bluuebunny/crossref_metadata_2025 huggingface dataset:
HER2
missense mutations have distinct effects on oncogenic signaling and migration
Authors: Zabransky Daniel J. , Yankaskas Christopher L. , Cochran Rory L. , Wong Hong Yuen , Croessmann Sarah , Chu David , Kavuri Shyam M. , Red Brewer Monica , Rosen D. Marc , Dalton W. Brian , Cimino-Mathews Ashley , Cravero Karen , Button Berry , Kyker-Snowman Kelly , Cidado Justin , Erlanger Bracha , Parsons Heather A. , Manto Kristen M. , Bose Ron , Lauring Josh , Arteaga Carlos L. , Konstantopoulos Konstantinos , Park Ben Ho
Published: October 2015

Significance

The discovery of human epidermal growth factor receptor 2 (
HER2
) missense mutations in breast and other cancers potentially make such tumors susceptible to current and future HER2-targeted therapies. However, the majority of
HER2
mutations occur in HER2 nonamplified cancers, and whether these mutations will predict for sensitivity to HER2-directed therapies remains unknown. Using genome editing, the data presented here suggest that
HER2
missense mutations are functionally distinct and require additional oncogenic input to impart cancerous phenotypes. These results suggest that
HER2
missense mutations by themselves may not be reliable predictors of response to HER2-targeted therapies, a hypothesis currently being tested in genomically driven clinical trials.
N-terminal additions to the WE14 peptide of chromogranin A create strong autoantigen agonists in type 1 diabetes
Authors: Jin Niyun , Wang Yang , Crawford Frances , White Janice , Marrack Philippa , Dai Shaodong , Kappler John W.
Published: October 2015

Significance

Type 1 diabetes is an autoimmune disease in which the insulin-producing beta cells within the islets of Langerhans of the pancreas are destroyed by T cell-mediated immune attack. The peptide epitopes derived from islet proteins that are targeted by CD4+T cells have been difficult to determine. We show in the nonobese diabetic (NOD) mouse model of the disease that a peptide (WE14) derived from chromogranin A is likely posttranslationally modified to create a target epitope. We hypothesize that the modification is caused by transpeptidation in which other peptides are fused to the N terminus of WE14. We propose that, in autoimmunity, new epitopes created in the target organs can be attacked by T cells that are normally nonreactive to natural self-antigens.
Physical activity intensity can be accurately monitored by smartphone global positioning system ‘app’
Authors: Gordon Brett Ashley , Bruce Lyndell , Benson Amanda Clare
Published: October 2015

Monitoring physical activity is important to better individualise health and fitness benefits. This study assessed the concurrent validity of a smartphone global positioning system (GPS) ‘app’ and a sport‐specific GPS device with a similar sampling rate, to measure physical activity components of speed and distance, compared to a higher sampling sport‐specific GPS device. Thirty‐eight (21 female, 17 male) participants, mean age of 24.68, s = 6.46 years, completed two 2.400 km trials around an all‐weather athletics track wearing GPSports Pro™ (PRO), GPSports WiSpi™ (WISPI) and an iPhone™ with a Motion X GPS™ ‘app’ (MOTIONX). Statistical agreement, assessed using t‐tests and Bland–Altman plots, indicated an (mean; 95% LOA) underestimation of 2% for average speed (0.126 km·h−1; –0.389 to 0.642; p < .001), 1.7% for maximal speed (0.442 km·h−1; –2.676 to 3.561; p = .018) and 1.9% for distance (0.045 km; –0.140 to 0.232; p < .001) by MOTIONX compared to that measured by PRO. In contrast, compared to PRO, WISPI overestimated average speed (0.232 km·h−1; –0.376 to 0.088; p < .001) and distance (0.083 km; –0.129 to –0.038; p < .001) by 3.5% whilst underestimating maximal speed by 2.5% (0.474 km·h−1; –1.152 to 2.099; p < .001). Despite the statistically significant difference, the MOTIONX measures intensity of physical activity, with a similar error as WISPI, to an acceptable level for population‐based monitoring in unimpeded open‐air environments. This presents a low‐cost, minimal burden opportunity to remotely monitor physical activity participation to improve the prescription of exercise as medicine.
Painlevé transcendents and

-symmetric Hamiltonians
Authors: Bender Carl M , Komijani Javad
Published: October 2015

Unstable separatrix solutions for the first and second Painlevé transcendents are studied both numerically and analytically. For a fixed initial condition, say

there is a discrete set of initial slopes

that give rise to separatrix solutions. Similarly, for a fixed initial slope, say y’(0) = 0, there is a discrete set of initial values

that give rise to separatrix solutions. For Painlevé I the large-n asymptotic behavior of b

n
is

(

) and that of c

n
is

(

), and for Painlevé II the large-n asymptotic behavior of b

n
is

(

) and that of c

n
is

(

). The constants

and

which are the coefficients in these asymptotic behaviors, are first determined numerically. Then, by using asymptotic methods, they are found analytically by reducing the nonlinear equations to the linear eigenvalue problems associated with the cubic and quartic

-symmetric Hamiltonians

and
Unipotent representations as a categorical centre
Authors: Lusztig G.
Published: October 2015

Let

G
(

F
q

)

G(F_q)

be the group of rational points of a split connected reductive group

G
G

over the finite field

F
q

F_q

. In this paper we show that the category of representations of

G
(

F
q

)

G(F_q)

which are finite direct sums of unipotent representations in a fixed two-sided cell is equivalent to the centre of a certain monoidal category of sheaves on the flag manifold of

G
×
G

G\times G

. We also consider a version of this for nonsplit groups.
Isotropic measures and stronger forms of the reverse isoperimetric inequality
Authors: Böröczky Károly , Hug Daniel
Published: October 2015

The reverse isoperimetric inequality, due to Keith Ball, states that if

K
K

is an

n
n

-dimensional convex body, then there is an affine image

K
~

\tilde {K}

of

K
K

for which

S
(

K
~

)
n

/

V
(

K
~

)

n
−
1

S(\tilde {K})^n/V(\tilde {K})^{n-1}

is bounded from above by the corresponding expression for a regular

n
n

-dimensional simplex, where

S
S

and

V
V

denote the surface area and volume functional. It was shown by Franck Barthe that the upper bound is attained only if

K
K

is a simplex. The discussion of the equality case is based on the equality case in the geometric form of the Brascamp-Lieb inequality. The present paper establishes stability versions of the reverse isoperimetric inequality and of the corresponding inequality for isotropic measures.
openBIS ELN-LIMS: an open-source database for academic laboratories
Authors: Barillari Caterina , Ottoz Diana S. M. , Fuentes-Serna Juan Mariano , Ramakrishnan Chandrasekhar , Rinn Bernd , Rudolf Fabian
Published: October 2015

Summary: The open-source platform openBIS (open Biology Information System) offers an Electronic Laboratory Notebook and a Laboratory Information Management System (ELN-LIMS) solution suitable for the academic life science laboratories. openBIS ELN-LIMS allows researchers to efficiently document their work, to describe materials and methods and to collect raw and analyzed data. The system comes with a user-friendly web interface where data can be added, edited, browsed and searched.

Availability and implementation: The openBIS software, a user guide and a demo instance are available at https://openbis-eln-lims.ethz.ch. The demo instance contains some data from our laboratory as an example to demonstrate the possibilities of the ELN-LIMS (Ottoz et al., 2014). For rapid local testing, a VirtualBox image of the ELN-LIMS is also available.

Contact:  brinn@ethz.ch or fabian.rudolf@bsse.ethz.ch
LOLA: enrichment analysis for genomic region sets and regulatory elements in R and Bioconductor
Authors: Sheffield Nathan C. , Bock Christoph
Published: October 2015

Summary: Genomic datasets are often interpreted in the context of large-scale reference databases. One approach is to identify significantly overlapping gene sets, which works well for gene-centric data. However, many types of high-throughput data are based on genomic regions. Locus Overlap Analysis (LOLA) provides easy and automatable enrichment analysis for genomic region sets, thus facilitating the interpretation of functional genomics and epigenomics data.

Availability and Implementation: R package available in Bioconductor and on the following website: http://lola.computational-epigenetics.org.

Contact: nsheffield@cemm.oeaw.ac.at or cbock@cemm.oeaw.ac.at
Detecting dispersed duplications in high-throughput sequencing data using a database-free approach
Authors: Kroon M. , Lameijer E.W. , Lakenberg N. , Hehir-Kwa J.Y. , Thung D.T. , Slagboom P.E. , Kok J.N. , Ye K.
Published: October 2015

Motivation: Dispersed duplications (DDs) such as transposon element insertions and copy number variations are ubiquitous in the human genome. They have attracted the interest of biologists as well as medical researchers due to their role in both evolution and disease. The efforts of discovering DDs in high-throughput sequencing data are currently dominated by database-oriented approaches that require pre-existing knowledge of the DD elements to be detected.

Results: We present dd_detection, a database-free approach to finding DD events in high-throughput sequencing data. dd_detection is able to detect DDs purely from paired-end read alignments. We show in a comparative study that this method is able to compete with database-oriented approaches in recovering validated transposon insertion events. We also experimentally validate the predictions of dd_detection on a human DNA sample, showing that it can find not only duplicated elements present in common databases but also DDs of novel type.

Availability and implementation: The software presented in this article is open source and available from https://bitbucket.org/mkroon/dd_detection

Contact:  kye@genome.wustl.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
Understanding the fabric of protein crystals: computational classification of biological interfaces and crystal contacts
Authors: Capitani Guido , Duarte Jose M. , Baskaran Kumaran , Bliven Spencer , Somody Joseph C.
Published: October 2015

Modern structural biology still draws the vast majority of information from crystallography, a technique where the objects being investigated are embedded in a crystal lattice. Given the complexity and variety of those objects, it becomes fundamental to computationally assess which of the interfaces in the lattice are biologically relevant and which are simply crystal contacts. Since the mid-1990s, several approaches have been applied to obtain high-accuracy classification of crystal contacts and biological protein–protein interfaces. This review provides an overview of the concepts and main approaches to protein interface classification: thermodynamic estimation of interface stability, evolutionary approaches based on conservation of interface residues, and co-occurrence of the interface across different crystal forms. Among the three categories, evolutionary approaches offer the strongest promise for improvement, thanks to the incessant growth in sequence knowledge. Importantly, protein interface classification algorithms can also be used on multimeric structures obtained using other high-resolution techniques or for protein assembly design or validation purposes. A key issue linked to protein interface classification is the identification of the biological assembly of a crystal structure and the analysis of its symmetry. Here, we highlight the most important concepts and problems to be overcome in assembly prediction. Over the next few years, tools and concepts of interface classification will probably become more frequently used and integrated in several areas of structural biology and structural bioinformatics. Among the main challenges for the future are better addressing of weak interfaces and the application of interface classification concepts to prediction problems like protein–protein docking.

Supplementary information: Supplementary data are available at Bioinformatics online.

Contact:  guido.capitani@psi.ch
Vitamin A deficient mice exhibit increased viral antigens and enhanced cytokine/chemokine production in nasal tissues following respiratory virus infection despite the presence of FoxP3 + T cells
Authors: Penkert Rhiannon R. , Surman Sherri L. , Jones Bart G. , Sealy Robert E. , Vogel Peter , Neale Geoffrey , Hurwitz Julia L.
Published: October 2015

The World Health Organization (WHO) estimates that 250 million children under the age of five suffer from vitamin A deficiencies (VAD). Individuals with VAD experience higher rates of mortality and increased morbidity during enteric and respiratory infections compared with those who are vitamin A sufficient. Previously, our laboratory has demonstrated that VAD mice have significantly impaired virus-specific IgA and CD8 + T-cell responses in the airways. Here, we demonstrate that VAD mice experience enhanced cytokine/chemokine gene expression and release in the respiratory tract 10 days following virus infection compared with control vitamin A sufficient animals. Cytokines/chemokines that are reproducibly up-regulated at the gene expression and protein levels include IFNγ and IL-6. Despite previous indications that cytokine dysregulation in VAD animals might reflect low forkhead box P3 (FoxP3)-positive regulatory T-cell frequencies, we found no reduction in FoxP3 + T cells in VAD respiratory tissues. As an alternative explanation for the high cytokine levels, we found that the extent of virus infection and the persistence of viral antigens were increased on day 10 post-infection in VAD animals compared with controls, and consequently that respiratory tract tissues had an increased potential to activate virus-specific T cells. Results encourage cautious management of viral infections in patients with VAD, as efforts to enhance FoxP3 + T cell frequencies and quell immune effectors could potentially exacerbate disease if the virus has not been cleared.
Chemical profile of the cutaneous gland secretions from male pampas deer (
Ozotoceros bezoarticus
)
Authors: Rossini Carmen , Ungerfeld Rodolfo
Published: October 2015

Various cutaneous glands have been identified as sources of chemical signals that mediate many social interactions in deer. The pampas deer, a species considered near threatened, inhabits grasslands of South America. In this work, the chemical compositions from preorbital, tarsal, and digital gland secretions of semi-captive males were characterized by gas chromatography–mass spectrometry. The composition of these secretions showed a great complexity, with 143 compounds detected. Hierarchical cluster and principal component analyses show no relation to age or secretion type. Five compound classes (esters, fatty alcohols, lactones, sterols, and sulphuretted) differed with glands. The chemical complexity of the secretions, the individual differences in the whole compounds composition, and the absence of clustering by age lead to the hypothesis that these secretions may encode at once for individual information and for social status information.

Varias glándulas cutáneas han sido identificadas como productoras de señales químicas que median interacciones sociales en losciervos. El venado de las pampas es una especie considerada casi amenazada que habita los pastizales de Sudamérica. En este trabajo se caracterizó la composición química de las secreciones de las glándulas preorbital, tarsal e interdigital de machos por cromatografía de gases-espectrometría de masas. Estas secreciones mostraron una gran complejidad en su composición, con 143 compuestos detectados. No se observó ninguna agrupación de compuestos relacionada con la edad o el tipo de secreción. Cinco clases de compuestos (ésteres, alcoholes grasos, lactonas, esteroles, y compuestos azufrados) difirieron de acuerdo al origen glandular. La complejidad química de las secreciones, las diferencias individuales en dicha composición, y la ausencia de agrupamiento por edad, llevan a postular la hipótesis de que estas secreciones pueden codificar a la vez tanto información individual como del estado social.
Kozai–Lidov cycles towards the limit of circumbinary planets
Authors: Martin David V. , Triaud Amaury H. M. J.
Published: October 2015

In this Letter, we answer a simple question: Can a misaligned circumbinary planet induce Kozai–Lidov cycles on an inner stellar binary? We use known analytic equations to analyse the behaviour of the Kozai–Lidov effect as the outer mass is made small. We demonstrate a significant departure from the traditional symmetry, critical angles and amplitude of the effect. Aside from massive planets on near-polar orbits, circumbinary planetary systems are devoid of Kozai–Lidov cycles. This has positive implications for the existence of highly misaligned circumbinary planets: an observationally unexplored and theoretically important parameter space.
Paleoaltimetry reconstructions of the Tibetan Plateau: progress and contradictions
Authors: Deng Tao , Ding Lin
Published: October 2015

Over the last two decades, many quantitative paleoaltimetry reconstructions of the Tibetan Plateau have been published, but they are still preliminary and controversial, although several approaches have been combined paleontology and geochemistry, including vertebrate, plant, and pollen fossils as well as oxygen, carbon, and hydrogen isotopes. The Tibetan Plateau is the youngest and highest plateau on Earth, and its paleoaltimetry reconstructions are crucial to interpret its geodynamic evolution and to understand the climatic changes in Asia. Uplift histories of the Tibetan Plateau based on different proxies differ considerably, and two viewpoints are pointedly opposing on the paleoaltimetry estimations of the Tibetan Plateau. One viewpoint is that the Tibetan Plateau did not strongly uplift to reach its modern elevation until the Late Miocene, but another one, mainly based on stable isotopes, argues that the Tibetan Plateau formed early during the Indo-Asian collision and reached its modern elevation in the Paleogene or by the Middle Miocene. With either a geochemical or paleontological approach, the present is used as the key to the past. However, there are great difficulties because modern processes of isotopic fractionation and species for creature distribution are not easily precisely determined. In addition, the climatic and environmental backgrounds of past geological times have massive differences from the present, and associated adjustments are influenced by many human factors. In the future work, the applications of multidisciplinary comprehensive methods and cross-checks of their results will be productive, and we look forward to achieving more reliable estimates for paleoelevations of the Tibetan Plateau.
Bargaining, Sorting, and the Gender Wage Gap: Quantifying the Impact of Firms on the Relative Pay of Women *
Authors: Card David , Cardoso Ana Rute , Kline Patrick
Published: October 2015

There is growing evidence that firm-specific pay premiums are an important source of wage inequality. These premiums will contribute to the gender wage gap if women are less likely to work at high-paying firms or if women negotiate (or are offered) worse wage bargains with their employers than men. Using longitudinal data on the hourly wages of Portuguese workers matched with income statement information for firms, we show that the wages of both men and women contain firm-specific premiums that are strongly correlated with simple measures of the potential bargaining surplus at each firm. We then show how the impact of these firm-specific pay differentials on the gender wage gap can be decomposed into a combination of sorting and bargaining effects. We find that women are less likely to work at firms that pay higher premiums to either gender, with sorting effects being most important for low- and middle-skilled workers. We also find that women receive only 90% of the firm-specific pay premiums earned by men. Importantly, we find the same gender gap in the responses of wages to changes in potential surplus over time. Taken together, the combination of sorting and bargaining effects explain about one-fifth of the cross-sectional gender wage gap in Portugal.
Exophiala phaeomuriformis Fungal Keratitis: Case Report and In Vivo Confocal Microscopy Findings
Authors: Aggarwal Shruti , Yamaguchi Takefumi , Dana Reza , Hamrah Pedram
Published: October 2015

Purpose:

Corneal infections, particularly fungal keratitis due to rare fungal species, pose a diagnostic and therapeutic challenge because of difficulty in identification and varying susceptibility profiles. In this study, we report the first case of fungal keratitis because of Exophiala phaeomuriformis.

Methods:

We report the clinical findings and microbial identification techniques of a case of fungal keratitis due to E. phaeomuriformis. An 84-year-old woman presented with redness, pain, and itching in the left eye for 2 weeks. Slit-lamp biomicroscopy revealed one broken suture from previous penetrating keratoplasty (PKP), black infiltrates at the 4-o'clock position, without an overlying epithelial defect and hypopyon. Microbial identification was based cultures on Sabouraud dextrose agar and DNA sequencing and correlations to laser in vivo confocal microscopy (IVCM; Heidelberg Retinal Tomograph 3/Rostock Cornea Module, Heidelberg Engineering) and multiphoton microscopy (Ultima Microscope; Prairie Technologies) images.

Results:

Slit-lamp biomicroscopy revealed one broken suture from previous PKP, black infiltrates at the 4-o'clock position, without an overlying epithelial defect and hypopyon. Based on a clinical suspicion of fungal keratitis, antifungals and fortified antibiotics were started. However, the patient did not respond to therapy and required urgent PKP. After surgery, the patient was maintained on topical and systemic voriconazole and also topical 2% cyclosporine for 5 months because of possibility of scleral involvement noticed during surgery. At the end of the treatment period, her vision improved from hand motion to 20/40, with no recurrence observed in a follow-up period of 1 year. Results of diagnostic tests were supported by fungal elements in stroma on IVCM. Culture from the infiltrate grew black yeast. DNA sequencing led to the diagnosis of E. phaeomuriformis keratitis. Antifungal susceptibility testing revealed sensitivity to voriconazole.

Conclusion:

This is, to our knowledge, the first reported case of E. phaeomuriformis fungal keratitis. Diagnostic testing included slit-lamp biomicroscopy, which revealed pigmented infiltrates, culture plates grew black yeast, microscopy showed branched fungal hyphae with budding conidia, and physiological features showed tolerance to high temperatures, nitrate assimilation, and ribosomal DNA sequencing. Collectively, these tests demonstrate unique features seen for this microorganism. High suspicion should be kept with pigmented infiltrates and with dark yeast on culture plates. Prompt and aggressive medical management with voriconazole or therapeutic PKP in nonresponsive cases is essential to prevent irreversible loss of vision.
Tear Osmolarity and Tear Film Parameters in Patients With Ocular Rosacea
Authors: Karaman Erdur Sevil , Eliacik Mustafa , Kocabora Mehmet Selim , Balevi Ali , Demirci Goktug , Ozsutcu Mustafa , Gulkilik Gokhan , Aras Cengiz
Published: October 2015

Objectives:

The aim of this study was to evaluate tear osmolarity and tear film parameters in patients with ocular rosacea.

Methods:

In a single center, 25 eyes of 25 patients with ocular rosacea (group 1), 25 eyes of 25 patients with rosacea without ocular involvement (group 2), and 20 eyes of 20 healthy individuals (group 3) were evaluated using the Ocular Surface Disease Index (OSDI) questionnaire, Schirmer I test, tear film break-up time (TBUT), scoring of ocular surface fluorescein staining using modified Oxford scale, and tear osmolarity.

Results:

Tear osmolarity values, OSDI and Oxford scale scores were significantly higher in group 1 than in groups 2 and 3 (P<0.001 for all). Schirmer I test and TBUT in group 1 were significantly lower than in groups 2 and 3 (P<0.001 for all). There were no significant differences in OSDI, Schirmer I test, TBUT, Oxford scores, or tear osmolarity between groups 2 and 3 (P=0.629, P=0.175, P=0.713, P=865, and P=0.388, respectively).

Conclusions:

This study showed that ocular rosacea is associated with tear hyperosmolarity and tear film dysfunction.
Reprofiling Metastatic Samples for Chromosome 9p and 14q Aberrations as a Strategy to Overcome Tumor Heterogeneity in Clear-cell Renal Cell Carcinoma
Authors: Massari Francesco , Ciccarese Chiara , Bria Emilio , Porta Camillo , La Russa Francesca , Knuutila Sakari , Artibani Walter , Porcaro Antonio Benito , Bimbatti Davide , Modena Alessandra , Sava Teodoro , Tortora Giampaolo , Cheng Liang , Eccher Albino , Cima Luca , Pedron Serena , Ghimenton Claudio , Martignoni Guido , Brunelli Matteo
Published: October 2015

Losses of chromosomes 9p and 14q are associated with worse outcomes in patients affected by clear-cell renal cell carcinoma (RCC) and are helpful for prognostic risk stratification. Both chromosomal loci harbor several hot-spot molecular pathways suitable for targeted therapeutic interventions. Intratumor heterogeneity may foster tumor adaptation and therapeutic failure. We sought to investigate the presence of losses of the hot spots of chromosomal loci 9p and 14q in primary clear-cell RCC and matched metastatic tissues. CD10 and CD13 were performed on 7 cases of clear-cell RCC with hematogenous tissue metastases. Cytogenetic fluorescence in situ hybridization analysis was performed on primary and matched metastatic tissues using specific probes mapping the 9p and the 14q loci. The loss of chromosome 9p was observed in 85% of both primary clear-cell RCCs and in matched metastases; 14% showed discordance between primary and matched metastases showing gains. The loss of chromosome 14q was observed in 58% of both primary and matched metastases. Only 3/7 (42%) did show an equal status of loss of chromosome 14q. Heterogeneity of the cytogenetic status between metastatic and primary clear-cell RCCs is observed for the loss of chromosome 14q rather than chromosome 9p. The impact of chromosome 14q cytogenetic status, harboring the HIF1 gene, a major driver for the angiogenenic switch, may drive the efficacy of targeted inhibitors, whereas the loss of chromosome 9p, harboring other hot-spot genes, seems to be related to the metastatic behavior per se, without cytogenetic modulation. Reprofiling the metastatic tissue, as compared with the primary tumor, in patients affected by metastatic RCC could be a novel approach to overcome resistance to VEGF(Rs)-targeting agents.
Association of Stromal Factors With the Histologic Risk Assessment Model in Oral Squamous Cell Carcinoma
Authors: Alaeddini Mojgan , Abachi Hasan , Abbasi Shima , Shamshiri Ahmad-Reza , Etemad-Moghadam Shahroo
Published: October 2015

The aim of the present study was to evaluate angiogenesis, lymphangiogenesis, and mast cell density in association with the histologic risk assessment (HRA) model in oral squamous cell carcinoma. One hundred oral squamous cell carcinomas were graded according to the HRA system and immunostained with antibodies against D2-40, CD34, and CD105 to determine lymphvessel density (LVD) and microvessel density (MVD). Mast cells were detected by toluidine blue and counted in all samples. Assessments were made between the evaluated factors and the histologic variables of HRA. Kruskal-Wallis and Mann-Whitney U test were used for statistical analysis and P<0.05 was considered significant. There were 32, 26, and 42 cases of low, intermediate, and high-grade neoplasms, respectively. Only LVD (P=0.05) and CD34MVD (P=0.03) showed significant associations with lymphocytic infiltration and were both higher in score 0 cases compared with score 3 tumors (P=0.05 and <0.001, respectively). None of the other variables showed significant relationships with the HRA risk scores or subcategories (P>0.05). According to our findings, it appears that the role of lymphangiogenesis and angiogenesis is limited in the HRA system. The significant relationship of lymphocytic infiltration with LVD and CD34MVD, but not CD105MVD, might indicate that “inflammatory lymphangiogenesis/angiogenesis” may differ from that induced by noninflamed neoplastic tissues. It also seems that the vasculature in inflamed tumor tissues is not entirely newly formed.
Oncogenic Activation of the Wnt/β-Catenin Signaling Pathway in Signet Ring Stromal Cell Tumor of the Ovary
Authors: Kopczynski Janusz , Kowalik Artur , Chłopek Małgorzata , Wang Zeng-Feng , Góźdź Stanisław , Lasota Jerzy , Miettinen Markku
Published: October 2015

Signet ring stromal cell tumor (SRSCT) of the ovary is a very rare benign ovarian neoplasm. To date, no underlying genetic mechanism has been identified. In this study, 50 oncogenes and tumor suppressor genes were evaluated for mutations in a typical SRSCT using the next-generation DNA sequencing approach. An in-frame deletion of 30 nucleotides in the glycogen serine kinase-3 beta phosphorylation region of the β-catenin gene (CTNNB1) was identified, and the finding was confirmed by Sanger sequencing. This deletion (c.68_97del) at the protein level would lead to a p.Ser23_Ser33delinsThr oncogenic-type mutation. Subsequent immunohistochemistry showed prominent nuclear accumulation of β-catenin and cyclin D1 in tumor cells. Thus, mutational activation of the Wnt/β-catenin pathway could be a crucial event in the molecular pathogenesis of SRSCT of the ovary. These findings may also assist in the diagnosis of this rare tumor.
Mitogenomic analysis of a 50-generation chicken pedigree reveals a rapid rate of mitochondrial evolution and evidence for paternal mtDNA inheritance
Authors: Alexander Michelle , Ho Simon Y. W. , Molak Martyna , Barnett Ross , Carlborg Örjan , Dorshorst Ben , Honaker Christa , Besnier Francois , Wahlberg Per , Dobney Keith , Siegel Paul , Andersson Leif , Larson Greger
Published: October 2015

Mitochondrial genomes represent a valuable source of data for evolutionary research, but studies of their short-term evolution have typically been limited to invertebrates, humans and laboratory organisms. Here we present a detailed study of 12 mitochondrial genomes that span a total of 385 transmissions in a well-documented 50-generation pedigree in which two lineages of chickens were selected for low and high juvenile body weight. These data allowed us to test the hypothesis of time-dependent evolutionary rates and the assumption of strict maternal mitochondrial transmission, and to investigate the role of mitochondrial mutations in determining phenotype. The identification of a non-synonymous mutation in
ND4L
and a synonymous mutation in
CYTB
, both novel mutations in
Gallus
, allowed us to estimate a molecular rate of 3.13 × 10
−7
mutations/site/year (95% confidence interval 3.75 × 10
−8
–1.12 × 10
−6
). This is substantially higher than avian rate estimates based upon fossil calibrations. Ascertaining which of the two novel mutations was present in an additional 49 individuals also revealed an instance of paternal inheritance of mtDNA. Lastly, an association analysis demonstrated that neither of the point mutations was strongly associated with the phenotypic differences between the two selection lines. Together, these observations reveal the highly dynamic nature of mitochondrial evolution over short time periods.
Elevated glucocorticoid concentrations during gestation predict reduced reproductive success in subordinate female banded mongooses
Authors: Sanderson J. L. , Nichols H. J. , Marshall H. H. , Vitikainen E. I. K. , Thompson F. J. , Walker S. L. , Cant M. A. , Young A. J.
Published: October 2015

Dominant females in social species have been hypothesized to reduce the reproductive success of their subordinates by inducing elevated circulating glucocorticoid (GC) concentrations. However, this ‘stress-related suppression' hypothesis has received little support in cooperatively breeding species, despite evident reproductive skews among females. We tested this hypothesis in the banded mongoose (
Mungos mungo
), a cooperative mammal in which multiple females conceive and carry to term in each communal breeding attempt. As predicted, lower ranked females had lower reproductive success, even among females that carried to term. While there were no rank-related differences in faecal glucocorticoid (fGC) concentrations prior to gestation or in the first trimester, lower ranked females had significantly higher fGC concentrations than higher ranked females in the second and third trimesters. Finally, females with higher fGC concentrations during the third trimester lost a greater proportion of their gestated young prior to their emergence from the burrow. Together, our results are consistent with a role for rank-related maternal stress in generating reproductive skew among females in this cooperative breeder. While studies of reproductive skew frequently consider the possibility that rank-related stress reduces the conception rates of subordinates, our findings highlight the possibility of detrimental effects on reproductive outcomes even after pregnancies have become established.
Grooming-at-a-distance by exchanging calls in non-human primates
Authors: Arlet Malgorzata , Jubin Ronan , Masataka Nobuo , Lemasson Alban
Published: October 2015

The ‘social bonding hypothesis' predicts that, in large social groups, functions of gestural grooming should be partially transferred to vocal interactions. Hence, vocal exchanges would have evolved in primates to play the role of grooming-at-a-distance in order to facilitate the maintenance of social cohesion. However, there are few empirical studies testing this hypothesis. To address this point, we compared the rate of contact call exchanges between females in two captive groups of Japanese macaques as a function of female age, dominance rank, genetic relatedness and social affinity measured by spatial proximity and grooming interactions. We found a significant positive relationship between the time spent on grooming by two females and the frequency with which they exchanged calls. Our results conform to the predictions of the social bonding hypothesis, i.e. vocal exchanges can be interpreted as grooming-at-a-distance.
Synchrony and exertion during dance independently raise pain threshold and encourage social bonding
Authors: Tarr Bronwyn , Launay Jacques , Cohen Emma , Dunbar Robin
Published: October 2015

Group dancing is a ubiquitous human activity that involves exertive synchronized movement to music. It is hypothesized to play a role in social bonding, potentially via the release of endorphins, which are analgesic and reward-inducing, and have been implicated in primate social bonding. We used a 2 × 2 experimental design to examine effects of exertion and synchrony on bonding. Both demonstrated significant independent positive effects on pain threshold (a proxy for endorphin activation) and in-group bonding. This suggests that dance which involves both exertive and synchronized movement may be an effective group bonding activity.
Early post-metamorphic, Carboniferous blastoid reveals the evolution and development of the digestive system in echinoderms
Authors: Rahman Imran A. , Waters Johnny A. , Sumrall Colin D. , Astolfo Alberto
Published: October 2015

Inferring the development of the earliest echinoderms is critical to uncovering the evolutionary assembly of the phylum-level body plan but has long proven problematic because early ontogenetic stages are rarely preserved as fossils. Here, we use synchrotron tomography to describe a new early post-metamorphic blastoid echinoderm from the Carboniferous (approx. 323 Ma) of China. The resulting three-dimensional reconstruction reveals a U-shaped tubular structure in the fossil interior, which is interpreted as the digestive tract. Comparisons with the developing gut of modern crinoids demonstrate that crinoids are an imperfect analogue for many extinct groups. Furthermore, consideration of our findings in a phylogenetic context allows us to reconstruct the evolution and development of the digestive system in echinoderms more broadly; there was a transition from a straight to a simple curved gut early in the phylum's evolution, but additional loops and coils of the digestive tract (as seen in crinoids) were not acquired until much later.
Cancer therapeutic potential of combinatorial immuno- and vasomodulatory interventions
Authors: Hatzikirou H. , Alfonso J. C. L. , Mühle S. , Stern C. , Weiss S. , Meyer-Hermann M.
Published: October 2015

Currently, most of the basic mechanisms governing tumour–immune system interactions, in combination with modulations of tumour-associated vasculature, are far from being completely understood. Here, we propose a mathematical model of vascularized tumour growth, where the main novelty is the modelling of the interplay between functional tumour vasculature and effector cell recruitment dynamics. Parameters are calibrated on the basis of different
in vivo
immunocompromised Rag1
−/−
and wild-type (WT) BALB/c murine tumour growth experiments. The model analysis supports that tumour vasculature normalization can be a plausible and effective strategy to treat cancer when combined with appropriate immunostimulations. We find that improved levels of functional tumour vasculature, potentially mediated by normalization or stress alleviation strategies, can provide beneficial outcomes in terms of tumour burden reduction and growth control. Normalization of tumour blood vessels opens a therapeutic window of opportunity to augment the antitumour immune responses, as well as to reduce intratumoral immunosuppression and induced hypoxia due to vascular abnormalities. The potential success of normalizing tumour-associated vasculature closely depends on the effector cell recruitment dynamics and tumour sizes. Furthermore, an arbitrary increase in the initial effector cell concentration does not necessarily imply better tumour control. We evidence the existence of an optimal concentration range of effector cells for tumour shrinkage. Based on these findings, we suggest a theory-driven therapeutic proposal that optimally combines immuno- and vasomodulatory interventions.
Thermodynamics of firms' growth
Authors: Zambrano Eduardo , Hernando Alberto , Fernández Bariviera Aurelio , Hernando Ricardo , Plastino Angelo
Published: October 2015

The distribution of firms' growth and firms' sizes is a topic under intense scrutiny. In this paper, we show that a thermodynamic model based on the maximum entropy principle, with dynamical prior information, can be constructed that adequately describes the dynamics and distribution of firms' growth. Our theoretical framework is tested against a comprehensive database of Spanish firms, which covers, to a very large extent, Spain's economic activity, with a total of 1 155 142 firms evolving along a full decade. We show that the empirical exponent of Pareto's law, a rule often observed in the rank distribution of large-size firms, is explained by the capacity of economic system for creating/destroying firms, and that can be used to measure the health of a capitalist-based economy. Indeed, our model predicts that when the exponent is larger than 1, creation of firms is favoured; when it is smaller than 1, destruction of firms is favoured instead; and when it equals 1 (matching Zipf's law), the system is in a full macroeconomic equilibrium, entailing ‘free’ creation and/or destruction of firms. For medium and smaller firm sizes, the dynamical regime changes, the whole distribution can no longer be fitted to a single simple analytical form and numerical prediction is required. Our model constitutes the basis for a full predictive framework regarding the economic evolution of an ensemble of firms. Such a structure can be potentially used to develop simulations and test hypothetical scenarios, such as economic crisis or the response to specific policy measures.
Dynamics of deceptive interactions in social networks
Authors: Barrio Rafael A. , Govezensky Tzipe , Dunbar Robin , Iñiguez Gerardo , Kaski Kimmo
Published: October 2015

In this paper, we examine the role of lies in human social relations by implementing some salient characteristics of deceptive interactions into an opinion formation model, so as to describe the dynamical behaviour of a social network more realistically. In this model, we take into account such basic properties of social networks as the dynamics of the intensity of interactions, the influence of public opinion and the fact that in every human interaction it might be convenient to deceive or withhold information depending on the instantaneous situation of each individual in the network. We find that lies shape the topology of social networks, especially the formation of tightly linked, small communities with loose connections between them. We also find that agents with a larger proportion of deceptive interactions are the ones that connect communities of different opinion, and, in this sense, they have substantial centrality in the network. We then discuss the consequences of these results for the social behaviour of humans and predict the changes that could arise due to a varying tolerance for lies in society.
Measured voluntary avoidance behaviour during the 2009 A/H1N1 epidemic
Authors: Bayham Jude , Kuminoff Nicolai V. , Gunn Quentin , Fenichel Eli P.
Published: October 2015

Managing infectious disease is among the foremost challenges for public health policy. Interpersonal contacts play a critical role in infectious disease transmission, and recent advances in epidemiological theory suggest a central role for adaptive human behaviour with respect to changing contact patterns. However, theoretical studies cannot answer the following question: are individual responses to disease of sufficient magnitude to shape epidemiological dynamics and infectious disease risk? We provide empirical evidence that Americans voluntarily reduced their time spent in public places during the 2009 A/H1N1 swine flu, and that these behavioural shifts were of a magnitude capable of reducing the total number of cases. We simulate 10 years of epidemics (2003–2012) based on mixing patterns derived from individual time-use data to show that the mixing patterns in 2009 yield the lowest number of total infections relative to if the epidemic had occurred in any of the other nine years. The World Health Organization and other public health bodies have emphasized an important role for ‘distancing’ or non-pharmaceutical interventions. Our empirical results suggest that neglect for voluntary avoidance behaviour in epidemic models may overestimate the public health benefits of public social distancing policies.
The survival–reproduction association becomes stronger when conditions are good
Authors: Robert Alexandre , Bolton Mark , Jiguet Frédéric , Bried Joël
Published: October 2015

Positive covariations between survival and reproductive performance (S–R covariation) are generally interpreted in the context of fixed or dynamic demographic heterogeneity (i.e. persistent differences between individuals, or dynamic variation in resource acquisition), but the processes underlying covariations are still unknown. We used multi-event modelling to investigate how environmental and individual features influence S–R covariation patterns in a long-lived seabird, the Monteiro's storm petrel (
Oceanodroma monteiroi
). Our analysis reveals that a strong positive association between individual breeding success and subsequent survival occurs only when conditions are favourable to reproduction (in favourable years, in high-quality nests and in nest-faithful breeders). This finding reflects differences in the main causes of breeding failure and mortality under favourable and unfavourable conditions, which in turn lead to distinct patterns of S–R covariation. We suggest, in particular, that resource-related sources of demographic heterogeneity do not generate a strong S–R covariation, in contrast with hidden and unpredictable sources of variation.
Polyspermy in birds: sperm numbers and embryo survival
Authors: Hemmings N. , Birkhead T. R.
Published: October 2015

Polyspermy is a major puzzle in reproductive biology. In some taxa, multiple sperm enter the ovum as part of the normal fertilization process, whereas in others, penetration of the ovum by more than one sperm is lethal. In birds, several sperm typically enter the germinal disc, yet only one fuses with the female pronucleus. It is unclear whether supernumerary sperm play an essential role in the avian fertilization process and, if they do, how females regulate the progression of sperm through the oviduct to ensure an appropriate number reach the ovum. Here, we show that when very few sperm penetrate the avian ovum, embryos are unlikely to survive beyond the earliest stages of development. We also show that when the number of inseminated sperm is limited, a greater proportion than expected reach and penetrate the ovum, indicating that females compensate for low sperm numbers in the oviduct. Our results suggest a functional role for supernumerary sperm in the processes of fertilization and early embryogenesis, providing an exciting expansion of our understanding of sperm function in birds.
A restatement of recent advances in the natural science evidence base concerning neonicotinoid insecticides and insect pollinators
Authors: Godfray H. Charles J. , Blacquière Tjeerd , Field Linda M. , Hails Rosemary S. , Potts Simon G. , Raine Nigel E. , Vanbergen Adam J. , McLean Angela R.
Published: October 2015

A summary is provided of recent advances in the natural science evidence base concerning the effects of neonicotinoid insecticides on insect pollinators in a format (a ‘restatement') intended to be accessible to informed but not expert policymakers and stakeholders. Important new studies have been published since our recent review of this field (Godfray
et al.
2014
Proc. R. Soc. B
281, 20140558. (
doi:10.1098/rspb.2014.0558
)) and the subject continues to be an area of very active research and high policy relevance.
Predicting the effects of human developments on individual dolphins to understand potential long-term population consequences
Authors: Pirotta Enrico , Harwood John , Thompson Paul M. , New Leslie , Cheney Barbara , Arso Monica , Hammond Philip S. , Donovan Carl , Lusseau David
Published: October 2015

Human activities that impact wildlife do not necessarily remove individuals from populations. They may also change individual behaviour in ways that have sublethal effects. This has driven interest in developing analytical tools that predict the population consequences of short-term behavioural responses. In this study, we incorporate empirical information on the ecology of a population of bottlenose dolphins into an individual-based model that predicts how individuals' behavioural dynamics arise from their underlying motivational states, as well as their interaction with boat traffic and dredging activities. We simulate the potential effects of proposed coastal developments on this population and predict that the operational phase may affect animals' motivational states. For such results to be relevant for management, the effects on individuals' vital rates also need to be quantified. We investigate whether the relationship between an individual's exposure and the survival of its calves can be directly estimated using a Bayesian multi-stage model for calf survival. The results suggest that any effect on calf survival is probably small and that a significant relationship could only be detected in large, closely studied populations. Our work can be used to guide management decisions, accelerate the consenting process for coastal and offshore developments and design targeted monitoring.