingface dataset:
Organic carbon fluxes of a glacier surface: A case study of Foxfonna, a small Arctic glacier
Authors: Koziol Krystyna A. , Moggridge Helen L. , Cook Joseph M. , Hodson Andy J.
Published: September 2018

Arctic glaciers are rapidly responding to global warming by releasing organic carbon (OC) to downstream ecosystems. The glacier surface is arguably the most biologically active and biodiverse glacial habitat and therefore the site of important OC transformation and storage, although rates and magnitudes are poorly constrained. In this paper, we present measurements of OC fluxes associated with atmospheric deposition, ice melt, biological growth, fluvial transport and storage (in superimposed ice and cryoconite debris) for a supraglacial catchment on Foxfonna glacier, Svalbard (Norway), across two consecutive years. We found that in general atmospheric OC input (averaging 0.63 ± 0.25 Mg a‐1 total organic carbon, i.e. TOC, and 0.40 ± 0.22 Mg a‐1 dissolved organic carbon, i.e. DOC) exceeded fluvial OC export (0.46 ± 0.04 Mg a‐1 TOC and 0.36 ± 0.03 Mg a‐1 DOC). Early in the summer, OC was mobilised in snowmelt but its release was delayed by temporary storage in superimposed ice on the glacier surface. This delayed the export of 28.5% of the TOC in runoff. Biological production in cryoconite deposits was a negligible potential source of OC to runoff, while englacial ice melt was far more important on account of the glacier's negative ice mass balance (–0.89 and –0.42 m a‐1 in 2011 and 2012, respectively). However, construction of a detailed OC budget using these fluxes shows an excess of inputs over outputs, resulting in a net retention of OC on the glacier surface at a rate that would require c. 3 years to account for the OC stored as cryoconite debris. © 2018 John Wiley & Sons, Ltd.
Breaking rocks made easy. Blending stress control concepts to advance geomorphology
Authors: Voigtländer Anne , Krautblatter Michael
Published: September 2018

All landscapes are subject to stress fields, conditioned by their formation and ongoing tectonic and geomorphic changes. With this ESEX Commentary we wish to stimulate a debate on this invisible but persistent stress control on landforms, processes and materials in geomorphology. We address the legacy of active and passive stress fields, which translates into the concept of ‘tectonic predesign’, in conjunction with a perspective of geomorphic processes being driven by subcritical stresses. These concepts complement each other as ‘subcritical processes’ are controlled by tectonic predesign and in turn modulate the stress fields. This offers new theoretical and practical perspectives on how landscapes evolve, processes form materials and how rocks break easily. © 2018 John Wiley & Sons, Ltd.
Developmental exposure to silver nanoparticles at environmentally relevant concentrations alters swimming behavior in zebrafish (Danio rerio)
Authors: González Eduardo A. , Carty Dennis R. , Tran Franklin D. , Cole Austin M. , Lein Pamela J.
Published: September 2018

Silver nanoparticles (Ag-NPs) are ubiquitous in household and medical products because of their antimicrobial activity. A consequence of the high volume of Ag-NP production and usage is increased amounts of Ag-NPs released into the environment. Their small size (1–100 nm) results in unique physiochemical properties that may increase toxicity relative to their bulk counterpart. Therefore, the goal of the present study was to assess the potential toxicity of environmentally relevant concentrations of Ag-NPs in zebrafish (Danio rerio). Wild-type tropical 5D zebrafish embryos were exposed to Ag-NPs from 4 to 120 h postfertilization at 0.03, 0.1, 0.3, 1, and 3 ppm (mg/L). Inductively coupled plasma–mass spectrometry confirmed concentration-dependent uptake of Ag into zebrafish as well as bioaccumulation over time. A morphological assessment revealed no significant hatching impairment, morphological abnormalities, or mortality at any concentration or time point examined. However, assessment of photomotor behavior at 3 d postfertilization (dpf) revealed significant hyperactivity in the 0.3, 1, and 3 ppm Ag-NP treatment groups. At 4 dpf, significant hyperactivity was observed only in the 3 ppm treatment group, whereas 5 dpf larvae exposed to Ag-NPs displayed no significant abnormalities in photomotor behavior. These findings suggest that nonteratogenic concentrations of Ag-NPs are capable of causing transient behavioral changes during development. Environ Toxicol Chem 2018;37:3018–3024. © 2018 SETAC
Characterizing toxicity of metal-contaminated sediments from the Upper Columbia River, Washington, USA, to benthic invertebrates
Authors: Besser John M. , Steevens Jeff , Kunz James L. , Brumbaugh William G. , Ingersoll Christopher G. , Cox Stephen , Mebane Christopher , Balistrieri Laurie , Sinclair Jesse , MacDonald Don
Published: September 2018

Sediments from the Upper Columbia River, Washington, USA, are contaminated with metals from smelting operations. We conducted short-term and long-term tests with the midge Chironomus dilutus and the amphipod Hyalella azteca and short-term tests with the freshwater mussel Lampsilis siliquoidea with 54 sediments from the Upper Columbia River to characterize thresholds for toxicity of metals to benthic invertebrates. Test sediments were screened for toxicity by comparisons with low-metal reference sediments. Toxic effects on amphipods occurred primarily in sediments from the upstream (riverine) reach, and toxic effects on midges occurred in sediments from both the upstream reach and the downstream (reservoir) reach. Little toxicity was observed in mussel tests. Toxicity thresholds (20% effect concentrations [EC20s]) for metals in sediment and porewater were estimated from logistic concentration–response models. Copper (Cu) concentrations in the simultaneously extracted metal fraction of sediments and bioavailable Cu in porewater, as characterized by biotic ligand models, had consistent associations with toxicity endpoints. Concentration–response models for sediment Cu produced EC20s for 6 endpoints, with long-term amphipod survival and reproduction being the most sensitive. A logistic regression model fitted to an endpoint sensitivity distribution for sediment Cu predicted that approximately one-half of the sediments tested would be toxic to at least one endpoint and that approximately 20% of test sediments would be toxic to more than half of the endpoints. These results indicate that sediments from the upstream reach of the Upper Columbia River, which contain high concentrations of metals associated with slags, cause a wide range of toxic effects in laboratory tests and are likely to have adverse effects on benthic invertebrate communities. Environ Toxicol Chem 2018;37:3102–3114. Published 2018 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America.
Does geographic location matter to stock return predictability?
Authors: Boubaker Sabri , Chkir Imed , Chourou Lamia , Saadi Samir
Published: September 2018

Building on recent and growing evidence that geographic location influences information diffusion, this paper examines the relation between firm's location and the predictability of stock returns. We hypothesize that returns on a portfolio composed of firms located in central areas are more likely to follow a random walk than returns on a portfolio composed of firms located in remote areas. Using a battery of variance ratio tests, we find strong and robust support for our prediction. In particular, we show that the returns on a portfolio composed of the 500 largest urban firms follow a random walk; however, all variance ratio tests reject the random walk hypothesis for a portfolio that includes the 500 largest rural firms. Our results are robust to alternative definitions of firm's location and portfolio formation.
Somatic mutational profiles of stage II and III gastric cancer according to tumor microenvironment immune type
Authors: Koh Jiwon , Nam Soo Kyung , Roh Hanseong , Kim Jonghyuk , Lee Byung‐Chul , Kim Jin Won , Ahn Sang‐Hoon , Park Do Joong , Kim Hyung‐Ho , Park Kyoung Un , Chung Jin Haeng , Kim Woo Ho , Lee Hye Seung
Published: September 2018

We aimed to determine somatic mutational profiles of stage II/III gastric cancers (GCs) according to their tumor microenvironment immune types (TMITs), which classify cancer based on co‐assessment of PD‐L1 expression and CD8+ tumor infiltrating lymphocytes. Eighty patients with stage II/III GC were classified as follows: TMIT I (PD‐L1+/CD8High), TMIT II (PD‐L1−/CD8Low), TMIT III (PD‐L1+/CD8Low), and TMIT IV (PD‐L1−/CD8High). Deep targeted sequencing using a panel of 170 cancer‐related genes was performed on an Illumina HiSeq‐2500 system. Most frequently mutated genes included GNAQ (41.3%), TP53 (38.8%), CREBBP (35.0%), and MAP3K1 (35.0%). PIK3CA mutations were observed more frequently in TMIT I (45.8%) and III (66.7%), than in II (12.0%) and IV (8.0%). Other genes with enriched mutations within TMIT I included ATM (33.3%), BRCA2 (33.3%), MAP3K4 (29.2%), and FLT4 (25.0%). FGFR3, MAP3K1, and RUNX1 mutations were more frequently found in TMIT II. TMIT III had a unique somatic mutation profile harboring enriched mutations of histone modifiers including CREBBP and KMT2A, and we found FGFR2 amplification exclusively within TMIT IV. Fuzzy clustering analysis based on somatic mutation frequencies identified a hypermutated group (cluster 1) and a hypomutated group (cluster 2). Cluster 1 had significant associations with TMIT I, EBV+ GCs, and MSI‐H GCs (P = .023, .014, and .004), and had better overall survival (P = .057) than Cluster 2. TMIT I, EBV+, and MSI‐H GCs were estimated to have greater tumor mutational burden (P = .023, .003, and .015). By analyzing somatic mutation profiles according to TMIT classification, we identified TMIT‐specific genetic alterations that provide clues for biological linkage between GC genetics and microenvironment.
Mapping adolescent reward anticipation, receipt, and prediction error during the monetary incentive delay task
Authors: Cao Zhipeng , Bennett Marc , Orr Catherine , Icke Ilknur , Banaschewski Tobias , Barker Gareth J. , Bokde Arun L. W. , Bromberg Uli , Büchel Christian , Quinlan Erin Burke , Desrivières Sylvane , Flor Herta , Frouin Vincent , Garavan Hugh , Gowland Penny , Heinz Andreas , Ittermann Bernd , Martinot Jean‐Luc , Nees Frauke , Orfanos Dimitri Papadopoulos , Paus Tomáš , Poustka Luise , Hohmann Sarah , Fröhner Juliane H. , Smolka Michael N. , Walter Henrik , Schumann Gunter , Whelan Robert ,   IMAGEN Consortium
Published: September 2018

The functional neuroanatomy and connectivity of reward processing in adults are well documented, with relatively less research on adolescents, a notable gap given this developmental period's association with altered reward sensitivity. Here, a large sample (n = 1,510) of adolescents performed the monetary incentive delay (MID) task during functional magnetic resonance imaging. Probabilistic maps identified brain regions that were reliably responsive to reward anticipation and receipt, and to prediction errors derived from a computational model. Psychophysiological interactions analyses were used to examine functional connections throughout reward processing. Bilateral ventral striatum, pallidum, insula, thalamus, hippocampus, cingulate cortex, midbrain, motor area, and occipital areas were reliably activated during reward anticipation. Bilateral ventromedial prefrontal cortex and bilateral thalamus exhibited positive and negative activation, respectively, during reward receipt. Bilateral ventral striatum was reliably active following prediction errors. Previously, individual differences in the personality trait of sensation seeking were shown to be related to individual differences in sensitivity to reward outcome. Here, we found that sensation seeking scores were negatively correlated with right inferior frontal gyrus activity following reward prediction errors estimated using a computational model. Psychophysiological interactions demonstrated widespread cortical and subcortical connectivity during reward processing, including connectivity between reward‐related regions with motor areas and the salience network. Males had more activation in left putamen, right precuneus, and middle temporal gyrus during reward anticipation. In summary, we found that, in adolescents, different reward processing stages during the MID task were robustly associated with distinctive patterns of activation and of connectivity.
Altered structural and functional brain network overall organization predict human intertemporal decision‐making
Authors: Chen Zhiyi , Hu Xingwang , Chen Qi , Feng Tingyong
Published: September 2018

Intertemporal decision‐making is naturally ubiquitous to us: individuals always make a decision with different consequences occurring at different moments. These choices are invariably involved in life‐changing outcomes regarding marriage, education, fertility, long‐term well‐being, and even public policy. Previous studies have clearly uncovered the neurobiological mechanism of the intertemporal decision in the schemes of regional location or sub‐network. However, it still remains unclear how to characterize intertemporal behavior with multimodal whole‐brain network metrics to date. Here, we combined diffusion tensor image and resting‐state functional connectivity MRI technology, in conjunction with graph‐theoretical analysis, to explore the link between topological properties of integrated structural and functional whole‐brain networks and intertemporal decision‐making. Graph‐theoretical analysis illustrated that the participants with steep discounting rates exhibited the decreased global topological organizations including small‐world and rich‐club regimes in both functional and structural connectivity networks, and reflected the dreadful local topological dynamics in the modularity of functional connectome. Furthermore, in the cross‐modalities configuration, the same relationship was predominantly observed for the coupling of structural–functional connectivity as well. Above topological metrics are commonly indicative of the communication pattern of simultaneous global and local parallel information processing, and it thus reshapes our accounts on intertemporal decision‐making from functional regional/sub‐network scheme to multimodal brain overall organization.
Functional plasticity of the dorsomedial prefrontal cortex in depression reorganized by electroconvulsive therapy: Validation in two independent samples
Authors: Bai Tongjian , Wei Qiang , Zu Meidan , Xie Wen , Wang Jiaojian , Gong‐Jun Ji , Yu Fengqiong , Tian Yanghua , Wang Kai
Published: September 2018

Previous studies have implied a key role for the prefrontal cortex in the antidepressive effect of electroconvulsive therapy (ECT). However, there is still ubiquitous inconsistency across these studies, partly due to several confounding effects induced by the use of different samples. Studies with independent samples are necessary for validations to minimize confounding effects. In the current study, resting‐state magnetic resonance imaging of 84 participants was collected using two scanners and two types of scanning parameters. One sample consisted of 28 patients and 23 healthy controls, and the other sample consisted of 33 patients. The local activity (indexed by the amplitude of low‐frequency fluctuations) and functional connectivity were used to examine functional plasticity in the two independent samples before and after ECT. Both samples showed increased local activity of the dorsomedial prefrontal cortex (DMPFC) and enhanced connectivity of the DMPFC with the posterior cingulate cortex (PCC) following ECT. The enhanced connectivity between the DMPFC and PCC was positively associated with clinical improvement for both samples. These findings provide relatively strong evidence to support the functional plasticity of the dorsomedial prefrontal cortex and reorganization by ECT. The functional plasticity of the DMPFC‐PCC may underlie the antidepressive effect of ECT.
Liver Fibrosis Markers Improve Prediction of Outcome in Non‐Acetaminophen‐Associated Acute Liver Failure
Authors: Ugamura Aya , Chu Po‐sung , Nakamoto Nobuhiro , Taniki Nobuhito , Ojiro Keisuke , Hibi Taizo , Shinoda Masahiro , Obara Hideaki , Masugi Yohei , Yamaguchi Akihiro , Shiba Shunsuke , Morikawa Rei , Usui Shingo , Ebinuma Hirotoshi , Kitagawa Yuko , Saito Hidetsugu , Kanai Takanori
Published: September 2018

A prognostic system for acute liver failure (ALF) with a higher predictive value is urgently needed. The role of extracellular matrix (ECM) remodeling in ALF has not been fully elucidated. We hypothesized that serologic fibrosis markers, which reflect ECM remodeling, are predictive of ALF outcome at first presentation. This observational study included 110 patients with acute liver dysfunction, of which 73 had non‐acetaminophen‐associated ALF (NAA‐ALF). We evaluated serum levels of hyaluronic acid, 7S domain of type IV collagen (4COL7S), and Wisteria floribunda agglutinin‐positive Mac‐2‐binding protein at first presentation to a tertiary center. Serologic fibrosis markers were significantly higher in NAA‐ALF compared with acute hepatitis. Elevated hyaluronic acid and 4COL7S levels at first presentation correlated significantly with worse clinical outcomes. 4COL7S, along with age, ammonia, and the Model for End‐Stage Liver Disease (MELD) score, was a significant prognostic factor in multivariate analysis; 4COL7S correlated significantly with coagulopathy, decreased hepatic synthetic functions, advanced hepatic encephalopathy, and liver atrophy and also predicted 180‐day transplant‐free survival. Cox regression models incorporating 4COL7S with the MELD system had profoundly improved predictive values that significantly surpassed the MELD system alone. Conclusion: Elevation of serologic fibrosis markers reflecting ECM remodeling in NAA‐ALF predicted a worse clinical outcome. Incorporation of 4COL7S at first presentation to a transplant center improves the specificity while retaining the sensitivity of the MELD system. External validation of a fibrosis marker as part of a clinical prediction tool in ALF warrants further investigation.
Serum Interleukin‐8, Osteopontin, and Monocyte Chemoattractant Protein 1 Are Associated With Hepatic Fibrosis in Patients With Nonalcoholic Fatty Liver Disease
Authors: Glass Oliver , Henao Ricardo , Patel Keyur , Guy Cynthia D. , Gruss Hans J. , Syn Wing‐Kin , Moylan Cynthia A. , Streilein Robert , Hall Russell , Mae Diehl Anna , Abdelmalek Manal F.
Published: September 2018

The severity of hepatic fibrosis is the primary predictor of liver‐related morbidity and mortality in patients with nonalcoholic fatty liver disease (NAFLD). Unfortunately, noninvasive serum biomarkers for NAFLD‐associated fibrosis are limited. We analyzed baseline serum samples for 24 cytokines of 97 patients with biopsy‐proven NAFLD. These patients were prospectively enrolled in a clinical study (ClinicalTrials.gov NCT00794716) to identify cytokines associated with liver fibrosis in patients with nonalcoholic steatohepatitis. Patients were stratified according to severity of hepatic fibrosis (mild, stage 0‐1, n = 37; moderate, stage 2, n = 40; and advanced, stage 3‐4, n = 20) while controlling for age, race, sex, body mass index, and diabetes mellitus. Interleukin‐8 (IL‐8), osteopontin (OPN), and monocyte chemoattractant protein 1 (MCP1) were associated with liver fibrosis (P < 0.001, P = 0.005, P = 0.016, respectively). After controlling for steatosis, lobular inflammation, hepatocyte ballooning, age, sex, body mass index, diabetes mellitus, hypertension, and metabolic syndrome status, IL‐8 remained strongly associated with fibrosis (P = 0.001). Furthermore, IL‐8 was also a strong predictor of increased fibrotic liver injury compared to established markers of hepatic fibrosis. Hepatic gene expression from 72 patients with NAFLD (n = 40 mild fibrosis; n = 32 advanced fibrosis) from the Duke University Health System NAFLD Clinical Database and Biorepository revealed IL‐8, MCP1, and OPN gene expression to be increased and differentially expressed in patients with advanced hepatic fibrosis. Thus, serum IL‐8, MCP1, and OPN may reflect up‐regulated gene expression during liver fibrosis in NAFLD. Conclusion: Serum IL‐8, MCP1, and OPN may serve as a test for advanced hepatic fibrosis in NAFLD and thus reveal novel targets for antifibrotic therapies. The increased serum IL‐8, MCP1, and OPN that correspond with associated hepatic gene expression lend strength to such analytes as ideal surrogate serum biomarkers for severity of hepatic fibrosis.
Amount, not strength of recollection, drives hippocampal activity: A problem for apparent word familiarity‐related hippocampal activation
Authors: Mayes Andrew R. , Montaldi Daniela , Roper Adrian , Migo Ellen M. , Gholipour Taha , Kafkas Alex
Published: September 2018

The role of the hippocampus in recollection and familiarity remains debated. Using functional magnetic resonance imaging (fMRI), we explored whether hippocampal activity is modulated by increasing recollection confidence, increasing amount of recalled information, or both. We also investigated whether any hippocampal differences between recollection and familiarity relate to processing differences or amount of information in memory. Across two fMRI tasks, we separately compared brain responses to levels of confidence for cued word recall and word familiarity, respectively. Contrary to previous beliefs, increasing confidence/accuracy of cued recall of studied words did not increase hippocampal activity, when unconfounded by amount recollected. In contrast, additional recollection (i.e., recollecting more information than the word alone) increased hippocampal activity, although its accuracy matched that of word recall alone. Unlike cued word recall, increasing word familiarity accuracy did increase hippocampal activity linearly, although at an uncorrected level. This finding occurred although cued word recall and familiarity memory seemed matched with respect to information in memory. The detailed characteristics of these effects do not prove that word familiarity is exceptional in having hippocampal neural correlates. They suggest instead that participants fail to identify some aspects of recollection, misreporting it as familiarity, a problem with word‐like items that have strong and recallable semantic associates.
Differential effects of adolescent and adult‐initiated exercise on cognition and hippocampal neurogenesis
Authors: O'Leary James D. , Hoban Alan E. , Murphy Ashley , O'Leary Olivia F. , Cryan John F. , Nolan Yvonne M.
Published: September 2018

Adolescence is a critical period for postnatal brain maturation and thus a time when environmental influences may affect cognitive processes in later life. Exercise during adulthood has been shown to increase hippocampal neurogenesis and enhance cognition. However, the impact of exercise initiated in adolescence on the brain and behavior in adulthood is not fully understood. The aim of this study was to compare the impact of voluntary exercise that is initiated during adolescence or early adulthood on cognitive performance in hippocampal‐dependent and ‐independent processes using both object‐based and touchscreen operant paradigms. Adult (8 week) and adolescent (4 week) male Sprague–Dawley rats had access to a running wheel (exercise) or were left undisturbed (sedentary control) for 4 weeks prior to behavioral testing and for the duration of the experiment. Results from touchscreen‐based tasks showed that reversal learning was enhanced by both adult and adolescent‐initiated exercise, while only exercise that began in adolescence induced a subtle but transient increase in performance on a location discrimination task. Spontaneous alternation in the Y‐maze was impaired following adolescent onset exercise, while object memory was unaffected by either adult or adolescent‐initiated exercise. Adolescent‐initiated exercise increased the number of hippocampal DCX cells, an indicator of neurogenesis. It also promoted the complexity of neurites on DCX cells, a key process for synaptic integration, to a greater degree than adult‐initiated exercise. Together the data here show that exercise during the adolescent period compared to adulthood differentially affects cognitive processes and the development of new hippocampal neurons in later life.
Modeling pharmaceutical emissions and their toxicity-related effects in life cycle assessment (LCA): A review
Authors: Emara Yasmine , Lehmann Annekatrin , Siegert Marc-William , Finkbeiner Matthias
Published: September 2018

Over the last few decades, worldwide detection of active pharmaceutical ingredients (APIs) in aquatic environments and the associated toxicological effects on wildlife and human health have become a matter of public and scientific debate. While life cycle assessment (LCA) and life cycle impact assessment (LCIA) models are increasingly used to assess the potential eco- and human-toxicological effects of chemical emissions, few studies have looked into the issue of modeling pharmaceutical emissions specifically and their toxicity-related effects in an LCA context. This paper reviews the state of the art to inventory and characterize API emissions in LCA with the goal to identify relevant gaps and challenges. A search for 208 environmentally relevant APIs in 2 life cycle inventory (LCI) databases revealed a meager representation of this group of chemicals. Similarly, the LCIA model USEtox was found to include characterization factors (CFs) for less than 60 APIs. First approaches to model API emissions in LCA were identified on the basis of an examination of 40 LCA case studies in the pharmaceutical sector and in the field of wastewater treatment. Moreover, CFs for 79 additional APIs, expressing their ecotoxicity and/or human toxicity potential, were gathered from literature. An analysis of the variability of API-CFs in different LCIA models showed a variation of about 2–3 orders of magnitude. Based on the review results, 3 main gaps in the modeling and characterization of API emissions in an LCA context were identified: (1) incomplete modeling of API flows and API emissions along the life cycle of human pharmaceuticals, especially during their use and end-of-life phase, (2) limited API coverage in existing LCIA toxicity models, and (3) missing pharma-specific impact pathways (e.g., endocrine disruption and antibiotic resistance) in existing LCIA models. Recommendations to tackle these gaps are provided, and priority action steps are discussed. Integr Environ Assess Manag 2019;15:6–18. © 2018 SETAC
Size matters: Dissecting key parameters for panel‐based tumor mutational burden analysis
Authors: Buchhalter Ivo , Rempel Eugen , Endris Volker , Allgäuer Michael , Neumann Olaf , Volckmar Anna‐Lena , Kirchner Martina , Leichsenring Jonas , Lier Amelie , von Winterfeld Moritz , Penzel Roland , Christopoulos Petros , Thomas Michael , Fröhling Stefan , Schirmacher Peter , Budczies Jan , Stenzinger Albrecht
Published: September 2018

Tumor mutational burden (TMB) represents a new determinant of clinical benefit from immune checkpoint blockade that identifies responders independent of PD‐L1 expression levels and is currently being explored in clinical trials. Although TMB can be measured directly by comprehensive genomic approaches such as whole‐genome and exome sequencing, broad availability, short turnaround times, costs and amenability to formalin‐fixed and paraffin‐embedded tissue support the use of gene panel sequencing for approximating TMB in routine diagnostics. However, data on the parameters influencing panel‐based TMB estimation are limited. Here, we report an extensive in silico analysis of the TCGA data set that simulates various panel sizes and compositions. We demonstrate that panel size is a critical parameter that influences confidence intervals (CIs) and cutoff values as well as important test parameters including sensitivity, specificity, and positive predictive value. Moreover, we evaluate the Illumina TSO500 panel, which will be made available for TMB estimation, and propose dynamic, entity‐specific cutoff values based on current clinical trial data. Optimizing the cost–benefit ratio, our data suggest that panels between 1.5 and 3 Mbp are ideally suited to estimate TMB with small CIs, whereas smaller panels tend to deliver imprecise TMB estimates for low to moderate TMB (0–30 muts/Mbp), connected with insufficient separation of hypermutated tumors from non‐hypermutated tumors.
Association between Trichomonas vaginalis and prostate cancer mortality
Authors: Tsang Sabrina H. , Peisch Samuel F. , Rowan Brendan , Markt Sarah C. , Gonzalez‐Feliciano Amparo G. , Sutcliffe Siobhan , Platz Elizabeth A. , Mucci Lorelei A. , Ebot Ericka M.
Published: September 2018

We previously observed a positive association between seropositivity for the parasite Trichomonas vaginalis and risk of clinically significant prostate cancer at diagnosis. Here, we examined whether T. vaginalis seropositivity was associated with increased prostate cancer‐specific or all‐cause mortality among prostate cancer patients. We studied 736 men with prostate cancer from the Physicians’ Health Study (PHS) and 749 men with prostate cancer from the Health Professionals Follow‐Up Study (HPFS). We used Cox proportional hazards regression models to estimate multivariable‐adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of the association between T. vaginalis serostatus and progression to death from prostate cancer and from all causes. In PHS, 423 men died of any cause during a median follow‐up of 13.8 years from the date of cancer diagnosis, among whom 131 died of prostate cancer. In HPFS, there were 287 deaths, including 77 deaths from prostate cancer, during a median follow‐up of 12.8 years. We found no association between T. vaginalis serostatus and either prostate cancer mortality or all‐cause mortality in either the PHS or HPFS. While previous studies suggest a possible role for T. vaginalis in the development of clinically significant prostate cancer, our findings do not support the hypothesis that T. vaginalis serostatus is associated with mortality among prostate cancer patients.
Personal values and immigrant group appraisal as predictors of voluntary contact with immigrants among majority students in Israel
Authors: Walsh Sophie D. , Tartakovsky Eugene , Shifter‐David Monica
Published: September 2018

What predicts whether young people will establish contacts with immigrants? Students are at a pivotal point in which the campus environment can enable substantial contact with immigrants, and where world views and behavioural patterns are formed which can follow through their adult lives. Through a value‐attitude‐behavior paradigm we examine a conceptual model in which appraisal of an immigrant group as a threat and/or benefit to the host society mediates the relationship between personal values and contact. Findings among 252 students in Israel showed that (1) threat/benefit appraisal of immigrants predicted voluntary contact; (2) personal values of self‐direction and hedonism directly predicted voluntary contact; and (3) Threat/benefit appraisal mediated the relationship between self‐direction and power and contact. Results suggest that increasing awareness of benefits of immigrants can promote positive inter‐group relations.
A degradable triple temperature‐, pH‐, and redox‐responsive drug system for cancer chemotherapy
Authors: Yu Bing , Song Na , Hu Hao , Chen Guihuan , Shen Youqing , Cong Hailin
Published: September 2018

In order to achieve a precise therapeutic effect of cancer treatment and improve the utilization of drugs, a temperature‐, pH‐, and redox‐responsive drug delivery system were synthesized. Methacrylic acid (MAA), poly(N‐isopropylacrylamide) (PNIPAM), 2‐hydroxyethylmethacrylate (HEMA), and N,N′‐bis(acryloyl)cystamine (BACy), a disulfide bond contained cross‐linker, were polymerized by a distillation‐precipitation polymerization. Doxorubicin (DOX), an anti‐cancer drug, can be loaded into the loose nanoparticle (NP) effectively. The prepared drug delivery remains stable during blood circulation and, when the vectors accumulated at tumor tissues, the pH‐response of MMA and temperature‐response of PNIPAM makes volume shrinkage of vectors which benefit the diffusion of vectors into tumor tissues. After being endocytosed into tumor cell, the disulfide bond that contained in the drug delivery can be cleaved by glutathione (GSH), causing the decomposition of NPs, and then release all of the drug. Under the influence of three trigger factors, the triple stimuli‐responsive drug delivery vectors can realize tumor accumulation, tumor penetration and controlled drug release. Thus, the prepared multi‐responsive NP is ideal drug carriers for developing novel drug delivery systems. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3203–3210, 2018.
Optimization of spider silk sphere formation processing conditions to obtain carriers with controlled characteristics
Authors: Florczak Anna , Jastrzebska Katarzyna , Bialas Wojciech , Mackiewicz Andrzej , Dams‐Kozlowska Hanna
Published: September 2018

Bioengineered spider silk is a focus of research due to its biocompatibility, biodegradability, and excellent mechanical properties. Functionalized silk can be processed into spheres and employed as selective drug delivery vehicles in targeted cancer treatment. Efficient, repeatable and controllable processing conditions are essential to drug carrier development. This study aimed to optimize the processing conditions of silk spheres formation, scale‐up, and automation of the silk spheres production process. The automated micromixing system provided substantial amounts of silk spheres under repetitive production conditions. Micromixing resulted in smaller sphere sizes and narrower sphere size distributions than mixing with a pipette. Furthermore, the particle size and size distribution of silk spheres could be tailored by varying mixing process parameters, such as protein concentration, silk and salting out buffer ratio, mixing speed, and the size of the tubes and mixing zone. In addition, the implementation of ultrafiltration techniques provided a fast and efficient concentration of spheres in water. Furthermore, the shear forces introduced by micromixing did not impede the properties of the Her2 binding peptide (H2.1) since the functionalized H2.1MS1:H2.1MS2 silk spheres selectively were internalized by Her2‐positive cancer cells. This study indicated that micromixing in combination with ultrafiltration enabled scale‐up of the sphere production process under controllable and repeatable conditions. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3211–3221, 2018.
Fabrication of polydopamine nanoparticles knotted alginate scaffolds and their properties
Authors: Shen Jiali , Shi Dongjian , Dong Liangliang , Zhang Zhuying , Li Xiaojie , Chen Mingqing
Published: September 2018

Polydopamine (PDA) can greatly affect polymer's properties, due to the chemical and physical interactions between the polymers and PDA. In this study, PDA was demonstrated to adjust the pore structures and increase the mechanical properties of alginate hydrogel‐based cartilage tissue scaffolds. Dopamine modified alginate (Alg‐DA) was firstly synthesized by modification of Alg with DA. Alg‐DA interacted with preprepared PDA nanoparticles and further crosslinked with calcium ions (Ca2+) to form the hydrogel scaffold (Alg‐DA/PDA). The Alg‐DA/PDA scaffold combined multiple advantageous features, including continuous pore structure, high level of porosity, well mechanical properties, good biocompatibility and appropriate cycle life of degradation. Moreover, it could provide an optimized forming environment for hydroxyapatite (HAp) by mineralization process, thus accelerating cartilage repair. The improved performances were mainly ascribed to physical enhancement of the PDA nanoparticles and crosslinking points among the polymers and catechol groups in DA. These findings might offer a guideline for fabricating robust biocompatible cartilage tissue scaffold. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3255–3266, 2018.
Cytoskeletal remodeling induced by substrate rigidity regulates rheological behaviors in endothelial cells
Authors: Jannatbabaei Atefeh , Tafazzoli‐Shadpour Mohammad , Seyedjafari Ehsan , Fatouraee Nasser
Published: September 2018

Altered microenvrionmental mechanical cues induce cytoskeletal remodeling in cells and have a profound impact on their functions as well as rheological properties. This article is aimed to characterize the viscoelastic behavior of endothelial cells, cultivated on variably compliant substrates. Synthetic tunable poly(dimethylsyloxane) substrates, with elastic moduli ranging from 1.5 MPa to 3 kPa, were used to trigger cytoskeletal remodeling of endothelial cells, verified by morphological analysis and actin fluorescent labeling. Elasticity and stress relaxation tests were conducted using an AFM, resulting in a wide range of data. To account for this heterogeneity, fuzzy c‐means clustering algorithm was applied to partition elastic data into biologically meaningful groups, representative of different regions in cells. Nanocharacterization of biomechanical properties, along with cytoskeletal studies, proved a significant correlation between substrate flexibility and viscoelasticity of the cells. Regardless of the viscoelastic model applied, increasing substrate rigidity was related to an overall increase in cell stiffness and apparent viscosity (2.95 ± 1.56 kPa and 921.45 ± 102.46 Pa.s for the stiff substrate; 2.17 ± 1.30 kPa and 557.37 ± 494.11 Pa.s for the intermediate substrate), associated with an organized actin cytoskeleton. Conversely, cells on soft substrate were more deformable (1.84 ± 1.3 kPa) and less viscous (327.13 ± 124.25 Pa.s), exhibiting an increased actin disorganization. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 71–80, 2019.
Esophageal cancer lymph node metastasis–associated gene signature optimizes overall survival prediction of esophageal cancer
Authors: Cai Weiyang , Li Yanyan , Huang Bo , Hu Changyuan
Published: September 2018

Esophageal cancer (EC) is characteristic of early regional lymph node metastasis (LNM) and most patients with metastasis have a poor prognosis. However, the current diagnostic techniques do not enable precise differentiation of EC LNM, prognostic stratification, and individual survival estimation. To identify potential molecular biomarkers for EC patients with LNM, we explored differently expressed genes in The Cancer Genome Atlas database between 77 non‐LNM cases and 88 LNM cases by limma package R. Then, according to univariate and multivariate Cox regression analyses, we constructed an 8‐messenger RNA (mRNA) prognostic signature model, which could predict the outcome in a more exact way. The area under the curve of the risk score is significantly higher than other clinical information, indicating that the 8‐mRNA–based risk score is a good indicator for prognosis. Then, combined with other individual risk factors, such as age, sex, T stage, M stage, etc, we could precisely calculate the individual 1‐, 3‐, and 5‐year survival rates. The Gene Set Enrichment Analysis, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes analysis indicate that the risk model is mainly associated with cancer‐related pathways, such as cell division, cellular meiosis, and cell cycle regulation. In summary, the 8‐mRNA–based risk score model that we developed successfully predicts the survival of EC. It is independent of clinical information and performing better than other clinical information for prognosis.
Association of single nucleotide autophagy‐related protein 5 gene polymorphism rs2245214 with susceptibility to non–small cell lung cancer
Authors: Nikseresht Mohsen , Shahverdi Maryam , Dehghani Mehdi , Abidi Hassan , Mahmoudi Reza , Ghalamfarsa Ghasem , Manzouri Leila , Ghavami Saeid
Published: September 2018

Introduction: Autophagy is a mechanism that is involved in the regulation of cellular life, apoptosis, and stemness while its intervening genes play important functions in various cancers including lung cancer.
ATG5 is one of the key genes for the regulation of the autophagy pathway. In this study, our team has investigated the potential relationship between
ATG5 gene polymorphism rs2245214 with non–small cell lung cancer (NSCLC) in a subpopulation of patients from southern Iran. In this study, 34 patients with NSCLC (20 males and 14 females [mean age: 12.86 ± 60.47 years]) and 50 healthy subjects (30 males and 20 females [mean age: 13.09 ± 56.62 years]) were studied in terms of the genotype of the
ATG5 gene. We used restriction fragment length polymorphism and analyzed the results using SPSS software (v.23). The results revealed that subjects harboring the guanine/cytosine (GC) genotype of the rs2245214
ATG5 gene polymorphism had suffered less from NSCLC, whereas the prevalence of the C‐allele of this polymorphism was significantly higher in patients with NSCLC (
P < 0.05). On the basis of the results of logistic regression, the presence of this C‐allele may predict the risk of lung cancer (
P value = 0.011; OR, 3.52; 95% CI, 1.33‐9.26). This study concludes that the C‐allele of the rs2245214
ATG5 gene polymorphism is associated with increased susceptibility to NSCLC, whereas the GC genotype of this polymorphism is associated with decreased risk and might therefore have a protective role in the development of NSCLC.
Curcumin‐induced autophagy and nucleophagy in Spodoptera frugiperda Sf9 insect cells occur via PI3K/AKT/TOR pathways
Authors: Veeran Sethuraman , Cui Gaofeng , Shu Benshui , Yi Xin , Zhong Guohua
Published: September 2018

Compounds from plants or microbes are important resources for new natural pesticides against a wide variety of pests. The growing attention on the role of autophagy (type II cell death) in regulation of insect toxicology has propelled researchers to investigate autophagic cell death pathways. Our previous study proved that the cytotoxic effect of curcumin in Spodoptera frugiperda cells is regulated by autophagy. However, the signaling pathways and molecular mechanisms had not been determined. The current study elucidates curcumin inhibition of survival signaling by blocking the activation of PI3K/AKT/TOR pathways to induce autophagy in S. frugiperda cells. The result demonstrates that nucleophagy associated with cell death following the curcumin treatment. Following the curcumin treatment, Atg8/LC3 immunostaining in both nucleus and cytoplasm was markedly increased. Further, messenger RNA expression level of Atg8 and Atg1 genes regulation by curcumin was examined using quantitative reverse transcription polymerase chain reaction, and the result exhibited increased level of expression after curcumin treatment in a time‐dependent manner. Our current study provides new insights to the autophagy occurring via PI3K/AKT/TOR pathways in S. frugiperda Sf9 insect cells induced by curcumin. Taken together, our results show for the first time that curcumin induced nucleophagy in lepidopteron insect cell line.
Multiple upstream start codons (AUG) in 5′ untranslated region enhance translation efficiency of cry2Ac11 without helper protein
Authors: Adalat Rooma , Saleem Faiza , Bashir Aftab , Ahmad Munir , Zulfiqar Soumble , Shakoori Abdul Rauf
Published: September 2018

Cry2Ac11, a 65 kDa insecticidal protein produced by Bacillus thuringiensis, shows toxicity against dipteran and lepidopteran larvae. It is encoded by
cry2Ac11 gene (
orf3), which is part of an operon comprising
orf1,
orf2, and
orf3. Orf2, a helper protein, helps in proper folding and prevents aberrant aggregation of newly produced molecules. In this study, we have elucidated the effect of different mutations in translation initiation region (TIR), particularly the ribosomal binding site and the start codon (RBS‐ATG) on
cry2Ac11 gene expression without helper protein. All recombinant constructs were expressed in acrystalliferous
B. thuringiensis subsp
israelensis 4Q7 under the control of strong chimeric promoter
cyt1AP/STAB. Of all the mutants,
mut/RBS2, with two consecutive AUGs after the spacer region in TIR, exhibited 89‐ and 2246‐fold higher transcript levels compared with 4Q7‐operSalI/RBS (
cry2Ac11 operon) and 4Q7‐w‐RBS (
cry2Ac11 gene), respectively. The analysis of
mut/RBS2 messenger RNA (mRNA) structure in the RBS‐AUG region showed the presence of RBS in the single‐stranded part of the moderately stable hairpin loop. The high expression efficiency of Cry2Ac11 mutant without helper protein is a cumulative and cooperative result of chimeric promoter
cyt1AP/STAB‐SD with the optimal context of RBS‐AUG region provided by multiple AUGs and stabilizer sequence at 3′ ends.
Baicalin attenuates myocardial ischemia‐reperfusion injury through Akt/NF‐κB pathway
Authors: Luan Yun , Sun Chao , Wang Jue , Jiang Wen , Xin Qian , Zhang Zhaohua , Wang Yibiao
Published: September 2018

Background

Baicalin can attenuate myocardial ischemia‐reperfusion (I/R) on damage. However, the mechanisms are still not fully understood. The study aimed to investigate the antiapoptosis and anti‐inflammatory effects of baicalin on myocardial I/R‐induced injury.

Methods

We established male rats I/R model, and baicalin was intragastric administration after ischemia onset. All experimental animals were randomly divided into five groups: group I, sham; group II, I/R; group III, 50 mg/kg; group IV, 100 mg/kg; and group V, 200 mg/kg baicalin. Postoperation, left ventricular (LV) function was recorded by transthoracic echocardiography. Myocardial infarct size, number of vessels and apoptosis were detected by histology and immunohistochemistry. Furthermore, the messenger RNA (mRNA) and protein levels of tumor necrosis factor α (TNF‐α), interleukin 1β (IL‐1β), IL‐6, IL‐8, IL‐10, Bcl2, Bax, caspase‐3, phosphatidylinositol 3‐kinase (PI3K), Akt, p‐Akt, and nuclear factor‐κB (NF‐κB) p65 in myocardial tissues were measured by quantitative real‐time polymerase chain reaction and Western blot analysis assays.

Result

When compared with I/R groups, baicalin could significantly improve LV hemodynamic parameters. Myocardial infarct size and apoptosis were significantly decreased, but the vessel density was increased. The mRNA levels of TNF‐α, IL‐1β, IL‐6, and IL‐8 were downregulated, but the levels of IL‐10, proapoptotic genes caspase‐3, and the ratio of Bax/Bcl2 were upregulated. Moreover, the protein expression of PI3K, p‐Akt, and Akt were upregulated but NF‐κB p65 was downregulated in the groups III, IV, and V than in group II.

Conclusion

Our current study suggested that baicalin attenuated myocardial I/R‐induced damage, inhibited myocardial apoptosis, and inflammation by activating PI3K/Akt but suppressing NF‐κB signaling.