bluuebunny/crossref_metadata_2025 huggingface dataset:
SEMI-ANALYTICAL SOLUTIONS FOR THE BRUSSELATOR REACTION–DIFFUSION MODEL
Authors: ALFIFI H. Y.
Published: October 2017

Semi-analytical solutions are derived for the Brusselator system in one- and two-dimensional domains. The Galerkin method is processed to approximate the governing partial differential equations via a system of ordinary differential equations. Both steady-state concentrations and transient solutions are obtained. Semi-analytical results for the stability of the model are presented for the identified critical parameter value at which a Hopf bifurcation occurs. The impact of the diffusion coefficients on the system is also considered. The results show that diffusion acts to stabilize the systems better than the equivalent nondiffusive systems with the increasing critical value of the Hopf bifurcation. Comparison between the semi-analytical and numerical solutions shows an excellent agreement with the steady-state transient solutions and the parameter values at which the Hopf bifurcations occur. Examples of stable and unstable limit cycles are given, and Hopf bifurcation points are shown to confirm the results previously calculated in the Hopf bifurcation map. The usefulness and accuracy of the semi-analytical results are confirmed by comparison with the numerical solutions of partial differential equations.
MULTIPLICATIVELY CLOSED MARKOV MODELS MUST FORM LIE ALGEBRAS
Authors: SUMNER JEREMY G.
Published: October 2017

We prove that the probability substitution matrices obtained from a continuous-time Markov chain form a multiplicatively closed set if and only if the rate matrices associated with the chain form a linear space spanning a Lie algebra. The key original contribution we make is to overcome an obstruction, due to the presence of inequalities that are unavoidable in the probabilistic application, which prevents free manipulation of terms in the Baker–Campbell–Haursdorff formula.
World health by place: the politics of international health system metrics, 1924–c.2010
Authors: Gorsky Martin , Sirrs Christopher
Published: October 2017

This article examines the development of health system metrics by international organizations, exploring their relationship to the politics of world health. Current historiography treats measurement either as progressive illumination or adopts a critical stance, viewing indicators as instruments of global governance by powerful nations. We draw on diverse statistical publications to provide an empirical overview of change and continuity, beginning with the League of Nations Health Organization, which initiated health system statistics, and concluding with theWorld health report 2000, with its controversial comparative rankings. We then develop analysis and explanation of these trends. Population indicators appeared consistently owing to their protective function and compatibility with development thinking. Others, related to provision, financing, and coverage, appeared more sporadically, owing to changing trends and assumptions in international health. While partly affirming the critical literature, metrics were also used by peripheral or resistant actors to challenge or influence policy at the centre.
CME
Authors: Frank Michelle , Oberhuber Daniela , Flammer Andreas J.
Published: October 2017

Zusammenfassung. Herzinsuffizienz ist ein komplexes klinisches Syndrom. Für die Diagnose nötig sind typische Anamnese, typische Klinik und Evidenz für eine strukturelle oder funktionelle Beeinträchtigung des Herzens. Erste Hilfsmittel der Diagnostik sind das EKG und der NT-ProBNP Wert. Sind beide Parameter negativ, ist eine Herzinsuffizienz ausgeschlossen, ansonsten ist eine Echokardiografie notwendig. Entsprechend der Auswurffraktion wird die Herzinsuffizienz in HFrEF (reduced EF), HFpEF (preserved EF) und HFmrEF (midrange EF) unterschieden. Medikamentös sind ACE-Hemmer, Beta-Blocker und Mineralokortikoid-Antagonisten die Pfeiler der HFrEF-Therapie. Der implantierbare Cardioverter sowie die kardiale Resynchronisation sind weitere therapeutische Optionen.
Psychometric Properties of the Severity Indices of Personality	Problems (SIPP) in Two Samples
Authors: Pedersen Geir , Arnevik Espen Ajo , Hummelen Benjamin , Walderhaug Espen , Wilberg Theresa
Published: October 2017

Abstract. This study investigated psychometric properties of a dimensional measure of maladaptive core pathology for personality disorders, the Severity Indices of Personality Problems (SIPP). The study analyzed data from 941 respondents in a community sample, 949 psychiatric patients with Personality Disorders (PD), and 413 psychiatric patients without PD in Norway. The facets of SIPP had acceptable internal consistency, but the construct validity of some facets had potentials for improvement. The original SIPP domains (the factor structures of the facets) were not supported, and factor analysis gave different results across the three current study samples. All facets of SIPP have good discriminative properties with respect to differentiating between a nonclinical sample, a clinical sample without PD, and a clinical PD sample. Further research and improvements in SIPP are suggested.
Perturbed Wnt signaling leads to neuronal migration delay, altered interhemispheric connections and impaired social behavior
Authors: Bocchi Riccardo , Egervari Kristof , Carol-Perdiguer Laura , Viale Beatrice , Quairiaux Charles , De Roo Mathias , Boitard Michael , Oskouie Suzanne , Salmon Patrick , Kiss Jozsef Z.
Published: October 2017

Perturbed neuronal migration and circuit development have been implicated in the pathogenesis of neurodevelopmental diseases; however, the direct steps linking these developmental errors to behavior alterations remain unknown. Here we demonstrate that Wnt/C-Kit signaling is a key regulator of glia-guided radial migration in rat somatosensory cortex. Transient downregulation of Wnt signaling in migrating, callosal projection neurons results in delayed positioning in layer 2/3. Delayed neurons display reduced neuronal activity with impaired afferent connectivity causing permanent deficit in callosal projections. Animals with these defects exhibit altered somatosensory function with reduced social interactions and repetitive movements. Restoring normal migration by overexpressing the Wnt-downstream effector C-Kit or selective chemogenetic activation of callosal projection neurons during a critical postnatal period prevents abnormal interhemispheric connections as well as behavioral alterations. Our findings identify a link between defective canonical Wnt signaling, delayed neuronal migration, deficient interhemispheric connectivity and abnormal social behavior analogous to autistic characteristics in humans.
BCL-XL directly modulates RAS signalling to favour cancer cell stemness
Authors: Carné Trécesson Sophie de , Souazé Frédérique , Basseville Agnès , Bernard Anne-Charlotte , Pécot Jessie , Lopez Jonathan , Bessou Margaux , Sarosiek Kristopher A. , Letai Anthony , Barillé-Nion Sophie , Valo Isabelle , Coqueret Olivier , Guette Catherine , Campone Mario , Gautier Fabien , Juin Philippe Paul
Published: October 2017

In tumours, accumulation of chemoresistant cells that express high levels of anti-apoptotic proteins such as BCL-XL is thought to result from the counter selection of sensitive, low expresser clones during progression and/or initial treatment. We herein show that BCL-XL expression is selectively advantageous to cancer cell populations even in the absence of pro-apoptotic pressure. In transformed human mammary epithelial cells BCL-XL favours full activation of signalling downstream of constitutively active RAS with which it interacts in a BH4-dependent manner. Comparative proteomic analysis and functional assays indicate that this is critical for RAS-induced expression of stemness regulators and maintenance of a cancer initiating cell (CIC) phenotype. Resistant cancer cells thus arise from a positive selection driven by BCL-XL modulation of RAS-induced self-renewal, and during which apoptotic resistance is not necessarily the directly selected trait.
Genomic variation in microbial populations inhabiting the marine subseafloor at deep-sea hydrothermal vents
Authors: Anderson Rika E. , Reveillaud Julie , Reddington Emily , Delmont Tom O. , Eren A. Murat , McDermott Jill M. , Seewald Jeff S. , Huber Julie A.
Published: October 2017

Little is known about evolutionary drivers of microbial populations in the warm subseafloor of deep-sea hydrothermal vents. Here we reconstruct 73 metagenome-assembled genomes (MAGs) from two geochemically distinct vent fields in the Mid-Cayman Rise to investigate patterns of genomic variation within subseafloor populations. Low-abundance populations with high intra-population diversity coexist alongside high-abundance populations with low genomic diversity, with taxonomic differences in patterns of genomic variation between the mafic Piccard and ultramafic Von Damm vent fields. Populations from Piccard are significantly enriched in nonsynonymous mutations, suggesting stronger purifying selection in Von Damm relative to Piccard. Comparison of nine Sulfurovum MAGs reveals two high-coverage, low-diversity MAGs from Piccard enriched in unique genes related to the cellular membrane, suggesting these populations were subject to distinct evolutionary pressures that may correlate with genes related to nutrient uptake, biofilm formation, or viral invasion. These results are consistent with distinct evolutionary histories between geochemically different vent fields, with implications for understanding evolutionary processes in subseafloor microbial populations.
Sliding of coherent twin boundaries
Authors: Wang Zhang-Jie , Li Qing-Jie , Li Yao , Huang Long-Chao , Lu Lei , Dao Ming , Li Ju , Ma Evan , Suresh Subra , Shan Zhi-Wei
Published: October 2017

Coherent twin boundaries (CTBs) are internal interfaces that can play a key role in markedly enhancing the strength of metallic materials while preserving their ductility. They are known to accommodate plastic deformation primarily through their migration, while experimental evidence documenting large-scale sliding of CTBs to facilitate deformation has thus far not been reported. We show here that CTB sliding is possible whenever the loading orientation enables the Schmid factors of leading and trailing partial dislocations to be comparable to each other. This theoretical prediction is confirmed by real-time transmission electron microscope experimental observations during uniaxial deformation of copper pillars with different orientations and is further validated at the atomic scale by recourse to molecular dynamics simulations. Our findings provide mechanistic insights into the evolution of plasticity in heavily twinned face-centered cubic metals, with the potential for optimizing mechanical properties with nanoscale CTBs in material design.
A potent small-molecule inhibitor of the DCN1-UBC12 interaction that selectively blocks cullin 3 neddylation
Authors: Zhou Haibin , Lu Jianfeng , Liu Liu , Bernard Denzil , Yang Chao-Yie , Fernandez-Salas Ester , Chinnaswamy Krishnapriya , Layton Stephanie , Stuckey Jeanne , Yu Qing , Zhou Weihua , Pan Zhenqiang , Sun Yi , Wang Shaomeng
Published: October 2017

The Cullin-RING E3 ubiquitin ligases (CRLs) regulate homeostasis of ~20% of cellular proteins and their activation require neddylation of their cullin subunit. Cullin neddylation is modulated by a scaffolding DCN protein through interactions with both the cullin protein and an E2 enzyme such as UBC12. Here we report the development of DI-591 as a high-affinity, cell-permeable small-molecule inhibitor of the DCN1–UBC12 interaction. DI-591 binds to purified recombinant human DCN1 and DCN2 proteins with Ki values of 10–12 nM, and disrupts the DCN1–UBC12 interaction in cells. Treatment with DI-591 selectively converts cellular cullin 3 into an un-neddylated inactive form with no or minimum effect on other cullin members. Our data firmly establish a previously unrecognized specific role of the DCN1–UBC12 interaction for cellular neddylation of cullin 3. DI-591 is an excellent probe compound to investigate the role of the cullin 3 CRL ligase in biological processes and human diseases.
Harnessing a catalytic lysine residue for the one-step preparation of homogeneous antibody-drug conjugates
Authors: Nanna Alex R. , Li Xiuling , Walseng Even , Pedzisa Lee , Goydel Rebecca S. , Hymel David , Burke Terrence R. , Roush William R. , Rader Christoph
Published: October 2017

Current strategies to produce homogeneous antibody-drug conjugates (ADCs) rely on mutations or inefficient conjugation chemistries. Here we present a strategy to produce site-specific ADCs using a highly reactive natural buried lysine embedded in a dual variable domain (DVD) format. This approach is mutation free and drug conjugation proceeds rapidly at neutral pH in a single step without removing any charges. The conjugation chemistry is highly robust, enabling the use of crude DVD for ADC preparation. In addition, this strategy affords the ability to precisely monitor the efficiency of drug conjugation with a catalytic assay. ADCs targeting HER2 were prepared and demonstrated to be highly potent and specific in vitro and in vivo. Furthermore, the modular DVD platform was used to prepare potent and specific ADCs targeting CD138 and CD79B, two clinically established targets overexpressed in multiple myeloma and non-Hodgkin lymphoma, respectively.
Generalist species drive microbial dispersion and evolution
Authors: Sriswasdi Sira , Yang Ching-chia , Iwasaki Wataru
Published: October 2017

Microbes form fundamental bases of every Earth ecosystem. As their key survival strategies, some microbes adapt to broad ranges of environments, while others specialize to certain habitats. While ecological roles and properties of such “generalists” and “specialists” had been examined in individual ecosystems, general principles that govern their distribution patterns and evolutionary processes have not been characterized. Here, we thoroughly identified microbial generalists and specialists across 61 environments via meta-analysis of community sequencing data sets and reconstructed their evolutionary histories across diverse microbial groups. This revealed that generalist lineages possess 19-fold higher speciation rates and significant persistence advantage over specialists. Yet, we also detected three-fold more frequent generalist-to-specialist transformations than the reverse transformations. These results support a model of microbial evolution in which generalists play key roles in introducing new species and maintaining taxonomic diversity.
HGF/R-spondin1 rescues liver dysfunction through the induction of Lgr5+ liver stem cells
Authors: Lin Yuan , Fang Zhe-Ping , Liu Hong-Juan , Wang Li-Jing , Cheng Zhiqiang , Tang Na , Li Tingting , Liu Tengfei , Han Hai-Xiong , Cao Guangwen , Liang Li , Ding Yan-Qing , Zhou Wei-Jie
Published: October 2017

Induction of endogenous adult stem cells by administering soluble molecules provides an advantageous approach for tissue damage repair, which could be a clinically applicable and cost-effective alternative to transplantation of embryonic or pluripotent stem cell-derived tissues for the treatment of acute organ failures. Here, we show that HGF/Rspo1 induce liver stem cells and rescue liver dysfunction. Carbon tetrachloride treatment promotes both fibrosis and Lgr5+ liver stem cell proliferation, whereas Lgr5 knockdown worsens fibrosis. Injection of HGF in combination with Rspo1 increases the number of Lgr5+ liver stem cells and improves liver function by attenuating fibrosis. We observe Lgr5+ liver stem cells in human liver fibrosis tissues, and once they are isolated, these cells are able to form organoids, and treatment with HGF/Rspo1 promotes their expansion. We suggest that Lgr5+ liver stem cells represent a valuable target for liver damage treatment, and that HGF/Rspo1 can be used to promote liver stem cell expansion.
Human microbiome signatures of differential colorectal cancer drug metabolism
Authors: Guthrie Leah , Gupta Sanchit , Daily Johanna , Kelly Libusha
Published: October 2017

It is well appreciated that microbial metabolism of drugs can influence treatment efficacy. Microbial β-glucuronidases in the gut can reactivate the excreted, inactive metabolite of irinotecan, a first-line chemotherapeutic for metastatic colorectal cancer. Reactivation causes adverse drug responses, including severe diarrhea. However, a direct connection between irinotecan metabolism and the composition of an individual’s gut microbiota has not previously been made. Here, we report quantitative evidence of inter-individual variability in microbiome metabolism of the inactive metabolite of irinotecan to its active form. We identify a high turnover microbiota metabotype with potentially elevated risk for irinotecan-dependent adverse drug responses. We link the high turnover metabotype to unreported microbial β-glucuronidases; inhibiting these enzymes may decrease irinotecan-dependent adverse drug responses in targeted subsets of patients. In total, this study reveals metagenomic mining of the microbiome, combined with metabolomics, as a non-invasive approach to develop biomarkers for colorectal cancer treatment outcomes.
Neutrophil-lymphocyte Ratio Plus Prognostic Nutritional Index Predicts the Outcomes of Patients with Unresectable Hepatocellular Carcinoma After Transarterial Chemoembolization
Authors: Liu Chang , Li Lei , Lu Wu-sheng , Du Hua , Yan Lu-nan , Yang Jia-yin , Wen Tian-fu , Zeng Guo-jun , Jiang Li , Yang Jian
Published: October 2017

For many malignancies, inflammation-based scores correlate with survival. The neutrophil-to-lymphocyte ratio (NLR) and prognostic nutritional index (PNI) are immunonutritional indices associated with postoperative outcomes in patients with hepatocellular carcinoma (HCC). We evaluated whether a combined preoperative NLR and PNI score was prognostically superior to either index alone in 793 patients with unresectable HCC after transarterial chemoembolization. Patient demographic, clinical, and pathological data were also collected and analysed. A receiver-operating characteristic (ROC) analysis was used to classify patients as follows: NLR-PNI 0 group (NLR ≤ 2.2 and PNI > 46), NLR-PNI 1 group (NLR > 2.2 or PNI ≤ 46) and NLR-PNI 2 group (NLR > 2.2 and PNI ≤ 46). Regarding 1-, 3-, and 5-year survival, the NLR-PNI score had superior discriminative abilities (i.e., higher area under the ROC curve), compared with either the NLR or PNI alone, and patients in the NLR-PNI 0, 1, and 2 groups had median survival times of 33 (95% confidence interval: 22.8–43.2), 14 (10.9–17.1), and 6 (9.9–14.1) months, respectively. In multivariate analyses, the Barcelona Clinic Liver Cancer, total bilirubin, vascular invasion, and NLR-PNI score adversely affected overall survival. In conclusion, the NLR-PNI score can improve the accuracy of prognoses for patients with unresectable HCC.
The liquid-glass-jamming transition in disordered ionic nanoemulsions
Authors: Braibanti Marco , Kim Ha Seong , Şenbil Nesrin , Pagenkopp Matthew J. , Mason Thomas G. , Scheffold Frank
Published: October 2017

In quenched disordered out-of-equilibrium many-body colloidal systems, there are important distinctions between the glass transition, which is related to the onset of nonergodicity and loss of low-frequency relaxations caused by crowding, and the jamming transition, which is related to the dramatic increase in elasticity of the system caused by the deformation of constituent objects. For softer repulsive interaction potentials, these two transitions become increasingly smeared together, so measuring a clear distinction between where the glass ends and where jamming begins becomes very difficult or even impossible. Here, we investigate droplet dynamics in concentrated silicone oil-in-water nanoemulsions using light scattering. For zero or low NaCl electrolyte concentrations, interfacial repulsions are soft and longer in range, this transition sets in at lower concentrations, and the glass and the jamming regimes are smeared. However, at higher electrolyte concentrations the interactions are stiffer, and the characteristics of the glass-jamming transition resemble more closely the situation of disordered elastic spheres having sharp interfaces, so the glass and jamming regimes can be distinguished more clearly.
Therapeutic potential of the phosphino Cu(I) complex (HydroCuP) in the treatment of solid tumors
Authors: Gandin Valentina , Ceresa Cecilia , Esposito Giovanni , Indraccolo Stefano , Porchia Marina , Tisato Francesco , Santini Carlo , Pellei Maura , Marzano Cristina
Published: October 2017

[Cu(thp)4][PF6] (HydroCuP) is a phosphino copper(I) complex highly soluble and stable in physiological media that has been developed as a possible viable alternative to platinum-based drugs for anticancer therapy. HydroCuP potently inhibited the growth of human cancer cells derived from solid tumors by inducing endoplasmatic reticulum (ER) stress thus leading to cell death through paraptosis with a preferential efficacy against cancer rather than non-cancer cells. Aim of the present study was to assess the therapeutic potential of HydroCuPin vivo, in syngenic and xenograft murine models of solid tumors by triggering the Unfolded Protein Response (UPR) pathway. With respect to platinum drugs, HydroCuP induced a markedly higher reduction of tumor growth associated with minimal animal toxicity. In human colorectal cancer xenografts, chemotherapy with HydroCuP was extremely effective in both oxaliplatin-sensitive and resistant models. The favorablein vivotolerability of HydroCuP was also correlated to an encouraging biodistribution profile. Additionally, no signs of drug-related neurotoxicity and nephrotoxicity were observed. Altogether, these results demonstrate that HydroCuP appears worth of further investigation to evaluate its therapeutic activity towards a broad spectrum of solid malignancies.
Towards an understanding of spiral patterning in the Sargassum muticum shoot apex
Authors: Linardić Marina , Braybrook Siobhan A.
Published: October 2017

In plants and parenchymatous brown algae the body arises through the activity of an apical meristem (a niche of cells or a single cell). The meristem produces lateral organs in specific patterns, referred to as phyllotaxis. In plants, two different control mechanisms have been proposed: one is position-dependent and relies on morphogen accumulation at future organ sites; the other is a lineage-based system which links phyllotaxis to the apical cell division pattern. Here we examine the apical patterning of the brown alga, Sargassum muticum, which exhibits spiral phyllotaxis (137.5° angle) and an unlinked apical cell division pattern. The Sargassum apex presents characteristics of a self-organising system, similar to plant meristems. In contrast to complex plant meristems, we were unable to correlate the plant morphogen auxin with bud positioning in Sargassum, nor could we predict cell wall softening at new bud sites. Our data suggests that in Sargassum muticum there is no connection between phyllotaxis and the apical cell division pattern indicating a position-dependent patterning mechanism may be in place. The underlying mechanisms behind the phyllotactic patterning appear to be distinct from those seen in plants.
Cytoplasmic cyclin D1 controls the migration and invasiveness of mantle lymphoma cells
Authors: Body Simon , Esteve-Arenys Anna , Miloudi Hadjer , Recasens-Zorzo Clara , Tchakarska Guergana , Moros Alexandra , Bustany Sophie , Vidal-Crespo Anna , Rodriguez Vanina , Lavigne Régis , Com Emmanuelle , Casanova Isolda , Mangues Ramón , Weigert Oliver , Sanjuan-Pla Alejandra , Menéndez Pablo , Marcq Bénédicte , Picquenot Jean-Michel , Pérez-Galán Patricia , Jardin Fabrice , Roué Gaël , Sola Brigitte
Published: October 2017

Mantle cell lymphoma (MCL) is a hematologic neoplasm characterised by the t(11;14)(q13;q32) translocation leading to aberrant cyclin D1 expression. The cell functions of cyclin D1 depend on its partners and/or subcellular distribution, resulting in different oncogenic properties. We observed the accumulation of cyclin D1 in the cytoplasm of a subset of MCL cell lines and primary cells. In primary cells, this cytoplasmic distribution was correlated with a more frequent blastoid phenotype. We performed immunoprecipitation assays and mass spectrometry on enriched cytosolic fractions from two cell lines. The cyclin D1 interactome was found to include several factors involved in adhesion, migration and invasion. We found that the accumulation of cyclin D1 in the cytoplasm was associated with higher levels of migration and invasiveness. We also showed that MCL cells with high cytoplasmic levels of cyclin D1 engrafted more rapidly into the bone marrow, spleen, and brain in immunodeficient mice. Both migration and invasion processes, both in vivo and in vitro, were counteracted by the exportin 1 inhibitor KPT-330, which retains cyclin D1 in the nucleus. Our data reveal a role of cytoplasmic cyclin D1 in the control of MCL cell migration and invasion, and as a true operator of MCL pathogenesis.
Obstetric outcomes in pregnant women with and without depression: population-based comparison
Authors: Huang Hui-Chun , Sung Fung-Chang , Chen Pei-Chun , Chang Cherry Yin-Yi , Muo Chih-Hsin , Shiue Huei-Sheng , Huang Jian-Pei , Li Tsai-Chung , Tzeng Ya-Ling , Wu Shu-I
Published: October 2017

This study used insurance claims data to evaluate obstetric outcomes in pregnant women with and without depression because population study for Asian women on the issue is limited. We identified 5,064 women with depression at pregnancy in 2005–2013, and 20,024 pregnant women without depression, frequency matched by age, pregnant year and parity. Obstetric events during pregnancy and deliveries were evaluated. The depression group had more events than comparisons for hyperemesis (39.3 vs. 35.5%), abortion (3.3 vs. 2.6%), malpresentation (12.3 vs. 10.3%), C-section (40.2 vs. 34.6%) and intrauterine fetal demise (0.7 vs. 0.4%); risks of these events were significant for childbearing depressed women, not for the 35+ years subgroup. These incidences were higher in depressed women taking antidepressant than those without the medication, but were significant in childbearing depressed subgroup for hyperemesis and C-section with odds ratios of 1.18 (95% confidence intervals (CI), 1.02–1.36) and 1.29 (95% CI, 1.11–1.49), respectively. Incident preterm and low birth weight births were also higher in the depression group than in comparisons, but weren’t significant. In conclusion, women with depression during pregnancy may develop more adverse events than comparisons and are more likely to have a C-section delivery.
ALK and IGF-1R as independent targets in crizotinib resistant lung cancer
Authors: Wilson Christabel , Nimick Mhairi , Nehoff Hayley , Ashton John C.
Published: October 2017

ALK positive non-small cell lung cancer is highly responsive to ALK inhibitors such as crizotinib, but drug resistance typically develops within a year of treatment. In this study we investigated whether IGF-1R is an independent druggable target in ALK-positive lung cancer cells. We confirmed that combination ALK and IGF-1R inhibitor treatment is synergistically cytotoxic to ALK-positive lung cancer cells and that this remains the case for at least 12 days after initial exposure to crizotinib. ALK-positive cells with acquired resistance to crizotinib did not acquire cross-resistance to IGF-1R inhibition, though combination treatment in the resistant cells gave additive rather than synergistic cytotoxicity. We concluded that IGF-1R is an independent druggable target in ALK-positive lung cancer and support the trial of combination treatment.
Specific neurophysiological mechanisms underlie cognitive inflexibility in inflammatory bowel disease
Authors: Petruo Vanessa A , Zeißig Sebastian , Schmelz Renate , Hampe Jochen , Beste Christian
Published: October 2017

Inflammatory bowel disease (IBD) is highly prevalent. While the pathophysiological mechanisms of IBD are increasingly understood, there is a lack of knowledge concerning cognitive dysfunctions in IBD. This is all the more the case concerning the underlying neurophysiological mechanisms. In the current study we focus on possible dysfunctions of cognitive flexibility (task switching) processes in IBD patients using a system neurophysiological approach combining event-related potential (ERP) recordings with source localization analyses. We show that there are task switching deficits (i.e. increased switch costs) in IBD patients. The neurophysiological data show that even though the pathophysiology of IBD is diverse and wide-spread, only specific cognitive subprocesses are altered: There was a selective dysfunction at the response selection level (N2 ERP) associated with functional alterations in the anterior cingulate cortex and the right inferior frontal gyrus. Attentional selection processes (N1 ERP), perceptual categorization processes (P1 ERP), or mechanisms related to the flexible implementation of task sets and related working memory processes (P3 ERP) do not contribute to cognitive inflexibility in IBD patients and were unchanged. It seems that pathophysiological processes in IBD strongly compromise cognitive-neurophysiological subprocesses related to fronto-striatal networks. These circuits may become overstrained in IBD when cognitive flexibility is required.
4-Hydroxybenzaldehyde accelerates acute wound healing through activation of focal adhesion signalling in keratinocytes
Authors: Kang Chan Woo , Han Ye Eon , Kim Jean , Oh Joo Heon , Cho Yoon Hee , Lee Eun Jig
Published: October 2017

4-Hydroxybenzaldehyde (4-HBA) is a naturally occurring benzaldehyde and the major active constituent of Gastrodia elata. While recent studies have demonstrated metabolic effects of 4-HBA, little is known about the physiological role of 4-HBA in acute wound healing. Here, we investigated the effects and mechanisms of 4-HBA on acute wound healing. Using an in vitro approach, we found that 4-HBA significantly promoted keratinocyte cell migration and invasion by increasing focal adhesion kinase and Src activity. In addition, 4-HBA treatment also promoted wound healing and re-epithelialization in an in vivo excision wound animal model. Combination treatment with 4-HBA and platelet-derived growth factor subunit B homodimer showed synergistic effects in promoting wound healing. Taken together, our results demonstrated that treatment with 4-HBA promoted keratinocyte migration and wound healing in mouse skin through the Src/mitogen-activated protein kinase pathway. Therefore, 4-HBA could be a candidate therapeutic agent with the potential to promote acute wound healing.
Genomic predictive model for recurrence and metastasis development in head and neck squamous cell carcinoma patients
Authors: Ribeiro Ilda Patrícia , Caramelo Francisco , Esteves Luísa , Menoita Joana , Marques Francisco , Barroso Leonor , Miguéis Jorge , Melo Joana Barbosa , Carreira Isabel Marques
Published: October 2017

The head and neck squamous cell carcinoma (HNSCC) population consists mainly of high-risk for recurrence and locally advanced stage patients. Increased knowledge of the HNSCC genomic profile can improve early diagnosis and treatment outcomes. The development of models to identify consistent genomic patterns that distinguish HNSCC patients that will recur and/or develop metastasis after treatment is of utmost importance to decrease mortality and improve survival rates. In this study, we used array comparative genomic hybridization data from HNSCC patients to implement a robust model to predict HNSCC recurrence/metastasis. This predictive model showed a good accuracy (>80%) and was validated in an independent population from TCGA data portal. This predictive genomic model comprises chromosomal regions from 5p, 6p, 8p, 9p, 11q, 12q, 15q and 17p, where several upstream and downstream members of signaling pathways that lead to an increase in cell proliferation and invasion are mapped. The introduction of genomic predictive models in clinical practice might contribute to a more individualized clinical management of the HNSCC patients, reducing recurrences and improving patients’ quality of life. The power of this genomic model to predict the recurrence and metastases development should be evaluated in other HNSCC populations.
Disulfide cross-linked multimers of TDP-43 and spinal motoneuron loss in a TDP-43A315T ALS/FTD mouse model
Authors: Bargsted Leslie , Medinas Danilo B. , Martínez Traub Francisca , Rozas Pablo , Muñoz Natalia , Nassif Melissa , Jerez Carolina , Catenaccio Alejandra , Court Felipe A. , Hetz Claudio , Matus Soledad
Published: October 2017

Tar DNA binding protein 43 (TDP-43) is the principal component of ubiquitinated protein inclusions present in nervous tissue of most cases of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Previous studies described a TDP-43A315T transgenic mouse model that develops progressive motor dysfunction in the absence of protein aggregation or significant motoneuron loss, questioning its validity to study ALS. Here we have further characterized the course of the disease in TDP-43A315T mice using a battery of tests and biochemical approaches. We confirmed that TDP-43 mutant mice develop impaired motor performance, accompanied by progressive body weight loss. Significant differences were observed in life span between genders, where females survived longer than males. Histopathological analysis of the spinal cord demonstrated a significant motoneurons loss, accompanied by axonal degeneration, astrogliosis and microglial activation. Importantly, histopathological alterations observed in TDP-43 mutant mice were similar to some characteristic changes observed in mutant SOD1 mice. Unexpectedly, we identified the presence of different species of disulfide-dependent TDP-43 aggregates in cortex and spinal cord tissue. Overall, this study indicates that TDP-43A315T transgenic mice develop key features resembling key aspects of ALS, highlighting its relevance to study disease pathogenesis.
Interaction Between the Trace Amine-Associated Receptor 1 and the Dopamine D2 Receptor Controls Cocaine’s Neurochemical Actions
Authors: Asif-Malik Aman , Hoener Marius C. , Canales Juan J.
Published: October 2017

Recent evidence suggests that the trace amine-associated receptor 1 (TAAR1) plays a pivotal role in the regulation of dopamine (DA) transmission and cocaine’s actions. However, the underlying mechanisms through which TAAR1 activation mediates these effects have not yet been elucidated. Here, we used fast-scan cyclic voltammetry to measure DA dynamics and explore such mechanisms. We show, first, that the full TAAR1 agonist, RO5256390, dose-dependently blocked cocaine-induced inhibition of DA clearance in slices of the nucleus accumbens. Second, subthreshold inhibition of PKA or PKC phosphorylation did not prevent TAAR1 suppression of cocaine effects whereas subeffective doses of the DA D2 receptor antagonist, L-741,626, rescued cocaine’s ability to produce changes in DA uptake in the presence of full TAAR1 activation, thus indicating that TAAR1 modulation of cocaine effects requires simultaneous DA D2 receptor activation. Predictably, inhibition of glycogen synthase kinase-3 (GSK-3), which results from activation of D2/TAAR1 heterodimers, fully reproduced the inhibitory effects of TAAR1 activation on cocaine-induced changes in DA transmission. Collectively, the present observations reveal that the ability of TAAR1 to regulate cocaine effects is linked to cooperative interactions with D2 autoreceptors and associated downstream molecular targets converging on GSK-3 and suggest a new mechanism to disrupt cocaine neurochemical actions.
Identification of MST1 as a potential early detection biomarker for colorectal cancer through a proteomic approach
Authors: Yu Jiekai , Zhai Xiaohui , Li Xiaofen , Zhong Chenhan , Guo Cheng , Yang Fuquan , Yuan Ying , Zheng Shu
Published: October 2017

Colorectal cancer (CRC) is a common malignant neoplasm worldwide. It is important to identify new biomarkers for the early detection of CRC. In this study, magnetic beads and the Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) platform were used to analyse CRC and healthy control (HC) serum samples. The CRC diagnosis pattern was established to have a specificity of 94.7% and sensitivity of 92.3% in a blind test. The candidate biomarker serine/threonine kinase 4 (STK4, also known as MST1) was identified by Tandem mass spectrometry (MS/MS) and verified with western blotting and enzyme-linked immunosorbent assay (ELISA). The results indicated that there was a higher concentration of MST1 in HC subjects than stage I CRC patients for the early detection of CRC and a lower concentration in stage IV patients than in other CRC patients. The sensitivity and specificity of MST1 combined with carcinoembryonic antigen (CEA) and faecal occult blood test (FOBT) in diagnosis of colorectal cancer were 92.3% and 100%, respectively. Additionally, low MST1 expression was associated with the poor prognosis. These results illustrate that MST1 is a potential biomarker for early detection, prognosis and prediction of distant metastasis of CRC.
Ocular antigen does not cause disease unless presented in the context of inflammation
Authors: Voigt Valentina , Wikstrom Matthew E. , Kezic Jelena M. , Schuster Iona S. , Fleming Peter , Makinen Kimmo , Daley Stephen R. , Andoniou Christopher E. , Degli-Esposti Mariapia A. , Forrester John V.
Published: October 2017

Ocular antigens are sequestered behind the blood-retina barrier and the ocular environment protects ocular tissues from autoimmune attack. The signals required to activate autoreactive T cells and allow them to cause disease in the eye remain in part unclear. In particular, the consequences of peripheral presentation of ocular antigens are not fully understood. We examined peripheral expression and presentation of ocular neo-self-antigen in transgenic mice expressing hen egg lysozyme (HEL) under a retina-specific promoter. High levels of HEL were expressed in the eye compared to low expression throughout the lymphoid system. Adoptively transferred naïve HEL-specific CD4+T cells proliferated in the eye draining lymph nodes, but did not induce uveitis. By contrast, systemic infection with a murine cytomegalovirus (MCMV) engineered to express HEL induced extensive proliferation of transferred naïve CD4+T cells, and significant uveoretinitis. In this model, wild-type MCMV, lacking HEL, did not induce overt uveitis, suggesting that disease is mediated by antigen-specific peripherally activated CD4+T cells that infiltrate the retina. Our results demonstrate that retinal antigen is presented to T cells in the periphery under physiological conditions. However, when the same antigen is presented during viral infection, antigen-specific T cells access the retina and autoimmune uveitis ensues.
Lateral Boundary of Cirrus Cloud from CALIPSO Observations
Authors: Fu Yunfei , Chen Yilun , Li Rui , Qin Fang , Xian Tao , Yu Lu , Zhang Aoqi , Liu Guosheng , Zhang Xiangdong
Published: October 2017

Absract

Due to the thinness and small scale of cirrus clouds, its lateral boundary may be missed by conventional passive remote-sensing techniques and climate models. Here, using satellite observations in June–August from 2006 to 2011, a global dataset for the cirrus cloud lateral boundary (CCLB) was established. The results indicate that the optical properties, such as the lidar backscatter, the depolarization ratio and the optical depth, sharply decrease from cloudy regions to clear-sky regions. There are significant regional differences in optical properties and height and thickness of the CCLB. Based on a quantitative estimation, the strongest longwave warming effects (>0.3 W m−2) are found near the Equator and over tropical continents. The global average longwave warming effect of the CCLB is at least 0.07 W m−2, which is much larger than some of the radiative forcings considered in the Intergovernmental Panel on Climate Change (IPCC) reports. Specifically, the CCLB in traditional “clear-sky” region may be totally missed by current models and IPCC reports, which contributes 28.25% (~0.02 W m−2) of the whole CCLB radiative effect, twice greater than contrail effect. It is recommended that the CCLB effect should be taken account in future climate models and the next IPCC reports.
Experimental imaging in orthotopic renal cell carcinoma xenograft models: comparative evaluation of high-resolution 3D ultrasonography, in-vivo micro-CT and 9.4T MRI
Authors: Linxweiler Johannes , Körbel Christina , Müller Andreas , Jüngel Eva , Blaheta Roman , Heinzelmann Joana , Stöckle Michael , Junker Kerstin , Menger Michael D. , Saar Matthias
Published: October 2017

In this study, we aimed to comparatively evaluate high-resolution 3D ultrasonography (hrUS), in-vivo micro-CT (μCT) and 9.4T MRI for the monitoring of tumor growth in an orthotopic renal cell carcinoma (RCC) xenograft model since there is a lack of validated, non-invasive imaging tools for this purpose. 1 × 106 Caki-2 RCC cells were implanted under the renal capsule of 16 immunodeficient mice. Local and systemic tumor growth were monitored by regular hrUS, μCT and MRI examinations. Cells engrafted in all mice and gave rise to exponentially growing, solid tumors. All imaging techniques allowed to detect orthotopic tumors and to precisely calculate their volumes. While tumors appeared homogenously radiolucent in μCT, hrUS and MRI allowed for a better visualization of intratumoral structures and surrounding soft tissue. Examination time was the shortest for hrUS, followed by μCT and MRI. Tumor volumes determined by hrUS, μCT and MRI showed a very good correlation with each other and with caliper measurements at autopsy. 10 animals developed pulmonary metastases being well detectable by μCT and MRI. In conclusion, each technique has specific strengths and weaknesses, so the one(s) best suitable for a specific experiment may be chosen individually.
Hollow optical fiber induced solar cells with optical energy storage and conversion
Authors: Ding Jie , Zhao Yuanyuan , Duan Jialong , Duan Yanyan , Tang Qunwei
Published: October 2017

Hollow optical fiber induced dye-sensitized solar cells are made by twisting Ti wire/N719-TiO2 nanotube photoanodes and Ti wire/Pt (CoSe, Pt3Ni) counter electrodes.
Pseudopolymorphism based on 1D metallacyclic chains constructed from an angular zwitterionic ditopic diacid organic linker
Authors: Huang Yong-Qing , Li Zong-Ge , Chen Huai-Ying , Cheng Hai-Di , Wang Yang , Ren Yong-He , Zhao Yue , Liu Li
Published: October 2017

Two pseudopolymorphs based on one dimensional metallacyclic chains display crystalline-form-dependent optical properties.
Coupled-cluster sum-frequency generation nonlinear susceptibilities of methyl (CH3) and methylene (CH2) groups
Authors: Tetsassi Feugmo Conrard Giresse , Liégeois Vincent , Champagne Benoît
Published: October 2017

CCSD benchmarks of the sum-frequency generation vibrational signatures of methyl and methylene groups.
Concomitant polymorphism and the martensitic-like transformation of an organic crystal
Authors: Ruggiero Michael T. , Axel Zeitler J. , Korter Timothy M.
Published: October 2017

Terahertz vibrational spectroscopy and solid-state density functional theory together reveal the true nature of a pseudo-continuous crystalline polymorphic phase transition.
Prediction of topological crystalline insulators and topological phase transitions in two-dimensional PbTe films
Authors: Jia Yi-zhen , Ji Wei-xiao , Zhang Chang-wen , Li Ping , Zhang Shu-feng , Wang Pei-ji , Li Sheng-shi , Yan Shi-shen
Published: October 2017

Topological phases, especially topological crystalline insulators (TCIs), have been intensively explored and observed experimentally in three-dimensional (3D) materials.
Mutation L1196M-induced conformational changes and the drug resistant mechanism of anaplastic lymphoma kinase studied by free energy perturbation and umbrella sampling
Authors: Chen Jianzhong , Wang Jinan , Zhu Weiliang
Published: October 2017

Anaplastic lymphoma kinase (ALK) has been regarded as a promising drug target in the treatment of tumors and the mutation L1196M induces different levels of drug resistance toward the existing inhibitors.
Photophysical dynamics of a binuclear Cu(i)-emitter on the fs to μs timescale, in solid phase and in solution
Authors: Bäppler F. , Zimmer M. , Dietrich F. , Grupe M. , Wallesch M. , Volz D. , Bräse S. , Gerhards M. , Diller R.
Published: October 2017

Photophysical analyses by applying different fs and ns time-resolved transient absorption and reflectivity spectroscopic methods to investigate fundamental processes in binuclear Cu(i) containing complexes.
Effect of cooling on droplet size in supersaturation-induced emulsions
Authors: Luo Shirui , Schiffbauer Jarrod , Luo Tengfei
Published: October 2017

In this work, the droplet size in a water-in-oil emulsion obtained by supersaturation is studied. The average size of water droplets in the emulsion is found to be proportional to the square root of the cooling rate.
Hydrogen evolution based on the electrons/protons stored on amorphous TiO2
Authors: Zeng Shuwen , Zhang Ling , Wang Wenzhong , Shao Dengkui , Hao Hongchang
Published: October 2017

The hydrogen evolution reaction (HER) using recyclable mediator is being actively pursued as a route for solar energy conversion.
Computer simulation of water desalination through boron nitride nanotubes
Authors: Liang Lijun , Li Jia-Chen , Zhang Li , Zhang Zhisen , Shen Jia-Wei , Li Lihua , Wu Jianyang
Published: October 2017

The selectivity of Na+over water could be attributed to the confinement and solvation structure of Na+.
Accumulation of counterions and coions evaluated by cryogenic XPS as a new tool for describing the structure of electric double layer at the silica/water interface
Authors: Škvarla Jiří , Kaňuchová Mária , Shchukarev Andrey , Brezáni Ivan , Škvarla Juraj
Published: October 2017

We introduce a new method of evaluating the structure of electric double layer (EDL) at the native solid/liquid interface using cryogenic X-ray photoelectron spectroscopy technique.
Chirality in adsorption on solid surfaces
Authors: Zaera Francisco
Published: October 2017

Chemical chirality on solid surfaces has important implications in analytical separations, selective crystallizations and catalysis, and may help explain the origin of homochirality in life.
Facile synthesis of highly biocompatible folic acid-functionalised SiO2nanoparticles encapsulating rare-earth metal complexes, and their application in targeted drug delivery
Authors: Xu Xiuling , Hu Fan , Shuai Qi
Published: October 2017

Herein, we report the facile synthesis of highly biocompatible folic acid-functionalized SiO2nanoparticles encapsulating rare-earth metal complexes, and their application in targeted metal complex delivery.
Cyclic ureas (DMI, DMPU) as efficient, sustainable ligands in iron-catalyzed C(sp2)–C(sp3) coupling of aryl chlorides and tosylates
Authors: Bisz Elwira , Szostak Michal
Published: October 2017

We report that cyclic ureas (DMI, DMPU) are efficient and sustainable alternatives to reprotoxic NMP in challenging iron-catalyzed C(sp2)–C(sp3) alkylations of aryl chlorides and tosylates with alkyl Grignard reagents.
Elucidation of the role of betaine hydrochloride in glycerol esterification: towards bio-based ionic building blocks
Authors: Journoux-Lapp C. , De Oliveira Vigier K. , Bachmann C. , Marinkovic S. , Estrine B. , Frapper G. , Jérôme F.
Published: October 2017

The esterification of betaine hydrochloride with glycerol does not involve any carbocation intermediate as usual. This finding permits the synthesis of bio-based ionic building blocks with unprecedented yield and with space time yield.
High-efficiency single cell encapsulation and size selective capture of cells in picoliter droplets based on hydrodynamic micro-vortices
Authors: Kamalakshakurup Gopakumar , Lee Abraham P.
Published: October 2017

Single cell analysis has emerged as a paradigm shift in cell biology to understand the heterogeneity of individual cells in a clone for pathological interrogation.