bluuebunny/crossref_metadata_2025 huggingface dataset:
Converging Perspectives on Antiochos III
Authors: Haubold Johannes
Published: August 2017

This chapter compares three texts about the Seleukid monarch Antiochos III: a decree of the Seleukid Greek city of Teos published shortly before the king’s war with Rome; a description of his conduct of the war written by the pro-Roman historian Polybios; and a cuneiform text from Babylon about Antiochos’ visit to the city just after the war. I argue that, despite differences in style, cultural background, historical context, and political allegiance, these texts converge around key themes of Seleukid imperial discourse, such as the king as benefactor and the importance of the royal couple. The chapter thus serves as a corrective to recent scholarship that tends to stress the differences between Greek and non-Greek perspectives on the Seleukid kings.
The Flow of Powers
Authors: Ehret Charles
Published: August 2017

In thirteenth-century philosophical psychology, it is commonly held that the powers of the soul, responsible for a living being’s various operations, “flow” from the soul’s essence. The phrase is used systematically by Albert the Great, who imports it from Avicenna. It suggests that the soul, considered as a separate substance, is ontologically distinct from its powers. This is how Albert understands Avicenna, and how modern interpreters understand both Avicenna and Albert. The aim of this paper is to call into question such an understanding, as a reading of Avicenna and as a philosophical doctrine. It argues that an ontological distinction between the soul and its powers isn’t intended in Avicenna, and isn’t successfully established in Albert. It further argues that psychological emanation yields such a distinction only in Aquinas, where the soul is no longer considered a separate substance, but a material form.
Coping with Time in Organizations
Authors: Spinosa Charles , Hancocks Matthew , Glennon Billy
Published: August 2017

Conceptions of time and practices for managing time play an important role in both popular management literature and process organization studies. In popular literature, managers have too little time. In organization studies, managers have multiple time-reckoning practices and experiences of time. In response, we explicate and defend Heidegger’s account of primordial time to show the inauthenticity of living with either too little time or many alternative temporal structurings. People are true to primordial (kairotic) time when they face their existential death—the emerging practices that will make their lives meaningless—accept the past emotions that well up on that account, and adjust themselves to accept the past and avoid existential death. They then do what is essential. Alternatively, taking over other temporal structurings amounts to living as another kind of self-interpreting being—an organization or tribe—and is inauthentic. An episode from Steve Jobs’ career illustrates authentic Heideggerian time management.
Commitment and Cooperation on High Courts
Authors: Alarie Benjamin , Green Andrew J.
Published: August 2017

This chapter sets out and justifies the building blocks of commitment and cooperation. These two dimensions allow the authors to situate high courts relative to each other. They use them to focus on the five main high courts in their study, namely, the US Supreme Court, the UK Supreme Court (and its predecessor House of Lords), the Supreme Court of Canada, the High Court of Australia, and the Indian Supreme Court. This chapter provides both a preliminary assessment of how these courts sit relative to each other along these two dimensions and a brief overview of the key design choices made by each of these courts.
What’s Good for Us is Good for You
Authors: Shadlen Kenneth C.
Published: August 2017

This chapter analyses the political economy of continuity in Mexico. High levels of patenting and accentuated transnational dominance of the pharmaceutical industry, both functions of the choices of the 1990s, created an environment that was inhospitable to efforts to reform the new pharmaceutical patent system. The chapter examines a set of revisions to the new pharmaceutical patent regime in the 2000s, all of which were resolved to the benefit of patent-holders seeking greater rights of exclusion. The analysis demonstrates that persistent over-compliance was not because of Mexico’s obligations under NAFTA, but rather despite the opportunities for tailoring that were allowed by this agreement. Within-case comparative analysis offered by these case studies provides variation on the preferences of health officials in the Mexican Executive, the interests and strategies of the local pharmaceutical sector, Mexico’s sensitivity to external pressures, yet the outcomes were similar, as a result of Mexico’s changed social structure.
The Protection of Intellectual Property in International Law
Authors: Grosse Ruse-Khan Henning
Published: August 2017

This chapter turns to the various approaches for addressing overlaps and resolving conflicts previously summarized. A range of specific conflict rules, the general conflict of norm principles referred to in the ILC Fragmentation Report, as well as alternatives such as conflict-of-laws concepts and the substantive law method are explored and applied to the rule relations assessed throughout prior chapters. The chapter then offers a birds-eye perspective on the relations within the international intellectual property (IP) system, those to alternative systems for protecting IP assets in international law, and to other global legal orders that interface the protection of IP. This perspective cannot claim to be objective and of course does not offer any sort of absolute truth. However, the chapter attempts to present this perspective as one that goes beyond the traditional realm of ‘international intellectual property law’ and truly engages with other rule systems in international law.
Introduction
Authors: de Bruyn Theodore
Published: August 2017

The Introduction explains the motivation for the book and introduces the questions it addresses. It describes the manuals and incantations that have survived from the Graeco-Roman world, and outlines how textual amulets changed in an increasingly Christian context. It discusses the individuality that scribes of amulets with Christian elements brought to the practice, both in how they worked with customary and Christian traditions and in the way they wrote their incantations. It argues that Christian rituals or ritualizing behaviour supplied resources that writers of amulets adopted and adapted in diverse ways. The Introduction outlines the contents of the book, and explains its use of the terms ‘incantation’ and ‘amulet’.
The foundations of literary rhetoric
Authors: Meyer Michel
Published: August 2017

Chapter 7 deals with one of the most traditional aspects of rhetoric, namely literature. It describes a basic law of literary rhetoric which accounts for the increasing problematicity of literary language in novels, poetry, and drama. This chapter also explains the evolution of literary criticism. The fact that literature is less and less linear in its narratives, and is increasingly enigmatic (Joyce or Kafka) is accounted for by the law of auto-contextualization of the problematic in the fictional answers. This law encourages the reader to provide the meaning of the text, even when it is considered as impossible or equivocal and pluralistic. The four main schools of literary interpretation correspond to our four basic operators of rhetoric: Mimetic for =, Hermeneutics for ±, Reception Theory for + (the reader is the “plus” of the interpretation of the text), and Deconstruction for –.
The negotiation of distance or the embodiment of the interpersonal
Authors: Meyer Michel
Published: August 2017

Chapter 11 analyzes how all the preceding elements of the new definition of rhetoric as the negotiation of distance fit together. What is meant by negotiation? People can, and do, maintain, increase, or diminish the distance between themselves on a daily basis. After the preceding accounts of logos, ethos, and pathos, this final chapter is devoted to the analysis of distance. It analyzes how rhetoric affects the variations in distance between individuals, and how the variations of distance in turn affect the rhetorical impact sought by the interlocutors. This is where the distinction between the projective view that one has of others plays just as much of a role as the effective situation of others. The discrepancy between the projective and the effective can make distance itself an object of rhetorical debate.
Revising Inconsistent Concepts
Authors: Scharp Kevin , Shapiro Stewart , Armour-Garb Bradley
Published: August 2017

This chapter investigates the question of when it is reasonable to replace an inconsistent concept. After surveying a number of proposals for how one might understand constitutive principles, it goes on to endorse Burgess’s (2004) account of being pragmatically analytic, as a possible source of insight into constitutive principles. The chapter then raises a question: If truth is an inconsistent concept, does it need to be replaced? According to the argument in the chapter, when an inconsistent concept paralyzes valuable projects, it is time to replace it. And if we are to replace a concept, our replacement should be able to do the work that the inconsistency-yielding one did. This, of course, raises a fundamental question concerning what work the notion of truth does for us. The chapter mounts a case for the claim that inflationists, but not obvious deflationists, about truth should offer a replacement for the concept of truth.
Resistance training reduces inflammation and fatigue and improves physical function in older breast cancer survivors
Authors: Serra Monica C. , Ryan Alice S. , Ortmeyer Heidi K. , Addison Odessa , Goldberg Andrew P.
Published: August 2017

Objective:

Resistance training (RT) reduces fatigue and improves physical function and quality of life (QOL) in breast cancer survivors (BCS). This may be related to reductions in systemic and tissue-specific inflammation. This pilot study examines the hypothesis that RT induces changes in systemic and tissue-specific inflammation that contribute to improvements in physical and behavioral function in postmenopausal BCS.

Methods:

Eleven BCS (60 ± 2 years old, body mass index 30 ± 1 kg/m2, mean ± SEM) underwent assessments of fatigue (Piper Fatigue Scale), physical function, QOL (SF-36), glucose and lipid metabolism, and systemic, skeletal muscle, and adipose tissue inflammation (n = 9) before and after 16 weeks of moderate-intensity whole-body RT.

Results:

Muscle strength improved by 25% to 30% (P < 0.01), QOL by 10% (P = 0.04), chair stand time by 15% (P = 0.01), 6-minute walk distance by 4% (P = 0.03), and fatigue decreased by 58% (P < 0.01), fasting insulin by 18% (P = 0.04), and diastolic and systolic blood pressure by approximately 5% (P = 0.04) after RT. BCS with the worst fatigue and QOL demonstrated the greatest improvements (absolute change vs baseline: fatigue: r = −0.95, P < 0.01; QOL: r = −0.82, P < 0.01). RT was associated with an approximately 25% to 35% relative reduction in plasma and adipose tissue protein levels of proinflammatory interleukin (IL)-6sR, serum amyloid A, and tumor necrosis factor-α, and 75% relative increase in muscle pro-proliferative, angiogenic IL-8 protein content by 75% (all P < 0.05). BCS with the highest baseline proinflammatory cytokine levels had the greatest absolute reductions, and the change in muscle IL-8 correlated directly with improvements in leg press strength (r = 0.53, P = 0.04).

Conclusions:

These preliminary results suggest that a progressive RT program effectively lowers plasma and tissue-specific inflammation, and that these changes are associated with reductions in fatigue and improved physical and behavioral function in postmenopausal BCS.
Clinical Characteristics of Benign Recurrent Vestibulopathy: Clearly Distinctive From Vestibular Migraine and Menière's Disease?
Authors: van Esch Babette F. , van Wensen Erik , van der Zaag-Loonen Hester J. , Benthem Peter Paul G. van , van Leeuwen Roeland B.
Published: August 2017

Objective:

We aimed to systematically investigate the clinical characteristics of benign recurrent vestibulopathy (BRV), vestibular migraine (VM), and Menière's disease (MD) and to assess whether clinical symptoms exist that are unique to BRV.

Study Design:

Prospective cohort study.

Setting:

Tertiary referral center.

Methods:

Between January 2015 and November 2016, patients were prospectively recruited at a specialized dizziness clinic. Patients were included if they met the diagnostic criteria for BRV, VM, or MD which was evaluated by simultaneous consultation of an otorhinolaryngologist and neurologist. All patients received a comprehensive clinical examination that included vestibular tests and pure-tone audiometry. A questionnaire was designed to systematically document symptoms of the three vestibular disorders.

Results:

A total of 122 patients were included in our study, 65 (53%) were females in whom 29 (24%) were postmenopausal. The mean age was 55.5 ± 13.7 years and the mean age of onset of vertigo attacks was 49.2 ± 14.8 years (n = 119). Forty-five (37%) patients had a clinical diagnosis of BRV, 34 (28%) of VM, and 43 (35%) of MD. No symptom could be identified which was specifically linked to BRV. In patients with BRV, similar to those with VM, we found a female preponderance (p = 0.05 in BRV, p = 0.001 in VM). Patients with VM reported significantly more often a positive history of motion sickness (p = 0.01). In addition, canal paresis was most profound in patients with MD (p = 0.001).

Conclusion:

We found no clinical characteristics that were distinctive for BRV. However, we did find several distinctive clinical features for VM and MD which may assist the physician in their history taking.
Nocebo Effect in Menière's Disease: A Meta-analysis of Placebo-controlled Randomized Controlled Trials
Authors: Dimitriadis Panagiotis A. , Zis Panagiotis
Published: August 2017

Objective:

To estimate the frequency and strength of nocebo effects in trials for Menière disease (MD).

Data Sources:

A literature search was conducted in PUBMED. The search terms we used were “ Menière or Menière's,” “treatment,” and “placebo.” Limitations included article type to be Clinical Trial or Randomized Controlled Trial, text availability to be Full text, Species to be Humans and Language to be English.

Study Selection:

We included placebo-controlled pharmaceutical RCTs that referred specifically to MD and recruited at least 10 adults in each arm. We excluded those studies with JADAD score ≤3.

Data Extraction:

Thirty-six articles were screened identifying 12 eligible studies. Studies were included after consensus of both authors.

Data Synthesis:

The meta-analysis was conducted using the RevMan programme as suggested by the Cochrane Collaboration Group. Data were analyzed using a random effects model.

Conclusion:

Nocebo is an important confounding factor of the reported AEs in RCTs for treatment of MD and subsequently in the clinical practice. The pooled estimate of the percentage of placebo-treated patients with at least one AE was 42.3% (95% CI 8.1% to 16.3%), in comparison to 53.8% (95% CI 48.0% to 59.5%) for active drug-treated patients. Reporting of RCTs in MD is suboptimal and we recommend authors to endorse the CONSORT checklist.
Condomless Sex Among Virally Suppressed Women With HIV With Regular HIV-Serodiscordant Sexual Partners in the Era of Treatment as Prevention
Authors: Patterson Sophie , Carter Allison , Nicholson Valerie , Webster Kath , Ding Erin , Kestler Mary , Ogilvie Gina , de Pokomandy Alexandra , Loutfy Mona , Kaida Angela ,   on behalf of the CHIWOS Research Team
Published: August 2017

Background:

Sexual HIV transmission does not occur with sustained undetectable viral load (VL) on antiretroviral therapy (ART). Awareness of ART prevention benefits and its influence on condom use among women with HIV (WWH) remain unexplored. We estimated prevalence and correlates of condomless sex with regular HIV-serodiscordant partners among WWH with undetectable VL on ART.

Methods:

We used baseline questionnaire data from the community-based longitudinal Canadian HIV Women's Sexual and Reproductive Health Cohort Study (CHIWOS). We included WWH self-reporting vaginal/anal sex with ≥1 HIV-negative/unknown status regular partner within 6 months, and undetectable VL (<50 copies/mL) on ART. We excluded participants exclusively reporting female partners or missing condom-use data. Condomless sex was defined as <100% condom use within 6 months. The primary explanatory variable was awareness of ART prevention benefits. Logistic regression identified factors independently associated with condomless sex.

Results:

Of 271 participants (19% of the CHIWOS cohort), median age was 41 (interquartile range: 34–47), 51% were in a relationship, 55% reported condomless sex, and 75% were aware of ART prevention benefits. Among women aware, 63% reported condomless sex compared with 32% of women not aware (P < 0.001). Factors independently associated with condomless sex included being aware of ART prevention benefits (adjusted odds ratio: 4.08; 95% confidence interval: 2.04 to 8.16), white ethnicity, ≥high-school education, residing in British Columbia, and being in a relationship.

Conclusions:

Virally suppressed women aware of ART prevention benefits had 4-fold greater odds of condomless sex. Advancing safer sex discussions beyond condoms is critical to support women in regular serodiscordant partnerships to realize options for safe and satisfying sexuality in the Treatment-as-Prevention era.
Differential Diagnosis Between Nasal Septal Schwannoma and Nasal Septal Neurofibroma
Authors: Min Hyun Jin , Kim Kyung Soo
Published: August 2017

Recently, as the authors experienced nasal septal schwannoma and nasal septal neurofibroma with similar clinical symptoms but different endoscopic findings, the authors tried to review all the literatures previously reported on the “Nasal septal schwannoma and Nasal septal neurofibroma.” The aim of this study is to thoroughly review previously reported patients with nasal septal schwannomas and neurofibromas and to describe similar and different features focusing on the differential diagnosis between the 2 entities. On the basis of our review, the authors made some important conclusions. First, benign peripheral nerve tumors originating from the nasal septum are uncommon. Especially, nasal septal neurofibroma is extremely rare that only 5 patients were reported. So, more clinical reports of benign peripheral nerve tumors are necessary to elucidate the differences between nasal septal schwannoma and nasal septal neurofibroma. Second, there are some similar features between nasal septal schwannoma and nasal septal neurofibroma such as clinical symptoms, endoscopic findings, and treatment strategy. However, since there seem to be some differences in nasal endoscopic findings, they may be helpful for the provisional diagnosis, and so more patients should be reported to verify that point. Third, image study, especially magnetic resonance imaging (MRI), is considered to be a useful tool for differential diagnosis of benign peripheral nerve tumors originating from the nasal septum. So, more clinical reports reporting MRI findings are needed to verify the differences. Last, because of distinctive histologic appearances of benign peripheral nerve tumors, it is usually not difficult to make the distinction between nasal septal schwannoma and nasal septal neurofibroma. However, immunohistochemical stains including S-100 protein, calretinin, CD 34, factor XIIIa, and CD56 are necessary when it is difficult to differentiate between 2 disease entities.
Esophageal Stricture in a Child With Habit of Acidic Drinks
Authors: Erdur Omer , Sekmenli Tamer , Ciftci Ilhan , Ozturk Kayhan
Published: August 2017

A 12-year-old boy with Down syndrome referred to the authors’ department with dysphagia and growth retardation. Dysphagia was especially with solid foods and had a 12-month history. When he was 7, he had started to drink Coke and from that time he had a Coke drinking habit. Every day he was drinking more than 2 L Coke and was eating meals in small amounts. Investigations of the patient revealed esophageal stricture related to acidic drink habit and gastro-oesephageal reflux. The patient was treated with recurrent bouginage, antireflux medication, and nutrional support. The patient became symptom free from 13 months and gained weight. The clinicians should take the nutrition habits into consideration when evaluating the esophageal stricture patients.
Osseous Flap of Galea and Periosteum Filled With Mesenchymal Stem Cells, Platelet-Rich Plasma, Bone Dust, and Hyaluronic Acid
Authors: Brock Ryane Schmidt , Viterbo Fausto , Deffune Elenice , Domingues Maria Aparecida Custodio , Mamprim Maria Jaqueline , Paschoalinotte Eloisa Elena
Published: August 2017

Reconstructive surgery to craniofacial deformities caused by tumor ressections, traumas or congenital malformation are frequent in medicine practice. It aims to provide the patients with better quality of life and functional improvement of speech, breathing, chewing, and swallowing. Many are the techniques described in the literature to recover bone defects. This study evaluated a vascularized galeal and periosteum flap in rabbits, which could possibly substitute the bone graft in reconstructive surgery, especially for facial defects. It involved rabbits, divided into 12 groups, submitted to a surgical procedure to construct the galea and periosteum cranial flap filled with fragments of cranial bone, platelet-rich plasma, mesenchimal stem cells, and hyaluronic acid. The evaluation methods included image examinations and histological analysis.

The results demonstrated bone formation with the use of platelet-rich plasma, mesenchimal stem cells, and bone fragments. The use of several enrichment materials of osseous cellular stimulation improved the quality and bone tissue organization. The more enrichment factor used, the better the tissue quality result was.

Much research should be done to improve the methods and to analyze if results in human have the same bone formation as it happened in rabbits.
Heating, weakening and shear localization in earthquake rupture
Authors: Rice James R.
Published: August 2017

Field and borehole observations of active earthquake fault zones show that shear is often localized to principal deforming zones of order 0.1–10 mm width. This paper addresses how frictional heating in rapid slip weakens faults dramatically, relative to their static frictional strength, and promotes such intense localization. Pronounced weakening occurs even on dry rock-on-rock surfaces, due to flash heating effects, at slip rates above approximately 0.1 m s−1(earthquake slip rates are typically of the order of 1 m s−1). But weakening in rapid shear is also predicted theoretically in thick fault gouge in the presence of fluids (whether native ground fluids or volatiles such as H2O or CO2released by thermal decomposition reactions), and the predicted localizations are compatible with such narrow shear zones as have been observed. The underlying concepts show how fault zone materials with high static friction coefficients, approximately 0.6–0.8, can undergo strongly localized shear at effective dynamic friction coefficients of the order of 0.1, thus fitting observational constraints, e.g. of earthquakes producing negligible surface heat outflow and, for shallow events, only rarely creating extensive melt. The results to be summarized include those of collaborative research published with Nicolas Brantut (University College London), Eric Dunham (Stanford University), Nadia Lapusta (Caltech), Hiroyuki Noda (JAMSTEC, Japan), John D. Platt (Carnegie Institution for Science, now at *gramLabs), Alan Rempel (Oregon State University) and John W. Rudnicki (Northwestern University).

This article is part of the themed issue ‘Faulting, friction and weakening: from slow to fast motion’.
Stromal Reactivity Differentially Drives Tumor Cell Evolution and Prostate Cancer Progression
Authors: Frankenstein Ziv , Basanta David , Franco Omar E. , Gao Yan , Javier Rodrigo A. , Strand Douglas W. , Lee MinJae , Hayward Simon W. , Ayala Gustavo , Anderson Alexander R.A.
Published: August 2017

We implemented a hybrid multiscale model of carcinogenesis that merges data from biology and pathology on the microenvironmental regulation of prostate cancer (PCa) cell behavior. It recapitulates the biology of stromal influence in prostate cancer progression. Our data indicate that the interactions between the tumor cells and reactive stroma shape the evolutionary dynamics of PCa cells and explain overall tumor aggressiveness. We show that the degree of stromal reactivity, when coupled with the current clinical biomarkers, significantly improves PCa prognostication, both for death and recurrence, that may alter treatment decisions. We also show that stromal reactivity correlates directly with tumor growth but inversely modulates tumor evolution. This suggests that the aggressive stromal independent PCa may be an inevitable evolutionary result of poor stromal reactivity. It also suggests that purely tumor centric metrics of aggressiveness may be misleading in terms on clinical outcome.
LOGAN: A framework for LOssless Graph-based ANalysis of high throughput sequence data
Authors: Bolger Anthony , Denton Alisandra , Bolger Marie , Usadel Björn
Published: August 2017

Recent massive growth in the production of sequencing data necessitates matching improve-ments in bioinformatics tools to effectively utilize it. Existing tools suffer from limitations in both scalability and applicability which are inherent to their underlying algorithms and data structures. We identify the key requirements for the ideal data structure for sequence analy-ses: it should be informationally lossless, locally updatable, and memory efficient; requirements which are not met by data structures underlying the major assembly strategies Overlap Layout Consensus and De Bruijn Graphs. We therefore propose a new data structure, the LOGAN graph, which is based on a memory efficient Sparse De Bruijn Graph with routing information. Innovations in storing routing information and careful implementation allow sequence datasets forEscherichia coli(4.6Mbp, 117x coverage),Arabidopsis thaliana(135Mbp, 17.5x coverage) andSolanum pennellii(1.2Gbp, 47x coverage) to be loaded into memory on a desktop computer in seconds, minutes, and hours respectively. Memory consumption is competitive with state of the art alternatives, while losslessly representing the reads in an indexed and updatable form. Both Second and Third Generation Sequencing reads are supported. Thus, the LOGAN graph is positioned to be the backbone for major breakthroughs in sequence analysis such as integrated hybrid assembly, assembly of exceptionally large and repetitive genomes, as well as assembly and representation of pan-genomes.
Identification and kinetics characterization of a wax ester hydrolase from a feather-degrading actinomycete
Authors: Barcus Matthew , Mizrachi Dario , Lei Xin Gen
Published: August 2017

Streptomyces fradiaevar. k11 is a Gram-positive soil microorganism capable of degrading chicken feathers. Apart from being mostly protein, chicken feathers have a considerable level of lipids, with wax esters being the largest lipid class. The waxes may pose a challenge while rendering the feathers into coproducts, such as feather meal, and so the identification of a wax-ester hydrolase is warranted. A draft genome sequence ofS. fradiaevar. k11 was used to identify 14 gene sequences of potential lipid-degrading enzymes. The genes were expressed inE. coliBL21(DE3) cells on a pET vector and screened for activity. Four of the 14 enzymes had detectable activity, with two of the enzymes, SFK3309 and SFK3087, active against p-nitrophenyl palmitate, a representative water-insoluble substrate. A modified enzymatic assay was designed to measure activity against three model wax substrates: jojoba oil, beeswax, and cetyl-palmitate. SFK3309 was characterized to hydrolyze all three wax substrates. Kinetic experiments for SFK3309 were performed with cetyl-palmitate at 37°C, pH 8.0. TheKmwas determined to be 850 µM and theKcatwas 11.63 s-1. Through the characterization of SFK3309 as a wax-ester hydrolase, biotechnological implications of wax ester hydrolases in the rendering of many industrial wastes can be substantiated for further studies.
CTCF mediated genome architecture regulates the dosage of mitotically stable mono-allelic expression of autosomal genes
Authors: Raanin Chandradoss Keerthivasan , Singh Sandhu Kuljeet
Published: August 2017

Mammalian genomes exhibit widespread mono-allelic expression of autosomal genes. However, the mechanistic insight that allows specific expression of one allele remains enigmatic. Here, we present evidence that the linear and the three dimensional architectures of the genome ascribe the appropriate framework that guides the mono-allelic expression of genes. We show that: 1) mono-allelically expressed genes are assorted into genomic domains that are insulated from domains of bi-allelically expressed genes through CTCF mediated chromatin loops; 2) evolutionary and cell-type specific gain and loss of mono-allelic expression coincide respectively with the gain and loss of chromatin insulator sites; 3) dosage of mono‐ allelically expressed genes is more sensitive to loss of chromatin insulationn associated with CTCF depletion as compared to bi-allelically expressed genes; 4) distinct susceptibility of mono‐ and bi-allelically expressed genes to CTCF depletion can be attributed to distinct functional roles of CTCF around these genes. Altogether, our observations highlight a general topological framework for the mono-allelic expression of genes, wherein the alleles are insulated from the spatial interference of chromatin and transcriptional states from neighbouring bi-allelic domains via CTCF mediated chromatin loops. The study also suggests that the three-dimensional genome organization might have evolved under the constraint to mitigate the fluctuations in the dosage of mono-allelically expressed genes, which otherwise are dosage sensitive.
Genome-wide association studies of brain structure and function in the UK Biobank
Authors: Elliott Lloyd T. , Sharp Kevin , Alfaro-Almagro Fidel , Shi Sinan , Miller Karla , Douaud Gwenaëlle , Marchini Jonathan , Smith Stephen
Published: August 2017

The genetic basis of brain structure and function is largely unknown. We carried out genome-wide association studies of 3,144 distinct functional and structural brain imaging derived phenotypes in UK Biobank (discovery dataset 8,428 subjects). We show that many of these phenotypes are heritable. We identify 148 clusters of SNP-imaging associations with lead SNPs that replicate at p<0.05, when we would expect 21 to replicate by chance. Notable significant and interpretable associations include: iron transport and storage genes, related to changes in T2* in subcortical regions; extracellular matrix and the epidermal growth factor genes, associated with white matter micro-structure and lesion volume; genes regulating mid-line axon guidance development associated with pontine crossing tract organisation; and overall 17 genes involved in development, pathway signalling and plasticity. Our results provide new insight into the genetic architecture of the brain with relevance to complex neurological and psychiatric disorders, as well as brain development and aging. The full set of results is available on the interactive Oxford Brain Imaging Genetics (BIG) web browser.
Design and specificity of long ssDNA donors for CRISPR-based knock-in
Authors: Li Han , Beckman Kyle A. , Pessino Veronica , Huang Bo , Weissman Jonathan S. , Leonetti Manuel D.
Published: August 2017

Update: November 12th, 2019. The conclusions of this pre-print are outdated. See Authors note on page 2. CRISPR/Cas technologies have transformed our ability to manipulate genomes for research and gene-based therapy. In particular, homology-directed repair after genomic cleavage allows for precise modification of genes using exogenous donor sequences as templates. While both single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) forms of donors have been used as repair templates, a systematic comparison of the performance and specificity of repair using ssDNA versus dsDNA donors is still lacking. Here, we describe an optimized method for the synthesis of long ssDNA templates and demonstrate that ssDNA donors can drive efficient integration of gene-sized reporters in human cell lines. We next define a set of rules to maximize the efficiency of ssDNA-mediated knock-in by optimizing donor design. Finally, by comparing ssDNA donors with equivalent dsDNA sequences (PCR products or plasmids), we demonstrate that ssDNA templates have a unique advantage in terms of repair specificity while dsDNA donors can lead to a high rate of off-target integration. Our results provide a framework for designing high-fidelity CRISPR-based knock-in experiments, in both research and therapeutic settings.
Association of mitochondria with microtubules inhibits mitochondrial fission by precluding Dnm1 assembly
Authors: Mehta Kritika , Chacko Leeba Ann , Chug Manjyot Kaur , Jhunjhunwala Siddharth , Ananthanarayanan Vaishnavi
Published: August 2017

Mitochondria are organized as tubular networks in the cell and undergo fission and fusion. While several of the molecular players involved in mediating mitochondrial dynamics have been identified, the precise cellular cues that initiate fission or fusion remain largely unknown. In fission yeast, mitochondria are organized along microtubule bundles. Here, we employed deletions of kinesin-like proteins to perturb microtubule dynamics, and determined that cells with long microtubules exhibited long, but fewer mitochondria, whereas cells with short microtubules exhibited short, but several mitochondria due to reduced mitochondrial fission in the former and elevated fission in the latter. Correspondingly, upon onset of closed mitosis in fission yeast, wherein interphase microtubules assemble to form the spindle within the nucleus, we measured increased mitochondrial fission. We determined that the consequent rise in the mitochondrial copy number was necessary to reduce partitioning errors while stochastically partitioning mitochondria between daughter cells. We discovered that the association of mitochondria with microtubules physically impeded the assembly of the fission protein Dnm1 around mitochondria, resulting in inhibition of mitochondrial fission. Taken together, we demonstrate a novel mechanism for regulation of mitochondrial fission that is dictated by the interaction between mitochondria and the microtubule cytoskeleton.
A major locus controls local adaptation and adaptive life history variation in a perennial plant
Authors: Wang Jing , Ding Jihua , Tan Biyue , Robinson Kathryn M. , Michelson Ingrid H. , Johansson Anna , Nystedt Björn , Scofield Douglas G. , Nilsson Ove , Jansson Stefan , Street Nathaniel R. , Ingvarsson Pär K.
Published: August 2017

Background

The initiation of growth cessation and dormancy represent critical life-history tradeoffs between survival and growth, and have important fitness effects in perennial plants. Such adaptive life history traits often show strong local adaptation along environmental gradients but despite their importance, the genetic architecture of these traits remains poorly understood.

Results

We integrate whole genome re-sequencing with environmental and phenotypic data from common garden experiments to investigate the genomic basis of local adaptation across a latitudinal gradient in European aspen (Populus tremula). We discover a single genomic region containing thePtFT2gene that mediates local adaptation in the timing of bud set and that explains 65% of the observed genetic variation in bud set. This locus is the likely target of a recent selective sweep that originated right before or during colonization of northern Scandinavia following the last glaciation. Field and greenhouse experiments confirm that variation inPtFT2gene expression affect the phenotypic variation in bud set that we observe in wild natural populations.

Conclusions

Our results reveal a major effect locus that determine the timing of bud set and that have facilitated rapid adaptation to shorter growing seasons and colder climates in European aspen. The discovery of a single locus explaining a substantial fraction of the variation in a key life history trait is remarkable given that such traits are generally considered to be highly polygenic. These findings provide a dramatic illustration of how loci of large-effect for adaptive traits can arise and be maintained over large geographical scales in natural populations.
Taking a semi-local dynamic snapshot as a possibility for local homing in initially naïve bumblebees
Authors: Lobecke Anne C. , Kern Roland , Egelhaaf Martin
Published: August 2017

For central place foragers, such as bumblebees, it is essential to return reliably to their nest. Instead of just flying away to forage, bumblebees, leaving their inconspicuous nest hole for the first time, need to gather and learn sufficient information about the surroundings to allow them to return to the nest at the end of their trip. Therefore, we assume an intrinsic learning program that manifests itself in the flight structure immediately after leaving the nest for the first time.

In this study, we recorded and analysed the first outbound flight of individually marked naïve bumblebees in an indoor environment. We found characteristic loop-like features in the flight pattern that appear to be necessary for the bees to acquire environmental information and might be relevant for finding the nest hole after a foraging trip.

Despite common features in their spatio-temporal organisation, the first departure flights from the nest are characterised by a high level of variability in their loop-like flight structure across animals. Changes in turn direction of body orientation, for example, are distributed evenly across the entire area used for the flights without any systematic relation to the nest location. By considering the common flight motifs as well as this variability, we came to the hypothesis, that a kind of dynamic snapshot is taken during the early phase of departure flights in the close vicinity of the nest location. The quality of this snapshot is hypothesised to be ‘ tested’ during the later phases of the departure flights concerning its usefulness for local homing.
A minimally sufficient model for rib proximal-distal patterning based on genetic analysis and agent-based simulations
Authors: Fogel J. L. , Lakeland D. L. , Mah I. K. , Mariani F. V.
Published: August 2017

For decades, the mechanism of skeletal patterning along a proximal-distal axis has been an area of intense inquiry. Here we examine the development of the ribs, simple structures that in most terrestrial vertebrates consist of two skeletal elements— a proximal bone and a distal cartilage portion. While the ribs have been shown to arise from the somites, little is known about how the two segments are specified. During our examination of genetically modified mice, we discovered a series of progressively worsening phenotypes that could not be easily explained. Here, we combine genetic analysis of rib development with agent-based simulations to conclude that proximal-distal patterning and outgrowth could occur based on simple rules. In our model, specification occurs during somite stages due to varying Hedgehog protein levels, while later expansion refines the pattern. This framework is broadly applicable for understanding the mechanisms of skeletal patterning along a proximal-distal axis.
Genetic and real-world clinical data, combined with empirical validation, nominate JAK-STAT signalling as a target for Alzheimer’s Disease therapeutic development
Authors: Nevado-Holgado Alejo J. , Ribe Elena , Thei Laura , Furlong Laura , Angel-Mayer Miguel , Quan Jie , Richardson Jill C. , Cavanagh Jonathan ,   NIMA Consortium, Lovestone Simon
Published: August 2017

As Genome Wide Association Studies (GWAS) have grown in size, the number of genetic variants that have been nominated for an increasing number of diseases has correspondingly increased. Despite this increase in the number of associated SNPs per disease, their biological interpretation has in many cases remained elusive. To address this, we have combined GWAS results with an orthogonal source of evidence, namely real-world, routinely collected clinical data from more than 6 million patients in order to drive target nomination. First we show that when examined at a pathway level, analysis of all GWAS studies groups Alzheimer’s disease (AD) in a cluster with disorders of immunity and inflammation. Using clinical data we show that the degree of comorbidity of these diseases with AD correlates with the strength of their genetic association with molecular participants in the JAK-STAT pathway. Using four independent open-science datasets we then find evidence for altered regulation of JAK-STAT pathway genes in AD. Finally, we use both in vitro and in vivo rodent models to demonstrate that Aβ induces gene expression of key drivers of this pathway, providing experimental evidence validating these data-driven observations. These results therefore nominate JAK-STAT anomalies as a prominent aetiopathological event in AD and hence potential target for therapeutic development, and moreover demonstrate a de-novo multi-modal approach to derive information from rapidly increasing genomic datasets.

One Sentence Summary

Combining evidence from genome wide association studies, real-world clinical and cohort molecular data together with experimental studies in rodent model systems nominates JAK-STAT signaling as an aetiopathological event in Alzheimer’s disease
Does no-till agriculture limit crop yields?
Authors: Tanadini Matteo , Mehrabi Zia
Published: August 2017

No-till is an agricultural practice widely promoted by governments, development agencies, and agricultural organisations worldwide. However, the costs and benefits to farmers adopting no-till are hotly debated1–4. Using a meta-analysis of unprecedented study size, Pittelkowet al.5reported that adopting no-till results in average yield losses of -5.7%, but that these losses can be limited with the added implementation of two additional conservation agriculture practices - crop rotation and crop residue retention, and in dry environments. They claimed that, as a result, resource limited smallholder farmers, that are unable to implement the whole suite of conservation agriculture practices are likely to experience yield losses under no-till. In a re-evaluation of their analysis, we found that they overly biased their results toward showing that no-till negatively impacts yields, and overlooked the practical significance of their findings. Strikingly, we find that all of the variables they used in their analysis (e.g. crop residue management, rotation, site aridity and study duration) are not much better than random for explaining the effect of no-till on crop yields. Our results suggest that their meta-analysis cannot be used as the basis for evidence-based decision-making in the agricultural community.
Inactivation of Capicua in adult mice causes T-cell lymphoblastic lymphoma
Authors: Simón-Carrasco Lucía , Graña Osvaldo , Salmón Marina , Jacob Harrys K.C. , Gutierrez Alejandro , Jiménez Gerardo , Drosten Matthias , Barbacid Mariano
Published: August 2017

CIC (also known as Capicua) is a transcriptional repressor negatively regulated by RAS/MAPK signaling. Whereas the functions of Cic have been well characterized in Drosophila, little is known about its role in mammals. CIC is inactivated in a variety of human tumors and has been implicated recently in the promotion of lung metastases. Here, we describe a mouse model in which we inactivated Cic by selectively disabling its DNA-binding activity, a mutation that causes derepression of its target genes. Germline Cic inactivation causes perinatal lethality due to lung differentiation defects. However, its systemic inactivation in adult mice induces T-cell acute lymphoblastic lymphoma (T-ALL), a tumor type known to carry CIC mutations, albeit with low incidence. Cic inactivation in mice induces T-ALL by a mechanism involving derepression of its well-known target, Etv4. Importantly, human T-ALL also relies on ETV4 expression for maintaining its oncogenic phenotype. Moreover, Cic inactivation renders T-ALL insensitive to MEK inhibitors in both mouse and human cell lines. Finally, we show that Ras-induced mouse T-ALL as well as human T-ALL carrying mutations in the RAS/MAPK pathway display a genetic signature indicative of Cic inactivation. These observations illustrate that CIC inactivation plays a key role in this human malignancy.
Identification of Nidogen 1 as a lung metastasis protein through secretome analysis
Authors: Alečković Maša , Wei Yong , LeRoy Gary , Sidoli Simone , Liu Daniel D. , Garcia Benjamin A. , Kang Yibin
Published: August 2017

Secreted proteins play crucial roles in mediating tumor–stroma interactions during metastasis of cancer to different target organs. To comprehensively profile secreted proteins involved in lung metastasis, we applied quantitative mass spectrometry-based proteomics and identified 392 breast cancer-derived and 302 melanoma-derived proteins secreted from highly lung metastatic cells. The cancer-specific lung metastasis secretome signatures (LMSSs) displayed significant prognostic value in multiple cancer clinical data sets. Moreover, we observed a significant overlap of enriched pathways between the LMSSs of breast cancer and melanoma despite an overall small overlap of specific proteins, suggesting that common biological processes are executed by different proteins to enable the two cancer types to metastasize to the lung. Among the novel candidate lung metastasis proteins, Nidogen 1 (NID1) was confirmed to promote lung metastasis of breast cancer and melanoma, and its expression is correlated with poor clinical outcomes. In vitro functional analysis further revealed multiple prometastatic functions of NID1, including enhancing cancer cell migration and invasion, promoting adhesion to the endothelium and disrupting its integrity, and improving vascular tube formation capacity. As a secreted prometastatic protein, NID1 may be developed as a new biomarker for disease progression and therapeutic target in breast cancer and melanoma.
From initiatives to employee-driven innovations
Authors: Haapasaari Arja , Engeström Yrjö , Kerosuo Hannele
Published: August 2017

Purpose

The purpose of this paper is to examine the generation of innovations by employees and the creation of initiative paths, and to discover which factors contribute to the implementation of an initiative.

Design/methodology/approach

Based on longitudinal qualitative research, the study explores the profiles of initiative paths and the types of innovations and relationships among the generated innovations.

Findings

It was found that, to become an innovation, an initiative followed different paths along which the processing and outcomes varied, as did the time needed for experimentation. The creation of initiative paths required the transformative agency of the actors involved. Power relations had an impact on the generation of initiatives and implementation of innovations.

Originality/value

Innovations research has concentrated on the generation of ideas and the implementation of innovations. This study focuses on the process path along which ideas become innovations and on the role of power relations in the innovations process.