bluuebunny/crossref_metadata_2025 huggingface dataset:
Recommendations for the Prevention, Detection, Treatment and Management of Prescription Opioid Analgesic Dependence: Outcomes From the Opioid Analgesic Dependence Education Nexus (OPEN) Meeting
Authors: Kraus Mark , Lintzeris Nicholas , Maier Christoph , Savage Seddon
Published: December 2015

The global consumption of opioids continues to rise, which has led to an increasing rate of diversion, misuse, addiction, and deaths related to prescription opioids. This has been particularly well documented in the USA; however, opioid analgesic dependence (OAD) is an increasing concern in Europe. More guidance is required for European healthcare professionals in the prevention, detection, treatment and management of OAD. The first Opioid Analgesic Dependence Education Nexus (OPEN) Mentor Meeting was held in Berlin in September 2014 to address this. An international Expert Panel, combining expertise in OAD from Australia, USA and Europe, invited 16 European experts in the pain and addiction fields to develop a best-practice approach to OAD that European practitioners can adopt. The outcomes from this meeting are presented here and included are a set of shared strategies that may be universally adopted by all healthcare professionals working with patients who use opioids.
La teoría de la evolución educativa y la formación de médicos especialistas
Authors: Vázquez Martínez Francisco Domingo
Published: December 2015

Resumen: La colaboración entre el sector salud y el sector educativo es fundamental para la formación de médicos especialistas. Para caracterizar el tipo de colaboración entre estos sectores se recurre a la teoría de la evolución educativa. Esta plantea que en la historia de la educación en un primer momento predomina el modelo artesanal y posteriormente aparece el modelo escolar, que desplaza al anterior. En el modelo artesanal el proceso educativo y el proceso laboral se confunden y son, prácticamente, uno mismo. En el modelo escolar los hechos educativos adquieren independencia y autonomía del proceso y del mercado de trabajo. Actualmente, en México y desde la perspectiva utilizada, la formación de médicos especialistas se desarrolla de acuerdo con el modelo artesanal: el proceso educativo se confunde con actividades laborales y de  prestación de servicios de salud, los alumnos y los profesores son, antes que nada y de manera prioritaria, trabajadores. Esta situación enfrenta las demandas educativas a las laborales y multiplica las exigencias a los alumnos y profesores de los programas educativos de especialidades médicas. La manifestación objetiva de la situación planteada se observa, entre otros aspectos en la sobrecarga de trabajo y el desgaste profesional de los médicos residentes. En este contexto, se dificulta la educación de excelencia para los médicos especialistas y, de manera consecuente, el logro de una calidad óptima de atención médica a la población.
Se propone separar el proceso educativo del laboral, sin perder de vista la importancia de la vinculación docente-asistencial, la única que garantiza los intereses académicos y la formación óptima de los médicos especialistas.
Study Design and Results of a Population-Based Study on Perceived Stress Following Hurricane Sandy
Authors: Schwartz Rebecca , Liu Bian , Sison Cristina , Kerath Samantha M. , Breil Trista , Murphy Lisa , Taioli Emanuela
Published: December 2015

Objective

Hurricane Sandy was one of the deadliest storms in US history, with at least 162 deaths and numerous injuries. This research aimed to quantify the impact of Hurricane Sandy on the New York metropolitan area.

Methods

The project included 601 volunteers aged at least 18 years who were recruited in Nassau, Suffolk, Queens, and Richmond counties and Staten Island between 2013 and 2014 through close partnerships with coalition community leaders. Participants completed a self-administered questionnaire on demographics and behavioral factors and a 35-point check off list on hurricane exposure. Perceived stress was assessed by using the 10-item Perceived Stress Scale (PSS).

Results

Participants had a mean stress score of 15.6 (SD=7.3; vs general population mean of 13.0), with 30.14% of the sample categorized as “high stress” (mean≥20). In the multivariable regression analysis, age was significantly negatively associated with PSS score. A reported history of mental health issues, Hispanic ethnicity, and overall exposure to Hurricane Sandy were statistically significantly associated with PSS score in a positive direction.

Conclusions

Perceived stress was high in areas affected by Hurricane Sandy and was significantly associated with individual hurricane exposure. This study is a first step toward defining what segments of the population are more vulnerable and informing intervention and emergency preparedness efforts. (Disaster Med Public Health Preparedness. 2015;10:325–332)
Fatty acid binding proteins 4 and 5 in overweight prepubertal boys: effect of nutritional counselling and supplementation with an encapsulated fruit and vegetable juice concentrate
Authors: Canas Jose A. , Damaso L. , Hossain J. , Balagopal P. Babu
Published: December 2015

Elevated fatty acid binding proteins (FABP) may play a role in obesity and co-morbidities. The role of nutritional interventions in modulating these levels remains unclear. The aim of thispost hocstudy was to determine the effect of overweight (OW) on FABP4 and FABP5 in boys in relation to indices of adiposity, insulin resistance and inflammation, and to investigate the effects of a 6-month supplementation with an encapsulated fruit and vegetable juice concentrate (FVJC) plus nutritional counselling (NC) on FABP levels. Apost hocanalysis of a double-blind, randomised, placebo-controlled study of children recruited from the general paediatric population was performed. A total of thirty age-matched prepubertal boys (nine lean and twenty-one OW; aged 6–10 years) were studied. Patients received NC by a registered dietitian and were randomised to FVJC or placebo capsules for 6 months. FABP4, FABP5, glucose, insulin, homeostasis model assessment-insulin resistance (HOMA-IR), glucose-induced acute insulin response (AIR), lipid-corrected β-carotene (LCβC), adiponectin, leptin, high-sensitivity C-reactive protein (hs-CRP), IL-6 and body composition by dual-energy X-ray absorptiometry were determined before and after the intervention. FABP were higher (P < 0·01) in the OWv.lean boys and correlated directly with HOMA-IR, abdominal fat mass (AFM), hs-CRP, IL-6, and LCβC (P < 0·05 for all). FABP4 was associated with adiponectin and AIR (P < 0·05). FVJC plus NC reduced FABP4, HOMA-IR and AFM (P < 0·05 for all) but not FABP5. OW boys showed elevated FABP4 and FABP5, but only FABP4 was lowered by the FVJC supplement.
GRB Orphan Afterglows in Present and Future Radio Transient Surveys
Authors: Ghirlanda G. , Burlon D. , Ghisellini G. , Salvaterra R. , Bernardini M. G. , Campana S. , Covino S. , D’Avanzo P. , D’Elia V. , Melandri A. , Murphy T. , Nava L. , Vergani S. D. , Tagliaferri G.
Published: December 2015

Orphan Afterglows (OA) are slow transients produced by Gamma Ray Bursts seen off–axis that become visible on timescales of days/years at optical/NIR and radio frequencies, when the prompt emission at high energies (X and γ rays) has already ceased. Given the typically estimated jet opening angle of GRBs θjet~ 3°, for each burst pointing to the Earth there should be a factor ~ 700 more GRBs pointing in other directions. Despite this, no secure OAs have been detected so far. Through a population synthesis code we study the emission properties of the population of OA at radio frequencies. OAs reach their emission peak on year-timescales and they last for a comparable amount of time. The typical peak fluxes (which depend on the observing frequency) are of few μJy in the radio band with only a few OA reaching the mJy level. These values are consistent with the upper limits on the radio flux of SN Ib/c observed at late times. We find that the OA radio number count distribution has a typical slope − 1.7 at high fluxes and a flatter ( − 0.4) slope at low fluxes with a break at a frequency–dependent flux. Our predictions of the OA rates are consistent with the (upper) limits of recent radio surveys and archive searches for radio transients. Future radio surveys like VAST/ASKAP at 1.4 GHz should detect ~ 3 × 10− 3OA deg− 2yr− 1, MeerKAT and EVLA at 8.4 GHz should see ~ 3 × 10− 1OA deg− 2yr− 1. The SKA, reaching the μJy flux limit, could see up to ~ 0.2 − 1.5 OA deg− 2yr− 1. These rates also depend on the duration of the OA above a certain flux limit and we discuss this effect with respect to the survey cadence.
Technological Change in American Manufacturing During the 1920's
Authors: Lorant John H.
Published: December 2015

It is well known that the average productivity of capital in American manufacturing increased at a comparatively high rate during the 1919–1929 decade. During the same period the accelerated application of scientific information stimulated important changes in manufacturing plant and equipment. This Note investigates the relationship between these two processes. The inquiry is of historical interest for two reasons: First, the study should help to support statistical observations of the increased efficiency of production facilities during the 1920's, thereby connecting observed productivity change as measured by economists with substantive technological improvements as described by economic historians. And second, it may be possible to characterize the 1920's as a period of unique technological growth in the history of American manufacturing.
Punctuated equilibria: the tempo and mode of evolution reconsidered
Authors: Gould Stephen Jay , Eldredge Niles
Published: December 2015

We believe that punctuational change dominates the history of life: evolution is concentrated in very rapid events of speciation (geologically instantaneous, even if tolerably continuous in ecological time). Most species, during their geological history, either do not change in any appreciable way, or else they fluctuate mildly in morphology, with no apparent direction. Phyletic gradualism is very rare and too slow, in any case, to produce the major events of evolution. Evolutionary trends are not the product of slow, directional transformation within lineages; they represent the differential success of certain species within a clade—speciation may be random with respect to the direction of a trend (Wright's rule).

As an a priori bias, phyletic gradualism has precluded any fair assessment of evolutionary tempos and modes. It could not be refuted by empirical catalogues constructed in its light because it excluded contrary information as the artificial result of an imperfect fossil record. With the model of punctuated equilibria, an unbiased distribution of evolutionary tempos can be established by treating stasis as data and by recording the pattern of change for all species in an assemblage. This distribution of tempos can lead to strong inferences about modes. If, as we predict, the punctuational tempo is prevalent, then speciation—not phyletic evolution—must be the dominant mode of evolution.

We argue that virtually none of the examples brought forward to refute our model can stand as support for phyletic gradualism; many are so weak and ambiguous that they only reflect the persistent bias for gradualism still deeply embedded in paleontological thought. Of the few stronger cases, we concentrate on Gingerich's data forHyopsodusand argue that it provides an excellent example of species selection under our model. We then review the data of several studies that have supported our model since we published it five years ago. The record of human evolution seems to provide a particularly good example: no gradualism has been detected within any hominid taxon, and many are long-ranging; the trend to larger brains arises from differential success of essentially static taxa. The data of molecular genetics support our assumption that large genetic changes often accompany the process of speciation.

Phyletic gradualism was an a priori assertion from the start—it was never “seen” in the rocks; it expressed the cultural and political biases of 19th century liberalism. Huxley advised Darwin to eschew it as an “unnecessary difficulty.” We think that it has now become an empirical fallacy. A punctuational view of change may have wide validity at all levels of evolutionary processes. At the very least, it deserves consideration as an alternate way of interpreting the history of life.
The Redevelopment of China's Construction Land: Practising Land Property Rights in Cities through Renewals
Authors: Lin George C.S.
Published: December 2015

Existing literature on China's urbanization focuses primarily on the expansion of cities and towns, with little attention being paid to urban renewals. The wasteful use of urban land has conventionally been attributed to the ambiguous definition and ineffective protection of property rights. This study examines recent practices in urban redevelopment in Guangzhou – a site chosen by the central authorities to pilot urban renewals (sanjiu gaizao). The research identifies a local practice in which institutional changes are made not in the delineation of land property rights but instead in the redistribution of the benefits to be made from land redevelopment. Current users of the land are offered a share of the land conveyance income previously monopolized by the state as an incentive to encourage them to engage in urban renewal. Land-use intensity and efficiency have increased, along with social exclusion and marginalization. Research findings cast doubt over the perceived notion that the uniform and unambiguous definition of property rights is the prerequisite for improved land-use efficiency and call for a critical evaluation of the current urban renewal policies that completely ignore the interests of the migrant population who outnumber local residents by a large margin.
The Judicial Cadre Evaluation System in China: From Quantification to Intra-state Legibility
Authors: Kinkel Jonathan J. , Hurst William J.
Published: December 2015

Performance evaluation systems fundamentally shape the behaviour of Chinese judges, but scholarship on the concrete implementation of these institutions is scarce. Relying on nearly 15 months of fieldwork in six cities in China, we explain how the judicial cadre evaluation system, as unified by the 2011 “Guiding opinion of the Supreme People's Court,” has been implemented. Over 30 indices quantitatively measure Chinese courts’ “fairness” (gongzheng公正), “efficiency” (xiaolü效率) and “impact” (xiaoguo效果), incentivizing court leaders to pressure their subordinate judges to resolve disputes as quickly as possible without unduly angering litigants or other actors. Under the hyper-quantified conditions of cadre evaluation, systemic praising and shaming bring about what we call “intra-state legibility,” which leads to a variety of informal worker reactions to these tactics. This study not only uses interviews and new documentary evidence to add necessary detail to our understanding of cadre evaluation systems, it also engages debates in comparative law and politics regarding bureaucratic influence on authoritarian judicial behaviour.
The Role of the Archdeacon Today
Authors: Ravenscroft R. L.
Published: December 2015

The office of archdeacon has its origins in the early history of the Church. The archdeacon is referred to by St. Jerome and other writers of the fourth century. He was the principal deacon of a local church. The eminent Victorian ecclesiastical lawyer, Sir Robert Phillimore wrote: ‘The primitive offices of the archdeacon may be enumerated under five heads. First, to attend the bishop to the altar and to order all things relating to the inferior clergy and ministrations in the church. Secondly, to assist the diocesan in the distribution and management of the ecclesiastical revenues.’
The Relationship between Oil, Exchange Rates, and Commodity Prices
Authors: Harri Ardian , Nalley Lanier , Hudson Darren
Published: December 2015

Exchange rates have long been thought to have an important impact on the export and import of goods and services, and, thus, exchange rates are expected to influence the price of those products that are traded. At the same time, energy impacts commodity production in some very important ways. The use of chemical and petroleum derived inputs has increased in agriculture over time; the prices of these critical inputs, then, would be expected to alter supply, and, therefore, the prices of commodities using these inputs. Also, agricultural commodities have been increasingly used to produce energy, thereby leading to an expectation of a linkage between energy and commodity markets. In this paper, we examine the price relationship through time of the primary agricultural commodities, exchange rates, and oil prices. Using overlapping time periods, we examine the cointegration relationship between prices to determine changes in the strength of the linkage between markets through time. In general, we find that commodity prices are linked to oil for corn, cotton, and soybeans, but not for wheat, and that exchange rates do play a role in the linkage of prices over time.
Macrophage migration inhibitory factor has a permissive role in concanavalin A-induced cell death of human hepatoma cells through autophagy
Authors: Lai Y-C , Chuang Y-C , Chang C-P , Yeh T-M
Published: December 2015

Concanavalin A (ConA) is a lectin and T-cell mitogen that can activate immune responses. In recent times, ConA-induced cell death of hepatoma cells through autophagy has been reported and its therapeutic effect was confirmed in a murinein situhepatoma model. However, the molecular mechanism of ConA-induced autophagy is still unclear. As macrophage migration inhibitory factor (MIF), which is a proinflammatory cytokine, can trigger autophagy in human hepatoma cells, the possible involvement of MIF in ConA-induced autophagy was investigated in this study. We demonstrated that cell death is followed by an increment in MIF expression and secretion in the ConA-stimulated human hepatoma cell lines, HuH-7 and Hep G2. In addition, ConA-induced autophagy and cell death of hepatoma cells were blocked in the presence of an MIF inhibitor. Knockdown of endogenous MIF by small hairpin RNA confirmed that MIF is required for both ConA-induced autophagy and death of hepatoma cells. Furthermore, signal pathway studies demonstrated that ConA induces signal transducer and activator of transcription 3 (STAT3) phosphorylation to trigger MIF upregulation, which in turn promotes Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3)-dependent autophagy. By using a murinein situhepatoma model, we further demonstrated that MIF contributes to anti-hepatoma activity of ConA by regulating STAT3–MIF–BNIP3-dependent autophagy. In summary, our findings uncover a novel role of MIF in lectin-mediated anti-hepatoma activities by regulating autophagy.
Legius Syndrome: two novel mutations in the SPRED1 gene
Authors: Bianchi Marika , Saletti Veronica , Micheli Roberto , Esposito Silvia , Molinaro Anna , Gagliardi Stella , Orcesi Simona , Cereda Cristina
Published: December 2015

The SPRED1 gene encodes a protein involved in the Ras/MAPK (mitogen-activated protein kinase) signaling pathway. Mutations in SPRED1 have been reported to cause Legius Syndrome, a rare developmental disorder that shares some clinical features with Neurofibromatosis-1. Direct sequencing was used to define SPRED1 mutations. We present two previously undescribed mutations: a frameshift mutation causing a stop codon, which was identified in an Italian family (p.Ile60Tyrfs*18) and a missense variation, which was identified in one sporadic Italian case (p.Pro422Arg). Our results led us to hypothesize that these modifications may contribute to the Legius Syndrome phenotype. Further studies will be needed to determine the roles of these mutations in the mechanisms of Legius Syndrome.
Ultralight shape-recovering plate mechanical metamaterials
Authors: Davami Keivan , Zhao Lin , Lu Eric , Cortes John , Lin Chen , Lilley Drew E. , Purohit Prashant K. , Bargatin Igor
Published: December 2015

Unusual mechanical properties of mechanical metamaterials are determined by their carefully designed and tightly controlled geometry at the macro- or nanoscale. We introduce a class of nanoscale mechanical metamaterials created by forming continuous corrugated plates out of ultrathin films. Using a periodic three-dimensional architecture characteristic of mechanical metamaterials, we fabricate free-standing plates up to 2 cm in size out of aluminium oxide films as thin as 25 nm. The plates are formed by atomic layer deposition of ultrathin alumina films on a lithographically patterned silicon wafer, followed by complete removal of the silicon substrate. Unlike unpatterned ultrathin films, which tend to warp or even roll up because of residual stress gradients, our plate metamaterials can be engineered to be extremely flat. They weigh as little as 0.1 g cm−2 and have the ability to ‘pop-back’ to their original shape without damage even after undergoing multiple sharp bends of more than 90°.
Structural insights into the DNA-binding specificity of E2F family transcription factors
Authors: Morgunova Ekaterina , Yin Yimeng , Jolma Arttu , Dave Kashyap , Schmierer Bernhard , Popov Alexander , Eremina Nadejda , Nilsson Lennart , Taipale Jussi
Published: December 2015

The mammalian cell cycle is controlled by the E2F family of transcription factors. Typical E2Fs bind to DNA as heterodimers with the related dimerization partner (DP) proteins, whereas the atypical E2Fs, E2F7 and E2F8 contain two DNA-binding domains (DBDs) and act as repressors. To understand the mechanism of repression, we have resolved the structure of E2F8 in complex with DNA at atomic resolution. We find that the first and second DBDs of E2F8 resemble the DBDs of typical E2F and DP proteins, respectively. Using molecular dynamics simulations, biochemical affinity measurements and chromatin immunoprecipitation, we further show that both atypical and typical E2Fs bind to similar DNA sequences in vitro and in vivo. Our results represent the first crystal structure of an E2F protein with two DBDs, and reveal the mechanism by which atypical E2Fs can repress canonical E2F target genes and exert their negative influence on cell cycle progression.
Gln40 deamidation blocks structural reconfiguration and activation of SCF ubiquitin ligase complex by Nedd8
Authors: Yu Clinton , Mao Haibin , Novitsky Eric J. , Tang Xiaobo , Rychnovsky Scott D. , Zheng Ning , Huang Lan
Published: December 2015

The full enzymatic activity of the cullin-RING ubiquitin ligases (CRLs) requires a ubiquitin-like protein (that is, Nedd8) modification. By deamidating Gln40 of Nedd8 to glutamate (Q40E), the bacterial cycle-inhibiting factor (Cif) family is able to inhibit CRL E3 activities, thereby interfering with cellular functions. Despite extensive structural studies on CRLs, the molecular mechanism by which Nedd8 Gln40 deamidation affects CRL functions remains unclear. We apply a new quantitative cross-linking mass spectrometry approach to characterize three different types of full-length human Cul1–Rbx1 complexes and uncover major Nedd8-induced structural rearrangements of the CRL1 catalytic core. More importantly, we find that those changes are not induced by Nedd8(Q40E) conjugation, indicating that the subtle change of a single Nedd8 amino acid is sufficient to revert the structure of the CRL catalytic core back to its unmodified form. Our results provide new insights into how neddylation regulates the conformation and activity of CRLs.
Nanoscale assembly processes revealed in the nacroprismatic transition zone of Pinna nobilis mollusc shells
Authors: Hovden Robert , Wolf Stephan E. , Holtz Megan E. , Marin Frédéric , Muller David A. , Estroff Lara A.
Published: December 2015

Intricate biomineralization processes in molluscs engineer hierarchical structures with meso-, nano- and atomic architectures that give the final composite material exceptional mechanical strength and optical iridescence on the macroscale. This multiscale biological assembly inspires new synthetic routes to complex materials. Our investigation of the prism–nacre interface reveals nanoscale details governing the onset of nacre formation using high-resolution scanning transmission electron microscopy. A wedge-polishing technique provides unprecedented, large-area specimens required to span the entire interface. Within this region, we find a transition from nanofibrillar aggregation to irregular early-nacre layers, to well-ordered mature nacre suggesting the assembly process is driven by aggregation of nanoparticles (∼50–80 nm) within an organic matrix that arrange in fibre-like polycrystalline configurations. The particle number increases successively and, when critical packing is reached, they merge into early-nacre platelets. These results give new insights into nacre formation and particle-accretion mechanisms that may be common to many calcareous biominerals.
The RNA-binding proteomes from yeast to man harbour conserved enigmRBPs
Authors: Beckmann Benedikt M. , Horos Rastislav , Fischer Bernd , Castello Alfredo , Eichelbaum Katrin , Alleaume Anne-Marie , Schwarzl Thomas , Curk Tomaž , Foehr Sophia , Huber Wolfgang , Krijgsveld Jeroen , Hentze Matthias W.
Published: December 2015

RNA-binding proteins (RBPs) exert a broad range of biological functions. To explore the scope of RBPs across eukaryotic evolution, we determined the in vivo RBP repertoire of the yeast Saccharomyces cerevisiae and identified 678 RBPs from yeast and additionally 729 RBPs from human hepatocytic HuH-7 cells. Combined analyses of these and recently published data sets define the core RBP repertoire conserved from yeast to man. Conserved RBPs harbour defined repetitive motifs within disordered regions, which display striking evolutionary expansion. Only 60% of yeast and 73% of the human RBPs have functions assigned to RNA biology or structural motifs known to convey RNA binding, and many intensively studied proteins surprisingly emerge as RBPs (termed ‘enigmRBPs’), including almost all glycolytic enzymes, pointing to emerging connections between gene regulation and metabolism. Analyses of the mitochondrial hydroxysteroid dehydrogenase (HSD17B10) uncover the RNA-binding specificity of an enigmRBP.
Optogenetic mutagenesis in Caenorhabditis elegans
Authors: Noma Kentaro , Jin Yishi
Published: December 2015

Reactive oxygen species (ROS) can modify and damage DNA. Here we report an optogenetic mutagenesis approach that is free of toxic chemicals and easy to perform by taking advantage of a genetically encoded ROS generator. This method relies on the potency of ROS generation by His-mSOG, the mini singlet oxygen generator, miniSOG, fused to a histone. Caenorhabditis elegans expressing His-mSOG in the germline behave and reproduce normally, without photoinduction. Following exposure to blue light, the His-mSOG animals produce progeny with a wide range of heritable phenotypes. We show that optogenetic mutagenesis by His-mSOG induces a broad spectrum of mutations including single-nucleotide variants (SNVs), chromosomal deletions, as well as integration of extrachromosomal transgenes, which complements those derived from traditional chemical or radiation mutagenesis. The optogenetic mutagenesis expands the toolbox for forward genetic screening and also provides direct evidence that nuclear ROS can induce heritable and specific genetic mutations.
Exome sequencing of osteosarcoma reveals mutation signatures reminiscent of BRCA deficiency
Authors: Kovac Michal , Blattmann Claudia , Ribi Sebastian , Smida Jan , Mueller Nikola S. , Engert Florian , Castro-Giner Francesc , Weischenfeldt Joachim , Kovacova Monika , Krieg Andreas , Andreou Dimosthenis , Tunn Per-Ulf , Dürr Hans Roland , Rechl Hans , Schaser Klaus-Dieter , Melcher Ingo , Burdach Stefan , Kulozik Andreas , Specht Katja , Heinimann Karl , Fulda Simone , Bielack Stefan , Jundt Gernot , Tomlinson Ian , Korbel Jan O. , Nathrath Michaela , Baumhoer Daniel
Published: December 2015

Osteosarcomas are aggressive bone tumours with a high degree of genetic heterogeneity, which has historically complicated driver gene discovery. Here we sequence exomes of 31 tumours and decipher their evolutionary landscape by inferring clonality of the individual mutation events. Exome findings are interpreted in the context of mutation and SNP array data from a replication set of 92 tumours. We identify 14 genes as the main drivers, of which some were formerly unknown in the context of osteosarcoma. None of the drivers is clearly responsible for the majority of tumours and even TP53 mutations are frequently mapped into subclones. However, >80% of osteosarcomas exhibit a specific combination of single-base substitutions, LOH, or large-scale genome instability signatures characteristic of BRCA1/2-deficient tumours. Our findings imply that multiple oncogenic pathways drive chromosomal instability during osteosarcoma evolution and result in the acquisition of BRCA-like traits, which could be therapeutically exploited.
CX3CR1 deficiency promotes muscle repair and regeneration by enhancing macrophage ApoE production
Authors: Arnold Ludovic , Perrin Hélène , de Chanville Camille Baudesson , Saclier Marielle , Hermand Patricia , Poupel Lucie , Guyon Elodie , Licata Fabrice , Carpentier Wassila , Vilar José , Mounier Rémi , Chazaud Bénédicte , Benhabiles Nora , Boissonnas Alexandre , Combadiere Béhazine , Combadiere Christophe
Published: December 2015

Muscle injury triggers inflammation in which infiltrating mononuclear phagocytes are crucial for tissue regeneration. The interaction of the CCL2/CCR2 and CX3CL1/CX3CR1 chemokine axis that guides phagocyte infiltration is incompletely understood. Here, we show that CX3CR1 deficiency promotes muscle repair and rescues Ccl2−/− mice from impaired muscle regeneration as a result of altered macrophage function, not infiltration. Transcriptomic analysis of muscle mononuclear phagocytes reveals that Apolipoprotein E (ApoE) is upregulated in mice with efficient regeneration. ApoE treatment enhances phagocytosis by mononuclear phagocytes in vitro, and restores phagocytic activity and muscle regeneration in Ccl2−/− mice. Because CX3CR1 deficiency may compensate for defective CCL2-dependant monocyte recruitment by modulating ApoE-dependent macrophage phagocytic activity, targeting CX3CR1 expressed by macrophages might be a powerful therapeutic approach to improve muscle regeneration.
Osteoclasts control reactivation of dormant myeloma cells by remodelling the endosteal niche
Authors: Lawson Michelle A. , McDonald Michelle M. , Kovacic Natasa , Hua Khoo Weng , Terry Rachael L. , Down Jenny , Kaplan Warren , Paton-Hough Julia , Fellows Clair , Pettitt Jessica A. , Neil Dear T. , Van Valckenborgh Els , Baldock Paul A. , Rogers Michael J. , Eaton Colby L. , Vanderkerken Karin , Pettit Allison R. , Quinn Julian M. W. , Zannettino Andrew C. W. , Phan Tri Giang , Croucher Peter I.
Published: December 2015

Multiple myeloma is largely incurable, despite development of therapies that target myeloma cell-intrinsic pathways. Disease relapse is thought to originate from dormant myeloma cells, localized in specialized niches, which resist therapy and repopulate the tumour. However, little is known about the niche, and how it exerts cell-extrinsic control over myeloma cell dormancy and reactivation. In this study, we track individual myeloma cells by intravital imaging as they colonize the endosteal niche, enter a dormant state and subsequently become activated to form colonies. We demonstrate that dormancy is a reversible state that is switched ‘on’ by engagement with bone-lining cells or osteoblasts, and switched ‘off’ by osteoclasts remodelling the endosteal niche. Dormant myeloma cells are resistant to chemotherapy that targets dividing cells. The demonstration that the endosteal niche is pivotal in controlling myeloma cell dormancy highlights the potential for targeting cell-extrinsic mechanisms to overcome cell-intrinsic drug resistance and prevent disease relapse.
Superbunching and Nonclassicality as new Hallmarks of Superradiance
Authors: Bhatti Daniel , von Zanthier Joachim , Agarwal Girish S.
Published: December 2015

Superradiance, i.e., spontaneous emission of coherent radiation by an ensemble of two-level atoms in collective states introduced by Dicke in 1954, is one of the enigmatic problems of quantum optics. The startling gist is that even though the atoms have no dipole moment they radiate with increased intensity in particular directions. Following the advances in our understanding of superradiant emission by atoms in entangled W-states we examine the quantum statistical properties of superradiance. Such investigations require the system to have at least two excitations in order to explore the photon-photon correlations of the radiation emitted by such states. We present specifically results for the spatially resolved photon-photon correlations of systems prepared in doubly excited W-states and give conditions when the atomic system emits nonclassial light. Equally, we derive the conditions for the occurrence of bunching and even of superbunching, a rare phenomenon otherwise known only from nonclassical states of light like the squeezed vacuum. We finally investigate the photon-photon cross correlations of the spontaneously scattered light and highlight the nonclassicalty of such correlations. The theoretical findings can be implemented with current technology, e.g., using ions in a linear rf-trap, atoms in an optical lattice or quantum dots in a cavity.
Miniaturized Swimming Soft Robot with Complex Movement Actuated and Controlled by Remote Light Signals
Authors: Huang Chaolei , Lv Jiu-an , Tian Xiaojun , Wang Yuechao , Yu Yanlei , Liu Jie
Published: December 2015

Powering and communication with micro robots to enable complex functions is a long-standing challenge as the size of robots continues to shrink. Physical connection of wires or components needed for wireless communication are complex and limited by the size of electronic and energy storage devices, making miniaturization of robots difficult. To explore an alternative solution, we designed and fabricated a micro soft swimming robot with both powering and controlling functions provided by remote light, which does not carry any electronic devices and batteries. In this approach, a polymer film containing azobenzene chromophore which is sensitive to ultra-violet (UV) light works as “motor” and the UV light and visible light work as “power and signal lines”. Periodically flashing UV light and white light drives the robot flagellum periodically to swing to eventually push forward the robot in the glass tube filled with liquid. The gripper on robot head can be opened or closed by lights to grab and carry the load. This kind of remotely light-driven approach realizes complex driving and controlling of micro robotic structures, making it possible to design and fabricate even smaller robots. It will have great potential among applications in the micro machine and robot fields.
MicroRNA-195 inhibits proliferation, invasion and metastasis in breast cancer cells by targeting FASN, HMGCR, ACACA and CYP27B1
Authors: Singh Richa , Yadav Vikas , kumar Sachin , Saini Neeru
Published: December 2015

De novo lipogenesis, a hallmark for cancers is required for cellular transformation. Further it is believed that resistance to apoptosis and epithelial-to-mesenchymal-transition(EMT) facilitates metastasis via over-expression of anti-apoptotic Bcl-2. Previously we demonstrated that hsa-miR-195 targets BCL2, induces apoptosis and augmented the effect of etoposide in breast cancer cells. However, the mechanism behind its function remains elusive. Herein gene expression profiling was done in presence/absence of hsa-miR-195 in Breast cancer cells. IPA revealed mitochondrial dysfunction, fatty acid metabolism and xenobiotic metabolism signalling among the top processes being affected. For the first time we herein identified ACACA, FASN (the key enzymes of de novo fatty acid synthesis), HMGCR (the key enzyme of de novo cholesterol synthesis) and CYP27B1 as direct targets of hsa-miR-195. We further showed that ectopic expression of hsa-miR-195 in MCF-7 and MDA-MB-231 cells not only altered cellular cholesterol and triglyceride levels significantly but also resulted in reduced proliferation, invasion and migration. We further demonstrated that over expression of hsa-miR-195 decreased the Mesenchymal markers expression and enhanced Epithelial markers. In conclusion we say that hsa-miR-195 targets the genes of de novo lipogenesis, inhibits cell proliferation, migration and invasion which potentially opens new avenues for the treatment of breast cancer.
Acetaminophen cytotoxicity is ameliorated in a human liver organotypic co-culture model
Authors: Nelson Leonard J. , Navarro Maria , Treskes Philipp , Samuel Kay , Tura-Ceide Olga , Morley Steven D. , Hayes Peter C. , Plevris John N.
Published: December 2015

Organotypic liver culture models for hepatotoxicity studies that mimic in vivo hepatic functionality could help facilitate improved strategies for early safety risk assessment during drug development. Interspecies differences in drug sensitivity and mechanistic profiles, low predictive capacity and limitations of conventional monocultures of human hepatocytes, with high attrition rates remain major challenges. Herein, we show stable, cell-type specific phenotype/cellular polarity with differentiated functionality in human hepatocyte-like C3A cells (enhanced CYP3A4 activity/albumin synthesis) when in co-culture with human vascular endothelial cells (HUVECs), thus demonstrating biocompatibility and relevance for evaluating drug metabolism and toxicity. In agreement with in vivo studies, acetaminophen (APAP) toxicity was most profound in HUVEC mono-cultures; whilst in C3A:HUVEC co-culture, cells were less susceptible to the toxic effects of APAP, including parameters of oxidative stress and ATP depletion, altered redox homeostasis and impaired respiration. This resistance to APAP is also observed in a primary human hepatocyte (PHH) based co-culture model, suggesting bidirectional communication/stabilization between different cell types. This simple and easy-to-implement human co-culture model may represent a sustainable and physiologically-relevant alternative cell system to PHHs, complementary to animal testing, for initial hepatotoxicity screening or mechanistic studies of candidate compounds differentially targeting hepatocytes and endothelial cells.
Identification of novel PKD1 and PKD2 mutations in a Chinese population with autosomal dominant polycystic kidney disease
Authors: Liu Bei , Chen Song-Chang , Yang Yan-Mei , Yan Kai , Qian Ye-Qing , Zhang Jun-Yu , Hu Yu-Ting , Dong Min-Yue , Jin Fan , Huang He-Feng , Xu Chen-Ming
Published: December 2015

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most frequently inherited renal diseases caused by mutations in PKD1 and PKD2. We performed mutational analyses of PKD genes in 49 unrelated patients using direct PCR-sequencing and multiplex ligation-dependent probe amplification (MLPA) for PKD1 and PKD2. RT-PCR analysis was also performed in a family with a novel PKD2 splicing mutation. Disease-causing mutations were identified in 44 (89.8%) of the patients: 42 (95.5%) of the patients showed mutations in PKD1 and 2 (4.5%) showed mutations in PKD2. Ten nonsense, 17 frameshift, 4 splicing and one in-frame mutation were found in 32 of the patients. Large rearrangements were found in 3 patients and missense mutations were found in 9 patients. Approximately 61.4% (27/44) of the mutations are first reported with a known mutation rate of 38.6%. RNA analysis of a novel PKD2 mutation (c.595_595 + 14delGGTAAGAGCGCGCGA) suggested monoallelic expression of the wild-type allele. Furthermore, patients with PKD1-truncating mutations reached end-stage renal disease (ESRD) earlier than patients with non-truncating mutations (47 ± 3.522 years vs. 59 ± 11.687 years, P = 0.016). The mutation screening of PKD genes in Chinese ADPKD patients will enrich our mutation database and significantly contribute to improve genetic counselling for ADPKD patients.
Simultaneous fNIRS and thermal infrared imaging during cognitive task reveal autonomic correlates of prefrontal cortex activity
Authors: Pinti Paola , Cardone Daniela , Merla Arcangelo
Published: December 2015

Functional Near Infrared-Spectroscopy (fNIRS) represents a powerful tool to non-invasively study task-evoked brain activity. fNIRS assessment of cortical activity may suffer for contamination by physiological noises of different origin (e.g. heart beat, respiration, blood pressure, skin blood flow), both task-evoked and spontaneous. Spontaneous changes occur at different time scales and, even if they are not directly elicited by tasks, their amplitude may result task-modulated. In this study, concentration changes of hemoglobin were recorded over the prefrontal cortex while simultaneously recording the facial temperature variations of the participants through functional infrared thermal (fIR) imaging. fIR imaging provides touch-less estimation of the thermal expression of peripheral autonomic. Wavelet analysis revealed task-modulation of the very low frequency (VLF) components of both fNIRS and fIR signals and strong coherence between them. Our results indicate that subjective cognitive and autonomic activities are intimately linked and that the VLF component of the fNIRS signal is affected by the autonomic activity elicited by the cognitive task. Moreover, we showed that task-modulated changes in vascular tone occur both at a superficial and at larger depth in the brain. Combined use of fNIRS and fIR imaging can effectively quantify the impact of VLF autonomic activity on the fNIRS signals.
A new sensitizer DVDMS combined with multiple focused ultrasound treatments: an effective antitumor strategy
Authors: Xiong Wenli , Wang Pan , Hu Jianmin , Jia Yali , Wu Lijie , Chen Xiyang , Liu Quanhong , Wang Xiaobing
Published: December 2015

Sonodynamic therapy (SDT) was developed as a promising noninvasive approach. The present study investigated the antitumor effect of a new sensitizer (sinoporphyrin sodium, referred to as DVDMS) combined with multiple ultrasound treatments on sarcoma 180 both in vitro and in vivo. The combined treatment significantly suppressed cell viability, potentiated apoptosis and markedly inhibited angiogenesis in vivo. In vivo, the tumor weight inhibition ratio reached 89.82% fifteen days after three sonication treatments plus DVDMS. This effect was stronger than one ultrasound alone (32.56%) and than one round of sonication plus DVDMS (59.33%). DVDMS combined with multiple focused ultrasound treatments initiated tumor tissue destruction, induced cancer cell apoptosis, inhibited tumor angiogenesis, suppressed cancer cell proliferation and decreased VEGF and PCNA expression levels. Moreover, the treatment did not show obvious signs of side effects or induce a drop in body weight. These results indicated that DVDMS combined with multiple focused ultrasounds may be a promising strategy against solid tumor.
Optimizing antibody expression by using the naturally occurring framework diversity in a live bacterial antibody display system
Authors: Lombana T. Noelle , Dillon Michael , Bevers III Jack , Spiess Christoph
Published: December 2015

Rapid identification of residues that influence antibody expression and thermostability is often needed to move promising therapeutics into the clinic. To establish a method that can assess small expression differences, we developed a Bacterial Antibody Display (BAD) system that overcomes previous limitations, enabling the use of full-length formats for antibody and antigen in a live cell setting. We designed a unique library of individual framework variants using natural diversity introduced by somatic hypermutation and screened half-antibodies for increased expression using BAD. We successfully identify variants that dramatically improve expression yields and in vitro thermostability of two therapeutically relevant antibodies in E. coli and mammalian cells. While we study antibody expression, bacterial display can now be expanded to examine the processes of protein folding and translocation. Additionally, our natural library design strategy could be applied during antibody humanization and library design for in vitro display methods to maintain expression and formulation stability.
Classification of octet AB-type binary compounds using dynamical charges: A materials informatics perspective
Authors: Pilania G. , Gubernatis J. E. , Lookman T.
Published: December 2015

The role of dynamical (or Born effective) charges in classification of octet AB-type binary compounds between four-fold (zincblende/wurtzite crystal structures) and six-fold (rocksalt crystal structure) coordinated systems is discussed. We show that the difference in the dynamical charges of the fourfold and sixfold coordinated structures, in combination with Harrison’s polarity, serves as an excellent feature to classify the coordination of 82sp–bonded binary octet compounds. We use a support vector machine classifier to estimate the average classification accuracy and the associated variance in our model where a decision boundary is learned in a supervised manner. Finally, we compare the out-of-sample classification accuracy achieved by our feature pair with those reported previously.
Shortfalls in the global protected area network at representing marine biodiversity
Authors: Klein Carissa J. , Brown Christopher J. , Halpern Benjamin S. , Segan Daniel B. , McGowan Jennifer , Beger Maria , Watson James E.M.
Published: December 2015

The first international goal for establishing marine protected areas (MPAs) to conserve the ocean’s biodiversity was set in 2002. Since 2006, the Convention on Biological Diversity (CBD) has driven MPA establishment, with 193 parties committed to protecting >10% of marine environments globally by 2020, especially ‘areas of particular importance for biodiversity’ (Aichi target 11). This has resulted in nearly 10 million km2 of new MPAs, a growth of ~360% in a decade. Unlike on land, it is not known how well protected areas capture marine biodiversity, leaving a significant gap in our understanding of existing MPAs and future protection requirements. We assess the overlap of global MPAs with the ranges of 17,348 marine species (fishes, mammals, invertebrates) and find that 97.4% of species have <10% of their ranges represented in stricter conservation classes. Almost all (99.8%) of the very poorly represented species (<2% coverage) are found within exclusive economic zones, suggesting an important role for particular nations to better protect biodiversity. Our results offer strategic guidance on where MPAs should be placed to support the CBD’s overall goal to avert biodiversity loss. Achieving this goal is imperative for nature and humanity, as people depend on biodiversity for important and valuable services.