bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proteomic signatures reveal a dualistic and clinically relevant classification of anal canal carcinoma
Authors: Herfs Michael , Longuespée Rémi , Quick Charles M , Roncarati Patrick , Suarez‐Carmona Meggy , Hubert Pascale , Lebeau Alizée , Bruyere Diane , Mazzucchelli Gabriel , Smargiasso Nicolas , Baiwir Dominique , Lai Keith , Dunn Andrew , Obregon Fabiola , Yang Eric J , Pauw Edwin De , Crum Christopher P , Delvenne Philippe 
Published: December 2016

AbstractAetiologically linked to HPV infection, malignancies of the anal canal have substantially increased in incidence over the last 20 years. Although most anal squamous cell carcinomas (SCCs) respond well to chemoradiotherapy, about 30% of patients experience a poor outcome, for undetermined reasons. Despite cumulative efforts for discovering independent predictors of overall survival, both nodal status and tumour size are still the only reliable factors predicting patient outcome. Recent efforts have revealed that the biology of HPV‐related lesions in the cervix is strongly linked to the originally infected cell population. To address the hypothesis that topography also influences both gene expression profile and behaviour of anal (pre)neoplastic lesions, we correlated both proteomic signatures and clinicopathological features of tumours arising from two distinct portions of the anal canal: the lower part (squamous zone) and the more proximal anal transitional zone. Although microdissected cancer cells appeared indistinguishable by morphology (squamous phenotype), unsupervised clustering analysis of the whole proteome significantly highlighted the heterogeneity that exists within anal canal tumours. More importantly, two region‐specific subtypes of SCC were revealed. The expression profile (sensitivity/specificity) of several selected biomarkers (keratin filaments) further confirmed the subclassification of anal (pre)cancers based on their cellular origin. Less commonly detected compared to their counterparts located in the squamous mucosa, SCCs originating in the transitional zone more frequently displayed a poor or basaloid differentiation, and were significantly correlated with reduced disease‐free and overall survivals. Taken together, we present direct evidence that anal canal SCC comprises two distinct entities with different cells of origin, proteomic signatures, and survival rates. This study forms the basis for a dualistic classification of anal carcinoma, with implications for management, outcome expectations, and possibly therapy. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Tumour‐associated macrophage‐mediated survival of myeloma cells through STAT3 activation
Authors: De Beule Nathan , De Veirman Kim , Maes Ken , De Bruyne Elke , Menu Eline , Breckpot Karine , De Raeve Hendrik , Van Rampelbergh Rian , Van Ginderachter Jo A , Schots Rik , Van Valckenborgh Els , Vanderkerken Karin 
Published: December 2016

AbstractOvercoming drug resistance is one of the greatest challenges in the treatment of multiple myeloma (MM). The interaction of myeloma cells with the bone marrow (BM) microenvironment is a major factor contributing to drug resistance. Tumour‐associated macrophages (TAMs) with different polarization states constitute an important component of this microenvironment. Previous studies have revealed a role of TAMs in MM cell survival and drug resistance; however, the impact of macrophage polarization (anti‐tumoural ‘M1’ versus pro‐tumoural ‘M2’‐like phenotype) in this process has not yet been described. Here, the presence of TAMs was confirmed in BM sections from MM patients, both at diagnosis and relapse, with two M2 markers, CD163 and CD206. By following different TAM subpopulations during disease progression in the syngeneic murine 5T33MM model, we demonstrated a decrease in the number of inflammatory monocytes and an increase in the number of M2‐oriented TAMs in BM. Co‐culture experiments demonstrated that macrophages provide a survival benefit to myeloma cells that is maintained after treatment with several classes of anti‐myeloma agent (melphalan and bortezomib); the greatest effect was observed with M2‐polarized macrophages. The pro‐survival effect was associated with activation of the STAT3 pathway in 5T33MM cells, less cleavage of caspase‐3, and thus less apoptosis. AZD1480, an ATP‐competitive JAK2 inhibitor, abrogated the observed TAM‐mediated MM cell survival, and partially inhibited resistance to bortezomib. Despite having only a small quantitative impact on myeloid cells in vivo, AZD1480 treatment alone and in combination with bortezomib significantly reduced tumour load. In conclusion, M2 TAMs are present in the MM microenvironment, and contribute to MM cell survival and protection from drug‐induced apoptosis. As a result of TAM‐induced activation of the STAT3 pathway, 5T33MM cells are sensitized to AZD1480 treatment. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Haematopoietic prolyl hydroxylase‐1 deficiency promotes M2 macrophage polarization and is both necessary and sufficient to protect against experimental colitis
Authors: Van Welden Sophie , De Vos Martine , Wielockx Ben , Tavernier Simon J , Dullaers Melissa , Neyt Sara , Descamps Benedicte , Devisscher Lindsey , Devriese Sarah , Van den Bossche Lien , Holvoet Tom , Baeyens Ann , Correale Carmen , D'Alessio Silvia , Vanhove Christian , De Vos Filip , Verhasselt Bruno , Breier Georg , Lambrecht Bart N , Janssens Sophie , Carmeliet Peter , Danese Silvio , Elewaut Dirk , Laukens Debby , Hindryckx Pieter 
Published: December 2016

AbstractProlyl hydroxylase domain‐containing proteins (PHDs) regulate the adaptation of cells to hypoxia. Pan‐hydroxylase inhibition is protective in experimental colitis, in which PHD1 plays a prominent role. However, it is currently unknown how PHD1 targeting regulates this protection and which cell type(s) are involved. Here, we demonstrated that Phd1 deletion in endothelial and haematopoietic cells (Phd1f/fTie2:cre) protected mice from dextran sulphate sodium (DSS)‐induced colitis, with reduced epithelial erosions, immune cell infiltration, and colonic microvascular dysfunction, whereas the response of Phd2f/+Tie2:cre and Phd3f/fTie2:cre mice to DSS was similar to that of their littermate controls. Using bone marrow chimeras and cell‐specific cre mice, we demonstrated that ablation of Phd1 in haematopoietic cells but not in endothelial cells was both necessary and sufficient to inhibit experimental colitis. This effect relied, at least in part, on skewing of Phd1‐deficient bone marrow‐derived macrophages towards an anti‐inflammatory M2 phenotype. These cells showed an attenuated nuclear factor‐κB‐dependent response to lipopolysaccharide (LPS), which in turn diminished endothelial chemokine expression. In addition, Phd1 deficiency in dendritic cells significantly reduced interleukin‐1β production in response to LPS. Taken together, our results further support the development of selective PHD1 inhibitors for ulcerative colitis, and identify haematopoietic cells as their primary target. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Determination of Polyphenolic Phytochemicals using Highly Deshielded –OH 1H‐NMR Signals
Authors: Charisiadis Pantelis , Kontogianni Vassiliki G. , Tsiafoulis Constantinos G. , Tzakos Andreas G. , Gerothanassis Ioannis P. 
Published: December 2016

AbstractIntroductionQuantitative analysis of plant extracts is a tedious and time consuming process requiring chromatographic techniques and/or the use of specilised hyphenated spectroscopic methods. Thus, investigation of a rapid method capable for the determination of bioactive constituents is of major importance.ObjectiveTo employ high resolution 1H‐NMR spectroscopy of the –OH spectral region, as a rapid method for the simultaneous determination and quantification of polyphenolic phytochemicals in crude oregano and olive leaf extracts without any prior isolation step.MethodologyA critical overview of experimental parameters that influence the resolution of the –OH groups is provided with emphasis on the nature of the extraction solvent, effects of dilution, pH, temperature and nature of the NMR solvent. The compounds were assigned with the use of 1H‐NMR, 2D 1H‐13C HMBC NMR and spiking experiments with model compounds.ResultsThe method was applied for the NMR analysis of natural product extracts and the results were found to be in good agreement with those obtained with the use of the time consuming HPLC‐DAD, preparative LC and LC‐SPE‐NMR.ConclusionThe method is rapid, selective, with very good analytical performance characteristics, which support the efficiency of the suggested methodology. Copyright © 2016 John Wiley & Sons, Ltd.
How Successful Has TANF Been? Taking Seriously a Thoughtful Analysis From the Right, With a Tip of the Hat to Peter the Citizen
Authors: Skidmore Max J. 
Published: December 2016

AbstractEditor Max J. Skidmore discusses a welcome exchange with the co‐author of a 1983 article on Social Security that he has severely criticized numerous times. Peter Germanis, now writing as “Peter the Citizen,” reached out to indicate that he now directs his attention to TANF, and has not considered Social Security for many years. The resulting communication clearly demonstrates that thoughtful conservatives can set aside ideological considerations and collaborate with those of differing views without sacrificing their basic principles. Despite claims of success, TANF has failed to achieve its goals, and has had disastrous results. His analyses are insightful, and should serve as the basis for reform of “welfare reform.” What should be rejected soundly is any use of TANF as a model for revision of policy.
Tuning BRCA1 and BARD1 activity to investigate RING ubiquitin ligase mechanisms
Authors: Stewart Mikaela D. , Duncan Emily D. , Coronado Ernesto , DaRosa Paul A. , Pruneda Jonathan N. , Brzovic Peter S. , Klevit Rachel E. 
Published: December 2016

AbstractThe tumor‐suppressor protein BRCA1 works with BARD1 to catalyze the transfer of ubiquitin onto protein substrates. The N‐terminal regions of BRCA1 and BARD1 that contain their RING domains are responsible for dimerization and ubiquitin ligase activity. This activity is a common feature among hundreds of human RING domain‐containing proteins. RING domains bind and activate E2 ubiquitin‐conjugating enzymes to promote ubiquitin transfer to substrates. We show that the identity of residues at specific positions in the RING domain can tune activity levels up or down. We report substitutions that create a structurally intact BRCA1/BARD1 heterodimer that is inactive in vitro with all E2 enzymes. Other substitutions in BRCA1 or BARD1 RING domains result in hyperactivity, revealing that both proteins have evolved attenuated activity. Loss of attenuation results in decreased product specificity, providing a rationale for why nature has tuned BRCA1 activity. The ability to tune BRCA1 provides powerful tools for understanding its biological functions and provides a basis to assess mechanisms for rescuing the activity of cancer‐associated variations. Beyond the applicability to BRCA1, we show the identity of residues at tuning positions that can be used to predict and modulate the activity of an unrelated RING E3 ligase. These findings provide valuable insights into understanding the mechanism and function of RING E3 ligases like BRCA1.
A misfolded dimer of Cu/Zn‐superoxide dismutase leading to pathological oligomerization in amyotrophic lateral sclerosis
Authors: Anzai Itsuki , Tokuda Eiichi , Mukaiyama Atsushi , Akiyama Shuji , Endo Fumito , Yamanaka Koji , Misawa Hidemi , Furukawa Yoshiaki 
Published: December 2016

AbstractMisfolding of mutant Cu/Zn‐superoxide dismutase (SOD1) is a pathological hallmark in a familial form of amyotrophic lateral sclerosis. Pathogenic mutations have been proposed to monomerize SOD1 normally adopting a homodimeric configuration and then trigger abnormal oligomerization of SOD1 proteins. Despite this, a misfolded conformation of SOD1 leading to the oligomerization at physiological conditions still remains ambiguous. Here, we show that, around the body temperature (∼37°C), mutant SOD1 maintains a dimeric configuration but lacks most of its secondary structures. Also, such an abnormal SOD1 dimer with significant structural disorder was prone to irreversibly forming the oligomers crosslinked via disulfide bonds. The disulfide‐crosslinked oligomers of SOD1 were detected in the spinal cords of the diseased mice expressing mutant SOD1. We hence propose an alternative pathway of mutant SOD1 misfolding that is responsible for oligomerization in the pathologies of the disease.
The membrane localization domains of two distinct bacterial toxins form a 4‐helix‐bundle in solution
Authors: Hisao Grant S. , Brothers Michael C. , Ho Mengfei , Wilson Brenda A. , Rienstra Chad M. 
Published: December 2016

AbstractMembrane localization domain (MLD) was first proposed for a 4‐helix‐bundle motif in the crystal structure of the C1 domain of Pasteurella multocida toxin (PMT). This structure motif is also found in the crystal structures of several clostridial glycosylating toxins (TcdA, TcdB, TcsL, and TcnA). The Ras/Rap1‐specific endopeptidase (RRSP) module of the multifunctional autoprocessing repeats‐in‐toxins (MARTX) toxin produced by Vibrio vulnificus has sequence homology to the C1‐C2 domains of PMT, including a putative MLD. We have determined the solution structure for the MLDs in PMT and in RRSP using solution state NMR. We conclude that the MLDs in these two toxins assume a 4‐helix‐bundle structure in solution.
Optimization of on‐line hydrogen stable isotope ratio measurements of halogen‐ and sulfur‐bearing organic compounds using elemental analyzer–chromium/high‐temperature conversion isotope ratio mass spectrometry (EA‐Cr/HTC‐IRMS)
Authors: Gehre Matthias , Renpenning Julian , Geilmann Heike , Qi Haiping , Coplen Tyler B. , Kümmel Steffen , Ivdra Natalija , Brand Willi A. , Schimmelmann Arndt 
Published: December 2016

RationaleAccurate hydrogen isotopic analysis of halogen‐ and sulfur‐bearing organics has not been possible with traditional high‐temperature conversion (HTC) because the formation of hydrogen‐bearing reaction products other than molecular hydrogen (H2) is responsible for non‐quantitative H2 yields and possible hydrogen isotopic fractionation. Our previously introduced, new chromium‐based EA‐Cr/HTC‐IRMS (Elemental Analyzer–Chromium/High‐Temperature Conversion Isotope Ratio Mass Spectrometry) technique focused primarily on nitrogen‐bearing compounds. Several technical and analytical issues concerning halogen‐ and sulfur‐bearing samples, however, remained unresolved and required further refinement of the reactor systems.MethodsThe EA‐Cr/HTC reactor was substantially modified for the conversion of halogen‐ and sulfur‐bearing samples. The performance of the novel conversion setup for solid and liquid samples was monitored and optimized using a simultaneously operating dual‐detection system of IRMS and ion trap MS. The method with several variants in the reactor, including the addition of manganese metal chips, was evaluated in three laboratories using EA‐Cr/HTC‐IRMS (on‐line method) and compared with traditional uranium‐reduction‐based conversion combined with manual dual‐inlet IRMS analysis (off‐line method) in one laboratory.ResultsThe modified EA‐Cr/HTC reactor setup showed an overall H2‐recovery of more than 96% for all halogen‐ and sulfur‐bearing organic compounds. All results were successfully normalized via two‐point calibration with VSMOW‐SLAP reference waters. Precise and accurate hydrogen isotopic analysis was achieved for a variety of organics containing F‐, Cl‐, Br‐, I‐, and S‐bearing heteroelements. The robust nature of the on‐line EA‐Cr/HTC technique was demonstrated by a series of 196 consecutive measurements with a single reactor filling.ConclusionsThe optimized EA‐Cr/HTC reactor design can be implemented in existing analytical equipment using commercially available material and is universally applicable for both heteroelement‐bearing and heteroelement‐free organic‐compound classes. The sensitivity and simplicity of the on‐line EA‐Cr/HTC‐IRMS technique provide a much needed tool for routine hydrogen‐isotope source tracing of organic contaminants in the environment. Copyright © 2016 John Wiley & Sons, Ltd.
Selected ion flow tube study of the reactions of H3O+ and NO+ with a series of primary alcohols in the presence of water vapour in support of selected ion flow tube mass spectrometry
Authors: Španěl Patrik , Žabka Jan , Zymak Illia , Smith David 
Published: December 2016

RationaleAlcohols are often present in foods and other biological media, including exhaled breath, urine and cell culture headspace. For their analysis by selected ion flow tube mass spectrometry (SIFT‐MS), the ion chemistry initiated by the reactions of the reagent ions H3O+ and NO+ with alcohol molecules in the presence of water molecules needs to be understood and quantitatively described.MethodsThe reactions of H3O+ and NO+ ions have been studied with the primary alcohols, methanol, ethanol, 1‐propanol, 1‐butanol, 1‐pentanol and 1‐hexanol, under the conditions used for SIFT‐MS analyses (1 Torr He; 0.1 Torr air sample; 300 K) and over a range of sample gas humidity from 1% to 5.5%.ResultsThe H3O+ reactions led to the formation of protonated alcohol molecules MH+ and their hydrates MH+(H2O)1,2,3 and (MH+‐H2O) fragment ions. The NO+ reactions were observed to proceed mainly via hydride ion transfer, resulting in the formation of [M–H]+ product ions. Formation of the NO+M adduct ions was also observed due to ligand switching between the NO+(H2O)1,2 hydrated reagent ions and M, and via direct NO+/M association in the case of ethanol. The variation in the percentages of the hydrated product ions with the air sample humidity is reported.ConclusionsThis detailed study has provided the kinetics data, including the secondary hydrated ion product distributions, for the reactions of a number of volatile primary alcohols with the SIFT‐MS reagent ions H3O+ and NO+, which allows their analyses by SIFT‐MS in humid air and also helps in the interpretation of proton transfer reaction (PTR)‐MS data. Copyright © 2016 John Wiley & Sons, Ltd.
Modeling the Relationships Among Reading Instruction, Motivation, Engagement, and Achievement for Adolescents
Authors: Guthrie John T. , Klauda Susan Lutz , Ho Amy N. 
Published: December 2016

AbstractThis study modeled the interrelationships of reading instruction, motivation, engagement, and achievement in two contexts, employing data from 1,159 seventh graders. In the traditional reading/language arts (R/LA) context, all students participated in traditional R/LA instruction. In the intervention R/LA context, 854 students from the full sample received Concept‐Oriented Reading Instruction (CORI) while the remainder continued to receive traditional R/LA. CORI emphasizes support for reading motivation, reading engagement, and cognitive strategies for reading informational text. Seven motivation constructs were included: four motivations that are usually positively associated with achievement (intrinsic motivation, self‐efficacy, valuing, and prosocial goals) and three motivations that are usually negatively associated with achievement (perceived difficulty, devaluing, and antisocial goals). Reading engagement was also represented by positive and negative constructs, namely dedication to and avoidance of reading. Gender, ethnicity, and income were statistically controlled in all analyses. In the traditional R/LA context, a total network model prevailed, in which motivation was associated with achievement both directly and indirectly through engagement. In contrast, in the intervention R/LA context, a dual‐effects model prevailed, in which engagement and achievement were separate outcomes of instruction and motivation. The intervention R/LA context analyses revealed that CORI was associated with positive changes in motivation, engagement, and achievement relative to traditional R/LA instruction. The discussion explains why there were different relations in the two instructional contexts and demonstrates the importance of simultaneously examining both positive (affirming) and negative (undermining) forms of motivation and engagement.
Morphological Contributions to Adolescent Word Reading: An Item Response Approach
Authors: Goodwin Amanda P. , Gilbert Jennifer K. , Cho Sun‐Joo 
Published: December 2016

AbstractThe current study uses a crossed random‐effects item response model to simultaneously examine both reader and word characteristics and interactions between them that predict the reading of 39 morphologically complex words for 221 middle school students. Results suggest that a reader's ability to read a root word (e.g., isolate) predicts that reader's ability to read a related derived word (e.g., isolation). After controlling for root‐word reading, results also suggest that the remaining variability in derived‐word reading can be explained by word and reader characteristics. The significant word characteristics include derived‐word frequency and root‐word frequency but not morpheme neighborhood size, average family frequency, number of morphemes, or semantic opaqueness. The significant reader characteristics include morphological awareness and vocabulary knowledge but not reading comprehension. Only phonological and orthographic‐phonological opaqueness interacted with the effect of root‐word reading, suggesting that students were less able to apply root‐word knowledge when the root word changed phonologically (with or without an orthographic change) in the larger derived word. Discussion is included regarding how findings from this study inform the development of models of word reading for adolescents.
Assessing the Effectiveness of Two Theoretically Motivated Computer‐Assisted Reading Interventions in the United Kingdom: GG Rime and GG Phoneme
Authors: Kyle Fiona , Kujala Janne , Richardson Ulla , Lyytinen Heikki , Goswami Usha 
Published: December 2016

AbstractWe report an empirical comparison of the effectiveness of two theoretically motivated computer‐assisted reading interventions (CARI) based on the Finnish GraphoGame CARI: English GraphoGame Rime (GG Rime) and English GraphoGame Phoneme (GG Phoneme). Participants were 6–7‐year‐old students who had been identified by their teachers as being relatively poor at reading. The students were divided into three groups. Two of the groups played one of the games as a supplement to normal classroom literacy instruction for five sessions per week for a period of 12 weeks. The third group formed an untreated control. Both games led to gains in reading, spelling, and phonological skills in comparison with the untreated control group. The two interventions also had some differential effects. The intervention gains were maintained at a four‐month follow‐up.