bluuebunny/crossref_metadata_2025 huggingface dataset:
Early fossil record of Euarthropoda and the Cambrian Explosion
Authors: Daley Allison C. , Antcliffe Jonathan B. , Drage Harriet B. , Pates Stephen
Published: May 2018

Euarthropoda is one of the best-preserved fossil animal groups and has been the most diverse animal phylum for over 500 million years. Fossil Konservat-Lagerstätten, such as Burgess Shale-type deposits (BSTs), show the evolution of the euarthropod stem lineage during the Cambrian from 518 million years ago (Ma). The stem lineage includes nonbiomineralized groups, such as Radiodonta (e.g.,Anomalocaris) that provide insight into the step-by-step construction of euarthropod morphology, including the exoskeleton, biramous limbs, segmentation, and cephalic structures. Trilobites are crown group euarthropods that appear in the fossil record at 521 Ma, before the stem lineage fossils, implying a ghost lineage that needs to be constrained. These constraints come from the trace fossil record, which show the first evidence for total group Euarthropoda (e.g.,Cruziana,Rusophycus) at around 537 Ma. A deep Precambrian root to the euarthropod evolutionary lineage is disproven by a comparison of Ediacaran and Cambrian lagerstätten. BSTs from the latest Ediacaran Period (e.g., Miaohe biota, 550 Ma) are abundantly fossiliferous with algae but completely lack animals, which are also missing from other Ediacaran windows, such as phosphate deposits (e.g., Doushantuo, 560 Ma). This constrains the appearance of the euarthropod stem lineage to no older than 550 Ma. While each of the major types of fossil evidence (BSTs, trace fossils, and biomineralized preservation) have their limitations and are incomplete in different ways, when taken together they allow a coherent picture to emerge of the origin and subsequent radiation of total group Euarthropoda during the Cambrian.
Stabilized single-injection inactivated polio vaccine elicits a strong neutralizing immune response
Authors: Tzeng Stephany Y. , McHugh Kevin J. , Behrens Adam M. , Rose Sviatlana , Sugarman James L. , Ferber Shiran , Langer Robert , Jaklenec Ana
Published: May 2018

Significance

Inactivated polio vaccine (IPV) must be administered two to three times, with a 1–2 month gap between administrations, for patients to be protected. However, in the developing world healthcare workers often have difficulty reaching their patients multiple times to administer booster shots. We formulated IPV into microspheres that need to be injected only once and will be released in pulses with the desired timing without needing additional visits by a healthcare worker. To achieve this, we stabilized IPV using biocompatible excipients that allow it to remain in its active conformation inside the particles for months, and showed that they elicited a strong neutralizing immune response in rats, similar to that elicited by two separate injections of the traditional vaccine.
CK1δ/ε protein kinase primes the PER2 circadian phosphoswitch
Authors: Narasimamurthy Rajesh , Hunt Sabrina R. , Lu Yining , Fustin Jean-Michel , Okamura Hitoshi , Partch Carrie L. , Forger Daniel B. , Kim Jae Kyoung , Virshup David M.
Published: May 2018

Significance

Our innate circadian clocks control myriad aspects of behavior and physiology. Disruption of our clocks by shift work, jet lag, or inherited mutation leads to metabolic dysregulation and contributes to diseases, including diabetes and cancer. A central step in clock control is phosphorylation of the PERIOD 2 (PER2) protein. Here we conclusively identify the elusive PER2 priming kinase and find it to be the well-known circadian kinase, casein kinase 1 (CK1). Surprisingly, different forms of CK1 have differing abilities to phosphorylate the PER2 priming site, adding to the complexity of circadian regulation. These insights into the phosphoregulation of PER2 will be of broad interest to circadian biologists, computational modelers, and those seeking to pharmacologically manipulate the circadian clock.
Topography of epithelial–mesenchymal plasticity
Authors: Font-Clos Francesc , Zapperi Stefano , La Porta Caterina A. M.
Published: May 2018

Significance

Cells can change their phenotype from epithelial to mesenchymal during development and in cancer progression, where this transition is often associated with metastasis and poor disease prognosis. Here we show this process involves the transit through a multitude of metastable hybrid phenotypes in a way that is similar to the driven dynamics of disordered materials. Our method shows that highly aggressive hybrid epithelial/mesenchymal cell phenotypes are located in metastable regions that can easily switch under external and internal perturbations. We propose a general mapping strategy that can be used for other pathways, providing a useful tool to visualize the ever increasing number of gene expression data obtained from single cells and tissues.
Oocyte stage-specific effects of MTOR determine granulosa cell fate and oocyte quality in mice
Authors: Guo Jing , Zhang Teng , Guo Yueshuai , Sun Tao , Li Hui , Zhang Xiaoyun , Yin Hong , Cao Guangyi , Yin Yaoxue , Wang Hao , Shi Lanying , Guo Xuejiang , Sha Jiahao , Eppig John J. , Su You-Qiang
Published: May 2018

Significance

MTOR (mechanistic target of rapamycin), an integrator of pathways important for cellular metabolism, proliferation, and differentiation, is expressed at all stages of oocyte development. Primordial oocytes constitute a nonproliferating, nongrowing reserve of potential eggs maintained for the entire reproductive lifespan of mammalian females. Using conditional knockouts, we determined the role of MTOR in both primordial and growing oocytes. MTOR-dependent pathways in primordial oocytes are not needed to sustain the viability of the primordial oocyte pool or their recruitment into the cohort of growing oocytes but are essential later for maintenance of oocyte genomic integrity, sustaining ovarian follicular development, and fertility. In growing oocytes, MTOR-dependent pathways are required for processes that promote completion of meiosis and enable embryonic development.
Amorphous boron oxide at megabar pressures via inelastic X-ray scattering
Authors: Lee Sung Keun , Kim Yong-Hyun , Chow Paul , Xiao Yunming , Ji Cheng , Shen Guoyin
Published: May 2018

Significance

When compressed above megabar pressures (100 GPa), glasses may undergo structural transitions into more densely packed networks that differ from those at ambient pressure. While inelastic X-ray scattering (IXS) provides a rare opportunity to probe the pressure-induced bonding transitions, a decade of efforts to collect an IXS signal from any matters beyond 100 GPa have not been successful. Here, IXS spectra for B2O3glasses up to ∼120 GPa revealed its unique densification paths characterized with the unexpected stability of four-coordinated boron ([4]B). This is in contrast to other prototypical glasses where highly coordinated cations ([4,5,6]Si and[4,5,6]Ge) form at much lower pressure, confirming that the cation with a smaller atomic radius undergoes coordination transformation at higher pressure.
Distinct encoding of decision confidence in human medial prefrontal cortex
Authors: Bang Dan , Fleming Stephen M.
Published: May 2018

Significance

Recent computational models propose that our sense of confidence in a choice reflects an estimate of the probability that the choice is correct. However, it has proven difficult to experimentally separate decision confidence from its component parts, such as our certainty about perceptual evidence or choice requirements. We have devised a task to dissociate these quantities and isolate a distinct encoding of decision confidence in the medial prefrontal cortex of the human brain. We show that activity in this area not only tracks expected performance on a task, but also is related to both within-subject and between-subject variation in a subjective sense of confidence. Our study illuminates why dysfunctional confidence often emerges following damage to the prefrontal cortex.
Efficient collective swimming by harnessing vortices through deep reinforcement learning
Authors: Verma Siddhartha , Novati Guido , Koumoutsakos Petros
Published: May 2018

Significance

Can fish reduce their energy expenditure by schooling? We answer affirmatively this longstanding question by combining state-of-the-art direct numerical simulations of the 3D Navier–Stokes equations with reinforcement learning, using recurrent neural networks with long short-term memory cells to account for the unsteadiness of the flow field. Surprisingly, we find that swimming behind a leader is not always associated with energetic benefits for the follower. In turn, we demonstrate that fish can improve their sustained propulsive efficiency by placing themselves at appropriate locations in the wake of other swimmers and intercepting their wake vortices judiciously. The results show that autonomous, “smart” swimmers may exploit unsteady flow fields to reap substantial energetic benefits and have promising implications for robotic swarms.
Imaging nanobubble nucleation and hydrogen spillover during electrocatalytic water splitting
Authors: Hao Rui , Fan Yunshan , Howard Marco D. , Vaughan Joshua C. , Zhang Bo
Published: May 2018

Significance

Due to the highly dynamic nature and intrinsic heterogeneity of the electrochemical interface, it is critical to develop new tools so that electrochemical activities can be imaged with high sensitivity and high spatial and temporal resolution. We demonstrate the unique ability to image nucleation and growth of individual hydrogen nanobubbles during electrocatalytic water splitting using superresolution fluorescence microscopy. This method allows us to compare electrocatalytic activity of different electrode materials toward hydrogen evolution reaction and observe in real time the effect of hydrogen spillover from electrode-supported gold nanocatalysts.
Coordination of the leucine-sensing Rag GTPase cycle by leucyl-tRNA synthetase in the mTORC1 signaling pathway
Authors: Lee Minji , Kim Jong Hyun , Yoon Ina , Lee Chulho , Fallahi Sichani Mohammad , Kang Jong Soon , Kang Jeonghyun , Guo Min , Lee Kang Young , Han Gyoonhee , Kim Sunghoon , Han Jung Min
Published: May 2018

Significance

LRS, an enzyme involved in protein synthesis, and Sestrin2, a stress-induced metabolic protein, are suggested to function as leucine sensors for the mTORC1 pathway, a central regulator of cell metabolism, growth, proliferation, and survival. The Rag GTPase cycle regulates mTORC1; however, regulators of the Rag GTPase cycle and their coordination remain unknown. We show the dynamics of the RagD–RagB GTPase cycle during leucine signaling and describe contrasting yet complementary roles for LRS and Sestrin2 in the Rag GTPase–mTORC1 pathway, functioning as “ON” and “OFF” switches, respectively. Our results extend the current view of amino acid sensing by mTORC1 and will be invaluable for the development of novel approaches to combat mTORC1-related human diseases such as cancer.
Associated patterns of insecticide resistance in field populations of malaria vectors across Africa
Authors: Hancock Penelope A. , Wiebe Antoinette , Gleave Katherine A. , Bhatt Samir , Cameron Ewan , Trett Anna , Weetman David , Smith David L. , Hemingway Janet , Coleman Michael , Gething Peter W. , Moyes Catherine L.
Published: May 2018

Significance

Malaria control programs rely on chemical insecticides to target mosquito vectors and are potentially threatened by the emergence of insecticide resistance in African vector populations. Insecticide resistance management initiatives require comprehensive quantification of resistance in field populations to the set of insecticides used in vector control. We analyzed patterns of variation and covariation in resistance to these insecticides, using statistical methods that handle the sparse spatiotemporal distribution of the available data. We found relationships across different insecticide types that are consistent across large parts of Africa, allowing prediction of resistance to be improved by incorporating observations across multiple insecticide types. We also found large-scale relationships between phenotypic resistance and patterns of genetic variation, demonstrating the potential utility of genetic markers.
Restoration of paper artworks with microemulsions confined in hydrogels for safe and efficient removal of adhesive tapes
Authors: Bonelli Nicole , Montis Costanza , Mirabile Antonio , Berti Debora , Baglioni Piero
Published: May 2018

Significance

From Dead Sea Scrolls to Federico Fellini and Lucio Fontana drawings, pressure-sensitive tapes (PSTs) have been used as adhesive fasteners or as part of temporary conservation treatments that frequently became permanent. Their safe and efficient removal poses ethical and aesthetic questions: Adhesive tape residues damage the paper substrate and, due to discoloring, prejudice the artwork enjoyment and conservation. Selective removal without affecting the underlying support is challenging and often impossible. We tackled this issue from a physicochemical and a colloidal perspective, by designing a system where nanosized solvent droplets are confined within a hydrogel. This method has the potential to revolutionize the approaches used so far in the removal of PSTs and coatings from a plurality of materials.
RETRACTED: Physiology underlies the assembly of ecological communities
Authors: Start Denon , McCauley Shannon , Gilbert Benjamin
Published: May 2018

Trait-based community ecology promises an understanding of the factors that determine species abundances and distributions across habitats. However, ecologists are often faced with large suites of potentially important traits, making generalizations across ecosystems and species difficult or even impossible. Here, we hypothesize that key traits structuring ecological communities may be causally dependent on common physiological mechanisms and that elucidating these mechanisms can help us understand the distributions of traits and species across habitats. We test this hypothesis by investigating putatively causal relationships between physiological and behavioral traits at the species and community levels in larvae of 17 species of dragonfly that co-occur at the landscape scale but segregate among lakes. We use tools borrowed from phenotypic selection analyses to show that physiological traits underlie activity rate, which has opposing effects on foraging and predator avoidance behaviors. The effect of activity on these behaviors ultimately shapes species distributions and community composition in habitats with either large-bodied fish or invertebrates as top predators. Remarkably, despite the inherent complexity of ecological communities, the expression of just two biomolecules accounts for a high proportion of the variation in behavioral traits and hence, dragonfly community composition between habitats. We suggest that causal relationships among traits can drive species distributions and community assembly.
VirB8 homolog TraE from plasmid pKM101 forms a hexameric ring structure and interacts with the VirB6 homolog TraD
Authors: Casu Bastien , Mary Charline , Sverzhinsky Aleksandr , Fouillen Aurélien , Nanci Antonio , Baron Christian
Published: May 2018

Significance

The overproduction and purification of membrane proteins are intrinsically difficult, making their analysis challenging. We purified the TraE membrane protein from a bacterial conjugation system that is involved in plasmid transfer. Our results suggest that this protein forms hexamers with a central pore, and we also show that it binds to the TraD protein. The structure of TraE is completely different from that of the previously characterized periplasmic domain. This has intriguing implications for the role of TraE and of its interaction partner TraD in substrate translocation across the bacterial cell envelope. This work makes an important contribution to understanding of the mechanism of plasmid transfer, contributing to the design of approaches to inhibit the spread of antibiotic resistance genes.
Deletion of
LRRTM1 and LRRTM2
in adult mice impairs basal AMPA receptor transmission and LTP in hippocampal CA1 pyramidal neurons
Authors: Bhouri Mehdi , Morishita Wade , Temkin Paul , Goswami Debanjan , Kawabe Hiroshi , Brose Nils , Südhof Thomas C. , Craig Ann Marie , Siddiqui Tabrez J. , Malenka Robert
Published: May 2018

Significance

Brain function requires high-fidelity transmission of information between individual brain cells at synapses, physical contacts that contain a specialized machinery for passing and receiving signals. Synaptic cell adhesion proteins form physical bridges between neurons and are critical for fine-tuning synaptic properties. Because of their roles in synaptic transmission, mutations in these proteins contribute to a wide range of neuropsychiatric diseases. Here, we study the role of two synaptic cell adhesion proteins, LRRTM1 and LRRTM2, in signaling at excitatory synapses utilizing a conditional knockout mouse line. Genetically deleting these proteins in mature neurons dramatically impairs basal synaptic transmission and disrupts long-term potentiation, a prominent form of synaptic plasticity that is critical for learning and memory.
Short-chain dehydrogenase/reductase governs steroidal specialized metabolites structural diversity and toxicity in the genus
Solanum
Authors: Sonawane Prashant D. , Heinig Uwe , Panda Sayantan , Gilboa Netta Segal , Yona Meital , Kumar S. Pradeep , Alkan Noam , Unger Tamar , Bocobza Samuel , Pliner Margarita , Malitsky Sergey , Tkachev Maria , Meir Sagit , Rogachev Ilana , Aharoni Asaph
Published: May 2018

Significance

Plants synthesize a vast repertoire of steroidal specialized metabolites. These include the well-known class of antinutritional steroidal glycoalkaloids (SGAs), which act as defensive chemicals in the Solanaceae, and the pharmacologically important and widespread steroidal saponins. Here, we uncover an elusive enzymatic step that acts on unsaturated steroidal metabolites. We find that GLYCOALKALOID METABOLISM25 (GAME25) acts at a key branch point in the biosynthesis pathways of steroidal specialized metabolites. The activity of GAME25 not only affects the enormous diversity of SGAs and steroidal saponins, which are produced in hundreds of plant species, but also modulates the molecules’ toxic effects. This work helps explain the extensive structural diversity in specialized metabolism through a relatively simple chemical modification in a single metabolite backbone.
cAMP-inducible coactivator CRTC3 attenuates brown adipose tissue thermogenesis
Authors: Yoon Young-Sil , Tsai Wen-Wei , Van de Velde Sam , Chen Zhijiang , Lee Kuo-Fen , Morgan Donald A. , Rahmouni Kamal , Matsumura Shigenobu , Wiater Ezra , Song Youngsup , Montminy Marc
Published: May 2018

Significance

Physiologic systems often maintain homeostasis through negative-feedback loops. Unlike most regulatory targets for the sympathetic nervous system, interscapular brown adipose tissue (BAT) lacks parasympathetic inputs that might otherwise counterbalance the stimulatory effects of catecholamines. We found that the cAMP response element-binding protein (CREB) coactivator cAMP-regulated transcriptional coactivator 3 (CRTC3) reduces BAT function by down-regulating sympathetic nerve activity and vascularization. Mice with a knockout of CRTC3 in BAT have reduced adiposity and are more cold tolerant. CRTC3 inhibits BAT activity by disrupting the expression of neurotrophins and proangiogenic factors that otherwise promote sympathetic innervation and vascularization of BAT. These studies highlight an important feedback mechanism that maintains energy homeostasis via its effects in brown fat.
The Moral Obligation of Nutrition and Hydration in the Tradition and Magisterium of the Catholic Church
Authors: Giovanelli Giorgio
Published: May 2018

The recent publication of the fifth edition of the Ethical and Religious Directives for Catholic Health Care Services on November 17, 2009, by mandate of the United States bishops, witnessed the eruption of a controversy in the U.S. with regard to nutrition and hydration for the seriously ill and dying. 1

Among the major philosophical and moral thinkers in the field, there are some on the one hand who—out of respect for the wishes of the patient as expressed in normal situations—see no need for nutrition and hydration if such are the patient's wishes, even though they may have been expressed before the patient became ill. On the other hand, there are those who—out of respect for human dignity and with the understanding that any act of euthanasia is morally unacceptable—do not see how the interruption of life support can be acceptable unless it comes to be a burden and no longer a benefit under end-of-life conditions.

In light of all this, the present article aims to provide reflections on the nature of assisted nutrition and hydration (ANH) and the obligation to use it in cases where clinical evidence requires it, with a particular focus on the ongoing bioethical debate in the U.S.
The Missing Premise in the HIV-Condom Debate
Authors: Napier Stephen
Published: May 2018

In a recent article in this journal, “Condoms and HIV: The State of the Debate,” William Newton argues that there are basically two issues around which parties dispute. The first is whether the use of a condom by a discordant couple amounts to performing a contraceptive act. At issue here is whether a couple's use of a condom to prevent disease transmission renders the act a contraceptive act. The second issue pertains to whether the use of a condom, apart from whatever the intentions of the agents are, is itself a failure to consummate a marital act. It is the second issue that I wish to address in this paper. I aim to argue that the Canon-Law argument, as I will call it, wishes to argue that because condomistic sex fails to consummate a marriage, the sexual act performed is immoral. I argue against this inference on two grounds: the first is that the conclusion succumbs to counterexamples, and second, the inference must rely on a premise that I show is false.
The Catholic Church in America, the Discipline of Bioethics, and the Culture of Life
Authors: Latkovic Mark S.
Published: May 2018

In this paper, I will first briefly discuss why the Catholic Church has always had and continues to have such a great concern for bioethics or health-care ethics, while I also highlight the biblical roots of this concern. Secondly, I will describe some of the ways in which the Catholic Church in America has exercised a positive influence in the field of bioethics, or what was in the mid-twentieth century often called medical ethics. Thirdly, I will sketch how and why the Church has to a large extent lost this influence, tracing how secularization both inside and outside the Church contributed to the destruction of the so-called “Catholic ghetto” and to the assimilation of ideas from the culture that were often alien to the Gospel and sound moral reasoning. Finally, I will offer some general reflections on how the Church can regain her influence in this area—especially with the goal in mind of building a culture of life in American society—and how Catholic scholars in particular can contribute to this effort by following the lead of the late Pope John Paul II's 1995 encyclical on bioethics, Evangelium vitae, whose twentieth anniversary is fast approaching.
Educating Openness: Umberto Eco’s Poetics of Openness as a Pedagogical Value
Authors: Campbell Cary
Published: May 2018

The poetics of openness, as formulated by Umberto Eco in his pre-semiotic work The Open Work (1962), has already been useful and applicable to cultural studies and textual analysis. I propose that this poetics of openness be applied to critical educational practices as well. In this article, I argue that a poetics of openness when coupled with active ‘on the ground’ “critical public pedagogics” can provide a flexible framework for approaching the education of interpretation. Through this framework, a text or sign system is understood as ‘closed’ if it elicits univocal meanings: expecting a predetermined response from a generic/average reader. A text is ‘open’ when it fosters a plurality of interpretative possibilities that actively engage the “existential credentials” of the interpreter. Aesthetic openness is part of adopting a semiotic perspective toward educational processes. A theory of model reader pedagogically helps protect against the kind of radical constructivism this interpretative approach can seem to foster. Openness is not presented as a system or methodology of education, but as a pedagogical value: encouraging both educators and students to bring a perspective of critical openness to all the sign systems and discourses they engage with.
Presence of Counterfeit Marlboro Gold Packs in Licensed Retail Stores in New York City: Evidence From Test Purchases
Authors: Kurti Marin , He Yi , Silver Diana , Giorgio Margaret , von Lampe Klaus , Macinko James , Ye Hua , Tan Fidelis , Mei Victoria
Published: May 2018

Background

There are no independent studies measuring the availability of premium brand counterfeit cigarettes in New York City from licensed retailers.

Methods

We forensically analyzed the cigarette packaging of Marlboro Gold (n = 1021) purchased from licensed tobacco retailers in New York City, using ultraviolet irradiation and light microscopy to determine whether they were counterfeit.

Results

We find that while only 0.5% (n = 5) of our sample exhibits at least one characteristic synonymous with counterfeit packaging, none of our packs can be conclusively classified as counterfeit.

Conclusions

We do not find any counterfeit Marlboro Gold packs purchased at full price from licensed cigarette retailers throughout New York City. Future research using test purchases should include other venues (eg, street and online) and specifically ask for discounts to ascertain the overall presence of counterfeit cigarettes.

Implications

This is the first study to independently measure the availability of counterfeit cigarette packs purchased at full price from licensed retailers in New York City. We find that none of the Marlboro Gold packs purchased from licensed cigarette retailers are counterfeit.
Performance of TEM-PCR vs Culture for Bacterial Identification in Pediatric Musculoskeletal Infections
Authors: Wood James B , Sesler Cheryl , Stalons Donald , Grigorenko Elena , Schoenecker Jonathan G , Creech C Buddy , Thomsen Isaac P
Published: May 2018

Improved diagnostics are needed for children with musculoskeletal infections (MSKIs). We assessed the performance of target-enriched multiplex polymerase chain reaction (TEM-PCR) in children with MSKI. TEM-PCR was concordant with culture in pathogen identification and antibiotic susceptibility testing, while increasing the overall yield of pathogen detection. This technology has the potential to inform judicious antimicrobial use early in the disease course.
Retromastoid Approach for Posterior Fossa Skull Base Rosai–Dorfman Disease—A Rare Pathology: 3-Dimensional Operative Video
Authors: Nanda Anil , Savardekar Amey R , Patra Devi Prasad , Dossani Rimal Hanif , Georgescu Maria-Magdalena
Published: May 2018

Rosai–Dorfman disease, originally described by Juan Rosai and Ronald F. Dorfman, is a rare benign histiocytic proliferative disorder, classically presenting with massive lymphadenopathy and a self-limiting clinical course.
1
Isolated intracranial skull base involvement is extremely rare and often resembles meningiomas, schwannomas, or other benign skull base lesions.
2
The disease is difficult to diagnose radiographically, and tissue diagnosis with open skull base approaches has significant perioperative risks.
2,3
We present the case of a 48-yr-old Caucasian male presenting with progressively worsening headaches, giddiness, hearing difficulty, and diplopia. Magnetic resonance imaging of the brain revealed T1-weighted isointense, T2-weighted hypointense, and contrast-enhancing dural-based lesion in the left cerebellopontine angle. The patient underwent maximally safe resection of the lesion through the retromastoid approach with careful preservation of the lower cranial nerve complex. The intraoperative findings of a variegated and lobulated mass adherent to the skull base, the surgical strategy of safe resection, and eventual good outcome in this patient are depicted in this 3-dimensional video presentation. The majority of patients with skull base Rosai–Dorfman disease reported in literature have had stable or regression of disease (78%) after initial conservative surgical treatment and hence aggressive surgical resection is of unproven efficacy.
3

 The patient has consented to depiction of his surgical video and intraoperative images in this video manuscript.
Microsurgical Resection of a Solitary Spinal Epidural Cavernous Angioma: 3-Dimensional Operative Video
Authors: Ceccato Guilherme H W , Henning Lucélio , Prado Julyana L , Rassi Marcio S , Borba Luis A B
Published: May 2018

Solitary spinal epidural cavernous angiomas are rare vascular malformations. Surgical excision is the treatment of choice, as these lesions tend to grow or bleed at some point. In this 3-dimensional, narrated video, we present the case of a 61-year-old male who presented with progressive pain in the right paravertebral region secondary to an epidural cavernous angioma located at the T6/T7 level. Under intraoperative neurophysiological monitoring, a laminectomy between T5 and T7 was performed. A reddish, well delimited, and highly vascularized epidural mass was identified and dissected from the adjacent dura and nerve root, and an en bloc total resection was achieved. The patient was discharged neurologically intact on postoperative day 4, presenting a remarkable improvement of his pain at 2-month follow-up. Total excision of these lesions is possible in most of cases, remaining the standard treatment, with minimum complications.

 All procedures were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All data related to patient identification were removed from this surgical video and manuscript, with no need of a written informed consent.
‘Less Stale, Only Slightly Less Male, but Overwhelmingly Less Pale’: the 2015 New Conservative Brexiters in the House of Commons
Authors: Alexandre-Collier Agnès
Published: May 2018

This article will study the new face of Conservative Euroscepticism in the House of Commons, with a special focus on the 2015 intake of MPs who were supposedly ‘less stale, male and pale’ and their attitudes to the British referendum on the EU. In this respect, this article will also take a specific interest in new Conservative Black and Asian Minority Ethnic (BAME) MPs who turned out to be more active on the ‘leave’ side of the referendum campaign, thus serving as a showcase for the party's strategy of ‘decontaminating’ the Brexit brand and its hyperglobalist geopolitical perspective.
A Study of Non-Urgent Demand to Identify Opportunities for Demand Reduction
Authors: Walley Paul , Jennison-Phillips Anna
Published: May 2018

Police forces often struggle to meet all demands placed upon them because of budgetary and other resource constraints. UK police forces are now embarking on a series of initiatives to find ways of managing demand so that there is a closer match between the resource requirements and those available. This article presents an in-depth analysis of a sample of demand and response to non-urgent incidents from one UK police region, so that there is a better understanding of how demand can be either reduced or more efficiently met. The concept of ‘failure demand’ is introduced as a means of identifying ways to reduce resource consumption.
New Insights into the Nucleolar Localization of a Plant RNA Virus-Encoded Protein That Acts in Both RNA Packaging and RNA Silencing Suppression: Involvement of Importins Alpha and Relevance for Viral Infection
Authors: Pérez-Cañamás Miryam , Hernández Carmen
Published: May 2018

Despite the fact that replication of plus-strand RNA viruses takes place in the cytoplasm of host cells, different proteins encoded by these infectious agents have been shown to localize in the nucleus, with high accumulation at the nucleolus. In most cases, the molecular determinants or biological significance of such subcellular localization remains elusive. Recently, we reported that protein p37 encoded by Pelargonium line pattern virus (family Tombusviridae) acts in both RNA packaging and RNA silencing suppression. Consistently with these functions, p37 was detected in the cytoplasm of plant cells, although it was also present in the nucleus and, particularly, in the nucleolus. Here, we searched for further insights into factors influencing p37 nucleolar localization and into its potential relevance for viral infection. Besides mapping the protein region containing the nucleolar localization signal, we have found that p37 interacts with distinct members of the importin alpha family—main cellular transporters for nucleo-cytoplasmic traffic of proteins—and that these interactions are crucial for nucleolar targeting of p37. Impairment of p37 nucleolar localization through downregulation of importin alpha expression resulted in a reduction of viral accumulation, suggesting that sorting of the protein to the major subnuclear compartment is advantageous for the infection process.
The Influence of Flower Anatomy and Apple Cultivar on the Apple Flower Phytobiome
Authors: Steven Blaire , Huntley Regan B. , Zeng Quan
Published: May 2018

The apple flower is a transient organ that can shed light on how plant-associated phytobiomes are established and structured. Stigmas, stamens, receptacles, and petals were dissected from flowers, and the microbiome of each structure was characterized. Each flower part harbored a largely overlapping set of bacterial taxa, predominantly within the groups Pseudomonas and Enterobacteriaceae. However, the structure of the communities differed. The stigmas showed a high dominance of a small number of operational taxonomic units (OTUs; 97% sequence identity) whereas OTUs on petals were more even in relative abundance. Results from the OTU analysis of phytobiomes from stigmas from three apple cultivars, Braeburn, McIntosh, and Sunrise, indicated cultivar did not significantly influence community structure. Correlation analysis of bacterial taxa in the apple phytobiome found a negative correlation between Pseudomonas and Enterobacteriaceae, suggesting a potential niche exclusion relationship between these taxa. In this respect, the phytobiome of the apple flower is relatively simple but different flower parts, particularly the stigma, enrich the relative abundance of specific bacterial populations. Correlations in the community structure point to potential antagonistic relationships, which could be used to manipulate the structure of the microbiome for biological control of pathogens or other orchard management strategies.
From skeletal development to the creation of pluripotent stem cell-derived bone-forming progenitors
Authors: Tam Wai Long , Luyten Frank P. , Roberts Scott J.
Published: May 2018

Bone has many functions. It is responsible for protecting the underlying soft organs, it allows locomotion, houses the bone marrow and stores minerals such as calcium and phosphate. Upon damage, bone tissue can efficiently repair itself. However, healing is hampered if the defect exceeds a critical size and/or is in compromised conditions. The isolation or generation of bone-forming progenitors has applicability to skeletal repair and may be used in tissue engineering approaches. Traditionally, bone engineering uses osteochondrogenic stem cells, which are combined with scaffold materials and growth factors. Despite promising preclinical data, limited translation towards the clinic has been observed to date. There may be several reasons for this including the lack of robust cell populations with favourable proliferative and differentiation capacities. However, perhaps the most pertinent reason is the failure to produce an implant that can replicate the developmental programme that is observed during skeletal repair. Pluripotent stem cells (PSCs) can potentially offer a solution for bone tissue engineering by providing unlimited cell sources at various stages of differentiation. In this review, we summarize key embryonic signalling pathways in bone formation coupled with PSC differentiation strategies for the derivation of bone-forming progenitors.

This article is part of the theme issue ‘Designer human tissue: coming to a lab near you’.
A human iPSC line capable of differentiating into functional macrophages expressing ZsGreen: a tool for the study and
in vivo
tracking of therapeutic cells
Authors: Lopez-Yrigoyen Martha , Fidanza Antonella , Cassetta Luca , Axton Richard A. , Taylor A. Helen , Meseguer-Ripolles Jose , Tsakiridis Anestis , Wilson Valerie , Hay David C. , Pollard Jeffrey W. , Forrester Lesley M.
Published: May 2018

We describe the production of a human induced pluripotent stem cell (iPSC) line, SFCi55-ZsGr, that has been engineered to express the fluorescent reporter gene, ZsGreen, in a constitutive manner. The CAG-driven ZsGreen expression cassette was inserted into the
AAVS1
locus and a high level of expression was observed in undifferentiated iPSCs and in cell lineages derived from all three germ layers including haematopoietic cells, hepatocytes and neurons. We demonstrate efficient production of terminally differentiated macrophages from the SFCi55-ZsGreen iPSC line and show that they are indistinguishable from those generated from their parental SFCi55 iPSC line in terms of gene expression, cell surface marker expression and phagocytic activity. The high level of ZsGreen expression had no effect on the ability of macrophages to be activated to an M(LPS + IFNγ), M(IL10) or M(IL4) phenotype nor on their plasticity, assessed by their ability to switch from one phenotype to another. Thus, targeting of the
AAVS1
locus in iPSCs allows for the production of fully functional, fluorescently tagged human macrophages that can be used for
in vivo
tracking in disease models. The strategy also provides a platform for the introduction of factors that are predicted to modulate and/or stabilize macrophage function.

This article is part of the theme issue ‘Designer human tissue: coming to a lab near you’.
Assessment of stem cell differentiation based on genome-wide expression profiles
Authors: Godoy Patricio , Schmidt-Heck Wolfgang , Hellwig Birte , Nell Patrick , Feuerborn David , Rahnenführer Jörg , Kattler Kathrin , Walter Jörn , Blüthgen Nils , Hengstler Jan G.
Published: May 2018

In recent years, protocols have been established to differentiate stem and precursor cells into more mature cell types. However, progress in this field has been hampered by difficulties to assess the differentiation status of stem cell-derived cells in an unbiased manner. Here, we present an analysis pipeline based on published data and methods to quantify the degree of differentiation and to identify transcriptional control factors explaining differences from the intended target cells or tissues. The pipeline requires RNA-Seq or gene array data of the stem cell starting population, derived ‘mature’ cells and primary target cells or tissue. It consists of a principal component analysis to represent global expression changes and to identify possible problems of the dataset that require special attention, such as: batch effects; clustering techniques to identify gene groups with similar features; over-representation analysis to characterize biological motifs and transcriptional control factors of the identified gene clusters; and metagenes as well as gene regulatory networks for quantitative cell-type assessment and identification of influential transcription factors. Possibilities and limitations of the analysis pipeline are illustrated using the example of human embryonic stem cell and human induced pluripotent cells to generate ‘hepatocyte-like cells'. The pipeline quantifies the degree of incomplete differentiation as well as remaining stemness and identifies unwanted features, such as colon- and fibroblast-associated gene clusters that are absent in real hepatocytes but typically induced by currently available differentiation protocols. Finally, transcription factors responsible for incomplete and unwanted differentiation are identified. The proposed method is widely applicable and allows an unbiased and quantitative assessment of stem cell-derived cells.

This article is part of the theme issue ‘Designer human tissue: coming to a lab near you’.
Cell-based liver therapies: past, present and future
Authors: Iansante Valeria , Chandrashekran Anil , Dhawan Anil
Published: May 2018

Liver transplantation represents the standard treatment for people with an end-stage liver disease and some liver-based metabolic disorders; however, shortage of liver donor tissues limits its availability. Furthermore, whole liver replacement eliminates the possibility of using native liver as a possible target for future gene therapy in case of liver-based metabolic defects. Cell therapy has emerged as a potential alternative, as cells can provide the hepatic functions and engraft in the liver parenchyma. Various options have been proposed, including human or other species hepatocytes, hepatocyte-like cells derived from stem cells or more futuristic alternatives, such as combination therapies with different cell types, organoids and cell–biomaterial combinations. In this review, we aim to give an overview of the cell therapies developed so far, highlighting preclinical and/or clinical achievements as well as the limitations that need to be overcome to make them fully effective and safe for clinical applications.

This article is part of the theme issue ‘Designer human tissue: coming to a lab near you’.
Modelling non-alcoholic fatty liver disease in human hepatocyte-like cells
Authors: Lyall Marcus J. , Cartier Jessy , Thomson John P. , Cameron Kate , Meseguer-Ripolles Jose , O'Duibhir Eoghan , Szkolnicka Dagmara , Villarin Baltasar Lucendo , Wang Yu , Blanco Giovanny Rodriguez , Dunn Warwick B. , Meehan Richard R. , Hay David C. , Drake Amanda J.
Published: May 2018

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease in developed countries. An
in vitro
NAFLD model would permit mechanistic studies and enable high-throughput therapeutic screening. While hepatic cancer-derived cell lines are a convenient, renewable resource, their genomic, epigenomic and functional alterations mean their utility in NAFLD modelling is unclear. Additionally, the epigenetic mark 5-hydroxymethylcytosine (5hmC), a cell lineage identifier, is rapidly lost during cell culture, alongside expression of the Ten-eleven-translocation (
TET
) methylcytosine dioxygenase enzymes, restricting meaningful epigenetic analysis. Hepatocyte-like cells (HLCs) derived from human embryonic stem cells can provide a non-neoplastic, renewable model for liver research. Here, we have developed a model of NAFLD using HLCs exposed to lactate, pyruvate and octanoic acid (LPO) that bear all the hallmarks, including 5hmC profiles, of liver functionality. We exposed HLCs to LPO for 48 h to induce lipid accumulation. We characterized the transcriptome using RNA-seq, the metabolome using ultra-performance liquid chromatography-mass spectrometry and the epigenome using 5-hydroxymethylation DNA immunoprecipitation (hmeDIP) sequencing. LPO exposure induced an NAFLD phenotype in HLCs with transcriptional and metabolomic dysregulation consistent with those present in human NAFLD. HLCs maintain expression of the
TET
enzymes and have a liver-like epigenome. LPO exposure-induced 5hmC enrichment at lipid synthesis and transport genes. HLCs treated with LPO recapitulate the transcriptional and metabolic dysregulation seen in NAFLD and additionally retain
TET
expression and 5hmC. This
in vitro
model of NAFLD will be useful for future mechanistic and therapeutic studies.

This article is part of the theme issue ‘Designer human tissue: coming to a lab near you’.
From plants to nematodes: Serratia grimesii BXF1 genome reveals an adaptation to the modulation of multi-species interactions
Authors: Nascimento Francisco , Vicente Cláudia , Cock Peter , Tavares Maria , Rossi Márcio , Hasegawa Koichi , Mota Manuel
Published: May 2018

Serratia grimesii BXF1 is a bacterium with the ability to modulate the development of several eukaryotic hosts. Strain BXF1 was isolated from the pinewood nematode, Bursaphelenchus xylophilus, the causative agent of pine wilt disease affecting pine forests worldwide. This bacterium potentiates Bursaphelenchus xylophilus reproduction, acts as a beneficial pine endophyte, and possesses fungal and bacterial antagonistic activities, further indicating a complex role in a wide range of trophic relationships. In this work, we describe and analyse the genome sequence of strain BXF1, and discuss several important aspects of its ecological role. Genome analysis indicates the presence of several genes related to the observed production of antagonistic traits, plant growth regulation and the modulation of nematode development. Moreover, most of the BXF1 genes are involved in environmental and genetic information processing, which is consistent with its ability to sense and colonize several niches. The results obtained in this study provide the basis to a better understanding of the role and evolution of strain BXF1 as a mediator of interactions between organisms involved in a complex disease system. These results may also bring new insights into general Serratia and Enterobacteriaceae evolution towards multitrophic interactions.
An outbreak of a rare Shiga-toxin-producing Escherichia coli serotype (O117:H7) among men who have sex with men
Authors: Baker Kate S. , Dallman Timothy J. , Thomson Nicholas R. , Jenkins Claire
Published: May 2018

Sexually transmissible enteric infections (STEIs) are commonly associated with transmission among men who have sex with men (MSM). In the past decade, the UK has experienced multiple parallel STEI emergences in MSM caused by a range of bacterial species of the genus Shigella, and an outbreak of an uncommon serotype (O117 : H7) of Shiga-toxin-producing Escherichia coli (STEC). Here, we used microbial genomics on 6 outbreak and 30 sporadic STEC O117 : H7 isolates to explore the origins and pathogenic drivers of the STEC O117 : H7 emergence in MSM. Using genomic epidemiology, we found that the STEC O117 : H7 outbreak lineage was potentially imported from Latin America and likely continues to circulate both in the UK MSM population and in Latin America. We found genomic relationships consistent with existing symptomatic evidence for chronic infection with this STEC serotype. Comparative genomic analysis indicated the existence of a novel Shiga toxin 1-encoding prophage in the outbreak isolates, and evidence of horizontal gene exchange among the STEC O117 : H7 outbreak lineage and other enteric pathogens. There was no evidence of increased virulence in the outbreak strains relative to contextual isolates, but the outbreak lineage was associated with azithromycin resistance. Comparing these findings with similar genomic investigations of emerging MSM-associated Shigella in the UK highlighted many parallels, the most striking of which was the importance of the azithromycin phenotype for STEI emergence in this patient group.