bluuebunny/crossref_metadata_2025_split huggingface dataset:
Semiparametric Dose Finding Methods
Authors: Clertant M. , O’Quigley J. 
Published: March 2017

Summary
We describe a new class of dose finding methods to be used in early phase clinical trials. Under some added parametric conditions the class reduces to the family of continual reassessment method (CRM) designs. Under some relaxation of the underlying structure the method is equivalent to the cumulative cohort design, the modified toxicity probability interval method or Bayesian optimal interval design classes of methods, which are non-parametric in nature whereas the CRM class can be viewed as being strongly parametric. The class proposed is characterized as being semiparametric since it corresponds to the CRM with a nuisance parameter. Performance is good, matching that of the CRM class and improving on it in some cases. The structure allows theoretical questions to be more easily investigated and to understand better how different classes of methods relate to one another.
Characterization of MicroRNA Expression Profiles and Identification of Potential Biomarkers in Leprosy
Authors: Jorge Karina T. O. S. , Souza Renan P. , Assis Marieta T. A. , Araújo Marcelo G. , Locati Massimo , Jesus Amélia M. R. , Dias Baptista Ida M. F. , Lima Cristiano X. , Teixeira Antônio L. , Teixeira Mauro M. , Soriani Frederico M. 
Published: March 2017

ABSTRACT
Leprosy is an important cause of disability in the developing world. Early diagnosis is essential to allow for cure and to interrupt transmission of this infection. MicroRNAs (miRNAs) are important factors for host-pathogen interaction and they have been identified as biomarkers for various infectious diseases. The expression profile of 377 microRNAs were analyzed by TaqMan low-density array (TLDA) in skin lesions of tuberculoid and lepromatous leprosy patients as well as skin specimens from healthy controls. In a second step, 16 microRNAs were selected for validation experiments with reverse transcription-quantitative PCR (qRT-PCR) in skin samples from new individuals. Principal-component analysis followed by logistic regression model and receiver operating characteristic (ROC) curve analyses were performed to evaluate the diagnostic potential of selected miRNAs. Four patterns of differential expression were identified in the TLDA experiment, suggesting a diagnostic potential of miRNAs in leprosy. After validation experiments, a combination of four miRNAs (miR-101, miR-196b, miR-27b, and miR-29c) was revealed as able to discriminate between healthy control and leprosy patients with 80% sensitivity and 91% specificity. This set of miRNAs was also able to discriminate between lepromatous and tuberculoid patients with a sensitivity of 83% and 80% specificity. In this work, it was possible to identify a set of miRNAs with good diagnostic potential for leprosy.
Quantitative Evaluation of Protein Heterogeneity within Herpes Simplex Virus 1 Particles
Authors: El Bilali Nabil , Duron Johanne , Gingras Diane , Lippé Roger 
Published: March 2017

ABSTRACT

Several virulence genes have been identified thus far in the herpes simplex virus 1 genome. It is also generally accepted that protein heterogeneity among virions further impacts viral fitness. However, linking this variability directly with infectivity has been challenging at the individual viral particle level. To address this issue, we resorted to flow cytometry (flow virometry), a powerful approach we recently employed to analyze individual viral particles, to identify which tegument proteins vary and directly address if such variability is biologically relevant. We found that the stoichiometry of the U
L
37, ICP0, and VP11/12 tegument proteins in virions is more stable than the VP16 and VP22 tegument proteins, which varied significantly among viral particles. Most interestingly, viruses sorted for their high VP16 or VP22 content yielded modest but reproducible increases in infectivity compared to their corresponding counterparts containing low VP16 or VP22 content. These findings were corroborated for VP16 in short interfering RNA experiments but proved intriguingly more complex for VP22. An analysis by quantitative Western blotting revealed substantial alterations of virion composition upon manipulation of individual tegument proteins and suggests that VP22 protein levels acted indirectly on viral fitness. These findings reaffirm the interdependence of the virion components and corroborate that viral fitness is influenced not only by the genome of viruses but also by the stoichiometry of proteins within each virion.

IMPORTANCE
The ability of viruses to spread in animals has been mapped to several viral genes, but other factors are clearly involved, including virion heterogeneity. To directly probe whether the latter influences viral fitness, we analyzed the protein content of individual herpes simplex virus 1 particles using an innovative flow cytometry approach. The data confirm that some viral proteins are incorporated in more controlled amounts, while others vary substantially. Interestingly, this correlates with the VP16
trans
-activating viral protein and indirectly with VP22, a second virion component whose modulation profoundly alters virion composition. This reaffirms that not only the presence but also the amount of specific tegument proteins is an important determinant of viral fitness.
MRI-based comparative study of different mild cognitive impairment subtypes: protocol for an observational case–control study
Authors: Yu Yang , Zhao Weina , Li Siou , Yin Changhao 
Published: March 2017

IntroductionAmnestic mild cognitive impairment (aMCI) and vascular mild cognitive impairment (VaMCI) comprise the 2 main types of mild cognitive impairment (MCI). The first condition generally progresses to Alzheimer's disease, whereas the second is likely to develop into vascular dementia (VD). The brain structure and function of patients with MCI differ from those of normal elderly individuals. However, whether brain structures or functions differ between these 2 MCI subtypes has not been studied. This study is designed to analyse neuroimages of brain in patients with VaMCI and aMCI using multimodality MRI (structural MRI (sMRI), functional MRI and diffusion tensor imaging (DTI)).Methods and analysisIn this study, 80 participants diagnosed with aMCI, 80 participants diagnosed with VaMCI, and 80 age-matched, gender-matched and education-matched normal controls (NCs) will be recruited to the Hongqi Hospital of Mudanjiang Medical University, Heilongjiang, China. All participants will undergo neuroimaging and neuropsychological evaluations. The primary outcome measures will be (1) microstructural alterations revealed by multimodal MRIs, including sMRI, resting-state functional MRI and DTI; and (2) a neuropsychological evaluation, including the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Auditory Verbal Learning Test (AVLT), Memory and Executive Screening (MES), trail making test, Stroop colour naming condition and Clinical Dementia Rating (CDR) scale, to evaluate global cognition, memory function, attention, visuospatial skills, processing speed, executive function and emotion, respectively.Trial registration numberNCT02706210; Pre-results.
Automated Generation of BSP Automata
Authors: Tachon Thibaut , Li Chong , Hains Gaétan , Loulergue Frédéric 
Published: March 2017

Bulk-Synchronous Parallel (BSP) is a bridging model between abstract execution and concrete parallel architectures that retains enough information to model performance scalability. In order to model BSP program executions, Hains adapted the theory of finite automata to the BSP paradigm by introducing BSP automata [12]. In the initial description of the theory, BSP automata had to be explicitly defined as structured sets of states and transitions. The lack of a clean and efficient algorithm for generating them from regular expressions would have prevented this theory from being used in practice. To alleviate this problem we introduce in this paper an algorithm that generates a BSP automaton recognizing a BSP language defined by a BSP regular expression. The main practical use of BSP automata developed in this paper is the parallelization of finite state automata with an explicit distribution and a performance model, that enable parallel matching of regular expressions. Secondarily, BSP regular expressions provide a convenient structure for automatic code generation of imperative BSP programs that is also developed in this paper.
Prebiotic milk oligosaccharides prevent development of obese phenotype, impairment of gut permeability, and microbial dysbiosis in high fat-fed mice
Authors: Hamilton M. Kristina , Ronveaux Charlotte C. , Rust Bret M. , Newman John W. , Hawley Melissa , Barile Daniela , Mills David A. , Raybould Helen E. 
Published: March 2017

Microbial dysbiosis and increased intestinal permeability are targets for prevention or reversal of weight gain in high-fat (HF) diet-induced obesity (DIO). Prebiotic milk oligosaccharides (MO) have been shown to benefit the host intestine but have not been used in DIO. We hypothesized that supplementation with bovine MO would prevent the deleterious effect of HF diet on the gut microbiota and intestinal permeability and attenuate development of the obese phenotype. C57BL/6 mice were fed a control diet, HF (40% fat/kcal), or HF + prebiotic [6%/kg bovine milk oligosaccharides (BMO) or inulin] for 1, 3, or 6 wk. Gut microbiota and intestinal permeability were assessed in the ileum, cecum, and colon. Addition of BMO to the HF diet significantly attenuated weight gain, decreased adiposity, and decreased caloric intake; inulin supplementation also lowered weight gain and adiposity, but this did not reach significance. BMO and inulin completely abolished the HF diet-induced increase in paracellular and transcellular permeability in the small and large intestine. Both BMO and inulin increased abundance of beneficial microbes Bifidobacterium and Lactobacillus in the ileum. However, inulin supplementation altered phylogenetic diversity and decreased species richness. We conclude that addition of BMO to the HF diet completely prevented increases in intestinal permeability and microbial dysbiosis and was partially effective to prevent weight gain in DIO. NEW & NOTEWORTHY This study provides the first report of the effects of prebiotic bovine milk oligosaccharides on the host phenotype of high-fat diet-induced obesity in mice.
Ventilation heterogeneity measured by multiple breath inert gas testing is not affected by inspired oxygen concentration in healthy humans
Authors: Hopkins Susan R. , Elliott Ann R. , Prisk G. Kim , Darquenne Chantal 
Published: March 2017

Multiple breath washout (MBW) and oxygen-enhanced MRI techniques use acute exposure to 100% oxygen to measure ventilation heterogeneity. Implicit is the assumption that breathing 100% oxygen does not induce changes in ventilation heterogeneity; however, this is untested. We hypothesized that ventilation heterogeneity decreases with increasing inspired oxygen concentration in healthy subjects. We performed MBW in 8 healthy subjects (4 women, 4 men; age = 43 ± 15 yr) with normal pulmonary function (FEV1 = 98 ± 6% predicted) using 10% argon as a tracer gas and oxygen concentrations of 12.5%, 21%, or 90%. MBW was performed in accordance with ERS-ATS guidelines. Subjects initially inspired air followed by a wash-in of test gas. Tests were performed in balanced order in triplicate. Gas concentrations were measured at the mouth, and argon signals rescaled to mimic a N2 washout, and analyzed to determine the distribution of specific ventilation (SV). Heterogeneity was characterized by the width of a log-Gaussian fit of the SV distribution and from Sacin and Scond indexes derived from the phase III slope. There were no significant differences in the ventilation heterogeneity due to altered inspired oxygen: histogram width (hypoxia 0.57 ± 0.11, normoxia 0.60 ± 0.08, hyperoxia 0.59 ± 0.09, P = 0.51), Scond (hypoxia 0.014 ± 0.011, normoxia 0.012 ± 0.015, hyperoxia 0.010 ± 0.011, P = 0.34), or Sacin (hypoxia 0.11 ± 0.04, normoxia 0.10 ± 0.03, hyperoxia 0.12 ± 0.03, P = 0.23). Functional residual capacity was increased in hypoxia ( P = 0.04) and dead space increased in hyperoxia ( P = 0.0001) compared with the other conditions. The acute use of 100% oxygen in MBW or MRI is unlikely to affect ventilation heterogeneity. NEW & NOTEWORTHY Hyperoxia is used to measure the distribution of ventilation in imaging and MBW but may alter the underlying ventilation distribution. We used MBW to evaluate the effect of inspired oxygen concentration on the ventilation distribution using 10% argon as a tracer. Short-duration exposure to hypoxia (12.5% oxygen) and hyperoxia (90% oxygen) during MBW had no significant effect on ventilation heterogeneity, suggesting that hyperoxia can be used to assess the ventilation distribution.
The Microtubule Network and Cell Death Are Regulated by an miR-34a/Stathmin 1/βIII-Tubulin Axis
Authors: Vetter Nancy S. , Kolb E.A. , Mills Christopher C. , Sampson Valerie B. 
Published: March 2017

Abstract
MicroRNA-34a (miR-34a) is a master regulator of signaling networks that maintains normal physiology and disease and is currently in development as a miRNA-based therapy for cancer. Prior studies have reported low miR-34a expression in osteosarcoma; however, the molecular mechanisms underlying miR-34a activity in osteosarcoma are not well-defined. Therefore, this study evaluated the role of miR-34a in regulating signal transduction pathways that influence cell death in osteosarcoma. Levels of miR-34a were attenuated in human osteosarcoma cells and xenografts of the Pediatric Preclinical Testing Consortium (PPTC). Bioinformatics predictions identified stathmin 1 (STMN1) as a potential miR-34a target. Biotin pull-down assay and luciferase reporter analysis confirmed miR-34a target interactions within the STMN1 mRNA 3′-untranslated region. Overexpression of miR-34a in osteosarcoma cells suppressed STMN1 expression and reduced cell growth in vitro. Restoration of miR-34a led to microtubule destabilization and increased βIII-tubulin expression, with corresponding G1–G2 phase cell-cycle arrest and apoptosis. Knockdown of the Sp1 transcription factor, by siRNA silencing, also upregulated βIII-tubulin expression in osteosarcoma cells, suggesting that miR-34a indirectly affects Sp1. Validating the coordinating role of miR-34a in microtubule destabilization, when miR-34a was combined with either microtubule inhibitors or chemotherapy, STMN1 phosphorylation was suppressed and there was greater cytotoxicity in osteosarcoma cells. These results demonstrate that miR-34a directly represses STMN1 gene and protein expression and upregulates βIII-tubulin, leading to disruption of the microtubule network and cell death.
Implications: The miR-34a/STMN1/βIII-tubulin axis maintains the microtubule cytoskeleton in osteosarcoma, and combining miR-34a with microtubule inhibitors can be investigated as a novel therapeutic strategy. Mol Cancer Res; 15(7); 953–64. ©2017 AACR.
An Acquired HER2 T798I Gatekeeper Mutation Induces Resistance to Neratinib in a Patient with HER2 Mutant–Driven Breast Cancer
Authors: Hanker Ariella B. , Brewer Monica Red , Sheehan Jonathan H. , Koch James P. , Sliwoski Gregory R. , Nagy Rebecca , Lanman Richard , Berger Michael F. , Hyman David M. , Solit David B. , He Jie , Miller Vincent , Cutler Richard E. , Lalani Alshad S. , Cross Darren , Lovly Christine M. , Meiler Jens , Arteaga Carlos L. 
Published: March 2017

Abstract
We report a HER2T798I gatekeeper mutation in a patient with HER2L869R-mutant breast cancer with acquired resistance to neratinib. Laboratory studies suggested that HER2L869R is a neratinib-sensitive, gain-of-function mutation that upon dimerization with mutant HER3E928G, also present in the breast cancer, amplifies HER2 signaling. The patient was treated with neratinib and exhibited a sustained partial response. Upon clinical progression, HER2T798I was detected in plasma tumor cell-free DNA. Structural modeling of this acquired mutation suggested that the increased bulk of isoleucine in HER2T798I reduces neratinib binding. Neratinib blocked HER2-mediated signaling and growth in cells expressing HER2L869R but not HER2L869R/T798I. In contrast, afatinib and the osimertinib metabolite AZ5104 strongly suppressed HER2L869R/T798I-induced signaling and cell growth. Acquisition of HER2T798I upon development of resistance to neratinib in a breast cancer with an initial activating HER2 mutation suggests HER2L869R is a driver mutation. HER2T798I-mediated neratinib resistance may be overcome by other irreversible HER2 inhibitors like afatinib.
Significance: We found an acquired HER2 gatekeeper mutation in a patient with HER2-mutant breast cancer upon clinical progression on neratinib. We speculate that HER2T798I may arise as a secondary mutation following response to effective HER2 tyrosine kinase inhibitors (TKI) in other cancers with HER2-activating mutations. This resistance may be overcome by other irreversible HER2 TKIs, such as afatinib. Cancer Discov; 7(6); 575–85. ©2017 AACR.
This article is highlighted in the In This Issue feature, p. 539
Joannsin, a novel Kunitz-type FXa inhibitor from the venom of Prospirobolus joannsi
Authors: Luan Ning , Zhou Chunling , Li Pengpeng , Ombati Rose , Yan Xiuwen , Mo Guoxiang , Rong Mingqiang , Lai Ren , Duan Zilei , Zheng Ruiqiang 
Published: March 2017

SummaryThe repugnatorial glands of millipedes release various defensive chemical secretions. Although varieties of such defensive secretions have been studied, none of them is protein or peptide. Herein, a novel factor Xa (FXa) inhibitor named joannsin was identified and characterised from repugnatorial glands of Prospirobolus joannsi. Joannsin is composed of 72 amino acid residues including six cysteines, which form three intra-molecular disulfide bridges. It is a member of Kunitz-type protease inhibitor family, members of which are also found in the secretory glands of other arthropods. Recombinant joannsin exhibited remarkable inhibitory activity against trypsin and FXa with a Ki of 182.7 ± 14.6 and 29.5 ± 4.7 nM, respectively. Joannsin showed strong anti-thrombosis functions in vitro and in vivo. Joannsin is the first peptide component in millipede repugnatorial glands to be identified and is a potential candidate and/or template for the development of anti-thrombotic agents. These results also indicated that there is Kunitz-type protease inhibitor toxin in millipede repugnatorial glands as in other arthropods secretory glands.
a influência de fatores climáticos na atividade externa de Tetragonisca angustula (Apidae, Meliponinae)
Authors: Iwama Satoko 
Published: March 2017

Foi estudada a influência de fatores climáticos (temperatura, intensidade luminosa e umidade relativa) na atividade externa de Tetragonisca angustula (jatai).A análise de regressão e correlação sugeriu que a temperatura seguida da intensidade luminosa e umidade relativa foram fatores importantes na saída efetiva das abelhas. Provavelmente a interação entre a temperatura e a intensidade luminosa foi a principal determinante da atividade de vôo, pois as Tetragonisca angustula não saiam de suas colmeias a temperaturas baixas, mesmo com boa intensidade luminosa.
General behavioral patterns and life-cycle of the colonial spider, Eriophora bistriata (Araneida: Argiopidae)
Authors: Gobbi Nivar , Zucchi Ronaldo , Sakagami Shoichi F. 
Published: March 2017

Neste estudo, apresentamos observações preliminares do comportamento e biologia da aranha gregária Eriophora bistriata. O trabalho inclui aspectos da organização social, obtidos através de estudos de laboratório e campo. São inicialmente descritos, além do ciclo básico, algumas interações como: construção de teia comum de caça, ausência de hostilidade inter-individual, alimentação comunal, comportamento reprodutor etc. Os resultados obtidos permitiram comparar Eriophora bistriata, com outras espécies gregárias segundo o esquema evolutivo de Shear (1970: pag. 73).
Microclima de cuevas y comportamientos de homeostasis en Ctenomis pearsoni del Uruguay (Rodentia, Octodontidae)
Authors: Altuna Carlos A. 
Published: March 2017

O microclima das tocas do roedor fossorial Ctenomys pearsoni Lessa & Langguth, 1983, foi estudado na zona de Carrasco, Uruguay (34º52'S, 56°04'W). No decorrer de um ano, foram feitas amostragens mensais da temperatura das tocas. Foram obtidas, na comparação com a temperatura exterior, diferenças significativas em dez amostragens (test t., P<0.01 a 0.001); em duas delas, as que correspondem aos meses temperados (março e novembro), não foi observada diferença alguma. A humidade relativa nas tocas é muito elevada (93.34+ou-5.69) e, em relação com a do exterior (69.7+ou-8.34), é significativamente diferente (Kolmogorov Smirnov, P<0.01). Para regulação do micro-clima, Ctenomys pearsoni desenvolve um conjunto de estratégias etológicas que chamamos comportamentos de homeostase. Entre elas destacam-se o permanente fechamento da abertura, a reparação dos danos naturais nos sistemas de galerias e a orientação das entradas preferencialmente em direção oposta ao vento (P<0.05). São estabelecidas algumas considerações sob a importância destes aspectos eco-etológicos em relação com a distribuição geográfica e ecológica dos "tucu-tucus" e seu êxito evolutivo.
Irewiae, um nuevo genero de la familia Glossoscolecidae (Annelida: Oligochaeta) hallado en la Amazonia Venezolana
Authors: Drachenberg Carlos E. 
Published: March 2017

Um novo gênero de Glossoscolecidae é descrito para a amazonia venezuelana. Irewiae capitmagnus gen. n., sp.n., distingue-se pela posição da moela no segmento VI, estrutura lamelar das glândulas calcíferas, sua posição em VII-IX,distribuição irregular das cerdas, presença de mais de um par de espermatecas por segmento, vesículas seminais atravessando alguns septos e sistema genital holândrico e metagínico.
On a new species of Alomasoma (Eichiura: Bonelliidae) from Antarctica
Authors: Ditadi A. S. F. 
Published: March 2017

Alomasoma lanai é uma nova espécie de Bonelliidae (Echiura) coletada na Antartica. A nova espécie é de tamanho médio e abriga muitos machos anões presos a pele do tronco. A espécie mostra uma característica única na forma de umsulco transversal que contem a cova genital.