bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic impact of bone marrow fibrosis in polycythemia vera: validation of the IWG-MRT study and additional observations
Authors: Barraco D , Cerquozzi S , Hanson C A , Ketterling R P , Pardanani A , Gangat N , Tefferi A 
Published: March 2017

AbstractIn 2012, the International Working Group for Myeloproliferative Neoplasms (MPN) Research and Treatment (IWG-MRT) reported an associations between mild bone marrow (BM) fibrosis (⩾grade 1) in polycythemia vera (PV) and a lower incidence of thrombosis during the clinical course and a higher risk of fibrotic progression. The objective in the current study of 262 patients with PV was to validate these observations and also identify other risk factors for myelofibrosis-free survival (MFFS). About 127 (48%) patients displayed ⩾grade 1 reticulin fibrosis at the time of diagnosis; presenting clinical and laboratory features were not significantly different between patients with or without BM fibrosis. In univariate analysis, BM fibrosis had no significant impact on overall, leukemia-free or thrombosis-free survival, whereas a significant association was noted for MFFS (P=0.009, hazard ratio 2.9; 95% confidence interval 1.32–6.78); other risk factors for MFFS included leukocytosis ⩾15 × 109/l, presence of palpable splenomegaly and abnormal karyotype. During multivariable analysis, leukocytosis ⩾15 × 109/l, palpable splenomegaly and ⩾grade 1 BM reticulin fibrosis remained significant. The current study validates the previously observed association between ⩾grade 1 BM reticulin fibrosis in PV and subsequent fibrotic progression, and identifies leukocytosis and palpable splenomegaly as additional risk factors for fibrotic progression; additional studies are required to clarify the impact of BM fibrosis on thrombosis and that of abnormal karyotype on MFFS.
Structure and assembly of scalable porous protein cages
Authors: Sasaki Eita , Böhringer Daniel , van de Waterbeemd Michiel , Leibundgut Marc , Zschoche Reinhard , Heck Albert J. R. , Ban Nenad , Hilvert Donald 
Published: March 2017

AbstractProteins that self-assemble into regular shell-like polyhedra are useful, both in nature and in the laboratory, as molecular containers. Here we describe cryo-electron microscopy (EM) structures of two versatile encapsulation systems that exploit engineered electrostatic interactions for cargo loading. We show that increasing the number of negative charges on the lumenal surface of lumazine synthase, a protein that naturally assembles into a ∼1-MDa dodecahedron composed of 12 pentamers, induces stepwise expansion of the native protein shell, giving rise to thermostable ∼3-MDa and ∼6-MDa assemblies containing 180 and 360 subunits, respectively. Remarkably, these expanded particles assume unprecedented tetrahedrally and icosahedrally symmetric structures constructed entirely from pentameric units. Large keyhole-shaped pores in the shell, not present in the wild-type capsid, enable diffusion-limited encapsulation of complementarily charged guests. The structures of these supercharged assemblies demonstrate how programmed electrostatic effects can be effectively harnessed to tailor the architecture and properties of protein cages.
Structural basis of homo- and heterotrimerization of collagen I
Authors: Sharma Urvashi , Carrique Loïc , Vadon-Le Goff Sandrine , Mariano Natacha , Georges Rainier-Numa , Delolme Frederic , Koivunen Peppi , Myllyharju Johanna , Moali Catherine , Aghajari Nushin , Hulmes David J. S. 
Published: March 2017

AbstractFibrillar collagen molecules are synthesized as precursors, procollagens, with large propeptide extensions. While a homotrimeric form (three α1 chains) has been reported in embryonic tissues as well as in diseases (cancer, fibrosis, genetic disorders), collagen type I usually occurs as a heterotrimer (two α1 chains and one α2 chain). Inside the cell, the role of the C-terminal propeptides is to gather together the correct combination of three α chains during molecular assembly, but how this occurs for different forms of the same collagen type is so far unknown. Here, by structural and mutagenic analysis, we identify key amino acid residues in the α1 and α2 C-propeptides that determine homo- and heterotrimerization. A naturally occurring mutation in one of these alters the homo/heterotrimer balance. These results show how the C-propeptide of the α2 chain has specifically evolved to permit the appearance of heterotrimeric collagen I, the major extracellular building block among the metazoa.
EGFR/ARF6 regulation of Hh signalling stimulates oncogenic Ras tumour overgrowth
Authors: Chabu Chiswili , Li Da-Ming , Xu Tian 
Published: March 2017

AbstractMultiple signalling events interact in cancer cells. Oncogenic Ras cooperates with Egfr, which cannot be explained by the canonical signalling paradigm. In turn, Egfr cooperates with Hedgehog signalling. How oncogenic Ras elicits and integrates Egfr and Hedgehog signals to drive overgrowth remains unclear. Using a Drosophila tumour model, we show that Egfr cooperates with oncogenic Ras via Arf6, which functions as a novel regulator of Hh signalling. Oncogenic Ras induces the expression of Egfr ligands. Egfr then signals through Arf6, which regulates Hh transport to promote Hh signalling. Blocking any step of this signalling cascade inhibits Hh signalling and correspondingly suppresses the growth of both, fly and human cancer cells harbouring oncogenic Ras mutations. These findings highlight a non-canonical Egfr signalling mechanism, centered on Arf6 as a novel regulator of Hh signalling. This explains both, the puzzling requirement of Egfr in oncogenic Ras-mediated overgrowth and the cooperation between Egfr and Hedgehog.
Laser-mediated rupture of chlamydial inclusions triggers pathogen egress and host cell necrosis
Authors: Kerr Markus C. , Gomez Guillermo A. , Ferguson Charles , Tanzer Maria C. , Murphy James M. , Yap Alpha S. , Parton Robert G. , Huston Wilhelmina M. , Teasdale Rohan D 
Published: March 2017

AbstractRemarkably little is known about how intracellular pathogens exit the host cell in order to infect new hosts. Pathogenic chlamydiae egress by first rupturing their replicative niche (the inclusion) before rapidly lysing the host cell. Here we apply a laser ablation strategy to specifically disrupt the chlamydial inclusion, thereby uncoupling inclusion rupture from the subsequent cell lysis and allowing us to dissect the molecular events involved in each step. Pharmacological inhibition of host cell calpains inhibits inclusion rupture, but not subsequent cell lysis. Further, we demonstrate that inclusion rupture triggers a rapid necrotic cell death pathway independent of BAK, BAX, RIP1 and caspases. Both processes work sequentially to efficiently liberate the pathogen from the host cytoplasm, promoting secondary infection. These results reconcile the pathogen's known capacity to promote host cell survival and induce cell death.
Moonshots and metastatic disease: the need for a multi-faceted approach when studying atypical responses
Authors: De La Torre Kristine , Cohen Elly , Loeser Anne , Hurlbert Marc ,   on behalf of the Metastatic Breast Cancer Alliance
Published: March 2017

AbstractClinical research generally focuses on results involving a statistical mean with little attention in trial design to patients who respond considerably better or worse than average. Exploring the reasons underlying an “atypical response” will increase understanding of the mechanisms involved in cancer progression and treatment resistance, accelerate biomarker identification, and improve precision medicine by allowing clinicians to prospectively select optimal treatments. Based on our review, we suggest two ways to move this field forward. First, we suggest that clear categorization of “atypical responders” is needed. This encompasses three sub-categories of patients: “exceptional responders” (those with an unusually favorable treatment response), “rapid progressors” (patients demonstrating an unusually poor or no therapeutic response), and “exceptional survivors” (patients who have far outlived their initial prognosis). Such categorization may depend upon the clinical context and disease subtype. Second, we suggest that atypical responses may be due not only to somatic mutations in tumors, but also to inherited polymorphisms in non-tumor tissue, host and tumor environments, lifestyle factors, co-morbidities, use of complementary and integrative medicine, and the interaction among these components. Here, we summarize new research initiatives exploring atypical responses, the potential reasons for atypical responses, and a strategic call to action. Rigorous studies of normal and atypical responses to treatment will be needed to strengthen understanding of the role of non-tumor factors. Clinical trial design for targeted and other types of therapies should be enhanced to collect data in a standardized manner beyond tumor genetics, resulting in more thorough study of the whole patient.
Serum FABP5 concentration is a potential biomarker for residual risk of atherosclerosis in relation to cholesterol efflux from macrophages
Authors: Furuhashi Masato , Ogura Masatsune , Matsumoto Megumi , Yuda Satoshi , Muranaka Atsuko , Kawamukai Mina , Omori Akina , Tanaka Marenao , Moniwa Norihito , Ohnishi Hirofumi , Saitoh Shigeyuki , Harada-Shiba Mariko , Shimamoto Kazuaki , Miura Tetsuji 
Published: March 2017

AbstractCholesterol efflux capacity (CEC) from macrophages, the first step in the reverse cholesterol transport pathway, is inversely associated with residual risk for atherosclerotic cardiovascular disease. Fatty acid-binding protein 4 (FABP4) and FABP5 are expressed in both adipocytes and macrophages and play significant roles in the development of insulin resistance and atherosclerosis. Both FABP4 and FABP5 are secreted from cells, and their circulating levels are associated with insulin resistance and atherosclerosis. We investigated the association between CEC and levels of FABP4 and FABP5 in 250 subjects without any medications. CEC was positively correlated with HDL cholesterol level and negatively correlated with concentrations of high-sensitivity C-reactive protein (hsCRP) and FABP5, but not FABP4. Multiple regression analysis demonstrated that FABP5 concentration was an independent predictor of CEC after adjustment of age, gender and levels of HDL cholesterol and hsCRP. In 129 of the 250 subjects who underwent carotid ultrasonography, mean intima-media thickness was negatively correlated with CEC and was positively correlated with concentrations of FABP4 and FABP5. In conclusion, in contrast to FABP4, circulating FABP5 is associated with decreased CEC and carotid atherosclerosis, suggesting that FABP5 level is a regulatory factor of CEC and a potential biomarker for residual risk of atherosclerosis.
Importance of Zinc Transporter 8 Autoantibody in the Diagnosis of Type 1 Diabetes in Latin Americans
Authors: Gomes Karla Fabiana Brasil , Semzezem Cintia , Batista Rodolfo , Fukui Rosa Tsuneshiro , Santos Aritania Sousa , Correia Márcia Regina , Passos-Bueno Maria Rita , Silva Maria Elizabeth Rossi da 
Published: March 2017

AbstractThere is a scarcity of data of zinc transporter-8 autoantibody (ZnT8A) on mixed populations such as Brazilian. Therefore, we evaluated the relevance of ZnT8A for type 1 diabetes (T1D) diagnosis and the role of ZnT8 coding gene (SLC30A8) in T1D predisposition.Patients with T1D (n = 629; diabetes duration = 11 (6–16) years) and 651 controls were genotyped for SLC30A8 rs16889462 and rs2466295 variants (BeadXpress platform). ZnT8 triple antibody was measured by ELISA; glutamic acid decarboxylase (GAD65A) and protein tyrosine phosphatase (IA-2A) autoantibodies by radioimmunoassay. Results: Znt8A was detected in 68.7% of recent-onset T1D patients and 48.9% of the entire patient cohort, similar to GAD65A (68.3% and 47.2%) and IA-2A (64.8% and 42.4%) positivities respectively. ZnT8A was the only antibody in 8.4% of patients. Znt8A and IA2A frequencies and titers were independent of gender and ethnicity, whereas GAD65A titers were greater in females. The diabetes duration-dependent decline in ZnT8A frequency was similar to GAD65A and IA-2A. The SLC30A8 rs2466293 AG + GG genotypes were associated with T1D risk in non-European descents (56.2% × 42.9%; p = 0.018), and the GG genotype with higher ZnT8A titers in recent-onset T1D: 834.5 IU/mL (711.3–2190.0) × 281 IU/mL (10.7–726.8); p = 0.027. Conclusion ZnT8A detection increases T1D diagnosis rate even in mixed populations. SLC30A8 rs2466293 was associated with T1D predisposition in non-European descents.
Resveratrol sequentially induces replication and oxidative stresses to drive p53-CXCR2 mediated cellular senescence in cancer cells
Authors: Li Boxuan , Hou Dong , Guo Haiyang , Zhou Haibin , Zhang Shouji , Xu Xiuhua , Liu Qiao , Zhang Xiyu , Zou Yongxin , Gong Yaoqin , Shao Changshun 
Published: March 2017

AbstractResveratrol (RSV) acts either as an antioxidant or a pro-oxidant depending on contexts. RSV-treated cancer cells may experience replication stress that can lead to cellular senescence or apoptosis. While both oxidative and replication stresses may mediate the anti-proliferation effect of RSV, to what extent each contributes to the impaired proliferation in response to RSV remains uncharacterized. We here report the study of the roles of replication and oxidative stresses in mediating cellular senescence in cancer cells treated with RSV. RSV induced S-phase arrest and cellular senescence in a dose-dependent manner in U2OS and A549 cancer cells as well as in normal human fibroblasts. We observed that nucleosides significantly alleviated RSV-induced replication stress and DNA damage response, and consequently attenuating cellular senescence. While the elevation of reactive oxygen species (ROS) also mediated the pro-senescent effect of RSV, it occurred after S-phase arrest. However, the induction of ROS by RSV was independent of S-phase arrest and actually reinforced the latter. We also demonstrated a critical role of the p53-CXCR2 axis in mediating RSV-induced senescence. Interestingly, CXCR2 also functioned as a barrier to apoptosis. Together, our results provided more insights into the biology of RSV-induced stress and its cellular consequences.
A Biologically-validated HCV E1E2 Heterodimer Structural Model
Authors: Castelli Matteo , Clementi Nicola , Pfaff Jennifer , Sautto Giuseppe A. , Diotti Roberta A. , Burioni Roberto , Doranz Benjamin J. , Dal Peraro Matteo , Clementi Massimo , Mancini Nicasio 
Published: March 2017

AbstractThe design of vaccine strategies and the development of drugs targeting the early stages of Hepatitis C virus (HCV) infection are hampered by the lack of structural information about its surface glycoproteins E1 and E2, the two constituents of HCV entry machinery. Despite the recent crystal resolution of limited versions of both proteins in truncated form, a complete picture of the E1E2 complex is still missing. Here we combined deep computational analysis of E1E2 secondary, tertiary and quaternary structure with functional and immunological mutational analysis across E1E2 in order to propose an in silico model for the ectodomain of the E1E2 heterodimer. Our model describes E1-E2 ectodomain dimerization interfaces, provides a structural explanation of E1 and E2 immunogenicity and sheds light on the molecular processes and disulfide bridges isomerization underlying the conformational changes required for fusion. Comprehensive alanine mutational analysis across 553 residues of E1E2 also resulted in identifying the epitope maps of diverse mAbs and the disulfide connectivity underlying E1E2 native conformation. The predicted structure unveils E1 and E2 structures in complex, thus representing a step towards the rational design of immunogens and drugs inhibiting HCV entry.
Short-Course, High-Dose Rifampicin Achieves Wolbachia Depletion Predictive of Curative Outcomes in Preclinical Models of Lymphatic Filariasis and Onchocerciasis
Authors: Aljayyoussi Ghaith , Tyrer Hayley E. , Ford Louise , Sjoberg Hanna , Pionnier Nicolas , Waterhouse David , Davies Jill , Gamble Joanne , Metuge Haelly , Cook Darren A. N. , Steven Andrew , Sharma Raman , Guimaraes Ana F. , Clare Rachel H. , Cassidy Andrew , Johnston Kelly L. , Myhill Laura , Hayward Laura , Wanji Samuel , Turner Joseph D. , Taylor Mark J. , Ward Stephen A. 
Published: March 2017

AbstractLymphatic filariasis (LF) and onchocerciasis are priority neglected tropical diseases targeted for elimination. The only safe drug treatment with substantial curative activity against the filarial nematodes responsible for LF (Brugia malayi, Wuchereria bancrofti) or onchocerciasis (Onchocerca volvulus) is doxycycline. The target of doxycycline is the essential endosymbiont, Wolbachia. Four to six weeks doxycycline therapy achieves >90% depletion of Wolbachia in worm tissues leading to blockade of embryogenesis, adult sterility and premature death 18–24 months post-treatment. Long treatment length and contraindications in children and pregnancy are obstacles to implementing doxycycline as a public health strategy. Here we determine, via preclinical infection models of Brugia malayi or Onchocerca ochengi that elevated exposures of orally-administered rifampicin can lead to Wolbachia depletions from filariae more rapidly than those achieved by doxycycline. Dose escalation of rifampicin achieves >90% Wolbachia depletion in time periods of 7 days in B. malayi and 14 days in O. ochengi. Using pharmacokinetic-pharmacodynamic modelling and mouse-human bridging analysis, we conclude that clinically relevant dose elevations of rifampicin, which have recently been determined as safe in humans, could be administered as short courses to filariasis target populations with potential to reduce anti-Wolbachia curative therapy times to between one and two weeks.
Compensation effect of winter wheat grain yield reduction under straw mulching in wide-precision planting in the North China Plain
Authors: Liu Xinhui , Ren Yujie , Gao Chao , Yan Zhenxing , Li Quanqi 
Published: March 2017

AbstractClimate change and the growing demand for food security force growers to identify ways both to improve food production and to reduce agricultural carbon emissions. Although straw mulching is known to decrease CO2 emissions, winter wheat grain yield in the North China Plain was declined under straw mulching. In an effort to determine the most effective way to increase winter wheat yield under straw mulching, a field experiment was conducted using two planting patterns (wide-precision planting and conventional-cultivation planting) and two straw mulching rates (0 and 0.6 kg/m2). The results showed the wide-precision planting/non-mulching treatment significantly increased the leaf area index more than the other three treatments at the early growth stage. This treatment improved aboveground dry matter accumulation and was conducive to increased spike weight in the late growth stage. By contrast, straw mulching significantly reduced winter wheat grain yields by lowering both spike number and 1000-grain weight at the mature plant stage. In the wide-precision planting/mulching treatment, a significantly increased spike number compensated for grain yield losses. The results support the idea that wide-precision planting combined with straw mulching has the potential to decrease the winter wheat grain yield reduction previously observed with straw mulching in the North China Plain.
ALK
G1269A mutation as a potential mechanism of acquired resistance to crizotinib in an ALK-rearranged inflammatory myofibroblastic tumor
Authors: Michels Sebastian Y. F. , Scheel Andreas H. , Wündisch Thomas , Heuckmann Johannes M. , Menon Roopika , Puesken Michael , Kobe Carsten , Pasternack Helen , Heydt Carina , Scheffler Matthias , Fischer Rieke , Schultheis Anne M. , Merkelbach-Bruse Sabine , Heukamp Lukas , Büttner Reinhard , Wolf Jürgen 
Published: March 2017

AbstractInflammatory myofibroblastic tumors are rare mesenchymal neoplasms frequently harboring oncogenic chromosomal rearrangements, most commonly, involving the ALK (anaplastic lymphoma kinase) gene. Treatment of this molecularly defined subgroup with the anaplastic lymphoma kinase inhibitor crizotinib has shown to be effective. However, comparable to lung adenocarcinoma, resistance inevitably develops. Second generation anaplastic lymphoma kinase inhibitors such as ceritinib are able to overcome acquired resistance to crizotinib. Here, we report the case of a patient with an inflammatory myofibroblastic tumors harboring a DCTN1-ALK fusion who developed resistance to crizotinib treatment. Next-generation sequencing of a rebiopsy sample revealed the acquisition of the ALK
G1269A
mutation as a mechanism of resistance. Therapy with ceritinib resulted in a short but profound clinical, metabolic and morphologic response. This case illustrates that (i) different tumor entities may share similar oncogenic driver mechanisms, rendering them vulnerable for the same therapeutic substances and (ii) likewise, the same mode of resistance may occur under targeted therapy among different tumor entities.
Mona Lisa is always happy – and only sometimes sad
Authors: Liaci Emanuela , Fischer Andreas , Heinrichs Markus , van Elst Ludger Tebartz , Kornmeier Jürgen 
Published: March 2017

AbstractThe worldwide fascination of da Vinci’s Mona Lisa has been dedicated to the emotional ambiguity of her face expression. In the present study we manipulated Mona Lisa’s mouth curvature as one potential source of ambiguity and studied how a range of happier and sadder face variants influences perception. In two experimental conditions we presented different stimulus ranges with different step sizes between stimuli along the happy-sad axis of emotional face expressions. Stimuli were presented in random order and participants indicated the perceived emotional face expression (first task) and the confidence of their response (second task). The probability of responding ‘happy’ to the original Mona Lisa was close to 100%. Furthermore, in both conditions the perceived happiness of Mona Lisa variants described sigmoidal functions of the mouth curvature. Participants’ confidence was weakest around the sigmoidal inflection points. Remarkably, the sigmoidal functions, as well as confidence values and reaction times, differed significantly between experimental conditions. Finally, participants responded generally faster to happy than to sad faces. Overall, the original Mona Lisa seems to be less ambiguous than expected. However, perception of and reaction to the emotional face content is relative and strongly depends on the used stimulus range.
Fabrication of Porous Ag/TiO2/Au Coatings with Excellent Multipactor Suppression
Authors: Wu Duoduo , Ma Jianzhong , Bao Yan , Cui Wanzhao , Hu Tiancun , Yang Jing , Bai Yuanrui 
Published: March 2017

AbstractPorous Ag/TiO2/Au coatings with excellent multipactor suppression were prepared by fabrication of porous Ag surface through two-step wet chemical etching, synthesis of TiO2 coatings by electroless-plating-like solution deposition and deposition of Au coatings via electroless plating. Porous structure of Ag surface, TiO2 coatings on porous Ag surface and Au coatings on porous Ag/TiO2 surface were verified by field-emission scanning electron microscopy, the composition and crystal type of TiO2 coatings was characterized by X-ray photoelectron spectroscopy and X-ray diffraction. Secondary electron yield (SEY) measurement was used to monitor the SEY coefficient of the porous Ag coatings and Ag/TiO2/Au coatings. The as-obtained porous Ag coatings were proved exhibiting low SEY below 1.2, and the process was highly reproducible. In addition, the porous Ag/TiO2/Au coatings showed excellent multipactor suppression with the SEY 1.23 and good environmental stability. It is worth mentioning that the whole preparation process is simple and feasible, which would provide a promising application in RF devices.